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+{"text": "Eucalyptus. Eucalyptus leaves can alter soil chemistry and negatively affect underground macro- and microbial communities. Amphibians serve as excellent models to evaluate the effect of Eucalyptus invasion on ground-dwelling species as they predate on soil arthropods and incorporate soil microbes into their microbiotas. The skin microbiota is particularly important to amphibian health, suggesting that invasive plant species could ultimately affect amphibian populations. To investigate the potential for invasive vegetation to induce changes in microbial communities, we sampled microbial communities in the soil and on the skin of local amphibians. Specifically, we compared Batrachoseps attenuatus skin microbiomes in both Eucalyptus globulus (Myrtaceae) and native Quercus agriflolia (Fagaceae) dominated forests in the San Francisco Bay Area. We determined whether changes in microbial diversity and composition in both soil and Batrachoseps attenuatus skin were associated with dominant vegetation type. To evaluate animal health across vegetation types, we compared Batrachoseps attenuatus body condition and the presence/absence of the amphibian skin pathogen Batrachochytrium dendrobatidis. We found that Eucalyptus invasion had no measurable effect on soil microbial community diversity and a relatively small effect (compared to the effect of site identity) on community structure in the microhabitats sampled. In contrast, our results show that Batrachoseps attenuatus skin microbiota diversity was greater in Quercus dominated habitats. One amplicon sequence variant identified in the family Chlamydiaceae was observed in higher relative abundance among salamanders sampled in Eucalyptus dominated habitats. We also observed that Batrachoseps attenuatus body condition was higher in Quercus dominated habitats. Incidence of Batrachochytrium dendrobatidis across all individuals was very low . The effect on body condition demonstrates that although Eucalyptus may not always decrease amphibian abundance or diversity, it can potentially have cryptic negative effects. Our findings prompt further work to determine the mechanisms that lead to changes in the health and microbiome of native species post-plant invasion.Invasive plants are major drivers of habitat modification and the scale of their impact is increasing globally as anthropogenic activities facilitate their spread. In California, an invasive plant genus of great concern is  Anthropogenic habitat modification has dramatic direct and indirect effects on wild animal populations . InvasivOne way that invasive plants impact native animal populations is by altering their microbial commensals. Plant invasions could influence the microbial community structure of native fauna by changing microbial communities that hosts are exposed to, by altering host physiology, or both . InvasioEucalyptus sp.  resulting in changes in soil microbial communities  and native Quercus agrifolia (Fagaceae) dominated forests in the San Francisco Bay Area. Specifically, we determined whether changes in microbial composition, diversity and stability in both soil and Batrachoseps attenuatus skin were associated with Eucalyptus or Quercus dominated habitat. To evaluate animal health across Eucalyptus and Quercus dominated habitats, we also measured and compared Batrachoseps attenuatus body condition and the presence/absence of the amphibian chytrid fungus Batrachochytrium dendrobatidis, which causes the lethal amphibian disease chytridiomycosis. Our results illustrate a decline in the richness of skin associated microbiota and a decrease in salamander body condition in Eucalyptus forest, illustrating that plant invasions may have consequences for native species.To investigate potential changes induced by invasive vegetation on environmental and host-associated microbial communities, we sampled microhabitat soil and Eucalyptus invasions on native fauna and their microbiotas. The Bay Area is home to numerous seed-producing stands of E. globulus, E. pulchella, and E. viminalis among a mosaic of mixed native evergreen forests and coastal scrublands. The discrete\u2014yet interspersed\u2014distribution of invasive and native vegetation types in the Bay Area make it an ideal location to evaluate vegetation effects on resident host-associated microbiotas while controlling for geography. In addition, multiple ground dwelling amphibians are distributed throughout the Bay Area and may be sensitive to effects of invasive Eucalyptus on the skin microbiome  because of their highly-limited dispersal  as it has been eroded by a nearby stream, and instead chose a new site with similar characteristics.The San Francisco Bay Area (Bay Area) provides an opportunity to test the effect of crobiome . One ampy campus . To miniBatrachoseps attenuatus skin swabs from Quercus and 28 from Eucalyptus dominated habitats . Access to off-campus sampling sites was granted by East Bay Regional Parks under permit # 965. We collected salamanders by hand using gloves through log flip surveys within ~100 m of the location coordinates. New gloves were donned between the handling of each salamander. To avoid resampling individuals and ensure that salamanders were later returned to their original capture site, we marked each capture log with the individual(s) identification number. We rinsed each salamander with 250 mL of sterile water and swabbed the dorsum with a sterile cotton swab 30 times. Following microbiota sampling, we measured each salamanders\u2019 total body length and mass. All salamanders were returned to their location of capture immediately after sampling. To characterize the microhabitat microbiota, we collected ~20 mg of soil or soil swabs directly from under the logs where each salamander was captured after releasing each individual. We collected 22 habitats . All samWe isolated DNA from skin swab samples using the DNeasy PowerSoil DNA Isolation Kit  following the modifications to the manufacturer\u2019s protocol described in We performed a second PCR on microbiota amplicons to ligate dual-index barcodes paired with Illumina sequencing adaptors  to the eBatrachochytrium dendrobatidis infection in our swabbed individuals, we performed real-time quantitative PCR (qPCR) reactions in duplicate following Batrachochytrium dendrobatidis zoospore standard dilution ranging from 100,000 to 0.1 genomic equivalents. These zoospore standards were prepared using the Bd-GPL strain CJB7\u2013originally isolated from Kings Canyon, CA. At least three reactions per 96-well plate were designated as negative controls, with each receiving five \u00b5L of water in lieu of template DNA. To reduce the risk of laboratory contamination we set up qPCR reactions in a laminar flow hood. We ran all qPCR reactions on an Applied Biosystems StepOnePlus Real-Time PCR System , and used the manufacturer\u2019s software for standard curve analysis. We considered an average qPCR quantification of less than one genomic equivalent per swab to be negative for Batrachochytrium dendrobatidis infection.To detect and quantify We processed raw sequencing reads using Trimmomatic  to removPRJNA574188).Our microbiota sequence analysis consisted of established sequence read processing pipelines to filter erroneous reads, generate an amplicon sequence variant  table, create a representative sequence phylogeny and assign taxonomy to ASVs. We chose to use ASVs rather than operational taxonomic units (OTUs), because ASVs provide greater resolution in amplicon differentiation . ASV varvegan and picante: community richness , evenness  and phylogenetic diversity . We calculated these metrics in order to evaluate differences in the number of ASVs (community richness), distribution of ASV frequencies within samples (Shannon diversity index), and phylogenetic representation (Faith\u2019s phylogenetic diversity) across sample groups. To assess differences in community composition across samples, we applied the R packages GuniFrac and vegan to calculate three separate beta diversity metrics: pairwise unweighted/weighted UniFrac distances and Bray\u2013Curtis dissimilarities. We chose to include these beta diversity metrics as they account for differences in presence/absence of phylogenetic lineages among samples (unweighted UniFrac), abundance-based differences in phylogenetic lineages among samples (weighted UniFrac), and non-phylogenetic abundance-based differences among samples (Bray\u2013Curtis). In addition, we computed the core microbiomes  of Eucalyptus soil, Eucalyptus salamander skin, Quercus soil and Quercus salamander skin samples.We transferred the rarefied ASV table and Newick phylogeny to R (version 3.5.1) for further analyses. A Shapiro\u2013Wilk test in R was implemented on all univariate dependent variables to evaluate normality prior to statistical model selection. We calculated three distinct alpha diversity metrics using the R packages Effects of Eucalyptus invasion on soil bacterial composition, diversity, and stability: We evaluated differences in soil community diversity, composition and community homogeneity between Quercus and Eucalyptus dominated habitats. To evaluate differences in alpha diversity between soil communities sampled in Quercus and Eucalyptus dominated habitats, we implemented community richness, Shannon diversity indices and phylogenetic diversity as dependent variables, habitat type as a fixed variable and site identity as a random variable in linear mixed models . The significance of the predictor variable was calculated with likelihood ratio tests (LRT). To characterize the strength and significance of soil community compositional and structural differentiation among habitat types, we implemented three PERMANOVA tests (R package vegan) using weighted UniFrac, unweighted UniFrac, and Bray\u2013Curtis dissimilarity matrices as dependent variables and site identity as a random variable. We produced NMDS plots using the three dissimilarity matrices to visualize clustering of samples by habitat and site identity using the R package phyloseq. To assess whether habitat type influenced variation in soil community structure, we performed three separate multivariate of homogeneity of group dispersions analyses (R package vegan) using the beta diversity metrics. For each beta diversity metric, we used a one-way ANOVA to test differences in point-to-centroid distances between soil samples obtained from Eucalyptus and Quercus dominated habitats. We implemented an indicator species analysis using the R package indicspecies to identify ASVs whose relative abundance differs between soil samples collected in Eucalyptus and Quercus dominated habitats.Effects of Eucalyptus invasion on Batrachoseps attenuatus bacterial composition, diversity and stability: To assess whether salamander skin microbiota sampled in Quercus or Eucalyptus dominated habitat differ in their overlap with microhabitat microbiota, we calculated average unweighted UniFrac, weighted UniFrac, and Bray\u2013Curtis dissimilarity values between every salamander skin sample and all environmental samples in its corresponding site. We used these dissimilarities as dependent variables in a generalized linear mixed model using a logit distribution with habitat type as a fixed variable and site as a random variable. We also evaluated whether skin microbial community diversity, composition and heterogeneity differed between Batrachoseps attenuatus sampled in Quercus and Eucalyptus dominated habitats. We assessed differences in community richness, Shannon diversity indices, and phylogenetic diversity between salamander skin communities sampled in Quercus and Eucalyptus dominated habitats using linear mixed models as described above. We ran PERMANOVA tests using weighted UniFrac, unweighted UniFrac, and Bray\u2013Curtis dissimilarities as dependent variables, habitat type as a fixed variable and site identity as a random variable to evaluate variation in community composition and structure. We produced NMDS plots using the three dissimilarity matrices to visualize clustering of skin samples by habitat and site identity. We also performed three separate multivariate of homogeneity of group dispersions analyses to evaluate how habitat type influenced variation in community structure among individuals in the same group. For each beta diversity metric, we used a one-way ANOVA to test differences in point-to-centroid distances between Eucalyptus and Quercus salamander skin microbial communities. We implemented an indicator species analysis using the R package indicspecies to identify ASVs whose relative abundance differs between salamander skin samples collected in Eucalyptus and Quercus dominated habitats. Lastly, we assessed patterns of isolation by distance (IBD) by comparing our three dissimilarity matrices of community composition to a Euclidean geographic distance matrix between sampling locations. We tested for significance of IBD through mantel tests using R package ade4  with site identity as a random factor. Lastly, we evaluated whether there were correlations between skin alpha diversity metrics  and body condition using Pearson correlation tests.tebrates . We omitEucalyptus and Quercus dominated habitats . The core microbial communities of Eucalyptus dominated habitat soil samples (16 ASVs) were composed of ASV\u2019s characterized as Actinobacteria  and Proteobacteria . In contrast, the core microbiome of Quercus dominated habitat soil samples was composed of eight ASV\u2019s characterized as Actinobacteria , Bacteroidetes , Proteobacteria , and Verrucomicrobia . The indicator species analysis identified 216 ASVs that differed significantly between habitat types with 122 associated with Eucalytpus soil samples and 94 associated with Quercus soil samples , weighted UniFrac , or Bray\u2013Curtis dissimilarities . Microbial community richness and phylogenetic diversity were significantly lower for salamanders in Eucalyptus dominated habitat compared to salamanders sampled in Quercus habitats  but not for Bray\u2013Curtis dissimilarities  but no patterns of IBD with both our weighted and unweighted UniFrac matrices .We did not observe differences in composition and structure between skin and corresponding soil samples among Eucalyptus dominated habitat was comprised entirely of ASVs assigned to the phylum Proteobacteria . The core microbiota of salamander skin samples collected in Quercus dominated habitat was richer in that it possessed 32 ASVs assigned to the phyla Actinobacteria , Chloroflexi , Proteobacteria , and Verrucomicrobia . As observed in the soil core microbial communities, salamander skin core ASVs consisted mostly of rare taxa . However, we found one skin ASV identified as Bordetella petrii to dominate skin communities in Eucalyptus (29.81%) and Quercus (20.45%) dominated habitats. The indicator species analysis identified 294 ASVs that differed significantly between habitat types with 36 associated with Eucalyptus salamander skin samples and 258 associated with Quercus salamander skin samples  compared to individuals collected in Quercus dominated habitats .The core microbiota of salamander skin samples collected in  samples . As obseEucalyptus and Quercus dominated habitats . Salamanders sampled in Quercus dominated habitat possessed higher body condition indices than those sampled from the Eucalyptus dominated habitat , Shannon diversity index , or Faith\u2019s phylogenetic diversity . One salamander (OHG-47_S202) tested positive for Batrachochytrium dendrobatidis with a low average infection load of 41.59 zoospore equivalents .Body condition indices differed significantly between salamanders sampled in  habitat . We did ivalents . The preEucalyptus and Quercus dominated sites. Thus, the filter acting on microbial richness is likely operating at the host level, rather than the passive uptake of different soil microbial communities. At the individual level, we found differences in native salamander skin microbial diversity and body condition associated with Eucalyptus invasion. We also observed higher salamander skin microbial composition heterogeneity and relative abundances of an ASV identified to the family Chlamydiaceae in salamanders inhabiting Eucalyptus dominated habitats.We observed no differences in richness, little variation in community composition and structure, and similar differentiation between soil and skin samples across Eucalyptus sites. In addition, a small fraction of the variation in community composition among soil samples was explained by vegetation type. This finding is surprising given the documented shifts in soil microbiomes following plant invasions \u2013in the Eucalyptus samples. While we cannot differentiate among these two possibilities using 16S rRNA amplicon sequencing alone, this pattern could reflect microbial community changes due to environmental filters present in the Eucalyptus dominated habitat. Changes in the relative abundance of core bacteria and alpha diversity have been documented in previous studies assessing the effects of environmental changes  on the skin microbiota of amphibians  has not been established . Additionally, Batrachoseps attenuatus\u2019 high site fidelity, relatively short dispersal distances and association with fallen logs may decrease differences compared to surrounding leaf litter, which may show greater microbial composition differences between sites  possess distinct skin microbial communities  and biotic factors  may have disproportionate effects on the persistence of distinct rare bacteria in these salamanders. The loss of bacterial species in salamanders inhabiting Eucalyptus habitat may vary by individual- and site-specific factors that were not measured in the current study. Heterogeneous responses of microbial communities have been demonstrated for soil microbes in response to silviculture and agricultural practices , it is possible that an increase in Chlamydiaceae in the skin of salamanders results from microbial dysbiosis  than those in native Quercus woodland . Interestingly, we found differences in the skin microbial community of the native salamander Batrachoseps attenuatus, but no differences in soil microbial communities between Eucalyptus and Quercus habitats. We also found decreased body condition of this native salamander in Eucalyptus dominated habitats. Our findings prompt further experimental work to determine the mechanisms causing these microbial changes and their potential effect on the fitness of native fauna following invasion.To our knowledge, our study is the first to demonstrate changes in the microbial communities of native hosts associated with plant invasion (10.7717/peerj.8549/supp-1Supplemental Information 1Click here for additional data file."}
+{"text": "Neoadjuvant therapy with conventional chemotherapies have visibly improved the prognosis of locally advanced pancreatic cancer (PCa). However, molecular targeted therapies that have provided durable responses in other tumor entities, have not yet found access into neoadjuvant therapy of PCa. In fact, due to the presence of the tumor burden serving as an antigen source for T cell priming, neoadjuvant chemotherapy may unleash a more potent antitumoral immune response than adjuvant or palliative chemotherapy. Despite tremendous efforts, successful therapy of pancreatic cancer (PCa) remains a major challenge . FindingCancer immunotherapy, led by immune checkpoint inhibitors (ICI) and cancer vaccines have shown notable long-term efficacy in many solid malignancies . The limAdoptive immunotherapy involves injecting antitumor-programmed immune cells into the patient. New directions are pointing to tumor lysate-pulsed dendritic cells , 12 or tThe failure of immunotherapy in PCa may be partly due to the exclusion of T cells by cancer-associated fibroblasts (CAF) and the impaired drug delivery caused by increased hydrostatic pressure and the poor vascularization in the highly fibrotic pancreatic stroma . Exploitin vitro and in the in vivo murine xenograft model and inhibited PCa growth [While metabolic plasticity has long been recognized as a hallmark of cancer, we have only recently started to exploit the differences between cancer cell and normal cell metabolism . Metabola growth .Our growing understanding of the PCa biology has led to the development of novel immunotherapies as well as drugs targeting key regulators of the stromal and tumor metabolism. However, the full potential of these agents has been hampered by the presence of therapeutic resistance, resulting from intrinsic compensatory signalling pathways and mutagenic evolution . Only co"}
+{"text": "Older residents often experience disruption in family relationships and social networks due to isolation once they move into public housing communities. While the need for social contact continues, the opportunity may diminish. Older African-American women living in one housing community attempted to cope with their personal safety fears through social isolation . Women in the study (N = 25) were survivors of one or more forms of interpersonal trauma, including childhood abuse, sexual assault and domestic violence. In contrast, a few women in the same sample spontaneously formed social networks within the community. This qualitative investigation will examine how the women adapted to an isolating and unsafe environment by developing social connections. As a social determinant of health, developing healthy social networks inside a housing community can reduce fear and improve well-being and quality of life for low-income older residents who are aging-in-place."}
+{"text": "Methamphetamines are commonly abused drugs for their stimulant and euphoric effects. Inhaled and intravenous use may cause damage to the respiratory system. Spontaneous pneumomediastinum is a condition where changes in intrathoracic pressure leads to alveolar rupture and dissection of air along the tracheobronchial tree. Massive subcutaneous emphysema may result from pneumomediastinum which may compromise the central airway. In this case report, we present an unusual case of spontaneous pneumomediastinum and severe subcutaneous emphysema following inhalation of methamphetamine. This case emphasizes the rising concern on the acute respiratory complications of methamphetamine use. Inhaled and intravenous use of stimulants may cause a variety of respiratory injuries. These injuries include but are not limited to nasal septum perforation, pulmonary vascular disease, pulmonary hemorrhage, thermal injury, pulmonary edema, and pneumothorax . SpontanA twenty-two-year-old previously healthy male presented to the emergency department for worsening facial and neck swelling. He noticed worsening dyspnea accompanied by facial swelling a few hours after smoking methamphetamine. Within a few minutes in the emergency room, the patient's mental status declined with more labored breathing; thus, the patient was electively intubated for airway protection. Differential diagnosis was acute allergic reaction to illicit drugs causing upper airway compromise versus acute inhalational injury. Initial chest computed tomography (CT) showed extensive pneumomediastinum with air dissecting to the peribronchovascular interstitial sheaths, interlobular septa, and visceral pleura Figures . There wMechanical ventilation was adjusted having very minimal to no positive expiratory pressure (PEEP) and prolonged expiratory phase. Placement of chest blow holes was not pursued as swelling on the face and neck improved after a few hours. The suspicion for tracheobronchial tree injury was low; thus, we did not perform bronchoscopic surveillance of the airway. Patient received empiric antibiotic treatment with ampicillin sulbactam. The patient was extubated in less than 24 hours after the improvement of peak inspiratory and plateau pressures with the positive cuff leak test. Repeat chest imaging showed decreased subcutaneous emphysema and resolution of pneumomediastinum. No dietary restriction was recommended after extubation as there was no evidence of aerodigestive organ injury. The patient was discharged after 72 hours with improved symptoms.Pulmonary complications have been reported with the use of illicit stimulants. Some recognized respiratory complications are nasal septum perforation, pulmonary vascular disease, pulmonary hemorrhage, pulmonary edema, and pneumothorax . Our casPlain chest X-ray including computed tomography (CT) is an adequate evaluation procedure after a thorough history and physical examination to exclude secondary pneumomediastinum . In one Spontaneous pneumomediastinum is often a self-limiting disease; however, due to concerns for the integrity of the aerodigestive tract, this finding usually results to unnecessary radiological investigations and antibiotic use. In one case series, spontaneous pneumomediastinum is overinvestigated and overtreated; thus, clinicians need to be more judicious with the use of hospital resources in managing patients with spontaneous pneumomediastinum . For thi"}
+{"text": "Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with significant mortality and morbidity. The central pathophysiological mechanisms by which repetitive cranial injury results in the neurodegeneration of CTE are poorly understood. Current well-established working models emphasize a central role for trauma-induced excessive phosphorylation and accumulation of insoluble tangles of Tau protein. In this review, we summarize recent data from preclinical animal models of CTE where a series of candidate treatments have been carefully evaluated, including kinase inhibitors, antibody therapy, and anti-inflammatory therapies. We discuss the overall translational potential of these approaches and provide recommendations for future bench-to-bedside treatment strategies. Initial symptoms manifest as non-specific cognitive and neuropsychiatric impairments, including depression and heightened aggression, and eventually progress to include a variety of motor impairments and cognitive decline . While tlistica) , it has listica) . In a relistica) . Militarlistica) . Aside fcted CTE .The initial symptoms of CTE may not occur until years or even decades after rmTBI and may affect cognitive and/or emotional domains. By one classification system, symptoms occurring in more than 50% of \u201cmild\u201d CTE (Stages 1 or 2) include impulsivity, depression, physical and verbal violence, memory loss, and suicidality. Severe CTE (Stages 3 or 4) is characterized by additional symptoms such as language impairments, visuospatial deficits, parkinsonism, and dementia-like deficits . CTE is While there remain many unknowns about the molecular and cellular pathological changes that are presumably incited by repeated cranial impact, a strong consensus has unified around the pathophysiological role of hyperphosphorylated tau (\u201cp-tau\u201d) accumulation and neurofibrillary tangle (NFT) formation . Thus, Cin vivo premortem diagnostic markers. In particular, PET imaging with radiotracers such as [F-18]FDDNP (which binds insoluble protein aggregates) has been used to identify tau and beta-amyloid patterns consistent with CTE  and CTE remains somewhat enigmatic. Both tauopathies share a series of culprit tau phosphorylation sites  and TBI Given the major knowledge gaps in our understanding of CTE pathogenesis, as well as limitations in available premortem diagnostic biomarkers, it is not surprising that there are currently no ongoing clinical trials for the treatment of CTE. However, in light of the proposed pathophysiological overlaps between AD and CTE, several therapies that have demonstrated preclinical success in AD models have now been applied to CTE models. This review summarizes key recent findings within this body of literature which have focused on accumulations of hyperphosphorylated tau aggregates as both a direct mediator of neuronal injury and a histological biomarker of disease severity.By definition, the vast majority of CTE diagnoses occur in individuals with a self-reported or witnessed history of contact-sport-related head injuries or military-related blast exposure . AccordiThis approach does have drawbacks: secondary injuries such as cranial fracture or intracranial hemorrhage do occur at some measurable rate . AdditioWhile the more nuanced aspects of CTE-related cellular and molecular derangements remain an active area of research, most agree that a valid preclinical model of CTE should demonstrate evidence of a phosphorylated tauopathy in response to rmTBI. In this regard, insights into CTE pathophysiology may be borrowed from transgenic Alzheimer\u2019s disease models such as TauP301L and 3xTg-AD, with the caveat that these mice develop amyloid and tau pathology even in the absence of rmTBI . Other myears of participation in a contact sport and include individuals who have only received sub-concussive impacts  permeability is one of the main factors limiting the efficacy of antibody treatment in CTE and other neurological diseases. Recent advances in ultrasound technology may be used to aid immune response or drug delivery across the BBB. Unilateral focused ultrasound (FUS) has been a candidate method used to increase BBB permeability by producing transient openings in endothelial tight junctions . Recentl the BBB . In an A the BBB . In conjrvention . While trvention . Low-intrvention  and AD  are also involved in pathological tau hyperphosphorylation. The potent CDK inhibitor roscovitine has been studied in models of TBI and demonstrated attenuation of neurodegeneration in a model of controlled cortical impact in mice . CombiniBeyond tau hyperphosphorylation, the progression of CTE is thought to include a complex cascade of secondary inflammatory and metabolic changes that may also represent potential targets for therapeutic intervention . Ionic iThe production of reactive oxidative species and mitochondrial stress likely plays a key role in driving neuronal ischemia in CTE . These pSadly, despite increasing recognition among athletes and military personnel, there are currently no available treatments for CTE or practical clinical diagnostic markers to identify at-risk individuals. Fortunately, with a detailed neuropathological description from postmortem samples combined with preclinical models that have been inspired by the Alzheimer\u2019s field, we are closer to obtaining a comprehensive pathophysiological understanding of CTE. Like AD, CTE is a progressive neurodegenerative disease that appears to propagate via tau phosphorylation and subsequent aggregation into neurofibrillary tangles. At the same time, trauma-induced changes in circuit function may borrow from prior research in severe traumatic brain injury. While research on these related conditions may shed light on CTE pathology, it also warns of potential pitfalls. In particular, both AD and severe TBI  have suftrans to pathogenic cis form has driven the development of isoform-specific phosphorylated tau monoclonal antibodies. The use of immunotherapy is one of the most promising strategies to treat CTE and other neurodegenerative diseases but suffers from poor translational efficiency. Techniques such as FUS/LIPUS may be used in conjunction with antibody treatment to improve the delivery of cis p-tau antibodies and immune agents across the blood\u2013brain barrier.Perhaps the most intuitive way to halt the progress of CTE is to inhibit processes directly affecting tau phosphorylation and aggregation. Given tau\u2019s multiple physiological functions, therapies must selectively inhibit formation and spreading of pathogenic tau. A profile of kinases directly phosphorylating tau in CTE has been developed and opened the door to a number of kinase inhibitors such as roscovitine and lithium which have shown promising preclinical results. The recent finding that tau is converted from a functional As these candidate therapies move forward to clinical phases, researchers should note the failure of dementia research to produce successful clinical trials . Why do PB and VK played significant roles in the initial manuscript drafts and subsequent revisions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The potential importance of germline genetic variation for identifying men at increased risk of prostate cancer has become increasingly recognised in recent years. We present an extensive review of the major developments in the identification of genetic loci, genes and individual variants associated with greater risk of prostate cancer, and what is currently known regarding whether these heritable prostate cancer risk factors can also inform likelihood of experiencing clinically significant rather than indolent forms of the disease. We finally discuss how these research discoveries might serve to inform clinical germline genetic testing guidelines and treatment options for prostate cancer in the future.Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine. Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in Europe and North America and second most common worldwide, with over 1.4 million diagnoses recorded in 2020 ,4.Although several promising molecular and genomic biomarkers for PrCa diagnosis or management have been identified in recent years , prostatNo consistent, consensus definition of aggressive PrCa has thus far been adopted within the research or clinical settings, which can hinder comparability of studies to identify risk factors and uniformity of clinical treatment application. Prior to the advent of PSA testing, aggressive PrCa had been considered to encompass only cancers which had advanced beyond the prostate itself . More reThe most clearly established risk factors for PrCa are increased age, ethnicity and family history of PrCa and certain other cancers. Familial aggregation of PrCa is one of the strongest risk factors, and provided support for the likely existence of genetic risk factors shared among families. Men with one male first-degree relative  diagnosed with PrCa themselves have an estimated relative risk of approximately 2.5, and risk of diagnosis with PrCa further increases for men with multiple affected FDRs and lower ages at their diagnoses ,14,15. REvidence has also been presented for clustering of aggressive clinical presentation of PrCa within families, suggestive for heritability of aggressive PrCa phenotypes. A number of studies from the Swedish population have demonstrated increased risk of high grade PrCa observed among brothers of cases with high grade disease , with grBRCA1 and BRCA2 genes, whilst Lynch syndrome is categorised by germline mutations in DNA mismatch repair genes. A strong family history of PrCa remains a more effective indicator of PrCa risk than family history of other cancer types however, especially with respect to early-onset and lethal disease . This is consistent with previous reports that the KLK3 GWAS SNP rs2735839 is associated with Gleason score in addition to overall disease risk  or remained associated with aggressive status among only patients with low PSA levels from two separate ancestral populations [KLK3 variation in PrCa susceptibility, risk of aggressive disease and serum PSA levels may therefore warrant more extensive investigation, especially in prospective or PSA na\u00efve cohorts, and may have the potential to enable the identification of a subset of individuals at lower risk of poor prognosis disease who could benefit from less interventionist treatment options.Case-only GWAS have to date reported at a genome-wide significant threshold two loci associated with Gleason score , one wit of PrCa , whilst  of PrCa ,242. Thease risk ,246,247.ulations . The fulWhilst these initial case-only reports imply that caution is warranted regarding the potential for GWAS loci to be able to accurately stratify PrCa patients more likely to develop clinically significant disease, increasing evidence supports the improving ability of genetic risk scores  incorporating ever larger numbers of established susceptibility variants to identify a population subset at greater lifetime risk of diagnosis with PrCa of any severity ,256,257.Although the ability of GRS to predict disease status within cohort studies has been demonstrated for various traits, their potential clinical utility to inform screening decisions for individual members of the population does however largely remain to be established at this point in time. Their potential consideration for implementation as a prospective risk-profiling tool prior to screening for PrCa may, however, soon become warranted. A polygenic hazard score (PHS) has demonstrated initial promise for the detection of clinically significant PrCa at younger age among higher PHS percentiles ,264, incAlthough many common loci have been identified which contribute substantially towards PrCa risk, rare variation is also estimated to play an important role in PrCa heritability , especiaBRCA2 gene, confirming earlier observations linking BRCA2 mutation carriers to more aggressive phenotypes through other approaches [ATM, BRCA1 and PALB2  and HOXB13. The latest National Comprehensive Cancer Network (NCCN) guidelines for germline testing also propose screening CHEK2 and PALB2 as part of their minimum recommended predisposition gene panel [TP53 plus additional DNA repair genes including BRIP1 and NBN have also been proposed for inclusion on screening panels, but await more definitive evidence to achieve consensus of utility [ATM, BRCA1, BRCA2 and potentially other DNA repair genes may inform response to PARP inhibitors [BRCA1, BRCA2 and other DNA repair genes sensitivity to platinum chemotherapy [Germline testing for rare moderate penetrance pathogenic variants in specific genes is becoming an increasingly important focus of PrCa management and treatment, with the additional promise of guiding tailored therapeutic interventions appropriate for targeting specific molecular vulnerabilities in individual patients\u2019 tumours. Although few genes have been conclusively identified to date in which rare variants confer higher risk of developing aggressive PrCa, as further larger, cross population sequencing studies and meta-analyses are performed, additional genes for which mutation carriers experience greater risk of aggressive disease and/or more favourable response to particular treatment options are likely to be established . At presne panel . The tum utility . In patihibitors ,305,306,otherapy ,308, andotherapy ,310. InvAlthough family history of the disease is usually the main reason for genetic testing of men without a diagnosis of PrCa, an appreciable proportion of PrCa patients without a family history sufficient to meet NCCN guidelines for germline genetic testing have also been demonstrated to carry rare germline putative PrCa susceptibility variants . Even grThe majority of samples included in studies investigating risk factors for PrCa to date have been from populations of European ancestry. However, given differing allelic architecture and frequencies of both rare and common variants between populations, in addition to the higher incidence and poorer prognosis of PrCa among men of African descent, reducing under-representation of additional ethnicities in PrCa research remains an unmet requirement in order to ensure applicability of discoveries across populations and pan-ethnic access to healthcare improvements ,312,313."}
+{"text": "On July 28, the correctional officer had multiplebrief encounters with six incarcerated or detained persons (IDPs)Subsequently, VDH and facility staff members reviewed July 28 quarantine unit videosurveillance footage and standard correctional officer shift duty responsibilities toapproximate the frequency and duration of interactions between the correctional officerand infectious IDPs during the work shift . AlthougThe correctional officer reported no other known close contact exposures to persons withCOVID-19 outside work and no travel outside Vermont during the 14 days preceding illnessonset. COVID-19 cumulative incidence in his county of residence and where thecorrectional facility is located was relatively low at the time of the investigation , suggesting that his most likely exposures occurred in thecorrectional facility through multiple brief encounters  with IDPs who later received apositive SARS-CoV-2 test result.Among seven employees with exposures to the infectious IDPs that did meet the VDH closecontact definition, one person received a positive test result. Among thirteen employees with exposures to the infectious IDPs that did notmeet the VDH close contact definition during contact tracing, only the correctionalofficer received a positive SARS-CoV-2 test result.Data are limited to precisely define \u201cclose contact\u201d; however, 15 minutesof close exposure is used as an operational definition for contact tracinginvestigations in many settings. Additional factors to consider when defining closecontact include proximity, the duration of exposure, whether the infected person hassymptoms, whether the infected person was likely to generate respiratory aerosols, andenvironmental factors such as adequacy of ventilation and crowding. A primary purpose ofcontact tracing is to identify persons with higher risk exposures and therefore higherprobabilities of developing infection, which can guide decisions on quarantining andwork restrictions. Although the initial assessment did not suggest that the officer hadclose contact exposures, detailed review of video footage identified that the cumulativeduration of exposures exceeded 15 minutes. In correctional settings, frequent encountersof \u22646 feet between IDPs and facility staff members are necessary; public healthofficials should consider transmission-risk implications of cumulative exposure timewithin such settings."}
+{"text": "With advancing age, the incidence rate of Alzheimer\u2019s disease and dementia gradually increases, and mortality from either Alzheimer\u2019s disease or dementia has increased in recent decades . RecentlPostmenopausal women experience a dramatic decrease in circulating estrogen level. Due to the cardio-protective effect of estrogen, premenopausal women are exposed to a lower risk of cardiovascular disease compared to postmenopausal women. Elastic conduit arteries including the aorta are more vulnerable to either internal or external stimulation than smaller muscular vasculatures because of their anatomical characteristics. Thus, central artery stiffness measures such as pulse wave analysis (augmentation index) and aortic pulse wave velocity are used as validated surrogate markers to predict future cardiovascular morbidity and mortality. Elastic central arteries in postmenopausal women older than 60 yr of age are in particular stiffer than pre- or postmenopausal women under 60 yr of age . In a reRegular physical activity including aerobic and resistance exercise is recommended for postmenopausal women to improve not only musculoskeletal and cardiovascular function, but also cognitive function. Three months of combined circuit exercise reduce arterial stiffness and other cardiovascular disease risks in hypertensive postmenopausal women. FurtherCompared to continuous exercise, high-intensity interval exercise can be more beneficial in enhancing cognitive function via not only decreased central artery stiffness but also facilitated neurotrophic factors production and increased neurotrophic factor bioavailability in postmenopausal women. The hypoxia state in high-intensity aerobic exercise increases VEGF production. In particular, intermittent hypoxia for high-intensity interval exercise facilitates the generation of BDNF, the most important neuroplasticity marker, in the cerebrovascular endothelium. Furthermore, lactate, a byproduct of high-intensity exercise, can be used to facilitate BDNF and VEGF generation in peripheral tissues and is an additional energy resource for brain neuron activity. Both the BDNF and VEGF produced in peripheral tissues can directly facilitate neuroplasticity in the central nervous system after passing through the blood brain barrier.Future studies are warranted to comprehensively investigate the effects of high-intensity interval training on central artery stiffness, neuroplasticity, and cognitive function, and elucidate the associated physiological mechanisms in postmenopausal women, the population most vulnerable to cardiovascular events and cognitive impairment."}
+{"text": "TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions , carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions . Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. Results: TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Conclusions: Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate.  TERT) promoter mutations occur in 60\u201380% of all urothelial bladder cancers (UBC) independent of tumor stage and grading thus, represent the most frequent alteration in this tumor entity [TERT [TERT promoter mutations in UBC are found in 99% of tissue samples at position \u2212124 and \u2212146 base pairs upstream from the ATG transcriptional start site position and are responsible for aberrant telomerase activity [TERT mutational incidence rates in UBC several studies proposed a possible role implementing these alterations in urinary testing and as a follow-up diagnostic tool [Telomerase reverse transcriptase  and CIS as well as the tumor mass [Archival material of the Institute of Pathology, Erlangen was retrospectively evaluated and available bladder cancer specimens diagnosed as MIBC were screened for mor mass . All themor mass . A schemmor mass . PatholoTERT promoter mutated tumor associated normal urothelium as well as non-invasive urothelial lesions from the whole-organ mapping bladder specimens were immunohistochemically evaluated for CK20, CD44, TP53 and MIB1 staining. CK20 and CD44 were chosen as differentiation markers, which show distinct staining patterns among normal urothelium as well as for non-invasive urothelial lesions thus, are used for routine diagnostic evaluation. P53 evaluation as well as MIB1 staining is also used for evaluation of distinguishing normal urothelium as well as for non-invasive urothelial lesions [TERT promoter mutations and used for immunohistochemistry as preformed with a Ventana BenchMark Ultra  and a Dako Link 48  autostainer accreditated by the German Accreditation Office (DAKKs) according to DIN EN ISO/IEC 17020. Detail information of the used antibodies are displayed in All  lesions . Whole t\u00ae 16 System, Promega, Mannheim, Germany) according to the manufacturer\u2019s instructions. The tissue component from each tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC was manually microdissected from marked areas on each consecutive tissue slide derived from its corresponding tissue block in order to achieve at least 80% purity. DNA isolation was performed using the DNA preparation kit . The usage of labelled dideoxynucleotides enables the identification of the nucleotide base at the site of interest . After a denaturation step at 90 \u00b0C for five minutes the detection was performed with capillary electrophoresis using an ABI 3500 Genetic analyzer .The digestion of the remaining primers and free deoxynucleotides after PCR amplification was performed with alkaline phosphatase  and an exonuclease . . The mulinterest . Two difTelomere length was analyzed by Relative Human Telomere Length Quantification qPCR Assay Kit  according to the Manufacturer\u2019s instruction. Telomere length is recognized and amplified by comparing samples to reference genomic DNA containing a 100-base pair (bp) telomere sequence located on human chromosome 17. The total as well as the average telomere length was then calculated. p-Values < 0.05 represented statistical significance.Descriptive statistical analysis was used to characterize the nominal variables in terms of frequency and percentages. A non-parametric Wilcoxon rank-sum test was used for comparison between continuous variables. All analysis was performed by GraphPad Prism 7.2  and JMP SAS 13.4 (SAS). TERT promoter mutated regions were identified. TERT promoter mutations identified among the different tissue regions within the whole-organ mapping bladder tumor specimens. Results showed that the percentages of mutated samples generally increased in a step-wise manner from 17.24% among tumor associated normal urothelium, 33.3% in hyperplasia, 14.3% in dysplasia to 46.1% of CIS specimens and 100% of all MIBC regions. Representative images of mutated tumor associated normal urothelium as well as CIS are shown in From 149 available tissue samples, 75 (50.33%) TERT promoter mutations within the whole-organ mapping bladder cancer specimens. As shown in TERT promoter mutation compared to the MIBC. Interestingly, in Bladder #9 the CIS housed a TERT \u2212124 mutation, which was also different to the MIBC (\u2212146). Detailed information of the tissue histologies as well as the mutational status for the TERT promoter for the polyclonal events are displayed in TERT promoter mutation compared to the MIBC.One objective of this study was to test for clonality events of TERT promoter mutations and total telomere length, some TERT mutated and wild type tissues as well as TERT mutated MIBC samples were analyzed. None of the determined telomere lengths were significantly different between mutated and wild type tissue samples (data not shown). To determine if there was an association between TERT promoter gene mutations throughout nine whole-organ mapping bladder cancer specimens thus, representing a full spectrum of tumorigenesis. Our results demonstrate that adjacent and non-adjacent tumor associated urothelium, non-invasive urothelium lesions as well as CIS surrounding the tumors are TERT mutated. Additionally, detection of mono- as well as polyclonal mutated specimens with identification of one or several TERT promoter mutations strengthen both clonality hypotheses. In this study, we evaluated the role of TERT promoter mutations have been identified in the vast majority of bladder tumors independent of pathological characteristics. The hot spot mutations detected in UBC and identified among this cohort locate at \u221257, \u2212124 and \u2212146 base pairs upstream from the ATG site of the TERT gene and generate novel transcription factor binding sites. Similar to the first descriptions of these mutations by Allory et al. the hot spot mutation at the \u2212124 nucleotide position was the most frequent substitution identified in our whole-organ mapping bladder cancer cohort [TERT promoter mutations in systematically collected normal urotheliums locating adjacent to non-invasive bladder tumor tissue. Additionally, even when the tumor was not mutated the associated normal urothelium showed a TERT promoter mutation. Moreover, if TERT mutations were initially observed, positive associations with bladder recurrence after therapy were shown indicating a potential use of TERT promoter gene mutations as a biomarker [TERT promoter mutations in tumor associated normal urothelium but also in non-invasive urothelial lesions adjacent to or non-adjacent to muscle invasive tumors. Considering TERT mutations in bladder tumors, it is interesting to note that we found in contrast to non-invasive tumors described above, all MIBC tissues presented with a specific mutation within a whole-organ mapping bladder specimen. Additionally, this observation also strengthens the fact that TERT promoter mutations seem to be an early and crucial event during bladder tumorigenesis and importantly are independent of pathological, histological and clinical characteristics [Evolution of especially epithelial cancers can be demonstrated by identifying distinct histologies including dysplasia or CIS sharing both mutational backgrounds with the tumor ,10. Due iomarker . In lineeristics ,15. TERT promoter gene were identified. Interestingly, all MIBC samples within its respective bladder specimen showed the same hot spot mutation. However, in contrast to MIBC polyclonal TERT mutations within the same bladder specimens were identified in tumor associated normal urothelium and non-invasive urothelial lesions. This finding supports the widely accepted idea that carcinogens in the urine could damage the urothelial layer and therefore mutational backgrounds could differ. On the other hand, four out of nine analyzed whole-organ mapping bladder tumors were monoclonal for TERT promoter mutations pointing to the fact of a possible seeding or migration of the cells [TERT promoter mutations and how they affect follow-up diagnostic tools has to be investigated in the future [Clonality is widely discussed regarding bladder tumorigenesis with poly- as well as monoclonal observations. In detail, whether the process of tumor formation is due to monoclonal events within the urothelium spreading through the bladder wall or by polyclonal, events resulting in several independent tumor clones is still under debate. Findings for both theories exist and with recent advances in molecular subtyping multifocal tumors and tumor heterogeneity will even be more important in terms of planning neoadjuvant treatment regimens for patients . We demohe cells . To whice future .TERT gene is to maintain and protect the ends of human chromosomes however, as we age they become shorter [TERT promoter mutation, functional investigations are still ongoing. In the study by Borah et al. [TERT mutated as well as wild type urothelial cell lines and observed an increased mRNA level of TERT transcripts, however neither the protein level nor the telomere length showed significant differences thus supporting non-translated mRNA. Additionally, Allory et al. [TERT between mutation carriers and wild types. These observations described above are comparable with our findings where there was no differences in telomere lengths. One further explanation could be that activation of the telomerase via mutations of the TERT promoter could also lead to other functions independent of telomere lengthening. These independent functions could affect many biological processes, including cell survival and apoptosis, DNA damage repair, mitochondrial function and stem cell activity. In addition, evidence exists that activating telomerase could also enable cells to acquire tumor-initiating mutations [TERT promoter mutations ultimately affect the urothelial tumor cells and additionally, implementing TERT promoter mutations as a diagnostic tool needs further investigation. Moreover, it was recently shown that cell lines from solid tumors with somatic TERT promoter mutations showed a significantly shorter telomere length compared to cell lines with a wild type TERT promoter [TERT promoter mutations compared to tumor associated urothelium and non-invasive urothelium as well as CIS possibly indicating a complex interplay between TERT mutational activation, telomere length variation and other cellular processes. The normal function of telomerase encoded by the  shorter . With aph et al.  the authy et al.  observedutations . How TERpromoter . AlthougTERT promoter gene have been analyzed and thereby other TERT promoter alterations could have been missed. Limitations of our study is the retrospective nature as well as the limited, partly heterogenous sampling of the bladder cancer specimens. In addition, only hot spot mutations of the TERT promoter gene mutations occur in tumor associated urothelium, non-invasive urothelial lesions and CIS thus, highlighting a crucial and important role of the TERT gene in the development of bladder tumors. Moreover, the evaluation of distinct promoter mutant positions strengthens both theories of a mono- as well as a polyclonal development of bladder tumors. To our knowledge, we demonstrate for the first time in tissues from whole-organ mapping bladder tumor specimens containing MIBC,"}
+{"text": "Contrast induced neurotoxicity (CIN) is a rare complication of cardiac catheterization and re-exposure to contrast medium carries the risk of recurrent CIN. We report a case of successful contrast re-challenge in a 60-year-old female patient who developed CIN after her first procedure of coronary angiography (CAG) which resulted in symptoms of disorientation, amnesia and cortical blindness. A non-contrast enhanced CT performed four hours after the CAG was normal, however, her MRI brain scan showed scattered tiny hyper intensities in posterior occipito-temporal and parietal regions suggesting CIN. Patient\u2019s symptoms resolved completely after 72 hours. Two months later, because of persistent exertional angina, patient was successfully re-challenged with lesser amount of contrast medium with administration of hydrocortisone prior to procedure, and PCI to LAD was completed without recurrence of CIN. Contrast induced neurotoxicity in form of fits, confusion, cortical blindness and encephalopathy is very rare complication after angiography of coronary arteries and bypass grafts.A-60-year old woman with history of hypertension, dyslipidemia and paroxysmal AF admitted for acute coronary syndrome and underwent CAG. Her CAG was performed through right radial access with 5F Judkins diagnostic catheters. There was significant tortuosity in her brachiocephalic trunk which resulted in difficult engagement of both left and right coronary systems, hence larger volume (300 ml) of contrast media (Iohexol) was administered during her coronary angiography. Patient did not have a previous history of any procedure with contrast agent exposure. Her CAG showed significant 70% & 90% tubular lesions in proximal and mid segments (respectively) of left anterior descending coronary artery (LAD) requiring intervention. However, patient started to become confused, aggressive and later developed amnesia and cortical blindness. Her neurological examination did not reveal any cranial, sensory or motor nerves abnormality. A non-contrast computerized tomography (CT) scan performed four hours after the start of symptoms showed no acute pathological findings. Her brain magnetic resonance imaging (MRI) demonstrated tiny hyperdensities in the posterior occipito-temporal and parietal regions suggesting contrast induced neurotoxicity . PatientContrast induced neurotoxicity (CIN) following cardiac catheterization is a rare but devastating complication. Its clinical presentation varies from mild symptoms of headache and vomiting to more serious presentation with seizures, hemiparesis, encephalopathy and cortical blindness.The exact mechanism of contrast induced CIN remains unknown. Disruption of blood brain barrier and direct contrast neuronal toxicity mainly in the occipital region of brain haven been postulated as a possible mechanism in many reports.8Contrast media re-challenge has not been widely reported in literature. We identified only three cases where re-challenge of contrast media did not result in recurrence of cortical blindness.9Herein, we propose that re-challenge with minimal amount of contrast medium after pre-treatment with intravenous corticosteroids can be considered in patients with previous history CIN if: i) a second procedure is mandated as was the case in our patient to have persistent angina despite optimal anti-anginal medical therapy ii) CIN resolves completely after the first contrast exposure and iii) larger volume of contrast is associated with CIN.CIN following coronary angiography is an extremely rare but usually reversible complication. Re-exposure of contrast media to patients with history of CIN carries the risk of recurrent CIN, hence it is not well documented. We successfully re-challenged contrast medium in our patient and proposed that contrast rechallenge may be considered in some patients if certain conditions are fulfilled However, it is difficult to conclude whether or not CIN will recur with contrast re-challenge but we are reassured with the fact that CIN is usually transient and resolves completely.MAS & MWA did manuscript writing. MMS edited the manuscriptSKN reviewed the manuscript. HAB gave final approval. MAS responsible and accountable for the accuracy or integrity of this study."}
+{"text": "The purpose of this study was to explore demographic differences in health personality. Data consisted of 3,907 participants, 65 years and older. Multivariate analysis of variance with post-hoc testing revealed that women had higher health neuroticism scores than men, but men had higher health extraversion scores than women. Those married reported higher health agreeableness than those not married and young-old participants had higher health extraversion and health openness compared to other age groups. Regional differences included Midwest participants reporting higher health openness but lower health conscientiousness scores when compared to participants from other regions. There were also significant interactions. For example, individuals from geographic areas with predominately White Midwest residents were significantly higher on health neuroticism when compared to Northwest, South, and West regions. The results are helpful for healthcare providers who can tailor intervention approaches to specific populations."}
+{"text": "Gs), net assimilation rate (A), and LOX and methanol emissions to varying MeJA concentrations (0.2\u201350 mM) in cucumber (Cucumis sativus) leaves with partly open stomata and in leaves with reduced Gs due to drought and darkness. Exposure to MeJA led to initial opening of stomata due to an osmotic shock, followed by MeJA concentration-dependent reduction in Gs, whereas A initially decreased, followed by recovery for lower MeJA concentrations and time-dependent decline for higher MeJA concentrations. Methanol and LOX emissions were elicited in a MeJA concentration-dependent manner, whereas the peak methanol emissions (15\u201320 min after MeJA application) preceded LOX emissions (20\u201360 min after application). Furthermore, peak methanol emissions occurred earlier in treatments with higher MeJA concentration, while the opposite was observed for LOX emissions. This difference reflected the circumstance where the rise of methanol release partly coincided with MeJA-dependent stomatal opening, while stronger stomatal closure at higher MeJA concentrations progressively delayed peak LOX emissions. We further observed that drought-dependent reduction in Gs ameliorated MeJA effects on foliage physiological characteristics, underscoring that MeJA primarily penetrates through the stomata. However, despite reduced Gs, dark pretreatment amplified stress-volatile release upon MeJA treatment, suggesting that increased leaf oxidative status due to sudden illumination can potentiate the MeJA response. Taken together, these results collectively demonstrate that the MeJA dose response of volatile emission is controlled by stomata that alter MeJA uptake and volatile release kinetics and by leaf oxidative status in a complex manner. Treatment by volatile plant hormone methyl jasmonate (MeJA) leads to release of methanol and volatiles of lipoxygenase pathway (LOX volatiles) in a dose-dependent manner, but how the dose dependence is affected by stomatal openness is poorly known. We studied the rapid (0\u201360 min after treatment) response of stomatal conductance ( Thexenals . The emi\u03a6M) and the total volatile emission bursts after (IT) during a period of 60 min after MeJA treatment were calculated as our previous report [To study the quantitative emission characteristics of LOX compounds and methanol, the emission maxima   and all statistical effects were considered significant at p < 0.05.All experiments were replicated at least three times with different plants and all data shown are averages \u00b1 SE. Effects of MeJA dose on foliage photosynthetic and emission traits were studied by linear or non-linear regressions depending on the shape of the response. Effects of abiotic factors combined with MeJA treatment on Gs that controls MeJA entry into the leaf. This implies that environmental stresses that reduce Gs are expected to reduce the plant sensitivity to airborne MeJA as was confirmed in our study for drought stress. Furthermore, changes in Gs alter the dynamics of water-soluble stress-volatile release from the plants, and this can have significant implications for stress propagation and signaling. A model of the relationships between rapid constitutive emission of volatiles and the role of stomata and cuticle by MeJA treatment interacting with light condition was put forwarded (Our experiments demonstrate that the response to MeJA strongly depends on orwarded . On the"}
+{"text": "Sadness is often thought of as unpleasant and dysfunctional. Yet, evolutionary-functionalist approaches and discrete emotional aging frameworks suggest that sadness is an emotion that helps us deal with loss and thus may become particularly salient and adaptive in late life. This talk presents findings from a multi-study, multi-method research program using age-diverse samples and experimental and longitudinal study designs. Findings show (1) intact or elevated levels of sadness responding in late life . Moreover, (2) higher levels of sadness responding are linked to adaptive outcomes in late life  with some effects generalizing across age groups . Implications for future research are discussed."}
+{"text": "Leishmania genus protozoan parasites. Inoculation by infected Phlebotamine sandflies results in asymptomatic infection or a diverse range of clinical manifestations. Leishmaniasis can present with tegumentary lesions or visceral disease with parasite dissemination and high mortality [Leishmania species cause this spectrum of human disease [Leishmaniasis is a vector-born disease, caused by ortality . The spe disease . HoweverLeishmania parasites encounter diverse environments, genetic adaptations may result in positive or negative trade-offs in other life-cycle stages. In addition, as humans are not the primary vertebrate reservoir, protective or pathologic immune responses may alter disease outcome but not parasite fitness. Thus, understanding how Leishmania genetics influences outcomes of human leishmaniasis requires consideration of selective pressures across life-cycle stages (Leishmania parasites to navigate its evolutionary landscape.Evolutionary biology can be applied to understand the genetic differences among parasites with different disease manifestations. Because e stages . For insLeishmania evolution provide challenges to investigating host range and parasite virulence, they also present opportunities to understand human susceptibility. The range of leishmaniasis is limited by interactions between vectors and animal reservoirs. As their habitat is altered due to climate change and social conflict, ecologic studies informed by evolutionary dynamics could predict changes in leishmaniasis distribution. Human pathogenesis varies with the infecting Leishmania species; however, infection with the same species can result in an appropriate immune response with resolution, impaired response with parasite proliferation, or excessive inflammation with immunopathology [Leishmania parasites encode mechanisms to influence host immunity, understanding molecular pathogenesis requires studies using a diverse collection of parasites. Synthesis of these approaches is needed to understand variation in leishmaniasis outcomes and improve human health.While the complex pressures shaping athology . To elucPlasmodium parasites by treating mosquito nets with anti-malarial compounds [This evolutionary complexity may prove advantageous in developing novel treatments. For example, targeting parasites in vectors and reservoirs can decrease transmission and minimize human toxicity. This strategy has shown promise against ompounds . Furtherompounds  uniquely"}
+{"text": "Multisite medical data sharing is critical in modern clinical practice and medical research. The challenge is to conduct data sharing that preserves individual privacy and data utility. The shortcomings of traditional privacy-enhancing technologies mean that institutions rely upon bespoke data sharing contracts. The lengthy process and administration induced by these contracts increases the inefficiency of data sharing and may disincentivize important clinical treatment and medical research. This paper provides a synthesis between 2 novel advanced privacy-enhancing technologies\u2014homomorphic encryption and secure multiparty computation (defined together as multiparty homomorphic encryption). These privacy-enhancing technologies provide a mathematical guarantee of privacy, with multiparty homomorphic encryption providing a performance advantage over separately using homomorphic encryption or secure multiparty computation. We argue multiparty homomorphic encryption fulfills legal requirements for medical data sharing under the European Union\u2019s General Data Protection Regulation which has set a global benchmark for data protection. Specifically, the data processed and shared using multiparty homomorphic encryption can be considered anonymized data. We explain how multiparty homomorphic encryption can reduce the reliance upon customized contractual measures between institutions. The proposed approach can accelerate the pace of medical research while offering additional incentives for health care and research institutes to employ common data interoperability standards. The current biomedical research paradigm has been characterized by a shift from intrainstitutional research toward multiple collaborating institutions operating at an interinstitutional, national or international level for multisite research projects; however, despite the apparent breakdown of research barriers, there remain differences between ethical and legal requirements at all jurisdictional levels . There aFor example, the International Cancer Genome Consortium endeavors to amass cancer genomes paired with noncancerous sequences in a cloud environment, known as pancancer analysis of whole genomes. The International Cancer Genome Consortium\u2019s data access compliance office was unable to establish an international cloud under the Pancancer Analysis of Whole Genomes Project because of conflicts between United States and European Union data privacy laws . These cIn this paper, we describe how traditional data-sharing approaches relying upon conventional privacy-enhancing technologies are limited by various regulations governing medical use and data sharing. We describe two novel privacy-enhancing technologies, homomorphic encryption and secure multiparty computation, that extend the capacity of researchers to conduct privacy-preserving multisite research. We then turn to analyze the effects of regulation on using these novel privacy-enhancing technologies for medical and research data sharing. In particular, we argue these privacy-enhancing technologies guarantee anonymity as defined under the EU GDPR and are, therefore, key enablers for medical data sharing. We focus on the GDPR, as it currently represents a global benchmark in data protection regulations. We argue that using these technologies can reduce the reliance upon customized data-sharing contracts. The use of standardized agreements for multiparty processing of data in concert with privacy-enhancing technologies can reduce the bottleneck on research. Finally, we turn to address how these novel privacy-enhancing technologies can be integrated within existing regulatory frameworks to encourage increased data sharing while preserving data privacy.Before examining novel privacy-enhancing technologies, it is necessary to examine the main models for exchanging medical data for research purposes and the limitations of conventional privacy protection mechanisms that are currently used to reduce the risk of reidentification. We synthesize the data-sharing models into three categories and analyze their main technological issues .The centralized model requires medical sites  that are willing to share data with each other to pool their individual-level patient data into a single repository. The data repository is usually hosted by one medical site or by an external third party , playing the trusted dealer role. The main advantage of this model is that the trusted dealer enables authorized investigators to access all the patient-level information needed for data cleaning and for conducting statistical analysis. Moreover, such a data-sharing model minimizes infrastructure costs at medical sites, as data storage and computation are outsourced. However, from a data privacy perspective the centralized model is often difficult to realize, especially when medical and genetic data should be exchanged across different jurisdictions. The central site hosting the data repository represents a single point of failure in the data-sharing process. All participating sites must trust such single entity for protecting their patient-level data .k-anonymity privacy model . Although homomorphic encryption and secure multiparty computation offer privacy guarantees, there is still an orthogonal risk of reidentifying individuals from aggregate-level results that are eventually decrypted and can be exploited by inference attacks [Nevertheless, any standards will need to be continually updated to respond to new technological changes. For example, one of the most significant drawbacks of fully homomorphic encryption is the complexity of computation. This computational complexity makes it hard to predict running times, particularly for low-power devices such as wearables and smartphones. For the foreseeable future, this may limit the devices upon which fully homomorphic encryption can be used . Therefo attacks ,21,27,74A final consideration relates to ethical issues that exist beyond whether homomorphic encryption, multiparty computation, and multiparty homomorphic encryption involve processing anonymized or personal data. First, the act of encrypting personal data constitutes further processing of those data under data protection law. Therefore, health care and research institutions must seek informed consent from patients or research participants . InstituMedical data sharing is essential for modern clinical practice and medical research. However, traditional privacy-preserving technologies based on data perturbation, along with centralized and decentralized data-sharing models, carry inherent privacy risks and may have high impact on data utility. These shortcomings mean that research and health care institutions combine these traditional privacy-preserving technologies with contractual mechanisms to govern data sharing and comply with data protection laws. These contractual mechanisms are context-dependent and require trusted environments between research and health care institutions. Although federated learning models can help alleviate these risks as only aggregate-level data are shared across institutions, there are still orthogonal risks to privacy from indirect reidentification of patients from partial results . Further"}
+{"text": "Approximately 400 million people throughout the world suffer from a rare disease. Although advances in whole exome and whole genome sequencing have greatly facilitated rare disease diagnosis, overall diagnostic rates remain below 50%. Furthermore, in cases where accurate diagnosis is achieved the process requires an average of 4.8\u00a0years. Reducing the time required for disease diagnosis is among the most critical needs of patients impacted by a rare disease. In this perspective we describe current challenges associated with rare disease diagnosis and discuss several cutting-edge functional genomic screening technologies that have the potential to rapidly accelerate the process of distinguishing pathogenic variants that lead to disease. Approximately 400 million individuals worldwide are directly affected by a rare disease  and whole genome sequencing (WGS) in a clinical setting. While the application of these technologies has greatly facilitated the identification of disease-associated genetic variants, the rate of diagnosis for rare disease remains below 50%  over the past several years now provide scalable mechanisms to assign functional properties to large catalogs of variants. These approaches can be used to rapidly distinguish clinically detected variants with an increased likelihood of pathogenicity and facilitate the prioritization of variants that warrant in-depth evaluation.One common experimental approach used to explore the functional consequences of a genetic variant has been the use of plasmid-based reporter assays. These assays can be engineered to harbor specific variant sequences within exons, introns, or even noncoding regulatory regions of a transgenic reporter gene. Individual reporter constructs can be introduced into cultured cells and transgene expression and/or function can be evaluated using relevant methods. In recent years several plasmid-based reporter approaches have been adapted to multiplexed formats that permit the characterization of thousands of genetic variants simultaneously using high-throughput sequencing-based readouts. These massively parallel genomic assays have been utilized to profile published catalogs of disease-associated genetic variants and distinguish variants with functional implications . Distinguishing the functional consequences of these variants may require assays that are capable of profiling cellular phenotypes. Advances in genome editing technology, specifically CRISPR/Cas9, have dramatically improved the ability to engineer cellular models with specific genetic alterations , inhibition (CRISPRi), or activation (CRISPRa) of protein-coding genes  or the repression/activation of targeted genomic regions (CRISPRi/CRISPRa). Consequently, these screens do not perfectly model the impact of clinically detected variants. As CRISPR-based screening methods continue to advance it may become possible to functionally screen large numbers of specific variants through pooled format adaptations of precision editing technologies  (Shen et al. The ability to rapidly assign experimentally determined functional properties to clinically detected genetic variants will have profound impacts on rare disease diagnosis. In addition to existing resources, clinical geneticists will have access to empirical data that will facilitate more informed decisions related to variant pathogenicity. This information will reduce the time required to analyze individual patient genomes, increase patient throughput, and ultimately translate to improved rates of diagnosis. Moreover, the barriers to generating this data are minimal as many high-throughput functional assays do not require modifications to existing laboratory infrastructure nor do they require patient specimens.The experimental strategies we discuss here are intended to complement, not replace, current standard practices in variant interpretation. Moreover, the functional assays we have described are mainly suited for Mendelian diseases. Experienced clinical geneticists will always be needed to critique experimental results and to investigate diseases with more complex genetic contributions. Rare disease diagnosis will remain a constant challenge, but bridging the gap between clinical and functional genomics could provide an accelerated path to diagnosis for many rare disease patients that are still searching for answers."}
+{"text": "There is limited literature on formal caregivers\u2019 communication with persons living with dementia (PLWD) in home settings. Most research comes from studies of long-term care home settings or informal home care contexts. Yet, there are expected needs and rising demands for formal caregiver support within home care. The aim of this study was to understand better the lived experiences of personal support workers (PSWs) regarding their communication with PLWD in home settings. A hermeneutic phenomenological approach guided this research. Semi-structured interviews were conducted with 15 PSW participants. Three major themes were identified through thematic analysis: (1) challenged by dementia-related impairments; (2) valuing communication in care; and (3) home is a personal space. PSWs experienced difficulties in their communication with PLWD despite recognizing the importance of communication in providing optimal home care. This suggests that while PSWs possess good intentions, they do not possess the skills necessary to ensure effective interactions. Dementia-specific education and training are recommended to improve PSWs\u2019 communication skills and to enhance quality of care. Findings highlight further the uniqueness of the personal home space itself on PSWs experiences with communication. Aspects of the home care environment can enable, but also complicate, successful communication between PSWs and PLWD. Consequently, findings also have implications for family members of PLWD and home care employers regarding optimizing practice and improving care."}
+{"text": "This review enhances the existing literature on relationships between problematic smartphone use (PSU), psychopathology, addictive personality, and online social engagement as regards young adults, giving attention to predictive determinants of addictive behavior in smartphone usage. My article cumulates previous research findings on the psychology of addictive smartphone behavior in terms of problematic use, social anxiety, and depressive stress by focusing on the relationship among mobile social media usage, smartphone addiction risk, mental health issues, and individual well-being. The inspected collected findings prove that depression and social anxiety constitute risk determinants for greater PSU and that particular categories of smartphone applications are positively related to well-being. State anxiety and motivations represent significant predictors of PSU. High PSU affects participation in social engagement. As limitations in the current review, my results point towards relevant avenues of research on social consequences of teenagers\u2019 smartphone problematic use. Future directions should clarify whether compulsive smartphone use adversely affects both mental and physical health in the long run. PSU hasPSU shapes subjective and psychological well-being, and may configure associated anxiety and depression psychopathology. Mental health and somatic symptoms are adversely impacted by PSU leading to impaired socio-emotional functioning and possibly causing psychological distress.Users\u2019 psychological features may not clarify every characteristic of PSU. High PSU affects participation in social engagement. Users\u2019 absence of social networks may hinder agreeable social communications  and emotParental neglect is considerably related to teenagers\u2019 smartphone addiction. In the link between parental neglect and PSU, the former is not relevantly connected with the relational instability with peers, negatively shaping PSU. The relational instability with teachers has a fragmentary mediation impact between parental neglect and PSU . ParentsParenting style and attachment may mediate young adults\u2019 smartphone use, improving interpersonal adaptation and self-control, while articulating family well-being. Young adults\u2019 addictive personality may be shaped by parental mediation practices and self-regulation.Significant research has considered lately the psychology of addictive smartphone behavior in terms of problematic use, social anxiety, and depressive stress. My article extends previous work by focusing on the relationship among mobile social media usage, smartphone addiction risk, mental health issues, and individual well-being. Progressively relevant degrees of smartphone ownership and utilization give rise to the implicit risk for addictive behaviors and adverse health results, shaping subjective and psychological well-being. The conclusions drawn\u00a0from the above analyses are that depression and anxiety symptoms are associated with PSU severity, generating, among others, emotion dysregulation, psychological distress, poor sleep\u00a0quality,\u00a0and diminished academic performance. Personality traits, social-emotional distress, and duration of daily smartphone use constitute antecedents of PSU, impacting subjective and psychological well-being. As limitations in the current review, my results point towards relevant avenues of research on social\u00a0consequences of young adults\u2019 smartphone addiction. Future directions should clarify whether compulsive smartphone use adversely affects both mental and physical health in the long run.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation. Recent pathological studies reported some of the COVID-19 patients with lung fibrotic lung features. Clinically, the main consequence of SARS-CoV-2 infection is cytokine storm, however previous studies indicate that anti inflammation therapy have no effects on pulmonary fibrosis, thus other mechanisms need to be provided to address this issue. Early micro injuries to alveoli increase local vascular permeability which provokes edema accompanied by inflammatory cytokines which prompt cytoskeletal remodeling and alter cellular mechanical forces. If these mild injuries could not be repaired properly, then fibroblasts will be activated and subsequent excessive deposition of extracellular matrix will result in a mechanical stretched niche. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize and the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.Pulmonary fibrosis (PF), which constitutes a broad range of heterogeneous end stage interstitial lung diseases, is characterized by excessive deposition of extracellular matrix and destruction of the pulmonary parenchyma  about 50\u201370\u00a0m2 Weibel , 20-time2 Weibel . In the 2 Weibel .Mechanical sensing and regulating of endothelial cells are involved in the process of lung disease (Fang et al. Taken together the mechanical stress exposed to the endothelial cells is translated to different signals for the initiation and progression of lung fibrosis.2+ to interact with specific intracellular target proteins (Donato et al. 2+ influx can be induced by mechanical stretch in human lung fibroblasts (Murata et al. 2+ mediated S1006A stimulation. Taken together, these data indicate that mechanical stress promotes fibrosis by both stimulating the proliferation and migration of fibroblasts.The migratory and proliferative fibroblasts organizing in distinct clusters is called fibroblastic foci and this depicts the typical phenotype of lung fibrosis featured by accumulation of exaggerated amounts of ECM that forms a stiff milieu  where fiMacrophages are involved in the cross-talk between innate and adaptive immunity (Epelman et al. Mast cells, originate from CD34-expressing haematopoietic stem cells in the bone marrow, are best known for their roles in allergic and acute inflammatory diseases (Wernersson and Pejler \u2212/\u2212 AECIIs cannot regenerate new alveoli which resulted in sustained elevated mechanical tension that subsequently activates a TGF-\u03b2 signaling loop in stem-like AECIIs and promote fibrosis (Wu Histologically, PF develops from microscopic fibrotic areas at the very peripheral regions of lung and slowly progress inward (Plantier et al. rosis Wu . Clinicarosis Wu . The lunrosis Wu . This coAccumulating evidence suggests abnormal metabolism in PF (Rowan et al. 6A modifications of pri-miRNA-126 was involved in the process of pulmonary fibrosis (Han The term \u201cepigenetics\u201d describes heritable changes in a cellular phenotype without alterations in the DNA sequence (Berger et al. osis Han . What\u2019s osis Han  which maosis Han . Indeed,osis Han . Thus, uIn this review, we highlight the importance of rigid fibrotic niche in orchestrating the mechanical response of alveolar cells in exacerbating lung fibrosis Fig.\u00a0. The alvFurthermore, mechanical stress exerts a more comprehensive impact via metabolic and epigenetic regulation, which should be a promising filed for treating PF since rapid advances have been made in developing drugs to adjust metabolic status and target the epigenetic landscape. Therefore, translating these mechanism insights into clinical utilization may enable novel approaches for alleviating lung fibrosis."}
+{"text": "Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways, but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, up-regulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents over-proliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target."}
+{"text": "Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are responsible for the majority of nosocomial infections  . Another study achieved successful phytomedited synthesis of green TiO2NPs that proved to be effective for treating biofilm-based bacterial and fungal infections .Seven original research articles spanning diverse disciplines describe the development of NATs for clinically-relevant MDR pathogens. One study describes the one-pot synthesis of Ag-ZnO nanoparticles at low temperatures and demonstrated remarkable antimicrobial activity of these nanoparticles against methicillin-resistant Enterobacterales (CPE). The authors showed how antimicrobial combinations synergized against most CPE expressing resistance genes. These antimicrobial combinations may facilitate the successful treatment of patients infected with CPE . Another original research article identified two potent combinations of antibiotics for clinical MRSA infection, both in vitro and in vivo . A separate study found that the compound 2,4-Di-Tert-Butylphenol isolated from an endophytic fungus substantially reduced the secretion of virulence factors and biofilm and its associated factors controlled by quorum sensing in a dose-dependent manner in Pseudomonas aeruginosa .Another research article assessed the therapeutic efficacy of antimicrobial combinations on carbapenemase-producing Streptococcus pneumoniae infections . New putative antimicrobial candidates were reported by Okella et al. They designed an antimicrobial peptide and performed target identification based on a putative antimicrobial peptide motif derived from fish. From all the peptide motifs generated in this work, the authors identified Pleurocidin (secreted by flatfish) as having strong antimicrobial potential.Furthermore, a study tested the anti-virulence activity of potential uridine diphosphate glucose pyrophosphorylase (UDPG:PP) inhibitors and showed that these inhibitors are a potential drug candidates against Le\u00f3n-Buitimea et al.). Another review explored the possibility of designing antimicrobial nanoparticle-based devices to exploit the potential of antimicrobial nanoparticles to combat MDR pathogens . Finally, a third review describes the mechanisms associated with drug resistance in pyogenic streptococci and discusses the advantages and limitations of innovative therapeutic strategies such as bacteriocins, bacteriophage, phage lysins, and metal nanoparticles .Three review articles included in this special issue address the use of NATs to face MDR bacteria. A mini-review discusses combination treatments  as a pathway to develop antimicrobial therapeutics with broad-spectrum antibacterial action, bactericidal instead of bacteriostatic activity, and better efficacy against MDR bacteria (In summary, this group of articles contributes to the search for new therapeutic strategies to combat antibacterial resistance. MDR and XDR infections are growing in incidence; the main challenges facing society are now to design, develop, and evaluate new therapeutic strategies that can spearhead the development of alternative therapies against clinically-relevant MDR pathogens.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Extracellular vesicles (EVs) are lipid bilayer-enclosed microparticles that have prominent roles in the intercellular crosstalk. EVs are secreted after fusion of endosomes with the plasma membrane (exosomes) or shed from the plasma membrane (microvesicles). These microparticles modulate bone marrow microenvironment and alter differentiation and expansion of normal hematopoietic cells. EVs originated from mesenchymal stromal cells have been shown to enhance expansion of myeloid-biased hematopoietic progenitor cells. In addition, megakaryocytic microparticles stimulate differentiation of hematopoietic stem and progenitor cells into mature megakaryocytes. The ability of EVs in induction of maturation and expansion of certain hematopoietic cells has implications in transfusion medicine and in targeted therapeutic modalities. Important prerequisites for these interventions are identification the specific targets of EVs, transferred biomolecules and molecular mechanisms underlying the fate decision in the target cells. EVs are also involved in the pathogenesis and progression of hematological malignancies including acute leukemia and multiples myeloma. In the current review, we provide a summary of studies which evaluated the significance of EVs in normal hematopoiesis and hematological malignancies. Extracellular vesicle, Hematopoiesis, Hematological malignancy Microvesicles (MV) and exosomes include two important kinds of EVs . While M2Normal hematopoiesis is influenced by biomolecules that exist in EVs. For instance, EVs originated from mesenchymal stromal cells have been shown to enhance expansion of myeloid-biased hematopoietic progenitor cells. This speculation is based on an experiment in murine stromal cells where EVs derived from these cells stimulated loss of quiescence in hematopoietic stem and progenitor cells (HSPCs) and enhanced expansion of myeloid progenitors. Such effects were exerted through the MyD88 adapter protein. Notably, inhibition of TLR4 could suppress this process to some extent. Canonical NF-\u03baB pathway and subsequent induction of Hif-1\u03b1 and CCL2 were also involved in this process . Megakar3EVs also mediate different roles in hematological malignancies.3.1Both primary acute myelocytic leukemia (AML) and AML cell lines have been shown to produce exosomes that are transferred to bystander cells. These EVs contain numerous coding and noncoding RNAs which are involved in the pathobiology of AML. EVs entrance into bone marrow stromal cells results in the modulation of their potential in growth factors production. The signals transmitted by these EVs change the proliferative, angiogenic, and migratory features of cocultured stromal and hematopoietic progenitor cells . EVs als3.2Exosomes originated from patients with chronic myelogenous leukemia (CML) patients are enriched in amphiregulin (AREG), therefor inducing EGFR signaling in stromal cells. Activation of this signaling pathway leads to over-expression of SNAIL, MMP9 and IL-8. Prior exposure of stromal cells with CML cells exosomes has enhanced expression of annexin A2 which increases the adhesion of leukemic cells to the stromal monolayer, facilitating the growth and invasion of leukemic cells . CML-der3.3Microvesicles released from MSCs from patients with myelodysplastic syndrome (MDS) have been shown to alter CD34 + cells characteristics .Multiple myeloma (MM) MSCs have also been shown to produce EVs that are conveyed to MM cells, thus changing tumor growth. Exosomal levels of miRNA such as miR-15a were different between MM and normal MSCs. Besides, EVs originated from MM bone marrow MSCs had greater amounts of oncogenes, cytokines, and adhesion molecules. While these EVs enhanced MM tumor growth, normal bone marrow MSC-derived EVs suppressed the growth of MM cells . MM pati4The presence of EVs in the body fluids including saliva, urine, peripheral blood and other body fluids indicates the potential of these vesicles in diagnostic and prognostic procedures . Notably5EVs have been shown to mediate critical functions during normal hematopoiesis and in the course of initiation and progression of hematological malignancies. The cell-cell communication mediated by EVs has important effects in bone marrow milieu and regulation of innate immune responses . The abiFinally, EVs which are released into bone marrow microenvironment might affect response of malignant cells to therapeutic modalities including tyrosine kinase inhibitors. Therefore, EVs components not only predict patients' outcome and their response to therapy, but also they represent potential manipulable resources for conferring drug resistance. Alteration in exosomal level of certain proteins might also reveal responses to chemotherapy. Moreover, the exosomal content may reflect the existence of residual disease in patients thought to be in complete remission . MalignaTaken together, EVs contain several protein and RNA molecules that could alter lineage differentiation, expansion and function of bone marrow cells in both physiological and pathologic conditions. The ability of these microparticles in specific targeting of the recipient cells potentiates them as vehicles for combating drug resistance in hematological malignancies. Moreover, malignant cells-derived EVs are potential diagnostic and prognostic markers in this kind of malignancy.All authors listed have significantly contributed to the development and the writing of this article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data will be made available on request.The authors declare no conflict of interest.No additional information is available for this paper."}
+{"text": "A 48-year-old-female presented to the emergency department with dislodgement of her percutaneous endoscopic gastrostomy (PEG) tube, necessitating bedside replacement. Replacement was done without difficulty and gastrografin radiography was obtained to confirm positioning. Radiography revealed contrast filling the colon at the splenic flexure and proximal descending colon suggestive of colocutaneous fistula formation.The patient required hospitalization with surgical consultation, initiation of parenteral nutrition, and conservative management of the fistula with surgical replacement of the PEG tube. Although rare, it is paramount for the emergency physician to be aware of this complication when undertaking bedside replacement of PEG tubes. A 48-year-old female with past medical history of failure to thrive requiring percutaneous endoscopic gastrostomy (PEG) tube placement presented to the emergency department (ED) with PEG tube dislodgement. Her PEG tube was initially placed in 2009, with surgical replacements in 2012 and 2018. Examination revealed a soft, nontender, non-distended abdomen with an open gastrostomy tract. ED course included placement of a new gastrostomy tube into the existing tract and confirmatory gastrografin radiography .The confirmatory radiography revealed contrast filling the colon at the splenic flexure and proximal descending colon suggestive of colocutaneous fistula formation, without peritoneal extravasation. This required hospitalization with surgical consultation for removal of the misplaced PEG tube, initiation of parenteral nutrition, intravenous antibiotics, and surgical reinsertion of the PEG tube after conservative management of the colocutaneous fistula. Colocutaneous fistulas are a rare complication of PEG tube insertion with incidence rates of 0.5\u20133%.CPC-EM CapsuleWhat do we already know about this clinical entity?Colocutaneous fistulas are a rare complication of percutaneous endoscopic gastrostomy (PEG) tube insertion mediated by PEG tube penetration of interposed colon between the stomach and abdominal wall.What is the major impact of the image(s)?Contrast filling the splenic flexure and proximal descending colon suggests colocutaneous fistula formation, requiring prompt recognition and surgical consultation.How might this improve emergency medicine practice?Emergency physicians change a large number of PEG tubes; therefore, recognition and awareness of this rare complication is important to clinical practice."}
+{"text": "Racial and ethnic disparities in age-related cognitive function and dementia risk in the US are well recognized. However, the psychosocial drivers of these disparities and underlying mechanisms are less well studied. This symposium will highlight novel research regarding our current understanding of racial/ethnic differences in brain and cognitive aging and the underlying mechanisms of the disparities. Frist, two papers will describe results regarding racial/ethnic differences in cognitive function and brain aging markers. Few studies have assessed racial/ethnic differences in cognitive function across age groups. Indira Turney will utilize data from a multigenerational study to explore how age impacts racial/ethnic differences in cognitive function. Underlying brain mechanisms of racial/ethnic differences in cognitive outcomes are also not well defined. Sara Godina will present a systematic review of racial/ethnic differences in structural markers of brain aging and neuropathology. Second, three papers will explore how various risk factors may explain the racial/ethnic disparities in cognitive outcomes. Melissa Lamar will demonstrate the differential associations of various blood pressure indicators with cognitive change among black older adults. B. Gwen Windham will present data from two studies that illustrate differential effects of common risk factors by race and region, highlighting inherent difficulties in race-place disparity research. Finally, Laura Zahodne will present results on how psychosocial factors, beyond socioeconomic status, contribute to racial/ethnic disparities in cognitive function. Jen Manly will lead a discussion on the implications of these results for the future of dementia prevention efforts for an increasingly diverse older US population."}
+{"text": "Using two studies, we examined the late life prevalence and health consequences of discrete positive emotions posited to motivate rest and recovery  or pursuit of novelty and stimulation (excitement). Study 1 assessed the salience of these discrete emotions in older adults  relative to younger adults  over a one-week period. Multilevel models showed that older (vs. younger) adults reported higher calmness and lower excitement. Study 2 examined the longitudinal health consequences of calmness and excitement in old age , as moderated by perceived control. Multilevel growth models showed that calmness, but not excitement, buffered against 10-year declines in psychological well-being  and physical health  for older adults with low perceived control. Results suggest that positive emotions with disparate motivational functions become more  or less (excitement) salient and have diverging implications for health in old age."}
+{"text": "Indices quantifying allostatic load (AL) and biological aging (BA) have received widespread use in epidemiological and health science literature. However, little attention has been paid to the conceptual and quantitative overlap between these indicators. By reviewing literature utilizing measures of AL and BA, we highlight differences with respect to biological markers employed and approach toward scale construction. Further, we outline opportunities where AL indices might be improved by adopting analytical features of BA measures. We demonstrate the utility of this approach using data from The MIDUS National Survey, constructing three indices of allostatic load: one standard approach modeled after Gruenewald et al, 2012, and two alternative formulations informed by BA procedures. The performance of AL indices are juxtaposed against two commonly employed indices of biological aging: Klemera-Doubal Method Biological Age and Homeostatic Dysregulation. All measures were significantly associated with chronological age. Alternative AL formulations were more strongly associated with biological aging measures than with the standard approach. MIDUS participants with increased allostatic load and older biological ages performed worse on tests of physical, cognitive, perceptual, and subjective functioning. Further, MIDUS participants with history of childhood-trauma and mental-health problems were measured as having increased AL and BA. Alternative AL formulations tended to have effect-sizes equivalent to or larger than those observed for BA measures. In conclusion, indices of allostatic load and biological age approximate similar processes when constructed with comparable biomarkers and rigor, in line with their conceptual overlap as proxies of cumulative wear and tear."}
+{"text": "Background: Hypoglossal nerve stimulators (HNS) are an increasingly popular form of upper airway stimulation for obstructive sleep apnea (OSA) in adults who are unable to tolerate positive pressure treatment. However, HNS use is currently limited in the pediatric population. Case presentation: We present a case series detailing the anesthetic management of three pediatric trisomy 21 patients receiving HNS for refractory obstructive sleep apnea. The patients tolerated the procedure well and experienced no complications. The average obstructive apnea\u2013hypopnea index (AHI) change was 87.4% with the HNS. Conclusions: Proper anxiolysis, safe and controlled induction, multimodal analgesia, and minimization of post-operative respiratory compromise are all necessary to ensure anesthetic and surgical success. After a tailored anesthetic regimen, proper device placement and close follow-up, our patients had a marked improvement in obstructive symptoms. Patients with trisomy 21 are predisposed to an increased risk of obstructive sleep apnea (OSA) at baseline with as many as 70% meeting criteria ,4. PersiThe HNS  is one of several implantable devices that aims to improve upper airway obstruction . The proA previous case series of twenty pediatric trisomy 21 syndrome patients receiving HNS has been published examining post-operative efficacy and safety . HoweverWe present the anesthetic management of the first three patients receiving an HNS at our institution. This manuscript adheres to the applicable EQUATOR guideline. Three patients, two female and one male, underwent hypoglossal nerve stimulator placement from 2017\u20132019 at Egleston Children\u2019s Hospital of Children\u2019s Healthcare of Atlanta as part of trial NCT02344108, \u201cA Pilot Study to Evaluate the HNS in Adolescents with Down Syndrome and OSA.\u201d Currently, HNS use in pediatric populations is still investigational under the Federal Drug Administration. All legal guardians for the subjects gave their informed consent for inclusion prior to participation in this case series.Baseline demographic characteristics are presented in All patients were diagnosed with severe refractory OSA despite previous surgery and non-invasive positive pressure ventilation (NIPPV). The previous surgeries included tonsillectomy and adenoidectomy (two patients) as well as lingual tonsillectomy with turbinate reduction and adenoidectomy (one patient). Despite surgical intervention, all patients then required NIPPV therapies including continuous positive airway pressure (CPAP) in two patients and bi-level positive airway pressure (BiPAP) in one patient. All patients failed NIPPV due to poor compliance, primarily caused by inability to tolerate the CPAP or BiPAP device. Each patient underwent a drug induced sleep endoscopy prior to HNS to characterize their residual OSA. Two patients received premedication with oral midazolam for pre-operative anxiety See . One patThe average case length was 244 min (range 227\u2013260 min). Intra-operative courses were overall uneventful. Glycopyrrolate was used for secretions in two patients. One patient received bolus doses of 0.32 mcg/kg epinephrine and 0.08 mg/kg ephedrine for transient bradycardia. Multimodal analgesia was used in all patients  and all All patients were extubated \u201cdeep\u201d during stage 3 of anesthesia, transferred to the post-anesthesia care unit (PACU), and placed on blow-by oxygen supplementation. One patient required post-operative oral airway placement, and one patient was placed on his home NIPPV. One patient required post-operative fentanyl and dexmedetomidine for residual pain in PACU. There was no reported post-operative nausea or vomiting. All patients were transferred to the floor for post-operative observation. No anesthetic complications were noted on follow-up. There were no reported complications to the Federal Drug Administration as no serious adverse events occurred at our institution. On follow-up PSG, all patients had notable improvement see . The aveThis case series specifically addresses the anesthetic management of HNS implants in pediatric trisomy 21 patients with refractory OSA. The patients tolerated the procedure well despite their pre-existing conditions, refractory OSA, and relatively prolonged case time. The unique nature of anesthetic management for HNS placement is in the balance between addressing the high-risk patient and operative factors with minimizing respiratory depression and adequately controlling pain. While the majority of our recommendations follow known anesthesia tenants for the care of trisomy 21 patients with OSA, we feel like our recommendations vary in three major ways: the use of premedication, inhalational induction, and deep extubation.Providing appropriate anxiolysis for parental separation in this patient population is essential. To balance preexisting OSA with the need for preoperative anxiolysis, we found judicious midazolam premedication beneficial in certain patients. Parental presence inductions or other sedative premedications are reasonable alternatives. However, caution should be exercised when administering any sedative medication to this patient population due to theoretical concern of airway obstruction. When sedative premedication is used, either continuous pulse oximetry or direct observation by the anesthesia team is recommended. Inhalational inductions are common in pediatric anesthesia in the United States and are to be used with caution in patients with a high risk of airway obstruction. Airway obstruction during stage 2 of an inhalational induction can limit oxygenation and ventilation, especially in a patient with known OSA. However, patients with trisomy 21 may benefit from an inhalational induction as it avoids awake intravenous line placement, anxiety, and fear of medical procedures. Our patient population had minimal obstruction with inhalational induction despite their refractory OSA. We believe that a smooth and controlled inhalational induction is a safe alternative in these patients. Certain equipment should be immediately available including nasopharyngeal and oropharyngeal devices, CPAP capabilities, intubating materials, and intramuscular doses of emergency medications including paralytic.The intra-operative components attempt to mitigate patient and surgical factors to optimize postoperative patient comfort and safety. We found that the use of primarily short-acting opioids such as fentanyl, multimodal pain control with dexmedetomidine and ketorolac, as well as local anesthetic injected by the surgeon at an insertion site provide satisfactory pain control while avoiding respiratory depression. Other key factors we have recognized include utilizing short-acting inhaled anesthetics such as sevoflurane to ensure timely emergence after deep extubation. We believe that low-dose dexamethasone can decrease the risk of postoperative tongue edema while also synergistically working with ondansetron to prevent post-operative nausea and vomiting, which has the potential to result in subsequent lead dislodgement . Other specific anesthetic considerations include placement of monitors and lines opposite of the operative side to avoid complications with use and secure endotracheal tube taping as the bed is turned 180 degrees. Neuromuscular blocking agents are avoided and bite block placed due to intra-operative nerve monitoring. Eye lubrication and careful pressure point padding is required given the case length. Given that sensing lead placement may be complicated by violation of the pleural space, nitrous oxide should be avoided once induction is complete.Despite the risk of postoperative airway obstruction, operative factors make extubation under a deep plane of anesthesia preferable. The coughing and bucking associated with awake extubation has the potential to cause significant impairment such as a post-operative airway hematoma or HNS lead dislodgement. While no surgical complications occurred in our group, a previous case series on HNS cite a surgical complication risk up to 10% [None of the patients experienced anesthetic complications despite their refractory OSA. There were no airway difficulties or significant post-operative respiratory depression that was not able to be managed with supplementary oxygen or home NIPPV. One patient experienced transient bradycardia without hypotension that was not associated with inhalational induction. While bradycardia is common in trisomy 21 patients during inhalational induction, this bradycardia was not thought to be related due its timing in the maintenance phase of anesthesia . The occPatient selection is an important consideration for success of this procedure. Appropriate patients should have high functional capacity with responsible and involved caretakers. As the device requires on/off capabilities, patients should be monitored during use of the device. Close follow-up immediately after implantation can identify early problems and maximize successful use. Our patients had excellent response to the HNS placement with an improvement in the obstructive AHI, meeting or exceeding previously reported percentages ,13.Pediatric trisomy 21 patients with refractory sleep apnea who present for HNS are a growing population ,13. Prop"}
+{"text": "Probabilistic Programming offers a concise way to represent stochastic models and perform automated statistical inference. However, many real-world models have discrete or hybrid discrete-continuous distributions, for which existing tools may suffer non-trivial limitations. Inference and parameter estimation can be exceedingly slow for these models because many inference algorithms compute results faster (or exclusively) when the distributions being inferred are continuous. To address this discrepancy, this paper presents Leios. Leios is the first approach for systematically approximating arbitrary probabilistic programs that have discrete, or hybrid discrete-continuous random variables. The approximate programs have all their variables fully continualized. We show that once we have the fully continuous approximate program, we can perform inference and parameter estimation faster by exploiting the existing support that many languages offer for continuous distributions. Furthermore, we show that the estimates obtained when performing inference and parameter estimation on the continuous approximation are still comparably close to both the true parameter values and the estimates obtained when performing inference on the original model."}
+{"text": "Orofacial pain comprises multiple pain conditions that affect oral, head, face, and neck area. Such pain can be divided into different types based on its origin, including neuropathic, musculoskeletal, neurovascular, psychogenic, and idiopathic pain. Patients with orofacial pain often show sex differences with high prevalence in women. However, mechanisms underlying orofacial pain conditions and their sexual dimorphism remain elusive. With obvious differences in anatomical structures, gonadal hormones, and immune responses between males and females, it is proposed that these factors contribute to sexual dimorphism in orofacial pain. In the Special Research Topic entitled \u201cMechanisms of Orofacial Pain and Sex Differences,\u201d we collected six relevant articles. These studies provide new insights into understanding orofacial pain and may aid target identification for future development of sex-specific therapies for orofacial pain.Bereiter et al.)  investigated the effects of ovarian hormones progesterone and allopregnanolone on estrogen-exacerbated nociception in TMJ inflammation model. Using a complete Freund's adjuvant-induced TMJ inflammation model, they observed that ovariectomized female rats show reduced nociceptive behavior in the TMJ inflammation model and daily administration with estradiol benzoate causes recurrence of the nociception in the TMJ, which is rapidly attenuated by the treatment with progesterone or allopregnanolone. This study suggests that supplying progesterone or its metabolite allopregnanolone when gonadal hormone levels get lower may be an effective approach to treating estrogen-evoked inflammatory TMJ pain. It has been demonstrated that estrogen plays a critical role in the pathogenesis of TMD pain. Besides ovarian sources, estrogen can also be synthesized in brain neurons. Interestingly, acute stimulation of nociceptors in the TMJ enhances estradiol secretion in the trigeminal subnucleus caudalis in a sex-dependent manner . In a varicella zoster virus infection-induced postherpetic trigeminal neuropathic pain model, aromatase-derived estradiol attenuates such orofacial nociception by interacting with estrogen receptors to increase \u03b3-aminobutyric acid-mediated neuronal inhibition in the thalamus . In addition, pituitary hormones can regulate nociceptive transmission in different orofacial pain conditions and may contribute to sex-dependent mechanisms of orofacial pain by intermodulation with gonadal hormones .Temporomandibular disorders (TMDs) are associated with chronic orofacial pain, which includes myofascial and/or Temporomandibular Joint (TMJ) pain. Women report TMD pain around three times more than men. Previous studies have demonstrated sex differences and sex hormonal effects in peripheral and central mechanisms of orofacial pain .In a masseter muscle tendon ligation-induced myogenic orofacial pain model, it has been reported . In an immune-competent oral cancer mouse model, neutrophil-mediated endogenous analgesia occurs only in male mice , suggesting that this immune cell-mediated endogenous analgesia for treating oral cancer pain is sex-specific.Additionally, in an oral cancer patient cohort, sex differences in prevalence and severity of oral cancer pain have been identified (In conclusion, giving that there are sex differences in the underlying mechanisms of orofacial pain, we need to consider outcome measurements for each sex in future animal studies and clinical investigations of such pain conditions. Further understanding of sexual dimorphism in orofacial pain will help us develop sex-selective pain therapies and improve pain management for patients with chronic orofacial pain.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Previous research has shown that despite experiencing more negative life events, older adults maintain relatively high levels of well-being compared to their younger counterparts. This effect appears to be at least partially mediated by trait mindfulness in older adults . The current study expanded into an investigation as to how trait mindfulness might intervene on the relationship between age and other well-being indicators: anxiety and depressive symptomology. Participants included 30 older adults (aged 60-83) and 41 young adults (aged 18-35). Trait mindfulness was examined using the Mindful Attention Awareness Scale (MAAS), while depressive symptoms and trait anxiety were measured using the Center for Epidemiological Studies Depression Scale (CES-D) and the State-Trait Anxiety Inventory (STAI), respectively. Two separate mediated multiple regression models were conducted using Hayes\u2019 PROCESS Macro in SPSS. Trait mindfulness exhibited a significant indirect effect on the relationship between age and depressive symptoms , which was also seen for the relationship between age and trait anxiety . Older age predicted higher trait mindfulness, which in turn predicted diminished self-reported anxiety and depressive symptomology. Controlling for mindfulness in these models reduced the direct effect of age on depression and anxiety to non-significance. These findings imply that the relationship between age and trait mindfulness can be extended to alternative markers of well-being."}
+{"text": "Social ecological models of health identify intrapersonal, interpersonal, institutional, community, and policy-level contexts as social factors influencing individual and population health outcomes. However how institutions such as Area Agencies on Aging (AAA) shape rural older adults\u2019 social networks and influence health is little explored. This research examines institutional influences of social networks for rural older adults, particularly the social connections resulting from their AAA services and programs. AAAs are local social service organizations that coordinate home- and community-based supports. Our 2020 case study of a rural AAA in upstate New York involved in-depth semi-structured interviews with AAA staff, volunteers and participants included key themes related to older adults\u2019 social networks, social wellbeing, and physical and mental health. Our findings have both theoretical implications for rural community social structure as experienced by older adults, and practical implications to build AAA\u2019s capacity to address social isolation for rural older adults. Part of a symposium sponsored by the Rural Aging Interest Group."}
+{"text": "Because prescribing practices in long-term care settings may reflect regional influences, we examined how potentially inappropriate antipsychotic and antianxiety medication prescribing in assisted living (AL) compared to prescribing in nursing homes (NHs) based on their proximity, using generalized linear models adjusting for facility characteristics and state fixed effects. Data were derived from a seven state sample of AL communities and data for the same seven states drawn from publicly available data reported on the Nursing Home Compare website. In adjusted analyses, AL rates of antipsychotic use were not associated with the rates in the nearest or farthest NHs. However, AL communities that were affiliated with a NH had lower rates of potentially inappropriate antipsychotic use . In a separate model, antianxiety medication prescribing rates in AL were significantly associated with neighboring NHs\u2019 rates of prescribing . Findings suggest efforts to change prescribing in NHs may influence prescribing in AL."}
+{"text": "The COVID-19 pandemic and the subsequent lockdown brought about an exogenous and unparalleled stock market crash. The crisis thus provides a unique opportunity to test theories of environmental and social (ES) policies. This paper shows that stocks with higher ES ratings have significantly higher returns, lower return volatility, and higher operating profit margins during the first quarter of 2020. ES firms with higher advertising expenditures experience higher stock returns, and stocks held by more ES-oriented investors experience less return volatility during the crash. This paper highlights the importance of customer and investor loyalty to the resiliency of ES stocks."}
+{"text": "Exposure to maltreatment during childhood can lead to increased risk for poor health outcomes in adulthood. Child maltreatment and later poor health may be linked by premature biological aging. We tested whether childhood sexual abuse (CSA) is associated with telomere length (TL) in adult females. We further tested the hypothesis of intergenerational transmission of trauma by measuring TL in both CSA-exposed and non-exposed mothers and their children. TL was measured in a subset of participants and their children from a prospective-longitudinal cohort study of sexually abused females and a demographically matched comparison group. Linear regression models were used to test for associations between CSA-exposure and age-adjusted TL in females . Multilevel linear models were used to test the intergenerational effect of maternal-CSA exposure on age-adjusted TL in their children (N=124 children mean age 10.5 years across 61 mothers). CSA-exposure was not associated with TL in females. Replicating previous work in this area, maternal TL and sex were significant predictors of child TL in all models tested. Longer maternal TL predicted longer TL in children, and female children had longer TL than male children. Maternal-CSA exposure did not predict TL in children. This finding is in line with some previous results on CSA and TL measured in adulthood. Previous significant results associating child maltreatment with shorter TL in adulthood may be capturing a population of individuals exposed to either multiple types of maltreatment or maltreatment in childhood with concurrent TL measurements."}
+{"text": "Measles is a highly contagious respiratory disease; both locally acquired and travel-associated cases continue to occur across the United States  after the exposure (The patient recovered and was discharged home from the hospital on April 27. None of his contacts developed measles, and no additional cases were identified through heightened surveillance, which included monitoring ED syndromic surveillance data in ESSENCE-FLThe Advisory Committee on Immunization Practices recommends that adults without documentation of measles immunity who are traveling internationally receive 2 documented doses of measles, mumps, and rubella virus vaccine ("}
+{"text": "Protamine sulfate is a common reversal agent of systemic heparinization used during procedures. While the exact epidemiology of adverse events is unknown, prior allergic response to protamine-containing compounds or concomitant use of neutral protamine Hagedorn (NPH) insulin is associated with an increased risk of tachyarrhythmias and bradyarrhythmias. We present a case of a 68-year-old woman with no prior history of protamine sulfate intolerance that suffered bradycardic arrest following protamine infusion.Healthcare providers should recognize the potential for life-threatening tachyarrhythmias and bradyarrhythmias following protamine reversal, especially in diabetic patients at risk for autonomic dysfunction; medication and allergy review are encouraged prior to heparin reversal, especially in diabetic patients. Protamine sulfate is a cationic polypeptide that binds to negatively charged unfractionated heparin and can be used to decrease the risk of bleeding during procedures in patients with systemic heparinization . Though A 68-year-old female with a past medical history of hypertension, peripheral artery disease, and type 2 diabetes complicated by peripheral neuropathy underwent a peripheral angiographic intervention on an occluded left femoral arterial stent, after which she received 20 mg of protamine. During the postoperative period, she experienced bradycardia and hypotension progressing to cardiac arrest. Cardiac monitoring at the time indicated no ventricular arrhythmias. Advanced cardiac life support (ACLS) was initiated and the patient received three rounds of epinephrine prior to transport to the emergency department (ED).In the ED, initial evaluation demonstrated agonal cardiac activity on cardiac ultrasound. The patient received three more rounds of epinephrine, two amps of bicarbonate, and one gram of calcium chloride. The initial cardiac monitoring demonstrated pulseless electrical activity, which progressed to ventricular fibrillation. Defibrillation was performed, resulting in the return of spontaneous circulation (ROSC).The patient was admitted to the medical intensive care unit. She was determined to be neurologically intact and targeted temperature management was not initiated. Medical history was notable for insulin NPH use. She had no prior allergic reaction to NPH, exposure to protamine sulfate, or history of food allergies.Labs showed a rise and fall in troponin I with a peak value of 6.21 mcg/L (reference range \u22640.030 mcg/L). Initial electrocardiogram (ECG) after ROSC showed diffuse ST depression suggestive of subendocardial ischemia  and potential medication reactions. Healthcare providers should recognize the potential for bradyarrhythmias and tachyarrhythmias before protamine administration, particularly in diabetic patients."}
+{"text": "Coronary involvement is rare but can be critical in patients with aortitis. Although cardiac ischemia can be resolved by coronary artery bypass grafting (CABG), patients complicated with cardiac ischemia, calcified aorta, and valve insufficiency pose difficult problems for surgeons.A 71-year-old woman was referred to our institution because of unstable angina. She had been previously diagnosed with aortitis and left subclavian artery occlusion. Contrast-enhanced computed tomography revealed severe left coronary main trunk stenosis, right coronary artery occlusion, and porcelain aorta. Ultrasonic echocardiogram showed severe aortic regurgitation. We performed emergent coronary artery bypass grafting, aortic valve replacement and ascending aorta replacement under hypothermic circulatory arrest.The technique of circumferential calcified intimal removal and reinforcement with felt strips was effective for secure anastomosis. Unilateral cerebral perfusion from the right subclavian artery enabled good visualization and sufficient time to perform distal anastomosis. Coronary involvement is rarebit can be critical in patients with aortitis. Although cardiac ischemia can be resolved by coronary artery bypass grafting (CABG), patients complicated with cardiac ischemia, calcified aorta, and valve insufficiency pose difficult problems for surgeons. We present a 71-year-old woman with left main coronary trunk stenosis, occluded right coronary artery, left subclavian artery occlusion, severe aortic valve regurgitation and porcelain aorta with aortitis.A 71-year-old woman was transferred to our institution because of unstable angina. She had been previously diagnosed with aortitis and left subclavian artery (LSCA) occlusion. Her past medical history included hypertension and dyslipidemia. Twelve-lead electrocardiogram showed marked ST-segment depression in the precordial and inferior leads. Contrast-enhanced cardiac computed tomography (CT) revealed severe left coronary main trunk (LMT) stenosis, which had not been detected 9\u2009months previously, right coronary artery (RCA) occlusion which had occurred previously Fig.\u00a0. These fAdditional file 1.Takayasu\u2019s arteritis (TA) is a chronic, granulomatous vasculitis that causes stenosis, occlusion and ectasia of the aorta and its branches. Although coronary involvement is rare, it can be critical. Coronary ostial stenosis (COS) with normal distal part of the artery is a specific feature of TA.In our case, the patient had not been in the active phase of TA for years. LMT stenosis progressively worsened over 9\u2009months. It is not clear whether LMT stenosis in our patient was associated with TA, because stenosis occurred in the distal part of LMT, and not at the coronary ostium. In view of her diagnosis of dyslipidemia, this might have caused LMT stenosis over a short time period.We had to perform emergent CABG because jeopardized left main coronary artery supplying the chronically occluded RCA caused global ischemia of the entire heart. Although percutaneous coronary intervention (PCI) for LMT stenosis can relieve ischemia quickly, it can be more dangerous compared with CABG because the RCA is already occluded and receives blood supply from the left coronary artery. Furthermore, PCI is not able to solve AR. Although the internal thoracic artery (ITA) is commonly used for CABG, it might not be adequate in patients with Takayasu\u2019s arteritis because stenosis often occurs in the subclavian artery. However, the ITAs have been used in young patients in whom the subclavian arteries did not have stenosis , 2. AlthAnother issue is calcified aorta, which is always a concern when surgeons try to clamp it. Transcatheter aortic valve insertion (TAVI)\u2009+\u2009off-pump CABG is the procedure of choice for patients with aortic valve stenosis, porcelain aorta and coronary ostial stenosis . HoweverAnother issue is how to acquire good visualization of the proximal arch during hypothermic circulatory arrest. The proximal aortic arch was severely calcified, and its diameter was normal. Usual elasticity of the aorta was lost. It seemed difficult to obtain good visualization and enough time to apply the abovementioned technique using usual antegrade selective cerebral perfusion (ASCP) in which three perfusion cannulas are inserted into the innominate artery, left common carotid artery and LSCA, respectively. We considered that three cannulas in the calcified proximal aortic arch with normal size would prevent us from performing any maneuvers. Although controversy exists whether UCP can provide sufficient blood supply to both the left and right hemispheres compared to usual ASCP, we believe it is acceptable in emergent surgery . In factAlthough the patient did not have active phase TA, LMT stenosis progressively worsened over a short period. The technique of circumferential calcified intimal removal and reinforcement with felt strips was effective for secure anastomosis and avoiding bleeding from the suture holes in the porcelain aorta. UCP from the RAXA provided good visualization and sufficient time to perform distal anastomosis."}
+{"text": "Nearly 48 million individuals worldwide have a neurocognitive disorder with projections estimating that as many as 75 million may be afflicted by 2050.Although approximations vary, a substantial portion of those affected live in the community alone, accounting for up to one-third of cases. The true proportion of persons with neurocognitive disorders living alone in the community may be underestimated as dementias are often underdiagnosed and underreported. As the baby boom generation ages and trends towards nuclear families, geographic dispersion of families, and fewer children continue, the number of live-alone persons with neurocognitive impairment is anticipated to rise; creating increased potential for difficult, ambiguous circumstances involving the rights and needs of this population. Despite these trends, available information about this population remains limited. This symposium represents papers from social gerontology, bioethics, and policy; offering unique, but complimentary perspectives on live-alone persons with neurocognitive impairment. The four papers explore 1) how non-traditional & absent support networks impact one\u2019s ability to live alone with dementia [NIA funded], 2) social isolation and vulnerabilities of living alone with dementia [NIA-funded], 3) how bioethics can inform gerontological dementia research [NIA bioethics supplement], and 4) exploration of how law enforcement and adult protective services policies influence the precarity of living alone with dementia. Together, these papers illuminate the importance of actively including live-alone persons with dementia into research and assessing this overlooked vulnerable population from multiple research perspectives ."}
+{"text": "A substantial number of studies have documented paradoxical findings when examining race differences in later life psychological well-being. Despite experiencing significant structural disadvantages, Black older adults have been found to report significantly higher overall life satisfaction and lower depressive symptoms than White adults. This study relies on double consciousness framework which allows us to understand why satisfaction with material conditions  among Black older adults could differ from their evaluation of overall well-being . Based on a survey of successful aging (n=409 aged 60 years or older) conducted by the Elderly Care Research Center (ECRC) in Cleveland, Ohio, we examined race differences in coping resources, and their role in shaping overall life satisfaction, domain-specific life satisfaction, and depressive symptoms. Findings show that Blacks on average have a higher likelihood of experiencing recent negative life events than their White counterparts. Despite adverse life circumstances, Blacks older adults expressed significantly higher overall life satisfaction than Whites. They, however, reported significantly lower domain-specific life satisfaction than their White counterparts. The differences in depressive symptoms between Black and White older adults was not statistically significant. The race differences in overall life satisfaction was explained by religiosity, religious coping, and social support. Education, income, and adverse life events were found to contribute to such differences in domain-specific life satisfaction. Our findings underscore the need to consider the unique role of racialized life course circumstances and coping resources in shaping disparities in later life psychological well-being."}
+{"text": "Older adults make up the majority of the U.S. patient population and age differences in information avoidance have potential implications for their ability to participate in informed medical decision making. Meta-analytic evidence suggests that older adults seek less information before making a decision than younger adults do . However, age differences in explicit information avoidance have yet to be quantified. We hypothesized that older adults would avoid decision-relevant information more strongly than younger adults do. We also examined the self-reported reasons for information avoidance and hypothesized that older adults would express more concern about unwanted information influencing their affect  and decision preferences , both of which are known predictors of information avoidance . To test these assumptions, we conducted a pre-registered online study involving three different health-related decision scenarios. For each scenario, an adult lifespan sample  chose to either receive or avoid information. Responses were highly correlated across scenarios and results were pooled into a single avoidance measure. Analyses indicated that concerns about consequences for decision preferences positively predicted decision avoidance (p<.001), whereas concerns about consequences for affect did not (p=.079). Contrary to predictions, older age was not significantly associated with information avoidance (p=.827). Further, self-reported concerns about the influence of unwanted information on affect and decision preferences were negatively associated with age (ps<.001). This suggests that interventions to foster pre-decisional information seeking should be tailored to the target age group."}
+{"text": "The recent opioid crisis is one of the rising challenges in the history of modern health care. New and effective treatment modalities with less adverse effects to alleviate and manage this modern epidemic are critically needed. The FDA has recently approved two non-invasive electrical nerve stimulators for the adjunct treatment of symptoms of acute opioid withdrawal. These devices, placed behind the ear, stimulate certain cranial nerves with auricular projections. This neural stimulation reportedly generates a prompt effect in terms of alleviation of withdrawal symptoms resulting from acute discontinuation of opioid use. Current experimental evidence indicates that this type of non-invasive neural stimulation has excellent potential to supplement medication assisted treatment in opioid detoxification with lower side effects and increased adherence to treatment. Here, we review current findings supporting the use of non-invasive neural stimulation in detoxification from opioid use. We briefly outline the neurophysiology underlying this approach of auricular electrical neural stimulation and its role in enhancing medication assisted treatment in treating symptoms of opioid withdrawal. Considering the growing deleterious impact of addictive disorders on our society, further studies on this emerging treatment modality are warranted. Approximately 36 million people are affected with opioid use disorder globally , the distress in the first few days after abrupt discontinuation can be rather severe. Without adequate treatment, many patients are unable to complete opioid discontinuation  . This stimulation provides relief from symptoms associated with opioid withdrawal, including cravings, anxiety, agitation and depression. The device can be worn up to 5\u00a0days at a time, and company officials report that symptoms have eased within an hour of wearing the device.Relatively recently, in June 2018, an additional auricular stimulation device, the \u201cDrug Relief\u201d aural neurostimulator mobile health device, developed by DyAnsys, also received FDA 510(k) premarket approval for patients dealing with opioid addictions (Fig.\u00a0Pain and emotional disturbances are common symptoms during opioid withdrawal. Of note, auricular neural stimulation had been used for chronic pain management with success in various health settings (e.g., reviewed in (Chen et al. Experimental evidence indicates that non-invasive device-generated auricular neural stimulation of certain cranial nerves, primarily vagus nerve, provides an innovative approach to alleviate opioid withdrawal symptoms. This approach may specifically help expedite the recovery phase during acute detoxification from opioids. This can ultimately reduce the need of supportive medications and can facilitate smooth transition from detoxification to commencing medication-assisted treatment in opioid dependent patients. This treatment modality has so far been associated with only minor local side effects at the device placement site. While this non-invasive modality appears to be an exciting new opportunity in alleviating the current opioid epidemic, more studies are clearly needed to further validate the potential of this intervention and support its use with the hope of helping our patients and their families."}
+{"text": "Portal vein thrombosis (PVT) poses a unique challenge in liver transplant. The management of PVT differs according to the extent of thrombosis. Anastomosis of a donor portal vein to a varix is a viable option when an adequate size varix is identified on preoperative imaging or intraoperatively. Here, we describe our experience in two liver transplant cases with cavernous transformation of the portal vein where the donor portal vein was anastomosed to a varix using a donor iliac vein interposition graft. In 1985, Shaw and colleagues described successful liver transplantation in seven patients with severely reduced or absent portal flow, and since that time, portal vein thrombosis (PVT) has no longer been considered an absolute contraindication to liver transplantation . As fibrOur first patient was a 58-year-old male with primary biliary cirrhosis and nonalcoholic steatohepatitis. Portal flow was not visualized on preoperative Doppler ultrasound. Contrast enhanced CT demonstrated complete PVT with cavernous transformation  and clotOur second case was a 61-year-old male with cryptogenic cirrhosis and hepatocellular carcinoma. Preoperative imaging revealed cavernous transformation with numerous portal venous collaterals most prominent in the paraesophageal  and periIntraoperative portal vein thrombovenectomySMV jump graftingEstablishing renal-portal inflow from left renal vein and donor ileac vein conduitVarix-to-portal anastomoses with or without conduitPortacaval transpositionPortal vein thrombosis can range from mild partial nonocclusive thrombus to complete occlusion with cavernous transformation, and varied surgical techniques are required to handle each scenario . QualityIn all cases, we consider left renal vein ligation or ligation of other collateral vessels to enhance portal inflow. Preoperative IR-guided portal vein recanalization has been described , as has Physiologic portal inflow is associated with better 1-, 5-, and 10-year outcomes than any alternative described , and theIn summary, successful surgical management of PVT requires preoperative imaging, thoughtful planning, surgical creativity, and adherence to a practice-based algorithm for establishing portal inflow."}
+{"text": "Providing interprofessional geriatric care via telehealth is a unique clinical skillset that differs from providing face-to-face care. The lack of clear guidance on telehealth best practices for providing care to older adults and their care partners has created a systems-based practice educational gap. For several years, GRECC Connect has provided interprofessional telehealth visits to older adults, frequently training interprofessional learners in the process. Using our interprofessional telehealth expertise, the GRECC Connect Education Workgroup created telehealth competencies for the delivery of care to older adults and care partners for interprofessional learners. Competencies incorporate key telehealth, interprofessional and geriatric domains, and were informed by diverse stakeholders within the Veterans Health Administration. During this symposium, comments will be solicited from attendees. Once finalized, these competencies will drive the development of robust curricula and evaluation measures aimed at training the next generation of interprofessional providers to expertly care for older adults via telehealth."}
+{"text": "Changing age demographics are reshaping societies and challenging institutions of higher education to consider how they can respond to aging populations through new approaches to teaching, research, and community engagement. As well, institutions are facing a range of challenges as they look to respond to the contemporary needs of traditional-aged students. The pioneering Age-Friendly University (AFU) initiative, endorsed by GSA\u2019s Academy for Gerontology in Higher Education (AGHE), offers a framework within which institutions can begin to address these issues through more age-friendly programs, practices, and partnerships. This symposium will feature AFU advocates discussing innovate ways in which older adults can serve as teaching allies and support the educational mission of higher education. Farah (Lasell University) will discuss how older adults can engage in diverse teaching and learning activities with examples as crime scenario developers in a forensics class, conversation partners in an international oral communication class, and professional interviewers in an internship skills class. Kaye (University of Maine) will discuss how older adults can serve as citizen scientists performing critical functions in participatory research and in community-based test-beds and co-design laboratories. Ermer (Montclair State University) will discuss how older adults can engage students in discourse as guest speakers and panel participants in classes across the curriculum. Manoogian (Western Oregon University) will describe the innovative ways that older adult students (for credit or audit) mentor and engage younger student peers in course activities as well as increase their own understanding of the aging process."}
+{"text": "Liquid biopsy has emerged in the last ten years as an appealing noninvasive strategy to support early cancer diagnosis and follow-up interventions. However, conventional liquid biopsy strategies involving specified biomarkers have encountered unexpected inconsistencies stemming from the use of different analytical methodologies. Recent reports have repeatedly demonstrated that integrated detection of multiple liquid biopsy biomarkers can significantly improve diagnostic performance by eliminating the influence of intratumoral heterogeneity. Herein, we review the progress in the field of liquid biopsy and propose a novel integrated liquid biopsy framework consisting of three categories: elementary, intermediate, and advanced integration. We also summarize the merits of the integration strategy and propose a roadmap toward refining cancer diagnosis, metastasis surveillance, and prognostication. Bodily fluids, such as blood, urine, cerebrospinal fluid, and saliva, contain numerous biomarkers corresponding to patient-specific pathological information. From the perspective of biodetection, any biomarkers that are highly associated with tumor growth and metastasis, including circulating proteins (CPs), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), extracellular vesicles (EVs), circulating tumor cells (CTCs), and tumor-educated blood platelets (TEPs), can be indicators of carcinomas. Liquid biopsy has been recognized as one of the most promising strategies for conquering cancers owing to its unparalleled advantages over classical solid biopsy in improving patient compliance, partially due to its noninvasive sample collection and reduced potential for surgical complications  e.g., protein-protein, RNA-RNA or DNA-DNA combinations e.g., protein-DNA combinations This review will intensively discuss the hurdles facing liquid biopsy prior to its clinical application and propose potential solutions. Here, we propose a novel analytical framework, termed \u201cintegrated liquid biopsy\u201d, that could be a useful toolkit bridging conventional liquid biopsy and clinical requirements. \u201cIntegrated liquid biopsy\u201d is defined as integrating multiple liquid biopsy biomarkers or detection methods for improved analytical sensitivity and specificity to refine cancer management. Since a single biomarker is inefficient in accurately identifying most cancers, integrated liquid biopsy using multiple markers might be a promising method to facilitate early detection and treatment of cancer. According to the complexity of the combined data types, we categorize integrated liquid biopsy into the following three groups: 1) Elementary integration refers to the combination of biomarkers or methods of the same type,e.g., CA19-9, CEA, AFP, and prostate-specific antigen (PSA)) achieved prevalence due to its convenience and low cost + exosomes containing diverse RNA and proteins may distinguish healthy subjects from patients with pancreatic cancer Liquid biopsies have been regarded as robust tools for routinely screening and identifying tumors before symptoms appear. Historically, the detection of a single CP  mutations and CA19-9 provided an improved sensitivity of 64%, compared to 30% for KRAS alone Regarding intermediate integration, CP-ctDNA integration is particularly attractive because ctDNA indicates specific genetic alterations and because the relatively high concentrations of CPs compensate for the drawback of low ctDNA abundance. Joshua et al. reported that the conjunction of Despite the popularity of liquid biopsy in a clinical setting, the conventional detection of a single biomarker has encountered numerous obstacles in assessing samples with tissue or organ heterogeneity. These reported discrepancies among different detection approaches primarily originate from the small amounts and easy degradability of these biomarkers, features that severely compromise their value in indicating abnormal clonal cell proliferation. The latest studies have revealed that a CP-ctDNA integration strategy significantly improves the sensitivity of earlier cancer detection without substantially decreasing specificity. Additionally, integrated assays of CPs and genetic alterations further localize the original organs of these cancers, which could greatly benefit further therapy. Meanwhile, the CP-ctDNA integration concept could be expanded to other liquid biomarkers, such as metabolites, mRNA transcripts, miRNAs, methylated DNA sequences, or markers in EVs to increase the efficiency of early cancer detection.N-ras and phosphatidylinositol 3-kinase mutations in ctDNA can predict drug resistance against monoclonal antibodies targeting EGFR, potential negative errors have been observed due to biological heterogeneity Surviving cancer cells tend to develop drug resistance due to mutation and evolutionary selection when different therapeutic means are employed on heterogenic tissues Figure  33. TherEGFR mutation detection in plasma, and significant improvement was observed in NSCLC patients without distant metastasis EGFR T790M detection, overcoming the limitation of low T790M abundance in the blood (58% sensitivity and 80% specificity using an FDA-approved cobas\u00ae test) Integrated liquid biopsy might be an effective means of eliminating such discrepancies and probing unknown mutations. RNA-seq is a typical form of detection included in elementary integration, and a recent ctDNA profiling method known as cancer personal profiling by deep sequencing (CAPP-seq) found a high frequency of inter- and intrapatient heterogeneity in resistance mechanisms after initial EGFR tyrosine kinase inhibitor therapy Dozens of studies employing integrated liquid biopsy have demonstrated its effectiveness in improving the sensitivity of cancer diagnosis, suggesting that this strategy is ideal for cancer management. Therefore, it is highly desirable to elucidate the biological origins and mutual interactions of different biomarkers in anticipation of clinical applications.CPs are secreted from diverse human cells, including immune cells and tumor-associated cells, and were the first such biomarkers to be exploited and commercialized. The demonstrated high specificity of CPs in reflecting tumor-associated characteristics makes them attractive for cancer surveillance. In contrast to CPs, ctDNA fragments are principally released from apoptotic or necrotic cells. Given the short circulating time of ctDNA (ranging from 16 min to 2.5 h), the dynamic and continuous monitoring of ctDNA fragments plays a paramount role in cancer prediction in vitro, it is necessary to use an indirect strategy involving an enrichment step prior to detection e EVs, comprising exosomes, microvesicles, and apoptotic bodies, are free-floating bodies enwrapped by lipid rafts and contain tumor-specific signatures of nucleic acids and proteins. Briefly, exosomes emerge by budding in multivesicular bodies and are released into the plasma by fusion of multivesicular bodies with the cell membrane, whereas microvesicles and apoptotic bodies are leaked from dying cells due to external stimulation. Notably, selective accumulation of certain functional mRNA, microRNA, and protein species in microvesicles can occur. In contrast to normal cell sprouting, CTCs are spontaneously released from primary tumors to the peripheral blood circulation, constituting seeds for subsequent metastases in distant organs epithelial cell adhesion molecule (EpCAM), human EGFR2, PSA and oncolytic viruses In vivo CTC enrichment using either an inserted metal wire or magnetic separation in vitro integration of biomimicry and nanotechnology have remarkably improved capture efficiency Integrating methods with distinctive principles to strengthen integrated liquid biopsy is likely the most reliable strategy for ideal cancer management. The quantification and characterization of CTCs/EVs represent major technological challenges in liquid biopsy due to the extremely low concentrations of these targets. All the methods developed to quantify CTCs and EVs in the peripheral blood could be categorized as biological or physical. Biological methods are typically based on antigen-antibody or ligand binding; these methods are involved in typical tests for + CTCs, which reduces cell adhesion and promotes polarization and metastasis. Meanwhile, platelets immediately adhere and mechanically protect CTCs from anoikis or destruction by forming a cell fibrin-platelet aggregate surrounding CTCs Tumorigenesis, metastasis and tumor evolution are the typical forms of cancer development, and the above-noted biomarkers can reflect the accumulation of either genetic mutations or epigenetic modifications Figure . During in vitroin silico target prediction.In summary, any detection approach based on a single biomarker reflects limited information that may result in misleading predictions regarding tumor progression. Thus, integrating multiple biomarker approaches provides comprehensive information that may compensate for the drawbacks of single biomarkers in facilitating early cancer detection and intervention Table . MeanwhiKRAS mutant cells effectively drive cancer progression after the suppression of the MEK1 mutant population by panitumumab and trametinib Early and accurate cancer diagnosis is the key to reducing the economic burden of cancer. Classical tissue biopsy has arguably presented a heavy burden according to US Medicare analysis: as of 2017, the average cost of a solid biopsy for lung cancer is $8,869, and the total cost per patient will reach $37,745 for the 20% of needle biopsies that lead to follow-up complications. Compared with single liquid biopsy alone, integrated liquid biopsy provides improved cost-effectiveness in the following ways. First, integrated liquid biopsy is less expensive per marker than its counterpart. For instance, the current cost for single ctDNA mutant detection with digital PCR is approximately $300, while the cost for elementarily integrated detection of all ctDNA mutants with DNA sequencing is < $1,000 with Illumina Several fundamental questions need to be answered prior to effective integration under physiological and pathophysiological conditions: What is the relationship between the degree of ctDNA variations and the RNA/protein abundance of hundreds of functionally coherent gene sets? What are the differences between primary circulating biomarkers such as ctRNA or CP and secondary biomarkers such as RNA/protein analysis from EVs or CTCs? Will different cancer stages  and mesenchymal-to-epithelial transition (MET)) or tumor cell status (primary or circulating) significantly affect the spatial and temporal distributions of ctDNA or exoRNA? Understanding the gene regulatory networks of biomarker integration will lead to significant insights and has tremendous implications for cancer intervention and management. Therefore, for integration detection, the core purpose is to reflect the real developmental stage and increase therapy efficiency for cancer.How can users predict and confront the inconsistent results stemming from different biomarkers or detection methods in integrated detection? Considering the complexity of tumorigenesis, any single-marker-based diagnosis will have a risk of error, integrated detection may naturally increase the possibility of exposing these errors by presenting contradictory results, by which the error can be significantly reduced in further diagnosis.What types of integration could be optimal? Both elementary integration and intermediate integration can provide characteristic molecular profiles of cancers in the spatial scale. Advanced integration might provide integrated information in a higher dimension by combining these comprehensive evidences, including medical imaging, tissue diagnosis, and molecular profiling, to map the characteristics of a cancer in detail based on the complementarity of these results.How can we establish a risk prediction model using the acquired integrated data from a time series? Integration in the temporal domain will help us characterize the law of cancer progress or metastases. Therefore, combining the dynamic changes in various biomarkers with previous medical records would facilitate the prognosis analysis of cancers. It is highly plausible that this type of dynamic method focusing on the whole process, including patient diagnosis and treatment, will become the mainstream of prognostic analysis in the near future.KRAS mutation rate reached 94% in a pancreatic intraepithelial neoplasm population The feasibility of integrated liquid biopsy is largely guaranteed by the quality control and standardization of each detection method. In particular, the standardization of annotations resulting from liquid biopsy is challenging due to varied cohort compositions  and diverse environmental factors  when analyzing the same biomarker. For instance, noticeable discordance exists among different populations: the Integrated liquid biopsy produces data that are substantially more complicated than data from any single biomarker, requiring a canonical big data processing methodology. Deep learning has recently been introduced to assist with diagnostic and therapeutic decision making by reading patients' medical images Liquid biopsy has demonstrated unparalleled advantages over conventional tissue biopsy and medical images in terms of earlier cancer detection and better surveillance of cancer metastasis and prognosis. Different from conventional imaging approaches, which mainly reveal changes in tumor size, profiling the dynamic distribution of various tumor-associated molecular biomarkers may provide continuous genetic mutation information, which will reflect different cancer stages and provide improved guidance for clinical therapy. Furthermore, the rational integration of liquid biopsy, solid biopsy, and medical imaging would prevent discordance or disagreements caused by tumor heterogeneity or individualized analytical methodologies. This advantage would facilitate cancer prevention and early intervention.Integrated liquid biopsy covers both the integration of different detection methods and the combination of multiple biomarkers, including proteomics, genomic sequencing, and DNA methylation profiling, that could reveal mechanistic differences in the development of different cancers. During carcinogenesis, integrated biomarkers could provide an earlier diagnosis than any single biomarker alone. Furthermore, ctDNA could identify the position of the tumor by detecting DNA methylation in an accurate and noninvasive manner Socioeconomic factors should also be considered in the clinical implementation of the integrated liquid biopsy strategy. In the early stage, additional blood tests for enriching the database will carry relatively high costs. However, with the gradual growth of the database, we will benefit from the mathematical model as it provides increasingly accurate and specific guidance on cancer management."}
+{"text": "Globally, conservation efforts have moved millions of people out of protected areas since the 1970s, yet quantitative studies on post-resettlement well-being remain a challenge due to poor documentation. Since 2008, the Indian forest department records demographic and financial details at the household level under standardized guidelines for resettlement. Here, we examine the food security of approximately 600 households\u2019 post-resettlement from Kanha National Park (KNP) in central India between 2009 and 2014. We compare food security of resettled households with host community households with a total of 3519 household surveys, conducted over three seasons within one year. We measure food security using food consumption scores (FCSs), coping strategies index (CSI) and household hunger scale (HHS). Food insecurity is widespread in the landscape, with over 80% of households reporting poor or borderline FCSs year-round. Additionally, we recorded food insecurity increases in monsoon for all households regardless of resettlement status. Results indicate that resettled households are comparable to their host community neighbors in FCS and all households use mild coping strategies to combat food insecurity. While widespread, food insecurity in the KNP landscape is not acute with very few (<10) reports of severe hunger (as measured by the HHS). Almost all foods are market bought (>90%) and sometimes supplemented by gathering locally prevalent greens or from kitchen gardens (forest dependency for food was negligible). Accruing assets and diversifying incomes from non-labor avenues would alleviate food insecurity for all households. The patterns of market dependence and food security associated with diversified stable incomes around protected areas is in contrast with many studies but is likely to occur in similar human-dominated landscapes. Conservation-related resettlements trace back to the establishment of Yellowstone National Park in 1872 and spread rapidly with fortress management policies to conserve endangered species habitats. Globally recognized areas of high biodiversity are inhabited by more than a billion people and populations in these regions continue to grow at a rapid pace \u20135. In InUnderstanding the impacts of conservation-related resettlement on people requires meaningful measures of human well-being. Income based metrics of well-being are unidimensional and do not reflect livelihoods reliant on goods with little economic value (for example\u2013wild foods or self-provisioning via non-economic landscape resources) , 25. MorIn India, the current resettlement policy is explicit in its goal to resettle people to expand and maintain critical tiger habitats within 50 protected areas (Tiger Reserves) with detailed resettlement records and standardized compensations . ResettlWe explore food security at resettled households compared to their neighbors at their new settlement locations across the Kanha National Park landscape to answer the following questions:Are resettled households moving into remote areas compared to all existing villages in the study site, specifically with respect to\u2013road access, food markets and forest availability?Do resettled households have comparable Food Consumption Scores (FCSs) and Coping Strategy Index (CSI) measurements to their host community neighbors? , leopard (Panthera pardus), wild dog , sambar (Cervus unicolor), chital (Cervus axis), barasingha (Cervus duvaucelii) and gaur (Bos gaurus) . We. We51]. The FCS and CSI are weighted scores based on the food groups consumed and coping behaviors exhibited in the last seven days in the surveyed household respectively , 57. We We used propensity scoring and visual inspection (of the overlap between resettled households and host community households) for all measured variables to test balance in our study sample, especially to ensure that our sampled host community households provided a comparable baseline for surveyed resettled households . AdditioIn the KNP landscape, households buy foods from weekly markets and therefore restock each week for fresh vegetables, meats and staples. For availability of market items and their prices, we visually compared market checklists as most markets in the landscape have the same produce with similar prices . We alsoWe used Euclidean nearest neighbor distances to find distances between household locations and nearest road, border of protected area (KNP core), market and built up area. We used existing GIS layers of roads, protected area borders, built up area and our GPS locations of markets , 59. We tehsil\u2014for all households) and origin village (only when modelling food access in resettled households) (http://www.r-project.org) and QGIS 2.10.0- Pisa . Data is available at (https://bit.ly/2GvxGid).To understand patterns and associations in our household level data we used cluster analyses (ClustVis PCA\u2013see ), randomseholds) . We stanResettled households have predominantly moved into existing villages in similar proportions to host community human densities across the KNP landscape . HoweverHouseholds in the KNP landscape typically access the bulk of their foods (>90%) from weekly markets at their village or a neighboring village See . Thus, rtehsil during summer, resettled households  had higher mean FCSs compared to host community households  . However, across all surveyed households with acceptable FCSs, vegetables were not consumed every day and meats very occasionally.Resettled households reported similar Food Consumption Scores when compared to their host community neighbors across all three survey seasons . The yeaResettled households had higher CSIs in monsoon across two administrative units (Baihar and Panderia) and higher CSIs than host community households in winter in Baihar and in summer in Panderia . MoreoveWhile resettled households consume food groups in similar frequencies to host community households, we find that approximately 80% of all households have inadequate levels of food consumption (borderline or poor) . ResettlAll households predominantly access food through market purchases (>90%) supplemented by self-provisioning  year round . Only a Our results of modelling livelihood characteristics associated with resettled and host community households highlight that increasing asset index values were positively associated with FCSs year-round . PredomiApart from the above livelihood associations with FCSs, resettled households supplement market bought foods  with self-provisioned foods  while host community households engage in winter cropping to attain similar FCSs . Owning Our study contributes to the growing quantitative assessment of resettlement on human well-being measurements, tying together conservation and social goals , 65, 66.Our study finds widespread food insecurity for all households. However, the current state of food insecurity around KNP is not acute with very few reports of hunger and coping strategies associated with higher food access. Food insecurity is largely due to the economic inability to access high nutrient food groups (tehsil (administrative block) there were seasonally changing differences in resettled and host community household FCSs and CSIs but these require further study to understand the underlying mechanisms  while host community households predominantly rely on winter cropping to end up with similar FCSs . Our resThese differences aside, both resettled and host community households with increasing assets and diversified incomes showed positive associations with FCSs. Households with incomes from poultry and agriculture had comparable positive associations with FCSs as salaried jobs. We suggest that gains from poultry farming might be an avenue for on-the-ground interventions that aid alleviation of poverty as well as food insecurity , 73. We The key objective of our study was to assess post-resettlement food security of resettled compared to their host community households at the new settlement location in the KNP landscape. Our findings suggest that the current resettlement does not constrain resettled households and that they are comparable to host community households in terms of livelihood opportunities, physical food availability and food access. Approximately 20% of our surveyed households are within the KNP buffer. Households within the administrative buffer of KNP are more similar to households outside the KNP than those previously living within the KNP core in terms of economic activities, access to the road network in the KNP landscape and commercial livelihoods . The multiuse buffer around KNP is predominantly agricultural land with more than 260 existing villages. Resettled households join existing villages outside of KNP and comprise a minor proportion of the total village population .To increase overall wealth, an obvious but difficult application of our results would be to generate more opportunities for salaried jobs and make agricultural practices more profitable. Such an obvious result seems a moot point to discuss but we do so to ensure our results are not seen as a contrast of two separate livelihoods\u2013resettled households with forest livelihoods separated from rural host community households with more wealth driven livelihoods. Our results confirm that the reality is one where rural livelihoods predominantly feature wealth accruement and market bought foods regardless of being resettled and host community households . Our stuOwning more cattle suggests that households have means to increase assets which are in turn associated with higher FCSs. Cattle are culturally important, most often as work animals and easily traded assets in times of distress. Cattle for dairy incomes are rare in the KNP landscape. Incomes from cattle might be occasional  or low (dairy farming practices). Similar findings about the complicated relationship between livelihoods and cattle owning have been found in Ghana . We alsoFood security for resettled households, and their host community neighbors, in the Kanha National Park landscape will be best achieved by integrating the poorer households into the economy with more opportunities, such as steady jobs and poultry farming, for higher incomes and seasonal stability. Managers for resettlement and rural development around KNP, and in other human-dominated conservation landscapes, might consider the importance of training for employment with steady incomes in future interventions. At the national policy level, the NTCA can use the methods from our study to explore links between livelihoods and social goals in resettlement from tiger reserves across India that vary ecologically, geographically and culturally. While this study concluded that steady incomes are highly relevant for food security in the KNP landscape, other landscapes around tiger reserves might indicate the need for access to forests or efforts to improve food availability.Our study focuses on a short time-frame after resettlement to look at immediate impacts on food security as a metric of human well-being. Longer studies or studies after a decade of resettlement might provide further insight into how compensations under the current guidelines allow resettled households to integrate into their new locations. Furthermore, studies that include metrics of well-being that are difficult to quantify are important to understand social impacts on people living around protected areas , 65. StuWe conclude that there is low level of food insecurity in the KNP landscape that is largely driven by low and unstable household incomes. Resettled households are comparable to their host community neighbors in food availability . We also found that resettled households are comparable to their host community neighbors in food security (FCSs and CSIs) and that households with higher food security had more assets as well as more income sources. Resettled households have more seasonal income sources and supplement foods locally (kitchen gardens) while their more established host community neighbors rely on winter cropping incomes to attain similar food security. Our results suggest that increased opportunities for diversifying non-labor incomes could be effective to alleviate food insecurity for both resettled and host community households in the KNP landscape. This result reinforces multiple studies that highlight livelihood diversification as a means for alleviating household food insecurity , 66. OurS1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.S4 File(PDF)Click here for additional data file.S5 File(PDF)Click here for additional data file.S6 File(PDF)Click here for additional data file.S7 File(PDF)Click here for additional data file.S8 File(PDF)Click here for additional data file.S9 File(PDF)Click here for additional data file.S10 File(PDF)Click here for additional data file."}
+{"text": "Older adults with subjective memory complaints (SMCs) are at increased risk for episodic memory decline. Episodic memory decline is an important predictor of objective memory impairment (one of the earliest symptoms of Alzheimer\u2019s disease) and an often-suggested criterion of successful memory aging. Therefore, it is important to explore the determinant factors that influence episodic memory in older adults with SMCs. Roy adaptation model and preliminary evidence suggest that older adults with SMCs undergo a coping and adaptation process, a process influenced by many health-related risks and protective factors. This study aimed to explore the relationship between coping capacity and episodic memory, and the mediating role of healthy lifestyle between coping capacity and episodic memory in a sample of 309 community-dwelling older adults with SMCs. Results from the structural equation modeling showed that coping capacity directly affects episodic memory , and there is a partial mediating effect (60.5%) of healthy lifestyle among this sample of older adults with SMCs. This study demonstrates that coping capacity and adaptation positively correlate with episodic memory in older adults with SMCs, and that these correlations are mediated by healthy lifestyle. The results suggest that older adults with poor coping capacity should be assessed and monitored regularly, and clear lifestyle-related interventions initiated by healthcare providers that promote healthy lifestyles may effectively improve coping capacity and episodic memory in this population group. Note: First author: Feilong Wang, Co-first author: Shijie li, Corresponding author: Yanni Yang"}
+{"text": "This study investigated the association between childhood socioeconomic status (cSES) risk of cognitive impairment but not dementia (CIND), cognitive impairment (dementia or CIND), and dementia and whether adult personality mediated this association. A sample of 10,289 participants (aged 50 and older) from the Health and Retirement Study (HRS) were followed across 2-year periods between 2006 - 2018. Estimates of mediation effects in Cox Proportional Hazards regressions were conducted using Mplus software to approximate the total effects of cSES on the cognitive outcomes and the natural indirect effects and natural direct effects derived when personality causally mediated this outcome. cSES was associated with increased risk of all three cognitive outcomes. Conscientiousness partially mediated the relationship between cSES and dementia, CIND, and cognitive impairment risk while neuroticism partially mediated dementia and impairment, but not CIND. Personality improved the overall model fit between cSES and both CIND and impairment, and conscientiousness was specifically associated with significantly lowered cognitive impairment risk over time. Conscientiousness and neuroticism substantially mediated the relationship between cSES and risk of impairment in old age. This research adds to lifespan models and suggests that distinct personality traits attenuate early childhood factors that contribute to lifespan development and cognitive aging. Conscientiousness in particular may act as a protective buffer mediating risk factors associated with cognitive impairment in old age."}
+{"text": "Cereals and legumes play a major role in the production systems and diets of farmers in the semi-arid eastern region of Kenya. Efficient postharvest management can tremendously contribute to food security in these regions. A study was carried out in three counties in eastern Kenya to assess pre and postharvest management practices among farmers. Data was collected using semi-structured questionnaires designed and administered using Kobo Toolbox via android tablets. Results showed that farmers cultivated three main crops: maize (98%), beans 66%), and pigeon peas (28%). The most saved seed crops were beans (80%) and pigeon peas (50%). Majority of the farmers (80%) experienced pre-drying losses due to insects (48%), rodents (40%) and birds (39%). Farmers stored grain for consumption (80%) and for sale (19%). About 48% of farmers stored the grain for more than 9 months. Challenges during grain storage were insects (57%) and rodents (43%). Primary methods of grain preservation included hermetic methods (61%) followed by insecticides (33%). While progress is being made in addressing storage challenges, there still a need to continue building awareness about improved storage technologies and find solutions for pest infestations in the field and drying after harvest. Cereals and legumes are the most important food staples in Sub-Saharan Africa , beans (Phaseolus vulgaris L.), green grams (Vigna radiata L.), pigeon peas (Cajanus cajan L.), millets (Pennisetum spps), sorghum (Sorghum bicolor L.), cowpea (Vigna uncguiculata L.) and dolichos lablab (Lablab purpureus L.) to ensure self-sufficiency in the face of climate change  in the Eastern region of Kenya . The surWe purposively selected 50 villages in the three counties . The number of villages per country was determined based on cereal and legume production. We targeted to interview 13 farmers randomly selected in each village. We were able to survey a total of 613 farmers . The selected farmers were interviewed using a semi-structured questionnaire with open and close-ended questions. Questions included qualitative and quantitative data focused on the socio-economic characteristics of the respondents; major cereal and legume crops produced, the quantity produced; seed sources and storage, grain drying before and after harvest, storage practices; farmers\u2019 knowledge of the causes of postharvest losses and loss prevention measures. The questionnaire was uploaded to Kobo Toolbox, deployed and administered via handheld devices (android tablets). Five enumerators collected data and received consent from individual farmers before each interview. Data collected were coded and analyzed using the SPSS 24.0 (IBM Corp., About half of the farmers were an aging demographic, above 50 years. Older farmers are usually viewed least productive because most field work require physical effort. In addition, this may be a hindrance to adoption of new technologies which has a negative impact on food security. This is a universal trend caused by youth migration to urban centers among other factors. Policy-makers need to develop programs that incentivize the youth to be involved in agriculture. The average household size was five members which is similar to the Kenyan national average of between 4.9 to 5.7 people Munene, . Bigger The three major crops grown across the three counties were maize, beans and pigeon pea. Most farmers grew at least two major crops including a cereal and a legume. This agrees with the report that farmers in semi-arid areas of eastern Kenya grow two major and one minor grain crops (Wambugu & Muthamia, There was little variation in postharvest practices among the three study sites. Ideally, rainfall in these regions is bimodal with the long rains occurring from March to May and short rains from October to December. However, all these counties have been experiencing an overall decrease in precipitation and increase in temperatures, with negative impact on crop yields (Ojwang\u2019 et al., Farmers had a good understanding of storage and its implications for food security. Studies have shown the importance of storage in enhancing food security in semi-arid areas (Nduku et al., The major challenges during storage were insects and rodents. Farmers reported using new storage technologies and insecticides to deal with these pest challenges. Farmers have relied on pesticides for grain preservation, but they have been shifting towards hermetic storage in recent years. Concerns with pesticides stem from food poisoning due to overuse and misuse of insecticides as well as their ineffectiveness linked to insect resistance (Nicolopoulou-Stamati et al., Overall, farmers have a greater understanding of postharvest practices in the three counties in Eastern Kenya. Maize and common beans are the most important crops grown by farmers in these areas. Postharvest challenges linked to drying and storage such as aflatoxins and insects are serious challenges. Farmers are increasingly accessing new technologies and solutions to deal with these issues. Maize being such a staple crop grown by all farmers, there is a need to improve and promote pre-harvest and postharvest management practices to increase the use of new technologies such as improved seed, dryers, and hermetic storages devices."}
+{"text": "Durable left ventricular assist device therapy has improved survival in patients with advanced heart failure refractory to conventional medical therapy, although the readmission rates due to device-related comorbidities remain high. Left ventricular assist devices are designed to support a failing left ventricle through relief of congestion and improvement of cardiac output. However, many patients still have abnormal hemodynamics even though they may appear to be clinically stable. Furthermore, such abnormal hemodynamics are associated with an increased risk of future adverse events including recurrent heart failure, gastrointestinal bleeding, stroke, and pump thrombosis. Correction of residual hemodynamic derangements post-implantation may be a target in improving longitudinal clinical outcomes during left ventricular assist device support. Automatic and timely device speed adjustments considering a patients\u2019 hemodynamic status  are potential improvements in forthcoming devices. Despite considerable improvement in available heart failure-specific medical therapies including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, aldosterone antagonists, angiotensin receptor-neprilysin inhibitors, and arginine vasopressin type II receptor antagonists, morbidity and mortality in patients with advanced heart failure remain exceedingly high .In addition to mechanical circulatory support technologies including the intra-aortic balloon pump, extra-corporeal membrane oxygenation, and percutaneous axial-flow left ventricular assist device (LVAD), cardiac replacement therapy (heart transplantation and durable LVAD) remains the gold-standard therapy for those with refractory stage D heart failure . Given tLVAD therapy improves survival in patients with advanced heart failure compared to medical therapies alone ,5; howevLVADs correct hemodynamic derangements by mechanically unloading the failing left ventricle that decreases intra-cardiac pressure and subsequently increasing systemic circulation that increases total cardiac output. However, one report showed that many LVAD patients have abnormal hemodynamics despite appearing clinically stable in the ambulatory setting . FurtherDurable LVAD technology is improving, from para-corporeal models to the implantable and smaller iterations, including both pulsatile and continuous-flow types. Notably, the dominant types in the current era are implantable continuous-flow devices  12]. Th. Th12]. 2. Notably, we can measure directly or calculate various other hemodynamic parameters using right heart catheterization, as discussed later.Nevertheless, our group recently found that many LVAD patients had abnormal hemodynamics despite showing no apparent clinical symptomology . Here, wParticularly, many LVAD patients seem to have inappropriately elevated central venous pressure indicative of sub-clinical right heart failure ,14. LVADFor several reasons, we believe that invasive right heart catheterization should be routinely performed following LVAD implantation . First, Our team recently demonstrated that the presence of abnormal hemodynamics post-LVAD implantation, even without heart failure symptoms, was associated with future instances of clinical volume overload and heart failure recurrence . As one Optimal device positioning also affects the device\u2019s ability to effectively unload the left ventricle, with malposition of the inflow cannula associated with an increased risk of future heart failure exacerbations . LateralBleeding, particularly gastrointestinal bleeding, is among the most common comorbidities during LVAD support with an estimated incidence of 25% . Some gaThe mechanism of gastrointestinal bleeding is multifactorial . In addiThe most apparent risk factor for LVAD-associated stroke is uncontrolled systemic blood pressure . This rePump thrombosis is one of the major causes of device malfunction that requires device exchange . AbnormaSeveral unique hemodynamic patterns vary by disease state including right heart failure, pulmonary hypertension, and aortic insufficiency.We should state at first that there is no comprehensive and consistently agreed-upon definition of right heart failure . Right hAs mentioned above, right heart failure remains a highly morbid complication of contemporary LVAD therapy. Despite the pump\u2019s purpose to restore systemic perfusion in the failing heart by unloading the left ventricle, adverse right ventricular remodeling resulting from longstanding left ventricular failure is common and challenging to correct by durable mechanical circulatory support alone. Following LVAD implantation, right ventricular preload dramatically increases due to improved systemic circulation. The right ventricle, however, is often unprepared for this drastic increase in flow due to maladaptive structural changes from the afterload of a chronically failing left heart. As a result, right heart failure can become apparent both early and in later periods following LVAD implantation. Furthermore, a decrease in the size of the left ventricle due to mechanical unloading also facilitates a geometrical unbalance between the left and the right ventricle, resulting in further impairment of normal right ventricular contractile mechanics .Elevated central venous pressures in the setting of normal pulmonary capillary wedge pressure are one of the hallmarks of right heart failure and tend to be difficult to correct alone through mechanical unloading . Right hInvasive right heart catheterization provides the clinician valuable information regarding right ventricular performance. Pulmonary artery pulsatility index, which is calculated as a pulse pressure of the pulmonary artery divided by the central venous pressure, is a recently proposed index of right ventricular function , with a Many patients with advanced heart failure have secondary pulmonary (combined pre and post-capillary) hypertension due to chronically elevated left-sided filling pressures . HoweverAortic insufficiency is a unique and progressive comorbidity during long-term LVAD support. Continuous left ventricular unloading leads to aortic valve closure and pressure increases in the aortic root via the outflow graft. This can lead to valvular degeneration, and subsequent continuous and eccentric valvular regurgitation . Aortic The severity of aortic insufficiency is assessed usually using conventional color Doppler echocardiography for visual estimation. Accurate quantification is challenging given non-physiologic continuous and eccentric regurgitant flow. Our group recently proposed several methods to more accurately quantify the severity of aortic insufficiency .First, we can estimate the degree of aortic insufficiency using a device flow monitor, which is equipped in the HeartWare LVAD . This stSecond, we can quantify the severity of aortic insufficiency using Doppler echocardiography obtained at outflow graft  53]. Th. Th53]. As discussed above, abnormal hemodynamics are associated with various adverse clinical outcomes during LVAD support. Furthermore, there are several hemodynamically unique comorbidities during LVAD support which have unique and specific management strategies.2. We simultaneously perform echocardiography to assess for aortic valve opening, to understand the interventricular septum position, and to determine the presence of mitral valve regurgitation at each speed interval . It. It61]. The CardioMEMS device might have the potential to be utilized in LVAD patients to monitor and adjust device parameters in response to hemodynamic status . This isReDS is another promising tool to noninvasively estimate intra-thoracic fluid levels , which mThe HeartWare LVAD provides an estimated instantaneous flow waveform that shows insights into patients and device properties. For example, low pulsatility and low mean flow indicate hypovolemia, whereas low pulsatility and high mean flow let us detect suspected device thrombosis. High pulsatility and low mean flow might indicate continuous suction, whereas high pulsatility and high mean flow indicate volume overload. LVAD flow is determined by the pressure difference between the aorta and left ventricle at a fixed device speed. When aortic pressure is assumed to be constant at the diastole phase, LVAD flow is dependent on left ventricular pressure. When left ventricular pressure increases, LVAD flow often increases. Given this mechanism, pulmonary capillary wedge pressure can be estimated by the slope of LVAD flow at the end-diastolic phase  66]. We. We66]. Future advances in durable mechanical support may include a smart pump concept, which can automatically adjust device speed by continuously monitoring hemodynamic data points. For example, a novel smart pump might automatically measure the HeartWare LVAD flow slope and adjust its rotational speed considering estimated intra-cardiac pressure . If the Despite durable LVAD support, many patients can have abnormal hemodynamics due to a variety of clinical conditions even when clinically stable. LVAD therapy has improved survival in patients with advanced heart failure, though considerable limitations remain including unacceptably high readmission rates due to these various comorbidities, including volume overload and hemocompatibility-related adverse events. Assessment and optimization of hemodynamics might be one of the modifiable targets which could reduce the burden of these common post-implant complications. Interventions to optimize the hemodynamic status by adjustments of device speed and medications might improve clinical outcomes, though further large-scale prospective randomized control trials are needed to study these interventions. In the interim, noninvasive methods that estimate hemodynamics, including CardioMEMS, ReDS, and HartWare LVAD waveform analyses, may prove to be useful in more precisely guiding daily LVAD management."}
+{"text": "Previous cross-sectional research suggests that age-related decreases in Rapid-Eye Movement (REM) sleep may contribute to poorer cognitive functioning (CF); however, few studies have examined the relationship at the intraindividual level by measuring habitual sleep over multiple days. Applying a 14-day daily diary design, the current study examines the dynamic relationship between REM sleep and CF in 69 healthy older adults . A Fitbit device provided actigraphy indices of REM sleep , while CF was measured four times daily on a smartphone via ambulatory cognitive tests that captured processing speed and working memory. This research addressed the following questions: At the within-person level, are fluctuations in quantity of REM sleep associated with fluctuations in next day cognitive measures across days? Do individuals who spend more time in REM sleep on average, perform better on cognitive tests than adults who spend less time in REM sleep? A series of multilevel models were fit to examine the extent to which each index of sleep accounted for daily fluctuations in performance on next day cognitive tests. Results indicated that during nights when individuals had more REM sleep minutes than was typical, they performed better on the working memory task the next morning . These results highlight the impact of REM sleep on CF, and further research may allow for targeted interventions for earlier treatment of sleep-related cognitive impairment."}
+{"text": "The house acts as both an environment of care and a vehicle to financially potentiate long-term community-based support. While housing can empower a diverse set of options for a person-centered aging process, inadequate housing can also impede healthy aging in the community. This symposium teases out the nodes where housing acts to benefit or limit safe community-based aging. The first paper in this symposium, Homeownership Among Older Adults, describes typologies of older adult homeownership and sensitively highlights trends, disparities and important considerations of homeownership in later life. The next two papers take these older adults and explores situations where their housing acts as an asset or as a burden. Identifying Cost Burdened Older Adults acknowledges that housing cost burdens look different for older adults than younger cohorts. A more precise definition of older adult housing cost burden is proposed to help researchers and policymakers better synthesize the complex relationships between older adult housing and their long-term care decisions. The Long-Term Care Financing Challenge then explores the role of home equity in expanding the community-based long-term care choice set for older adults. This paper demonstrates benefits  in home equity and suggests policy implications moving forward. Finally, Cardiometabolic Risk Among Older Renters and Homeowners disentangles the relationship between housing and health by demonstrating health disparities that are associated with housing tenure, conditions and affordability. Taken together, this symposium explores the complex and multidirectional relationships between housing, long-term care and older adult health."}
+{"text": "Loneliness is a distressing yet adaptive emotional experience that alerts us to socially re-engage. However, loneliness can also lead to social withdrawal and isolation. To reconcile the seemingly contradictory consequences of loneliness, we unpack the timing of the underlying processes by distinguishing between the roles of state loneliness  and trait loneliness  in predicting social re-engagement. Using ten days of electronic daily assessments from 95 older adults , initial findings indicate that trait loneliness moderates time-varying associations between state loneliness and prosocial behavior: On days of elevated state loneliness, older adults low in trait loneliness report increases in prosocial behavior, whereas older adults high in trait loneliness show decreases in prosocial behavior. Findings suggest that transient loneliness may motivate older adults to actively re-engage with others; chronic loneliness may undermine such adaptive responses."}
+{"text": "Emerging data from epidemiological studies have confirmed elevated prevalence rates for mental health conditions among the lesbian, gay, bisexual and transgender (LGBT) populations. An estimated 2.8% of Asian Americans identify as LGBT and 26% of Asian LGBT are 40 years or older. This study analyzed the California Health Interview Survey to examine differences in psychological distress between LGBT and non-LGBT older Asian Americans, and further evaluated the role of discrimination in medical care and intimate violence on psychological distress. Regression results showed older LGBT Asians had a higher psychological distress score compared to non-LGBT Asians. After adjusting for discrimination or violence, this association no longer existed. Experiencing discrimination in medical care and intimate violence were associated with higher levels of psychological stress. This study increases our knowledge of mental health among older Asian LGBT, enhancing our ability to design culturally-targeted and trauma-informed psychosocial interventions to improve outcomes in this population."}
+{"text": "Existing evidence suggests that individuals\u2019 subjective experience of cognitive decline may be a risk state for dementia. However, whether self-awareness of positive changes confer cognitive protection is unknown. We examined the extent to which awareness of positive (AARC gains) and negative (AARC losses) age-related changes explains variability in objective cognitive performance in a sample of 6,231 UK residents  without cognitive impairment. We tested a structural equation model with AARC gains and losses as predictors of cognitive performance and depressive symptoms as a mediator of the association of AARC losses with cognitive performance. The model fit the data well. The correlation between AARC gains and losses was negligible, yet higher levels of both AARC gains and losses predicted poorer cognitive scores. Hence, higher AARC gains did not confer cognitive protection. This unexpected pattern of results underscores the complexity of mapping individuals\u2019 awareness onto objective outcomes."}
+{"text": "Cancer cells directly control nutrient uptake and utilization in a different manner from that of normal cells. These metabolic changes drive growth, proliferation of cancer cells as well as their ability to develop resistance to traditional therapies. We review published studies with pre-clinical models, showing the essential roles of lipid metabolism in anticancer drug resistance. We also discuss how changes in cellular lipid metabolism contribute to the acquisition of drug resistance and the new therapeutic opportunities to target lipid metabolism for treating drug resistant cancers.Metabolic reprogramming is crucial to respond to cancer cell requirements during tumor development. In the last decade, metabolic alterations have been shown to modulate cancer cells\u2019 sensitivity to chemotherapeutic agents including conventional and targeted therapies. Recently, it became apparent that changes in lipid metabolism represent important mediators of resistance to anticancer agents. In this review, we highlight changes in lipid metabolism associated with therapy resistance, their significance and how dysregulated lipid metabolism could be exploited to overcome anticancer drug resistance. Many oncogenic mutations resulting in the aberrant activation of several signaling pathways can reprogram cancer cell metabolism to such an extent that metabolic reprogramming is considered one of the major hallmarks of cancer . Cancer i) overproduction of neutral lipids such as triacylglycerols stored in LD that accumulate in cancer to provide a reserve of energy; (ii) production of phospholipids is used to build cancer cell membranes to satisfy the increased demand for cancer proliferation. Moreover, phospholipids also act as lipid messengers and intracellular signaling molecules in cancer . Among r review . Particur review ,17. Humar review . Orlistar review . Besidesr review . Many enr review .Secondly, apart from lipogenesis, it was observed that FAs, either from extracellular sources or mobilized from internal lipid stores, can be oxidized in cancer cell mitochondria B. Under Furthermore, lipolysis and lipogenesis may coexist in cancer cells . Lipid mEmerging evidence also suggest that dysregulated lipid metabolism could play a role in resistance to anticancer drugs. Furthermore, the dependence of cancer cells on aberrant lipid metabolism could point to lipid metabolism being a potential source of new attractive targets to eradicate cancer cells. This review highlights the role and mechanisms of lipid metabolism reprogramming induced by anticancer drugs during the development of chemoresistance in cancer cells. In addition, we discuss the potential of reversing chemoresistance via lipid metabolism regulation.It is now well-established that lipid metabolism changes are associated with resistance to conventional chemotherapies and targeted therapies in several cancers. Lipid metabolic reprogramming of resistant cancer cells includes both changes in de novo lipogenic synthesis and/or lipolytic pathway. With some exceptions , cancer Secondly, changes in the lipid metabolism of resistant cells vary depending on the environment and cellular context. Thus, radiation resistance was associated with a significant increase in CPT1A-dependent lipolysis in nasopharyngeal carcinoma whereas radiation resistance was linked to de novo lipogenesis in head and neck squamous carcinoma ,51. MechOverall, these data indicate that changes in lipid metabolism of resistant cells are treatment specific but also environmental and cellular context-dependent resulting in a high heterogeneity of lipid metabolisms.Of note, it is interesting to stress out that lipid metabolism changes, de novo lipogenesis or lipolysis, can be unveiled upon anticancer drug exposure. Comparison of paired NSCLC tumor tissues from patients before and after Gefitinib treatment revealed a significant increase in lipid droplet content and in SCD1 expression . Upon 5-Firstly, several studies suggested that aberrant lipid metabolism could be seen as metabolic shift allowing cancer cells to adapt to treatment-induced cellular stress. Almost all anticancer drugs including conventional chemotherapies and targeted therapies induce cancer cell stress that can ultimately lead to cell death. It was reported that several cellular stressors like lack of nutrients, high levels of reactive oxygen species (ROS) promote de novo lipogenesis . Thus, lSecondly, apart from an adaptive process, cancer cell exposure to anticancer drugs can result in an enrichment of a pre-existing cellular subpopulation characterized by aberrant lipid metabolism. According to this hypothesis, lipid metabolism is a metabolic state allowing a sub-population of cancer cells to escape the effects of anticancer drugs when other cancer cells die. This subpopulation could be represented by cancer stem cells (CSCs), a highly resistant subset of cancer cells. Indeed, it is well established that even if a successful cancer therapy abolishes the bulk of tumor cells, CSCs can survive to standard cancer treatments and are at the core of clinical relapse . InteresIn many preclinical models, lipid metabolism inhibition can reverse the resistance of cancer cells to cancer drugs suggesting that lipid metabolism may play a role in drug resistance. The question is how can lipid metabolic reprogramming contribute to anticancer drug resistance?The oxidative stress induced by anticancer drugs result in peroxidation of lipid membranes, oxidative modifications of proteins and DNA. Doxorubicin, which possesses an anthracycline skeleton, generates ROS leading to DNA damage followed by anticancer activity. Likewise, vinca alkaloids increase intracellular ROS production by depleting the intracellular GSH causing DNA damages. Changes in lipid metabolism elicit a cytoprotective response to oxidative stress in several different ways: (i) lipid droplets decrease ROS toxicity thereby increasing cancer cell survival  ProductiLipid droplet accumulation was evidenced to support colorectal cancer resistance to 5-fluorouracil (5-Fu) and oxaliplatin by inhibiting ER stress . Indeed,Overexpression of FAS, the key enzyme of de novo lipogenesis pathway, triggers cancer resistance to genotoxic drugs by increasing DNA repair . MechaniTargeted therapies such as MAPK inhibitors inhibit glucose uptake and antiglycolytic effects triggering energy stress conditions contributing to the promotion of cancer cell death (see above). Acetyl-CoA derived from fatty acid oxidation can fuel the mitochondrial TCA cycle to reduce energetic stress. This metabolic shift towards FAO, is often orchestrated by the AMP-dependent protein kinase (AMPK). Activation of AMPK in response to low energy levels boosts energy production through a mitochondrial FAO increase  and therLipid metabolism can also interfere with the process of apoptotic cell death induced by anticancer drugs through two distinct mechanisms: (i) LDs were shown to remove apoptosis-related proteins, such as BCl-2 family members, from mitochondria by direct contact between outer mitochondrial membrane and lipid droplet surface . This pr+ CSC content in the MCF7 breast cancer cell line [A large body of evidence indicates that human cancers emerge from CSCs, which are intrinsically resistant to many anticancer treatments including conventional chemotherapies, targeted drugs and radiation. CSCs are also the main source of cancer relapse. Interestingly, lipid metabolic reprogramming contributes to CSCs expansion and survival therefore enhancing the occurrence of chemoresistance . Severalell line . Activatell line  converseell line . HMG-CoAell line ,94,95,96ell line . Similarell line .Overall, these observations identify the rewiring of lipid metabolism as a novel and important mechanism of adaptive resistance to anticancer drugs.As detailed above, recent studies have shown that cancer cells develop changes in lipid metabolism, which is different from that of non-proliferative differentiated cells. These observations open up new avenues for the exploitation of lipid metabolism as a source of new therapeutic targets. Natural and synthetic agents that affect lipid metabolism in cancer is a rapidly growing field that was recently reviewed elsewhere . The focNumerous pharmacological inhibitors have been developed for almost all enzymes of lipid metabolism and some compounds are used in clinical trials in association with conventional therapies . CombinaBesides, due to the role of lipid metabolism in the acquisition of treatment resistance, targeting lipid metabolism could be used to re-sensitize cancer cells to standard treatments. FAS inhibitors have shown in-vivo and in-vitro anticancer effects and are also responsible for re-sensitization of cancer cells to conventional therapy ,106,107.One major interest in lipid targeting for cancer treatment is the possibility of using existing clinically-approved drugs originally developed for other lipid-related diseases. This drug repositioning in oncology has the main advantage of improving safety and reducing costs. Besides the anti-obesity drug, orlistat (see above), statins represent a classic example of drug repositioning in oncology. Statins are currently the most efficient drugs to reduce circulating cholesterol, with few side effects including muscle pain and occasionally liver inflammation, and thereby are used in preventing the development of cardiovascular diseases . MoleculBased on preclinical data presented above, combination therapy consisting of standard anticancer therapies and lipid metabolism inhibitors would be effective for treating resistant cancers.Lipid metabolism plays a central role in cancer resistance, not only via an increased availability of lipids conferred by adipocyte environment but also through profound changes in cancer cell lipid metabolism. It is particularly interesting to note that CSCs, cells that are known to be at the center of resistance mechanisms and relapse, have an increased dependence on lipid metabolism. This could offer a very large number of potential targets, as reported in this review. Changes in the lipid metabolism of cancer cells has been overlooked since conventional 2D cell culture is unable to recapitulate the tumor environment. Moreover, conventional culture medium does not recapitulate normal fatty acid environment as reported by Else . Optimiz"}
+{"text": "Teaching point: Hoarseness is a common condition that can be the initial symptom of cardiovascular disorder. A 76-year-old women who quitted smoking ten years earlier presented with recent-onset hoarseness of the voice. She had history of pulmonary commissurotomy. Fiberoptic laryngoscopy revealed paramedian left vocal cord paralysis. Chest computed tomography showed hiatus hernia and left pulmonary artery aneurysm (largest diameter 66 mm) Figures  and 2 wiThe recurrent laryngeal nerves originate from the vagus nerves at different levels. The right recurrent laryngeal nerve exits anterior to the right subclavian artery and runs underneath and behind it. On the left side, the recurrent laryngeal nerve leaves the vagus nerve on the anterior surface of the aortic arch, running inferiorly around it through the aortopulmonary window posterior to the ligamentum arteriosum. Then they both rise up between the trachea and esophagus to reach larynx and innervate the intrinsic laryngeal muscles, except the cricothyroid muscle. Because of its longer course in mediastinum, the left recurrent laryngeal nerve is more vulnerable . This neThere are various mediastinal causes for vocal cord paralysis including surgical or iatrogenic injuries, traumatic lesions, inflammatory or infectious diseases, amyloidosis, tumours, and cardiovascular diseases. Ortner syndrome  refers to hoarseness resulting from left recurrent laryngeal nerve paralysis caused by cardiovascular disease . It was Pulmonary artery aneurysms are rare, predominantly involving main pulmonary arteries, and may be idiopathic or result from congenital  or acquired  causes. It has been reported that early pulmonary valve commissurotomy may induce pulmonary artery aneurysm development due to eccentric right ventricular outflow jet.This case emphasizes the need to investigate neck and chest when looking for a causative lesion to hoarseness."}
+{"text": "Anabaena sp. ATCC 33047 is a marine, heterocyst forming, nitrogen fixing cyanobacteria with a very short doubling time of 3.8 h. We developed a comprehensive genome-scale metabolic (GSM) model, iAnC892, for this organism using annotations and content obtained from multiple databases. iAnC892 describes both the vegetative and heterocyst cell types found in the filaments of Anabaena sp. ATCC 33047. iAnC892 includes 953 unique reactions and accounts for the annotation of 892 genes. Comparison of iAnC892 reaction content with the GSM of Anabaena sp. PCC 7120 revealed that there are 109 reactions including uptake hydrogenase, pyruvate decarboxylase, and pyruvate-formate lyase unique to iAnC892. iAnC892 enabled the analysis of energy production pathways in the heterocyst by allowing the cell specific deactivation of light dependent electron transport chain and glucose-6-phosphate metabolizing pathways. The analysis revealed the importance of light dependent electron transport in generating ATP and NADPH at the required ratio for optimal N2 fixation. When used alongside the strain design algorithm, OptForce, iAnC892 recapitulated several of the experimentally successful genetic intervention strategies that over produced valerolactam and caprolactam precursors.Nitrogen fixing-cyanobacteria can significantly improve the economic feasibility of cyanobacterial production processes by eliminating the requirement for reduced nitrogen.  As production hosts, cyanobacteria have several advantages over eukaryotic plants and algae, including faster growth and higher photosynthetic efficiency 68]. The ming FVA . Unfortubacteria . Among tna 33047  was usedg strain . The fluiAnC892, for the fast-growing, N2-fixing cyanobacteria, Anabaena 33047 by pooling together annotation information from diverse databases. Because Anabaena 33047 forms heterocysts under diazotrophic conditions, the iAnC892 model featured two super-compartments: vegetative cell and heterocyst. iAnC892 was able to accurately capture several aspects of the diazotrophic metabolism of heterocyst forming cyanobacteria. Reaction content comparison with Anabaena 7120 and Anabaena 29413 indicated that iAnC892 is different from these models in terms of its reaction content. Cell specific shutdown of heterocyst-LETC revealed its importance in generating ATP and NADPH at ratios optimal for N2 fixation. Similar analysis of heterocyst central carbon metabolism revealed the existence of alternative routes other than PPP that can supply reducing equivalents for N2 fixation. The usefulness of iAnC892 was further tested by using it alongside OptForce to predict genetic interventions for overproduction of valerolactam and caprolactam. The study recapitulated several of the experimentally successful strategies. Further improvement in predictions can be achieved by using flux distributions specifically generated for Anabaena 33047. Availability of species-specific flux distribution would also help pin down exchanges between vegetative cell and heterocysts which would provide a clearer picture of the energy production pathways active in the heterocyst.In this study we constructed a comprehensive GSM model,"}
+{"text": "Assessment of metabolic cost as a metric for human performance has expanded across various fields within the scientific, clinical, and engineering communities. As an alternative to measuring metabolic cost experimentally, musculoskeletal models incorporating metabolic cost models have been developed. However, to utilize these models for practical applications, the accuracy of their metabolic cost predictions requires improvement. Previous studies have reported the benefits of using personalized musculoskeletal models for various applications, yet no study has evaluated how model personalization affects metabolic cost estimation. This study investigated the effect of musculoskeletal model personalization on estimates of metabolic cost of transport (CoT) during post-stroke walking using three commonly used metabolic cost models. We analyzed walking data previously collected from two male stroke survivors with right-sided hemiparesis. The three metabolic cost models were implemented within three musculoskeletal modeling approaches involving different levels of personalization. The first approach used a scaled generic OpenSim model and found muscle activations via static optimization (SOGen). The second approach used a personalized electromyographic (EMG)-driven musculoskeletal model with personalized functional axes but found muscle activations via static optimization . The third approach used the same personalized EMG-driven model but calculated muscle activations directly from EMG data . For each approach, the muscle activation estimates were used to calculate each subject\u2019s CoT at different gait speeds using three metabolic cost models . The cal Metabolic cost has been used to evaluate human performance during daily activities such as walking  and athlin silico. Specifically, within the field of exoskeleton design, musculoskeletal models can eliminate the time and expense of iteratively designing and building physical prototypes. With advances in computational biomechanics, musculoskeletal models incorporating metabolic cost models have emerged as tools to estimate metabolic cost. These tools have been used to predict human movement and response to mechanical interventions . AlthougPrevious studies that estimated metabolic cost during walking have focused on using scaled generic musculoskeletal models. However, several studies have reported that personalization of anatomical and physiological characteristics of a musculoskeletal model can influence prediction of muscle forces, joint moments, and novel movements, factors that also play a role in metabolic cost calculations. This study evaluated the influence of musculoskeletal model personalization on metabolic cost estimates of walking post-stroke. To evaluate the physical realism of different metabolic cost modeling methods, we compared metabolic cost estimates to trends reported in the literature for individuals post-stroke. Experimental walking data collected from two male stroke survivors\u2013one high functioning and one low functioning\u2013were used as inputs to the metabolic cost analyses see , 2008.tf Hz (tf is the period of the gait cycle being processed (tf Hz) using a fourth-order zero-phase lag Butterworth filter. EMG amplitudes for each muscle were normalized to the maximum value over all trials and resampled to 101 time points per gait cycle, as described in The experimental data were processed using standard methods. The ground reaction and marker motion data were low-pass filtered using a fourth-order zero-phase lag Butterworth filter with a cut-off frequency of 7/tf Hz , where trocessed . On averA generic full-body OpenSim musculoskeletal model  served alsqnonlin algorithm, which iteratively ran OpenSim Inverse Kinematics analyses to calculate marker location errors.Personalization of the joint functional axes for the hip, knee, and ankle of each leg was performed by following a two-step process. First, the geometry of the generic OpenSim model was scaled to match the dimensions of each subject using the OpenSim Scale Model tool and the static standing trial data. Second, marker positions and functional axes of the model\u2019s lower body joints were personalized as described in Experimental data from ten gait trials collected at each available walking speed were used to calibrate an EMG-driven model of both legs for each subject. Before performing EMG-driven model calibration, we analyzed marker data from each gait trial using the OpenSim Inverse Kinematics tool to generate joint angle trajectories. The OpenSim Inverse Dynamics tool was then used to calculate the joint moments produced by muscle forces. Next, a surrogate model of each subject\u2019s musculoskeletal geometry was generated to allow the EMG-driven model to modify musculoskeletal geometry , 2017. Tfmincon algorithm with sequential quadratic programming, we adjusted the model parameter values to best match calculated experimental inverse dynamic joint moments and published passive joint moments , Hill-type muscle-tendon model parameters , and surrogate musculoskeletal geometry parameters. Using Matlab\u2019s  moments . In addi moments , S2. A dTo evaluate the extent to which model personalization affects estimated metabolic cost, we developed three musculoskeletal models for each subject with varying levels of personalization. The least personalized model was a scaled generic OpenSim model where muscle activations were calculated via static optimization using quadratic programming (SOGen) . The intTo evaluate the physical realism of each musculoskeletal model/metabolic cost model combination, we identified five experimental trends in the literature for how CoT varies as a function of other clinically relevant quantities for individuals post-stroke. The first three quantities were step length asymmetry, stance time asymmetry, and double-support time asymmetry, all of which have been reported to increase as the CoT increases . The twoWe performed statistical analyses to evaluate whether trends in CoT as a function of the five quantities described above were different between each musculoskeletal model/metabolic cost model combination and the experimental data published in p-values tended to increase as the level of musculoskeletal model personalization increased, with the EMGCal musculoskeletal model generally exhibiting the largest p-values and thus the greatest statistical similarity to experimental measurements. In contrast, the p-values tended to be comparable across the three levels of musculoskeletal model personalization.The ability to predict CoT trends consistent with experimental measurements varied across the nine modeling combinations \u20135. Overap-values < 0.05). However, when absolute values of y-intercept differences were calculated , and the subject provided written informed consent prior to participation.CP and BF performed the experiments. MA performed all model personalization tasks, prepared the figures, and drafted the manuscript. MA and MS analyzed the data. MA, MS, and BF interpreted the results of analyses. All authors revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Aging is a major risk factor for chronic diseases and is directly linked to increasing mortality and healthcare costs worldwide. A key contributing factor to the aging process is a loss of stem/progenitor cell function which leads to a dysregulated tissue microenvironment and reduced repair/regeneration . Over thThe bone marrow is an important reservoir of stem/progenitor cells which cross-talk with peripheral organs to help maintain tissue function. Hematopoietic stem/progenitor cells (HSCs) are responsible for producing blood cells throughout life and these downstream cells play an active role in maintaining tissue homeostasis. With aging reduced function of bone marrow cells correlates with dysfunction of peripheral organs. For example, the decline in immune function with age, referred to as immuno-senescence, contributes to the accumulation of senescent cells, persistent low grade inflammation, and reduced responses to injury . The bon+ bone marrow stem cells and examined 4 months later to allow cross talk between the bone marrow and heart. Young bone marrow reconstitution rejuvenated cardiac endothelial cells which contributed to improved repair and better outcome following myocardial infarction. Mechanistically, young cells which migrated to the heart expressed more Cxcl12 and Vegf, key cytokines involved in angiogenic responses. This correlated with greater expression of CXCR4 and phospho-AKT in resident cardiac endothelial cells isolated from mice receiving young vs. old bone marrow. In addition to improved angiogenesis, our lab has shown that rejuvenation using reconstitution of young cells improves multiple repair processes. Young bone marrow cell transplantation increases the proliferation of resident cardiac cells [We recently utilized this bone marrow rejuvenation approach to study the effect aging has on the repair processes initiated post-myocardial infarction . Aged miac cells , increasac cells , and enhac cells . TogetheBeyond cardiac repair, we have shown that bone marrow cells interact with other tissues and that bone marrow rejuvenation can benefit multiple organ systems. Reconstituting aged mice with young cells leads to the repopulation of the retina with young bone marrow derived microglia . Within Together our studies as well as studies by others demonstrate that introducing young bone marrow into aged mice is an effective rejuvenation strategy with systemic benefits . Bone ma"}
+{"text": "The journal retracts the article, Dinitrosopiperazine-Mediated Phosphorylated-Proteins Are Involved in Nasopharyngeal Carcinoma Metastasis  cited abFollowing publication, concerns were brought to the attention of the publisher regarding the figures. Some stained tissue pictures in Figure 6  are duplWe apologize to our readership that this went undetected until now."}
+{"text": "Bipolar disorder (BD) is a complex and serious psychiatric disorder characterized by mood dysregulation difficulties (American Psychiatric Association Emotion-related urgency (hereto referred as ERU) is defined as a tendency to act rashly in the context of extreme emotions, including trouble inhibiting impulses and risk-taking behaviors (e.g., Cyders and Smith negative urgency (defined as the tendency to behave rashly during extreme negative emotions; e.g., Whiteside and Lynam positive urgency (defined as the tendency to behave rashly during extreme positive emotions; Cyders This brief letter suggests the importance of considering impulsivity during mixed states. Both negative and positive ERU have been implicated in BD (Giovanelli et al. We suggest increased investigation into transdiagnostic presentations and clinical implications of ERU. Indeed, recent recognition of mixed features also occurring in the context of major depressive disorders underscores the important transdiagnostic utility of ERU across mood disorders. We suggest three key areas for future research. First, it will be important to develop well-validated assessment tools to measure mixed-mood ERU across self-report and clinician-rated instrument domains. Second, it will be important to carefully assess the maladaptive behaviors that may predict, and result from, ERU during mixed states and differentiate those from more general risk-taking behavior. Third, future research should carefully consider lifespan approaches that consider ERU in the context of BD onset, risk and recurrence at critical developmental junctures. We believe the time is ripe to call greater attention to examining risky and potentially fatal consequences of impulsivity during strong and co-occurring negative and positive emotion states."}
+{"text": "Sepsis survivorship is associated with cognitive decline and complex post-acute care needs. Family caregivers may be unprepared to manage these needs, resulting in decline or no improvement in patient outcomes. Using a national dataset of Medicare beneficiaries who were discharged from the hospital for sepsis and received post-acute HHC between 2013 and 2014 , we examined the relationship between unmet caregiving needs and improvement or decline in cognitive functioning. Multivariate logistic regression was used to determine associations between unmet caregiving needs at the start of HHC and changes in cognitive functioning. Unmet caregiving needs included seven items from the start of care Outcome and Assessment Information Set (OASIS). Changes in cognitive functioning were measured using the start of care and discharge OASIS assessments. Twenty-four percent of patients either declined or did not improve in cognitive functioning from HHC admission to discharge, with variation seen by unmet need type. Sepsis survivors with unmet caregiving needs for activities of daily living assistance , medication assistance , and supervision and safety assistance  were more likely to decline or not improve in cognitive functioning, even after accounting for clinical and demographic characteristics. Older sepsis survivors with both cognitive impairment and unmet caregiving needs in the post-acute HHC setting are at high-risk for worsening cognition. Alerting the care team of cognitively impaired sepsis survivors with unmet caregiving needs may trigger evidence-based strategies to enhance caregiver training and reduce unmet caregiving needs."}
+{"text": "Prior studies suggesting associations between cortical brain areas and gait speed has been largely cross-sectional and limited to one modality neuroimaging. Using machine learning from 506 cognitively normal BLSA participants aged 55+ who had repeated measures of brain volumes, diffusion tensor imaging (DTI), and gait speed, we examined multimodal neuroimaging predictors of gait decline, accounting for demographics, body composition, and grip strength. Significant predictors of gait decline included changes in volumes and DTI measures of gray matter in selected frontal, parietal, temporal, and subcortical areas, as well as white matter changes in both fractional anisotropy and diffusivity of tracts connecting frontal areas to subcortical motor areas. This predictive model highlights the importance of atrophy and microstructural deterioration in selected frontal and subcortical motor areas in predicting gait speed decline."}
+{"text": "C. elegans. As shown in et al. 1986). Serotonin and Gao signaling, which regulate egg laying behavior, can also signal to inhibit defecation . Because evidence shows that both the egg-laying active state and the defecation motor program (DMP) are both linked to changes in forward and reverse locomotion , we reasoned there may be a similar relationship between expulsive behaviors that drive either egg laying or defecation. Our experiments document an association between HSN Ca2+ activity and a reduced frequency of defecation (Ravi and Collins 2019) [See accompanying microPub Ravi and Collins (I) 2019]. Animals lacking HSNs have a reduced defecation frequency (Garcia and Collins 2019) [See accompanying microPub Garcia and Collins (II) 2019]. We hypothesize that egg-laying and defecation behaviors are coordinated because they use the same internal hydrostatic pressure to drive expulsion of uterine or intestinal contents, respectively.We have identified a relationship between egg-laying and defecation behaviors in et al. 2002; Gilpin et al. 2015; Fechner et al. 2018), releasing waste about once per minute and ~3-5 fertilized eggs (~20 pL each) about every 20 minutes . During defecation, sequential activity of the anterior and posterior body wall muscles contracts the animal, increasing internal pressure that drives expulsion of liquid waste through the anus . Mutations that eliminate the defecation motor program still expel gut contents at much reduced frequency. This is thought to be caused by a gradual accumulation of internal pressure by ongoing pharyngeal pumping of food that eventually ejects waste through the anus independent of circuit activity or muscle contractility (Avery and Thomas 1997).Worms continuously internalize bacterial food via pumping of a muscular pharynx . Animals lacking HSNs still enter active states with strong vulval muscle contractions driving release of embryos which additionally supports this model . Electrical silencing of the postsynaptic muscles renders animals egg-laying defective with embryos often hatching inside the mother . Unlike gut contents which are more fluid, fertilized embryos are more mechanically rigid, requiring full opening of the vulva for efficient release . We propose that changes in the internal hydrostatic pressure that accompany food consumption and embryo production activate mechanoreceptors that facilitate the onset of defecation and egg-laying behaviors. As animals age, they continue to eat and grow larger, but their defecation frequency decreases . Egg laying frequency also increases with age for as long as animals have sufficient sperm for oocyte fertilization . This increase in egg laying in older adults reflects both an increase in the number of eggs expelled with each vulval opening and longer active behavior states. We propose that the timing of expulsive behaviors including defecation and egg laying is regulated by sensory mechanisms that detect changes in internal pressure and/or stretch to maintain homeostasis. Feedback of successful egg laying might also signal to the germ line to ensure the continued production of oocytes for fertilization.Our recent data suggest egg-laying behavior is regulated by a stretch-dependent homeostat. Feedback from embryo accumulation in the uterus activates the postsynaptic muscles which drives burst-firing in the presynaptic HSNs as visualized by Ca"}
+{"text": "Stroke is a devastating condition characterized by widespread cell death after disruption of blood flow to the brain. The poor regenerative capacity of neural cells limits substantial recovery and prolongs disruptive sequelae. Current therapeutic options are limited and do not adequately address the underlying mitochondrial dysfunction caused by the stroke. These same mitochondrial impairments that result from acute cerebral ischemia are also present in retinal ischemia. In both cases, sufficient mitochondrial activity is necessary for cell survival, and while astrocytes are able to transfer mitochondria to damaged tissues to rescue them, they do not have the capacity to completely repair damaged tissues. Therefore, it is essential to investigate this mitochondrial transfer pathway as a target of future therapeutic strategies. In this review, we examine the current literature pertinent to mitochondrial repair in stroke, with an emphasis on stem cells as a source of healthy mitochondria. Stem cells are a compelling cell type to study in this context, as their ability to mitigate stroke-induced damage through non-mitochondrial mechanisms is well established. Thus, we will focus on the latest preclinical research relevant to mitochondria-based mechanisms in the treatment of cerebral and retinal ischemia and consider which stem cells are ideally suited for this purpose. Stroke is currently the fifth leading cause of death in the United States and can cause disabling neurological deficits including cognitive impairment, hemiparesis, sensory disturbance, and aphasia . StudiesThe ischemic cascade  triggereMitochondrial dysfunction plays a key role in the pathological progression of ischemic stroke . MitochoThe body has multiple mechanisms to combat oxidative stress and clear damaged mitochondria. Cells can sequester functional mitochondria while degrading dysfunctional mitochondria via mitophagy ,16. In aThe discovery that stem cells can replace dysfunctional mitochondria in damaged cells has primed the field of stroke therapy for critical improvements in treatment outcomes . In the The ideal cell source to leverage the therapeutic benefits of mitochondrial transfer is bone marrow-derived mesenchymal stem cells (BM-MSCs). This cell type gives rise to endothelial progenitor cells (EPCs), which produce nearly all of the endothelial cells in the body . In the An in vitro stroke model proved that EPCs could successfully discharge their mitochondria . ProteinThe next step in confirming a mechanism of EPC-mediated mitochondria transfer is to assess whether endothelial cells take up these extracellular mitochondria and whether this would aid the recipient cell. In that same study, confocal microscopy demonstrated evidence of mitochondria-containing, EPC-derived extracellular vesicles within endothelial cells in the cerebral vasculature . TherefoAlthough at this point there is considerable evidence for the role of EPCs in restoring mitochondrial function via a transfer mechanism, there was still much uncertainty surrounding the benefits of stem cell mitochondrial therapy. Additional studies on EPC-derived mitochondria addressed these concerns. FACS-assisted proteome analysis of OGD-exposed brain endothelial cells reveals that uptake of EPC-derived mitochondria enhances the production of angiogenic and BBB proteins, including Serpin E1, plasminogen, FGF-4, and bFGF . These fThe ischemic conditions brought about by stroke damage endothelial cells and predispose them towards undergoing intrinsic pathway apoptosis, which is mediated by mitochondrial dysfunction . IntegraImportantly, astrocytes can also transfer their mitochondria to damaged neurons but do so in a transient fashion. Thus, they do not produce the same neuroprotective effects that occur via stem cell transplantation and cannot prevent secondary cell death . Given tExamination of the electron transport chain (ETC), specifically complexes I\u2013IV, can be performed using ETC complex inhibitors to study each portion of the chain in isolation. Mouse models with mutated mitochondria are instrumental in this investigation in order to definitively determine whether it is the mitochondria themselves that confer the neuroprotection or whether a different characteristic of the stem cell is responsible . When diThe safety of BM-MSCs compared to other sources of stem cells is relatively well established . NeverthUp to this point, we concentrated on literature that characterizes the transfer of mitochondria from stem cells to endothelial cells and neurons in the context of the ischemic brain. However, stroke patients often suffer maladies that extend beyond the brain, and complete functional improvement must address these aspects of recovery as well. A prime example of this is that ischemic stroke may cause damage to the eye, leading to visual impairment and a significant delay in recovery ,37. ImpoIt is valuable to understand the role of mitochondrial dysfunction in cerebral and ocular disease post-stroke due to the markedly similar pathology and treatment options between these two conditions . In addiThere are considerable benefits to using MSC therapy to treat ischemia-induced eye damage, such as enhanced preservation of retinal ganglion cells. The decreased cell death is likely due to improved mitochondrial function, which may be due to MSC-derived mitochondrial transfer to the retinal ganglion cells . MSC traThe interaction of creatine and phosphocreatine conversion prevents lapses in cellular energy supplies under healthy conditions. However, it is still possible for the energy supply to be damaged under ischemic conditions, worsening mitochondrial dysfunction. Creatine supplementation possesses therapeutic characteristics in various neurodegenerative disorders that may address the lack of energy supply and the normal function of the mitochondria . TherefoBased on previously mentioned studies, transferring healthy mitochondria by exogenous MSCs can potentially restore respiratory functions in ischemic retinal cells, reducing cell loss. Future studies should investigate how MSCs successfully transfer healthy mitochondria to retinal ganglion cells. Studies should also observe and describe the metabolic and proteomic properties of MSC-derived mitochondria post-transplantation into ischemic retinal cells. EPCs\u2019 affinity for BBB repair makes them a favorable MSC subtype. EPCs are known for being safe and effective to use in stem cell therapy. Additionally, their ability to donate healthy mitochondria justifies the need to further investigate its effects on retinal ischemia. However, the study presents a significant limitation. Specifically, no known study provides a detailed report regarding the physical characteristics of MSC that are involved in the mitochondrial transfer in retinal ischemia . The funStroke-induced ischemia results in insufficient oxygen delivery to cells and prevents mitochondria from performing cellular respiration. The ensuing loss of ATP is not compatible with cellular viability and ultimately precipitates mitochondrial dysfunction and cell death. In response to stroke and stroke-like lesions, cells upregulate mitochondrial synthesis to compensate for damaged mitochondria . A varieDespite the innovations in stroke therapy over the past decade, novel methods of research continue to elucidate fundamental information on the mechanistic role of mitochondria in stroke and enable the development of powerful new therapeutic strategies. A novel technology, Seahorse XFe24, measures mitochondrial respiration and allows investigators to directly detect changes in cellular energetics, rather than relying on cellular signaling . This teSeveral pharmaceutical agents, such as the dopamine D2 receptor antagonist pramipexole (PPX), facilitate neuroprotection through the action of mitochondria. Administration of PPX to transient MCAO model rats after an ischemic stroke reduces infarct volume, neurological deficit severity, mitochondrial ROS formation, mitochondrial calcium concentration, and swelling of the mitochondrial membrane, while simultaneously increasing oxygen consumption and the respiratory control ratio . TherefoThe pharmacological administration of tetrahydrocurcumin (THC) also alleviates mitochondrial dysfunction and improves functional capacity and motor coordination. THC epigenetically reduces plasma and tissue homocysteine (Hcy) levels and Hcy-induced mitochondrial oxidative stress . THC treAnother drug-based approach to mitochondrial dysfunction is the use of nicotinamide mononucleotide (NMN) to increase NAD+ levels. NMN extends the lifespan of mice with the mitochondrial disease Leigh Syndrome by normalizing NAD+ redox imbalance and lowering H1F1a accumulation in skeletal muscle . FurtherCationic arginine-rich peptides (CARPs) are another candidate pharmacological therapeutic that specifically enhance mitochondria-mediated neuroprotection in stroke. CARPs are small peptides, composed of up to 30 amino acids, that cross the BBB and localize to mitochondria in neurons. This property alone highlights their value as a pharmacologic treatment for stroke, as many other promising drugs do not effectively cross the BBB, making their administration difficult or ineffective. Once in the mitochondria, CARPs efficiently eliminate ROS that accumulate during ischemia and restore proper function of the mitochondria, rescuing the cell from free radical damage and reestablishing cellular viability .Although restoring the respiratory functions of mitochondria improves stroke outcomes, this is not the only strategy for recovery. Autophagy, the process of degrading and recycling damaged or unnecessary cellular components, can also mitigate mitochondrial dysfunction. A high salt diet is particularly dangerous because it increases the risk of hypertension-related stroke occurrence, reduces the efficiency of autophagy, and downregulates the production of the electron transport chain enzyme NDUFC2 . HoweverThe proteins ULK1, NDP52, and TANK-Binding Kinase 1 (TBK1) are also meaningful targets for stroke therapies through targeting autophagy. TANK1 recruits the ULK1 complex to the NDP52 receptor to initiate autophagy under conditions of starvation . TherefoAnother potential target of autophagy-based treatments involves the small molecule Compound R6 and its regulation of mitochondria-mediated apoptosis. The release of cytochrome c from damaged mitochondria activates the intrinsic apoptotic caspase-9/3 cascade and results in cell death . CompounAlong with autophagy, manipulating the discrete molecular mechanisms of mitochondria to enhance mitophagy is another approach to ameliorate stroke-induced mitochondrial dysfunction. Cell cycle progression in the presence of impaired mitochondria generates damaged daughter cells, further exacerbating tissue injury and delaying recovery. However, the serine/threonine kinase PINK1 and the E3 ubiquitin ligase Parkin mediate the elimination of these impaired mitochondria through induction of TBK1 to upregulate mitophagy, the targeted recycling of mitochondria. By directing TBK1 to the mitochondrial membrane, away from its role at the centromere during mitosis, PINK1 and Parkin halt the cell cycle at the G2/M phase . TherefoIn addition to enhancing TBK1-mediated mitophagy, PINK1 upregulates the Parkin-induced mitophagy pathway in the presence of damaged mitochondria. During an ischemic injury, the depleted mitochondrial membrane potential inhibits PINK1 importation to the inner mitochondrial membrane (IMM). Instead, PINK1 binds to Tom 7, accumulates on the outer mitochondrial membrane (OMM), then activates Parkin-induced mitophagy. However, the IMM-resident protease OMA1 cleaves PINK1 in the absence of Tom 7, abolishing mitophagy . Hence, While the PINK1/Parkin pathway is valuable to preserve non-neuronal cells, Parkin-induced mitophagy is not as effective in neurons as only a small fraction of mitochondria in axons undergo mitophagy . HoweverMultiple cellular pathways spur mitochondrial deterioration in ischemic stroke. Apoptosis in mitochondria is upregulated during ischemic stroke and is associated with continuous mitochondrial permeability transition pore (MPTP) opening in the inner and outer mitochondrial membranes . ROS proMitochondrial transporters are also important in preventing atherosclerosis, the accumulation of fatty plaques on the inner wall of arteries, which is a significant risk factor for stroke. Poor metabolism or excess intake of lipids intensifies atherosclerotic plaque buildup and heightens the chance of stroke and ischemic brain injury. The mitochondrial calcium uniporter (MCU) prevents lipid accumulation and maintains appropriate bioenergetics by facilitating oxidative phosphorylation in the mitochondria . HoweverAnother source of mitochondrial dysfunction that may exacerbate stroke pathology is the mitochondrial ADP/ATP carrier. Mitochondrial ADP/ATP carriers are located in the impermeable mitochondrial membrane and transport ADP into the mitochondrial matrix and ATP out for use as energy . InapproAstrocytes transfer their healthy mitochondria to neurons in the peri-infarct area post-stroke, and this endogenous neuroprotective mechanism is a candidate for stroke-therapy. In particular, the nuclear and desmosome-associated protein Pinin (Pnn) upregulates anti-apoptotic Bcl-2 expression, promotes ERK signaling, reduces pro-apoptotic cleaved caspase-3 production, and enhances astrocyte survival. Therefore, therapeutically augmenting Pnn expression may improve the endogenous capacity of astrocytes to protect neurons and repair ischemic tissue in the brain .Hyperbaric oxygen therapy (HBOT), which delivers pure oxygen to patients in special high-pressure rooms, modulates inflammation in traumatic brain injury (TBI) when given after the onset of tissue damage. However, pretreatment with HBOT also reduces cell death and improves post-stroke outcomes by inducing endogenous astrocyte-based mitochondrial transfer to neuronal cells. The prophylactic use of HBOT to enhance neuroprotection circumvents the need for invasive surgical treatment and potentially toxic drug-based approaches . AdditioMitochondrial repair for stroke highlights the integral role of mitochondrial function on cell survival and neurological improvement. Mitochondrial dysfunction closely accompanies post-stroke secondary cell death. The hypoxic environment reduces energy production, further exacerbating stroke symptoms. Identifying a reliable method of mitochondrial transfer represents the first step towards developing an effective stroke treatment and is crucial to restoring cell function . To thisWhile the benefits of stem cell therapy are clear, the mechanism is not. Determining the precise location of transfer between the donor and recipient cells will provide crucial insights into the mechanism and therapeutic actions of mitochondria. Such knowledge will guide efforts to optimize transfer conditions and maximize the beneficial effects of stem cells . To thisAlthough mitochondrial transfer is theoretically bidirectional, molecular signals released by damaged cells preferentially direct the movement of mitochondria and mtDNA from MSCs to damaged neurons . One sucDeleting mitochondria from stem cells abolishes the regenerative benefits they confer to damaged endothelial cells, supporting the hypothesis that these organelles are responsible for repair. Furthermore, transferring mitochondria directly into ischemic brain tissue restores cellular energetics, facilitates homeostasis of the central nervous system (CNS), and resolves the inflammation that causes secondary cell death . Stem ceMSCs are the most common stem cell source for mitochondrial transfer and provide a protective mechanism to save damaged cells from mitochondrial dysfunction in response to stress. The transfer of MSC-derived mitochondria to endothelial cells can repress apoptosis after an IR injury by restoring aerobic respiration. The results of studies investigating this transfer are encouraging, paving the way for stem cell transplantation therapy for ischemic stroke . An in vMSCs achieved efficacy of mitochondrial transplantation via intravenous transplantation into a middle cerebral artery occlusion (MCAO) mouse model. Here, retinal ischemia caused ganglion cells to deteriorate, impairing mitochondrial activity. These findings suggest that MSCs ameliorate mitochondrial dysfunction and ganglion cell death, as was observed 14 days after the stroke . In vitrThe effect of OGD on MSCs derived from the perivascular region, cord lining, and Wharton\u2019s jelly of the human umbilical cord also implicated a key role of mitochondria in these specific MSC tissue sources. The mitochondria in the perivascular region MSCs showed the greatest activity while the MSCs from the cord lining demonstrated the highest survival rate. These findings suggest that hUC-MSCs may be a good source for mitochondrial transplantation for ischemic stroke treatment . AdditioHuman induced pluripotent stem cells (iPSCs) are also the subject of recent studies of mitochondrial transfer. PD model astrocytes derived from human iPSCs spontaneously release healthy mitochondria in damaged neuron cultures. This iPSC-induced mitochondrial transfer significantly ameliorates dopaminergic neuron damage and imparts neuroprotective effects . iPSC\u2019s Spinal cord injury (SCI) models of mitochondrial transfer via bone marrow mesenchymal stem cells (BMSC) show promising results as well. Symptoms of both diseases are very similar: hypoxia, mitochondrial degeneration, oxidative stress, vascular injury, and axonal degeneration . HealthyThe omnipresent phenomenon of mitochondrial transfer allows for many applications in combination with stem cells. Contemporary literature details the efficacy of mitochondrial transfer in improving stroke, cardiovascular injury, spinal cord injury, and Parkinson\u2019s disease outcomes. The regenerative capacity demonstrated in a variety of tissues warrants its consideration as a primary therapeutic option. In particular, the physiological and pathological improvements seen in treating ischemic stroke illustrate the capability of mitochondrial transfer therapy. However, before moving into clinical trials, the optimal stem cell type must be identified to maximize the efficacy and potency of treatment. Further investigation is needed to discover the true potential of stem cell-based mitochondrial transfer therapy and improve long-term stroke outcomes."}
+{"text": "Research has shown the amount of effort we expend towards our goals depends on a sense of self-efficacy, perception of task difficulty, and likelihood of achieving our goal. All of these processes are susceptible to the influence of affect. For example, negative moods may impede goal achievement by increasing perceptions of difficulty . Negative experiences (such as past failures) can encourage these negative moods and subsequently impact self-efficacy . Findings from self-efficacy research  suggest that older adults may be particularly susceptible to the impacts of negative affect on effort mobilization, especially when tasks already seem challenging, with little chance of success. Perception of task difficulty, then, impacts the amount of effort exerted in completing the task. The present study sought to examine the factors that impact perceptions of difficulty and subsequent effort expenditure, represented by systolic blood pressure responsivity (SBP-R). Younger (N = 41) and Older (N = 163) adults completed a difficult cognitive task as part of a larger, longitudinal study, as well as measures of trait affect before study sessions. Our findings indicate younger adults exert less effort overall than older adults; however, when negative trait affect is considered, we find that higher levels of negative affect in older adults reduced task engagement. These results provide support for an effect of negative affect on task appraisals and posited age-related differences in effort mobilization."}
+{"text": "Brain pathologies are increasingly understood to confer mobility risk, but the malleability of functional brain networks may be a mechanism for mobility reserve. In particular, white matter hyperintensities (WMH) are strongly associated with mobility and alter functional network connectivity. To assess the potential role of brain networks as a mechanism of mobility reserve, 116 participants with MRI from the Brain Networks and Mobility Function (B-NET) were categorized into 4 groups based on median splits of SPPB scores and WMH burden: Expected Healthy , Expected Impaired , Unexpected Impaired  and Unexpected Unhealthy . Functional brain networks were calculated using graph theory methods and white matter hyperintensities were quantified with the Lesion Segmentation Toolbox (LST) in SPM12. Somatomotor cortex community structure (SMC-CS) was similar between UH and EH with both having higher consistency than EI and UI. However, UH displayed a unique increase in second-order connections between the motor cortex and the anterior cingulate. It is possible that this increase in connections is a signal of higher reserve or resilience in UH participants and may indicate a mechanism of compensation in regards to mobility function and advanced WMH burden. These data suggest functional brain networks may be a mechanism for mobility resilience in older adults at mobility risk due to WMH burden."}
+{"text": "The recurrence of symptoms present before cholecystectomy may be caused by a cystic duct remnant. The resolution of cystic duct remnant syndrome may require surgical resection, but identification of the duct remnant during laparoscopic surgery may be difficult because of adhesions following the previous procedure. Open surgery, which is more invasive than laparoscopic surgery, is frequently chosen to avoid bile duct injury.The patient was a 24-year-old woman with previous laparoscopic cholecystectomy for chronic cholecystitis and repeated attacks of biliary colic. The postoperative course was uneventful, but computed tomography revealed a remnant cystic duct calculus. Ten months after surgery, the patient returned to our department for right hypochondriac pain. Laparoscopic remnant cystic duct resection was performed with intraoperative near-infrared (NIR) fluorescence cholangiography to visualize the common bile duct and remnant cystic duct. The postoperative course was uneventful and the patient was discharged on day 3 after surgery. At the 6-month follow-up, she had no recurrence of pain.Laparoscopic surgery with NIR cholangiography is a safe and effective alternative for the removal of a cystic duct remnant calculus after cholecystectomy. Post-cholecystectomy syndrome (PCS) is a recurrence of upper abdominal and right hypochondriac pain, jaundice, dyspepsia, gastrointestinal disorders, and vomiting experienced before cholecystectomy . PCS mayA 24-year-old woman with chronic cholecystitis and episodes of biliary colic underwent laparoscopic cholecystectomy at our hospital. Although preoperative computed tomography (CT) revealed a cystic duct calculus, the complete removal of the calculus could not be confirmed considering bile duct injury because there were moderate chronic inflammations around the cystic duct. The postoperative course was uneventful and without pain. Ten months later, the patient visited the outpatient clinic because of hypochondriac pain. Laboratory results showed normal liver function, and inflammation and jaundice were absent. CT revealed a cystic duct remnant calculus at the same site as before Fig. . MagnetiPCS is characterized by the recurrence of symptoms experienced before cholecystectomy . In CDRSPrevious systematic reviews have described the potential advantages of fluorescence cholangiography over conventional cholangiography during laparoscopic cholecystectomy . In addiThis patient was safely and successfully treated for a cystic duct remnant calculus by relatively noninvasive laparoscopic surgery in combination with NIR fluorescence cholangiography and ICG."}
+{"text": "Viruses on \u201cPlant Virus Pathogenesis and Disease Control\u201d give new, important information addressing different aspects of this topic.Plant viruses are emerging and re-emerging to cause important diseases in many plants that humans grow for food and/or fiber, and sustainable, effective strategies for controlling many plant virus diseases remain unavailable. However, cutting-edge technological approaches in cell and molecular biology and rapidly accumulating virus sequence datasets are allowing us to gain new insights into mechanisms involved in pathogenesis and how interactions between plants and viruses affect disease development. In some cases, these offer opportunities for novel approaches to target plant viruses and help control the diseases they cause. Seven original articles in this Special Issue of Solanum lycopersicum) in several parts of the world. Klap and colleagues show further complexity associated with TBRFV-induced disease. They show that when TBRFV co-infects plants with the potexvirus, pepino mosaic virus (PepMV), more severe symptoms develop [Tomato brown rugose fruit virus (TBRFV) is a recently described and rapidly spreading tobamovirus affecting tomatoes ( develop . PepMV cGlycine max) are a globally important crop plant and soybean mosaic virus (SMV) occurs wherever soybeans are grown, in part due to its seed transmissibility. Bao and colleagues developed a GFP-recombinant SMV system to assess SMV-soybean interactions [Soybeans  technology to assess the role of microRNA nbe-miR1919c-5p in infections of N. benthamiana plants by tobacco curly shoot virus (TbCSV) and its betasatellite (TbCSB) DNA [Three groups addressed the roles of non-coding RNAs in plant virus infections ,6,7. LiuThese papers are representative of the approaches and opportunities that are available now to gain a better fundamental understanding of plant virus-induced pathogenesis. Obtaining a more fundamental understanding of plant-virus interactions is necessary if we are going to develop efficacious, environmentally sound approaches to control plant diseases caused by plant viruses. We now have fantastic new tools including NGS and bioinformatics approaches to look at virus diversity and host responses to virus infection at the transcriptome but also small and large non-coding RNA levels, not only in different plant genotypes but also in different plant tissues. However, the diversity of papers here also shows that we cannot ignore virus-host biology, and we must consider biology to help us accurately interpret and use what we are finding with modern technologies."}
+{"text": "Although the physical and cognitive benefits of moderate-vigorous intensity physical activity (MVPA) for older adults is well documented, this population often faces age-related functional and physical limitations impeding recommended MVPA participation. Recently, there has been a surge of interest in the independent health benefits of light-intensity physical activity (LPA) and its association with morbidity and mortality risk. LPA is the most common form of activity among older adults and its potential to combat cognitive aging needs to be investigated. The purpose of this scoping review was to catalog existing evidence on the association between device-based or technologically measured LPA and cognition among healthy older adults, identify trends in the literature, and pinpoint future areas of research. Six electronic databases were searched between January and August 2020. Eighteen published studies met the inclusion criteria: one acute exercise study, two randomized control trials (RCTs), twelve cross-sectional studies, and three longitudinal studies. Overall, n=9 studies  reported a significant, positive relationship between LPA and one or more cognitive outcomes including memory, attention, executive function and global cognition (MMSE/MOCA). These heterogeneous findings can largely be attributed to the diverse study designs, inconsistent definitions of LPA and numerous assessments used to test the cognitive domains. Collectively, these findings suggest LPA may be a potential lifestyle intervention to improve cognition among healthy older adults. However, the inconsistent approaches used among these studies suggests a more concerted, unified scientific approach and rigorous methodology are needed to further understand the LPA-cognition relationship."}
+{"text": "Social engagement may confer cognitive benefits in older adulthood, but studies have typically been restricted to largely non-Hispanic White (NHW) samples. Levels of social engagement vary across race such that NHW report larger social networks, more frequent participation in social activities, and greater social support than non-Hispanic Blacks (NHB). Associations between social engagement and cognition may also vary by race, but research is sparse. The current cross-sectional study examined associations between different aspects of social engagement and episodic memory performance, as well as interactions between social engagement and race among NHB and NHW participants in the Michigan Cognitive Aging Project . Social engagement  was self-reported. Episodic memory was a z-score composite of immediate, delayed, and recognition trials of a list-learning task. Separate hierarchical linear regression models quantified interactions between race and each of the three social engagement variables on episodic memory, controlling for sociodemographics, depressive symptoms, and health conditions. Results showed a main effect of more frequent social activity on better episodic memory, as well as an interaction between race and social support indicating a significant positive association in NHB but not NHW. These preliminary findings suggest that participating in social activities may be equally beneficial for episodic memory across NHB and NHW older adults and that social support may be particularly beneficial for NHB. Future research is needed to determine the potential applications of these results in reducing cognitive inequalities through the development of culturally-relevant interventions."}
+{"text": "Choir interventions confer psychological benefits for persons with dementia (PwD) and their caregivers. However, less is known about whether physiological function also exhibits improvements pursuant to such social-cognitive interventions. The present study, based upon a subsample of the Voices in Motion (ViM) project, explored whether participation in an intergenerational choir results in systematic improvements in gait velocity  for both informal caregivers  and PwD . Longitudinal burst data from the first of three cohorts spanning 4 assessments over 3.5 months was analysed using multilevel modeling. Whereas caregivers exhibited significant improvements (p<.05) in gait velocity, PwD showed no improvement. Ongoing analyses are exploring additional cohorts, and whether improvements in gait dynamically covary with reductions in comorbidities . These results underscore the potential of choir for facilitating both psychosocial and physiological function for caregivers and PwD."}
+{"text": "An integrated approach for assessing ventricular pump function, diastolic compliance (EDPVR), myocontractility and pulmonary vascular resistance would be of clinical interest. In addition to pump function, MRI guided catheterization was demonstrated to accurately measure myocontractility and vascular resistance. We now extended this method for acquisition of the EDPVR. Subsequently, this approach was applied in patients with Fontan hemodynamic in which abnormalities in pulmonary vascular, myocontractile and diastolic properties are debated.The EDPVR was determined by synchronizing invasive ventricular pressures with cine and real-time MRI derived ventricular volumes and pulmonary/aortic blood flow measurements.In 7 pigs the MRI and conductance-catheter method (gold standard) were compared for measuring the EDPVR at rest and during dobutamine.Parameters of global function, myocontractility (ESPVR), vascular resistance and EDPVR were measured with MRI at rest and under dobutamine in 14 patients with Fontan circulation.Bland-Altman test showed agreement between the conductance-catheter and MRI method. In the pigs, there was in both ventricles during dobutamine a right/bottom shift of the EDPVR, the stiffness co efficient decreased slightly (p < 0.051). In the patients during dobutamine we noted failure to increase stroke volumes despite increased contractility and evidenced diastolic dysfunction. Active relaxation was inconspicuous but the EDPVR shifted towards the left/top, the stiffness constant remained unchanged. Pulmonary resistance decreased slightly (p = 0.058) and thus showed adequate response to augmented cardiac outputs.This novel MRI method provides differential information about diastolic, systolic and vascular function. The method evidenced that in Fontan patients diastolic dysfunction is an important pathophysiologic cause of heart failure."}
+{"text": "Chronic stress creates vulnerability to adverse mental and physical health outcomes in later life. While claims about the negative effects of stress on health are primarily based on self-report, it is unclear how subjective stress measures (chronic or perceived stress) and other environmental or individual characteristics  relate to physiological stress response. This study examines which contextual features contribute to differences in physiological stress reactivity among adults at risk of type II diabetes . Psycho-social stress was induced via Trier Social Stress Test. Using advanced selection methods, we simultaneously explore multiple predictors and illustrate how different sets of risk and protective factors contribute to normal or abnormal stress reactivity profiles. Preliminary results suggest that the top five important predictors are education, contact with friends, perceived stress, ruminative coping, and sedentary behavior. Implications for research and targeted interventions are discussed."}
+{"text": "Our purpose was to document the swept source optical coherence tomography (SSOCT) findings in a patient with Shaken baby syndrome (SBS).SSOCT was obtained without sedation in a six-month-old girl with bilateral multilayered retinal hemorrhages due to SBS. It documented vitreoretinal interface abnormalities, including internal limiting membrane (ILM) detachment with retinal traction, in association with other specific changes in the inner and outer retinal layers. Six weeks later, retinal hemorrhages had substantially resolved, and there was optic disc pallor. OCT showed ILM reattachment with release of retinal traction and the development of severe diffuse retinal atrophy involving the fovea.SS OCT can provide useful information in SBS, revealing a wide variety of vitreoretinal interface, inner, and outer retinal changes not detected by clinical examination. It also may have a prognostic value over follow-up. Shaken baby syndrome (SBS), also known as abusive head trauma, refers to a constellation of clinical findings including bilateral retinal hemorrhages, subdural hemorrhage, and anoxic encephalopathy . RetinalA previously healthy six-month-old girl was brought to the emergency department for paroxysmal crying with brief episodes of loss of consciousness. On physical examination there was a bulging fontanel with associated weak axial posture. A cerebral computed tomography (CT)-scan demonstrated extensive bilateral subdural hemorrhages. The child was admitted to the Pediatric Intensive Care Unit. Ophthalmological examination revealed a poor pupillary response to bright light in both eyes. There were no external signs related to ocular trauma. Fundus examination by indirect ophthalmoscopy revealed bilateral preretinal and intraretinal hemorrhages involving the posterior pole and midperiphery. There was a bilateral boat-shaped premacular hemorrhage. This hemorrhage was larger and associated with a prominent surrounding ring-shaped white retinal fold in the right eye Fig.\u00a0. A diagnThree days after hospitalization, the patient underwent swept source OCT imaging with the DRI OCT Triton plus . Multiple SS-OCT scans could be obtained without sedation, the infant being held and her eyelids kept open by an assistant. OCT confirmed multilayered retinal hemorrhages in both eyes. It showed a dome-shaped detachment of the internal limiting membrane (ILM) overlying the macular hematoma bilaterally, with associated perifoveal retinal traction corresponding to the retinal fold seen clinically in the right eye Fig. . Other SSequential follow-up examinations showed gradual resolution of the neurological symptoms and improvement of pupillary response to light. Six weeks after initial examination, retinal and preretinal hemorrhages had substantially resolved, and there were bilateral areas of subretinal fibrosis and optic disc pallor, mainly in the right eye Fig.\u00a0.Fig. 2aSS OCT, six weeks after initial presentation, showed complete reattachment of the detached ILM, with release of retinal traction and resolution of other acute findings. There was a bilateral marked diffuse retinal atrophy involving the fovea with associated subretinal hyperreflective lesions corresponding to the areas of subretinal fibrosis seen clinically Fig. .To the best of our knowledge, this report is the first to describe the use of SS OCT in the assessment and monitoring of retinal disease associated with SBS. Thanks to the faster acquisition times of SSOCT technology, OCT scans could be obtained without sedation, although an assistant was required to hold the infant\u2019s head. Until recently, time domain and conventional or hand-held spectral domain (SD)-OCT have been rarely used in very young children with acute SBS \u20135. OCT iAnother dimension of ocular changes in SBS was described in the field of forensic pathology. OCT findings may provide valuable information suggestive of child abuse in the absence of external evidence of trauma .Our study expands the OCT spectrum of SBS to include a wide variety of previously undescribed vitreous and retinal changes, including alterations of the outer retinal layers. On follow-up OCT examination, severe retinal atrophic changes became evident after resolution of hemorrhages and other acute findings. Our data show that macular atrophy may be an important causative mechanism of severe vision loss in children with SBS.In conclusion, thanks to its faster acquisition time and deeper penetration, SSOCT may be useful in the evaluation and monitoring of ocular disease in awake young children with SBS. It can provide useful information, revealing a wide variety of vitreoretinal interface, inner, and outer retinal changes not detected by clinical examination. It also may have a prognostic value over follow-up."}
+{"text": "The geometric framework for nutrition has largely been applied to macronutrients in experimental settings. Here, we utilize the framework to examine both macro and micronutrient intake patterns in observational human data. We used nutritional intake patterns  of 1754 older Quebecers from the NuAge cohort to predict multi-system homeostatic dysregulation scores calculated from 30 biomarkers. Intermediate intake of both macro- and micronutrients was generally associated with lower dysregulation scores . Furthermore, there were often nutrient-nutrient interactions, such that the optimal level of one nutrient depends on the intake level of others. However, higher protein intake was generally associated with better health, and results varied substantially across different dysregulation systems. Accordingly, even though nutrition does have important effects on health trajectories during aging, it will be challenging to arrive at population-level recommendations to fine-tune nutrient intake patterns to optimize health beyond \u201ceverything in moderation.\u201d Part of a symposium sponsored by the Nutrition Interest Group."}
+{"text": "The current study takes a dyadic perspective to understand how self-perceptions of aging are associated with C-reactive protein, an inflammation marker, among older adult married couples. The potential moderating role of marital support and strain are also examined. Respondents include 668 married couples who participated in the 2014 wave of the Health and Retirement Study. Actor-Partner Interdependence Models were conducted in Mplus. Age, functional limitations, income, and race served as covariates. Husbands\u2019 greater positive perceptions of aging were significantly associated with their own lower levels of inflammation. Husbands\u2019 greater positive perceptions of aging were significantly associated with lower levels of inflammation for women who reported lower levels of marital strain; this was not the case for women who reported higher levels of marital negativity. This study exemplifies how relationship factors are necessary to consider when examining age perceptions and health among marrieds."}
+{"text": "The knowledge regarding hypothalamic integration of metabolic and endocrine signaling resulting in regulation of food intake is scarce in fish. Available studies pointed to a network in which the activation of the nutrient-sensing  systems would result in AMP-activated protein kinase (AMPK) inhibition and activation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). Changes in these signaling pathways would control phosphorylation of transcription factors cAMP response-element binding protein (CREB), forkhead box01 (FoxO1), and brain homeobox transcription factor (BSX) leading to food intake inhibition through changes in the expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), pro-opio melanocortin (POMC), and cocaine and amphetamine-related transcript (CART). The present mini-review summarizes information on the topic and identifies gaps for future research. Two neuronal populations in the mammalian hypothalamic arcuate nucleus respond to a rise in the levels of circulating metabolites  . They renucleus lateralis tuberis (NLTv), an analog of arcuate nucleus , specific fatty acid receptors (FFAR), fatty acid translocase, and lipoprotein lipase. Evidence is also available in other species like grass carp  induced a rise in hypothalamic Bsx mRNA abundance (In fish, evidence regarding BSX role in hypothalamus is limited  with a f nucleus  as well  nucleus  in paralbundance .Npy and Agrp leading to a decrease in food intake (Npy and Agrp (cAMP response-element binding protein is another transcription factor hypothesized to be involved in the connection between brain metabolism and neuropeptides expression. Accordingly, in mammals, a decrease in CREB levels induced a decrease in mRNA abundance of d intake . CREB prand Agrp  while leand Agrp  or food and Agrp .In fish, available information regarding CREB involvement in food intake regulation is restricted to rainbow trout. In this species, CREB phosphorylation status decreased in response to raised levels of oleate , octanoaAgrp mRNA values while those of Pomc decreased, changes favoring a decrease in food intake (Forkhead box01 is likely involved in the relationship between metabolic changes in hypothalamus and the production of neuropeptides . Thus, id intake .Foxo1 to changes in nutrient levels. However, changes observed in fish would be comparable with those observed in mammalian hypothalamus under anorectic conditions like feeding a high-fat diet (In fish, FoxO1 was characterized in brain in rainbow trout  and turbfat diet  or treatfat diet . Akt actfat diet , which afat diet . In fishfat diet , octanoafat diet , or insufat diet  but not fat diet . These rAgRP/NPY and CART/POMC neurons involved in the integration of signals from nutrient sensors also have receptors for hormones like leptin, ghrelin, insulin, CCK, or GLP-1, among others . The binbsx and mtor mRNA abundance as well as in the presence of oleate for Akt phosphorylation status, and foxo1 and creb1 mRNA abundance. No other studies characterized in fish putative interactions in hypothalamus. However, in rainbow trout treatment with different hormones alter nutrient sensing mechanisms in hypothalamus (In fish, only two studies carried out in rainbow trout demonstrated interactive effects in hypothalamus between nutrient-sensing mechanisms and hormones such as ghrelin and insulin. The presence of oleate counteracted ghrelin effects on AMPK . In the thalamus  as demonThe knowledge available in fish about hypothalamic integration of information of metabolic and endocrine nature eliciting changes in expression of neuropeptides ultimately regulating food intake is limited . StudiesThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Introduction. We present a case of serpiginous choroidopathy (SC) with novel OCTA and en face OCT reflectance findings which help identify subclinical disease progression. Case Presentation. En face OCT reflectance images demonstrated outer retinal tubules (ORT) at the serpiginous lesion margins of affected and unaffected retina on multimodal imaging. OCTA findings demonstrate variable dropout of choriocapillaris in \u201cnormal\u201d retina beyond lesion borders which was not visible on standard imaging and which demonstrated a clear transition zone beyond the ORT. Discussion. This is the first report of choriocapillaris atrophy identified on OCTA not identified on traditional multimodal imaging in serpiginous choroidopathy. Damage to vasculature only visible with OCTA may help characterize the distribution of inflammation, aiding in monitoring of suppression not illustrated by traditional imaging and which may threaten the central macula. ORT in SC suggest death and reorganization of outer segments from dysfunction of the choriocapillaris and RPE, as well as serve to demarcate the area of chronic or old inflammation, supporting the hypothesis that the choriocapillaris is the primary site of inflammation in SC. Based on these findings, we recommend OCTA on all patients with serpiginous choroidopathy to monitor underlying state of inflammation and help determine immunosuppressive threshold. The pathogenesis of SC is poorly understood, with clinical and histologic studies suggesting autoimmune, infectious, vasculopathic, and retinal degenerative etiologies , 2. ReceA 37-year-old female with no past medical or ocular history presented with 2 weeks of redness, pain, and photophobia of her right eye (OD). She was diagnosed with acute anterior uveitis by an outside provider and started on topical difluprednate four times daily (QID) and cyclopentolate once daily (QD) OD. Upon presentation to our facility, she reported slight improvement in her symptoms 2 weeks into treatment.On initial examination, visual acuity was 20/20 in her right and 20/20 in her left eye (OS) with unremarkable pupillary exam and normal intraocular pressure. Anterior segment examination of the right eye (OD) revealed 2 areas of anterior corneal stromal scarring and 0.5+ anterior chamber cell without flare. One area of anterior stromal scarring and trace cell without flare was seen OS. Fundoscopy revealed 0.5+ vitreous cell without haze in both eyes (OU); healthy appearing optic nerves OU; and extensive, serpentine peripapillary chorioretinal scarring OU with extension into the macula Figures . There wThe patient rapidly improved, and immunomodulatory therapy was initiated with a standard steroid taper. At one-month follow-up, en face OCT reflectance and OCTA imaging were obtained, which demonstrated severe atrophy with outer retinal tubules and patchy dropout of choriocapillaris in areas of otherwise normal-appearing retina, respectively . Over thWe present a case of serpiginous choroidopathy (SC) imaged with OCTA and en face OCT reflectance imaging. Images were obtained and processed based upon previously described methodologies in the literature , 4.OCTA imaging showed dropout of the choriocapillaris at lesion margins and discontinuously in adjacent areas centrally which appeared normal on traditional imaging such as FA . Prior tOCT angiography allows a noninvasive assessment of choroidal and deep vasculature sometimes not evident on fluorescein angiography (FA). Recently, several small case series of OCTA in SC have suggested extensive inflammation in deep retinal vessels, RPE, and choriocapillaris. Desai et al. reported a series of 6 eyes of 3 patients with active and inactive SC. In this series, active patients demonstrated absence of choriocapillaris with thickening of overlying RPE and outer retinal layers on OCTA in areas of atrophic serpiginous lesions . InactivWe analyzed en face OCT reflectance image slabs, as well as cross-sectional OCT images. En face OCT reflectance imaging demonstrated outer retinal tubules at the quiescent serpiginous margins just adjacent to those areas of atrophic choriocapillaris on OCT which were normal-appearing on funduscopy and FA . Cross-sOn SD-OCT imaging, outer retinal tubules appear as circular areas of hyporeflectivity with a ring of hyperreflectivity contained within the outer nuclear layer. Prior investigations of outer retinal tubules have centered around age-related macular degeneration (AMD) and spectral domain OCT (SD-OCT) but never reported in SC. Of the 69 eyes with outer retinal tubules identified in one study, 81% were attributable to AMD , 11. GivSevere choriocapillaris inflammation may be the cause of outer retinal atrophy in serpiginous choroidopathy, with the presence of ORT signifying reorganization of photoreceptors localizing inflammation to this area. Current multimodal imaging without use of OCTA is widely accepted for the diagnosis and monitoring of SC. In this report, we describe a patient with OCTA findings of choriocapillaris atrophy demonstrating subclinical disease beyond serpiginous lesion borders visible on standard imaging. Loss of choriocapillaris integrity in areas outside of the serpiginous borders suggests subclinical activity which, if followed with OCTA, may aid in earlier identification of progression or more targeted timing for tapering of immunomodulatory therapy if stable. This suggests that OCTA may be more sensitive than SD-OCT and FA in identifying activity in SC and should be more widely adopted in the long-term management of these patients."}
+{"text": "Understanding age-related change in cognition and identification of pathological changes requires sensitive and valid measurement of cognitive performance across time. Technological advances, such as ambulatory assessment of cognition using smartphones, have enabled intensive longitudinal methods where data is collected with many measurements over time. Our research group has developed novel ambulatory assessments that provide reliable, sensitive, and ecologically valid measurement of cognition across multiple timescales; from momentary changes to change across years. This symposium will present a spectrum of approaches to analysis of intensive longitudinal data that can inform models of cognitive aging. All three presentations will draw on data from measurement burst studies that apply our ambulatory cognitive assessment methods in community-based samples . For each measurement burst, participants undergo assessment consisting of brief surveys and cognitive tests via smartphone, up to 7 times per day across 14 days. Oravecz et al. will discuss the application of a Bayesian multilevel implementation of the double exponential model to account for retest effects while quantifying change in peak cognitive performance across time. Kang et al., will demonstrate a growth curve modeling approach for assessing the effects of between-person variables  on change in cognition across measurement bursts. Harrington et al., will demonstrate a model-based cluster analysis approach, leveraging ambulatory assessments of subjective and objective cognitive function to unpack latent groups as a function of age and loneliness. Measurement, Statistics, and Research Design Interest Group Sponsored Symposium."}
+{"text": "Evidence suggests a growing retirement crisis in the United States among older adults placing many of them at risk of falling into poverty. While Social Security provides income assistance to retirees, the average monthly benefit is $1,300. Among older adults nearing or in retirement, the use of public assistance programs is increasing. Using data collected by the Associated Press-NORC Center for Public Affairs Research we examine retirement preparedness, borrowing from retirement plans, and use of social welfare programs. Findings indicate increased borrowing from retirement plans due to debt, significant differences in racial and gender groups accessing and receiving services among those 75 and older. Increasing rates of unpreparedness for retirement exist among older Americans, particularly among adults of color. An increase in the use of safety net services among older adults is occurring concurrently with severe funding reductions in social welfare programming."}
+{"text": "Migraine is a multifaceted brain disorder where multisensory disturbances are associated with headache. Yet sensory symptoms are conventionally justified by dysfunctions confined to the cerebral cortex, a perspective through the complex interplay of thalamocortical network would provide the entire picture, more pertinent to the central sensory processing. It is important to consider thalamus as a hub that integrates multiple domains via extensive connections among anatomically and functionally separate cortical areas. Accordingly, cortical spreading depression (CSD), implicated in migraine pathophysiology can be seen as a tool to disconnect thalamocortical network by functionally eliminating cerebral cortex. Hence, including thalamic reticular nucleus and higher order thalamic nuclei, which conveys the information transthalamically among visual, somatosensory, language and motor cortical areas, would greatly improve our current understanding of migraine. Migraine is the most prevalent brain disorder under age of 50 all around the globe and the first cause of disability due to severe headache and associated sensory disorders [1]. The characteristic features of pain are one sided, severe, pulsating headache attacks, worsening by daily movements and lasting 4\u201372 h. Accompanying sensorial symptoms suggesting hyperresponsivity in the somatosensory, visual, auditory, and olfactory systems are distinguishing features of migraine attacks and multisensory stimuli may worsen the headache severity [2]. Additionally, prior to the headache phase more pronounced sensorial disruptions can occur in the visual and somatosensory system such as scintillations, scotoma or paresthesia, numbness in the extremities. These slowly propagating sensory deficits are recognized as aura symptoms and implicated by underlying cortical spreading depression (CSD) waves [3]. CSD is a neuronal and glial depolarization wave that slowly propagates within the cerebral cortex, causing transient electrical and functional silence of the involved area. Propagation of massive depolarizations and accompanying electrical DC shift and regional blood flow increase along the cortex, left long-lasting decreased neuronal excitability and reduced regional blood flow behind . The sensory aura symptoms are considered solely due to cerebral cortical dysfunction by CSD. However, this conventional approach disregards several facts that i) propagation of CSD in gyrencephalic brains such as humans, primates and even felines is very restricted [4], ii) cerebral cortex functions in a synchrony with thalamus and brain network systems. In that sense CSD was essentially used to generate functional ablation of cerebral cortex in thalamic studies [4]. Understanding the function of cerebral cortex requires knowledge of complex interaction between the cortex and the thalamus, known as thalamocortical network. The cerebral cortex and the thalamus operate in continuous interaction during the process of any information particularly related to somatosensory, visual and auditory sensory systems, movement, language, cognition and consciousness . The thalamus sends projections to majority of the cerebral cortex, and receives cortical outputs in return. Thalamic nuclei transmitting peripheral sensory inputs to the primary cerebral cortical areas are considered as the first-order relay nuclei such as the ventral posteromedial (VPM) and lateral geniculate nucleus (LGN) that relay cephalic somatosensory inputs and visual stimuli respectively. Likewise, the higher-order thalamic nuclei receive inputs from the deep cerebral cortical layers and relay information from one cortical area to another . By this means, higher-order thalamic nuclei function as hubs that synchronize distant cerebral cortical areas via transthalamic cortico-cortical connections [7]. The deep cortical cells particularly from the 6th layer, also project to inhibitory neurons in the thalamic reticular nucleus (TRN) and modulate the frequency-dependent thalamic function [6\u20138]. The TRN consists of GABAergic inhibitory neurons and surrounds the dorsal thalamus. While the TRN exclusively projects to the thalamus and inhibits thalamic drive to the cortex, its neurons are driven by the first- and higher-order thalamic nuclei as well as the cerebral cortex . TRN involvement during CSD was demonstrated in awake, consciously behaving experimental animals . CSD induced SD waves were recorded in TRN and neuronal activation was demonstrated. It is likely that either SD in the cerebral cortex could provoke SD in TRN or SD waves propagate from cerebral cortex to the TRN, as subcortical structures are more susceptible compared to highly convoluted cerebral cortex in humans [4]. Involvement of the TRN may play a role in reduced sensory discrimination, lateral inhibition and increased response to sensory stimuli in different modalities such as light, sound and touch during migraine attacks. A subset of cortical deep projection neurons was shown to project selectively to higher order thalamic nuclei in mice and recently the higher order thalamic dysfunction was proposed to be involved in the development of migraine symptoms . Instead of attributing sensory dysfunctions merely to the cerebral cortex, alternative view proposes a complex interaction of first- and higher-order thalamocortical areas along with TRN . A minimum critical volume of 1 mm3 rodent cortical brain tissue was estimated to be depolarized to ignite CSD [11]. Even if the propagation of CSD is blocked, such a depolarized cortical focus is sufficient to create a change in ongoing cortico-thalamic drive on thalamic relay nuclei and thalamic reticular nucleus. During CSD, abrupt cessation of cortical neuronal firing, would result in decreased excitatory glutamatergic drive from cortexto the thalamus, leading to a reduced GABAergic output from TRN on to thalamic relay nuclei and increased sensory impulses through thalamic relay to the cortex . That would account for the increased sensory excitation, sensory hyperresponsivity, reduced discrimination and reduced lateral inhibition and bidirectional role of sleep in migraine. Therefore, the processing of somatosensory stimulus and sensory discrimination was investigated in migraine patients [12\u201316]. For that purpose, somatosensory temporal discrimination (STD) test was employed. STD detects the temporal threshold to perceive two consecutive somesthetic stimuli as undoubtedly distinct [12\u201314]. STD was remarkably prolonged during the migraine attack while STD threshold values outside the migraine attacks were comparable to healthy volunteers [12]. STD studies also revealed that such a prolongation was specific to migraine attacks and was not detected during tension type headache, which is another common headache disorder [14]. It is an intriguing finding that discrimination of somatosensory stimuli applied to the hand that is transmitted through a pathway via thalamic ventral posterolateral nucleus (VPL), is disturbed during migraine attacks. Indeed, migraine headache is transmitted through a different pathway via trigeminal nerve to the thalamic ventral posteromedial nucleus (VPM). Hence, it is unlikely that prolonged temporal discrimination of somatosensory stimulus applied to hand is merely mediated as a direct result of trigeminal nerve or thalamic VPM activation. Transient impairment in the ability of discriminating the exact entry of somatosensory stimuli suggested a central processing dysfunction. Further study was conducted by short afferent inhibition (SAI) paradigm using transcranial magnetic stimulation [16]. SAI evaluates integration of somatosensory input through the thalamic relay neurons in the sensorimotor cortex. The SAI results revealed that impaired sensorimotor integrity and reduced cortico-cortical inhibition between somatosensory and motor cortices were associated with migraine attacks [16]. SAI impairment during migraine attacks, indicated a disinhibition in the sensorimotor integration. Remarkably, the facilitation of motor responses to a conditioned sensory stimulus was detected even several hours prior to the onset of migraine headache [16]. Therefore, the possible involvement of higher order centers seems undisputable. In the higher order thalamic nuclei such as pulvinar, that would be manifested by the disrupted visual information processing and may be related to positive visual hallucinations superimposed on to a first-order incoming information, similar to the patients\u2019 visual auras [4]. Also, higher order visual areas and somatosensory areas are associated with medial and anterior part of the pulvinar that is a multimodal sensory integration area [17]. Therefore, loss of any incoming information by CSD from one of the interconnected cortical areas such sensorimotor cortex or visual cortex to the pulvinar would change impulse trafficking and may yield multisensory sensory symptoms synchronously and/or sequentially.Thus, the view of thalamocortical network dysfunction would clarify positive aura symptoms and simultaneous manifestation of different symptoms related to distant cortical areas such as visual, sensorimotor and language cortices interconnected through a thalamic hub. Additionally, sensorial disruptions in more than one domain accompanying migraine headache can be attributed to multisensory integration dysfunction of the higher order thalamocortical network. Involvement of TRN would contribute sensory hypersensitivity in multiple sensory modalities, lateral inhibition and sensory discrimination problems associated with migraine headache. Additionally, activation of trigeminal pain nucleus through central pathways as a result of thalamocortical dysfunction could also contribute to the development of lateralized migraine headache."}
+{"text": "The proportion of women of reproductive age who are overweight or obese is increasing globally. Gestational obesity is strongly associated in both human studies and animal models with early-onset development of adult-associated metabolic diseases including metabolic syndrome in the exposed offspring. However, animal model studies have suggested that gestational diet in obese pregnancies is an independent but underappreciated mediator of offspring risk for later life metabolic disease, and human diet consumption data have highlighted that many women do not follow nutritional guidelines prior to and during pregnancy. Thus, this review will highlight how maternal diet independent from maternal body composition impacts the risk for later-life metabolic disease in obesity-exposed offspring. A poor maternal diet, in combination with the obese metabolic state, are understood to facilitate pathological in utero programming, specifically through changes in lipid handling processes in the villous trophoblast layer of the placenta that promote an environment associated with the development of metabolic disease in the offspring. This review will additionally highlight how maternal obesity modulates villous trophoblast lipid processing functions including fatty acid transport, esterification and beta-oxidation. Further, this review will discuss how altering maternal gestational diet may ameliorate these functional changes in lipid metabolic processes in the obese placenta.  Throughout the gestational period, maternal nutrient handling must adapt to the increasing needs of the growing fetal-placental unit to ensure developmental processes continue in a healthy and physiological manner. For example, maternal insulin sensitivity diminishes, and fasting serum lipid levels rise late in gestation to preserve necessary macronutrients for trans-placental transport into fetal circulation ,2,3. HowFurthermore, alterations in lipid processing functions of the placenta\u2014including fatty acid (FA) transport, lipid esterification and FA beta-oxidation\u2014have been thought to modulate materno-fetal lipid transport and the resulting changes to fetal lipid exposures may underlie metabolic disease programming. This review will additionally highlight how maternal obesity modulates these lipid handling processes in the placenta and discuss how maternal diet may program these placental processes independently from increased maternal adiposity.The study of the impacts of maternal gestational environment on fetal growth and development is encompassed within the field of research known as The Developmental Origins of Health and Disease (DOHaD) ,5. This 2), whereby a BMI > 25 is overweight and a BMI > 30 is obese palmitate oxidation rates in cultured villous trophoblast cells from otherwise healthy obese Ohioan women [Maternal diet has been identified to impact placental lipid oxidative function in some obese women. Specifically, obese Hawaiian women, who consume the Pacific diet, have been found to have similar mRNA expression levels of mitochondrial and peroxisomal beta-oxidation enzymes as lean Hawaiian women  Figure . This maan women . While POne potential method to quantify placental beta-oxidative function is to examine the acylcarnitine profiles of maternal blood products. Under normal physiological conditions, complete beta-oxidation occurs whereby all carbon atoms in the FA backbone are converted into acetyl-CoA molecules that are oxidized for ATP production ,96. HoweAcylcarnitine profiles have previously been examined as potential biomarkers for the early detection of other placental diseases such as pre-eclampsia ,111. SpeAccumulation of shortened acylcarnitine species has also previously been linked to an increased expression of pro-inflammatory molecules . For exaOverall, acylcarnitine analysis may represent a relatively unexplored field in placenta physiology. Analysis of differences within these profiles of obese and lean women may allow clinicians to diagnose placental mitochondrial dysfunctions in conjunction with inflammatory responses early during the gestation period. In turn, acylcarnitine biomarkers may allow clinicians to monitor the impact of dietary interventions on placental lipid handling during gestational period and modulate the course of treatment to limit the risks of offspring development of later life disease.A maternal consumption of a diet high in saturated FA species and low in PUFA species during the gestational period may promote adverse placental function that underlies the development of placental and fetal metabolic dysfunction, independent to maternal body composition. Understanding the mechanisms that underlie placental metabolic dysfunctions associated with dietary fat in obese pregnancies and the accompanying offspring metabolic disorders will require a robust understanding of placental lipid transport, esterification and oxidation . A great"}
+{"text": "Human brain organoids cultured from human pluripotent stem cells provide a promising platform to recapitulate histological features of the human brain and model neural disorders. However, unlike animal models, brain organoids lack a reproducible topographic organization, which limits their application in modeling intricate biology, such as the interaction between different brain regions. To overcome these drawbacks, brain organoids have been pre-patterned into specific brain regions and fused to form an assembloid that represents reproducible models recapitulating more complex biological processes of human brain development and neurological diseases. This approach has been applied to model interneuron migration, neuronal projections, tumor invasion, oligodendrogenesis, forebrain axis establishment, and brain vascularization. In this review article, we will summarize the usage of this technology to understand the fundamental biology underpinning human brain development and disorders. The human central nervous system (CNS) develops from several distinct vesicles into multiple intertwined regions. During this process, a range of migratory streams arise where progenitors generated in one place migrate and integrate into other areas : the medial ganglionic eminence (MGE) and the caudal ganglionic eminence /CGE cells were observed to migrate into dorsal regions. Slice culture of dorso-ventral fusion organoids and time-lapse imaging analysis revealed characteristic interneuron migratory dynamics. Administration of the CXCR4 antagonist AMD3100 onto organoid slice cultures perturbed the migration, supporting a potential application of the fusion platform for drug screening.Bagley et al.  also estNKX2-1::GFP reporter human embryonic stem cell (hESC) line. RNA-seq, scRNA-seq, and chromatin accessibility analysis revealed that hMGEOs exhibited a strong correlation with the transcriptional signature of the MGE tissues from of human fetal brain. By fusing human cortical organoids (hCOs) and hMGEOs, they established hMGEOs-hCOs fusion organoids, named hfMCOs. GFP+ but RFP\u2212 interneuron progenitors migrated into the neuronal layer of hCOs. Their migration can be inhibited by the application of blebbistatin, a myosin II inhibitor. Besides, functional synapses in hfMCOs were also observed by calcium imaging analysis.Further, Xiang et al.  generateFurthermore, using a dorsoventral organoid fusion model, Yuan et al.  showed tLong distance-projections play essential roles in brain functions. According to recent reports, corticothalamic interactions are relevant for sensorimotor interplay, selective attention, and arousal behaviors  is the deadliest and most widespread primary brain tumor in adults. Their property to spread through infiltration in the host brain tissue is associated with high resistance and recurrence rate. To understand the mechanism underpinning this invasive phenotype, organoid-GBM fusion models are particularly appropriate. Ogawa et al.  fused tuv\u03b25 axis as a potential mechanism for ZIKV tropism. Thus, organoid-GSC fusion models could be used as in vitro platforms to characterize GBM invasiveness and screen for potential therapeutics.Tumor-organoid fusion models have been used for preclinical therapeutic studies. Previously, the Zika virus (ZIKV) has been proven to be a potential oncolytic virus for brain tumor therapy because of its tropism towards tumor cells  are the myelinating glial cells of the brain and the last type of neural cells to be generated after neurons and astroglial cells during mammalian brain development  spheroids, endothelial cell (iEC) spheroids, and mesenchymal stem cells (MSCs; Song et al., in vivo vascularization during brain development, and significant improvements still need to be done before obtaining functional vascular networks in organoid cultures.During brain development, the vasculature is one of the important niche components for neural stem cells and plays critical roles in neurogenesis (Bjornsson et al., in vitro. The fusion strategy should not be limited to the fusion of brain tissues as it can be applied to assemble brain organoids with other types of organoids to study the interaction between different organs. For instance, hepato-biliary-pancreatic organogenesis has been modeled using a multi-organoid fusion approach (Koike et al., Brain organoid fusion technology allows us to study more complicated biology during human brain development and neural disorders using hESCs or patient-derived iPSCs, including interneuron migration, and neuronal projections. Using the same technique, researchers can also study other pathological processes and potential mechanisms, such as corpus callosum deformity. Assembling multiple different brain regions would be the next step towards a more complete human \u201cmini-brain,\u201d which could then be used to study biological mechanisms requiring the interaction of several brain regions AC, ZG, and LF wrote the manuscript. AC and ZG prepared the figures. SB directed the manuscript preparation and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We discuss synergies between sequencing and imaging techniques for the discovery and validation of local molecular signaling mechanisms regulating synaptic development, plasticity, and maintenance in circuits.A key challenge in developmental neuroscience is identifying the local regulatory mechanisms that control neurite and synaptic refinement over large brain volumes. Innovative molecular techniques and high-resolution imaging tools are beginning to reshape our view of how local protein translation in subcellular compartments drives axonal, dendritic, and synaptic development and plasticity. Here we review recent progress in three areas of neurite and synaptic study  In neuroscience, physical maps of synaptic connections between neurons (\u201cconnectomes\u201d) help to refine hypotheses about neural computation and provide a shared anatomical resource to guide investigations of circuit function and pathologies associated with human brain disease. Physical maps of developing circuits can also help to identify progressive structural changes across stages of neuronal and synaptic maturation. Connectomic maps are produced using volumetric electron microscopy (EM) techniques that provide dense reconstructions of all cellular processes and synaptic connections in brain tissue. Continued progress in automated sample collection, high-throughput imaging, and computational analysis  molecular-genetic approaches for quantifying mRNA diversity, abundance, and regulation of the local transcriptome/translatome in targeted subcellular compartments; (2) proteomic techniques for labeling, isolating, and quantifying nascent proteins and protein-protein interaction networks in specific synaptic connections; and (3) super-resolution fluorescence microscopy for multi-scale imaging and quantitative analysis of subsynaptic molecular organization within developing microcircuits. When applied together, advanced techniques in these areas have important synergies that facilitate discovery, validation, and throughput in new experiments designed to study the local molecular regulation of neural circuit development.In this review article, we discuss a bottom-up \u201cdevelopmental molecular connectomics\u201d approach for investigating the regulation of local molecular remodeling during circuit refinement . We highNeural circuit development requires the precise formation and selective plasticity of synaptic connections distributed across each neuron\u2019s polarized geometry (axons/dendrites) at significant distances from the soma. Because each synapse is an intricate molecular machine assembled from thousands of proteins, the development of circuit connections creates a significant metabolic demand for individual neurons  and perform RNA sequencing analysis of compartment-specific isolates for comparison . Such exTo address questions about directed trafficking and mRNA enrichment in specific spatiotemporal contexts, an immunopurification approach called Translating Ribosome Affinity Purification (TRAP) was developed for isolating genetically-tagged ribosomes and their associated mRNAs in targeted circuits  uses the transgenic expression of synapse-specific fluorescent fusion proteins to purify specific synapse types from total synaptosomal fractions based on fluorescence-activated cell sorting  granules over long distances to dendrites and axons to establish local transcriptome pools  axons is developmentally-regulated and shifts during different stages of circuit refinement  where mRNAs encoding essential respiratory chain complex proteins are locally translated and assembled into mitochondria in response to stimulation . The induction of hippocampal LTP/LTD Direct evidence for local (synaptic) protein production in response to synaptic stimulation comes from glutamate photouncaging experiments which drive spine growth and local protein synthesis in single activated spines  to isolate proteins for quantitative analysis , genetically-encoded proximity-labeling tools have been developed to selectively tag and purify interacting protein complexes from synapses Proximity-labeling experiments with APEX2 fused to presynaptic terminal protein alpha-synuclein identified hundreds of interactors including synaptic proteins, vesicle trafficking proteins, RBPs, and translation initiation factors important for local protein synthesis  has been mapped both with BioID  or inhibitory (gephyrin) scaffolding molecules conjugated to BirA, the promiscuous biotin ligase  was used to study the developmental maturation of olfactory projection neurons  provides unparalleled image resolution for synapse analysis but is difficult to combine with conventional molecular labeling tools due to challenges imposed by the use of strong chemical fixatives and epoxy resins in the sample preparation. Further development of EM-compatible transgenic labeling tools will be useful for identifying specific molecular targets and cell/synapse types in EM images  patterned excitation approaches [e.g., STimulated Emission Depletion (STED) microscopy , a structural protein at the Drosophila neuromuscular junction (NMJ) essential for the developmental positioning of Ca2+ channels and synaptic vesicles  to reconstruct the relative spatial positions of pre/postsynaptic proteins in thin cryosections of brain tissue to map synaptic structure with molecular specificity and nanoscale resolution  organization  and antibody elution on ultrathin sectioned brain material to achieve multiplexed proteomic imaging with improved axial image resolution while further enabling correlative electron microscopy (Micheva and Smith, in situ (Lein et al., in situ RNA sequencing (FISSEQ; Lee et al., in situ hybridization methods such as multiplexed error-robust fluorescence in situ hybridization (MERFISH; Chen K. H. et al., in situ hybridization (seqFISH; Lubeck et al., in situ and has been further used to identify cell populations that are specifically active during social behaviors (Moffitt et al., in situ hybridization has been performed with expansion microscopy (Chen et al., Multi-round labeling has also been used to develop spatial transcriptomic approaches for mapping RNA identity and position in vitro using PAINT (Guo et al., in situ hybridization strategies for spatial transcriptomic imaging (Chen K. H. et al., In a step toward this goal, multiplexed super-resolution synaptic proteome imaging has been achieved using DNA-oligo-linked primary antibodies which are imaged across multiple rounds of hybridization using complementary detection oligos (Wang et al., The developmental connectomics strategy presented here enables new experiments to determine the molecular blueprint for synaptic development and plasticity in neural circuits. The application of complementary techniques in transcriptomics, translatomics, proteomics, and super-resolution structural imaging establishes an integrative framework for investigating mechanistic links between mRNA trafficking, local protein synthesis regulation, and changes in subsynaptic molecular organization underlying circuit development.Molecular sequencing experiments, both at the RNA and protein levels, generate foundational databases identifying regulators of connectome development and plasticity. Also, proteomic (Sharma et al., Several analytical approaches for integrating multiomic data have been applied to better define cell types in the mature and developing brain (Stuart et al., Though deep learning methods have thus far been developed for analyzing cell types and spatial organization, related approaches should facilitate integrative analysis of subcompartment-specific multiomic and super-resolution imaging data to characterize molecular networks driving synaptic/neurite maturation and plasticity (Poulopoulos et al., JM and CS wrote the manuscript and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Continuous, long-term monitoring with remote capabilities using wearable technology is ideal for capturing information about patient/participant symptoms synced to sensor-based information. The Real-time Online Assessment and Mobility Monitor (ROAMM) is a smartwatch framework configured to collect data in free-living settings from both sensor-based (location and movement) and responses to symptom notifications through a visual display. The symposium presents the overall framework and preliminary findings from a demonstration study in older adults with knee osteoarthritis. Karnati will present the general framework of ROAMM explaining the data flow from the smartwatch to end users (clinicians and research). He will highlight components in the design that makes the framework unique and highly flexible to serve different studies with different research questions. Rouzaud evaluated satisfaction, usability and compliance wearing a smartwatch and using the ROAMM app. Participants were compliant to ecological prompts about pain, fatigue and mood three times a day (82.5% compliance rate). Additionally, > 70% reported being satisfied with the function/usability and comfort with using ROAMM and wearing the smartwatch. Mardini examined the temporal relationship between ecological pain and derived life-space mobility features from Global Positioning System coordinates. Results suggested that higher level of knee pain in older adults was associated with lower life-space mobility. Manini examined physician perception towards an electronic health record (EHR) graphical interface of top ranked patient attributes of pain, falls, hydration and mobility patterns. Results indicated a relatively high level of usability of the EHR interface depicting smartwatch data."}
+{"text": "We propose that trauma history is important context for understanding the adaptive capacity of aging adults to achieve a suitable person-environment fit. We conducted a scoping review using bibliographic databases to identify studies focused on aging in place, vulnerability and traumatic personal experiences, and aging adults\u2019 maladaptive behaviors. Our review showed little research directly exploring the connection between trauma-related needs and aging in place and limited research about the community\u2019s role in supporting those needs. Literature about the impacts of trauma revealed that trauma could stem from adverse childhood experiences  and adult adverse experiences . Adults who have experienced trauma may have increased physiological  and psychological  conditions. Sensory sensitivities in the home environment\u2014including sounds , air quality , and lighting \u2014can substantially decrease quality-of-life. Strong emotional reactions can make interpersonal relationships, such as those with a landlord or neighbors, difficult and increase the likelihood of eviction. Aging adults with trauma histories also experience greater poverty rates, increasing the likelihood of substandard housing . Because the housing environment is a significant aspect of overall well-being, challenges to aging in place for adults with trauma histories warrants further research, as does the role of community supports in mitigating housing-related stressors. Examples may include trauma-informed approaches in universal design, the availability of safe affordable housing, community education, and funding for intermediaries who can support aging adults."}
+{"text": "Suillus brevipes, a mycorrhizal fungus adapted to coastal and montane habitats in California. In order to assess whether gene copy number variation mirrored population structure and selection in this species, we investigated two previously studied locally adapted populations showing a highly differentiated genomic region encompassing a gene predicted to confer salt tolerance. In addition, we examined whether copy number in the genes related to salt homeostasis was differentiated between the two populations. Although we found many instances of CNV regions across the genomes of S. brevipes individuals, we also found CNVs did not recover population structure and known salt-tolerance-related genes were not under selection across the coastal population. Our results contrast with predictions of CNVs matching single-nucleotide polymorphism divergence and showed CNVs of genes for salt homeostasis are not under selection in S. brevipes.Gene copy number variation across individuals has been shown to track population structure and be a source of adaptive genetic variation with significant fitness impacts. In this study, we report opposite results for both predictions based on the analysis of gene copy number variants (CNVs) of  Brachipodium distachyon (Zymoseptoria tritici and Aspergillus fumigatus (Copy-number variants (CNVs) are genes or genomic regions of varying size with different numbers of copies across individuals. Copy-number differences can arise through genomic rearrangements  or produce functional divergence across gene copies resulting in differentially adaptive phenotypes . Furthermore, no SNP variation was found in this gene across coastal individuals strongly suggesting a selective sweep for adaptive alleles allowing colonization of saline environments in coastal California. Nha-1 homologs have been reported as important for salt tolerance in other organisms, including increased Nha-1 expression levels in Arabidopsis thaliana allowing survival in high sodium concentrations  and montane  California populations previously analyzed in Suillus brevipes is a dikaryotic fungus which means two haploid genomes inhabit the same cell, we therefore assumed diploidy of our samples and followed ST following ST formula is available from https://github.com/abazzical/sbrevCNV). Given the reference genome is rather fragmented .We estimated gene copy number variation from the processed Illumina reads of 27 ape package  enrichment analysis on the top 1% diverged CNVs between the two Suillus brevipes reference genome , there were no significant differences in CNV number or CNV size between montane and coastal populations (Wilcoxon rank sum test P > 0.05). The vast majority of CNVs were losses across the whole genome , suggesting salt homeostasis genes are not under selection for different copy numbers in the two populations. However, as shown in the heatmap in We found 83 genes involved in salt homeostasis across the Nha-1-like gene; ProteinID 1095265) showed a range of copy numbers across individuals  and its annotation incomplete and based on sequence similarity-based gene predictions  and there might be adaptive CNVs related to salt tolerance in the remainder of the genome that remained undetected.Both biological and technical factors likely contributed for the absence of concordance between CNVs and SNPs in lifornia , the preS. brevipes (In conclusion, our results complement findings from previous studies on environmental adaptation in the mycorrhizal fungus"}
+{"text": "Biliary and pancreatic cancers occur silently in the initial stage and become unresectable within a short time. When these diseases become symptomatic, biliary obstruction, either with or without infection, occurs frequently due to the anatomy associated with these cancers. The endoscopic management of these patients has changed, both with time and with improvements in medical devices. In this review, we present updated and integrated concepts for the endoscopic management of malignant biliary stricture. Endoscopic biliary drainage had been indicated in malignant biliary obstruction, but the concept of endoscopic management has changed with time. Although routine endoscopic stenting should not be performed in resectable malignant distal biliary obstruction (MDBO) patients, endoscopic biliary drainage is the treatment of choice for palliation in unresectable MDBO patients. Self-expanding metal stents (SEMS) have better stent patency and lower costs compared with plastic stents (PS). For malignant hilum obstruction, PS and uncovered SEMS yield similar short-term outcomes, while a covered stent is not usually used due to a potential unintentional obstruction of contralateral ducts. Percutaneous transhepatic biliary drainage was introduced ~40 years ago  for the Differences in the level of obstruction of the biliary system allow for a further division of these kinds of problems into resectable or unresectable hilum or distal biliary obstructions. Computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), and even endoscopic ultrasound sonography (EUS) should be used to evaluate the stage and primary source of a malignancy ,10.Treatment plans for malignancies with different primary origins differ from one another when resectable biliary obstructive malignancy diseases are discussed. In general, routine endoscopic stenting has no obvious clinical benefits for patients with malignant distal biliary obstruction (MDBO) ,12,13,14For cholangiocarcinoma, the Bismuth classifications  have beeFor hilum cholangiocarcinoma without distant metastasis, resectable tumors present the possibility of resection of the involved intra- and extrahepatic bile ducts as well as the associated hepatic lobes and caudate lobe. Some recent reports have shown excellent results after surgical resection in patients with Bismuth III and IV disease ,23, but Endoscopic stenting is the mainstream endoscopic management approach for malignant distal biliary obstruction of cholangiocarcinoma or pancreatic cancers, but most clinical studies ,24 and mIn ampullary neoplasms, EUS and intraductal ultrasound sonography (IDUS) can assess the depth of invasion as well as the intraductal extension. Importantly, surgical ampullectomy can reduce medical expenses yet have similar clinical outcomes for those that are achieved via pancreaticoduodenectomy  for ampuEndoscopic biliary drainage with biliary stent placement is the treatment of choice for palliation in patients with distal malignant biliary obstruction that is caused by unresectable neoplasms, with a success rate of up to 95% ,29,30 anIn some situations, PTCD has been used as part of a rendezvous endoscopic approach. A comparison in 2016 between EUS-guided and PTCD rendezvous drainage after the failure of primary ERCP in MDBO showed that EUS rendezvous had a significantly lower success rate than the PTCD rendezvous . HoweverDifferent stent types are available for the treatment of MDBO. SEMS  have a lEUS is a valuable diagnostic modality for the staging of hilum cholangiocarcinomas, particularly for the evaluation of unresectable perihilar cholangiocarcinoma for liver transplantation . PercutaSome evidence indicates that in cases of bilateral biliary opacification, bilateral drainage offers a better survival benefit when compared to unilateral drainage ,70. AfteThe evidence is still insufficient and no clear consensus has been reached regarding the benefits of unilateral versus bilateral drainage for hilar malignant obstruction, although the bilateral approach can be used by most experts using the SEMS stent-within-stent placement ,76 with Plastic stents and uncovered SEMS yield similar short-term outcomes in patients with malignant hilar strictures due to stent migration in SEMS . SEMS prEUS-guided biliary drainage via EUS-guided hepaticogastrostomy (EUS-HGS) is a good alternative for draining malignant hilar biliary obstruction following the failure of an initial ERCP. An EUS-guided rendezvous procedure with the conventional ERCP access ,86 is tyIn cases of malignant biliary obstruction, CT, MRI, MRCP, and EUS should be used for tumor staging and further drainage planning. For resectable malignant biliary obstruction lesions, routine endoscopic drainage or ERCP are not advised, except in cases of concurrent infection. Endoscopic drainage is the treatment of choice for unresectable biliary obstructions. PTCD and EUS-guided biliary drainage can serve as alternative approach methods. EUS-guided biliary drainage can provide equal clinical benefits without increasing complications in a high-tech endoscopy center. In addition, PTCD plays an important role in community hospitals, where the ERCP and/or EUS approaches are not available.For MDBO, single-stent insertion is adequate, and SEMS have better patency than plastic stents; however, the superiority of FCSEMS, PCSEMS, and UCSEMS remains under debate. For malignant hilar biliary obstructions, drainage of >50% of the liver volume should be achieved by either bilateral stenting or multi-segmental stenting, and SEMS\u2019 longer biliary patency when compared with plastic stents should be considered. The general approaches to malignant biliary obstruction are summarized in the flow chart presented in"}
+{"text": "The effects of retirement on cognition are still unclear and empirical evidence is conflicting. Especially for retirement from cognitively demanding jobs, positive as well as negative effects have been reported. Leisure activity engagement has been hypothesized to play an important role in explaining the mixed evidence. In this study, we examine the interplay between job demands before retirement and changes in leisure activities before and after retirement and their relation to post-retirement cognitive functioning. Using data from the HEalth, Aging and Retirement in Sweden (HEARTS) study, cognitive trajectories before and after retirement were modeled in a multi-level piecewise model (N = 2688 observations). Post-retirement memory and reasoning ability were predicted by self-reported work demands and changes in leisure activity engagement. Results imply a stable increase in memory over the retirement transition and less steep increase in abstract reasoning after retirement. Work demands and leisure activity participation were not related to post-retirement cognitive change. Job demands and leisure activity engagement may not play an important role for short-term post-retirement cognitive functioning. These findings support the conclusion that retirement, independent of prior work demands, does not affect cognitive functioning negatively."}
+{"text": "The purpose of our Geriatric Workforce Enhancement Program is to provide geriatric and primary care education and training to long-term care (LTC) providers and staff, health professions students and community members. Our LTC partners and the communities we serve are often very rural and travel to urban areas for training can be difficult. Therefore, we have developed four online training that are offered free to our partners and rural communities statewide. These programs are designed to integrate the aims of the Age-Friendly 4M\u2019s model . The LTC nurse residency program provides gerontological nursing and inter-professional leadership training , in a synchronous online environment. The asynchronous Alzheimer\u2019s Disease and Related Dementias training modules educate LTC staff and family caregivers about types, diagnosis and care of older adults with dementia (Mentation and Medication). The asynchronous Opioid Use in LTC modules were developed with partners to deliver live at LTC staff trainings about opioid stewardship (Medication). The LTC Learning Communities are monthly tele-health sessions for inter-professional LTC teams to discuss current issues and propose solutions . We have successfully leveraged different synchronous and asynchronous online modalities to increase educational opportunities for formal and informal caregivers, including those in rural areas whose educational opportunities are geographically limited. To date our programs have reached over 500 individuals across our state, increasing knowledge about geriatric concepts, communication and team leadership. Moving forward, we will continue to develop and refine educational programs that promote the Age-Friendly geriatric-focused health care."}
+{"text": "The widespread consumption of \u2018western\u2019-style diets along with sedentary lifestyles has led to a global epidemic of obesity. Epidemiological, clinical and preclinical evidence suggests that maternal obesity, overnutrition and unhealthy dietary patterns programs have lasting adverse effects on the physical and mental health of offspring. We review currently available preclinical and clinical evidence and summarise possible underlying neurobiological mechanisms by which maternal overnutrition may perturb offspring cognitive function, affective state and psychosocial behaviour, with a focus on (1) neuroinflammation; (2) disrupted neuronal circuities and connectivity; and (3) dysregulated brain hormones. We briefly summarise research implicating the gut microbiota in maternal obesity-induced changes to offspring behaviour. In animal models, maternal obesogenic diet consumption disrupts CNS homeostasis in offspring, which is critical for healthy neurodevelopment, by altering hypothalamic and hippocampal development and recruitment of glial cells, which subsequently dysregulates dopaminergic and serotonergic systems. The adverse effects of maternal obesogenic diets are also conferred through changes to hormones including leptin, insulin and oxytocin which interact with these brain regions and neuronal circuits. Furthermore, accumulating evidence suggests that the gut microbiome may directly and indirectly contribute to these maternal diet effects in both human and animal studies. As the specific pathways shaping abnormal behaviour in offspring in the context of maternal obesogenic diet exposure remain unknown, further investigations are needed to address this knowledge gap. Use of animal models permits investigation of changes in neuroinflammation, neurotransmitter activity and hormones across global brain network and sex differences, which could be directly and indirectly modulated by the gut microbiome. The worldwide prevalence of obesity has tripled since 1975, accompanied by a sharp increase in obesity among women of reproductive age . MaternaObservations regarding neurodevelopmental impacts of maternal obesity have emerged more recently, building on extensive evidence linking higher maternal body mass index (BMI) to adverse offspring metabolic and cardiovascular outcomes. This literature has been reviewed elsewhere and is not examined here ,8,9. RatHuman and preclinical studies of the impacts of maternal obesity and overnutrition on offspring behaviour can be categorised into three areas: cognition, affective states and psychosocial behaviour. Although human studies have shown associations between these domains and maternal body weight and diet  on offspring cognition. One of the challenges in interpreting behavioural data regarding cognition is the heterogeneity in tests and test parameters employed across studies, as noted in a recent meta-analysis and systematic review  which coIncreased proinflammatory signals including IL1\u03b2 and TNF\u03b1 were found in the whole brain of male and female mouse offspring of obese mothers at P0, with mixed effects seen at P7 and P21 . ElevateResults from several studies in humans indicate that maternal obesity alters affective states in children. For example, extreme maternal obesity (pre-pregnancy BMI \u2265 40) was associated with hyper-reactivity and affective changes in children, independent of demographic variables, prenatal factors or maternal anxiety and depression . A populBy contrast, preclinical studies using affective measures in rodents show mixed results, with maternal obesity found to increase ,39,41,53Although behavioural measurements differ between studies, preclinical studies have often sought to link affective changes to dysfunctional HPA axis activity, altered neuronal plasticity and increased neuroinflammation. The HPA axis regulates physiological stress responses and modulates behaviour in response to stressful stimuli, and its function is programmed by maternal obesity. An association between hyper- and hypo-active HPA axes and anxiety- and depressive-like behaviour, respectively, has been well documented . Two stuApart from differences in experimental research protocols  one possible reason for the discrepancy between the results seen in human research and the mixed results from animal models might relate to methodological differences in reporting negative emotional states in humans and rodents. Human studies tend to use parental reports regarding child emotional states, whereas studies using rodents monitor anxiety- and depressive-like behaviour using ethologically relevant tests in the offspring themselves, such as forced swim, open field, elevated plus maze, dark-light box and sucrose preference tests, which cannot fully capture the breadth of negative affective states in human children. We argue that despite these challenges, the ability to associate behavioural outcomes with neurohumoral and molecular readouts in preclinical research has merit.The potential link between maternal obesity and Autism Spectrum Disorder (ASD) has been extensively investigated over the past decade or so. Several recent meta-analyses and reviews indicate an increased risk of ASD in children of mothers who were overweight or obese at the time of conception ,50. In aDespite growing interest in the link between maternal obesity and aspects of psychosocial behaviour in children in human studies, few studies have explored this relationship in animal models. Research to date has examined social interaction, anxiety and locomotor activity. Several studies have found evidence that neuroinflammation might contribute to impaired social behaviour in offspring of overfed dams: Kang et al.  reportedObesity during pregnancy alters neuroendocrine, metabolic and inflammatory status and these exposures might affect foetal development, in turn influencing behaviour, emotion and cognition. In addition to neuroinflammation, altered neuronal plasticity and dysregulated brain metabolism  likely contribute. Another mechanism attracting recent attention is changes in the composition of the gut microbiome, which contains trillions of bacteria, and plays a crucial role in health and disease of the host . In the Rodent models of maternal obesity have shown evidence of hypothalamic inflammation in offspring, characterised by elevated levels of TNF\u03b1, IL1b, and IL6 in adulthood, both in rats  and miceAnother possibility is the involvement of glial cells. Glial cells such as microglia and astrocytes are essential for regulating immune responses and act as metabolic sensors . SeveralIn the context of maternal obesity and effects on offspring behaviour, an experimental study showed changes in glial cell proliferation and reactivity in mouse offspring of obese mothers, characterised by astrocyte proliferation and elevated levels of IL6 in the hypothalamic arcuate nucleus (ARC) and the supraoptic nucleus (SON) compared with offspring from normal weight dams . This evLactobacillus reuteri suppressed neuroinflammation by binding to a receptor expressed on astrocytes [L.reuteri produces gamma-aminobutyric acid (GABA) which has inhibitory effects on neuronal circuity [L.reuteri regulates social behaviour in mice via the vagus nerve pathway interacting with oxytocin in the VTA [Lastly, increasing evidence suggests an intriguing relationship between glial cells and the gut microbiome. Preclinical studies using conventional and germ-free mice showed that the gut microbiota indirectly regulate homeostasis and immune reactivity of microglia . Gut mictrocytes . Neurointrocytes . Notablycircuity . A recen the VTA . In summStudies in rodents and humans link maternal obesity to neurological changes in offspring. A recent human study reported a negative association between maternal BMI and hippocampal volume in male children at 7\u201311 years of age . FurtherRecent studies using functional magnetic resonance imaging technology indicate an association between higher pre-pregnancy BMI and altered white matter microstructure , neuronaDopamine is a neurotransmitter regulating motivational and reward-related functions. A recent preclinical study showed that consumption of cafeteria diets during pregnancy induced epigenetic changes in the dopamine receptor (DAT), dopamine transporter 1 (DRD1) and dopamine transporter 2 (DRD2) genes in the nucleus accumbens (NAc) and VTA, two key regions of the dopaminergic pathway . In the Perinatal exposure to maternal obesity and poor diet induces lasting effects on the central serotonergic system in female offspring . High faEvidence from animal models shows maternal obesity programs the rat offspring\u2019s health trajectory towards obesity by impaired lipid and glucose metabolism and appetite regulators ,94. InteMaternal overnutrition also alters the endocannabinoid system through impaired leptin signalling in the hypothalamus. Interestingly, only male rat offspring of HFD-fed dams exhibited impaired leptin signalling, with epigenetic changes in promoter regions of sex hormone signalling at birth . The sexThe adverse changes in brain metabolism in offspring from obese dams include altered mammalian target of rapamycin (mTOR) signalling in the rat hypothalamus  and in tOxytocin is another brain hormone for which there is evidence of a relationship between maternal obesity and aberrant offspring behaviour. Oxytocinergic neurons in the PVN project to the amygdala, hippocampus, NAc and VTA, and peripherally project to the pituitary into the blood stream ,115. OxyThe \u2018gut-brain axis\u2019 describes the complex communication network between the gut and brain, comprising the enteric nervous system, sympathetic and parasympathetic branches of the autonomic nervous system, in addition to neuroendocrine signalling pathways, and neuroimmune systems . Emerginlactobacillus spp. abundance in the infant gut [Only limited evidence is currently available for an association between maternal diet and offspring gut microbiome composition in humans. Savage et al. showed a weak but positive association between maternal diet, characterised by high vegetable intake and low processed/fried food intake, and fant gut . A recenfant gut . Exposinfant gut . A caveafant gut . We havefant gut . Therefofant gut .Staphylococcus and Lactobacillus and lower numbers of Bifidobacterium bacteria relative to normal weight mothers [Lactation is another key period that shapes the offspring\u2019s gut microbiome, immune system and behaviour. Breast milk is comprised of non-nutrient components such as immunoglobulins, oligosaccharides, growth factors, and epithelial and immune cells, which could reflect maternal health, and DNA\u2014essential bioactive compounds that foster the development of the gastrointestinal, immune and neurological systems in offspring . Indeed, mothers . A recen mothers . What isThere is now broad evidence from human and animal studies indicating that maternal obesity, overnutrition and unhealthy dietary patterns induce adverse effects on behaviour and neurodevelopment in offspring. This review has identified possible underlying neurobiological mechanisms for these effects, which include neuroinflammation, disrupted neural circuitries and connectivity and dysregulated brain hormones. Dynamic interactions between these factors shape behaviour during gestation and lactation through the offspring\u2019s exposure to maternal obesity via the placenta, gut microbiome and breast milk. Future research should continue to examine behaviour and brain changes in maternal obesity models beyond the hippocampus and hypothalamus, given recent evidence from imaging studies suggesting that aberrant behaviour might be a result of dysregulated global network in the brain, in addition to region-specific dysfunctions. In addition, future research should be targeted at characterising the intriguing sex differences evident in many maternal obesity studies, given that current preclinical studies are still skewed towards males. Human studies using advanced imaging techniques could provide a useful resource to guide animal studies to further elaborate underlying mechanisms. Further, animal models need to incorporate experimental protocols that maximise translational relevance to align with human studies in terms of dietary components, feeding duration and behavioural tests, to allow behavioural and molecular outcomes to be systematically assessed longitudinally and compared across species where possible. Studies currently underway should yield more valuable data on the longer-term effects in humans."}
+{"text": "Diffuse gliomas, such as glioblastoma (GBM), represent the most common and aggressive form of brain cancer with an unfortunate dearth of treatment advances despite decades of ongoing research . PerhapsDespite this prospect, the aggressive biology and low incidence of gliomas make them poor candidates for conventional screening strategies. Case reports of serial neuro-imaging studies of GBM, with scans taken as few as 68\u2009days apart, show that even small cortical lesions can rapidly evolve into established disease within a very short clinical time frame (<\u20093\u2009months) . This shConsequently, when conceptualizing an effective screening tool for gliomas, brain health changes would need to be monitored over short intervals (days to weeks) using tools that could be practically applied to the general population. Herein lies the immense potential of using emerging non-invasive electroencephalography (EEG)-based biotracking devices to serve as agents that gather continuous health data from our nervous system Fig.\u00a0a. These With these exciting prospects in mind, several potential limitations at present are worth highlighting. Current EEG wearables, designed for niche application , only require a handful of sensors for their intended uses. The optimal quantity and spatial distribution of sensors for effective screening of central nervous system pathologies therefore still need to be defined. Additionally, the amount and timing of daily wear needed to detect subtle baseline changes would also need optimization and balance with enthusiasm to wear such devices. Despite these current unknowns, rapid and widespread acceptance of other smart wearables offers encouraging insights. For example, despite only debuting in 2015, Apple shipped >\u200940 million smartwatches in 2018 with the global wearable market expected to grow to >\u2009279 million users by 2023. This estimate of the wearable market alone could allow the detection of tens of thousands of brain tumors annually! With increasing possibilities and interest at the intersection between artificial intelligence and brain-machine interfaces , such devices may soon even become essential tools to intellectually compete in society. It is therefore possible that consumer demand for brain wearables may quickly mirror the rapid growth of their hardware manufacturers and extend far beyond current niche applications and existing smartwatch demands . Lastly,The ability of these devices to provide continuous longitudinal and personalized data, along with the advent of modern deep learning computational tools, could provide new solutions for the early detection and differentiation of various nervous system pathologies. Large-scale detection of incipient tumor formation could also provide new epidemiological insights of unappreciated risk factors and mechanisms of gliomagenesis. Deployment of these devices to existing brain tumor patients could also help monitor disease recurrence and understand treatment-related neurocognitive sequalae.Brain tumors such as GBM carry a dismal prognosis which has challenged conventional treatment paradigms for decades. Conceptualizing novel early detection-based approaches for these tumors may provide success in a patient population where conventional late-stage diagnosis and treatment have failed. While the role of early detection in the management of brain tumors is still unclear, recent innovations in personal brain wearables, artificial intelligence, and evidence for the benefits of aggressive surgery offer new opportunities to refine our clinical approach to these challenging clinical entities."}
+{"text": "Under physiological conditions, a balance between oxidants and antioxidants exists. Reactive oxygen species (ROS) are continuously generated by aerobic cells and eliminated through scavenging systems to maintain redox homeostasis. Disruption of redox homeostasis results in oxidative stress and altered ROS signaling. Higher ROS levels can lead to DNA mutation and genomic instability which can play causal role in cancer development and progression. These mutations coupled with distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation, and inefficient repair mechanisms.Cancer cells are energy intensive, owing to their high rate of proliferation. However, due to impaired TCA cycle and poor blood perfusion, cancer cells switch towards glycolytic pathway for energy generation termed as \u201cWarburg effect.\u201d Such pathways lead to a higher oxidative environment. The oxidative environment is also enhanced by tumor-infiltrating macrophages and neutrophils. Thus, cancer cells are used to a high ROS environment. This redox imbalance allows for protumorigenic cell signaling. In this issue, we explore the relation between ROS and cancer. The issue comprises of twenty original articles and comprehensive reviews.Reactive oxygen species (ROS) mediates cisplatin-induced cytotoxicity in tumor cells. However, when cisplatin-induced ROS do not reach cytotoxic levels, cancer cells may develop chemoresistance. Di Vito et al. reported the association of ferritin heavy subunit (FHC)-ROS axis with cisplatin resistance in ovarian cancer cells. Thus, implying that inhibition of FHC might be a potential approach for restoring cisplatin sensitivity of resistant ovarian cancer cells. The authors investigated whether the modulation of H-Ferritin might affect cisplatin-induced cytotoxicity in ovarian cancer cells. H-Ferritin knockdown strengthened cisplatin-mediated ROS increase and significantly restored sensitivity resistant ovarian cancer cells.via a ROS-dependent mitochondria-mediated pathway. H\u00e4m\u00e4l\u00e4inen et al. investigated the expression of redox regulator nuclear factor erythroid-2-related factor (NRF)1 and NRF2 in skin lesions like naevi and melanoma from 172 patients. NRF1 and NRF2 are transcription factors essential for maintaining redox homeostasis and coordinating cellular stress responses. The study found the association of redox microRNAs (miRs)  with aggressive melanoma feature. This study opens up avenues to test these redox miRs as possible prognostic value in larger cohorts. The research article by Pires et al. described label-free mass spectrometry- (MS) based proteomics of breast cancer (BC) plasma to investigate the differences between circulating proteins between chemoresponsive and chemoresistant luminal A breast cancer. Protein-protein interaction networks were created utilizing using in silico tools. The study reports interesting findings on differences in inflammatory, complement system, and oxidative stress pathways in both BC phenotypes which holds potential clinical implications. Moreira et al. presented their findings about the antitumor effect of celastrol, a natural pentacyclic triterpenoid, in colon cancer cells with acquired resistant to cytotoxic drugs. Yang et al. have evaluated the anticancer and anti-invasive properties of alpha-lipoic acid (ALA) in gastric cancer cells. ALA is a naturally occurring thiol antioxidant which is known to exhibit antiproliferative and cytotoxic effects on several cancers. The study found that the Mucin 4 (MUC4) gene was strongly expressed in human gastric cancer tissues. ALA administration reduced the proliferation and invasion of human gastric cancer cells by suppressing MUC4 expression. Helfinger et al. reported expression of Nox4 in macrophages and the role played by them in determining the polarization and the phenotype of macrophages. In the report by Acheva et al., authors showed epithelial to mesenchymal transition (EMT) in lung cancer cells postexposure to oxidative stress of gamma radiation. The authors conclude that induction of EMT in bronchial epithelial cells by radiation requires more than single acute exposure to gamma radiation and that the presence of stromal component might enhance the effect through free radical production and accumulation.Studies by Zhao et al. in osteosarcoma cells found that metformin (drug for type 2 diabetes) suppressed the self-renewal ability of osteosarcoma stem cells (OSCs) and induced G0/G1 phase arrest by blocking the activity of cyclin-dependent kinases. Metformin triggered apoptosis in these cells, which promoted cell death Gao et al. investigated the association of nitric oxide metabolites and lung cancer incidence through a matched case-control study based on the German ESTHER cohort. The study deduced that subjects with high urinary nitrite/nitrate concentrations had an increased risk of lung cancer. Butturini et al. highlighted plant-derived Sesquiterpene as a potential for cancer therapeutics. The authors exhibited that the compound downregulated STAT3 signaling leading to an antitumor effect and correlated the anti-STAT3 activity with their ability to decrease GSH levels in cancer cells. These properties make them lead compounds for the development of a new therapeutic strategy for cancer treatment.In addition to these original works, Kim et al. listed a comprehensive report on the ROS-inducing strategy in anticancer therapy. The review by Xian et al. summarized the role of ROS in cutaneous carcinogenesis and skin cancer progression. Akanji et al. provides a comprehensive account of hypoxia-inducible factors (HIFs). In the review by Lv et al., the authors discussed recent understanding in the involvement of Glutathione (GSH) in cell death pathways such as apoptosis, necroptosis, ferroptosis, and autophagy. Goh et al. performed online literature search to identify studies reporting metabolic biomarkers of aerodigestive squamous cell carcinomas (ASCC). Akbari et al. have focused on the role of hydrogen sulfide in bladder, kidney, and prostate malignancies.In the review by Tataranni et al., the authors have addressed the therapeutic potential of dichloroacetate (DCA) in cancer therapy. DCA is a 150 Dalton, water-soluble acid molecule, analog of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. The authors have summarized recent reports suggesting the employment of DCA in cancer therapy, in combination with chemotherapy agents, radiotherapy, and other chemical or natural compounds showing anticancer properties. Paz et al. in their review have discussed the pharmacological effects and toxicogenetic impacts of omeprazole in context of cancer. This extensive report highlights that omeprazole therapy may induce genomic instability and increase the risk of certain types of cancer and hence advocates for taking adequate precautions, especially in long-term therapeutic strategies. The review by Fiocchetti et al. focused studies conducted on Neuroglobin (NGB), a globin primarily described in neurons as an oxidative stress sensor and cytoprotective factor against redox imbalance.Although ROS sustain tumorigenesis and cancer progression, these can also be efficient therapeutic tools to fight cancer. Oxidative stress-based therapies like radiotherapy, chemotherapeutic agents, and photodynamic theory increase ROS levels in the tumor niche and take advantage of the cytotoxic face of ROS for killing tumor cells by a nonphysiologically sudden, localized, and intense oxidative burst. Clinical efficacy of anticancer therapies is often subdued by multidrug resistance (MDR). Redox therapy by using redox-active drugs or inhibitors of inducible antioxidant defense in tumor microenvironment has reported to be effective against MDR tumors. Further insight into such redox biology will enable precisely targeted manipulation of ROS for effective medical therapies against carcinomas."}
+{"text": "Caenorhabditis elegans. We discuss how cell surface receptor complexes link to and modulate actin dynamics to regulate dendritic and axonal branch formation. The mechanisms of neurite branching are often coupled with other neural circuit developmental processes, such as synapse formation and axon guidance, via the same cell-cell surface molecular interactions. We also cover ectopic and sex-specific neurite branching in C. elegans in an attempt to illustrate the importance of these studies in contributing to our understanding of conserved cell surface molecule regulation of neurite branch formation.The high synaptic density in the nervous system results from the ability of neurites to branch. Neuronal cell surface molecules play central roles during neurite branch formation. The underlying mechanisms of surface molecule activity have often been elucidated using invertebrates with simple nervous systems. Here, we review recent advances in understanding the molecular mechanisms of neurite branching in the nematode  An extensive neurite branching morphology is a fundamental aspect of neuronal structure. Each axon and dendrite contain numerous neurite branches that enhance neural circuit complexity by allowing for interaction with a large number of target neurons and non-neuronal cells. For example, a single neuron can synapse onto multiple target neurons due to the extensive branching of the axonal shaft. Dendrites have an extremely complex branching thereby producing a large dendritic field to receive synaptic or sensory inputs. These neurite branch networks allow for the formation of highly complex neural circuits that integrate and process information, thereby coordinating specific nervous system functions. Growing evidence suggests that dysregulation of neurite branching could underlie various neurological and neurodevelopmental disorders such as autism, schizophrenia, and Down syndrome  or synaptic output functions  of the posterior section of the body. These neurons extend elaborate dendritic branches throughout the body excluding the head , leading to defects in harsh touch response , an IgSF cell surface protein  and their modifying enzymes , it also possesses 294 sex-shared neurons, some of which show notable sex differences in neuronal structure, branching pattern, and synaptic connectivity  and regulated by conserved cell surface molecules , DD06 neurons , and PHC neurons (male-specific axon extension; Cook et al., Drosophila brain revealed several conserved, but previously unidentified, cell surface molecules that act as regulators of neural circuit formation (Li et al., Over the past decades, studies have identified numerous cell surface molecule interactions implicated in neural circuit formation processes including neurite branching. Most of these molecules possess conserved structural domains, such as LRR, Ig domains, and cadherin repeats, which mediate protein-protein interactions necessary during neuronal morphogenesis (De Wit and Ghosh, HJ and BK developed the concept. Both have written and edited the text.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Benevolence directed towards older adults can cross the line between respect and overaccommodation that undermines their physical and cognitive capabilities ; however, little research has examined the subtleties of the influence of benevolent ageism on older adults\u2019 ratings of their own functioning. Because stereotypes about older adults include the decline of mental abilities, this study examined whether their (N= 155) experiences with benevolent ageism, or overaccommodative offers of assistance and protection, influenced their own appraisals of memory abilities through their feelings of self-compassion. Older adults with fewer benevolent ageist experiences had higher rates of self-compassion, which in turn translated into better evaluations of their memory abilities. Future research should consider the potential pernicious influences that benevolent ageism has on older adults\u2019 self-evaluations and performance, consider self-compassion as a buffer in these relationships, and test whether these relationships have downstream consequences on well-being outcomes."}
+{"text": "This symposium will examine positive and negative aspects of older adults\u2019 relationships and their impacts on health and well-being. We will begin by reviewing the past decade of research on family gerontology. Seidel\u2019s meta-analysis of 995 articles will identify prominent theories and methods, as well as remaining research gaps. The subsequent presentations provide current, cutting-edge research. Marini examines how associations between rumination and sleep unfold within a social context. The findings highlight how spousal support protects older adults\u2019 sleep quality from rumination, whereas support from family and friends is vulnerable to rumination. Using an actor-partner approach, Novak investigates the dynamics of support and control on health among older gay couples. Results reveal the benefits of support and risks of control for partners\u2019 diet quality and depression. Ermer adopts a dyadic perspective to examine links between self-perceptions of aging and inflammation. Results highlight how wives\u2019 inflammation is sensitive to husbands\u2019 aging perceptions, particularly if marital strain is low. Finally, Wilson characterizes age-graded patterns of relationship narratives and their protective effects on emotional well-being. The findings demonstrate how older-adult couples\u2019 narratives are less self- and present-focused, which helps explain protective linkages between age and negative mood. The symposium will conclude with remarks from discussant Katherine Fiori, a GSA Fellow and internationally recognized scholar on older adults\u2019 social networks. She will synthesize the research and put forth her new theory about the importance of peripheral ties in later life to help direct the future of research on older adults within a social context."}
+{"text": "Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a focal ischemic stroke rat model with a focus on blood\u2013brain barrier (BBB) integrity and related pathogenic processes in contralateral brain areas. Additionally, we discuss BBB competence in chronic diaschisis in a similar rat stroke model, highlighting the pathological changes in contralateral brain areas that indicate progressive morphological brain disturbances overtime after stroke onset. With diaschisis closely approximating stroke onset and progression, it stands as a treatment of interest for stroke. Indeed, the use of stem cell transplantation for the repair of microvascular damage has been investigated, demonstrating that bone marrow stem cells intravenously transplanted into rats 48 h post-stroke survive and integrate into the microvasculature. Ultrastructural analysis of transplanted stroke brains reveals that microvessels display a near-normal morphology of endothelial cells and their mitochondria. Cell-based therapeutics represent a new mechanism in BBB and microvascular repair for stroke. Stroke is currently the fifth leading cause of death in the US, and someone dies of one approximately every 4 min. Stroke occurs due to the interruption of blood flow to the brain, and is typed as ischemic or hemorrhagic. Ischemic stroke makes up approximately 87% of total strokes. Ischemic stroke survivors may not fully recover and develop long-term disabilities ,2,3, sucCerebral functional insufficiency in chronic stroke might be due to pathological changes in brain areas remote from the initial ischemic lesion, for example, diaschisis. In this review, the BBB is implicated in subacute diaschisis. Additionally, BBB competence in chronic diaschisis using a transient middle cerebral artery occlusion (tMCAO) rat model is discussed as well. BBB alterations can be demonstrated in not only the ipsilateral hemisphere, but also the contralateral hemisphere, an area with remote brain structures not directly affected by ischemia. The microvascular damage in the subacute phase likely reveals ischemic diaschisis, and should be considered in the development of treatment strategies for stroke. The direct targeting of cell delivery into the injured vasculature might be a feasible approach for stroke treatment, and endothelial progenitor cells (EPCs) serve as a promising cell source for BBB restoration in stroke. The ability to preserve the mitochondria and increase these organelles\u2019 pinocytosis via cell-based therapeutics represents a new neurorestorative mechanism in BBB repair.Microvascular damage in ischemic stroke demonstrates ischemic diaschisis. In this review, the investigation of subacute diaschisis in ischemic stroke rat models exhibits stroke-induced pathological disturbances in ipsilateral and contralateral brain areas, and causes microvascular damage with BBB breakdown in remote brain microvessels. Additionally, widespread microvascular alterations in ipsilateral and contralateral brain hemispheres suggests continued BBB damage in chronic ischemic stroke. Because of the rampant pathological microvascular changes in remote brain areas in both subacute and chronic ischemic diaschisis, such vascular damage presents as a therapeutic target for stroke. The use of bone marrow-derived mesenchymal stem cells has been initiated to treat patients with acute ischemic stroke. Here, we discuss the potential use of EPCs as an effective cell source for BBB restoration in stroke by promoting neurovascular repair and preserving the mitochondrial morphology of the microvasculature.Following an ischemic stroke, substantial alterations in both cellular and molecular activity take place due to stroke-induced cerebral pathology ,6. StrokStroke pathology due to vascular injury is time-dependent and can be classified into three types: acute (minutes to hours), subacute (hours to days) and chronic (days to months). The acute and subacute stages of ischemic stroke can be grouped into one period, as secondary cell death following both phases drastically overlap ,6,8. NotIn-depth investigations into stroke pathology have brought about the phenomenon of diaschisis, an abrupt change in activity in regions of the brain far-off from the ischemic lesion generated by stroke-induced impairments. Transhemisphere diaschisis was first recognized through blood flow and metabolism alterations in unilateral and contralateral ischemic hemispheres in the brain . After iNevertheless, in the context of the subacute phase, BBB functionality and the associated pathology in distal brain regions have received less focus . A comprThe effects of subacute diaschisis on BBB stability and associated pathological mechanisms in contralateral regions of the brain were evaluated in focal ischemic stroke rat models . Using tMoreover, BBB impairment in distal cerebral microvessels and endothelial autophagosome build-up could be correlated with the injuries observed in the ipsilateral and contralateral brain regions spurred by focal ischemic stroke . ImportaBy utilizing a focal ischemic stroke rat model, subacute diaschisis could be explored ,29,36,37A major pathologic characteristic of subacute tMCAO involves BBB impairment in the ipsilateral and contralateral striatum and motor cortex ,29,36,37Parenchymal extravasation plays a role in secondary cell death following an ischemic stroke, and can be linked to diaschisis and BBB impairment. An in vivo study illustrated that EB extravasation was amplified in the MCAO group when compared to the control group, and could be associated with exacerbated BBB integrity . A high Autophagy in capillary ECs following ischemic stroke may heavily contribute to cell impairment and BBB alteration. It is still unknown whether enhanced autophagy is part of cell survival or death in an ischemic environment. Autophagosome accumulated in ipsilateral and contralateral capillary ECs following tMCAO. Autophagy plays a pivotal role in managing cell homeostasis by the degradation of cytosolic components via an autophagosomal\u2013lysosomal pathway . ExcessiAdditionally, reactive astrocytes and activated microglia populated in remote striatum, motor and somatosensory cortices 7 days post-tMCAO, potentially indicating an inflammatory response. Inflammation is a major event in ischemic stroke ,53,54. INeuronal pyknosis was also found in subacute ischemia in remote striatum, motor and somatosensory cortices. This post-ischemia damage potentially contributes to stroke pathology and inhibits recovery processes. Secondary neuronal damage and glial cell reactions were explored via two ischemic rat models . The resIn the ipsilateral hemisphere, diminished myelin was found in brain structures with neuronal damage. Decreased myelin was found in the contralateral hemisphere with reduced striatosome size. Communication between different regions of the brain is vital to normal brain function, making white matter damage harmful ,60. In oThe magnitude of the primary stroke lesion is important in predicting patient outcomes. However, the location of the lesion is also essential, especially during chronic stages. Motor recovery and functional outcome in hemiplegic stroke patients during the chronic stage had a stronger correlation with brain lesion size and location compared to that of only lesion size . Post-stAs noted in the preceding section, BBB pathological changes occur in both the ipsilateral hemisphere and contralateral brain regions, indicating the presence of subacute ischemic diaschisis . An assoChronic parenchymal extravasation was also revealed via electron microscopy imaging in ipsilateral and contralateral hemispheres ,74. The Excessive autophagosome production in both ipsilateral and contralateral striatum and motor cortex areas was observed in previous studies, primarily in subacute post-tMCAO settings, which was also exhibited in ECs in chronic stages due to the upregulation of Belcin-1 expression ,74. IncrThe analysis of vascular damage, such as BBB impairment, in cerebral brain structures represents a key pathological feature of chronic tMCAO at the ultrastructural levels ,74. AbnoAstrocyte reactivity in both ipsilateral and contralateral hemispheres displayed significant increases in glial fibrillary acid protein (GFAP) immunoreactivity in striatal areas of the ipsilateral hemisphere, while significant increases in GFAP expression were observed in the dorsal area of the contralateral striatum despite enhanced astrocyte reactivity in the striatum regions. The overexpression of bilateral astrocyte was only present in the dorsal striatum, but the causation of this phenomenon is unknown. Astrogliosis in the striatum may indicate spatial differences in astrocyte reactivity due to the structural location of the striatal area relative to the corpus callosum. Studies have demonstrated the degeneration of transcallosal fibers in subacute and chronic stroke settings using MRI . To explInvestigation of damaged BBB integrity in the cerebral hemisphere capillaries  in chronic post-ischemic rats may reveal chronic diaschisis. Large autophagosome accumulation and astrocyte degeneration led to EC impairment, ultimately inducing extensive microvascular damage and neuronal degeneration in chronic ischemia. Chronic diaschisis should be included in stroke therapeutic strategies, primarily reviving endothelial and astrocytic integrity for BBB repair. Cell therapy is a possible stroke treatment option for BBB repair by replacing dysfunctional ECs through EPC transplantation. Combining cell therapy with pro-inflammatory inhibitors may prove to be a worthy stroke treatment.Currently, the only FDA-approved treatment for ischemic stroke is tissue plasminogen activator (tPA) for dissolving the blood clot and improving blood flow in the brain. When tPA is administered intravenously up to 4.5 h after stroke onset in patients with acute ischemic stroke, it reduces mortality and increases the rates of independent ambulation when thrombolytic treatment is given early . HoweverIn MCAO-induced rat models, various cell types including bone marrow stromal cells , umbilicA feasible approach for stroke treatment may involve directly targeting cell delivery into the injured vasculature. Since pervasive BBB impairment is an important factor in ischemic stroke pathogenesis, BBB repair might serve as a primary target for cell therapy development. An early study has shown that the intrastriatal transplantation of bone marrow stromal cells in MCAO rats restored local cerebral blood flow and decreased BBB permeability . AdditioThe ability of transplanted human bone marrow EPCs (hBMEPCs) to repair the BBB in adult Sprague-Dawley rats subjected to tMCAO can be evaluated via electron microscopy . When \u03b2-With intravenously transplanted \u03b2-gal pre-labeled hBMEPCs into rats 48 h after tMCAO, the rats experienced vascular repair in the brain structures of both hemispheres via transplanted cell engraftment into the vascular wall, which helped to re-establish BBB integrity post-stroke . BBB repAt 7 days post-tMCAO, BBB damage in the ipsilateral and contralateral striatum and motor cortex was observed , consistIntravenously transplanted hBMEPCs in tMCAO rats provide beneficial effects that are visualized by quantitative mitochondrial morphology analysis within ECs and perivascular astrocytes. Mitochondrial alterations can lead to cellular energy deficits and oxidative stresses that result in cell death, and mitochondrial dysfunction can occur after stroke which results in the reduced number and size of the mitochondria in astrocytes , neuronaIn cell-treated post-tMCAO animals, numerous pinocytic vesicles found solely in engrafted hBMEPCs were present . TypicalThe pinocytic vesicles were found only in engrafted hBMEPCs within the cerebral capillaries of cell-treated post-tMCAO rats, and represent a new line of investigation for cell therapy . AdminisAlthough intravenously transplanted hBMEPCs replaced post-stroke damaged ECs, it is possible that the administered cells were involved in capillary sprouting, or might have extravasated to the brain parenchyma via paracellular migration across cell\u2013cell junctions similarly to leukocyte diapedesis in various pathological conditions, given the new vessel formation ,127. TraAdditionally, transplanted hBMEPCs might not only exogenously but also endogenously enhance post-stroke vasculogenesis, via the secretion of angiogenic or growth factors. Local transplantation of the human EC cell line improved endogenous vasculogenesis and neurogenesis by the VEGF signaling pathway . SignifiIn conclusion, \u03b2-gal pre-labeled hBMEPCs intravenously transplanted into rats 48 h after tMCAO engrafted within the capillary wall at 5 days after its administration and closely participated in the vasculature repair of the BBB in subacute stroke . The anaStroke is a devastating disease, and further investigation regarding the underlying pathophysiological changes is warranted so as to unveil an effective neurodegenerative treatment. Acute and chronic microvascular damage, as a result of ischemia, may act as a potential mechanism to target when contemplating stem cell therapy . Similar"}
+{"text": "Sex and gender are important sources of variation in Alzheimer\u2019s disease and related dementias (ADRD) and associated caregiving. Women comprise 2/3 of ADRD cases and the majority of ADRD caregivers. Sex encompasses biological differences due to sex chromosomes, reproductive tract, and hormones, while gender constitutes socioculturally constructed psychosocial aspects of sex. Several lines of research have begun to interrogate sex differences, but less is known about the relation of gender and lesbian, gay, bisexual, transgender, and/or queer (LGBTQ) status with ADRD. In this symposium featuring both trainees and faculty we highlight novel research addressing these factors from multiple perspectives. Two presentations address how psychosocial characteristics and their strengths of association with brain health may vary by gender. C. Elizabeth Shaaban presents analyses testing whether gendered psychosocial factors explain sex differences in white matter hyperintensities, a neuroimaging marker of cerebral small vessel disease and risk factor for ADRD. Justina Avila-Rieger presents results testing region of birth-based spatial patterning of dementia risk among Black men and women. Next, Jason Flatt presents prevalence estimates of subjective memory problems and dementia and describe factors associated with dementia among LGBTQ older adults. Finally, gender may also impact perceptions of individuals with dementia. Shana Stites explores gender differences in AD stigma and discuss implications for who is willing to be an AD caregiver. Michelle Mielke, an expert in sex and gender differences in neurodegenerative and age-associated diseases will facilitate conversation about these results and place them in the context of current sex and gender-based ADRD research."}
+{"text": "Recent conceptualizations of depression and supporting empirical work suggests that elevations and allievations of depressive symptoms can be understood from a dynamic systems perspective. Specifically, depression is proposed to result from strong-feedback loops in a system comprised of highly interdependent component parts . Supporting this perspective, individual differences in emotional interia and strong connections across emotions at micro-level timescales have been consistently associated with individual differences in depressive symptomatology such that individuals with greater emotional inertia and cross-emotion relations show higher levels of depressive symptoms. Importantly, however, individual differences do not necessarily translate to intraindividual change. The present study explores whether emotional connectivity at the daily timescale differs within individuals across a ten-year span and how these associations relate to intraindividual changes in depressive symptomatology. The results of these individual-level analyses will help further a dynamic systems perspective of depression and help inform clinical interventions for depression."}
+{"text": "The SmartPrompt phone-based reminder application was designed according to neuropsychological theory and pilot testing to facilitate everyday functioning. A laboratory-based pilot of ten participants with MCI and mild dementia showed significantly greater task completion with significantly fewer checking behaviors when using the SmartPrompt versus a control condition. Younger individuals and those who engaged in more checking behaviors completed more tasks in the control condition, but these relations were not significant when using the SmartPrompt. After 15 minutes of training, caregivers achieved near perfect scores on a SmartPrompt configuration quiz. Participant and caregiver usability ratings were strong, even though participants reported relatively low computer proficiency and neutral/unfavorable attitudes towards technology. Piloting informed modifications of the SmartPrompt to enhance personalization  and improved human-computer-interaction for in-home testing. Preliminary in-home test data on individually-owned smartphones and conclusions regarding barriers and facilitators to the effectiveness of the modified SmartPrompt will be discussed."}
+{"text": "Dear Editor:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder and affects up to 12 million individuals worldwide. Radiologic imaging is critical for successful management. Until recently, the treatments were only symptomatic but EMA in 2017 and FDA in 2018 approved Tolvaptan for ADPKD therapy. Renal imaging provide important diagnostic and management guidance in the monitoring of disease progression. In the past, standard radiographic imaging has not provided the accuracy necessary to reliably measure renal volume. With diagnostic advances, kidney volume growth is considered the principal surrogate marker predicting the decline of renal function in ADPKD; therefore the role of total kidney volume (TKV) has been investigated as surrogate endpoint in randomized clinical trials. TKV can be measured by ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) using manual, semiautomated, or fully automated data processing techniques.Using high-resolution MRI, the Consortium of Radiologic Imaging Studies of PKD (CRISP), observational cohort study of ADPKD subjects, investigated the ADPKD progression highlighting that MRI could accurately and reliably measure TKV cystic kidneys."}
+{"text": "This paper explored the effect of the type of health insurance on dentist visits among older adults in China. The data were drawn from the CHARLS-II (2013). The sample included older adults aged 60 and older =3272, n=3495). Multivariate logistic regression models indicated that in urban and rural places, respondents with a governmental/civil servants\u2019 insurance and those with an urban-employee insurance are more likely to visit a dentist in the survey year. Household registration status (hukou) does not play a significant role in dentist visits when insurance types are adjusted for. In other words, employment status, and the coverage of health insurance presented more significant effects on dentist visits. Differing from previous studies about urban-rural health disparities, this study disclosed substantial institutional influences on dental care access among older adults."}
+{"text": "Pulmonary vein stenosis or occlusion is a rare but one of the most devastating complications after catheter ablation for cardiac arrhythmias, and surgical repair is an option in severe cases. The sutureless technique, which avoids direct suture of vessel walls, was initially described for congenital pulmonary vein stenosis and has been widely performed due to its good restenosis-free rate.A 52-year-old male developed left pulmonary vein occlusion after catheter ablation for atrial fibrillation. The surgical repair with sutureless technique using the left atrial appendage was performed without any complications. Postoperative computed tomography demonstrated the revascularization of the pulmonary vein.The sutureless technique using the left atrial appendage is significantly reasonable particularly in case of left pulmonary vein stenosis or occlusion after catheter ablation for atrial fibrillation since it reduces the risks of restenosis and thromboembolism. Pulmonary vein (PV) stenosis occurs as a complication of catheter ablation for cardiac arrhythmia in 1\u20133% of patients [A 52-year-old male with AF underwent catheter ablation for two times. Eight months after the second maneuver for recurring AF, he presented with hemoptysis and exertional dyspnea. Computed tomography (CT) showed multiple consolidation in the left lung and ipsilateral pleural effusion Fig. . Three-dPV stenosis often develops as a congenital anatomical anomaly or anastomotic stenosis occurring after the repair of total anomalous PV connection, and several surgical repairs including endovenectomy, re-implantation of PV with direct anastomosis, or patchplasty have been described , 3. HoweThe sutureless technique using the LAA for the left PV stenosis or occlusion after catheter ablation for AF is a significantly reasonable procedure in terms of reducing the risks of restenosis and thromboembolism. Since the long-term outcome of this technique is still unknown, careful follow-up is required."}
+{"text": "Empathy for pain is a complex phenomenon incorporating sensory, cognitive and affective processes. Functional neuroimaging studies indicate a rich network of brain activations for empathic processing. However, previous research focused on core activations in bilateral anterior insula (AI) and anterior cingulate/anterior midcingulate cortex (ACC/aMCC) which are also typically present during nociceptive (pain) processing. Theoretical understanding of empathy would benefit from empirical investigation of shared and contrasting brain activations for empathic and nociceptive processing.Thirty-nine empathy for observed pain studies  were selected by systematic review. Coordinate based meta-analysis (activation likelihood estimation) was performed and novel contrast analyses compared neurobiological processing of empathy with a comprehensive meta-analysis of 180 studies of nociceptive processing (Conjunction analysis indicated overlapping activations for empathy and nociception in AI, aMCC, somatosensory and inferior frontal regions. Contrast analysis revealed increased likelihood of activation for empathy, relative to nociception, in bilateral supramarginal, inferior frontal and occipitotemporal regions. Nociception preferentially activated bilateral posterior insula, somatosensory cortex and aMCC.Our findings support the likelihood of shared and distinct neural networks for empathic, relative to nociceptive, processing. This offers succinct empirical support for recent tiered or modular theoretical accounts of empathy. Empathy is a critical concept in human emotional and social experience. The ability to share in the affective states of those around us brings evolutionary advantages, enabling us to respond to the needs of others, predict their behaviour and support decision-making about our own actions  and sociNociceptive (pain) processing is associated with wide-reaching patterns of neural activation which briefly encompass bilateral anterior, mid-and-posterior insula cortices, primary and secondary somatosensory cortex, inferior frontal gyri (IFG) and supramarginal gyri, as well as medial clusters in anterior cingulate/anterior midcingulate cortices (ACC/aMCC), thalami and brainstem .The Perception\u2013Action Model (PAM) of empathy , suggestHowever, current definitions of empathy suggest the involvement of automatic affective processing but also include aspects of higher order cognition. For example, empathy requires isomorphic sharing of feelings with another, but also necessitates awareness that one\u2019s state originates from observation of the target . In suppThe Russian-Doll model of empathy posits a tiered system with progressive levels of empathy from basic affective  to higher order processes such as sympathetic concern and emotional perspective taking . SimilarNeuroimaging studies demonstrate a heterogeneous profile of activation foci for empathy for pain , as were supplementary and manual searches. Both authors were responsible for assessment of articles for inclusion, and decisions over article inclusion were determined by discussion, disagreements where resolved via discussion or presented to a third arbiter (A.S.). One author (N.F.) extracted the relevant coordinate data, which was cross-checked and confirmed by a second (C.R.). Studies that reported coordinates in the Talairach space were converted into MNI using GingerALE software for the purposes of analysis and reporting.P\u2009<\u20090.001 uncorrected voxelwise throughout the whole brain with at least P\u2009<\u20090.05 cluster level correction  declared. We excluded papers which only reported ROI results.The criteria for inclusion were: (i) human fMRI studies published up until October 2019; (ii) original English language articles; (iii) published in a peer-reviewed journal; (iv) utilizing a paradigm including visual pain stimuli i.e. images, videos or animations of pain scenes or pain facial expressions; (v) employed an appropriate contrast with a suitable control stimulus ; (vi) coordinates were reported in the paper or supplementary material of the direct (pain > non-pain) contrast in either Montreal Neurological Institute  was implemented followed by cluster-level Family-wise error (FWE) correction (P\u2009<\u20090.05) to identify relevant ALE regions as recommended in recent publications (P\u2009<\u20090.05) and a minimum cluster size of 200\u00a0mm3 as previously recommended  middle frontal gyrus, and bilateral supramarginal regions .Contrast analysis comparing the ALE maps of concordant activations for each process pointed to significantly greater likelihood of activation during empathy for pain relative to directly perceived pain in 6 clusters encompassing bilateral supramarginal, IFG and occipitotemporal regions .The reverse contrast revealed six clusters indicative of increased activation likelihood estimates for directly perceived pain relative to empathy for observed pain. These regions encompassed two large bilateral clusters encompassing parietal opercular cortices (S2), posterior insula and S1. Right putamen was also evident for directly perceived pain relative to empathy. A right frontal cluster encompassing right prefrontal and dorsolateral prefrontal cortices was also elicited. Two medial clusters demonstrated increased concordance of activation in direct, relative observed, pain in aMCC .The findings of the ALE meta-analysis of empathy for pain revealed concordant activations to observed pain stimuli located in aMCC and bilateral AI which accords with previous investigations  were also performed for the first time. Empathy, compared to direct pain experience, demonstrated preferential bilateral activation in supramarginal regions, which extended superiorly to the supramarginal gyrus. Although supramarginal activations are frequently reported in fMRI empathy literature, their specific relevance is often not subject to discussion or interpretation, particularly if the basic empathy contrast is not the primary aim of the research . This poContrast analyses also pointed to bilateral occiptotemporal activations that were more likely to be engaged during observed pain, but not direct pain experience. Previous fMRI research have explained these activations for empathic viewing in terms of enhanced visual processing  or attenContrast analyses also revealed greater bilateral activation in ventral IFG during empathy for pain relative to direct experience of pain. The IFG is frequently activated during motor imagery or action observation type paradigms , it has ALE of directly perceived pain, compared to empathy, demonstrated preferential concordance of activation in bilateral S1, posterior insula and parietal operculum, right putamen, right prefrontal cortices and aMCC. Posterior insula and parietal opercular cortices represent the primary targets of nociceptors in the spinothalamic tract  and the From a theoretical perspective, the patterns of ALE seen in conjunction and contrast analyses show alignment with a tiered theoretical understanding of empathic processing such as the Russian-Doll model  or indepThe role of inferior parietal and occipitotemporal cortices for a broad range of social processing is a topic of considerable research, and a nexus of social processing extending from the angular gyrus of the TPJ anteriorly to supramarginal gyrus and posteriorly to occipitotemporal cortices was posited . Others The present study has some limitations. As mentioned, we focused on empathy for observed pain rather than more complex iterations of cognitive empathy such as paradigms which utilize learning to associate abstract cues with pain stimulation delivered to another person located outside of the scanner. The former design is more prevalent in fMRI research , allowinTo surmise the impact of the present study, elucidation of a rich functional brain network of empathy for pain, extending beyond AI and aMCC, is important for theoretical understanding of the phenomenon. The conjunction and contrast analyses reveal, for the first time, shared and distinct networks for observed and direct pain which supports the concept of tiered levels of processing of empathy as were previously theorized . The finTo conclude, the findings reveal concordance in an extensive bilateral network of brain regions for empathy for observed pain. This encompassed bilateral AI, supramarginal gyri, lateral occipitotemporal cortices IFG and aMCC, regions with functional relevance for interoception, pain processing, social cognition and self-other distinction. Utilizing novel contrast analyses for empathy for pain and direct pain experience, we demonstrated a broad network of shared brain representations which align to automaticity of response or emotional contagion, and empathy-specific activation patterns with relevance for higher order responses such as self-other distinction. Knowledge of these shared and distinct brain networks offers a novel insight into the neurobiological underpinnings of our subjective experience of empathy with relevance for theoretical, clinical and social applications.None declared.File013_nsaa090Click here for additional data file."}
+{"text": "Introduction: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality in the United States. Preexisting chronic health conditions may be confer increased CVD risk, specifically fibromyalgia (FM), a chronic condition characterized by widespread pain, fatigue, stiffness, and concentration problems. CVD risk increases with normal aging; however, characteristics of FM are suggested to exacerbate health profiles in normal aging processes that may contribute to increased CVD risk. Method: The sample included 221 older adults  and 55% reported an FM diagnosis. CVD risk factors were entered separately in a five-block hierarchical binary logistic regression model as predictors and included: cardiorespiratory fitness using the six-minute walk, BMI, standing and lying mean arterial pressure (MAP), and depression using the Beck Depression Inventory. Results: Logistic regression analyses revealed that poorer cardiorespiratory fitness , greater depressive symptoms  and lower standing MAP  were associated with higher odds of an FM diagnosis. However, no differences in lying MAP  or BMI  for an FM diagnosis emerged. Discussion: These data support the importance of examining the health profiles of persons with FM in the context of CVD risk. Experiences of FM may produce distinct health profiles with characteristics that serve as both protective and risk factors in the context of CVD."}
+{"text": "Some lower vertebrates such as zebrafish and axolotl have incredible cardiac regenerative potential while mammals have very limited ones. Comparative studies among species have revealed that cardiomyocyte polyploidy, endothermy, and injury-induced activation of certain transcriptional factors including AP1 complexes are critical for cardiomyocyte proliferation and heart regeneration during animal evolution. Gaining insights into these evolutionarily conserved mechanisms will likely lead to achieving heart regeneration in non-regenerative mammals including humans. Regenerative potential in the animal kingdom is a fundamental topic of regenerative biology and medicine. With the development of genome science and genetics technology, many investigators started to address how regenerative potential is lost or gained during the evolutionary courses of particular animal species. It is now documented that either whole-animal or organ regeneration is achieved by activating adult stem cells , by inducing Muller glia reprogramming into neurons in adult zebrafish retinas, or by promoting cardiomyocyte (CM) proliferation in adult zebrafish hearts, and neonatal mouse, rat, and pig hearts  are mononuclear diploid CMs during development, but they become mostly polyploid CMs at late gestation or early postnatal stages. The appearance of CM polyploidy conincides with the loss of cardiac regenerative potential in mice, rats, and pigs  increases CM proliferation and the percentage of MNCMs in neonatal and adult mice, and results in an evident improvement in cardiac function and fibrosis after myocardial ischemic reperfusion in adult mice. Consistently, exogenous application of thyroid hormone T3 inhibits heart regeneration with evident CM polyploidization and decreased CM proliferation in zebrafish. Thus, thyroid hormone signaling promotes CM polyploidy and decreases cardiac regenerative potential during animal evolution.Another elegant work has reported that the loss of cardiac regenerative potential is highly related with CM polyploidization via phylogenetic analysis of CM nucleation and polyploidy in a large collection of non-vertebrates and vertebrates, and the percentage of MDCMs inversely correlates with metabolic rate, body temperature, and serum total thyroid hormone T4 levels  for regulating CM nucleation and polyploidization, as well as non-coding DNA elements (regenerative enhancers) and binding factors (AP-1 complexes) for regulating CM proliferation. These and future studies will likely reveal a network of transcription factors and enhancers for coordinating CM proliferation and heart regeneration. In addition to these critical factors and regenerative enhancers, the field will take advantage of genome editing and chemical biology approaches to identify factors and small molecules that are sufficient for promoting non-regenerative heart regeneration in the coming years."}
+{"text": "Of the estimated 16 million U.S. family members currently providing essential yet unpaid caregiving for persons with dementia (PWD), many will also make end-of-life (EOL) care decisions as surrogates, a process that can be fraught with uncertainty. Even with dementia death rates rising, many families delay advanced care planning (ACP) discussions, and surrogate decision makers often lack crucial information and support, implicating the need to further study this topic in aging. While decision aids (DA) serve as a support tool for caregivers, they can be less effective when failing to address unresolved decisional needs. Utilizing the Ottawa Decision Support Framework (ODSF), which asserts caregiver decision needs affect decision quality, this study sought to identify surrogate decision-support needs extending beyond general ACP. This mixed study used cognitive interviews and focus groups with family caregivers (N=13) and healthcare professionals (n=14) to assess their knowledge and understanding of hospice and artificial hydration and nutrition. Data were audio-recorded, transcribed verbatim, and analyzed with thematic content analysis. Three main themes were identified: DAs alone aren\u2019t enough to foster quality decision making for surrogates; individualized communication is necessary to clarify PWD and caregiver value priorities and disease trajectories; and clarification of the impact of care choices within situational contexts is quintessential. Further development is needed to create a practice protocol from these themes to inform professionals assisting surrogates in ACP at EOL. Practical implications from this study include highlighting the importance of individualized communication between PWD, providers, and caregivers in addressing EOL care decisional needs."}
+{"text": "Community-dwelling older adults often experience cognitive symptoms, and three common conditions that contribute to changes in cognition are dementia, depression and delirium. Despite the clinical inter-connectedness among these medical conditions, hereafter referred to collectively as cognitive vulnerability, little is known about the potential for success of clinical interventions that simultaneously address these conditions. From the perspective of older adults with cognitive vulnerability and their families, hospital admissions and emergency department (ED) visits are disorienting and often lead to declines in functional capacity and well-being, and significant family distress, threatening continued independent living. In this Symposium, we present details about an ongoing clinical trial testing a novel in-home, multidisciplinary team care management intervention for older adults with cognitive vulnerability and their families. This care management intervention led by nurse practitioners, called the3D Team care model, aims to help reduce ED visits and hospitalizations and achieve other health-related outcomes. The first presentation will provide study background and design features as well as characteristics of study participants. The next two presentations by the3D Team nurse practitioners will provide details about how the multidisciplinary team works, and how each team member provides interventions intended to address risk factors for adverse health outcomes. The fourth presentation by the3D Team community health educator will explain how needs related to social determinants of health are addressed. The Discussant will place this clinical trial within the broader context of multidisciplinary team care for older adults with cognitive vulnerability led by nurse practitioners trained in geropsychiatry."}
+{"text": "Background\uff1aGratifying the elderly health-care demands and promoting high-quality of nursing services are based on the effort of long-term care(LTC) nurses. However, the high turnover rate of LTC nurses has become very serious in China. What remains unclear is whether the organizational justice and job characteristics affect the LTC nurses\u2019 intention to stay. Objective: The aim was to investigate intention to stay among LTC nurses in relation to organizational justice and job characteristics. Method: A cross-sectional study was conducted with a convenience sample of 545 LTC nurses. Data collection was performed between July and November 2019. Data were analyzed using structural equation modeling. Results: Most of LTC nurses reported to stay in nursing or current work place, however they still had strong desire to leave if there were other job opportunities. Organizational justice and job characteristics were significant predictors of LTC nurses intent to stay. LTC nurses job characteristics partially mediates the relationship between organizational justice and intent to stay. Conclusion: This would suggest the importance of administrators/ managers understanding how to promote organizational justice, foster a justice climate and increase LTC nurses\u2019 perceived job characteristics. The organizational justice culture programs should be develop as LTC nurses retention strategy."}
+{"text": "Post-traumatic bronchobiliary fistulas (BBF) are extremely rare with high morbidity and mortality rates. Accurate and timely diagnosis of these entities is critical for appropriate treatment, which usually requires a multidisciplinary approach. We describe two post-traumatic cases using a multimodality approach including computed tomography (CT), magnetic resonance imaging (MRI)/Magnetic Resonance Cholangiopancreatography (MRCP), and hepatobiliary scintigraphy with specific emphasis on the imaging features for each modality. Management of hepatobiliary fistulas is complex, involving extensive diagnostic work up followed by a conservative and/or surgical approach. Bronchobiliary fistula (BBF) is communication of biliary system and bronchial tree. It was first described by Peacock in 1850 . Post-trCase 1A 16-year-old male with history of penetrating injury (gunshot) to the right upper quadrant and right lower hemithorax complicated by biliary leak, diaphragmatic injury, and bilomas. Initial contrast-enhanced CT demonstrated multiloculated fluid collections in the right subphrenic space and small pleural effusion Figure , 1B . ThCase 2A 40-year-old male and victim of gun violence with surgical history of laparotomy, left hepatectomy, cholecystectomy and removal of two foreign bodies. Six days later, he underwent an endoscopic retrograde cholangiopancreatography (ERCP) which revealed extravasation of contrast from the common bile duct and he returned to the operating room for drainage of intraabdominal abscesses and a Roux-en-Y hepaticojejunostomy.Since then over several months he suffered from many hepatic abscesses, bilomas, cholangitis, and gram negative bacteremia, primarily managed with percutaneous drains and antibiotics. His clinical course was further complicated by misplaced drains and a biliarycutaneous fistula.Multiple admissions were made for management of the biliarycutaneous fistula, a most recent CT of the abdomen and pelvis demonstrated loculated collection in the hepatic dome extending into the right subdiaphragmatic space Figure , 2B. ThiThere is paucity of large case series in literature since post-traumatic BBFs are extremely uncommon. Most of the publications consists of case reports and small series. A systematic literature review of 68 cases published in 30 years by Liao et al. revealed only seven cases 10.2%) secondary to trauma [% secondaA significant clinical symptoms in patients with BBFs is bilioptysis. Bilioptysis is presence of bile in the sputum and believed to be pathognomonic finding for BBFs. Other common symptoms include irritating cough, fever, and jaundice .Penetrating injuries rather than blunt traumas are reported in etiology of bronchopulmonary fistulas .\u00a0Both ofInitial evaluation usually starts with CT which is useful to demonstrate liver injury, abdominal and thoracic fluid collections, as well as abnormal lung findings. The widespread availability, decreased variability between operators, imaging speed, and relatively few contraindications make it ideal in immediate traumatic assessment ,8.\u00a0HowevConventional MRI of the abdomen with MRCP (Magnetic Resonance Cholangiopancreatography) can provide good anatomical information of the biliary system. However, contrast-enhanced magnetic resonance cholangiography using hepatobiliary contrast agents was reported to demonstrate bronchobiliary fistula since it depicts biliary excretion from injured ducts . UnfortuHepatobiliary scintigraphy, similar to MR cholangiopancreatography with hepatobiliary contrast agents provide functional information. Image acquisition may be obtained for a prolonged time to trace bile movement. The precise location of bronchobiliary connection could not be confidently determined with this method even when SPECT was performed in the past. SPECT/CT as a hybrid imaging technique combining the functional information of hepatobiliary scintigraphy and anatomical information of CT overcomes the shortcoming and may clearly define fistulous tract .Management of BBF varies from a conservative approach to definitive surgical management. The conservative approach is preferred in the initial management of bile leaks. Biliary decompression or diversion using endoscopic sphincterotomy, biliary stent placement, or nasobiliary drainage and percutaneous image-guided catheter collections alone may be successful. More definitive treatment would require surgical resection of the fistula with pulmonary segmentectomy, especially in the presence of lung injury -15. ReceA multimodality approach is critical for stepwise diagnosis of BBFs. Although CT is used in initial evaluation of BBFs, hepatobiliary scintigraphy can confirm biliary leaks and differentiate bilomas from other fluid collections. Bile excretion and movement may be traced by sequential dynamic imaging. SPECT and more recently SPECT/CT may reveal connections between the bile ducts, bilomas and other structures such as bronchial tree and may play an important role in management of complex cases. MR cholangiopancreatography with hepatobiliary contrast agents also allows dynamic biliary imaging. It is an alternative to hepatobiliary scintigraphy and SPECT/CT and may demonstrate fistulous communications of the biliary system with high accuracy."}
+{"text": "Motor impairments, including slow walking, are common in older age in the absence of prototypical Parkinson\u2019s disease (PD). The etiology of such disturbances is heterogeneous and multi-system in nature. Dopamine is a key neurotransmitter involving motor, cognitive and behavioral circuitry. Normal aging is associated with substantial dopaminergic losses in the brain. Dopaminergic vulnerability of aging can be augmented by genotypic changes that may further compromise dopaminergic signaling, such as polymorphisms in the COMT gene. These observations may augur dopaminergic pharmacotherapy studies to treat gait disturbances in older adults. Prior dopaminergic therapy studies have shown overall limited effects in non-PD older adults. A major limitation of these studies is the non-targeted selection calling for personalized medicine approaches. Recent dopaminergic treatment studies targeting specific sub-groups of non-PD older adults conducted by us and others will be discussed."}
+{"text": "In the coming years, inevitably growing numbers of older populations will yield more older Americans with extensive medical and long-term care needs. This will lead to an increasing need for long-term services and supports (LTSS) to assist older adults with routine daily activities . There is a growing interest in understanding how social and physical environments contribute to health outcomes and the provision of services and resources for older persons with disabilities requiring assistance from LTSS. Decisions about care and subsequent experiences are likely a result of factors that extend beyond personal preference or individual factors, such as neighborhood quality, housing context, and living situations  among community-dwelling older adults. Given population aging and the shift of LTSS from nursing homes toward community settings, there is a pressing need for more information about contextual factors that might help better develop supports for vulnerable older adults. This symposium will feature four presentations that provide novel insight regarding social and physical contextual factors contributing to LTSS. Presentations leverage data from the National Health and Aging Trends Study (NHATS), a nationally representative survey of Medicare beneficiaries aged 65 and older, and will describe: 1) associations between individual and home environment risk-factors, neighborhood-level social deprivation, and falls; 2) the relationship between neighborhood-level social deprivation and caregiving intensity (number of hours of caregiving per week) among community-dwelling older adults; 3) associations between living in single-family vs. multi-unit housing and social networks; and 4) community tenure among homebound older adults."}
+{"text": "Novel technologies like navigation and robotic surgery are very costly and not easily available in all centres, especially in developing countries. We describe a simple method to assess the HKA alignment while performing coronal deformity correction around the knee using external fixator components which are commonly available with every centre.Coronal plane deformities of lower limb are often challenging and require a thorough pre-operative planning, accurate intra-operative assessment and execution. Intra-operative confirmation of correct restoration of lower limb alignment [Hip-Knee-Ankle (HKA) axis] is more often than not assessed by gross visual inspection, which can be fallacious. Various methods described in literature for intra-operative assessment include cable method, axis board, specialised alignment rods  with a connector, computer assisted surgeries, etcApparatus required for assessment of alignment includes external fixator rods and tube to tube connector clamps . ConnectWe have shown the application of this method using external fixator set from Greens\u00ae Surgicals Private Limited. However, external fixators from any manufacturer can be utilised for this purpose. We believe this simple method can be easily used by any orthopaedic surgeon in any centre without any additional efforts or cost."}
+{"text": "Neural injury in mammals often leads to persistent functional deficits as spontaneous repair in the peripheral nervous system (PNS) is often incomplete, while endogenous repair mechanisms in the central nervous system (CNS) are negligible. Peripheral axotomy elicits growth-associated gene programs in sensory and motor neurons that can support reinnervation of peripheral targets given sufficient levels of debris clearance and proximity to nerve targets. In contrast, while damaged CNS circuitry can undergo a limited amount of sprouting and reorganization, this innate plasticity does not re-establish the original connectivity. The utility of novel CNS circuitry will depend on effective connectivity and appropriate training to strengthen these circuits. One method of enhancing novel circuit connectivity is through the use of electrical stimulation, which supports axon growth in both central and peripheral neurons. This review will focus on the effects of CNS and PNS electrical stimulation in activating axon growth-associated gene programs and supporting the recovery of motor and sensory circuits. Electrical stimulation-mediated neuroplasticity represents a therapeutically viable approach to support neural repair and recovery. Development of appropriate clinical strategies employing electrical stimulation will depend upon determining the underlying mechanisms of activity-dependent axon regeneration and the heterogeneity of neuronal subtype responses to stimulation. Following injury to the adult mammalian central nervous system (CNS), neural circuits are permanently disrupted as severed axons fail to undergo spontaneous regeneration. The limited regenerative response of injured CNS neurons is due to both intrinsic and extrinsic factors. These growth-restrictive mechanisms play a large part in the poor clinical outcomes following brain or spinal cord trauma; however, despite limited regenerative capacity, mounting evidence has shown extensive spontaneous sprouting of CNS axon collaterals in the injured adult CNS.The mammalian nervous system has an intrinsic capacity for structural and functional reorganization in response to a variety of stimuli during development, learning, or in response to pathological insults . This inRecent findings suggest that manipulation of neuronal activity can drive plasticity related growth mechanisms and augment collateral sprouting, thereby enhancing the functional effect of axonal remodeling . ElectriIn contrast to most CNS neurons, neurons of the peripheral nervous system (PNS) have a more robust regenerative response to injury . This owDespite the innate regenerative potential of PNS neurons after injury, recovery of function remains limited. Several factors can hamper recovery, such as age, extent of injury and disruption of endoneurium, perineurium, or epineurium, and neuroma formation. One critical factor is the slow rate of regeneration in the adult PNS of 1\u20133 mm per day . Axons nThe innate regenerative ability of adult mammalian PNS neurons has been used as a model to study the intrinsic mechanisms underlying the regenerative program. Primary sensory neurons are located in the DRG and extend axons into both CNS and PNS. Each axon exhibits a distinct response to injury in the adult. As described above, the peripheral axon retains the ability to regenerate following axotomy. In contrast, the CNS axon of the same cell will fail to regenerate after spinal cord injury. Intriguingly, the regenerative program activated by peripheral nerve injury conditions DRG neurons to mount an enhanced regenerative response to a second injury, whether in the peripheral or central axon . The proAnother important change after conditioning lesion is the transient increase of second messenger cyclic nucleotide cAMP levels. Artificial elevation of cAMP can support a limited amount of sensory axon regeneration in the injured spinal cord . DownstrActivation of the pro-regenerative transcriptional response in the somata of regenerating neurons requires a retrograde signal from the injury site. One candidate for this rapid signal is the early influx of calcium at the injury site . Rapid cin vitro injury  stimulation   . Nitric (CamKII) . Piezo-m in vivo . Further in vivo . Genetic calcium . Blockad in vivo .PTEN deletion from RGCs and other CNS neurons leads to elevated PI3K/mTOR  signaling, enhanced phosphorylation of S6, and an increased capacity for axonal growth after injury  by high-contrast visual stimulation or via chemogenetics approaches can enhance optic nerve regeneration . In contr injury . Alternadeletion .suppressor of cytokine signaling 3 (SOCS3) increases optic nerve regeneration  have been largely defined as the coordinated and complementary genes activated by peripheral conditioning paradigms in PNS neurons. These include developmental growth-associated proteins , transcription factors , and signaling pathways  . In muchWhile electrical stimulation activates many of the same molecular pathways as peripheral conditioning via crush injury, it does not fully recapitulate the growth-promoting effects of conditioning. Following a subsequent peripheral injury, previous exposure to low-frequency electrical stimulation enhances the initiation of regeneration, but does not increase the rate of peripheral motor or sensory axon regeneration . The limin vivo by low frequency (20 Hz) electrical stimulation, 20 Hz trains separated by 5 min intervals arrested neurite outgrowth of primary sensory neurons in vitro  stimulation of the soleus muscle in the rabbit was used to shorten the time for recovery of soleus function after axonotmesis of the soleus motor nerve . This mod injury  is likeld injury .trans-spinal direct current stimulation after cervical spinal cord injury results in a strengthening of novel connections in the spinal cord. Furthermore, this paired stimulation paradigm can support the recovery of dextereous forelimb movements that depend on corticospinal function  is a non-invasive and painless neuromodulation strategy that augments motor and sensory function after SCI . CervicaAmong the different approaches that have been proposed to enhance post-lesion plasticity, extrinsic manipulation of neuronal activity by electrical stimulation is an attractive therapeutic approach. Electrical stimulation has been demonstrated to engage plasticity mechanisms in several central and peripheral neural circuits and has already shown feasibility in clinical settings. Development of appropriate strategies will likely depend upon the selective activation of desired neural subtypes in a temporally and spatially organized manner. Non-targeted electrical fields have been used to trigger population responses; however, it may be that distinct electrical stimulation parameters can selectively affect neuronal subtype responses and circuit-specific functional outcomes. Whether the molecular mechanisms activated by electrical stimulation are consistent across neuronal populations is unknown. The sprouting response of corticospinal axons to electrical stimulation contrasts with the elongation observed in stimulated PNS axons. These differences may arise from disparate stimulation parameters, discrete responses of these distinct populations to electrical stimulation, or from interactions of conserved stimulation-mediated molecular pathways with the intrinsic limitations of adult CNS neurons to axon elongation. Further studies will be required to identify whether CNS-tuned parameters of electrical stimulation can drive a regenerative response in transected corticospinal axons.In the context of SCI, preclinical and clinical studies have clearly demonstrated that the stimulation of local spinal networks can drive lasting functional improvements . CorticaJJ and EH wrote and edited the manuscript. SA created the illustrations. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We summarize how older women face intersectional experiences that affect their retirement security. These include differential trends in aging, life expectancy, labor supply, work history, retirement savings, and poverty at old age. We also highlight research showing that older women experience significantly more age discrimination than older men. affecting the ability for older women to improve their retirement security by working longer. We demonstrate through examples that these differential trends and intersectional experiences of older women have important policy implications. We provide examples of how Social Security policies, such as increases in the full benefit retirement age and changes to the retirement earnings test, have differential effects on older women. We also discuss how age and gender employment discrimination law fails to protect older women from intersectional sex-plus-age discrimination. We conclude by urging policymakers to consider how older women experience different challenges and how policy should consider their unique experiences."}
+{"text": "High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas. Intracranial gliomas are the most common primitive malignant neoplasms of the central nervous system, accounting for approximately 24.1% of all primary brain tumors .,56.55,56"}
+{"text": "This pilot study assessed a novel intervention to enhance both walking and executive function in older adults. The primary hypothesis was that eighteen sessions of frontal lobe tDCS combined with walking rehabilitation would be feasible, safe, and show preliminary efficacy. Eighteen participants were randomized to one of three intervention groups: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking . Outcome measures included multiple tests of walking function, executive function, and prefrontal activity during walking as measured by functional near infrared spectroscopy (fNIRS). Of the three groups, the Active/Complex group demonstrated the broadest improvements across outcome measures including for prefrontal activity. The functional range of prefrontal activity in this group was increased considerably, as conceptualized by the Compensation Related Utilization of Neural Circuits Hypothesis. Frontal tDCS is a promising adjuvant to walking rehabilitation."}
+{"text": "Older adults\u2019 psychosocial factors, including personality, are correlated with driving performance and driving cessation. However, the relationship between personality and driving styles has been examined only among young and middle-aged drivers. This study examined the relationships of personality factors and self-reported driving styles among 72 healthy older drivers aged 65-85  using the Multidimensional Driving Style Inventory (MDSI) scale to measure reckless and careless, anxious, angry and hostile, and patient and careful driving styles. Personality was accessed with the Big Five Personality questionnaire. Correlational results indicated that less conscientiousness was significantly correlated with increased reckless and careless and less patient and careful driving styles; and lower agreeableness was significantly correlated with greater angry and hostile and less patient and careful driving styles. Being a man was associated with greater reckless and careless and angry and hostile driving styles. Age was not associated with driving styles. Accordingly, three regressions were tested. After controlling for gender, only lower conscientiousness was associated with greater reckless and careless driving style . Men had a higher risk of reckless and careless  and angry and hostile  driving styles. Our results highlight the relationship between personality traits and self-reported driving styles among older adults, and how gender may influence some of these relationships. Future research should further investigate the associations between gender and personality traits and older adults\u2019 driving mobility and safety."}
+{"text": "Certain emotion regulation (ER) strategies are often considered to be more or less demanding of cognitive resources. However, age-related differences in the perceptions of these demands are not yet understood. Older adults might perceive greater demands for certain strategies due to differences in cognitive ability and motivation to maintain emotional well-being. In the present study, we examined age and cognitive ability as predictors of perceived effort required to use ER strategies that span all families of the process model. A diverse sample of community participants (age 22-83) completed assessments of cognitive ability and perceived demands associated with ten ER strategies. Overall, response-focused strategies were rated as highest in demands whereas situation selection and savoring were perceived as least demanding. Older adults reported higher demands associated with situation selection, distraction, and detached reappraisal  compared with younger adults. Cognitive ability was not associated with perceived demands for ER strategies traditionally viewed as cognitively demanding . Rather, higher cognitive ability only predicted lower perceived demands for strategies often considered low in demand: situation selection and savoring. Perceived ER success was not consistently associated with age or cognitive demands. Results suggest that older adults view some, but not all, ER strategies as more demanding than younger adults do. The role of cognitive ability in age-related changes in ER may be more complex than previously expected. Notably, the lack of findings with perceived ER success suggest effort requirements associated with ER may not impede ability to successfully regulate across adulthood."}
+{"text": "E. coli and quantify ppGpp within several strains using a recently developed analytical method. We find that although the inverse correlation between ppGpp and growth rate is robust across strains and analytical methods, absolute ppGpp concentrations do not absolutely determine RNA synthesis rates. In addition, we investigated the consequences of two separate RNA polymerase mutations that each individually reduce (but do not abolish) sensitivity to ppGpp and find that the relationship between ppGpp, growth rate, and RNA content of single-site mutants remains unaffected. Both literature and our new data suggest that environmental conditions may be communicated to RNA polymerase via an additional regulator. We conclude that basal ppGpp is one of potentially several agents controlling ribosome abundance and DNA replication initiation, but that evidence for additional roles in controlling macromolecular synthesis requires further study.The molecule guanosine tetraphophosphate (ppGpp) is most commonly considered an alarmone produced during acute stress. However, ppGpp is also present at low concentrations during steady-state growth. Whether ppGpp controls the same cellular targets at both low and high concentrations remains an open question and is vital for understanding growth rate regulation. It is widely assumed that basal ppGpp concentrations vary inversely with growth rate, and that the main function of basal ppGpp is to regulate transcription of ribosomal RNA in response to environmental conditions. Unfortunately, studies to confirm this relationship and to define regulatory targets of basal ppGpp are limited by difficulties in quantifying basal ppGpp. In this Perspective we compare reported concentrations of basal ppGpp in  Escherichia coli, the small molecule guanosine tetraphosphate (ppGpp) is closely tied to growth rate control. However, due to the circumstances of its discovery, ppGpp is more familiar as a stress or starvation signal. ppGpp and guanosine pentaphosphate (pppGpp), collectively called (p)ppGpp, were first identified in E. coli as compounds produced in strains that inhibit stable RNA synthesis upon amino acid starvation, a phenomenon known as the stringent response (\u20131 for ppGpp) (E. coli (How might a bacteria cell measure its own growth rate? In the model bacterium response . The souresponse . The higr ppGpp)  drive prr ppGpp) . The ove(E. coli  we focusE. coli in the absence of stress (between 10 and 90 pmol OD\u20131). When growth rate is varied by nutritional quality, basal ppGpp correlates inversely with growth rate. Basal ppGpp is essential in minimal media as it is required to activate transcription of amino acid pathways ppGpp0] does not vary DNA replication initiation in response to growth rate, suggesting that ppGpp participates in regulating the DNA-biomass ratio  like an emergency brake.The observation that high ppGpp concentrations inhibit biomass synthesis suggests that basal ppGpp concentrations might also directly regulate all biomass synthesis pathways during steady-state growth, in addition to regulating stable RNA synthesis. This hypothetical layer of regulation would complement control of rRNA transcription, which determines the maximum rate of is PurF,  or transis PurF,  or the fis PurF, . Basal pis PurF, , as highis PurF, . In thisE. coli controls growth. To further encourage the recent revival of interest in the mechanisms of steady-state growth regulation and homeostasis  its low abundance; (2) its chemical instability; (3) the presence of environmentally sensitive enzymes that rapidly hydrolyze and synthesize ppGpp. This means the analytical method must both chemically stabilize ppGpp and immediately denature all enzymes that synthesize or hydrolyze ppGpp. Moreover, in order to study ppGpp dynamics relevant to the rapid ppGpp response (<5 s), the method must enable fast sampling.Actual ppGpp measurements are essential for determining which cellular processes are watching the growth rate speedometer. The rarity of basal ppGpp measurements is understandable as basal ppGpp is difficult to accurately quantify. The main challenges in measuring basal ppGpp Despite these difficulties, several (p)ppGpp measurement methods have been developed, including thin layer chromatography (TLC) , high peA survey of reported basal ppGpp concentrations combined with our own measurements  indicateE. coli show an inverse correlation between growth rate and basal ppGpp (15\u201390 pmol OD\u20131)  . Early sol OD\u20131) . Khan aned trend . Howevered trend .Reported ppGpp concentrations may differ perhaps due to differences in strains, turbidimeter calibration, or sampling method . InteresE. coli K-12 strains using LC-MS (rph+ but not isogenic with the MG1655 reported here) has been used to demonstrate correlation between the RNA/protein ratio and the growth rate  artificially elevates ppGpp, inhibits rRNA synthesis and decreases growth rate. Data from ppGpp titrations using RelA\u2032 are compared in E. coli NCM3722 in both LB medium and glucose minimal medium yields a ppGpp-growth rate curve steeper than the curve obtained in nutrient-limited NCM3722   . Howeverincreases in parallel with growth rate. E. coli mutants unable to synthesize specific nucleotides [carAB- guaB(ts)]. When growth rate was titrated with pyrimidine and purine sources, the authors inverted the correlation between ppGpp and growth rate  supply? First, uracil limitation does not activate ppGpp synthesis in wild-type strains , indicatE. coli glucose cultures. Pseudomonic acid causes accumulation of uncharged tRNA and increases ppGpp. High concentrations of pseudomonic acid abruptly increased ppGpp and rapidly arrested growth, consistent with the stringent response. Low concentrations of pseudomonic acid also triggered ppGpp synthesis (up to 60\u2013100 pmol OD\u20131) and an immediate but smaller decrease in rRNA synthesis. However, the instantaneous growth rate  was not perturbed in the short term by small increases in ppGpp concentrations.Steady-state correlations such as the correlation between ppGpp and growth rate imply but do not establish regulatory connections. Hypotheses inspired by correlations must be tested by environmental perturbations. \u20131) do not seem to immediately inhibit biomass synthesis (with the exception of stable RNA). This undermines any notion that basal ppGpp directly regulates the instantaneous translation rate. Finally, two additional studies demonstrate that ppGpp and the rate of stable RNA synthesis can be transiently decoupled during nutritional upshifts, suggesting that additional signals may regulate rRNA synthesis  retains regulation by basal ppGpp if its two ppGpp binding sites are disrupted, we measured basal ppGpp levels, growth rates and cellular RNA in  mutants , 2016. ArpoZ(wt) rpoC R362A R417A K615A; rpoC N680A K681A; We transferred mutations that disrupt ppGpp binding site 1 [rpoC2- mutant in LB medium. At first glance, this is consistent with the notion that the RNAP mutants are less sensitive to ppGpp, as apparent from the slopes of cellular RNA content vs. ppGpp (P < 10\u20136). In other words, higher ppGpp concentrations may be required to inhibit RNA synthesis in these strains. While it might be expected that the cultures expressing ppGpp-insensitive RNAP thus contain a higher RNA abundance than wild-type, we found that for every medium aside from MOPS/acetate, both mutant strains exhibit equivalent or even less RNA per OD unit than does the wild-type  deserve fuller exploration as they likely hint at poorly understood facets of ppGpp biology. Disrupting either individual ppGpp binding site of RNAP did not eliminate the correlation between growth rate, RNA content, and basal ppGpp concentrations. Despite compelling evidence for basal ppGpp control of rRNA synthesis, incorporating ppGpp into quantitative models of cell behavior requires a better understanding of both transcriptional and post-translational targets. In order to advance this goal, we suggest several questions for the field:1.What targets are responsive to basal ppGpp concentrations? As basal ppGpp varies with growth rate in parallel with all biosynthetic fluxes during balanced growth, it is tempting to overextend models of ppGpp control. Targets thought to be regulated during the stringent response may prove insensitive to basal ppGpp. Experiments that monitor ppGpp during growth transitions already suggest that small changes in basal ppGpp do not immediately affect instantaneous protein synthesis or total biomass production. Studies of basal ppGpp concentrations during growth transitions are essential for distinguishing what is influenced by ppGpp. We suggest experiments that monitor protein synthesis during small controlled variations in basal ppGpp (\u00b150 pmol OD\u20131).2.What establishes basal ppGpp concentrations? It is unknown which metabolic cues drive RelA and SpoT to generate basal ppGpp.3.What regulates stable RNA synthesis during steady-state growth, aside from basal ppGpp? Our observation that RNA polymerase mutants lacking either one of the two ppGpp binding sites still exhibit an inverse relationship between RNA content and ppGpp concentrations implies that other factors also regulate RNA content, as has been suggested  would also determine whether basal ppGpp is an accurate growth rate speedometer.5.Do all species with RSH proteins also maintain basal concentrations of ppGpp (or pppGpp) during steady-state growth? As RSH proteins are widely distributed  and defined media to enable comparisons between labs.We further recommend the use of common reference strains (preferably All datasets generated for this study are included in the article/NI and GB conceived and designed the experiments and wrote the manuscript. NI performed experiments and data analysis. NI, NB, and MN developed the LC-MS method. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This study compared gait speed changes after CSF tap test in patients with idiopathic normal pressure hydrocephalus presenting with various gait phenotypes . All patients improved, except those with parkinsonian gait. Gait disorders are the hallmark feature of patients with idiopathic normal pressure hydrocephalus (iNPH) /[(gait speedpost-CSF tap test\u2009+\u2009gait speedpre-CSF tap test)/2]. Univariable linear regressions evaluated the relationship between gait speed changes  and each gait phenotype . Multivariable linear regressions were adjusted for age, gender, comorbidities, white matter changes assessed by the age-related white matter change scale . Frontal gait was significantly associated with gait speed improvement after CSF tap test, even after adjusting on age, gender, comorbidities, white matter changes, and MMSE . Normal gait, parkinsonian gait, and other gait abnormalities were not significantly associated with gait speed improvement, after adjusting on age, gender, comorbidities, white matter changes, and MMSE .Clinical characteristics are presented in Table This study showed that gait improvement after CSF tap test varies across gait phenotypes: frontal gait is associated with the greatest gait improvement after CSF tap test, while patients with parkinsonian gait did not show any significant gait speed changes.p value\u2009<\u20090.001). Patients with frontal gait presented the lowest gait speed at baseline and, therefore, had the greatest potential of improvement, as previously described  may be explained by the following reasons. First, patients were included at an early stage of the disease course, where clinical gait abnormalities may not be evident. Second, patients have been referred, because the suspicion of iNPH was solely based on cognitive impairment and/or urinary incontinence. Third, patients may complain of gait impairments in challenging situations  or balance impairments that were not clinically evident in the secure setting of a gait laboratory. Fourth, they presented fewer comorbidities that may affect gait. These results suggest that CSF tap test could also be considered at the earliest stages of iNPH when patients complain about their gait, but no clinical gait abnormality is diagnosed by physicians.The variability of the gait phenotypes in our cohort of iNPH patients may be explained by comorbidities . However, the validity of the clinical examination  is not perfect and prone to an interrater variability. Having a better quantification of neurological and non-neurological comorbidities would allow a better sense of the influence of comorbidity on each gait phenotype. A post-mortem pathological examination is missing and would be of interest, especially in this cohort including mainly patients with possible iNPH (87%), who may present either a comorbid neurological condition along with iNPH or present an iNPH mimic. Finally, future studies should confirm these results by evaluating the predictive value of clinical gait phenotypes after shunting.Among gait phenotypes, frontal gait in patients with iNPH is associated with the largest gait improvement after CSF tap test. This study suggests that a clinical classification of gait phenotypes in patients with iNPH may inform about the reversibility of gait disabilities. Future studies should include long-term clinical outcomes after shunt procedure to confirm that frontal gait in iNPH patients may present a good clinical outcome in comparison to other gait phenotypes."}
+{"text": "Calcifications play an essential role in early breast cancer detection and diagnosis. However, information regarding the chemical composition of calcifications identified on mammography and histology is limited. Detailed spectroscopy reveals an association between the chemical composition of calcifications and breast cancer, warranting the development of novel analytical tools to better define calcification types. Previous investigations average calcification composition across broad tissue sections with no spatially resolved information or provide qualitative visualization, which prevents a robust linking of specific spatially resolved changes in calcification chemistry with the pathologic process.Method: To visualize breast calcification chemical composition at high spatial resolution, we apply hyperspectral stimulated Raman scattering (SRS) microscopy to study breast calcifications associated with a spectrum of breast changes ranging from benign to neoplastic processes, including atypical ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. The carbonate content of individual breast calcifications is quantified using a simple ratiometric analysis.Results: Our findings reveal that intra-sample calcification carbonate content is closely associated with local pathological processes. Single calcification analysis supports previous studies demonstrating decreasing average carbonate level with increasing malignant potential. Sensitivity and specificity reach >85% when carbonate content level is used as the single differentiator in separating benign from neoplastic processes. However, the average carbonate content is limiting when trying to separate specific diagnostic categories, such as fibroadenoma and invasive ductal carcinoma. Second harmonic generation (SHG) data can provide critical information to bridge this gap.Conclusion: SRS, combined with SHG, can be a valuable tool in better understanding calcifications in carcinogenesis, diagnosis, and possible prognosis. This study not only reveals previously unknown large variations of breast microcalcifications in association with local malignancy but also corroborates the clinical value of linking microcalcification chemistry to breast malignancy. More importantly, it represents an important step in the development of a label-free imaging strategy for breast cancer diagnosis with tremendous potential to address major challenges in diagnostic discordance in pathology. Calcifications associated with breast disease are critical to breast cancer screening as they are often the only discernible indicator of risk in mammography Despite their diagnostic and prognostic potential, the morphologic and chemical features of calcifications are poorly understood, in part due to technological limitations. Morphological features of calcifications identified by mammography are insufficient for accurate diagnosis and prognosis. In addition, smaller calcifications (<0.1mm) are undetectable using mammography Moving beyond morphology and distribution patterns in breast calcification, studies utilizing X-ray diffraction and electron microprobe analysis with scanning electron microscopy (SEM) have contributed to an earlier understanding of calcification chemical differences While offering information about calcification chemistry, most spectroscopic methods average calcifications within multiple ducts within a tissue section, irrespective of the heterogeneous pathologic processes among adjacent ducts. Spatially resolved methods such as FTIR imaging have limited resolution and throughput, prohibiting visualization of calcification composition variation within adjacent ducts and lobules. Moreover, tissue protein content is recognized to correlate with malignancy We utilize the high resolution and chemical specificity SRS offers to deliver an unprecedented level of detail when analyzing calcifications. Additionally, we incorporate second harmonic generation (SHG) which has been proven effective at visualizing collagen in the tumor microenvironment -1 for total of 90 frames per stack. For SHG, a dichroic mirror (Chroma 695dcxr) is placed before the objective to allow for epi-collection of SHG signal from the sample. The SHG signal is detected by a photo-multiplier tube (Hamamatsu H10770PA-40) using 485 nm long pass and 650 nm short pass filters.A broadband femtosecond dual-beam laser system (Insight DS + from Spectra-Physics) was used for SRS and SHG Figure . The detCalcium hydroxyapatite (HAP) and 10% carbonated hydroxyapatite (CHAP) were obtained from Sigma Aldrich and Clarkson Chromatography Products respectively. Both solid controls were ground using mortar and pestle. A total of five mixtures were prepared for calibration purposes . The calibration samples were placed between a coverslip and a microscope slide for SRS imaging.Breast tissue was obtained from 17 patient archival cases (including biopsy and resection) managed by Northwest Biotrust, Seattle, WA. The initial case selection was based on the pathology report . Slides were subsequently reviewed to confirm the histologic diagnoses . Formalin-fixed paraffin-embedded tissue blocks were retrieved from archives and sectioned at 4-microns and mounted on charged slides. One section was H&E stained to identify pathological process. The adjacent section was deparaffinized and coverslipped for SRS and SHG analysis. The areas of interest were identified in the bright field based on selected areas of interest on adjacent H&E stained slides. A total of 214 breast calcifications were imaged, including: 31 non-neoplastic calcifications , 27 fibroadenoma (FA) associated calcifications, 8 atypical ductal hyperplasia (ADH) associated calcifications, 36 ductal carcinoma in situ (DCIS) associated calcifications, 112 invasive ductal carcinoma (IDC) associated calcifications. -1) and phosphate (~960 cm-1) peaks corrected for background Calibration samples with 0%, 2.5%, 5.0%, 7.5%, 10% carbonate content in calcium hydroxyapatite mixtures were imaged using the hyperspectral SRS microscope described above. Using SRS intensities at carbonate (~1070 cm-1) was used to visualize tissue morphology of the FOV  the average, for a given category , was calculated with the standard deviation reported as an error bar. The differences between categories were assessed using p-values calculated from Student's t-tests. The receiver operator curves (ROC) were calculated using R software to assess the sensitivity and specificity for each parameter. Maximum Youden's index was used to determine sensitivity and specificity values.Previously, the carbonate content in hydroxyapatite has been measured using RS Figures Breast tissue submitted for pathological examination often contains calcifications in multiple ducts, which may represent various pathologic processes. In previous spectroscopic studies, multiple ducts are frequently measured together, which can average calcifications associated with different processes. Isolating individual breast ducts and detailing the histopathology within the ducts allows for correlation of variation in carbonate content with local pathology.Here, we group calcifications by specific pathological processes and not by overall case diagnosis. In Figure Figure The two cases illustrate that calcifications in the same patient case can have differing chemical composition. Although ducts are present in the same tissue section, the carbonate content associated with individual ducts is markedly different and reflects underlying pathological process. The high spatial resolution of hyperspectral SRS imaging is important to resolve calcification heterogeneity within the same patient sample and to establish the relationship between chemical composition and pathological process.Previous studies using FTIR have demonstrated that breast calcifications with lower carbonate content of CHAP correlate with malignancy Figures The neoplastic progression from benign ducts to IDC is associated with an overall decrease in calcification carbonate content Figure F and 6G Although precise quantification of the spatial distribution of carbonate in large calcifications is challenging due to sectioning artifact, our findings suggest that the carbonate content decrease on the edges of the calcifications directly reflects the changing microenvironment (i.e. higher acidity) associated with neoplastic cells and necrotic debris -1) to phosphate (~960 cm-1) ratio is used to quantify protein content in calcifications  and specificity (88%) when identifying benign and invasive processes. SHG data provides a parameter separating FA from IDC cases with high sensitivity (94%) and specificity (85%). Phenylalanine to phosphate ratio provides additional separation between DCIS and IDC. Together, spectroscopy and morphology can be utilized to better establish the malignant potential in cases with ambiguous morphology on H&E alone.CHAP is not the only microcalcification species that was identified in breast cancer. Although whitlockite typically accounts for a tiny percentage of breast calcifications -1 to 970 cm-1) Typically, whitlockite can be identified using Raman spectroscopy due to unique spectral features . This problem can be addressed in future studies by imaging either fixed tissue or fresh tissue, where calcifications remain intact.Besides carbonate content of calcifications, we have elucidated the unique features that distinguish chemical composition of calcifications between FA and IDC. For the first time, we demonstrate that SHG data confirms collagen in FA makes an organic matrix upon which hydroxyapatite accumulates. This matrix observed in FA calcifications is one of the main differences between FA and IDC. This collagen matrix enables robust differentiation of FA and IDC, which exhibit similar carbonate content.In conclusion, we imaged a diverse set of breast calcifications associated with benign processes, and a range of neoplastic processes including FA, ADH, DCIS and IDC. Our findings support previous reports of carbonate content decreasing on average with increasing malignant potential. Importantly, we showed that a detailed spatial map of calcifications and their complex underlying organic matrix is highly correlated with underlying neoplastic processes and could potentially be used for breast cancer diagnosis. Additionally, the spatial heterogeneity of carbonate content could potentially be a diagnostic indicator of malignancy. Calcification underlying organic matrix, visualized using SHG in conjunction with SRS, assisted in the diagnostic differentiation of patient lesions. Our study suggests that SRS imaging of calcification can be used as an important tool for breast cancer diagnosis. The diagnosis capability will be significantly improved when combined with stimulated Raman histology (SRH), a technique that has already been shown to provide H&E equivalent information in unsectioned tissue Supplementary figures and tables.Click here for additional data file."}
+{"text": "Recent changes in health care practices - shorter hospital stays, increased complexity of disease management, and greater management of chronic illnesses at home - have left family members increasingly responsible for medical tasks. Although these family caregivers represent the vital front line of care, they remain mostly excluded from the formal health care team. Based on interviews with multi-sector stakeholders representing patients/caregivers, providers, and payers, we identified several barriers to fully incorporating family caregivers into the health care team. They fall under five key themes: identification of caregivers; communication and information; time and resources; trust and cultural barriers; and Medicaid coverage. We discuss these barriers and potential solutions that could be undertaken by different stakeholder groups to improve family caregiver integration into the care team."}
+{"text": "The number of older populations raising their grandchildren has increased. Past research has indicated the distress custodial grandparents\u2019 experience is related to their family relationships . Family relationships are also influenced by a variety of factors such as social history, culture, family structure, and individual differences . The current study evaluated the influence of culture on the relationship between caregiver relationship quality and mental health by examining 885 children . This study also compared the difference in cultural impact between custodial grandparents-grandchildren and biological parents-children. Measures included the Network of Relationships Inventory, Hofstede Cultural Questionnaire, and Adult Behavior Checklist. Path analysis was conducted using AMOS 26.0 which resulted in an interaction between relationship closeness and collectivism to predict custodial grandparent depressive symptoms. Custodial grandparents who reported a lower level of closeness with their grandchildren in a higher collectivistic culture reported a significantly higher level of depression symptoms than those in a more individualistic culture, particularly for custodial grandmothers. However, custodial grandparents who reported a higher level of closeness with their grandchildren in a higher collectivistic culture reported significantly lower levels of depressive symptoms than those in a more individualistic culture. Furthermore, compared to biological parents, custodial grandparents reported significantly lower levels of depressive symptoms when reporting higher collectivistic culture. These findings will inform the need for more research to assess factors of cultural features that reduce psychological problems and support family relationships to adapt psychological therapies in older adults."}
+{"text": "This study examined the relationships between several attributes of living environment and attitudes towards aging among persons of age 75 years and older in Shanghai, China. The data were collected using self-administered surveys in a study of successful aging in 2018. Respondents included 139 persons of age 75 years and older living in 12 neighborhoods in Shanghai. Attitudes towards aging were measured by indices of happiness, time use and worry about the future. Using BaiduMap and GIS ArcPro, we quantified accessibility to neighborhood living resources as numbers of recreational facilities, medical facilities, parks, and grocery stores located within 500 meters of each respondent\u2019s home. The analysis found that more positive attitudes towards aging were correlated with less depressive symptom as measured by CES-D and greater numbers of neighborhood resources near home, especially greater number of grocery stores near home. In conclusion, accessibility to neighborhood resources may influence attitudes towards aging."}
+{"text": "As a consequence of the Affordable Care Act\u2019s enhancements of Medicare benefits, certain recommended clinical preventive services became available to Medicare beneficiaries without cost-sharing. We study the impact of these mandates on racial/ethnic disparities in the use of preventive services among traditional Medicare beneficiaries. We analyze nationally representative data on non-institutionalized Medicare seniors from the 2006-2016 Medical Expenditure Panel Survey . Our preventive services of interest include yearly receipt of cholesterol check, blood pressure test, flu shot, endoscopy, blood stool test, clinical breast examination, mammography and prostate exam. We estimate propensity score weighted difference-in-difference (DID) models to test for differences in preventive services utilization by race/ethnicity. Among traditional Medicare beneficiaries, we do not observe significant change in the use of most preventive services for Blacks and Hispanics compared to their White counterparts. However, Hispanics have significantly increased their use of blood stool tests relative to whites. Overall, we do not find major evidence to support a differential effect of reforms on race/ethnic minorities\u2019 uptake of preventive services following the mandates. Our results suggest that despite an overall benefit trough services expansion and cost-sharing elimination race/ethnic group differences persist. As such, disparities might continue and would require additional interventions. Reduction in disparities is a stated goal of US policy for many decades and achieving equity might require additional work and more varied and targeted interventions."}
+{"text": "Metastatic cancer patients undergo numerous treatment strategies with known cognitive side effects. It is unclear how medical decision-making capacity (MDC) is impacted by cognitive deficits in metastatic cancer. This study examines reliability of an objective measure of MDC compared with self-report. Participants with newly diagnosed metastasis to the brain and other sites were enrolled at the University of Alabama at Birmingham over seven years. At the study visit, participants completed a comprehensive neuropsychological battery including memory and executive functioning, and the Capacity to Consent to Treatment Instrument (CCTI) assessing medico-legal domains of MDC. The CCTI is a reliable and valid instrument containing two vignettes of hypothetical medical situations assessing four standards of consent. We examined reliability between the CCTI and self-reported MDC using Gwet\u2019s AC1 statistic. Participants with brain metastasis with impairment on the CCTI demonstrated significantly lower executive functioning and memory skills than those without impairment . There were no significant differences between intact and impaired participants with other metastases. Low reliability was observed between self-report and all medico-legal standards on the CCTI across both metastatic groups . Self-rating of MDC is unreliable in metastatic cancer patients. Patients with metastases (particularly brain metastases) may lack awareness of deficits in their MDC, so providers must affirm proper autonomy in their decisions."}
+{"text": "A paradoxical double challenge has emerged in the last decades with respect to nutrition and nutrition-related clinical conditions. Hunger-related undernutrition continues to represent an unacceptable burden, although its prevalence has been encouragingly reduced worldwide. On the other hand, the prevalence of overweight and obesity, defined as fat excess accumulation with negative impact on individual health, has dramatically increased due to increasingly pervasive obesogenic lifestyle changes. Undernutrition and obesity may coexist in world regions, Countries and even smaller communities and households, being referred to as double burden of malnutrition. It is however important to point out that fat accumulation and obesity may also induce additional nutritional derangements in affected individuals, both directly through metabolic and body composition changes and indirectly through acute and chronic diseases with negative impact on nutritional status. In the current narrative review, associations between fat accumulation in obesity and malnutrition features as well as their known causes will be reviewed and summarized. These include risk of loss of skeletal muscle mass and function (sarcopenia) that may allow for malnutrition diagnosis also in overweight and obese individuals, thereby introducing a new clinically relevant perspective to the obesity-related double burden of malnutrition concept. Natu2 \u20135. Indee2 , 7, 3, 4e groups , 6, 9.Based on the above observations, new complex nutritional challenges have emerged in recent times, with epidemiological shifts and coexistence of under- and overnutrition. The latter concept has indeed been recently described under the definition of \u201cdouble burden of malnutrition\u201d, indicating that both under- and overnutrition are commonly observed not only at global level but may indeed coexist in the same world regions and often in the same Countries and communities. Coexistence of seemingly opposite nutritional patterns may obviously partly reflect social and economic inequalities, but additional important reasons should be pointed out. In particular, enhanced life expectancy is increasing older adult population worldwide, and elderly individuals are commonly more prone to undernutrition due to multifactorial reasons that include psychological, social and health-related factors \u201312. EvenThe ongoing unprecedented shift in body weight paradigms is however posing larger dramatic individual, family, socio-economic and healthcare challenges . ObesityNegative obesity- and disease-related influences on skeletal muscle mass and function maintenance are summarized below. It is increasingly clear that profound alterations in skeletal muscle metabolism may occur in obesity with potential negative impact on whole body muscle mass and function , 26. Bodprimary metabolic abnormalities and insulin resistance: although a sizable portion of the obese population is not insulin resistant, a large majority of insulin resistant persons is either overweight or obese, or it presents with excess fat accumulation in the abdominal visceral compartment , 30. Subectopic muscle fat accumulation: muscle lipid accumulation commonly results in obesity from impaired adipose tissue expansion in the presence of excess lipid availability. Skeletal muscle fat accumulation is conversely closely associated with tissue and systemic insulin resistance , 48. Mecmitochondrial dysfunction: mitochondrial changes may not occur in obese individuals and become relatively common only in relatively late stages; their onset may however lead to excess ROS production resulting in oxidative stress and related complications that may exacerbate insulin resistance and directly favor muscle loss , 31, 44.stem cell dysfunction: altered muscle stem cell function with excess adipocyte differentiation  have beeIntermediate and energy metabolism changes.metabolic complications: metabolic syndrome or overt type 2 diabetes and hyperglycemia are common in insulin resistant obese individuals and their onset may exacerbate pro-oxidative and inflammatory alterations as well as mitochondrial dysfunction. These enhanced abnormalities may further promote muscle loss and functional alterations , 48;chronic disease: chronic organ failure syndromes result in enhanced inflammation and oxidative stress through various mechanisms at tissue and systemic level, thereby also synergistically promoting muscle loss and damage . Obesitysurgery: bariatric procedures are becoming increasingly common and almost invariably lead to skeletal muscle catabolism at least in the initial rapid weight loss phase characterized by profoundly negative energy balance , 58; lowComorbidities and treatment.Lifestyle and physical inactivity: low physical activity levels play a key role in the onset of obesity and physical activity is commonly further progressively reduced with disease duration, aging and increased body weight, with direct negative impact on muscle protein turnover as well as muscle fitness . ObesityBased on the above observations, a multifactorial cluster of obesity-induced or obesity\u2013associated alterations leads to skeletal muscle loss and dysfunction with low muscle strength and endurance, that are likely caused at least in part by low muscle mass, mitochondrial dysfunction with altered bioenergetics and fat accumulation with reduced muscle density. These changes become progressively more likely in patients with longer obesity duration, complications and older age, that may be per se independently associated with muscle loss and dysfunction.Skeletal muscle changes in obesity have a profound clinical impact. Obese individuals with low muscle mass and function have higher risk of developing frailty and disability, and may generally present with poorer quality of life. Importantly, low or declining muscle mass is emerging as a negative prognostic factor associated with higher morbidity and mortality in obese patients with various chronic complications and diseases and in aging , 64, 65.The potential relevance of muscle mass maintenance as a priority therapeutic target in obesity is regrettably hampered by inadequate awareness. Definition and diagnosis of this condition are problematic. Definition of sarcopenic obesity may combine obesity with the geriatric concept of primary sarcopenia, a combination of low muscle mass and function (particularly strength) that almost invariably occurs in old age. While diagnostic criteria for aging-associated primary sarcopenia have been proposed , they arOverall, despite relevant practical limitations, recognizing skeletal muscle depletion or dysfunction in obese individuals by body composition measurement techniques, strength measurement or other functional tests should be a priority to alert clinicians to enhanced risk for negative outcome \u201378.Routine nutritional screening to identify patients at risk for malnutrition is recommended in most chronic and acute disease conditions and in hospitalized patients. Validated and widely utilized screening tools include Nutritional Risk Screening-2002 (NRS-2002) . ImportaMost importantly, major guidelines have started to take nutritional needs of obese patients into account with specific recommendations for nutritional support that may combine a limitation in calorie with high protein administration aimed at preventing loss of skeletal muscle mass and function , 86. PreIn conclusion, the ongoing obesity epidemics, along with population aging and increased chronic disease prevalence is profoundly modifying fundamental clinical nutrition and healthcare priorities worldwide. A true double burden of malnutrition exists beyond coexistence of obesity and undernutrition in Countries and communities. Indeed individuals with obesity may present with true malnutrition due to inability to preserve body composition and performance with loss of skeletal muscle loss and function that exert major negative influences on morbidity and survival. Recognition of this new double burden is a relevant priority in order to more effectively identify diagnostic and therapeutic tools."}
+{"text": "Isolated coronary Takayasu arteritis is a rare form of ischemic heart disease that typically appears as an aorto-ostial lesion. Although several vascular imaging modalities including ultrasonography, computed tomographic angiography, magnetic resonance angiography or catheter angiography, play crucial roles for diagnosing Takayasu arteritis, the intravascular ultrasound imaging of Takayasu arteritis is not well studied.A 55-year-old woman who was diagnosed with heterozygous familial hypercholesterolemia underwent coronary angiography due to effort angina, which showed ostial left anterior descending coronary artery (LAD) stenosis. Although directional coronary atherectomy followed by drug-coated balloon was successfully performed, 6\u2009months later restenosis occurred at the ostial LAD, and the ostial left circumflex coronary artery (LCx) progressed significantly. The intravascular ultrasound imaging in these lesions was noteworthy, in which the media was partly unrecognizable and an echo intensity similar to fibrotic intimal thickening traversed from the intima to the adventitia, thereby causing the whole image of the coronary artery to become unclear. Directional coronary atherectomy followed by drug-coated balloon procedures for both LAD and LCx lesions were performed again. Systemic examination of computed tomographic angiography found no other stenotic lesions except for those in the coronary arteries. Five months later, the LAD and LCx lesions progressed diffusely, therefore the coronary artery bypass graft was done. The histopathological findings of specimens of the coronary artery that were obtained during the bypass graft showed excessive fibrous thickening of the intima and adventitia, with granulomatous inflammation in the media, which led to the diagnosis of isolated coronary Takayasu arteritis. Systemic corticosteroid therapy was then started.We described an extremely rare case of isolated and non aorto-ostial Takayasu arteritis. The characteristic intravascular ultrasound images of diseased coronary arteries may help in the diagnosis of coronary Takayasu arteritis. Takayasu arteritis is an idiopathic chronic inflammatory arteritis characterized by stenosis, occlusion or dilatation of the aorta and its major branches, predominantly prevalent among young women . CoronarA 55-year-old woman was referred to our hospital because of chest pain on effort that had worsened in the last 3 months. The patient had no significant past medical history and was not on any medication. Family history revealed that her mother was diagnosed as having stable angina pectoris at 70. The patient had no evident physical findings of fever, lymphadenopathy, joint pain or left-right deference of blood pressure. Electrocardiogram showed regular sinus rhythm and no significant abnormalities Fig.\u00a0. The echPercutaneous coronary intervention with coronary plaque atherectomy using directional coronary atherectomy (DCA) catheter  followed by paclitaxel-coated balloon  was performed on the LAD lesion, and plain old balloon angioplasty was performed on the high lateral branch lesion Fig. c and d. Five months later, she suffered from chest pain on effort again and coronary angiography showed a restenosis of the ostial LAD, as well as a stenosis of the distal left main coronary artery (LMCA) and the ostial LCx Fig. e and f. Single photon emission computed tomography myocardial perfusion imaging at 6 months after the second coronary intervention revealed significant apical and lateral wall ischemia. Coronary angiography showed the restenosis of the ostial LCx and the diffuse stenotic progressions of the mid LAD and LCx  was then started. Since the administration of corticosteroids, at the time of writing, the patient has been free from chest pain for 1\u2009year.Takayasu arteritis is an idiopathic chronic inflammatory arteritis characterized by stenosis, occlusion or dilatation of the aorta and its major branches, and is predominantly prevalent among young women . CoronarIVUS imaging of the lesion revealed intimal fibrotic thickening without lipid-rich plaque, in which the media was partly unrecognizable and the echo intensity similar to fibrotic intimal thickening traversed from the intima to the adventitia. The histopathologic characteristics of Takayasu arteritis are granulomatous inflammation of the media and adventitia with giant cells, diffuse productive inflammation consisting of lymphocytes and plasma cells infiltration, diffuse or nodular fibrosis accompanied by disintegration and loss of elastic fibers, and reactive intimal fibrotic thickening. These conditions caused marked intimal and adventitial fibrosis . The disDirectional coronary atherectomy is a useful method especially for bifurcated lesions . The comBoth Takayasu arteritis and familial hypercholesterolemia provoke arterial stenosis as a result of inflammatory disorder of the arterial wall; however, the correlation of these diseases is unclear , 14. TheWe here described an extremely rare case of isolated and non aorto-ostial coronary Takayasu arteritis, and IVUS images of coronary lesions in Takayasu arteritis. Characteristic IVUS images may help for diagnosing coronary arteritis."}
+{"text": "Avian influenza A viruses (AIVs), as a zoonotic agent, dramatically impacts public health and the poultry industry. Although low pathogenic avian influenza virus (LPAIV) incidence and mortality are relatively low, the infected hosts can act as a virus carrier and provide a resource pool for reassortant influenza viruses. At present, vaccination is the most effective way to eradicate AIVs from commercial poultry. The inactivated vaccines can only stimulate humoral immunity, rather than cellular and mucosal immune responses, while failing to effectively inhibit the replication and spread of AIVs in the flock. In recent years, significant progresses have been made in the understanding of the mechanisms underlying the vaccine antigen activities at the mucosal surfaces and the development of safe and efficacious mucosal vaccines that mimic the natural infection route and cut off the AIVs infection route. Here, we discussed the current status and advancement on mucosal immunity, the means of establishing mucosal immunity, and finally a perspective for design of AIVs mucosal vaccines. Hopefully, this review will help to not only understand and predict AIVs infection characteristics in birds but also extrapolate them for distinction or applicability in mammals, including humans. Avian influenza A viruses (AIVs) remain one of the important viral pathogens that cause respiratory tract infections in various animal species, such as poultry and humans, and aquatic birds are considered the primordial source of AIVs infecting other animal species . InfluenInfluenza viruses undergo antigen mutations through antigen drift and shift. Circulating AIVs evolve constantly, resulting in the occurrence of new strains with variable antigenicity. Particularly, mutations occurring in the HA or NA usually cause antigenic drift, subsequently leading to an escape from earlier immune responses. Besides, an antigenic shift can take place in AIVs. In this case, co-infection of a host cell with AIVs strains of different origins can lead to the generation of novel virus subtypes via induced genetic reassortment; a newly formed HA subtype of AIVs can transmit easily in immunologically na\u00efve individuals . To dateVaccination remains one of the most effective ways to control and prevent AIVs transmission in poultry. Current influenza vaccines are generally effective against antigenically matched strains. It has been demonstrated that the antigenic mismatch between the vaccine and circulating strains or inadequate vaccine protocols can cause an antigenic drift and failed vaccination ,14. AlthThe innate immune response constitutes the first line of protection from invading pathogens. AIV infection results in a recognition of viral conserved components called pathogen associated molecular patterns (PAMPs) by host pathogen recognition receptors (PRRs), including Toll-like receptors (TLRs), retinoic acid inducible gene-I (RIG-I) receptors (RLRs), and NOD-like receptors (NLRs); the above recognition subsequently activates innate immune signaling and induces various proinflammatory cytokines as well as antiviral molecules ,19. ThenTLRs were identified as the first PRRs family that are expressed on either the plasma membrane  or the surface of endosomes and lysosomes  . To dateThe RLRs\u2014RIG-I and melanoma differentiation-associated protein 5 (MDA5)\u2014recognize the cytoplasmic viral non-self RNA and transcripts. RIG-I preferentially binds cytoplasmic single-strand 5\u2032-triphosphate RNA, while MDA5 is activated by long dsRNA species . Upon inThe roles of NLR signaling in bacterial infection have been broadly investigated . IAV infThe adaptive immune response comprising humoral and cellular responses at both systemic and mucosal levels constitutes the second line of defense against influenza viruses; this multifaceted immune response is complex  36]. In. In36]. Infection with influenza viruses initiates virus-specific cellular immune response involving CD4+ T and CD8+ T cells . Upon inDuring IAV infection, CD8+ T cells, a vital subset of immune cells, are activated after recognition of viral epitopes on DCs that migrate from the lung tissue to T-cell areas in the draining lymph nodes, resulting in their proliferation and differentiation into CTLs . CD8+ T The mucosal immune system plays a crucial role in controlling infection with influenza viruses in the URT . The URTAbs, particularly IgG and IgA, are the major immune components acting in the protective response to IAVs . IgG is In response to antigen stimulation, IgA class switching and IgA secretion occur in B cells stimulated by specific signals such as co-stimulatory molecules and cytokines and in Th cells via T-cell-dependent and T-cell-independent pathways . The aboAt present, the commercial vaccines against influenza available on the market mainly comprise inactivated influenza A virus (IIV) vaccine and recombinant influenza A virus (RIV) vaccine. Strains used in commercial influenza vaccines are selected based on the compositions of viruses from the surveillance, laboratory, and clinical observations . These vThe respiratory mucosa is the first target of influenza virus, constituting the first line of defense against the infection, which can effectively prevent the virus from entering . MucosalMoreover, it has been shown that mucosal vaccines induce cross-reacting Ab in the respiratory tract, providing cross-protection against heterologous virus infection. Inoculating the influenza HA vaccine together with cholera toxin B subunit (CTB) or B subunit of heat-labile enterotoxin (LTB) supplemented with cholera toxin (CT) intranasally enhanced anti-HA lgA and IgG Ab responses in nasal wash or serum, which protect mice against variant virus infection . OkamotoResearchers have been attempting to create universal influenza vaccines for providing broad and sustainable protection against diverse influenza viruses. In recent years, research on the prevention of influenza infection by nasal immunity has gained more and more attention. To effectively work in mucosal immunization, mucosal vaccines must be designed to possess the characteristics of mucosa and promote the specific immune responses to vaccine antigens in the mucosa. Currently, generating effective mucosal vaccines mainly involves the identification of efficient means for antigen delivery to the mucosal immune system and the development of safe and effective mucosal adjuvants or immunoregulatory agents.A growing number of pre-clinical studies and clinical trials have advanced our understanding of how live attenuated influenza vaccines (LAIVs) elicit mucosal antibodies via intranasal administration. Contrary to the wild-type forms, attenuated viruses have the capacity to replicate well at temperatures around 25 \u00b0C rather than at 37 \u00b0C, deterring their replication in the lower airway, including lung tissue, and the subsequent occurrence of influenza-like disease . The mosAmong developing live attenuated mucosal vaccines, the major class of vaccines, oral vaccines, are currently being assessed in clinical studies. Oral vaccines are classified into intranasal and sublingual vaccines that are developed for the control of influenza, rotavirus, norovirus and measles viruses . ExperimSuccessful development of LAIVs largely rests on the proper balance between attenuation and immunogenicity. It has been reported that serial virus passage in the host cells during vaccine development causes a decrease in the virulence of effective live attenuated vaccines for rotavirus . As a reAdjuvants can potentially increase the immunogenicity of mucosal influenza vaccines, while enhancing the efficacy of vaccines through modulating the quantity and quality of host immune responses. Commonly used adjuvants include a wide range of compounds . The comAdjuvants act via the following mechanisms: (1) a depot formation at the site of injection, which enables the vaccine agents to be slowly released and the host immunity to be constantly stimulated; (2) enhancement of the agent uptake via APCs and APC activation and maturation; (3) immune cell recruitment; and (4) innate immune receptor activation. Moreover, adjuvants can shape subsequent adaptive immunity for producing the most effective and protective responses to a given pathogen through targeting the subsets of innate immune cells and forming a unique cytokine milieu associated with Th1, Th2, and/or Th17.A number of adjuvants for inactivated influenza vaccines including TLR agonists are widely used to enhance the vaccine immunogenicity . StudiesDNA vaccines are capable of expressing immunogenic antigens in vivo, thereby inducing cellular and humoral immunities without causing host exposure to live viruses . ExtraceIt has been shown that intranasal administration of DNAs in mice leads to a fast and relatively even distribution of plasmid DNAs all over the body . DNA vacParticulate vaccines are capable of forming a close contact with the epithelial cells in the mucosa via included anchoring devices with adhesive properties  or included immunomodulating factors  ,121. TheRecombinant technology has been employed to engineer live vector vaccines to express target antigens. The vectors usually have minimal replicative ability to allow immune stimulation without causing infection. Delivery of vector vaccines via the mucosal routes mimics the natural infection, inducing strong mucosal, systemic, and cellular immunities against micro-organisms. Many candidate vectors. e.g., bacillus subtilis , FowlpoxAdministration of mucosal vaccines via the oral route is strongly recommended because it avoids an injection, is safe and painless, and does not require professionals for delivery. However, the efficacy of oral vaccination has proven less satisfactory due to the fact that vaccine degradation occurs in the harsh environment of the gastrointestinal tract, and mucosal tolerance suppresses immune responses to a foreign antigen. Thus, oral vaccination may require highly sophisticated formulations involving approaches for cell-specific targeting and immunomodulation. In the mucosal tissues, epithelial cells are coated by a viscous fluid called mucus containing a layer of glycoproteins (mucins). The layer of mucus serves as a physical barrier between the epithelium and invaded pathogens while harboring competitive binding sites for entrapping microbes and S-IgA Abs for binding to and neutralizing pathogens. Structurally, the intestinal epithelium formed by a single-cell layer constitutes the largest and most important barrier to the entry of foreign substances and functions as a selective barrier that only allows for nutrients and electrolytes to be absorbed while preventing the entry of intra-luminal antigens, toxins, and microorganisms ,134. TheThere exist continued efforts in developing oral live attenuated vaccines. However, compared with live-attenuated pathogen based vaccines with limitations in safety, recombinant subunit vaccines or non-living or non-infectious vector vaccines could be more attractive, albeit more difficult to deliver ,135. HenAs a major entering portal for pathogens, the nasal route becomes a promising option for mucosal vaccination due to its unique physiological and immunological characteristics. Intranasal vaccination is capable of stimulating immune responses in the nasopharynx-associated lymphoid tissue, eliciting systemic and mucosal immunities in the gastric mucosa and the respiratory and/or genital tract . Most soVaccination via the nasal cavity is the earliest mean of mucosal delivery, and nasal immunity can effectively prevent respiratory diseases. At present, mucosal immunity has made great contributions to human medicine from theory to practice, and various influenza vaccines such as LAIVs and cold-adapted influenza attenuated vaccines have been developed ,140. TheAvian influenza is a serious respiratory disease. Although currently used inactivated vaccines are effective, circulation of antigenically different strains could reduce the efficacy of vaccines due to the fact that almost all vaccines are administered via the i.m. route. The rate of antigenic variation of AIVs is accelerating, thereby increasing the risk of human infection and harm to the economy and society. Therefore, speeding up the research on AIVs vaccines and improving vaccine safety and reliability will have huge economic and social benefits. Mucosal immunity constitutes the first line of defense against AIVs; the mucosal delivery route elicits mucosal and systemic immunities simultaneously. Compared to inactivated vaccines, mucosal vaccines stimulate both cellular and humoral immunities and can be more effective in protecting against influenza variant strains, hence producing more cross-reactive and longer-lasting comprehensive immune responses. Overall, mucosal vaccines and delivery routes should play an irreplaceable role in remarkably reducing AIVs-caused burden."}
+{"text": "Examining the neural correlates underlying racial differences in cognitive functioning is necessary to help clarify mechanisms and to improve the generalizability of findings related to brain-behavior relationships. This systematic review aimed to determine whether there are racial differences in structural markers of brain aging among community-dwelling, neurologically healthy adults aged 18 and older. We identified studies  from searches in Ovid Medline, Ovid PsychINFO, and Elsevier EMBASE published until February 13, 2020. We included original articles that examined structural markers of brain aging and neuropathology across individuals from more than one race or ethnicity. These measures included magnetic resonance imaging, positron emission tomography amyloid and tau, cerebrospinal fluid amyloid, tau, and neurofilament light chain and computed tomography. Two reviewers independently screened full-text articles. We will present ongoing results and discuss the current state of knowledge, quality of existing studies, and gaps in the literature and highlight potentially key next steps."}
+{"text": "Stem cells have improved the treatment of several diseases. Their efficacy has been widely debated over the last few decades, but their contribution to medical research has constantly increased .Recently, a pivotal study supported by the National Institute of Dental and Craniofacial Research (NIDCR), leaded by Prof. Yang Chai, investigated stem cell-based therapies for children with craniosynostosis. Authors demonstrated that Mesenchymal Stem Cells (MSCs) combined with hydrogel were able to regenerate functional cranial sutures previously undergone craniosynostosis, restoring not only skull anatomy but also neurocognitive functions in an animal model . This stSeveral research groups have worked on the role of genetic and epigenetic factors on craniosynostosis development, confirming a pivotal role of TWIST-1 gene mutations in Saethre\u2013Chotzen syndrome (SCS). The discovery of genetic and molecular pathways has increased attention on alternative treatments to surgery: the group of Prof. Stan Gronthos demonstrated that pharmacological targeting of Kdm6a/b genes activity may regulate aberrant osteogenesis by TWIST-1 mutant cranial suture mesenchymal progenitor cells via deregulation of epigenetic modifiers, thus preventing cranial prefusion and the related functional impairment . On the The use of stem cell therapy to reactivate functional sutures is a clinical breakthrough also in the light of the high incidence of resynostosis after complex cranial vault reconstruction. Nevertheless, an early combined surgical and regenerative approach to craniosynostosis, may reduce or definitely prevent several related dental and maxillofacial implications , in addiThe crosstalk among stem cell therapy and clinical outcomes has been investigated also in studies on muscular , neural Therefore, the results reached by Prof. Yang Chai and his group are a milestone that will promote novel less-invasive, stem cell-based therapeutic approaches that will benefit patients affected by craniofacial developmental disorder involving related brain and organs alterations. Overall, stem cell research has obtained an important achievement towards its future clinical application in minimally invasive therapeutic procedures."}
+{"text": "Emergency providers should recognize that pneumothorax is a rare but serious complication of shoulder arthroscopy that may require a unique approach to decompression.We present a case of a 60-year-old female who presented to the emergency department with right-sided facial swelling, voice change, and shortness of breath three hours after an elective arthroscopic right rotator-cuff repair and was noted to have a right-sided pneumothorax. We also describe a potential novel approach to chest tube decompression that maintains shoulder adduction in patients with recently repaired rotator cuffs.Although most cases of post-arthroscopy pneumothoraces are reported in patients who received regional anesthesia or have underlying lung pathology, it can occur in lower-risk patients as was demonstrated in our case. We also suggest considering an alternative anterior approach between the midclavicular and anterior axillary lines for chest decompression in select patients when a traditional approach is less ideal due to the need to maintain shoulder immobilization postoperatively. Over the past few decades shoulder arthroscopy has become an increasingly common technique to treat shoulder pathology. Proponents cite a decreased complication rate when compared to open procedures.A 60-year-old female presented to the ED with right-sided facial swelling, voice change, and shortness of breath three hours after an elective, arthroscopic, right rotator cuff repair. The outpatient surgery comprised a subacromial decompression, major glenohumeral joint debridement, and rotator cuff repair for right shoulder chronic impingement syndrome, intra-articular biceps tear, and full thickness rotator cuff tear. The surgery was performed in the lateral decubitus position under general anesthesia and without regional nerve block. The anesthesia report was reviewed and showed no major complications or episodes of hypotension or desaturation. The patient reported feeling well postoperatively; however, three hours later she developed right-sided face and neck swelling , voice cThe patient denied significant past medical history including any history of smoking or underlying lung or connective tissue disease. On arrival, her vitals were heart rate 92 beats per minute, blood pressure 135/80 millimeters mercury, respiratory rate 18 breaths per minute, and pulse oximetry was 96% on room air. Her physical exam was notable for predominately right-sided facial swelling, diminished right-sided lung sounds, and crepitus of the right neck, face, and chest. A chest radiograph showed a right-sided pneumothorax of approximately 70% with mediastinal shift and extensive subcutaneous emphysema .A pigtail catheter-type chest drain was placed in the fifth intercoastal space between the right midclavicular and anterior axillary line so as to not abduct or displace the patient\u2019s shoulder given her recent rotator cuff repair. Successful expansion of the lung was noted .On the third day of admission, the chest tube was removed and the patient was discharged home without further complications. At her two-week follow-up, her shoulder was healing well and she had no significant sequelae from her pneumothorax.Only a handful of case reports and case series describe an association between arthroscopic shoulder surgery and postoperative pneumothorax3CPC-EM CapsuleWhat do we already know about this clinical entity?Pneumothoraces have been reported as a possible complication of shoulder arthroscopy.What makes this presentation of disease reportable?We present a case of a rare complication of a common procedure and suggest a less common procedural approach to treating pneumothorax.What is the major learning point?Pneumothorax is a rare but serious complication of shoulder arthroscopy that may require a unique approach to decompression.How might this improve emergency medicine practice?This variation to traditional pneumothorax decompression technique could help avoid re-injury of the rotator-cuff repair site.Emergency providers have traditionally placed tube thoracostomy drains at the fourth or fifth intercostal space at the midaxillary or anterior axillary line11Limitations to this new approach include left-sided pneumothorax , obese patients, large area of breast tissue, or use of larger caliber chest tubes. Placing the pigtail catheter at the second intercostal space midclavicular line is a viable alternative in these casesEmergency providers should recognize pneumothorax as a rare but serious complication of shoulder arthroscopy. Although most cases reported are in patients who received regional anesthesia or have underlying lung pathology, it can occur in lower-risk patients as was demonstrated in our case. Patients may present with classical findings of pneumothorax including dyspnea, decreased breath sounds, and signs of tension including mediastinal shift. Postarthroscopy pneumothoraces nearly always present with crepitus on exam or subcutaneous air on imaging. The majority of these cases tolerate decompression without issues and patients are discharged within several days without complications. Providers may consider follow-up computed tomography imaging in patients without prior lung disease to assess for underlying lung disease or structural pathology including blebs. We also suggest considering an alternative anterior approach between the midclavicular and anterior axillary lines for chest decompression in select patients when a traditional approach is less ideal due to the need to maintain shoulder immobilization postoperatively; however, more research is needed to confirm safety and efficacy."}
+{"text": "Previous research has identified cancer and cancer-treatment related effects on survivors\u2019 mental impairment including memory and concentration. However, research has not systematically examined the relative impact of cancer in the context of age and other age-related health challenges common in later life. This paper compares the effects of cancer-related factors with other health challenges faced by 471 older adult long-term survivors from an NCI-funded study of a randomly selected tumor registry sample from a major comprehensive cancer center. Having had chemotherapy is associated with several cognitive outcomes including memory and concentration. Survivors who reported more cancer-related symptoms during treatment reported a greater number of cognitive symptoms even decades after treatment. Importantly, other comorbid health problems as well as social factors were found to be important in explaining symptoms of cognitive impairment in this older adult sample. These findings suggest that health care and mental health providers consider the range of health challenges, including those related to cancer and its treatment, as they provide patient centered care."}
+{"text": "This special issue includes seven articles. We have a brief review of mental health issues among Asian and Pacific Island (API) communities. Two papers examine non-biological factors that may be associated with mood disorders, using a nationally representative sample of Asian Americans (AA). These papers are particularly informative because they report disaggregated results across four AA subgroups. Another two articles examine different interventions and their efficacy to improve mood and quality of life among APIs. Finally, the case of a clinical encounter during COVID-19 was examined through the lens of Asian critical theory. Although these papers differ in their focuses and methodologies, collectively, they provide valuable information about mental health issues among the API community."}
+{"text": "Influenza viruses rapidly diversify within individual human infections. Several recent studies have deep-sequenced clinical influenza infections to identify viral variation within hosts, but it remains unclear how within-host mutations fare at the between-host scale. Here, we compare the genetic variation of H3N2 influenza within and between hosts to link viral evolutionary dynamics across scales. Synonymous sites evolve at similar rates at both scales, indicating that global evolution at these putatively neutral sites results from the accumulation of within-host variation. However, nonsynonymous mutations are depleted between hosts compared to within hosts, suggesting that selection purges many of the protein-altering changes that arise within hosts. The exception is at antigenic sites, where selection detectably favors nonsynonymous mutations at the global scale, but not within hosts. These results suggest that selection against deleterious mutations and selection for antigenic change are the main forces that act on within-host variants of influenza virus as they transmit and circulate between hosts. As influenza viruses replicate within infected hosts, they quickly mutate into genetically diverse populations. A small proportion of within-host variants transmit between individuals , and somSeveral recent studies have used deep sequencing to identify within-host mutations in hundreds of clinical influenza infections . HoweverHere, we compare the genetic variation of H3N2 influenza virus within and between human hosts to infer the fates of within-host mutations in the global viral population. Individual within-host mutations are challenging to track on a global scale, but by comparing large numbers of genetic variants identified within and between hosts, we can infer the evolutionary forces that act on different classes of mutations. We analyze within-host viral variation in 308 acute influenza infections from three deep-sequencing datasets , and we Evolutionary rates provide a simple, quantitative framework for comparing viral variation across scales. Under neutral evolution, we expect within-host and global evolutionary rates to be identical, and deviations from these neutral expectations shed light on how selection acts across evolutionary scales. For instance, HIV and hepatitis C virus both evolve more rapidly within than between hosts, probably because viruses acquire adaptations to specific hosts that often revert after transmission .We sought to calculate the within-host and global evolutionary rates of influenza virus. Influenza\u2019s global evolutionary rate is easily estimated from phylogenies of patient consensus sequences, which represent transmitted strains , but evoTo overcome these challenges, we developed a method to estimate rates of within-host evolution from deep sequencing of acute viral infections. In brief, we identified within-host mutations that were present in at least 0.5 per cent of sequencing reads  to estimWe tested the sensitivity of this method to common technical considerations. Estimates of evolutionary rates can be influenced by the frequency threshold used to identify within-host variation . We focuIn calculating within-host evolutionary rates, we sought to limit the influence of outlier samples with unusually high within-host variation . This hiWe calculated rates of within-host influenza evolution from deep-sequencing data in three published studies that together represented 308 acute H3N2 influenza infections  Dinis e. We estiTo assess sources of variation in our estimates, we calculated evolutionary rates separately for each deep-sequencing dataset . We alsoTo compare rates of evolution in acute and chronic influenza infections, we also calculated rates of influenza evolution in four chronic H3N2 infections that lasted multiple months  Supplem. We findWhat kinds of mutations reach detectable frequencies within hosts? We compared how quickly synonymous, nonsynonymous, and stop-codon (nonsense) mutations accumulate within hosts. Differences in how quickly these three classes of mutations accumulate can reveal how selection acts within hosts. Most synonymous mutations are nearly neutral; many nonsynonymous mutations are deleterious; and premature stop codons are lethal. In the absence of selection, all three types of mutations accumulate at the same rate. However, purifying selection purges deleterious mutations, and positive selection increases the frequency of any beneficial mutations.We find that deleterious mutations are purged detectably but incompletely within infected individuals. Synonymous mutations accumulate about twice as quickly as nonsynonymous mutations within hosts, with some variation across genes . Stop-coHow do mutations that arise within hosts fare as they circulate between hosts? We compared rates of evolution within hosts and globally to determine how selection acts across different scales of viral evolution. Neutral mutations should have similar rates of evolution within and between hosts. Purifying selection that acts between hosts to eliminate deleterious mutations will decrease global evolutionary rates compared to rates within hosts. Conversely, positive selection that acts on a global scale will increase rates of evolution between hosts relative to their within-host expectations for beneficial classes of mutations.To calculate the global evolutionary rates of influenza virus, we analyzed H3N2 influenza sequences in the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database, where each sequence represents the consensus sequence of one patient infection . We usedSynonymous mutations accumulate at similar rates within hosts and globally . This coIn contrast, nonsynonymous mutations accumulate more slowly globally than within hosts in all six viral genes analyzed. In addition, while stop-codon mutations accumulate at appreciable rates within hosts, they never fix during global evolution. These discrepancies in evolutionary rates within and between hosts suggest that many nonsynonymous mutations that reach detectable frequencies within hosts are later purged by purifying selection as viruses transmit and circulate between hosts.An important exception to this trend occurs in the antigenic regions of the HA gene, which evolve more rapidly on a global scale than non-antigenic regions of HA  Caton e. Within The previous section shows that nonsynonymous mutations are less common among mutations that fix globally than they are within hosts. This result suggests that purifying selection eliminates many nonsynonymous within-host variants before they fix in the global population of influenza viruses. However, it remains unclear from this analysis how quickly deleterious, nonsynonymous mutations that are generated within hosts are eliminated as viruses transmit and circulate between hosts.de novo mutations are expected to be nonsynonymous. However, purifying selection reduces the fraction of nonsynonymous mutations by removing deleterious mutations after they arise and before they fix. By examining when nonsynonymous mutations are depleted from circulating viral strains, we can identify where in the evolutionary process most purifying selection takes place . The fraction of nonsynonymous mutations is even lower among between-host mutations that reach higher frequencies, and eventually, fewer than 20 per cent of the mutations that fix in these genes are nonsynonymous. Previous work has shown that rare variants in global viral populations are dominated by transient deleterious mutations , so thisMore nonsynonymous mutations are present between hosts in the viral surface proteins HA and NA. Nonsynonymous mutations are especially enriched between hosts in antigenic sites of HA, which experience strong positive selection on the global scale  Murphy,. In antiOur analyses show that transient deleterious mutations make up a large proportion of influenza\u2019s genetic variation within hosts. Deleterious variation is common at the between-host scale as well  and can In this study, we quantitatively compared influenza virus\u2019s genetic diversity within and between human hosts. Our results show that although viral diversity may seem low within acute human influenza infections, it is sufficient to explain the virus\u2019s rapid global evolution. Synonymous mutations accumulate at similar rates within and between hosts, as expected for neutral genetic changes. Most nonsynonymous mutations that reach detectable frequencies within hosts are eventually purged between hosts, suggesting that within-host influenza diversity consists mostly of transient, deleterious mutations that are eliminated at transmission and global evolution. Antigenic sites of HA are the only region of the influenza genome where mutations are consistently favored between hosts beyond their frequencies within hosts.Our findings show how purifying and positive selection act on viral populations at different evolutionary scales. Influenza populations within hosts accumulate genetic variation as they expand during the first few days of an infection. However, most of this variation, which is deleterious, is purged as viruses circulate between hosts. One recent study estimates that influenza\u2019s transmission bottleneck consists of one to two viral genomes , and furin vitro  mutations within hosts in each influenza gene . Random To calculate rates of viral divergence per day, we normalized per-site viral divergence by the timing of sample collection. Of the 308 H3N2 samples that we analyzed, 251 had metadata describing the number of days post-symptom-onset after which the sample was collected. For the remaining samples sequenced by For comparison, we calculated rates of evolution in acute patient infections through both the \u2018point\u2019 method described above, which averages rates of evolution calculated from each patient infection, as well as through linear regression . We perfTo calculate within-host rates of evolution in antigenic sites of HA, we used the antigenic sites defined by We downloaded all full-length H3N2 influenza coding sequences in the GISAID EpiFlu database collected from 1 January 1999 to 31 December 2017 . We randWe used a molecular-clock approach to calculate global evolutionary rates. We performed linear regression of the distances from a reference sequence by the timing of sample collection to estimate the rate of between-host evolution . MoleculWe previously deep-sequenced longitudinal samples of influenza from four chronic H3N2 influenza infections . We downTo calculate the fraction of mutations that are nonsynonymous within hosts, we tallied the total number of synonymous and nonsynonymous mutations in each frequency bin for each sample. Stop-codon mutations were counted as nonsynonymous mutations in this analysis. We then summed the variants in each frequency bin across samples. We calculated confidence intervals by performing 100 bootstrap resamplings of the viral samples and plotted the 95 per cent confidence interval from these bootstrap replicates .To calculate the fraction of mutations that are nonsynonymous between hosts, we must be able to determine when the same mutation has arisen multiple times in the global influenza population. We downloaded all full-length H3N2 influenza coding sequences in the GISAID EpiFlu database collected from 1 July 2015 to 30 June 2018, together representing the 2015\u20136, 2016\u20137, and 2017\u20138 Northern Hemisphere flu seasons . We grouhttps://github.com/ksxue/within-vs-between-hosts-influenza. Sequences downloaded from the GISAID Epiflu database are not available due to data-sharing restrictions, but acknowledgement tables for the sequences we analyzed are available at https://github.com/ksxue/within-vs-between-hosts-influenza/tree/master/data/GISAID/acknowledgements/H3N2.Raw sequencing data are publicly available from the NCBI SRA database for Bioprojects PRNJA577940 , PRJNA34Virus Evolution online.veaa010_Supplementary_DataClick here for additional data file."}
+{"text": "Older age has often, but not always, been associated with greater risk aversion. Some have suggested that age differences in risk may reflect age-related declines in cognitive abilities. This study investigated the robustness of age differences in risk aversion across three different risk-taking measures, after controlling for cognitive abilities. Community-dwelling younger  and older  adults completed self-report and behavioral measures of risk aversion and several measures of cognitive abilities. Results showed that older adults reported significantly greater risk aversion than young adults on the behavioral measure of risk , but not on the self-report measures (Framing Task and Choice Dilemmas Questionnaire). Greater risk aversion on BART was significantly associated with lower analytic thinking, slower processing speed, and worse shifting of attention. Therefore, we tested the relation between age and risk aversion on the BART while controlling for these three cognitive abilities. Age differences in risk aversion remained significant even after accounting for cognitive abilities. Our results suggest that the lack of consistent age differences in risk aversion in the literature may at least partly be due to measurement differences, which raises concerns about the construct validity of these measures of risk aversion. Moreover, cognitive decline may not explain age differences in risk. Further research is needed to understand factors that dampen and heighten risk aversion in people of diverse ages."}
+{"text": "The Latinx population is disproportionately affected by HIV-infection and older Latinx persons living with HIV (PLWH) are at greater risk for neurocognitive impairment (NCI). However, no studies have examined whether intersectionality  increases NCI risk. This study investigated whether LGBT status increases NCI risk in 126 PLWH  who completed a comprehensive NC battery. Domain average T-scores were based on demographically-corrected norms. Multiple regressions revealed that after accounting for covariates  and other dimensions of intersectionality , LGBT status significantly contributed to NCI risk in attention/working memory  and executive functioning . LGBT status, a key dimension of intersectionality, should be considered in NC assessment of PLWH. Future research is needed to identify factors  that may confer increased NCI risk in this population."}
+{"text": "The vagus nerve-based inflammatory reflex regulates inflammation and cytokine release. Recent successful clinical trials using implantable bioelectronic devices to modulate the inflammatory reflex in patients with rheumatoid arthritis and inflammatory bowel disease have demonstrated the efficacy of targeting neural circuits as an efficient alternative to drug treatments. However, the optimal vagus nerve stimulation parameters to achieve efficacious symptomatic relief for inflammation are still unknown. In this issue of Bioelectronic Medicine, Tsaava et al. tested whether altering these electrical stimulation parameters would change circulating cytokine levels in healthy mice. They found that specific combinations of parameters produced significant increases in serum TNF while other parameters selectively lowered serum TNF levels, as compared to sham stimulated mice. These results have considerable implications for determining the optimal stimulation parameters to better treat common conditions and diseases that involve immune regulation. Recent successful clinical trials using implantable bioelectronic devices that modulate the inflammatory reflex have reported efficacy of vagus nerve stimulation in the treatment of inflammatory diseases. However, the optimal neurostimulation parameters to achieve significant cytokine changes are still unknown.In healthy mice without inflammation, specific combinations of pulse width, pulse amplitude, and frequency produce significant increases of the pro-inflammatory cytokine TNF but other parameters selectively lower serum TNF levels. Serum levels of the anti-inflammatory cytokine IL-10 were also significantly increased by selective parameters but remained unchanged with others.These findings provide guidance for design of future studies on the neural regulation of inflammation based on the selection of optimal parameters to relieve conditions and improve organ function.Bioelectronic medicine is based on neuromodulation of the nervous system restoring organ functions and health with less adverse effects than drugs, thus minimizing adherence issues (Olofsson and Tracey i) invasive with surgical implantation of an electrode around the left VN linked to a neurostimulator positioned under the collarbone or ii) non-invasive through transcutaneous cervical (on the path of the VN) or auricular stimulation, based on the innervation of the cymba conchae by the auricular branch of the VN (Peuker and Filler VN stimulation (VNS) is approved for the treatment of drug-resistant epilepsy and well tolerated   vagal A-fibers are the largest and myelinated fibers and carry afferent visceral information and motor input, ii) vagal B-fibers are small and myelinated fibers carrying parasympathetic input, and iii) vagal C-fibers are small and unmyelinated and carry afferent visceral information. Antiepileptic property of VNS was supposed to be related to vagal C-fibers, but their destruction did not alter VNS-induced seizure suppression in rats (Krahl et al. Importantly, these results argue that serum cytokines may be controlled by specific fiber sets and firing patterns. The specific VN fibers mediating the inflammatory reflex are not known. The VN contains A-, B-, and C-fibers, defined in accordance to their conduction velocity, which, in myelinated fibers, is proportional to their size (Erlanger and Gasser Patients under VNS for epilepsy may experience improved seizure reduction by increasing the frequency and/or duty cycle of stimulation while VNS for heart failure is limited by the inability to activate the nerve fibers mediating therapeutic benefit without co-activation of side effect-inducing fibers (Musselman et al. The results of Tsaava et al.  indicate"}
+{"text": "As the US population continues to age, it is important to gain a better understanding of factors that differ between independently living older adults and those that require assisted living. Accidental falls contribute to decreased quality of life for many older adults, and considerable research has been conducted examining measures of fall-risk and potential interventions. In this pilot study, we investigated fall-risk via assessment of spatio-temporal variables associated with gait in independent and assisted-living older adults aged 65+. Two gender-matched groups of participants were tested on seven gait variables  utilizing Opto-Gait technology. Each group included sixteen participants. Independent living participants were recruited through word of mouth and flyers at local senior centers. Assisted living participants all resided in one local health care facility and were recruited via word of mouth and flyers posted in the facility. A one way ANOVA with an alpha level of .05 revealed significant differences between groups in contact time, foot flat, propulsive phase, and average speed. The independent living group performed better on each variable. These findings indicate that older adults living in assisted living facilities may be at much greater risk of accidental fall than their independent living counterparts. While this study identified several key factors related to instability among old adults, additional investigation is warranted to further examine the relationships among gait, fall-risk, and differentiators between independently living and assisted living older adults in these variables."}
+{"text": "This systematic review examines current randomized clinical trials of therapeutic agents to treat coronavirus disease 2019 (COVID-19). In this systematic review, we characterize the landscape of current COVID-19 trials to better quantify these potential issues.High-quality evidence generated by appropriately powered and controlled trials is needed to advance care for patients with coronavirus disease 2019 (COVID-19) and those who are susceptible to it.PRISMA) reporting guideline.3Institutional review board approval of this study was waived because it exclusively used publicly available data without any protected health information. Screening and trial selection adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses . Data analysis was performed in June 2020.We performed a data query of the ClinicalTrials.gov registry for interventional trials in any clinical phase regarding COVID-19 on June 8, 2020. Advanced search parameters included Our search yielded 674 trials after removing suspended and halted trials . Most we4We found a high rate of trial multiplicity, particularly with chloroquines, which are being tested in 143 studies. Although these overlapping trials may afford opportunities for replication and validation, the high degree of multiplicity also enhances the likelihood of finding a positive result through chance alone, potentially resulting in widespread use of an ineffective and possibly hazardous intervention.5 Because the projected participant accrual for US-only COVID-19 treatment trials is approximately 45\u2009942 participants , it seems unlikely that this target will be achieved given the intrinsic challenges of participant accrual during an active pandemic.The fragmentation of efforts could also lead to unnecessary competition for participants, which potentially compromises trial accrual and statistical power for all trials. This worrisome scenario has already occurred in China.Notably, our study is limited through the use of a single US-based clinical trials registry, potentially representing only a fraction of the worldwide COVID-19\u2013related trials portfolio. Furthermore, the ever-changing landscape of COVID-19 clinical research amid this pandemic may complicate future interpretation of this report.6 Together, these factors endanger the capacity to rapidly produce meaningful evidence that is vital during this critical time. Avoiding these pitfalls requires coordination of efforts. This could be achieved, in part, through makeshift cooperative groups to improve participant accrual and decrease duplicative efforts. Institutional review boards and regulators (including the US Food and Drug Administration) must also work together to responsibly ease roadblocks to coordinate pooled analyses across trials. These efforts should include synchronization and standardization of end points, focusing on the most meaningful and objective outcomes . It is hoped that these measures will expedite generation of high-quality prospective data to guide effective treatments while maximizing resource allocation.Although current trials have been initiated with the best intentions, the medical community must be mindful of the potential issues of incomplete participant accrual and publication bias that are introduced by enabling dozens of similar trials simultaneously."}
+{"text": "This is commonly accomplished by the timed addition of soluble signaling factors, in conjunction with cell-handling steps such as the formation of 3D cell aggregates. Interestingly, when stem cells at the pancreatic progenitor stage are transplanted, they form functional insulin-producing cells, suggesting that in vivo microenvironmental cues promote beta cell specification. Among these cues, biophysical stimuli have only recently emerged in the context of optimizing pancreatic differentiation protocols. This review focuses on studies of cell\u2013microenvironment interactions and their impact on differentiating pancreatic cells when considering cell signaling, cell\u2013cell and cell\u2013ECM interactions. We highlight the development of in vitro cell culture models that allow systematic studies of pancreatic cell mechanobiology in response to extracellular matrix proteins, biomechanical effects, soluble factor modulation of biomechanics, substrate stiffness, fluid flow and topography. Finally, we explore how these new mechanical insights could lead to novel pancreatic differentiation protocols that improve efficiency, maturity, and throughput.Insulin-producing beta cells sourced from pluripotent stem cells hold great potential as a virtually unlimited cell source to treat diabetes. Directed pancreatic differentiation protocols aim to mimic various stimuli present during embryonic development through sequential changes of  Cell therapies involve the transplantation of human tissues or cells to treat illnesses that progressively damage or degrade functional tissues. These treatments are typically limited by access to a reliable and cost-effective cell source. For a successful transplant, allogeneic matching requires identification, procurement and transport of donor material; and variations in quality of the donated tissue may affect therapeutic potential. Therefore, the large-scale production of biological material for cell therapies is a rapidly growing area of interest. The primary goal of such research is to produce adequate quantities of functional therapeutic cells in a cost-effective manner.Treatment of type 1 diabetes by islet transplantation is one example of a currently approved cell therapy. Here, donor islets are used to replace the insulin-secreting functionality lost from the autoimmune destruction of pancreatic beta cells. The Clinical Islet Transplantation Consortium trial (CIT-07) reported that 87.5% of patients were free from severe hypoglycemic events and achieved normal or near normal glycemic control at the 1 year end point . As with+ cells  (in vivo (in vitro (The production of insulin-secreting beta-like cells from pluripotent stem cells (PSCs) is a potential solution to the donor supply issues of islet transplantation. The first report of stem-cell derived insulin-producing cells via spontaneous differentiation was almost two decades ago and reported only 1\u20132% insulin+ cells . However+ cells . Therefo+ cells . More re 20 days . One of  20 days  and subs 20 days . Since teptide+) . Howevereptide+) . Maturat interactions , which cin vivo. Studies of developmental mechanobiology are challenging, and these parameters are often not considered as it is unclear what mechanics are present during human embryogenesis. Furthermore, the complexity of the in vivo microenvironment makes it difficult to control these biomechanical signals and to delineate their effects on differentiation from other correlated stimuli. Therefore, the field relies mainly on studies of biochemical pathways with in vivo mouse models or in vitro human models for information.Embryonic development is guided via highly dynamic signals from the surrounding cell microenvironment with remarkable precision and robustness. As cells differentiate, they relay different signals to neighboring cells by secreting soluble factors and matrix proteins. The soluble signaling cues associated with pancreatic differentiation have been well-studied using animal models and include the Wnt, Activin/Nodal, fibroblast growth factor (FGF), bone morphogenetic protein (BMP), retinoic acid, and sonic hedgehog (Shh), and Notch signaling pathways . HoweverCells respond to mechanical stimuli through mechanotransduction mechanisms, in which biomechanical stimuli are converted into biochemical signals . ReciproResident cells communicate with their neighbors during development by secreting soluble signaling molecules which can bias differentiation . The devin vivo cellular microenvironment is much more intricate than can be modeled by current in vitro systems. Although directed differentiation protocols that focus solely on the timed addition of soluble signaling factors can generate insulin-producing cells  perhaps due to improved paracrine signaling and cell\u2013cell contacts . Paracricultures . In theiskeleton .In vitro, larger non-vascularized islets may develop central necrosis due to high metabolic demand and low oxygenation , thus retaining ECM proteins composition. Utilizing decellularized pancreas matrix scaffolds in bioartificial pancreas designs could also be a fruitful strategy to improve islet functionality by retaining pancreas stiffness and matrix architecture . HydrogeIn addition to the combinatorial effects of individual ECM components, the composition of the ECM is dynamically changing during development. While one composition may promote early pancreatic differentiation, the same composition may hinder downstream differentiation stages. During hESC differentiation, ECM and MMPs are secreted which remodels the exogenous ECM on the culture substrate . PSCs cuin vivo, a recent successful strategy has been to target specific mechanotransduction-associated pathways during directed differentiation to promote pancreatic differentiation and thus improve the capacity to produce insulin-secreting cells. Such factors include H1152 (a ROCK II inhibitor)  , vertepohibitor) , and lathibitor) . Nuclearhibitor) . Timed ihibitor) . Depolymhibitor) . AltogetCells interact with ECM proteins by binding with integrin receptors spanning across the cell membrane. These receptors can then activate downstream integrin-related signaling pathways that alter cell function and bias cell specification. In pancreas development, integrin-ECM signaling regulates collective cell migration and function . When plThe surrounding ECM matrix also propagates stress  which al+ endocrine progenitors, fibronectin promotes high cell spread area while laminin-coated surfaces were associated with lower spreading  or stiffness (MMP-mediated degradation or UV-based) could better accommodate the constantly changing requirements for beta cell differentiation. Finally, as our knowledge progresses, increasingly complex co-culture systems involving defined compositions of PSC-derived endothelial, islet endocrine cells, and other cells present during development, may be the route to a functional cell source for islet transplantation.To address these questions, some technologies that could be used to specifically identify the effect of these factors are highlighted in Overall, better understanding the mechanobiology of pancreas development could lead to new strategies to more efficiently produce functional glucose-responsive, insulin-secreting cells for cell therapies. Interdisciplinary approaches combining advances in materials science and developmental biology could accelerate the development and scale up of culture systems tailored for diabetes cell therapy.RT conducted the literature search and drafted the manuscript in consultation with CM and CH. All authors contributed to writing the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Most studies of middle-aged adults find blacks have higher levels of psychological distress compared to whites but have lower risk of common psychiatric disorders. For instance, there is evidence of lower rates of depressive and anxiety disorders among blacks relative to whites despite large disparities in stress, discrimination and physical health in midlife\u2014commonly referred to as the black-white mental health paradox. We examine evidence of the black-white paradox in anxiety and depressive symptoms among older adults. Data come from 6,019 adults ages 52+ from the 2006 Health and Retirement Study. Unadjusted models show older blacks report more anxiety and depressive symptoms than whites. After adjusting for socioeconomic factors, everyday discrimination, chronic conditions, and chronic stress, there are no black-white differences in anxiety and depressive symptoms. Findings suggest the black-white mental health paradox only extends into older adulthood for blacks living under similar stress and health landscapes as whites."}
+{"text": "Initially described as pneumonia of unknown aetiology in December 2019 in populations of Wuhan (China), the coronavirus disease (Covid-19) rapidly disseminated around the world . They alActually, nearly three billions people are confined at homes or in quarantine around the world. Brooks et al. in a recently published review including studies comparing psychological outcomes between people quarantined and not quarantined, found that quarantine had negative psychological effects such as post-traumatic stress symptoms, confusion and anger . All theShanghai government organized psychological care in four levels. At the first level, an onsite psychological support is provide to patients with severe symptoms of novel coronavirus pneumonia (NCP) by front-line medical staff, Centre for Disease Control researchers or administrative staff . The secThe current Covid-19 pandemic has tremendous consequences on population health around the world, with various degrees of mental health repercussions. Actual strategies are mainly targeting Covid-19 patients and healthy general populations, and are chiefly based on clear and secured communication as well as continuous onsite and online psychological support by appropriates professionals. However, these strategies should be disseminated to all countries, especially sub-Saharan African ones, and approved by concerned governments. Also, adequate psychological care policies have to be developed for health care workers fighting against this pandemic. All these measures would help to maintain optimal care of Covid-19 patients and prevent deleterious mental health outcomes including suicides.All authors declare no competing interests."}
+{"text": "Dear Editor, Recently, Wu and colleagues published a study about hepatobiliary organoids generated from human induced pluripotent stem cells . For thSeveral studies have used human stem cells including hiPSC and reported that differentiation via definitive endoderm resulted in hepatocyte-like features  associated genes, potentially limiting hepatocyte maturation, which could be investigated by monitoring TWIST and SNAIL transcription factor activity. It should be considered that hepatocytes in vivo are arranged in sheets along sinusoids  is that19 is thaal., 2019). The usal., 2014; Hoehme al., 2014; Reif etin vitro systems for toxicity tests . Also, al., 2018), althouThe author declares no conflict of interest."}
+{"text": "Creutzfeldt-Jakob disease (CJD) is a rare prion disease characterized by rapidly progressive dementia.A 76-year-old woman exhibited pronounced signs and symptoms of dressing apraxia for about seven weeks before the disease progressed and probable CJD was diagnosed supported by imaging and CSF findings.Dressing apraxia as the initial manifestation of CJD has been sparsely reported. This remarkably focal syndrome should be considered with view on movement and neuropsychological disorders in early CJD. Creutzfeldt-Jakob disease (CJD) is a rare prion disease mainly characterized by rapidly progressive dementia. Neuropsychological disorders however frequently occur in the initial phase of the disease with amnesia, impaired attention and frontal lobe syndrome as the most frequent . RecentlA 76-year-old woman developed difficulties in dressing. She had progressive problems dressing herself. In particular, she had difficulty handling buttons and arranging her clothing articles on her body. Dressing became more and more prolonged, and she began to manipulate her clothes incoherently until finally needing support from her husband. Her medical history included stable plasmocytoma, atrial fibrillation and residual effects from a minor stroke, and she was orally anticoagulated with phenprocoumon. Her neurological examination on admission revealed a slight right-sided motor impairment with finger tapping and slight dysarthria, which resulted from the previous minor stroke. Neuropsychologically pronounced signs and symptoms of dressing apraxia were found whereby performing simple gestures and pantomiming object use were preserved. Otherwise, there were no signs of constructional and limb ataxia, optic ataxia and visual disturbances. The MoCA test showed 28 of 30 points with slight impairment in the visuospatial items. Her family history was unremarkable. She had not had any previous neurosurgical procedures or corneal transplants [Her first cranial magnetic resonance images (MRI) showed marked cortical restriction of diffusion bilaterally (positive \u201cribbon sign\u201d), most prominent in the parietal regions Figure . A cerebWith this case report, we wish to complement the observations on neuropsychological disorders in CJD for three reasons. First, dressing apraxia as an initial and for a certain time exclusive symptom of CJD has sparsely been reported . Most re465810"}
+{"text": "This study enhances the existing literature on the role of trust and online perceived risk in shaping consumer purchase decision-making in social commerce. The aim of this article is to investigate consumers\u2019 purchase decision-making process, the determinant components of social commerce purchase intentions and attitudes, the effect of perceived risk on intention to go shopping in online settings, and consumer trust and buying behavior on online retailing platforms. The insights obtained from our research extend current knowledge as regards determinants of consumer attitudes and intentions toward online purchases, consumers\u2019 perceived shopping risk and repurchase behavior when buying products online, and perceived consumer online trust and purchase decisions. Limited research has considered consumers\u2019 decision-making processes on social commerce platforms by investigating how their perceptual attitudes, behavioral intentions, and immediate gratifications affect the purchase of products and services online. Our study addresses this gap and extends prior research by focusing on the relationship between online consumer purchase intention, social commerce adoption behavior, and consumers\u2019 trust together with risk factors affecting online buying decisions, in light of the characteristics of source credibility. Our findings point toward important avenues of research on psychological determinants of consumer engagement in social media, decision mechanisms lying behind evaluation of prices, the types of perceived risk incurred, and online repurchasing behavior and intention on social commerce platforms. Subsequent directions should clarify whether adoption of mobile payment services may shape online consumers\u2019 impulsive buying behavior and decision-making, especially under the influence of online product reviews. Our study cumulates evidence that consumers\u2019 decision-making process is a dynamic performance , but thaUsing exclusively empirical sources published recently (2017\u20132019) in Web of Science- and Scopus-indexed journals, our paper fills the gap in the literature by elucidating consumers\u2019 evaluation, commitment, and choice throughout online decision-making, insisting on their cognitive processing behaviors and on how expectations shape their pre-purchase and post-purchase satisfaction.On Wu J. et al. (2017)\u2019s reading, trust is the essential component of consumer purchase intention when buying things on peer-to-peer temporary rental platforms where both hosts and renters do not know each other. The empirical evidence we reviewed supports the belief that social platform users\u2019 purchase intentions can be constituted taking into account the relationship between online trust and perceived risk. Limited research has considered consumers\u2019 decision-making processes on social commerce platforms by investigating how their perceptual attitudes, behavioral intentions, and immediate gratifications affect the purchase of products and services online.Our study addresses this gap and extends prior research by focusing on the relationship between online consumer purchase intention, social commerce adoption behavior, and consumers\u2019 trust together with risk factors affecting online buying decisions, in light of the characteristics of source credibility. As limitations in the present article, our findings point toward important avenues of research on psychological determinants of consumer engagement in social media, decision mechanisms lying behind evaluation of prices, the types of perceived risk incurred, and online repurchasing behavior and intention on social commerce platforms. Subsequent directions should clarify whether adoption of mobile payment services may shape online consumers\u2019 impulsive buying behavior and decision-making, especially under the influence of online product reviews.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Medicare is the primary insurance provider for approximately 51 million older adults, including those who seek mental health care. Medicare provider eligibility was last updated in 1989, and approximately one-third of the graduate-level mental health workforce  is excluded from Medicare, despite these professionals participating in Medicaid, TRICARE, the Veterans Administration, and private insurance plans. This Medicare mental health coverage gap (MMHCG) raises concerns about older adults\u2019 access to mental health care, resulting in a policy misalignment between Medicare\u2019s provider regulations and a growing number of older adults seeking mental health care. However, little is known about the precise impact of the MMHCG. To better understand how the MMHCG impacts older adults, we interviewed 17 Medicare-insured individuals about their experiences accessing mental health services. Using a phenomenological framework to analyze our data, we found that Medicare recipients described several consequences, such as: 1) a detrimental impact on their mental health and well-being; 2) concerns about having to start over with new providers due to commencing mental health treatment only to have services interrupted once the provider is no longer Medicare-reimbursable; and 3) relying on pro bono services from Medicare-excluded providers with uncertainty about the long-term sustainability of these arrangements. The presenters will describe how these findings fit within the current Medicare mental health service context, including the direct impact on older adults\u2019 mental health. Discussion will also focus on policy implications of the findings and possible solutions for addressing the MMHCG."}
+{"text": "Pathogens and pests are one of the major threats to agricultural productivity worldwide. For decades, targeted resistance breeding was used to create crop cultivars that resist pathogens and environmental stress while retaining yields. The often decade-long process of crossing, selection, and field trials to create a new cultivar is challenged by the rapid rise of pathogens overcoming resistance. Similarly, antimicrobial compounds can rapidly lose efficacy due to resistance evolution. Here, we review three major areas where computational, imaging and experimental approaches are revolutionizing the management of pathogen damage on crops. Recognizing and scoring plant diseases have dramatically improved through high-throughput imaging techniques applicable both under well-controlled greenhouse conditions and directly in the field. However, computer vision of complex disease phenotypes will require significant improvements. In parallel, experimental setups similar to high-throughput drug discovery screens make it possible to screen thousands of pathogen strains for variation in resistance and other relevant phenotypic traits. Confocal microscopy and fluorescence can capture rich phenotypic information across pathogen genotypes. Through genome-wide association mapping approaches, phenotypic data helps to unravel the genetic architecture of stress- and virulence-related traits accelerating resistance breeding. Finally, joint, large-scale screenings of trait variation in crops and pathogens can yield fundamental insights into how pathogens face trade-offs in the adaptation to resistant crop varieties. We discuss how future implementations of such innovative approaches in breeding and pathogen screening can lead to more durable disease control. R genes) e.g. fungicides, insecticides) Feeding the world population requires a stable production of safe food, which is threatened by factors such as climate change, land degradation and diseases. Pathogens and pests cause significant reductions in agricultural productivity worldwide, and control strategies remain ineffective for many pathogens Sustainable agricultural management practices critically rely on an understanding of the biology and evolutionary potential of the major crop pathogens. Emerging or re-emerging pathogens can only be contained by investigating their origins and migration routes, as well as their potential to counter-adapt to deployed control measures. Advancements in genomics, transcriptomics and proteomics have been instrumental to elucidate these questions and unravelled a broad range of molecular mechanisms governing host-pathogen interactions leading to more effective control strategies 1.1e.g. appressoria) i.e. temperature, pH, humidity) to thrive, changes in the environment can alter the pathogen's ability to cause damage 2 and ozone can affect plant disease severity e.g. wash-off of fungicides following strong rainfall). Hence, the challenge to contain pathogen damage in agriculture is to predict the emergence of virulent strains and the rise of fungicide resistance.Major crop diseases are caused by pathogens including fungi, bacteria and viruses . In addii.e. biotrophs) can feed on plant nutrients for a long period without causing apparent infection symptoms Given the possibly severe consequences, the early detection of resistance breakdowns in crops or loss of sensitivity to pesticides is critical. Detection early in the growing season and identifying previously uncharacterized pathogens remain major challenges. Classic plant disease diagnostics usually relies on visual symptom scoring by trained individuals categorizing disease severity on linear scales e.g. leaves, Disease symptoms may include any range of changes in the color, shape or functioning of the plant as it responds to a pathogen and can be visualized at specific wavelengths A. Depend1.2e.g. GF-1 from China or SPOT from Europe, can provide time-resolved phenotyping of individual fields at the meter scale Technologies suitable for screening plant diseases even in early infection stages have become widely deployed 1.3Proximal phenotyping is mostly deployed in greenhouse experiments or in well-controlled field experiments. Sensors covering a broad range of spectra can be mounted on stationary platforms or, for outdoor use, on suspension cables, robots and tractors i.e. qPCR) are often required to clearly establish what is likely to cause a disease. Interesting developments to overcome these limitations are e.g. the differential reflectance spectra (400\u20131050\u00a0nm) of sugar beet leaves, which helps distinguish three different fungal pathogens including Cercospora beticola, Erysiphe betae, and Uromyces betaeOidium neolycopersiciCorynespora cassicola and bacterial spot caused by Xanthomonas perforans on tomato in the asymptomatic phase. The multi-spectral imaging approach was successful both under laboratory and field conditions. Such robust phenotyping methods could make it possible to detect infection foci in the field. Emerging infections could then be isolated and treated individually by the deployment of specific fungicides.Current plant phenotyping technologies and image processing algorithms struggle to reliably differentiate disease symptoms originating from multiple or unknown pathogens Plant phenotyping technologies have generated data to populate public image databases  with a fluorescent readout sensitive to changes in gene expression or subcellular localization. The main goal of the technology is to accelerate drug discovery by screening large antimicrobial compound libraries at a rate of thousands of compounds per week. Efforts are as well made in the development of high-throughput approaches to generate mutated versions of drug targets in vitro screening of diverse pathogen population scans is very informative about possible standing resistance, which can prevent rapid efficacy failures under field conditions High-throughput phenotyping platforms for microbial organisms have dramatically advanced in automating cell culturing, liquid handling, spotting on culture medium as dense arrays and integration of fluorescence measurements and microscopy The wealth of information on phenotypic trait variation in pathogen species combined with low-cost sequencing can be exploited for GWAS 1.5etc.) influence the outcome of infections. The complexity arises in part from complex pathogen infection cycles starting from initial host contact to transmission to new hosts The application of imaging combined with computational techniques enabled enormous progress in breeding resistant crops and detecting the emergence of new pathogen threats. To reduce complexity, most studies until now focused either on variation on the plant or the pathogen side. However, the nature of host-pathogen interactions can vary across space and time omics datasets to build biological networks (e.g. gene co-expression or protein\u2013protein interaction networks) has become a powerful approach to unravel genetic factors controlling biological interactions Arabidopsis thaliana - Xanthomonas arboricola interaction, Wang et al. Z. tritici, a large set of loci associated with pathogen virulence and reproduction on different hosts were identified Botrytis cinerea and 90 plant genotypes of eight species revealed a highly polygenic architecture of pathogen virulence and host specialization e.g. blackleg in canola) or at different growth stages. Bigger sample sizes in both host and pathogen will also improve heritability estimates (e.g. as shown in human studies Integration of different 1.6Plantago lanceolata-Podosphaera plantaginis interactions C. beticola have shown that resistant isolates have significantly lower virulence and spore production than sensitive isolates Ralstonia solanacearum mutants lacking the gene for synthesizing an exopolysaccharide virulence factor show increased growth rates compared to the wild-type strain Z. tritici. Performance of a global strain collection on twelve wheat varieties and in various abiotic conditions revealed a broad pleiotropic control of pathogen performance on and off the host How successful pathogens cope in diverse environments depends on life-history trade-offs, which arise from resource allocation dilemmas and antagonistic gene actions. A trade-off indicates that an increase in one trait is associated with a decrease in another trait. Such trade-offs are typically dependent on the host genetic background and abiotic conditions. Some pathogen strains have evolved specialization on certain hosts or climatic conditions to maximize their performance. Classic examples include the wild pathosystem of 2Technological progress in assessing susceptibility of large collections of crop plants to pathogen damage is crucial for modern resistance breeding efforts. A variety of image capture techniques allow to monitor plant damage at the cellular, leaf, whole plant or field level. Most applications focus on the visible spectrum but hyperspectral imaging platforms have recently gained the ability to detect pathogen infestation even before the appearance of symptoms. A major area of going research is to improve image analyses algorithms to detect and classify pathogen damage. Variation within individual pathogen species can be highly informative about the rise of new virulence or pesticide resistance. Robotics applied to automate the culturing of thousands of pathogen strains enables screening for metabolic variation, drug susceptibility and production of secondary metabolites improving our understanding how pathogens cope with the agricultural environment. Both high-throughput plant and pathogen phenotyping efforts can be combined with genome sequencing and GWAS applications. Unraveling the genetic basis of host resistance helps to speed up breeding efforts through marker-assisted selection. Analysis of pathogen populations can be informative about possible trade-offs in the emergence of virulence or pesticide resistance.Future directions of research should focus on a set of complementary research areas.- Create efficient pipelines merging imaging and molecular assays for pathogen detection. Such integrated systems could help farmers deploy appropriate counter-measures in the field prior to widespread damage and reduce overall pesticide application.- The susceptibility of crop cultivars to major pathogens should be re-assessed continuously to detect changes in the virulence profile of the prevalent pathogens. Rapid evolution in pathogens can lead to catastrophic resistance breakdowns and must be detected early enough. High-throughput imaging systems capturing disease symptoms should be combined with machine learning to effectively recognize changes in virulence profiles. The lack of curated and open access disease image databases is currently slowing progress.- Regional monitoring efforts of resistance breakdowns or the loss of pesticide efficacy can be achieved by high-throughput genomic screening of infected leaf material. Efficient genotyping assays focusing on major genes are likely to scale well to broad applications. Bioinformatic procedures for such genomic data analyses are largely in place. A successful implementation of such genomic monitoring will also help to detect the arrival of new pathogens early enough to deploy resistant cultivars or implement changes in pesticide application regimes.- The systematic identification of trade-offs faced by pathogens adapting to pesticides and resistant crop cultivars could lead to more durable control measures.Nikhil Kumar Singh: Conceptualization, Writing - original draft, Visualization. Anik Dutta: Writing - original draft, Visualization. Guido Puccetti: Writing - original draft, Visualization. Daniel Croll: Conceptualization, Writing - original draft, Supervision, Funding acquisition.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Intracortical bone pins are introduced as gold standard for analysing skeletal motion because of eliminating soft tissue artefact. However, excluding this methodological error might be in cost of intervening movement pattern by local anaesthesia and pain of external tool within body. The purpose of this study was to examine whether intracortical bone pins alter shoulder joint kinematics or coordination. Three subjects were analysed during arm elevation/depression in frontal and sagittal planes. Retroreflective skin markers captured the motion in two sessions, before and after inserting bone pins (SKIN and PIN sessions), respectively. Thoracohumeral and scapulothoracic kinematics and scapulohumeral rhythm (SHR) were compared between two sessions. Thoracohumeral exhibited lower elevation and internal rotation in PIN session especially close to maximum arm elevation. The highest differences were observed for scapulothoracic kinematics, with higher retraction during abduction as well as higher posterior tilt, lateral rotation and retraction during flexion in PIN session. In addition, no systematic changes in SHR between subjects was found. Statistically significant lower SHR in PIN session was observed over 87-100% of thoracohumeral elevation/depression cycle in frontal plane and over 25-61% in sagittal plane. Further studies should treat carefully toward the clinical validity of shoulder joint kinematics after inserting bone pins. Retroreflective markers mounted on either skin or intracortical bone pins are used to highly accurately capture shoulder motion and evaluate the shoulder dynamics  represents any changes in scapulothoracic/scapulohumeral movement and their coordination  at 300 Hz.Data collection was performed in two sessions in a single day, for each participant. For session 1 (SKIN), 22 skin markers were attached to the left clavicle (5), scapula (4), humerus (7) and thorax (6) based on the model introduced by Jackson et al. . Their lAnatomical and relaxed static positions were primarily recorded for each person per session. Thereafter, each participant was asked to perform movements in SKIN session and repeat these movements in PIN session. The movements included functional motion tasks and main tasks. Functional motion tasks were arm flexion, rotation, and circumduction performed in each session to find functional joint centres and axes. Main tasks involved 10 trials of arm elevation/depression in frontal plane (abduction/adduction) and sagittal plane (flexion/extension). In S4, the location of the scapula\u2019s pin interfered with the skin markers which had to be repositioned more laterally. The post-surgery skin markers on the scapula were quasi-collinear. This resulted in the impossibility of accurate kinematics calculations. S4 data were removed.t-tests using statistical parametric mapping (SPM) were implemented, during elevation and depression separately, to determine whether any significant differences exist between SKIN and PIN sessions. The open-source SPM1d toolbox (http://www.spm1d.org) in MATLAB  was used for our SPM analysis.The systems of coordinates and sequences were defined based on International Society of Biomechanics (ISB) recommendations , while thoracohumeral kinematics just altered slightly. In fact, the subjects reduced their axial rotation and the plane of elevation after inserting pins. These alterations are consistent with findings of previous studies about shoulder abnormalities. Mell et al.  showed aThe changes in joint kinematics before and after pin insertion , Table 1n = 3) in our cross-comparison study, we compared the kinematics of each subject separately between SKIN and PIN sessions. In addition, the obvious differences in SHR between subjects might be due to individual movement strategies rather than different compensatory mechanisms. It is recommended that validation studies which mount both skin markers and bone-pin markers on the body estimate how they will interact with each other before data collection. Otherwise, repositioning skin markers because of interference with bone pins would deteriorate the kinematic results. In our study, one of our four available subjects was excluded due to this issue. A well-organized protocol especially for such invasive studies with small sample sizes will help in minimizing the between-subject differences derived from methodological errors. While only kinematics were assessed in the present study, electromyography and/or muscle force estimation may provide additional information about the effect of pin insertion on the upper-limb biomechanics. However, the estimation of muscle forces at the shoulder remains challenging due to co-contraction and the complex trajectories of (multi-articular) muscles (Behm et al. In addition to joint rotations, SHR was selected to look at the effect of inserting bone pins, since it can represent the movement quality index for shoulder complex for several reasons. The most important reason is that kinematic redundancy enables the central nervous system to generate a specific shoulder motion with different contribution of bony structures (Yang et al. Our results showed that inserting shoulder bone pins dominantly deteriorates the pattern and RoM of scapulothoracic joint rather than thoracohumeral joint. It was also observed that SHRmight be partially reproduced after pin insertion. Eliminating methodological errors from soft tissue artefacts using intracortical pins would not necessarily add more clinical value to the kinematic results, while the approach remains relevant to model/algorithm validation."}
+{"text": "Public mental health response to coronavirus disease is essential. After reviewing systemic and local efforts in China, we found efficient coordination and human resources. We recommend better symptom assessment, monitoring of organizations, and basic needs protection. This recommendation can inform how other countries can overcome mental health challenges during this pandemic. The coronavirus disease (COVID-19) outbreak and quarantines have caused major distress in China   and psycCoordination and resource allocation were compiled from local efforts at the Wuhan epicenter . On JanuThe MoE and CPS recruited professionals and volunteers across China, which suggests adequate resource allocation (The Inter-Agency Standing Committee calls for assessment of mental well-being and program evaluation of psychsocial support effectiveness (CPS published a list of approved hotline organizations based on survey evaluation of organizations (Although COVID-19 does not cause intentional harm, there are human rights issues on access to basic needs (Our review suggests that China has overcome resource shortages with coordination and resource allocation in its mental health response. The government, universities, and academic societies provide coordination, and independent organizations provide local support. We recommend integration of assessment in direct support, monitoring of organizations, and advocating for affected persons. These recommendations can inform how other countries can overcome shortage of mental health resources when facing this pandemic.Additional information on review of mental health response to COVID-19, China."}
+{"text": "Zostera marina). Sampling seawater along transects extending alongshore outward from eelgrass beds, we demonstrate that eDNA provides meter-scale resolution of communities in the field. We evaluate eDNA abundance indices for 13 major phylogenetic groups of marine and estuarine taxa along these transects, finding highly local changes linked with proximity to Z. marina for a diverse group of dinoflagellates, and for no other group of taxa. Eelgrass habitat is consistently associated with dramatic reductions in dinoflagellate abundance both within the contiguous beds and for at least 15 m outside, relative to nearby sites without eelgrass. These results are consistent with the hypothesis that eelgrass-associated communities have allelopathic effects on dinoflagellates, and that these effects can extend in a halo beyond the bounds of the contiguous beds. Because many dinoflagellates are capable of forming harmful algal blooms (HABs) toxic to humans and other animal species, the apparent salutary effect of eelgrass habitat on neighboring waters has important implications for public health as well as shellfish aquaculture and harvesting.Seagrass beds provide a variety of ecosystem services, both within and outside the bounds of the habitat itself. Here we use environmental DNA (eDNA) amplicons to analyze a broad cross-section of taxa from ecological communities in and immediately surrounding eelgrass ( Seagrass species are ecosystem engineers throughout the world\u2019s coastal zones , generatIn addition to these broad ecological and chemical functions, such habitats demonstrate important antimicrobial properties. Seagrass meadows have been shown to reduce exposure to bacterial pathogens affecting humans and marine life, relative to areas lacking such meadows . AdditioZostera marina) is the dominant seagrass along temperate coasts of the Northern Hemisphere  or ostrich (genus Struthio) tissue. We selected these organisms because they are absent from the sampling sites and common molecular biology reagents, but amplify well with the universal primer set used in this study. Additionally, they can be used to identify possible cross-contamination: reads from other taxa that appear in these positive control samples allow us to estimate and account for the proportion of sequences that are present in the incorrect PCR reaction (see \u201cBioinformatics\u201d below). We also amplified negative controls (molecular grade water) in triplicate alongside environmental samples and positive controls, and verified by gel electrophoresis that these PCR reactions contained no appreciable amount of DNA.Finally, we generated amplicons with the same replication scheme for positive controls, comprised of extractions from either kangaroo . We then performed sequencing on an Illumina MiSeq  platform in four different sets of samples: two MiSeq V.2 runs and two MiSeq V.3 runs. We processed each batch separately through the initial bioinformatics analysis (see below). We employed hierarchical clustering on transects containing six PCR replicates sequenced across two different runs  and found that these samples were each other\u2019s nearest neighbors ; thus seWe followed updated versions of previously published procedures for bioinformatics, quality control, and decontamination . This pr11), false-positive rate (P10) and commonness (psi) in a Bayesian binomial model. We then used these parameters to estimate the overall likelihood of occupancy (true presence) for each ASV; those with low likelihoods (<20%) were deemed unlikely to be truly present in the dataset, and therefore culled. 25 million reads from 3143 ASVs survived this step.To address possible cross-sample contamination , we subtLastly, we removed samples whose PCR replicates were highly dissimilar: we calculated the Bray\u2013Curtis dissimilarity amongst PCR replicates from the same bottle of water and discarded those with distance to the sample centroid outside a 95% confidence interval. Of 84 bottles of water collected, 3 technical replicates survived QC in 72 cases (86%), two replicates in 9 cases (11%), one replicate in 2 cases (2%), and zero replicates in a single case (1%) . The finPRJNA606519).All bioinformatic and analytical code is included in GitHub repositories , and proe-values of 10\u221230 (culling limit = 5), and reconciling conflicts among matches using the last common ancestor approach implemented in MEGAN 6.4 .Our analysis revealed strong habitat associations for dinoflagellates and not for other taxa (see \u201cResults\u201d). To examine patterns specifically within the phylum Dinoflagellata, we further refined our annotations for these ASVs. Specifically, we considered the geographic range of taxa involved (restricting possible annotations to those taxa known from the North Pacific) and assigned taxonomy conservatively to the level of family  only in cases of >95% sequence identity between the subject and query sequence; ASVs we could not confidently assign to the level of family we excluded from further analyses. Multiple dinoflagellate sequences with identical amino-acid translations occurred within To confirm the spatial resolution of our eDNA communities, we used non-metric multidimensional scaling (nMDS) ordination of eDNA indices for all ASVs within each technical replicate . To deriTo examine the relative abundance of phyla in eelgrass habitat relative to bare substrate, we determined eDNA indices for the sum of sequences within each phylum at the two transect extremes (within-eelgrass versus bare), calculating a relative eDNA abundance measure by subtracting the mean eDNA abundance index over bare substrate for each site-month combination from the corresponding mean eDNA abundance index in the eelgrass habitat. Positive values of this measure thus denote higher abundance in eelgrass, while negative values of this index indicate higher abundance over bare substrate. To assess the statistical significance of these phylum-level differences between habitat types, we compared the distributions of mean eDNA abundance indices for individual phyla in samples taken from eelgrass relative to their counterparts taken over bare substrate, using a paired Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons.k-means function of the R stats package . Next, to determine whether dinoflagellate abundance measures at intermediate alongshore transect samples  were more closely associated with eelgrass habitat or bare substrate, we additionally performed Gaussian mixture modeling with two groups . We thenWe assigned over 3,000 unique ASVs to 13 eukaryotic phyla comprising a diverse set of single- and multicellular taxa including Arthropoda (arthropods), Annelida (annelid worms), Bacillariophyta (diatoms), Chlorophyta , Chordata (chordates), Cnidaria (cnidarians), Dinoflagellata (dinoflagellates), Echinodermata (echinoderms), Heterokonta (stramenopiles), Mollusca (molluscs), Nemertea (ribbon worms), Ocrophyta  and Rhodophyta . This represents a broad\u2014although by no means comprehensive\u2014survey of eukaryotic communities in and around our sampled eelgrass beds.Ordination via nMDS revealed consistent differentiation between eDNA communities across transects within a sampling site and date; technical replicates consistently clustered together. An example plot of samples gathered along the transect from eelgrass to bare substrate at Willapa Bay in July  shows thR2 = 0.186, p = 0.001), month , and transect distance  each explain a significant portion of the variance in the dataset. Thus, despite strong effects of location and time, these results confirm that we can consistently distinguish nearshore eDNA communities (as sampled by our primers) at spatial scales of meters for each site and month of sampling. Moreover, we see a highly significant effect of proximity to eelgrass on the complement of organisms present.PERMANOVA apportioned the variance in Bray\u2013Curtis distance among samples as follows: site . Other single-celled microalgae such as diatoms (Bacillariophyta) and green algae (Chlorophyta) have no significant relationship with eelgrass.To determine the habitat preference of major taxa in our dataset at a coarse spatial scale, we classified ASVs to the level of phylum and plotted an index of their relative sequence abundance in eelgrass versus bare positions . Positivk-means clustering) to define a set of high- and low-abundance transects for each dinoflagellate sequence across all sites and months .In this subset of high-abundance transects, the negative interaction of eelgrass and dinoflagellates is taxonomically universal. The taxa represented include two unique variants from the genus  species . All arep < 0.02; p > 0.85).After demonstrating a preference of all dinoflagellate taxa towards the bare substrate extreme (when highly-abundant), we then characterized their patterns as a function of distance from the edge of the contiguous eelgrass beds, using data from entire transects . ExaminiIn a broad-spectrum eDNA survey of the organisms living in and near to eelgrass, we track the relative abundance of a diverse group of taxa from thirteen phyla. We demonstrate the ability of eDNA to distinguish communities represented in samples taken only meters apart, and to reveal a significant axis of variance based on proximity to habitat type, despite strong influences of geography and time across sampling events. One major and significant pattern emerges in our analysis: dinoflagellate taxa are more common over bare substrate than within eelgrass beds when highly-abundant, and this effect extends at least 15 m beyond the edge of the contiguous beds themselves. Because ours was an observational field study, rather than an experiment, we cannot rigorously distinguish among plausible mechanisms for the observed dinoflagellate distributions. Instead, we use the patterns in our own data as well as the relevant scientific literature to evaluate a number of potential hypotheses.One plausible mechanism is that of an ecological edge effect acting in nearshore zones at the interface between eelgrass and non-eelgrass habitat. \u201cEdge effects\u201d are changes in the distribution or abundance of a species at a boundary between habitats , such tA third possibility is that predatory taxa exist in greater abundance within eelgrass beds and thereby consume dinoflagellates in larger quantities within this habitat , and is mediated locally by a variety of strains of eelgrass-associated algicidal and growth-inhibiting bacteria, particularly from Erythrobacter, Teredinibacter, Gaetbulibacter and Arthrobacter genera  causes paralytic shellfish poisoning via production of saxitoxin  produce yessotoxins (YTXs), whose effects on human consumers of contaminated shellfish are complex and unclear (reviewed in Alexandrium) are intensifying with recent ocean warming in the North Pacific  gigas, in particular, has recently been shown to lessen the effects of eelgrass wasting disease on Z. marina , transect direction , transect position , month, technical replicate, and sequencing run.Click here for additional data file.10.7717/peerj.8869/supp-2Supplemental Information 2Click here for additional data file."}
+{"text": "Cross-sectional findings showed that education differences in memory performance were moderated by frequent cognitive activity . The present study examined whether frequent cognitive activity could compensate for lower education when focusing on change in cognitive performance across nine years. The study also explored whether cognitive activity can slow down declines in retired adults as previous research suggested that retiring is associated with an increased risk of cognitive decline . Longitudinal data from the MIDUS study included N = 3,325 middle-aged and older adults. Outcome variables were two factors of cognitive performance: Episodic Memory (EM) and Executive Functioning (EF). Independent variables were years of education, work status (working vs. retired), and frequency of cognitive activity. The results suggest that cognitive activity moderated the effect of educational attainment on change in EM. Individuals with both higher education and cognitive activity showed the smallest declines in EM. Individuals with lower educational attainment but high cognitive activity had less decline in EM compared to their low education counterparts. Those who increased their cognitive activity over time showed less decline in EF. In terms of work status, working adults had less decline in EM and EF compared to retired adults and retired adults who did not maintain their cognitive activity declined more in EF. The results emphasize the importance of frequent engagement in cognitive activity across the lifespan, which can attenuate cognitive declines especially among those who have lower education or have retired."}
+{"text": "Tropical rainforest disturbance and conversion are critical drivers of biodiversity loss. A key knowledge gap is understanding the impacts of habitat modification on mechanisms of community assembly, which are predicted to respond differently between taxa and across spatial scales. We use a null model approach to detect trait assembly of species at local- and landscape-scales, and then subdivide communities with different habitat associations and foraging guilds to investigate whether the detection of assembly mechanisms varies between groups. We focus on two indicator taxa, dung beetles and birds, across a disturbance gradient of primary rainforest, selectively logged rainforest, and oil palm plantations in Borneo, Southeast Asia. Random community assembly was predominant for dung beetles across habitats, whereas trait convergence, indicative of environmental filtering, occurred across the disturbance gradient for birds. Assembly patterns at the two spatial scales were similar. Subdividing for habitat association and foraging guild revealed patterns hidden when focusing on the overall community. Dung beetle forest specialists and habitat generalists showed opposing assembly mechanisms in primary forest, community assembly of habitat generalists for both taxa differed with disturbance intensity, and insectivorous birds strongly influenced overall community assembly relative to other guilds. Our study reveals the sensitivity of community assembly mechanisms to anthropogenic disturbance via a shift in the relative contribution of stochastic and deterministic processes. This highlights the need for greater understanding of how habitat modification alters species interactions and the importance of incorporating species\u2019 traits within assessments.The online version contains supplementary material available at 10.1007/s00442-020-04829-z. Habitat modification via selective logging and forest conversion to agriculture is widespread across the tropics , and interactions with other species that are characteristic of anthropogenic disturbance . The majority of the concession (~\u200990%) has been selectively logged, primarily between the 1970s and 2008 across two rotations of logging  logging concession in eastern Sabah, Malaysian Borneo  across all four habitats]. Each site consisted of one line transect for bird sampling and two-line transects (a minimum of 500\u00a0m apart) for dung beetle trapping (see below for further methods). Sampling for birds and dung beetles occurred at the same sites across the forested habitats and at three of the oil palm sites, however the fourth oil palm site, for each taxa, was sampled in different locations due to logistical reasons  (Online resource 1a). Sampling within oil palm was restricted to mature plantations (10\u201315\u00a0years old). The environmental conditions across sampling years remained similar . Primary forests are heterogeneous in structure with a dense canopy, extended vertical strata, and an open understorey with low densities of lianas when compared to logged forests . Sampling effort was equalised across habitat types for dung beetles and birds ; Online Resource 1c; following Edwards et al. Dung beetles (Coleoptera: Scarabaeidae: Scarabaeinae) were sampled using standardised baited pitfall traps across all habitats [nMicrosites\u2009=\u2009192 ; Online Resource 1c; following Edwards et al. Unlimited-radius point counts were used to sample birds across all habitats [Functional traits that reflect the key functional roles of dung beetles and birds were assessed for use with trait assembly null models described below. We combined both behavioural  and morphological (body size and bill structure) traits to capture a greater proportion of the variation across species as per Edwards et al.  to creatTo assess how functional traits and species abundances influence community assembly, we used a null model approach to test for trait divergence or convergence across our disturbance gradient  and landscape (n\u2009=\u20094) scale (Online resource 1), and tested whether SESRaoQ values were significantly different from zero (indicating a random trait distribution) using a student\u2019s t-test.To then be able to assess community assembly patterns across our disturbance gradient we compared the deviation of observed RaoQ from the expected null distribution, using the standardised effect size (SES) (SES_RaoQ), taking the approach of Gottelli and McGabe . SESRaoQnMicrosites\u2009=\u200940 per habitat; birds: nMicrosites\u2009=\u200948 per habitat) and landscape (nSites\u2009=\u20094 per habitat) scales. Therefore, for any given subset of the community (see variations of community subsets below), four models were run for each taxa. All null model randomisations were run with 10,000 permutations and with abundance data, which has been shown to maximise detection power . This model has the effect of removing any relationship between the traits and abundances of species co-occurring at a sampling site while maintaining the sample species richness and the total sample abundance . Importantly, this maintains the link between species abundances and traits (thus differing from model 1), while also maintaining species frequencies and total abundances, but allowing sample abundance and richness to vary . Habitat specialists were defined as those species that were unique to either oil palm  or forested habitats  . We analysed both subsets of species using the same null models at both the local and landscape scales. To ensure our definition of habitat association was not influenced by rare species , we re-analysed these models with singletons removed. The results mirrored those from the full community; we, therefore, present only the full community results in the main text and provide both model outputs in the supplementary material (Online resource 5).To explore whether any changes in co-occurrence patterns related to changes in interactions determined by species\u2019 habitat associations, we tested whether assembly mechanisms differed between those species shared across all habitats  and those that were not (non-shared). Habitat generalists were defined as those species found in all four habitats  described in the Elton Trait database, which are based on the summed proportion of five individual diet components for each species , at the local scale dung beetle communities varied considerably. Random trait assembly was found in primary and twice-logged forests, while trends in once-logged forest indicated trait convergence (t-test: P\u2009<\u20090.01) and in oil palm trait divergence (t-test: P\u2009<\u20090.01) , we found no evidence of non-random trait assembly for dung beetle communities at either spatial scales .Nesting guilds of dung beetles indicated uniform trait-based assembly across habitats for rollers, which displayed trait convergence at both scales using model 1. Insectivore communities indicated strong trait convergence across all habitats and scales .Dominant avian feeding guilds showed variation in trait-based assembly patterns using We explored the manner in which tropical land-use change influences species co-occurrence patterns to infer community assembly mechanisms in two indicator taxa. To our knowledge, this is the first assessment of dung beetle co-occurrence patterns, and the first multi-taxon, multi-spatial scale analysis of co-occurrence in relation to anthropogenic habitat change. In revealing evidence of non-random assembly at local scales in dung beetles, and variation between trait convergence and random assembly in birds across the disturbance gradient Fig.\u00a0e\u2013h, our Model 1, which can detect limiting similarity, varied across the disturbance gradient, whereas model 2, which reliably detects environmental filtering  and conversion . Critically, we highlight the potential hidden effects of land-use change beyond altered community structure Below is the link to the electronic supplementary material."}
+{"text": "The successful implementation of antiretroviral therapy (ART) in women living with HIV (WLWH), either for their own health or for prevention of mother-to-child transmission (MTCT), has reduced MTCT risk of HIV to <5% . Yet, inIn addition to the risk of HIV infections that occur early in life via breastfeeding, sexual transmission during adolescence and adulthood also represents a significant and ongoing mode of infection . A pediaSeveral recent studies have indicated that the early life immune system may present some advantages for elicitation of HIV-specific antibody responses. The purpose of this review is to summarize these studies and highlight the unique ability of the early life developing immune system to mount robust and durable immune responses against HIV, compared to adults. Additionally, the potential of harnessing neonatal immune ontogeny to develop an effective earlylife HIV vaccine is emphasized.Owing to maturational differences in the early life and adult immune systems, the ability of infants to generate vaccine-specific immune responses has traditionally been considered as impaired [reviewed in ]. AdditiNeonatal nonhuman primate (NHP) studies have provided encouraging results regarding the ability of infants to mount durable immune responses against HIV or simian immunodeficiency virus (SIV) vaccines \u201319. In fTo date, only a few pediatric HIV vaccine trials have been completed . While nAlthough the induction of cross-clade bNab is 1 of the major goals of any HIV vaccination strategy ,37, so fWhile elicitation of bNabs remains a priority of HIV vaccine development, a combination of neutralizing and non-neutralizing effector responses might be crucial for an efficacious vaccine. A recent study has indicated that polyfunctional antibody responses are predictive of bNab development , suggestNewborns transition from a relatively sheltered intrauterine environment to an environment with multiple antigenic exposures. To obtain survival benefits during the period of immune maturation, newborns establish a highly tolerogenic environment and exhibit a distinct immune profile than adults [reviewed in ]. TherefWhile alum has been the standard adjuvant of choice for commercial pediatric vaccines, HlV pediatric vaccine trials have reported the superiority of MF-59 adjuvant in mounting potent and durable antibody responses when compared to alum. In PACTG 230 trial, the MF-59-adjuvanted vaccine formulation was associated with durable anti-Env IgG responses, which was associated with higher breadth and durability as compared to the alum-adjuvanted counterpart . This inEmerging evidence suggests that an individual\u2019s microbiome can influence immune responses to vaccination . TherefoNeonates and infants possess unique immunological characteristics that promote the development of protective immunity via immunological and molecular pathways distinct from those of adults. Therefore, a deeper understanding of the infant immune system is needed to develop novel HIV immunization regimens tailored to the infant\u2019s immune landscape. The fact that the most recent adult HIV vaccine trial HVTN 702), done in South Africa, which tested a canarypox vector-based vaccine (ALVAC-HIV) with HIV subtype C gp120 protein adjuvanted with MF-59, was recently discontinued due to lack of efficacy  highligh2, done iThe pediatric HIV vaccine protocol HVTN 135 is currently in development to assess the safety and immunogenicity of HIV CH505 transmitted-founder (T/F) gp120 adjuvanted with the TLR4 agonist GLA-SE in HIV-exposed infants. This Phase I trial will use the CH505 T/F protein that is currently being tested in an adult HIV vaccine trial, and the results from HVTN135 will determine if this vaccine is safe to be used in infants. Additionally, this trial will indicate whether infants develop a distinct immune response to this vaccine as compared to adults, hence providing valuable information for the design of future pediatric HIV vaccine trials. Ultimately, additional clinical trials will be required to assess if immunization at birth can protect infants from vertical HIV transmission during infancy and against sexual HIV transmission during adolescence."}
+{"text": "Using a stress process framework model, this study is the first to comprehensively examine the role that religious/spiritual struggles play in the lives of informal dementia caregivers. A convenience sample of 156 informal dementia caregivers completed a scale measuring six domains of religious/spiritual struggles, as well as other measures of primary stressors, background/contextual variables, and mental health outcome (depression). Overall levels of religious/spiritual struggle were low, but 26 percent of the sample were classified as possible cases of clinically significant religious/spiritual struggle for at least one of the six domains. Of this group, 49 percent acknowledged struggles with ultimate meaning. Religious/spiritual struggles predicted greater self-reported depression over and above number of care recipient problem behaviors (primary stressor), caregiver sex, and caregiver personality . Although no individual domain of religious/spiritual struggle emerged as most salient, caregivers reported significantly more ultimate meaning struggles than demonic or interpersonal struggles. These findings support the growing body of research suggesting that religious/spiritual struggles serve as a secondary stressor, adding predictive power to background/contextual factors and to primary stressors for informal dementia caregiver mental health outcomes. Further research in this area may advance efforts to better equip both secular and religious professionals to provide evidence-based counsel to informal dementia caregivers."}
+{"text": "Excellent pulmonary function is one of the strongest predictors of longevity across animal models and human populations. Unfortunately, none of the major age-associated pulmonary diseases \u2013 obstructive lung disease, pulmonary fibrosis, and increased susceptibility to pneumonia \u2013 have strongly effective disease modifying therapies. There is growing evidence that normal age-associated decline in pulmonary function and major age-associated pulmonary diseases are linked to the hallmarks of aging including senescence, nutrient signaling dysregulation, mitochondrial dysfunction, and telomere disorders. This presents opportunities for collaboration between gerontologists and pulmonologists to unravel age-associated developmental mechanisms and design novel treatments. In this symposium, leaders in pulmonary aging research will present novel data on links between aging and pulmonary health and geroscience-based interventions under study. Dr. Sanders will provide an overview of the scientific and clinical space and present epidemiologic associations between aging biomarkers, early pulmonary fibrosis, and mortality. Dr. Le Saux will discuss senescence and specifically how eicosanoid biology may explain organ-specific patterns of senescence-associated fibrosis. Dr. Thannickal will discuss age-associated perturbations in metabolism and mitochondrial function and targeting these pathways to improve lung function and treat pulmonary diseases. Dr. Newton will discuss mechanisms and clinical applications of telomere biology to pulmonary aging. Symposium attendees will (1) be poised to generate collaborations between gerontologists and pulmonologists to address existing knowledge gaps in mechanisms of pulmonary aging, and (2) develop a better understanding of translational opportunities to design geroscience-based diagnostics and therapeutics to improve pulmonary health with aging."}
+{"text": "Ovarian cancer, cervical cancer and endometrial cancer are three relatively common malignant cancers of the female reproductive system. Despite improvements in female genital tract cancer detection and development of new therapeutic approaches, there are still poor prognoses and some do not respond to therapeutic patterns, displaying low survival and high frequency of recurrence. In an era of personalized medicine, novel therapeutic approaches with greater efficacy for these cancers represent an unmet need. One of the actionable signaling pathways is the fibroblast growth factor receptor (FGFR) signaling pathway. Several mutations and alterations in FGF/FGFR family members have been reported in human cancers. FGF/FGFR signaling pathway has become a new target for cancer therapy. This review will summarize the role of FGFR pathway and the genetic alterations of the FGF/FGFR related to female reproductive system cancer. We will describe the available inhibitors of FGFR pathway for potential treatment of female reproductive system cancer. Furthermore, we will discuss FGFR-targeted therapies under clinical development for treatment of female reproductive system cancer. Endometrial cancer, ovarian cancer and cervical cancers are three relatively common malignant tumors of the female reproductive system. Endometrial cancer that accounts for more than 95% of cases of uterine cancer is one of the most prevalent forms of gynecological cancers. It is thought to be caused by increasing estrogen levels relative to progesterone in the body. Endometrial cancer at stages I and II responds well to surgical interventions, but the disease at stages III and IV has poor prognosis with low survival rates. Ovarian cancer is the third leading gynecological malignancy worldwide and carries the highest mortality. Most ovarian cancers initiated from epithelial cells and are thus composed of poorly differentiated epithelial cells in vitro and in vivo tumor models harboring FGFR aberrations, an increasing number of researchers have selected FGFRs as targets for anticancer drug development Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinase (RTKs) encoded by four different genes FGFR1-4), among them, FGFR1-FGFR3 generate two major splice variants of immunoglobulin-like domain III, referred to as IIIb and IIIc, which are essential determinants of ligand-binding specificity , among tSome of the most striking clinical findings regarding FGFRs relate to how these receptors are implicated in female genital tract cancers. In this article, we describe recent advances of FGFR signaling pathway in endometrial, ovarian and cervical carcinogenesis and progression. Moreover, we highlight the genetic variations (including somatic mutation and gene amplification) of FGF or FGFR family members and summarize the FGFR-targeted therapies under clinical development for treatment female genital tract cancers.FGFRs in response to fibroblast growth factors (FGFs) transmit signals. The FGF family belongs to a large family of growth factors with significant expression profiles in the female reproductive tract and potentially important roles on fertility. This family is composed of 18 secreted proteins that are grouped into 5 subfamilies according to sequence homology Figure 1).Notably, dysregulation of the FGFR pathway is associated with various human cancers and is considered as an oncogenic signaling pathway FGF/FGFR signaling governs fundamental cellular processes such as cell survival, proliferation, migration, differentiation, embryonic development, organogenesis, tissue repair/regeneration, and metabolism Figure 2). Recent study suggested that the fibroblast FGF/FGFR family could interact with PI3K/AKT pathway and subsequently involve in the carcinogenesis of ovarian cancer. In endometrial cancer cell lines, loss of PTEN has been suggested as apotential mechanism of resistance to FGFR inhibition Genetic variations, especially SNPs, and genomic alterations, such as gene amplification, chromosomal translocation, and point mutation, are involved in the transcriptional upregulation of FGFR mRNAs and the functional activation of FGFR proteins during carcinogenesis . The main challenges have included (i) determining optimal diagnostic procedures for FGFR molecular alterations, and standardizing the definition of FGFRs amplification; (ii) detecting rare-frequency fusion genes involving various partners; (iii) discriminating between passenger and driver alterations; (iv) integrating the available information within a specific cellular and tumor heterogeneity context.In clinical, although anti-FGFR therapy represents a promising targeted cancer treatment, early phase clinical trials have had mixed success, with response to therapy dependent on several factors, including cancer type, tumor histology, and presence or absence of certain biomarkers Cervical cancer is the fourth most common female malignancy worldwide. Each year, more than half a million women are diagnosed with cervical cancer and the disease results in over 300,000 deaths worldwide et al. The oncogenic significance role of the FGFRs has been elucidated in cervical cancer. Choi et al. Ovarian cancer is the leading cause of death from gynecologic cancers in vitro and in vivo have shown that silencing FGFR4 and inhibiting ligand-receptor binding significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells, suggesting that FGFR4 protein expression is a new therapeutic modality for this disease and will improve its survival in clinical trials FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian cancer. Experiments In vivo experiment has shown that FGFR inhibitor decreased the growth of FGFR2-mutated endometrial cancer xenograft models Endometrial cancer is the most common gynecologic malignancy among women in developed countries, with an estimated 63,230 new cases in 2018  et al. Table The FGF/FGFR signaling pathway is frequently deregulated in human cancers. Over the last years, several mutations and alterations in FGF-FGFR pathway have been reported in cancer et al. et al. Previous studies of germline FGFR mutations indicate that point mutations can result in differential localization and signaling et al. Besides FGFR aberrations, a number of studies have also shown that genetic variations of FGF are associated with the disease. Take FGF2 for example, our group previously found that the polymorphisms of FGF2 gene are significantly associated with obesity and osteoporosis in Chinese population Since FGF/FGFR signaling plays a crucial role in cancers, a variety of small molecule FGFR inhibitors target FGF/FGFR signaling pathway have been developed and shown significant therapeutic effects in pre-clinical and clinical studies Actually, the most clinically advanced compounds are non-selective TKIs, such as brivanib, dovitinib, lenvatinib, ponatinib, nintedanib, and cediranib. Most of these inhibitors target ATP binding pocket in the TK domains of FGFRs through reversible or covalent bonds To date, the most clinically advanced FGFR TKIs in FGFR targeted treatment is dovitinib (TKI258), which is now being tested in endometrial cancer patients with FGFR2 mutation (NCT01379534). Brivanibis another dual TKI against FGFRs and VEGFRs, which was found to be effective in metastatic solid malignancies resistant to standard therapy and is currently being developed as an anti-angiogenic agent in Phase II clinical trials AL3818 (anlotinib) is a receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors , stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFA), and fibroblast growth factor receptors . This study evaluates the efficacy of AL3818 studying tumor regression in endometrial cancer model Table 2).Several other TKIs are also summarized in Table in vitro and in vivo models of endometrial cancer characterized by FGFR activation due to genetic alteration Table 3). Phase II trials with genomic enrichment are ongoing. A number of clinical trials use AZD4547 in cancer. One recent finding revealed that combined treatment of BGJ398 and rapamycin may be a promising therapeutic strategy in the treatment of patients with ovarian cancer AZD4547 is a famous selective TKI that specific target for FGFRs (FGFR1-3) Table 3). Pre-clinical cancer models with genetic aberrations in the FGFR pathway, including FGFR2-mutated endometrial cancer, are particularly sensitive to FP-1039 mediated tumor inhibition Anti-FGFR mAbs as well as small molecules acting as traps for the ligands of the FGFR family might represent a new strategy for the treatment of tumors. Based on the identification and characterization of FGF ligands, FGF ligand traps have allowed the development of promising FGF-targeting molecules with potential implications for the therapy of FGF-driven tumors Figure A large effort to develop FGF/FGFR inhibitors as anticancer treatments is underway. The most clinically advanced anti-FGFR drugs are small-molecule TKIs, some of them are monoclonal anti-FGFR antibodies and FGF-trapping molecules. Those anti-FGFR drugs that have entered the clinical phases of development are summarized in The cancers of the female genital tract represent a leading cause of morbidity and mortality among women worldwide. Undoubtedly, in the past decade, FGF/FGFR signaling therapies are under development for the treatment of gynecologic malignancies as well as in many other solid tumors. Therefore, dissecting canonical FGF/FGFR signaling pathways is still valuable. Deregulation of the FGF/FGFR signaling axis is observed in a wide variety of human cancers In conclusion, targeting FGFR is a promising strategy in the treatment of female reproductive system cancer. It is plausible to hope that in the following years the research efforts in pre-clinical and clinical fields allow to establish an optimal treatment strategy in FGFR-addicted female reproductive system cancer population."}
+{"text": "Preparedness of residents in long-term care (LTC) in the face of hurricane emergencies is a contested and largely unanswered question. Our prior work involving the U.S. Gulf Coast hurricanes of 2005-08 showed that exposure to various storms on nursing home (NH) residents resulted in significantly more deaths than reported by health care officials. This work also highlighted that evacuation of NH residents, compared to sheltering in place, was independently associated with morbidity and mortality. Hurricane Irma struck Florida on Sept. 10, 2017, prompting the evacuation of thousands of NH and assisted living community (ALC) residents. This symposium will discuss the effects of Hurricane Irma on vulnerable older adults residing in NHs and ALCs using mixed quantitative and qualitative methodologies. The first presentation will discuss morbidity and mortality of NH residents exposed to Hurricane Irma and will stratify by long stay/short stay status and hospice enrollment. The second presentation will discuss improvements and continued barriers to NH preparedness based on interviews with 30 administrators following Hurricane Irma. Using a novel methodology to identify residents of ALCs using secondary data sources, the third presentation will document AL resident morbidity and mortality risk following Hurricane Irma. The final presentation will highlight results of interviews with 70 stakeholders from small and large ALCs concerning the hurricane experiences of residents, including those with dementia. This symposium offers a multi-faceted view of a disaster\u2019s effects on LTC residents across Florida, including novel data from the NH environment and lesser-examined ALCs."}
+{"text": "Background: Preterm infants with hemodynamically significant patent ductus arteriosus (HsPDA) are exposed to low cerebral tissue oxygen saturation (rScO2) values. Additionally, infants requiring surgical ligation are at risk of further changes in cerebral oxygenation and postligation cardiac syndrome (PLCS). Previous studies have assessed the effect of PDA ligation on rScO2 with variable results.Cases description: In this report we analyse near-infrared spectroscopy (NIRS) and echocardiographic findings of two patients who underwent ligation of PDA and presented low cardiac output. Literature on regional tissue oxygenation saturation (rSO2) before and after PDA ligation was briefly reviewed.Discussion: Cerebral oxygenation values before and after PDA ligation may be influenced by gestational age, vasopressor use, ductal shunt volume, time of exposure HsPDA, chronological age and the presence of cerebral autoregulation. PLCS complicates 28\u201345% of all PDA ligations and is associated with higher mortality. Cerebral and somatic NIRS monitoring in the postoperative period may enhance the identification of PLCS at early stages.Conclusion: Cerebral oxygenation in the perioperative period of PDA ligation may be influenced by numerous clinical factors. Early detection of PLCS using multisite NIRS after ligation could prevent further alterations in cerebral hemodynamics and improve outcomes. A decrease in somatic-cerebral difference and/or a significant drop in somatic NIRS values may precede clinical signs of hypoperfusion. NIRS values should be interpreted as trends along with echocardiographic findings to guide goal directed interventions. After PDA ligation, a significant reduction (>20%) in rSrO2 and somatic-cerebral difference concurred with low LVCO in both cases in the absence of hypotension, oliguria and/or delayed capillary refill. In case 1, cerebral oxygenation decreased significantly at the end of measurement period compared to preligation baseline values (60 vs. 80%). In case 2, rScO2 remained unvaried.In the aforementioned cases, rSrOEarly detection of PLCS using multisite NIRS after ligation could prevent further alterations in cerebral hemodynamics and improve outcomes. A decrease in somatic-cerebral difference and/or a significant drop in somatic NIRS values may precede clinical signs of hypoperfusion. Further studies are needed to investigate the applicability of somatic-cerebral difference in preterm infants. Our report has many weaknesses. Firstly, we describe only two cases and no conclusions can be drawn regarding our findings. Secondly, somatic-cerebral difference although physiologically founded, has not been used in preterm infants. We consider that continuous and long lasting NIRS recording is a strength of this report, as well as the review of literature on NIRS findings before and after treatment.A prospective cohort study is recommended to evaluate the utility of two-site NIRS monitoring in the detection of PLCS. NIRS values should be interpreted as trends along with echocardiographic findings to guide goal directed interventions.Written informed consent was obtained from parents of both patient for the publication of any potentially identifiable images or data included in this article.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Diurnal cortisol slopes are stress-sensitive HPA-axis biomarkers implicated in cardiometabolic health outcomes and disparities. This study used two longitudinal cohort studies (CREATE and TRIAD) with harmonized variables to comprehensively examine what types of exposure to stressors are most salient for cortisol dysregulation in later life, and whether the characteristics of stressor exposure accounts for Black-White disparities in cortisol dysregulation . Black participants reported greater stressor exposure than Whites along some dimensions  but comparable exposure in others . Stressor exposure measures that captured psychological components  and pervasiveness  were more closely related to cortisol dysregulation than more objective measures . Everyday discrimination was associated with racial disparities."}
+{"text": "This study aimed to identify accelerometer measured daily physical activity patterns and to examine how they associate with health-related physical fitness among 258 participants  from the Finnish Retirement and Aging Study. Wrist-worn ActiGraph accelerometer was used and health-related physical fitness measures included body composition, cardiorespiratory fitness and muscular fitness. Based on latent class trajectory analysis, six different patterns of daily physical activity was identified on workdays and two on days off. Having low activity throughout the workday was associated with poorest health-related physical fitness, whereas a combination of low or moderate activity during working hours and increase of activity level in the evening was associated with most favorable body composition and better physical fitness compared to the other trajectories. In conclusion, a large variation in the workday physical activity patterns and health-related physical fitness was observed among aging workers."}
+{"text": "Opioid overdose risk is particularly high in immigrant communities partly due to limited English proficiency . Previous studies reported that social determinants of health (SDH) have been associated with risk for opioid overdose . The current study examines the association between SDH and literacy of opioid overdose risk among the immigrant population living in a rural area. Specifically, we examine the association in various age groups including young adults (aged 20 to 34), middle-aged (aged 35 to 49), and older adults (ages 50 to 75). Data were drawn from a sample of Korean American immigrants residing in rural Alabama (N=225). The participants administered the Brief Opioid Knowledge (BOOK) Questionnaire . Multiple regression analyses were conducted for three age groups to identify predictors of opioid literacy. Overall, older adults had lower levels of opioid literacy relative to their younger counterparts. Among young adults, low English proficiency, more chronic conditions, and greater depressive symptoms were significant predictors of limited opioid literacy. For the middle-aged adults, lower levels of health literacy and more pain symptoms were associated with limited opioid literacy. Among older adults, women, those with higher English proficiency, and lower health literacy had lower levels of opioid literacy. The findings demonstrated a greater vulnerability of older immigrants to limited opioid literacy. Different predictors based on SDH of limited opioid literacy across age groups have implications for tailored health promotion strategies to reduce opioid overdose risk."}
+{"text": "Background: Surgical root canal retreatment is required when peri-radicular pathosis associated with endodontically treated teeth cannot be treated by non-surgical root canal therapy (retreatment), or when retreatment was ineffective, not feasible or contraindicated. Endodontic failures maybe happen when irritants remain within the confines of the root canal, or when an extra-radicular infection cannot be eradicated by orthograde root canal treatment. Following enhanced microsurgical techniques in the last years, the success rates of surgical root canal retreatment have improved considerably.Objective: The aim of this systematic review is to gather updated data in regard to the surgical root canal (retrograde) retreatment to heal the periapical lesions.Materials and methods: The electronic databases PubMed and Google Scholar were searched in this review using specific inclusion and exclusion criteria. The search was performed in June 2019 and updated in November 2019. Among 3900 studies, 10 studies satisfied the eligibility criteria and were included in the review to be analyzed.Results: The 10 studies showed the importance of surgical root canal retreatment as a treatment option in removing infections within the root canal system and its efficiency in periapical tissue healing. These studies investigated different aspects of healing of periapical lesion after surgical (retrograde) retreatment including success rates, follow-up duration, and updated studies in surgical (retrograde) retreatment.Conclusions: Surgical root canal (retrograde) retreatment demonstrates its efficiency in reducing the period needed for healing of the periapical lesions in short-term follow-up compared to conventional orthograde retreatment. Periapical lesions are one of the common pathological conditions affecting periradicular tissues . The micThe preliminary purpose of all endodontic procedures, especially cleaning and shaping, is to eliminate necrotic tissue and infective bacteria . Large pThere are several studies that were conducted to discuss the healing of periapical lesion after nonsurgical (orthograde) retreatment or surgical root canal treatment. However, few studies have investigated the healing of periapical lesion after surgical (retrograde) retreatment. Consequently, the aim of this review was to collect all updated and available studies including imperative information concerning the surgical root canal (retrograde) retreatment to heal periapical lesions.Material and methodsThis review has been compiled according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.Research QuestionThe following was the research question for the systematic review: \u201cThe best endodontic treatment option for the healing of periapical lesions: is it surgical retrograde retreatment or conventional orthograde retreatment?\u201d.Literature SearchWith respect to the question of the study, we searched the literature and identified relevant studies. The literature search was formulated in June 2019 and then updated in November 2019. A web search was done through PubMed (2009-2019) and Google Scholar (2009-2019) with MesH terms and/or in various combinations .Relevant articles had been read and assessed by the introduction of the close meaning ideas by the study reviewers. Full articles were obtained for most of the titles and abstracts that met the inclusion criteria, the full text was accessed. From each included article, study design, interventions, and findings were extracted. Articles used were categorized into two main groups (free and restricted). Free ones have been downloaded directly by the URLs generated from the database. The restricted group has been downloaded by the institutional access of the King Abdulaziz University (KAU) library. Even though some articles did not match the main idea, they have been reviewed again & decided to be either relevant or irrelevant.Inclusion Criteria1. Native research released in the English language.2. Time framed articles released within 10 years (2009 - 2019).3. Studies carried out on human subjects only.Exclusion Criteria1. Articles that described healing of periapical lesion with management techniques excluding the surgical root canal retreatment.2. Articles that discussed healing of periapical lesion after surgical root canal retreatment by percentages and samples taken from animals.3. Review articles.Critical AppraisalEligible studies were independently analyzed by all reviewers according to the eligibility criteria as well as PRISMA guidelines. Any disagreement between the reviewers was resolved using discussion.Data Extraction and PresentationThe search strategy using the keywords and MeSH of the databases like PUBMED and Google Scholar yielded a total of 3,900 studies, of which 3,580 were either unrelated or duplicate topics. Among the potential 140 studies, the eligibility criteria were applied and ten studies were included in this systematic review. The summary of the search flow chart for this systematic review has been depicted in  retreatment including success rates, follow-up duration, and updated studies in surgical root canal (retrograde) retreatment. The studies included in this systematic review were one randomized controlled trial study, two prospective studies, one retrospective study, and six case reports -19,20-25DiscussionThe systematic review presents a comprehensive compilation of evidence taken from ten articles which included original studies. The sample size was up to 376 subjects seeking endodontic retreatment by the use of surgical retrograde retreatment. All included studies confirmed faster treatment time by surgical root canal (retrograde) retreatment Table . The recAlso, Del Fabbro et al. in 2007 and Torabinejad et al. in 2009 have compared the success rates of non-surgical orthograde and surgical retrograde endodontic retreatment ,28. TheySurgical root canal (retrograde) retreatment is defined as an important invasive procedure that permits fast treatment options minus the necessity of the extensive traditional method. Surgical retrograde retreatment demonstrates its efficiency in reducing the period needed for healing of the periapical lesions and suggests benefits that will result in better recognition among patients seeking faster results in short-term follow-up, but on the long-term follow-up\u00a0showed not significant difference for healing of periapical lesions compared to conventional orthograde retreatment. However, more clinical trials are encouraged to inspect the results of surgical retrograde retreatment on the healing of periapical lesions."}
+{"text": "The Long Life Family Study (LLFS) has longitudinally measured key aging phenotypes on 4,953 participants (539 pedigrees) in the USA and Denmark selected for exceptional familial longevity. On average, both generations of the LLFS sample are healthier than average for their age/sex, for many phenotypes. However, the pedigrees are heterogeneous, with different families showing familial clustering of protection for different phenotypes. Linkage analyses identified extremely strong genetic linkage peaks for many cross-sectional as well as longitudinal trajectory rates of change phenotypes. These peaks are NOT explained by GWAS SNPs (either measured or imputed). Pedigree specific HLODs and preliminary deep sequencing suggests that these peaks are driven by rare, protective variants running in selected pedigrees. Whole Genome Sequencing, a third longitudinal visit, and extensive OMICs  will help us resolve the mechanisms behind these protective genetically linked variants, and could illuminate new biology and enable new therapeutics."}
+{"text": "The amygdala is a central hub for fear learning assessed by Pavlovian fear conditioning. Indeed, the prevailing hypothesis that learning and memory are mediated by changes in synaptic strength was shown most convincingly at thalamic and cortical afferents to the lateral amygdala. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in many areas of the mammalian brain including the amygdala, where BDNF signalling via tropomyosin-related kinase B (TrkB) receptors is prominently involved in fear learning. This review updates the current understanding of BDNF/TrkB signalling in the amygdala related to fear learning and extinction. In addition, actions of proBDNF/p75NTR and NGF/TrkA as well as NT-3/TrkC signalling in the amygdala are introduced. The amygdala is a telencephalic group of diverse, interconnected nuclei in the brain  receptors preferentially activated by NGF (nerve growth factor), TrkB receptors activated by BDNF as well as NT-4/5 (neurotrophin-4/5) and TrkC receptors by NT-3 (neurotrophin-3) Barbacid .While many findings regarding BDNF/TrkB signalling in cellular aspects of learning were initially reported for hippocampal and cortical circuits, BDNF/TrkB pathways in the amygdala emerged soon thereafter to be prominently involved in fear learning (see below). TrkB receptor as well as BDNF mRNA and protein were detected at moderate to high levels in various amygdala subnuclei , the posterior intralaminar nucleus (PIN) and the suprageniculate nucleus (SG)  or Y515 (Shc) phosphorylation site of the TrkB receptor, respectively , which drives the expression of Met-BDNF and leads to decreased activity-dependent BDNF secretion  were unaffected or impaired when assessed by skin conductance response or fear-potentiated startle, respectively  from tones not paired with the aversive US (CS\u2212) in a discriminative fear learning task  (Meis et al. Interestingly, chronic BDNF reduction to about 50% of wild-type levels in BDNFThe LA is highly interconnected with the BA (Pitkanen et al. AR\u03b11 subunits in amygdala cell cultures, which was supposed to elicit a transient hyper-excitability in the amygdala, thereby contributing to cellular mechanisms of memory consolidation (Mou et al. +/\u2212 mice displayed neither impaired basal synaptic GABAergic transmission nor altered inhibitory synaptic plasticity in the LA. However, positive modulation of interneuron activity by noradrenaline was significantly decreased by chronic BDNF reduction (Meis et al. Beside glutamatergic synaptic transmission, BDNF/TrkB signalling also regulates GABAergic neurotransmission (Gottmann et al. Beside the basolateral amygdala, the central nucleus is now considered as an important site of associative plasticity involved in fear memory (Ehrlich et al. In conclusion, BDNF/TrkB signalling increases excitatory synaptic transmission in different subnuclei of the amygdala and enables LTP. At GABAergic synapses, acute BDNF/TrkB signalling may lead to reduced inhibition and elevated excitability necessary for memory formation, while chronic BDNF reduction results in impaired interaction of GABAergic synaptic transmission with modulatory transmitters like noradrenaline and serotonin.After fear learning, repeated exposure to the conditioned stimulus alone leads to diminished fear responses (Myers and Davis +/\u2212 mice display an age-dependent deficit in extinction learning (Psotta et al. Val/Met or BDNFMet/Met mice as well as human Met allele carriers were impaired in extinguishing a conditioned fear response, associated with abnormal fronto-amygdala activity in humans (Soliman et al. +/\u2212 mice but was mimicked by overexpression of BDNF in the BLA from the end of extinction training onward (Karpova et al. A critical contribution of BDNF signalling in extinction was recently demonstrated. BDNFNeurotrophins are at first synthesized as precursor proteins, which are processed to the mature form by proteolytic cleavage (Lessmann and Brigadski Conflicting results are available about the distribution of TrkA receptors in the amygdala. While initially neither TrkA receptor mRNA nor immunoreactive cells for TrkA receptors were detected (Gibbs and Pfaff While neither NT-3 mRNA nor immunoreactive neurons were found in the amygdala (Phillips et al. Accumulating evidence indicates that BDNF/TrkB signalling in the amygdala plays a pivotal role in fear learning and memory as well as fear extinction. In the amygdala circuitry, BDNF/TrkB signalling contributes significantly to synaptic plasticity, which is widely accepted as a cellular mechanism underlying fear memory learning. In addition, downstream molecular signalling pathways triggered by TrkB activation are well documented. However, actions of BDNF/TrkB signalling in amygdala synaptic processes involved in fear extinction learning are far less understood. While behavioural studies suggest a significant contribution of BDNF signalling within the amygdala in extinction learning, analysis of the underlying cellular mechanisms warrants further studies."}
+{"text": "Filial caregivers  are a part of the growing number of family caregivers in midlife and late adulthood. The responsibilities that filial caregivers navigate in midlife and late adulthood may expose them to multiple types of discrimination that may decrease their physical health, though this relationship has been understudied. As numbers of family caregivers grow, it is important to examine the potential vulnerability of younger and older filial caregivers\u2019 physical health in the context of discrimination. Informed by the life course perspective, this study compares the physical health of younger (aged 34-64) and older (aged 64-74) filial caregivers who experience discrimination. Filial caregivers  from the Midlife in the United States (MIDUS-II) Survey reported on demographics, family caregiving, daily discrimination, self-rated physical health, and chronic conditions via questionnaires and phone interviews. Regression analyses showed no differences between younger and older adults\u2019 self-rated physical health or average chronic conditions. However, moderation analyses revealed that younger filial caregivers who experienced greater discrimination reported poorer self-rated physical health than their older counter parts as well as younger and older filial caregivers who experienced less discrimination. Additionally, younger caregivers with greater discrimination exposure exhibited more number of chronic conditions as compared to other caregivers. The study results highlight the impact of the intersection between filial caregivers\u2019 age and discrimination on physical health. Findings have the potential to inform programs that could promote the health of filial caregivers in the face of discrimination."}
+{"text": "Although nonalcoholic fatty liver disease (NAFLD) is more prevalent in older individuals, the underlying mechanisms by which aging processes accelerate NAFLD are not fully understood. NAFLD can progress to nonalcoholic steatohepatitis (NASH), which in turn can lead to the development of cirrhotic liver disease and hepatocellular carcinoma (HCC). Since NAFLD, NASH, and HCC are rapidly increasing in the aging population, understanding the mechanism of how NAFLD progresses to NASH is crucial. NASH is emerging as the leading cause of chronic liver disease and the most rapidly growing indication for liver transplantation worldwide, with liver fibrosis being the most important predictor of liver failure in NASH . HoweverCRMertk) mouse model, the authors further showed that all-trans retinoic acid (ATRA)\u2013induced ADAM metallopeptidase domain 17 (ADAM17)\u2013mediated MerTK cleavage decreased the levels of MerTK receptor on macrophages and suppressed NASH fibrosis. ATRA is a major active metabolite of retinol stored in quiescent HSCs in healthy liver. In damaged liver, as HSCs are activated, they release retinol. Livers of subjects with NASH show lower levels of retinol than livers of subjects with simple steatosis [in vivo. However, given that MerTK is critical for maintaining tissue homeostasis in other settings, including atherosclerosis and myocardial infarction [Liver fibrosis is driven by the activation of hepatic stellate cells (HSCs) that produce collagen and other types of extracellular matrix. It has been widely reported that liver macrophages, including resident Kupffer cells and infiltrated monocyte-derived macrophages, can activate HSCs through releasing growth factors including TGF\u03b2 and PDGF . Howeverteatosis . Consistfarction , global In summary, Cai et al. uncover a previously unrecognized function of macrophage MerTK in NASH fibrosis and provide constructive insight on the potential therapeutic targeting of MerTK. However, this study opens up new questions worth exploring. Since MerTK is often seen as a protective regulator for tissue homeostasis, why doesn\u2019t MerTK signaling trigger beneficial effects, including efferocytosis, dampening of inflammation, and resolution of inflammation in the context of NASH? Moreover, some studies have shown that Kupffer cells are protective in non-NASH liver injury models. However, Kupffer MerTK is detrimental in NASH. Does MerTK express in a unique subset of Kupffer cells that promote NASH progression? Finally, what are the mechanisms of decreased liver ATRA and increased GAS6 during NASH?"}
+{"text": "Coastal wetlands provide many critical ecosystem services including carbon storage. Soil organic carbon (SOC) is the most important component of carbon stock in coastal salt marshes. However, there are large uncertainties when estimating SOC stock in coastal salt marshes at large spatial scales. So far, information on the spatial heterogeneity of SOC distribution and determinants remains limited. Moreover, the role of complex ecological interactions in shaping SOC distribution is poorly understood. Here, we report detailed field surveys on plant, soil and crab burrowing activities in two inter-tidal salt marsh sites with similar habitat conditions in Eastern China. Our between-site comparison revealed slight differences in SOC storage and a similar vertical SOC distribution pattern across soil depths of 0\u201360 cm. Between the two study sites, we found substantially different effects of biotic and abiotic factors on SOC distribution. Complex interactions involving indirect effects between soil, plants and macrobenthos (crabs) may influence SOC distribution at a landscape scale. Marked differences in the SOC determinants between the study sites indicate that the underlying driving mechanisms of SOC distribution are strongly system-specific. Future work taking into account complex interactions and spatial heterogeneity is needed for better estimating of blue carbon stock and dynamics. It points to the necessity of incorporating these indirect effects for better understanding the mechanisms underlying carbon stock in coastal ecosystems. It also calls attention to spatial heterogeneity and system specificity for estimating blue carbon stock and dynamics.By comparing between two inter-tidal salt marsh sites with similar habitat conditions in Eastern China, we observed minor differences in SOC storage and a similar vertical SOC distribution pattern across the soil depths of 0\u201360 cm. Despite these similarities, we found strongly different effects of biotic and abiotic environmental factors on SOC density distribution between the two study sites. Complex interactions involving indirect effects between soil, plants and macro-benthos (crabs) can provide important additional explanatory power to the models explaining SOC distribution, suggesting that these interactions may underpin SOC distribution at a landscape scale. Marked differences in the SOC determinants between the study sites indicate that the underlying driving mechanisms of SOC distribution are strongly system-specific. Future work, taking into account spatial heterogeneity and system specificity, is needed for improving the accuracy of estimates of blue carbon stock and dynamics."}
+{"text": "The current pandemic due to the coronavirus disease 2019 (COVID-19) outbreak has forced physicians to review their current clinical practice and guidelines. Although elective procedures using assisted reproductive technologies (ART) should be preferably canceled or postponed at this time, this does not always apply to urgent procedures such as those in patients with cancer. A complete oncofertility counseling balancing the benefits and risks of undergoing fertility preservation before commencing gonadotoxic therapies (chemotherapy and/or radiotherapy) should also be provided during the COVID-19 outbreak. This article briefly highlights what patients, oncologists and fertility specialists need to keep in mind during oncofertility counseling at the time of the COVID-19 outbreak. Some anticancer treatments can affect fertility , 2. OncoPatients face hurdles that can be as basic as getting to the tertiary hospital that offers both cancer care and fertility preservation treatments to more complex emotional thoughts dealing with the fear of both the known and unknown risks of complications from COVID-19 during cancer treatment and the additional fertility preservation treatments involving further hospital visits, potential surgery and in some units additional costs relating to COVID-19 testing and personal protective equipment (PPE) gear. Moreover, the anxieties from the fear of contracting the virus during hospital visits leading to isolation and quarantine are real enough for some to even consider opting out of fertility preserving treatments whilst fighting their most basic desire to procreate. For healthcare providers, the novel challenges of providing safe and optimal care while dealing with the undefined risks remain.Nonetheless, where resources allow, with extra caution and strict adherence to the COVID-19 safety protocols and local guidelines, oncofertility is a feasible option, giving hope for young patients with cancer.Newly diagnosed eligible cancer patients should discuss before commencing treatment with their oncologist and oncofertility specialists the wish to have children to see if it is possible to safely balance this option without compromising their cancer care and further increase the risk of infections by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Outline various fertility preservation procedures that can be undertaken safely with the precautions recommended by various national and international organizations including having protected pathways.For male patients, sperm banking before starting anticancer treatments is standard of care.For female patients, embryo/oocyte cryopreservation before starting anticancer treatments is the first option to be discussed .Ovarian tissue cryopreservation in patients that cannot wait 2-3 weeks before starting anticancer treatments can be discussed .Ovarian transposition can be considered before starting pelvic radiotherapy .Temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) during chemotherapy is an available option to protect ovarian function during treatment .Detailed oncofertility counseling should clearly discuss the additional concerns during the COVID-19 outbreak whist defining all the established safety protocols in place to minimize these risks.Triage patients for SARS-CoV-2 testing in accordance with local guidelines before starting any of the ART procedures.Train additional members of the team  on how to refill the liquid nitrogen tanks in case the lab staff is quarantined.If local resource allocation allows, consider having two teams  working by rota. An alternate team can take over in case one team comes in contact with an infected patient .The advances in oncofertility have given a lot of hope on preserving future fertility to cancer patients. Hence, we urge oncologists and fertility specialists to consider oncofertility counseling (which includes COVID-19-related safety concerns at this time) and work as a dedicated team to support young cancer patients optimizing their future fertility and reproductive health even during this pandemic. Let us not allow the COVID-19 outbreak to sidetrack us on this important issue.Tanya Buckshee Rohatgi has no conflicts of interest. Bhawna Sirohi has received honoraria from Bayer and Roche outside the submitted work . Matteo Lambertini acted as a consultant for Roche, and received honoraria from Theramex, Takeda, Roche, and Lilly outside the submitted work.No funding was received for this work."}
+{"text": "Salmonella (NTS) enterica subspecies enterica is associated primarily with a self-limiting diarrhoeal illness, invasive bacterial infections  were also reported. Human outbreaks of NTS were reported in several countries all over the world including developing as well as high-income countries. Conventional laboratory methods such as pulsed field gel electrophoresis (PFGE) do not display adequate discrimination and have their limitations in epidemiological surveillance. It is therefore very crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological characterisation and outbreak investigation.Salmonellosis is one of the most common foodborne diseases worldwide. Although human infection by non-typhoidal Salmonella Typhimurium and Salmonella Dublin that occurred in 2013 in UK and Ireland respectively.Here, we used different whole genome sequence (WGS)-based subtyping methods for retrospective investigation of two different outbreaks of Salmonella Typhimurium genomes revealed well supported clades, that were concordant with epidemiologically defined outbreak and confirmed the source of outbreak is due to consumption of contaminated mayonnaise. SNP-analyses of Salmonella Dublin genomes confirmed the outbreak however the source of infection could not be determined. The core genome multilocus sequence typing (cgMLST) was discriminatory and separated the outbreak strains of Salmonella Dublin from the non-outbreak strains that were concordant with the epidemiological data however cgMLST could neither discriminate between the outbreak and non-outbreak strains of Salmonella Typhimurium nor confirm that contaminated mayonnaise is the source of infection, On the other hand, other WGS-based subtyping methods including multilocus sequence typing (MLST), ribosomal MLST (rMLST), whole genome MLST (wgMLST), clustered regularly interspaced short palindromic repeats (CRISPRs), prophage sequence profiling, antibiotic resistance profile and plasmid typing methods were less discriminatory and could not confirm the source of the outbreak.Single nucleotide polymorphism (SNP)-based cluster analysis of Foodborne salmonellosis is an important concern for public health therefore, it is crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological surveillance and outbreak investigation. In this study, we showed that SNP-based analyses do not only have the ability to confirm the occurrence of the outbreak but also to provide definitive evidence of the source of the outbreak in real-time. Salmonella enterica, which includes more than 2600 serovars [Salmonella infections are classically divided into diseases caused by typhoidal or non-typhoidal salmonella (NTS). Typhoid fever is caused by the human restricted Salmonella enterica serovars Typhi and Paratyphi [Salmonella (NTS) serovars, predominantly cause a self-limiting diarrhoeal illness they have adapted to cause invasive extra-intestinal disease known as invasive NTS (iNTS) which can result in bacteraemia and focal systemic infections [Salmonella serovars responsible for typhoid fever kill over 250,000 humans per year [Salmonella (NTS) serovars responsible for diarrhoeal illness cause over 155,000 deaths annually [Salmonella Typhimurium and Salmonella Dublin have been associated with systemic illness [Salmonella Typhimurium and Salmonella Dublin were reported in developed countries [Foodborne salmonellosis is an important concern for public health. It is caused by the enteric pathogen serovars . Human Sfections , 4 . Thefections  moreoverper year  while noannually . Interesannually . Salmoneountries \u201311.Salmonella enterica and have their limitations in epidemiological surveillance, it is therefore crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological characterisation and outbreak investigation.Conventional laboratory methods such as pulsed field gel electrophoresis (PFGE) do not usually provide adequate discrimination among outbreak and non-outbreak strains of Salmonella Typhimurium and Salmonella Dublin that occurred in 2013 in UK and Ireland respectively [Here, we evaluate different whole genome sequence (WGS)-based subtyping methods (including single nucleotide polymorphism (SNP)-based cluster analysis, multilocus sequence typing (MLST), ribosomal MLST (rMLST), whole genome MLST (wgMLST), core genome MLST (cgMLST) as well as clustered regularly interspaced short palindromic repeats (CRISPRs), prophage sequence profiling, antibiotic resistance profile and plasmid typing) for retrospective investigation of two outbreaks of ectively , 12.Salmonella Dublin that occurred in 2013 in Ireland [Salmonella Typhimurium occurred in 2013 in UK [Salmonella Typhimurium and Salmonella Dublin respectively. Non-outbreak strains were also included for comparison. Details of all Salmonella Dublin and Salmonella Typhimurium isolates analysed in this study are provided in supplementary Tables We carried out retrospective investigation of a human outbreak of  Ireland  and anot13 in UK . We inclSalmonella Dublin [Salmonella Dublin were indistinguishable by PFGE. Although multiple loci VNTR analysis (MLVA) was of value in discriminating the outbreak strains from an epidemiologically unrelated isolate in 2013 it was not able to provide a conclusive link between the outbreak strain and a historical isolate from 2011 (11F310) since all outbreak strains had the same MLVA pattern (3-6-1-10-2-3-12) and the historical isolate had similar MLVA pattern (3\u20136\u20131-10-2-3-11/12).PFGE was of a limited value for the investigation of the outbreak of a Dublin  since alSalmonella Typhimurium [Despite the technical limitation of phage typing, it was of value for investigating the outbreak of himurium  and confdenovo assembly for the raw Fastq paired end (PE) reads for all Salmonella Dublin and Salmonella Typhimurium strains using two different assemblers including Velvet available at Centre for genomic epidemiology (CGE) (http://www.genomicepidemiology.org/) and SPAdes available at Enterobase (http://enterobase.warwick.ac.uk/). We then assessed the quality of the assembly for each strain was assessed using Quast assessment tool (http://quast.bioinf.spbau.ru/).We carried out https://cge.cbs.dtu.dk/services/CSIPhylogeny/) where raw reads were mapped to reference sequences  using BWA software (http://bio-bwa.sourceforge.net). The depth at each mapped position was calculated using genomeCoverageBed, which is part of BEDTools (https://bedtools.readthedocs.io/en/latest/). High quality SNPs were called using mpileup which is part of SAMTools (http://samtools.sourceforge.net). Genome mappings were then compared and an alignment of the SNPs are then created by concatenating the SNPs. A maximum likelihood (ML) phylogenetic tree was then created based on the concatenated alignment of the high quality SNPs.SNP analysis was carried out using CSIPhylogeny (http://enterobase.warwick.ac.uk/) and CGE (http://www.genomicepidemiology.org/).The assembled sequences of each strain were analyzed to detect the MLST, rMLST, cgMLST and wgMLST available at Enetrobase .Prophages were determined with the draft genomes generated by Velevt and SPAdes for all http://www.genomicepidemiology.org/) to construct a phylogenetic tree based on the SNPs of detected prophages. Phylogenetic trees were constructed using assembled genomes generated by Velvet and SPAdes assemblers to check if the assembly could affect the tree.We then used CSI phylogeny available at CGE .Spacers sequence within the draft genomes of all Salmonella Dublin and Salmonella Typhimurium strains using the plasmid database; PLSDB (https://ccb-microbe.cs.uni-saarland.de/plsdb/).We determined the plasmids within the draft genomes of all Salmonella Dublin and Salmonella Typhimurium strains using ResFinder (https://cge.cbs.dtu.dk/services/ResFinder/).We determined acquired antibiotic resistance genes and mutations within the draft genomes of all Salmonella Typhimurium were grouped together in two clades and they are very closely related to strains isolated from mayonnaise . Interestingly, outbreak isolates of Salmonella Dublin displayed identical rMLST (type 1429) however, some of the non-outbreak strains showed the same rMLST. Moreover, the wgMLST was different among the outbreak strains however, the cgMLST was unique among outbreak strains and can easily separate the outbreak strain from the non-outbreak strains including the 2011 historical isolate (11F310).As illustrated in Table\u00a0Salmonella Typhimurium as illustrated in Table\u00a0On the other hand, MLST, rMLST, cgMLST and wgMLST could not discriminate between the outbreak and non-outbreak strains of Salmonella Dublin isolates including outbreak and non-outbreak strains harbour one CRISPR locus and we observed 3 to 5 unique spacers for CRISPR1 locus. Identical spacers were detected among the outbreak and non-outbreak strains as shown in Table All Interestingly, the number of spacers in three isolates  changed from (4 spacers) based on Velvet to (5 spacers) based on SPAdes.Salmonella Typhimurium isolates harbour 3 CRISPR loci. Identical spacers were detected among the outbreak and non-outbreak strains as shown in Table All Salmonella Dublin strains including the outbreak strains are lysogenic for three prophages . However, phylogenetic analyses of Salmonella Dublin strains based on the SNPs of prophages showed that outbreak strains are intermixed with the non-outbreak strains based on velvet assembler  and the Edwardsiella specific phage (GF-2).All Salmonella Typhimurium genomes assembled by Velvet were lysogenic for two Salmonella specific prophages (Gifsy 2 and RE-2010). All strains except one outbreak isolate (H132940750) harbour Salmonella 118970_sal3 phage.On the other hand, Interestingly, all strains harbour Edwardsiella GF-2 prophage except three outbreak isolates .Salmonella Typhimurium strains based on the SNPs of prophages showed that outbreak strains are intermixed with the non-outbreak strains using velvet assembler  as shown in Table\u00a0All outbreak and non-outbreak strains of Same plasmids were determined using Velvet and SPAdes assemblers.Salmonella Typhimurium harbour 3 plasmids  except the outbreak strain H133300609 which did not carry plasmid pATCC14028 but it harbours a different plasmid (pSLT_VNP20009) instead -Iaa gene. No mutations were detected against gyrA and parC genes in all isolates except one isolate (MF038630) that carried a non-synonyms mutation within the gyrase protein and it is associated with bacterial resistance to nalidixic acid -Iaa gene\u201d. No known mutations were detected against gyrA and parC -based cluster analysis of Salmonella Typhimurium strains. However, cgMLST defined the genetic relatedness among Salmonella Dublin isolates more precisely and confirmed there is no relation among the 2013 outbreak isolates and the 2011 historical isolate (11F310) of Salmonella Dublin.On the other the WGS-subtyping methods including MLST, rMLST, wgMLST, cgMLST showed limited discrimination for the outbreak and non-outbreak isolates of It was reported that MLST might not be the most suitable epidemiological tool  but it iThe cgMLST bridges the classic MLST with the novel WGS-based approach since it combines the discriminatory power of MLST with large-scale data obtained from WGS enabling to exploit a considerable number of gene targets throughout the bacterial genome which would maximize the quality and resolution for surveillance and research works.Salmonella Enteritidis in Europe [A recent study showed that cgMLST has shown the robustness of cgMLST as a tool to investigate multi-country outbreak of n Europe .Escherichia coli (VTEC) O157:H7 in Canada showed that wgMLST provided higher discrimination than PFGE and MLVA [The difference between the cgMLST and wgMLST is that unlike cgMLST, wgMLST indexes the variation of pre-defined set of genes from both core and accessory genes . Anotherand MLVA .Salmonella Dublin isolates of outbreak group from the non-outbreak group. However, both cgMLST and wgMLST were unsuccessful in differentiating outbreak-related Salmonella Typhimurium isolates from outbreak-unrelated isolates.Research studies have shown that cgMLST and wgMLST are viable typing methods for outbreak surveillance. In our study, cgMLST proved to provide higher discriminatory resolution for differentiating Salmonella serovars [Salmonella subtyping is the sensitivity and accuracy of the assembly as some prophage regions might be lost during assembly. We used two different denovo assemblers (SPAdes and Velvet) and found that prophage sequence profiling could not differentiate between the outbreak and non-outbreak isolates.Bacterial genome comprises a considerable amount (10 to 20%) of prophages integrated in their core genome . Prophagserovars . HoweverSalmonella outbreaks [Salmonella enetrica outbreaks as we showed in our previous studies [Salmonella serovars.Recent studies have suggested that high throughput CRISPR typing has the potential to be used for epidemiological surveillance and investigation of utbreaks , 27. How studies , 29 howePlasmid profiles and antimicrobial- susceptibility profiling have been used as an epidemiological tool since many decades. However, it was reported that analysis of plasmid profiles provided higher discrimination in the outbreak investigations than analysis of antimicrobial-susceptibility pattern , 31. In In this study, we compared several retrospective WGS-based subtyping methods and we showed that SNP-based cluster analysis is superior to other subtying methods to define the source of outbreak in real-time.In conclusion, foodborne salmonellosis is an important concern for public health therefore, it is crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological surveillance and outbreak investigation. The rapid development of next-generation sequencing (NGS) technology and bioinformatics tools have enabled WGS of any bacterial strain feasible. Various typing tools have been proposed by using WGS data but currently, the adoption of WGS-based methods have proved to be difficult due to lack of standardization. There are many layers on obtaining WGS data and there is need of standardization from the type of sequencers used to the bioinformatics analysis. Therefore, the emerging genetic analysis techniques should be combined with conventional phenotypic and molecular methods for routine surveillance and outbreak investigation until the WGS-based methods can be fully exploited, improved and standardized.Additional file 1: Supplementary Table\u00a01. Details of Salmonella Dublin strains analysed in this study. Supplementary Table\u00a02. Details of Salmonella Typhimurium strains analysed in this study"}
+{"text": "Dual-task gait performance is a marker of motor-cognitive interactions modulated by the frontal lobes. After a stroke, gait disturbances are more evident, particularly when concurrently completing a mental task and walking, an effect called high dual-task cost (DTC). Following a stroke, the potential association of high-DTC, integrity of the frontal lobes and cognitive functioning is unclear. This study screened 161 participants with stroke history from the Ontario Neurodegenerative Disease Research Initiative (ONDRI)-cerebrovascular disease cohort . Individuals scoring zero in the National Institute of Health Stroke Scale were analyzed (n=102). DTC was the percentage change in gait speed from the single to dual-task condition. Standardized normal-appearing white matter (NAWM) and grey matter (NAGM) volumes from superior, middle and inferior frontal lobe were compared between DTC quartiles  using a multivariate model (MANOVA), with total frontal lobe volume as a covariate. Another model compared group performance across 5 adjusted cognitive domains . Univariate tests revealed that NAWM volume in the superior frontal lobe  was significantly different across DTC quartiles. Contrast tests suggested that the first quartile had larger NAWM than the second and fourth. DTC quartiles also showed differences in attention  and contrast tests indicated that the first quartile performed significantly better than second and fourth. DTC poststroke may be a proxy for structural integrity of superior frontal lobe regions and attention."}
+{"text": "Microbacteriaceae from plants infested by plant-parasitic nematodes were obtained using Illumina technology. The sequence data will provide useful baseline information for the development of comparative genomics and systematics of Microbacteriaceae and facilitate understanding of molecular mechanisms involved in interactions between plants and nematode-associated bacterial complexes.Draft genome sequences of 28 strains of  Microbacteriaceae from plants infested by plant-parasitic nematodes were obtained using Illumina technology. The sequence data will provide useful baseline information for the development of comparative genomics and systematics of Microbacteriaceae and facilitate understanding of molecular mechanisms involved in interactions between plants and nematode-associated bacterial complexes.Draft genome sequences of 28 strains of  Microbacteriaceae (class Actinobacteria) inhabit various terrestrial and aquatic ecosystems and often occur in plants as endophytes and pathogens   , 4. Alonragariae , 5\u20138.Microbacteriaceae were isolated from plant galls induced by different anguinids and from plant tissues affected by Aphelenchoides species (Corynebacterium agar (http://www.vkm.ru).Novel nematode-associated strains of  species . The airium agar  or Reasoium agar , 11 and For genome sequencing, DNA was extracted with a QIAamp DNA minikit  from biomass grown in liquid peptone-yeast medium as described previously  or usingDefault parameters were used for all software unless otherwise specified. The quality of the reads was checked with FastQC 0.11.8 . AdapterAdditional comparative phenotypic study of the sequenced strains, along with genome-wide analyses of phylogenetically closely related plant endophytes and pathogens, will facilitate understanding of their role in bacterial-nematode complexes, including mechanisms of molecular interactions between members of these complexes and plants.These whole-genome shotgun projects have been deposited in DDBJ/ENA/GenBank under the accession numbers listed in"}
+{"text": "Despite some insurance plans now paying for home-based palliative care, recent reports have suggested that coverage for palliative care may be insufficient to expanding patient access to home-based palliative care. Research has yet to explore palliative care barriers from the perspective of palliative care-eligible patients and their caregivers. To identify patients and caregivers\u2019 perceived barriers to home-based palliative care and their recommendations for overcoming these barriers, we conducted a qualitative study using semi-structured individual interviews. Participants  who were eligible for a randomized controlled trial of home-based palliative care were interviewed via telephone. Our interview protocol elicited participants\u2019 perspectives on home-based palliative care services; positive and negative aspects of the program explanation; and suggestions for improving messaging around home-based palliative care. Researchers used grounded theory to identify the themes within the transcripts. Two researchers independently coded the transcripts and then met to compare coding and reconciled discrepancies until 100% consensus was reached. Identified themes related to home-based palliative care referral barriers included reluctance to have home visits, timing, lack of palliative care knowledge, misconceptions of palliative care, and patients\u2019 self-perceived health condition . Themes related to recommendations for overcoming these barriers included preferring a palliative care referral from healthcare providers or from insurance company and clearer presentation of palliative care service. Findings reinforce the need for additional palliative care education among patients with serious illness and the importance of delivering the information from a trusted source."}
+{"text": "Physical frailty is an age-related clinical syndrome that is related to adverse health outcomes, including cognitive impairment and dementia. Recent studies have shown structural neuroimaging correlates with frailty. However, most existing evidence relies on brain volumetric measures. Whether brain microstructure is associated with frailty and its spatial distribution have not been explored. In the Baltimore Longitudinal Study of Aging, we identified 776 cognitively normal participants aged 50 and older who had concurrent data on frailty and brain microstructure by diffusion tensor imaging (DTI), including mean diffusivity (MD) of gray matter and fractional anisotropy (FA) of white matter. We first identified neuroimaging markers that were associated with frailty score (0-5) and further examined their relationships with frailty status  using multivariate linear regression. Models were adjusted for age, sex, race, years of education, and Apolipoprotein E e4 carrier status. DTI-based neuroimaging markers that were associated with frailty status were localized in the supplementary motor area of the frontal lobe, several subcortical regions , and body and splenium of corpus callosum. This study demonstrates for the first time that microstructure of both gray and white matter differs by frailty levels in cognitively normal older adults. Brain areas were not widespread, but mostly localized in gray matter subcortical motor areas and white matter corpus callosum. Whether changes in brain microstructure precede future frailty development warrants further investigation."}
+{"text": "Sambucus nigra lectin-reactive) fibronectin in prediction of gestational diabetes mellitus (GDM).To evaluate the performance of first trimester maternal serum glycosylated . There was no difference in assay formats for adiponectin.There was no difference in maternal serum glycosylated fibronectin concentrations between women with consequent GDM  and control women . Maternal serum fibronectin levels were significantly lower in GDM group , compared to the control group  fibronectin and GDM. Meanwhile, this study provides information on the screening performance of glycosylated fibronectin in women with GDM. This study also evaluated glycosylated fibronectin levels in different BMI subgroups.According to our results, neither first trimester maternal serum glycosylated fibronectin nor serum fibronectin are effective in screening for GDM. Further larger studies in prospective settings are needed to evaluate first trimester glycosylated fibronectin as a screening method for GDM alone and in combination with other markers."}
+{"text": "Central retinal artery occlusion (CRAO) represents one of the most devastating ophthalmic emergencies, since the inner two-thirds of the retina lose their blood supply. The acute obstruction of the central retinal artery is characterized by severe, sudden and unilateral painless visual loss and usually occurs secondary to an embolus of cardiovascular origin. A paradoxical thromboembolic event of the central retinal artery through patent foramen ovale is an exceptionally unusual clinical entity as well as a great diagnostic challenge since the source of initial thrombus formation requires extensive investigation. Herein, we aim to describe a patient with no significant comorbidities who experienced a paradoxical thromboembolic episode of central retinal artery associated with patent foramen ovale. Central retinal artery occlusion represents the ophthalmic analogue of ischemic stroke and is typically manifested with sudden, severe and painless loss of vision . HoweverCRAO is usually the result of an embolus, either of cardiac origin or dislodged from an unstable atherosclerotic plaque of carotid bifurcation. Subsequently, the most common risk factors for CRAO include carotid atherosclerosis, cardiac valvular disease and cardiac arrhythmias, mainly atrial fibrillation . CongeniThe most important and well-documented clinical manifestation of PFO is the cryptogenic ischemic stroke due to a paradoxical embolus. CRAO or branch retinal artery occlusion (BRAO) associated with PFO represents an unexpected site of systemic paradoxical embolism that requires high index of clinical suspicion and meticulous laboratory investigation in order to unravel the concealed initial source of thrombus generation .Herein, we aim to present a middle-aged male patient who experienced an episode of severe, painless and unilateral visual loss due to CRAO associated with PFO. We also discuss the clinical complexity of such a diagnosis as well as we briefly review the current literature regarding similar published case reports.A 62-year-old Caucasian male, with no previous ocular or neurological symptoms, experienced a sudden and painless loss of vision in the left eye while swimming. He had no significant past medical history apart from an episode of deep vein thrombosis of the left lower extremity four years ago, provoked by a non-displaced fracture of the tibia after a motor vehicle accident. He also reported a previous history of hospitalization due to an episode of acute left-sided loin pain associated with macroscopic haematuria at the age of\u00a060 years. Then the patient had been thoroughly investigated and no specific diagnosis of renal infarct of unknown origin had been made. Otherwise, he did not take any regular medication and he neither smoked tobacco nor drank alcohol.On initial examination, he was afebrile and his pulse rate was 82/min and regular. His blood pressure was 130/85 mmHg and there were no abnormalities to find in the cardiovascular or respiratory systems. No carotid or over the umbilicus bruits were audible and pedal pulses were palpable. Physical examination was otherwise normal apart from a clearly swollen left lower extremity accompanied with engorged superficial veins, hyperpigmentation and trophic skin changes. On palpation, there was no tenderness of his left calf muscles and no venous ulcerations were observed. As regards neurological examination it was also unremarkable including the muscle tone, reflexes, coordination and sensation as well as power, in all muscle groups.\u00a0Afterwards, the patient was immediately evaluated on the basis of fundoscopic examination that revealed left retinal whitening, macular edema and cotton-wool spots compatible with CRAO Figure . The aboOnce CRAO with sparing of cilioretinal artery diagnosis had been made, a meticulous investigation was performed in order to unwind the thread of this unanticipated thromboembolic event.Routine hematological and biochemical investigations were unremarkable barring the slightly elevated creatinine and urea levels, up to 1.6 mg/dL and 60 mg/dL respectively, but accordant with a prolonged history of chronic kidney disease stage III with GFR estimated at 46ml/min/1.73m2. Inflammatory markers (C- Reactive Protein and Erythrocyte Sedimentation Rate) and clotting parameters including d-dimers and fibrinogen levels were within normal values. Further investigation for autoimmune diseases, occult infectious conditions and thrombophilic disorders were also negative. More specifically, thrombophilia testing was performed including factor V Leiden, prothrombin gene mutation, antithrombin III, protein C and protein S, lupus anticoagulant screen as well as antinuclear antibodies, anti-dsDNA antibodies, anti-cardiolipin antibodies (ACA) and anti-beta 2 glycoprotein antibodies (anti-\u03b22GPI).Regarding radiological examination, a renal ultrasound confirmed the previously mentioned asymmetrical kidney size and showed a small as well as echogenic left kidney, consistent with the past history of renal infarction without apparent cause. Carotid Doppler ultrasound did not identify any extracranial vulnerable atherosclerotic plaque potentially at risk for disruption and thromboembolic ischemic retinal event. Similarly, abdominal aorta ultrasound imaging and ultrasonographic assessment of renal arteries did not depict any atherosclerotic lesions that could be possibly the source of the reported renal vaso-occlusive event.Venous ultrasound imaging unveiled no relapse of the previously recorded deep vein thrombosis although the diagnosis of post-thrombotic syndrome was made on the basis of post-thrombotic popliteal valve incompetence accompanied with significant reflex at the same level. Residual thrombi were also recognized mainly in the left popliteal vein and partially recanalization of both popliteal and gastrocnemius veins was described. Residual thrombi in left popliteal vein raised the question of whether a paradoxical embolus could explain not only the CRAO event but also the past embolic event in renal artery circulatory system.With the completion of these steps, a meticulous cardiologic examination was undertaken and included 48-hour Holter monitoring and transthoracic echocardiography followed by bubble contrast echocardiography testing. Holter monitoring results excluded the possibility that CRAO event could be correlated with an obscured supraventricular arrhythmia, predominantly an episode of paroxysmal and symptomless atrial fibrillation. Transthoracic echocardiography examination also eliminated the option that the embolic event originated from a cardiac valvular defect. Surprisingly, bubble contrast echocardiography testing revealed more than 25 saline microbubbles in the left atrium of the heart at the first three cardiac cycles while the patient was asked to perform a Valsava maneuver  in a quarter of the population .The frequency and significance of PFO in association with ocular circulatory disturbances were evaluated in forty patients with acute arterial occlusions of the posterior bulb segment through transthoracic and transesophageal echocardiography by Steuber and colleagues . PFO wasCertainly, the emerging association between undiagnosed PFO and retinal artery occlusion has been predominantly reported in young patients. An example of this is the report of a 35-year-old man with branch retinal artery occlusion (BRAO) and concomitant PFO, which was firstly diagnosed during the evaluation of BRAO, by Chatziralli and colleagues . In a siHence, it could be conceivably argued that retinal artery occlusion in an otherwise healthy adult patient, should always consider the PFO as a differential that requires meticulous cardiologic examination. Despite the fact that transesophageal echocardiography (TEE) is a potentially useful and effective tool for detecting possible sources of retinal artery emboli , in our Patent foramen ovale (PFO) is a common congenital intracardiac defect that can cause right-to-left shunting under certain conditions and may predispose individuals to paradoxical embolic events from the venous to arterial district. Rarely, PFO has been correlated to central retinal artery occlusion and branch retinal artery occlusion with visual sequelae not only in young but also in advanced-aged patients at low atherosclerosis or cardioembolic risk, concomitant with a propensity for deep vein thrombosis."}
+{"text": "Pharmacoresistance and adverse drug events designate a considerable group of patients with focal epilepsies that require alternative treatments such as neurosurgical intervention and neurostimulation. Electrical or magnetic stimulations of cortical brain areas for the treatment of pharmacoresistant focal epilepsies emerged from preclinical studies and experience through intraoperative neurophysiological monitoring in patients. Direct neurostimulation of seizure onset zones in neocortical brain areas may specifically affect neuronal networks involved in epileptiform activity without remarkable adverse influence on physiological cortical processing in immediate vicinity. Noninvasive low-frequency transcranial magnetic stimulation and cathodal transcranial direct current stimulation are suggested to be anticonvulsant; however, potential effects are ephemeral and require effect maintenance by ongoing stimulation. Invasive responsive neurostimulation, chronic subthreshold cortical stimulation, and epicranial cortical stimulation cover a broad range of different emerging technologies with intracranial and epicranial approaches that still have limited market access partly due to ongoing clinical development. Despite significant differences, the present bioelectronic technologies share common mode of actions with acute seizure termination by high-frequency stimulation and long-term depression induced by low-frequency magnetic or electrical stimulation or transcranial direct current stimulation. Epilepsies are characterized by unpredictable seizures and affect more than 70 million people worldwide Beghi . Focal sPharmacoresistance and TEAEs designate a considerable group of patients with focal epilepsies that requires alternative treatments such as neurosurgical intervention and neurostimulation. Whereas neurosurgical resection can only be applied to non-eloquent brain areas in a minority of patients  that compared repetitive TMS with sham or placebo controls  in the period from 2014 to 2018 as compared to the meta-analysis done in 2014 by the same group  on a localized epileptic focus  was significantly larger than in the sham patients (17%)  (Xia and Storm LFS induces LTD by N-Methyl-D-aspartate (NMDA) receptor activation and the subsequent slight increase in CaNoninvasive cathodal tDCS is suggested to provoke transient and long-term effects on cortical excitability (Antal et al. Electrical or magnetic stimulations of cortical brain areas for the treatment of pharmacoresistant focal epilepsies emerged from preclinical studies and experience from intraoperative neurophysiological monitoring in patients Table . Noninva"}
+{"text": "Oregon\u2019s Behavioral Health Initiative for Older Adults and People with Disabilities is entering its fifth year. This novel state-level Initiative seeks to better coordinate services and resources for older adults and people with disabilities who have behavioral health needs by assigning a Behavioral Health Specialist (BHS) for every 60,000 adults 65 + and embedding them within local service agencies around Oregon. BHS primary job functions include improving coordination and collaboration between local service agencies, providing complex case consultations (CCC), and delivering workforce development training and community education. Five years of data from Portland State University\u2019s Institute on Aging\u2019s ongoing evaluation of the Initiative suggests significant impact in terms of workforce development trainings, community education, and new community partnerships. Data are collected from BHS and Initiative stakeholders . Data collection tools include quarterly reports from the BHS, including a CCC reporting instrument; semi-structured interviews with stakeholders assessing Initiative involvement; and an electronic post-training survey (and two-month follow-up survey) for stakeholders attending BHS trainings. After five years, the evaluation appears to show the Initiative has delivered an abundance of innovative collaborations, workforce trainings, and educational opportunities aimed at better supporting the behavioral health of older Oregonians. It also highlights several persistent systemic barriers including a need for additional public funding of behavioral health, the challenges of accessing Medicare for behavioral health, and siloed agencies and organizations. Future evaluative efforts could explore adding outcomes-based assessments of the Initiative, including local-level quality improvement projects initiated by BHS within their communities."}
+{"text": "Cytokine storms, defined by the dysregulated and excessive production of multiple pro-inflammatory cytokines, are closely associated with the pathology and mortality of several infectious diseases, including coronavirus disease 2019 (COVID-19). Effective therapies are urgently needed to block the development of cytokine storms to improve patient outcomes, but approaches that target individual cytokines may have limited effect due to the number of cytokines involved in this process. Dysfunctional macrophages appear to play an essential role in cytokine storm development, and therapeutic interventions that target these cells may be a more feasible approach than targeting specific cytokines. Nanomedicine-based therapeutics that target macrophages have recently been shown to reduce cytokine production in animal models of diseases that are associated with excessive proinflammatory responses. In this mini-review, we summarize important studies and discuss how macrophage-targeted nanomedicines can be employed to attenuate cytokine storms and their associated pathological effects to improve outcomes in patients with severe infections or other conditions associated with excessive pro-inflammatory responses. We also discuss engineering approaches that can improve nanocarriers targeting efficiency to macrophages, and key issues should be considered before initiating such studies. Circulating levels of pro-inflammatory cytokines correlate with the severity of many infections. Severe infections can result in uncontrolled immune responses accompanied by excessive release of pro-inflammatory cytokines, frequently referred to as a \u201ccytokine storm\u201d, that can be responsible for a significant degree of the pathology and mortality associated with severe infections Effective therapeutic strategies to prevent or suppress cytokine storms and attenuate their effects, or other conditions prone to this response, during severe infection do not yet exist Macrophages and related monocyte-lineage immune cells, which reside in most body tissues and play essential roles in regulating cytokine-mediated inflammatory responses and innate and adaptive immune reactions, are good potential targets for such strategies In this mini-review, we focus on the pathology of cytokine storms in severe infections, highlight the role of macrophage dysfunction in this process, and discuss nanomedicine-based therapies that could be used to target macrophage dysfunction to improve clinical outcomes in patients with severe acute infections.via chemotaxis in response to concentration gradients Many cytokines released during pro-inflammatory immune responses can activate specific leukocyte populations and target their recruitment to sites of inflammation e.g., CCL2 and CCL3) that promote local accumulation of other pro-inflammatory immune cells, including neutrophils, monocytes, and dendritic cells that can release more cytokines and reactive oxygen species to increase the severity of lung injury The term cytokine storm, first used in 1993 in reference to runaway inflammatory responses in graft-versus-host disease Most individuals are vulnerable to SARS-CoV-2 infection, but can exhibit a broad range of symptom severity, and several risk factors are associated with cytokine storm development, including age (> 60 years old), smoking, poor nutrition and pre-existing conditions that can affect immune responses, including obesity, diabetes, hypertension, cardiovascular and chronic lung disease, and cancer No specific therapeutic strategies have yet been developed to attenuate cytokine storm mediated pathology, despite the established link between cytokine storms and disease pathology and mortality.COVID-19 offers a compelling example of the effect of cytokine storms on pathology and mortality. The precise mechanisms responsible for the pathological changes observed in severe COVID-19 cases are not well understood, but several studies have reported that most patients with severe pathology have markedly elevated circulating levels of multiple pro-inflammatory cytokines, including IL-1, IL-6, IL-8, IL-21, TNF-\u03b1, and MCP-1 Macrophages are multifunctional and heterogeneous innate immune cells that reside in most tissues and play essential roles in innate immunity, the regulation of adaptive immunity, and pro-inflammatory responses to control the virulence and pathology of infectious diseases in vitro characterization studies Macrophages act as an initial defense against infection Macrophages can also display pathogen-derived proteolytic peptides on their type I and type II major histocompatibility complexes (MHCI and MHCII) to activate T lymphocytes that recognize these peptides and initiate a pathogen-specific adaptive immune response A rapid and well-coordinated innate immune response is the first line of defense against infection, but excessive immune responses can cause local and systemic tissue dysfunction and damage Figure 1) + macrophages containing SARS-CoV-2 nucleoprotein, which exhibit IL-6 up-regulation, have also been detected in the spleen and lymph node marginal sinuses of patients who died from COVID-19 Macrophage dysfunction can initiate uncontrolled cytokine release leading to the development of cytokine storms observed in many severe infectious diseases, including SARS and COVID-19  family Macrophage dysfunction also plays important roles in the pathology of other infections caused by viral and microbial pathogens, particularly when these infections progress to sepsis, due to overlap of monocyte/macrophage responses to these pathogens. Macrophages are normally activated in response to recognition of danger-associated stimuli produced upon recognition of various components of viral and bacterial pathogens (PAMPs) via therapies that exhibit macrophage-specific or -selective toxicity; (ii) inhibiting macrophage invasion to limit inflammatory responses at disease sites by blocking chemotactic monocyte surface receptors  Both clinical and experimental findings strongly suggest that dysfunctional macrophages are a major source of inflammatory cytokines in severe infections, and thus therapeutic interventions that target these macrophages may prove beneficial in attenuating cytokine storms that contribute to the increased pathology and mortality of severe infections. Therapeutic approaches designed to manipulate macrophage responses using conventional drug delivery mechanisms have been studied in preclinical models of inflammatory diseases and cancer Table 1).Nanomedicine, the medical application of nanotechnology, has emerged as a powerful platform to resolve issues associated with conventional therapeutics, including bioavailability, tissue specificity, and toxicity in vitro studies indicate that some nanoparticles are also preferentially engulfed via clathrin- or caveolin-mediated endocytosis mechanisms via different approaches that add macrophage-specific molecules to their surfaces Nanoparticles employed for macrophage targeting approaches can vary markedly in their origin  and composition, but macrophage uptake generally occurs through one of two distinct pathways: non-specific phagocytosis (passive targeting) regulated by nanoparticle physical properties, or receptor-mediated endocytosis (active targeting). Passive targeting is usually responsible for macrophage uptake of unmodified nanoparticles of medium size (10~300 nm diameter), which include most extracellular vehicles (EVs) and liposomes. These nanoparticles primarily accumulate at infection or inflammation sites as a result of phagocytosis and/or macropinocytosis by monocyte/macrophage-lineage cells that are abundantly present at these sites Figure 1). These studies used synthetic liposomes, FDA-approved nanocarriers composed of one or more lipid bilayers surrounding a hollow core that can contain therapeutic cargoes via disruption of the mitochondrial electron transport chain and cytosolic release of cytochrome C At least two studies have now examined the efficacy of nanoparticle-mediated drug delivery to transiently deplete macrophages to attenuate dysfunctional macrophage responses . EVs are natural nanoparticles (~50-500 nm) that facilitate cell-to-cell communication, and are readily engulfed by circulating monocytes and tissue resident macrophages following their infusion into mouse models of human disease ex vivo model in which perfused human lungs rejected for transplant were injured by E. coli exposure to induce severe bacterial pneumonia e.g., miR-21, miR-124) and proteins  shuttled by MSC-EVs Other studies examined the potential of unmodified EVs with anti-inflammatory properties to suppress macrophage dysfunction  e.g., solid-lipid, polymeric, or metallic nanoparticles) using this strategy have been developed for macrophage-targeted drug delivery in models of inflammatory and infectious diseases Functionalizing nanoparticle therapeutics with ligands or peptides that have high affinity for extracellular macrophage membrane factors can enhance their specific uptake to attenuate dysfunctional macrophage responses , which contain viral coat proteins but lack viral genetic material, have recently been considered as nanoparticle platforms for drug delivery, imaging, and vaccine approaches A growing body of evidence indicates the potential of macrophage-targeted nanomedicines to reduce excessive cytokine production during severe infection. We therefore believe that nanomedicine approaches designed to regulate macrophage-mediated inflammatory responses should receive greater consideration as alternative therapies for conditions where macrophage dysfunction has the potential to induce a cytokine storm and its associated pathological effects. To the best of our knowledge, studies have yet to examine the therapeutic potential of macrophage-targeted nanomedicines in animal models of COVID-19, the most recent disease where cytokine storms have been shown to play a central role in disease pathology and mortality. At minimum, we propose that EV and liposome studies should be performed using commercially available human ACE2 (hACE2) transgenic mice, which can serve as a model of human COVID-19 disease, to clarify whether nanomedicine-mediated macrophage depletion or attenuation of macrophage activation is beneficial in severe COVID-19 disease. Nanomedicine delivery approaches may also be useful to increase the targeted bioavailability or reduce potential side effects of anti-inflammatory small molecule drugs and antibody therapeutics currently under investigation for treatment of COVID-19 in clinical trials. It will be important to comprehensively evaluate the therapeutic effects of these and other potential nanomedicines using clinically relevant indicators, including, but not limited to, effects on survival, lung lesions, and cytokine profiles.e.g., at or immediately prior to the hyperinflammatory phase), to have a beneficial effect, since suppression of the innate immune response in the early phase virus infection is likely to be harmful. Since cytokine storm development can be highly dynamic during severe infections, serial evaluation using a well-designed cytokine panel is necessary to determine the most effective therapeutic period and the specific effects of an intervention. Combination therapies that employ both nanomedicines and conventional antiviral drug delivery may also provide synergistic beneficial effects. Finally, it is also necessary to address the potential for increased risk of immune disorders and bacterial infections that may be associated with any strategy to deplete macrophages or attenuate their activity. Even if data from animal models proven to be promising, additional preclinical studies are required to address biosafety, mechanisms of action, and optimal administration routes and doses. Clinical translation will also require the development of nanomedicine manufacturing approaches with standard processes and quality control early in these studies. The massive degree of collaboration now ongoing across diverse disciplines and industries, offers hope for an unprecedent rate of development for new therapies and therapeutics to combat severe infectious diseases such as COVID-19. We believe that novel nanomedicine approaches are a worthy target of such efforts.Some key issues should be considered before initiating such studies, however. Macrophage-targeted nanomedicines may need to be given at the correct stage of infection ("}
+{"text": "Despite recommendations to include a distinct intervention phase in Adult Protective Services (APS), most APS programs close cases following investigation/substantiation phases without engaging in a defined intervention phase. This study implements and evaluates a novel APS service planning/intervention model in the state of Maine. Using an experimental efficacy trial design with stratified random sampling at the level of Maine APS offices, this study compares standard APS care with an enhanced/integrated APS intervention model involving \u201celder advocates\u201d. Advocates were trained in motivational interviewing, supported decision-making, teaming, restorative justice, and goal attainment scaling to develop capacity to work with both the older adult victim and perpetrator and to strengthen the family and social systems surrounding the victim-perpetrator dyad. This presentation will present results on the efficacy of this integrated APS/elder advocate model and discuss the challenges and successes in conducting elder abuse intervention research in collaboration with APS and APS clients. Part of a symposium sponsored by Abuse, Neglect and Exploitation of Elderly People Interest Group."}
+{"text": "Unconventional oil and gas exploration generates an enormous quantity of wastewater, commonly referred to as flowback and produced water (FPW). Limited freshwater resources and stringent disposal regulations have provided impetus for FPW reuse. Organic and inorganic compounds released from the shale/brine formation, microbial activity, and residual chemicals added during hydraulic fracturing bestow a unique as well as temporally varying chemical composition to this wastewater. Studies indicate that many of the compounds found in FPW are amenable to biological degradation, indicating biological treatment may be a viable option for FPW processing and reuse. This review discusses commonly characterized contaminants and current knowledge on their biodegradability, including the enzymes and organisms involved. Further, a perspective on recent novel hybrid biological treatments and application of knowledge gained from omics studies in improving these treatments is explored. Technological advances have led to unprecedented growth in unconventional oil and gas extraction in the US over the last few decades . This enCurrent disposal methods mainly rely on reinjecting FPW into newly drilled wells or disposal into deep Underground Injection wells. Disposal into underground injection wells irreversibly removes water from the hydrological cycle and has raised concerns due to induced seismicity . AlternaAmong the 1,198 chemical compounds identified in FPW, only 14% have existing toxicity data and 24% can be detected through standard analytical methods . PresencThis review aims to summarize recent trends in biological treatment of FPW with an emphasis on organic contaminants and microbial groups involved in their degradation . We brie1, are fairly well-documented and generally involve gas chromatography paired with mass spectrometry (GC-MS), the methods developed for surface and groundwater have to be modified to account for the complex matrix in FPW  using non-targeted Liquid Chromatography-Electrospray Ionization-Mass spectrometry (LC-ESI-MS) approaches, many of which provide semi-quantitative estimation of identified compounds , especially Benzene/Toluene/Ethyl Benzene/Xylenes (BTEX), are the most commonly analyzed hydrocarbons in FPW with concentrations varying from a few ormation . BTEX arormation . Microbiormation . However+) as the dominant cation, with calcium (Ca2+), magnesium (Mg2+), and potassium (K+) as minor cations, and chloride (Cl\u2013) as the major anion, along with small amounts of bicarbonate  . Trace m (SO42-) . Though A meta-analysis of published data on biological treatment of oilfield wastewater found average COD removal in actual wastewaters to be about 74% when TDS was low  . IncreasTreatment of a complex matrix like FPW should not only meet the requirements of the intended application but also be cost-effective. TDS greater than 40,000 mg/L leads to elevated desalination costs, thus, low TDS western brines  are more likely to be treated and reused .Experiments simulating a PW spill  on soil concluded that the high salt content of PW can disrupt soil structure and mobilize metal ions like copper, lead, aluminum and manganese during subsequent rainfall events . StudiesHF involves addition of several chemicals to water that regulate viscosity to perform various functions ranging from generating fissures to ensuring smooth flowback from the formation . Among aBiocides are added to prevent biofouling by sulfate-reducing bacteria during HF and to prevent growth of microbes that clog the pipelines during gas production . BiocideGA, a non-oxidizing, electrophilic biocide, inactivates bacteria by crosslinking amines present on bacterial membrane proteins . HypersaDBNPA  is the second most commonly used biocide , howeverPseudomonas  are frequently used amphiphilic biocides that have been found to persist in FPW . Benzalkudomonas , Thalassiabensis  isolatedpduCDE) from dominant Firmicutes was predicted to be responsible for surfactant degradation under anaerobic conditions. In another study on PEG and PPG degradation under aerobic conditions in sediment-groundwater microcosms amended with PW  mapped to Halanaerobium in PW samples and in laboratory experiments with an isolate, Halanaerobium congolense WG10.Non-ionic surfactants, including both unsubstituted polyglycols [Polyethylene glycol (PEG) and Polypropylene Glycol (PPG)] and substituted ethoxylates [Alkyl ethoxylates (AEOs) and Nonylphenol ethoxylates (NPEOs)], are employed as emulsifiers, corrosion inhibitors and crosslinkers in HF. These surfactants are generally present as a mixture of homologs and are identified by calculation of Kendrick mass defect from LC-MS data . A few r with PW , authorsin situ. Reaction with persulfate (added as a breaker in the fracturing fluid) and other abiotic processes were implicated in the production of these halogenated organic compounds, along with biotic transformation by iodide-oxidizing bacteria, specifically Roseovarius spp.  HF operations, those based on oilfield PW with comparable TDS  have also been included. The reactor configurations and dominant microbial groups identified are summarized in Activated sludge (AS) systems are the most popular form of biological reactor for wastewater treatment around the globe. A typical AS system consists of an aerated tank for mixing microbial biomass with wastewater, followed by a settling/sedimentation unit to separate biomass (sludge) from treated water. Such systems are operated in continuous flow conditions and a portion of the settled sludge is often recycled back into the aeration tank. A sequencing batch reactor (SBR) consists of a single tank to perform all the steps  of an activated sludge and hence is operated in a batch mode. Both these approaches have been used to treat FPW, and a few studies have investigated the microbes found in these systems.Pseudomonas, Ochrobactrum, Corynebacterium and Burkholderia were major bacterial groups identified from the reactor sludge using a Biolog MicrologTM System.Cellvibrionaceae, Rhodocyclaceae, Rhodobacteraceae, and Phyllobacteriaceae were some dominant groups that were found to be enriched at a TDS of 50,000 mg/L.A typical membrane bioreactor (MBR) consists of an aerated tank containing sludge fed with wastewater and a submerged membrane module to filter out the treated effluent. In high salinity wastewater like PW where bacterial floc formation is disrupted, MBRs can overcome the floc settling requirement and retain the biomass in the reactor.A lab-scale MBR was acclimated to high salinity in phases using PW from different wells to investigate impact of salinity on the microbial community . Upon inIdiomarina genus and Rhodospirillaceae family in Sample A1/2 and B, respectively.Emulating the naturally occurring stratified microbial consortia (or mats) often found in hypersaline environments, engineered microbial mats have been grown and evaluated for PW treatment in the laboratory. Biological treatability of PW samples from Utica and Bakken shale was also studied using microbial mats . These sBiologically active filters (BAF) employ microbial biofilms attached to a filter media (most commonly activated carbon) to adsorb and degrade organic compounds in wastewater along with removal of suspended solids. BAF successfully removed organic matter  from three different wastewaters  with varying salinity  and organic composition (DOC: 35.6\u2013732 mg/L) as a pretreatment to ultrafiltration and nanofiltration . This BAFlavobacteria (predominantly genus Fluviicola) and Gammaproteobacteria) over non-aerated filters .The scalability of BAF was tested using bench-scale and lab-scale columns fed with different wastewaters  under different operating conditions like aeration, pretreatment, operating temperature and empty bed contact time . AeratioBioelectrochemical systems (BES) can simultaneously achieve reduction in organic carbon and salinity, making them a promising technology, and an advancement over other biological systems to treat PW. BES harness the microbial capacity to degrade organic compounds anaerobically to generate electrons. These electrons can then be transported, via a pair of electrodes (anode to cathode), to terminal electron acceptors like oxygen or the system can be maintained anaerobic to produce hydrogen.Several configurations of BES have been tested to treat PW. Microbial Fuel Cell (MFC) is the simplest design consisting of two electrodes separated by an ion-exchange membrane in which the wastewater to be treated is added to the anode. Microbial Desalination Cell (MDC) is a modification of MFC with a pair of ion exchange membranes between anode and cathode resulting in three chambers. Microbial Capacitive Desalination Cell (MCDC), like MDC, has three chambers but the middle chamber contains electrodes for Capacitive Deionization. These electrodes have a large surface area that adsorbs organic and inorganic ions under applied electrical potential . On the MCDC desalinated 18 times faster than MDC and 5 times faster in COD removal during treatment of Piceance basin PW . A literHalanaerobium prevalens and Marinobacter hydrocarbonoclasticus, both originating from the PW  (Cyanobacterium aponinum and Parachlorella kessleri) with halophilic bacteria could grow in PW over a wide range of salinities  and the harvested algal biomass was suitable for biodiesel production. Researchers are now looking beyond traditional methods to treat FPW. l value) . HopkinsThough biological treatment of FPW is promising and can be initiated with a readily available inoculum , most reactors need lengthy acclimation periods  which may not be practical for a field-operating full-scale reactor. Reactor parameters such as temperature, mixing/oxygenation and retention time will affect both reactor performance and community composition. Faster, more effective strategies are needed to achieve a consortium that can both tolerate the varying inorganic and organic composition of FPW and efficiently remove chemically diverse contaminants. Biological processes also have the potential to create new potentially harmful contaminants, e.g., iodinated organic compounds detected in the effluent of a BAF attributed to the activity of iodide-oxidizing bacteria . Thus, iRoseovarius  was shown to be capable of leaching gold from its ore in the presence of iodide, in a process more ecofriendly than traditional cyanide leaching  , particularly the dominant phosphate-accumulating organism is (CAP) . In factis (CAP) . That stis (CAP) .Another application of metagenomics and metatranscriptomics to wastewater treatment involved studies of reactors degrading terephthalate, a plastics byproduct, where a preliminary multi-organism pathway postulated based on early metagenome sequencing efforts was later expanded upon with a complex network of cross-feeding relationships that highlights the multilayered nature of these systems . FinallyHalanaerobium  and methanogenic archaea during later PW, when anoxic conditions develop and TDS rises , were described based on their genomes, which in turn explained the changes in key metabolites observed in the samples collected. Viral predation of these major groups was also implicated in community dynamics and nutrient cycling. Further research revealed the viral (phage) diversity in shales and phage-induced lysis of dominant Halanaerobium was shown to release intracellular metabolites that support microbes in such ecosystems  have further shed light on microbes that reside in shale with the help of metagenomics and metabolite profiling combined with supporting laboratory experiments. osystems . As a byaerobium , Frackibkibacter , Marinobnobacter , Methanolophilus , and Arccobacter  \u2013 have bin silico tests. Thorough molecular characterization of bioreactor communities with varying performance combined with machine learning could identify biomarkers of successful treatment and potentially enable current monitoring strategies to be augmented or even replaced by molecular methods, allowing early warning of adverse events affecting reactor performance. Eventually, molecular methods will become a key part of a wastewater engineer\u2019s toolkit.On the other hand, there are few metagenomic studies on bioreactors optimized to treat FPW or even petroleum refinery wastewater. Molecular-level understanding of FPW treatment, however, is critical to successfully targeting multiple high-priority contaminants under a wide range of environmental conditions. Accurate, predictive models of FPW treatment bioreactors would dramatically accelerate optimization by replacing empirical manual parameter adjustments with rapid Treatment of FPW is challenging due to its complex chemical composition coupled with geographical and temporal variability. The low cost and effective treatment options offered by biological treatment systems in treating municipal wastewater have made them ubiquitous. Only in the past decade have we been able to understand core microbes and microbial processes behind treatment efficacy and resilience of these systems to shocks and overloads. Many studies have shown that FPW is amenable to biological treatment and different treatment modules to treat FPW have been discussed. Several studies indicate halophiles are effective for FPW treatment, but a systematic study to identify these halophiles during operation of a reactor and understand the key degradation pathways is not available. Omics guided study of core microbes should aid in constructing a core microbial community with broad metabolic potential to handle diverse contaminants and salinities as are common in FPW. Aided with optimized reactor design and robust microbial communities, a hybrid decentralized treatment module capable of handling fluctuations in composition as well as quantity of FPW could be a reality. Such a system could reduce the impacts of accidental release, promote a sustainable hydrological cycle and safeguard the environment.SA wrote the manuscript with inputs and edits from ST and RC. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A 59-year-old man fell onto his outstretched hands. He was diagnosed with a left-sided transscaphoid transcapitate perilunate fracture-dislocation in the setting of previous scaphoid open reduction internal fixation (ORIF), resulting in a nonunion and scaphoid nonunion advanced collapse (SNAC). Wrist salvage in the form of primary partial wrist fusion was performed and resulted in excellent clinical and functional outcomes.What are perilunate dislocations and/or perilunate fracture-dislocations?What physical and radiologic examination findings are typically encountered with perilunate dislocations and fracture-dislocations?How are perilunate dislocations and fracture-dislocations managed?When a perilunate fracture-dislocation presents in the setting of previous scaphoid nonunion and SNAC wrist, what is the best surgical option to give the best functional outcome?Perilunate dislocations and fracture-dislocations are debilitating wrist injuries resulting from high-energy trauma. Dislocations can be purely ligamentous or involve a combination of bony and ligamentous structures. When involving only ligaments surrounding the lunate, these dislocations are referred to as lesser arc injuries. When the dislocation is associated with a radial styloid or carpal bone fractures, they are referred to as greater arc injuries.Physical examination often reveals a grossly swollen wrist with limited range of motion with or without signs of acute median neuropathy. The presence of acute carpal tunnel syndrome is an indication for urgent operative intervention if closed reduction has failed. Posteroanterior radiographic evaluation may demonstrate alteration of Gilula's lines with loss of carpal height . There m,Surgical correction involves acute carpal tunnel decompression, relocation of the carpus, repair of the capsular rent, and stabilization of the carpus with percutaneous pin fixation. Controversy exists whether acute scapholunate ligament reconstruction should be performed.4We present a case of a patient who suffered a transscaphoid transcapitate perilunate fracture-dislocation in the setting of a prior scaphoid nonunion and SNAC wrist. Radiographs revealed a greater arc injury with transmission of force through the previous scaphoid nonunion site, resulting in displacement of the cannulated screw from the proximal pole of the scaphoid  and 2. S"}
+{"text": "Understanding food web responses to global warming, and their consequences for conservation and management, requires knowledge on how responses vary both among and within species. Warming can reduce both species richness and biomass production. However, warming responses observed at different levels of biological organization may seem contradictory. For example, higher temperatures commonly lead to faster individual body growth but can decrease biomass production of fishes. Here we show that the key to resolve this contradiction is intraspecific variation, because (i) community dynamics emerge from interactions among individuals, and (ii) ecological interactions, physiological processes and warming effects often vary over life history. By combining insights from temperature-dependent dynamic models of simple food webs, observations over large temperature gradients and findings from short-term mesocosm and multi-decadal whole-ecosystem warming experiments, we resolve mechanisms by which warming waters can affect food webs via individual-level responses and review their empirical support. We identify a need for warming experiments on food webs manipulating population size structures to test these mechanisms. We stress that within-species variation in both body size, temperature responses and ecological interactions are key for accurate predictions and appropriate conservation efforts for fish production and food web function under a warming climate.This article is part of the theme issue \u2018Integrative research perspectives on marine conservation'. A key link in these feedbacks underlying observed warming responses is population size structure, because of how it arises from, as well as influences, individual body growth and survival figures\u00a0a and 2."}
+{"text": "Complication in acute kidney injury (AKI) is significantly associated with developing acute respiratory failure (ARF), while ARF is one of the most important risks for AKI. These data suggest AKI and ARF may synergistically worsen the outcomes of critically ill patients and these organ injuries may not occur independently. Organ crosstalk between the kidney and the lung has been investigated by using animal models so far. This review will focus on innate immune response and neutrophil activation among the mechanisms that contribute to this organ crosstalk. AKI increased the blood level of an inflammatory mediator in high-mobility group box 1, which induces an innate immune reaction via toll-like receptor 4. The remarkable infiltration of neutrophils to the lung was observed in animal AKI models. IL-6 and IL-8 have been demonstrated to contribute to pulmonary neutrophil activation in AKI. In addition, the formation of a neutrophil extracellular trap was also observed in the lung after the exposure of renal ischemia reperfusion in the animal model. Further investigation is necessary to determine whether targeting innate immune response and neutrophil activation will be useful for developing new therapeutics that could improve multiple organ failure in critically ill patients. Acute kidney injury (AKI) is a common complication in critically ill patients treated in the intensive care unit (ICU). Reportedly, AKI occurs in ~30\u201360% of patients admitted to the ICU and is associated with significantly poor outcomes including morbidity and mortality . ICU patThough the primary roles are different, lung and kidney functions are intimately related regarding the maintenance of homeostasis. The blood acid-base balance is regulated by carboxy dioxide excretion by the lung and bicarbonate reabsorption by the kidney. A compensative mechanism will activate when one organ fails to keep these levels within a normal range by the other organ. Thus, respiratory complication in AKI patients is particularly important. Clinical studies revealed AKI patients were twice as likely to require invasive mechanical ventilation . On the In this review, we provide a brief overview regarding (1) the clinical data on AKI and ARF/ARDS and (2) the potential mechanisms by which AKI leads to lung injury. Recently identified mechanisms of the innate immune system including toll-like receptors (TLRs) and damage-associated molecular patterns (DAMPs) were evaluated in the kidney-lung crosstalk using animal models. Neutrophil extracellular traps (NETs) was identified as another player in the innate immune response. NETs were also demonstrated to contribute to AKI-induced lung injury.Many clinical studies suggested associations between AKI and ARF/ARDS in critically ill patients. AKI often occurs in ARF/ARDS patients, while ARF/ARDS is often observed in AKI patients. First, clinical data about AKI complication in ARF/ARDS are described below. The secondary analysis of a randomized control trial conducted by the ARDS network reported AKI occurred in ~25% of ARDS patients. The mortality rate of AKI patients was significantly higher than the non-AKI patients . AnotherSecond, ARF/ARDS complication in AKI is described below. Severe ARF requiring MV was observed in more than 70% of AKI patients in a multinational, multicenter prospective observational study. MV requirement was significantly associated with higher mortality . TherefoThird, AKI and ARF/ARDS are organ failures that can be simultaneously complicated in a critically ill patient. An observational study conducted in 18 French ICUs reported ARDS occurrence as 23%, while AKI occurrence was at 31%. Hospital mortality was 14% in this population and it increased to 42% in patients with both AKI and ARDS . In a laThe pathophysiological mechanisms of respiratory failure in patients with AKI can be categorized into inflammatory and non-inflammatory mechanisms . Non-infRabb and colleagues first demonstrated increased inflammatory gene expressions in the lung after exposure of renal ischemia reperfusion injury by using microarray analysis . Faubel Although these studies suggested that the induction of an inflammatory reaction by AKI is involved in lung injury, other studies demonstrated AKI suppressed inflammatory reactions and subsequently worsened pulmonary infection. Neutrophil function against pneumonia was evaluated in the model of bacterial pneumonia in mice complicated with AKI by folic acid administration or glycerol injection (rhabdomyolysis) . NeutropTaken together, increased humoral mediators by reduced clearance and increased expression in AKI seem to contribute to lung injury. On the other hand, few studies revealed the mechanisms of the opposite direction of crosstalk, i.e., ARF/ARDS-induced kidney injury. Slutsky et al.  reportedNeutrophil infiltration is a major finding in lung injury induced by AKI. A remarkable neutrophil infiltration in the lung together with increased neutrophil elastase (NE) activity in blood and lung tissues were observed in a mouse AKI model and specific NE inhibitor reduced lung injury . Toll-liin vitro caused by hypoxia stimulated neutrophils to form NETs by extracellularly released histones. In a mouse intestinal ischemia-reperfusion model, extracellular histone accumulation and NETs formation were observed in the liver rather than the intestine , that comprise DNA studded with histones and proteases, including neutrophil elastases . Extracentestine . Extracentestine . Human r animals .These findings above suggest that extracellular histones and NETs formation might be responsible for AKI-induced lung injury, although other pathways of inflammatory mediators such as IL-6 also contribute to AKI-induced lung injury. For the development of new therapeutics against organ crosstalk between the kidney and lung, targeting multiple pathways will be necessary. In addition, extracellular histones and NETs formation have not been sufficiently evaluated in human ARDS  and no cThe novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan in December 2019, which has spread around the world. SARS-CoV-2 dominantly affects the respiratory system and recent clinical studies reported AKI as a significant comorbidity in COVID-19 . The celMultiple organ failure frequently observed in critically ill patients was previously considered as the \u201csum\u201d of each organ failure. The sequential organ failure assessment (SOFA) score, which is widely used for evaluating the severity of ICU patients, is calculated by summing up each organ injury score. No consideration for organ crosstalk can be found in these scoring systems. Several clinical studies demonstrated possible organ crosstalk in ICU patients by applying network analysis , 35. As This review covers kidney-lung crosstalk mostly regarding lung injury caused by AKI. The opposite pathological mechanism in which ARF/ARDS causes AKI should also be considered. As described above, only a limited number of basic studies reported possible mechanisms in animal experiments. In clinical studies, ARF/ARDS caused a systemic release of pro-inflammatory mediators , which could induce or worsen AKI .Mechanical ventilation-induced lung injury has been investigated so far. Low tidal ventilation strategy against ARDS is recommended based on evidence obtained by both basic and clinical studies . Does MVAM, NH, and KD contributed to the writing of the manuscript and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Endometriosis, an estrogen-dependent inflammatory disease, is commonly observed in gynecologic practice. Spontaneous hemoperitoneum is a rare but serious complication of endometriosis. Most cases of endometriosis-induced hemoperitoneum are attributable to a ruptured endometrioma or utero-ovarian vessel hemorrhage. We report a case of massive hemoperitoneum secondary to intra-abdominal bleeding from the peritoneal endometriotic deposits with spontaneous abortion that was misdiagnosed as a ruptured ectopic pregnancy.A 36-year-old Korean woman was admitted to our hospital for acute abdominal pain and vaginal bleeding. She was suspected of ruptured ectopic pregnancy on the basis of a positive serum human chorionic gonadotropin test result and ultrasonographic evidence of pelvic fluid collection. During hospitalization, her symptoms deteriorated with peritoneal irritation sign on physical examination, hypotension, and tachycardia. Emergency exploratory laparoscopy was performed and revealed active bleeding from the peritoneal endometriotic deposit, which was treated with laparoscopic electrocoagulation. The patient\u2019s postoperative course was uneventful. Spontaneous abortion was diagnosed on the basis of decreased serial serum human chorionic gonadotropin level estimation.Although rare, gynecologists should consider endometriosis-induced hemoperitoneum with spontaneous abortion in the differential diagnosis in women of reproductive age presenting with a positive serum human chorionic gonadotropin test result and acute abdomen with intra-abdominal bleeding. Endometriosis is an estrogen-dependent inflammatory disease characterized by the deposition of endometrial tissue at extrauterine (ectopic) sites. It is a relatively common condition that mainly affects women of reproductive age . CurrentA 36-year-old gravida 1, para 1 Korean woman presented to our emergency department with a 1-day history of acute abdominal pain and vaginal bleeding. Her physical examination showed lower abdominal tenderness, and her speculum examination revealed a small amount of vaginal bleeding. Her menstrual cycle was regular at 30-day intervals, and her last menstrual period had been approximately 5\u2009weeks prior to presentation.Upon admission, her vital signs were stable . Her laboratory test results showed mild anemia with a serum hemoglobin level of 10.1\u2009g/dl and hematocrit of 29.0%. Her urine pregnancy and serum human chorionic gonadotropin (hCG) (1149 mIU/ml) tests showed positive results.Transvaginal ultrasonography revealed a large amount of complex fluid and material of mixed echogenicity compatible with blood and blood clots in the pelvic cavity. The bilateral ovaries were not well visualized by ultrasonography, and a normal gestational sac was not identified in the endometrial cavity.During her hospitalization, the patient developed pallor with dizziness, and physical examination showed positive peritoneal irritation signs along with hemodynamic instability , necessitating emergency exploratory laparoscopy.Laparoscopy revealed approximately 1800\u2009ml of fresh liquid and clotted blood in the abdominal cavity. After suctioning the blood, we explored the entire abdominal cavity to identify the source of bleeding. Continuous active bleeding was observed from the peritoneal wall of the pouch of Douglas. Excisional biopsy was performed at the site of bleeding, and bleeding was controlled using electrocoagulation . The gold standard for definitive diagnosis remains visual inspection via laparoscopy and histopathological examination of biopsy specimens .Our patient presented with vaginal bleeding and acute abdominal pain and had a positive serum hCG test result. Transvaginal ultrasonography revealed hemoperitoneum without a normal gestational sac in the endometrial cavity. Considering that she presented with a positive serum hCG test result and that her serum hCG level was less than the discriminatory level (3510 mIU/ml), we could not exclude the possibility of a normal intrauterine pregnancy despite the absence of an intrauterine gestational sac on transvaginal ultrasonography . TherefoSeveral complications related to endometriosis that most gynecologists can overlook have been reported. Endometriosis-related spontaneous hemoperitoneum in pregnancy causes increased maternal and fetal morbidity and mortality, and endometriosis-related ascites often cause a diagnostic dilemma due to symptoms similar to an ovarian malignancy \u20135. In adet al. reported a case of hemoperitoneum caused by active bleeding from a peritoneal endometriotic deposit on the pouch of Douglas. The patient presented with sudden onset of lower abdominal pain from day 5 of her menstrual cycle and showed a negative serum hCG test result [Acute abdomen and hemoperitoneum are rarely attributable to intra-abdominal bleeding from endometriotic deposits, and only a few cases have been reported previously in the literature. Togami t result . Mutihirt result .Our patient\u2019s case is similar to the two aforementioned cases in that endometriosis-induced hemorrhage occurred during progesterone withdrawal , 10. TheSeveral studies have reported differences in the incidence of abortion between women with and without endometriosis or the possibility of reducing the incidence of abortion in women treated for endometriosis; however, convincing clinical evidence is unavailable . EndometGynecologists should consider hemoperitoneum secondary to intra-abdominal bleeding from endometriotic deposits with spontaneous abortion, as well as ruptured ectopic pregnancy or intrauterine pregnancy with corpus luteal hemorrhage in women of reproductive age presenting with acute abdomen and hemoperitoneum and a positive serum hCG test result."}
+{"text": "Widespread transmission of a novel coronavirus, COVID-19, has caused major public health and economic problems around the world. Significant mitigation efforts have been implemented to reduce the spread of COVID-19 but the role of ambient noise and elevated vocal effort on airborne transmission have not been widely reported. Elevated vocal effort has been shown to increase emission of potentially infectious respiratory droplets, which can remain airborne for up to several hours. Multiple confirmed clusters of COVID-19 transmission were associated with settings where elevated vocal effort is generally required for communication, often due to high ambient noise levels, including crowded bars and restaurants, meat packing facilities, and long-stay nursing homes. Clusters of COVID-19 transmission have been frequently reported in each of these settings. Therefore, analysis of COVID-19 transmission clusters in different settings should consider whether higher ambient noise levels, which are associated with increased vocal effort, may be a contributing factor in those settings. Mitigation strategies that include reduction of ambient noise, softer speech practices, and the use of technology such as microphones and speakers to decrease vocal effort will likely reduce the risk of transmitting COVID-19 or other airborne pathogens. They calculated a 0.37% probability that a 10-\u03bcm droplet contains at least one virion, which suggests that the risk of transmission is significantly increased during loud speech when large numbers of respiratory droplets are emitted. Several recent studies have characterized respiratory droplets emitted during different types of speech, which are potential vectors of viral particles. et al., of social distancing impacts on COVID-19 transmission found that closing restaurant dining rooms and bars and/or entertainment centers/gyms led to statistically significant reductions in COVID-19 cases (These findings have important implications for settings with increased ambient noise where elevated levels of vocal effort are required for communication . A recen19 cases . In theiOther settings have also been associated with increased transmission of COVID-19, and there appears to be a significant association between centers of outbreaks and areas of increased ambient noise and/or elevated vocal effort in most cases. Significant outbreaks of COVID-19 have been reported in senior living centers and nursing homes . These lSignificant levels of COVID-19 transmission have also been reported in meat packing plants (These studies reveal that high levels of vocal effort due to increased ambient noise could be an important factor in the airborne transmission of COVID-19 in settings where physical distancing is limited. Broad implementation of countermeasures to promote softer speech and reduce vocal effort could have a significant impact on decreasing emission of potentially infectious respiratory droplets. This has important implications for businesses, schools, and other venues that are implementing policies to reduce the risk of COVID-19 transmission in their facilities.There is substantial evidence that softer speech and decreased vocal effort may have an impact on reducing COVID-19 transmission. This suggests that settings with lower levels of ambient noise may have reduced risks of COVID-19 transmission. Strategies to reduce the risk of COVID-19 transmission may include community-based emphasis on approaches to decrease ambient noise exposures when feasible, combined with steps to promote softer speech practices and reduce vocal effort. Masks and face coverings can provide some protection by filtering infectious respiratory droplets in situations where vocal effort is required , but oth"}
+{"text": "Medicare home health providers are required to offer family caregiver training; however, there is little information regarding the impact of family caregiver training on home health care intensity. A better understanding of this relationship is necessary to inform development and prioritization of caregiver training interventions in this setting. This research assesses whether and how family caregiver need for training affects care intensity during Medicare home health. We examine 1,217  fee-for-service Medicare beneficiaries who participated in the National Health and Aging Trends Study (NHATS) between 2011-2015 and received Medicare-funded home health care within one year of survey. Using propensity score adjusted, multivariable logistic and negative binomial regression, we model the relationship between family caregiver need for activity-specific training and the number/type of visits received during Medicare home health. We found that older adults whose family caregiver required training on self-care tasks had greater odds of receiving any therapy visits , aide visits , or training visits . Older adults whose family caregiver required training on medication management had greater odds of receiving any nursing visits  and incurred 1.06  additional nursing visits. Findings support the importance of connecting family caregivers to training resources. Additionally, findings suggest that home health providers should consider prioritizing training interventions which focus on caregiving activities most closely tied to resource utilization: self-care and medication management."}
+{"text": "Nonalcoholic fatty liver disease is a major global health concern with increasing prevalence, associated with obesity and metabolic syndrome. Recently, quantitative ultrasound-based imaging techniques have dramatically improved the ability of ultrasound to detect and quantify hepatic steatosis. These newer ultrasound techniques possess many inherent advantages similar to conventional ultrasound such as universal availability, real-time capability, and relatively low cost along with quantitative rather than a qualitative assessment of liver fat. In addition, quantitative ultrasound-based imaging techniques are less operator dependent than traditional ultrasound. Here we review several different emerging quantitative ultrasound-based approaches used for detection and quantification of hepatic steatosis in patients at risk for nonalcoholic fatty liver disease. We also briefly summarize other clinically available imaging modalities for evaluating hepatic steatosis such as MRI, CT, and serum analysis. Nonalcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of metabolic syndrome and is dramatically increasing in prevalence, paralleling the global obesity epidemic Early detection of NAFLD, continuous monitoring, and early therapeutic intervention, such as lifestyle modifications as well as treatment with pharmaceutical agents  can improve overall patient outcomes and potentially decrease the economic burden on healthcare costs. Other patient subgroups such as those undergoing chemotherapy or bariatric surgery are at risk of development of fatty liver and may also benefit from monitoring of hepatic fat fraction. Non-targeted liver biopsy remains the gold standard for diagnosis and grading of hepatic steatosis, fibrosis, and inflammation Here, we summarize methods in grading of NAFLD, including non-imaging biomarkers and corresponding scoring systems currently in use for managing hepatic steatosis. We then provide a comprehensive review of imaging in liver fat quantification, focusing on innovative QUS approaches studied in human subjects Table . FinallySeveral non-imaging biomarkers such as electrical impedance tomography Conventional ultrasound  is the most common imaging modality for subjective evaluation of hepatic steatosis, with good sensitivity and specificity in detecting moderate to severe levels of steatosis  Several QUS techniques have been studied to improve the diagnosis and classification of hepatic steatosis in NAFLD. These include controlled attenuation parameter (CAP) measured by transient elastography (TE) device; attenuation (AC) and backscatter coefficients (BSC); computerized calculation of hepatorenal index (HRI); and ultrasound envelope statistic parametric imaging . Speckle statistics include acoustic structure quantification (ASQ) and Nakagami imaging; QUS spectroscopy; speed of sound (SoS); and shear wave elastography (SWE) metrics such as dispersion and viscosity. Emerging QUS techniques, integrating statistical methods most notably attenuation-based Nakagami imaging and backscatter-derived quantitative ultrasound spectroscopy show promise and could potentially become the noninvasive imaging method of choice in screening, grading, and monitoring NAFLD patients on therapy. These techniques compared to liver biopsy, could be implemented for screening purposes, compared to an ordinal scale, or provide an accurate continuous measurement of liver fat; the latter two would be most useful for the longitudinal follow-up of NAFLD patients to assess treatment response. Limitations of QUS techniques include confounding effects of body habitus and ascites. Further, QUS cannot simultaneously quantify fat in other organs as can be done with MRI based techniques. Finally, multiple simultaneously emerging QUS techniques from different vendors may prohibit widespread-buy in and may limit inter-vendor comparisons.Controlled attenuation parameter (CAP) is the best-studied and clinically available technique for liver fat quantification, with the first clinical studies dating back to 2010  volume, which is significantly larger than the region analyzed through a liver biopsy, decreasing the potential risk for sampling bias. Limitations of CAP include poorly standardized cut-off values in classifying hepatic steatosis and the potential for CAP estimation of hepatic steatosis to be affected by differences in skin-to-capsule ratio, which may also confound other fat quantification methods. Furthermore, although CAP is an ultrasound technique, measurements are obtained without visualization of the liver. Thus, blind estimation of liver fat may result in inadvertent inclusion of masses, vessels, ducts, or uneven steatosis, any of which may limit accurate assessment. As such, there is a need for QUS parameters to be associated with radiological ultrasound machines to overcome these challenges.Measuring CAP has multiple advantages, including simultaneous assessment of hepatic steatosis and fibrosis, which is valuable in predicting progression and treatment strategies in NAFLD. Measurement of CAP is typically performed by a hepatologist in an office setting in less than five minutes. Values are obtained from a 3 Acoustic waves are attenuated differently by steatotic versus normal liver parenchyma, and this difference is quantified in AC measurements. Unlike CAP, AC values are obtained from ultrasound systems Figure . AttenuaBackscatter coefficient (BSC) is another widely studied QUS parameter first described in 1973 In conventional ultrasound, the diagnosis of hepatic steatosis is typically made by comparing the echogenicity of the liver and right kidney in the same image. Multiple factors affect this comparison, including variations in machine parameters such as gain/depth/power, time-gain- compensation settings and patient anatomy such as attenuation caused by rib shadow or subcutaneous fat, etc. These variations can result in variability of results Prior studies have shown an excellent correlation between HRI and fat fraction obtained through MRS Ultrasound-based envelope statistical imaging, also known as speckle statistics, is based on the passive parametrization of ultrasonic speckle patterns using established statistical distributions/models, which in turn relate to the structural and acoustic properties of tissues (scatterer density and size) Nakagami imaging is one of the most popular model-based speckle statistic methods, first introduced in 2000 . Only a few animal studies have explored the utility of spectroscopy techniques in evaluating fatty liver and demonstrated the potential of spectroscopy parameters to detect and characterize steatosis Quantitative ultrasound spectroscopy uses frequency-dependent parameters extracted from raw RF ultrasound data related to characterize tissue microstructures 82Speed of sound (SoS) measurement is a QUS parameter used for evaluating hepatic steatosis, and can be used to characterize tissue properties based on alterations in ultrasound echo wave speeds in various media Transient elastography and SWE are ultrasound-based elastography methods that measure liver stiffness, which have been successfully adopted clinically to detect and classify hepatic fibrosis Hepatic fat fraction estimated by MRS has proven to be an accurate substitute for liver biopsy and noninvasive imaging standard reference for liver fat quantification The MRI-PDFF is a newer method to estimate liver fat utilizing chemical-shift imaging (CSI) in a single breath-hold. Water protons precess faster than fat protons by about 3.5 parts per million (ppm) Hepatic steatosis can be detected with unenhanced and contrast-enhanced computed tomography (CT) when absolute attenuation of the liver is \u2264 40 Hounsfield units (HU), especially when hepatic fat is > 30% In conclusion, nonalcoholic fatty liver disease is a major health issue with a worldwide increase in prevalence, paralleling the global obesity epidemic. Accurate noninvasive alternatives to liver biopsy in evaluating and monitoring levels of hepatic steatosis are have evolved significantly in the past decade. Emerging quantitative ultrasound-based approaches, integrating innovative statistical methods are promising new technologies to non-invasively assess hepatic steatosis."}
+{"text": "An 85-year-old man with cardiac history notable for atrial fibrillation diagnosed 10 years ago which was being treated with atenolol and warfarin presented to our institution with persistent atrial fibrillation. His echocardiogram showed ejection fraction (EF) of 56%, no regional wall motion abnormalities, mild mitral and pulmonary regurgitation, and trivial tricuspid regurgitation. Despite this treatment, he had recurrent episodes of paroxysmal symptomatic atrial fibrillation with a rapid rate requiring multiple emergency department visits and hospital admissions. Given difficulty to control the rate, he underwent atrioventricular (AV) nodal ablation and leadless pacemaker insertion. Fifteen days after the procedure, he was found to have a severe mitral regurgitation murmur. Leadless pacemakers have been shown to have lesser risk of complications such as pocket infections, endocarditis, pacemaker-induced tricuspid regurgitation, and tamponade. However, this newer technology can lead to significant mitral regurgitation due to iatrogenic LBBB and left ventricular (LV) dyssynchrony.An 85-year-old man presented to our institution complaining of recurrent fever and a mitral regurgitation murmur. He has a past history significant for atrial fibrillation being treated with apixaban status post leadless pacemaker implantation and AV nodal ablation 15 days ago, hypertension, hyperlipidemia, obstructive sleep apnea on continuous positive airway pressure, diverticulosis and diverticulitis, dental caries, melanoma in situ, and persistent pulmonary coccidioidomycosis on fluconazole.He underwent a transthoracic echocardiogram which showed normal left ventricular size and no wall motion abnormalities, LVEF of 56%, severe mitral regurgitation due to incomplete coaptation of the mitral valve leaflets Figures , mild riHis cardiac history is notable for atrial fibrillation diagnosed 10 years ago which was treated with atenolol and warfarin. Despite this treatment, he had recurrent episodes of paroxysmal symptomatic atrial fibrillation with a rapid rate requiring multiple emergency department visits and hospital admissions . Given dGiven the absence of degenerative mitral valve abnormality and no evidence of cardiomyopathy, his diagnosis of new-onset severe mitral regurgitation is the direct result of abnormal electrical conduction related to iatrogenic LBBB due to AV nodal ablation and single-chamber paced rhythm.Mitral regurgitation in majority of cases is related to primary mitral valve diseases such as mitral valve prolapse, endocarditis, or rheumatic heart disease which was not the case in our patient . Mitral In conclusion, given the prior absence of mitral valve abnormality and cardiomyopathy, this diagnosis of new-onset severe mitral regurgitation is the direct result of abnormal electrical conduction related to iatrogenic LBBB  due to A"}
+{"text": "Arterial stiffness assessed by arterial tonometry \u2013 in particular pulse wave velocity and augmentation index \u2013 is associated with increased cardiovascular risk. It is now possible to use cardiovascular magnetic resonance imaging (CMR) for direct imaging of aortic function. This provides a precise assessment of the elastic properties of the aorta within distinct regions of the aorta. We therefore studied what parameters of aortic function are related to arterial tonometry-derived indices of arterial stiffness.We compared aortic stiffness assessed by cardiovascular magnetic resonance (CMR) pulse wave velocity (PWV) based on flow, velocity or acceleration, and aortic distensibility (AD)) to widely used arterial stiffness estimates provided by arterial tonometry (pulse wave velocity (PWVS) and pulse wave analysis (AI)).Thirty young healthy volunteers (aged 23\u201333) underwent tonometry (Sphygmacor) for determination of carotid to femoral PWVS and radial pulse wave analysis for AI estimation. They then underwent CMR to assess aortic elastic properties.Aortic distensibility was assessed from breath-hold ECG-gated, steady state free precession (SSFP) images  acquired at the level of the right pulmonary artery through the ascending and proximal descending aorta and through the distal aorta below the diaphragm to determine aortic distensability. Distensibility was calculated as the relative change in area divided by the central pulse pressure.Pulse wave velocity was measured by an ECG-gated, free breathing, spoiled gradient echo phase-encoded acquisition  at the same locations as the aortic cine images. Three variations of the transit time method were used for calculation of pulse wave velocity (PWV). Arrival of the pulse wave was defined as a) the foot of the curve of mean blood velocity of the blood during the cardiac cycle b) the foot of the curve of total blood flow during the cardiac cycle c) maximum blood acceleration rate  during the cardiac cycle  Figure  but withAortic pulse wave velocity calculated by all three MR methods yielded an inverse correlation with descending aortic distensibility  Figure  but PWVSPWVS and AI most closely reflect acceleration-based CMR PWV measurements of overall aortic stiffness. Arterial tonometry has been validated in large scale clinical studies suggesting this CMR method may be most useful for interpretation of clinical risk. Regional and overall aortic measures of elasticity were not strongly related. However, CMR PWV measures inversely correlated with aortic distensibility, suggesting that MR PWV values may provide a closer estimate of local aortic elastic properties."}
+{"text": "Internal jugular vein (IJV) thrombosis is an unusual condition, especially when it develops bilaterally. This is a case of bilateral IJV thrombosis in a 77-year old female who presented to the emergency department with neck and arm swelling after discontinuing apixaban and undergoing an oropharyngeal procedure. The diagnosis of bilateral IJV thrombosis was made with the use of point-of-care ultrasound to evaluate bilateral jugular vein distention and bilateral upper extremity pitting edema found on her physical examination. A 77-year-old female with a history of atrial fibrillation currently taking apixaban presented to the emergency department (ED) with swelling of her neck and arms for the past seven days. Two weeks prior, she underwent an embolization of a greater palatine pseudoaneurysm, for which she stopped taking apixaban. After being discharged from the hospital, she continued to experience neck swelling, and had an upper extremity ultrasound evaluation which was negative for thrombus. She returned to the ED for worsening neck swelling. She denied shortness of breath, chest pain, fever, or a history of thromboembolic disease. Her physical exam showed pitting edema on bilateral upper extremities and bilateral jugular vein distention. Point-of-care ultrasound was performed on patient\u2019s neck and upper extremities, revealing thrombosis in bilateral internal jugular veins (IJV) as seen in the IJV thrombosis is an uncommon condition and very rare when it occurs bilaterally. Previous studies indicate that it usually occurs in patients with a history of malignancy, oropharyngeal infections, or deep vein thrombosis.What do we already know about this clinical entity?Internal jugular vein (IJV) thrombosis may develop in patients with malignancy or oropharyngeal infections.What is the major impact of the image(s)?IJV thrombosis may develop bilaterally in patients presenting with jugular vein distention without exhibiting the common causes of bilateral thrombosis of the internal jugular veins.How might this improve emergency medicine practice?Point-of-care ultrasound is effective at providing a prompt diagnosis of bilateral IJV thrombosis and should be monitored after anticoagulation is provided.Video.A) Thrombus in the right internal jugular vein (arrow) seen on transverse view. B) Sagittal view of right internal jugular vein thrombus (arrow) with color doppler showing obstruction of venous outflow and turbulence proximal to the thrombus. C) Thrombus in the distal left internal jugular vein (arrow) seen on transverse view. D) Color doppler of the left internal jugular vein thrombus (arrow) showing partial occlusion of the lumen seen on transverse view."}
+{"text": "Subjective cognitive decline (SCD) is a construct of high interest in aging and dementia because individuals endorsing it are at higher risk of developing cognitive problems. It is unclear how individuals arrive at the judgement that they have SCD. Here we aimed to understand which SCD symptoms give rise to the perception of decline as older adults age. Community-dwelling adults , completed the Subjective Cognitive Decline Questionnaire (SCD-Q) online, using an online crowdsourcing site. The SCD-Q consists of one global question regarding self-perceived decline (yes/no) and 24 questions about everyday functioning which we utilized to form a memory, language, and executive functioning domain score, higher for greater perceived decline. Logistic regression revealed that memory and language domains predicted the likelihood of endorsing SCD for adults aged >64 . Only the memory domain predicted the likelihood of endorsing SCD for adults <63 . Executive functioning domain scores did not play a role in the relationship between SCD likelihood in either age group. The higher the self-perceived memory or language decline, the more likely older adults are to conclude they have SCD. Our results suggest there is an age-related trajectory in how people evaluate their cognition, with younger people only considering memory and older people considering both memory and language. Clinicians should be aware of this trajectory when examining patients with SCD. Executive functions should be specifically queried because they may not emerge from older adults\u2019 self-reported cognitive problems."}
+{"text": "Engaging in physical activity (PA) in adulthood has multiple protective health effects in later ages. However, unknown are the extent to which PA habits are laid down earlier in life and persist into adulthood, and the extent to which greater opportunities for PA during adolescence stem from differences in socioeconomic status (SES) which then affect opportunities for PA. We investigated potential mechanisms underlying these relationships using the longitudinal Project Talent Twin and Sibling Study (assessments in 1960 and 2014). With this design, we are able to hold genetics constant by modeling relationships between monozygotic twins (who share 100% of their genes) and therefore isolate effects of contextual factors on later-life PA (mean age ~70). We found that higher family SES  and sports participation in adolescence  predicted PA 55 years later, adjusted for gender and physical limitations. This held true when partialling out genetic variation that could otherwise explain these relationships. More education also predicted later-life PA  separately from family SES and partially mediated the effect of family SES on PA. While school-level resources  did not predict later life PA, they did associate with adolescent sports participation . Overall, later-life physical activity was influenced by earlier life sports participation and education, with family rearing resources being more important than high school resources. As twin pair correlations suggest gender differences, future research will examine whether family or school resources differentially benefit males or females for later-life physical activity."}
+{"text": "HighlightsAt the acute phase of epidermal necrolysis, patients requiring mechanical ventilation had more alveolar macrophages and higher alveolar concentrations of IL-13 than age- and sex-matched patients with the acute respiratory distress syndromePatients with epidermal necrolysis also showed longer duration of mechanical ventilation and more frequent ventilator-acquired pneumonia episodesTo the Editor,+ T lymphocytes, monocytes/macrophages, and natural killer cells. Yet, the pathophysiology of respiratory system involvement during the acute phase of EN is not well understood. The current study aimed at exploring the clinical and biological characteristics of acute lung injury during the acute phase of EN in mechanically ventilated patients.During the acute phase of epidermal necrolysis , mucosal lesions involving the tracheo-bronchial tract have been reported , 2 and aThis is a retrospective monocentric cohort study including patients with EN admitted in the intensive care unit (ICU) of the French National Reference Center for EN during 2011 and 2015 who required endotracheal intubation for acute respiratory failure. This observational cohort study was approved by the institutional ethics committee . Patients received information during hospital stay that data abstracted from their medical charts could be used for research purposes.i.e. percent of neutrophils, macrophages and lymphocytes) cell counts were measured as recommended [2 or Fisher tests for qualitative variables and the Mann\u2013Whitney test for continuous variables. Ventilator-associated pneumonia was defined according to the presence of clinical findings suggesting infection  along with a radiographic infiltrate that is new or progressive and a positive distal quantitative sample [EN patients were age- and sex-matched with a historical control cohort of patients with pneumonia-associated acute respiratory distress syndrome (ARDS) . As stanommended . Cytokine sample .2/FiO2 ratios both at ICU admission and during ICU stay and lower SOFA scores at admission. Yet, EN patients had longer durations of mechanical ventilation than ARDS patients and underwent more frequent ventilator-acquired pneumonia. Total BAL cell counts were not significantly different between EN and ARDS patients . Patients received information during hospital stay that data abstracted from their medical charts could be used for research purposes.Not applicable.The dataset used during the current study is available from the corresponding author upon reasonable request.All authors declare no competing interest for this work."}
+{"text": "Previous studies show that physical activity is beneficial for emotional well-being. This study extends prior research by examining whether engagement in physical activity moderates the association between daily stressor severity and daily emotional well-being. We used data from the second wave of the National Study of Daily Experiences, a sub-project of the Midlife in the United States (MIDUS) study. Respondents  reported their daily experiences across eight consecutive days. Multilevel models explored concurrent and lagged interaction effects between daily stressor severity and physical activity on negative and positive affect and whether these associations differed by age. Physical activity was measured by engagement in vigorous physical activity for at least 30 minutes. Results showed significant interactions between stressor severity and physical activity on same-day negative and positive affect. Specifically, stressor severity was associated with smaller elevation in daily negative affect on physically active days  compared to non-active days . Reductions in daily positive affect were greater on physically inactive days  compared to active days . These associations did not differ by age, but additional findings revealed that stressor severity was associated with greater elevation in negative affect among younger respondents  than older adults . These results highlight the importance of engagement in physical activity for emotional well-being under stressful situations in daily context."}
+{"text": "This paper investigated whether experiencing a major asset shock  changed the cognitive health trajectories of older adults (aged 65+ at baseline)? There is a robust literature supporting a relationship between potentially modifiable environmental and individual risk factors and cognitive health and emerging literature supporting a relationship between physical health shocks and later-life financial stability in both the US and internationally. This analysis employed six waves of Health and Retirement Study Core Data (2006-2014) to estimate the causal effect of major asset losses in the period of the 2008 financial crisis. We matched respondents using a rich variety of covariates including education, race/ethnicity, income, total assets, chronic health conditions, depressive symptoms, frequency of physical activity engagement, and engagement with religious activities. Using both propensity score-matched growth curve and difference-in-differences models, we found a small, but significant, negative relationship between major asset shocks and total cognition scores. We also identified a significant overall negative effect on total cognition on all older adults in this sample regardless of exposure to asset shocks. Additionally, both the frequency of asset shock exposure and magnitude of effect on total cognition scores was larger for low-income African-American and Hispanic older adults. These findings suggest in part that recovery from large economic crises may be especially difficult for older adults occupying vulnerable socioeconomic positions and that such events may accelerate the cognitive decline of those who are at or near retirement when asset shocks occur."}
+{"text": "Bos mutus f. grunniens) and cattle (B. primigenius f. taurus)), which resulted in the higher loss. Further, compensation and insurance schemes were dysfunctional, with few households insuring their livestock and receiving compensation for depredated livestock over the past two years. We recommend improving herding practices and the implementation of compensation and insurance schemes to lower the economic loss faced by herders due to predation and creating positive avenues for the co-existence of snow leopards and humans.Conflict between snow leopards and humans across the trans-Himalaya is a pressing conservation concern. Conflict severely impacts the socio-economy of the local pastoralist community and threatens snow leopard survival. We investigated the socio-economic factors influencing such conflict and pastoralist attitudes towards snow leopard conservation using semi-structured interviews for a better understanding of what factors influence the variability in losses among the households in the Narphu valley, Nepal. While snow leopards caused significant losses to impoverished pastoralist households, respondents were generally accepting of their presence due to religious reasons and strict law enforcement. We observed poor herding and guarding practices with households owning larger numbers of total livestock  using semi-structured questionnaires targeting herders in the Narphu valley of the Annapurna Conservation Area, Nepal. During the two years (2017/18 and 2018/19), 73.9% of the households interviewed (n = 65) lost livestock to snow leopards, with an annual average loss of two livestock per household. Of the total depredation attributed to snow leopards, 55.4% were yak , 31.7% goat, 6.8% sheep, 3.2% horse and 2.8% cattle. Results from applying Generalized Linear Mixed Models (GLMMs) revealed the total number of livestock owned and the number of larger bodied livestock species as the main explanatory covariates explaining livestock depredation. Forty-one (41%) of all herders considered snow leopard\u2019s preference for domestic livestock as the main factor in livestock predation, whereas only 5% perceived poor herding practice as the main reason for the loss. Our study found poor and changing herding practices in the valley, whereby 71% herders reported careful herding as a solution to snow leopard depredation, and 15% of herders considered the complete extermination of snow leopards as the best solution to the problem. Tolerance levels and awareness among herders towards snow leopard conservation is increasing, mainly due to the Buddhist religion and strict law enforcement within this protected area. We recommend the effective implementation of a community-based livestock insurance scheme to compensate the economic loss of herders due to predation and improved herding practices as the recommended mitigation measures for ensuring livestock security and snow leopards\u2019 conservation in the valley.Livestock depredation across the trans-Himalaya causes significant economic losses to pastoralist communities. Quantification of livestock predation and the assessment of variables associated with depredation are crucial for designing effective long-term mitigation measures. We investigated the patterns and factors of livestock depredation by snow leopards ( Panthera uncia) and Himalayan wolf (Canis lupus chanco) are key mountain species across Himalayan range countries  with their presence indicative of a healthy ecosystem . Th. Th17]. The total mean attitude scores of respondents close to zero suggests that local people were very weakly accepting the presence of snow leopards, probably due to the high level of livestock losses by snow leopard . On the We found a decrease in livestock holdings with higher predation from snow leopards over the study period. Herders owning larger livestock size and larger bodied livestock incurred more economic loss due to livestock depredation. The livestock herding trend is decreasing mainly due to livestock predation by snow leopards and outmigration of village youths to urban centers. In order to reduce economic losses, we recommend encouraging small bodied livestock  while encouraging other appropriate changes in livestock composition (number and livestock species). Moreover, the effective implementation of a community-managed insurance program, with education toward improvement of herding practices and equitable compensation for depredation losses would help in building positive attitudes among herders for supporting snow leopard conservation and minimize these conflicts in the Narphu valley. Similarly, conservation programs focused on empowering herders through educational programs to improve herding techniques and herder motivations  would likely reduce overall losses, especially when livestock are grazed on open pastures or housed in poorly constructed corrals at night. Programs that reduce out-migration of the younger generation and encourage them towards herding could help preserve traditional herding practices in the Narphu valley. For reasons stated above, this paper highlights conflict between snow leopard and humans as a complex phenomenon requiring holistic, multi-pronged approaches for minimizing negative impacts and ensuring positive species coexistence with pastoral-dependent communities."}
+{"text": "Bats play important roles as pollen disseminators and pest predators. However, recent interest has focused on their role as natural reservoirs of pathogens associated with emerging infectious diseases. Prior to the outbreak of severe acute respiratory syndrome (SARS), about 60 bat virus species had been reported. The number of identified bat viruses has dramatically increased since the initial SARS outbreak, and most are putative novel virus species or genotypes. Serious infectious diseases caused by previously identified bat viruses continue to emerge throughout in Asia, Australia, Africa and America. Intriguingly, bats infected by these different viruses seldom display clinical symptoms of illness. The pathogenesis and potential threat of bat-borne viruses to public health remains largely unknown. This review provides a brief overview of bat viruses associated with emerging human infectious diseases."}
+{"text": "Coronary angiography (CAG) sometimes shows nonobstructive coronary arteries in patients with suspected angina or acute coronary syndrome (ACS). The high prevalence of nonobstructive coronary artery disease (CAD) in those patients has recently been reported not only in Japan but also in Western countries, and is clinically attracting attention. Coronary spasm is considered to be one of the leading causes of both suspected stable angina and ACS with nonobstructive coronary arteries. Coronary spasm could also be associated with left ventricular dysfunction leading to heart failure, which could be improved following the administration of calcium channel blockers. Because we rarely capture spontaneous attacks of coronary spasm with electrocardiograms or Holter recordings, an invasive diagnostic modality, acetylcholine (ACh) provocation test, can be useful in detecting coronary spasm during CAG. Furthermore, we can use the ACh-provocation test to identify high-risk patients with coronary spasm complicated with organic coronary stenosis, and then treat with intensive care. Nonobstructive CAD includes not only epicardial coronary spasm but also microvascular spasm or dysfunction that can be associated with recurrent anginal attacks and poor quality of life. ACh-provocation test could also be helpful for the assessment of microvascular spasm or dysfunction. We hope that cardiologists will increasingly perform ACh-provocation test to assess the pathophysiology of nonobstructive CAD. We often perform percutaneous coronary intervention (PCI) with coronary stent implantation for significant organic coronary artery stenosis with induced myocardial ischemia. PCI has become a useful treatment for relief of chest symptom in patients with significant coronary organic stenosis. However, coronary angiography (CAG) sometimes shows nonobstructive coronary arteries that do not need revascularization in patients with suspected angina \u201311. IndeYasue and coworkers previously reported that the intracoronary injection of acetylcholine (ACh) is a useful test for the provocation of coronary spasm \u201323. SincAlthough the etiologic mechanisms of stable angina and acute coronary syndrome (ACS) in patients with nonobstructive CAD remain obscure, coronary spasm can play an important role in the pathogenesis of these diseases , 36, 37.In this review article, we discuss the significance of ACh-provocation test as a tool for pathophysiological evaluation in nonobstructive CAD including coronary spasm.Coronary spasm usually occurs at rest, particularly from midnight to early morning \u201327. CoroACh usually causes vasodilation by releasing nitric oxide from the endothelium, and intracoronary injection of ACh in humans provokes coronary vasodilation in young healthy subjects, whereas it causes vasoconstriction in patients with coronary endothelial dysfunction such as coronary atherosclerosis \u201351. The Nonobstructive CAD includes not only angina with epicardial coronary spasm but also microvascular spasm \u20137, 62. H\u00ae (ACh chloride) was approved as an inducer of coronary spasm during CAG in 2017 in Japan. This approval will lead to more testing for provocation of coronary spasm in Japan, adaptation of the treatment based on the patient's progress, and detailed pathophysiological evaluation of nonobstructive CAD including coronary spasm.OvisotIn addition to ACh, ergonovine (ER) is also useful for pharmacological provocation of coronary spasm. According to the Japanese Circulation Society (JCS) Guidelines , the intStudies in Japan have made many contributions to the pathophysiology, diagnosis, and treatment of coronary spasm, leading to the development of the Guidelines for Diagnosis and Treatment of Patients with Vasospastic Angina by the JCS , 75\u201378. According to the JCS Guidelines for Vasospastic Angina (Coronary Spastic Angina)  Fig.\u00a02)2), we caWe and others previously reported different patterns of angiographic changes including focal  and diffuse spasm (severe diffuse vasoconstriction) during the spasm provocation test , 81, 82.According to the JCS Guidelines, ACh-provocation test is not recommended during emergent CAG in patients with ACS . The AmeT/C single nucleotide polymorphism in endothelial nitric oxide synthase gene were associated with ACh-provoked myocardial lactate production in patients with coronary spasm [Epicardial coronary spasm can be seen angiographically during the ACh-provocation test; however, it is unclear whether the coronary spasm causes myocardial ischemia. For this reason, we usually measure myocardial lactate production in the coronary circulation during ACh-provocation tests in the left coronary artery as a supporting diagnostic marker for the evaluation of coronary spasm-induced myocardial ischemia , 86. OurCoronary spasm can occur at sites of varying arteriosclerosis severity. We and others previously reported that coronary spasm could be associated with the progression of atherosclerosis \u201391. PatiWe previously reported that ACh-provoked coronary spasm occurring at the site of significant coronary artery stenosis was a more significant prognostic factor for MACE than ACh-provoked coronary spasm occurring at the site other than the site of organic stenosis, suggesting that coronary spasm can be associated with the cause of MACE when the coronary spasm occurs at the site of organic stenosis , 101. ThAt present, we often perform PCI with coronary stent implantation for significant organic coronary artery stenosis. Coronary spasm occurring after coronary stent implantation has become a clinical problem , 102\u2013107Recent studies reported that epicardial coronary spasm could be associated with left ventricular (LV) dysfunction \u201341. We pA previous study reported that the ACh-provocation test induced coronary spasm in 20/42 patients (48%) who had idiopathic DCM-like LV dysfunction without significant organic coronary arteries stenosis . PatientOn the other hand, ACh-provoked coronary vasomotor abnormality  in our previous study was shown to be closely associated with myocardial fibrosis (expressed as late gadolinium enhancement in cardiac MRI) in patients with heart failure and without organic coronary artery stenosis , 112. CoThe coronary arterial tree consists of not only the epicardial coronary arteries, but also smaller arteries and arterioles (<\u2009500\u00a0\u03bcm). The latter feed the capillaries and play an important role in the coronary microcirculation, being the main site of regulation of myocardial blood flow , 119. EpModalities for diagnosing obstructive CAD such as CAG or CTA have improved remarkably. However, in patients with suspected angina, we can sometimes see both nonobstructive epicardial coronary arteries and non-ACh-provoked epicardial coronary spasm. Nonobstructive CAD has included not only angina with epicardial coronary spasm but also microvascular spasm or dysfunction , 124 5). We de2, respectively. These clinical features of the microvascular spasm, such as female sex, middle age, and low body mass index, are reminiscent of postmenopausal phenomena, which invites speculation of an association between the pathogenesis of microvascular spasm and age-dependent estrogen deficiency in those patients.Our report mentioned above  of the 1The ACh-provocation test has several limitations. The ACh-provocation test cannot provoke coronary spasm in all patients with coronary spasm, although our previous study showed high sensitivity and specificity of the test in patients with variant angina , 21. In ACh-provocation test has several potential complications. In our institution, the number of life-threatening arrhythmias during ACh-provocation test was 9 (0.5%) of 1637 patients who underwent this test . A previAs summarized in this review, ACh-provocation test can be a safe and reliable method not only to diagnose epicardial coronary spasm but also to assess the pathophysiology of nonobstructive CAD. The ACh-provocation test is not often performed in routine clinical cardiovascular practice because multiple procedures of this test are required. However, the pathophysiology showed by ACh-provocation test can be associated with prognosis in patient with nonobstructive CAD. We can identify the high-risk patient with coronary spasm or microvascular spasm diagnosed by ACh-provocation test and treat with intensive care for the patients.We hope that cardiologists will routinely perform the ACh-provocation test to assess the pathophysiology of nonobstructive CAD."}
+{"text": "Prior research has established transitions into and out of nursing homes as periods of suicide risk for older adults. Deaths by suicide were found to be 2.4 times as likely among Veterans within six months of discharge from US Veterans Health Administration (VA) nursing homes when compared with gender and age-matched Veterans from the general VA patient population . Despite these trends, suicide prevention interventions implemented during nursing home and post-acute care transitions, including those taking place from Centers for Medicare and Medicaid Services regulated nursing homes, are lacking. Suicide Awareness for Veterans Exiting the Community Living Center (SAVE-CLC) was piloted as a quality improvement intervention to reduce suicide risk for older Veterans discharging from VA nursing homes. VA clinicians from three sites provided a friendly contact by phone after discharge (n = 66) to screen for depression, facilitate a strengths-based discussion about service needs, and provide service referrals. Compared to a group of patients discharged prior to the start of the intervention , SAVE-CLC patients received more depression screening within 30 days after discharge  and were seen more quickly for mental health care  when indicated. Implications for suicide prevention with older Veterans and for the general population of older adults receiving short stay services in US nursing homes will be addressed."}
+{"text": "Microplastics in the biosphere are currently of great environmental concern because of their potential toxicity for aquatic biota and human health and association with pathogenic microbiota. Microplastics can occur in high abundance in all aquatic environments, including oceans, rivers and lakes. Recent findings have highlighted the role of microplastics as important vectors for microorganisms, which can form fully developed biofilms on this artificial substrate. Microplastics therefore provide new microbial niches in the aquatic environment, and the developing biofilms may significantly differ in microbial composition compared to natural free-living or particle-associated microbial populations in the surrounding water. In this article, we discuss the composition and ecological function of the microbial communities found in microplastic biofilms. The potential factors that influence the richness and diversity of such microbial microplastic communities are also evaluated. Microbe-microbe and microbe-substrate interactions in microplastic biofilms have been little studied and are not well understood. Multiomics tools together with morphological, physiological and biochemical analyses should be combined to provide a more comprehensive overview on the ecological role of microplastic biofilms. These new microbial niches have so far unknown consequences for microbial ecology and environmental processes in aquatic ecosystems. More knowledge is required on the microbial community composition of microplastic biofilms and their ecological functions in order to better evaluate consequences for the environment and animal health, including humans, especially since the worldwide abundance of microplastics is predicted to dramatically increase. Plastics have been produced since the 1940s, and world production reached 360 million metric tons in 2018, which has resulted in severe plastic pollution of the environment worldwide  were also enriched in microplastic biofilms  and one plant pathogen (Pseudomonas syringae) were exclusively found in microplastic biofilms  biofilms represent the major groups of bacteria capable of degrading PHBH  represented important microbial associations within microbial communities of the plastisphere  microplastic characteristics (\u201csubstrate-specific\u201d), (ii) period/succession (\u201ctime-specific\u201d), (iii) microbial community and (iv) environmental conditions Fig.\u00a0. The lasAlphaproteobacteria and Gammaproteobacteria, while Burkholderiales (formerly Betaproteobacteria) dominated on polyethylene microplastic biofilms in the North Atlantic garbage patch  for microbial growth, pollutants , physicochemical parameters  and aquatic biota  are critical factors controlling microbial biofilm formation and succession on microplastics. In lake water, temperature, nutrient levels and suspended particle concentrations determined microbial assemblages on various plastics (Chen et al. Mytilus edulis developed a similar bacterial community composition as the mussel\u2019s gut microbiome (Kesy et al. Aquatic plants and animals play an important role in the transfer of microplastics across complex food webs (Au et al. The formation and development of the microbial community structure of microplastic biofilms to a large extend depend on \u201clocation-specific\u201d, \u201ctime-specific\u201d and \u201csubstrate-specific\u201d characteristics. However, most studies reveal that location-specific characteristics play a more important role than substrate-specific\u201d factors in shaping the bacterial community composition of microplastic biofilms (Amaral-Zettler et al. Factors influencing microbial community composition and function require further studies to better understand underlying processes and mechanisms. Most prior studies have been restricted to traditional non-degradable plastics, but the worldwide increasing use of degradable plastics means that these less refractory polymeric compounds also need to be carefully considered. A total of 127 countries have adopted some form of legislation to regulate the use of plastic bags UNEP , but mosThe advantages and limitations of current research methods for microplastic biofilms have been summarized (see Arias-Andres et al. The focus of future studies on microbial biofilms on microplastics should concentrate on functional and ecological aspects affecting aquatic food web dynamics and biogeochemical processes. Meta-transcriptomics, metaproteomics and metabolomics are now well established and important tools to assess functions and ecological roles of microbial communities Fig. . These m"}
+{"text": "Frail community-dwelling older adults increasingly receive home care and continue to face barriers to participating in physical activity (PA) that could help maintain their function. Home care aides (HCAs) are well-positioned to promoting PA among older home care recipients because of their established relationship and regular interpersonal exchanges; yet, the role of HCAs in promoting and supporting PA in home care settings is seldomly studied. Using the quantitative and qualitative data from a 4-month home-based gentle PA intervention delivered by HCAs to their clients in a Medicaid-funded home care setting, the current study examined whether outcome expectations for exercise (OEE) held by HCAs led to client PA outcomes  through social support for exercise (SSE) provided by HCAs. Longitudinal mediation analysis of 46 HCA-client dyads showed that higher baseline OEE held by HCAs were related to greater SSE reported by clients after the intervention , controlling for client-level covariates, including baseline OEE, age, gender, comorbidity, and whether HCA was client\u2019s family member. Unexpectedly, SSE did not have significant association with client PA outcomes nor mediated the relationship between OEE held by HCAs and client PA outcomes. Qualitative data suggested alternative factors may explain the results, such as clients\u2019 family beliefs in the intervention and clients\u2019 participation experiences (such as expectation fulfillment). Future research should consider older home care clients\u2019 family contexts to enhance our understanding of HCAs\u2019 roles in preserving the function of growing numbers of older home care recipients."}
+{"text": "This knowledge is critical to understand how crust-forming processes are related to metal accumulations at specific time and conditions of Earth evolution. To this end, high-precision absolute geochronology utilising the rhenium-osmium (Re-Os) radiometric system in specific sulphide minerals is becoming a method of choice. Here, we present a procedure to obtain mineral separates of individual sulphide species that may coexist within specific mineralized horizons in ore deposits. This protocol is based on preliminary petrographic and paragenetic investigations of sulphide and gangue minerals using reflected and transmitted light microscopy. Our approach emphasizes the key role of a stepwise use of a Frantz isodynamic separator to produce mineral separates of individual sulphide species that are subsequently processed for Re-Os and sulphur isotope geochemistry. Specifications TablePolished thin sections of the arsenopyrite-pyrite-mineralised samples were studied using transmitted and reflected light microscopy in order to establish the paragenetic relationships and constrain the workflow  for optiAll sulphide samples were cut into slabs that were thoroughly cleaned using silicon carbide grit, milli-Q water and ethanol to remove any metal traces potentially introduced through hammering or sawing . These clean sulphide-bearing samples were then crushed using a zirconia ceramic dish and puck and sieved through disposable home-made nylon sieves to produce 70\u2012200 mesh size fractions . Each 70An aliquot of each arsenopyrite and pyrite mineral separate was embedded in epoxy to operate a quality control of these mineral separates . The mounts were studied by reflected light microscopy. We recommend the use of a scanning electron microscope (SEM) operated in backscattered electron mode (SEM-BSE) if doubts persist regarding the quality of mineral separates. Qualitative observations may then be complemented by point wavelength-dispersive spectroscopy (WDS) quality control analyses of arsenopyrite and pyrite in the mounts using the following suite of elements: S, Fe, Ni, Cu, As.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies. Identification of a general and suitable target that is unambiguously oncogenic or tumor suppressive is a foundation on which cancer therapeutic strategies could be designed and developed. Fibronectin (FN) A has lonAccomplishment of cancer development, a rather slow and chronic process, temporally and spatially requires various cellular activities across different tissues. Tumor cells originate from healthy, often epithelial, cells that acquire hereditary mutations  or somatIn contrast to such intratumor heterogeneity, immune and stromal cells in the tumor microenvironments (TMEs) initially arise to eliminate pre-tumor abnormal cells and early transformed cells that encounter environmental stresses. Consequently, these stresses impose early transformed cells enormous selective pressures to force evolution, rendering tumor cells staying in the equilibrium stage for a long while before being able to escape immunosurveillance and make a malignant progression ,26,27. HOxygen delivery within the TMEs is inefficient mainly due to various abnormalities in the tumor vasculature . Indeed,The liberation and survival of circulating tumor cells (CTCs) is a requirement for the colonization of disseminated tumor cells (DTCs) in secondary organs and finally outgrowth and macrometastasis development ,34. Like+ bone marrow-derived cells (BMDCs) that have been driven by cytokines or exosomes secreted by the metastatic competent tumor cells in primary tissues long before extravasation of DTCs in distant tissues    formed ted data]  [unpubli435 DTCs . Uncouplt organs . Such pht organs ,350, likhigh CTCs colonize more and form more metastatic tumor nodules in distant organs, unless there are strategies to reverse FNhigh CTCs back to pro-epithelial phenotypes that tend to render CTCs suffer more from anoikis and mechanical stresses and injuries.Since how cancerous FN and ECM FN participate in tumor progression remains obscure and paradoxical, FN-based cancer therapies have so far only been focused on the functions of drug delivery. For example, EDA- and EDB-containing oncofetal variants have often been utilized for that purpose ,351,352.At the same stage of tumor patients, FN deposition in ECM of TMEs exacerbates tumor growth and subsequent progression. Therefore, approaches targeting such matrix-depositing FN may be ideal for effectively slowing down the tumor progression. FN secretion and deposition may due in part to tumor-infiltrating pro-tumor stromal cells including CAFs and TAMs . Ablatiohigh CTCs prior to extravasation in distant organs as DTCs. Blockade of the attachment of FNhigh CTCs to DPP IV-expressing endothelia can be an ideal strategy to prevent tumor metastasis and improve patients\u2019 prognosis. Indeed, in experimental metastasis assays, polypeptides derived either from FN harboring DPP IV-binding sites [In later stages of tumor progression, tumor cells with the metastatic potential begin to intravasate into the circulation and become FNng sites  or from ng sites ,2 have bng sites . More imng sites . Intrigung sites .high CTCs become highly metastatic and capable of colonizing distant organs. The prevailing therapeutic strategies are to switch to a second line of tumor-killing drugs or combinatory therapies including immune checkpoint blockade, which may cause further genetic or epigenetic evolutions and eventually lead to another drug resistance. These problems may be avoided by finding a drug that by itself has no cytotoxic effect on tumor cells but is able to sensitize the resistant tumor cells to the original drugs. Efforts can be exerted to screening such drug from either small molecule library or a series of less harmful natural phytochemicals. By combining such drug with periFN/DPP IV binding blockade treatments, the drug-resistant tumor cells can be re-sensitized and controlled in the primary sites and FNhigh CTCs can simultaneously prevented from entering distant sites.In most cases, tumor patients receive either tradition chemo/radiotherapies or targeted anti-tumor therapies. As aforementioned, tumor patients often develop resistance to these anti-cancer drugs, driving tumor evolution, malignant progression, intravasation of tumor cells to become CTCs, and metastatic recurrence simultaneously with the upregulation of endogenous FN. Although therapy-elevated FN expression in resistant tumor cells slow down the tumor growth, the blood-borne FNIn summary, after extensively reviewing the bulk literature regarding the roles of FN in cancer progression, we provided intriguing possibilities that reasonably reconcile the seemingly paradoxical roles FN plays. We hypothesized that cancerous FN and FN mactrices in TMEs can coordinately regulate tumor transformation and malignant progression in temporal and spatial manners. Upon accomplished experimental proof of concept, FN can be carefully targeted at the right location and in the right time. We finally provided a few FN-based therapeutic strategies as future perspectives. Hopefully, this review article can attract more cancer researchers to be delved into concerted efforts in unveiling and validating what had been proposed here."}
+{"text": "Despite the well-understood benefits of vaccination in older adults, national rates still fall below public health targets, especially among certain racial and ethnic groups. Recent scholarship examining healthcare use patterns in adults revealed that health care providers miss several opportunities to provide vaccination during regular healthcare encounters, including Medicare annual wellness visits. Several barriers to older adult vaccination have been identified, including lack of patient and provider understanding of the importance of vaccination, financial barriers to vaccines covered under Medicare Part D, and patient hesitancy about the safety and effectiveness of vaccines. Strategies to address these barriers will be discussed, including the use of national quality measures to strengthen incentives for adult vaccination. Part of a symposium sponsored by the Health Behavior Change Interest Group."}
+{"text": "Individual sensory deficits have been associated with adverse outcomes, including dementia, in older adults. Using data from the Baltimore Longitudinal Study of Aging (BLSA) (N=259) and Atherosclerosis Risk in Communities Study (ARIC) (N=962), we examined the prevalence of one, two, or three sensory deficits  among older adults \u226570 years. Any hearing loss was the most prevalent sensory deficit , followed by vision loss and olfactory loss. Hearing and vision impairments were more prevalent than hearing and olfactory losses as well as vision and olfactory losses in both age groups and studies There were few people with deficits in all three senses . Further research should investigate the potential impact of multisensory impairments on older adults."}
+{"text": "PLOS Genetics publications that exemplify recent progress in human genetic admixture studies, and we discuss potential areas for future work.Throughout human history, large-scale migrations have facilitated the formation of populations with ancestry from multiple previously separated populations. This process leads to subsequent shuffling of genetic ancestry through recombination, producing variation in ancestry between populations, among individuals in a population, and along the genome within an individual. Recent methodological and empirical developments have elucidated the genomic signatures of this admixture process, bringing previously understudied admixed populations to the forefront of population and medical genetics. Under this theme, we present a collection of recent  One of the major insights from the modern genomic era is the ubiquity of migration and admixture throughout human history \u20137. Admix\u2014the population origins of material within a genome. This is related to, but distinct, from genetic similarity and from genealogical ancestry, with the relationship further discussed by Mathieson and Scally [Human population movement frequently lacks historical records. Many migration events have occurred through colonization or forced displacement, and ancient admixture often predates historical records. Therefore, genetic studies provide an opportunity to understand population history and the forces generating variation. Recent empirical work has shown that studying the genetics of a wider set of human populations can yield historical insights as well as medically relevant information about health and phenotypes. The mosaic ancestry patterns of admixed populations can also be used to elucidate the mechanisms and timescales of evolution in humans more generally. For example, ancestry patterns in admixed populations have been used to infer recombination rates \u201315 and td Scally .PLOS Genetics publications. This compilation is a limited selection of work that exemplifies recent key advances and stimulates discussion about priorities for the future.Here, we highlight recent progress and discuss future directions for the study of admixed human populations . The terBroader genetic sampling of populations worldwide is increasingly being combined with advances in theory and computational methods to elucidate human history.Genetic ancestry often varies along a chromosome within an individual and between individuals within an admixed population . SummariClassic statistical methods in population genetics typically rely on allele frequencies, patterns of linkage disequilibrium (LD), and interpopulation sequence differences. However, the admixture process may distort patterns of LD, break up runs of homozygosity, and combine allele frequency distributions from distinct parental populations \u201329. Yet,PLOS Genetics that improve our understanding of the demographic processes shaping genetic variation in admixed populations and human evolutionary history. Ragsdale and colleagues (2019) generalize 1- and 2-locus genetic summary statistics in a computationally efficient algorithm able to explore complex demographic models [A number of major theoretical and methodological advances have recently been published in c models . Other rc models . Methodoc models . Identifc models \u201338. Browc models \u201341. A rec models .Intricate sociocultural practices such as marriage customs, colonization events, and phenotypic preferences direct how parental populations interact to form admixed human populations. Whereas computational methods are increasingly considering these intricacies, empirical studies of admixed populations have already made substantial progress on fine-scale demography providing insight into how sociocultural practices shape the admixture process and within-region variation.Using these new methods, empirical studies have brought to the forefront within-continent variation, particularly for historically excluded and under-sampled populations. Analyses of genomic ancestry within the context of geography have revealed between and within continent population structure . For exaEmpirical studies such as these highlight the role social processes play in shaping genetic variation; for example, male and female demographic histories can differ. Considering population structure, sex-biased admixture, and effective population size changes, Font-Porterias and colleagues (2019) clarified the dynamic demographic history of European Roma groups, including showing that they share a common South Asian origin but have complex contributions from West Eurasian groups . AnotherSelective pressures, such as those from environments and pathogens, play an important role in genetic variation and disease risk. Admixture both obscures genetic signatures of selection in source populations and provides new genetic material upon which selection can rapidly act.Despite major progress on theory and methods to study demography in admixed human populations, methodological advances to study other processes such as adaptation and phenotypic variation remains an open area with substantial room for growth. Recent admixture may obscure genetic signatures of selection in the source populations by distorting linkage, rapidly changing allele frequencies, and breaking up homozygosity ,56. TherDARC locus is protective against malaria-causing Plasmodium vivax infection, which is estimated to be one of the strongest selective pressures in recent human history. The Duffy-null allele is nearly fixed in sub-Saharan African populations and mostly absent in non-African populations, producing a classic signal in which the DARC locus is an outlier in its proportion of local African ancestry in multiple admixed populations [DARC locus is not typical of human adaptation. These local ancestry outlier approaches likely miss many loci under weaker or polygenic selection or those not highly differentiated in the sources. Additionally, outlier approaches generate false positives due to drift or long-range LD and discard other genetic information along the genome. For example, in Western African rainforest hunter\u2013gatherer populations, Jarvis and colleagues (2012) found reduced levels of switching between ancestry types in a genomic region that may contribute to adaptive phenotypes such as short stature [A common approach to identify candidate regions under selection post-admixture looks for outliers in local ancestry \u201321,59,60ulations . However stature . DespiteDespite the challenges of identifying phenotypically important loci and regions under selection in admixed populations, recent empirical studies have highlighted the importance of using admixed populations to understand how selective pressures shape genetic variation and disease risk. Discovering phenotypically important loci in admixed populations requires careful consideration of the data, including strategies to integrate genotypes, local ancestry, and information from source populations. Once phenotypically important loci are identified, admixed populations can provide insight into how these loci interact with different ancestral backgrounds and how characteristics of the source populations shape post-admixture selection.ApoE is the strongest known risk gene for late-onset Alzheimer disease; Rajabli and colleagues (2018) showed that variation in risk for Alzheimer disease across populations may be at least partially explained by the ancestral background interacting with the risk allele [In addition to looking for correlations between genotype and phenotype, phenotypically important loci in admixed populations can be identified by looking for correlation between local ancestry and phenotype when the phenotype differs in the source populations . A combik allele . The relk allele . In Latik allele . Going fNotably, these types of studies of quantitative variation and disease risk in admixed populations rely on careful consideration of the genotype and local ancestry calls, including reference-bias and characteristics of the source populations. Identifying phenotypically important loci in admixed populations is challenging in the absence of appropriate reference panels and knowledge of the source populations. The growing availability of genetic data from diverse groups shows that the unique LD structure of admixed groups and limited availability of suitable reference panels can particularly impair variant mapping and detection for novel or rare alleles. For example, Kowalski and colleagues (2019) recently analyzed a large cohort of phased genomes from African and Hispanic/Latino individuals (NHLBI TOPMed), revealing significant phenotypic associations for rare variants that were not detected with imputation using 1000 Genomes reference data .Contributing source populations also have their own distinct selective and demographic histories. Although recent admixture obscures genetic signatures of selection in the source populations, consideration of past selective pressures can help identify important loci and clarify the genetic basis of disease risk. For example, Yao and colleagues (2018) found that in African ancestral backgrounds, past selection for the Duffy-null allele may also contribute to population differences in plasma levels of chemokines involved in a variety immune processes and diseases . In IndiThe set of papers highlighted here exemplifies recent advances and important areas for future work in the study of genetic admixture and its roles in human evolution. Recent theoretical and methodological advances have improved our understanding of the dynamic and complex demographic histories of modern human populations. New empirical insights will continue to emerge with the development of approaches that consider complex sociocultural variables, account for within-population heterogeneity, and avoid reference bias. With increasing genomic and phenotypic data available from populations around the world, we are only beginning to characterize genetic underpinnings of traits, the importance of their genetic background, and mechanisms of adaptation. Importantly, as we move forward, the field must emphasize the inclusion of local communities, ensure that people maintain agency over their genomic information, prioritize infrastructure for science, and improve scientific theories by collaborating across disciplinary knowledge \u201375."}
+{"text": "According to the World Health Organization, the global population is aging, but ageism may now be the most socially \u201cnormalized\u201d of any prejudice, more pervasive than sexism or racism. Ageism produces avoidant and disrespectful treatment of older adults and contributes to a shortage of college students seeking careers with older adults. To foster positive intergenerational contact and combat ageism, we organized life-story sharing by older adult community members in four undergraduate psychology courses with lifespan themes . A panel visited each class; instructors and graduate students facilitated discussion between students and panelists. Students completed pre- and post-surveys of ageism and attitudes toward aging. A majority of students recommended integrating the activity into future semesters. In free-responses, students also frequently expressed surprise that panelists reported not feeling different than they had at age 20, and that this information challenged previously held stereotypes."}
+{"text": "Nineteen percent (13 million) older adults have incomes below 150% of the Federal Poverty Level, leaving them with limited means to afford basic living expenses. Public benefits can help bridge the gap allowing older adults to afford food, home energy, and health expenses. There are studies demonstrating the positive health outcomes associated with public benefits in older adults. It remains unclear how benefits may also improve subjective measures of well-being in older adults. To examine this question, baseline measures of well-being including the CFPB Financial Well-Being Scale were administered to older adults before they enrolled in benefits and again six months after receiving benefits to examine changes in well-being as a result of accessing benefits to help ease some of their financial burdens. Results revealed that older adults experience subjective, psychological improvements from benefits. These findings have implications for the social and behavioral determinants of health in older adults."}
+{"text": "Older adults in the deep south are living with high food insecurity rates; this is exacerbated by challenges with rural-living, like transportation limitations and no grocery stores. To address this, we must increase emergency food assistance offerings and adopt best practices for food pantries including choice food pantry approaches, which empowers clients with some autonomy in choosing the foods they receive as part of their pantry distribution. Coalitions in eight income-limited, aging, rural Mississippi Delta counties received support from a Centers for Disease Control and Prevention Grant to enhance the food-related infrastructure in their communities through technical assistance and economic investments. A detailed process evaluation was conducted on this effort. Each coalition adopted food pantry-related policies like adding new food pantries and adapting their existing food pantries with the choice model. Both aging volunteers and clients indicated positive outcomes from the process of adding pantries and adapting existing ones."}
+{"text": "Military service during early life can result in exposure to traumatic events that can reverberate throughout life. Although much attention is focused on the negative effects of military service, many veterans report positive effects. These papers explore life course effects of military service on veterans\u2019 health and well-being. Three used national US longitudinal cohorts ; two sampled veterans from Oregon or from Korea. Three compared veterans to non-veterans; two examined veterans only. Cheng and colleagues found that veterans in HRS are more likely to be risk-averse than non-veterans. Risk aversion matters because it determines how people make decisions and predicts a wide array of health and economic outcomes. Kurth and colleagues examined Oregon veterans from several wars, finding PTSD symptoms were highest among Vietnam combat veterans, the oldest cohort; there were no differences among non-combat veterans. Piazza and colleagues examined in MIDUS the impact of veteran status on cortisol, a stress biomarker, finding older veterans more likely had non-normative patterns than did younger or non-veterans. Lee and colleagues studied patterns of mental health among Korean Vietnam veterans, identifying two patterns as \u2018normal\u2019 and \u2018resilient\u2019 encompassing half the sample; these veterans demonstrated positive outcomes of military service. Frochen and colleagues compared depression trajectories between veterans and non-veterans in HRS, finding veterans had less depression than non-veterans, but among veterans, trajectories varied based on extent of service. in sum, these papers demonstrate that military service can have positive as well as negative effects on veterans\u2019 health and well-being in later life. Aging Veterans: Effects of Military Service across the Life Course Interest Group Sponsored Symposium."}
+{"text": "Person-centered caregiving approaches emphasize efforts to protect and maintain the personhood of people living with dementia (PLWD). The influence on person-centered caregiving approaches on PLWD have predominantly focused on deficit-oriented outcomes, such as absence or reduction of behavioral symptoms. While important to quality of life, the absence of measurable \u201cpositive\u201d responses to person-centered caregiving approaches limit opportunities to specify sensitive and meaningful outcome measures that more holistically represent PLWD\u2019s care experiences as more than the absence of a negative outcome. To address these gaps, we conducted a secondary analysis of video-observations of PLWD (N=9) surrounding mealtime cares using a descriptive ethnographic approach. Our objectives were to descriptively summarize specific responsive behaviors demonstrated by PLWD surrounding person-centered caregiving interactions, specifying observable features of these responses and consider their utility in future video-observational research. Findings indicate PLWD contribute both verbal and non-verbal communication surrounding person-centered approaches which can be characterized as conversational , expressing preferences , emotional responses , and reflexive (mirroring of caregiver\u2019s actions), with overlap between categories. Findings suggest that PLWD not only contribute and respond in meaningful ways to person-centered interactions, but also initiate a significant number of these interactions. This study contributes to a growing body of research and advocacy that examines the personhood and abilities of PLWD and establishes the utility of observational data in studying PLWD contributions."}
+{"text": "Almost a hundred and thirty years ago, Emil Kraepelin described important weight changes in patients diagnosed with dementia praecox during the acute state of psychosis outbreaks . KraepelTwenty years later Eugenie Bleuler in his seminal book \u201cDementia praecox oder Gruppe der Schizophrenien\u201d described that body weight of patients underwent irregular and severe variations from which no cause had been identified (being sometimes as much as 25 Kg), suggesting that it could not be considered as a compensation mechanism after the stressful circumstances of a psychotic outbreak . He alsoNevertheless the link faded with the introduction of chlorpromazine in 1952 like other medical conditions . HoweveWith the reintroduction of clozapine in the market, new studies regarding this association in patients diagnosed with schizophrenia or schizoaffective disorder appeared in the literature. Lamberti, without aiming at it, showed an inverse correlation between clinical symptom severity change and weight gain in 36 inpatients evaluated for 6 months with the brief psychiatric rating scale (BPRS) . LeadbetThe same approach was taken with olanzapine in patients diagnosed with schizophrenia spectrum disorders. Czobor showed a significant correlation between weight gain and improvement in 38 patients  . GaryfalThe placebo effect found in some studies is remarkable regarding previous considerations. Ascher-Svanum described that patients under placebo treatment presented a significant association between greater weight gain and greater therapeutic improvement suggesting that weight gain may serve as an important indicator of improved clinical status among acutely ill patients with schizophrenia who do not receive antipsychotic medication , 24. AlsDespite the paradox that a secondary side effect of antipsychotics such as weight increase might underlie clinical improvement, these mechanisms are worth being discussed. Initially authors underlined this issue suggesting hospital diet, physical inactivity, and the psychological and physical shelter provided by hospitalization as the cause . Later sNevertheless, recent research suggests that the gut-brain axis (GBA), specifically its neurohormones, might behave as a potential pathway underlying both conditions and a key player in promoting weight gain and clinical improvement. The biological effect on the central nervous system of leptin, adiponectin, ghrelin, cholescytokinin (CCK), neuropeptide Y (NPY), glucagon like protein I (GLP-I), and insulin has accumulated further evidence . InitialGBA has been described as a pathophysiological mechanism implicated in antipsychotic-induced weight gain , 34, howConsidering specifically clozapine or olanzapine, the two pharmacological agents more related with weight gain, they seem to display a direct effect on the hormonal pathways of energy homeostasis (adiponectin and ghrelin) rather than on weight gain . Indeed Overall, previous literature suggests that GBA might be a necessary element in both conditions and so underlie the undeciphered association between weight gain and clinical improvement. However, this association lacks specific studies evaluating the issue and so further studies are required to prove its implication .The author confirms being the sole contributor of this work and has approved it for publication.CC-R has received honoraria/speaker fees/research and travel support/from Adamed, Alter, Angelini, Janssen-Cilag and Lundbeck."}
+{"text": "The world\u2019s population is aging at an alarming rate, and the incidence of osteoporosis is skyrocketing. One major consequence of the decline in skeletal health is increased fracture risk in patients 65 years and older. Osteoporosis-related fractures are predicted to result in more than $25 billion in annual health care costs by 2025. For elderly patients, who demonstrate poor capacity for regeneration and a limited physiologic reserve, surgery has increased complication rates and higher risk of failed healing outcome which is potentially devastating and can result in morbidity and mortality . CurrentStem cell therapy has emerged as a potent new strategy to repair and replace injured tissue. Readily available bone marrow aspirates and adipose tissue have been used as a source for the isolation, study, and transplantation of bone forming cell populations. Despite often being called \u2018stem cells\u2019 the isolation of these cells has been largely retrospective in nature and relying on inexact separation criteria such as plastic adherence which produces highly variable and heterogeneous cellular mixtures of multiple tissue types including bone, blood vessels, blood, fat, and fibroblast cells which makes treatment outcomes difficult to evaluate or predict . In contIn our recent study, we applied this methodology to isolate human fracture derived SSCs (hSSC) from a broad cohort of patients to test if changes in SSC function were associated with patient age . We prosWe analyzed genetic regulation of aged SSC traits such as fibrogenicity by performing gene expression analysis on purified hSSCs. We utilized microarray analysis to compare global gene expression in purified hSSCs from young versus aged patients along with corresponding functional evaluation in vitro. Consistent with age-related functional changes, we found downregulation of genes related to bone formation in aged hSSCs. Moreover, aged hSSCs upregulated genes that are related to fibroblast-like extracellular matrix secretion and cellular senescence. Curiously, we also observed that the histone deacetylase Sirtuin1 was significantly downregulated in geriatric hSSCs, which hints at epigenetic mechanisms underlying hSSC aging. We showed that specific blockade of Sirt1 in young hSSCs impairs osteogenic potential in vitro. Excitingly, Resveratrol and a Sirtuin1-specific small molecule restored mineralization capacity in impaired hSSCs thus providing a rationale for future translational strategies.In summary, our report of an association between patient age and hSSC function opens new possibilities to identify diagnostic, prognostic, and therapeutic strategies for poor fracture healing and potentially even the preservation of youthful bone health and prevention of skeletal injuries. Targeted molecular therapies that inhibit cellular senescence pathways may reverse age-related fracture phenotypes without broad off-target systemic side effects of current regimens. Continued investigation of larger groups of patients will reveal if simple in vitro assays of hSSCs, or antigens associated with aged hSSCs might serve as a prognostic tool to predict healing outcome of fractures. Furthermore, analyzing hSSCs isolated from nonunions will yield insights into the involvement of hSSCs in the etiology of failed fracture healing. A more comprehensive approach including the analysis of all cells present at the fracture site might also help to elucidate the role of the stem cell microenvironment or \u201cniche\u201d in facilitating proper bone regeneration ."}
+{"text": "Research shows regular physical activity (PA) is associated with better health and longevity; however, few studies consider contextual factors related to PA among African American (AA) older adults living in socioeconomically disadvantaged neighborhoods. The Physical and Cognitive Health Pilot Study (n=50) was used to examine associations between PA and level of neighborhood socioeconomic disadvantage among sedentary, AA older adults from four public housing communities in Durham, NC and Annapolis, MD . Participants were administered the Community Healthy Activities Model Program for Seniors (CHAMPS), a self-report questionnaire measuring weekly frequency and duration of PAs. Neighborhood socioeconomic disadvantage was defined by the Neighborhood Atlas Area Deprivation Index (ADI), which ranks neighborhoods according to Census block group/neighborhoods within each state and nationally. For the present sample, two of the Durham housing facilities were located in communities in the most disadvantaged block groups. Meanwhile, one Durham location and the Annapolis community were located in the least disadvantaged block groups. Bivariate correlations showed greater neighborhood socioeconomic disadvantage was associated with less participation in various PAs (p<.05). Next, ANOVA revealed the Annapolis group participated in statistically significantly more PAs, including visiting the senior center, church attendance, and light gardening (p<.05) compared to the most disadvantaged groups. The present findings suggest there are benefits to living in advantaged contexts despite lower-income status. These findings also suggest barriers within disadvantaged neighborhoods that limit access to recreational activities favorable to health status. Future research should address ways to overcome such barriers."}
+{"text": "Exposure to harmful substances and chemicals such as tobacco smoke, chemicals  and metal dust has been associated with increased risk of developing cancer, cardiovascular disease, and other diseases that contribute to shorter life expectancy. Associations with brain health in relation to these exposures are less well studied. We examined the relationship between brain health and prolonged exposure to different harmful substances in 498 male participants average age 68 (range 61 to 73) from the Vietnam Era Twin Study of Aging (VETSA). For self-reported tobacco smoke, herbicides/pesticides, and metal dust we created three groups reflecting recency of exposure (current/former/never). For Agent Orange we examined two exposure groups (ever/never). Brain health, defined as predicted brain age (PBAD), was evaluated by applying Brain-Age Regression Analysis and Computation Utility software (BARACUS) to magnetic resonance images collected at age 68. Tobacco smoking  was significantly correlated with PBAD and remained significant  in multivariate analyses adjusted for age, socioeconomic status (SES), age 20 general cognitive ability, and non-independence of twins within pairs. Never smokers had significantly younger brains than current or former smokers. PBAD did not differ for current versus former smokers. In other analyses, more advanced PBAD was associated with non-amnestic MCI. In this sample, tobacco smoking had the strongest relationship with overall brain health in late midlife compared with other types of environmental exposures, reinforcing its role in pathological aging and its importance as a public health priority."}
+{"text": "Recent findings suggest that childhood exposures can lead to chronic inflammation decades later, but the mechanisms underlying this relationship are relatively unknown. We investigate how childhood exposures influence adult chronic inflammation (measured by C-reactive protein) and examine five potential mediators comprising two midlife domains: socioeconomic status (SES) and health lifestyles. Using a sample of 8,891 adults aged 51 and older from the Health and Retirement Study (HRS), the analysis tests whether these life course mediators operate differently for Black, White, and Hispanic Americans. Among the six childhood domains examined, low SES and risky parental behaviors predict adult chronic inflammation, but adult health lifestyles mediate the effects of childhood SES and parental behavior. Adult SES also mediates the effect of childhood SES. Smoking and wealth exert stronger direct and indirect effects on adult inflammation for White Americans compared to Black Americans whereas BMI and exercise exert stronger direct and indirect effects for White Americans compared to Hispanic Americans. Although education mediated the effect of childhood SES on adult chronic inflammation, its effects did not vary by race. These results demonstrate that the physiological consequences of childhood exposures are carried into late-life via adult lifestyle factors and SES. In addition, the life course antecedents of chronic inflammation are distinct for Black, White, and Hispanic Americans. Future research investigating the early origins of adult health should consider not only multiple midlife mechanisms but also how resource mediation varies by race and ethnicity."}
+{"text": "The nonunion of distal phalangeal communized fracture is relatively rare in hand fractures. However, if it occurred, the surgical treatment is quite difficult because of small piece of fragmentations. We developed a new fixation method that involves the insertion of two wires and external wire compression fixation using a metal clamp. The aim of this technique was to increase the compression force between fragments and rigidity of conventional percutaneous Kirschner wire fixation. Here, we present a patient with the nonunion of distal phalangeal communized fracture who was satisfactorily treated with open reduction and percutaneous interfragmentary compression fixation with a linking external wire fixator (the Ichi-Fixator system). Such a treatment that enables compression fixation for communized distal phalangeal fracture of nonunion will clearly boost bone healing. Linked external wire-type compression fixator (the Ichi-Fixator system) enables enhanced security of fixation and facilitates the bone healing. Distal phalangeal fractures can be managed conservatively with good outcomes if diagnosed early. However, if the initial reduction is imperfect with total displacement between fragments such as communized fracture, then it may be necessary to use headless screw or Kirschner wire (K-wire) for fixation after closed or open reduction. Moreover, if conservative treatment failed, fracture site was occupied by soft tissue and fibrous connective tissues and finally become nonunion. Treatment of nonunion will need to firmly fix at fracture site after sufficient refreshment for increasing the bone union rate. The treatment options for nonunion of distal phalangeal fracture include conservative management with use of ultrasound , bone grrd distal phalangeal fracture was made based on radiographs and computed tomography scans. Anteroposterior, lateral, of the right middle finger showed dorsal displacement of the distal phalangeal fracture, with communized fracture  treatment of distal phalangeal nonunion. This system enables to increase the compression force at the nonunion site compared with conventional percutaneous K-wire fixation."}
+{"text": "Cardiac regenerative therapy is expected to be a promising therapeutic option for the treatment of severe cardiovascular diseases. Artificial tissues or organoids made from cardiovascular cell lineages differentiated from human induced pluripotent stem cells (iPSCs) are expected to regenerate the damaged heart. Even though immune rejection rarely occurs when iPSC-derived graft and the recipient have the same HLA type, in some cases, such as tissue transplantation onto hearts, the HLA matching would not be sufficient to fully control immune rejection. The present review introduces recent immunomodulatory strategies in iPSC-based transplantation therapies other than MHC matching including the induction of immune tolerance through iPSC-derived antigen-presenting cells, simultaneous transplantation of syngeneic mesenchymal stem cells, and using the universal donor cells such as gene editing-based HLA modulation in iPSCs to regulate T cell compatibility. In addition, we present future perspectives for proper adjustment of immunosuppression therapy after iPSC-derived tissue/organoid-based cardiac regenerative therapies by identifying biomarkers monitoring immune rejection. Cardiovascular diseases are leading causes of death and medical expenditure worldwide even recent progresses in medical treatments . TherapeAn immunological privilege of iPSCs in regenerative medicine is that autologous iPSCs which are considered to be immunologically identical with the host can be established from the host somatic cells and used for transplantation therapies . HoweverMacaca fascicularis). iPSCs from MHC-homozygous animals were differentiated into cardiomyocytes (iPSC-CMs) and subsequently transplanted to MHC-matched monkeys by direct intramyocardial injection. The grafted cardiomyocytes showed electrically coupling to the host heart and survived without immune rejection in monkeys treated with clinically relevant doses of immunosuppressants, whereas the transplantation of iPSC-CMs to MHC-mismatched monkeys even treated with immunosuppressants exhibited immune rejection of grafted cardiomyocytes with severe infiltration of T lymphocytes [Several allogeneic transplant models have been tested to validate whether the use of HLA-homozygous iPSCs can mitigate immune rejection. The experiments using cynomolgus monkeys demonstrated that immune rejection is rarely detected in allograft transplantation differentiated from major histocompatibility complex (MHC) type-matched iPSC. In transplantation experiments of retinal pigment epithelial (RPE) cells derived from monkey MHC-homozygous iPSCs, fair engraftment of RPE cells transplanted to MHC-matched animal models was confirmed without the use of immunosuppressants . Anotherphocytes .On the other hand, the benefits of MHC-matching seem to be alleviated in transplantation of iPSC-derived bioengineered heart tissues which is a promising strategy in cardiac regenerative medicine to promote therapeutic efficiency \u201323. KawaIn this context, several attempts have been made to overcome immune rejection through strategies other than HLA-matching so far. One of the promising strategies is the induction of immune tolerance in iPSC-based transplantation. There are two pathways in immune tolerance: central pathway by selective elimination of self-antigenic immune cells in the thymus and bone marrow and peripheral pathway. An important mechanism for this peripheral pathway of immune tolerance is the immunosuppression mediated by regulatory T cells (Tregs) Fig. a. Tregs Therapeutic approaches for the establishment of immune tolerance are reported so far Table . Otsuka + cytotoxic T cells against the transplants which accordingly achieved the induction of immune torelance [In addition to the induction of immune tolerance by antigen-presenting cells of identical MHC type, tolerance induction using syngeneic mesenchymal stem cells (MSCs) has also been reported Fig. b. Yoshidorelance .+ cytotoxic T cells. The modulated iPSCs were also protected from immune responses from natural killer cells because HLA-C, HLA-E, HLA-F, and HLA-G were preserved. Differentiated cells from the modulated iPSCs would be considered as an immunologically ideal cell source for transplantation therapies with enhanced immunocompatibility suppressing immune rejection after transplantation. It is also estimated that only 12 strains of iPSCs with HLA modulation theoretically cover more than 90% of the population worldwide which encourages the establishment of clinical-grade human iPSC bank covering almost all mankind [Another intriguing approach is HLA modulation in iPSCs to regulate T cell compatibility which depends on HLA types Fig. c. Xu et  mankind . Even thCRISPR-Cas9 and other gene-editing systems have recently been used to create donor cells that escape interference from the immune system . As previously described, it is not only possible to genetically modify the expression patterns of HLA class I and class II, but also to apply the immune escape mechanisms that occur in nature, such as cancer cells and placentas, to prevent the expansion of T cells and NK cells and promote Treg cell responses. Recently, some groups reported the creation of universal donor cells expressing immunomodulatory transgenes that have improved viability in allogeneic transplants . On the Although aforementioned approaches may possibly solve the problems in iPSC-based transplantation immunity, it remains to be further investigated whether these approaches will sufficiently work in iPSC-based cardiac regenerative therapies considering possible severe immunological circumstances of the heart. Another immunological consideration in iPSC-based cardiac regenerative therapies is the possible transition of transplantation subjects from \u201ccells\u201d to \u201ctissue/organoids\u201d . This paIt also means that immune regulation strategies which would even work in organ transplantation would be required in future iPSC-based cardiac regenerative therapies based on iPSC-derived tissue/organoid transplantation. Given the long history of research on immune rejection in organ transplants , it woulA strategy for the alleviation of immunosuppressant-related complications is to establish a system that can detect immune rejection in daily clinical practices to precisely control the immunosuppression level Fig. . To consIn the present review, we introduced present status and possible immunological problems in iPSC-based transplantation therapies including ongoing research attempts for immune regulation such as production of \u201ccells that control the immune system\u201d and \u201ccells that get past the immune system.\u201d Further investigations on immune regulation are required for standardization of iPSC-derived cardiac regenerative therapy based on distinctive features of iPSC-based tissue/organoid transplantation of the heart."}
+{"text": "With the emergence of affordable, clinical-orientated gait analysis techniques, clinicians may benefit from a general understanding of quantitative gait analysis procedures and their clinical applications. This article provides an overview of the potential of a quantitative gait analysis for decision support in three clinically relevant scenarios of early stage gait disorders: scenario I: gait ataxia and unsteadiness; scenario II: hypokinesia and slow gait; scenario III: apparently normal gait with a specific fall tendency in complex mobility situations. In a first part, we justify the advantages of standardized data collection and analysis procedures including data normalization and dimensionality reduction techniques that facilitate clinical interpretability of instrument-based gait profiles. We then outline typical patterns of pathological gait and their modulation during different walking conditions  and highlight key aspects that are particularly helpful to support and guide clinical decision-making. Gait instability is prevalent in patients with balance problems, vertigo, and dizziness, and is associated with adverse health outcomes. Depending on the underlying disease entity, the risk of falling and consequent injuries is markedly increased . Falls aIn this context, quantitative, instrument-based gait analysis is a promising tool to capture and accurately assess gait function. Clinical approaches with a justifiable trade-off between the clinical benefit and infrastructural resources have been recently established. Central for clinical implementation of these techniques is application of standardized protocols for the recording, the analysis, and the interpretation of clinical gait profiles. Clinical experience and evidence from several studies emphasize that clinical gait examination should in particular assess patients\u2019 gait function during different walking conditions , 8, 15. This article provides an overview of typical alterations of spatial and temporal gait features related to three basic syndromic scenarios: (1) gait ataxia and unsteadiness of gait with fall risk; (2) hypokinesia and slow gait; (3) fall tendency in complex situations . A special emphasis is placed on the relevance of gait findings for supporting clinical differential diagnosis.\u00ae, CIR System, Franklin, NJ, USA). A multi-condition assessment protocol with walking at self-chosen walking speed (PWS), at slow speed (SS), at maximally fast speed (MS), with reclination of the head (HR), with eyes closed (EC), with performance of a serial seven dual task (DTC), with performance of a verbal fluency dual task (DTS), and while carrying an empty tray (DTM) was performed as described elsewhere [The clinical gait profiles, which are discussed in the subsequent paragraphs were recorded on a pressure-sensitive gait carpet . The healthy control group was collected by direct recruitment and covers the age spectrum from 18 to 99\u00a0years. The resulting data are arranged in a color-coded data matrix that at first glance provides a rapid overview on the individual patient\u2019s gait performance under various challenging conditions in comparison to age- and gender-matched healthy reference performance  , gait paThe hallmarks of the gait impairments in patients with sensory deficits, cerebellar disorders, or functional ataxia comprise\u00a0distinct alterations in variability and support domains of walking. Accordingly, the spatial and temporal variability of stepping is typically increased in these cohorts \u2014a gait aWalking pace in patients with cerebellar and sensory ataxia  is typically preserved or only slightly decreased. This observation can be explained by the fact that sensory integration for gait stabilization is speed dependent and less essential during fast locomotion . AccordiThe characteristic modulation of ataxic gait impairments during multi-condition gait assessment can further support the differential diagnosis in the context of gait ataxia. Slow walking modes accentuate gait instability in patients with vestibular and cerebellar disorders, in particular in terms of a considerably increased gait variability . As mentHypokinetic gait patterns can be observed in patients with Parkinsonism, patients with subcortical vascular encephalopathy (SAE), and patients with normal pressure hydrocephalus (NPH). The general identification of hypokinetic gait is not challenging for experienced neurologists. Typical features of gait impairments related to this syndromic category include a reduction of stepping pace, a reduced stride length, and reduced foot clearance during swing phases. Variability measures can be increased, especially in the late course of disease or when freezing-of-gait episodes are present . PatientIn hypokinetic gait disorders, alterations of gait parameters typically persist during all examination conditions. Patients with SAE or NPH show a further decline of walking performance during cognitive dual task , 26, 30\u2014Besides the interaction of sensory feedback with supraspinal and spinal locomotor regions, human postural control also relies on cognitive and attentional capacities. Patients with mild cognitive dysfunctions frequently consult clinical centers for balance problems due to apparent locomotion impairments. They typically report a slowing of gait during real-world mobility and the occurrence of falls in complex mobility situations. The clinical examination of sensory functions and simple motor tasks does not show any significant findings in these patients. Instrument-based gait analysis shows normal gait performance during single-task walking, but typically yields strikingly abnormal findings during cognitive dual-task conditions. Accordingly, walking pace and stride length become considerably decreased  and walkDisturbances of mobility and gait are major symptoms of patients with balance disorders, dizziness, or vertigo. They are related to deteriorations of the functional status and to severe health outcomes, such as falls and fall-related morbidity . The cli"}
+{"text": "Mild traumatic brain injury (mTBI) represents more than 80% of total TBI cases and is a robust environmental risk factor for neurodegenerative diseases including Alzheimer\u2019s disease (AD). Besides direct neuronal injury and neuroinflammation, blood\u2013brain barrier (BBB) dysfunction is also a hallmark event of the pathological cascades after mTBI. However, the vascular link between BBB impairment caused by mTBI and subsequent neurodegeneration remains undefined. In this review, we focus on the preclinical evidence from murine models of BBB dysfunction in mTBI and provide potential mechanistic links between BBB disruption and the development of neurodegenerative diseases. Traumatic brain injury (TBI) is a leading cause of death and long-term disability around the world . Based oThe BBB is a highly selective membrane that mainly encompasses endothelial cells, sealed by tight junctions, and fortified by pericytes and astrocytic endfeet . This coMore importantly, clinical data indicated that BBB impairment can persist for many years and is highly associated with long-term neurological deficits in mTBI patients . TherefoMurine models have helped us tremendously to understand the pathogenic events after mTBI, including cerebral microvascular injury and BBB dysfunction. We searched over 6,000 publications related to mTBI on PubMed and found 232 studies potentially covering cerebrovascular impairment and BBB dysfunction . Among tin vivo imaging techniques including magnetic resonance imaging (MRI) and multi-photon imaging; and (iii) additional methods such as brain water content calculation for cerebral edema (wet/dry weight ratio). Analysis of the protein and mRNA expression of tight junction protein was also reported.We surveyed the BBB dysfunction and relevant pathologic changes found in mouse or rat models, covering the acute and subacute stages that evolve within the first 2 weeks after mTBI and the chronic stage that usually takes place 2 weeks after mTBI. The methods commonly used for BBB functional analysis in murine models are (i) histological assessment using plasma proteins such as immunoglobulin G (IgG) and/or exogenous tracers such as Evans blue dye, horseradish peroxidase (HRP), or fluoresce labeled albumin; (ii) via the in vivo two-photon imaging of intravenously injected rhodamine B. They showed that BBB disruption in wild-type C57BL/6 mice occurred at a very early stage of mTBI (between 5 and 60 min), which was even exacerbated in Slit2-Tg mice  when compared with controls. Similar situations were also reported from patients diagnosed with concussion in adolescent sports  and military service, which can be exacerbated by repetitive mild trauma injury . There aMechanistically, impairment of BBB can initiate a series of adverse events, including the leakage of serum-derived circulating agents into the brain parenchyma and improper activation of signaling pathways . As someMild traumatic brain injury is considered a long-term risk for neurobehavioral changes, cognitive decline, and neurodegenerative disease including AD . CognitiIn this review, we focused on BBB dysfunction after mTBI in murine models and found that BBB breakdown and microvascular impairment are important pathological mechanisms for cognitive impairment after mTBI. Restoring vascular functions might be beneficial for patients with mTBI and reduce the risk of developing cognitive impairments post-insult.ZZ and YW designed the review outline, wrote and reviewed the review, did the literature search, and data extraction and interpretation. HW, XG, and BP provided critical reviews, revised the manuscript, and provided relevant insights and edits. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "During recent years, Graduate Medical Education (GME) leaders in the United States of America have witnessed many substantive changes, including movement to a single accreditation system under the Accreditation Council for Graduate Medical Education. Both MD- and DO-trained residents and faculty must now meet an increasingly stringent set of accreditation standards outlined in Next Accreditation System standards. Specifically, updated scholarly activity standards emphasize a consistent volume and quantity of quality improvement/research projects and dissemination products. The GME literature to date has frequently provided general commentaries regarding individual project strategies or oriented to settings with greater project-related resources. There have also been few articles offering scholarly activity planning strategies for community-based GME officials striving to increase scholarly activity levels.The authors propose a customizable assessment-planning framework, largely derived from their combined decades of consultation experiences with hundreds of community-based resident and faculty projects. The authors will first describe the primary elements of their proposed scholarly activity planning approach for GME leaders so often subject to worsening resource constraints. They will describe six ongoing developmental strategies with several exemplars described. Such a framework will likely require ongoing reassessments and modification.The authors hope that this proposed planning framework will offer GME administrators, faculty and residents with a pragmatic set of strategies to develop scholarly activity projects and supports. Ideally, GME leaders can use this approach to inform their design of a sustainable system-customized infrastructure of scholarly activity supports. Next Accreditation System (NAS) standards.During recent years, the nation\u2019s graduate medical education (GME) leaders in the United States have witnessed substantive changes, including movement to a single accreditation system under the Accreditation Council for Graduate Medical Education (ACGME). Both MD and DO-trained resident and faculty physicians must now meet an increasingly stringent set of accreditation standards outlined in scholarly activity (SA) projects.SA to refer to both research and systems-oriented QIPS designs. Although both academic and community-based GME physicians contend with increasing resource constraints, a growing number of authors have contended that these types of challenges may be greater (or certainly different) in community-based GME settings.One particular standard that many GME authors have struggled to address relates to the enhanced requirements for Unfortunately, GME officials still lack a uniform definition of what comprises a minimal level of SA.More GME experts have concluded that community-based physicians may typically experience greater difficulty planning and conducting SA projects due to fewer available resources .Some GME authors have implemented SA resident teams, generally comprised of residents from multiple programs with complementary SA project interests.GME administrators have appointed later-year residents to chief research/QIPS resident positions to coordinate SA projects in some settings.Many authors have argued that any such mechanisms need to be modified due to system or program-specific influences, and that a standardized rollout approach is unlikely to work across diverse GME settings.Numerous experts have already shown that customized SA planning tools  can help facilitate SA project development.non-sequential and ongoing strategies to enable community-based GME leaders to facilitate increased SA levels. The authors will also describe several exemplary settings with ongoing SA infrastructure developments.The SCS authors have developed this comprehensive planning approach from their 2016-2017 experiences consulting on over 210  community-based SA projects. Resident and faculty project leaders have requested SA consultations from many of the 190+ SCS-affiliated residency programs based at 37 healthcare systems. This paper will: a) describe the key elements of the authors\u2019 suggested SA developmental planning approach, and b) discuss six The first goal of this proposed SA planning framework is to provide community-based GME leaders with a specific set of criteria to assess their current in-house project resources and complexities. The authors propose that this approach will prove especially important for GME officials striving to first develop or improve their SA project supports. The authors have repeatedly seen that many community-based leaders\u2019 success in increasing their SA levels have required a broader perspective than simply completing a series of individual projects and dissemination products. In this paper, they assert that the longer-term development of a sustainable SA infrastructure of project supports will prove integral for maintaining SA productivity in lesser-resourced GME settings.lessons learned from earlier SA projects in their healthcare system. GME experts have increasingly supported this broader type of ongoing self-learning model of SA development that entails ongoing reassessments and modification efforts.stop and start approach to SA will impede the development of a sustainable SA project support infrastructure so later project leaders may feel as if they are starting from scratch.The key elements of this planning framework  are largely derived from the authors\u2019 successful workshop, online module and individual consultation experiences with community-based GME leaders. They have concluded that many faculty and residents develop idealized  projects without capitalizing on on-site resources, and/or conduct projects without the cultural realities: Faculty and resident SA attitudes and beliefs, varied specialty perspectives, perceived availability of project supports and mentoring.Referring to the upper-left of Figure 1, an effective SA support infrastructure should be oriented toward first developing projects that specifically capitalize on available specific resources, such as institutional review board (IRB) guidance, health library and data-capable personnel,Referring to the middle of Figure 1, certainly each SA project will need to be developed within the context of each project team\u2019s competing role demands .Referring to the right of Figure 1, over time, both the volume and quality of SA projects and dissemination products  can be expected to increase and GME leaders may be able to realistically expect that improved SA levels will eventually impact patient care processes and outcomes.The following ongoing developmental strategies are encouraged for community-based GME leaders striving to attain an organized SA project support infrastructure:Periodically assess your project planners\u2019 SA learning needs and preferences by promoting available resources in an ongoing manner.It is also been shown to be necessary to periodically gauge the key learning needs of faculty and residents concerning SA projects.The SCS authors have generally concluded that many primary care physicians tend to prefer GME or QIPS project designs than surgical/procedure-oriented clinicians more oriented to complex research designs .Plan-Do-Check-Act planning sheets, pertinent articles, project conduction checklists, etc.) can prove key for first meeting the needs and preferences of lesser experienced project learners.GME leaders can certainly improve perceptions of available SA project resources by purposefully disseminating information concerning library, electronic health record and QIPS department materials and resources.non-human subjects, exempt, expedited, full review).GME officials should also periodically consider how their respective IRB have been distinguishing different types of SA projects by perceived level of research risks or types of suggested IRB applications  program.One exemplar Te4Q learner was an emergency medicine physician who completed the program in 2016 after testing a QIPS curriculum with his senior chief resident.He had subsequently delivered this curriculum to two cohorts of residents with little SCS support. His curriculum-related projects have subsequently contributed at least a dozen regional/national resident poster presentations and two SA publications to date.Systematically embed SA planning activities into your pre-existing GME processes/groups.The GME literature contains a growing number of examples of how SA experts have incorporated project planning/evaluation activities into their current GME program/staff meetings.regular part of doing business in the minds of more residents and faculty.This approach may help SA activities become perceived as a Conduct a postmortem evaluation of every SA project and attempt to derive pragmatic system-specific knowledge for future projects.football coach analogy to GME officials striving to strengthen their SA team over several years by evaluating SA project successes and lessons. This routine practice of informing project novices about earlier project successes/failures may be integral for them to develop system-compatible projects. It is also unrealistic to expect a subset of residency programs or personnel to conduct most ongoing SA projects.writing mentor mechanisms since the responsibility of project leaders to report their community-based results in the GME literature remains increasingly important.GME officials may underestimate the impetus for future projects potentially derived from completed SA projects.The growing complexities of publishing one\u2019s final project results in many GME journals due to increased article processing fees and greater publication competition certainly needs to be acknowledged.Consider how to attain maximal SA efficiencies in your GME environment.Desire To Learn online course management software. QIPS in Healthcare: Origins and Principles, b) Research and QIPS: Differences and Similarities, c) Feasible Project Design Strategies, d) Preparing your IRB Application, and e) Building a Program of Scholarly Activity as a GME Leader. Between January 2016 and March 2018, 87 users have been enrolled and made over 280 group/individual module hits.Since many community-based GME leaders continue to experience worsening resource constraints, it may only be realistic to offer workshop/training content through coordinated asynchronous and online mechanisms.A growing number of GME experts have also indicated that it may become increasingly impractical for individual settings or programs to achieve sustainable SA progress without some type of intuitional/consortium coordination.There will never likely be any standardized solutions for development of sustainable project support SA infrastructures across our nation\u2019s diverse GME settings.This paper presents a non-sequential developmental planning approach comprised of strategies for community-based GME officials striving to address emerging accreditation standards. As GME setting conditions change, leaders\u2019 implemented SA project supports may require ongoing trial and error adjustments.The authors declare no conflict of interest."}
+{"text": "Studies using data from longitudinal health survey of older adults usually assumed the data were missing completely at random (MCAR) or missing at random (MAR). Thus subsequent analyses used multiple imputation or likelihood-based method to handle missing data. However, little existing research actually examines whether the data met the MCAR/MAR assumptions before performing data analyses. This study first summarized the commonly used statistical methods to test missing mechanism and discussed their application conditions. Then using two-wave longitudinal data from the Health and Retirement Study , this study applied different approaches to test the missing mechanism of several demographic and health variables. These approaches included Little\u2019s test, logistic regression method, nonparametric tests, false discovery rate, and others. Results indicated the data did not meet the MCAR assumption even though they had a very low rate of missing values. Demographic variables provided good auxiliary information for health variables. Health measures  met the MAR assumptions. Older respondents could drop out and die in the longitudinal survey, but attrition did not significantly affect the MAR assumption. Our findings supported the MAR assumptions for the demographic and health variables in HRS, and therefore provided statistical justification to HRS researchers about using imputation or likelihood-based methods to deal with missing data. However, researchers are strongly encouraged to test the missing mechanism of the specific variables/data they choose when using a new dataset."}
+{"text": "Infections induce dramatic rearrangements in host macro- and micronutrient processes  and like\u201cAntagonistic\u201d interactions between a host and a microbe involve host defense mechanisms that maintain the host\u2019s fitness status while having a negative impact on microbial fitness. By contrast, \u201ccooperation\u201d between a host and a microbe involves host mechanisms that promote host fitness while having a neutral to positive influence on microbial fitness . These mThe role of iron regulatory pathways in immunity against pathogens has been well studied (reviewed in ). HoweveSiderophores are molecules that chelate external iron with high affinity and transport iron into microorganisms through dedicated transport systems . Thus, sCaenorhabditis elegans physiological development [Fig 1A). Microbe-derived Ent was found to bind to the alpha subunit of the host mitochondrial ATP synthase, thereby increasing mitochondrial iron levels and host development under both low and high iron conditions. We propose that this work exemplifies iron-mediating cooperative host\u2013microbe interactions because development of the host facilitates replication, nutrient acquisition, and transmission of enterobacteria. Given that other canonical virulence factors for acquiring host iron are present in commensal or beneficial microbes, future work should reassess the role of these systems with the perspective of cooperative host\u2013microbe interactions.In addition to the role of siderophores in antagonistic host\u2013microbe coevolution, siderophores are also critical for interspecies competition between members of the microbiota . These ielopment  Escherichia coli and Vibrio vulnificus, suggesting that transient hypoferremia is an effective metabolic defense to restrict certain extracellular pathogens [Salmonella enterica, Burkholderia pseudomallei, Chlamydia spp., and Legionella pneumophila [During acute infections, individuals experience inflammation-dependent hypoferremia . Hepcidiathogens , 21. Intumophila \u201324.Fig 1B). Regulation of iron levels was necessary for proper microbiome composition and mucosal repair because cDC-specific hepcidin-deficient mice were slower to recover following intestinal damage [In addition to hepatocytes, myeloid cell types are also a source of hepcidin production . In respl damage . TherefoDuring infections, microbial and host-derived toxic compounds can be generated that cause tissue damage. Detoxification mechanisms serve as antivirulence mechanisms to promote cooperative defenses by preventing damage to the host without affecting pathogen burdens . During Plasmodium or subjected to intestinal perforation leading to systemic bacterial infection [Plasmodium infection [Research into heme recycling and detoxification demonstrates the importance of these pathways for cooperative defenses . Heme denfection , 30. Thinfection , therebynfection . The HO-nfection . Given tFig 1C). Weis and colleagues established that the ferritin, the intracellular iron storage protein, regulates hepatic gluconeogenesis and is critical for host survival during polymicrobial sepsis [Recent dietary and metabolic studies in animals and humans link iron metabolism to glucose homeostasis at many levels (l sepsis . Knockoul sepsis . These sCitrobacter rodentium [C. rodentium infection caused increased tissue iron levels in the WAT and insulin resistance. The insulin resistance caused a reduction in the amount of glucose absorbed from the intestine into the bloodstream, increasing the amount of glucose available to the pathogen to metabolize, which suppressed the virulence program of C. rodentium [Sanchez and colleagues found that administration of dietary iron and transient insulin resistance promotes survival of mice given oral doses of the diarrheal pathogen odentium . Dietaryodentium . Consistodentium . The worodentium . TogetheAn entire field, called nutritional immunity, has focused on iron and other micronutrients in antagonism between host and invading microorganisms . Some in"}
+{"text": "Background: An estimated 25% of older adults with diabetes (DM) may have co-occurring Alzheimer\u2019s Disease and Related Dementias (ADRD), complicated by multiple treatment plans and providers. Assessing treatment burden has been limited to patients\u2019 perspectives; little is known about caregiver perceptions of treatment burden despite their important role in personal care and treatment adherence. The purpose of this qualitative study was to describe caregiver perceptions of treatment burden for older adults with DM-ADRD. Methods: This qualitative study was conducted in the formative phase of \u201cEnhanced Quality in Primary care for Elders with DM-ADRD (EQUIPED-ADRD) a pragmatic randomized controlled trial in a large, diverse healthcare system. A diverse sample of caregivers (n=15) of patients enrolled in the RCT participated in interviews about their caregiver role and perceptions of treatment burden of DM-ADRD clinical management. Qualitative data were analyzed using content analysis and themes about treatment burden were compared to domains on the Treatment Burden Questionnaire (TBQ). Results: Caregivers reported high levels of burden related to treatment plans for patients with DM-ADRD. Themes related to complexity and burden of medication management, monitoring , dietary and physical activity regimens, navigating healthcare providers and financial burden were reported. Caregivers also described high levels of emotional burden that was associated with patient\u2019s cognitive decline and family functioning stress. Conclusions: Interventions to reduce treatment burden for patients and caregiver should include activating social/nursing services, respite care and care coordination that may support caregivers especially as patient treatment increases in complexity over time."}
+{"text": "Chronic condition discordance  has adverse mental health implications but little is known about mechanisms accounting for these links. We considered how chronic condition discordance at the individual level and the couple level  was associated with perceived control among 2,676 couples from three waves  of the Health and Retirement Study. Dyadic growth curve models revealed that when wives had greater individual-level discordance, they reported lower initial health-related control and personal mastery and steeper reductions in personal mastery. When husbands had greater individual-level discordance, they reported lower initial health-related control and faster declines in health-related control and personal mastery, and wives had faster declines in personal mastery. When there was greater couple-level discordance, wives reported lower initial health-related control. Targeting increases in perceived control among older couples managing complex conditions may be beneficial. Part of a symposium sponsored by Dyadic Research on Health and Illness Across the Adult Lifespan Interest Group."}
+{"text": "A standardized approach to annotating computational biomedical models and their associated files can facilitate model reuse and reproducibility among research groups, enhance search and retrieval of models and data, and enable semantic comparisons between models. Motivated by these potential benefits and guided by consensus across the COmputational Modeling in BIology NEtwork (COMBINE) community, we have developed a specification for encoding annotations in Open Modeling and EXchange (OMEX)-formatted archives. Distributing modeling projects within these archives is a best practice established by COMBINE, and the OMEX metadata specification presented here provides a harmonized, community-driven approach for annotating a variety of standardized model and data representation formats within an archive. The specification primarily includes technical guidelines for encoding archive metadata, so that software tools can more easily utilize and exchange it, thereby spurring broad advancements in model reuse, discovery, and semantic analyses."}
+{"text": "Over one in four older adults (65 years and older) in the US reports falling annually with estimated medical costs of $50 billion. Evidence-based strategies exist that can reduce falls with one of the most promising being multifactorial, clinically-based initiatives such as the Centers for Disease Control and Prevention\u2019s STEADI  Initiative. STEADI includes three core components for health care providers: screen for risk factors, assess modifiable factors, and intervene to reduce falls with evidence-based strategies. Barriers to implementation include competing patient demands and limited time during patient visits. Efficient, effective implementation of clinical fall prevention is important to increase the use of multifactorial interventions. In addition, understanding older adult attitudes about the preventability of falls is needed to increase patient adherence to prescribed interventions. This symposium will cover:1. Background data on older adult falls over time,2. Description of an initial implementation of STEADI in an outpatient, Southeastern clinical practice including lessons learned,3. Attitudes of older adults toward fall prevention with implications for health promotion,4. Process evaluation of an ongoing implementation of STEADI in New York State with lessons learned. Understanding practical methods of implementing the three core components of fall prevention into practice supports wider dissemination of evidence-based fall prevention, while understanding patient attitudes toward falls informs the design of health promotion approaches to increase patient uptake of prescribed interventions. Wider dissemination and increased patient adherence in combination can reduce older adult falls and their associated medical costs."}
+{"text": "Late-life suicide is a complex public health issue, and older adults have a higher risk threshold than the national average . Most late-life suicide research focuses on elevated risk of older white males, and less is known about risk factors among Black older adults . Although fewer Black older adults die by suicide than White older adults, forms of suicidality do not differ between Black and White older adults . Suicide risk factors, such as psychological distress  and chronic pain , are prevalent among Black older adults. According to the Interpersonal Theory of Suicide , thwarted belongingness and perceived burdensomeness inform the development of suicidal desire. These findings have been corroborated among older adult samples, though lacking racial diversity. To better understand how the IPTS functions for older adults, and probe whether suicide risk pathways operate differently depending on race, we used data from over 400 homebound older adults residing in a U.S. metropolitan area to clarify if this suicide risk pathway is similar for Black and White older adults. Race moderated the relationship between physical and psychological pain and thwarted belongingness and perceived burdensomeness, with pain among Black older adults having a greater impact on their sense of belonging and burdensomeness. Findings illuminate the need for culturally nuanced understandings of suicidality in older adulthood. The presenters will demonstrate these results and discuss implications for cross-cultural suicide prevention frameworks."}
+{"text": "Assisted living (AL) communities are increasingly home to frail, chronically ill older adults who remain until death. State laws mandate that AL facilities request copies of any advance care planning documents residents have and make forms available upon request. Using secondary data from a larger study funded by the National Institute on Aging (R01AG047408) that focuses on end-of-life (EOL) care in AL, this project investigated barriers and facilitators to conducting advance care planning in AL. Data included in-depth interviews (of 86 minute average length) with 20 administrators from 7 facilities around the Atlanta metropolitan area and aggregate data collected from each facility regarding facility, staff, and resident characteristics. Findings from thematic analysis of qualitative data showed that key barriers to planning in AL included lack of staff training and reluctance among administrators and families to discuss advance care planning and EOL care. Important facilitators included periodic follow-up discussions of residents\u2019 wishes, often during care plan meetings, educating families about the importance of planning, and external support for staff training and family education from agencies such as hospice and home health. Three study facilities exceeded state requirements to request and store documents by systematically encouraging residents to complete documentation. These facilities, whose administrators discuss advance care planning and residents\u2019 EOL wishes with residents and families during regular care plan meetings, were more likely to have planning documents on file, demonstrating the potential of long-term care communities, such as AL, to successfully promote advance care planning among residents and their family members."}
+{"text": "Adenosarcoma is an extremely rare malignancy of the female genital tract composed of stromal sarcoma with a benign epithelial component. Current treatment recommendations include total hysterectomy with bilateral salpingo-oophorectomy, precluding future fertility. Although most frequently diagnosed in postmenopausal women, it is occasionally present in younger women of reproductive age with desire for future fertility. In 2015, we reported the case of a 23-year-old patient diagnosed with uterine adenosarcoma, who having strong desire of future fertility, opted for fertility sparing surgery. At a follow-up five years later, we can now report her case of spontaneous pregnancy and livebirth. A review of the literature concerning fertility outcomes in patients with uterine adenosarcoma undergoing fertility sparing therapeutic options is presented. Uterine adenosarcoma (UA) is a rare gynaecological malignancy composed of sarcomatous stroma and a benign epithelial component . While tLee et al.  describeA proposed fertility sparing treatment protocol includes fertility sparing surgery (FSS) consisting of a complete resection of the lesion followed by medical treatment with megestrol acetate 160 mg/day for at least 6 months. Once the desire for fertility is fulfilled, hysterectomy with bilateral salpingo-oophorectomy is recommended. A fertility sparing treatment protocol must be performed only in low-risk cases  and close longterm follow-up is needed . PatientIn 2015, a nulliparous 23-year-old woman referred to our institution was diagnosed with UA stage IA according to FIGO 2009 criteria. Due to her strong desire of future fertility, after extensive counselling she opted for FSS. Hysteroscopic complete resection of the tumour was performed, followed by oral megestrol acetate 160 mg/d as adjuvant therapy . This waMullerian adenosarcoma is a rare gynaecological cancer composed of a benign epithelial component with sarcomatous stroma . Total hAdenosarcoma is an extremely rare gynaecological malignancy with only a few cases reported in patients of reproductive age. The current recommended treatment is hysterectomy with bilateral salpingo- oophorectomy, however, fertility sparing treatment options are feasible in selected patients.In cases of focal tumours without sarcomatous overgrowth and without sign of infiltration or metastasis, a fertility sparing approach may be proposed to young women diagnosed with UA and who strongly wish to preserve their fertility. There is currently insufficient evidence regarding the ideal follow up protocol for patients diagnosed with UA who are managed with FSS."}
+{"text": "Diversity and inclusion are essential perspectives on university campuses. In recent years, there has been a nationwide decline in admissions resulting in changes to traditionally FTIAC driven college campuses. An environmental scan was completed at a mid-sized midwestern university to explore age-inclusive barriers and opportunities for change. In-depth interviews were held with 28 EMU stakeholders representing a wide variety of ages in leadership positions across campus. Students aged 40 and above (N=248) were also surveyed about their experiences on campus. Qualitative analysis revealed ageist attitudes about older adults and older students from at all levels of the university. Results demonstrate that initial responses to \u2018age-friendly\u2019 focused on stereotypes of older adults, but attitudes adjusted when reframed as older learners and further refined when older learners were defined as 40 and above. Additionally, there was a distinct disconnect between ageist perceptions towards older adults and older students which highlights the importance of intergenerational opportunities as an approach to combat ageist attitudes on campus. While these barriers require long-term and complicated solutions, participants described the many benefits that older learners bring to enrich the campus. Results of this research revealed opportunities to reframe aging in the context of diversity and inclusion efforts on campus. Adopting diversity efforts to include age can benefit universities in not only admissions, classroom experiences, and connections to surrounding communities."}
+{"text": "Tachycineta bicolor). We address two questions: (1) do the cloacal bacterial communities differ between female and male tree swallows within a population? and (2) do pair-bonded social partners exhibit more similar cloacal bacterial communities than expected by chance? To answer these questions, we sampled the cloacal microbiome of adults during the breeding season and then used culture-independent, 16S rRNA gene amplicon sequencing to assess bacterial communities. Overall, we found that the cloacal bacterial communities of females and males were similar, and that the communities of pair-bonded social partners were not more similar than expected by chance. Our results suggest that social monogamy does not correlate with an increased similarity in cloacal bacterial community diversity or structure. As social partners were not assessed at the same time, it is possible that breeding stage differences masked social effects on bacterial community diversity and structure. Further, given that tree swallows exhibit high variation in rates of extra-pair activity, considering extra-pair activity when assessing cloacal microbial communities may be important for understanding how these bacterial communities are shaped. Further insight into how bacterial communities are shaped will ultimately shed light on potential tradeoffs associated with alternative behavioral strategies and socially-transmitted microbes.Host-associated microbial communities can influence the overall health of their animal hosts, and many factors, including behavior and physiology, can impact the formation of these complex communities. Bacteria within these communities can be transmitted socially between individuals via indirect  or direct  pathways. Limited research has been done to investigate how social interactions that occur in the context of mating shape host-associated microbial communities. To gain a better understanding of these interactions and, more specifically, to assess how mating behavior shapes an animal\u2019s microbiome, we studied the cloacal bacterial communities of a socially monogamous yet genetically polygynous songbird, the North American tree swallow ( Host-associated microbial communities can contribute to the overall health of their animal hosts \u20134, and mTachycineta bicolor) and house sparrows (Passer domesticus). More recent work using culture-independent methods has revealed that pair-bonded social partners experimentally blocked from making cloacal contact have significantly less similar cloacal bacterial communities compared to control pairs in black-legged kittiwakes (Rissa tridactyla) )munities . Given tStaphylococcus spp., Campylobacter spp., Salmonella spp., and Shigella spp. In our study, we used culture-independent, next-generation sequencing. We did not find that any of the cloacal bacteria they cultured were members of the core bacterial communities of birds within our study population. While Staphylococcus spp. and Lactobacilli were detected, their relative abundances were <0.001%. This suggests that culturing of cloacal bacteria may not consistently result in isolation of the most dominant bacteria in the system. It is also possible that the bacteria cultured by Lombardo et al. [Previous work examining the similarity of the cloacal bacteria of social partners in tree swallows used culture-dependent methods . The isoo et al.  are rareIn conclusion, our results suggest that the cloacal bacterial communities of female and male tree swallows are similar within our study population and that pair-bonded social partners do not share more similar cloacal bacterial communities than expected by chance. Given that tree swallows exhibit high variation in rates of extra-pair activity, we argue that considering rates of extra-pair activity or the number of sexual partners per bird when assessing cloacal bacterial communities may be important for understanding how cloacal bacterial communities are structured. Also, since cloacal bacterial communities comprise bacteria derived from both the reproductive and digestive tract, diet should also be considered when assessing cloacal bacterial communities. Lastly, we suggest that pair-bonded social partners should be sampled simultaneously to control for any temporal shifts in individual behavior and physiology that may influence shifts in cloacal bacterial community structure across breeding stages."}
+{"text": "The Tailored Activity Program (TAP) is a proven program delivered primarily by occupational therapists addressing dementia-related clinical symptoms including caregiver well-being. Although used in 9 countries including the United States, scaling and widespread dissemination is challenging. We discuss key revisions to TAP to facilitate dissemination including matching assessments to those used in different practice settings, translation of materials into different languages, providing worksheets to help trainees adapt TAP to local contexts and a training/certification online experience using story board, an interactive media integrated onto the Blackboard learn management system, to provide on-demand training modules. The learning platform allows learners to engage with others, preview modules and share experiences. Revisions enable greater flexibility for program adaptation yet adherence to its core principles. With over 150 trainees, we use REAIM to evaluate effectiveness of modifications and to understand implications for its reach. Part of a symposium sponsored by the Behavioral Interventions for Older Adults Interest Group."}
+{"text": "Hematopoiesis and bone interact in various developmental and pathological processes. Neurogenic heterotopic ossifications (NHO) are the formation of ectopic hematopoietic bones in peri-articular muscles that develop following severe lesions of the central nervous system such as traumatic cerebral or spinal injuries or strokes. This review will focus on the hematopoietic facet of NHO. The characterization of NHO demonstrates the presence of hematopoietic marrow in which quiescent hematopoietic stem cells (HSC) are maintained by a functional stromal microenvironment, thus documenting that NHOs are neo-formed ectopic HSC niches. Similarly to adult bone marrow, the NHO permissive environment supports HSC maintenance, proliferation and differentiation through bidirectional signaling with mesenchymal stromal cells and endothelial cells, involving cell adhesion molecules, membrane-bound growth factors, hormones, and secreted matrix proteins. The participation of the nervous system, macrophages and inflammatory cytokines including oncostatin M and transforming growth factor (TGF)-\u03b2 in this process, reveals how neural circuitry fine-tunes the inflammatory response to generate hematopoietic bones in injured muscles. The localization of NHOs in the peri-articular muscle environment also suggests a role of muscle mesenchymal cells and bone metabolism in development of hematopoiesis in adults. Little is known about the establishment of bone marrow niches and the regulation of HSC cycling during fetal development. Similarities between NHO and development of fetal bones make NHOs an interesting model to study the establishment of bone marrow hematopoiesis during development. Conversely, identification of stage-specific factors that specify HSC developmental state during fetal bone development will give more mechanistic insights into NHO. Heterotopic ossification (HO) is an abnormal development of bone tissue within soft tissue. HO can be hereditary such as Fibrodysplasia Ossificans Progressiva (FOP) or acquired following traumatic injuries and burns . Among aACVR1 gene encoding a type I BMP receptor  . The patIt is currently admitted that NHOs are the result of an endochondral ossification process although intramembranous ossification has also been suggested . Foley eThe development of heterotopic bones in muscles after severe CNS trauma raises interesting stem cell biology questions particularly regarding the cells-of-origin of NHO. Adult skeletal muscles contain two major types of progenitor cells participating in muscle regeneration. Myogenic satellite cells (SCs) are CD56 expressing stem cells located between the basal lamina and myofiber plasma membrane. To regenerate damaged myofibers, activated SCs proliferate, differentiate into myoblasts and fuse to form multinucleated myofibers with the support of macrophages, endothelial cells (ECs), fibroblasts and pericytes  or FAPs (via a Prrx1 gene enhancer transgene) are specifically labeled, we find that following SCI, NHO are derived from Prrx1 expressing FAPs, not from Pax7 expressing SCs  and central (SCI) neurologic lesions have an effect on FAPs, inducing STAT3 activation, high IL-6 secretory activity and abnormal proliferation . FurtherThe presence of ectopic hematopoietic bones developing in muscles following CNS injuries is puzzling for the hematologist since, in adults, hematopoiesis is physiologically restricted to the BM of skeletal bones.During fetal development, blood formation occurs in discrete anatomical extraembryonic and intraembryonic niches, generating different hematopoietic cell (HC) types . First HSchofield first used the term \u201cniche\u201d to describe a putative HSC-specific environment in the BM that \u201cpreserved the reconstituting ability of stem cells\u201d . SuccessWithin these niches, HSCs are maintained quiescent by a complex molecular interplay between cells from mesenchymal origin, ECs, neuronal cells and HSC progenies, such as megakaryocytes and macrophages. Diffusible factors including inflammatory cytokines and extra-cellular matrix components perfect this molecular network, subtly controlling the fate of HSCs .Apart from stromal cells, macrophages are essential to HSC regulation within niches. They are the most abundant HCs in the dorsal aorta when the number of intra-aortic hematopoietic cluster peaks, and are suggested to promote definitive HSC formation from the dorsal aorta hemogenic endothelium through pro-inflammatory signaling cascades . Among tIn the context of NHO, it is noteworthy to integrate the role of the nervous system as an important regulator of bone remodeling and hematopoiesis homeostasis. Since the discovery of skeleton innervation by Besides its role in energy homeostasis, leptin plays a major role in neuroendocrine regulation and bone metabolism. The expression of leptin receptor on adult MSCs, osteoblasts and chondrocytes, suggests direct effects on bone growth and metabolism. Leptin can also indirectly modulate bone formation through effectors downstream of the hypothalamus such as estrogen, cortisol, IGF-1 and parathyroid hormone, and through activation of local adrenergic signaling at the osteoblast level via \u03b22 adrenergic receptors (AR) . SensoryAs reported above, HSCs are mainly located in perivascular areas of the adult BM, comprising both sinusoidal and arteriolar blood vessels. The arteriolar structures are highly innervated by SNS fibers. The neuroreticular complex formed by SNS nerves and perivascular MSCs has been reported to be a central regulator of HSC quiescence within BM niches  mice that lack osteoblasts and osteolineage cells, the vasculature within the nascent bones and bone marrow can sustain multilineage proliferative progenitors but not long-term HSCs. As a result, wild-type HSC transplanted in Osx embryos engraft the liver but not the nascent BM. Therefore, interactions with osteoblasts within fetal bone regulate HSC quiescence and homing ability (Cxcl12 or Kitl gene from Osx+ osteoprogenitors has more effect on hematopoietic progenitors than on proper HSCs (Lepr+ MSCs (that form osteoprogenitors) for HSCs to be maintained (In Osterix-null (Osx ability . In the per HSCs . In contintained . These rUnderstanding the development of hematopoiesis in an adult osteogenic muscle environment as observed in NHO could help gain further insights on the role of bone forming cells in this process. Identification of stage-specific factors that orientate HSC developmental state during fetal bone development must be harnessed to gain more mechanistic insights into NHO development. Similarly, understanding the cellular origin of NHO, the role of inflammation and muscle environment might contribute to a better understanding of the impact of specific niche components on fetal BM HSC properties.In the recent few years, knowledge about NHO pathogenesis has been considerably improved as accredited by the rapidly increasing number of publications in the field. These progresses were mainly due to the development of more suitable animal models and to the availability of patient samples thanks to well organized cohorts. The current review focusing on the hematopoietic features of NHO ossifications, attempts to recapitulate how a favorable environment for the development of bone with HSC niches can develop in adult muscles following central neurological lesions. It emphasizes the role of a persistent inflamed muscle environment driving FAPs to an osteogenic fate initiating the development of ossification followed by the establishment of a mature hematopoietic bone tissue.However, there are still numerous questions in respect to the molecular mechanisms underlying this complex and multifactorial pathological process. Among those, the potential differences between normal endochondral ossification and neurogenic HO in terms of signaling events, cell type involvement and environment remains unanswered. Likewise, how an inflamed adult muscle environment becomes pro-osteogenic and thereafter hematopoietic, and what is the influence of altered nervous and neuroendocrine systems as well as hypoxia in this process? Does the neoformation of hematopoietic bones in muscles mimic what happens during development and can we learn from NHO for a better identification of stage-specific factors that specify HSC developmental state during fetal bone development? Is the impaired mobility of patients a trigger in the development of NHO and does an early and adequate mobilization of patients can avoid or at least reduce its evolution?Gathering surgeons, clinicians, specialists in physical medicine/rehabilitation and researchers within a European/International consortium would be a provocative initiative for developing translational collaborative projects to better understand NHO pathogenesis and, armed with this knowledge, enable the identification of new targets to treat and if possible prevent NHO development. Moreover, such knowledge may also provide new insights for cell therapy needs and for improving treatment of blood and bone disorders.DG, FT, EO, KA, JG, H-WT, MS, J-PL, M-CL, and SB wrote the manuscript. DG, EO, M-CL, and SB prepared the figures. All authors revised the manuscript and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Family caregivers often manage complex medical/nursing tasks (MNTs) for older adults returning home after a hospitalization. The purpose of this qualitative study was to describe caregivers\u2019 experiences leveraging diverse resources to manage MNTs for older adults receiving post-acute home health care services (HHC). In-depth telephone interviews were conducted with 20 caregivers of older adults who received HHC following hospitalization. Interviews were digitally audio-recorded, transcribed, and analyzed using directed content analysis. The Theory of Dependent-Care informed the analytical framework. We organized codes using three theoretical constructs related to managing older adults\u2019 MNT care needs (\u201ctasks related to the other\u201d), accessing existing social/environmental resources (\u201ctasks related to the situation of care\u201d), and working with the healthcare system (\u201ctasks related to the system of care\u201d). Caregivers\u2019 descriptions of MNTs included the complexity and socioemotional impact of assisting in these tasks . When needed, caregivers\u2019 accessed social  and environmental  resources to help address the older adults\u2019 care needs. Caregivers also identified challenges and strategies for navigating and coordinating care and services within HHC and the larger healthcare system. Caregivers assisting with complex MNTs in the post-acute HHC setting need additional training and support. HHC providers can actively engage caregivers by tailoring training and support strategies, assessing social and environmental contexts and resources, and facilitating caregivers\u2019 navigation of the healthcare system. Future research could elucidate social and environmental factors associated with successful collaborative relationships among providers, older adults and their caregivers in the post-acute HHC setting."}
+{"text": "Research demonstrates reciprocal relationships between personality and depression as well as the important role interpersonal conflicts play, but rarely explores these risk factors in older adults. This study aimed to examine relationships of personality traits, processes, and the impact of emotional involvement and distress during an interpersonal conflict on depression in older adults. The study also investigated whether emotional involvement or interpersonal distress moderate the relationship between personality pathology and depression. Depressed middle and older adult inpatients  completed self-reports and interview-based assessments regarding personality traits , interpersonal problems (IIP-25), and depression (GDS). Narrative responses regarding an interpersonal conflict were obtained and rated for contamination themes as well as emotional involvement and distress. Overall, findings indicated that living with others predicted higher depression (p= .046) and was related to higher neuroticism and interpersonal problems. Personality traits (Neuroticism)  and processes  , as well as higher levels of emotional distress  and involvement  in an interpersonal conflict were also tied to depression in bivariate but not multivariate analyses. The moderating effects of emotional involvement or distress on the relationship between personality and depression were not supported. Depressed older inpatients who live with others appear at higher risk of depression. Personality traits and processes may be more distal risk factors for depression. Findings are discussed in relation to stress generation as well as clinical implications targeting emotional regulation."}
+{"text": "Dear Editor th, they confirmed that they had identified a new coronavirus, which is a family of microRNA respiratory viruses including the common cold, and viruses such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). This new virus was temporarily named \u201c2019-nCoV\u201d. Wuhan city is a major international transport hub. This report to World Health Organization (WHO), raised global public health concern because this is the third coronavirus \u2013associated acute respiratory illness outbreak. On 31 December 2019, Chinese authorities reported the increase in incidence of severe pneumonia in Wuhan city, Hubei province of China. One week later, on January 7Currently, up to the date of submitting this letter, 4593 cases of 2019-nCoV infections have been confirmed globally, both in China  and outside of China (56 confirmed in 14 countries.). WHO risk assessment of 2019-nCoV infection is Very High in China and High in other countries  or severe pneumonia, Acute Respiratory Distress Syndrome (ARDS), sepsis and septic shock. Patients with pre-existing medical comorbidities develop a more severe disease and have higher mortality rates compared to patients who do not have any comorbidity.Clinical care of patients with suspected 2019-nCoV should focus on early recognition, immediate isolation (separation), implementation of appropriate infection prevention and control (IPC) measures and provision optimized supportive care. At the triage of an Emergency room, early recognition of suspected patients allows for timely initiation of IPC. 2019-nCoV should be considered as a possible etiology of influenza like illness (ILI) under certain situations according to case definitions of WHO  or non-invasive ventilation (NIV) should be used in selected patients with hypoxemic respiratory failure. Hypoxemic respiratory failure due to ARDS among these patients commonly results from intrapulmonary ventilation-perfusion mismatch or shunt and usually requires mechanical ventilation. Thus, rapid sequence intubation should be performed using airborne precautions. Implementation of mechanical ventilation using lower tidal volumes (4-8 ml/kg predicted body weight) and higher positive end-expiratory pressure (PEEP) is suggested. Patients with SARI should be treated cautiously with intravenous fluids when there is no evidence of shock, because aggressive fluid resuscitation may worsen oxygenation. For resuscitation of septic shock in adults, at least 30 ml/kg of isotonic crystalloid should be infused in the first 3 hours of shock identification and in children rapid bolus of 20 ml/kg as loading dose and up to 40-60 ml/kg of isotonic crystalloid infusion in the first hour of shock identification is needed. Vasopressor should be administered when shock persists during or after fluid resuscitation. If signs of poor perfusion persist despite reaching mean arterial pressure (MAP) target (i.e. >65 mmHg) with fluids and vasopressor, consider administering an inotrope such as dobutamine. Empiric antimicrobials should be initiated within one hour of identification of sepsis to treat all likely pathogens causing SARI. Empiric antibiotic treatment should be based on the clinical diagnosis of severe pneumonia or sepsis, local epidemiology and susceptibility data as well as treatment guidelines. If influenza is also a concern and there is a local circulation of influenza virus, a neuraminidase inhibitor should be adjoined to empiric therapy. Empiric antibiotic therapy should be de-escalated on the basis of microbiology results and clinical judgment. Systemic corticosteroids should not be routinely adding to therapy unless indicated for another reason. Collection of clinical specimens for laboratory diagnosis is suggested in early outbreak period and after that it is only advised for investigational purposes. If laboratory diagnosis is considered, serology is recommended only when RT-PCR is not available. Otherwise, HCW should collect specimens from both the upper respiratory tract and lower respiratory tract for testing 2019-nCoV via RT-PCR  should be developed and implemented in the emergency departments, as the frontline of treating human infections of 2019-nCov in the hospitals."}
+{"text": "Increased systolic blood pressure (SBP), pulse pressure and carotid-femoral pulse wave velocity (cfPWV) are strong predictors of cardiovascular events. The aorta and carotids are both elastic arteries susceptible to arterial stiffening and its deleterious complications. The relative importance of ascending aortic and carotid stiffness on central arterial stiffness remains unclear.Our aim was to study the relationship of local arterial stiffness in the carotid and ascending aorta to central arterial stiffness assessed by cfPWV and peripheral BP.We studied 22 healthy subjects . Central arterial stiffness was determined using carotid and femoral tonometry and transit surface distances (cfPWV). Distensibility of the ascending aorta was calculated as the ratio of its transverse area change on MRI to the central pulse pressure from radial tonometry arterial waveforms using a transfer function. Carotid distensibility was calculated as the ratio of transverse area change by sonography to carotid pulse pressure by tonometry. Local stiffness indexes of carotid and aorta were calculated from distensibility by the reverse Moens-Korteweg equation. Peripheral SBP and pulse pressure were averages of 6 brachial measurements. Linear regression was used to study correlations between aortic and carotid stiffness and cfPWVAortic stiffness has a significantly stronger correlation than carotid stiffness with: age , peripheral SBP , pulse pressure , and cfPWV . In multivariate analysis with simultaneous adjustment for age, body mass index, SBP, pulse pressure, aortic stiffness and carotid stiffness, aortic stiffness is the strongest independent determinant of cfPWV (p = 0.013), SBP (p = 0.005) and pulse pressure (p = 0.01).Stiffness of the ascending aorta is a stronger predictor of cfPWV and peripheral SBP and pulse pressure than carotid stiffness among healthy individuals. This is consistent with heterogenous age-related stiffening of large arteries."}
+{"text": "This study reviews the existing literature on psychiatric interventions for individuals affected by the COVID-19 epidemic. My article cumulates previous research on how extreme stressors associated with COVID-19 may aggravate or cause psychiatric problems. The unpredictability of the COVID-19 epidemic progression may result in significant psychological pressure on vulnerable populations. Persons with psychiatric illnesses may experience worsening symptoms or may develop an altered mental state related to an increased suicide risk. The inspected findings prove that psychological intervention measures for patients affected by the epidemic should be designed and personalized adequately. Preventive measures seek to decrease infection rates and cut down the risk of the public healthcare system to eventually be overburdened. Throughout the COVID-19 crisis, people with psychiatric illnesses may confront a decrease in mental health services. As limitations in the current review, by focusing only on articles published in journals indexed in Web of Science, Scopus, and ProQuest, I inevitably disregarded other valuable sources. Subsequent research directions should clarify the effectiveness of online mental health services in providing remote psychiatric interventions to individuals affected by the COVID-19 epidemic. COVID-19 has placed a significant strain on health systems on a large scale . There mAdequate conformity to spatial distancing in addition to home confinement, self-isolation, and quarantine may have the repercussion of social disconnection with adverse effects for psychological wellbeing . The manOn The COVID-19 epidemic has generated extreme stressors that may aggravate or cause psychiatric problems, affecting the brain or generating immune reactions. Emotional responses comprise intense psychosocial distress and insecurity. Such patients need timely, precise information concerning approaches for diminishing risk.COVID-19 pandemic-related, compulsory self-isolation, home confinement, and quarantine are related to poor psychological and physical health . Taking On Infectious disease outbreaks such as COVID-19 bring about mental health conditions as individuals\u2019 emotional reactions tend to comprise extreme fear and confusion, while their anxious responses may lead to socially disruptive behaviors. Symptoms such as anxiety, nervousness, and insomnia may occur in COVID-19 infected patients with psychiatric disorders.The level of risk of COVID-19 spread among persons having a severe mental illness may be more significant than that in the general population, as a consequence of constant unhealthy behaviors and standards of living . IndividAs On People with mental health disorders may be more considerably affected by the emotional reactions generated by the COVID-19 epidemic. Affected individuals are exposed to mental health disorders and suicidal ideation and behavior, resulting in pervasive emotional distress and heightened risk for psychiatric disorders. Social relationships are pivotal in suicide prevention.The swift spread of COVID-19 and important death rate may aggravate the risk of mental health issues and intensify current psychiatric symptoms, damaging their proper functioning and cognition to a greater extent . The conThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Long-term care residents with and without cognitive impairment may experience undertreatment of persistent pain . Certified nursing assistants (CNAs) are important sources of information about resident pain as they provide the majority of residents\u2019 hands-on care. Therefore, assessing the accuracy of CNAs\u2019 pain assessments and potential influencing factors may provide insight regarding the undertreatment of pain. Informed by prior research, this study examined resident pain catastrophizing and cognitive status as predictors of CNAs\u2019 pain assessment accuracy. CNA empathy was examined as a moderating variable. Analyses confirmed a relationship between pain catastrophizing and CNA pain rating accuracy , reflecting lower accuracy of ratings for residents higher in catastrophizing. Hypotheses predicting a relationship between resident cognitive status and CNA pain rating accuracy and moderating effects of empathy were disconfirmed. Challenges of conducting research in long-term care are discussed."}
+{"text": "Objective: Using the stress-coping theory, the aims of the present study were to test what levels of caregiving intensity  posed the most negative influence on caregiver burden as well as how social support moderated such associations among dementia caregivers. Methods: Data from the baseline assessment of the Resources for Enhancing Alzheimer\u2019s Caregiver Health (REACH II) (N = 637) were used. Caregiver burden , caregiving intensity (caregiving hours), and social support  were the main measurements. Separate multivariate regression models were conducted with Stata 16. Results: The results showed that the relationships between caregiving hours and caregiver burden were nonlinear after controlling all of the socio-demographic variables. Further analyses showed that when caregiving hours reached 13.50 hours per day, the levels of burden were the highest. In addition, received social support, satisfaction with social support, and social network significantly moderated the relationship between caregiving hours and caregiver burden among dementia caregivers when they were examined separately. However, only social network played a significant moderator role when examining the four social support indicators simultaneously. Discussion and conclusion: These findings suggest the need for programs and practices on educating caregivers regarding how to identify, approach, and gain social support/s, especially in how to broaden the caregivers\u2019 social network while caring for a family member with dementia."}
+{"text": "Carefully maintained and precisely inherited chromosomal DNA provides long-term genetic stability, but eukaryotic cells facing environmental challenges can benefit from the accumulation of less stable DNA species. Circular DNA molecules lacking centromeres segregate randomly or asymmetrically during cell division, following non-Mendelian inheritance patterns that result in high copy number instability and massive heterogeneity across populations. Such circular DNA species, variously known as extrachromosomal circular DNA (eccDNA), microDNA, double minutes or extrachromosomal DNA (ecDNA), are becoming recognised as a major source of the genetic variation exploited by cancer cells and pathogenic eukaryotes to acquire drug resistance. In budding yeast, circular DNA molecules derived from the ribosomal DNA (ERCs) have been long known to accumulate with age, but it is now clear that aged yeast also accumulate other high-copy protein-coding circular DNAs acquired through both random and environmentally-stimulated recombination processes. Here, we argue that accumulation of circular DNA provides a reservoir of heterogeneous genetic material that can allow rapid adaptation of aged cells to environmental insults, but avoids the negative fitness impacts on normal growth of unsolicited gene amplification in the young population. E. coli and asexual yeasts reveal that strains with high mutation rates outperform those with low mutation rates, showing that mutation provides an adaptive advantage  to several megabases   are highly focused in aged cells and are suggested to drive premature ageing and shortened lifespan , and is instead generated from chromosomal DNA at such a high rate that simple asymmetric retention of the newly generated copies in the mother cell is sufficient for CUP1 accumulation , the most transcribed protein-coding gene in muscle tissue, is also the largest producer of circular DNA per gene (Moller et al. Excitingly we have observed that the rate of copy number variation events including circular DNA formation is not completely random, which may improve this cost\u2013benefit balance for aged cells (Hull et al. By itself, an adaptive phenotype in an individual aged cell is of little use if the causal circular DNA is selfishly retained in the mother cell, as would be the case if asymmetric segregation is maintained, and we must consider how circular DNA accumulation is translated into a heritable advantage. First, once circular DNA has accumulated, segregation can be relaxed under stress allowing circles with replication origins to propagate at high copy number in the population Fig.\u00a0, step 5aThe idea that a sub-population trades short-term growth for adaptive capacity is formalised in bet-hedging (concisely reviewed in (Levy et al."}
+{"text": "The primary impact of ventilation and ventilatory efforts on left ventricular (LV) function in left ventricular dysfunction relate to how changes in intrathoracic pressure (ITP) alter the pressure gradients for venous return into the chest and LV ejection out of the chest. Spontaneous inspiratory efforts by decreasing ITP increase both of these pressure gradients increasing venous blood flow and impeding LV ejection resulting in increased intrathoracic blood volume. In severe heart failure states when lung compliance is reduced, or airway resistance is increased these negative swings in ITP can be exacerbated leading to LV failure and acute cardiogenic pulmonary edema. By merely reversing these negative swings in ITP by the use of non-invasive continuous positive airway pressure (CPAP), these profoundly detrimental forces can be immediately reversed, and cardiovascular stability can be restored in moments. This forms the clinical rationale for the immediate use of CPAP for the treatment of acute cardiogenic pulmonary edema. Increasing ITP during positive pressure ventilation decreases the pressure gradients for venous return and LV ejection decreasing intrathoracic blood volume. In a hypovolemic patient even with LV dysfunction this can result in hypotension due to inadequate LV preload. Minor increases in ITP as occur using pressure-limited positive-pressure ventilation primarily reverse the increased LV afterload of negative swings in ITP and if fluid overload was already present, minimally alter cardiac output. The effect of changes in lung volume on LV function are related primarily to its effects on right ventricular (RV) function through changes in pulmonary vascular resistance and overdistention (hyperinflation). In acute lung injury with alveolar collapse, positive pressure ventilation may reduce pulmonary vascular resistance if alveolar recruitment predominates. Hyperinflation, however, impedes diastolic filling while simultaneously increasing pulmonary vascular resistance. Thus, increasing lung volume can reduce RV afterload by reversing hypoxic pulmonary vasoconstriction or increase afterload by overdistention. Hyperinflation can also impede RV filling. All of these processes can be readily identified at the bedside using echocardiography. Understanding the hemodynamic coupling of the heart and lungs plays a significant role in managing patients in the critical care setting. The basic heart-lung physiology has been discovered earlier in the collection of papers. Understanding diastolic and systolic left heart failure is of upmost importance when treating patients with a variety of other common medical conditions such as sleep apnea, ARDS and COPD as these conditions are deeply intertwined. These interactions are magnified in the setting of decreased left ventricular (LV) function. Here we seek to explain how clinical presentations affect the left ventricle and how management of these conditions can have a profound effect on LV function. For simplistic sake, the forces that cause clinically relevant heart-lung interactions are illustrated in There are multiple aspects of cardiopulmonary physiology that affect patients with heart failure. Lung volume and hyperinflation affect autonomic tone and pulmonary vascular resistance. In 1966 de Burgh Daly et al. showed that the correlation between systemic vascular resistance and ventilation was secondary to reflexes from intrapulmonary receptors altered by changes in lung volume. Lung inflation by either negative or positive intrathoracic pressure (ITP), in the setting of blocked carotid sinus and aortic arch baroreceptors, led to an immediate decrease in systemic vasomotor tone . FurtherHere we will discuss the importance of heart-lung interactions in various clinical scenarios including acute cardiogenic pulmonary edema (ACPE), ventilatory weaning, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), and acute respiratory distress syndrome (ARDS).Left heart failure can be characterized by systolic dysfunction, diastolic dysfunction, or both. In developed countries, systolic ventricular failure is most commonly associated with ischemia  and hypertension, which also contributes to diastolic dysfunction. In other parts of the world, Chagas disease and rheumatic heart disease are more prevalent causes. Understanding heart lung interactions is essential for the management of all left heart failure patients. Negative intrathoracic pressure leads to increased LV transmural pressure increasing LV afterload. In patients with left heart failure, negative swings in intrathoracic pressure can markedly decrease LV ejection leading to rapid increases in LV filling pressure and secondary (hydrostatic) pulmonary edema. The spontaneous breathing efforts also represent a metabolic stress on the body. During periods of increased work of breathing, spontaneous ventilation increases oxygen demand of respiratory muscles as well as of the myocardium and may induce circulatory insufficiency and visceral organ ischemia .Based on these principles the primary treatment of acute cardiogenic pulmonary edema should be the immediate abolishment of negative swings in ITP. While hypovolemic patients may decrease their cardiac output when positive pressure ventilation is initiated due to the decrease in preload (moving leftward on the ventricular function curve), these effects are minimized if continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) are used in patients with acute heart failure, because the spontaneous inspiratory efforts remain but the negative swings in ITP are markedly diminished or abolished. Thus, CPAP and BiPAP selectively reduce LV afterload shifting the ventricular function curve upward in patients with acute heart failure without decreasing venous return. Numerous clinical trials have shown the immediate beneficial cardiovascular effects of initiating CPAP or BiPAP. These findings were reinforced by a meta-analysis by Weng et al. showing less need for endotracheal intubation and a trend toward reduced mortality when non-invasive ventilation is initiated on patients presenting with acute cardiogenic pulmonary edema . UnfortuPatients subjected to hyperinflation and increased juxtacardiac pressure will experience a drop in biventricular volumes. Furthermore, some of these effects, including decreased vasomotor tone, may be affected by induction of anesthesia during initiation of mechanical ventilation. Lung inflation with volumes less than 10\u00a0mL per kilogram of body weight leads to vagal tone withdrawal and, consequently, an increase in heart rate. This is known as respiratory sinus arrhythmia. On the other hand, lung hyperinflation with volumes greater than 15\u00a0mL per kilogram of body weight leads to vagal tone activation and sympathetic tone withdrawal. In such cases, patients exhibit a decrease in blood pressure secondary to vasodilation from a decrease in systemic vasomotor tone. Many patients with LV failure are also hypervolemic owing to increased antidiuretic hormone activation. Thus, in volume overloaded patients with heart failure, initiation of mechanical ventilation and some degree of lung hyperinflation will decrease preload, cause vasodilation and, thereby, decrease intrathoracic blood volume. In those settings, the slight decrease in LV afterload may augment LV ejection keeping cardiac output constant despite a sustained increase in ITP. These are the reasons why patients with LV failure usually tolerate intubation and positive-pressure ventilation well without secondary post-intubation hypotension .Weaning patients from positive pressure ventilation results in several processes occurring simultaneously. First, respirations change from positive swings in ITP to negative swings in ITP. This must increase venous return and LV afterload. The combined effects of these two processes lead to an increase in intrathoracic blood volume. Second, metabolic demand increases as respiratory muscles resume their normal activity. Patients with increased work of breathing during weaning will experience sympathetic hyperactivation and catecholamine surge leading to increased heart rate and hypertension, which in turn will increase myocardial oxygen demand. If the work of breathing is excessive or LV functional reserve is too limited, then the patient will fail weaning. Weaning failure will manifest as acute cardiovascular collapse, hypotension, tachycardia, and even acute cardiogenic pulmonary edema. These hemodynamic changes can be ameliorated by restricting fluids, having the patients slightly hypovolemic and treating bronchospasm prior to extubation. Optimizing bronchodilation, avoiding volume overload and controlling afterload prior to weaning trials will facilitate liberation from mechanical ventilation .Patients with COPD can also have LV failure. Both COPD and obesity are associated with terminal airway collapse with increased shunt. COPD patients are more likely to experience hyperinflation owning to the increased airway resistance combined with increased lung compliance. These patients experience limitations in expiratory flow secondary to airway collapse. Both hyperinflation and dynamic hyperinflation can increase pulmonary vascular resistance and compress the heart within the cardiac fossa. The combined effects can worsen RV dysfunction by minimizing RV end-diastolic volume (EDV) while simultaneously increasing RV afterload. Patients with LV failure need a higher LV filling pressure and EDV to sustain LV stroke volume. Since hyperinflation compresses the heart, LV end-diastolic volume also decreases, and thus cardiac output often decreases during acute exacerbations of COPD in patients with LV dysfunction .Commonly, patients with LV failure develop RV failure. In such cases, increases in transpulmonary pressure secondary to lung hyperinflation lead to increased RV afterload and decreased RV ejection and RV stroke volume leading to systemic hypotension. In these circumstances, patients may experience acute cor pulmonale and RV ischemia. COPD exacerbations can cause hypoxemia, hypercapnia and increased sympathetic tone. Passive increases in pulmonary artery pressure due to increased LV filling pressure rarely cause enough increases in pulmonary artery pressure to result in acute RV failure. These three mechanisms increase pulmonary vasomotor tone. Patients with COPD may also have chronic pulmonary hypertension leading to RV hypertrophy. Increasing RV afterload increases RV end-systolic volume and, by extension, RV EDV. Clinically, these patients may present with increased jugular venous distension during spontaneous inspiration (Kussmaul\u2019s sign) and the shift in the intraventricular septum will decrease LV end diastolic compliance leading to decreased cardiac output  Mooney . LimitataCO2 beyond the apneic threshold. Furthermore, episodes of hypoxia and waking from sleep lead to sympathetic activation, which further increases LV afterload and contributes to an increase in myocardial oxygen demand. Patients with OSA have intermittent hypoxemia and formation of free radicals and inflammatory molecules that lead to vascular remodeling. The negative swings in ITP during OSA lead to a combined increase in LV afterload and systemic hypoxemia. Thus, at the time that LV wall stress is increasing, myocardial oxygen delivery is being compromised. Over months, these repetitive OSA events lead to the development of congestive heart failure and a downward shift in the ventricular function curve. Acutely, the negative swings in ITP, hypoxia, and sympathetic surge lead to increased LV afterload and reactive systemic hypertension leading to increased myocardial metabolic demand. Chronically, these factors worsen LV hypertrophy, which in turn affects LV diastolic function. OSA has been associated with LV remodeling and increased incidence of cardiovascular disease . Nocturnal CPAP or BiPAP have been shown to improve outcomes in patients with disordered sleep. Specifically, OSA patients with heart failure demonstrate improvement in daytime off-CPAP LV function if the CPAP treatment abolishes the obstructive breathing patterns .Noncardiogenic pulmonary edema or ARDS is characterized by decreased lung volumes secondary to alveolar collapse and pulmonary congestion, increased dead space ventilation, hypoxemia and increased work of breathing. Often hypoxemia is not responsive to non-invasive ventilation and intubation with positive end-expiratory pressure (PEEP) is required to sustain gas exchange and minimize receptive alveolar collapse at end-expiration. The resultant higher mean and end-inspiratory airway pressure often further increase dead space ventilation. Dead space ventilation along with hypoxic pulmonary vasoconstriction secondary to alveolar collapse lead to increased pulmonary vascular resistance. This must impede RV ejection and increase RV EDV, which in turn decreases LV diastolic compliance by the process of ventricular interdependence. Indeed, Jardin et al. demonstrated many years ago that when ARDS patients were given high levels of PEEP their LV stroke volume decreased despite a high pulmonary artery occlusion pressure, used as a surrogate of LV EDV. However, when these same patients were fluid resuscitated to restore their LV EDV to their pre-PEEP levels, LV stroke volume also returned to its pre-PEEP value even though PEEP was still being used. This seminal work clearly demonstrated that lung hyperinflation and high levels of PEEP impair LV filling by decreasing LV diastolic compliance through the process of ventricular interdependence and increased juxtacardiac ITP. These points are described elsewhere in this series in greater detail .2 and optimal cardiac output for a given blood volume. Titrating PEEP based on RV systolic function and lung compliance is an important technique to monitor for developing RV failure and preventing PEEP too low that would worsen alveolar collapse and hypoxia or PEEP too high that would worsen PVR and RV afterload and, consequently, worsen LV diastolic filling  and overdistention (increasing resistance). This elusive \u201csweet spot\u201d mean airway pressure that balances these two opposing effects is often equated to the point where PEEP maximizes lung compliance. Clinical studies suggest that the highest PEEP associated with the best value of lung compliance is also associated with better RV systolic function as measured using transesophageal echocardiography, least dead space ventilation, assessed as end-tidal CO filling .aCO2 levels are all predictive of the development of cor pulmonale in ARDS. Clearly, all these effects are predictable based on the above logic. Driving pressure is a surrogate of lung stress due to its effect on hyperinflation and pulmonary vascular resistance. Likewise, higher PaCO2 levels are indicative of increased dead space and lead to pulmonary vasoconstriction and increased pulmonary vascular resistance. Mitigating these factors is critical to avoid right heart failure, RV dilation and, consequently, poor LV diastolic filling and low output heart failure (Other investigators looked at variables that are prominent in patients with ARDS that develop cor pulmonale. These investigators concluded that pneumonia being the etiology of ARDS, driving pressure, worsening P:F ratio and rising P failure .Heart-lung interactions play a crucial role in understanding and managing patients with left heart failure under most conditions independent of ventilatory mode."}
+{"text": "Behavioural supersensitivity may be a result of increased glutamate sensitivity of D2-MSN and reduced sensitivity to dopamine. We propose that clozapine may address behavioural supersensitivity by modulating glutamate activity which may partially explain its unique effectiveness in the setting of treatment resistant schizophrenia. The mainstay of schizophrenia treatment is chronic antipsychotic medication to prevent relapse of a psychotic episode. These antidopaminergic drugs reduce D2 dopamine receptor-mediated transmission. It has been proposed that relapse rates following antipsychotic discontinuation may be due to withdrawal phenomenon rather than due to illness recurrence . The leai intracellular signalling, behavioural supersensitivity was reversed [Kruyer et al. studied the mechanism of antipsychotic-induced behavioural supersensitivity and did not find any change in D2-receptor expression or function in mice administered chronic haloperidol, in the ventral striatum, dorsal striatum or midbrain and concluded neither D2-receptor expression nor the hypothesized increased function of the receptor could explain behavioral supersensitivity . Insteadreversed .Based on the above, Kruyer et al. propose D2-medium spiny neurons hyperexcitation in the nucleus accumbens core underpins neuropathology during chronic antipsychotic treatment, antipsychotic discontinuation and behavioural supersensitivity, such that chronic antipsychotic treatment possibly reduces modulatory dopaminergic input making D2-medium spiny neurons hyperexcitable to incoming excitatory transmission from glutamate . BehavioAntipsychotic-induced behavioural supersensitivity is postulated to reduce the efficacy of antipsychotic medication leading to increasing antipsychotic doses, tolerance and treatment resistance. It has also been possibly linked to the development of tardive dyskinesia which is a motor disorder known to be caused by prolonged antipsychotic exposure . A recenClozapine is a unique medication acting upon multiple receptors , and is 14and may also potentiate glutamate transmission by regulating glutamate transport [It has been hypothesised that clozapine may specifically modulate brain glutamate and that this effect could contribute to its unique efficacy for patients with treatment-resistant schizophrenia , 15. Gluransport . Tanahasransport  also demransport . Clozapiransport . In an aransport  and thisransport . Glutamaransport . Deficitransport .However, despite the evidence for glutamatergic dysfunction in schizophrenia, specific pharmacological strategies have so far been largely unsuccessful . These aThere is indirect evidence to support that the efficacy of clozapine in refractory schizophrenia may be related to its modulatory effect on glutamate activity \u201330. HoweThe efficacy of clozapine in reversal of tardive dyskinesia can provide indirect links to understand this mechanism further. Antipsychotic-induced behavioral supersensitivity has been considered a possible aetiological factor for the development of both treatment resistant schizophrenia and tardive dyskinesia . Meta-anKruyer et al., show antipsychotic-induced behavioural supersensitivity may be a consequence of hyperexcitation of D2 medium spiny neuron in the nucleus accumbens core, due to enhanced glutamatergic transmission . TherefoKruyer et al., have suggested the potential role of deep brain stimulation and transcranial magnetic stimulation, in reducing and preventing excitatory plasticity in D2 medium spiny neuron . HoweverUnderstanding the mechanistic basis for antipsychotic-induced behavioural supersensitivity may lead to better prevention efforts (reducing both antipsychotic dose and usage) as well as facilitate targeted treatments for supersensitivity psychosis and tardive dyskinesia. Future research should specifically investigate clozapine\u2019s role in antipsychotic-induced behavioural supersensitivity  and the mechanism by which clozapine (and other therapeutic approaches) may modulate glutamate-induced excitability specifically within the striatum and the nucleus accumbens. Future controlled trials should be conducted studying the effect of clozapine, electroconvulsive therapy, deep brain stimulation, transcranial magnetic stimulation and other glutamate modulating compounds for the treatment of supersensitivity psychosis with concomitant assessment of glutamate activity within the striatum and nucleus accumbens. These studies may also help identify biomarkers for treatment resistant schizophrenia and possible predictors of clozapine response.The aetiology of treatment resistant schizophrenia is likely complex and treatments that just target either dopamine or glutamate transmission are less likely to be successful . There i"}
+{"text": "IntroductionIn 2019, the Centers for Medicare & Medicaid Services (CMS) combined all autologous breast flap procedures under one billing code, effective from December 31, 2024. This change will result in equal insurance reimbursement rates for popular flap options, such as transverse rectus abdominis muscle (TRAM) and deep inferior epigastric perforator (DIEP) flaps, which were previously billed separately using S-codes based on complexity.MethodsThis study aimed to analyze insurance code changes for autologous breast reconstruction flap procedures. Data were collected from the American Society of Plastic Surgeons' annual plastic surgery statistics reports, including specific insurance codes and case volumes from 2007 to 2020. A comprehensive analysis was conducted to assess recent trends in flap utilization rates, documenting any modifications or additions to the existing codes and their implementation years.ResultsThe study analyzed billing codes and case volumes for autologous breast reconstruction procedures, with a focus on the DIEP flap and other alternatives. Non-autologous breast reconstruction procedures showed consistently higher case volumes compared to autologous procedures from 2007 to 2020. Notably, the popularity of the DIEP flap surpassed that of other flap options after 2011.ConclusionThe removal of S-codes for autologous breast reconstruction by CMS and the subsequent potential decrease in insurance coverage for the DIEP flap may lead to a decrease in its utilization and a shift toward\u00a0more invasive options, like the TRAM flap. This change could result in financial burdens for patients and widen socioeconomic disparities in breast reconstruction, limiting access to preferred reconstructive methods and impacting patient autonomy and overall well-being. In 2019, the Centers for Medicare & Medicaid Services (CMS) implemented a protocol to combine all autologous breast flap procedures under a single billing code, 193464 [Currently, most plastic surgeons receive reimbursement from insurance companies for specific flap reconstruction procedures with S-codes, such as S2068 for DIEP flap surgery, S2066 for the superior gluteal artery perforator (SGAP) flap surgery, and S2067 for stacked flap surgery, where multiple flaps are stacked on top of one another to accommodate for lack of flap volume with a single flap .\u00a0This diData collectionThe primary objective of this study was to comprehensively analyze insurance code changes concerning flap procedures for autologous breast reconstruction. To achieve this, we employed a meticulous data collection approach that involved gathering relevant information from multiple reliable sources.Sources of dataWe collected the necessary data from the annual plastic surgery statistics reports, which are published by the esteemed American Society of Plastic Surgeons . These rInsurance code identificationTo ensure a robust analysis, we first identified and compiled a comprehensive list of specific insurance codes associated with autologous breast reconstruction flap procedures . This liCase volume recordsThe case volume data for the autologous flap procedures were meticulously gathered from the annual plastic surgery statistics report . These cData analysisAfter obtaining the insurance codes and corresponding case volumes, we performed a detailed analysis to assess the impact of insurance code changes on the utilization of the DIEP flap procedure. First, we identified instances of insurance code changes related to the DIEP flap procedure by comparing the codes recorded in consecutive annual plastic surgery reports. Any modifications or additions to the existing codes were noted, and the corresponding years of implementation were documented. To examine the effect of code changes on the utilization of the DIEP flap, we compared the case volumes before and after each identified code change. This allowed us to assess any fluctuations in procedure frequency and identify potential trends related to insurance code modifications.Billing codes assessed through the annual plastic surgery statistics reportThe analysis focused on the insurance codes and case volumes associated with the DIEP flap procedure and other autologous flap alternatives, as obtained from the CMS . Table 1Case volume of autologous and non-autologous breast reconstructionNon-autologous breast reconstruction procedures had a higher case volume  compared to autologous breast reconstruction procedures 168,652 cases) , \"stacked\" flaps, DIEP, and superficial inferior epigastric artery (SIEA) flaps. The findings are summarized in Table In 2021, the CMS discontinued S-codes for autologous breast reconstruction, making the 193464 billing code the sole source of insurance reimbursement for reconstructive breast procedures. In anticipation of these changes, several insurance companies have pre-emptively ceased coverage for the DIEP flap under S2068; other insurance companies are expected to follow [With the removal of appropriate additional reimbursement for the DIEP flap procedure, there is concern that breast reconstruction surgeons will decrease their DIEP flap case volume and potentially revert to utilizing more invasive autologous options, such as the TRAM flap ,7. WhileThere has been an increase in the frequency of DIEP flaps performed following the introduction of S-codes . This trWithout the additional reimbursement provided by S-codes, there is fear that surgeons cannot cover the DIEP procedure costs . For theFurthermore, these insurance changes may broaden the socioeconomic disparities in breast reconstruction . PatientSociodemographic factors currently represent disparities in autologous breast reconstruction and implant-based reconstruction ,20. PatiImplant-based reconstruction is another standard method for breast reconstruction. Some individuals prefer autologous tissue options due to their more natural feel and appearance. Additionally, increased reports and awareness of breast implant illness (BII) and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has decreased interest in implant-based reconstructive options . The decLimitationsDespite the rigorous data collection and analysis, certain limitations must be acknowledged. The reliance on aggregated case volume data from annual reports might have introduced sampling bias, and the lack of individual patient data limited our ability to explore patient-specific factors. Additionally, the focus on a specific time frame (2007 to 2020) and the potential variability in insurance coding practices should be considered when interpreting the results. Nonetheless, our research serves as a foundation for further exploration and underscores the importance of monitoring insurance code updates in the realm of plastic surgery practices.Limiting access to alternative autologous reconstructive options for those recently afflicted by a life-threatening breast cancer diagnosis revokes patient autonomy and heightens socioeconomic health disparities. Introducing and popularizing the DIEP flap was a productive step forward in the field of breast reconstruction. In recent years, the usage and popularity of the DIEP flap have skyrocketed; however, recent changes in reimbursement can potentially result in an inflection point in the number of cases performed in the future. Limiting access to this option only to those who can pay out-of-pocket may dramatically impact\u00a0our patients' physical, mental, and overall well-being."}
+{"text": "Spatial transcriptomics technologies developed in recent years can provide various information including tissue heterogeneity, which is fundamental in biological and medical research, and have been making significant breakthroughs. Single-cell RNA sequencing (scRNA-seq) cannot provide spatial information, while spatial transcriptomics technologies allow gene expression information to be obtained from intact tissue sections in the original physiological context at a spatial resolution. Various biological insights can be generated into tissue architecture and further the elucidation of the interaction between cells and the microenvironment. Thus, we can gain a general understanding of histogenesis processes and disease pathogenesis, etc. Furthermore, in silico methods involving the widely distributed R and Python packages for data analysis play essential roles in deriving indispensable bioinformation and eliminating technological limitations. In this review, we summarize available technologies of spatial transcriptomics, probe into several applications, discuss the computational strategies and raise future perspectives, highlighting the developmental potential. Human organs and systems are comprised of distinct cell subpopulations whose physiological processes and functions are deeply correlated with their spatial distributions and cellular interactions. To gain a deeper understanding of tissue architecture as well as heterogeneity and to subsequently obtain biological insights into intercellular communication and microenvironment, it is crucial to decipher the disparities among tissue regions and cells in their original spatial context. Previously developed single-cell RNA sequencing (scRNA-seq)  has provAlthough current cutting-edge spatial transcriptomics techniques are confronted with some drawbacks such as relatively low resolution and comparatively insufficient sequencing depth , they arSpatial transcriptomics technologies have been continuously making significant progress. Multiple technologies have emerged in recent years, and their applications and advantages and disadvantages are comprehensively reviewed. In this article, we summarize the landscapes of available spatial transcriptomics technologies, present the employment of spatial techniques in extensive fields of biomedical research and focus on the status quo of computational strategies of data analysis.Since the initial spatial transcriptomics workflow was established in 2016 , this fiLaser capture microdissection (LCM)  is a micJunker and colleagues  devised In summary, microdissection-based methods provide a competent approach to obtaining regions of interest from tissue samples with high sensitivity. These techniques enable focused research into the microanatomical structures and gene expression information of specific regions. However, Geo-seq, which integrates LCM and scRNA-seq (Smart2-seq), offers only a ten-cell resolution due to the limitations of microdissection-based techniques. During the laser-capturing and tissue segregation procedures of LCM, the quality of RNA molecules and the intactness of obtained cells may not be fully maintained. Additionally, microdissection is time-consuming and labor-intensive, limiting the throughput and the capacity to handle large tissue samples. Despite these shortcomings, microdissection-based technologies can still provide robust methods for gene expression profiling.In situ hybridization is a strategy that enables the visualization of RNA molecules within their original context via probes complementary to the objective transcripts rather than extracting them from tissue sections. An early iteration of in situ hybridization technique termed single-molecule fluorescent in situ hybridization (smFISH)  is compeTo overcome the drawbacks of accumulating errors, Chen and colleagues  devised in-situ-hybridization-based techniques allow for the visualization of RNA molecules within their original tissue context by hybridizing probes with complementary targets. This enables the detection of target genes for biological validation of bioinformatic analysis results and the study of gene expression patterns. However, the nature of FISH methods imposes an intrinsic limitation on throughput. Additionally, specific probes must be synthesized before the hybridization process, necessitating the use of ready-made kits to overcome this challenge [Overall, hallenge .In situ sequencing (ISS) method developed by Ke and colleagues  enables To examine transcripts without prior knowledge of tissue, Lee and colleagues  devised in-situ-sequencing-based methods enable spatial-level gene expression analysis and avoid the bias introduced by transcript extraction. However, these techniques still face challenges. For example, prior knowledge of the tissue may be required to design specific padlock probes, and read length may be limited. Additionally, in situ sequencing may not be feasible for unconventional or rare cell types and genes. Potential applications of these methods include studying gene expression regulation within tissues or cells and localizing gene variants.In contrast to traditional sequencing methods that separate cells from their spatial context, St\u00e5hl and colleagues  proposedImprovement of the resolution of spatial barcoding strategies has been continuously pursued. In 2019, Rodriques and colleagues  developeSlide-seq, HDST and Seq-Scope introduced above can provide much higher and even subcellular resolutions, generating more refined spatial distribution information. The approaches to improving the resolutions of Slide-seq and HDST are similar, involving bead arrays with 10-\u03bcm- and 2-\u03bcm-diameter beads, respectively , 45. It Overall, spatial-barcoding-based techniques allow for the simultaneous acquisition of gene expression and spatial location information. However, selecting the appropriate resolution requires careful consideration. Low resolution may obscure the intrinsic tissue structure and require further decomposition analysis to gain comprehensive insights, while high resolution may introduce those aforementioned challenges. Additionally, capture efficiency may be relatively low. Despite these limitations, spatial-barcoding-based techniques are widely used to study tissue architecture, tumor heterogeneity, the tumor microenvironment, etc.Spatial transcriptomics technologies are potent tools for studying the intricate structure, the dynamics of tissue and organ systems and inherent mechanisms within their original context. These technologies can provide valuable biological insights by revealing tissue architecture, developmental patterns and diseases, among which tumor biology may be one of the most extensive applications of spatial transcriptomics. Primary application scenarios of implementing spatial transcriptomics techniques are presented Fig.\u00a0 and seveDecoding intercellular interaction and identifying cell subpopulations are of fundamental significance in delineating tissue architecture and defining structural components through the establishment of a transcriptome atlas of a specific tissue or organ, thus facilitating the perception of tissue dynamics. Hildebrandt and colleagues  managed Furthermore, spatial transcriptomics technologies are generally utilized in developmental biology to reveal spatiotemporal gene expression patterns and uncover tissue morphogenesis throughout the entire development course or multiple pivotal stages. Asp and colleagues  profiledBeyond the above insights about tissue architecture and development, spatial transcriptomics techniques have a robust capacity for clarifying disease microenvironments and pathogenesis. Boyd and colleagues  combinedA substantial part of disease research is the study of tumor biology which could be the most extensive application of spatial transcriptomics. Significant challenges in devising tumor treatment procedures are induced by tumor heterogeneity. Moncada and colleagues  utilizedTo comprehensively interrogate the tissue sections, bioinformatic analyses have to be performed to unravel the intertwined and multiplexed bioinformation and minimize the impact of current technological limitations and subsequently derive biological significance more accurately from raw spatial transcriptomics data. These bioinformatics analyses range from spatially-variable genes identification and clustering analysis to gene imputation, etc., which can be handily effectuated through a substantial number of computational strategies devised in recent years. Herein, circumstantial comparisons of algorithms and usages among the existing R or Python packages are presented Table .Table 4CDistinguishing cell types and subpopulations is a fundamental task in the bioinformatic analysis of spatial transcriptomics data. This can be resolved with the help of clustering analysis where spatially-variable genes can be discovered and data dimensions can be reduced through approaches such as principal component analysis (PCA), t-distributed stochastic neighbour embedding (t-SNE) and uniform manifold approximation and projection (UMAP). These methods calculate similarity among barcode spots and define clusters within a tissue. A robust clustering procedure is provided by a widely-distributed R package Seurat , on whicWithin a certain tissue, some genes exhibit conspicuous spatially-variable expression whereas some other genes such as housekeeping genes are expressed equally among the cells. The specific pattern in which the expressions of genes spatially vary can convey indispensable bioinformatic insights into identifying cell types and subpopulations and corresponding spatial information and underlying spatial functions. Some program packages perform outstandingly in identifying spatially-variable genes. Svensson and colleagues  describeA common issue in spatial transcriptomics technology is that a single barcode-capturing spot may be overlaid by multiple cells. Thus, the detected expression is an aggregation of a heterogeneous set of cells within the spot, which may impact the efficiency and accuracy of identifying cell subpopulations and delineating tissue atlas. For example, 10\u2009\u00d7\u2009Genomics Visium offers a resolution of 55\u00a0\u03bcm meaning the diameter of each capturing spot is 55\u00a0\u03bcm which is several-fold larger than a typical tissue cell. The spatial decomposition process through various deconvolution algorithms can address this discrepancy, which is to disentangle the mixture of mRNAs and subsequently predict the proportions of each cell type in one capturing spot. A spatial decomposition method devised by Ma and colleagues  is termeGene imputation refers to the task of inferring lost gene expression information or \u201cdropouts\u201d caused by factors such as low protocol sensitivity, mitigating errors during gene measurement and facilitating deconvolution. Biancalani and colleagues  introducThe aforementioned strategies, including spatial decomposition and gene imputation, have demonstrated considerable efficacy in enhancing the resolution of spatial transcriptomics data and compensating for lost gene expression information. Nevertheless, certain limitations persist. These approaches are based on computational models for predicting cell locations and gene information and therefore, their predictions may be subject to error, potentially resulting in imprecise and spurious results. Further investigation and refinement are necessary to more effectively leverage these technologies and derive more reliable biological insights.Cellular interaction operated within the microenvironment where cells are adjacent to each other can convey significant perceptions into tissue dynamics and the way the communication networks change when experiencing conditions such as disease. A Graph Convolutional Neural networks for Genes (GCNG) method was introduced to infer extracellular interactions from gene expression by depicting a cellular relationship graph transformed from spatial transcriptomics data and subsequently encoding gene expressions, and the graph is then convolved with expression information . Cang anCopy number variation (CNV) refers to the increase or decrease in the copy number due to gene segment rearrangements. Typically, CNVs involve segments longer than 1000 base pairs and are mainly manifested as submicroscopic deletions or duplications. CNVs are a common form of genetic variation in the human genome, with 5%\u2009~\u200910% of the genome affected by CNVs, which is much higher than other forms of genetic variation. Ascertaining the transition from benign to malignant tissue forms the foundation for improving early cancer diagnosis, as genomic instability in histologically benign tissue can signal an early event in cancer evolution. Furthermore, the spatial distribution and activity of CNVs can impact phenotype, making mapping their spatial distribution valuable for comprehending, diagnosing, and treating diseases. Previously, gene expression was utilized to infer CNVs in individual cells, successfully identifying regions of chromosomal gain and loss . EricksoGene expression within a tissue is influenced by the spatial position of cells in the tissue microenvironment. Spatial transcriptomic data can provide valuable insights into tissue regions, as they contain information on spatial position matrices, HE region staining of sections, and relative distances between individual cells, which can be used to delineate spatial regions. MULTILAYER is an algorithm that utilizes agglomerative clustering and community detection methods for graphical partitioning, enabling digital imaging of spatial transcriptomic analysis . This alSpatial trajectory analysis is an analytical method frequently employed in spatial transcriptomics to uncover dynamic cellular evolution and differentiation processes. This approach infers evolutionary trajectories and differentiation relationships between cells by analyzing their spatial positions and gene expression levels within tissue sections. The stLearn package can visualize spatial trajectories in tissue slices and infer biological processes from transcriptional state gradients across tissues . SimilarBoth spatial transcriptomics and scRNA-seq are effective methods for obtaining biological insights into tissues and diseases. However, each method has its limitations. By integrating spatial transcriptomics and scRNA-seq data, these methods can complement each other to provide comprehensive biological information. For instance, RCTD generates spatial decomposition by assigning cell types to spatial transcriptomics spots , whereasMethods for analyzing spatial transcriptomics data are generally similar and can be divided into data preprocessing and downstream analysis. Data preprocessing typically involves quality control and normalization to improve data quality for downstream analysis and obtain more reliable biological information. For spatial-barcoding-based methods, quality control aims to remove low-quality spots and genes from spatial transcriptomics data. Quality control parameters can be adjusted based on tissue type, research requirements, and other factors. These parameters may include removing spots with fewer than a certain number of transcripts, removing genes expressed in fewer than a certain number of spots, and removing spots with a high proportion of mitochondrial genes. Normalization accounts for the difference in sequencing depth among different spots. Since differences among spots in spatial transcriptomics data can be relatively large, effective normalization is essential.After preprocessing, downstream analysis can be performed. The data should first undergo dimensionality reduction and clustering analysis to distinguish spots with different features. Biological information can then be interpreted through these clusters in subsequent analysis. Algorithms such as PCA, t-SNE, and UMAP can be used for this purpose and are available in many data analysis packages. Next, gene expression patterns in the data can be analyzed, including differential expression analysis and spatially variable gene analysis, which can be performed using packages such as Seurat and SpatialDE, respectively. Additionally, cell information from tissue slices can be annotated onto spatial transcriptomics data. Since the sequencing unit  of some spatial transcriptomics technologies may contain more than one cell, spatial decomposition can infer the proportion of various cells in each sequencing unit based on the data to obtain cell locations in the spatial context. This step can be achieved using packages with deconvolution algorithms such as RCTD and cell2location. Gene imputation can also predict the positions of low-expressed or missing genes in space due to possible dropout using packages like Tangram. Furthermore, personalized analysis can be conducted based on research objectives. For instance, packages such as Giotto can be used to analyze the communication between cells or spatial regions, including receptor-ligand interactions. SpatialInferCNV can perform copy number variation analysis at the spatial level, while stLearn and SPATA can be used for spatial trajectory analysis and MULTILAYER for spatial region identification. These analytical methods and packages provide excellent visualization during data analysis, facilitating step-by-step comprehension of current analytical outcomes to guide subsequent analysis. Moreover, it is essential to integrate spatial transcriptomics data with scRNA-seq data and other omics data to obtain a more comprehensive understanding of biological information.Explosive advances in spatial transcriptomics technologies have been made in recent years to expand our understanding of miscellaneous tissues and organs. However, current spatial transcriptomics methods are confronted with some challenges of low resolution, sensitivity, throughput, etc., hindering our precise perception of normal and abnormal tissues, which calls for further innovations in technologies to overcome these deficiencies. Given that each technology bears its biological strengths, we envision the integration across these technologies which complement each other in the drawbacks before a novel and robust technology is launched. With future technology revolutions, intercellular signaling could be resolved at higher and even single-cell resolution. In addition, larger-scale tissue specimens may be investigated to allow for depicting organ-level tissue topography, enabling a more holistic and consecutive interpretation of tissue structures, which latently poses challenges for accelerating bioinformatic analysis with higher efficiency and accuracy and more powerful information processing capacity. Beyond the prospective advancement in refining and optimizing current protocols of spatial transcriptomics, we also envisage the integration with multi-omics including epigenomics, proteomics, and metabolomics to shed light on the intrinsic convoluted mechanisms of cellular interactions and disease and better probe into tumor progression and growth course. In addition to advances in spatial transcriptomics technologies, innovations in data analysis strategies are also anticipated. As deep learning technology continues to progress, its application in spatial transcriptomics data analysis is expected to become more widespread. In the future, more deep-learning-based methods may be developed to process and analyze spatial transcriptomics data to improve data resolution and interpretation reliability. Furthermore, as data scale and complexity increase, visualization and interactive analysis will become important tools for spatial transcriptomics data analysis. Future spatial transcriptomics data analysis methods will need to integrate visualization and interactive analysis technologies to better understand and interpret data.Since some spatial transcriptomics techniques, especially some widespread spatial-barcoding-based techniques, are not capable of offering single-cell resolution at the spatial level and scRNA-seq cannot reflect the spatial distribution of each cell, we envision a more organic and efficient alignment of single-cell datasets and corresponding spatial information. The alignment can be achieved by mapping single cells to spatial data, where each cell is matched with a spatial location in an ideal condition. Nevertheless, current methods for integration cannot generate precise matching due to technological limitations, which calls for further breakthroughs in the effectiveness and efficiency of data integration algorithms. By integrating both datasets, we can decipher potential intercellular communication pathways, including ligand-receptor interactions and juxtacrine and paracrine signaling. This may provide insights into previously unclear physiological and disease mechanisms and help discern more refined classifications of certain diseases, facilitating precise and individualized medical treatment. Additionally, publicly-available datasets can be interrogated retrospectively with the integration of spatial transcriptomics and scRNA-seq data to obtain novel biological cues which may be concealed in the raw data before.Moreover, we anticipate the translational medicine research into the clinical significance of spatial transcriptomics, particularly with the compatibility of the 10\u2009\u00d7\u2009Genomics Visium platform with FFPE tissue blocks allowing retrospective analysis into previously opaque tissue specimens to glean more sufficient information on clinical diagnostics and prognostics as well as therapeutic methods and targets. For example, research into human DLPFC distinguished the layer-enriched genes that may be associated with schizophrenia and autism spectrum disorder, implicating the potential of neuropsychiatric disorders progression in those bearing the risk gene expression . In tumo"}
+{"text": "The clinical spectrum of atrial fibrillation means that a patient-individualized approach is required to ensure optimal treatment. Cardiac computed tomography can accurately delineate atrial structure and function and could contribute to a personalized care pathway for atrial fibrillation patients. The imaging modality offers excellent spatial resolution and has been utilised in pre-, peri- and post-procedural care for patients with atrial fibrillation. Advances in temporal resolution, acquisition times and analysis techniques suggest potential expanding roles for cardiac computed tomography in the future management of patients with atrial fibrillation. The aim of the current review is to discuss the use of cardiac computed tomography in atrial fibrillation in pre-, peri- and post-procedural settings. Potential future applications of cardiac computed tomography including atrial wall thickness assessment and epicardial fat volume quantification are discussed together with emerging analysis techniques including computational modelling and machine learning with attention paid to how these developments may contribute to a personalized approach to atrial fibrillation management. Atrial fibrillation is conventionally classified according to a single domain - the temporal pattern of the arrhythmia. Whilst the use of classification systems has increased our understanding of atrial fibrillation to some extent, such an approach can overlook the importance of the interplay of factors related to the patient, their symptom severity, risk factors and the atrial electrophysiological substrate underpinning atrial fibrillation. Given these interactions, the management of atrial fibrillation necessitates the delivery of a coordinated patient-individualized care pathway to ensure optimal treatment. Whilst more research to explore the patient-specific pathophysiological basis of atrial fibrillation is necessary, the principles of patient-individualized care have been encapsulated in the 4S-AF scheme which aims to provide a structured, pathophysiology-based characterisation of a patient's atrial fibrillation comprising four domains - stroke risk, symptom severity, severity of atrial fibrillation burden and substrate severity.Within this framework, computed tomography may provide useful information to guide atrial fibrillation management by enabling assessment of cardiac structure and function. Advances in computed tomography temporal and spatial resolution have strengthened its utility in the field of electrophysiology.This review will discuss the current state-of-the-art for computed tomography in atrial fibrillation management together with potential future applications that form part of ongoing research .Fig.\u00a01Th22.1In atrial fibrillation, cardiac computed tomography has been used prior to direct current cardioversion, radiofrequency catheter ablation and left atrial appendage closure to investigate for contraindications, delineate anatomy and guide procedures.In the context of atrial fibrillation ablation procedures, pre-procedural atrial imaging can define patient-specific atrial anatomy.Prior to percutaneous left atrial appendage occlusion, pre-procedural imaging is utilised to guide left atrial appendage occluder device selection and sizing, and to facilitate procedure planning.2.2In patients with sub-therapeutic anticoagulation (missed anticoagulant doses or short duration of therapy), investigation for left atrial appendage thrombi prior to direct current cardioversion or atrial instrumentation is required.,Computed tomography can be used to differentiate between left atrial appendage thrombus and slow blood flow by comparing early arterial and delayed phase images.2.32) score. In a recent simulation study by Qureshi et\u00a0al., it has been demonstrated that left atrial appendage morphology may affect coagulation dynamics in blood flow during sinus rhythm and atrial fibrillation, and subsequent risk of thrombus formation.Cardiac computed tomography can be used to accurately characterize left atrial appendage morphology . Left at2.4Prior to radiofrequency catheter ablation of the pulmonary veins in atrial fibrillation, an awareness of a patient's left atrial and pulmonary vein anatomy can enable accurate targeting and planning through the measurement of ostial diameter, characterization of variants in pulmonary vein anatomy such as accessory pulmonary veins or common pulmonary vein ostia, and the identification of anomalies such as anomalous pulmonary venous return, pulmonary vein occlusion or the presence of a persistent left superior vena cava.Variations in pulmonary vein anatomy are common and can be easily assessed with computed tomography.2.5Pulmonary vein stenosis is a recognized complication of atrial fibrillation ablation close to or within the pulmonary vein ostia. Symptoms typically take weeks to months to manifest and include shortness of breath, dry cough and, in some instances, chest pain.2.6Injury to extra-cardiac structures is a recognized, but fortunately rare, complication of atrial fibrillation ablation. The esophagus lies adjacent to the posterior wall of the left atrium leaving it vulnerable to injury during radiofrequency catheter ablation.Methods to reduce risk of atrio-esophageal fistula formation such as active esophageal coolingThe proximity of the right and left phrenic nerves with the right superior pulmonary vein and left atrial appendage roof respectively also leaves these structures vulnerable to injury during ablation.3Advances in computed tomography image acquisition and analysis provide the opportunity for its role in atrial fibrillation assessment to expand. Techniques including computational modelling, artificial intelligence-based imaging, atrial wall thickness assessment and epicardial adipose tissue characterisation may enable an individualized precision-cardiology approach to atrial fibrillation management. This section summarizes these approaches and suggests areas where future research developments using computed tomography may address knowledge gaps in the management of atrial fibrillation.3.1The ability of cardiac computed tomography to accurately delineate atrial structure can enable the acquisition of complex three-dimensional human atrial geometry which can form the basis of computational organ-level atrial models .45 TheseComputational models could be used to characterize an individual's substrate severity and lead to personalized atrial fibrillation ablation therapy. Hwang et\u00a0al. used cardiac computed tomography to create atrial models which could be used to compare different ablation strategies for atrial fibrillation.ClinicalTrials.gov, #NCT05057507) study will aim to use computational modelling to define patient-specific mechanisms of atrial fibrillation.Computational modelling for personalized atrial fibrillation procedure planning is an area of active research, offering the potential to better understand arrhythmia pathophysiology and improve clinical arrythmia prevention, risk stratification and treatment.Future research developments using computational models will require three-dimensional anatomical geometry and cardiac computed tomography is therefore likely to play a role in the generation of these models. A key advantage of cardiac computed tomography in this setting is the high spatial resolution of image acquisition which enables accurate anatomical assessment of wall thickness and left atrial appendage morphology. Previous studies using magnetic resonance imaging to evaluate the role of computational modelling in atrial fibrillation therapy have been unable to include variations in left atrial wall thickness or appendage morphology.3.2Machine learning is likely to be beneficial for personalized atrial fibrillation care in the future.Improved image quality with machine learning-based reconstruction algorithms may improve the ability to assess thin structures such as the atrial wall.The ability of cardiac computed tomography to characterise atrial structure may prove to be of prognostic importance as structural parameters such as left atrial volume3.3Changes in the structure and electrical behavior of the left atrium are associated with conditions which predispose to atrial fibrillation, although it is also recognized that these changes may occur in response to atrial fibrillation itself.Furthermore, we have developed reference values for left atrial wall thickness measurements on computed tomography, measured left atrial wall thickness at two locations (roof and floor) using computed tomography in 100 persistent atrial fibrillation patients., measured thickness around the pulmonary vein antra in patients undergoing repeat ablation procedures and found that antral wall thickness was higher in areas of pulmonary vein reconnection., found no association between left atrial wall thickness measurements and pulmonary vein isolation success rates.Studies have also been performed to examine for an association between left atrial wall thickness measurements and atrial fibrillation ablation success rates. Zuo et\u00a0al.The use of computed tomography to assess atrial wall thickness and provide non-invasive substrate determination may enable us to identify areas where the risk of recurrence is potentially higher and personalize therapy to improve outcomes. The utility of computed tomography-derived left atrial wall thickness in guiding catheter ablation approach has been demonstrated by Teres et\u00a0al., who found that personalized ablation approaches adapted to left atrial wall thickness allowed pulmonary vein isolation with lower radiofrequency delivery, fluoroscopy, and procedure times.3.4Cardiac computed tomography enables a three-dimensional assessment of the volume, thickness, and attenuation of the epicardial adipose tissue C.71 Some,Several studies have shown that patients with atrial fibrillation have increased epicardial adipose tissue thickness, mass and volume compared with patients without atrial fibrillation . A meta-,,,Recently, assessment of the pericoronary adipose tissue attenuation has gained attention due to its association with subsequent cardiac events.Notably these studies have considered only single-plane analysis or peri-atrial fat attenuation limited to the posterior left atrium. Furthermore, cut-off values to accurately define abnormal epicardial adipose tissue attenuation have not been defined and vary between research studies. Further mechanistic studies are therefore needed to study the role of global peri-atrial fat and fat attenuation in atrial fibrillation pathogenesis.In a study by Zhang et\u00a0al., it has been shown that the radiomic characteristics of epicardial adipose tissue may improve the identification of patients who have atrial fibrillation compared to quantification of epicardial adipose tissue volume.At present it is unknown whether changes in epicardial adipose tissue are a cause or consequence of atrial fibrillation. Epicardial adipose tissue, which contains ganglionated plexi, actively secretes cytokines and adipokines which may lead to inflammation and atrial remodelling. The secretion of pro-fibrotic factors by epicardial adipose tissue may contribute to atrial myocardial fibrosis and this may act as a substrate for atrial fibrillation.4Cardiac computed tomography can provide important anatomical information for patients with atrial fibrillation and has been used in the pre-, peri- and post-procedural stages of management. New techniques such as computational modelling and machine learning are improving our understanding of the development of atrial fibrillation and responses to therapy. In the future information such as atrial structure, atrial wall thickness, and epicardial adipose tissue from computed tomography may be used to provide a personalized approach for the management or prevention of atrial fibrillation.MCW has given talks sponsored by Canon Medical Systems, Siemens Healthineers and Novartis. SN receives research funding from Siemens for computed tomography image analysis. SEW has consulting agreements with EPD/Phillips, GSK and Biosense Webster."}
+{"text": "Most mental disorders, when examined individually, are associated with an increased risk of cardiometabolic complications. However, these associations might be attributed to a general liability toward psychopathology or confounded by unmeasured familial factors.To examine whether the associations between psychiatric diagnoses and increased risk of cardiometabolic complications are attributable to a general liability toward psychopathology, or confounded by unmeasured familial factors.We conducted a cohort study in Sweden and identified all individuals and their siblings born in Sweden 1955-1962 with follow-up through 2013. After excluding individuals who died or emigrated before 1987, the final sample consisted 672 823 individuals. We extracted ICD-coded diagnoses (recorded 1973-1987) for ten psychiatric conditions and criminal convictions when participants were aged 18-25 years, and ICD-coded diagnoses (recorded 1987-2013) for five cardiometabolic complications  when the participants were 51-58 years old. Logistic regression models were used to estimate the bivariate associations between psychiatric conditions or criminal convictions and cardiometabolic complications in individuals. A general factor model was used to identify general, internalizing, externalizing, and psychotic factors based on the psychiatric conditions and criminal convictions. We then regressed the cardiometabolic complications on the latent general factor and three uncorrelated specific factors within a structural equation modeling framework in individuals and across sibling pairs.Each psychiatric conditions significantly increased the risk of cardiometabolic complications; however, most of these associations were attributable to the general factor of psychopathology, rather than to specific psychiatric conditions. There were no or only small associations between individuals\u2019 general psychopathology and their siblings\u2019 cardiometabolic complications, suggesting that the associations were not attributable to genetic or environmental confounding factors shared within families. The same pattern was evident for the specific internalizing and psychotic factors.Individuals with mental disorders in early life had an increased long term risk of cardiometabolic complications, which appeared attributable to a general liability toward psychopathology. Sibling analyses suggested that the elevated risk could not be attributed to confounds shared within families.This highlights the importance of transdiagnostic and lifestyle based interventions to reduce the risk of cardiometabolic complications, particularly in patients with several mental disorders.None Declared"}
+{"text": "Transcranial magnetic stimulation (TMS) is a non-invasive FDA-approved therapy for major depressive disorder (MDD), specifically for treatment-resistant depression (TRD). Though offering promise for those with TRD, its effectiveness is less than one in two patients . Limits on efficacy may be due to individual patient variability, but to date, there are no established biomarkers or measures of target engagement that can predict efficacy. Additionally, TMS efficacy is typically not assessed until a six-week treatment ends, precluding interim re-evaluations of the treatment. Here, we report results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation indexed by functional magnetic resonance imaging (fMRI). Among responders, synchronized rTMS produces two systematic changes in brain dynamics: a reduction in global cortical excitability and enhanced phase entrainment of cortical dynamics. These effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly biomarker tracking enables efficacy prediction and dynamic adjustments through a treatment course, improving the overall response rates. This innovative approach advances the prospects of individualized medicine in MDD and holds potential for application in other neuropsychiatric disorders."}
+{"text": "BMC Cardiovascular Disorders invites authors to submit articles investigating what drives and affects Cerebrovascular disorders to improve patient care.Cerebrovascular disorders pose a global health concern. Advances in basic and clinical research, including induced pluripotent stem cell models and multi-omic approaches, have improved our understanding and management of these disorders. However, gaps in our knowledge remain.  BMC Cardiovascular Disorders welcomes submissions to its new \u201cCerebrovascular Disorders\u201d collection to help further our understanding of such conditions and open new avenues for risk stratification and therapeutic intervention.Cerebrovascular disorders comprise a range of distinct pathologies, including ischaemic and haemorrhagic stroke, transient ischaemic attack, and other intracranial vascular disorders , and significantly increase the risk of vascular dementia. Cerebrovascular disorders represent a significant medical and economic challenge anticipated to rise due to the increasing age of the global population . The pasHDAC9 large-vessel stroke risk to screen for histone deacetylase (HDAC) small molecule inhibitors ) We look forward to the \u201cCerebrovascular Disorders\u201d article collection bringing together basic and clinical research to develop our understanding of what drives and affects such conditions to improve patient care."}
+{"text": "Climate change poses new threats to plant production as environmental stresses increase significantly. Biotic and abiotic stress that have adverse effects on plant growth and crop productivity and can be major constraints on yield. This will particularly affect major food crops, including legumes and cereals. Biotic and abiotic stresses, such as salinity, drought, chemical toxicity, extreme temperatures and oxidative stress are often interrelated and become serious threats to agriculture. These extreme conditions induce cellular damage and disruption of plant growth and development by a series of morphological, physiological, biochemical and molecular changes. For example, these extreme stresses are often leading to oxidative damage and excessive creation of reactive oxygen species (ROS) in plant cells. Usually, plants interact with these extreme conditions by their innate antioxidative defense system that including enzyme and non-enzyme elements . HoweverTherefore, enhancing the productivity of these important crops is important for the food security of growing populations worldwide. High heterozygosity imposes severe limitations on breeding new varieties of major food crops with desired traits. Conventional plant breeding and genetic research have significantly evolved in recent decades. However, to meet the growing human population\u2019s food demand, especially for major staple cereal and legume crops, genetic gain must be enhanced, making it necessary to exploit genetic diversity within cultivated crops and wild relatives. With modern technologies, plant breeders can use these additional resources of diversity to address problems like biotic and abiotic stresses and yield by combining methods from genomics, and advanced analytics in cereal and legume breeding programs on a massive scale. This topic explores how the recent advances in genomics and plant biotechnology approaches are helping researchers to answer questions related to crop improvement. Therefore, we encouraged contributions to this Research Topic to advance and disseminate knowledge across various facets of this critical field. Our goal is to illuminate the molecular mechanisms that underlie biotic and abiotic stress tolerance, enhance comprehension of plant stress biology, with a particular focus on legumes and cereals. This effort ultimately contributes to bolstering sustainable agriculture and global food security. In this topic, recent advances in genomics and stress tolerance studies of cereals and legumes are presented in six publications, contributed by 52 authors.2+), which plays a crucial role in transmitting signals and regulating numerous physiological processes. This is accomplished through Ca2+ sensors and their target proteins, as highlighted by previous research  IQM genes  using genome-wide bioinformatics analysis and molecular biology techniques. They discussed the phylogenetic relationships, gene structure, conserved motifs, chromosome location, evolutionary pattern analysis, yeast two-hybrid analysis, and expression profile in response to abiotic stress and hormones of the soybean IQM family. Their results provide a theoretical basis for subsequent functional analysis of soybean IQM genes and insights into improving soybean resistance to biotic and abiotic stresses. Furthermore, Hu et al. indicated that the multiple members of CDPKs in wheat (Triticum aestivum) have diverse and vital functions in plant growth, development regulation and stress responses. They reported that every TaCDPKs member has a specific function. Their results clearly provide an important foundation for in-depth exploring the function and the signaling pathways of CDPK family members, especially the interactions between TaCDPKs and TaNOXs in wheat.Many complex signaling pathways are involved in the response of plants to biotic and abiotic stresses . For exaresearch . SpecifiXue et\u00a0al. performed a research toward deep RNA sequencing to depict long non-coding RNAs (lncRNAs) profiles in rice associated with BPH feeding using the resistant Near-Isogenic Line (KW-Bph36-NIL). They elaborated insightful information on the genome-wide differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) expression profiles of rice under BPH invasion by high throughput sequencing. They suggested that NILs could be used in BPH resistance breeding programs.Insect pest infestation is a serious threat to cereal crops and causes extensive damage to crop production annually. The brown planthopper (BPH) is a major threat to rice production. Host-plant resistance is a key component of pest management strategies to reduce the damage caused by BPH in rice production worldwide. Maanju et\u00a0al. to determine the genetic diversity and population structure of corn leaf aphid (CLA) Rhopalosiphum maidis (Fitch) resistance in barley to identify sources of resistance against R. maidis that considered as a common pest of cereals worldwide. In this study, 10 aphid specific simple-sequence repeats (SSR) markers were used to investigate the genetic diversity and population structure of 109 barley genotypes against R. maidis. Cluster analysis from the agro-morphological features grouped all the germplasm in four subpopulations and approximately 87.52% of the 109 barley genotypes shared a common major allele at any locus and finally they identified two genotypes having high resistance against CLA which highlighted their potential for inclusion in the future CLA resistance breeding programs.A study was undertaken by Park et\u00a0al. analyzed the transcriptome changes associated with the callus formation process in soybean under the influence of wounding signals and phytohormones. They identified key genes associated with transcription factors, biosynthesis, transporters, and signaling pathways related to phytohormones. The obtained results demonstrated the importance of the coordinated interplay of wounding, auxin, cytokinin, and brassinosteroid signaling pathways to activate the genes involved in determining the fate of meristematic cells. This study provides insights into the regulatory network of callus formation in soybean.With the aim of uncovering facts related to the biological mechanism underlying soybean callus induction and developmental process, Wu et\u00a0al. reported the analysis of the sugar beet WD40 proteins. They identified 177 bvWD40 from sugar beet and analyzed their evolutionary characteristics, protein structure, gene structure, protein interaction network and gene ontology. They concluded that BvWD40-82 gene is a salt-tolerant candidate gene. Transgenic Arabidopsis thaliana seedlings expressing BvWD40-82 showed enhanced tolerance to salt stress by elevating the contents of osmolytes and antioxidant enzyme activates, maintaining intracellular ion homeostasis and increasing the expression of genes related to salt overly sensitive (SOS) and abscisic acid (ABA) pathway. The obtained results hypothesized the importance of BvWD40-82 as a promising candidate gene for improving crop stress resilience.Salinity is a major environmental stress on crop productivity. Understanding the molecular and physiological mechanisms underlying salt stress tolerance will facilitate efforts to improve crop performance under salinity. In line with this aim, Biotic and abiotic stresses will remain major concerns for future food production and sustainability. The use of the most recent technologies in leveraging genomics, phenomics, machine learning approaches and plant biotechnology along with conventional breeding strategies is the most appropriate way to identify multifactorial interactions networks involved in plant defenses against stress conditions towards improving abiotic and biotic stress tolerance in major crops.PL: Writing \u2013 review & editing. MH: Writing \u2013 review & editing. RT: Writing \u2013 review & editing. MR: Writing \u2013 review & editing. HS: Writing \u2013 review & editing. H-JJ: Writing \u2013 review & editing."}
+{"text": "Saccharomyces cerevisiae has been studied in hopes of understanding its causes and identifying conserved pathways that also drive aging in multicellular eukaryotes. While the short lifespan and unicellular nature of budding yeast has allowed its aging process to be observed by dissecting mother cells away from daughter cells under a microscope, this technique does not allow continuous, high-resolution, and high-throughput studies to be performed. Here, we present a protocol for constructing microfluidic devices for studying yeast aging that are free from these limitations. Our approach uses multilayer photolithography and soft lithography with polydimethylsiloxane (PDMS) to construct microfluidic devices with distinct single-cell trapping regions as well as channels for supplying media and removing recently born daughter cells. By doing so, aging yeast cells can be imaged at scale for the entirety of their lifespans, and the dynamics of molecular processes within single cells can be simultaneously tracked using fluorescence microscopy.For several decades, aging in Key featuresThis protocol requires access to a photolithography lab in a cleanroom facility.Photolithography process for patterning photoresist on silicon wafers with multiple different feature heights.Soft lithography process for making PDMS microfluidic devices from silicon wafer templates. Saccharomyces cerevisiae, the traditional method of manual microdissection of mother and daughter cells in order to count replicative lifespan has been largely supplanted by the use of microfluidic devices, which efficiently trap individual mother cells in place while removing newly budded daughter cells . As a reference, yeast cells growing in the device can be seen in Paxman et al. (2022). Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with challenges to proteostasis. eLife ("}
+{"text": "Plasmodium malaria parasites [P. falciparum and highlight critical future questions to answer.Isoprenoid precursor synthesis is an ancient and fundamental function of plastid organelles and a critical metabolic activity of the apicoplast in arasites \u20133. Over arasites , due in arasites ,6. In th Malaria parasites retain a non-mevalonate/methylerythritol phosphate (MEP) pathway for isoprenoid precursor synthesis in the apicoplast organelle. This pathway synthesizes two 5-carbon isoprene subunits, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), whose sequential condensation is critical for making diverse longer-chain isoprenoids required for a variety of key cellular functions that include protein prenylation, dolichol synthesis for protein glycosylation, and biosynthesis of mitochondrial ubiquinone and heme A . Core enPlasmodium therefore requires the apicoplast and the pathways that support and maintain this key organelle.Within the apicoplast, isoprenoid precursor synthesis requires the support of several additional metabolic pathways. The final 2 enzymes in the MEP pathway, IspG and IspH, contain essential Fe-S cluster cofactors that receive electrons from apicoplast-targeted ferredoxin, which also contains an Fe-S cluster. These critical Fe-S cofactors are produced by the apicoplast Suf pathway, which is therefore essential for isoprenoid synthesis \u201310. One Plasmodium focused almost exclusively on cellular roles for isoprenoids outside of the apicoplast, since exogenous IPP can rescue parasites from loss of the apicoplast and the attendant ablation of endogenous IPP synthesis. Nevertheless, multiple prior papers reported that MEP pathway inhibitors like fosmidomycin (FOS) blocked apicoplast biogenesis and prevented elongation of the organelle in blood-stage parasites . Sev. Sev4]. The foundational discovery that exogenous IPP could rescue parasites from apicoplast-specific dysfunctions and organelle loss enabled many opportunities to probe the functional properties of the apicoplast and its constituent proteins . BecauseP. falciparum [Plasmodium will be required for organelle maintenance due to a critical role in IPP synthesis and/or in other aspects of apicoplast biogenesis apart from IPP synthesis. Future studies of apicoplast functions can test this prediction and extend or revise its validity to different parasite stages in distinct host environments, where additional apicoplast pathways like type II fatty acid synthesis can produce essential outputs [Current knowledge specifies IPP and coenzyme A (CoA) as the only biosynthetic outputs of the apicoplast that are essential for blood-stage lciparum ,19,20. Ulciparum ,19. Base outputs ,22 that Plasmodium, this paradigm of metabolic interdependence does not appear to hold throughout the phylum Apicomplexa. Toxoplasma gondii parasites express 2 PPS homologs but neither appears to localize to the apicoplast [T. gondii, loss of isoprenoid precursor synthesis has no apparent impact on apicoplast biogenesis [Plasmodium and Toxoplasma presumably reflect the differing selective pressures that guided evolution of these parasites over the 600 Myr timeline of their divergence from a common ancestor. Multiple PPS homologs are also retained by other hematozoan parasites  that are more closely related to Plasmodium than Toxoplasma, but a possible role for PPS in apicoplast biogenesis is unexplored in these organisms. Understanding the similarities and differences in isoprenoid metabolism between broader apicomplexan parasites can unveil and unravel the biochemical forces that have spurred evolution of intracellular parasitism along distinct pathways.The MEP pathway for isoprenoid precursor synthesis is a hallmark of apicoplast retention in apicomplexan parasites . Althougicoplast ,23,24. Aogenesis ,25. ThesP. falciparum parasites that we hope will stimulate future studies in these areas.Below, we lay out several key questions at the frontier of our understanding of the apicoplast and isoprenoid metabolism in Why does apicoplast biogenesis require long-chain linear isoprenoids? We hypothesize that these lipids are critical to tune the biophysical properties and flexibility of apicoplast membranes, such that their deficiency impairs membrane expansion during organelle biogenesis. It remains unknown if these isoprenoids are enriched in specific or all apicoplast membranes and/or serve other roles in organelle biogenesis. It may be possible to test our hypothesis with small-molecule dyes whose fluorescence properties are sensitive to variations in membrane fluidity, together with chemical rescue experiments using a homologous series of progressively longer-chain polyprenols to bypass loss of PPS.How are isoprenoids transported into and out of the apicoplast? Isoprenoid precursors synthesized in the apicoplast, including IPP and DMAPP, are required and utilized outside the organelle. Chemical rescue experiments suggest that IPP and longer isoprenoids can enter the apicoplast. Charged metabolites face an unfavorable energetic barrier to diffuse across the 4 hydrophobic membrane bilayers that encircle the apicoplast, but specific protein transporters that enable their passage into and out of the organelle remain undefined.What prenyl synthase supports the biosynthesis of ubiquinone required in the Plasmodium mitochondrion? Ubiquinone, which has a polyprenyl tail, is critical for function of the mitochondrial electron transport chain. A mitochondrial-targeted polyprenyl synthase has been identified in T. gondii [Plasmodium remain obscure and poorly studied. Apicoplast PPS was proposed to play this role in Plasmodium [. gondii , but theasmodium , but theasmodium .Are there additional metabolic uses of isoprenoids by malaria parasites beyond currently defined products? Plasmodium lacks enzyme homologs for terpene and carotenoid biosynthesis, and recent work found no evidence to support IPP incorporation into carotenoids [otenoids ,3,15. Ne"}
+{"text": "Patients with traumatic brain injury (TBI) or head trauma present challenges for emergency physicians and neurosurgeons. Traumatic brain injury is currently a community health issue. For the best possible care, it is crucial to understand the various helpful therapy techniques in the pre-operative and pre-hospital phases. The initial rapid infusion of large volumes of mannitol and a hypertonic crystalloid solution to restore blood pressure and blood volume is the current standard of care for people with combined hemorrhagic shock (HS) and traumatic brain injury. The selection and administration of fluids to trauma and traumatic brain injury patients may be especially helpful in preventing subsequent ischemic brain damage because of the hemodynamic stabilizing effects of these fluids in hypovolemic shock. Traumatic brain injury is an essential factor that may lead to disability and death in a patient. Traumatic brain damage can develop either as a direct result of the trauma or as a result of the initial harm. Significant neurologic problems, such as cranial nerve damage, dementia, seizures, and Alzheimer's disease, can develop after a traumatic brain injury. The comorbidity of the victims may also be significantly increased by additional psychiatric problems such as psychological diseases and other behavioral and cognitive sequels. We review the history of modern fluid therapy, complications after traumatic brain injury, and the use of fluid treatment for decompressive craniectomy and traumatic brain injury. The term \"traumatic brain injury\" (TBI) is most often used to describe brain dysfunction brought on by external trauma. Many types of traumatic injuries happen worldwide, and traumatic brain injury is one of the most contentious health issues in modern society . The CenAn essential part of surgical treatment is administering perioperative fluids, although this process is frequently not completely understood and is still primarily empirical. There are lingering concerns regarding its effectiveness and potential consequences ,11. FluiMethodologyWe undertook a\u00a0search through PubMed, CENTRAL and other government sources in November 2022 using keywords such as \"traumatic brain injury\", \"fluid resuscitation\", \"brain injury\", \"brain trauma\", and \"colloid solutions\"((( traumatic brain injury [Title/Abstract]) OR (\"traumatic brain injury\" [MeSH Terms]), (\"fluid resuscitation\" [Title/Abstract])) OR (\"fluid resuscitation\" [MeSH Terms]), ((\"brain injury\" [Title/Abstract]) OR (\"brain injury\" [MeSH Terms]) AND (\"brain trauma\" [Title/Abstract]) OR (\"brain trauma\" [MeSH Terms]). One reviewer independently checked the papers retrieved based on title and abstract against the inclusion criteria before moving on to the full texts. Another reviewer also reviewed 20% of these studies to validate inclusion studies. The selection of studies Figure  dependedThe evolution of modern fluid therapyThe importance of intravenous fluid therapy in treating cholera initially emerged in the 1830s, thanks to William Brooke O'Shaughnessy's findings on the blood observations of his suffering cholera patients ,25. It wCrystalloidsSmall, water-soluble molecules that make up a crystalloid fluid can quickly diffuse across semi-permeable barriers. These solutions' tonicity  and sodium content (which affects how they are distributed throughout the body compartments) together greatly influence their features . They reColloidsColloids are liquids that impose oncotic pressure on semi-permeable membranes because they are composed of larger, more soluble molecules that are difficult to penetrate. Through osmosis, water is retrieved from the interstitial and international classifications of functioning based on their shape, molecular weight, capillary permeability, and ionic charge. They exit the intravascular region and act for a specific time . All colTraumatic brain injury and fluid therapyOedema development is not significantly impacted by clinically appropriate fluid restriction. The first investigation on human fluid therapy showed that decreasing the standard maintenance volume by 50% for neurosurgical patients causes an increase in serum osmolality over about a week . TherefoFluid treatment for decompressive craniectomyBased on experience, it is suggested that decompressive craniectomy in traumatic epidural hematoma patients improves these patients' outcomes . The genPhysiological reactions in the perioperative stageThe effects of surgery alone and the resulting adjustments to the hormonal environment inside the body are exacerbated in critically ill patients by a systemic inflammatory response that leads to capillary leak development. As a result, the interstitium endures losses that are challenging to balance and frequently display oedema. Additionally, nutritional support and actions that alter acid-base homeostasis can actively or inadvertently influence the fluid and electrolyte imbalances that result in severe illness . The effTable Traumatic brain injury (TBI) is a greater community or social health problem that increases mortality and disability. Traumatic brain injuries can result from physical attacks, sports-related injuries, traffic accidents, etc. The development of therapeutic procedures for TBI recovery has been ongoing for many years, even though there is currently no effective treatment for TBI rehabilitation. For the best possible care, it is crucial to understand the various helpful therapy techniques in the pre-operative and pre-hospital phases. There are still questions concerning the benefits and dangers of perioperative fluid therapy. The rapid infusion of large crystalloids to restore blood volume and blood pressure is now the standard treatment for patients with combined traumatic brain injury (TBI) and hemorrhagic shock (HS). Crystalloid fluid therapy is more effective than colloid fluid therapy in patients with TBI. There are no standards of care or evidence-based guidelines for managing fluid treatment in patients having decompressive craniectomy."}
+{"text": "Suicide is a major health problem, mostly related to mental health disorders. However psychological autopsies have revealed the presence of unexpected suicide factors such as dietary patterns particularly folate intake. Which is a naturally occurring form of B9 essential for neurogenesis, nucleotide synthesis and methylation of homocysteine.The aim of our study is to identify the link between folate intake and suicidality.Our literature review was based on the PubMed interface and adapted for 2 databases: Science Direct and Google Scholar using the following combination ( suicide [MeSH terms]) AND (folate [MeSH terms]) AND (prevention [MeSH terms]).Stress-induced neuronal dysfunctions interact with genetic and environmental factors, including diet, to precipitate mental health disorders in vulnerable or predisposed individuals especially mood disorders.In one hand, studies showed delayed onset of clinical improvement even treatment resistance in depressive patients treated with fluoxetine associated with low folate levels.In the other hand Folate depletion has been linked to serotoninergic metabolism disturb.Moreover, co-administration of methylfolate, a highly absorbable form of folic acid, has been found to augment the effects of SSRIs .A duration-response analysis (1-mg dosage) revealed a 5% decrease in suicidal events per month of additional treatment.Accumulating data have shown that these nutrients can enhance neurocognitive function, and may have therapeutic benefits for depression and suicidal behaviors . But the pathological mechanism remains unclear that\u2019s why further studies are needed for a better comprehension and efficiency.None Declared"}
+{"text": "Other distinct clinical features include keratocystic odontogenic tumors, dyskeratotic palmar and plantar pitting, and skeletal abnormalities. Clinicopathological findings of the syndrome are very diverse, and many symptoms manifest during a certain period of life. We present the compelling whole-body bone scan and"}
+{"text": "Synthetic glucocorticoids (sGCs) are a well-investigated and standard drug therapy for disorders associated with CNS inflammation. Less is known about treating psychiatric disorders associated with neural autoantibodies. Our aim is to elucidate the repositioning of sGCs in psychiatric diseases that co-exist with neural autoantibodies. We used PubMed to identify articles for this narrative review. To our knowledge, no randomized, placebo-controlled trials have yet been conducted on applying sGC to treat neural autoantibody-associated psychiatric disorders. We describe initial results of cohort studies and single cases or case series often associated with autoantibodies against membrane-surface antigens demonstrating a largely beneficial response to sGCs either as monotherapy or polytherapy together with other immunosuppressive agents. However, sGCs may be less efficient in patients with psychiatric diseases associated with autoantibodies directed against intracellular antigens. These results reveal potential benefits of the novel usage of sGCs for the indication of neural autoantibody-associated psychiatric disease. Further large-scale randomized, placebo-controlled trials are needed to discover whether sGCs are safe, well tolerated, and beneficial in subgroups of neural autoantibody-associated psychiatric diseases. The term drug repurposing refers to employing old drugs for a new purpose, as for another disease category. Two additional subconditions of drug repurposing beyond its superordinate concept are distinguished, namely, drug repositioning and drug reformulation. Drug repositioning means employing an old formula for a new indication, whereas drug reformulation requires either the application of a novel dosage or a novel route, or even both. In our review, we focus on the drug repositioning of steroids in psychiatric disease limited to those patients presenting serum and/or CSF neural autoantibodies. In our review article, we refer only to synthetic glucocorticoids  as they are currently applied in treating diseases involving CNS inflammation. sGCs orchestrate various cellular functions, such as inflammation  application. We excluded patients with neurological disorders apart from dementia, internal medicine diseases, such as pancreatitis, autoimmune encephalitis with a mixed neuropsychiatric or no pure psychiatric symptoms, and psychiatric syndromes associated with non-neural antibodies, such as thyroid antibodies. The efficacy of sGCs has been proven in patients with autoimmune encephalitis associated with membrane-surface autoantibodies  antibodies]. Concerning autoimmune encephalitis following the Graus criteria . There is evidence that the origin of neural autoantibody-associated psychiatric disease is organic, as in autoimmune encephalitis  antibodies and partly responsive to polyimmunotherapy, including sGCs  who underwent this therapy for autoimmune dementia  of patients Table , whereasA large recent chart review study by Endres et al.  showed tDifferent sGC mechanisms with a major impact on neural autoantibody-associated psychiatric disease should be mentioned. First, sGCs can enhance emotional memory by increasing hippocampal activity during the encoding of emotional stimuli , our review data point to a new direction in psychiatry that has emerged in recent years and should be pursued further. However, the use of sGCs must be seriously reconsidered when potent alternative immunotherapeutic drugs such as IVIGs and plasmapheresis are available, in case side effects such as exacerbation of psychiatric symptoms should occur. In every case, a critical risk\u2013benefit evaluation should be made especially in cases with isolated psychiatric syndromes and lacking neural autoantibody detection in CSF."}
+{"text": "Waiting and stopping are essential and distinct elements of appropriate behavioral control with its dysfunction implicated in various impulsivity related mental disorders. Although rodent and human studies have investigated both phenomena, the role of preparing to stop in waiting impulsivity has rarely been investigated. Furthermore, convergent evidence from multi-modal investigation tools remains a poorly utilized approach in addressing such questions.Here, we conducted two separate, but hierarchical studies, using functional magnetic resonance imaging (fMRI) to map the neural circuit involved in waiting impulsivity and proactive stopping, and subsequently provide mechanistic and causal evidence of disruption of this circuit by transcranial magnetic stimulation (TMS). In the second study, based on our fMRI study data, we attempted to investigate possible causation between the LIFG and waiting impulsivity by modulating LIFG, i.e. non-invasively producing a \u201cvirtual lesion\u201d with an inhibitory transcranial magnetic stimulation (TMS) protocol called continuous theta burst stimulationWe recruited 41 healthy volunteers who performed an adapted version (1CSRT) of the well-established 5 choice serial reaction time task to capture waiting impulsivity. We developed a novel task measuring proactive inhibition. We scanned participants while completing these two tasks. Our fMRI data showed a strong association between LIFG activity and waiting impulsivity on the 1CSRT task. We conducted a single-blind, randomized, between-subjects design of cTBS of the LIFG on a sample of 51 healthy volunteers who completed an adapted version of the 1CSRT task (2CSRT task). Our a priori hypothesis was that cTBS would transiently decrease local cortical activity of the LIFG and increase the frequency of premature responses on both fixed and delayed cue-target interval trials on the 2CSRT task.We first show a shared neural network comprising the pre-supplementary motor area and bilateral anterior insula underlying both waiting impulsivity and proactive stopping. We further demonstrate activity in dorsomedial prefrontal cortex and left inferior frontal gyrus (LIFG) negatively correlated with waiting impulsivity in trials with additional target onset delay. We demonstrate active stimulation significantly increased waiting impulsivity.In these two studies, we validated a novel task measuring proactive inhibition. We further validated the significance of task structure for assessing distinct aspects of impulsivity, which is of translational interest. We further established a causal role of lIFG for waiting impulsivity thus highlighting the integrity of LIFG and related neural circuitry required in waiting impulsivity.None Declared"}
+{"text": "In November 2022, the Centers for Disease Control and Prevention updated a 2016 practice guideline for opioid prescription.The 2022 Centers for Disease Control and Prevention guideline reiterates that clinicians should prescribe opioids at the lowest effective dose for the expected duration of pain warranting opioid use. The guideline also endorses patient-centered approaches to the initiation or taper of opioids. Clinicians should discuss benefits and risks of opioids and consider patient preference. The 2022 guideline further suggests that clinicians \u201cevaluate benefits and risks with patients within 1-4 weeks of starting opioid therapy for subacute or chronic pain or of dosage escalation.\u201d This recommendation is particularly relevant to the chronic management of patients who begin opioids for hidradenitis suppurativa, erosive lichen planus, or chronic ulcerating conditions, or even in the emergency department, where opioids are frequently prescribed for cellulitis and abscess.Postsurgical pain management comprises the majority of opioid prescriptions among dermatologists.An added 2022 recommendation outlines the use of prescription drug monitoring or high-sensitivity screening questions to mitigate opioid prescriptions to patients at higher risk for substance use. This recommendation is accompanied with the caveat that prescription drug monitoring data should be used with \u201call patients rather than differentially on the basis of assumptions about what [clinicians] will learn about specific patients.\u201d The 2022 guideline also uses five new guiding principles, which emphasize an individualized, flexible, and multidisciplinary approach to opioid prescription. The fifth guiding principle encourages culturally informed communication to promote access to affordable, diversified pain management regimens and recognizes the role of bias in pain management. The 2022 guideline update is an important step toward thoughtful, safe, and patient-centered opioid stewardship. Dermatologists should continue to build on this national policy update and consider more specific opioid appropriateness recommendations for chronic, nonsurgical dermatologic conditions.None disclosed."}
+{"text": "N-glycans stabilized the ligand-binding domain dimer via cation/anion binding and modulated receptor gating properties using electrophysiology. Our findings provide vital structural and functional insights into the unique KAR gating mechanisms.Kainate receptors (KARs) belong to the family of ionotropic glutamate receptors (iGluRs) and are tetrameric ligand-gated ion channels that regulate neurotransmitter release and excitatory synaptic transmission in the central nervous system. While KARs share overall architectures with other iGluR subfamilies, their dynamics are significantly different from those of other iGluRs. KARs are activated by both full and partial agonists. While there is less efficacy with partial agonists than with full agonists, the detailed mechanism has remained elusive. Here, we used cryo-electron microscopy to determine the structures of homomeric rat GluK2 KARs in the absence of ligands (apo) and in complex with a partial agonist. Intriguingly, the apo state KARs were captured in desensitized conformation. This structure confirms the KAR desensitization prior to activation. Structures of KARs complexed to the partial agonist domoate populate in domoate bound desensitized and non-active/non-desensitized states. These previously unseen intermediate structures highlight the molecular mechanism of partial agonism in KARs. Additionally, we show how"}
+{"text": "Magnetic resonance imaging (MRI) has several advantages over computerized tomography (CT) in the treatment planning of central nervous system (CNS) malignancies. The adoption of hybrid MRI and linear accelerators (MRLs) has allowed for more effective tumor control and reduced unnecessary neurotoxicity through precise daily adaptations. In this review, we provide a summary of the evidence for MRLs in the management of various CNS tumors. Additionally, we discuss the potential of multiparametric MRI and genomically guided radiotherapy to enhance patient outcomes.Magnetic resonance imaging (MRI) provides excellent visualization of central nervous system (CNS) tumors due to its superior soft tissue contrast. Magnetic resonance-guided radiotherapy (MRgRT) has historically been limited to use in the initial treatment planning stage due to cost and feasibility. MRI-guided linear accelerators (MRLs) allow clinicians to visualize tumors and organs at risk (OARs) directly before and during treatment, a process known as online MRgRT. This novel system permits adaptive treatment planning based on anatomical changes to ensure accurate dose delivery to the tumor while minimizing unnecessary toxicity to healthy tissue. These advancements are critical to treatment adaptation in the brain and spinal cord, where both preliminary MRI and daily CT guidance have typically had limited benefit. In this narrative review, we investigate the application of online MRgRT in the treatment of various CNS malignancies and any relevant ongoing clinical trials. Imaging of glioblastoma patients has shown significant changes in the gross tumor volume over a standard course of chemoradiotherapy. The use of adaptive online MRgRT in these patients demonstrated reduced target volumes with cavity shrinkage and a resulting reduction in radiation dose to uninvolved tissue. Dosimetric feasibility studies have shown MRL-guided stereotactic radiotherapy (SRT) for intracranial and spine tumors to have potential dosimetric advantages and reduced morbidity compared with conventional linear accelerators. Similarly, dosimetric feasibility studies have shown promise in hippocampal avoidance whole brain radiotherapy (HA-WBRT). Next, we explore the potential of MRL-based multiparametric MRI (mpMRI) and genomically informed radiotherapy to treat CNS disease with cutting-edge precision. Lastly, we explore the challenges of treating CNS malignancies and special limitations MRL systems face. Central nervous system (CNS) tumors pose unique and significant challenges for oncologists. As the understanding of CNS tumors continues to improve, innovative approaches and advancements in radiotherapy techniques are needed to take advantage of these insights to improve patient outcomes. The integration of magnetic resonance imaging (MRI) with linear accelerators (MRLs) has allowed for adaptive magnetic resonance-guided radiotherapy (MRgRT), which has emerged as a promising modality for increased personalization in radiation therapy for treating CNS tumors.MRI plays a central role in both the diagnosis and evaluation of CNS tumors due to its excellent soft tissue imaging and ability to visualize the boundaries between the tumor and normal tissues ,2. High-2 fluid-attenuated inversion recovery (FLAIR) sequence and a true fast imaging with steady-state free precession (TRUFI) sequence [The advent of MRLs marked a revolutionary step in the field of MRgRT for CNS tumors ,7. In adsequence  of a heaIn the subsequent sections, we discuss the unique challenges and limitations associated with treating adult patients with CNS tumors using traditional radiotherapy methods and how MRgRT offers a potential solution to address these issues. Specifically, we explore the role of MRgRT in the treatment of glioblastoma (GBM) and the unique ability of MRLs to detect subtle soft tissue changes and plan adaptation to improve tumor targeting and reduce dose to surrounding healthy tissue . FurtherIn accordance with the guidelines established by the Radiation Therapy Oncology Group (RTOG), the postoperative GBM target includes both the surgical cavity and the adjacent edema . This apAlthough conducting MRI scans throughout RT to account for these changes would be ideal, it is not feasible due to limited scanner availability and cost constraints. Unfortunately, CT-guided radiotherapy (CTgRT) does not adequately account for parenchymal changes because of its inadequate soft tissue contrast. MRLs may offer a solution, as they allow for superior soft tissue contrast to detect subtle geometric changes and for online plan adaptation to account for tumor and post-operative bed changes during therapy. The need for geometric plan adaptation is highlighted in a prospective study involving 61 GBM patients who underwent chemoradiotherapy (CRT) and received diagnostic brain MRIs at planning, fraction 10, fraction 20, and one-month post-CRT. Significant anatomical changes were observed throughout therapy . The stup = 0.036) versus 20.6 Gy (p = 0.005), respectively [A recent study investigated the potential benefits of adaptive radiotherapy for GBM patients using an MRL system . The stuectively . MultiplIn summary, treatment of GBMs with MRLs is associated with improvements in dosimetry and treatment planning due to its ability to detect subtle soft tissue changes and facilitate plan adaptation. Additionally, MRLs can account for changes in the tumor and tumor bed throughout treatment to ensure better target coverage while minimizing unnecessary dose to normal brain parenchyma. Future studies are needed to determine if this translates into better disease control durability and if better normal tissue sparing results in quality-of-life improvements for these patients.SRT is an important modality in the management of brain metastases and other intracranial tumors . An MRL Several studies have explored the dosimetric feasibility of MRgRT for intracranial SRT ,18,19,20Another study examined the dosimetric feasibility of direct post-operative MRL-based SRT for resection cavities of brain metastases, concluding that direct post-operative MRL-based SRT is dosimetrically acceptable, with benefits including increased patient comfort and logistics . StreamlCollectively, the above studies indicate that MRgRT using an MRL has the potential to offer dosimetric and logistical advantages over conventional linear accelerators for intracranial SRT treatment. However, further clinical investigations are necessary to evaluate the clinical benefit of this technology.Spine SRT plays a critical role in managing metastatic disease by alleviating pain, preventing pathological fractures, and reducing neurological morbidity. Stereotactic body radiotherapy (SBRT) has been shown to provide improved efficacy compared with conventional radiotherapy methods . For spiMRLs offer several advantages over CTgRT, including MR imaging in treatment position to allow for easier fusion with the planning CT and superior spinal cord delineation during setup compared with cone-beam CT (CBCT) ,23. DosiSeveral clinical trials are currently investigating the use of MRL in spine SRS/SBRT. These studies will provide valuable insights into the feasibility and effectiveness of this technique for spine treatment. For example, a phase I/II trial is examining the use of Stereotactic MR-guided Adaptive Radiotherapy (SMART) for treating various disease sites, including the spine (NCT04115254). Additionally, the Pilot Study of Same-session MR-only Simulation and Treatment with SMART for Oligometastases of the Spine (NCT03878485) focuses specifically on spine treatment.As more clinical data emerge from these studies, the potential benefits of MRL in spine SRT will become clearer. The integration of MRI with linear accelerators for spine treatment may lead to improved tumor targeting, reduced normal tissue exposure, and better patient outcomes. Ultimately, these advancements may help optimize radiotherapy for patients with metastatic spine disease and contribute to the ongoing evolution of spine SRT techniques.HA-WBRT is a promising technique that aims to achieve the local control benefits of whole brain RT for both macro- and micro-metastatic lesions, while reducing neurotoxicity by specifically avoiding the hippocampus . HA-WBRTParticularly for patients with numerous brain metastases of radioresistant histology, HA-WBRT with a simultaneous integrated boost to gross disease may be an effective strategy ,56, one One of the fundamental goals of radiotherapy is maximizing the dose to target tissue while minimizing the dose to surrounding OARs. In a significant first step towards this aim, MRLs have facilitated treatment plan adaptation to observable anatomic changes throughout therapy. MRLs, however, may be able to enable biological plan adaptation by leveraging MRI\u2019s capability to track biological and physiological changes through advanced mpMRI techniques. These techniques may allow radiation oncologists further insight into a tumor\u2019s biology as it responds to RT over the course of treatment.The treatment paradigm of radiotherapy has traditionally been based on empirical large cohort data rather than individual biology, resulting in a one-size-fits-all approach. However, recent advancements in genomics and radiomics have begun to pave the way towards a more personalized approach based upon individual tumor biology. The synergy between genomically informed radiotherapy, treatment of high-risk sub-volumes based on extraction of radiographic data, and daily mpMRI-guided plan adaptation has the potential to usher in a new treatment paradigm in radiation oncology. Pre-treatment genomic and radiomic analyses of the tumor may improve patient selection for MRL-based dose escalation ,57,58. DThe currently active phase II Habitat Escalated Adaptive Therapy (HEAT), With Neoadjuvant Radiation for Soft Tissue Sarcoma (NCT05301283) is an example of a cutting-edge study utilizing genomic and mpMRI radiomic biomarkers to guide the initial treatment and adaptive treatment approach for high-grade soft tissue sarcomas. Utilizing a similar approach for CNS tumors appears to be technically feasible currently. For example, genomic-adjusted radiation therapy (GARD) could be similarly utilized to identify GBM patients who could benefit from higher doses  with MRIMRL is poised to take a central role at the forefront of this paradigm shift to allow for plan adaptation based not only upon geometric shifts but also on a tumor\u2019s evolving treatment response throughout therapy. An ultra-personalized treatment approach like this allows for total dose, dose distribution , and fractionation changes throughout the course of therapy to improve clinical outcomes for patients. Historically, daily MRgRT plan adaptation has been utilized to manage interfractional geometric changes. However, MRI is also capable of assessing biological and physiological information using advanced mpMRI techniques ,67,68,69One such technique is diffusion-weighted imaging (DWI), which enables the detection of water mobility changes . These a1 relaxation time following a bolus injection of gadolinium [1, T2, and ADC [Dynamic contrast-enhanced (DCE) MRI is another functional imaging technique that investigates perfusion by dynamically evaluating changes in the Tdolinium ,83. Thisdolinium . DCE hasdolinium . As a redolinium . DCE has and ADC . While D and ADC .Additional MR-based techniques, such as magnetic resonance spectroscopic imaging (MRSI) , chemicaAlthough none of the CNS-specific trials within Genomics provides another powerful avenue towards personalized radiation treatment, which when combined with the advances in image guidance listed above, may provide an even more sophisticated approach for challenging malignancies such as GBM. Several such signatures have been introduced as a potential means for genomically guided RT ,109,110.In summary, MRL can be leveraged by incorporating genomically guided RT and mpMRI radiomics to enable a biologically adaptive RT paradigm. Various mpMRI techniques, including DWI, DCE, MRSI, and CEST, have the potential to offer valuable insights into tumor biology and physiology, ultimately leading to more personalized and effective treatment strategies. Using these technologies to identify intratumoral heterogeneity and tumoral sub-volumes at risk may allow for focal dose escalation or avoidance, respectively. As research and development continues in this area, we expect significant advancements in the application of these techniques, potentially revolutionizing the management of CNS tumors.MRgRT offers significant advancements for image-guided radiation therapy (IGRT) and personalized oncology in CNS tumor treatment, but there are certain limitations to be considered. These include substantial financial and time investments for training and operation, development of MR-safety protocols, and unique physical challenges related to the concurrent use of MR and external beam radiotherapy ,116,117.Treating CNS tumors on an MRL presents several unique challenges. The complex anatomy of the CNS, with its highly radiosensitive normal tissues, requires precise targeting and dose delivery. The proximity of critical structures, such as the optic nerves, brainstem, and spinal cord, demands meticulous treatment planning and delivery. Furthermore, CNS tumors often exhibit infiltrative growth patterns, making it almost impossible to accurately delineate tumor boundaries.MRL systems suffer the same limitations as diagnostic MRIs. As such, they\u2019re sensitive to the magnetic susceptibility artifacts that arise from air\u2013tissue  and boneGeometric distortion represents one of the most difficult challenges to account for with any MRgRT. Geometric distortion occurs due to imperfections in the magnetic field, gradient nonlinearities, and magnetic susceptibility differences at tissue interfaces . This caTreatment of CNS tumors on MRLs represents a promising direction for the advancement of personalized cancer care. MRLs provide excellent soft tissue visualization, real-time monitoring of targets and normal tissues with gating capabilities, and the ability for daily plan adaptation. These unique advantages hold the potential to improve radiation delivery to patients with intracranial or spine tumors. Clinical trials are currently underway and seek to clarify the role of MRLs in the treatment of CNS malignancies. Future clinical studies are needed to explore the integration of mpMRIs and genomics to develop a biologically adapted radiation therapy paradigm for CNS tumors."}
+{"text": "Fungal infections are increasingly associated with critical illness, especially in major burn injury. The risk factors of invasive fungal infections include central venous catheter (CVC) placement, mechanical ventilation, broad-spectrum antibiotics, renal replacement therapy (RRT), and total parental nutrition. Critically ill burn patients have additional risk factors including extensive wounds, impaired immune system, and repeated surgical intervention. Despite significant morbidity and mortality caused by invasive fungal infections, efforts to prevent them with antifungal prophylaxis have not improved outcomes. In patients who develop invasive fungal infection, appropriate empiric antifungal therapy is imperative to reduce morbidity and mortality especially in the setting of delayed culture and sensitivity data. The purpose of this study was to characterize risk factors associated with the development of invasive fungal infection, invasive fungal infection organisms and surgical and pharmacological management.A retrospective chart review was completed of adult patients admitted to the burn ICU found to have an invasive fungal infection . The primary outcome was to identify common fungal organisms. Secondary outcomes included susceptibility pattern of the organism, location of infection, surgical management including debridement and amputation, pharmacological management, median ICU and hospital length of stay, and in hospital mortality.A total of 10 patients of a goal of 100 patients with a median 54% TBSA burns were evaluated at this time. The most common yeast species included candida albicans; mold species included a variety of organisms such as fusarium, zygomycete and paecilomyces. Common risk factors among these patients included CVC access (57%), mechanical ventilation (43%), and RRT (43%). Yeast infections were primarily treated with anidulafungin and fluconazole, while mold infections were managed with systemic amphotericin as backbone in addition to voriconazole or isavuconazole. Patients underwent aggressive surgical debridement for source control. Median ICU stay was 53 days with a median hospital stay of 63 days, and 42% mortality.Fungal infections among critically ill burn patients are associated with the high morbidity and mortality rates. Therefore, mitigation of modifiable risk factors is of utmost importance. This retrospective review of common fungal growth in our unit will inform future empiric antifungal management for patients with concern of invasive fungal infections.Fungal infections present a clinical challenge for burn practitioners, especially in geographically moist areas. Prevention and informed surgical and pharmacological management are key to overcoming this infectious disease threat."}
+{"text": "Obesity has become a global health epidemic with profound implications for various medical specialties, including reproductive medicine. This comprehensive review focuses on the anesthetic evaluation and management of obese patients undergoing in vitro fertilization (IVF) procedures. Obesity, as defined by BMI, is associated with infertility and poses unique challenges for anesthetic care. The review also addresses the timing of anesthesia concerning IVF procedures, the impact of obesity on IVF success rates, and the importance of emotional and psychological support for obese patients undergoing IVF. Challenges and future directions in the field are highlighted, focusing on ongoing research, emerging technologies, and the role of multidisciplinary teams in managing these complex cases. In conclusion, this review underscores the critical role of tailored anesthesia and perioperative care in optimizing outcomes for obese patients undergoing IVF. It provides valuable insights for anesthetic providers, reproductive specialists, and healthcare teams, emphasizing the need for a patient-centered approach to address the unique challenges posed by obesity in the context of assisted reproductive technology. Obesity has emerged as a global health epidemic, affecting millions of individuals worldwide and presenting a significant public health challenge. In 2005, approximately 1.6 billion adults globally were overweight BMI: 25-30 kg/m2), and at least 400 million were obese (BMI: >30 kg/m2). By 2015, these numbers had escalated to 2.3 billion and 700 million, respectively [0 kg/m2, Obesity and IVF: an overviewDefinition of Obesity and Its ClassificationObesity is a complex health condition marked by excessive adipose tissue accumulation in the body. BMI is the most commonly used metric for defining and categorizing obesity, as classified by the WHO in Table Prevalence of Obesity and Its Association With InfertilityThe global prevalence of obesity has witnessed a concerning and continuous rise in recent decades, emerging as a significant public health issue. Research indicates that this surge in obesity rates has far-reaching consequences, including its profound impact on reproductive health, both in men and women. The association between obesity and infertility is a growing concern within the medical community, as it sheds light on the intricate interplay between body weight and reproductive function .In womeImportance of IVF as a Fertility Treatment OptionOvercoming ovulatory disorders: Obesity is often intricately linked with ovulatory disorders, such as PCOS, which can hinder natural conception. IVF is particularly advantageous as it effectively bypasses these ovulatory challenges. Through IVF, eggs are directly harvested from the ovaries, ensuring a steady supply of eggs for fertilization, thereby circumventing the irregular ovulation associated with PCOS .ControlAnesthetic evaluation of obese women patientsPreoperative Assessment and Patient HistoryEvaluation of comorbidities: The preoperative assessment of comorbid conditions is paramount, particularly in obese patients undergoing surgical procedures. Obesity is often accompanied by a higher prevalence of medical comorbidities, necessitating a thorough evaluation to manage patient risks comprehensively. Conditions such as diabetes, hypertension, cardiovascular disease, and obstructive sleep apnea (OSA) are frequently encountered in the obese population and can significantly influence anesthesia management. Assessing these comorbidities' nature, severity, and control is critical in determining the patient's perioperative risk profile. This assessment is a foundation for tailoring anesthetic strategies and optimizing patient safety .MedicatPhysical Examination in Obese PatientsAssessment of airway anatomy: Obese patients often present unique challenges related to their airway anatomy. Limited neck mobility, short and thick necks, and excess tissue in the oropharyngeal and supraglottic areas may characterize their airways. These anatomical variations can complicate airway management significantly during anesthesia induction and intubation. Anesthesiologists must carefully consider these factors and employ suitable airway management strategies, such as specialized equipment or alternative airway approaches, to mitigate potential difficulties and ensure safe ventilation .EvaluatLaboratory Tests and InvestigationsComplete blood count (CBC): Rather than delving into the definition of a CBC, it is pertinent to elucidate the changes observed in CBC counts within the obese population. Such insights can prove invaluable for healthcare professionals, especially physicians, as they navigate the challenges presented by obesity. In this context, the CBC becomes an essential tool that scrutinizes various blood components, including RBCs, WBCs, and platelets. Each component within the CBC bears crucial information for anesthesia providers during the preoperative evaluation process. For instance, the RBC count and hemoglobin levels are pivotal in assessing the patient's oxygen-carrying capacity. Low values may indicate anemia, a condition that, if left unaddressed, can adversely impact tissue oxygenation during surgery. WBC counts offer insights into the patient's immune status. Deviations from the normal range may indicate underlying infections or inflammatory conditions, necessitating preemptive action before surgery. Platelet counts, vital for normal blood clotting, help in assessing bleeding risks and guiding decisions regarding blood transfusions or medications such as anticoagulants. By examining these hematological parameters and understanding their variations within the obese population, anesthesia providers can make informed decisions to mitigate bleeding risks, optimize oxygen delivery, and ensure a safer perioperative experience .CoagulaAnesthetic Risk StratificationFollowing the comprehensive preoperative assessment, anesthetic risk stratification should be performed. This involves categorizing patients into risk groups based on their comorbidities, physical status, and the nature of the surgical procedure. Standard classification systems include the American Society of Anesthesiologists (ASA) Physical Status Classification and the Charlson Comorbidity Index . AnestheAnesthetic management strategiesPreoperative OptimizationWeight loss and lifestyle modification: Preoperative weight loss and lifestyle modification are proactive and potentially transformative strategies for obese patients embarking on elective surgery, including IVF procedures. These initiatives are driven by the recognition that obesity can engender complex health concerns and perioperative challenges. Here, we delve deeper into the multifaceted aspects of preoperative weight loss and lifestyle modification, elucidating their manifold benefits .ImproveGlycemic ControlCrucial for surgical success: Elevated blood glucose levels in patients with diabetes can heighten the risk of surgical complications, including impaired wound healing, increased infection susceptibility, and cardiovascular events. Achieving and maintaining optimal glycemic control before surgery can mitigate these risks, promoting a smoother and safer perioperative experience .ImplicaAnesthetic choicesGeneral Anesthesia vs. Regional AnesthesiaTable Sedation OptionsPatient comorbidities: Comorbid conditions like cardiovascular disease or OSA should be carefully considered when choosing sedation options. Some medications used for sedation may have hemodynamic effects or exacerbate respiratory compromise, necessitating a tailored approach that minimizes these risks. Additionally, anesthetic providers must monitor vital signs and promptly address adverse reactions .Airway Equipment considerationsSpecially Designed Operating Room Tables and EquipmentBariatric operating tables: Bariatric operating tables are designed to support the weight and dimensions of obese patients effectively. They offer enhanced stability and durability, which is essential during surgical procedures. These tables are more comprehensive and feature robust mechanisms for adjusting patient positioning. This ensures that patients are adequately supported, minimizing the risk of complications related to positioning, such as pressure ulcers or nerve injuries .More coAirway management challengesAdvanced Airway Management SkillsAnesthesia providers should possess advanced airway management skills, allowing them to adapt to the anatomical nuances of obese patients. This includes expertise in various intubation techniques and strategies for optimizing ventilation. Providers should be prepared to handle scenarios where conventional intubation methods may prove challenging .Video LaryngoscopesVideo laryngoscopes are invaluable tools in managing obese patients with difficult airways. These devices incorporate a camera at the tip of the laryngoscope blade, offering a clear view of the airway and vocal cords. This visual aid enhances the accuracy of intubation attempts, even in cases where direct laryngoscopy may be challenging due to anatomical factors .Supraglottic Airway DevicesSupraglottic airway devices, such as the laryngeal mask airway (LMA), are crucial in securing the airway in obese patients. These devices are inserted above the vocal cords and are particularly useful in scenarios where endotracheal intubation is challenging. LMAs provide a secure airway for positive pressure ventilation and can be a bridge to definitive airway management if needed .Comprehensive TrainingAnesthesia providers should undergo comprehensive training in advanced airway management tools and techniques, especially when caring for obese patients. Regular simulation exercises and ongoing education help maintain proficiency and ensure readiness to address airway challenges effectively .Medication dosing in obese patientsInduction AgentsAdjusting for altered pharmacokinetics: Obesity is associated with significant drug distribution and metabolism changes. In particular, the increased adipose tissue content and expanded volume of distribution can lead to prolonged drug effects. As a result, dosing of induction agents like propofol and etomidate should be cautiously approached in obese patients .Consideration of ideal body weight or lean body mass: To prevent the risk of overdosing and subsequent prolonged sedation or respiratory depression, anesthesia providers often base dosing on ideal body weight or lean body mass rather than total body weight in obese patients. Ideal body weight is calculated based on a healthy BMI, which allows for a more accurate alignment of drug dosing with the patient's physiological characteristics .Maintenance AgentsCareful titration based on patient response: Maintenance agents, including inhalational anesthetics and intravenous infusions, require precise titration based on the patient's response. Continuous monitoring of the depth of anesthesia is essential throughout the procedure. Technologies like bispectral index (BIS) monitoring provide real-time feedback on the patient's level of consciousness, enabling anesthesia providers to adjust maintenance agent dosages as needed .Balancing anesthesia depth: The primary goal is to achieve a balanced anesthetic state that ensures patient comfort while minimizing the risks associated with excessive or inadequate anesthesia depth. Overly deep anesthesia can result in delayed emergence, whereas insufficient depth may lead to intraoperative awareness .Neuromuscular Blocking AgentsHigher dosing requirements: Due to the increased volume of distribution in obese patients, higher initial doses of neuromuscular blocking agents (NMBAs) like rocuronium or vecuronium may be necessary to achieve the desired level of muscle relaxation for surgical procedures. This adjustment is crucial to ensure the effectiveness of NMBA-induced paralysis .Monitoring neuromuscular blockade: Train-of-four (TOF) monitoring is paramount when administering NMBAs to obese patients. TOF monitoring assesses the depth of neuromuscular blockade, aiding anesthesia providers in precise dose titration. This approach ensures that the degree of paralysis aligns with the requirements of the surgical procedure, preventing both inadequate blockade and excessive paralysis. Continuous monitoring continues throughout the surgery to guide the administration of reversal agents when necessary, facilitating a smooth recovery .AnalgesicsWeight-adjusted dosing: Pain management is crucial for obese patients during and after surgery. The dosing of analgesics, whether opioids or non-opioid alternatives, should be adjusted to account for weight-related factors. This adjustment ensures that analgesic effects are adequate to control pain effectively while minimizing the risk of overdose .Multimodal analgesia: In obese patients, a multimodal analgesic approach is often favored to reduce reliance on opioids and mitigate their associated side effects, including respiratory depression and postoperative nausea and vomiting. This approach may encompass non-opioid analgesics, regional anesthesia techniques, and adjunct medications like non-steroidal anti-inflammatory drugs (NSAIDs). By combining multiple analgesic modalities, anesthesia providers can enhance pain control and improve the overall safety profile of pain management in obese patients .Ventilation strategiesRisk of Hypoventilation and Respiratory ComplicationsIncreased vulnerability: Obese patients have unique anatomical and physiological characteristics that make them more susceptible to hypoventilation, oxygen desaturation, and postoperative respiratory complications. These challenges stem from decreased lung compliance, reduced functional residual capacity, and a propensity for upper airway obstruction .Positive end-expiratory pressure (PEEP): PEEP\u00a0is often employed to address these concerns. PEEP helps maintain lung volume by preventing alveolar collapse during expiration. This technique aids in improving oxygenation and mitigating atelectasis, which is a common issue in obese individuals during anesthesia and surgery .Monitoring oxygen saturation: Continuous monitoring of oxygen saturation (SpO2) is essential throughout the surgical procedure to promptly detect any declines in oxygen levels. Obese patients may experience rapid desaturation during periods of hypoventilation, making vigilant monitoring crucial for patient safety .Monitoring end-tidal CO2 (ETCO2): Continuous monitoring of end-tidal carbon dioxide (ETCO2) levels, known as capnography, is a fundamental component of anesthesia for obese patients. ETCO2 monitoring provides real-time feedback on ventilation and allows anesthesia providers to detect hypoventilation early. Rising ETCO2 levels can be an early sign of inadequate ventilation, enabling timely intervention to prevent hypercapnia and associated complications .Elevation of the Head of the BedImproved ventilation: During surgery, elevating the head of the bed in obese patients can help improve ventilation. This adjustment assists in reducing the risk of upper airway obstruction, which is more prevalent when patients are supine. Proper positioning is critical to optimize lung mechanics and maintain effective ventilation .Positioning and Pressure Sore PreventionProper patient positioning is crucial to ensure access to the surgical site and prevent pressure sores, especially in obese patients with limited mobility. Pressure-relieving pads and regular position changes should be employed to minimize the risk of skin complications during prolonged procedures. A thorough understanding of these anesthetic management strategies tailored to obese patients is essential for anesthesia providers and healthcare teams to ensure safe and effective care during IVF procedures .Intraoperative and postoperative considerationsHemodynamic MonitoringContinuous surveillance of hemodynamics is paramount in the care of obese patients undergoing IVF procedures. A higher prevalence of cardiovascular comorbidities, such as hypertension, coronary artery disease, and heart failure, often accompanies obesity. As a result, meticulous attention to hemodynamic parameters is essential to detect and manage potential perioperative cardiovascular issues .Blood Pressure MonitoringClose and continuous blood pressure monitoring, including systolic and diastolic measurements, is crucial. Automated non-invasive blood pressure cuffs should be appropriately sized to ensure accurate readings. This ongoing assessment enables anesthesia providers to detect and respond promptly to changes in blood pressure, whether due to surgical manipulation, anesthesia effects, or underlying cardiovascular conditions .Heart Rate MonitoringContinuous heart rate monitoring is vital to detect any arrhythmias or hemodynamic fluctuations promptly. Anesthesia providers must be prepared to address bradycardia or tachycardia as needed during the surgery, ensuring that the patient remains stable throughout the procedure .Cardiac Output AssessmentIn certain high-risk or complex cases, assessing cardiac output may be necessary. This can be achieved through various techniques, including thermodilution or less invasive methods like pulse contour analysis. Monitoring cardiac output provides valuable insights into the patient's circulatory status and helps guide fluid management and vasopressor/inotropic support when indicated .Temperature managementMaintaining normothermia is of paramount importance in the intraoperative care of obese female patients undergoing IVF. These patients present unique considerations due to their larger body surface area and altered thermoregulation. Such factors elevate their susceptibility to perioperative hypothermia, a condition that can have detrimental consequences, including coagulopathy, heightened vulnerability to surgical site infections, and increased cardiovascular stress .To safeguard the well-being of these patients, it is imperative to employ active warming measures specifically tailored to their needs. One widely utilized method involves the use of forced air warming blankets, which deliver warm air directly to the patient's body, helping to counteract the challenges posed by their altered thermoregulation. Furthermore, warmed intravenous fluids can be employed as an effective means to maintain the core body temperature within the desired range for this patient population. Continuous temperature monitoring throughout the IVF procedure is essential, enabling immediate intervention in case of any deviations from the optimal normothermic range .Fluid managementIn fluid management during surgical procedures, particularly for obese patients, two crucial considerations demand attention. Firstly, obese patients are at a heightened risk of overhydration, which can result in severe complications, including pulmonary edema and cardiovascular strain. Therefore, healthcare providers must exercise caution when administering fluids to this patient population. Implementing individualized fluid management strategies tailored to each patient's unique needs is essential. These strategies should be guided by hemodynamic monitoring, and in some cases, invasive measures might be required to ensure precise fluid balance and prevent overhydration .Secondly, preventing complications like pulmonary edema is paramount when caring for obese surgical patients. To achieve this, it is imperative to avoid excessive fluid administration. Instead, the focus should be on optimizing oxygenation levels. Continuous monitoring of oxygen saturation and end-tidal CO2 and a vigilant assessment for early signs of fluid overload, such as crackles during auscultation, must be integral to the surgical team's protocol. By adhering to these meticulous fluid management and monitoring practices, healthcare providers can minimize the risks associated with overhydration and pulmonary edema, ultimately ensuring safer surgical outcomes for obese patients .Postoperative considerationsPostoperative care for obese patients demands a comprehensive and tailored approach to ensure their safety and well-being during recovery. Firstly, transitioning from the operating room to the recovery room necessitates vigilant monitoring. Healthcare providers must closely observe vital signs, oxygen saturation levels, and consciousness levels and remain alert to any signs of postoperative complications, such as respiratory distress or cardiovascular instability. This heightened level of surveillance is crucial in the immediate postoperative phase to promptly address any issues that may arise .Effective pain management is another critical facet of postoperative care for obese patients. Recognizing that they may require higher doses of analgesics due to altered pharmacokinetics, healthcare teams should adopt multimodal analgesic approaches. These approaches should incorporate non-opioid options to minimize the potential for opioid-related side effects while optimizing pain control and ensuring patient comfort .Early mobilization is a cornerstone of postoperative care for obese individuals. Promptly getting patients up and moving helps mitigate the risk of complications associated with immobility, such as atelectasis (lung collapse) and DVT. Collaboration between physical therapists and nursing staff is vital in facilitating early ambulation and encouraging deep breathing exercises, which can significantly contribute to a smoother recovery .Obese patients are particularly susceptible to postoperative complications, notably atelectasis and DVT. Reduced lung compliance and hypercoagulability make them prone to these issues. Therefore, preventive measures should be integrated into the postoperative care plan. This may include using incentive spirometry to promote lung expansion, early ambulation to improve circulation and lung function, and pharmacological thromboprophylaxis to minimize the risk of DVT formation. By implementing these strategies and maintaining a vigilant postoperative care regimen, healthcare providers can help obese patients recover safely and minimize the potential for complications .Special considerations for IVFTiming of Anesthesia and IVF ProceduresThe timing of anesthesia in conjunction with IVF procedures is a critical and intricately coordinated aspect of patient care. Firstly, anesthesia providers must establish a close and seamless collaboration with the IVF team to ensure that anesthesia induction and surgery are perfectly synchronized with the patient's specific IVF protocol. This synchronization is vital to optimize the timing of crucial IVF procedures, including oocyte retrieval, insemination, and embryo transfer, thereby maximizing the chances of a successful outcome .Oocyte retrieval stands out as a pivotal moment within the IVF process. To ensure patient comfort and minimize discomfort during the transvaginal follicular aspiration, anesthesia should be administered before this procedure. The timing and administration of anesthesia at this stage are critical to ease the patient's experience and allow the IVF team to perform the retrieval smoothly and efficiently .Regarding embryo transfer, the anesthesia approach may differ from oocyte retrieval. In many cases, patients may not require general anesthesia for this procedure. Instead, conscious sedation or regional anesthesia techniques may be more appropriate and well-tolerated by patients. The choice of anesthesia should consider the patient's preferences, comfort, and any specific medical considerations. This personalized approach ensures that the patient remains as relaxed as possible during this crucial step of the IVF process, contributing to a positive overall experience .Implications of Obesity on IVF Success RatesReduced oocyte quality: One of the primary consequences of obesity in the context of IVF is the potential for reduced oocyte (egg) quality in obese women. This decline in oocyte quality can manifest as abnormalities, such as irregular chromosome structure and spindle formation. As a result, obese individuals may experience lower fertilization rates and reduced embryo implantation rates during IVF. These challenges can pose significant obstacles to achieving a successful pregnancy .Altered hormonal profiles: Obesity disrupts hormonal profiles in several ways. Notably, it often leads to increased insulin resistance, a condition in which cells become less responsive to the effects of insulin. Additionally, obesity can alter sex hormone levels, causing elevated estrogen and androgen levels while reducing levels of sex hormone-binding globulin (SHBG). These hormonal imbalances can negatively impact ovarian function, potentially leading to irregular menstrual cycles and suboptimal reproductive outcomes .Increased risk of miscarriage: Obese patients undergoing IVF are at an elevated risk of experiencing miscarriages. This heightened risk emphasizes the importance of preoperative health and weight management optimization. Furthermore, during pregnancy, obese individuals require close monitoring to promptly identify and manage any complications that may arise, given the increased risk associated with their condition .Diminished response to medications: Obesity can result in a diminished response to fertility medications used in IVF, particularly gonadotropins. Due to altered pharmacokinetics, obese patients may require higher doses of these medications to stimulate ovarian follicular development effectively. Tailoring medication dosages to individual patient needs is crucial in optimizing IVF outcomes .Increased risk of complications: Obesity is associated with a heightened risk of complications during IVF procedures. Notably, obese individuals may be at an increased risk of developing ovarian hyperstimulation syndrome (OHSS), characterized by enlarged ovaries and fluid accumulation in the abdomen and chest. Additionally, they may face an elevated risk of thromboembolic events, such as blood clots, during the IVF process. Careful management and monitoring are essential to mitigate these risks and ensure the safety and success of IVF procedures in obese patients .Emotional and Psychological Support for Obese Patients Undergoing IVFPatient counseling: Preoperative counseling tailored to IVF's emotional and psychological aspects is essential for obese patients. It's important to create a safe and non-judgmental space where patients can openly discuss their anxieties, body image concerns, and expectations related to fertility treatment. Addressing these issues early can help patients better cope with the emotional rollercoaster often accompanying IVF .Support groups: Obese patients undergoing IVF can benefit immensely from participating in support groups or counseling sessions for individuals facing similar challenges. These groups provide a supportive environment where patients can share their experiences, express their emotions, and receive advice and encouragement from peers who have undergone similar journeys. Connecting with others who understand their unique struggles can be comforting and empowering .Multidisciplinary approach: A holistic approach involving a team of healthcare professionals is crucial. This multidisciplinary team may include psychologists, social workers, dietitians, and reproductive specialists collaborating to provide comprehensive support. Psychologists and social workers can help patients address the emotional impact of infertility and obesity on their mental health, offering coping strategies and emotional resilience tools .Education: Providing patients with accurate and detailed information about the relationship between obesity, IVF, and fertility outcomes is key. Clear and open communication helps patients make informed decisions and manage their expectations realistically. Educating patients about the specific challenges they may face due to obesity and the potential impact on IVF success can help alleviate anxiety and uncertainty .Challenges and future directionsOngoing Research in the FieldObesity-related factors: Researchers are delving into specific obesity-related factors that can influence fertility and IVF outcomes. This includes studying adipokines (hormones produced by fat tissue), inflammatory markers, and genetic predispositions that may impact reproductive health. Understanding the molecular mechanisms underlying these factors can provide insights into potential interventions to improve fertility and IVF success rates in obese patients .Anesthetic techniques: Research in this area evaluates the safety and efficacy of various anesthetic techniques tailored to obese patients undergoing IVF. This may include investigating the benefits and risks of regional anesthesia options, optimizing sedation strategies, and developing drug dosing protocols that account for the altered pharmacokinetics and pharmacodynamics often seen in obese individuals. Finding the safest anesthesia approach can improve patient comfort and procedural outcomes .IVF protocols: Modified IVF protocols designed to address the unique challenges presented by obesity are a critical area of research. Scientists and clinicians are working on optimizing ovarian stimulation regimens to improve oocyte quality and quantity in obese women. Additionally, researchers aim to develop protocols that reduce the risk of complications like ovarian hyperstimulation syndrome (OHSS) in this patient population, ensuring safer and more successful IVF cycles .Long-term outcomes: Research efforts also extend to studying the long-term outcomes of obese patients and their offspring following IVF. This includes assessing the impact of maternal obesity on maternal and neonatal health and investigating potential epigenetic changes that may occur during IVF procedures. Understanding the lasting effects of IVF in obese patients is crucial for providing comprehensive healthcare and counseling to these individuals and their families .Emerging Technologies and TechniquesPrecision medicine: The application of precision medicine in IVF involves tailoring treatment protocols and anesthesia management to each patient's specific genetic and metabolic characteristics. By analyzing an individual's genetic and metabolic profile, healthcare providers can make more informed decisions regarding fertility medications, dosages, and anesthesia techniques. This personalized approach can optimize treatment outcomes and minimize risks for obese patients, who often exhibit unique physiological variations .RoboticThe Role of Multidisciplinary Teams in Managing Obese Patients Undergoing IVFCollaboration: Effective care for obese patients undergoing IVF requires close collaboration among healthcare specialists. This includes anesthesiologists, reproductive endocrinologists, bariatric specialists, nutritionists, psychologists, and other relevant professionals. These experts work together to develop integrated care plans that address both the medical and psychosocial aspects of obesity and fertility treatment. This collaborative effort ensures that all aspects of a patient's health and well-being are considered .TailoreIn conclusion, the anesthetic evaluation and management of obese patients undergoing IVF procedures is multifaceted and demands precision, empathy, and a multidisciplinary approach. This comprehensive review has underscored the significance of addressing obesity's impact on IVF success rates, the importance of tailored anesthesia and perioperative care, and the need for emotional support throughout the IVF journey. Obesity poses unique medical and psychological challenges, necessitating a holistic approach that bridges the realms of anesthesia, reproductive medicine, and patient well-being. As we move forward, ongoing research, emerging technologies, and collaborative efforts among healthcare providers promise to enhance further the care of obese individuals seeking fertility treatments. By refining our practices and understanding, we can empower these patients to achieve the dream of parenthood while ensuring their safety, comfort, and overall success."}
+{"text": "During the COVID-19 pandemic, clinical trials of vaccines received unprecedented publicity; whether this interest might be transferred to vaccine trials generally is unknown. Enrolment in paediatric COVID19 vaccine trials was slower than uptake of adult vaccine trials, and lessons learned are, therefore, of importance for future recruitment and participant experience. Previous studies have investigated motivations for participation in adult vaccine trials , paediatPreviously, we have observed response rates of 2%-4% for similar trials. We therefore hypothesised that prior vaccine trial experience and exposure might modulate the threshold for trial participation, and descriptively studied motivations and barriers to paediatric vaccine trial participation in this context. Ethical approval and feedback from the Oxford Vaccine Centre Public and Patient Involvement (PPI) group was received. Motivations for trial participation were dichotomised by prior trial participation Table ; self-deThis survey has limitations, being an unvalidated survey instrument, the reliance on self-report, and the inability to ascertain motivations among those who declined to participate. Further research including representative sample of the general UK population and better controlling for social desirability bias may shed further light on the nature and magnitude of differences in motivation, providing a basis for targeting adjustments to enrolment\u2014and improve generalisability especially post-pandemic. Parental motivations for enrolling children in clinical trials are understudied and merit detailed exploration to maximise successful recruitment in future trials.Additional file 1: Supplementary Table 1. Baseline characteristics of 81 respondents. P-values are for chi-squared tests."}
+{"text": "Catatonia is a complex psychomotor syndrome that often goes unrecognized and, consequently, untreated. Prompt and correct identification of catatonia allows for highly effective treatment and prevention of possible complications. Benzodiazepines and electroconvulsive therapy (ECT) are the most widely studied treatment methods. However, no uniform treatment method has yet been brought forward and no previous attempts to treat catatonia on a patient suffering concomitant major depressive disorder (MDD) with NMDA receptor antagonists have been documented so far.To describe the unknown and novel management of catatonia and MDD with intranasal esketamine, a NMDA receptor antagonist.A 55-year-old woman with a diagnosis of long-standing recurrent major depressive disorder who was admitted to the psychiatric inpatient unit of UniversityHospital Marqu\u00e9s de Valdecilla  suffering a complex catatonic, mutative state framed on a severe MDD. Different ineffective therapeutic interventions were deployed during the course of her illness. After failing to improve under conventional pharmacological treatment and ECT, and given the complexity of peripheral venous access on this patient (which disabled the option for iv ketamine use), we decided to initiate compassionate treatment with intranasal esketamine.Intranasal esketamine was effective in the resolution of patient\u2019s complex catatonic state. Clinical response from catatonia was observed after 6 intranasal esketamine administrations (2-week follow-up), reaching full catatonia and MDD remission after 12 sessions in absence of significant adverse eventsEsketamine showed promising effectiveness for the treatment of catatonia in the context of MDD, although further research on this topic is needed.None Declared"}
+{"text": "Cardiac fibrosis is a pathological response characterized by excessive deposition of fibrous connective tissue within the heart. It typically occurs following cardiac injuries or diseases. However, the lack of suitable models for disease modeling and high-throughput drug discovery has hindered the establishment of an effective treatments for cardiac fibrosis. The emergence and rapid progress of stem-cell and lineage reprogramming technology offer an unprecedented opportunity to develop an improved humanized and patient-specific model for studying cardiac fibrosis, providing a platform for screening potential drugs and synchronously elucidating the underlying molecular mechanisms. Furthermore, reprogramming cardiac fibroblasts into cardiomyocyte-like cells to reduce scar volume and induce myocardial tissue regeneration is a promising approach in treating cardiac fibrosis. In this review, we summarize the current advancements in stem cell technologies applied to study cardiac fibrosis and provide insights for future investigations into its mechanisms, drug discovery as well as therapy method. Cardiac fibrosis is a prevalent pathological alteration observed in the advanced stages of most cardiovascular diseases (CVDs). This debilitating condition is frequently associated with various cardiac disorders, resulting in impaired heart function and potentially life-threatening complications such as heart failure  plays a pivotal role in initiating cardiac fibrogenesis in response to mechanical stress  Leask , mitogenFollowing myocardial damage, a plethora of signaling molecules such as chemokines, cytokines and growth factors are released, triggering the activation of cardiac fibroblasts through diverse pathways. The RAAS is activated during the process of cardiac fibrosis and interacts with pathways that contribute to fibrosis , including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), have substantially expanded the availability of human cells for modeling cardiac fibrosis and discovering drugs due to their ability to unlimitedly self-renew and differentiate into types of cells within the body  (about 40%) derived from hESCs better mimics the pathological process of cardiac fibrosis . The transplantation of hPSC-CMs holds the potential to directly enhance cardiac function in individuals with reduced fibrosis and increased vascular density. Additionally, hPSC-CMs can enhance cardiac tissue regeneration and repair processes by secreting growth factors, cytokines, and other signaling molecules . This feature illustrates the potential to obtain abundant cardiomyocytes for transplantation\u00a0  in the implantation of hPSC-CMs in a subacute myocardial infarction pig model , mesoderm posterior bHLH transcription factor 1 (MESP1), myocardin (MYOCD), and zinc finger protein, multitype 2 (ZEPM2) to convert human fibroblasts into human induced cardiomyocyte-like cells (hiCMs)  from mouse and human fibroblasts, which possess multipotency to differentiate into various types of cardiovascular cells using a transgene-free reprogramming approach involving six small molecules: CHIR99021, A83-01, GSK126, Forskolin (an adenylyl cyclase activator), CTPB (a P300 histone acetyltransferase activator), and AM580 (a RAR\u03b1 activator) (Wang et al. Despite the considerable potential of stem cell therapy in addressing cardiac fibrosis, there are still several obstacles need to be overcome. These challenges encompass the selection of appropriate stem cells sources, concerns regarding biosafety during cell transplantation, and the necessity to improve cell survival and retention rates, among other factors. The advantages and disadvantages of stem cell transplantation and cell reprogramming for cardiac fibrosis therapy are summarized in Table In summary, stem cell therapy for cardiac fibrosis is an advancing field with promising prospects for the future. Ongoing research and technological advancements are propelling these therapeutic approaches towards potential success. However, several challenges persist in current stem cell treatments. Further investigation is required to address issues such as the selection of appropriate stem cell sources, biosafety concerns, and the feasibility to monitor treatment efficacy. Moreover, ensuring the successful engraftment and survival of transplanted stem cells into the heart remains to be tackled. Many transplanted cells do not exhibit long-term viability or fail to differentiate into functional cardiac cells, thereby impeding the overall effectiveness of this therapy. To ensure the safety and efficient implementation of these stem cell-based approaches, rigorous clinical studies and repeated validation are indispensable. Efforts are underway to establish a high-throughput drug screening platform for the development of novel therapies. Striking a balance between complexity and user-friendliness is pivotal for this platform. Through comprehensive research and validation, we can surmount these challenges and unlock the full potential of stem cell therapy for cardiac fibrosis in the future."}
+{"text": "Long-term success of peritoneal dialysis as a kidney replacement therapy requires a well-functioning peritoneal dialysis catheter. With ongoing reductions in infectious complications, there is an increased emphasis on the impact of catheter-related and mechanical complications. There is currently a marked variation in the utilization of various types of catheters , methods of catheter insertion , timing of catheter insertion, location of catheter placement  and peri-operative practices. Specialized approaches to catheter placement in clinical practice include use of extended catheters and embedded catheters. Marked variations in patient lifestyle preferences and comorbidities, specifically in high acuity patient populations  necessitate individualized approaches to catheter placement and care. Current consensus guidelines recommend local procedural expertise, consideration of patient characteristics and appropriate resources to support catheter placement and long-term functioning. This review focuses on an overview of approaches to catheter placement with emphasis on a patient-centered approach. It is reported that approximately 424,000 patients worldwide utilize peritoneal dialysis (PD) as a method of kidney replacement therapy . A well-Knowledge of best practices in catheter insertion can minimize the risk of catheter complications leading to early PD failure. Guideline committees under the sponsorship of the International Society for Peritoneal Dialysis (ISPD) recommend optimal PD catheter implantation be based on individualized patient factors, facility resources and operator expertise . Currentvia trocar and blind insertion via Seldinger technique  at the time of catheter placement , 22. EarAnother strategy for timely initiation of PD is the embedded catheter technique, with the external limb of catheter embedded in subcutaneous tissue until the need for dialysis initiation. This allows for early patient commitment to PD, more predictable operating room scheduling, and immediate utilization of the catheter after exteriorization. However, there is a risk of non-usage of catheters, in addition to catheter dysfunction rates secondary to fibrin accumulation \u201328.No specific catheter placement approach has been proven to produce superior outcomes. Comparison of percutaneous placement, open surgical dissection and basic surgical laparoscopy have shown equivalent patient outcomes , 29\u201331. The goals of PD catheter placement involve a balance between pelvic position of catheter tip to facilitate inflow and outflow of dialysate along with an easily visible and accessible exit site. Operator expertise and experience necessitates selection of appropriate available catheter type suited to patient specific conditions. Placement includes the consideration of body habitus, belt-line, skin creases, prior scars, stomas, gastrostomy tubes, recreational habits and occupation. An ideal exit site is either above or below the beltline, with a lateral and inferior directed exit site . In the via a 2- piece extended catheter system, with a long subcutaneous section, while maintaining optimal catheter tip position. Alternatively, single piece catheters with long intercuff segments are also utilized in certain centers  necessitate a specialized approach for successfully conducting PD as a dialysis modality. This includes not only optimal exit site and catheter tip position, but utilization of focused interventions to ensure ideal long term function. Patients with obesity require creation of an easily visible upper abdomen/presternal exit site requiring an extended catheter approach. The catheter should be allowed to heal completely for several weeks prior to PD initiation. Ideally, a laparoscopic approach is recommended, utilizing selective omentopexy along with resection of epiploic appendices of sigmoid colon if needed. The upper abdominal and chest exit sites are located in areas with relatively thin subcutaneous layer, minimizing tubing stresses from mobility of the subcutaneous fat layer with postural changes. Data suggests longer time to first exit site infections in patients with extended catheters . MoreovePatients with autosomal dominant polycystic kidney disease (ADPKD) present a unique set of concerns regarding limited peritoneal space, peritonitis risk and hernias. Several studies have reported the feasibility of PD in ADPKD patients \u201340. WithPatients with cirrhosis present their own unique challenges with regards to potential bacterial peritonitis, nutritional challenges, and concerns for leaks \u201349. SeveSafe and effective placement of PD access is critical to the ultimate outcomes of PD as a home dialysis modality. SK and MR were responsible for preparation, writing and editing of this manuscript. Both authors contributed to the article and approved the submitted version."}
+{"text": "Furthermore, the SVM model could distinguish MDD patients with different suicidality gradients . In conclusion, we have identified that disrupted brain connections were present in MDD patients with different suicidality gradient. These findings provided useful information about the pathophysiological mechanisms of MDD patients with suicidality.Suicidal behavior is a major concern for patients who suffer from major depressive disorder (MDD). However, dynamic alterations and dysfunction of resting-state networks (RSNs) in MDD patients with suicidality have remained unclear. Thus, we investigated whether subjects with different severity of suicidal ideation and suicidal behavior may have different disturbances in brain RSNs and whether these changes could be used as the diagnostic biomarkers to discriminate MDD with or without suicidal ideation and suicidal behavior. Then a multicenter, cross-sectional study of 528 MDD patients with or without suicidality and 998 healthy controls was performed. We defined the probability of dying by the suicide of the suicidality components as a \u2018suicidality gradient\u2019. We constructed ten RSNs, including default mode (DMN), subcortical (SUB), ventral attention (VAN), and visual network (VIS). The network connections of RSNs were analyzed among MDD patients with different suicidality gradients and healthy controls using ANCOVA, chi-squared tests, and network-based statistical analysis. And support vector machine (SVM) model was designed to distinguish patients with mild-to-severe suicidal ideation, and suicidal behavior. We found the following abnormalities with increasing suicidality gradient in MDD patients: within-network connectivity values initially increased and then decreased, and one-versus-other network values decreased first and then increased. Besides, within- and between-network connectivity values of the various suicidality gradients are mainly negatively correlated with HAMD anxiety and positively correlated with weight. We found that VIS and DMN-VIS values were affected by age ( Major depressive disorder (MDD) is a common psychiatric disorder characterized by an inability to experience pleasure/reward (anhedonia) , affecti. Furthermore, previous studies aver that cortical thickness of ten regions within fronto-temporal-parietal system act as top-ranked classifiers that could differentiate suicide attempts from SI in MDD patients [Neuroimaging and behavioral studies have recently centered on network-based structural and functional alterations of individuals at risk of suicide. Previous studies postulated that fronto-limbic system is the central circuit underlying the suicidal process under depressive conditions \u201315. MDD patients . In addipatients . These fBased on prior studies, we hypothesized that suicidal gradient in MDD patients might arise from disturbances in macroscale brain RSNs and altered brain connections may represent powerful diagnostic biomarkers to discriminate MDD with or without SI and SB. First, the current study mapped the dynamic trajectory of large-scale RSNs roles and their clinical significance with dynamic network-based analysis in MDD patients with suicidality gradient. Second, common and specific network connections associated with different suicidal gradients were identified in MDD patients. Third, the support vector machine (SVM) model was used to explore the role of these abnormal neuroimaging characteristics as objective diagnostic biomarkers in classifying MDD patients with different suicidal gradients. Depression shows gender specificity in which the incidence rate of MDD is approximately twofold higher in women than in men . TherefoAmong the previously mentioned MDD patients, 169 individuals had a medication history; nevertheless, they had refrained from taking medication for a duration of at least three weeks at the time of enrollment. Based on a 17-item HAMD suicide item score, MDD patients were categorized into five categories: a score of 0 was defined as MDD without suicidal ideation (MDDNSI); score of +1 was defined as MDD with mild suicidal ideation (MDDmSI); score of +2 was defined as MDD with moderate suicidal ideation (MDDmoSI); score of +3 was defined as MDD with severe suicidal ideation (MDDSSI); and score of +4 was defined as MDD with SB (MDDSB). HCs were randomly divided into HC and verification groups. Detailed information on all subjects is shown in Table A total of 528 MDD patients and 998 HCs were recruited from the REST-meta-MDD consortium  and the All study sites obtained approval from their local institutional review boards and ethics committees. Also, these research protocols were approved by the Ethics Committee of Henan Provincial Mental Hospital Affiliated with Xinxiang Medical University . All participants, their legal guardians, or their legally authorized representatives provided informed consent prior to their involvement in the study.Scan acquisition was completed within 1 week of assessments. Resting-state fMRI and structural T1-weighted MRI brain scans were acquired at each of the 24 participating study sites (see STable These networks comprise the auditory network (AUD), the cingulo-opercular network (CON), the dorsal and ventral attention network (DAN and VAN), the default mode network (DMN), the fronto-parietal network (FPN), the salience network (SAN), the sensorimotor network (SMN), the subcortical network (SUB), and the visual network (VIS). Network connectivity between all pairs of 10 RSNs, as well as between each RSN and all other RSNs  were computed.A power atlas  was usedp\u2009<\u20090.05 for all tests. In addition, a one-way analysis of variance (ANOVA) test was used to analyze continuous variables, with post hoc least significance difference (LSD) tests for pair-wise comparisons. Chi-squared tests were also used for categorical variables. Notably, each network metric ) was compared across groups using generalized linear model (GLM) analysis adjusted for age, gender, education, and study site as covariables. All p values were adjusted for multiple comparisons  using FDR correction.Group comparisons of demographic characteristics and network metrics across MDD subgroups were undertaken using analysis of covariance (ANCOVA) and significance levels were set at p\u2009<\u20090.001.The current study first generated a 226 * 226 connectivity matrix for each subject. Network-based statistical analysis (NBS) method was then used to identify common and differential connections of networks between healthy control (HC) and disease groups, as well as various disease subgroups. Each connection identified by NBS with Bonferroni correction satisfied Due to the potential effects of age and sex in dynamic network analysis, Wilcoxon rank sum tests were used to compare the abnormality of network and clinical variables in sex and age. Specifically, all patients were split into younger (age: 18\u201337) and older (age: 38\u201365) participants or females and males to obtain sex- and age-related alterations in networks and clinical variables, separately.The current study computed Pearson\u2019s correlation between network variables and clinical data.SVM was used in the current study to classify MDD subgroups and HCs in MATLAB based on a library (LIBSVM) . The curAll described analyses were repeated using another set of healthy subjects that included 499 subjects to validate whether network role construction could be replicated and whether selected functional connections could be used for classification.p\u2009<\u20090.001) and subscales scores including anxiety (p\u2009=\u20090.0003), weight (p\u2009<\u20090.0001), retardation (p\u2009<\u20090.0001), and sleep (p\u2009=\u20090.0001), compared with those of MDNSI subjects, indicating that MDD patients R1\u20132 with suicidality had severer depression compared with MDNSI patients. Furthermore, there were no statistically significant differences in additional clinical characteristics upon enrollment, including total disease duration and frequency of episodes among the subgroups of individuals with MDD.Demographic information and characterization of all study subjects are outlined in Table  R1\u20133 and pairwise BNC in HC group and suicidality-related MDD patients Fig. . SpecifiTo further map abnormal network connections with significant group differences in within-, between- or one versus other networks of ten RSNs in MDD patients, the current study first established increased and decreased network connections in the suicidality-related MDD patients compared with the HC group as shown in Fig. To understand the clinical significance of abnormal WNC and BNC in MDD subgroups, the current study conducted Pearson\u2019s correlation between FC strength within- and between networks and clinical variables including HAMD total scores and subfactor scores, including HAMD-Anxiety, HAMD-Weight, HAMD-Retardation, and HAMD-Sleep in MDD patients after controlling for covariables of age, gender, education, and study site. Correlation patterns showed group-level associations of WNC and BNC with depressive severity in MDD subgroup patients and established that distinctive network basis was associated with different symptom dimensions in MDD patients with or without suicidality Fig. . These nThe SVM model was used to explore the role of abnormal FC as an objective diagnostic biomarker in MDD patients. Mean FCIs from 31 pairs of network connections were used as input features to the linear support vector classifier (SVC). AUC showed that these FCIs demonstrated a higher capacity to discriminate MDD patients with SB from the HC group (AUC\u2009=\u20090.96). The use of the SVM-trained model as a classifier demonstrated that the SVM-trained model showed better power in separating MDD patients with SI or SB from MDDNSI patients . Furthermore, FCIs also showed greater potential to discriminate suicidality gradient-related MDD patients  except for MDDmSI from MDDmoSI patients AUC\u2009=\u20090.73). Detailed information is described in Fig. 3. DetailWilcoxon rank sum tests were used to determine the potential effects of age and sex on large-scale brain networks and clinical variables in females and males, or in younger and older participants, separately. The current study established that age and sex had significantly different impacts on the two variables Fig. . SpecifiThe current study repeated these analyses to validate current findings in independent cohorts that included new 499 HCs and the original 528 MDD patients. More females and lower educational years were found in MDD subgroup patients compared with the new HC group. In addition, large-scale network roles analysis showed similar network dynamics in MDD subgroups compared with the HC validation group . These findings indicate that the use of large-scale network connection approaches to identify more robust diagnostic neuroimaging biomarkers may vary depending on whether the prediction goal pertains to diagnosis. Therefore, the established key features of large-scale network dynamics are crucial for early recognition and timely diagnosis of individuals with suicidality in depression and achieve much greater progress towards understanding and preventing suicide, as well as reducing patients\u2019 risk of morbidity from suicide ideation and attempts and their risks of suicide death. In clinical translational practice, measured imbalanced network links in the current study served as functional endophenotypes to particularly characterize depressive patients who tend to disguise real suicide intent without apparent symptoms. In addition, the current study used this endophenotype to guide informed treatment and monitor if medications target these networks.Several previous studies have established the effects of age and gender on large-scale network dynamics in healthy and depressive disorders \u201362. In mThe current study had some limitations. First, this was a cross-sectional study involving multiple centers. A longitudinal study should be undertaken to validate these findings. Second, the suicidality gradient in depression was assessed using HAMD suicidal factor scores, which may limit findings. Therefore, the use of improved suicidality assessment instruments is necessary to precisely evaluate the severity of suicide in MDD patients in future studies. Third, future studies are needed to establish whether these abnormal networks are long-lasting and how they may interact with environmental and genetic factors.In conclusion, the current study demonstrated that the dynamic trajectory of network roles at a large-scale level was associated with suicidality gradient in MDD patients. Abnormal overlapping network connections were used as neuroimaging biomarkers in the diagnostic identification of subjects who are vulnerable to suicide under depressive conditions. The current study achieved much greater progress towards understanding the pathologic mechanism of suicide and precisely preventing suicidal occurrence via targeting these circuits with effective medical or physical instruments.supplemental material"}
+{"text": "In recent few years, high-flow nasal oxygenation (HFNO) has been widely used for management of acute hypoxemic respiratory failure and during postextubation periods, including after endotracheal intubation general anesthesia (ETGA). However, HFNO generates positive pressure in the injured airway following removal of endotracheal tube may cause airway leaks. This is the first case report of severe airway leak syndrome following postextubation use of HFNO in surgical patients.This case report describes a 75-year-old female with critical aortic stenosis who underwent an emergency Bentall procedure. HFNO (flow rate of 45\u2009L/min) was applied after weaning from mechanical ventilation and removal of the endotracheal tube.At 6 hours after HFNO application, subcutaneous emphysema in the neck bilaterally and face was noted, and the emphysema extended into the supraclavicular regions.The HFNO cannula was removed soon after and the patient was re-intubated with an endotracheal tube the following day due to progressive respiratory insufficiency. Unfortunately, the patient general condition deteriorated, as the subcutaneous air collections progressed into deep tissue infections of the neck, mediastinal abscesses, and left-sided empyema. Patient received surgical interventions repeatedly to drain the mediastinal abscess and empiric antimicrobial therapy was given.The patient passed away about 2 months later due to uncontrollable sepsis.Air leaks in the upper airway can occur during the use of post-extubation HFNO use, and the resulting subcutaneous emphysema can progress to severe intrathoracic infections in surgical patients who have a sternotomy wound. Therefore, HFNO-induced subcutaneous emphysema should be treated more aggressively in open thoracic or sternotomy surgeries to prevent the development of intrathoracic sepsis. HFNO is currently used to prevent hypoxic events during anesthesia induction, procedural sedation and as an alternative to respiratory support in critically ill patients.,2 A large-scale multi-center clinical trial further demonstrated that HFNO is not inferior to standard noninvasive mechanical ventilation for preventing reintubation and respiratory failure within 72 hours post endotracheal tube removal in high-risk critically ill adults. Compared with conventional oxygen therapy, HFNO also significantly reduces reintubation rates and rates of respiratory support escalation immediately after endotracheal general anesthesia (ETGA) in adult surgical patients. Therefore, HFNO is recommended over conventional oxygen therapy for the management of acute hypoxemic respiratory failure and for postextubation periods in emergency departments, hospital wards, intermediate or step-down units, and intensive care units. Although clinical studies did not find major complications in postextubation use of HFNO,,6 positive pressure in the upper airway from high gas flow may cause air-leaks into the subcutaneous tissues from the injured airway mucosa.,8 This case report describes a patient who was successfully weaned from invasive mechanical ventilatory support day 1 after a Bentall procedure, but developed extensive subcutaneous emphysema and pneumomediastinum within few hours after switching from endotracheal intubation to HFNO.Specially equipped high-flow nasal oxygenation (HFNO) provides a high flow rates (up to 70\u2009L/min) of warm and humidified mixed oxygen/gas to generate continuous positive pressure in the upper airways, wash-out of dead space in the nasopharyngeal cavity, increase alveolar recruitment and functional residual capacity, reduce work of breathing and respiratory muscle fatigue, enhance airway secretion clearance, and improve hypercapnia post endotracheal tube extubation.A 75-year-old woman with a medical history of chronic hypertension and aortic stenosis developed progressive shortness of breath and orthopnea a few days before surgery. She presented to the emergency department with hypotension and low peripheral oxygen saturation. An echocardiographic study showed calcified and severely stenotic aortic valves with a mean transvalvular pressure gradient of 60\u2009mm Hg and left ventricle dysfunction. The proximal aortic root was dilated to a diameter of 10\u2009cm. Acute cardiac failure was evidenced by elevated serum levels of B-type natriuretic peptide (>500 pg/mL) and pulmonary edema on chest radiography. An urgent Bentall procedure, including graft replacement of the ascending aorta and aortic valves was performed under ETGA and cardiopulmonary bypass. An endotracheal tube was inserted smoothly on the first attempt using a video laryngoscope without complications.The whole surgical procedure was completed within 10 hours. After successfully weaning off cardiopulmonary bypass in the operating room, the patient was transferred to intensive care unit for postoperative care under mechanical ventilatory support. Mechanical ventilation was switched from pressure control and pressure support mode when the patient had regained consciousness and had shown effort of spontaneous respiration the morning after her operation. Following a successful spontaneous breathing trial for an hour, the endotracheal tube was removed and HFNO  was applied with 40% fraction of inspired oxygen at a flow rate of 45\u2009L/min via a nasal cannula . The patient settled comfortably with HFNO, and adequate peripheral oxygen saturation was maintained. Six hours later, the patient claimed to have insidious attacks of sharp pain and swelling in the neck and face. Subcutaneous crepitus was detected at the neck bilaterally, extending to the lower jaw and the upper chest. HFNO was discontinued and the patient was put on a non-rebreathing mask for oxygen supplementation. A portable chest radiography taken at bedside confirmed the presence of subcutaneous emphysema in the neck and supraclavicular regions with no signs of pneumothorax or pneumomediastinum  who were treated with HFNO after endotracheal tube removal. Two of these patients developed pneumothoraxes and one developed pneumomediastinum at 4 to 5 hours after HFNO use. Air leak problems in these pediatric patients were diagnosed by routine chest radiographies rather the presence of subcutaneous emphysema or hypoxic events. There was another case of an adult female with hemophagocytic lymphohistiocytosis who received endotracheal intubation and mechanical ventilatory support due to acute respiratory failure. HFNO therapy was applied at a flow rate of 40\u2009L/min after weaning from mechanical ventilation. Four days later, the patient developed dyspnea and hypoxemia. A series of radiological studies were performed to investigate and found pneumothorax, subcutaneous emphysema, and massive pneumomediastinum. After HFNO cessation, the patient respiratory conditions improved. Air-leak syndrome during postoperative HFNO use after ETGA in surgical patients have not been reported in the literature.It is generally believed that positive airway pressure generated by HFNO in the upper airway and trachea can squeeze air into subcutaneous tissues via micro-tears in the airway mucosa. However, our case progressed rapidly to intrathoracic sepsis and empyema due to gram negative nosocomial pathogen infections and she eventually expired because of uncontrollable sepsis. We speculated that the sternotomy wound might have precipitated the invasion of nosocomial organisms into the mediastinal subcutaneous air collection. Hence, more aggressive empirical antimicrobial treatment should be considered early stages subcutaneous emphysemas are found in surgical patients with a sternotomy or thoracotomy wound.We reported the first fatal air-leak complication following use of postextubation HFNO in a patient with a sternotomy after cardiac surgery. While most of the other case reports were associated with pneumothorax due to distal airway or lung tissue tears, the leak in our case was most likely located in the upper trachea, as the air-leak was not detected before removal of the cuffed endotracheal tube nor after tracheal re-intubation, and pneumothorax was also not found in our case. The initial clinical signs of air-leak syndrome in our patient were focal pain and detection of subcutaneous emphysema as opposed to being clinically asymptomatic or presence of hypoxia at the late stage in other cases. Therefore, detection of emphysema underneath the neck or facial subcutaneous tissues could be an early sign of upper airway leak when HFNO is applied after tracheal extubation. The outcomes of subcutaneous emphysema due to airway leak is usually self-limiting and requires mainly conservative management.In conclusion, the use of postextubation HFNO is generally safe after ETGA, but air-leak syndrome may still happen in unrecognized airway mucosal injuries, as continuous positive pressure is generated by the HFNO. The presence of subcutaneous emphysema can be an early sign of airway leak following application of HFNO and subcutaneous emphysema should be treated more aggressively in open thoracic or sternotomy surgery to prevent the development of intrathoracic sepsis.Conceptualization: Yu-Yang Liao, Hsuan-Yin Wu, Chen-Fuh Lam, Yi-Ming Wang.Data curation: Yu-Yang Liao, Yi-Ming Wang.Supervision: Chen-Fuh Lam, Yi-Ming Wang.Validation: Hsuan-Yin Wu, Chen-Fuh Lam.Writing \u2013 original draft: Yu-Yang Liao, Hsuan-Yin Wu.Writing \u2013 review & editing: Chen-Fuh Lam, Yi-Ming Wang."}
+{"text": "Dear EditorWe thank Lightner and colleagues for their study on surveillance pouchoscopy in ulcerative colitis patients. The authors reported that neoplasia following ileal pouch-anal anastomosis (IPAA) is rare. They recommended pouch surveillance with random biopsies of the anal transition zone (ATZ) for patients with a personal or family history of colorectal neoplasia (CRN)It is unknown whether routine surveillance improves outcomes of pouch neoplasia, since pouch neoplasia is usually diagnosed after symptom development. As such, all patients in this study had a negative surveillance pouchoscopy in the 2\u2009years prior to pouch carcinoma detectionWe question whether random biopsies lead to earlier detection of (pre)cancerous pouch lesions. The authors reported six pouch carcinomas and none were detected in random biopsies. Moreover, six of seven dysplastic lesions identified with random ATZ biopsies were not confirmed in follow-up biopsies and it could be questioned whether the initial lesions contained \u2018true\u2019 dysplasiaFinally, we disagree with the recommendation of pouch surveillance in patients with a family history of CRN. The authors reported a positive family history in only one of 13 patients and previous studies did not identify this as a risk factor for pouch neoplasia.In conclusion, we only advocate pouch surveillance with random ATZ biopsies in high-risk patients with prior CRN. Nevertheless, current data remain scarce and uniform, widely adopted pouch surveillance guidelines are needed to unify practice.Disclosure. The authors declare no conflicts of interest."}
+{"text": "The natural amino acid asparagine (Asn) is required by cells to sustain function and proliferation. Healthy cells can synthesize Asn through asparagine synthetase (ASNS) activity, whereas specific cancer and genetically diseased cells are forced to obtain asparagine from the extracellular environment. ASNS catalyzes the ATP-dependent synthesis of Asn from aspartate by consuming glutamine as a nitrogen source. Asparagine Synthetase Deficiency (ASNSD) is a disease that results from biallelic mutations in the ASNS gene and presents with congenital microcephaly, intractable seizures, and progressive brain atrophy. ASNSD often leads to premature death. Although clinical and cellular studies have reported that Asn deprivation contributes to the disease symptoms, the global metabolic effects of Asn deprivation on ASNSD-derived cells have not been studied. We analyzed two previously characterized cell culture models, lymphoblastoids and fibroblasts, each carrying unique ASNS mutations from families with ASNSD. Metabolomics analysis demonstrated that Asn deprivation in ASNS-deficient cells led to disruptions across a wide range of metabolites. Moreover, we observed significant decrements in TCA cycle intermediates and anaplerotic substrates in ASNS-deficient cells challenged with Asn deprivation. We have identified pantothenate, phenylalanine, and aspartate as possible biomarkers of Asn deprivation in normal and ASNSD-derived cells. This work implies the possibility of a novel ASNSD diagnostic via targeted biomarker analysis of a blood draw. ASNS gene occupies 35 kb within chromosome 7q21.3 and is composed of a total of 13 exons glucose to analyze central carbon metabolism, [U-13C]aspartate to assess the specific fate of the ASNS reaction, and [U-13C]glutamine to assess TCA cycle turnover. Additionally, the significant decrements in lactate and central metabolism suggest that in vivo [2H7]glucose metabolic imaging may potentially be utilized to assess the effects of Asn deprivation on brain metabolism [In summary, our findings demonstrate that Asn deprivation leads to a broad-based disruption of the metabolic profiles of patient cells deficient for ASNS. We have identified potential metabolic signatures of Asn deprivation in healthy and ASNSD cells. This observation is of high interest for ASNSD and metabolic research as it warrants future work to establish the relevance of these metabolic signatures and their potential roles as diagnostic and prognostic biomarkers in an in vivo and clinical setting. While our results indicate a certain global metabolic insult caused by Asn deprivation in ASNS deficient cells, further work must be done to discern pathway-specific changes using isotopomer tracer and metabolic flux analysis. The research reported here warrants future studies on ASNSD cell models to assess the utilization of [U-tabolism ."}
+{"text": "Conversely, no statistically significant difference in oral microbiota composition was observed, thus further revealing a close relationship between ICI response and gut microbiota diversity in NSCLC patients. Extracellular vesicles (EVs) were broadly classified into three main categories based on their biosynthetic or secretory processes: exosomes, microvesicles/particles/extracellular bodies, and apoptotic vesicles  due to their association with both nutritional and inflammatory status. vesicles . With tharcinoma . A modelarcinoma . In addiarcinoma . Gao et Using Multi-Omics to Develop New Strategies for Improving Prognosis and Immunotherapy Outcomes in Cancer\u201d serves as a platform for sharing innovative strategies developed through multi-omics to enhance the effectiveness of immunotherapies and improve patient outcomes. These studies integrate data from various layers, providing valuable insights into the molecular structure of tumors and expanding the scope of cancer biology. Although clinical applications of these techniques are still in the early stages, we believe that several of these new approaches will not only advance our understanding of tumor biology but also significantly shape the future of precision cancer therapies.The Research Topic \u201c"}
+{"text": "Escherichia coli bacteremia. Larvae of Strongyloides stercoralis were also observed in stool smears after a centrifugation concentration method. This diagnosis was confirmed by qPCR detection of Strongyloides spp. using the Allplex GI-Helminth (I) Assay (Seegene) (The definitive diagnosis was disseminated strongyloidiasis with concurrent Seegene)  in the tS. stercoralis is a soil-transmitted nematode that is endemic in tropical and subtropical countries, especially in areas with inadequate sanitary conditions, and it is recognized as a neglected tropical disease  in the gut, resulting in autoinfection. This unique property allows infection to persist for decades (chronic strongyloidiasis) and cause overwhelming infection if people become immunosuppressed later in life, leading to Strongyloides Hyperinfection Syndrome (SHS) or disseminated infection (Strongyloides infection in patients treated with dexamethasone needs to be considered to avoid precipitating SHS and disseminated strongyloidiasis (nfection , 7. Concnfection , so asym"}
+{"text": "Plant genotype influences interactions among associated bacteria and fungi;Plant-growth-promoting bacterial communities lead to outcomes exceeding the sum of individual effects; andEnvironmental conditions impact how microbes in communities interact.Soils are home to a wide variety of microorganisms. The collective genome of these organisms is vast, and so individual strains perform some functions that few others can. In addition to the consumption of specific metabolites, many soil microbes excrete unique compounds into their direct environment in soils, at root surfaces, and inside plants as endophytes. The ensuing localized build-up of compounds impacts other organisms by exerting a variety of functions: promoting growth, activating signal transduction, suppressing cellular functions, or changing the physicochemical environment. Microorganisms share soils with plants, whose roots exude cocktails of organic compounds ,2 that fOryza rufipogon wild rice and male parent Oryza sativa cultivated rice had significantly different bacterial and fungal communities than either of the parental lines. Similarly, sorghum lines have different rhizo- and endosphere bacterial communities that contribute to plant performance to different degrees under low nitrogen stress conditions [Plant breeding has focused largely on improved agronomic traits, such as yield and disease resistance, invariably losing some parental traits not selected for. Rhizomicrobiome analysis of modern cultivars versus ancestral accessions has revealed significant differences in the bacterial and fungal communities of rice . The pronditions . Cultivanditions .A unique three-way interaction has been reported among plants, their endophytes, and the associated rhizomicrobial community. Fungal endophytes of Tall Fescue are not only associated with improved biomass yield and stress tolerance, but also with soil fungal community composition and increased diversity . These sStreptomyces [Physicochemical conditions are well known to affect the growth of individual microbial cultures. Invariably, shifts in environmental conditions also impact the fitness of individual species and strains. Farda et al. reviewed the literature on actinomycetes in caves . The scaptomyces . Tarin eptomyces .Various microbial strains isolated from soils have been shown to benefit crop production through mechanisms such as nutrient acquisition or suppression of pathogens. Wang et al. present an analysis of how the consortia of disease-suppressing microorganisms bring about enhanced protection when compared to individual strains . They goThe contributions to this Special Issue all point to the complexity of specific interactions that lead to shifts in microbial communities under specific conditions. Much remains to be done to unravel the specific components of these interactions."}
+{"text": "Environmental transmission of bacteria, including multidrug-resistant organisms (MDROs), persists within hospitals despite routine cleaning. In prior work, we identified discordance between 16S profiles of room surfaces and culture of MDROs, suggesting unique environments for MDRO persistence within rooms. To build on this work, we used culture-enriched metagenomic sequencing to identify a broad range of viable taxa on surfaces with strain-level assignment and resistome profiling. Additionally, we evaluated the role of room proximity on sharing bacterial taxa and resistance genes between rooms.We selected three intensive care unit (ICU) rooms at the Hospital of the University of Pennsylvania with varying proximity and sampled 12 surfaces per room divided into three composite samples (Table 1). Sampling was repeated for 3 consecutive days. Samples underwent liquid media enrichment, DNA extraction and shotgun metagenomic sequencing. Strain-level assignment was performed with MetaPhlAn 4.0 and resistance genes assigned  via the Comprehensive Antibiotic Resistance Database (CARD).Each composite sample represents approximately 350 square inches of surface areaWe identified 40 strain-level assignments, with 18 shared between rooms. Within individual patient rooms, we identified microenvironments of bacterial strains and resistance genes  and an increased probability of detecting cephalosporin resistance genes as distance increased from the patient\u2019s bed and neared bathroom sites . Using mixed effects regression, we found that distance between patient rooms was associated with decreased similarity in microbiomes of the distant in-room sites , while an opposite pattern was observed in the bathroom sites  .Rooms that were closer had greater similarity of microbiomes at the distant in-room site. Focused interventions on this microenvironment within patient rooms may be highest yield in reducing room-to-room transmission of bacteria. Shared microbiota at the bathroom site may be linked to plumbing infrastructure, but further research is needed to support this hypothesis.All Authors: No reported disclosures"}
+{"text": "Open Biology, titled \u2018Advances in Quantitative Bioimaging\u2019, proposes an overview of the latest advancements in quantitative bioimaging techniques and their wide-ranging applications. The articles cover various topics, including modern imaging methods that enable visualization on a nanoscale, such as super-resolution microscopy and single-particle analysis. These techniques offer unparalleled insights into complex molecular structures and dynamic cellular processes in situ, such as mapping nuclear pore proteins or tracking single histone deposition events throughout the cell cycle. The articles presented in this edition showcase cutting-edge quantitative imaging techniques coupled with advanced computational analysis capable of precisely measuring biological structures and processes. Examples range from correlating calcium release events to underlying protein organization in heart cells to pioneering tools for categorizing changes in microglia morphology under various conditions. This editorial highlights how these advancements are revolutionizing our understanding of living systems, while acknowledging challenges that must be addressed to fully exploit the potential of these emerging technologies, such as improving molecular probes, algorithms and correlation protocols.This special feature of  Recent progress in quantitative bioimaging technologies has empowered us to visualize complex molecular architectures, track individual proteins, compare cellular dynamics with nanoscale precision and single-molecule resolution. This leap forward holds significant potential for driving our understanding into uncharted territory by offering fresh mechanistic insights into living systems. In this special feature issue of . 2et al. discusses the power of combining super-resolution microscopy (SRM) with single-particle analysis (SPA). Several primary research articles in this special edition leverage advanced imaging methods to shed light on important cellular processes: Hurley et al. explore the relationship between calcium signalling events and the structural organization of calcium channels in cardiac muscle cells; Lando et al. use single-particle tracking to understand histone CENP-A molecule deposition in fission yeast; Ragaller et al. propose novel smart probes to measure membrane properties, which are crucial for understanding cellular processes. On the computational front, Martinez et al. have developed machine learning-based tools to characterize morphological alterations and behavioural shifts in microglia during neuroinflammation.This special edition features articles highlighting the ground-breaking applications of quantitative bioimaging techniques in various areas of biology. A review by Mendes et al., in their review entitled \u2018Mapping molecular complexes with super-resolution microscopy and single-particle analysis\u2019, discuss the combined power of SRM and SPA [Mendes  and SPA . SRM's aMiriam E. Hurley and her colleagues in their paper \u2018Correlative super-resolution analysis of cardiac calcium sparks and their molecular origins in health and disease' have successfully linked calcium release events, referred to as \u2018sparks\u2019, with the nanoscale arrangement of calcium channels known as ryanodine receptors RyR2) in rat heart cells [ in rat hIn vivo assessment of mechanical properties during axolotl development and regeneration using confocal Brillouin microscopy\u2019 by Riquelme-Guzm\u00e1n et al. used confocal Brillouin microscopy to uncover tissue mechanical changes in vivo throughout development and regeneration in the highly regenerative axolotl, with a particular focus on limb and digit cartilage [The article \u2018artilage . Probinget al., the authors used image analysis tools to examine the morphology and phagocytic behaviour of microglia in healthy and pathological conditions in vitro and in brain tissue [In the article titled \u2018Characterization of microglia behaviour in healthy and pathological conditions with image analysis tools\u2019 by Martinez n tissue . The autet al., in their work \u2018Dissecting the mechanisms of environment sensitivity of smart probes for quantitative assessment of membrane properties', present smart probes\u2014Pro12A, NR12S and NR12A\u2014to assess membrane properties [The research presented in this special issue has important implications for various fields. For instance, Ragaller operties . In thei. 3The studies presented here highlight scientific progress made possible by advanced quantitative bioimaging techniques and image analysis. These tools allow us to better understand the intricate layers of cellular functions and expand our perception of how living systems operate across different scales. Over time, these advancements will help bridge the gap between experimental observation and theoretical vision, progressively tackling the formidable complexity intrinsic to biology."}
+{"text": "Nitrospirota and Nitrospinota have received significant research attention due to their unique nitrogen metabolisms important to biogeochemical and industrial processes. These phyla are common inhabitants of marine and terrestrial subsurface environments and contain members capable of diverse physiologies in addition to nitrite oxidation and complete ammonia oxidation. Here, we use phylogenomics and gene-based analysis with ancestral state reconstruction and gene-tree\u2013species-tree reconciliation methods to investigate the life histories of these two phyla. We find that basal clades of both phyla primarily inhabit marine and terrestrial subsurface environments. The genomes of basal clades in both phyla appear smaller and more densely coded than the later-branching clades. The extant basal clades of both phyla share many traits inferred to be present in their respective common ancestors, including hydrogen, one-carbon, and sulfur-based metabolisms. Later-branching groups, namely the more frequently studied classes Nitrospiria and Nitrospinia, are both characterized by genome expansions driven by either de novo origination or laterally transferred genes that encode functions expanding their metabolic repertoire. These expansions include gene clusters that perform the unique nitrogen metabolisms that both phyla are most well known for. Our analyses support replicated evolutionary histories of these two bacterial phyla, with modern subsurface environments representing a genomic repository for the coding potential of ancestral metabolic traits.The phyla  Bacteria and Archaea are presumed to have retained ancient traits due to the environments being analogous to early-Earth, in some cases isolated from the surface world on geologic timescales . Ge. GeNitroses Fig.\u00a0. Gene clly Figs.\u00a0, 8.Fig. Nitrospirota and Nitrospinota as direct relatives . In. InnxrABota Fig.\u00a0. This susmatales . The verNitrospirota and Nitrospinota are markedly different than the later branching groups that have received much attention due to their ecological prominence, especially in the marine environment, and unique nitrogen-based metabolisms. Despite some differences in particular metabolic functions, the similar evolutionary histories of Nitrospirota and Nitrospinota demonstrate how multiple modes of evolution can shape closely related phyla that occupy similar ecological niches. These data demonstrate that gene loss, de novo origination, or lateral acquisition of new genes is a replicated pattern in later-branching clades of phyla whose extant subsurface-inhabiting members resemble ancestral lineages that initially evolved in a primordial habitat.Here we demonstrate that the ancestral metabolisms of early branching clades for the sister phyla Supplmental Methods and FiguresSupplemental Data 1Supplemental Data 2Supplemental Data 3Supplemental Data 4Supplemental Data 5Supplemental Data 6Supplemental Data 7"}
+{"text": "Burgeoning evidence demonstrates that effects of environmental exposures can be transmitted to subsequent generations through the germline without DNA mutations1,2. This phenomenon remains controversial because underlying mechanisms have not been identified. Therefore, understanding how effects of environmental exposures are transmitted to unexposed generations without DNA mutations is a fundamental unanswered question in biology. Here, we used an established murine model of male-specific transgenerational obesity to show that exposure to the obesogen tributyltin (TBT) elicited heritable changes in chromatin interactions (CIs) in primordial germ cells (PGCs). New CIs were formed within theIdegene encoding Insulin Degrading Enzyme in the directly exposed PGCs, then stably maintained in PGCs of the subsequent (unexposed) two generations. Concomitantly,IdemRNA expression was decreased in livers of male descendants from the exposed dams. These males were hyperinsulinemic and hyperglycemic, phenocopyingIde-deficient mice that are predisposed to adult-onset, diet-induced obesity. Creation of new CIs in PGCs, suppression of hepaticIdemRNA, increased fat mass, hyperinsulinemia and hyperglycemia were male-specific. Our results provide a plausible molecular mechanism underlying transmission of the transgenerational predisposition to obesity caused by gestational exposure to an environmental obesogen. They also provide an entry point for future studies aimed at understanding how environmental exposures alter chromatin structure to influence physiology across multiple generations in mammals."}
+{"text": "Editorial on the Research TopicRecent advances in the assessment and management of thoracic traumaThoracic trauma presents a significant global public health challenge, comprising approximately 25% of all injuries and contributing to up to 50% of trauma-related fatalities . SurvivoHoepelman et al.). This initiative aimed to delve into the clinical outcomes and quality of life experienced by individuals after surgical rib fixation for flail chest injuries. The findings showed a significant trend, with low complication rates and a favourable one-year quality of life, as assessed with the EQ-5D-5l questionnaire. Nonetheless, it is pertinent to note that substantial variability was observed among patients in this context.The majority of the articles included in this compilation scrutinized outcomes following surgical stabilisation of rib fractures in distinct patient cohorts. A noteworthy endeavour was carried out by the NEXT study group, encompassing a prospective cohort study that spanned six institutions across Switzerland and the Netherlands (Zhang et al. embarked on an evaluation of outcomes following surgical stabilisation of rib fractures in elderly patients. Employing a single-centre, propensity score matching analysis, their investigation identified a nuanced dichotomy. Patients who underwent surgery exhibited a modestly prolonged hospital stay by an average of two days when compared with their counterparts receiving conservative treatment. Nevertheless, the surgical cohort demonstrated markedly improved rates of fracture healing and a shorter duration of analgesic regimens, delineating a balance between hospitalisation duration and therapeutic efficacy.Becker et al. contributed a matched pairs analysis by using data from the German trauma registry. Their study focused on determining the optimal timing for rib fracture surgery. The findings highlighted a distinct advantage for surgical stabilisation within the initial 48\u2005h post-trauma, resulting in significantly shorter durations of intensive care unit and hospital stays compared to fixation performed between three and ten days following the injury.van Veelen et al., a unique perspective emerged as the authors explored outcomes after surgical fixation of chest wall fractures incurred during cardiopulmonary resuscitation efforts. It is worth mentioning that this retrospective, single-centre study included 19 patients, representing the largest reported cohort to undergo fracture fixation due to cardiopulmonary resuscitation. The authors reported a lack of complications associated with rib fixation, with only one infection observed following sternal fixation. Furthermore, the long-term follow-up demonstrated a favourable quality of life, as measured with the EQ-5D-5l questionnaire.Shifting our attention to the study by While the studies included in this Research Topic make substantial contributions to the evidence base, it is essential to acknowledge certain limitations. In the domain of thoracic trauma, the predominant body of research is characterized by retrospective observational studies and non-randomized prospective trials. Moreover, there is a pronounced heterogeneity in surgical techniques and outcome reporting, making comparisons between studies a challenging endeavour . RegardiWhile the studies featured in this Research Topic undeniably advance our understanding of the assessment and management of thoracic trauma, they also reveal a multitude of unanswered questions. Key areas requiring further research include the definition of optimal patient selection criteria for surgical stabilisation of rib fractures. Currently, it remains uncertain whether fixation should be extended to include a broader spectrum of non-flail chest fracture patterns. There is also a pressing need for comparative effectiveness studies examining different surgical techniques. The role of thoracoscopic visualization in fracture management is an interesting topic that also requires more comprehensive evaluation. Moreover, the absence of standardized protocols for perioperative analgesia and rehabilitation is conspicuous. In addition, there is a dearth of research into long-term, patient-centred outcomes, such as persistent disability and return to work. Formal cost-effectiveness analyses comparing surgical stabilisation to non-operative management are also relatively absent. To address these knowledge gaps effectively, it is necessary to conduct high-quality randomised controlled trials with standardised treatment protocols and well-defined outcomes. Multicentre studies can facilitate larger sample sizes, leading to improved generalizability. Overall, continued research is crucial in honing best practices for thoracic trauma care and ultimately enhancing outcomes for these patients. The studies presented in this Research Topic are indeed promising strides forward, but they highlight that a plethora of unanswered questions awaits exploration in future research.Thoracic trauma continues to exact a substantial toll on global health, contributing significantly to morbidity and mortality rates. The research shared in this Topic signifies prominent advancements, yet further investigations are imperative to delineate optimal practices more precisely. Persistent research efforts in this pivotal domain are warranted to mitigate the global public health repercussions of chest injuries and ultimately improve patient outcomes."}
+{"text": "Editorial on the Research TopicArtificial intelligence and advanced technologies in neurological surgerySurgical treatment of neurologic disorders has always benefited from technologic advancements in operative techniques and equipment, imaging, predictive analytics, and many others. In recent years, almost all neurosurgical subspecialties have seen a substantial effort to develop, validate, and utilize artificial intelligence and machine learning models in a clinical manner . Unique In this research topic, we explore recent technologic advancements made in neurosurgery, including supervised machine learning models aimed at predicting postoperative survival in glioma patients, customized 3D printing and laser navigation applied to minimally invasive hematoma evacuation, an advanced cerebrospinal fluid (CSF) drainage method for use in posterior fossa tumor resection, and a novel endoscopic approach for treatment of oculomotor nerve palsy, all of which may help to inspire future work in similar topics of interest.Li et al. at an academic institution in China compared the accuracy of traditional statistical models and supervised machine learning models in predicting patient survival following resection for gliomas. Multivariate Cox proportional hazards regression, support vector machine (SVM), random survival forest (RSF), and tree and component gradient boosting (GB) models were evaluated using patient-specific clinical and biomarker variables and were subsequently compared in performance using concordance indexes. Predictably, the traditional Cox proportional hazards regression model performed poorly in both training and testing sets when compared to the supervised machine learning models, of which the GB models produced superior performance in predicting survival. Time-dependent survival performance was additionally assessed between tree GB and component GB models, which displayed good discrimination (area under the curve >0.8) at all evaluated time points. The authors of this study recognized many important patient variables found to influence survival based on these models, including functional status, tumor size, and resection type, which can be utilized to develop patient-specific perioperative plans with the goal of extending survival and limiting morbidity.At the forefront of advancements in neurosurgical outcomes analysis is artificial intelligence and machine learning. A retrospective cohort study conducted by Yuan et al. studied hypertension-induced intracerebral hematoma external drainage techniques based on two new methods in a retrospective analysis: three-dimensional (3D) printing and laser guidance for navigation during puncture and debridement. In the 3D printing method, computed tomography (CT) image reconstructions were utilized to plan endoscope entry and trajectory into hematomas, which were then 3D printed in combination with patient face molds for customized intraoperative guidance. Laser guidance additionally utilized Xper-CT scans and 3D reconstructed images to emit a continuous focus directed towards the hematoma throughout the duration of the procedure. In direct intraoperative and postoperative comparisons, patients treated with 3D printing assistance were found to have significantly shorter operative durations than those treated with laser navigation assistance. However, outcomes including hematoma clearance rate, Glasgow Coma Sale improvement, and hospitalization time were similar between the two groups. The authors noted advantages to both techniques, including real-time navigation feedback and customized care, but may come at increased costs or extended preoperative setup time. Minimally invasive techniques in neurosurgery can be further improved with advancements in imaging and navigation, such as 3D printing and laser guidance.Beyond predictive analytics, developments in imaging technology have been utilized to improve intraoperative techniques. Recent work done by Roethlisberger et al. In their recent work, the authors utilized image-guided ipsilateral trigonal ventriculostomy for cerebellar pressure control during retrosigmoid craniotomy for cerebellopontine angle (CPA) tumor resection, after which outcomes were evaluated in a cohort of 52 patients. Prior to durotomy, the authors performed ventriculostomy of the ipsilateral trigone of the lateral ventricle using CT or magnetic resonance image (MRI) guidance, advancing an external ventricular drain (EVD) to release CSF and decompress the cerebellum. In the prospectively evaluated cohort, cerebellar swelling was avoided in 98% of cases using this technique. However, authors reported an 8% incidence of postoperative intracerebral or intraventricular hemorrhage without clinical complications. Ultimately, the authors recommended consideration of this technique for large posterior fossa tumors but not for small lesions.Developments in image guidance technology have been additionally explored in cerebrospinal fluid (CSF) diversion approaches to reduce cerebellar contusion, such as in the study described by Wang et al. The authors of this work describe detailed anatomic landmarks encountered in their endoscopic approach, focusing on correct identification of the optic strut triangle, consisting of the internal carotid artery, optic nerve, and superior orbital fissure, in preparation for oculomotor nerve decompression. Hollowing of the optic strut by sequential drilling under endoscopic visualization achieved decompression of the optic and oculomotor nerves, resulting in rapid neurologic symptom improvement in 2 presented patient cases. Although still requiring further trials, the techniques described in this study may introduce alternatives to invasive approaches that arise with often extensive complications.New surgical methodologies for conditions previously lacking standardized treatment plans have been developed with the aid of technological advancements including endoscopic approaches. A novel transnasal endoscopic approach for treatment of traumatic oculomotor nerve palsy associated with superior orbital fissure fracture is described in a recent study by Advancements in clinical and intraoperative technology have enabled neurosurgeons to create patient-specific management plans and improve postoperative outcomes for a range of conditions. In this research topic, four original studies were included that demonstrate the breadth of developments made in artificial intelligence-based predictive analytics, intraoperative imaging and navigation technologies, and novel cranial approaches aimed at improving patient outcomes. Further incorporation of machine learning algorithms, reconstructive software, and minimally invasive technology into daily medical practice will allow future generations of surgeons to provide personalized care to patients based on unique comorbidities and anatomic variations.We certainly live in an era of rapid technologic advancement, but this also comes with great responsibility. As physicians and surgeons, it is our duty to question these technologies and understand their limitations before implementing them in our clinical practice. However, it is also our duty to embrace and use them when they can improve our patients\u2019 lives. As our techniques and devices continue to evolve, we look forward to exploring the positive impacts made to neurosurgery and beyond."}
+{"text": "The need for high quality evidence is recognized for optimizing practices of parenteral nutrition (PN). The purpose of the present systematic review is to update the available evidence and investigate the effect of standardized PN (SPN) vs. individualized PN (IPN) on protein intake, immediate morbidities, growth, and long-term outcome in preterm infants. A literature search was performed on articles published in the period from 1/2015 to 11/2022 in PubMed and Cochrane database for trials on parenteral nutrition in preterm infants. Three new studies were identified. All new identified trials were nonrandomized observational trials using historical controls. SPN may increase weight and occipital frontal circumference gain and lower the value of maximum weight loss. More recent trials suggest that SPN may easily increase early protein intake. SPN may reduce the sepsis incidence, but overall, no significant effect was found. There was no significant effect of standardization of PN on mortality or stage \u22652 necrotizing enterocolite (NEC) incidence. In conclusion SPN may improve growth through higher nutrient  intake and has no effect on sepsis, NEC, mortality, or days of PN. Parenteral Nutrition (PN) is a lifesaving therapy for preterm infants. PN is indicated when oral or enteral nutrition is not possible, insufficient, or contraindicated in order to avoid undernutrition and related adverse consequences. The nutrient stores of very low birth weight  and extremely low birth weight  preterm infants are low. Bridging PN ensures adequate fluid intake and nutrient supply for weight gain and possibly neurodevelopmental long-term outcome. VLBW infants are vulnerable to postnatal growth failure because the gut is immature, and provision of nutrients is challenging. The evidence showing the beneficial effects of enhanced PN to VLBW infants is accumulating. Providing amino acids and energy immediately after birth with PN is a standard practice to promote positive nitrogen retention . SP. SP18]. However, the currently available commercial SPN solutions may not be the optimum approach. Commercial SPN may need an additional amino acid supply to achieve recommended target intakes and consequently adequate growth defined as intrauterine growth velocity .Beyond improved nutrient intake, the umbrella aim in introduction of SPN is to improve patient safety  possibly at the cost of increased PN solution wastage . Due to However, SPN did not significantly prevent hospital associated complications . EspeciaStandard PN Solutions (SPN) Should Generally Be Used over Individualized PN Solutions (IPN) in the Majority of Preterm Infants, Including VLBW Premature Infants .Individually Tailored PN Solution should Generally Be Used When the Nutritional Requirements Cannot Be Met by the Available Range of Standard PN Formulations  .It has been estimated that the majority of preterm infants receiving PN via central catheters may actually be treated by SPN, although, the optimum composition is not known ,38. SPN Adequately Powered Randomized Controlled Trials Based on Up-To-Date Parenteral Nutrition Recommendations Are Required to Evaluate the Real Clinical Benefits of SPN vs. IPN .Strengths of the present review are its exhaustive search of the available literature, reproducibility, systematic assessment of evidence and grading of recommendations. However, there are important limitations. Neonatology is rapidly developing and changing. E.g., nutritional recommendations changed several times within the last 20 years. Using historical controls rather than contemporaneous controls carries a high risk of bias and grossly limits the level of evidence. Improvements in nutritional status may rather be a consequence of increased nutritional awareness than a consequence of new developed PN approaches. The observed effects may have been noticed by chance and adequately powered, randomized controlled trials based on up-to-date parenteral nutrition recommendations are urgently required to evaluate the real clinical benefits of SPN bags. Given current parenteral nutrition recommendations a considerable proportion of infants of the reported trials are undernourished. In addition, the composition of SPN and IPN nutritional regimens and consequently the observed nutritional status, varied across and within the different studies, limiting the validity of the results of the meta-analyses. In the clinical experience of the authors, one SPN does not fit all preterm infants. The smaller the infants are, the more often adjustments are required, commercial SPN bags are more expensive than hospital pharmacy produced SPN bags, and finally commercial SPN bags still require pharmacy-based adjustments .We conclude that SPN may improve growth through higher nutrient  intake and has no effect on sepsis, NEC, mortality, or days of PN. These observations may have been noticed by chance and adequately powered randomized controlled trials are required to evaluate the real clinical benefits of SPN."}
+{"text": "Arachis hypogaea is a segmental allotetraploid in the section Arachis of the genus Arachis along with the Section Rhizomataceae. Section Arachis has several diploid species along with Arachis hypogaea and A. monticola. The section Rhizomataceae comprises polyploid species. Several species in the genus are highly tolerant to biotic and abiotic stresses and provide excellent sets of genotypes for studies on differential gene expression. Though there were several studies in this direction, more studies are needed to identify more and more gene combinations. Next generation RNA-seq based differential gene expression study is a powerful tool to identify the genes and regulatory pathways involved in stress tolerance. Transcriptomic and proteomic study of peanut plants under biotic stresses reveals a number of differentially expressed genes such as R genes , pathogenesis related proteins  and defense related genes  that are the most consistently expressed genes throughout the studies reported so far. In most of the studies on biotic stress induction, the differentially expressed genes involved in the process with enriched pathways showed plant-pathogen interactions, phenylpropanoid biosynthesis, defense and signal transduction. Differential gene expression studies in response to abiotic stresses, reported the most commonly expressed genes are transcription factors , LEA proteins, chitinase, aquaporins, F-box, cytochrome p450 and ROS scavenging enzymes. These differentially expressed genes are in enriched pathways of transcription regulation, starch and sucrose metabolism, signal transduction and biosynthesis of unsaturated fatty acids. These identified differentially expressed genes provide a better understanding of the resistance/tolerance mechanism, and the genes for manipulating biotic and abiotic stress tolerance in peanut and other crop plants. There are a number of differentially expressed genes during biotic and abiotic stresses were successfully characterized in peanut or model plants (tobacco or Arabidopsis) by genetic manipulation to develop stress tolerance plants, which have been detailed out in this review and more concerted studies are needed to identify more and more gene/gene combinations.Peanut  Arachis hypogaea L.) is one of the most important legume crops economically worldwide and its seed a source of high quality edible oil, proteins, minerals and vitamins. It is widely cultivated across developing countries from semi-arid tropics to subtropical regions (st and 2nd respectively based on FAOSTAT data for the year 2020 (Peanut ( regions . China aear 2020 . ProductArabidopsis (135 Mb), rice (430 Mb), Medicago (904 Mb) and soybean (1.1 Gb). Large genome size and polyploidy nature  is quite large in size  in contry nature  hamper cArachis comprises many wild species at different ploidy levels that exhibit resistance/tolerance to several biotic and abiotic stresses, which makes it a rich resource of suitable genes for commercial applications. Some wild species were deployed in the experiments with the aim of transferring the genes for tolerance/resistance to different stresses from the related wild species to the cultivated peanut genotypes in crop improvement programs  is well-established and versatile technique with application to detects the enriched sequences in specific tissues at specific time points and used to characterize differential gene expression of plant responses to biotic and abiotic stresses . To inveRalstonia solanacearum , late leaf spot (LLS), rust, aflatoxin contamination and bacterial wilt disease by nacearum Figure\u00a01nacearum . To manaCercospora arachidicola [Hori] and Phaeosariopsis personata [Berk & M. A. Curtis] respectively, are the major foliar fungal diseases in peanut, which cause complete defoliation of leaves leading to significant losses in plant productivity upto 50 to 70%  protein, transcription factors , peroxidases and genes related to secondary metabolites in the resistant variety upon pathogen invasion, while there was downregulation of genes including F-box, cytochrome p450, LRR protein kinase and terpene synthase that are associated with several biological processes in the susceptible variety. There is another recent report of DEGs of resistant and susceptible peanut cultivars to early leaf spot infection, which revealed the expression of resistance associated genes like CC-NB-LRR (NLR) type resistance gene, Phytoalexin deficient 4 (PAD 4) and polyphenol oxidase (PPO) that play important roles in mediating early leaf spot resistance  and late leaf spot (LLS) diseases also collectively known as \u2018Tikka\u2019 disease caused by 0 to 70% . Early l0 to 70% . Advance0 to 70% . Upon pa0 to 70% . Candidasistance . IdentifPheaosariopsis personata (Cercospora personata) is the most devastating disease in peanut and can lead to yield losses up to 70% under favorable conditions . Furthermore, they identified TDFs (transcript derived fragments) that are associated with defense, signal transduction and metabolism, and further reported several genes for proteins involved in hypersensitive cell death, cell wall fortification and defense mechanism. Differential gene expression analysis in wild type and mutant peanut cultivar against late leaf spot pathogen was also reported by There are several methods available to study differential gene expression during plant-pathogen interactions in peanut, such as Genefishing DEG kit, suppression subtractive hybridization (SSH), cDNA-AFLP and cDNA-microarray techniques . These ansferase . In an e pathway . Kumar aR-genes (381) associated with leaf spot disease was predicted by a RGA-PCR based technique , receptor like proteins (RLPs) and receptor like cytoplasmic kinases (RLCKs), which co-ordinate and initiate protection responses against the invading pathogen , as potential resistance (R) genes play important roles in recognition and activation of disease resistance responses and the identification of putative peanut echnique . Furtherpathogen . Recentlpathogen .Puccinia arachidis that often occurs along with leaf spot disease also because of its rain fed nature, which leads to further yield losses. There are several studies on quantitative trait locus (QTL) in cultivated peanut to identify molecular marker or genetic map for rust resistance  technique, which is based on next-generation sequencing (NGS) for genotyping and this resulted in the identification of six candidate genes for rust resistance  protein were significantly upregulated in the resistant genotype revealing their important roles in plant defense mechanism. These findings will be helpful in understanding the molecular mechanism of peanut plant defense against the rust pathogen and may assist the breeders in the development of resistant varieties through molecular approaches.Rust is another serious foliar disease of peanut caused by sistance , but thesistance . RecentlAspergillus flavus is an opportunistic saprophytic fungal pathogen that infects a number of seed crops   and microarray technology. Furthermore, they identified sixty two genes in the resistant cultivar that were upregulated in response to Aspergillus infection including defense related genes like PR10 protein, defensin, calmodulin, metallothionein like protein, Cu/Zn superoxide dismutase etc. and a large number of hypothetical proteins as the complete genome sequence was not available at that point of time. A similar study has reported the identification of Aspergillus resistance genes in peanut cultivars by comparing transcriptome profiles in resistant and susceptible peanut genotypes using microarray technique  and identified hub genes positively associated with resistance to A. flavus in peanut. Their analysis also revealed that upregulation of genes encoding pathogenesis-related protein (PR10), MAPK kinase, 1-aminocyclopropane-1-carboxylate oxidase (ACO1), a serine/threonine kinase, cytochrome P450, pectin esterase, SNARE protein SYP121, pentatricopeptide repeat (PPR) protein and disease resistance response proteins in the esistant peanut cultivar that play major roles in resistance to infection from A. flavus. These studies provide new insights into the molecular mechanism of peanut defense against aflatoxin contamination and further the safety and management of peanut products for human consumption.on etc.)  and prodon etc.) . Peanut nditions  that cauechnique . Their rchnology . This grRalstonia solanacearum) is the most devastating soil borne disease in peanut (Arachis hypogaea L.) leading to significant yield losses because of reduced plant stand on the field at the seedling stage of the crop. Molecular mechanism of peanut response to R. solanacearum remains unnknown and needs to be studied in detail. In an attempt to explore the molecular mechanism of bacterial wilt resistance in peanut using Genefishing DEG kit, several differentially expressed candidate genes encoding a cyclophilin, ADP-ribosylation factor, antibacterial peptide and disease resistance response proteins were identified by studying the differences in gene expression between inoculated and control peanut seeds  into six groups as resistant/susceptible response genes, which included PAMPs induced resistant/susceptible response genes and type III effectors (T3Es) induced resistant/susceptible response genes. Further more, KEGG enrichment pathway analysis of differentially expressed genes showed that MAPK signaling, plant-pathogen interaction, and plant hormone signal transduction pathways were upregulated. WRKY Transcription factors play an important role in plant disease resistance. Differential gene expression analysis of WRKY genes in cultivated peanut displayed different expression patterns in resistant and sensitive peanut cultivars infected with R. solanacearum. The identification of candidate WRKY genes with possible role in peanut resistance to R. solanacearum infection may contribute in the improvement of a resistant peanut variety , pathogenesis related proteins , defense related genes , glutathione S-transferase) and the genes involved in phenylpropanoid pathway are the most commonely expressed ones (Arabidopsis) through genetic manipulation and successfully developed biotic stress resistant plants  for functional characterization of genes that integrated into the corresponding genome. There are limited reports on differentially expressed peanut genes for further characterization using genetic engineering to develop stress tolerance plants. The transgenic plants that were developed for functional characterization of diffrentially expressed peanut genes are given in Several peanut genes, which were differentially expressed during biotic stress conditions were further characterized by transgenic approach. Presently, genetic engineering technique such as Cyclophillin (AdCyp) gene that was differentially expressed in wild peanut A. diogoi during late leaf spot infection was incorporated into tobacco genome under a constitutive promoter through the Agrobacterium method and this resulted in enhanced resistance to Ralstonia solanacearum and reduced susceptibility toward Phytophthora parasitica var. nicotianae. Further, the resistance phenomenon was associated with the up-regualtion of various defense related genes  genotype enhanced resistance to late leaf spot pathogen and this expression was associated with the co-expression of resistance-related genes, CC-NB-LRR and some protein kinases, while heterologous expression in tobacco enhanced its resistance against Phytophthora parasitica var. nicotianae, Alternaria alternata var. nicotianae and Rhizoctonia solani  like cell death and positively regulated defense response genes. Furthermore, ectopic expression of AdVPE in tobacco resulted in enhanced resistance against Phytophthora parasitica var. nicotianae, Alternaria alternata var. nicotianae and Rhizoctonia solani (AdZADH2) was also differentially upregulated in Arachis diogoi, a wild peanut upon challenge with the late leaf spot (LLS) pathogen. Transient over-expression of AdZADH2 under an estradiol inducible promoter (XVE) exhibited hypersensitive response (HR)-like cell death in tobacco leaf and the cell death was associated with the upregulation of antioxidative enzymes such as SOD, CAT and APX and pathogenesis-related (PR) proteins (Vacuolar processing enzymes (VPEs) are cysteine proteases exhibiting caspase-1-like activity, which mediate cell death and upregulated during pathogen infections . AdVPE wa solani . A novelproteins .R gene products, which can directly or indirectly recognize pathogen effector proteins and induce signaling pathways for resistance against the impending pathogen  in Nicotiana benthamiana and AhRLK1 overexpression in transgenic tobacco significantly enhanced resistance to R. solanacearum by triggering EDS1 and PAD4 in the R gene signaling pathway that possibly contributed to defense responses against the pathogen  protein was found to be upregulated in both approaches . Wang etranensis .Soil salinity is another major abiotic stress factor that affects plant growth and development reducing crop productivity. Peanut is considered to be a moderately salt sensitive species, which makes salinity a liming factor for peanut cultivation. In general, plants respond to salt stress by changing their gene expression, which leads to an increase in the concentrations of several metabolites to protect themselves against high salinity. Transcriptome study has become an important tool for studying the possible mechanism and elucidating signal pathways underlying salt stress tolerance in plants. However, limited information is available about the networks of gene expression regulation related to salt stress in peanut. A microarray study has been carried out in peanut roots under salt stress conditions, which revealed that metabolic pathway, biosynthesis of unsaturated fatty acids and plant-pathogen interaction were upregulated, while photosynthesis and phenylalanine metabolism were downregulated . TranscrTIP3 gene is significantly upregulated in response to salt stress. Furthermore, TIP3 overexpression in Arabidopsis resulted in enhanced seed germination under salt stress corroborating its important role in seed germination under salt stress.A comprehensive study of drought tolerance in cultivated peanut has been performed under salt stress environment and this concurrent stress application has detected several differentially expressed genes and transcription factors (TFs) such as MYB, WRKY, bHLH and AP2/ERF in response to salinity. Moreover, differentially expressed genes related to cell wall growth, antioxidant and peroxidase activity were significantly enriched while DEGs related to metabolic processes, oxidoreductase and catalytic activity were downregulated . AquaporPMP34 that encodes a peroxisomal nicotinamide adenine dinucleotide carrier, and Sodium/H+ antiporters (NHX7 and NHX8), and downregulated expression of proline dehydrogenase 2. This resulted in the accumulation of soluble sugars and proline to maintain the osmotic balance with an additional up-regulation of the aquaporin gene TIP2-1. Moreover, exogenous EBL application upregulated the expression of NHX7 and NHX8 to balance the ion concentrations across membranes with increased peroxidase activity to scavenge reactive oxygen species, and glutathione levels to improve salt tolerance in peanut.Brassinosteroids (BRs) are essential for plant growth and development, and play crucial roles in stress tolerance . HoweverLow temperature is a major environmental factor that limits plant growth, development and yield. Cold stress causes different degrees of damage to the peanut plant at the seedling, flowering, and all other growth stages. A transcriptome or differential gene expression analysis in response to cold or metal stress could provide a deeper insight into the transcriptional mechanism of plants and their protective role against damage. Differentially expressed peanut genes in response to different temperature regimes was carried out using suppression subtractive hybridization (SSH) for cultivated peanut seeds and this study identified genes that are involved in functional categories including metabolism, defense, stress response, signal transduction and transcriptional regulation .2H2, ERF, MYB, NAC and WRKY in response to cold stress, which could be crucial for peanut cold tolerance  are non-coding small RNAs that play important roles in various abiotic stresses by modulating gene expression. However, there is no report on the role of miRNAs in cultivated peanuts during cold stress. Very recently, cold-responsive miRNAs and candidate target genes were identified in peanut cold tolerant and sensitive varieties during cold stress using a deep sequencing method. Their analysis revealed several specific cold responsive microRNAs, which appear to mediate cold response. And, several transcription factors including WDRL, GRF and ARF, and genes such as  peanuts .EIL (EIN3-like), which reveals a link between ethylene signal transduction and Al resistance related genes in peanut (Aluminum (Al) is the most abundant metal element in the Earth\u2019s crust, and has toxic effects on plant growth in acidic soils . The tarn peanut . An ultrn peanut . The samn peanut .Arachis accessions under drought, salt, cold and metal stress conditions will provide a better understanding of the tolerance mechanism, and will further provide reference for improving abiotic tolerant peanut cultivar through genetic manipulation.Differential gene expression study of peanut plants in response to abiotic stresses, reported by the most of the studies Table\u00a03,Agrobacterium tumefaciens mediated genetic transformation. There are several reports on the characterization of differentially expressed genes in peanut and/or model plants to develop stress resistance plants. The list of transgenic plants deploying differentially expressed peanut genes is provided in Further characterization of differentially expressed genes during various abiotic stresses by genetic manipulation like transgenic approach would aid in developing stress tolerance peanut cultivars, which can help achieve increased crop productivity. Till today, different types of transgenic plants were generated by genetic engineering technique using AhERF019 in Arabidopsis resulted in enhanced tolerance to drought, heat, and salt stresses (LEA) gene was differentially expressed in wild peanut upon infection with late leaf spot pathogen and overexpression of AdLEA in tobacco resulted in enhanced tolerance of plants to dehydration, salinity and oxidative stress. Furthermore, AdLEA overexpressed tobacco plants maintained better photosynthetic efficiency under drought conditions implying that it could be a potential gene for genetic modification in crop plants  gene and overexpression of AdGolS3 gene in Arabidopsis resulted in increased raffinose production and tolerance to drought, salt and osmotic stresses  plays a significant role in regulating gene expression in plant responses to stresses and was identified from peanut EST sequences available in the NCBI database. Ectopic expression of stresses . Late Emp plants . In silistresses . A CBL-in plants .TIP3 was found differentially upregulated under salt stress condition in cultivated peanut. Furthermore, the ectopic expression of AhTIP3;1 contributed to improved seed germination under salt stress in Arabidopsis  was found upregulated during plant-microbe interaction in peanut and further, the overexpression of AhCytb6 gene in tobacco resulted in enhanced seed germination under N2 deficit and salt stress conditions  gene was observed to be upregulated  was found to be differentially expressed in the wild peanut after late leaf spot infection  stress in tobacco  are important endogenous non-coding RNAs with an average size of 21 to 23-nt in length that regulate gene expression in plants and animals by regulating mRNA expression post-transcriptionally . RNA polAspergillus flavus  under Al stress, root tips of Al-sensitive and Al-tolerant peanut cultivars were analyzed under Al stress condition. Further intergrated analysis of transcriptomics, sRNAs, and degradome data sets revealed differential expression of 89 miRNA-mRNA interactions that might be involved in PCD under Al stress . In respArachis species using differential expression analysis for stress tolerance. However, commercially cultivated transgenic plants were not developed in peanut so far using the identified genes. There could be several reasons for this. Since peanut is a crop of high commercial significance whose produce is of prime importance in human nutrition, it is not easy to get regulatory approvals from the respective Governmental authorities across the world for the deployment of transgenic plants for field- level cultivation. Probably, many major efforts were not made in peanut in this direction because of this reason. With the advent of genome editing technology for various plant systems, the future is very optimistic for developing genome edited crops including peanut for stress tolerance as genome-edited crops might get regulatory approvals more easily compared to transgenic plants.The biological stresses mainly comprise attack from pathogenic fungi, bacteria, viruses, nematode and insects, whereas the abiotic constraints include drought, salinity, cold, metal, waterlogging and temperature changes. To overcome these various stress environments, plants must be capable of tolerating these stress conditions by modulating their metabolism in the right direction. In this direction, the genetically modified crops are considered to be good candidates for sustainable food production. It is to be noted that there were several genes identified in Agrobacterium tumefaciens or Rhizobium rhizogenes mediated genetic transformation technique through either in vitro or in planta methods for improvement. Transgene expression is highly dependent on the promoter selection for gene expression followed by protein synthesis. Several promoters of various origins have been tested for transgene expression besides viral gene promoter CaMV35S in peanut. In the backdrop of this, no meaningful progress of gene editing technique that is gaining enormous attention recently has been made so far in peanut.Genome modifications allow improvements in stress and weed tolerance, plant breeding procedure, productivity, food quality and safety. However, introduction of genetically modified crops may adversely affect the environmental conditions exercising harmful effects on animals and humans and this has been the main concern of the environmentalists . There aThere are several powerful plant-targeted genome editing tools for functional and applied genetic manipulations that include engineered nucleases, such as Zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short palindromic repeats (CRISPR) systems .Recently developed prokaryotic immune system based CRISPR technology is a high-throughput genome editing tool that has been found to be very successful in a variety of plant species . The CRIBiotic stress tolerance where crop yield and quality are largely affected by biotic stresses like viral, fungal, bacterial and insects were improved by using CRISPSR/Cas9 system. For instance, wheat and rice have been made tolerant to their respective viral, bacterial and fungal diseases . Tomato,FAD2) gene in peanut. This gene codes for the desaturase that is responsible for the conversion of monounsaturated oleic acid into polyunsaturated linoleic acid. The knock out mutation in FAD2 resulted in high oleic acid content in peanut oil (AhNFR gene through hairy root transformation system and validated the function for nodule formation in peanut. Using the CRISPR/Cas9 system, AhFatB genes Arahy4E7QKU and ArahyL4EP3N were knocked out in peanut, and mutation at Arahy.4E7QKU displayed low palmitic acid and high oleic acid content significantly improving oil quality in peanut (Application of CRISPR/Cas9-based gene editing technique would provide genetic improvement in peanut cultivars against biotic and abiotic stresses. However, application of this breakthrough gene editing technology to peanut is still rare. Till date, there is limited report of CRISPAR/Cas9-based gene editing in peanut. This technique is used for knocking out fatty acid desaturase2 (anut oil . Shu et\u00a0n peanut . PotentiArachis divided into various Sections is a boon to the investigators undertaking differential expression studies using the previously popular techniques like cDNA-AFLP and the highly efficient RNA-Seq studies using the Next Generation Sequencing technologies that became available recently. The goal of these studies is to understand molecular mechanisms during stress conditions and identify the genes responsible for stress tolerance in peanut plants. Depending on the availability of financial resources, the choice of the technology can be made. The primary advantage with the NGS technologies is that they give faster results on gene expression at whole genome level compared to the earlier technologies. The wild Arachis germplasm offers excellent material for the differential expression studies because of the availability of genotypes that are both susceptible and highly resistant to corresponding trait, be it biotic or abiotic stress tolerance. The alloploid species belonging to the Section Rhizomataceae are very highly tolerant to abioic stresses like high temperature and water limited conditions. Hence, the germplasm can be used for identifying tolerance genes within the tolerant genotype itself by comparing sets with and without treatments. Otherwise, a more efficient option would be to compare the resistant and susceptible genotypes at the same ploidy level with and without suitable treatments. Information from such studies could lead to novel genes that would actually decide the trait under consideration. The genes identified can be used in other related legume crop plants. This is particularly because of the possible colinearity of different related genomes in legumes. Hence, the opportunities are enormous when the investigator uses the material judiciously.The wild germplasm belonging to the genus DK: Conceptualization, Writing \u2013 original draft. PBK: Conceptualization, Writing \u2013 review & editing."}
+{"text": "Liquid biopsy assays for minimal residual disease (MRD) are used to monitor and inform oncological treatment and predict the risk of relapse in cancer patients. To-date, most MRD assay development has focused on targeting somatic mutations. However, epigenetic changes are more frequent and universal than genetic alterations in cancer and circulating tumor DNA (ctDNA) retains much of these changes. Here, we review the epigenetic signals that can be used to detect MRD, including DNA methylation alterations and fragmentation patterns that differentiate ctDNA from noncancerous circulating cell-free DNA (ccfDNA). We then summarize the current state of MRD monitoring; highlight the advantages of epigenetics over genetics-based approaches; and discuss the emerging paradigm of assaying both genetic and epigenetic targets to monitor treatment response, detect disease recurrence, and inform adjuvant therapy. MRD does not cause clinical symptoms and is not detectable by traditional methods such as imaging  or abnormal blood serum protein levels. MRD assays must be sensitive enough to detect as little as 1 cancerous cell in a background of 1 million noncancerous cells. This extreme sensitivity makes MRD assay development complex, but overcoming this barrier imbues MRD assays with the potential for much earlier detection of cancer recurrence than traditional methods, and thus earlier intervention with adjuvant chemotherapy or second and third-line treatments.Detection of MRD indicates the failure of treatment to eliminate all cancerous cells which implies greater probability of future disease recurrence. Monitoring MRD signals during the remission period allows early detection of disease progression . Assayin22.1DNA methylation is a covalent modification of the DNA strand that, in mammals, occurs almost exclusively within the sequence context of cytosine followed by guanosine (CpG) dinucleotides. The genomic acquisition of DNA methylation is an essential developmental process with diverse roles including repressive associations at gene promoters and mobile genetic elements or, conversely, increased transcriptional activity when found within gene bodies [reviewed in Greenberg & Bourc\u2019his ]. GenomeMost DNA methylation-based liquid biopsies target cancer-specific aberrations that separate cancer from its normal tissue counterpart. However, within healthy tissues DNA methylation exhibits highly cell type specific patterns across the genome . This un2.2The term \u201cfragmentomics\u201d describes the study of ccfDNA fragmentation patterns and the use of these patterns to decern biologically relevant information such as nucleosome positioning. Although few assays to-date utilize ccfDNA fragmentation patterns, numerous properties of ctDNA compared to healthy ccfDNA instill fragmentomics with the potential for use in oncological assays ; (ii) shAs for nucleosome positioning, ccfDNA fragmentation patterns downstream of transcription start sites have been shown to reflect differential nucleosome positioning between expressed and unexpressed genes . These cGoing forward, the most sensitive and universal MRD assays will likely combine these epigenomic approaches. Until recently, the combination of DNA methylation and fragmentomics in a single assay was not possible due DNA methylation detection relying on bisulfite conversion . Bisulfi3The marketplace for MRD liquid biopsy assays is new, but several MRD diagnostic tests have now received early regulatory approvals Table\u00a01.While there are only a few somatic mutation-based MRD panels in the marketplace, there are a host currently in development and undergoing clinic trials. For example, Strata Oncology are also exploring a two-staged tumor-informed panel design in their Sentinel trial for cancer recurrence . BurningNotably, genetic mutations are not broadly shared across cancers and the two-stage solutions to this shortcoming are limited by tumor heterogeneity and the volume of a tissue biopsy. That is, because only a subset of a tumor is sequenced there is still a high probability that mutations will be missed. However, a multi-omics approach can augment this shortcoming. The greater frequency and universality of epigenetic changes makes them more sensitive and universal markers for evidence of cancer after curative intent treatment, and somatic mutation testing highlights actionable variants that can inform subsequent treatment. This promise of MRD assays that incorporate epigenetics with somatic mutation testing is being realized. Guardant Health has combined somatic mutations, DNA methylation and fragmentomics into their LUNAR panel, which they have progressed into clinical trials for both primary detection and MRD of early-stage colorectal cancer .Multiple companies are also progressing purely epigenetic-based MRD panel approaches. MethylGene is undertaking a clinical trial on multiple myeloma patients that will utilize DNA methylation sequencing of ctDNA for MRD detection . While GWhile most product development for MRD is concentrated around sequencing large panels of markers, simple DNA methylation-based PCR tests can also be highly efficacious. Colvera, developed by Clinical Genomics, is available as an LDT in the USA and has Medicare coverage for MRD and recurrence monitoring of colorectal cancer. This methylated ctDNA test detected 66.0% of recurrence, significantly higher than the 31.9% sensitivity of carcinoembryonic antigen (CAE), the current standard of care , and alsInterestingly, a simple well-designed PCR test can have adequate diagnostic power when compared to a large NGS panel. This is illustrated when comparing the rates of primary detection of colorectal cancer across the GRAIL-sponsored circulating cell-free genome atlas (CCGA)  study T (Trial i4Liquid biopsy is a powerful, multifaceted, and minimally invasive method for MRD detection and hence for monitoring therapeutic response, disease recurrence, or patient resistance to therapy. Although a relatively new field, liquid biopsy assays are showing promising results when compared to current standards of care. Two-staged somatic mutation approaches, where tumor sequencing informs MRD assay targets, allow clinicians to track actionable mutations and monitor for signs of treatment resistance. However, the time required to establish theses assays does not fit well with the patient journey, as clinicians need to know sooner than 5-6 weeks whether a patient is not responding to treatment. Therefore, epigenetic-based MRD assays are preferable at treatment onset, as epigenetic changes are typically more widespread and likely to be shared among a greater number of cancers than somatic mutations. With the recent advent of enzymatic methylation conversion, targeted sequencing approaches combining DNA methylation, fragmentomics and machine learning will likely come to predominate. However, DNA methylation-based PCR tests currently offer the most cost-effective solution within this niche. In fact, a compelling paradigm may be the combination of inexpensive serial testing with a DNA methylation-based assay, then following a positive MRD/recurrence result with a broad NGS-based somatic mutation panel to identify actionable mutations.AJ, JR, CM, KF, and WL wrote and revised this review. All authors contributed to the article and approved the submitted version."}
+{"text": "Editorial on the Research TopicRecent advances in hypospadiologyHypospadias is one of the most common genital anomalies in men and displays a wide range of complex phenotypes. Multiple studies have reported a marked global increase in hypospadias cases over the past three decades, although the underlying basis for this remains unclear , 2. WhilBaray et al., developed an automated deep learning-based method for accurate PC measurement using 2D images, which could significantly improve patient assessment by surgeons and researchers alike. The novel pipeline they propose includes three key consecutive steps: penile localization, shaft segmentation, and angle measurement considering only the proximal and distal parts of the penile shaft. This method may overcome current limitations encountered by conventional approaches to measuring arc-type PC.Penile curvature (PC) is a key anatomical component of many hypospadias phenotypes and can have long-lasting effects on patients\u2019 psychosexual health and quality of life. While several prior studies have attempted to establish criteria for evaluating PC, there is still no standardized method for doing so. Despite significant challenges with assessing PC in both clinical practice and research settings, numerous procedures are now being investigated that have potential to resolve longstanding issues. Zhou et al., one-stage correction of severe hypospadias was achieved using a free preputial tube graft in conjunction with urethral plate urethroplasty and a Buck's fascia integral covering (BFIC) to protect the neourethra and minimize fistula risk. Using an alternative approach, Li et al., report their experience with transverse preputial island flap urethroplasty (TPIFU) in a retrospective cohort study. In 136 patient who underwent single-stage TPIFU, re-operation to address postoperative complications was required in 39% of cases, the majority of which were due to urethrocutaneous fistulas .Among the wide spectrum of hypospadias anomalies, proximal cases include a subset of severe phenotypes that can significantly impact treatment protocols and post-operative results. In these instances, choice of surgical approach is heavily influenced by surgeon experience and personal preference in addition to patient anatomy . There is still considerable disagreement about the optimal method for treating proximal hypospadias, but surgeons are increasingly testing new approaches to achieve better patient outcomes. In a study by Tian et al., present the results of a retrospective cohort of 195 patients who underwent hypospadias repair and subsequently developed postoperative fistulas. Patients with recurrent fistulas after initial closure were compared with patients who achieved successful fistula closure, which revealed an association of catheter type used for drainage with local purulent discharge after surgery.Weidler et al., report their results from a multicenter collaboration evaluating the controversy surrounding optimal timing of surgery. In particular, their study focuses on decision making in individuals with differences in sexual development, as well as their caregivers and healthcare providers. Using a semi-structured interview, the authors evaluated potential determinants of successful outcomes in 110 participants. They identify several key themes including; (1) the nature/type of decision being made, (2) person involved in decision making, (3) timing of conversations about surgery, (4) barriers to decision-making surrounding surgery, (5) elements involved in these discussions, and (6) optimal approach to surgical decision-making. Priority was given to children and adolescents with disorders of sexual differentiation to ensure their involvement in all discussions. In summary, while many issues remain unresolved in the field of hypospadiology, novel approaches and improved understanding of surgical and patient-reported outcomes will be crucial to the continuing evolution of this challenging field."}
+{"text": "Iatrogenic ST elevation myocardial infarction (STEMI) after aortic valve surgery is a rare complication. Myocardial infarction (MI) due to mediastinal drain tube compression on the native coronary artery is also seen rarely. We present a case of ST elevation inferior myocardial infarction due to post-surgical drain tube placed after aortic valve replacement compressing on the right-sided posterior descending artery (rPDA).A 75-year-old female presented with exertional chest pain and was found to have severe aortic stenosis (AS). After a normal coronary angiogram and proper risk stratification, the patient underwent surgical aortic valve replacement (SAVR). One day after surgery in the post-operative area, the patient was complaining about central chest pain suggestive of anginal pain. Electrocardiogram (ECG) revealed that she has ST elevation myocardial infarction in the inferior wall. Immediately, she was taken to the cardiac catheterization laboratory, which revealed that she has occlusion of the posterior descending artery due to compression by a post-operative mediastinal chest tube. All features of myocardial infarction resolved after simple manipulation of the drain tube.The compression of the epicardial coronary artery after aortic valve surgery is very unusual. There are a few cases of other coronary artery compression due to mediastinal chest tube, but posterior descending artery compression causing ST elevation inferior myocardial compression is unique. Though rare, we need to be vigilant about mediastinal chest tube compression, which can cause ST elevation myocardial infarction after cardiac surgery. The iatrogenic compression of the native epicardial artery is a rare phenomenon. There are a few cases of bypass graft -4 or natA 74-year-old female with no past medical illness presented with exertional chest pain and was found to have severe aortic stenosis (AS). Electrocardiogram (ECG) shows features of left ventricular hypertrophy (LVH). On echocardiography, her mean pressure gradient across the aortic valve was\u00a047 mmHg. As she had symptomatic severe aortic stenosis (AS) without any other significant comorbidities, the plan was made to do surgical aortic valve replacement (SAVR). She underwent preoperative left heart catheterization, which shows normal epicardial coronary arteries.Eventually, the patient underwent a surgical replacement of the stenosed aortic valve with a bioprosthetic valve. The surgery was uneventful, and the patient was sent to the cardiac ICU for monitoring. A mediastinal drain tube was put in to prevent fluid accumulation after cardiac surgery. On post-operative day 1, the patient was complaining of central chest pain with radiation to the arm. ECG was done showing ST elevation in leads II, III, and arteriovenous fistula (aVF) with baseline LVH. It was puzzling as previously, she had no ECG changes suggestive of ischemic heart disease (IHD), and left heart catheterization was also normal. Bedside echocardiogram revealed wall motion abnormality in the middle and distal inferior wall with mildly reduced LV function. STEMI alert was activated, and the patient was taken to the catheterization laboratory emergently.A coronary angiogram revealed that the chest tube is intermittently compressing on the right-sided posterior descending artery (rPDA) limiting blood flow distal to the compression Figure . The draWe present a case of posterior descending artery compression by a mediastinal drain tube placed after SAVR, which is the first reported case. In the past, there were a few reports of native coronary artery or graft compression.Most complications of chest tube placement come from closed pleural chest tube placement, which could be benign to serious complications . There hComplications from open mediastinal tube placement after cardiac surgery are usually benign and underreported. Pneumothorax after removing such tubes or patients suffering from pain due to the tube placement is most encountered by cardiac surgeons . Yet, thAfter surgical aortic valve replacement (SAVR), myocardial ischemia or infarction could be due to supply-demand mismatch as a result of aortic cross-clamping causing ischemia in hypertrophied left ventricle (LV) . STEMI aBeing vigilant about post-surgical drain tubes that may cause compression in the coronary artery can be an easy fix and prevent dreaded complications. Mediastinal chest tubes causing the occlusion of the native coronary arteries are unexpected and easily overlooked."}
+{"text": "Objective. To evaluate the impact of setup uncertainty reduction (SUR) and adaptation to geometrical changes (AGC) on normal tissue complication probability (NTCP) when using online adaptive head and neck intensity modulated proton therapy (IMPT). Approach. A cohort of ten retrospective head and neck cancer patients with daily scatter corrected cone-beam CT (CBCT) was studied. For each patient, two IMPT treatment plans were created: one with a 3 mm setup uncertainty robustness setting and one with no explicit setup robustness. Both plans were recalculated on the daily CBCT considering three scenarios: the robust plan without adaptation, the non-robust plan without adaptation and the non-robust plan with daily online adaptation. Online-adaptation was simulated using an in-house developed workflow based on GPU-accelerated Monte Carlo dose calculation and partial spot-intensity re-optimization. Dose distributions associated with each scenario were accumulated on the planning CT, where NTCP models for six toxicities were applied. NTCP values from each scenario were intercompared to quantify the reduction in toxicity risk induced by SUR alone, AGC alone and SUR and AGC combined. Finally, a decision tree was implemented to assess the clinical significance of the toxicity reduction associated with each mechanism. Main results. For most patients, clinically meaningful NTCP reductions were only achieved when SUR and AGC were performed together. In these conditions, total reductions in NTCP of up to 30.48 pp were obtained, with noticeable NTCP reductions for aspiration, dysphagia and xerostomia . While SUR had a generally larger impact than AGC on NTCP reductions, SUR alone did not induce clinically meaningful toxicity reductions in any patient, compared to only one for AGC alone. Significance Online adaptive head and neck proton therapy can only yield clinically significant reductions in the risk of long-term side effects when combining the benefits of SUR and AGC. For this purpose, a retrospective cohort of ten head and neck squamous cell carcinoma patients with daily cone-beam CT (CBCT) was used to compare NTCP for six toxicities using three distinct scenarios. Differences in NTCP between each scenario was evaluated to assess the impact of SUR alone, AGC alone and SUR and AGC combined. Finally, the clinical significance of NTCP reductions associated with each mechanism was established using a decision tree inspired by a model-based patient selection algorithm.Our patient cohort consisted of ten head and neck squamous cell carcinoma patients treated at the Massachusetts General Hospital with volumetric modulated arc therapy, since CBCT imaging was not available for our proton therapy patients at the time of this study. Each patient dataset consisted of a planning CT acquired on a wide bore GE scanner  as well as a series of daily CBCT obtained on an Elekta XVI system  using a 100 kVp tube voltage and a 220-degree acquisition. The number of CBCTs available for each patient ranged between 30 and 35, for a total of 328 scans analyzed. No patient of this cohort had their treatment interrupted and no offline replanning was deemed necessary during the treatment courses.et alTwo clinical target volumes (CTV) were delineated on each planning CT by a trained radiation oncologist: a high-risk CTV including the primary tumor and high-risk lymph nodes, as well as a low-risk CTV, including bilateral lymph nodes considered at risk for subclinical disease. The constrictor muscles, larynx, oral cavity, spinal cord, brainstem, esophagus and both parotid glands were delineated on the planning CT. The esophagus, constrictor muscles and larynx were contoured following published guidelines for swallowing OARs . The first plan was robustly optimized to both CTVs using the minimax method  and adaptation schemes (fast daily OA versus no adaptation). As done in similar studies, our data analysis was focussed on NTCP differences between each scenario rather than absolute NTCP values (Van De Water ar et al . Differeet alFocussing on AGC alone, our results indicate that online adaptive proton therapy can induce NTCP reductions that go beyond what is achieved when applying SUR only. Indeed, total NTCP reductions per patient for xerostomia, dysphagia, aspiration and oral mucositis reported in figure et alet alThe clinical significance of the reductions in NTCP induced by SUR and AGC was assessed using a decision tree inspired by the Dutch model-based selection system (Tambas et alet alet alet alThe fact that clinically meaningful toxicity reductions were observed in five out of ten patients also illustrates the heterogeneous effect of online adaptive proton therapy on toxicity reductions across our patient cohort. This is even more apparent in figure et alet alet alet alet alet alet alet alThis study had some limitations worth mentioning. First, uncertainties in image deformation, contour propagation and residual setup errors beyond treatment adaptation were neglected. NTCP reductions achieved in this work shall therefore be interpreted as the best-case scenario for AGC and might not be fully achievable in a clinical setting. However, it is also worth noting that several strategies have been suggested to mitigate the impact of these uncertainties in the context of online adaptive proton therapy: the integration of structure uncertainties in plan re-optimization (Nenoff et al (et alAnother limitation to consider is the fact that NTCP models were derived from photon patients. Blanchard et al  showed tal et al. An evalIn conclusion, this study highlighted for the first time the impact of online adaptive proton therapy on toxicity risks. Combining effects from a reduction of the setup uncertainty setting by 3 mm and the AGC, online adaptive proton therapy based on a limited spot-intensity re-optimization workflow was shown to allow clinically meaningful toxicity reductions in 50% of our patient cohort, with total NTCP reductions up to 30.48 pp for the four main toxicities considered in this work."}
+{"text": "POT-PUFF sign has been introduced as a potential alternative for detecting malapposition during coronary bifurcation procedures. Here, we present two clinical cases from a developing country where the POT-PUFF sign was employed to assess the result of proximal optimization therapy after stent implantation. The POT-PUFF sign exhibits potential as an affordable and feasible approach for assessing stent malapposition in settings with limited resources.Acute stent malapposition poses a significant risk for adverse cardiac events following percutaneous coronary intervention. Detection of acute stent malapposition traditionally relies on intracoronary imaging techniques, such as intravascular ultrasound and optical coherence tomography, which may be limited in developing countries due to accessibility issues. A new angiographic sign called the  Acute stent malapposition (ASM) refers to post-procedure lack of contact of stent struts with vessel walls. This condition can be detected using intracoronary imaging techniques such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Identifying and addressing malapposition is crucial as it can result in various complications, including impaired stent function, heightened risk of stent thrombosis, and potential adverse cardiac events . RecentlCase oneA 58-year-old man, hypertensive and a weaned smoker, had been suffering from exertional angina for several months. The electrocardiogram showed lateral biphasic T waves. Echocardiography revealed hypokinesia of the anterolateral wall with a moderately impaired ejection fraction of 45%. Coronary angiography revealed significant stenosis at the start of the main marginal artery Figure . After pCase twoOur second case was a 64-year-old hypertensive patient with dyslipidemia on statins. She was admitted for management of chronic coronary syndrome with New York Heart Association class 2 exertional dyspnea. The electrocardiogram was unremarkable. Echocardiography showed left ventricular hypertrophy without segmental contractility abnormalities and a preserved ejection fraction. Stress echocardiography showed ischemia in two segments of the right coronary artery territory. Coronary angiography revealed a long, significant stenosis in the middle segment of the right coronary artery Figure . After pAfter stent implantation, IVUS and OCT can identify remediable irregularities associated with both the stent and the underlying vessel wall. These irregularities include stent under-expansion, geographic plaque miss, strut malapposition, and stent edge dissection, and they have been linked to adverse percutaneous coronary intervention (PCI) outcomes . Strut mThe POT-PUFF sign presents a promising new angiographic indicator for detecting stent malapposition during POT after PCI. While further research is required to validate its effectiveness, the POT-PUFF sign shows great potential in enhancing stent apposition evaluation and improving PCI outcomes in resource-constrained settings."}
+{"text": "Glioblastoma (GBM) is an aggressive brain tumor with limited prognosis despite multimodal treatment approaches. Various immunotherapies have been investigated to address the need for novel therapeutic options in GBM with limited success. Recently, alterations in the metabolism of cancer cells which allow for tumor proliferation, but simultaneously alter immune populations leading to an immunosuppressive tumor microenvironment, have been investigated as contributory to therapeutic resistance. This review discusses metabolic alterations in GBM tumor cells which have been investigated as contributory to immunosuppression and resistance to immunotherapies.Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients  has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism. Glioblastoma (GBM) is the most common primary brain tumor with a limited prognosis and a median survival of 15 months despite an aggressive standard of care treatment consisting of maximal safe surgical resection followed by radiation and chemotherapy with temozolomide . DevelopOne novel emerging area of cancer therapeutics is immunotherapies, which target one of the hallmarks of cancer\u2014the ability to evade cellular immunity that would otherwise result in immunological targeting of tumor cells . While iThe tumor microenvironment is affected by unique cancer cell metabolism that not only promotes tumor cell growth but also alters the pH, oxygen, and metabolite contents that affect the survival and function of immune cells in the tumor microenvironment . MetabolGlycolysis is the most prominent metabolic pathway implicated in cancer metabolism as contributory to sustaining the energetic cost of growth and proliferation. During glycolysis, glucose is catabolized to pyruvate which is then converted to lactate to either be secreted or enter the TCA cycle generating ATP and NADH in the process. Glucose metabolism plays a significant role in the brain microenvironment given the high metabolic demand of the brain and lack of glycogen storage within the brain. High blood glucose levels and increased neuronal expression of glucose transporters have been linked to decreased survival in glioblastoma patients . HK2, PKFP, ALDOA, PGAM1, ENO1, ENO2, or PDK1 inhibits GBM tumor growth and prolongs survival in a mouse xenograft model . Gl. Gl13]. Glycolysis requires export of lactate from cells by transporters which co-transport lactate and protons (H+), leading to their accumulation in the tumor microenvironment and resulting in tumor acidosis which impacts the function of immune cells in the tumor microenvironment. Acidosis has been described in other cancers as contributory to immunosuppression . Lactic Strategies that free T cell glycolytic metabolism from the restrictions imposed on these cells by the tumor microenvironment have been evaluated in preclinical models. For example, genetic modification of tumor specific CD4 and CD8 T cells to overexpress phosphoenolpyruvate carboxykinase 1 (PCK1) increased the production of the glycolytic metabolite phosphoenolpyruvate, resulted in increased T cell glycolysis, increased T cell effector function, and restricted tumor growth and prolonged survival in a melanoma mouse model . FurtherLactic acid production has also been suggested to not only reduce anti-tumoral immune cell populations but also promote immunosuppressive populations. Notably, myeloid cells are resistant to lactic acid-induced apoptosis . In factGlycolytic alterations may also specifically impact neutrophils. While less is understood about the metabolic utilization of neutrophils in the tumor microenvironment than leukocytes, neutrophils are generally regarded as highly glycolytic. Neutrophil function has been described to highly depend on glucose availability with lack of glucose abrogating function . suggestInterestingly, the interplay between glycolytic tumor metabolism and immune cell function may be bidirectional with immune cells able to regulate metabolic pathways as well. Zhang et al. show that macrophages produce interleukin-6 which leads to downstream phosphorylation of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and facilitates a PGK1-catalyzed reaction towards glycolysis rather than gluconeogenesis through altered substate affinity . PGK1 phENO1, promoted M2 microglia polarization promoting immunosuppression and glioblastoma cell malignancy. Another recent study utilizing differentially expressed genes between high and low glycolytic activity to assign risk scores to classify high and low risk GBM patients found differential infiltration of immune cells and immune checkpoints, suggesting a relationship between glycolytic activity and immunosuppression in patients with GBM [Studies of glycolysis in glioblastoma have paralleled the findings in other cancer types of the significance of increased glycolysis in creating an immunosuppressive tumor microenvironment. The shift to increased aerobic glycolysis from oxidative phosphorylation in glioblastoma is associated with immunosuppression and tumor progression . In GBM,with GBM . Glutamine, an amino acid highly expressed in cancer cells, plays a critical role for cellular function and the generation of energy and metabolic precursors for macromolecule synthesis which help sustain anabolic growth. Glutamine is converted by glutaminase into glutamate which is then converted to \u03b1-ketoglutarate, a critical component of the TCA cycle and in the production of metabolic intermediates utilized in the production of lipids, nucleic acids, and proteins. Upregulated glutamine metabolism in cancer cells promotes tumor growth through supporting macromolecule biosynthesis, altered signaling pathways, and cancer cell proliferation and survival. The metabolism of glutamine provides carbons for the TCA cycle to sustain accelerated anabolism in cancer cells and promotes tumor growth ,40,41.Glutamine is amongst the most prevalent amino acids in the brain as a precursor to the excitatory neurotransmitter glutamate . GlutamaGlutamine metabolic pathways are also upregulated in glioblastoma. Glutamate dehydrogenase (GDH), an enzyme which catalyzes the conversion of L-glutamate into \u03b1-ketoglutarate as part of glutaminolysis, is upregulated in many human cancers and shown to promote tumor growth . An isoeGlutamine metabolism in cancer cells impacts the tumor microenvironment and the immune populations within it in ways similar to glucose metabolism . Cancer Increased uptake of glutamine by tumor cells may result in its depletion in the tumor microenvironment and affect the function of immune cells which utilize glutamine for their own metabolic programs. Activated T cells upregulate glutamine metabolism to generate \u03b1-ketoglutarate to enter the TCA cycle and generate ATP to fulfill the energetic demands of T cell proliferation . GlutamiTargeting glutamine metabolism in a mouse model of colon cancer through a glutamine antagonist 6-Diazo-5-oxo-L-norleucine, which broadly inhibits several glutamine-using enzymes, led to suppression of both oxidative phosphorylation and glycolytic metabolism in cancer cells and decreased tumor-related changes in the microenvironment with decreased hypoxia, acidosis, and nutrient depletion . In contAdditionally, glutamine metabolism by cancer cells leads to the enrichment of various immunosuppressive populations in cancer. Notably, \u03b1-ketoglutarate generated through glutaminolysis restricts anti-tumoral macrophage M1 activation . A separTargeting glutamine metabolism in cancers with known resistance to checkpoint blockade (triple negative breast cancer and lung carcinoma) with a small molecule inhibitor led to the marked inhibition of the generation and recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs) through apoptosis of these MDSCs . AdditioTargeting glutamine metabolism may enhance endogenous anti-tumor immunity through independent mechanisms promoting the metabolic programs of cytotoxic populations while inhibiting immunosuppressive populations. Given the success of combining targeting glutamine metabolism with checkpoint inhibitors in other immunotherapy resistant tumors, it may be worthwhile to explore this combination in GBM. Tryptophan is an essential amino acid utilized for protein biosynthesis and a biochemical precursor to physiologically important compounds such as serotonin and melatonin. The majority of tryptophan which is not incorporated into proteins is broken down into degradation products (kynurenines) via the kynurenine pathway . PhysiolTryptophan catabolism and alterations in kynurenine pathway has been implicated in poor prognosis in several cancer types, including in GBM . The corIDO1- and TDO2- mediated degradation of tryptophan by cancer cells is a driver of immune suppression in the tumor microenvironment through recruitment and activation of myeloid-derived suppressor cells (MDSCs) and induction of anergy of CD8+ T cells . DegradaTryptophan utilization by tumor cells leads to metabolic starvation of T cells which are unable to utilize tryptophan for their own functions and thus promotes immunosuppression in the tumor microenvironment. Inhibition of tryptophan degrading enzymes blocks enzymatic activity and restores cytotoxic T cell activity in vitro and in vivo . T cellsGiven the role of IDO through kynurenine synthesis in generating the tumor microenvironment allowing for immune escape in cancer, IDO inhibition has been explored as an attractive therapeutic option in multiple cancers. Inhibition of IDO was found to effectively normalize plasma kynurenine levels in patients with various tumor types . InteresKynurenine metabolites activate a ligand-activated transcription factor, aryl hydrocarbon receptor (AhR) which results in increased expression of IDO1 and IDO2 in a positive feedback loop. Targeting AhR in vitro led to decreased glioma cell viability . Opitz eTryptophan catabolism and its downstream metabolic pathways are known to contribute to the immunosuppressive tumor microenvironment and contribute to resistance to novel immunotherapies for malignant gliomas. Increased expression of IDO and TDO has been suggested as an acquired resistance mechanism to PD-1 and CTLA blockade in pre-clinical models of multiple cancers, including GBM ,74. The The combination of targeting tryptophan metabolism with immune checkpoint blockade has been also explored in glioblastoma. Combining 1-methyltryptophan, which inhibits IDO, with dual immune checkpoint blockade significantly improved survival in an orthotropic mouse GBM model correlating with increased T-cell survival and synergistic decrease of Treg infiltration . LikewisPotential limitations of IDO1 inhibition that led to failure in this phase 3 trial combining this approach with a PD-1 inhibitor include: insufficient inhibition of IDO1 at the doses being used; the ability of other enzymes involved in tryptophan metabolisms such as TDO2 or pathways downstream of IDO1 inhibition to compensate and still generate immunosuppressive tryptophan metabolites such as kynurenine and its derivatives when IDO1 is inhibited; and lack of patient selection based on IDO1 expression ,78. IDO1Targeting tryptophan metabolism may also have implications for vaccine related cancer therapies which rely on T cell mediated antitumoral responses. IDO expression correlated with lack of specific T cell enrichment at the tumor site and prevented the rejection of tumor cells in mice who have been preimmunized against tumor antigens with a vaccine . This efLipid metabolism physiologically functions to allow for cellular energy storage, synthesis of cellular membranes, and cellular signaling. In cancer, alterations in lipid metabolism help meet high bioenergetic demands by generating energy through beta-oxidation. Utilization of fatty acid oxidation in addition to increased glycolysis allows for bioenergetic flexibility in promoting aggressive tumor growth and metastasis . Glioma cells utilize lipid oxidation and upregulate transport of ketones generated from lipid metabolism to sustain growth . Lipid mAltered lipid metabolism in GBM impacts immune cell function, particularly that of T cells . T cellsWhile less is understood about the metabolic requirements of Treg cells, utilizing fatty acid oxidation over glycolysis may promote Treg survival over the survival of CD4 and CD8 T cells . Lipid sGBM cells are also able to evade the anti-tumor immune response due to altered lipid metabolism impacting the function of antigen presenting cells. Exogenous induction of lipid peroxidation and ferroptosis resulted in release of damage-associated molecular patterns from glioma cells that stimulate dendritic cell activation and maturation and can lead to activation of cytotoxic T lymphocytes by dendritic cells ,95. RecuWhile initially the central nervous system was thought to be an immune-privileged site, current thought points to the presence of immune surveillance in the brain following findings revealing the presence of dedicated lymphatic channels running parallel to dural venous sinuses and allowing for lymphocyte priming from antigen presenting cells in the brain ,100. DesThe most studied immunotherapeutic approaches for GBM are vaccines, immune checkpoint inhibitors, and biologic therapies . The mosImmune checkpoint inhibitors targeting PD-1/PD-L1 and/or CTLA-4 are also being investigated in phase 3 trials in GBM, with initial results suggesting no clinical benefit ,105. WhiBiologic therapies for GBM can be viral or cellular. Oncolytic viruses have overall met with limited success in GBM, and initial anti-tumor T cell immune responses generated by viral infiltration into tumor do not persist without serial treatment . MetabolMetabolic pathways implicated in maintaining immunosuppression in the GBM microenvironment have been well elucidated. However, the potential for targeting these metabolic pathways to condition the tumor microenvironment to become more responsive to immunotherapies remains underexplored in GBM. Preclinical data targeting metabolic pathways in conjunction with immunotherapies largely come from models of more immunogenic cancers. This presents an attractive avenue for further study in GBM, in which modifying a largely immunosuppressive environment may meaningfully alter immunotherapeutic response. While this review discusses the most studied metabolic pathways with respect to immunosuppression in GBM, several other metabolic pathway alterations occur to meet the energetic demands of GBM progression. Arginine metabolism reprogramming in GBM leads to increased intake and decreased degradation of arginine by tumor cells and has been linked to impaired T cell responses due to altered bioavailablity of arginine . TargetiWhile many immunotherapies are being investigated in GBM patients, none have resulted in major improvements in survival outcomes. Negative results from phase II and phase III clinical trials of vaccines and immune checkpoint inhibitors have challenged the potential of these approaches in GBM. Future directions for immune-based strategies for glioblastoma require treatment modalities that can convert a \u2018cold\u2019 tumor with significant local immunosuppression into a \u2018hot\u2019 tumor. The uniquely immunosuppressive environment generated by tumor cellular metabolism in GBM presents an opportunity for augmenting responses to immunotherapy. Combining immunotherapy with agents that target the metabolic alterations resulting in an immunosuppressive microenvironment may have greater success in generating an antitumor immune response. These combinations should be evaluated rigorously preclinically in order to ensure that the most biologically sound combination approaches addressing the antitumor immune response along with tumor metabolism are advanced to clinical trials."}
+{"text": "The United States FDA has approved daprodustat (DPD) as the first oral treatment option for anemia due to chronic kidney disease (CKD) in dialysis patients. Clinical trials have demonstrated DPD\u2019s efficacy and safety, showing non-inferiority to darbepoetin and suggesting reduced IV iron usage. DPD also holds potential for treating chronic kidney disease anemia in non-dialysis patients and may have benefits for patients with coexisting renal anemia and heart failure, pending further research and trials. The United States Food and Drug Administration (FDA) has approved daprodustat (DPD) for treating anemia due to chronic kidney disease (CKD) for patients undergoing dialysis for at least 4\u00a0months . This isAnother Randomized, Double-Blind, Phase 3 Study was carried out in Japanese hemodialysis patients with anemia to compare the effects of DPD and darbepoetin. With most participants obtaining and maintaining hemoglobin levels within the target range, the results showed DPD\u2019s non-inferiority to darbepoetin. Also, it was strongly advised to continuously check the hemoglobin response following the start of the DPD treatment. This study also suggested using less IV iron to regulate hemoglobin in individuals receiving DPD . AnotherDPD has not yet been approved for patients with CKD anemia without dialysis, but ASCEND-ND  trial has demonstrated safety and efficacy of DPD in treating anemia due to CKD in patients not undergoing dialysis. . DPD wouData from the FDA\u2019s adverse event reporting system (FAERS) may indicate an elevated risk of GI bleeding when HIF-PHIs are used to treat renal anaemia. DPD treatment may also raise the risk of vascular calcification in CKD patients with hyperphosphatemia. Serum copper excess may also be noted in some patients in the treatment.Anemia in Heart Failure is a poor prognostic factor in both acute and chronic heart failure. Although anemia in heart failure is multifactorial, renal anaemia is one of the major causes. Coexisting renal and heart failure is reported to be associated with increased mortality . The StuProvenance and peer review: Not Commissioned, externally peer-reviewed."}
+{"text": "Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer related-death in the worldDespite reported benefits, colonoscopy outcomes may differ depending on quality of the endoscopist performing the procedure. Among others, this relates to differences in ability of endoscopists to accurately assess polyp characteristics such as locationOver the last decade, artificial intelligence (AI) in biomedical science has received growing attention. AI can be defined as the simulation of human intelligence by computer systemsWhile evidence is currently scattered, we aimed to write a narrative review to provide a broad overview of current developments within the field of AI and computer science for computer-aided assessment of colorectal polyps. This includes assessment of polyp location, size, morphology and histology, including degree of dysplasia (low grade dysplasia [LGD] versus high grade dysplasia [HGD]) and, in case of suspected malignancy, invasion depth. Since computer-aided polyp detection concerns an already more thoroughly studied and evaluated topicthof July 2022. Key search terms used were \u201ccolorectal,\u201d \u201cpolyp,\u201d \u201cartificial intelligence,\u201d \u201csize,\u201d \u201clocation,\u201d \u201cmorphology,\u201d \u201chistology,\u201d \u201cdysplasia\u201d and \u201cinvasion depth.\u201d Only studies published in English were screened. Reference lists of retrieved studies were manually screened to identify other relevant publications.A comprehensive literature search was performed in the MEDLINE/PubMed, Embase and Cochrane Libraries from the inception of the databases up to and including the 17Accurate determination of polyp location is important to facilitate identification of a polyp or polypectomy site during consecutive colonoscopies and/or surgical procedures. In addition, polyp location can aid in polyp histology predictionTo determine the location of the endoscope tip during colonoscopy procedures, and hence the location of observed polyps, endoscopists often rely on identification of various endoscopic anatomical landmarks and differences in colonic caliber, color tones and vasculature of different colon segmentsSeveral deep learning approaches for orientation in the colon based on analysis ofendoscopic videos and images have been proposed 45464Proposed systems could possibly aid endoscopists in orientation within the colon. However, current studies still concern feasibility studies and accuracy is mostly still limited. Besides, usage of a segment classification that assumes that all colons and segments are of similar length currently limits feasibility of the proposed motion-based localization systemToward the future, the issue of a lack of a solid reference standard could possibly be addressed by using magnetic endoscopic imaging (MEI) devices. These devices can improve accuracy of determination of location within the colon during colonoscopyPolyp size has been shown to be associated with the risk that a polyp harbors advancedhistological featuresIn daily practice, polyp size is based on visual estimation by the endoscopist. However, this strategy is prone to interobserver variabilityWhile most studies showed promising results, some issues should be addressed. Most importantly, similar to polyp location, a robust reference standard is not available for polyp size. This is illustrated by the fact that different reference standards were used in the different studies, limiting robustness and comparison of performance of the different systems. Additionally, several studies used binary polyp size classificationsNext steps for the development of more robust computerized polyp size measurement methods should include prospective evaluation of proposed systems in real-time clinical settings. Simultaneously, the problem concerning the lack of a solid reference standard might possibly be addressed through usage of recently developed endoscope-integrated or -attached polyp measurement toolsPolyp morphology is an important feature for polyp malignancy risk-assessmentColorectal polyps can generally be subdivided into neoplastic and non-neoplastic.Neoplastic lesions concerns both lesions yielding malignant potential and malignant lesions,while non-neoplastic lesions do not yield malignant potential. Hence, removal and analysisof non-neoplastic lesions is often unnecessaryA wide variety of studies describing computer systems trained to differentiateneoplastic and non-neoplastic lesions based on polyp phenotype has been published. For thisreview, we will highlight available prospective clinical trials evaluating the performanceof such systems in real-time clinical settings and using either white light, (magnified)narrow band imaging (NBI) or blue light imaging (BLI) imaging modalities 77787To facilitate implementation of optical diagnosis strategies in daily practice, the Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) initiativeFrom clinical perspective, the fact that different studies managed sessile serrated lesions (SSLs) in different ways should also be addressed. While SSLs are estimated to make up 15\u201330% of CRC casesDespite remaining limitations and need for further optimization of system performances to reach PIVI and SODA thresholds, most CADx systems for differentiation of neoplastic and non-neoplastic lesions showed to be able to meet expert endoscopist performance in real-time clinical settings. In addition, a significant optical diagnosis learning curve for \u2018non-expert\u2019 endoscopists was illustratedTable S1)Several studies assessing the feasibility of deep learning approaches for differentiation of polyps with different degrees of dysplasia (LGD versus HGD) are available  innovations in upcoming years will likely aid in improving accuracy of existing CADx systems, while there are also still numerous purposes for which possibilities of computer-aided diagnosis is yet to be explored. In example, besides computer systems that could aid endoscopists in assessment of polyp morphology, systems for purposes such as suggestion of appropriate polyp resection method or assessment of completeness of resection might yield significant clinical potential.The strength of this review is that, to the best of our knowledge, this is the first review to provide such a broad overview of available studies on computer-aided diagnosis of all polyp characteristics essential for clinical decision making. However, in the context of the extensive scope of the aim of this review, we decided to comply to a narrative rather than a systematic review approach. While this might have resulted in accidental miss of relevant publications, this can be considered a limitation.To conclude, with recent breakthroughs in the field of AI and computer science, a major increase in research on the topic of computer-aided colorectal polyp assessment is seen. With commercial availability of CADx systems for differentiation between neoplastic and non-neoplastic polyps, first steps toward improved endoscopy quality with use of CADx systems in daily practice might be ahead. However, optimization of performance is still required to ensure that these CADx systems meet all performance thresholds. Besides, toward the future, further innovation, exploration and clinical validation of computer-aided diagnosis approaches for diagnosis of other polyp characteristics is required for realization of complete computer-aided polyp assessment."}
+{"text": "Pleural infection, or pleural empyema, is a severe medical condition associated with high morbidity and mortality rates. Timely and accurate prognostication is crucial for optimizing patient outcomes and resource allocation. Rapid scoring systems have emerged as promising tools in pleural infection prognostication, integrating various clinical and laboratory parameters to assess disease severity and quantitatively predict short-term and long-term outcomes. This review article critically evaluates existing rapid scoring systems, including CURB-65 , A-DROP , dehydration, respiratory failure, orientation disturbance, and low blood pressure), and APACHE II , assessing their predictive accuracy and limitations. Our analysis highlights the potential clinical implications of rapid scoring, including risk stratification, treatment tailoring, and follow-up planning. We discuss practical considerations and challenges in implementing rapid scoring such as data accessibility and potential sources of bias. Furthermore, we emphasize the importance of validation, transparency, and multidisciplinary collaboration to refine and enhance the clinical applicability of these scoring systems. The prospects for rapid scoring in pleural infection management are promising, with ongoing research and data science advances offering improvement opportunities. Ultimately, the successful integration of rapid scoring into clinical practice can potentially improve patient care and outcomes in pleural infection management. Pleural infection, commonly known as pleural empyema, is a serious medical condition characterized by the accumulation of infected fluid in the pleural space, the thin, fluid-filled cavity surrounding the lungs. It can arise as a complication of various respiratory infections, such as pneumonia, and may result from both bacterial and, less frequently, fungal pathogens. Pleural infection poses a significant health burden worldwide, with high morbidity and mortality rates, especially in vulnerable populations such as the elderly, immunocompromised individuals, and those with pre-existing lung diseases -4. ManagPrognostication is pivotal in determining the most appropriate therapeutic approach and predicting patient outcomes in pleural infection. Identifying patients with severe diseases and poor prognoses can aid clinicians in tailoring treatment plans and allocating resources more efficiently. Traditional prognostic indicators such as clinical signs, laboratory parameters, and radiological findings are valuable but may lack the desired accuracy to predict disease progression reliably -10. The Rapid scoring systems have emerged as promising tools in the prognostication of pleural infection. These scoring systems leverage clinical, radiological, and laboratory parameters to generate a quantifiable score, enabling clinicians to quickly evaluate the severity of the disease and predict the likelihood of specific outcomes, such as mortality, treatment response, and length of hospital stay ,15. By sThis review aims to comprehensively evaluate the predictive potential of rapid scoring systems in pleural infection. By critically analyzing the existing literature and summarizing the findings from various studies, we aim to provide an in-depth understanding of the utility and limitations of these scoring systems in clinical practice. We will compare their performance in predicting short-term and long-term outcomes. Additionally, we will explore the factors that may influence the accuracy of these scoring systems, such as patient demographics, microbiological and radiological findings, and the presence of comorbidities.Overview of existing rapid scoring systems for pleural infectionsIn recent years, significant advancements have been made in developing and validating rapid scoring systems tailored for pleural infection prognostication. These scoring systems represent a crucial step toward enhancing clinical decision-making and optimizing patient care in the management of this complex condition. By providing a swift and reliable method to assess disease severity and predict outcomes, these rapid scoring systems offer a valuable tool for healthcare providers . Three pThe CURB-65 ScoreOriginally devised for predicting outcomes in community-acquired pneumonia, the CURB-65 score has been adapted and validated for use in pleural infection scenarios. It is based on five readily available clinical variables: confusion, urea level, respiratory rate, blood pressure, and age \u226565 years. By incorporating these parameters, the scoring system offers a simple yet effective approach to risk stratification and prognostication in pleural infection cases .The A-DROP ScoreOriginally designed for predicting severe pneumonia, the A-DROP score has found relevance in the context of pleural infection prognostication. This scoring system comprises five essential parameters: age, dehydration, respiratory failure, orientation disturbance, and low blood pressure. By encompassing these key variables, the A-DROP score assists in identifying patients at higher risk of adverse outcomes, and guiding appropriate interventions .The APACHE II ScoreWidely employed in intensive care units, the APACHE II score is a comprehensive scoring system that incorporates various physiological parameters to assess disease severity and predict outcomes in critically ill patients, including those with pleural infection. While the APACHE II score may involve more extensive laboratory measurements and clinical evaluations, it offers a more detailed and nuanced assessment of patient status, aiding in precise prognostication .These rapid scoring systems serve as valuable tools for healthcare providers, enabling them to assess disease severity and anticipate patient outcomes rapidly. These scoring systems offer a standardized and objective approach to pleural infection prognostication by integrating key clinical and laboratory parameters. By promptly identifying patients at higher risk of adverse outcomes, clinicians can optimize treatment plans, allocate resources effectively, and potentially improve patient outcomes .Despite their effectiveness, it is essential to recognize that these scoring systems are adjunctive tools and should not replace clinical judgment. The context of each patient's presentation, comorbidities, and response to therapy remains crucial in the overall management of pleural infection. Continued research, validation, and refinement of these rapid scoring systems are vital for maximizing their clinical utility and further improving patient care in pleural infection management. With ongoing efforts and multidisciplinary collaboration, rapid scoring systems promise to positively impact pleural infection management in the future .Comparison of different scoring systemsScoring Criteria and ComponentsScoring criteria and components form the foundation of rapid scoring systems in pleural infection prognostication, as they determine the variables used to generate a numerical score reflecting disease severity. These variables' selection varies among scoring systems based on their intended scope and underlying concepts .Some rapid scoring systems like CURB-65 and A-DROP utilize more straightforward and easily accessible clinical parameters to calculate the score. These criteria typically include age, respiratory rate, blood pressure, and mental status. These variables can be quickly assessed at the bedside and are commonly available in most healthcare settings. By focusing on straightforward clinical indicators, these scoring systems offer a convenient and time-efficient approach to prognostication, particularly in resource-limited environments .On the other hand, the APACHE II score takes a more comprehensive approach by integrating a wide range of physiological and laboratory measurements. These variables encompass arterial pH, oxygenation, serum creatinine levels, and hematocrit. The APACHE II score was originally designed for assessing the severity of critically ill patients in intensive care units and has been adapted for use in various clinical settings, including pleural infection. Including a broader array of physiological parameters enhances the APACHE II score's discriminative ability, allowing for a more detailed evaluation of disease status and patient outcomes .The choice between simpler clinical variables and more complex physiological measurements depends on the scoring system's intended use and clinical context. While rapid scoring systems like CURB-65 and A-DROP offer practicality and ease of use, the APACHE II score provides a more nuanced assessment, especially for critically ill patients. When selecting the most appropriate rapid scoring approach for pleural infection prognostication, healthcare providers must consider the scoring system's applicability to their specific patient population and available resources. These scoring criteria and components are essential for risk stratification and clinical decision-making, contributing to improved patient care and outcomes .Pros and Cons of Each Scoring SystemThe CURB-65 and A-DROP scores offer practical benefits due to their straightforwardness and ease of calculation. These scores utilize easily obtainable clinical parameters, including age, respiratory rate, blood pressure, and mental status, which can be swiftly evaluated at the patient's bedside. Their limited reliance on extensive laboratory tests makes them particularly suitable for settings with limited resources, where access to advanced medical facilities might be constrained. Furthermore, their uncomplicated nature allows for rapid risk assessment, enabling timely interventions in patients with pleural infection. However, the simplicity of the CURB-65 and A-DROP scores might result in some degree of oversimplification in disease evaluation. The sensitivity, specificity, positive predictive value, and negative predictive value of CURB-65 were 71%, 69%, 35%, and 91%, respectively. The best-performing version of the systemic inflammatory response syndrome (SIRS) criteria showed rates of 62%, 73%, 35%, and 89%, respectively, while the standardized early warning scoring system (SEWS) exhibited rates of 52%, 67%, 27%, and 86%, respectively. By concentrating on a restricted set of criteria, these scoring systems may not fully encompass the intricacies and variations present in cases of pleural infection. This limitation could potentially impact their accuracy in predicting outcomes .On the contrary, the APACHE II score provides a more advanced and comprehensive evaluation of a patient's condition, which holds particular significance for those critically ill with pleural infections. The APACHE-II score demonstrated a sensitivity of 89.9% and a specificity of 97.6%. By amalgamating various physiological measurements and laboratory results, the APACHE II score delivers a thorough assessment of the severity of the disease and the dysfunction of organs. This renders it especially pertinent within intensive care units (ICUs) confines. Its capacity to consider multiple variables enables a more subtle and precise classification of risk, thereby assisting healthcare practitioners in customizing treatment strategies for critically ill patients. Nevertheless, the reliance on the APACHE II score on multiple intricate laboratory measurements and complex computations could impede its immediate application within standard clinical practice, particularly in non-ICU environments. In scenarios with limited time and resources, the extensive data collection demanded by the APACHE II score might not always be feasible or pragmatic. Consequently, this could diminish its practicality and clinical influence .Current Challenges in Prognostication Using Rapid ScoringWhile rapid scoring systems hold promise in aiding prognostication for pleural infection, several challenges must be addressed to maximize their clinical utility. Firstly, these scoring systems' validation and external applicability pose significant concerns. Many of these systems are developed and validated in specific patient populations, which may limit their generalizability to diverse cohorts or healthcare settings. To ensure their reliability across various contexts, it is crucial to conduct rigorous validation studies in different patient populations representative of real-world scenarios .Secondly, successfully integrating rapid scoring systems into routine clinical practice requires overcoming practical hurdles. Healthcare providers must receive adequate training and awareness regarding the use and interpretation of scoring results. Seamless incorporation into existing clinical workflows and overcoming potential resistance to change are essential steps in maximizing the impact of these scoring systems on patient care .Another critical challenge is centered around predicting long-term outcomes. While rapid scoring systems often concentrate on short-term outcomes like hospital mortality or length of stay, complexity arises when predicting long-term outcomes, including factors like recurrence rates and functional recovery. These aspects demand a more extensive follow-up period and meticulous data collection. The development of scoring models that can reliably forecast these long-term outcomes holds significant importance, as it can greatly enhance patient management strategies and the support provided post-infection .Addressing these challenges requires continued research and collaboration among healthcare institutions and researchers. External validation across diverse patient populations, transparent reporting of findings, and prospective studies can enhance the reliability and credibility of rapid scoring systems. Additionally, advances in data science and integrating novel biomarkers may offer opportunities to refine these scoring approaches, leading to more accurate and personalized prognostication for pleural infection .By overcoming these challenges and refining existing rapid scoring systems, clinicians can make more informed decisions, tailor treatments, and allocate resources effectively, ultimately leading to improved patient outcomes and enhanced management of pleural infection. With ongoing efforts and future advancements, rapid scoring systems have the potential to revolutionize the way pleural infection is managed, providing valuable tools for healthcare providers and better care for patients .Prognostic value of rapid scoring in pleural infectionEvaluating the Predictive Accuracy of Rapid Scoring SystemsSensitivity and specificity analysis: Sensitivity measures the proportion of true positive cases correctly identified by the scoring system, i.e., the ability to classify patients with adverse outcomes correctly. Specificity, on the other hand, measures the proportion of true negative cases correctly identified, i.e., the ability to classify patients with favorable outcomes correctly. A comprehensive analysis of sensitivity and specificity provides valuable insights into the scoring system's ability to discriminate between patients with different outcomes. High sensitivity and specificity indicate a scoring system's ability to accurately identify positive and negative cases, thereby increasing its reliability in distinguishing patients with better or worse prognoses .Receiver operating characteristic (ROC) curves: ROC curves graphically illustrate the trade-off between sensitivity and specificity at various score thresholds. By plotting sensitivity against (1 - specificity) for different threshold values, the ROC curve visually represents the scoring system's performance in distinguishing between patients with different outcomes. The area under the ROC curve (AUC) quantifies the overall discriminative ability of the scoring system. An AUC value close to 1 indicates excellent discriminative power, meaning the scoring system can effectively differentiate between patients with favorable and adverse outcomes. Conversely, an AUC value close to 0.5 suggests poor discrimination, equivalent to random chance, rendering the scoring system less effective in predicting patient outcomes . ResearcPredictive Potential for Short-Term OutcomesMortality prediction: Mortality prediction is a critical aspect of managing pleural infection, as identifying patients at higher risk of death enables healthcare providers to initiate timely interventions and allocate resources effectively. By integrating clinical and laboratory parameters, rapid scoring systems aim to quantify the mortality risk in infected patients. The scores generated by these systems can serve as an early warning system, alerting clinicians to patients with a higher likelihood of adverse outcomes. Studies that analyze the association between rapid scoring system scores and actual mortality rates are of paramount importance. Evaluating the accuracy and reliability of these scoring systems in predicting mortality is essential for their successful implementation in clinical practice. Validated scoring systems can support evidence-based clinical decision-making, guiding aggressive treatment approaches for high-risk patients and potentially improving overall survival rates in pleural infection cases .Treatment response: Assessing the predictive potential of rapid scoring systems on treatment response is equally significant. Identifying patients less likely to respond to standard therapies is crucial for early intervention and alternative treatment strategies. Rapid scoring systems can assist in predicting treatment response by considering factors such as disease severity, pathogen characteristics, and patient-specific variables. By flagging non-responsive or slow-responding cases, clinicians can promptly modify treatment regimens, thereby preventing disease progression and minimizing complications. This proactive approach to treatment tailoring may improve therapeutic efficacy and enhance patient outcomes. Furthermore, predicting treatment response can aid in the judicious use of healthcare resources, optimize medication utilization, and reduce unnecessary interventions .Length of hospital stay: Prolonged hospital stays in pleural infection cases impact patient well-being and impose a substantial economic burden on healthcare systems. Rapid scoring systems that accurately predict the length of hospitalization can provide valuable insights for resource management and discharge planning. By estimating the expected duration of hospital stay, healthcare providers can allocate resources more efficiently, including hospital beds, staff, and medications. This allows for smoother patient flow and reduces overcrowding in medical facilities. Additionally, accurate predictions of hospital stay duration enable healthcare teams to engage in proactive discharge planning, ensuring that patients receive appropriate care and support after discharge. By minimizing unnecessary hospitalization, rapid scoring systems can contribute to optimizing healthcare resources and improve overall patient care in the context of pleural infection management ,37.Predictive Potential for Long-Term OutcomesRecurrence rates: Pleural infection recurrence is a vexing issue that poses challenges in patient management. Identifying individuals at higher risk of recurrence is crucial for implementing appropriate surveillance and follow-up strategies. Rapid scoring systems, with their ability to provide a quantitative assessment of disease severity, may offer valuable insights into the likelihood of recurrence. Clinicians can tailor long-term treatment planning and preventive measures for high-risk patients by analyzing the correlation between scoring system scores and recurrence rates. A scoring system capable of predicting recurrence can prompt intensified monitoring, early interventions, or targeted therapies to reduce the burden of recurrent pleural infections and improve patient outcomes ,39.Functional outcomes and quality of Life: Beyond short-term outcomes such as mortality and recurrence rates, the impact of pleural infection on functional outcomes and quality of life is paramount. Many survivors of pleural infection experience impaired lung function, reduced exercise capacity, and diminished overall quality of life. Scoring systems that can predict long-term functional outcomes may prove instrumental in optimizing rehabilitation efforts and post-infection support. By identifying patients at risk of poor functional recovery, clinicians can initiate timely interventions such as pulmonary rehabilitation, physical therapy, and psychological support to enhance the patient's overall well-being and quality of life ,41.Understanding the predictive value of rapid scoring systems for both short-term and long-term outcomes is essential for their effective clinical application. The analysis of various studies investigating these aspects provides a comprehensive overview of the potential benefits and limitations of using rapid scoring systems in pleural infection management. Integrating rapid scoring into clinical practice can facilitate risk stratification, personalized treatment planning, and informed decision-making. However, it is crucial to recognize these scoring systems' limitations and potential biases and address them through rigorous validation and future research. By refining and enhancing the accuracy and utility of rapid scoring systems, healthcare providers can optimize patient care and improve outcomes in pleural infection management. Ultimately, the successful integration of rapid scoring into routine clinical practice can positively impact patient well-being and healthcare resource allocation, bringing us closer to more effective and patient-centered pleural infection management strategies ,21.Factors affecting the prognostic accuracy of rapid scoringAccurate prognostication is a critical aspect of managing pleural infection effectively. Rapid scoring systems offer a quantifiable and standardized approach to assessing disease severity and predicting patient outcomes. However, to ensure their reliability and usefulness in clinical practice, it is essential to consider various patient-specific factors that can influence the predictive accuracy of these scoring systems . One sucMicrobiological and radiological findings are another crucial aspect of pleural infection management. The causative microorganisms, their antibiotic sensitivity, and the extent of lung involvement and pleural effusion on imaging can significantly affect disease severity and treatment response. Rapid scoring systems incorporating these findings into their algorithms may offer more accurate prognostic predictions . ComorbiMoreover, interpreting scoring results in the context of the severity of pleural infection is crucial. In mild or moderate cases, scoring systems may have limited discriminatory ability due to the relatively uniform nature of the patient population. However, scoring systems can offer more accurate prognostic insights in severe or complicated infections, guiding clinicians towards more aggressive interventions and monitoring strategies .Impact of Patient DemographicsPatient demographics, specifically age and sex, influence disease progression and outcomes in pleural infection. Age-related factors can significantly impact the clinical course of the infection. As patients age, changes in immune function and physiological reserves may increase infection vulnerability, making elderly individuals more susceptible to severe pleural infection. Additionally, comorbidities commonly accompanying aging can complicate disease management and influence treatment response. Therefore, considering age-related variations in prognostic scoring systems is essential to accurately predict disease severity and outcomes in different age groups .Furthermore, gender-related differences in pleural infection outcomes have been observed in some studies. While the underlying reasons for these disparities are not yet fully understood, it is believed that hormonal and immunological differences between males and females may contribute to varying disease outcomes. For instance, estrogen is known to have immunomodulatory effects that might influence the body's response to infection. Some studies have suggested that female patients with pleural infection may experience milder disease courses and have better treatment responses than males. By incorporating gender as a parameter in prognostic scoring systems, it is possible to account for these gender-specific differences and improve the accuracy of predicting outcomes for both male and female patients .Addressing patient demographics in rapid scoring systems is essential for personalized medicine and individualized patient care. Tailoring treatment strategies based on age and gender considerations can help clinicians optimize therapeutic interventions and improve patient outcomes. However, it is crucial to ensure that any consideration of demographics in scoring systems is evidence-based and supported by rigorous research. Understanding the impact of age and gender on pleural infection outcomes is an ongoing area of investigation, and continued research in this domain will further enhance the accuracy and utility of rapid scoring systems in pleural infection prognostication .Role of Microbiological and Radiological FindingsMicrobiological and radiological findings are integral components in diagnosing and managing pleural infection. Identifying causative microorganisms and their susceptibility to antibiotics is crucial for guiding appropriate antimicrobial therapy, significantly impacting treatment response and overall patient outcomes. Rapid scoring systems that consider microbiological data have the potential to enhance predictive accuracy, particularly in cases where tailored antibiotic treatment is necessary .Microbiological data can reveal valuable information about the type of pathogen causing the infection, its virulence, and its antibiotic resistance. Scoring systems that incorporate microbiological findings can aid clinicians in identifying high-risk patients who may require prompt escalation to targeted and more aggressive therapies. This enables timely adjustments to treatment regimens, potentially preventing treatment failure and the development of complications .Conversely, evaluating disease severity and tissue involvement heavily relies on radiological characteristics. Essential insights regarding pleural effusion, lung parenchymal engagement, and necrosis are provided through imaging techniques like chest X-rays and computed tomography (CT) scans. These radiological attributes mirror both the local and systemic effects of the disease, thereby enhancing clinicians' comprehension of the disease's status and possible complications .Scoring systems integrating radiological parameters offer a more comprehensive and nuanced disease evaluation. Such assessments can assist in risk stratification, allowing healthcare providers to identify patients with more severe infections who may require more intensive management, such as drainage procedures or surgical interventions . By consInfluence of Comorbidities on Scoring SystemsComorbidities significantly shape the clinical course of pleural infection, influencing disease progression, treatment response, and patient outcomes. Conditions such as diabetes, chronic kidney disease, heart failure, and immunosuppressive states can weaken the immune system, impair lung function, and increase the risk of complications. Consequently, patients with comorbidities are often at higher risk of adverse outcomes, including prolonged hospital stays, treatment failure, and increased mortality .Incorporating comorbidities into rapid scoring systems can enhance their prognostic accuracy by providing a more comprehensive assessment of the patient's overall health status. Scoring models considering these additional risk factors can better identify high-risk patients requiring more aggressive interventions or closer monitoring. Tailored treatment plans based on accurate risk stratification can improve clinical outcomes and resource utilization, ensuring that the most vulnerable patients receive the necessary care . HoweverAdditionally, choosing which comorbidities to include in the scoring systems must be carefully considered. Not all comorbidities may impact pleural infection outcomes equally, and some may be more relevant in specific patient populations. Thus, the selection of comorbidities should be based on their clinical significance and the availability of data . MoreoveInterpreting Scoring Results in the Context of Pleural Infection SeverityThe interpretation of scoring results in the context of pleural infection is critical when utilizing rapid scoring systems. It is important to recognize that these scoring systems' accuracy and predictive power may vary depending on the overall severity of the pleural infection in a given patient population . The disDespite their potential usefulness, clinicians need to understand that rapid scoring systems are adjunctive tools and not definitive predictors of outcomes. These systems are designed to aid in risk stratification and decision-making but should not be solely relied upon to make critical clinical decisions. Instead, they should be used with clinical judgment and other diagnostic assessments, such as radiological findings, microbiological data, and the patient's overall clinical status . By inteClinical implications and application of rapid scoringRole of Rapid Scoring in Clinical Decision-MakingRapid scoring systems in pleural infection management have the potential to significantly impact clinical decision-making by providing a quantitative and standardized assessment of disease severity and prognostication. These scoring systems offer valuable information to healthcare providers, aiding in risk stratification, treatment tailoring, and follow-up planning .Risk stratification: Rapid scoring systems excel in identifying patients at higher risk of adverse outcomes, such as mortality or treatment failure. These systems can efficiently classify patients into risk categories by analyzing clinical and laboratory parameters. This enables clinicians to prioritize interventions and allocate resources effectively, especially in resource-constrained settings where optimal utilization of healthcare resources is paramount .Treatment tailoring: One of the key challenges in pleural infection management is selecting the most appropriate treatment strategies for individual patients. Rapid scoring systems play a pivotal role by providing insights into disease severity and potential response to treatment. The scoring results can guide clinicians in choosing the most suitable antimicrobial therapy and drainage procedures and tailoring treatment plans based on the predicted disease severity. This personalized approach enhances therapeutic efficacy, minimizes the risk of treatment failure, and reduces the likelihood of complications .Follow-up planning: Beyond short-term prognostication, rapid scoring systems offer valuable information for long-term follow-up planning. By predicting disease trajectory and long-term outcomes, such as recurrence rates, these systems can inform healthcare providers about the need for post-discharge care and surveillance. Timely detection of potential complications and recurrent infections allows for proactive intervention, leading to better disease management and patient outcomes .Integrating rapid scoring systems into clinical practice empowers healthcare providers with evidence-based decision-making tools, aiding in more informed and precise patient care. The ability to quickly assess disease severity, predict outcomes, and tailor treatments based on individual patient characteristics enhances the overall management of pleural infection, ultimately leading to improved patient outcomes and enhanced healthcare resource utilization. However, ongoing research and validation are essential to continually refine and optimize these scoring systems, ensuring their effectiveness and reliability in real-world clinical settings. By harnessing the full potential of rapid scoring systems, healthcare providers can revolutionize pleural infection management and elevate the standard of care for patients affected by this challenging condition .Integration of Rapid Scoring into Current Management GuidelinesValidation and adaptation: Thorough validation is essential before implementing rapid scoring systems. This involves evaluating the performance of the scoring system in diverse patient populations to ensure its generalizability across different contexts. Validation studies should encompass various demographic profiles, disease severities, and geographic locations. In some cases, adaptation of the scoring system to specific local contexts may be necessary to account for variations in patient characteristics and healthcare practices .Education and training: Effective education and training programs are crucial to familiarize healthcare providers with the rapid scoring system's use and interpretation. Clinicians need to understand the rationale behind the scoring criteria, the significance of specific variables, and how to calculate the scores accurately. Additionally, emphasizing that the scoring system is an adjunctive tool to support clinical judgment can help mitigate any concerns of over-reliance on the scoring results .Standardized documentation: Consistent and standardized documentation of scoring system parameters in patient records is vital for continuity of care. Healthcare providers should diligently record the data used to calculate the score, the actual score itself, and any updates during treatment. Standardized documentation enables clinicians to track disease progression over time and aids in assessing the effectiveness of treatment strategies based on changes in the scoring results .Interdisciplinary collaboration: Pleural infection management involves the collaboration of various medical specialists, each contributing their expertise to patient care. Effective interdisciplinary collaboration is essential for integrating rapid scoring systems seamlessly into the overall management approach. Collaborating with pulmonologists, infectious disease specialists, radiologists, and other relevant disciplines like cardiothoracic\u00a0ensures that all aspects of patient care are considered, and the scoring system's results are interpreted comprehensively .Practical Considerations and Challenges in Implementing Rapid ScoringAccessibility of data: The availability of necessary clinical and laboratory data required for rapid scoring may vary across different healthcare settings. In some facilities, electronic health records (EHRs) might be well-established, allowing easy access to relevant patient data. However, in resource-limited or smaller healthcare facilities, the absence of comprehensive EHR systems could hinder data accessibility. Efforts should be made to streamline data collection and ensure the completeness of data inputs for accurate scoring. This may involve improving data capture and recording practices, and fostering interoperability between healthcare information systems .Scoring system selection: Choosing the most appropriate rapid scoring system for a specific clinical setting requires careful consideration of various factors. Different scoring systems may have been developed and validated in diverse patient populations or healthcare contexts. As such, it is essential to evaluate the applicability and accuracy of each scoring system in the specific patient cohort and resource constraints of the healthcare facility. Factors such as patient demographics, available resources, and the overall clinical context should be considered during the selection process to ensure that the chosen scoring system aligns with the needs and capabilities of the healthcare setting .Time constraints: Rapid scoring systems are designed to provide quick and efficient disease severity and prognosis assessments. However, the practicality of their implementation can be impacted by time constraints, particularly in busy clinical settings where healthcare professionals have limited time to dedicate to scoring calculations. The scoring process should be user-friendly, intuitive, and time-efficient to integrate rapid scoring into routine clinical practice seamlessly. Implementing user-friendly electronic scoring tools or incorporating scoring algorithms into electronic medical record systems can help minimize the time investment required for scoring calculation .Future Directions and Potential Improvements in Rapid Scoring SystemsComprehensive scoring models: To enhance the accuracy of prognostication, future scoring systems could be developed as more comprehensive models. By incorporating additional variables, such as molecular biomarkers or novel radiological parameters, these systems can provide a more nuanced and detailed assessment of disease severity and progression. Integrating biomarkers reflecting the host's immune response or pathogen virulence may offer valuable insights into disease outcomes and treatment responses .Artificial intelligence (AI) integration: Leveraging AI algorithms could revolutionize rapid scoring systems by analyzing vast datasets and identifying patterns that might not be apparent through conventional methods. AI integration can significantly improve the predictive power of these systems. Machine learning algorithms can adapt and refine scoring models based on real-world data, ensuring continuous improvement and adaptability to evolving clinical scenarios .External validation and standardization: It is essential to rigorously validate and standardize rapid scoring systems across diverse patient populations and healthcare settings for widespread clinical adoption. Continued research and collaboration among healthcare institutions and research centers can facilitate the validation process, ensuring the reliability and generalizability of these scoring approaches .Longitudinal predictions: Advancements in scoring methodologies may enable dynamic and longitudinal predictions, offering real-time updates on patient outcomes throughout treatment. Longitudinal assessments can provide insights into disease progression, response to therapies, and potential complications, allowing clinicians to adjust treatment strategies proactively .Top of form critique and limitations of rapid scoring systemsCriticism of Current Scoring ApproachesWhile rapid scoring systems have demonstrated their potential in aiding prognostication for pleural infection, they are not exempt from criticism. Several key criticisms of current scoring approaches warrant consideration:Oversimplification: One significant critique of some rapid scoring systems is their tendency to oversimplify the complexity of pleural infection. By focusing on a limited set of parameters, these scoring systems may not fully capture the multifaceted nature of the disease. The oversimplification could lead to inadequate prognostic accuracy, particularly in cases with diverse clinical presentations and variable disease trajectories .Generalizability: Many rapid scoring systems have been developed and validated in specific patient populations, often based on data from single institutions or regions. Consequently, there may be concerns regarding the applicability of these scoring approaches to more diverse patient cohorts. The lack of external validation across different healthcare settings and populations hinders their generalizability and raises questions about their reliability in real-world clinical scenarios .Lack of longitudinal assessment: Rapid scoring systems typically provide static assessments of disease severity at a particular time point. The absence of dynamic or longitudinal assessments limits their ability to predict changes in disease trajectory over time. In pleural infection, disease progression and response to treatment may evolve over days or weeks, and a single snapshot may not capture the full clinical picture .Limited predictive value for long-term outcomes: While rapid scoring systems have shown promise in predicting short-term outcomes, such as mortality and treatment response, their ability to predict long-term outcomes remains a challenge reliably. Variables influencing long-term recovery, recurrence rates, and functional outcomes are complex and multifactorial, making their inclusion in scoring systems more complex .Limitations of Available Studies and DataSmall sample sizes: Many studies evaluating rapid scoring systems may have limited sample sizes due to the rarity of severe pleural infections or other logistical constraints. Small sample sizes can reduce statistical power, making it challenging to draw definitive conclusions. Moreover, findings from such studies may lack generalizability to larger, more diverse patient populations, potentially limiting the external validity of the scoring systems .Heterogeneity of studies: Studies evaluating rapid scoring systems often utilize varying patient populations, methodologies, and outcome measures. This heterogeneity can complicate direct comparisons between different scoring approaches, hindering the establishment of a consensus on the most effective scoring system for pleural infection prognostication. A standardized approach to study design and outcome measurements would facilitate meaningful comparisons and enhance the reliability of the findings .Retrospective nature: Many studies assessing rapid scoring systems in pleural infection rely on retrospective data, which can introduce inherent biases and limitations. Retrospective data collection may be subject to selection bias, as patient data may not have been originally collected for scoring system evaluation. Additionally, retrospective data might lack completeness, leading to missing or incomplete information that could impact the accuracy and reliability of prognostic evaluations .Missing data and follow-up: Incomplete data and loss to follow-up present significant challenges in prognostic evaluations using rapid scoring systems. Missing data can result from various factors, including patients' refusal to participate in follow-up assessments or incomplete medical records. This missing data can lead to underestimation or overestimation of prognostic accuracy and potentially introduce bias into the results. Ensuring complete and accurate data collection, as well as adequate follow-up, is essential to minimize these potential biases and enhance the validity of prognostic assessments .Addressing Potential Sources of BiasLarge, prospective multicenter studies: Conducting well-designed prospective studies with large and diverse patient populations is essential. By collecting data from multiple healthcare centers, these studies can improve the generalizability of the findings and ensure that the results represent the broader patient population. Prospective studies also allow for standardized data collection, minimizing the risk of data inconsistencies and enhancing the statistical robustness of the scoring system .External validation: External validation of rapid scoring systems is critical to establishing their predictive accuracy in different clinical settings and patient cohorts. Validating the scoring systems in settings beyond their original development ensures that they perform consistently and reliably across diverse healthcare contexts. Such validation strengthens the evidence base supporting the use of these scoring systems and increases confidence in their clinical applicability .Longitudinal assessment: Incorporating longitudinal assessments into rapid scoring systems can provide more accurate predictions of disease trajectories over time. By tracking changes in patient status and outcomes throughout treatment and follow-up, longitudinal assessments can offer insights into the dynamic nature of pleural infection and its response to interventions. This temporal dimension can further enhance the predictive value of the scoring systems, guiding clinicians in making more informed decisions throughout the patient's healthcare journey .Transparent reporting: Transparent reporting of study methods, data collection, and potential sources of bias is crucial for ensuring the credibility and reproducibility of research findings. Comprehensive and clear reporting allows other researchers and healthcare professionals to understand and evaluate the study's methodology and potential limitations. It fosters an environment of scientific rigor and encourages transparency in research, which is vital for building trust in the validity and applicability of rapid scoring systems in pleural infection prognostication .This review article has comprehensively assessed the predictive potential of rapid scoring systems in pleural infection prognostication. Pleural infection is a significant health concern, demanding accurate prognostic tools for effective management. Our analysis of existing scoring systems such as CURB-65, A-DROP, and APACHE II revealed their strengths and limitations in predicting short-term and long-term outcomes. While rapid scoring systems show promise in aiding clinical decision-making and risk stratification, they are not without drawbacks and face challenges related to data limitations and potential biases. However, their integration into clinical practice can potentially improve patient outcomes and optimize resource allocation. Moving forward, rigorous validation, reporting transparency, and data science advances offer promising avenues for refining rapid scoring systems. Multidisciplinary collaboration and prospective studies are critical to unlocking the full potential of rapid scoring in pleural infection management, ultimately contributing to better patient care and outcomes."}
+{"text": "Extracellular RNAs are an emerging research topic in fungal-plant interactions. Fungal plant pathogens and symbionts release small RNAs that enter host cells to manipulate plant physiology and immunity. This communication via extracellular RNAs between fungi and plants is bidirectional. On the one hand, plants release RNAs encapsulated inside extracellular vesicles as a defense response as well as for intercellular and inter-organismal communication. On the other hand, recent reports suggest that also full-length mRNAs are transported within fungal EVs into plants, and these fungal mRNAs might get translated inside host cells. In this review article, we summarize the current views and fundamental concepts of extracellular RNAs released by plant-associated fungi, and we discuss new strategies to apply extracellular RNAs in crop protection against fungal pathogens.Extracellular RNAs are an emerging topic in plant-fungal communication.\u2022 Fungi utilize RNAs to manipulate host plants for colonization.\u2022 Extracellular RNAs can be engineered to protect plants against fungal pathogens.\u2022  Fungal-plant interactions can have beneficial, detrimental, or neutral effects on plant hosts. Pathogenic fungi pose serious threats to agronomic yield and ecosystems  that is largely conserved between fungi and plants. Key factors of RNAi, namely RNA-dependent RNA polymerase (RDR), Dicer-like (DCL), and Argonaute (AGO) proteins, are highly conserved in both plants and fungi . EVs are nanoparticles encasing cytoplasmic molecules including proteins and RNAs in a lipid bilayer, which are secreted into the extracellular space   into the root cortex of its host plant Eucalyptus grandis. Treatment of roots with synthetic Pisolithus milRNAs mimicked regulation of Eucalyptus target genes and strengthened formation of deep Hartig net during root colonization  roots in order to establish root nodule symbiosis  into the soybean AGO1b to induce cross-kingdom RNAi of nodule-repressive plant genes. Interestingly, both cases of cross-kingdom RNAi help to establish distinct forms of root symbiosis, in which microbial small RNAs seem to act as early stage interaction signals, because RNA delivery into plant cells occurs before the formation of fungal Hartig net and bacterial nodules.The fungal vascular pathogen Zymoseptoria tritici 11 and RH37, which all specifically bind to the EV small RNAs, as well as the two non-specific RBPs annexins (ANN)1 and ANN2  and mRNAs with cognate motifs for targeting them to sites of EV biogenesis. In mammalian systems, multiple RBPs have been implicated in RNA loading into EVs siRNAs into infecting B. cinerea. These A. thaliana small RNAs are suggested to be transported via plant EVs  RNAs was found in the plant extracellular fraction . Accordingly, essential field trials in the USA are proceeding to pave the way for final approval. Such development of successful SIGS application keeps high hopes that RNA spray also becomes conceivable for plant protection against fungal pathogens in the near future.Since the discovery of cross-kingdom RNAi and its technological implementation into HIGS application, RNAs have been engineered to confer resistance in plants against diverse pathogenic organisms with significant success  and DCLs (RNAi pathway)  on cotton (Jain et al. B. cinerea infection in tomato and chickpea under controlled conditions (Nino-Sanchez et al. B. cinerea infection (Qiao et al. Since extracellular RNA stability and delivery have been identified as the major challenges to bring SIGS into a success story against fungal pathogens (Hernandez-Soto and Chacon-Cerdas The SIGS approach stands for a more eco-friendly plant protection strategy that is already in transition into potential field application in first trails (Rank and Koch"}
+{"text": "Pancreatic cancer is currently the fourth most common cause of cancer-related deaths and is predicted to be the second leading cause of cancer-related mortality by the year 2030. Most of the malignant neoplasms of the pancreas are ductal adenocarcinomas (PDAC). For several reasons, the prognosis of PDAC is exceedingly poor. Surgical resection is the only curative treatment option, but only about 10\u201320% of patients present with resectable tumors at the time of diagnosis. Moreover, most pancreatic carcinomas are resistant to conventional (radio)chemotherapy. Current clinical standard treatment regimens comprise either mFOLFIRINOX or gemcitabine (with nab-paclitaxel). The selection of either of these regimens is currently based on the patient performance status and comorbidities, while the underlying individual tumor biology is commonly not considered. Although multiple studies aimed at establishing molecular profiles and identification of actionable molecular targets of PDACs, targeted therapies for PDAC patients have not (yet) become an integral part of clinical routine practice. In addition to treatment prediction based on molecular profiling, e.g., in the context of a molecular tumorboard, preclinical culture models that reflect the complex interactions of tumor cells with their microenvironment are promising tools to understand molecular mechanisms of PDAC and to test individual treatment responses. These patient-derived models comprise adherently growing primary cell lines, organoid cultures, organotypic slice cultures and patient-derived xenografts.Garcia et al. recently published a comprehensive review on two-dimensional (2D) cell cultures, 3D organoid cultures, and genetically engineered mouse models (GEMMs) with a special focus on patient derived xenograft (PDX) models . AdherenIn light of the limitations of PDXs as a preclinical model for individual therapy response prediction in personalized medicine, 3D organoid cultures are a highly promising tool. Frappart and Hofmann comprehensively reviewed the methodology and potential use of organoid cultures to improve clinical management of PDAC . EfficieAs mentioned above, most preclinical culture models lack the immune cell compartment. However, multiple suppressive immune cell types including macrophages, myeloid-derived suppressor cells (MDSCs) and regulatory T cells are found in early pancreatic lesions and persist through cancer progression. Holokai et al. described an elegantautologous pancreatic cancer organoid-immune cell co-culture model that may be able to predict the efficacy of targeted therapies . Based oAnother model system that should be mentioned in this context are organotypic slice cultures (OTSCs). We recently established this ex vivo model in our laboratory to explore its potential use for ex vivo response prediction . OTSCs aIn summary, we conclude that to date there is no optimal model system for preclinical response prediction of individual PDAC patients to therapy. Each model system discussed here has its benefits and weaknesses and does not fully reflect the individual patient\u2019s tumor biology in vivo. However, since they complement each other, they may be used in combination rather than singly for reliable response prediction. All of these preclinical patient-derived culture models are certainly highly promising tools in personalized treatment of PDAC; their clinical implementation, though, requires further evaluation and fine tuning."}
+{"text": "The clinical use of cellular immunotherapies is gaining momentum and the number of approved indications is steadily increasing. One class of cellular therapies\u2014chimeric antigen receptor (CAR)-modified T cells\u2014has achieved impressive results in distinct blood cancer indications. These existing cellular therapies treating blood cancers face significant relapse rates, and their application beyond hematology has been underwhelming, especially in solid oncology. Major reasons for resistance source largely in the tumor microenvironment (TME). The TME in fact functionally suppresses, restricts, and excludes adoptive immune cells, which limits the efficacy of cellular immunotherapies from the onset. Many promising efforts are ongoing to adapt cellular immunotherapies to address these obstacles, with the aim of reshaping the tumor microenvironment to ameliorate function and to achieve superior efficacy against both hematological and solid malignancies. Cellular immunotherapies, encompassing the use of modified autologous or allogeneic immune cells as treatment against disease, have recently advanced to become part of the standard of care in a few types of relapsed and refractory hematological malignancies. Recent evidence suggests that they might even progress to earlier lines of treatment at least in some indications, highlighting the untapped potential of these approaches.Overall, cellular immunotherapies have so far employed dendritic cell (DC), T cells, or natural killer cells (NK) into patients for treatment of disease. DC vaccines, which utilize mature dendritic cells or monocyte-derived dendritic cells derived from patient blood, harness the natural role of the dendritic cell in antigen presentation and T cell licensing to target cancer. Dendritic cells are pulsed with tumor-associated antigens and neoantigens that would then be presented to T cells in lymph nodes to induce cytotoxic lymphocyte priming and polarization to mount a specific immune response. Various DC vaccines have shown promising safety and efficacy in clinical trials against pediatric solid tumors and other forms of solid tumors \u20133. TheseMeanwhile, TCRs and CARs are receptors genetically engineered into T cells isolated from patient blood and reintroduced into the patient to target cancers. TCRs used are derived from natural sequences that bind the desired antigen and behave similarly to normal TCRs . In contThe tumor microenvironment\u2014comprises malignant cells together with their immediate environment consisting of immune cells, fibroblasts, extracellular matrix (ECM), blood vessels, and secreted factors. The TME can support the survival and proliferation of tumor cells and tumor-associated cell populations and thus contributes a major share to cancer hallmarks Fig.\u00a0. Crucial. Along these lines, the TME profoundly regulates and suppresses immune responses and appears as the aspect to beat to enable cell therapy efficacy.Chemokines released by tumor cells recruit and retain other populations of immunosuppressive cells into the tumor microenvironment Fig.\u00a0. T-regulMany insights have already been gained into improving existing cellular therapy. For instance, application via intratumoral injection leads to increased efficacy of adoptive CAR-T cells in certain tumor indications by physically circumventing the issue of TME exclusion and adoptive cell infiltration , 43. To Chemokines are mediators signaling for directed migration towards the source they originate from . Chemokines orchestrate the localization of cells within the body and accordingly play a crucial role in the trafficking of immunosuppressive cells to the TME , 50. HowChemokine engineering into therapeutic immune cells has been incorporated into cellular therapies with the goal of increasing the migration of both endogenous inflammatory cells and also adoptively transferred cells into the tumor Fig.\u00a0. The cheAnother related strategy to increase immune infiltration is endogenous activation and proliferation, ultimately leading to higher anti-tumor effector cell numbers at the tumor site. In this sense, T cells can be genetically engineered to express immune checkpoint inhibitors, with anti-PD-1 or anti-PD-L1 antibodies being the most utilized avenue \u201361. AntiThe TME is typically rich in cytokines such as IL-1, favoring expansion and polarization of immune suppressive cell populations of myeloid and lymphoid origin . In contThe aforementioned strategies remodeling the cytokine environment in the TME indirectly affect TAMs, MDSCs, and T-regs by antagonizing their suppressiveness or reversing their suppression program. However, other cellular therapy approaches aim to directly target these immunosuppressive populations for elimination or remodeling Fig.\u00a0. For exaSignificant obstacles of cellular immunotherapy in solid tumors do not only arise from immunosuppressive cell populations and a lack of immune cell activation within the TME but are additionally characterized by the establishment of CAF-mediated tumor stroma as a physical barrier, diminishing cellular therapy effectiveness. Along these lines, therapy can be enhanced if either the cellular components creating stroma are depleted or acellular stromal components are digested Fig.\u00a0. FibroblA different strategy to surmount the desmoplastic stroma of the TME and enable superior immune cell infiltration is the direct targeting of fibrous proteins, glycosaminoglycans, and proteoglycans composing the ECM via matrix-degrading components. Heparanase (HPSE) is an enzyme that decomposes heparan sulfate proteoglycans and has been found to be insufficiently expressed in CAR-T cells, thereby limiting their capacity to infiltrate stroma-rich tumors . EquippiVarious strategies have also been developed to address the secondary issue of physical tumor-exclusion\u2014aberrant and dysfunctional vasculature that leads to poor T cell infiltration Fig.\u00a0. One strRecent efforts to remodel the tumor microenvironment with cellular therapies have advanced with the advent of engineering CARs or CAR-like receptors on myeloid lineage cells, notably on macrophages and in some instances dendritic cells Fig.\u00a0. TraditiWhile cellular therapies have come a long way to become an established method of cancer treatment, their future potential for increased efficacy in hematological malignancies and even meaningful efficacy in solid tumor indications largely relies on their ability to address the obstacles posed by the TME. This review highlights the current considerable efforts that have been made to improve various aspects of cellular therapies to reshape the TME to become more permissible for treatment: novel concepts that target immunosuppressive cell populations, inflame an immune-restricted tumor, and address chemotactic signaling and physical barriers excluding immune infiltration. The improvements made on these therapies have been shown to lead to superior anti-tumor efficacy compared to more standard cellular therapies. Moreover, many cellular therapies covered here that target the TME as an entity have been combined with other treatments that primarily target the tumor, forming a dual-pronged targeting approach that in many cases shows synergistic efficacy. Additionally, concepts incorporating combinatorial improvements that address multiple TME obstructions show further enhanced function, demonstrating additionally the promising and synergistic nature of reshaping the tumor microenvironment, and hints at robust effects for combinatorial treatments with existing therapies such as ICB. Promising pre-clinical and clinical results of many of the therapies listed bode well for the application of cellular immunotherapies for the treatment of both hematological and solid tumors in the future."}
+{"text": "Introduction: Chediak-Higashi syndrome (CHS) is rare autosomal recessive disorder caused by bi-allelic variants in the Lysosomal Trafficking Regulator (LYST) gene. Diagnosis is established by the detection of pathogenic variants in LYST in combination with clinical evidence of disease. Conventional molecular genetic testing of LYST by genomic DNA (gDNA) Sanger sequencing detects the majority of pathogenic variants, but some remain undetected for several individuals clinically diagnosed with CHS. In this study, cDNA Sanger sequencing was pursued as a complementary method to identify variant alleles that are undetected by gDNA Sanger sequencing and to increase molecular diagnostic yield.Methods: Six unrelated individuals with CHS were clinically evaluated and included in this study. gDNA Sanger sequencing and cDNA Sanger sequencing were performed to identify pathogenic LYST variants.Results: Ten novel LYST alleles were identified, including eight nonsense or frameshift variants and two in-frame deletions. Six of these were identified by conventional gDNA Sanger sequencing; cDNA Sanger sequencing was required to identify the remaining variant alleles.Conclusion: By utilizing cDNA sequencing as a complementary technique to identify LYST variants, a complete molecular diagnosis was obtained for all six CHS patients. In this small CHS cohort, the molecular diagnostic yield was increased, and canonical splice site variants identified from gDNA Sanger sequencing were validated by cDNA sequencing. The identification of novel LYST alleles will aid in diagnosing patients and these molecular diagnoses will also lead to genetic counseling, access to services and treatments and clinical trials in the future. Chediak-Higashi syndrome  is a rare autosomal recessive disorder characterized by partial oculocutaneous albinism, bleeding diathesis, recurrent infections, an increased risk of developing the hyperinflammatory condition called hemophagocytic lymphohistiocytosis (HLH), and neurologic impairment . The preCHS has significant clinical overlap with several other genetic disorders, emphasizing the importance of a molecular diagnosis. Other disorders that include gray or silvery hair as observed in CHS include Griscelli syndrome , Elejalde neuroectodermal melanolysosomal syndrome (MIM 256710), and oculocerebral syndrome with hypopigmentation (MIM 257800) . There aLYST) gene is the only known molecular cause of CHS and bi-allelic pathogenic variants in LYST establish a molecular diagnosis  detects the majority of pathogenic variants, but for some individuals clinically diagnosed with CHS, pathogenic variants remain undetected, likely due to large-scale indels and deep intronic variants or synonymous exonic variants that lead to aberrant splicing. Uniparental disomy leading to the inheritance of two copies of a pathogenic LYST variant from one parent has also been reported as a molecular mechanism for CHS  or the Diagnosis and Treatment of Patients with Inborn Errors of Metabolism or Other Genetic Disorders protocol 76-HG-0238  approved by the National Human Genome Research Institute\u2019s Institutional Review Board. Written informed consent was obtained prior to the study. Clinical evaluation included collecting the medical and family history, physical examination, complete blood count (CBC) blood test. Peripheral blood smear analysis and microscopic hair examination were used to assess the presence of giant inclusions in leukocytes and pigment clumping in hair shafts, pathognomonic features of CHS.Six patients clinically diagnosed with classical or atypical CHS were included in this study. These patients were enrolled over the course of 10\u201320\u00a0years in the Investigation of Chediak-Higashi Syndrome and Related Disorders protocol 00-HG-0153 . Quantitative PCR was performed using TaqMan gene expression assays according to the manufacturer\u2019s specifications. Further details are presented in the Supplementary Data.Total RNA was extracted from cultured primary dermal fibroblasts or melanocytes using the RNeasy Mini Kit (Qiagen). Genomic DNA was removed by on-column DNase I digestion (Qiagen) during total RNA extraction. Reverse transcription was performed using the Omniscript Reverse Transcription Kit (Qiagen) and Oligo (dT)LYST (NM_000081.3) coding sequence (exons 3\u201353), including intron-exon boundaries, were amplified by PCR using the primers listed in Genomic DNA (gDNA) was extracted from peripheral blood or cultured primary dermal fibroblasts using standard procedures. gDNA from cultured primary fibroblasts was used if the gDNA from peripheral blood was no longer available. Regions of the LYST coding sequence (exons 3\u201353) were amplified by PCR using the primers listed in Total RNA was extracted from cultured primary dermal fibroblasts or melanocytes using the RNeasy Mini Kit (Qiagen). cDNA was synthesized by reverse transcription with the High-Capacity RNA-to-cDNA Kit (Applied Biosystems). Regions of the PCR products were cloned into the pCR4-TOPO TA vector using the TOPO TA Cloning Kit (Invitrogen). Single clones were Sanger sequenced to individually analyze the cDNA alleles for which chromatograms obtained from the initial cDNA Sanger sequencing were difficult to interpret.Variant pathogenicity classification was performed according to the standards and guidelines presented by the ACMG-AMP and the ACGS . Furtherp-value of less than 0.05 was considered statistically significant.Statistics were performed using GraphPad Prism 8 version 8.4.3 . A two-tailed Mann-Whitney test was performed for experiments comparing two sets of data. A CHD3 presented with silvery hair, pale skin, and ocular albinism as well as a history of recurrent respiratory and skin infections and nose bleeds. He was clinically diagnosed with classical CHS at the age of 7\u00a0years. Abnormal pigment clumping was observed in his hair shafts . He receStaphylococcus aureus (MRSA). She also had learning difficulties and a mood disorder. Pathognomonic giant inclusions were observed in her leukocytes and abnormal pigment clumping in her hair shafts . These cellular findings substantiate prior cellular findings reported in human CHS and in the beige mouse model  (Pathogenic variants have been identified throughout the ication) . Eight oication) ; Table 1ication) . AlthougLYST-expressing cell types, including dermal fibroblasts, melanocytes, NK cells, and lymphoblastoid cell lines, for the preparation of total RNA. Archiving cells from each parent and all available family members would also be useful for variant phasing and segregation studies.cDNA Sanger sequencing in combination with conventional gDNA Sanger sequencing offers several advantages. First, cDNA Sanger sequencing can detect variant alleles that are not readily detectable by conventional gDNA Sanger sequencing. While establishing a clinical diagnosis is valuable, the confirmation of a molecular diagnosis is critical for optimal patient care, genetic counseling for the individual and their family members, and eligibility in future clinical trials. Second, cDNA Sanger sequencing is relatively easy to incorporate into the molecular genetic testing workflow, requiring only routine cell culture and total RNA extraction techniques. An important consideration is patient sample archiving of LYST. Furthermore, only cDNA from each of the six patients was analyzed in this study due to sample availability. While we were unable to assess cDNA from cells derived from family members due to sample availability, cDNA Sanger sequencing could be performed to segregate LYST alleles in a family even if the variant at the level of gDNA is unknown.A key limitation of this study was that we were unable to identify the cause of the full or partial exon skipping at the gDNA level for some alleles. While efforts were made to sequence nearby intronic regions and identify exonic synonymous variants that might lead to the aberrant splicing, proving the consequence of such variants requires further functional validation. With the decreasing costs of genome sequencing and targeted next-generation sequencing, these are becoming viable options for the identification of deep intronic variants leading to splicing changes in LYST gene in CHS. Because of the increasing access to next-generation sequencing and its rapid turnaround time, we recommend the utilization of clinical genome sequencing to include copy number variant analysis for patients in which CHS is suspected. When available, RNA sequencing using lymphoblastoid cell lines and melanocytes could help delineate the resulting splice site abnormalities from intronic variants. For standard clinical practice using exome sequencing and when clinical genome sequencing is not available, targeted gDNA Sanger sequencing and copy number detection is recommended for patients highly suspected to have clinical CHS, followed by RNA sequencing (as above) or cDNA Sanger sequencing if only one or no variants are detected by gDNA Sanger sequencing. It will also be interesting to pursue efforts on long-read sequencing technologies to identify deletions in these large genes and to phase variants in the absence of parental samples in the future. Overall, the identification of disease-causing variants will aid in the future diagnosis and care of individuals with CHS.In this study, the integration of thorough clinical phenotyping and conventional gDNA Sanger sequencing in combination with cDNA Sanger sequencing increased the mutational spectrum of CHS. Based on our experience from this study, we provide the following recommendations for molecular genetic testing of the"}
+{"text": "Inhaled medications, including beta-agonists, muscarinic antagonists, and corticosteroids, are the backbone of chronic obstructive pulmonary disease (COPD) treatment, and pharmacotherapy plans are frequently optimized during and following hospitalization. Clinical practice guidelines acknowledge that patients living with COPD may experience medication errors from inadequate inhaler technique or device faults, but inhaled medication errors within COPD pharmacotherapy plans remain unreported. This literature review aimed to collect and present studies describing medication errors occurring with inhaled medications in patients living with COPD during and following hospitalization. The databases searched included Ovid MEDLINE, Embase, and International Pharmaceutical Abstracts. One hundred forty-five unique studies were collected, and 10 studies were included. The rate of inhaled medication errors reported across the 10 studies ranged between 2.5% and 66% of patients living with COPD and who were hospitalized or discharged. The incidence and types of medication errors reported across the studies varied significantly. Standardization in categorizing and reporting inhaled medication errors is necessary for future studies to determine the true incidence of inhaled medication errors occurring in patients living with COPD who are hospitalized or discharged. Patients living with chronic obstructive pulmonary disease (COPD) may take medications to palliate symptoms, improve health status, tolerate exercise, and reduce the risk and severity of exacerbations of COPD (ECOPD) . InhaledHowever, the comprehensive formulary of inhaled medications may be overwhelming for both patients and prescribers and thus there is potential for medication errors. Hospitalization is a critical time wherein inhaled medication errors may occur and between 7% and 33% of patients living with COPD will experience at least one COPD-related hospitalization annually . PatientThe purpose of this review is to collect and present literature describing medication errors occurring with inhaled medications in patients living with COPD during and following hospitalization.Review methodsThis was a literature review utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol . The resAn electronic literature search was performed using Ovid MEDLINE, Embase, and International Pharmaceutical Abstracts on February 14, 2023. Search strings for each database are included in Appendix A and adhered to the PRISMA-S extension for literature search reporting . Study rResults from each database search were exported as a Research Information Systems file and then imported into Covidence . During the initial file upload, Covidence automatically de-duplicated identical records retrieved across databases. Abstracts were independently screened by two authors (KH and MG) and screening conflicts were resolved by a third author (PB). Full texts were independently screened by two authors (KH and MG) and screening conflicts were resolved by a third author (PB). Data abstraction was independently performed by two authors (KH and MG). To minimize heterogeneity across the articles and among authors, extraction was performed using a template in Covidence. Data collected included study location, study design, characteristics of the cohort , characteristics of patients living with COPD , and medication errors. There are many frameworks for reporting medication errors, medication error research, and outcomes attributable to medication errors . BecauseFigure Ten studies were ultimately included and are charted in Table Medication-related problemsIn a pilot study conducted at an academic medical center, pharmacists performing admission and discharge medication reconciliation discovered a medication-related problem (MRP) in 96% of patients during admission and discharge transitions of care, with an average of six MRPs encountered per patient . These MOne Veterans Affairs health care center conducted a pre-post study and found an absolute decrease of greater than 10% in prescribing errors upon discharge in each of the categories of SABA, LABA/LAMA, and ICS upon implementing an order set for ECOPD . DecreasPrescribing errors and omissionsOne retrospective cohort study of older adults hospitalized in Palestine leveraged the Screening Tool of Older Persons\u2019 Prescriptions and Screening Tool to Alert to Right Treatment (STOPP/START) to determine potentially inappropriate prescribing via inappropriate medications and omissions . The autIn one multisite retrospective cohort study conducted in Australia, 93.2% of hospitalized COPD patients received nebulized ipratropium, with 48% of these patients deemed as having received inappropriate nebulized ipratropium because they were ordered (duplicative) inhaled ipratropium concomitantly . At discDiscussionThe rate of inhaled medication errors was heterogeneous across the 10 studies in this review -16. BrowThis literature review is not without limitations. Although the authors utilized a systematic approach to searching, assessing, and presenting the included studies, this literature review did not meet the technical standards of either a systematic or scoping review. Future systematic reviews on the themes and topics raised within this literature review are necessary to answer patient-specific questions. The authors did not perform a bias assessment of each article and doing so would have qualified the methodologic rigor of the included studies; although six studies were retrospective designs ,13,14,16As few as 2.5% or as many as 66% of patients living with COPD who are hospitalized may experience an error in their inhaled medication pharmacotherapy plan. Pharmacologic classes with reported errors include short- and long-acting beta-agonists, muscarinic antagonists, and inhaled corticosteroids. Standardization in categorizing and reporting inhaled medication errors is necessary in subsequent studies; the Pharmacy Quality Alliance Frameworks or Medication Error Reporting and Prevention Index are validated and widely used instruments that may be considered in future studies. Future research should aim to clearly compare and contrast findings across clinical settings and investigations and determine the true incidence of inhaled medication errors."}
+{"text": "Maiato and Silva discuss the origin and fate of chromosome segregation errors that satisfy the spindle assembly checkpoint, focusing on anaphase surveillance/correction mechanisms and post-mitotic clearance pathways. Enduring chromosome segregation errors represent potential threats to genomic stability due to eventual chromosome copy number alterations (aneuploidy) and formation of micronuclei\u2014key intermediates of a rapid mutational process known as chromothripsis that is found in cancer and congenital disorders. The spindle assembly checkpoint (SAC) has been viewed as the sole surveillance mechanism that prevents chromosome segregation errors during mitosis and meiosis. However, different types of chromosome segregation errors stemming from incorrect kinetochore\u2013microtubule attachments satisfy the SAC and are more frequent than previously anticipated. Remarkably, recent works have unveiled that most of these errors are corrected during anaphase and only rarely result in aneuploidy or formation of micronuclei. Here, we discuss recent progress in our understanding of the origin and fate of chromosome segregation errors that satisfy the SAC and shed light on the surveillance, correction, and clearance mechanisms that prevent their transmission, to preserve genomic stability. Saccharomyces cerevisiae [300 billion cell divisions must take place every day in the human body to ensure tissue homeostasis and function . In vitrrevisiae ), these Somatic cell aneuploidy is implicated in tumorigenesis, genomic instability, tumor evolution, metastasis, drug resistance, and reduced cancer patient survival, whereas germline aneuploidy directly accounts for infertility, pregnancy loss, and developmental disorders . HoweverCell cycle checkpoints are constitutive feedback control mechanisms that delay cell cycle progression until completion of a critical event, providing time for the correction of potential errors . EliminaRecent high-resolution live-cell studies tracking kinetochore or chromosome behavior through metaphase and anaphase in human somatic cells in culture have revealed that many more chromosomes tend to lag behind in anaphase than previously anticipated . This beThe role of anaphase spindle mechanics was first established through the observation that merotelic kinetochores with uneven microtubules facing the poles experience a significant stretch and elongate under tension, eventually favoring segregation to the correct daughter cell. Only a small fraction (<10%) of the merotelic kinetochores that persist through anaphase show an even microtubule ratio facing the poles and result in long-lasting lagging chromosomes that missegregate . Live imMore recently, it was demonstrated that spindle elongation is directly required for anaphase error correction . The acuAurora B kinase activity at centromeres plays a key role in error correction during early mitosis . HoweverTwo possible models have been proposed to explain how a midzone-based Aurora B activity gradient mediates error correction during anaphase . One is An alternative model favors the idea that midzone Aurora B activity mediates anaphase error correction of merotelic kinetochores by assisting the mechanical transmission of spindle forces to a stable kinetochore\u2013microtubule interface on lagging chromosomes . Live-ceDirect measurements of kinetochore\u2013microtubule half-life during anaphase revealed a low kinetochore\u2013microtubule turnover , which wThe finding of a distinct phosphorylation state on Aurora B substrates at kinetochores of anaphase lagging chromosomes  suggestsBut why is the spatiotemporal control of NER important? On one hand, preventing premature NER on incompletely separated chromosomes during normal anaphase protects against polyploidy. Whole-genome duplication is a common evolutionary event that is also frequent in >30% of human tumors early in tumorigenesis and is thought to promote chromosomal instability and metastasis by providing a selective advantage in certain contexts . On the One may argue that a delay of just a few minutes in a process that is normally completed within 5\u201310 min in human somatic cells cannot be explained by a robust checkpoint mediated by Aurora B at the spindle midzone. Instead, midzone microtubules may act independently of Aurora B activity by forming a physical barrier that selectively prevents the recruitment of non-core nuclear envelope proteins , includIn an attempt to separate the role of microtubules from that of Aurora B at the spindle midzone in the spatiotemporal control of NER, high-resolution live-cell microscopy was used to simultaneously monitor Aurora B activity on chromosomes, the recruitment of NPC proteins, and the distribution of spindle midzone microtubules throughout anaphase, upon manipulation of Aurora B midzone localization . These eQuantitative microscopy analyses further revealed that even just a small but significant delay in the completion of NER relative to the main segregating chromosome masses allows most anaphase lagging chromosomes in human cells to gradually correct and move away from the spindle midzone. Moreover, this delay depended on the establishment of a midzone-based Aurora B phosphorylation gradient that prevented formation of micronuclei . TherefoConcerning potential targets involved in the spatiotemporal regulation of NER, Aurora B may regulate Condensin I removal and/or recruitment of HP1 and LBR as chromosomes separate during anaphase  or may mAnaphase lagging chromosomes that escape surveillance and correction mechanisms operating in anaphase rarely missegregate to give rise to aneuploidy, but they may lead to the formation of micronuclei . ImportaMicronuclei derived from chromosome segregation errors have four possible outcomes upon mitotic exit: (1) persistence as independent structures; (2) reincorporation into the main nucleus; (3) degradation; or (4) extrusion  sensor that mounts a type-I IFN innate immune response through its adaptor protein STING, referred to as the cGAS-STING pathway . The actGiven the possible role of p53 in limiting the proliferation of aneuploid and micronucleated cells, an outstanding question is whether the cGAS-STING pathway somehow crosstalks with p53. Recently, a mutant form of p53 was shown to suppress innate immune signaling through the cGAS-STING pathway, resulting in immune evasion and tumor progression . In thisWhile a lot remains to be known regarding the mechanisms underlying cGAS-STING\u2013mediated immunosurveillance of mitotic errors and their respective implications for tumor evolution, defective micronuclei are now well established as potential hubs for chromothripsis . ChromotWhile the high rates of aneuploidy during female meiosis have been linked to a weakened SAC and intrinsically unstable kinetochore\u2013microtubule attachments , aneuploIn addition to direct missegregation from misaligned chromosomes, late-aligning chromosomes associated with peripheral nuclear positioning during interphase are also more prone to lag behind in anaphase and missegregate at higher frequencies . LikewisOverall, these recent findings instigate future studies to determine the underlying mechanisms that normally prevent aneuploidy during mitosis and meiosis, while continuing to evaluate the contribution of aneuploidy-inducing events of different origin and how cells deal with them in health and disease contexts."}
+{"text": "Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult Caucasian women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Disease rarity and wide geographic patient distribution has previously limited substantive mechanistic investigation into iSGS pathogenesis.By harnessing pathogenic mucosa from an international iSGS patient cohort and single-cell RNA sequencing, we unbiasedly characterize the cell subsets in the proximal airway scar and detail their molecular phenotypes. Results show that the airway epithelium in iSGS patients is depleted of basal progenitor cells, and the residual epithelial cells acquire a mesenchymal phenotype. Observed displacement of bacteria beneath the lamina propria provides functional support for the molecular evidence of epithelial dysfunction. Matched tissue microbiomes support displacement of the native microbiome into the lamina propria of iSGS patients rather than disrupted bacterial community structure. However, animal models confirm that bacteria are necessary for pathologic proximal airway fibrosis and suggest an equally essential role for host adaptive immunity. Human samples from iSGS airway scar demonstrate adaptive immune activation in response to the proximal airway microbiome of both matched iSGS patients and healthy controls. Clinical outcome data from iSGS patients suggests surgical extirpation of airway scar and reconstitution with unaffected tracheal mucosa halts the progressive fibrosis.Our data support an iSGS disease model where epithelial alterations facilitate microbiome displacement, dysregulated immune activation, and localized fibrosis. These results refine our understanding of iSGS and implicate shared pathogenic mechanisms with distal airway fibrotic diseases. Idiopathic subglottic stenosis (iSGS) is a rare  but devaHistologically, iSGS cases show pronounced fibrosis restricted to the proximal airway mucosa . DiverseIn iSGS the functional alterations underlying airway remodeling remain poorly understood. In this study, we harnessed tissue samples from an international iSGS patient cohort and cutting-edge molecular tools to define the molecular phenotype of the proximal airway mucosa at single-cell resolution. Our results provide an unbiased assessment of the cell types within the normal human subglottis and illuminate the changes accompanying iSGS. The results suggest epithelial barrier dysfunction and immune infiltration are key components of iSGS pathogenesis. Matched superficial and deep tissue microbiomes support displacement of the native microbiome into the lamina propria of iSGS patients rather than disruption of bacterial community structure. However, animal models confirm that bacteria are necessary for pathologic proximal airway fibrosis and suggest an equally essential role for host adaptive immunity in remodeling after mucosal injury. Clinical data support the role of epithelial dysfunction in treatment response. Our data suggests that in iSGS the native microbiome is displaced across a dysfunctional epithelial barrier leading to an adaptive immune response which drives obstructive airway fibrosis. These novel results reshape our understanding of iSGS, implicate shared pathogenic mechanisms with distal airway fibrotic diseases, and open new avenues for therapy.Supplemental Table T1) and performed scRNAseq using the 10x Genomics Chromium platform . The samples were collected and processed at two different sites ; however, both sites collected cases and controls. To maximize our ability to identify rare cell populations, we jointly analyzed data from all samples. We defined inclusion criteria for cells based on observations from the entire dataset, removed low-quality cells accordingly, applied normalization and variance stabilization of the 25,974 recovered cells using Seurat. Initially one small CD8 effector T cell population was grouped together with a larger CD8 T effector population due to observations that cell cycle activity was driving distinct cluster identity. All cell types were identified both in airway scar and healthy mucosa. Notably, we did not observe overt batch effects driven by processing site or sequencing batch in our dimensionality reduction and visualization . Cell types/states were also manually grouped into 4 broad tissue classes  based on their identity . Quantification of cell types demonstrated significant differences between iSGS airway scar and matched healthy mucosa controls. Airway scar showed significantly more Immune cells  and significantly fewer epithelial cells  . When grouping cells into their tissue layer, the epithelium demonstrated significantly more DEG than immune cells   . In addi< 0.001)  (DEG: P = 0.007) . The dif= 0.007) .Supplemental Figure S4). Gene ontology (GO) pathway analysis supported the Hallmark geneset EMT findings; iSGS airway scar showed enrichment for mitochondrial matrix genes . In parallel, proliferating epithelial cells in iSGS airway scar showed down-regulated glycosylation and junctional protein complexes . Both aerobic respiration and loss of cell-cell adhesion are consistent with EMT.Molecular and functional evidence of epithelial dysfunction in iSGS scar. We further analyzed the epithelial clusters  and idenTo provide functional evidence of epithelial barrier dysfunction, we investigated if native bacterial displacement into the deeper lamina propria was a unique feature of iSGS. Employing fluorescence in situ hybridization (FISH) with the pan-bacterial probe, Eub338, we investigated if mucosal biopsies from iSGS and healthy controls evidenced bacteria in the deep layers of the proximal airway mucosa. Representative FISH stains show iSGS mucosa possessed signal for bacteria in the deeper lamina propria while healthy control did not . In a seCharacterization of the mucosal microbiome in iSGS. Given the observed bacterial displacement into the lamina propria of the airway mucosa, we investigated if alterations in microbiome community structure were also observed in iSGS. We first quantified the number of 16S rRNA gene copies in deep tissue biopsies via qPCR . We deteSupplemental Figure S6). The majority of bacterial species present in healthy subglottis were consistent with the established healthy lung microbiome composed of supraglottic predominant taxa . Using ptococcus).Supplemental Fig. 7A) nor between disease severity and alpha diversity  or richness .Additional microbial community structure testing using established diversity and richness indices confirmed no detectable differences between iSGS, iLTS and healthy controls. ANOVA testing of alpha diversity  and richness .Anatomic location of bacterial species in iSGS mucosal scar. To validate our findings and explore if superficial and deep tissue sampling methods produced unique bacterial communities, we next compared published 16S rRNA sequencing data of superficial swabs of iSGS scar (n = 5) with ourSupplemental Fig. 8). As expected, wild-type mice developed mucosal inflammation and significant thickening of the lamina propria 14 days after injury . Interestingly however, no significant thickening of the lamina propria was observed when using either germ-free mice , or severe combined immunodeficient mice (SCID) lacking ce (SCID) & B.eff cells in scar , along with more CD4 + Treg  and more NK cluster 2 cells . In contrast, the NK cluster 1 population was significantly reduced in scar   .The native proximal airway microbiome generates an antigen-specific immune response in infiltrating CD4 + and CD8 + T cells. In order to probe the function of the observed immune infiltrate, tissue biopsies acquired during the operative endoscopy of 5 unique iSGS patients were used to create fresh single-cell suspensions as described. Suspensions were rested for 6 hours, then cultured in the presence of a matched iSGS airway microbiome, the microbiome from an unrelated healthy subject, or left untreated.After 24 hours of stimulation, cells were washed and stained for markers of T cell activation (CD154) and analyzed via flow cytometry . For CD4Clinical data suggest that restoring epithelial barrier function is associated with a more durable treatment response. Treatment outcomes of iSGS patients in an ongoing cohort study  demonstrIdiopathic subglottic stenosis (iSGS) is a debilitating localized fibrosis of the proximal airway. Affected patients possess tightly conserved clinical demographics, histopathology, and physiologic impairment . Our humThe pseudostratified epithelium lining the human airway comprises several distinct populations of cells with specialized effector functions. Airway epithelium and the overlying mucociliary layer maintain a physical barrier against environmental insults . Many primary respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma, and idiopathic pulmonary fibrosis (IPF), display substantial pathological alterations in the airway epithelium. Evidence suggests that impairment of the epithelial barrier allows bacteria to penetrate the overlying mucociliary layer, intercalate within the epithelium, and activate host immunity. When sustained inappropriately, this inflammation can culminate in fibrotic tissue remodeling and physiologic impairment.in vitro human data and genetic evidence suggest that the airway epithelium plays a central role in disease susceptibility  of the residual epithelial cells showed a mechanistic target of rapamycin (mTORC1) pathway activation and enhanced aerobic metabolism. mTOR is a master sensor that integrates environmental factors to regulate cell growth. In general, activation of mTOR stimulates proliferation, mitochondrial biogenesis, and oxidative phosphorylation . The GESAlthough an often-overlooked anatomic subsite, the subglottis is uniquely enriched in antigen-presenting dendritic cells and T lymphocytes . AdditioPrior small case series examining environmental factors contributing to iSGS have implicated disruption of the proximal airway microbiome, one using pathogen-specific molecular approaches, and anoHowever, the displaced microbiome may not be the sole target of the adaptive immune response observed in iSGS mucosal scar. A feed-forward inflammatory loop may become established when peptides from microbial proteins share suffi cient structural similarity with self-peptides and activate autoreactive T cells, termed \u201cmolecular mimicry\u201d. InflammAlthough we acknowledge the limited ability to assign causality in pathologic studies involving human tissue, single-cell transcriptional profiling provides an unbiased assessment of the cell types within the human subglottis and illuminates the epithelial and immune alterations accompanying disease. Histologic localization of pathogens deep in the lamina propria and bacterial community profiling support the functional impact of the observed epithelial dysfunction rather than suggest microbiome disruption is a primary driver of disease. Animal models confirm the importance of both bacteria and host immunity in the pathogenesis of airway fibrosis after epithelial injury and robust clinical data suggests restoring the epithelial barrier with healthy mucosa minimizes disease recurrence.Despite the inherent limits involved in rare disease research, our findings dramatically shift our concept of iSGS disease pathogenesis . UnbiaseDetailed experimental methods are included in the Supplemental Material."}
+{"text": "Integrating robotics into orthopedic healthcare represents a transformative paradigm shift driven by technological advancements. This editorial explores the profound impact of robotics on the diagnosis, treatment, and rehabilitation of musculoskeletal conditions. Robotics redefines precision in orthopedic surgery through advanced imaging and real-time feedback, resulting in minimized disruption to tissues and faster recovery. Personalized treatment plans leverage robotics' capabilities to tailor procedures to individual anatomical characteristics, enhancing outcomes and reducing complications. Minimally invasive procedures, facilitated by robotics, mitigate trauma and expedite patient recovery. This collaboration between surgeons and robotic systems enhances precision without supplanting human expertise. Moreover, robotics extends to postoperative rehabilitation, utilizing exoskeletons and motion-capture systems to optimize mobility and strength recovery. While challenges of cost and training exist, proactive collaborations are shaping the future of robotics in orthopedic care. Ethical considerations underline the importance of balancing human intervention with robotic assistance. As robotics evolves, orthopedic healthcare embraces a future where technology and human expertise synergize, ultimately conquering musculoskeletal conditions. In recent years, the realm of healthcare has been undergoing a transformative journey fueled by remarkable technological advancements. Among the most impactful areas experiencing this revolution is orthopedic healthcare, where robotics catalyzes a paradigm shift in approaching the diagnosis, treatment, and rehabilitation of musculoskeletal conditions. As the symbiotic relationship between robotics and orthopedic care continues to evolve, a future brimming with the potential for enhanced precision, swifter recovery times, and overall improved outcomes comes into view.Orthopedic conditions, an extensive array of musculoskeletal disorders, have long posed challenges due to the intricate complexity of human anatomy and the delicate nature of bone and joint structures. Robotics' assimilation into orthopedic care has introduced a new dimension, addressing these challenges with unprecedented precision and efficacy.Robotic systems revolutionizing orthopedicsSeveral robotic systems have emerged as game-changers in orthopedic surgery, each offering unique features and benefits.MAKO Surgical SystemThe MAKO system  is renowned for its application in joint replacement surgeries. Advanced imaging and real-time feedback assist surgeons in precise bone preparation and implant positioning, resulting in improved alignment and joint function. Its haptic feedback mechanism aids in accurate bone resection. MAKO utilizes computed tomography (CT) scans to create patient-specific 3D models. Surgeons plan implant placement virtually, ensuring optimal alignment. The robotic arm is guided by the surgical plan in the operating room and provides haptic feedback to prevent excessive bone resection. Surgeons retain control while benefiting from enhanced accuracy.ROSA ROSA  is widely utilized in neurosurgery and spine procedures. Its features include real-time intraoperative data, image guidance, and robotic arms for enhanced surgical precision. ROSA facilitates minimally invasive surgeries and assists in complex spinal deformity corrections. ROSA integrates with various imaging modalities\u00a0like CT and X-ray, to create a comprehensive surgical plan. It assists in cranial and spinal surgeries by providing real-time data, enabling precise targeting and trajectory planning. The system's robotic arms are guided by the surgeon's commands, enhancing procedural accuracy.NAVIO Surgical SystemNAVIO  offers robotics-assisted procedures in orthopedics, focusing on knee surgeries. It employs intraoperative planning and a handheld robotic-assisted tool for precise bone resurfacing. NAVIO's image-free registration enhances accuracy and outcomes in knee arthroplasty. NAVIO operates without preoperative imaging, utilizing a computer-assisted tool for intraoperative planning. Surgeons use tactile guidance to create a patient-specific plan and execute bone resurfacing accurately. This system enhances implant alignment, potentially improving implant longevity and patient satisfaction.Stryker Mako Total Hip Arthroplasty SystemThe Stryker Mako total hip arthroplasty system (Stryker) is tailored specifically for total hip arthroplasty. It provides a combination of 3D preoperative planning and robotic arm assistance during surgery. Surgeons benefit from real-time feedback, facilitating accurate acetabular cup positioning and leg length restoration. This system combines preoperative planning with intraoperative robotic assistance. Surgeons use a handheld robotic arm to prepare the acetabulum and place the cup precisely. Real-time feedback ensures accurate leg length restoration and hip offset, minimizing complications.RAS (Robotic Arm System) in Spine SurgeryRAS systems  are designed to enhance the accuracy of pedicle screw placement in spine surgeries. They utilize advanced imaging and robotic arms to guide surgeons in complex procedures, reducing the risk of nerve injury and revision surgeries. RAS employs advanced imaging and navigation to guide robotic arms for pedicle screw placement. Surgeons create a preoperative plan, and the robotic arm assists in accurate trajectory execution. This reduces radiation exposure, enhances accuracy, and potentially reduces revision surgeries.TM Robotic Guidance SystemMAZOR X Stealth EditionThe MAZOR X Stealth\u2122 Edition robotic guidance system  offers both preoperative and intraoperative planning capabilities. With features like customizable implant options, optimal trajectories for implants, and advanced 3D analytics, this planning functionality empowers surgeons to enhance construct optimization and achieve a more predictable surgical procedure. The foundation of robotic precision lies in cutting-edge registration and mechanical stability. The MAZOR X\u2122 platform establishes a closed-loop connection between the robotic arm mounted on the operating table, the securely positioned patient, and a rigid link between the robot and the patient's skeletal structure. This robotic system is table-mounted, optimizing the operating room space while ensuring unparalleled precision. The Stealth\u2122 Navigation technology provides real-time visualization of implant placement within the patient's anatomy, aligning with the pre-operative plan. By seamlessly integrating two guidance technologies into a comprehensive platform, surgeons can confidently execute procedures during surgery, effectively bridging the gap between planning and execution. The navigation feature offers the visibility required to complete the surgical plan. With an accuracy rate of up to 100%, the MAZOR X Stealth\u2122 Edition ensures precise screw placement.Precision redefinedAmong the most compelling contributions of robotics to orthopedics is its capacity to elevate surgical precision. Conventional surgical techniques often hinge on the surgeon's manual dexterity, leaving room for inadvertent errors. Robotic systems, fortified with advanced imaging and real-time feedback mechanisms, empower surgeons to meticulously plan and execute procedures with a degree of accuracy measured in sub-millimeters . This lePersonalized treatment plansIntroducing robotics in orthopedic surgery marks a revolutionary phase in tailored treatment plans. Robotic systems enable surgeons to intricately strategize procedures that cater to each patient's unique anatomical characteristics . This hiMinimally invasive proceduresRobotics has been instrumental in fostering the proliferation of minimally invasive procedures within orthopedics . ConventAdvantages of robotic systems in orthopedicsThe following are the advantages of\u00a0robotic systems in orthopedics.Enhanced precision: Robotic systems offer unmatched precision and accuracy in executing surgical tasks, leading to improved implant alignment and surgical outcomes.Personalized treatment: Robotic platforms allow for the customization of surgical procedures based on each patient's unique anatomy, potentially reducing complications and improving long-term outcomes.Minimized tissue trauma: Robotic-assisted procedures often require smaller incisions and result in less disruption to surrounding tissues, leading to reduced postoperative pain and faster recovery times.Improved implant placement: Robotic systems enable precise implant positioning, potentially increasing implant longevity and patient satisfaction.Real-time feedback: Many robotic platforms provide real-time feedback to surgeons during procedures, allowing for adjustments and ensuring optimal outcomes.Complex maneuvers: Robotic arms can execute complex maneuvers that might be challenging for a human hand, enhancing the surgeon's capabilities.Reduced radiation exposure: In procedures such as spine surgery, robotics can reduce the need for fluoroscopy, leading to lower radiation exposure for both patients and surgical staff.Disadvantages of robotic systems in orthopedicsThe following are the disadvantages of\u00a0robotic systems in orthopedics.High initial costs: Robotic systems require substantial investments in terms of equipment and training, potentially increasing the overall cost of procedures.Learning curve: Surgeons need to undergo specialized training to operate robotic systems effectively, and the learning curve can initially extend procedure times.Limited flexibility: Robotic systems follow preplanned trajectories, which might limit the surgeon's ability to make spontaneous adjustments during the procedure.Dependency on technology: Technical malfunctions or software glitches could interrupt surgeries or lead to suboptimal outcomes, highlighting the system's reliance on technology.Time-consuming setup: Setting up the robotic system and registering patient data can add time to the overall surgical process, especially during the learning phase.Complexity of integration: Integrating robotic systems into existing surgical workflows might be challenging and require adjustments in hospital processes.Ongoing maintenance and costs: Beyond the initial investment, robotic systems require maintenance, software updates, and potential hardware upgrades, leading to ongoing costs.Surgeon-support collaborationA fundamental tenet of understanding robotics in orthopedics is that it augments, rather than supplants, the role of surgeons. Robotic systems are invaluable tools, furnishing real-time insights, haptic feedback, and unparalleled visualization during procedures. Surgeons retain complete control while benefiting from the precision and data-driven guidance offered by the robotic platform . This coPostoperative rehabilitationThe impact of robotics resonates beyond the confines of the operating room, extending to the rehabilitation phase. Robotics-assisted rehabilitation devices, including exoskeletons and motion-capture systems, are revolutionizing how patients regain mobility and strength after orthopedic procedures . These dChallenges and ethical considerationsWhile integrating robotics into orthopedic healthcare holds great promise, it concurrently presents challenges and ethical considerations. The initial expenses associated with procuring and implementing robotic systems can be substantial, engendering concerns about accessibility and healthcare inequities. Furthermore, specialized training to proficiently operate these systems necessitates ongoing education and skill development investments. Ethical dilemmas arise in cases where the equilibrium between human expertise and robotic assistance is at issue. Striking the right balance between surgeon intervention and robotic autonomy necessitates meticulous deliberation. The focus should invariably remain on safeguarding patients\u2019 well-being and ensuring that the benefits of automated technologies outweigh any potential risks.The path aheadAs the realm of robotics in orthopedic healthcare continues its expansion, a proactive and visionary approach is indispensable. Collaborative endeavors involving engineers, medical practitioners, and regulatory authorities are pivotal in refining existing technologies and conceiving novel solutions that cater to the evolving needs of patients. Investments in research and development will be instrumental in fostering innovation, thereby propelling the creation of even more sophisticated robotic systems capable of redefining the boundaries of orthopedic care.Integrating robotics into orthopedic healthcare marks a watershed moment in the medical arena. Its precision, personalization, and minimally invasive approach reshape the landscape of orthopedic procedures, offering patients renewed hope and an enhanced quality of life. As the medical community, policymakers, and technology innovators navigate the challenges and ethical considerations, the collective responsibility lies in shaping a future where robotics and human expertise harmoniously converge, redefining the horizons of orthopedic healthcare. With each surgical procedure and rehabilitation session, robotics propels us closer to a world where musculoskeletal conditions are not merely treated but unequivocally conquered."}
+{"text": "To describe clinical features and the course of a case of non-necrotizing herpetic retinitis secondary to Varicella zoster virus (VZV).A single case report documented with multimodal imaging.A 52-year-old female patient with a past medical history of diabetes mellitus who presented with painful red right eye (OD). Ophthalmic examination showed perilimbal conjunctival nodule, granulomatous anterior uveitis, sectoral iris atrophy and increased intraocular pressure. Fundus examination in OD revealed posterior multifocal retinitis. Left eye examination was unremarkable. Polymerase chain reaction (PCR) of aqueous humor sample confirmed the presence of VZV DNA. Systemic antiviral therapy allowed the improvement of intraocular inflammation and disappearance of the retinal non necrotizing retinitis after one year of regular follow-up.Non-necrotizing retinitis is an underdiagnosed form of VZV ocular infection. Herpesviridae are common worldwide. Among the spectrum of viral retinitis, acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN), and Cytomegalovirus (CMV) retinitis are the most severe and sight threatening viral infections [Viral infections due to fections . Besidesfections . The purA 52-year-old female with a past medical history of diabetes mellitus, presented with progressive pain, redness and vision loss of the right eye (OD). Her best corrected visual acuity (BCVA) in OD was 20/200 and 20/20 in the left eye (OS). Anterior segment examination of OD showed a perilimbal nodular conjunctival lesion, granulomatous anterior uveitis with sectoral iris atrophy Fig.\u00a0. IntraocCase reports of NNHR have been described in five patients with positive test results for HSV or VZV in AH who had non-necrotizing retinitis consisting mainly of vasculitis, papillitis, or vitritis . Other cPCR was shown to be a powerful technique that allows detection of small quantities of DNA and RNA in ocular fluids. Various infectious agents can be detected with high specificity and sensitivity, including viruses. Results of PCR analysis of ocular fluids, being available within 24 to 48\u00a0h, have greatly improved the diagnosis of ocular viral infections, particularly those caused by human herpesviruses. AH analysis was contributory in 86.4% of patients with necrotizing viral retinopathies . BodaghiThe viral retinitis described in our patient is different from most cases of atypical viral retinitis reported in the literature, but resembles the cases reported by Hazirolan et al., with retinal lesions that are smaller and focally situated at the posterior pole without progression with antiviral treatment .The underlying reason for the variable clinical manifestations and severity of herpetic posterior uveitis is unknown but could be, in addition to pathogen-related factors, influenced by the variation in patients\u2019 immune capacity. Bodaghi et al. hypothesized that necrotizing herpetic retinitis were due to an intracellular presence of the virus with subsequent cytopathic damage, whereas the NNHR were assumed to be associated with tissue damage based on immunological processes . WensingHazirolan et al. suggested that viral retinopathies might constitute a continuous spectrum of diseases, which clinical presentations depend on the patient\u2019s immune status. Our patient, as well as theirs, with focal posterior non-necrotizing viral retinitis may be located at the starting point of the spectrum of herpetic retinopathies and constitute the mildest form of the disease . HoweverA remission was obtained in all cases after reaching the proper etiological diagnosis and initiating antiviral treatment. Oral acyclovir is mostly used for 6\u00a0weeks , but thiAlbert et al. reported several recurrences after arrest of antiviral treatment, it was the first case of anterior uveitis recurrence after NNHR described in the literature . Long-stFuture studies including a larger number of NNHR patients could reveal characteristics we were unable to identify here. The differential diagnosis of atypical viral retinitis is difficult clinically as it can mimic various other retinal conditions. In agreement with the previous studies, we propose viral analysis of ocular fluids in patients with retinitis, even in the absence of retinal necrosis, before initiation of immunomodulatory therapy and/or in those patients whose symptoms worsen while undergoing immunomodulatory treatments.Varicella zoster virus can cause a wide spectrum of clinical manifestations ranging from severe ARN to slow-progressing necrotizing and non-necrotizing types of inflammation. Non-necrotizing herpetic retinitis are currently underdiagnosed. PCR analysis of ocular fluids along with multimodal imaging could contribute to the confirmation and thus an earlier recognition of the diagnosis and the initiation of appropriate therapy."}
+{"text": "A review exploring biological, chemical, and physiological processes that occur between aboveground plant components and belowground (rhizosphere) networks that may be altered due to waterlogged conditions. Above- and belowground linkages are responsible for some of the most important ecosystem processes in unmanaged terrestrial systems including net primary production, decomposition, and carbon sequestration. Global change biology is currently altering above- and belowground interactions, reducing ecosystem services provided by natural systems. Less is known regarding how above- and belowground linkages impact climate resilience, especially in intentionally managed cropping systems. Waterlogged or flooded conditions will continue to increase across the Midwestern USA due to climate change. The objective of this paper is to explore what is currently known regarding above- and belowground linkages and how they impact biological, biochemical, and physiological processes in systems experiencing waterlogged conditions. We also identify key above- and belowground processes that are critical for climate resilience in Midwestern cropping systems by exploring various interactions that occur within unmanaged landscapes. Above- and belowground interactions that support plant growth and development, foster multi-trophic-level interactions, and stimulate balanced nutrient cycling are critical for crops experiencing waterlogged conditions. Moreover, incorporating ecological principles such as increasing plant diversity by incorporating crop rotations and adaptive management via delayed planting dates and adjustments in nutrient management will be critical for fostering climate resilience in row-crop agriculture moving forward. Above- and belowground linkages have long been identified as critical for numerous ecological processes in both natural and managed systems . The mosGlobal change biology influences above- and belowground interactions, altering chemical, biological, and physiological processes and overall plant survival in natural landscapes. Climate stress can drastically alter biogeochemical cycles due to shifts in biomass allocation, whereby plants often allocate more resources belowground . From a 2 of land globally  had a greater rate of mycorrhizal colonization, greater alkaline phosphomonoesterase-producing bacteria, and greater overall abundance of bacterivorous nematodes relative to the native species in a mixed polyculture community. This demonstrates that invasives are able to exploit available nutrients by fostering bacteria\u2013nematode interactions more efficiently than their counterpart native species. As climatic extremes such as flooding and drought increase, exploitation of resources and alteration of chemical and biological processes by invasive species will only continue , though the degree of the flooding effect was greater for some taxa than others suggesting variability in their tolerance levels  . Successful weed control in corn was determined to need 5\u201310 cm precipitation within 15 d of application to effectively incorporate herbicides and facilitate \u00aduptake by weeds  or winter barley (Hordeum vulgare) should be considered. These crops will all be in the ground with living roots during the winter months prior to any extreme precipitation that might impact the growing season. Small-seeded brassica species such as camelina, carinata, and most recently oilseed pennycress may also have utility as a winter annual option. Inclusion of these species into rotations with altered growth habits, nutritional content, and low C:N components may further influence above- and belowground cycling dynamics. Extending crop rotations and including three or more species often enhances soil C accumulation  has been developed and marketed as Perennial Kernza\u00ae. Kernza has been shown to drastically reduce nitrate leaching and improve soil health . The goal of perennial grain production is to develop a crop that can compete with annual crops but delivers ecosystem services like perennials found in nature due to deep and extensive root systems. For example, intermediate wheatgrass , though it is unclear ultimately how or when these webs will begin to stabilize and what the ultimate influence will be on the ecosystem. Species shifts in weed populations are anticipated, and existing methods for control may be less effective under extreme weather conditions. Adaptive management in row-crop agriculture, including increased biodiversity and perenniality that bolsters trophic interactions and nutrient balance, will be critical within flooded agroecosystems to mitigate the level of destabilization that is anticipated. Furthermore, we have demonstrated major areas in research especially in regard to rhizosphere processes, including plant\u2013microbe interactions that may foster climate resilience within cropping systems. More research addressing both above- and belowground responses to flooded conditions and how these influences crop productivity and ecosystem function within agroecosystems is needed. Lastly, breeders should consider above- and belowground linkages when identifying key traits for flood-tolerant cultivars."}
+{"text": "Nature depicted the genomic differences between late-stage treated metastatic cancers and early-stage untreated primary cancers via a pan-cancer whole-genome sequencing (WGS) analysis.1 This study characterizes unique features of metastatic solid tumors and provides a valuable resource for further investigating tumor evolution and treatment resistance.Recently, a study by Edwin Cuppen\u2019s group published in 2 about 90% of cancer-related death can be attributed to advanced metastatic diseases, and unfortunately, most are incurable by aggressive treatment regimes.3 Therefore, it is important to identify genome differences between metastatic and primary tumors and evaluate their influence on treatment resistance. This may help in understanding and leveraging therapeutic interventions, thus to create more effective therapeutic regimens. The study by Edwin Cuppen and colleagues established a harmonized WGS dataset of 7108 tumor samples from 71 cancer types, including more than 4700 metastatic cancer samples from Hartwig Medical Foundation (Hartwig) dataset and more than 2300 untreated primary cancer samples from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium , including single-base substitutions (SBSs), double-base substitutions (DBSs) and indels (IDs). This result indicates that TMB does not inevitably reflect the status of cancer progression, and the entire mutation spectrums are formed before or during primary cancer progression. Further comparison of mutational process activity revealed the existence of exogenous (such as exposure to platinum or radiation-based treatments) and endogenous (such as increase in APOBEC and SBS1 mutation burden) mutational processes that generate TMB differences. By investigating the divergence of SBS1 mutation burden in detail, the authors revealed a highly cancer type-specific SBS1 mutation burden per age. The majority of tumor types showed a prominent enrichment of SBS1 mutations along with age in both primary and metastatic lesions, however, 4 cancer types  only displayed increased SBS1 mutation burdens in metastatic cohorts in an age-independent manner.Compared with TMB, an elevated frequency of structural variants (SVs) was noticed in most tumor types included in metastatic cohorts. The underlying genomic instability signatures linked to this phenomenon are TP53 alterations and genome ploidy, which exhibited significant pan-tumor correlations with duplications and deletions, thus likely to play an essential role in SV increase in metastatic cancers. In addition, the researchers found a modest overall increase of driver gene alterations in patients with metastatic cancers. The majority of genetic drivers enriched by cancer metastasis were tumor-type specific, including some well-known driver genes related to resistance to anticancer treatments, whereas 3 genetic drivers  exhibited significant enrichment in metastatic cohorts across various cancer types, suggesting that changes in such genes may promote invasiveness via interfering with tumorigenesis hallmarks of pan-cancer. When comparing therapeutically actionable variants for each type of cancer, the authors found that the metastatic cohort had an overall higher proportion of patients with such variants, although the distribution was highly cancer type specific.The presence of treatment-resistant genetic drivers in advanced cancers led the authors to identify therapeutically enriched drivers (TEDs) that were either treatment enriched or exclusively found in a treatment-specific and cancer type-specific manner. Ultimately, 61 TEDs related to 33 therapeutic groups were identified, and most top hits were well-established resistant drivers to anticancer treatments. Notably, TP53 alterations were found to be frequently relevant with multiple treatment resistances, indicating such variants are potential predictive markers for augmented cancer plasticity and aggressiveness instead of the resistance mechanism for a specific tumor type. Overall, TEDs could be found in 53% of patients in metastatic cohort. After excluding TEDs, the raw difference between primary and metastatic tumors will be reduced by 36% in the number of drivers per sample, suggesting that a significant portion of the metastatic-enriched drivers are very likely linked to anticancer treatment resistance.5 Despite the aforementioned contributions, this study was also limited by the usage of distinct laboratory workups and sequencing procedures for the tumor samples from different datasets and the finite sample sizes of some cancer cohorts. Therefore, it is important to enlarge cancer cohorts and further uniform sample collation and sequencing processes to facilitate and validate the present understanding of cancer development. Moreover, genomic alterations are unable to fully elucidate cancer metastasis and resistance, and using the information from tumor microenvironment and additional cancer omics will also be essential for further anatomizing and better understanding the underlying mechanisms.Taken together, this study confirmed previous findings observed in certain cancer types and provided novel biological insights into the unique characteristics of metastatic cancers and their genomic differences with primary tumors, such as low intratumor heterogeneity, high genomic instability and elevated SVs. Nevertheless, the extent of genetic differences between metastatic and primary cancers varied significantly across cancer types and was affected by anticancer treatment exposure. Among the 23 tumor types, breast, clear cell renal cell, thyroid, prostate and pancreatic neuroendocrine cancers showed strong transformation in genomic landscape in advanced stages. In addition, this study provides a valuable resource for further investigating other aspects of cancer progression, such as the study on genetic immune escape alterations between metastatic and primary cancers conducted also by Edwin Cuppen\u2019s group recently."}
+{"text": "Biomaterials offer numerous opportunities to preserve spheroid function and guide spheroid behavior by tailoring the local microenvironment.Spheroids are three-dimensional cell aggregates that mimic fundamental aspects of the native tissue microenvironment better than single cells, making them a promising platform for the study of tissue development and therapeutics. Spheroids have been investigated for decades as models in cancer research, yet we have only just scratched the surface of their potential clinical utility in cell-based therapies. Like many cells, spheroids commonly exhibit a loss of key attributes upon implantation, motivating the need for strategies to regulate their function  Systemic or localized injection of cells results in poor survival and inconsistent behavior due to the lack of instructional cues or aberrant signaling from the diseased microenvironment. As an alternative to monodisperse cells, spheroids are three-dimensional cell aggregates that retain key aspects of the cellular microenvironment including cell-cell interactions, engagement with an endogenous cell-secreted extracellular matrix (ECM), and gradients in signaling that result in heterogeneous nutrient distribution that better recapitulate native tissues. Furthermore, spheroids secrete substantially more endogenous trophic factors that promote neovascularization and influence the inflammatory microenvironment Biomaterials have an essential role in the development and application of spheroid-based technologies. Beyond materials-based approaches for spheroid formation, entrapment of spheroids in tunable biomaterials has emerged as a promising strategy to instruct spheroid function and differentiation and regulate cell migration from the spheroid into the surrounding tissues. The synergistic effects of biomaterial properties and spheroid signaling, although not fully understood, directly influence cytokine production, cell spreading and migration, viability, and differentiation. Thus, intelligent selection of a biomaterial is required and should be taken into consideration to instruct spheroid behavior and achieve the desired therapeutic effect.2Our group has predominantly studied spheroids formed of mesenchymal stromal cells (MSCs) to potentiate their secretion of regenerative trophic factors and guide their direct contributions to tissue formation. Spheroids of other cell types are under investigation, and key factors such as cell type and spheroid diameter are intrinsically related to their desired application. Nonetheless, the interplay of additional environmental cues can affect spheroid function and instruct behavior for specific applications. Spheroid function is regulated by the biophysical properties of the spheroid carrier material or entrapment of other components within the spheroid to guide cell function and differentiation.Spheroid function has been widely controlled by encapsulation in engineered hydrogels and controlling biophysical properties such as adhesivity, stiffness, and viscoelasticity. Alginate hydrogels covalently modified with cell-adhesive RGD (Arg-Gly-Asp) peptides are widely used as model systems and vehicles for cell transplantation. RGD-modification regulated cell adhesion, outgrowth, and tissue formation using MSC spheroids e.g., Yes-associated protein, YAP). These findings demonstrate the potential of cell-based materials to increase biomineralization without the need for exogenous osteoinductive cues or growth factors. Recent advances in macromolecular crowding approaches may open the door to improve growth factor retention and influence other relevant ECM properties such as protein content or fiber alignment Instructive materials can also be incorporated within the spheroid itself to guide cell function. As spheroids initially lack an endogenous ECM, our group formed spheroids with an engineered, MSC-secreted ECM to activate integrin signaling In many applications, it may be necessary to leverage biomaterials that provide structure or regulate spatial patterning to achieve desired tissue formation using spheroids. For example, silicon nanowires were applied to promote differentiation of human induced pluripotent stem cell spheroids (hiPSC) into hiPSC-derived cardiomyocytes for cardiac repair 32) that promote angiogenesis, modulate the inflammatory microenvironment, and stimulate wound repair, and MSC spheroids secrete more trophic factors than monodisperse MSCs. MSC spheroids entrapped in fibrin hydrogels with higher elastic moduli (\u223c45\u00a0kPa) secreted significantly more VEGF, while PGE2 secretion was greater for spheroids in softer gels (\u223c5\u00a0kPa) The MSC secretome is a potent collection of bioactive factors that stimulates host cell migration and tissue repair. MSCs secrete endogenous factors such as vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE4Spheroids have enormous promise for use as building blocks for tissue regeneration. Although initial applications injected spheroids into diseased tissues without supportive biomaterials, substantial evidence confirms the capacity for material-driven approaches to potentiate spheroid function. However, we have yet to create materials that accurately model the complex characteristics and behavior exhibited by many human tissues. The use of biomaterials that mimic the biophysical properties of native tissues will increase the therapeutic potential of spheroids in clinical applications.via ultrasound, light, or delivery of fast-reacting small molecules that rapidly stiffen or weaken the biomaterial. Just as spheroids better recapitulate native tissues by increasing complexity from conventional 2D culture systems, we must embrace the same logic of increased complexity and multilayer design when developing biomaterials. This is made more challenging by the need to maintain biocompatibility. Nonetheless, new materials will propel the effective instruction of cell spheroids and establish them as a powerful tool for regenerative medicine, drug discovery, and disease modeling (The development of biomaterials possessing gradients in stiffness, composition, and soluble cues that imitate the heterogeneity of native tissues is a step in the right direction. These attributes can be enabled by chemistries that facilitate non-invasive tunability modeling .Fig. 1BiThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests:J. Kent Leach reports financial support was provided by UC Davis Health System. David H. Ramos Rodriguez reports financial support was provided by UC Davis Health System."}
+{"text": "Neuroinflammation is a key secondary event after spinal cord injury (SCI) and can increase barriers to regeneration, leading to various neurological disorders. Infiltrated hematogenous innate immune cells into the injured site are considered the main effector cells of the inflammatory responses after SCI. Glucocorticoids were the standard of care for spinal cord trauma for years due to their anti-inflammatory properties yet were also associated with unwanted side effects. While the administration of glucocorticoids is controversial, immunomodulatory strategies that limit inflammatory responses provide the potential therapeutic approaches to promote functional regeneration following SCI. Herein, we will discuss emerging therapeutic strategies to modulate inflammatory responses to enhance nerve recovery after spinal cord trauma. Traumatic Spinal Cord Injury (SCI) results in an initial primary injury, followed by secondary events including ischemia, anoxia, and excitotoxicity for the first minutes, hours, and days after injury \u20134. As a Various gene therapy-based approaches have been introduced in the last twenty years and continue to be utilized as a powerful therapeutic approach to alter or correct defective genes for the treatment of multiple diseases ,13. WhilNanomedicine employing polymeric nanoparticle (NP) has received significant attention due to its inherent therapeutic potential to modulate immune responses to cure inflammatory responses-mediated disorders including SCI \u201322. PrevStem cells can proliferate and differentiate into any cell type present in the body. Considering their therapeutic potential and abilities of self-renewal and differentiation, stem cells are widely used following SCI ,32. In aImmunotherapeutic approaches for the treatment of SCI have the capacity to indirectly and/or directly enhance functional recovery. Although many preclinical studies have demonstrated therapeutic effects of immunomodulatory factors on SCI, the introduction of these strategies in the clinic faces various limitations for SCI victims. Further investigations will be required to assess how each of the immunomodulatory factors can be employed synergistically to reprogram the immune system to promote functional recovery after SCI while limiting life-threatening side effects."}
+{"text": "Background: Overall, ~12% of outpatient visits result in an antibiotic prescription, and 30% of those prescriptions are inappropriate. Behavioral nudges help influence practitioner behavior. We hypothesized that peer comparison combined with a behavioral nudge  would influence prescribers to reduce antibiotic prescriptions and improve antimicrobial stewardship in the outpatient setting. We pilot-tested this intervention in outpatient primary care clinics associated with a large Veterans Affairs (VA) medical center. Methods: We conducted a clustered randomized controlled trial of 12 community-based outpatient clinics. All practitioners in the intervention arm received quarterly comparative feedback reports and, when indicated, quarterly patient alert letters. Comparative feedback reports gave personalized feedback about antibiotic prescriptions for upper respiratory tract infections, comparing the recipient\u2019s antibiotic prescriptions to the average for all practitioners at the primary care clinics included in our study. Patient alert letters notified practitioners to patients in their panel with recently detected Clostridioides difficile or resistant organism and their antibiotic exposures. We assessed outpatient visits during the preintervention period (April\u2013September 2020), the intervention period (October 2020\u2013September 2021), and the postintervention period (October 2021\u2013September 2022). A mixed-effects logistic regression model predicting antibiotic prescriptions compared the arms across these periods. Results: The outpatient populations observed in the intervention and control arms were similar during each phase of the study. Prior to the intervention, the average proportion of visits with an antibiotic prescription was lower among clinics in the intervention arm . This difference broadened slightly during the intervention period  and the postintervention period  . Throughout the study, clinics in the intervention arm typically used more doxycycline and azithromycin and less amoxicillin-clavulanate and sulfamethoxazole-trimethoprim compared to clinics in the control arm. . In the 6-month preintervention period, which coincided with the early phase of the COVID-19 pandemic, antibiotic prescriptions in the intervention compared to control clinics were similar. During the intervention and postintervention periods, the proportion of visits with an antibiotic prescription remained steady for clinics in the intervention arm and increased for those in the control arm. These results suggest that this pilot study using a low-intensity intervention consisting of comparative feedback reports and patient alert letters was successful in influencing the antibiotic prescribing behavior of primary care clinicians practicing in community-based outpatient clinics affiliated with a VA medical center.Financial support: This study was funded by Merck.Disclosures: None"}
+{"text": "Cervical cancer is the fourth-leading cause of cancer incidence and death among females according to Global Cancer Statistics 2018.This video demonstrates the fertility-sparing surgery procedure containing radical trachelectomy and pelvic lymphadenectomy with bilateral ascending branches of uterine arteries preservation. The patient was a 34-year-old woman diagnosed with International Federation of Gynecology and Obstetrics stage IB1 moderately differentiated squamous cervical cancer who expressed a strong desire for reproduction. After sufficient consultation, she decided to receive a fertility-sparing treatment protocol. This video highlights the feasibility of sufficiently dissecting paracervical structures and exposing uterine artery branches with complex procedures and no assistance via TU-LESS. We adopted a simplified uterine manipulator, which minimized the squeezing and injury to the cervix, to assist exposure of the surgical field. Resection of the cervix was accomplished transvaginally with a cold knife to ensure sufficient margin. Pathology examination of surgical margin, lymph node specimens, and lymphovascular invasion were negative. The umbilical incision was closed by Zheng\u2019s anchor suturing technique to prevent incisional complications and improve cosmetics.Minimally invasive surgery is safe and effective for fertility-sparing without compromising oncologic outcomes, especially in patients with a tumor size <2\u2009cm."}
+{"text": "Bipolar patients (BP) frequently have cognitive deficits, that impact on prognosis and quality of life. Finding biomarkers for this condition is essential to improve patients\u2019 healthcare. Given the association between cognitive dysfunctions and structural brain abnormalities, we used a machine learning approach to identify patients with cognitive deficits.The aim of this study was to assess if structural neuroimaging data could identify patients with cognitive impairments in several domains using a machine learning framework.Diffusion tensor imaging and T1-weighted images of 150 BP were acquired and both grey matter voxel-based morphometry (VBM) and tract-based white matter fractional anisotropy (FA) measures were extracted. Support vector machine (SVM) models were trained through a 10-fold nested cross-validation with subsampling. VBM and FA maps were entered separately and in combination as input features to discriminate BP with and without deficits in six cognitive domains, assessed through the Brief Assessment of Cognition in Schizophrenia.The best classification performance for each cognitive domain is illustrated in Table 1. FA was the most relevant neuroimaging modality for the prediction of verbal memory, verbal fluency, and executive functions deficits, whereas VBM was more predictive for working memory and motor speed domains.Overall, the tested SVM models showed a good predictive performance. Although only partially, our results suggest that different structural neuroimaging data can predict cognitive deficits in BP with accuracy higher than chance level. Unexpectedly, only for the attention and processing speed domain the best model was obtained combining the structural features. Future research may promote data fusion methods to develop better predictive models.None Declared"}
+{"text": "Sickle cell disease (SCD) is a prevalent inherited hemoglobin disorder encompassing a cluster of congenital hemolytic anemias, each distinguished by the prevalence of sickle hemoglobin (HbS) . Anemia,Numerous novel agents are currently undergoing clinical development or have been introduced into clinical practice. In addition, the attempts to reduce long-term complications and enhance quality of life continue. This Special Issue aims to delineate both our current understanding and future options in SCD. All articles submitted to this Special Issue underwent a meticulous peer review process. Ultimately, two articles, two brief reports and one review were published. These five manuscripts are discussed below.(i)Forte and colleagues provided important data on the timely issue of COVID-19 and SCD, updating outcomes after two years of the pandemic .(ii)Tsitsikas and colleagues presented the rate of dental extractions in SCD, providing up-to-date knowledge on an understudied complication .(iii)Biswas and colleagues reviewed the role of mitochondria as an emerging consequential in SCD, highlighting pathophysiological and therapeutic challenges .(iv)Kuo and colleagues reported that thromboprophylaxis reduced venous thromboembolism in SCD patients with central venous access devices, studying a large retrospective cohort .(v)Gavriilaki and colleagues studied the immune response of adult SCD patients after their vaccination against COVID-19, providing the experience of a Greek center.Considering the multi-faceted challenges of SCD, we hope that this Special Issue will inspire researchers and clinicians to continue their explorations into novel advances in this field ."}
+{"text": "Artificial intelligence (AI) algorithms have been applied in abundant medical tasks with high accuracy and efficiency. Physicians can improve their diagnostic efficiency with the assistance of AI techniques for improving the subsequent personalized treatment and surveillance. AI algorithms fundamentally capture data, identify underlying patterns, achieve preset endpoints, and provide decisions and predictions about real-world events with working principles of machine learning and deep learning. AI algorithms with sufficient graphic processing unit power have been demonstrated to provide timely diagnostic references based on preliminary training of large amounts of clinical and imaging data. The sample size issue is an inevitable challenge for pediatric oncology considering its low morbidity and individual heterogeneity. However, this problem may be solved in the near future considering the exponential advancements of AI algorithms technically to decrease the dependence of AI operation on the amount of data sets and the efficiency of computing power. For instance, it could be a feasible solution by shifting convolutional neural networks (CNNs) from adults and sharing CNN algorithms across multiple institutions besides original data. The present review provides important insights into emerging AI applications for the diagnosis of pediatric oncology by systematically overviewing of up-to-date literature. The exponentially growing knowledge and techniques have explored innovative perspectives for multi-layered diagnoses in pediatric oncology that the expectation of patients and their families have been developed for their specific situation to receive optimized care instantly and comprehensively. Artificial intelligence (AI) strategies can tackle enormous amounts of original data in a short time to solve complex tasks with high accuracy , 2. PhysAI has developed into various computer-assisted theories and is mainly implemented with working principles of machine learning (ML) and deep learning (DL). AI algorithms fundamentally capture data, identify underlying patterns, achieve preset endpoints, and provide decisions and predictions about real-world events. ML, as a main subset of AI, indicates a different flowchart compared with traditional hard-coded software programs which apply algorithms to construct predictive models dynamically by training large amounts of historical data. DL, as a growing aspect of AI, represents benefits in learnable weights and high efficiency with minimal pre-processing based on the structure of convolutional neural networks (CNNs) with multiple inter-connected layers. DL-CNNs composed of multiple stacked CNN layers have advantages in accurate, faster, vendor-independent processing compared with ML algorithms applied previously . NotablyThe application of AI not only makes full use of the various aspects of clinical diversity but also helps to address the current lack of objectivity and universality in expert systems . The appDespite the current AI advancements, the sustainable development of health AI tools relies on the availability of large datasets with strict quality control . SeveralThe prosperous development of AI techniques promotes numerous potential applications in pediatric oncology with two main bottlenecks for successful utilities, including the need for large data entry and a strong graphic processing unit (GPU) with appropriate computer and memory power. AI algorithms provide timely references based on large amounts of clinical and imaging data and sufficient GPU power . MeanwhiClinicians make clinical diagnoses depending on their professional knowledge and clinical experience through signs, symptoms, laboratory, and imaging examinations. It seems hard to guarantee diagnostic accuracy and consistency by dealing with abundant and multidimensional data from the human brain. The AI algorithms have advantages in learning and training vast amounts of data and integrating it into a certain outcome in a very short time, which allows efficiency and effectiveness of computer-aided diagnosis (CAD) in clinical practices. DL algorithms have recently made significant progress in extracting and processing information from medical images, which have been applied in various medical tasks extensively not only in radiology and pathology with satisfactory performance comparable to or even superior to that of human experts. Notably, DL algorithms could identify underlying information from medical images associated with tumor diagnosis . The AI A performance comparison of diagnosis in pediatric hematological malignancies using AI strategies is shown in A performance comparison of diagnosis in pediatric intracranial tumors using AI strategies is shown in versus non-tumor/hemorrhagic and classify subtypes of brain tumors.Attallah , 43 propversus benign diseases [AI techniques have been applied in the diagnosis of pediatric extracranial tumors, mainly including soft-tissue and bone tumors . For bondiseases , 54. TheZhang et al.  and FranAI-based principles have been used for the detection and segmentation of pediatric malignant tumors. For example, Wu et al.  used a rH3 K27M amplification status in children with midline glioma with significantly greater accuracy ranging from 0.788 to 0.867 than prediction by chance. Giwa et al. [The AI algorithms have represented strengths in detecting tumor patterns by identifying underlying genetic and molecular characteristics associated with specific macroscopic tumor features based on medical images and/or high-throughput data. Zhao et al.  reporteda et al.  applied The application of AI technology faces some important challenges that must be resolved to ensure its use in pediatric cancer diagnosis . For exaAI techniques have revolutionized the diagnostic field of oncology. Although AI approaches have been widely implemented in adult tumors, specialized applications of AI algorithms in childhood cancer are still limited probably attributed to the insufficient amounts of available data sets. There are limited opportunities to transfer well-trained CNN architectures built on adults into pediatric oncology few CNNs are directly generalizable from adults to children. Therefore, it\u2019s warranted urgently to develop dedicated AI algorithms applied in pediatric oncology. Although the data sets of pediatric oncology are not large enough to perform standardized DL analysis in medical imaging , the int"}
+{"text": "The purpose of this report is to provide a comprehensive account of an exceptional case involving the presentation of congenital rubella syndrome (CRS) in a newborn. Furthermore, it aims to document the successful regression of CRS through medical treatment alone. We present the case of a five-day-old infant who was referred to our facility as a CRS case. The patient presented with bilateral white corneal opacity, which was observed shortly after birth. The mother was diagnosed as rubella-positive during pregnancy. Upon the initial examination under anesthesia, both eyes exhibited central white corneal opacity accompanied by large intrastromal cysts. Although a few breaks in Descemet's membrane were observed in both eyes, there were no signs of vascularization or the presence of iridocorneal or lenticular-corneal adhesions. After undergoing medical treatment consisting of topical sodium chloride and steroids, the cysts in both eyes completely regressed. Subsequently, the patient underwent penetrating keratoplasty to further address the dense scar. This case enhances our comprehension of ophthalmological complications associated with CRS and provides valuable insights into alternative therapeutic approaches for corneal stromal cysts. Congenital rubella syndrome (CRS) is a prevalent congenital infection known for its wide range of severe ophthalmic and systemic complications . It typiA five-day-old male infant with a confirmed diagnosis of CRS was referred to our facility for examination due to the presence of white corneal opacification in both eyes. The patient's mother also had a confirmed diagnosis of reactive rubella during pregnancy. Upon the initial examination under anesthesia, both eyes exhibited central white corneal opacity along with large intrastromal cysts. Although a few breaks in the Descemet membrane were identified in both eyes, no signs of neovascularization or iridocorneal or lenticular-corneal adhesions were observed Figure . UltrasoCRS is a prevalent congenital infection characterized by various clinical manifestations, including heart defects, hearing impairments, and ophthalmological abnormalities . The mosIn conclusion, this case study brings attention to the infrequent presentation of corneal stromal cysts in a newborn with CRS, emphasizing the importance of identifying uncommon ophthalmological manifestations associated with CRS. The effective nonsurgical management of corneal stromal cysts demonstrates a noninvasive treatment option. This case contributes to a broader understanding of ophthalmological complications and provides valuable insights into alternative therapeutic approaches for corneal stromal cysts."}
+{"text": "The objective was to study clinical cases and understand the link betweencesarean section scar defect with hydrometra and secondary infertility. Aretrospective case series from an assisted reproductive center and infertilitytreatment clinic in the United Arab Emirates. We had five patients withsecondary infertility diagnosed with cesarean section scar defect withpersistent hydrometra based on high resolution transvaginal ultrasoundassessment. The patients underwent surgical repair for the cesarean section scardefect followed by infertility treatment. Transvaginal ultrasound examinationshowed a normal endometrial cavity with triple lining endometrium and absence ofhydrometra; and clinical pregnancy was the main outcome measure. Surgicalcorrection of cesarean section scar defect was successfully performed in thecases presented. The patients had their fertility restored. Clinical studiesrevealed that cesarean section scar defect may lead to abnormal uterinebleeding, dysmenorrhea, pre-/post-menstrual spotting, heavy or prolonged menses,pelvic pain and secondary infertility. Theoretically, an inflammatory response,such as a wound healing process in the uterus due to hydrometra associated withscar defect may impair embryo implantation. The clinical case studies presentedhere are based on the correct diagnosis of the cesarean section scar defect withhydrometra and its successful surgical repair. The patients in our study hadtheir symptoms resolved and attained clinical pregnancy. The number of cesarean sections (C-section) performed is steadily increasing acrossthe world .C-section scar defect can be visualized using transvaginal ultrasound andhysteroscopy . ThisfiThere are only a few studies on the clinical association between secondaryinfertility and C-section scar defect .Repair of C-section scar defect is done by using a minimally invasive surgical methodsuch as hysteroscopy or/and laparoscopy and vaginal procedures ; presented to Al Ain Fertility Centerbetween January 2016 and December 2020. Exclusion criteria:Infertility cases presented with C-section scar defect without hydrometra.Clinical characteristics of patients: all the patients were agedbetween 28 to 41 years who underwent surgical management for cesarean sectionscar defect with hydrometra to treat secondary infertility.Diagnosis: Symptoms related to cesarean section scar defect were reported. Clinical diagnoses were confirmed by transvaginalultrasound imaging. Surgical Treatment: All the surgicalprocedures were performed by hysteroscopy and laparoscopy as per explainedbelow: - Hysteroscopic resection: The uterine cavity isdistended using NaCl solution. Positive pressure is ensured with an automaticpressure infuser. The inferior and superior edges of the defect are resectedusing a cutting loop and coagulation is performed on the thinnest part of thescar  approval was obtainedbefore the beginning of the study. The data presented are with completeanonymity of published information and the images used are undernon-identifiable category (ultrasound). In addition, careful case-by-caseassessment was made to ensure that content is fully anonymous and presents norisk to confidentiality of the study participants.invitro fertilization (IVF) treatment under standard antagonistprotocol with preimplantation genetic testing , fluid-filled pouch at the scar site due to impaired woundhealing and thinning of the anterior uterine wall , dysmenorrhea, pelvic pain, postmenstrual spotting, adenomyosis,endometriosis, abscess formation, cesarean scar ectopic pregnancy, and infertility demonstrated that 80% of thepatients diagnosed with a C-section scar defect that had surgical treatments(hysteroscopic and laparoscopic isthmoplasty) became pregnant within 24 months anddelivered before 36 months of treatment. In cases of infertility treatment, thereproductive performance after the scar defect correction surgery shows theeffectiveness of the accurate diagnosis and treatment of patients using efficienttechniques , and when no normalendometrial lining can be visualized. Studies postulated various mechanisms by whichscar defect hydrometra may interfere with embryo implantation ("}
+{"text": "As previous studies have shown, indications of drugs adjudicated by these RCTs often get expanded m ensues .A combination of patient-specific factors very often acting wholly significant impact on ability to both adhere to and deal with consequences of rising medication counts in patients with CKD. These often take form of sub-optimal medication adherence, worsening cognitive impairment. The latter is both a factor of declining kidney function itself as well as incident on it due to overall frailty. These factors generally makes it challenging to manage medications in CKD patients.Potentially inappropriate medications maintain a bidirectional relationship with polypharmacy, and both share similar unwanted downstream consequences. Restricting the definitional threshold of polypharmacy in chronic kidney disease patients regardless of underlying primary etiology to only Kidney specific medications is key to reliably identifying patient cohorts for directed interventions. To compliment this, and additionally optimize the management of PIMs and polypharmacy in CKD patients, utility of established structural therapeutic frameworks such as pharmacotherapy optimization and or medication therapy management (MTM) may also prove invaluable long term."}
+{"text": "Scher,3 This additional risk is not only due to the association of perinatal inflammation with cerebral haemorrhage and white matter injury,4 but also to the neuronal toxicity of supra-physiological serum concentrations of interleukin-1 beta observed in this situation.5 Even in preterm children without severe neonatal brain injury, perinatal inflammation remains independently associated with decreased motor and social abilities at 30 months of corrected age.3Perinatal inflammation exposure represents an additional risk factor for impaired developmental trajectory in preterm infants.6 This identification is crucial to provide individualised early developmental intervention programmes for these infants. Such programmes have been shown to improve motor and cognitive outcomes in preterm children.7EEG is the primary tool for functional evaluation of brain activity in preterm infants hospitalised within the neonatal unit. Serial longitudinal EEG recordings before term age can accurately assess brain maturation in preterm infants, and identify infants with an unfavourable early developmental trajectory.8 Beyond the estimation of discontinuity and amplitude offered by aEEG evaluation, conventional multi-channel EEG provides key information about other network-based brain activity, such as synchrony, frequency, and reactivity.9 It also delivers crucial information on the dynamics of transient endogenous generators occurring through the complex process of brain maturation.9 The two studies included in our systematic review were limited to aEEG analysis and reported inconsistent findings associated with perinatal inflammation exposure.2 Nevertheless, perinatal inflammation led to a modification of EEG frequencies in most of the preclinical studies assessing its effect on foetal sheep EEG, underlying the importance of the quantitative analysis of conventional EEG in the assessment of early brain maturation.2We agree that amplitude-integrated EEG (aEEG) is currently a useful tool to supervise the brain activity of critically ill preterm infants hospitalised in neonatal units that do not have 24/7 access to conventional EEG. However, aEEG provides a limited assessment compared to conventional EEG, particularly in very preterm neonates who do not demonstrate distinguishable sleep-wake cycling before 29 weeks of gestational age.10Conventional multi-channel EEG is essential to assess brain maturation in preterm infants, especially in those exposed to additional developmental risk factors such as perinatal inflammation. The need for a specialist to apply and interpret conventional multi-channel EEG has often been seen as an impediment to its widespread use within the neonatal unit. However, rather than simplifying the process by utilising fewer channels with less information, we believe that modern engineering solutions will allow the widespread introduction of conventional multi-channel EEG in neonatal units. There have been tremendous recent advances in the development of quantitative analysis and machine learning to develop automated algorithms for conventional multi-channel EEG analysis; such automatisation will soon assist in the further introduction of conventional multi-channel EEG beyond specialist centres."}
+{"text": "Aim/ObjectiveWithin the dynamic healthcare technology landscape, this research aims to explore patient inquiries within outpatient clinics, elucidating the interplay between technology and healthcare intricacies. Building upon the initial intelligent guidance robot implementation shortcomings, this investigation seeks to enhance informatic robots with voice recognition technology. The objective is to analyze users' vocal patterns, discern age-associated vocal attributes, and facilitate age differentiation through subtle vocal nuances to enhance the efficacy of human-robot communication within outpatient clinical settings.MethodsThis investigation employs a multi-faceted approach. It leverages voice recognition technology to analyze users' vocal patterns. A diverse dataset of voice samples from various age groups was collected. Acoustic features encompassing pitch, formant frequencies, spectral characteristics, and vocal tract length are extracted from the audio samples. The Mel Filterbank and Mel-Frequency Cepstral Coefficients (MFCCs) are employed for speech and audio processing tasks alongside machine learning algorithms to assess and match vocal patterns to age-related traits.ResultsThe research reveals compelling outcomes. The incorporation of voice recognition technology contributes to a significant improvement in human-robot communication within outpatient clinical settings. Through accurate analysis of vocal patterns and age-related traits, informatic robots can differentiate age through nuanced verbal cues. This augmentation leads to enhanced contextual understanding and tailored responses, significantly advancing the efficiency of patient interactions with the robots.ConclusionIntegrating voice recognition technology into informatic robots presents a noteworthy advancement in outpatient clinic settings. By enabling age differentiation through vocal nuances, this augmentation enhances the precision and relevance of responses. The study contributes to the ongoing discourse on the dynamic evolution of healthcare technology, underscoring the complex synergy between technological progression and the intricate realities within healthcare infrastructure. As healthcare continues to metamorphose, the seamless integration of voice recognition technology marks a pivotal stride in optimizing human-robot communication and elevating patient care within outpatient settings. In recent years, the healthcare sector has witnessed significant advancements in technology integration, exemplified by the deployment of informatic robots across various medical settings. Notably, incorporating mobile intelligent guidance robots (IGRs) within outpatient clinics has emerged as a catalyst for enhancing operational efficiency, optimizing processes, and elevating patient experiences . These aIn 2021, we published a comprehensive assessment in Cureus, critically examining the initial implementation of IGRs within an outpatient clinic setting [To address inefficiencies such as frivolous inquiries and childlike interactions, this study involves augmenting the IGR with voice recognition technology. The primary objective of this augmentation is to analyze users' vocal patterns and discern age-related vocal characteristics, thereby enabling the differentiation of age through subtle vocal nuances. This process entails utilizing advanced voice analysis techniques and machine learning algorithms . This apVoice recognition operates on algorithms that evaluate vocal cadences and establish correlations with age-associated vocal attributes. It's crucial to acknowledge that while voice recognition technology possesses inherent limitations that may affect absolute accuracy, it grants the capability to approximate users' ages. By leveraging the IGR's proficiency in comprehending and analyzing conversational context, the robot can glean generational references and contextual cues, thereby facilitating an estimative boundary of the user's age range.Subsequently, in November 2022, an enhanced IGR equipped with voice recognition technology was deployed at the central lobby of an outpatient setting for 20 days, mirroring the temporal framework of the previous 2019 study. Following data accrual, the collected dataset underwent meticulous analysis, focusing on content accuracy and the frequency of successful human-robot interactions. This investigation relied on quantitative and comparative methodologies, comprehensively assessing user inquiries and data efficiencies post-upgrade. The research attempts to pinpoint areas amenable to refinement and offers strategic insights to guide future enhancements.In this study, 101,672 outpatient visits were documented throughout the designated study duration, resulting in 30,301 human-robot interactions transpiring within 20 days. Notably, within this extensive corpus, 22,423 interactions were classified as successful interactions, a criterion defined by the robot's provision of a relevant response to the inquiry presented. Acknowledging that the IGR could not respond to languages other than Mandarin Chinese and English due to inherent programming constraints is imperative. Furthermore, notable categories such as numerically focused queries, inquiries unrelated to the hospital context, childlike interactions, and nuisance inquiries were substantially minimized or systematically omitted from the recorded dataset.Quantitative data comparing the two distinct study periods is presented in Table Characterized by the continuous enhancement of system applications, Figure Compellingly, health triage-related inquiries and appointment issues emerge as the second and third most frequent themes within the top 10 questions. This observation carries implications that resonate with the existing healthcare framework within China. It mirrors the contemporary state of the healthcare landscape wherein the primary health system remains in a formative phase, accompanied by a noteworthy lack of coordination within the broader healthcare infrastructure. Simultaneously, appointment-related concerns underscore the challenges within the appointment scheduling process, potentially reflecting disparities in resource allocation and logistical intricacies.Drawing a comparative lens to the antecedent year 2019, Figure Nevertheless, amid this trajectory of advancement, latent challenges persist. Foremost among these challenges is the constraint of language selection. In a global healthcare landscape where linguistic diversity prevails, the current scope of our informatic robots remains predominantly confined to Mandarin Chinese and English. The necessity for an expanded linguistic horizon aligns with the multifaceted nature of patient demographics and the imperative of inclusivity within healthcare automation.The incorporation of voice recognition technology marks a significant milestone in the domain of informatic robots deployed in outpatient clinics. This innovative augmentation has yielded notable successes, particularly in improving patient-robot interactions. The capacity of voice recognition technology to analyze users' vocal patterns and identify age-related voice characteristics has effectively addressed a crucial communication challenge, facilitating a more tailored and efficient exchange of information between patients and robots . MoreoveOutpatient clinics consistently serve as crucial windows for patients seeking medical care. However, the introduction of informatic robots, while enhancing efficiency, potentially erodes the essential trust inherent in healthcare interactions . PatientMitigating these apprehensions necessitates comprehensive patient education initiatives . Such inBy equipping patients with relevant knowledge, the significance of the interaction is reinforced, reducing the likelihood of frivolous or childlike interactions . Design Future advancements include the integration of machine learning algorithms, which will support continuous learning from patient interactions, thereby refining responses and adapting to evolving patient needs . CarefulInformatic robots possess the potential to catalyze a transformative shift in outpatient clinics, optimizing efficiency and elevating patient care. However, the intricacies associated with their use require careful consideration . A harmoThe successful integration of voice recognition technology into informatic robots has delivered substantial benefits for patient-robot interactions within outpatient clinics. This technology is a promising step toward optimizing healthcare automation by enabling more accurate age differentiation, fostering personalized engagements, and contributing to a growing knowledge base. As the healthcare landscape evolves, voice recognition technology emerges as a cornerstone in the ongoing quest to refine patient care and enrich the human-robot interaction paradigm.In summary, the narrative surrounding the integration of informatic robots within outpatient clinics embarks on an evolutionary trajectory characterized by dynamic refinement. This narrative underscores the intricate nexus of technology and healthcare services, resonating with repercussions transcending societal and clinical paradigms. As progress is championed, the pursuit of enhancing the precision of patient inquiries resonates with overarching themes of technological amalgamation. Simultaneously, a steadfast commitment to embracing linguistic diversity epitomizes the ethos of inclusivity intrinsically linked to healthcare. Each advancement is an echelon of progress within this narrative, propelling unwavering dedication toward shaping a more nuanced and responsive healthcare future."}
+{"text": "Long-acting injectable antipsychotics (LAIAs) are currently the most effective alternative for patients with schizophrenia who exhibit poor adherence. LAIAs can lead the course of treatment with the potential to increase adherence in schizophrenia treatment.Present the results of a network metaanalysis on the comparative efficacy of LAIs in schizophrenia.Included trials of adults with schizophrenia compared the efficacy of LAI vs LAI or placebo through the Positive and Negative Syndrome Scale (PANSS). Efficacy was evaluated through the standarized mean differences (SMD) from baseline to endpoint in the PANSS total scores.Results from 15 studies reported usable results for PANSS score (five antipsychotics compared) are shown in Figure 1. In hierarchical order, haloperidol, aripiprazole, risperidone, and paliperidone reduced the PANSS score significantly more than other drugs.Image:Most LAIAs are equally efficient at reducing overall symptoms, and differences between individual LAIAs are non-significant.None Declared"}
+{"text": "New-generation vaccines and novel vaccinal strategies against infectious diseases of livestock, wild and companion animals\u201d highlights advances and innovations in animal vaccines.Vaccination against infectious disease is an invaluable tool to protect humans against severe morbidity and mortality. For this reason, significant advances in human vaccines have propelled the field of vaccinology forward. Emerging and neglected diseases still pose an important challenge ; fortunaTargeted delivery of oral vaccine antigens to aminopeptidase N (APN) protects pigs against pathogenic Escherichia coli challenge infection\u201d describes the complications of oral subunit vaccines and the significant hurdles in overcoming the barriers of the gastrointestinal tract, limiting their development and efficacy. However, by utilizing APN-specific antibody-antigen fusion constructs, researchers have demonstrated the induction of both mucosal and systemic immune responses in a piglet model of bacterial infection, providing a stepping stone toward the realization of an effective and protective oral subunit vaccine targeting APN. The manuscript by Souto et\u00a0al. provides data to support the development of a bivalent vaccine candidate to protect fish from viral hemorrhagic septicemia (VHS) and viral encephalopathy and retinopathy (VER), major threats in aquaculture. By modifying the genome of viral hemorrhagic septicemia virus (VHSV) and introducing an expression cassette encoding the protective antigen domain of nervous necrosis virus (NNV) capsid protein, the authors successfully demonstrated the safety, immunogenicity, and protective efficacy of the recombinant VHSVs (rVHSV) in trout and sole. These findings hold promise for the development of a valuable bivalent live attenuated vaccine for commercially valuable fish species. Anotherstudy assessed the immune responses in calves to vaccines targeting Mycobacterium avium subspecies paratuberculosis (MAP), a cause of chronic enteritis in ruminants. Here, the authors analyzed the immune response induced by truncated MAP antigens as a fusion either on protein particles or as a soluble recombinant MAP (rMAP) fusion protein and compared this to a commercial vaccine. The rMAP fusion protein vaccine displayed the strongest immune response and showed promise in providing protective immunity against MAP infection while avoiding interference with bovine tuberculosis diagnostic tests. In another article, the authors describe a promising vaccination strategy for East Coast fever, a prevalent bovine disease in Africa caused by Theileria parva. In this study, using a recombinant lumpy skin disease virus (LSDV), the authors engineered virus-like particles (VLPs) containing a modified form of the T. parva p67 surface antigen and the bovine leukemia virus (BLV) gag gene. Studies in mice demonstrated the vaccine\u2019s immunogenicity, showing higher antibody titers in the group vaccinated with the recombinant LSDV. This encouraging progress paves the way for further investigations and potential applications of this dual vaccine candidate in cattle. Using recombinant bovine herpesvirus (BHV)-4 expressing nonstructural protein 5 (NSP5) and M fusion protein of porcine reproductive and respiratory syndrome virus (PRRSV), a study suggested that a T cell response induced in recombinant viral vector primed pigs can help in reducing PRRSV-1\u2013associated tissue damage without reducing the viral load. A separate study explored the potential of an adenoviral-vectored Epigraph vaccine as a promising alternative to current Swine Influenza A Virus (IAV-S) vaccines. Their findings demonstrated encouraging results, with the vaccine inducing robust and durable antibody responses in vaccinated pigs, as well as significant protection against viral challenge 6 months after initial vaccination.Within this Research Topic, both original research and review articles are presented. The original article \u201cRecent advances in antigen targeting to antigen-presenting cells in veterinary medicine\u201d outlines the dynamic field of veterinary medicine, where the quest for innovative strategies to combat challenging diseases has gained considerable momentum. Notably, groundbreaking advancements in antigen targeting, with a particular focus on antigen-presenting cells such as dendritic cells, through the use of DC peptides and MHC-II, have emerged as a beacon of hope. Moreover, another review describes the complications of vaccination in wildlife animals. Prion diseases, such as chronic wasting disease (CWD), pose significant challenges due to their unique biology and potential zoonotic risks. Current efforts to manage CWD have been largely ineffective, emphasizing the need for new tools such as vaccines. Despite the hurdles of overcoming immune tolerance and vaccinating wild animals, progress has been made in identifying safe antigens and effective strategies for formulation and delivery, including oral delivery to wild cervids.To complement the original research outlined above, this Research Topic also delves into important questions regarding new vaccine strategies and considerations for future approaches in detailed reviews. \u201cImmune responses in the uterine mucosa: clues for vaccine development in pigs\u201d explores the pursuit of effective strategies, with intrauterine immunization emerging as a promising approach, aiming to elicit localized or systemic immunity that safeguards against potential threats. Finally, Type I interferons (IFNs-\u03b1/\u03b2) are vital components of the innate immune response against viral infections. However, viruses have developed clever strategies to evade the antiviral effects of IFNs, compromising the efficiency of the immune system and vaccines. Understanding these evasion mechanisms can pave the way for the development of innovative vaccines that counteract viral IFN antagonism and induce robust immune responses for enhanced protection against a wide range of pathogens. The review article \u201cReprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses\u201d explores advances in developing IFN antagonism-deficient viruses, their immune evasion, and attenuated phenotypes in natural host animal species.The intricate immune system of the upper reproductive tract (URT) serves a remarkable purpose: shielding against sexually transmitted pathogens while simultaneously embracing immune tolerance toward sperm and the developing fetus. The review \u201cThis Research Topic brings a diverse selection of topics outlining advances in the field of veterinary vaccinology. The importance of generating protective vaccines against disease in animals is critical to ensuring their health and wellness, thus favoring production systems and reducing zoonotic disease risk .BP: Writing \u2013 original draft, Writing \u2013 review & editing. RM-R: Writing \u2013 review & editing. ST: Writing \u2013 review & editing. CC: Writing \u2013 review & editing. DA: Writing \u2013 review & editing."}
+{"text": "Verticillium wilt (VW), Fusarium wilt (FW) and Root-knot nematode (RKN) are the main diseases affecting cotton production. However, many reported quantitative trait loci (QTLs) for cotton resistance have not been used for agricultural practices because of inconsistencies in the cotton genetic background. The integration of existing cotton genetic resources can facilitate the discovery of important genomic regions and candidate genes involved in disease resistance. Here, an improved and comprehensive meta-QTL analysis was conducted on 487 disease resistant QTLs from 31 studies in the last two decades. A consensus linkage map with genetic overall length of 3006.59\u00a0cM containing 8650 markers was constructed. A total of 28 Meta-QTLs (MQTLs) were discovered, among which nine MQTLs were identified as related to resistance to multiple diseases. Candidate genes were predicted based on public transcriptome data and enriched in pathways related to disease resistance. This study used a method based on the integration of Meta-QTL, known genes and transcriptomics to reveal major genomic regions and putative candidate genes for resistance to multiple diseases, providing a new basis for marker-assisted selection of high disease resistance in cotton breeding. Upland cotton , the most widely cultivated cotton species in the world, has excellent qualities, high yield and is widely adaptable .The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Large proportion of patients with ADHD experience sleep problems. Well conducted, good quality clinical research could identify non-pharmacological sleep improvement interventions that would benefit patients with ADHD and would inform evidence based guidelines for sleep management in ADHD.To conduct a novel meta-research assessment of available clinical trials in the field of light therapy and non\u2011pharmacological sleep improvement interventions for people with ADHD.Peer-reviewed publications of clinical trials were analysed. An advanced literature search strategy was performed in major medical databases, including EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials and PsycINFO. Available data at WHO-approved clinical trial registries were searched and linked to the published literature. Detailed methodological assessment of results was conducted using the Cochrane Risk of Bias Tool version 2.0 (ROB2), conflict of interest, spin and favourability of findings. Reduction in ADHD symptom severity and improvement of sleep quality served as primary outcomes for the efficacy analysis. Any adverse events were recorded. Statistical analysis of the primary outcomes was conducted by calculating standardised mean difference and transformed as necessary. Publication bias was evaluated with contour enhanced funnel plots and the trim-and-fill procedure, and by summarising unpublished trials.Analysed clinical trials often had a high risk of bias . The primary outcome interpretation and overall trial conclusions frequently favoured the trial intervention. Clinical trials showed an association between primary outcome effect size and interpretation, and risk of bias. Clinical research in this field faces many of the same challenges identified for complex interventions in mental health, such as small sample size, lack of funding and difficulties with blinding.Clinical research regarding light therapy and non\u2011pharmacological sleep improvement interventions for ADHD patients indicates safety and effectiveness but studies often lack methodological rigour.None Declared"}
+{"text": "In this critical analysis, we investigate the profound impact of natural disasters and pandemics on the care and adherence to treating diabetic retinopathy, a severe complication of diabetes requiring continuous monitoring and treatment to prevent vision loss. Our study also sheds light on the social and economic context of Puerto Rico, emphasizing recent emergency events that have exacerbated existing public health challenges. Through a comprehensive review of relevant literature from PubMed, Google Scholar, and the George Washington University Himmelfarb Health Sciences Library database, we identified 31 pertinent articles out of 45 evaluated, focusing on the effects of these crises on healthcare delivery, diabetic retinopathy screening, and treatment. The evidence strongly indicates that during such emergencies, barriers to healthcare escalate, leading to significant treatment delays and a reduction in diabetic retinopathy screening and diagnosis, ultimately resulting in deteriorated visual outcomes. Thus, our review underscores the urgent need for the development of effective emergency plans tailored specifically to diabetic retinopathy, particularly in Puerto Rico, where diabetes prevalence and its complications are notably higher. Such plans should not only incorporate established emergency measures but also harness emerging technological advances in the field of ophthalmology to ensure optimal preparedness for future pandemics and natural disasters. Diabetes, characterized by elevated blood glucose levels, poses a global health challenge with both macrovascular and microvascular complications. The incidence of diabetes is rising worldwide, affecting vulnerable populations, especially in disaster-prone regions . The IntThe prevalence of DR is escalating, especially in regions like North America and the Caribbean, with Puerto Rico experiencing a notable burden ,8. This Prior research underscores the exacerbation of diabetes and its complications in disaster settings ,12. DiabDR management revolves around prevention and progression control . While bThis critical analysis aims to elucidate the influence of natural disasters and pandemics on DR care and adherence to treatment. Moreover, it sheds light on Puerto Rico's recent public health challenges, magnified by its susceptibility to disasters . ThroughMaterials & methodsA comprehensive literature review was conducted to identify relevant publications on managing DR during pandemics or natural disasters worldwide. The study also aimed to identify recent public health challenges in Puerto Rico that may have affected the care of DR on the island during and after Hurricane Irma, Hurricane Maria, the 2019-2020 earthquakes, and the COVID-19 pandemic. Additionally, the research sought to assess the presence of diabetes emergency preparation procedures on the island. Furthermore, given the ongoing COVID-19 pandemic, the literature review explored suggested methods and new technological breakthroughs for managing DR.Literature searches were conducted using PubMed, Google Scholar, and the George Washington University Himmelfarb Health Sciences Library database. The search queries focused on terms related to DR, as it is the primary disease of interest in this critical analysis. Similarly, words related to disaster preparedness were included. The search terms used had \"diabetic retinopathy\" (\"retinopatia diab\u00e9tica\"), \"retinopathy\" (\"retinopatia\"), \"retina,\" \"diabetes,\" \"diabetic eye disease,\" \"diabetes mellitus,\" and \"diabetics\" (\"diab\u00e9ticos\"), along with \"disaster preparedness,\" \"emergency preparedness,\" \"natural disasters\" , \"hurricanes\" (\"huracanes\"), \"Hurricane Maria\" (\"Hurac\u00e1n Maria\"), \"Hurricane Irma\" (\"Hurac\u00e1n Irma\"), \"earthquakes\" (\"terremotos\"), \"pandemic\" (\"pandemia\"), \"covid,\" \"covid-19,\" and \"coronavirus.\" Additional terms such as \"prevalence\" , \"Puerto Rico,\" \"intravitreal injections,\" \"anti-vascular endothelial growth factor,\" and \"anti-VEGF\" were used to achieve specific aims.Appendix A provides a list of combinations of the search terms mentioned above. Studies included in the literature review were limited to those written in English or Spanish, available as free full-text, and published from 2017 onwards.ResultsThis study conducted an extensive literature review spanning the period from 2017 to 2022, with the aim of delving into the intricate dynamics between natural disasters, pandemics, and the provision of care for DR. A meticulous analysis of 24 relevant articles provided valuable insights into the challenges faced by DR patients during times of adversity, as depicted in Figure Remarkably, as highlighted in Table\u00a0Intriguingly, the literature appeared to have a significant gap in the specific domain of disaster preparedness strategies tailored to DR during natural disasters\u00a0, a pointThe synthesis of the literature convincingly underscores the susceptibility of DR care to the disruptions posed by natural disasters and pandemics. The aftermath of events like hurricanes and the ongoing COVID-19 pandemic has underscored challenges in timely care provision, leading to delays in vital interventions such as anti-VEGF injections and DR screenings. These delays can potentially worsen the prognosis of DR and heighten the risk of vision loss. Of significant note, the region of Puerto Rico, having endured multiple natural disasters in the past decade alongside the ongoing pandemic, is a vivid example of the disproportionate impact on individuals with chronic illnesses. These crises have laid bare shortcomings in the healthcare system and accentuated the pressing need for robust contingency plans to mitigate considerable health and visual consequences. It is imperative that such plans encompass both established emergency protocols and the integration of emerging technological advancements within the field of ophthalmology.Impact of Pandemics and Natural Disasters on Diabetic Retinopathy: Challenges and Preparedness StrategiesThe ramifications of pandemics and natural disasters on DR care have garnered significant attention within the medical community. This section synthesizes key findings from the literature, shedding light on the barriers encountered by DR patients during these emergency situations and proposing effective preparedness strategies to mitigate their impact.Barriers to care during the COVID-19 pandemic: The COVID-19 pandemic highlighted several barriers that disrupted the continuity of DR\u00a0care. As depicted in Table Impact of recent emergency situations in Puerto Rico: Existing healthcare challenges and socioeconomic factors amplified Puerto Rico's vulnerability to emergencies. Table Proposed pandemic and disaster preparedness plan for DR: To address the challenges highlighted by the impact of emergencies on DR care, a multifaceted preparedness plan is proposed. Table DiscussionThe prevalence of DR, a significant microvascular complication of diabetes mellitus, presents a formidable challenge due to its potential to cause vision impairment and blindness among working-age individuals. This condition is chiefly characterized by diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), necessitating timely intervention and vigilant monitoring . The conTo mitigate the repercussions of these care disruptions, ophthalmological institutions have outlined recommendations for managing intravitreal anti-VEGF injections during pandemics . These gTelemedicine has proven invaluable when conventional medical access is limited, as witnessed in situations like natural disasters and infectious disease outbreaks. The COVID-19 pandemic has expedited the adoption of telemedicine, enabling remote healthcare delivery through digital platforms. Ophthalmology has particularly benefited from this shift, leveraging advanced hardware, sophisticated software, and high-speed communication technologies to remotely diagnose and manage eye conditions ,28. The Teleophthalmology, mainly via portable devices, has the capacity to bridge accessibility gaps in remote and underserved communities. Research has demonstrated the feasibility of cost-effective DR screening tools utilizing smartphones and telemedicine, resulting in improved DR screening coverage in rural areas . FurtherIn addition to leveraging telemedicine, public health initiatives should prioritize infrastructure enhancements to bolster visual healthcare accessibility. Strengthening hospitals, medical facilities, and primary care clinics, ensuring consistent power supply and backup generators, improving provider communication, expanding the healthcare workforce, enhancing surveillance systems, and refining patient records are imperative. Special attention should be directed toward\u00a0high-risk groups, such as elderly individuals with chronic conditions and immobile patients . ExpandiCommunity pharmacists play a pivotal role in disaster preparedness and response, offering access to medications and healthcare services, thereby mitigating barriers to care . They caNational-level protocols should be established to ensure uninterrupted critical treatment schedules for DR patients. These protocols must recognize the debilitating nature of the disease and prioritize patients at high risk of DR-related blindness, exempting them from lockdown measures and ensuring their protection . SimilarThe COVID-19 pandemic has instigated transformative shifts in care delivery and spurred innovative standards in ophthalmic care. As the global population ages, the prevalence of DR and similar conditions will escalate, further straining healthcare services. In regions like Puerto Rico, where diabetes mellitus is highly prevalent, and healthcare infrastructure and resources might be less stable, swift integration of alternative care methods, such as telemedicine, is crucial to alleviate patient burden while ensuring essential disease management . TelemedFinally, developing an emergency contingency plan for DR management is essential to provide uninterrupted care during crises. Clinicians bear a moral and ethical responsibility to devise strategies to minimize treatment interruptions. Key elements of such a plan include maintaining a comprehensive database of DR patients and their demographics for guided medication distribution and personnel deployment, implementing backup power sources for electricity outages, ensuring access to electronic medical records, and refrigeration for temperature-sensitive medications. Adequate medication and supply reserves ahead of disasters and establishing post-disaster patient communication methods are also vital.It is essential to acknowledge the limitations of this study, including the absence of specific data on the intersection of DR and natural disasters, as well as the lack of tailored recommendations for the unique circumstances in Puerto Rico. However, this critical analysis aims to provide guidance to ophthalmologists in Puerto Rico for effectively managing DR patients during responses to hurricanes, earthquakes, and potential future pandemics like COVID-19. The findings should inspire collaborative efforts among scientists and stakeholders in Puerto Rico to address barriers hindering patient access to teleophthalmology services, especially during times of crisis.In conclusion, given the heightened risks posed by pandemics and natural disasters, developing a robust emergency plan for managing DR is imperative. This urgency is underscored by the heightened vulnerability of regions like Puerto Rico, where the prevalence of diabetes and its complications is substantial. An effective plan should encompass established emergency measures and embrace emerging technological advancements within the field of ophthalmology."}
+{"text": "Opioid use for perioperative pain management in burn patients is associated with a high risk of developing chronic opioid use. Ketamine is commonly used as an analgesic adjunct due to its opioid-sparing effects. The purpose of this study is to determine whether analgesia with adjunctive ketamine reduces the risk of developing chronic opioid use in burn patients.Burn patients who underwent burn-related surgeries were identified using relevant ICD-10 Codes. Data were collected using the TriNetX Research Network, a national research database providing de-identified patient medical records.Burn patients undergoing surgical procedures were identified based on their use of opioids alone or in combination with ketamine as adjunctive analgesia. Both groups excluded patients with a prior history of opioid-related and psychiatric disorders to control for potential pre-existing conditions affecting the study outcomes. Outcome analysis included continued opioid use and related psychiatric disorders, including nicotine dependence and anxiety, up to one year after burn injury. Risk ratios for each outcome were then generated using a measure of association analysis through TriNetX.We identified 107,270 patients across 51 health care organizations who underwent burn-related surgeries within one month after burn injury. Excluded from the study were 3,296 (3.07%) patients who had a prior history of opioid-related and psychiatric disorders. The remaining 103,974 patients were sorted into respective groups that received opioids with ketamine  and without ketamine . The two cohorts were balanced using (1:1) propensity score matching for age, sex, race, ethnicity, and burn surface area.Patients without ketamine had a higher risk of continuing opioid use , developing nicotine dependence , and developing anxiety disorders  at least one year after burn injury.Burn patients whose pain management included adjunctive ketamine ceased opioid use sooner and demonstrated a lesser risk of developing various psychiatric disorders associated with chronic opioid use.This study supports the use of adjunctive ketamine as part of a multimodal approach to pain management in burn patients in order to minimize the risk of chronic opioid use."}
+{"text": "Ophiophagus hannah; Cantor, 1836) is distributed in diverse habitats, forming independent populations, which confer differing scale markings, including between hatchlings and adults. Furthermore, king cobra venoms possess unique cytotoxic properties that are used as a defensive trait, but their toxins may also have utility as promising anticancer-agent candidates. However, the impact of geographical distribution and age on these potential venom applications has been typically neglected. In this study, we hypothesised that ontogenetic venom variation accompanies the morphological distinction between hatchlings and adults. We used non-transformed neonatal foreskin (NFF) fibroblasts to examine and compare the variability of venom cytotoxicity between adult captive breeding pairs from Malaysian and Chinese lineages, along with that of their progeny upon hatching. In parallel, we assessed the anticancer potential of these venoms in human-melanoma-patient-derived cells (MM96L). We found that in a geographical distribution and gender-independent manner, venoms from hatchlings were significantly less cytotoxic than those from adults . This is consistent with neonates occupying a semifossorial habitat, while adults inhabit more above-ground habitats and are therefore more conspicuous to potential predators. We also observed that Malaysian venoms exhibited a slightly higher cytotoxicity than those from the Chinese cobra cohorts , which is consistent with Malaysian king cobras being more strongly aposematically marked. These variations are therefore suggestive of differential anti-predator strategies associated with the occupation of distinct niches. However, all cobra venoms were similarly cytotoxic in both melanoma cells and fibroblasts, limiting their potential medical applications in their native forms.Snake venoms constitute a complex, rapidly evolving trait, whose composition varies between and within populations depending on geographical location, age and preys (diets). These factors have determined the adaptive evolution for predatory success and link venom heterogeneity with prey specificity. Moreover, understanding the evolutionary drivers of animal venoms has streamlined the biodiscovery of venom-derived compounds as drug candidates in biomedicine and biotechnology. The king cobra ( Venom is generally defined as a functional trait: a complex secretion produced by a specialised gland tissue that is delivered into the body of another animal via a wound for use in antagonistic interactions . By thisThe scale of mining venoms for drug candidates is immense, as this mixture often contains hundreds of toxins and isoforms that undergo accelerated rates of evolution . This biStudying the natural history and evolution of venomous species provides key insights regarding the biological sources reflecting toxin diversity. Snake venoms function at the ecological and biochemical interface between predator and prey, aiming mainly to facilitate predation . This haOphiophagus hannah; Cantor, 1836) belongs to the Elapidae family and is widely distributed from India to southern China and Southeast Asia in numerous geographically isolated mainland and island populations. These populations form at least four genetically distinct lineages, which are likely separate species  prism function. Data were graphed and analysed using GraphPad Prism version 9 for iOS . For the MTT assays, venom cytotoxicity data were normalised to the vehicle-treated cells (100% cell viability) to calculate the percentage of viable cells following venom treatment. Data were then tested for normality using Shapiro\u2013Wilk tests (significance set to"}
+{"text": "Perioperative management of estradiol therapy varies considerably among plastic surgeons performing aesthetic surgeries. This study aimed to review available literature regarding perioperative management of estradiol therapy in aesthetic surgery patients, and the risk it poses for developing VTE in the perioperative period.A literature search was performed using online databases to identify studies evaluating VTE in aesthetic surgery patients taking oral contraceptives (OCPs) or hormone replacement therapy (HRT), and transgender patients on feminizing hormone therapy undergoing non-flap feminization surgery . Reported outcomes were extracted from these studies and summarized.A systematic review of the literature yielded 225 studies. Five of these studies met inclusion criteria. One study that was excluded, referenced an article that met inclusion criteria, which was ultimately included in our review for a total of six studies, representing 3,635 patients.Data regarding perioperative management of estrogen therapy is limited in the literature, and standardized guidelines for aesthetic surgery patients have not been elucidated. This has led to inconsistencies in how estrogen is managed for elective, cosmetic procedures. Further research is needed to determine standardized practice guidelines. In the meantime, case-by-case evaluation of surgical appropriateness should continue. Surgeons should also consider risk-mitigating strategies, such as a focus on patient education, more intentional patient questioning regarding estrogen-containing product use, a preoperative coagulability workup for patients with a personal or family history indicative of possible coagulopathy, and specialty-wide efforts to create an aesthetics database and evidence-based guidelines."}
+{"text": "BackgroundMeniscal tears are the most common injury of the knee. Surgical treatment has fallen into contention recently and includes arthroscopic meniscectomy and meniscal repair. The primary aim of this study was to quantitatively evaluate patients with isolated meniscal tears and compare their outcomes with patients who have undergone arthroscopic meniscus surgery. The secondary aim of this study was to compare the clinical outcomes of patients who have undergone arthroscopic meniscectomy with patients who have undergone arthroscopic meniscal repair.MethodsThis comparative clinical study screened 334 patients to identify subjects who underwent arthroscopic knee surgery for isolated meniscal tears and compare them to patients with symptomatic isolated meniscal tears awaiting surgery using validated patient-reported outcome measures. These included the Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee Subjective Knee Form, Lysholm score, Tegner score, EuroQol-5 Dimension, and the 12-Item Short Form Health Survey.ResultsA total of 117 patients , Meniscectomy group (n=64), and Meniscal Repair group (n=17)) were included in the final data analysis. Both the Meniscectomy group and the Meniscal Repair group (mean 55-month follow-up) showed significantly better clinical outcomes than patients in the Meniscal Tear group (p<0.05). Overall, the Meniscal Repair group demonstrated superior clinical outcomes when compared to the Meniscectomy group (p<0.05).ConclusionArthroscopic knee surgery showed significant clinical benefit at medium-term follow-up in treating patients with isolated meniscal tears. When feasible, meniscal repair should be performed preferentially over meniscectomy. The menisci are crescentic wedge-shaped structures formed from fibrocartilage located within the medial and lateral compartments of the knee between the corresponding femoral condyle and tibial plateau ,2. MenisTreatment for meniscal tears broadly falls into two categories: conservative vs. surgical, the latter of which includes arthroscopic meniscectomy and arthroscopic meniscal repair. The choice depends on many factors including age, type and severity of tear, the presence of other pathology, and general patient fitness for anesthesia and surgery ,3,4. WheIn general, the treatment for traumatic meniscus tears differs from that of degenerative tears. The latter are less likely to be amenable to repair as by their very definition their blood supply is poor ,2. FurthSurgical management includes arthroscopic meniscectomy and meniscal repair. An arthroscopic partial meniscectomy (APM), in which only the torn section of the meniscus is removed, is now the most frequently performed orthopedic operation in the United States .As compared to meniscectomy, meniscal repair is a more biologically preserving procedure as it retains the native meniscal tissue within the knee joint. Multiple repair techniques have been described in the literature, the most common of which include all-inside, inside-out, and outside-in, with no significant differences in failure rates, complication rates, or clinical outcomes . OutcomeThe decision to proceed with either meniscectomy or meniscal repair involves evaluating both meniscus tear characteristics  and patient factors . Meniscal repair has been shown to decrease the incidence of early chondral degeneration and better preserve the knee\u2019s biomechanical properties as compared to meniscectomy . Both prMeniscal repairs are more commonly performed in younger patients and have shown superior outcomes over meniscectomy in patients under 45 years of age . IncreasThere are a limited number of studies directly comparing clinical outcomes between meniscectomy and meniscal repair, with those identified only having short-term follow-up periods, meniscal repairs performed concomitant with anterior cruciate ligament (ACL) reconstruction, and a limited variety of patient-reported outcome measures (PROMs) included in the clinical evaluation.PROMs quantify clinical symptomatology as directly projected by the patients themselves. Varying from general health to disease-specific, PROMs aid clinical decision-making, inform health policy strategies, and develop and refine patient-centered care . GenericThe primary aim of this study is to quantitatively evaluate patients with isolated meniscal tears using validated PROMs and compare their outcomes with patients who have undergone arthroscopic meniscus surgery. The secondary aim of this study is to compare the clinical outcomes of patients who have undergone arthroscopic meniscectomy with patients who have undergone arthroscopic meniscal repair. The primary hypothesis is that arthroscopic surgery improves symptoms of meniscus tears. The secondary hypothesis is that arthroscopic meniscal repair has superior clinical outcomes as compared to arthroscopic meniscectomy.This is a retrospective observational clinical study. All the patients included in this study attended a specialist knee clinic and underwent arthroscopic knee surgery following clinical assessment and radiological investigation. This study was exempt from Institutional Review Board (IRB)/Ethics Committee approval as it was a pragmatic study evaluating the existing clinical practice of the senior author (consultant orthopedic surgeon). This study was registered with the hospital\u2019s Clinical Effectiveness Department (registration number CA9828). This therapeutic research study constituted the first author\u2019s Masters dissertation.This study compared the clinical outcomes of three separate groups. The Pre-Operative group included patients with isolated meniscal tears of the knee joint, the Meniscectomy group included patients who had undergone an arthroscopic meniscectomy, and the Meniscal Repair group included patients who had undergone an arthroscopic meniscal repair.Exclusion criteria consisted of further surgery or further injury to the affected limb, any functionally limiting illness or disease, advanced knee osteoarthritis and concurrent ACL, posterior cruciate ligament (PCL), or lateral collateral ligament (LCL) tears. The presence of any of these factors could confound surgical outcomes reported. Exclusion of these cases ensured any symptoms expressed were attributable only to the original meniscal injury and their surgical treatment. Patients with medial collateral ligament (MCL) tears were not excluded as concurrent MCL tears are relatively common with meniscus tears and the former are predominantly treated conservatively and unlikely to confound the outcome of meniscus surgery.Subjects in the Pre-Operative group constituted a cohort of patients currently on the waiting list for knee surgery who have been clinically  and radiologically (magnetic resonance imaging (MRI)) diagnosed with an isolated meniscal tear and whose symptoms were refractory to conservative treatment . The Pre-Operative group allowed for a benchmark from which to compare both surgical treatment options.Surgically treated patients in both the Meniscectomy group and the Meniscal Repair group were identified through the consultant\u2019s surgical logbook and theatre records. All arthroscopic knee surgeries performed from August 2013 to June 2021 were reviewed using the hospital electronic health record system; MediTech version 6 . The Novel Coronavirus (COVID-19) global pandemic had implications for this study as all routine elective surgical procedures (including knee arthroscopies) were canceled for an extended period of time (March 2020 onward), reducing the number of potential participants that could be recruited into this study .o to 90o for six weeks in order to protect the meniscal repair site at the initial healing phase, thereafter the brace was discontinued, and full ROM progressed. All meniscectomies were performed using standard a basket punch followed by a motorized oscillating shaver (Smith & Nephew plc.) whereby only the torn and damaged area of meniscal tissue was resected back to a stable rim . Post-operative physiotherapy rehabilitation included full weight and full ROM without any knee brace or functional restrictions. Patient notes were perused to ascertain the type of arthroscopic knee surgery performed, conformance with the inclusion and exclusion criteria, and documenting intra-operative findings, including meniscus tear laterality , tear configuration, and specific anatomic location .All meniscal repairs included in this study were performed by using an all-inside technique using FAST-FIX 360  for tears located at the posterior horn and middle third (body) of the meniscus. For anterior horn meniscus tears, an outside-in meniscal repair technique was performed using a 1 PDS II (polydioxanone) violet suture . Microfracture around the margin of the intercondylar notch was performed at the same time in order to perforate the subchondral bone and introduce mesenchymal stem cells into the knee joint which in turn optimizes the biological milieu for the meniscal tissue healing process . Post-opData from validated patient-reported outcome measures (PROMs) regarding meniscus-related symptomatology was collected from all three groups. This included the Knee Injury and Osteoarthritis Outcome Score (KOOS) ,17, InteStatistical analysisPlotted histograms with fitted curve lines, box plots, normal Q-Q plots, and the Shapiro-Wilk statistic were used to test the normality of data distribution. Almost all the PROM data (continuous variables) displayed a skewed distribution and therefore the relevant non-parametric statistical tests were used for the data analysis. The Kruskal-Wallis H test accompanied with Dunn\u2019s post-hoc pairwise comparison test was used for the three-way group data analysis. The level of statistical significance was set at p<0.05. Statistical analysis was performed using SPSS for Windows version 26.0 .Figure Baseline demographics for all three groups are summarized in Table Table Figure This study has shown that patients with isolated meniscus tears clinically improved following arthroscopic knee surgery as determined by validated PROM scores. Overall, the clinical outcome of arthroscopic meniscal repair surgery was superior to that of arthroscopic meniscectomy.This study found significantly different outcomes between pre-operative patients with an isolated meniscal tear and those who had undergone either a meniscectomy or meniscal repair surgery. The highest scores across all PROMs were observed in the Meniscal Repair group, with the lowest scores mostly seen in the Pre-Operative group. This study is the first to quantitively evaluate pre-operative patients with isolated meniscal tears using a wide variety of validated PROMs , allowing a standardized benchmark from which to compare surgical interventions and other modalities aimed at treating meniscus pathology. The results from this study demonstrate significant clinical benefit from both meniscectomy and meniscal repair surgery at a mean 55-month follow-up, a finding also shown by a similar study by Engler et al. ,10,22. THistorically, APM has been used in a non-specific manner in patients with knee pain and any form of tear ,22. ThisThe secondary hypothesis of this study was affirmed, finding significantly superior scores in the Meniscal Repair group across almost all PROMs, suggesting Meniscal Repairs have superior outcomes to Meniscectomy for isolated meniscal tears at medium-term follow-up. This finding is corroborated by a meta-analysis by Xu et al. , which sThe superior outcomes observed in this study in the Meniscal Repair cohort could be attributed to preservation of the meniscal tissue and therefore retaining the three key functions they play in the knee. First, they absorb axial loading forces through the joint, by converting them into hoop stresses within the tissue. Second, the menisci stabilize the knee by improving articular congruency between the flat tibial plateaus and concave femoral condyles. Third, they modulate the gliding of the articular surfaces. The removal of the meniscal tissue by meniscectomy impacts its ability to perform such functions and could be attributed to the greater rate of secondary osteoarthritis other studies have observed in this group .The menisci are innervated by the posterior articular branch of the tibial nerve. Similar to the ACL, they too contain mechanoreceptors that contribute to the proprioceptive function of the knee . StudiesA general comparison between the two operations shows that despite meniscal repair having greater day-of-surgery costs  , greaterThe main limitation of this study was patient participation and recruitment. This clinical research study was conducted during the novel coronavirus (COVID-19) global pandemic, during which all routine elective surgery had ceased due to nationwide restrictions, resulting in a reduction of individuals eligible to take part. Additionally, due to the nature of postal questionnaires, patients were understandably apprehensive about receiving an envelope that had originated from a hospital during this time, further reducing the compliance rate. This study did not analyze longitudinal patient data of the two surgical groups as pre-operative data was not collected for these patients specifically.\u00a0However, a suitable comparable group of pre-operative patients, refractory to conservative treatment, on a waiting list for meniscal surgery was identified and used as a benchmark from which to assess and compare surgical outcomes. The range of follow-up periods was relatively broad for both groups. However, with a mean follow-up period of 57 and 47 months for the meniscectomy and meniscal repair cohorts, respectively, this study provides a useful perspective on medium-term outcomes following meniscal surgery.Despite limitations forced upon clinical research studies performed during the global pandemic, this analysis is based on comprehensive selection criteria and contributes key interpretation regarding the direct comparison between meniscectomy and meniscal repair in isolated meniscal tears, something only a limited number of papers have done in the past ,35. ThesSuggestions for future research in this field include undertaking a multicenter study that can allow for a larger cohort of patients to be investigated, particularly in the Meniscal Repair group, whilst encompassing various meniscal surgical techniques, to provide more generalizable results. It is likely that specific patient subgroups benefit by varying amounts from each surgical procedure. Larger cohorts would also aid identification of these predictive factors, allowing adequate treatment selection. Implementation of a national database of meniscal operations, similar to the National Joint Registry and the National Hip Fracture Database in the United Kingdom, would also confer these benefits on a larger scale.This study has demonstrated a significant clinical benefit in patients with isolated meniscal tears undergoing arthroscopic knee surgery. The outcomes of meniscal repair\u00a0were superior to that of meniscectomy at medium-term follow-up. Meniscal repair is a more biologically preserving procedure of the knee joint and should be performed preferentially over meniscectomy in isolated meniscal tears when feasible. The findings of this study will greatly benefit both clinicians and patients regarding the management of meniscal tears and better inform public health resource allocation."}
+{"text": "Major depressive disorder (MDD) is a highly prevalent mental illness that often first occurs or persists into adulthood and is considered the leading cause of disability and disease burden worldwide. Unfortunately, individuals diagnosed with MDD who seek treatment often experience limited symptom relief and may not achieve long-term remission, which is due in part to our limited understanding of its underlying pathophysiology. Many studies that use task-based functional magnetic resonance imaging (fMRI) have found abnormal activation in brain regions in adults diagnosed with MDD, but those findings are often inconsistent; in addition, previous meta-analyses that quantitatively integrate this large body literature have found conflicting results.This meta-analysis aims to advance our understanding of the neural basis of MDD in adults, as measured by fMRI activation studies, and address inconsistencies and discrepancies in the empirical literature.We employed multilevel kernel density analysis (MKDA) with ensemble thresholding, a well-established method for voxel-wise, whole-brain meta-analyses, to conduct a quantitative comparison of all relevant primary fMRI activation studies of adult patients with MDD compared to age-matched healthy controls.We found that adults with MDD exhibited a reliable pattern of statistically significant  hyperactivation and hypoactivation in several brain regions compared to age-matched healthy controls across a variety of experimental tasks.This study supports previous findings that there is reliable neural basis of MDD that can be detected across heterogenous fMRI studies. These results can be used to inform development of promising treatments for MDD, including protocols for personalized interventions. They also provide the opportunity for additional studies to examine the specificity of these effects among various populations-of-interest, including youth vs. adults with depression as well as other related mood and anxiety disorders.None Declared"}
+{"text": "To review the pathophysiology of allergic asthma and information on the pharmacology, clinical efficacy, safety profile, and direct drug costs for omalizumab to provide a basis for a defined role of this agent in allergic asthma therapy in managed care organizations.Omalizumab is a monoclonal antibody targeting the high-affinity receptor binding site on human immunoglobulin E (IgE). When bound by omalizumab, IgE does not bind to basophils. As a result, degranulation is attenuated and allergic asthma symptoms are reduced. In asthma trials, omalizumab reduced inhaled corticosteroid and rescue medication requirements and improved asthma control and asthma quality of life in moderate-to-severe allergic asthmatics with disease poorly controlled by inhaled corticosteroids. Omalizumab has generally been well tolerated. However, injection site reactions occur in nearly 1 of every 2 patients, a problem that generally becomes less with continued dose administration. Severe injection site reactions are reported in 12% of patients. Other adverse events commonly reported in clinical trials include viral infections (23%), upper respiratory infections (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). Because the acquisition cost of omalizumab is high , its use is cost-prohibitive in all but the most severe, poorly controlled allergic asthmatic patients who are utilizing large amounts of emergency health care resources to manage exacerbations. Experience with use of this drug beyond 52 weeks is lacking.Although omalizumab has demonstrated efficacy and safety in adults and adolescents with uncontrolled moderate-to-severe allergic asthma, its use should be restricted to a narrowly defined population of allergic asthmatics who utilize large amounts of health care resources. If targeted only toward this population, cost-of-care studies suggest that the high cost of this product in these patients could be offset by savings resulting from the less frequent use of high-intensity medical services for asthma exacerbations. The use of omalizumab beyond 52 weeks needs evaluation."}
+{"text": "Mental Illness Stigma is a barrier in access to healthcare. Stigma also influences population health outcomes by worsening, undermining adequate processes. The healthcare professionals show several stigmatising behavirous and cognitions, which may impair the adequate provision of care of this population with mental illness.We aimed to measure mental health stigma in healthcare professionals at a portuguese hospital center.A cross-sectional study of health profissionals was performed using a survey that included socio-economic and job related questions, personal and familiar questions regarding mental health, and Attribution Questionnaire 27 (AQ-27), a translated and validated stigma questionnaire with nine stigma sub-scales .The sample included a total of 388 participants. The majority of the respondants were female . The age ranged from 22 to 69 . According to the job place distribution, we found statistically significant differences in various stigma subscales among several healthcare settings within our center. The inpatient unit professionals showed lesser stigmatising attitudes in anger, coercion, segregation and avoidance domains; and higher stigmatising attitudes in pity and help domains. However, professionals who work at surgery room showed higher stigmatising attitudes in danger and fear, but lesser levels of help domains. We also found differences in five stigma subscales among various health professions. The study didn\u2019t show differences in stigma domains regarding personal or professional contact with mental illness, neither academic studies in mental health.Our findings suggest that workplace environment and profession may impact mental ilness stigma levels in healthcare professionals. We propose that future studies could be done to investigate methods to mitigate mental illness stigma, tailored to address different stigma domains in different workplace settings.None Declared"}
+{"text": "Alzheimer's disease (AD) is classified as a tauopathy and is the most common neuropathological correlate of dementia/cognitive impairment. AD is neuropathologically characterized by the presence of beta-amyloid immunoreactive senile plaques and tau positive neurofibrillary tangles. Neuropsychiatric symptoms of AD however continue to be underscored, and therefore, neuropathological correlates of these neuropsychiatric symptoms are not readily studied. Presented here is a case of 60-year-old female who initially presented with anxiety and depression, and continued to be the predominant symptoms although mild cognitive impairment was noted as per the available clinical notes. Postmortem examination of the brain revealed severe Alzheimer's type neuropathological changes, which included significant tau and beta-amyloid pathology in limbic regions, which were thought to represent correlates of the patient's depression and anxiety. This case report illustrates the possible neuropathological correlates of neuropsychiatric symptoms in patients with AD. The author hopes that such a case will promote more in-depth studies into the pathophysiology of neuropsychiatric manifestations in AD. Alzheimer's disease (AD) is regarded as a tauopathy associated with cognitive and functional decline in typically elderly (>65\u2009years) patients although cases of early-onset (before age of 65\u2009years) are possible . NeuropaLimited clinical information was available on the electronic medical chart. As per the information available, this female patient who was 60\u2009years-old at first presentation reported difficulty with short-term memory along with difficulty sleeping. Psychiatric history included depression and anxiety. Neurological examination was notable for mini mental status (MMSE) of 25/30. The patient was clinically diagnosed with mild cognitive impairment based on the MMSE score. Unfortunately, no additional clinical information regarding her cognition could be found. With regards to her depression and anxiety, the patient reported feeling sad about some aspects of her life, and the episodes of sadness were exacerbated by difficulty in her first marriage and from having to switch employment. Clinically, she was diagnosed with major depressive disorder, generalized anxiety disorder, and mild cognitive decline.The patient passed away at hospice facility. After passing, a restricted autopsy limited to postmortem examination of the brain was requested to determine the etiology of her cognitive impairment.The weight of the unfixed brain was recorded at 1330\u2009g. The cerebral hemispheres did not seem to display any significant atrophy. The coronal slices of the cerebral hemispheres did not reveal evidence of atrophy. Ventricular caliber appeared unremarkable. Hippocampus and amygdala did not appear shrunken. Pigment was visible in both the substantia nigra of the midbrain and locus ceruleus of the pons.Histologic examination with immunohistochemical work-up revealed evidence of cerebral amyloid angiopathy in the form of thickened blood vessels in the leptomeninges that were stained by beta amyloid immunohistochemistry. Sampled sections from the cerebral hemispheres showed several beta amyloid positive diffuse plaques and moderate amount of senile plaques throughout neocortex, including cingulate, calcarine, and entorhinal cortices, as well as in the thalamus. There were also scattered tau positive neurofibrillary tangles, neurites, and neuropil threads throughout the cortical gray matter including the superficial and deep layers of the calcarine cortex and entorhinal cortex. Thickened blood vessels that were not stained by beta amyloid immunohistochemistry, and hence consistent with arteriolosclerosis, were noted in the subcortical white matter. Left amygdala showed scattered tau positive neurofibrillary tangles, pretangles, neurites, neuropil threads, and argyrophilic grains. There were also numerous beta-amyloid positive diffuse and senile plaques in the amygdala. Examples of these findings are shown in Midbrain showed some beta amyloid positive diffuse and senile plaques. Although beta amyloid staining was observed in blood vessels of the cerebellar leptomeninges, no definite beta amyloid staining is seen within the cerebellar parenchyma.The final neuropathological diagnosis was reported as Alzheimer's type neuropathological changes ; Braak (neurofibrillary tangle) stage\u2009=\u20096 of 6; CERAD (senile plaque) score\u2009=\u2009C2 (moderate)); cerebral amyloid angiopathy; relatively mild arteriolosclerosis.n\u2009=\u2009906) that psychotic symptoms  were more strongly related to the continuum of AD-associated cognitive dysfunction than other neuropsychiatric symptoms. The group also observed a negative correlation between psychotic symptoms and brain volume [n\u2009=\u20091038) that included AD and Lewy body disease pathology. The authors reported higher neurofibrillary tangle (NFT) stages to be associated with depression and agitation and hallucinations associated with higher Lewy body stages [To the author's knowledge, this case is one of the first case examples to demonstrate neuropathological correlation between Alzheimer's type neuropathological changes and clinical history of neuropsychiatric symptoms. Neuropsychiatric symptoms are described in patients with Alzheimer's disease, and animal models have suggested that behavioural and psychological symptoms increase with progressive neuropathology . Depressy stages . These rAPOE-region, respectively. Association analysis excluding the APOE-region identified numerous SNPs corresponding to 40 genes, 9 of which were known LOAD-risk loci primarily in chromosome 11 regions containing the SPI1gene and MS4A genes cluster, and others were novel pleiotropic risk-loci for LOAD conditional with MDD [Interestingly, genetic etiologies shared between AD and depression have been reported. Chiba\u2010Falek et al. performed pleiotropy analysis using genome-wide association studies (GWAS) from publicly accessible websites of AD GWAS and major depressive disorder (MDD) GWAS. The group found moderate enrichment of single nucleotide polymorphism (SNP) associated with late-onset AD (LOAD) across increasingly stringent levels of significance with the MDD GWAS association (LOAD|MDD), of maximum four and eight-folds, including and excluding the Herein, the author has presented neuropathologically severe Alzheimer's type neuropathological changes in a patient whose predominant presentation seems to be neuropsychiatric in the form of anxiety and depression. It is hoped that such a case will encourage further studies of the neuropathological correlates and pathophysiology of neuropsychiatric symptom in AD and other neurodegenerative disorders."}
+{"text": "During the COVID-19 pandemic, mental health services often used remote technology to deliver care. However, the rise in remote consultation was largely unplanned. Furthermore, while many patients found remote technology a useful way to access care, others did not. Going forwards, remote technology will continue to play an important role in the delivery of mental healthcare. Research on the most effective ways for mental health services to implement remote technology is thus urgently needed.Electronic health records (EHRs) have been widely adopted in mental healthcare services. EHRs not only support individual patient care, but also open the door to largescale research through the analysis of de-identified clinical data. The South London and Maudsley (SLaM) Biomedical Research Centre (BRC) Case Register is a large EHR dataset comprising structured and unstructured clinical information on patients receiving specialist mental healthcare. In this talk, I will present findings from an analysis of the SLaM BRC Case Register using the Clinical Record Interactive Search tool (CRIS) to evaluate the uptake of remote mental healthcare during the COVID-19 pandemic and its association with medication prescribing. I will discuss the implications of these findings for psychiatrists delivering community mental healthcare and how mental health services can harness remote technology to optimise clinical outcomes.R. Patel Grant / Research support from: NIHR (NIHR301690); MRC (MR/S003118/1); Academy of Medical Sciences (SGL015/1020); Janssen, Consultant of: Induction Healthcare Ltd; Holmusk"}
+{"text": "Teaching Point: Subarachnoid hemorrhage is a rare complication of spinal dural arteriovenous fistulas (dAVF) with very characteristic imaging features, knowledge of which is crucial for positive diagnosis and rapid management. We report the case of 45-year-old male without a known history of neurological disease, presenting progressive weakness of lower limbs and tingling-like paresthesia. The evolution of the disease is marked by the onset of thunderclap headache. An endocranial computed tomography (CT) performed in the emergency department showed no particular anomaly. Then, a cerebral magnetic resonance imaging (MRI) was performed showing on axial images hyperintensity in the subarachnoid compatible with a peri mesencephalic subarachnoid hemorrhage space on T2 FLAIR with a normal time of flight (TOF) angiography .Cerebral angiography showed no specific findings.A medullar MRI was then suggested and demonstrated on T2-sagittal MRI  intramedAlso, it showed on axial T2  and postPatient was put under surveillance with symptomatic treatment and showed a recovered partial recovery of his motricity and sensitivity.Spinal dural arteriovenous fistulas (dAVF) are the most common spinal vascular malformations (75 to 80%) and more frequently affect male subjects over 50 years that exhibits arteriovenous shunting at the level of the internal leaflet dura mater, corresponding to an abnormal connection between the arterial supply from the medullary dura mater and the medullary venous system and no exact etiology has been fully elucidated .The clinical presentation of sdAVF is often progressive and non-specific mimicking demyelinating or degenerative diseases of the spine, which explains a frequent delay in diagnosis, resulting in an irreversible damage despite an endovascular or surgical intervention.Hemorrhage is very rare but occasionally encountered and may be a source of unexplained subarachnoid hemorrhage.MRI shows an association of centrally located hyperintense signal on T2-weighted images on TSE sequence, corresponding to chronic hypoxic congestive myelopathy attributable to venous hyper pressure hindering venous circulation, dilated peri medullary vessels, hypointense \u2018flow void\u2019 phenomena hypo intense in T2w images, appearing as enlarged and serpiginous veins anteriorly and/or posteriorly to the cord, enhancing after administration of gadolinium The absence of dilated peri medullary vessels do not formally eliminate the diagnosis of Davf. Dynamic MRA (angio-MRI) sequences are more sensitive assets to detect this abnormality.Principal differential diagnosis on imaging includes intramedullary neoplasm, spinal arteriovenous malformation where hemorrhage is common with acute onset, affecting males and females equally.Our case is unique as it depicts the importance of including spinal cord malformations in unexplained cerebral sub arachnoid hemorrhages."}
+{"text": "ObjectiveCaregivers support individuals undergoing cancer treatment by assisting with activities, managing care, navigating healthcare systems, and communicating with care teams. We explored the quantity and quality of caregiver participation during recorded clinical appointments in women with metastatic breast cancer.MethodsThis was a convergent parallel mixed methods study. Caregiver participation quality was operationalized using a summative thematic content analysis to identify and sum caregiver roles performed during appointments. Caregiver participation quantity was measured by calculating the proportion of speaking time. Participation quality and quantity were compared to patient activation, assessed using the Patient Activation Measure.ResultsFifty-three clinical encounters were recorded. Identified caregiver roles included: General Support; Management of Treatment or Medication; Treatment History; Decision-Making; Insurance or Money; Pharmacy; Scheduling; Travel Concerns; General Cancer Understanding; Patient Specific Cancer Understanding; Caregiver-Initiated or Emphasis on Symptom Severity; and Caregiver Back-Up of Patient Symptom Description. Caregivers averaged 5 roles (SD 3): 48% of patients had low quality (<\u20095 roles) and 52% had high quality (>\u20096 roles). Regarding quantity, caregivers spoke on average for 4% of the encounter, with 60% of patients having low quantity (<\u20094%) and 40% of patients having high quantity (>\u20094%). Greater quality and quantity of caregiver participation was associated with greater patient activation.ConclusionsCaregivers perform a variety of roles during oncological decision-making visits aiding both patient and provider. Greater participation in terms of quantity and quality by the caregiver was associated with greater patient activism, indicating a need for better integration of the caregiver in clinical decision-making environments."}
+{"text": "Populations face a suite of anthropogenic stressors acting simultaneously, which can combine additively or interact to have complex effects on population persistence. Yet we still know relatively little about the mechanisms underlying population-level responses to multifactorial combinations of stressors because multiple stressor impacts across organisms\u2019 life cycles have not been systematically considered in population models. Specifically, different anthropogenic stressors can have variable effects across an organism\u2019s life cycle, resulting in non-intuitive results for long-term population persistence. For example, synergistic or antagonistic interactions might exacerbate or alleviate the effects of stressors on population dynamics, and different life-history stages or vital rates might contribute unequally to long-term population growth rates. Demographic modelling provides a framework to incorporate individual vital rate responses to multiple stressors into estimates of population growth, which will allow us to make more informed predictions about population-level responses to novel combinations of anthropogenic change. Without integrating stressors\u2019 interactive effects across the entire life cycle on population persistence, we may over- or underestimate threats to biodiversity and risk missing conservation management actions that could reduce species\u2019 vulnerability to stress. As humans alter multiple facets of the environment simultaneously, addressing multiple, potentially interacting stressors will be critical for predicting species' responses. Yet the effects of multiple stressors across organisms' life cycle has not been systematically considered in demographic studies. Here, Zettlemoyer proposes a framework to explore the role of multiple stressors on population dynamics in order to make realistic predictions about population viability under different conservation scenarios. Specifically, demographic modelling provides a method to integrate stressors' potential additive and non-additive effects across the entire life cycle, provide mechanistic explanations of species loss and spread under combinations of novel conditions, and improve conservation and management plans. Reviews report that only 136 studies integrate multiple vital rate responses into plant demographic models  interactions among anthropogenic stressors and (ii) counteracting effects of stressors on different vital rates might influence population dynamics. Finally, I outline potential experimental designs that integrate multiple stressor effects across the life cycle to predict extinction risk under future environmental conditions.sensuadditive effects, wherein the combined effects of two stressors are equal to the sum of their individual effects (Alliaria petiolata (garlic mustard) interacts additively with deer herbivory to reduce population growth rates of Trillium erectum , only the combination of high levels of interspecific competition and insect herbivory results in population decline  and Viola palustris   .Eurybia furcata (forked aster), but only when site-level woody encroachment and deer herbivory are high (Cypripedium candidum (white lady\u2019s slipper) under moderate climate change scenarios. However, as drought stress increases, protecting groundwater recharge zones in sites near this hydrologically sensitive species becomes increasingly important  (\u03bb as a function of multiple interacting (a)biotic environmental conditions . In order to examine differences in \u03bb between multiple stressors and determine the most relevant vital rate, log-transforming \u03bb will help interpret the impact of vital rates on \u03bb  can quantify the sensitivity of \u03bb to changes in each vital rate and/or environmental variable  drive differences in \u03bb. For example, invasion and deer herbivory affect multiple vital rates in T. erectum (red trillium), including growth and seedling recruitment, but an LTRE revealed that decreases in fertility largely drive declines in plant fitness , growth and survival show compensatory responses to warming that buffers overall population growth , compensatory responses of ramet growth and clonal reproduction buffer populations from the effects of grazing and harvest , density-dependent mortality due to post-dispersal seed consumption decreases seedling density, resulting in increased fecundity and therefore compensating for low seedling numbers (Pityopsis aspera var. aspera (pineland silkgrass), increasing density decreases \u03bb, but this effect is alleviated by fire . Thus, IPMs, by incorporating environmental covariates in sub-regressions and allowing the use of size-based regression than discrete size classes, can overcome potential pitfalls of underpowered designs or smaller datasets , temperature and precipitation affect fecundity but not growth or survival  matrix population models, which use stage- or age-structured state variables and (ii) IPM, which use continuous (often size-dependent) state variables to predict population growth rates as well as (iii) population viability analyses that estimate population size (e.g. count data) from one monitoring event to the next.Vital rates: Rates corresponding to an organism\u2019s individual life stages or progression through development .Additive effects: Type of interaction when the combined impact of two or more stressors on an ecological response is equal to than their algebraic sum; in this case, studies of single stressors can be added to estimate their combined effect.Non-additive interactions: Type of interaction when the combined impact of two or more stressors on an ecological response is not equal to their algebraic sum, such that the intensity of response to one stressor changes with the presence of the other; can be synergistic or antagonistic.Synergistic: Type of non-additive interaction when the combined impact of two or more stressors on an ecological response is greater than their algebraic sum; one stressor can exacerbate the effects of another.Antagonistic: Type of non-additive interaction when the combined impact of two or more stressors on an ecological response is less than their algebraic sum; one stressor can alleviate the effects of another.Perturbation analyses: Demographic analyses exploring how population growth rates respond to changes in vital rates; types of perturbation analysis include (i) prospective analyses (e.g. sensitivity and elasticity) that test how much \u03bb depends on vital rates independent of variability and (ii) retrospective analyses (e.g. LTRE) that decompose variance in \u03bb as a function of variance in vital rates.Demographic compensation: Opposing vital rate responses to stressors wherein the positive effects of one vital rate can negate the negative effects of another.Density-dependent processes: Population-level processes  that are sensitive to fluctuations in population density .Kernel: A probability density function that maps the change in the size distribution of individuals at time t to the size distribution after one timestep (t + 1)."}
+{"text": "Acne vulgaris is a common skin condition that affects both adolescents and adults worldwide and frequently results in acne scars . AtrophiA 2016 Cochrane study  providedData from some of the included RCTs showed that fractional laser, chemical peeling (with and without skin needling), and injectable fillers were more effective than comparator treatments. Many studies that compared other treatment modalities to each other or to placebo concluded no significant difference in either participant-reported or investigator-assessed scar improvement. This review  found moP=.0005). Another multicenter, randomized, prospective study [P=.0136). These studies further support the efficacy of injectable fillers for treating acne scars, though additional research with long-term follow-up is warranted to assess the durability of outcomes.Results of clinical trials published subsequent to this review  provide"}
+{"text": "Angioleiomyoma, a rare variant of leiomyoma, is a benign tumor of mesenchymal origin. Angioleiomyomas of the female urogenital tract are extremely rare, with only six cases of uterine cervical angioleiomyoma previously reported in the literature. In this case study, we report on a 49-year-old female patient who presented with menorrhagia whose initial magnetic resonance imaging (MRI) findings suggested cervical squamous cell carcinoma (SCC). However, following the hysterectomy, histological examination confirmed the lesion to be angioleiomyoma. To the best of our knowledge, there have been no previously reported cases of angioleiomyomas presenting with MRI findings that are suggestive of uterine SCC. Recognizing that angioleiomyomas can mimic uterine malignancies on MRI may prove beneficial for future diagnostic and treatment strategies."}
+{"text": "Background: Measles is a highly transmissible respiratory virus that presents with nonspecific prodromal symptoms followed by a characteristic cephalocaudal rash. In the prodromal phase, children with measles can be challenging to differentiate from children with other circulating respiratory viral infections. A measles outbreak in Central Ohio starting in October 2022 coincided with a national surge in children with viral respiratory infections which presented unique challenges in preventing healthcare transmission in the pediatric ambulatory setting. Methods: Following initial identification of presumed community transmission of measles in Central Ohio in November 2022, a multidisciplinary measles response team was convened at Nationwide Children\u2019s Hospital (NCH) to prevent secondary healthcare transmission via rapid-cycle quality improvement. Prevention efforts were focused broadly across NCH ambulatory locations in Central Ohio, including the main campus and offsite emergency departments, regional urgent cares, and primary care network. Preliminary risk factors were identified via chart review of initial cases, which included vaccine status, ZIP code of residence, and known daycare or household exposure. These risk factors were used to guide an intervention bundle comprising enhanced screening at registration and triage, creation of electronic medical record alerts to identify at-risk patients, increased clinician education, and expanded community messaging. As the outbreak evolved, risk factors were updated, and interventions were adjusted to adapt response. Outcome metrics included total patient exposures as well as the relative exposure score. The exposure score was an internal metric derived using the vaccine status of exposed patients and ventilation at the site of exposure to assess likelihood of secondary cases occurring from an exposure. Results: In total, 65 patients with measles were seen at NCH facilities between October 29 and December 8, 2022. The outbreak response was divided into 4 periods: (1) cases identified retrospectively prior to first diagnosis , (2) initial case discovery , (3) implementation of prevention bundle , and (4) updates to the response . Ambulatory healthcare exposures and incidence of secondary cases decreased over the outbreak periods in response to implementation of the prevention bundle . Conclusions: An outbreak of measles occurring simultaneously with peak respiratory viral season presented challenges in early identification of suspected cases and mitigation of healthcare exposure. Transmission was effectively prevented following rapid deployment of a prevention bundle adjusted in real-time through rapid-cycle quality improvement. Ongoing longitudinal vaccination efforts are needed to sufficiently mitigate transmission risk in communities with under-vaccinated populations.Disclosures: None"}
+{"text": "Background: A sustainable, continuous supply of alcohol-based hand rub (ABHR) is essential for healthcare workers in health facilities. The WHO provides guidance for production in individual health facilities. In Uganda, using this guidance, an innovative approach was implemented at the district local government level to produce and subsequently distribute ABHR to primary-care health facilities that have limited capacity for local facility-level production. This project was supported by the CDC in collaboration with the Infectious Diseases Institute (IDI) and targeted governmental or district engagement with local partners to ensure sustainability. Methods: District stakeholders were engaged to obtain buy-in and define roles and responsibilities. Overall, 4 staff members in each of 6 supported districts were nominated by District Health Officers for training: 2 staff members were trained to produce ABHR and conduct internal quality control and 2 were trained on external quality control. Districts provided ABHR production-unit facilities and facilitated integration within the government essential supplies delivery system, National Medical Stores in Uganda, which supports last-mile delivery to facilities. An implementing partner purchased initial raw materials necessary for production. The cost of materials for local production was compared to the price of commercial ABHR available in Uganda. Results: Between January and August 2021, 23 staff members were trained, and 380 batches of quality-assured ABHR  were produced and distributed to 278 health facilities. Consumption of ABHR in the first distribution was used to benchmark predicted ABHR consumption per targeted facility in subsequent months. Increased demand for ABHR due to the COVID-19 pandemic and the Ebola virus disease outbreak in central Uganda (September 2022) was addressed through emergency requests on a case-by-case basis. ABHR local production costs $3 per liter for materials, less than half of commercial ABHR ($8 per liter). Conclusions: Early results suggest that this approach is potentially sustainable but requires national advocacy as well. Leveraging existing distribution systems while building local capacity for ABHR production and distribution may improve longevity of such innovations in similar resource-limited settings.Disclosure: None"}
+{"text": "Mild traumatic brain injury is a complex neurological disorder of significant concern among athletes who play contact sports. Athletes who sustain sport-related concussion typically undergo physical examination and neurocognitive evaluation to determine injury severity and return-to-play status. However, traumatic disruption to neurometabolic processes can occur with minimal detectable anatomic pathology or neurocognitive alteration, increasing the risk that athletes may be cleared for return-to-play during a vulnerable period and receive a repetitive injury. This underscores the need for sensitive functional neuroimaging methods to detect altered cerebral physiology in concussed athletes. The present study compared the efficacy of Immediate Post-concussion Assessment and Cognitive Testing composite scores and whole-brain measures of blood oxygen level\u2013dependent signal variability for classifying concussion status and predicting concussion symptomatology in healthy, concussed and repetitively concussed athletes, assessing blood oxygen level\u2013dependent signal variability as a potential diagnostic tool for characterizing functional alterations to cerebral physiology and assisting in the detection of sport-related concussion. We observed significant differences in regional blood oxygen level\u2013dependent signal variability measures for concussed athletes but did not observe significant differences in Immediate Post-concussion Assessment and Cognitive Testing scores of concussed athletes. We further demonstrate that incorporating measures of functional brain alteration alongside Immediate Post-concussion Assessment and Cognitive Testing scores enhances the sensitivity and specificity of supervised random forest machine learning methods when classifying and predicting concussion status and post-concussion symptoms, suggesting that alterations to cerebrovascular status characterize unique variance that may aid in the detection of sport-related concussion and repetitive mild traumatic brain injury. These results indicate that altered blood oxygen level\u2013dependent variability holds promise as a novel neurobiological marker for detecting alterations in cerebral perfusion and neuronal functioning in sport-related concussion, motivating future research to establish and validate clinical assessment protocols that can incorporate advanced neuroimaging methods to characterize altered cerebral physiology following mild traumatic brain injury. et al. report that blood oxygen level\u2013dependent signal assessed by functional MRI outperforms a standard post-concussion neurocognitive test for classifying concussed athletes and predicting post-concussion symptoms. Blood oxygen level\u2013dependent signal variability may hold promise as a neurobiological marker for alterations in cerebral perfusion and functioning following concussion.Anderson   Athletes with minimal physiological and neurocognitive symptoms may therefore be cleared to return-to-play prematurely, which can exacerbate symptoms, increase risk for severe secondary injuries and complicate or prolong recovery.8 Thus, current research aims to discover neurobiological markers that can be used to objectively assess the presence and severity of SRC and to determine when the brain has recovered sufficiently to permit safe return-to-play.Clinicians rely on a variety of assessments to diagnose SRC, including brief neurological examinations, symptom checklists, neurocognitive tests 9 Acute biomechanical injury\u2014sudden stretching of neuronal and axonal membranes\u2014triggers a cascade of neurometabolic changes including the abrupt release of neurotransmitters, ionic fluxes and unregulated extracellular glutamate release, ultimately leading to hyperglycolysis and axonal injury or cell damage.8 This intricate \u2018neurometabolic cascade\u20198 can manifest sequelae including dizziness, nausea, headache, insomnia, amnesia, attentional issues and other physiological and neurocognitive symptoms.11Concussion symptoms reflect a complex series of neurometabolic events that occur during and after the initial impact. Physiological damage from SRC typically occurs in stages, starting with the initial impact or change in velocity  and subsequent structural deformation.13 Repetitive TBI in these areas is a particularly serious concern in SRC, as secondary blows that occur during this vulnerable metabolic window can produce catastrophic secondary impairments,14 highlighting the need for accurate diagnostics for safely clearing individuals to return to normal activity following a concussion.Several brain regions, including anterior frontal and temporal areas, medial temporal structures, corpus callosum and subcortical white matter pathways, are particularly vulnerable to bruising and injuries caused by inertial forces.15 researchers have increasingly utilized more advanced functional neuroimaging techniques to elucidate underlying changes in neuropathology post-injury.16 Functional MRI (fMRI) has shown promise for characterizing alterations in neural function post-mTBI across multiple domains. Task-based fMRI studies have demonstrated changes in activation in the parietal cortex, dorsolateral prefrontal cortex and the hippocampus in concussed athletes relative to healthy controls.17 Further, functional connectivity assessed from resting-state fMRI revealed altered connectivity within the default mode, fronto-parietal and motor-striatal networks relative to controls in individuals with mTBI.19 fMRI methods may provide objective biomarkers of neurophysiological injury, affording greater sensitivity and specificity for SRC diagnoses. Recent research suggests that while structural imaging and neurocognitive tests did not accurately discriminate mTBI patients from controls, resting-state functional connectivity measures correctly classified SRC status and predicted long-term cognitive sequealae.20 Functional neuroimaging methods may facilitate SRC evaluation through identification of altered haemodynamics and neurometabolism, detecting impaired neurovascular coupling, cerebral blood flow (CBF) and oxygen metabolism associated with abnormal brain function.21As neurobiological correlates of cognitive and mental health dysfunction from SRC are difficult to detect with standard axial neuroimaging techniques ,23 and that patterns of variability as measured from blood oxygen level\u2013dependent (BOLD) signal are closely linked to neural information processing, cognitive function and brain health.25 Recent studies have demonstrated that BOLD variability can detect vascular pathologies in cerebral small vessel disease,26 Alzheimer\u2019s disease,27 post-traumatic stress disorder28 and stroke29 by capturing underlying differences in cerebrovascular compliance26 that alter haemodynamic function and neurovascular coupling, motivating the investigation of BOLD variability for detecting neurophysiological alterations in mTBI.Neuroscience evidence demonstrates that regional brain activity is inherently variable over time31 increased reactivity of smooth muscle in microvessel walls32 and reduction in the density and diameters of capillaries both proximal and distal to the site of injury.33 Furthermore, altered BOLD variability can indicate sites of neural proliferation and synaptogenesis, indexing post-mTBI neuroplasticity that drives changes in neural signalling and BOLD activation during recovery.15 BOLD variability may therefore serve as a biomarker of changes in individuals\u2019 cerebral vascular status during and following traumatic neurophysiological insult, potentially assisting in the diagnosis of SRC.Mechanisms that may alter BOLD variability following mTBI may include changes in cerebral perfusion,The aim of the present study is to compare regional measures of BOLD variability and cognitive assessment scores for their complementary roles in the evaluation of SRC. Neuroimaging indices of BOLD variability may represent a novel lens for objectively evaluating SRC status by detecting functional disruption, providing information beyond conventional neuropsychological assessment batteries that may improve the detection and management of concussion pathology. While clinically informative, neurocognitive assessments remain limited in their ability to assess the extent of injury or identify neurophysiologically vulnerable individuals. To investigate the potential role of neurocognitive testing and functional neuroimaging in SRC diagnosis, we examined group differences in regional BOLD signal variability and neurocognitive performance on ImPACT in athletes diagnosed with SRC (compared against age-matched control athletes without SRC). We then applied a supervised machine learning algorithm (bagged ensemble random forests) to assess whether whole-brain BOLD variability measures, ImPACT module scores or BOLD and ImPACT composite scores together can discriminate healthy, concussed and repetitive concussion patients. We further applied bagged random forests to assess the extent to which regional BOLD variability measures and ImPACT scores in isolation or combination accurately predict clinical symptom load. Our study therefore assessed BOLD variability in both classification and regression machine learning frameworks for detecting SRC status or post-concussion symptoms from functional neuroimaging data .This study was carried out in accordance with the recommendations and approval of the University of Birmingham Research Ethics Committee. The protocol was also approved by the National Institute of Health Research Centre for Surgical, Reconstruction and Microbiological Research Centre (NIHR SRMRC\u2014Ethics Ref. 11-0429AP28). All subjects gave written informed consent in accordance with the Declaration of Helsinki. Deidentified data from this cohort may be made available by the authors on request.34 Participants included 29 semi-professional rugby athletes diagnosed with SRC and 6 additional rugby athletes diagnosed with repetitive SRC over a 21-day window. Athletes were excluded if they required hospital admission after initial assessment for concussion; presented with intracranial blood, brain tissue injury or non-concussion\u2013related pathologies on initial CT/MR scan; or had history of neurodegenerative pathology or chronic alcohol or drug abuse. In addition, 15 age-matched controls who have not received a concussion in the previous 3 months were enrolled. Other study design features are reported in Yakoub et al.34Study participants were recruited through the Surgical Reconstruction and Microbiology Research Centre (SRMRC), based at Queen Elizabeth Hospital of Birmingham (United Kingdom), as part of the repetitive concussion in sport (RECOS) study.1-weighted magnetization-prepared gradient echo structural image was acquired for each participant .All data were collected on a 3 Tesla Philips Achieva MRI scanner in Birmingham University Imaging Centre (BUIC). A high-resolution multi-echo T35 sensitive to BOLD contrast .The functional neuroimaging data were acquired using an accelerated single-shot gradient echo echoplanar imaging (EPI) sequenceDuring the resting-state fMRI scan, participants were asked to keep their eyes closed. Visual contact could be established at any time to the control room via a coil-mounted reverse mirror. All participants were instructed to lie still, keep their eyes closed and to try and think of nothing.fMRIPrep 20.2.037 and XCP Engine 1.0.39 Pre-processing entailed slice timing correction, motion correction, spatial smoothing [3\u2005mm full width at half maximum (FWHM) kernel], nuisance signal regression, temporal bandpass filtering, linear registration of functional images to structural images and non-linear registration of structural images to a standard-space MNI152 brain template (2\u2005mm isotropic voxel resolution).All MRI data processing was performed using containerized processing pipelines for reproducible analysis of neuroimaging data. Pre-processing steps were performed using 40 All nuisance variables were modelled via a single generalized linear model (GLM), to remove spurious correlations and noise introduced by head motion and variables of no interest. In addition to ICA-AROMA components classified as noise, these included head motion correction parameters, individual volume motion outliers estimated using DVARS41 with outliers flagged above 1.5 standardized DVAR, framewise displacement exceeding 0.5\u2005mm and mean white matter and cerebrospinal fluid signals averaged across all voxels identified from the segmentation of the high-resolution magnetization-prepared rapid gradient echo (MPRAGE). The fully pre-processed resting-state fMRI data were taken as the residuals from this GLM model. The residual image was transformed into normalized MNI152 space and resampled to 4\u2005mm isotropic voxels.Head motion parameters were accounted for using independent component analysis with automatic removal of motion artefacts (ICA-AROMA) analysis.43 BOLD signal variability was computed as the standard deviation of successive differences in the time-series signal extracted for each of the 200 grey matter regions defined by the Schaefer parcellation atlas.44 MSSD mean-centres the amplitude of difference in BOLD signal between frames, providing a more reliable metric of BOLD variability than standard deviation by avoiding inflated estimates of variability. The Schaefer 200 atlas provided sufficient spatial resolution and functional homogeneity within each parcel for examining regional MSSDBOLD signal across the entire cortex.Resting-state mean square successive difference (MSSD)45 The test was designed in the early 1990s specifically to assess concussed players of the National Football League46 and is now a Food and Drug Administration (FDA)\u2013approved neuropsychological testing tool in SRC.47 Inclusion of this particular cognitive test has been demonstrated to increase the sensitivity of post-concussion assessment beyond symptomatic evaluation and physical examination.48Participants completed the 25\u2005min computerized ImPACT assessment under identical administration conditions. ImPACT is a multi-domain online neuropsychological test that has been used as a standard technique documenting baseline cognitive function, characterizing the effects of concussive injury and monitoring the progress of recovery.49 and test\u2013retest reliability.50ImPACT includes a demographic survey, a brief medical history questionnaire and a post-concussion symptom scale consisting of 22 commonly reported symptoms. All participants indicated whether they endorsed each symptom and rated the extent of symptom severity on a seven-point Likert scale (0 = \u2018not experiencing the symptom\u2019 to 6 = \u2018severe\u2019). Scores were summed with higher scores reflecting more post-concussive symptoms. The six neurocognitive ImPACT sub-tests consist of word memory, design memory, X\u2019s and O\u2019s, symbol match, colour match and three letters. Five neurocognitive domain scores are derived from the sub-tests: verbal memory, visual memory, visual\u2013motor processing speed, reaction time and impulse control. Higher scores on the verbal memory, visual memory and visual\u2013motor processing speed composites reflect stronger performance, whereas a higher score on the reaction time composite reflects slower or worse performance. The impulse control composite provides a measure of errors on testing and is used to determine test validity. Test scores were converted to percentile measures and adjusted for age, gender, learning disability and level of education. ImPACT has adequate psychometric properties, including good construct validity34 Measures collected include Digit Span,51 Digit Symbol Coding and Symbol Search,52 a nine-hole peg test of fine motor dexterity53 and balance assessments including a virtual reality system,54 gait analysis56 and the modified balance error scoring system (mBESS),57 facilitating precise concussion diagnosis. Additional assessments, inventories and neuroimaging components collected by the RECOS protocol are reported in Yakoub et al.34As part of the RECOS study protocol, study participants completed additional screening and assessment inventories to examine clinical presentation of SRC.BOLD measures and ImPACT module composite scores, statistical unpaired t-tests were performed and corrected for multiple comparisons using Benjamini\u2013Hochberg control of the false discovery rate (FDR). These comparisons provide for interpretable identification of the specific ImPACT scores and modules most readily associated with SRC status, assessing for group-level effects of SRC and repetitive mTBI that emerge in variables used by our machine learning framework.To identify between-group differences in regional MSSD58 RF machine learning achieves high prediction accuracy when presented with a large number of input variables relative to the sample size,60 as is the case for our neuroimaging data, while still performing well with small numbers of input variables (as is the case for ImPACT scores). This importantly affords the ability to directly compare predictions of concussion status and post-concussion symptoms made by modelling BOLD variability and ImPACT composite scores using the same machine learning approach. Other motivations for selecting RF machine learning for this study include RF\u2019s understood performance, ease of use and resistance to outliers, as well as its capability to consider all BOLD variability regions jointly, avoiding an initial feature selection or engineering step in support of the exploratory nature of this study. Critically, this approach avoids using the results from between-group feature comparisons of BOLD variability to subset regional BOLD variability features that build a smaller and better-performing RF model, as feature engineering BOLD variability metrics is not a goal of the present study.BOLD variability indices and ImPACT composite scores were further assessed for their ability to differentiate healthy, concussion and repetitive concussion subjects and predict clinical symptom load using a random forest (RF) machine learning approach. RF is an ensemble machine learning method that trains an ensemble (i.e. forest) of decision trees to perform either classification or regression.BOLD measures and ImPACT composite scores were used variously as input features (i.e. independent variables), with output features (i.e. dependent variables) being group membership (classification) or post-concussion symptoms (regression). Each RF ensemble was parameterized using leave-one-out crossfold validation, with the minimum leaf size being the only tuned parameter. For ImPACT score models, minimum leaf size was tuned to 5 (preventing overfitting); otherwise, minimum leaf size was tuned to 20. Trees were grown by splitting input variables to maximize reduction in the Gini impurity index,61 repeated iteratively until maximum depth is reached or when all samples belong to a single class. The number of decision trees was increased until mean squared error (MSE) of out-of-bag (OOB) classification or regression predictions stabilized . Forests were grown to 5000 trees total.In our approach, bagged RF regression and classification were performed using built-in functions in MATLAB R2021a. MSSDK from a model fold (i.e. bag) that has been trained with resampling from all other athletes in our data set N, affording a direct test of RF models\u2019 ability to generalize their training data to unseen test set (i.e. OOB) subjects. The overall OOB prediction performance of RF machine learning evaluate three separate sets of input features: (i) ImPACT module composite scores, (ii) whole-brain MSSDBOLD measures and (iii) ImPACT score and MSSDBOLD measures jointly combined. This approach allows us to assess the utility of BOLD variability or ImPACT scores in isolation or combination when predicting SRC status and post-concussion symptoms. One versus all receiver operating characteristic (ROC) curves were calculated for the classification of each group across the three classes of RF models, indicating the true positive rate (i.e. correctly predicting group membership) versus the false positive rate (i.e. incorrectly predicting group membership in the next most likely classification).Individual RF machine learning predictions were generated from an ensemble of OOB decision trees, where the ensemble of decision trees that generate a prediction did not include the test subject\u2019s data in any resampled training data set. Restated, the set of decision trees used to make a prediction for test predicts subject The ROC area under the curve (AUC) was computed for all combinations of group and model to diagnose the overall prediction performance of each class. This AUC is the integral of the ROC curve\u2014i.e. the probability that the conditional probability of a random positive observation is greater than the conditional probability of a random negative observation. Thus, larger probabilities represent greater sensitivity and specificity for the positive label, suggesting greater utility for detecting SRC.For regression models, RF machine learning was instead trained to predict total reported post-concussion symptoms from the same combinations of input BOLD variability and ImPACT score variables (while ignoring group membership). Importantly, control subjects may incidentally report low levels of concussion symptoms in the absence of SRC\u2014further motivating the investigation of functional neuroimaging metrics for detecting SRC status.P value = 0.11). Impulse control is a measure of test validity, used to discard tests with a value above 30. The highest observed impulse control score in our sample was 15 , suggesting all ImPACT scores represent valid administrations and should be included in our analysis.Statistically significant between-group differences were not observed for ImPACT\u2019s composite measures of verbal memory, visual memory, visual\u2013motor processing speed, reaction time and impulse control between healthy control, concussed individuals and repetitive concussion individuals. BOLD measures for concussion or repetitive concussion athletes compared with healthy controls. In contrast with ImPACT score findings, reliable regional differences in MSSDBOLD signal are found in occipital and inferior temporal lobes, premotor areas and the ventral anterior cingulate. We observe that regional MSSDBOLD values are significantly decreased in concussed subjects relative to healthy controls, displaying significantly less fluctuation in BOLD signal amplitude over time. In contrast, all significant regions in repetitive concussion patients show greater MSSDBOLD than in healthy controls, reflecting significantly more pronounced variability in regional BOLD signal relative. This dissociation between BOLD signal decreases in concussion and increases in repetitive concussion suggests that unique pathophysiological mechanisms that implicate functional alterations may underlie the more severe sequelae observed in repetitive SRC.BOLD metrics and ImPACT scores were used to train RF machine learning models. BOLD demonstrated the highest classification accuracy, with ImPACT scores alone producing models with the lowest classification accuracy.Despite evidence for group-level differences in regional BOLD signal variability, no feature selection was performed prior to training RF classifier models, and therefore, all regional MSSDBOLD data. Only the model trained on ImPACT scores alone under-performs this baseline value for classifying concussion subjects . Here, we observe the greatest difference in classification performance between ImPACT scores and MSSDBOLD measures, suggesting BOLD variability is both a more sensitive and specific index of signal associated with repetitive SRC than ImPACT scores.BOLD variability in combination). Ground truth positive labels are reflected along rows, with OOB classification labels in columns . Label confusion suggests this best-performing RF model (correctly classifying 31/50 athletes in our sample) is most sensitive for detecting concussion and repetitive concussion. However, the RF model also displays markedly lower specificity for concussion, misclassifying a majority (11/15) of healthy control subjects as concussed. This suggests that while BOLD variability indeed facilitates detection of SRC and repetitive mTBI, models trained to include BOLD variability measures may require more targeted feature engineering to better distinguish between health controls and subjects with lower SRC severity, as has been shown using functional connectivity data.20 This model\u2019s performance for classifying control subjects (4/15) is also an improvement over the RF model trained using only ImPACT composite scores, which misclassifies all control subjects as concussion subjects (0/15). This performance likely reflects the large label size of concussion athletes and the lack of reliable between-group differences observed with ImPACT scores. These results suggest that MSSDBOLD measures indeed contribute to a classification model with improved prediction accuracy for distinguishing healthy and concussed individuals.BOLD holds promise as a sensitive biomarker for detecting symptomatic abnormalities in cerebrovascular status in athletes with SRC. We briefly review the findings with respect to regional MSSDBOLD and ImPACT modules by examining (i) between-group differences, (ii) their classification accuracy using the categorical RF model and (iii) their regression accuracy using the continuous RF model.The present study demonstrates that MSSD12 Our results identify several cortical areas in those regions that demonstrate significant differences in MSSDBOLD measures in the presence of SRC or repetitive mTBI. Specifically, MSSDBOLD measures in occipital and inferior temporal regions  and midline structures (premotor cortex and anterior cingulate) significantly differ between control and concussed athletes. These regions are particularly vulnerable to injury due to inertial forces, either front to back or rotational. We also observed a dissociation in the directionality of BOLD variability changes. Concussed athletes displayed universally decreased BOLD variability across affected brain regions. In addition to reflecting altered neurovascular coupling, patterns of low regional BOLD variability observed for concussion patients may also in part reflect functional hyperconnectivity commonly observed following mTBI,62 such that stronger functional coupling of distal regions entrains BOLD signal amplitude to a more limited band. In contrast, repetitive concussion subjects display uniformly elevated BOLD signal variability in affected regions. As the elapsed duration between most recent SRC and clinical assessment is comparable for concussion and repetitive concussed athletes . In these models, the majority of features ranked as highly important represented BOLD variability measures, not ImPACT scores. Classification based on the categorical RF models demonstrated a higher sensitivity or true positive rate for accurately identifying individuals with repetitive concussions when using BOLD variability (AUC = 0.66) than was observed using ImPACT scores (AUC = 0.25). Overall multi-label classification accuracy was also increased when BOLD variability data were included, with classification error decreasing from 46%  to 38% when ImPACT scores and BOLD variability were jointly modelled. This was partially due to increases in classification accuracy for identifying subjects with high overall symptom loads as belonging to concussion or repetitive concussion groups. Classification accuracy of control subjects, while still low, also increased when BOLD variability data were included in the RF models, suggesting that BOLD variability may have greater specificity than ImPACT for detecting SRC. The left middle frontal gyrus, left frontal pole and temporal occipital fusiform gyrus had the largest effects in the RF model classification, which is in line with research suggesting regions in the frontal and temporal lobes are commonly affected in mTBI.BOLD data in a single model produced the best prediction performance with a MSE of 26.9. Feature importance scores indicated that the main variables used to generate predictions for this model were BOLD variability measures, suggesting that variance associated with ImPACT scores is of lower importance than BOLD variability during forest growth and model training. Results from these continuous RF models indicate that MSSDBOLD is a more sensitive predictor of post-concussion symptom totals and that jointly considering functional and neurocognitive data together is a useful approach for machine learning models to improve the accuracy of predictions for total SRC symptom load.Prediction accuracy was highest for RF models trained to predict the total number of post-concussion symptoms using the combination of ImPACT composite scores and BOLD variability variables. The continuous prediction model trained only on ImPACT scores converges during training to a MSE of 30.5 when predicting post-concussion symptoms, showing the largest error and the worst performance. A continuous RF model that trained only on BOLD variability data demonstrated lower MSE (28.7), reflecting improvements to predictive performance. Jointly including ImPACT and MSSDBOLD can be generalized to other populations (i.e. children and adolescents with SRC and non-athletic populations with mTBI). Second, MSSDBOLD cannot currently be used to assess severity of an injury itself, only the extent of the symptom load that it produces, and additional screening methods involving structural neuroimaging techniques will be still required to reveal the extent of injury and changes in pathology during recovery. Third, the analysis approach using MSSDBOLD cannot reveal the actual damage to the vasculature and surrounding neural cells at the site of injury. Fourth, while our study observes high performance for predicting total clinical symptom load in healthy and SRC athletes, our SRC classification models will often mistake healthy controls for concussed subjects. This may be due to our sample\u2019s imbalance between control (N = 15) and concussion (N = 29) subjects or may suggest that more a more precise feature selection step is required to identify MSSDBOLD regions more specific for SRC, possibly requiring higher-resolution cortical parcellation schemes. On the other hand, mismatches in performance may potentially be addressed by methods that do heavily subset BOLD variability as an initial feature selection step, potentially inducing parity in the number of BOLD and ImPACT input variables to afford comparison of prediction accuracy through alternative ML approaches . While random forests appear to be sufficient for our purposes in this manuscript, we do not intend to suggest they are necessary. Fifth, there may be other representations of variability besides MSSDBOLD that better capture the extent of underlying functional alterations in SRC, including representations that jointly consider resting static or dynamic functional correlation or large-scale intrinsic brain network organization. Future research should consider investigating these elements at a fine-grained level to further elucidate neurobiological pathologies in SRC. Sixth, and finally, functional MRI acquisition remains prohibitive in many outpatient clinical settings, though we believe our results at do least motivate further exploration of BOLD variability for monitoring athletes before and after SRC, particularly from a personalized or precision medicine perspective.In this study, we demonstrate that BOLD signal variability holds promise as a diagnostic biomarker for detecting functional neural alterations following SRC. While our approach motivates systematic exploration into BOLD variability\u2019s utility for detecting injury in clinical neuroimaging of concussion, there are several limitations and challenges to this approach. First, given that the concussed group is a highly homogenous athletic population, future studies should examine whether the observed deviations in MSSD73 consistent with the present findings. Executive dysfunction can be a pernicious consequence of TBI,75 implicating alterations to network topology and dynamics in neurological sequela following mTBI.76 Future research may wish to examine brain network alterations for their impact on other cognitive domains or as a potential neurobiological marker of injury and recovery status.These findings emphasize the need for future research to examine how network topology and dynamics are altered by TBI. Recent research has highlighted the importance of global brain network topology for facilitating cognitive abilities,BOLD assessed from resting-state fMRI are sensitive to abnormalities in cerebrovascular status in athletes with SRC. Further, we show that regional MSSDBOLD measures can more sensitively and specifically identify concussed and repetitive concussed individuals within a RF machine learning framework compared with standardized neurocognitive tests. In contrast, ImPACT composite scores do not capture reliable between-group differences in concussion status and cannot be used in isolation to build an RF model that discriminates between concussion, repetitive concussion and healthy athletes. Combining BOLD variability and ImPACT scores leads to the highest prediction performance, supporting the claim that altered BOLD variability provides novel information about altered cerebral vascular status that can aid diagnosis and return-to-play decisions when collected alongside existing assessment protocols for the detection of SRC. Further, we provide evidence that MSSDBOLD contributes to prediction of total post-concussion symptoms, outperforming ImPACT scores across healthy and concussed patients. In conclusion, this paper provides initial evidence that BOLD variability holds promise as a potential clinical marker for SRC, motivating a more systematic exploration of BOLD variability as a candidate biomarker in future work. To investigate the sensitivity and efficacy of MSSDBOLD in diagnosing SRC, future neuroimaging research may wish to deploy MSSDBOLD measures alongside neuropsychological testing protocols and structural neuroimaging methods, providing a more complete assessment of athlete health that includes cerebrovascular alterations and associated cognitive deficits to better facilitate detection of injury in SRC and guide return-to-play decisions.Diagnosis of SRC can be difficult due to the low sensitivity of assessments designed to identify cognitive deficits in athletes with suspected injuries. In addition, clinical evaluation of SRC using structural imaging methods is limited to characterizing anatomic pathology and cannot detect haemodynamic or neurometabolic disruptions. In this work, we provide evidence that functional neuroimaging indices of MSSD"}
+{"text": "Sparsity finds applications in diverse areas such as statistics, machine learning, and signal processing. Computations over sparse structures are less complex compared to their dense counterparts and need less storage. This paper proposes a heuristic method for retrieving sparse approximate solutions of optimization problems via minimizing the [[EQUATION]] quasi-norm, where $0<p<1$. An iterative two-block algorithm for minimizing the [[EQUATION]] quasi-norm subject to convex constraints is proposed. The proposed algorithm requires solving for the roots of a scalar degree polynomial as opposed to applying a soft thresholding operator in the case of $\\ell_{1}$ norm minimization. The algorithm's merit relies on its ability to solve the [[EQUATION]] quasi-norm minimization subject to any convex constraints set. For the specific case of constraints defined by differentiable functions with Lipschitz continuous gradient, a second, faster algorithm is proposed. Using a proximal gradient step, we mitigate the convex projection step and hence enhance the algorithm's speed while proving its convergence. We present various applications where the proposed algorithm excels, namely, sparse signal reconstruction, system identification, and matrix completion. The results demonstrate the significant gains obtained by the proposed algorithm compared to other [[EQUATION]] quasi-norm based methods presented in previous literature."}
+{"text": "Medical use of chemically modified synthetic estrogens caused toxic complications; thromboembolic events and increased cancer risk in female organs as they proved to be endocrine disruptors deregulating estrogen receptors (ERs) rather than their activators. Synthetic estrogen treatment exhibits ambiguous correlations with cancer risk at different sites, which may be attributed to an inhibition of the unliganded activation of estrogen receptors (ERs) coupled with compensatory liganded activation. The principle of estrogen induced breast cancer led to the introduction of antiestrogen therapies against this tumor; inhibition of the liganded activation of estrogen receptors and aromatase enzyme activity. The initial enthusiasm turned into disappointment as the majority of breast cancers proved to be primarily resistant to antiestrogens. In addition, nearly all patients showing earlier good tumor responses to endocrine therapy, later experienced secondary resistance leading to metastatic disease and fatal outcome. Studying the molecular events in tumors responsive and unresponsive to antiestrogen therapy, it was illuminated that a complete inhibition of liganded ER activation stimulates the growth of cancers, while a successful compensatory upregulation of estrogen signal may achieve DNA restoration, tumor regression and patient\u2019s survival. Recognition of the principal role of endogenous estrogens in gene expression, gene edition and DNA repair, estrogen treatment and stimulation of ER expression in patients may bring about a great turn in medical practice.This work presents the history of the recognition of principal regulatory capacities of estrogen hormones having been mistakenly regarded as breast cancer promoting agents for more than 120\u00a0years. Comprehensive analysis of the results of clinical, epidemiological, immunological and molecular studies justified that endogenous estrogens are the principal regulators of embryonic development, survival and reproduction  The role of estrogen hormones in the carcinogenesis of female breasts has long been debated based on the ambiguous results of menopausal hormone therapy (MHT), however, the exact mechanism of their tumor inducing effect is not entirely clarified till now .via estrogen withdrawal by oophorectomy  approved marketing of synthetic estrogens, non-steroidal diethylstilbestrol (DES) and steroidal ethinylestradiol (EE) as well as conjugated equine estrogens (CEEs) for medical purposes .In 1944, Haddow et al. proposed the concept of \u201cthe estrogen paradox\u201d suggesting that in spite of the well known stimulating effect of estrogen hormones on breast cancer, high doses of DES is a promising therapy against this tumor . DespiteIn the meantime, the controversial results of great menopausal hormone therapy (MHT) studies strengthened the presumed role of estrogen treatment in the development and progression of breast cancer , 9. AmonSeparated evaluation of the effects of specific HRT types applying natural and synthetic hormones justified that horse urine derived CEE alone is an outstanding formula decreasing the risk for breast cancer, coronary heart disease and bone loss. Conversely, synthetic estrogens and their combination with synthetic progestins may have unforeseeable toxic and carcinogenic impacts .The presumed carcinogenic capacity of endogenous estrogens promoted the introduction of current antiestrogen therapies against breast cancer. In 1971, Cole et al. reported the use of tamoxifen, a selective inhibitor of liganded activation of estrogen receptor (ER) for the treatment of advanced breast cancer in postmenopausal women . The expde novo (primary) antiestrogen resistance (Antiestrogen therapy of advanced breast cancer yielded many difficulties and failures from the onset. Tamoxifen as a first line therapy induced moderate tumor regression rate (<40%\u201350%) even among the targeted ER-positive breast cancer cases, while the remaining patients could not exhibit tumor responses or experienced tumor growth. Therapeutic failures were designated as sistance . During sistance . In addisistance .De novo or acquired resistance to AI treatment also developed in the vast majority of patients with advanced breast cancer.Aromatase inhibitors (AIs) also were developed for the therapeutic reduction of estrogen synthesis in breast cancer cases . Among AFollowing the failures in high dose estrogen treatment the development of antiestrogen therapy could also not realize the enthusiastic expectations for breast cancer defeat. In breast cancer cases diagnosed and treated at the earliest stage, unforeseeable tumor recurrence and fatal outcome may occur even after decades . Tumor rThe comparison between the major anticancer capacity of endogenous estrogens and the ambiguous effects of the endocrine disruptor synthetic estrogens and antiestrogens shows some parallelism with the history of Rosetta stone. It is a stele composed of granodiorite inscribed with three versions of a decree issued in Memphis, Egypt, in 196. The texts are in ancient Egyptian hieroglyphic scripts, in Demotic scripts and in Ancient Greek. The comparison of the three versions made Rosetta stone a key to deciphering the ancient Egyptian scripts.In 2007, estrogen deficiency was exposed as a newly recognized risk factor for oral cancer in a Hungarian clinical-epidemiological study . Oral caOral cancer induced by decreased estrogen levels seemed to be highly controversial to the old principle of estrogen induced breast cancer as the regulation of genomic processes may not be quite different at various sites. Analyzing the literary data, defective estrogen signaling proved to be a strong cancer risk factor for several organs including female breasts . The corEstrogen deficiency emerged as a new cancer risk factor directly deteriorating the signaling functions of mammalian cells. Moreover, results of clinical and experimental studies justified that behind insulin resistance associated chronic diseases a defect of estrogen signal may always be revealed suggesting their strong partnership in cancer development .Studies on breast cancer epidemiology suggested that the better the reproductive capacity of women the lower is their breast cancer risk. In healthy premenopausal women having higher estrogen levels, the breast cancer risk is much lower as compared with postmenopausal cases showing extremely low serum estrogen concentrations . StudiesImmunohistochemical imaging of ERs, progesterone receptors (PRs) and human epidermal growth factor receptors (HER2s) in breast cancers provided further possibilities to clarify the risk factors and therapeutic possibilities of variously differentiated tumors .Experimental and clinical studies examined the correlation between ER expression and the development and progression of breast cancer. The differences between ER-positive and ER-negative tumors regarding their gene expressions and genomic mutations remained to be clarified . HoweverIn postmenopausal women with decreased estrogen levels, the majority of tumors proved to be highly differentiated with abundant ER expression  showing In animal experiments, high estrogen concentrations in pregnancy and short term exposure to pregnancy mimicking high estrogen levels prevented mammary carcinogenesis induced by either chemicals or tumor inoculation . GeneticIn conclusion, either estrogen deficiency or ER-resistance to estrogen activation may lead to genomic disorders increasing the risk of breast cancer . MoreoveThe genome of living organisms is inherited; however, it shows a great plasticity through appropriate self-mediated changes continuously updating the regulatory processes throughout the life. Bio-intelligence means that the genome of living creatures is capable of perception of its environment (outer and inner) . Genome Malignant tumor cells are mistakenly regarded as enemies to be killed similarly like exogenous microbes. Presumably, \u201chostile\u201d tumor cells develop survival techniques so as to escape from the regulatory commands of patient\u2019s body. In reality, tumor cells are dysregulated human cells having more or less remnants of the same regulatory network like patients\u2019 healthy cells have. The tumor initiator is an inherited or acquired failure of the principal regulator of the genomic machinery. Variously differentiated tumor cells exhibit spontaneous efforts for the improvement of their genomic regulation; however, this work in itself may rarely lead to a successful tumor regression. Tumor cells need medical help for the self directed repair of genomic alterations instead of crude inhibition of their spontaneous gene repairing efforts .Over the past decades, we acquired a deeper appreciation on the roles of estrogen receptors in human physiology and pathology . EstrogeIn humans, ER-alpha and ER-beta isoforms are co-expressed in many cells and tissues, and they control key physiological functions in all organ systems in strong interplay. ER alpha primarily drives and controls the proliferation and DNA stability of cells, while ER beta regulates cell growth in particular . Both ERER\u03b1 is the highly predominant isoform in mammary gland, uterus, ovary , bone, male reproductive organs (testes and epididymis), prostatic stroma, liver, and adipose tissue. By contrast, ER\u03b2 is highly expressed in the prostatic epithelium, bladder, ovary (granulosa cells), colon, adipose tissue, and immune system. Both subtypes are markedly expressed in the cardiovascular and central nervous systems . This lavia unliganded pathway (ERs have possibilities for liganded (estrogen bound) activation through their activation function 2 (AF2) domain and for unliganded activation by several transduction molecules through the ancient activation function 1 (AF1) domain . In the  pathway . Ligand- pathway . Balance pathway . Artificvia regulatory circuits  and insulin-like growth factor-1 receptors (IGF-1Rs) . Ligandelear ERs . In preglear ERs . The eme pathway .regulatory circuit of fuel supply, activated ERs drive and control all steps of cellular glucose uptake and the maintenance of glucose homeostasis (via facilitating the expression and translocation of intracellular glucose transporters (GLUTs)  . Disorde (GLUTs) . In insu (GLUTs) . In MCF- pathway . In tumo pathway .ERs expressed in the adipose tissue mass regulate the energy supply of the whole body of mammalians. Abdominally located fatty tissue is a hub of the signaling network providing energy and ER signal to the work of visceral organs. Fatty tissue in the pericardium regulates heart, while fat positioned along great vessels drives and controls the function of arteries and veins . IncreasConversely, estrogen deficiency or ER resistance deregulates the signaling functions of adipocytes. In women, menopause associated estrogen loss may increase the risk for both metabolic disorders and weight gain . AdipocyFrom the early 1940s, synthetic estrogens DES and EE in high doses were introduced as promising treatments for patients with advanced breast cancer . High doIn female transgenic mice with inactivated AF2 domain of ERs, DES treatment could not induce an estrogen-like uterotrophic response through the activation of AF1 domain . This exvia high dose synthetic estrogen treatment led to controversial tumor responses and serious toxic complications via alterations in the expression of estrogen regulated genes.In pregnant rats, exposure to excessive DES and EE induced mammary tumor development in both mothers and their offsprings. These synthetic estrogens equally provoked persistent alterations in the expression of estrogen regulated genes, in DNA methylation and histone modifications . These ovia an additive deregulation of ER activation  comprising steroidal EE were developed in the early 1960s and EE became a standard component of near all forms of contraceptive pills . OCs comtivation .via a strong compensatory upregulation of the AF2 domain of ERs.In contrast, OCs comprising low doses of EE may decrease endometrial cancer  and ovarIn conclusion, EE is an endocrine disruptor compound even in low doses as it is rather a partial antagonist of ER activation instead of being an agonist. Since EE has been regarded as a bioidentical estrogen, the experienced thromboembolic events and increased breast cancer risk in OC users were mistakenly regarded as complications of elevated estrogen levels .Xenoestrogens deriving from the environment have endocrine disrupting properties acting as false ligands of nuclear receptors including estrogen receptors. Deregulation of estrogen receptors lead to changes in DNA methylation and histone modification leading to genomic instability. Environmental endocrine disruptor compounds may be natural like phytoestrogens and resveratrol or synthetic substances like solvents, pesticides, cleaning products and cosmetics. Many observations are suggesting that exposure to environmental endocrine disruptors do contribute to cancer, diabetes, obesity, metabolic syndrome and infertility .During the development of menopausal hormone therapy (MHT) both synthetic estrogens  and conjugated equine estrogens (CEEs) with natural origin were applied . Before Increased endometrial cancer risk was reported in postmenopausal women using miscellaneous exogenous estrogens . From 19In 2002, the results of a great, prospective, placebo controlled Women\u2019s Health Initiative (WHI) study strengthened that combined CEE plus medroxyprogesterone-acetate (MPA) treatment  increased the risk of breast and colon cancer, thromboembolism, cardiovascular diseases and hip fracture . FollowiEvaluating the controversial results of MHT studies; the FDA US established several times that various approved estrogen and progestin formulations may alleviate menopausal symptoms in postmenopausal women. However, their use is associated with ambiguous \u201crisks and benefits\u201d concerning coronary heart disease, thromboembolism as well as for endometrial and breast cancers .In 2004, the results of a further great, prospective placebo controlled WHI study showed strikingly decreased breast cancer risk after using oral CEE alone; and the risk for total cancer also was slightly reduced . ConsideCritical analysis of the results of MHT studies revealed that the use of estrogens with different origin and even their combinations with synthetic progestins may explain the chaos of quite controversial clinical experiences among hormone user women . PremariIn 2021, the results of a new WHI randomized, placebo-controlled trial were published. Conjugated equine estrogen treatment  significantly reduced ER-positive, PR-negative cancers and deaths from breast cancer also were reduced by 40% . This fiThe pharmaceutical industry developed the first drugs for the inhibition of estrogen induced activation of ERs and they were introduced into the practice of breast cancer care. Tamoxifen was regarded as a selective estrogen receptor modulator, while letrozole worked as aromatase inhibitor reducing estrogen synthesis in breast cancer patients .Considering the whole population of breast cancer patients, antiestrogen treatment could not surpass the \u201cmagic\u201d 30% of tumor response rate, similarly to the weaknesses of other endocrine therapies; such as oophorectomy or high doses of synthetic estrogens . The majDespite the 50\u00a0years practice and advance of antiestrogen therapy, the inhibition of liganded ER activation could not become the key to the tumor free survival of breast cancer cases. Enormous efforts have been exerted worldwide to overcome the tumor \u201cresistance\u201d to antiestrogen therapy, which develops near in all ER-positive breast cancer patients following long term treatment.via higher expression of ERs and activation of estrogen synthesis. In the meantime, the blockade of liganded ER activation is a crisis even for tumors promoting the upregulation of estrogen signal and DNA stabilization leading to apoptosis. Tumor response may be regarded as a common success based on the repaired genomic regulation of both patients and their tumors .In patients, non-responsive to antiestrogens, various toxic side effects are experienced suggesting a genome wide blockade of the estrogen signal in the whole body. Tumor cells remain without regulatory help, similarly, like tumor cell lines Molecular events behind the response and resistance of antiestrogen treated breast cancer cells were thoroughly analyzed. Different mechanisms of endocrine resistance were suggested, such as compensatory increased expression of ER coactivators , and a ctumor cells responsive to endocrine therapy, the increased expression and activation of ERs were typical observations counteracting the endocrine disruptor treatment  template stimulating the expression of a foreign protein via translation (In 1989, Malone and coworkers published a landmark experiment on inducing protein production in cell cultures nslation . In 1990nslation . These snslation .via mRNA technology may have great possibilities in human practice beyond vaccination. Considering that ERs are the chief regulators of all genomic processes, Malone\u2019s mRNA technology may be an excellent method for the stimulation of appropriate ER protein production in patients. Theoretically, ESR1 mRNA treatment in patients with low ER levels or ER resistance may prevent breast cancer development by stimulation of ER production and increase in estrogen regulated gene expression. In addition, in patients with advanced ER negative and TNBC type tumors, a preoperative ESR1 mRNA treatment may achieve marked tumor regression coupled with stimulating defensive reactions in the adjacent tissues. In the postoperative phase, local ESR1 mRNA treatment improves the genomic functions in the remaining breast tissue and inhibits the development of recurrent tumor. In breast cancer cases with multiple metastatic lesions, systemic ESR1 mRNA treatment may achieve regression of tumors at all sites besides improvement of the metabolic and immunological status of patients. The dream of perfectly selective tumor therapy and the concomitant safeguarding of healthy tissues seem to be realized.The production of a desired protein The developing new trends in anticancer fight are targeting mutated genes by gene therapy and attacking their altered protein products by immunotherapy. However, the accumulation of altered genes and their abundant protein products in tumors may not show a parallelism with the progression of the disease as they are rather spontaneous compensatory efforts for DNA repair instead of oncogenic activities. All developed new methods of gene therapies are targeting the compensatory genome improving processes, while tumor cells need rather medical help supporting their DNA restoration so as to achieve apoptotic death.via synthetic estrogen and antiestrogen treatment, helped to reveal the omnipotent curing capacity of endogenous estrogens via balanced liganded and unliganded activation of ERs.Recognition of the molecular mechanisms of estrogen receptor deregulation"}
+{"text": "This letter to the editor discusses \u201cthe use of video-EEG monitoring to guide antiseizure medication (ASM) withdrawal in patients with epilepsy\u201d . The aut Dear Editor,I read with great interest the recent article by Dhaenens-Meyer et al.  on \u201cThe One of the primary challenges in epilepsy care revolves around the safe and appropriate withdrawal of ASM. While ASM can effectively control seizures, it may entail significant side effects and financial burden for patients . AdditioThe study by Dhaenens-Meyer et al.  suggestsNonetheless, as the authors astutely acknowledge, further research is warranted to fully comprehend the effectiveness of this approach and to refine patient selection criteria for ASM withdrawal. Future studies should explore the utility of video-EEG monitoring in diverse patient populations and settings. For instance, investigations could delve into the model\u2019s applicability in pediatric epilepsy or drug-resistant epilepsy cases, providing deeper insights into its broader suitability.Comparative analyses between video-EEG monitoring and other ASM withdrawal methods could also shed light on the model\u2019s unique advantages. In this regard, Lamberink et al.  presenteMoreover, the implications of the study\u2019s findings stretch beyond clinical practice and extend to public health policies related to epilepsy management. Existing policies that prioritize ASM access might necessitate reevaluation in light of the possibility of ASM withdrawal. Policymakers should contemplate how to best support individuals with epilepsy who opt for ASM withdrawal, including the provision of resources to manage withdrawal symptoms and continuous monitoring of seizure activity during the withdrawal process .In conclusion, the study by Dhaenens-Meyer and colleagues highlights the potential benefits of incorporating video-EEG monitoring into epilepsy management. By offering a more objective and data-driven approach to ASM withdrawal, video-EEG monitoring could substantially mitigate the risk of seizure recurrence and improve overall patient outcomes. I am optimistic that ongoing research will further explore and enhance this approach, and I strongly encourage healthcare providers to consider implementing video-EEG monitoring when appropriate.Sincerely,Apochi Obed Okwoli."}
+{"text": "The specialty pharmaceuticals market is expanding more rapidly than the traditional pharmaceuticals market. Specialty pharmacy operations have evolved to deliver selected medications and associated clinical services. The growing role of specialty drugs requires new approaches to managing the use of these drugs. The focus, expectations, and emphasis in specialty drug management in an integrated health care delivery system such as Kaiser Permanente (KP) can vary as compared with more conventional health care systems. The KP Specialty Pharmacy (KP-SP) serves KP members across the United States. This descriptive account addresses the impetus for specialty drug management within KP, the use of tools such as an electronic health record (EHR) system and process management software, the KP-SP approach for specialty pharmacy services, and the emphasis on quality measurement of services provided.\u00a0 Kaiser Permanente\u2019s integrated system enables KP-SP pharmacists to coordinate the provision of specialty drugs while monitoring laboratory values, physician visits, and most other relevant elements of the patient\u2019s therapy. Process management software facilitates the counseling of patients, promotion of adherence, and interventions to resolve clinical, logistic, or pharmacy benefit issues. The integrated EHR affords KP-SP pharmacists advantages for care management that should become available to more health care systems with broadened adoption of EHRs. The KP-SP experience may help to establish models for clinical pharmacy services as health care systems and information systems become more integrated."}
+{"text": "Bacteriophages, the viruses that infect and replicate within bacteria, have long been recognized as potential therapeutic agents against bacterial infections. The rise of antibiotic resistance and the limitations of traditional antibiotics have prompted researchers to explore innovative strategies in the field of drug discovery. Bacteriophage bioengineering represents a promising avenue that offers targeted and precise solutions to combat bacterial pathogens . EngineeBacteriophages possess a high degree of specificity in targeting bacterial hosts . This exIn terms of refining bacteriophages for therapeutic purposes, genetic engineering techniques have played a crucial role . The manAs bacteriophages have specific host selectivity, bioengineered bacteriophages can be used to rapidly identify pathogenic bacteria in food products via reporter or labeled nanoprobe-mediated fluorescence or luminescence-based sensing systems . The purThe concept of utilizing bacteriophages for both vaccine development and cancer therapy demonstrates the versatility of these biological entities . In the Although bacteriophage bioengineering holds immense promise, it is not without its challenges. One significant obstacle is the potential for the emergence of phage-resistant bacteria . As bactBacteriophage bioengineering represents an innovative approach to drug discovery, offering precise solutions for targeting harmful bacteria while preserving beneficial counterparts. Through precision engineering techniques, such as CRISPR-Cas systems, bacteriophages are equipped with specialized antimicrobial tools to enhance their efficacy and scope. This transformative field addresses challenges posed by bacterial resistance and regulatory complexities, presenting boundless potential. Furthermore, integrating treatment and real-time monitoring through theranostics reshapes infectious disease management. Bacteriophage bioengineering is at the forefront of drug discovery, influencing antibiotic resistance, diagnostics, and innovative theranostics, positioning it as a promising frontier despite obstacles. Ongoing research, requiring collaboration among researchers, pharmaceutical companies, and regulatory bodies with adaptive strategies, is crucial to address the obstacles and unlock the full potential of bioengineered bacteriophages. As highly adaptable biologics, they offer innovative disease management and precision therapeutics solutions, reshaping the healthcare landscape. The era of \"Designer Phages\" heralds a new chapter in addressing critical healthcare challenges ."}
+{"text": "Colorectal surgery has witnessed a transformative shift with the advent of minimally invasive techniques, offering patients reduced postoperative discomfort, shorter hospital stays, and accelerated recovery compared to conventional open surgery. This comprehensive review aims to assess the current state of minimally invasive approaches in colorectal surgery, encompassing various techniques such as single-incision laparoscopic surgery, robot-assisted surgery, and conventional laparoscopic surgery. The article meticulously explores the benefits and drawbacks of each technique, delves into the established criteria for their application, delineates cautious circumstances, and analyzes the outcomes of minimally invasive colorectal surgery. Additionally, the integration of virtual reality and augmented reality for surgical planning and training is discussed, shedding light on the future trajectory of this field. Surgeons and researchers striving to enhance patient care and surgical outcomes in colorectal surgery will find this review article an invaluable resource, presenting crucial components of minimally invasive colorectal surgery and paving the way for continued advancements in the field. Over the past three decades, surgical innovation has been focused on the desire to lessen surgical stress and improve endoscopic access. Since Semm performed the first laparoscopic appendectomy in 1981, minimally invasive colon surgery has seen remarkable progress. Laparoscopic and minimally invasive surgery have been greatly advanced by recent developments in video and robotic technology . QualityA lengthy process spanning three decades has led to the examination and implementation of minimally invasive surgery for colorectal cancer, particularly for rectal cancer. Due to its intricacy involving many quadrants and early worries about a greater frequency of port site recurrences, colon cancer surgery offered hurdles in contrast to procedures like gallbladder and appendectomy. Prior to the publication of adequately planned trials in the mid-2000s, laparoscopic procedures were thoroughly assessed for colon cancer through a number of non-randomized observational studies. Notably, individuals with rectal cancer were frequently omitted from these studies. Randomized controlled trials (RCTs) contrasting laparoscopic and open surgery for colon cancer, including the Barcelona, Clinical Outcomes of Surgical Therapy (COST), Colon Cancer Laparoscopic or Open Resection (COLOR), and Conventional vs. Laparoscopic-Assisted Surgery in Patients With Colorectal Cancer (CLASICC) trials, consistently showed at least equivalent oncologic outcomes, comparable complications, a modestly shorter hospital stay, and the restoration of bowel function following laparoscopic surgery . But desThe Medical Research Council's (MRC) CLASICC experiment, which included patients with both colon and rectal cancer, featured the first randomized controlled trial contrasting laparoscopic versus open surgery for rectal cancer . There wMethodologyThis comprehensive analysis used a methodical process to compile and examine pertinent research on minimally invasive colorectal surgery techniques. To achieve a thorough grasp of the issue, the study included both qualitative and quantitative research studies and academic articles. To find pertinent materials, a thorough search was carried out across many academic databases, including PubMed, Scopus, and Google Scholar. A database like PubMed\u00a0was searched using relevant keywords and phrases like \"laparoscopy,\" \"robotic,\" \"non-invasive,\" \"colorectal,\" and \"surgery.\" There were only English-related results shown. The most recent report from a similar study was utilized if there were multiple published reports. We only considered review publications that also included original data. Figure ObjectiveThis research paper aims to conduct a thorough examination of the current status of minimally invasive colorectal surgery, highlighting progress, results, and future outlooks.Assessing ProgressThe main goal of this review is to examine current developments in laparoscopic and robot-assisted minimally invasive colorectal surgical techniques . Our objEvaluating Medical ResultsA comprehensive evaluation of the clinical results associated with minimally invasive colorectal surgery is another key goal . We willIdentifying Patient Selection CriteriaFinding the best criteria for selecting individuals for minimally invasive colorectal surgery is the aim of the research we are conducting. We will analyze factors including age, pre-existing health issues, tumor location, and cancer stage to determine which patients would benefit most from less invasive treatments . We willExploring Future PerspectivesThis review's objectives go beyond just reviewing the state of minimally invasive colorectal surgery today. It also explores potential directions for progress and the prospects for the future . We willDiscussionRobot-Assisted Laparoscopic Surgery for Rectal Cancer: The Ideal Solution?Robot-assisted laparoscopic prostatectomy is becoming increasingly common. Straight laparoscopic tools have limits in small anatomical areas; however, with EndoWrist instruments and a modern three-dimensional vision system, these restrictions are addressed. Particularly in the extraperitoneal area of the pelvic cavity, surgeons are drawn to the idea of robot-assisted laparoscopic surgery for rectal cancer . HoweverTechniques: Total Robotic or Hybrid Approach?There is continuous discussion over the placement of ports, docking methods, and tactics for controlling splenic flexure during robot-assisted laparoscopic TME. One fully robotic surgery and one hybrid strategy, which differs depending on the tool used for the splenic flexure takedown, are the two main procedures that are primarily employed. Some surgeons use a hybrid technique, depending on a straight laparoscopy for mobilizing the splenic flexure while using a robotic surgical system for vascular control and pelvic dissection . The goaSingle-Incision Laparoscopic SurgeryThe benefits of conventional multiport laparoscopy (CML) over open surgery are well-known and include less discomfort, shorter hospital stays, fewer wound problems, and a better outward look. By performing the whole process through a single abdominal incision, single port laparoscopic surgery (SILS) can maximize the benefits of CML while minimizing surgical stress. Single port laparoscopic surgery is a development in the direction of scar-free, minimally invasive surgeries. This method deviates from the basic \"triangulation\" idea of laparoscopy and poses difficulties by containing all laparoscopic ports within a single incision. Compared to CML, SILS requires more advanced laparoscopic skills, is more complicated, has poorer ergonomics and early studies suggest longer operating times than with CML . Beyond Learning Curve for Laparoscopic Surgery for Rectal Cancer: Is There a Magic Number?Rectal resections are more difficult to do than colectomies, as previously indicated, because of the complicated pelvic architecture, the significance of maintaining autonomic nerve function, and the effects of neoadjuvant therapy. Achieving enough exposure is essential in traditional open surgery, especially in male patients with a big mesorectal tumor and a restricted pelvis, where the retractor plays a significant role. For the necessary total mesorectal excision, a precise and crisp dissection is required to produce the best oncologic outcomes. All of these elements work together to make laparoscopic rectal resection more challenging . A JapanThis brings up a crucial issue: How can operators get the essential abilities without putting patients in danger? The utility of simulation, animal training, and cadaver courses in appropriately preparing surgeons for resection surgeries on human patients is yet unknown . From ouFindings from multiple studies are listed in Table The physical restrictions imposed by the bony pelvis and the necessity to preserve autonomic nerves make minimally invasive surgery for rectal cancer challenging. Straight laparoscopic, hand-assisted, and robot-assisted laparoscopic surgery have all been proposed as solutions to these problems. Laparoscopic rectal cancer surgery offers similar short-term benefits to other minimally invasive procedures. According to the available data, survival and recurrence rates for long-term oncological outcomes are comparable. It is anticipated that ongoing prospective, randomized, controlled trials will support the idea that laparoscopic surgery is superior to open surgery. Additionally, it seems that both methods have similar short- and long-term oncological consequences. Robotic surgery seems to promote a faster recovery of sexual and urogenital function. Three less invasive methods of local excision are now available, and they are all as effective as traditional local excision. In conclusion, minimally invasive surgery for rectal cancer has developed into a recognized and well-studied procedure over the past 30 years. However, concerns about the superiority of one modality over another persist, and future technological improvements are anticipated to put the present established platforms under pressure."}
+{"text": "Another systematic meta-analysis reported that combined exercise protocols such as aerobic and low-intensity resistance exercises dampen oxidative damage and suggested additional antioxidants are unnecessary during exercise . As mentioned above, resistance exercise may disperse the local oxidative damage, and aerobic exercise may help carry this effect to the entire system. Nevertheless, this should be established with the proper oxidative damage-related mechanism. Several studies have reported the use of antioxidants for preventing exercise-induced oxidative damage. In this Research Topic, Wang et al. used taurine as an external antioxidant for preventing inflammation during running and concluded that taurine affects reducing inflammatory markers. Another study reported that treadmill exercise maintains a balanced oxidative-reductive environment within the joint by regulating inflammation . Apart from these, two studies reported the effect of exercise on different biomechanical properties, which helps recommend exercise as one of the essential strategies for preventing injury.The current Research Topic covers seven articles dealing with exercise effects on various physio-pathological functions, primarily related to oxidative stress as a main platform for inducing exercise benefits. An article dealt with the role of strenuous exercise as a potential candidate for inducing myocardial damage. It is reported that an increased volume of cardiac load can increase oxidative stress causing myocardial damage, suggesting the careful need for exercise before recommending it. This may be due to the increased HMGB1 and sRAGE reverted after 72\u00a0h, indicating the transient ischemic alteration rather than direct necrosis in the cardiac system (ammation . AnotherIn summary, this Research Topic addressed several aspects of physical exercise-induced oxidative damage-related diseases. In particular, this Research Topic covered how physical activity can be recommended for maintaining a healthy lifestyle. Nevertheless, revealing a specific mechanism of exercise types with different intensities can control the ROS production within the limit or induce the adaptation with the specific ROS concentration will firmly support the exercise as an essential tool for improving health benefits. Finally, we thank all the authors, reviewers, and editors who contributed and spent their precious time making this Research Topic successful."}
+{"text": "Scedosporium aurianticum infection developed in 2 recipients of kidney transplants in India, acquired from the same deceased near-drowning donor. Given the substantial risk for death associated with Scedosporium infection among solid-organ transplant recipients, safety protocols for organ transplantation from nearly drowned donors should be thoroughly revaluated and refined. Scedosporium spp. fungal infection, which causes pneumonia with a high mortality rate among nearly drowned children and young adults  from nearly drowned donors (NDD) have been linked to substantial allograft loss and increased risk for death among kidney transplant recipients  recently introduced a distinct category for fatal cerebral infections after near-drowning incidents linked to Scedosporium, which has been documented to precipitate potentially fatal disseminated infections in 70% of immunocompetent and 100% of immunocompromised hosts , limited sensitivity of culture based methods, and relatively slow growth of cultured isolates compared to other common saprophytic molds. Those factors collectively lead to delayed diagnoses, elevated therapeutic failures, and increased relapse rates  has been operational for more than a decade, specific risk factors for DDSI transmission from NDDs have not yet been defined. The passive reporting system used by the Disease Transmission Advisory Committee and frequent omissions of crucial NDD data in donor medical records impede comprehensive understanding of DDSI transmission risks (Although the Disease Transmission Advisory Committee of the Organ Procurement and Transplant Network/United Network for Organ Sharing (Routine PCR screening of organs from NDDs for fungi would ensure accurate identification, timely detection, prompt management, and well-informed decision-making. In addition, uniform international guidelines regarding use of organs from NDDs are needed to address critical technical and procedural issues essential for mitigating risk for DDSI transmission. Scedosporium infection in kidney transplant recipients from deceased near-drowning donorAdditional information about study of"}
+{"text": "Bioengineered allogeneic cellularized construct (BACC) has recently been proven to be effective for treatment of burn wounds and now has FDA approval. There is a paucity of data describing long term (\u22651 year) scar characteristics following treatment with BACC, including its potential to modulate the formation of hypertrophic scar (HTS). HTS causes significant physical and psychosocial implications which can result in diminished quality of life. This study aims to characterize post-burn scars resulting from BACC-treated wounds compared to within subject matched autografted wounds using clinical and histologic metrics.Adult patients (n=5) were previously enrolled in a Phase III clinical trial for treatment of their deep partial thickness acute burn wounds. Subjects had clinical scar examinations including imaging, Scar Assessment Scales (POSAS), and non-invasive skin measurements to quantify skin elasticity, erythema, and melanin. Punch biopsies were collected and fixed in formalin from the autograft-treated site (A), the BACC-treated site (B), the donor-site (D), and an area of normal skin (NS). The formalin-fixed biopsies were then embedded in paraffin, sectioned, and stained with H&E, Picrosirius Red, and Herovici.The use of BACC produced no difference in POSAS score and achieved elasticity measurements comparable to NS (Table 1). The erythema measurement demonstrated differences between scar sites and each scar site was different from NS. The donorsite also had some variation from NS. The measured melanin levels were different between each scar site, and both were different from NS. The donorsite also had detectable differences in melanin from NS. Measurements of epidermal thickness demonstrated differences between scar sites with BACC being similar to NS. Rete ridge ratio were different between scar sites and between autograft vs. NS. Papillary dermis cellularity had minor differences between scar sites and both scar sites were different from NS. Reticular dermis cellularity was equivalent between autograft and BACC sites and both were different from NS. Papillary and reticular alignment were not different between scar sites. Reticular orientation was not different between autograft and BACC but was different in BACC vs. NS. Papillary dermal thickness was different between autograft and BACC.The HTSs resulting from wound closure achieved using BACC are similar to autografting in metrics related to clinical POSAS scores, extracellular matrix, and collagen structure. Scars following autografting or the use of BACC to achieve wound closure differ in metrics related to pigmentation, epidermal structure, and papillary dermal thickness and cellularity.These findings may suggest that the use of BACC is a more optimal treatment for certain burn depths in certain patients because some HTS outcomes are equivalent, and it eliminates the need for a donor site."}
+{"text": "CardiCatheter ablation is a viable therapy for ventricular tachycardia \u20133. It isConsidering advancements in clinical therapy and methods for cardiopulmonary support, cardiogenic shock and electrical storm are primary causes of death and morbidity in heart failure individuals \u20138. In paIndividuals with cardiogenic shock are prone to ventricular arrhythmias, which, despite the administration of effective antiarrhythmic medications, may compromise or prevent successful weaning off cardiopulmonary support , 3. The 2.Despite cardiopulmonary support, many ventricular arrhythmias are poorly tolerated hemodynamically, which might be due to a decrease in right ventricle output or inadequate hemodynamic left ventricle support in relation to tachycardia cycle durations and the degree of left ventricular failure . HoweverThe treatment of cardiogenic shock continues to be arduous, with a substantial fatality rate . This isThe higher mortality and morbidity documented in cardiogenic shock individuals indicate their underlying severe condition . The assIn addition, a number of investigations have demonstrated that patients who originally displayed cardiogenic shock demanding cardiopulmonary support and afterward formed ventricular tachycardia possess a greater in-hospital fatality rate than patient populations who at first needed hemodynamic support for both cardiogenic shock and ventricular tachycardia , 3.In certain circumstances, the rationale for extremely early ablation could be to regulate hemodynamics with the intention of decreasing the impact of arrhythmia . During A few individuals who are released from the hospital could experience ventricular tachycardia reappearance under the monitoring threshold of their implanted cardioverter-defibrillator (ICD) .In these contexts, clinical management is challenging and must consider comorbidities and baseline cerebral and cognitive state.3.In individuals receiving catheter ablation of ventricular tachycardia with complex substrates, several comorbidities, and a current record of repeated ventricular tachycardia-related ICD shocks, the initiation of cardiopulmonary support is crucial . These iThe Milan cohort of 74 extracorporeal membrane oxygenation (ECMO)-supported ablation treatments revealed equivalent outcomes. In addition, faster ventricular tachycardias were found in the five patients in whom ECMO was used as an intra-procedure rescue method, lowering the effectiveness of ECMO in avoiding end-organ hypoperfusion .The University of Pennsylvania described a cohort of 21 individuals undergoing ablation of ventricular tachycardia who needed ECMO support due to severe cardiac damage . Even wiNonetheless, the outcomes of ablation with preemptive support (Impella or Tandem Heart) are encouraging. The direct contrast of rescue vs. preemptive ventricular assist device (VAD) vs. the lack of cardiopulmonary support throughout ablation of ventricular tachycardia in a population of 21 individuals revealed a higher 30-day fatality rate in the rescue cluster, with a longer procedure time, apart from comparable ablation outcomes . ConsequOn the basis of clinical factors at hospitalization, efficient risk classification of newly admitted individuals is possible . Six demThe PAINESD risk score was created by a team from the University of Pennsylvania . Age, isIn a cohort of 75 individuals receiving scar-related ventricular tachycardia ablation, preemptive VAD placement directed by the PAINESD scoring system was helpful, yielding greater benefits than a propensity-matched cohort of 75 individuals receiving ablation absent VAD placement . DespiteThese findings suggest that ventricular tachycardia individuals must be accurately risk-stratified prior to the procedure . Even whWhen a bailout catheter ablation technique is required to address recalcitrant rhythm disturbances, cardiopulmonary support is an efficient therapy for cardiogenic shock caused by recalcitrant ventricular arrhythmias \u20133. PreveMS: wrote the first draft of the report. DZ, ES, DI, and GS: helped to wrote the final version. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Twisted layered material junctions, and in particular twisted graphene interfaces, exhibit fascinating physical properties of diverse nature including unique structural, tribological, electronic, as well as heat and electron transport characteristics . These pIn the paper entitled \u2018Deducing the internal interfaces of twisted multilayer graphene via moir\u00e9-regulated surface conductivity\u2019 by the groups of Prof. Qunyang Li and Prof. Wengen Ouyang , the autThe measurement results are rationalized by fully atomistic anisotropic force-field simulations, demonstrating the propagation of the intra-layer atomic reconstruction from the embedded twisted interface towards the stack surface. Based on these results, the authors construct a phenomenological classical electronic conductivity model that utilizes the registry index approach  to explaThe innovative development of recent experimental microscopy techniques for characterizing twisted layered interfaces, suggests that intricate momentum space interference effects may dominate interlayer transport . InteresThe joint experimental and theoretical tools developed by Li and Ouyang, thus pave the way for the non-invasive high resolution spatial characterization of twisted interfaces embedded within layered material stacks."}
+{"text": "Editorial on the Research TopicBiomarkers of neonatal brain injuryDiagnosing brain injury in newborns is crucial because early intervention can significantly impact long-term development and overall quality of life. The brain undergoes rapid development during the neonatal period, and any injury to the brain can disrupt this delicate process. Neurodevelopment is a major concern in several conditions including preterm birth, intrauterine growth restriction, periventricular leukomalacia, white matter injury, neonatal encephalopathy (NE), hypoxic-ischemic encephalopathy (HIE), and neonatal stroke. Premature infants are particularly susceptible to brain injury due to their underdeveloped organs and fragile systems. Although survival rates of infants born extremely preterm continue to increase , one-thiPavel et al. conducted a cohort study to assess heart rate variability (HRV) as a potential biomarker for predicting the severity of EEG grade in neonates with HIE within the first 12\u2005h of birth. The study included 120 infants with HIE, and HRV features were analyzed alongside clinical parameters. The results demonstrated that early HRV, combined with clinical information, accurately predicted EEG grade, providing valuable objective information on HIE severity when EEG monitoring was not available in the early postnatal period. HRV was analyzed using custom software and manual artifact detection in a process that would need to be simplified or automated prior to bedside use.Kyng et al. investigated the potential of neurofilament light chain (NfL) as a biomarker for brain injury in a newborn piglet model of hypoxia-ischemia. The study analyzed serum NfL levels in 48 piglets subjected to hypoxic-ischemic insults, along with brain imaging and histologic assessments. The results revealed a significant increase in NfL levels after hypoxia-ischemia, with the highest values observed at 72\u2005h post-insult. NfL levels at 72\u2005h were predictive of a poor outcome on cortical histopathology and magnetic resonance spectroscopy basal ganglia Lac/NAA ratio, indicating its potential as a sensitive and specific biomarker for moderate\u2013severe HIE.Balog et al. conducted a prospective, observational study to analyze cardiac function parameters using non-invasive hemodynamic monitoring in neonates with moderate\u2013severe HIE undergoing therapeutic hypothermia (TH). The study included 26 neonates, and heart rate (HR), stroke volume (SV), and cardiac output (CO) data were collected throughout TH and rewarming. The findings demonstrated that patients with adverse outcomes had lower SV and higher HR during TH, indicating differences in cardiac function associated with neurodevelopmental outcomes. HR during hypothermia was found to be independently associated with neurodevelopmental outcomes, emphasizing its relevance in guiding cardiovascular supportive therapy.Efstathiou et al. explored the kinetics of circulating progenitor cells (CPCs) in preterm neonates with encephalopathy, aiming to understand the brain's endogenous regeneration processes after injury. The study enrolled 47 preterm neonates and analyzed peripheral blood samples using flow cytometry to assess CPCs, along with brain injury biomarkers and clinical factors. The results indicated an enhanced mobilization of CPCs following brain injury, suggesting the presence of an endogenous brain regeneration process. The findings contribute to understanding the related pathophysiology and highlight the potential of CPCs as biomarkers for evaluating brain injury and predicting outcomes.Exploring the utility of biomarkers across different neonatal brain injuries can provide valuable insights into shared mechanisms and pathways. Investigating biomarkers that have the potential for cross-disease validation may lead to the identification of common therapeutic targets and facilitate the development of targeted interventions for multiple conditions. The studies discussed above highlight the progress made in this field, focusing on diverse biomarkers including physiological, biochemical, hemodynamic, and functional biomarkers. Incorporating these biomarkers into clinical practice has the potential to enhance early detection, risk stratification, and individualized management of neonates at risk of brain injury. Challenges for the future include the development and validation of biomarkers that can predict acute injury, cross-disease validation of biomarkers, validation of previous findings in larger cohorts, and establishing correlations with long-term neurodevelopment to assist in personalized care. Most likely not a single biomarker will make the diagnostic breakthrough but the intelligent combination of many. Thus, further research and validation are warranted to establish the utility of these biomarkers and their integration into routine neonatal care, ultimately leading to improved neurodevelopmental outcomes for affected infants."}
+{"text": "Botulinum neurotoxin A (BoNT) is the first line treatment for cervical dystonia (CD) and treatment outcome significantly depends on the correct identification of the muscles involved.In a case with insufficient response to BoNT treatment further work up with magnetic resonance imaging (MRI) of the neck revealed a hypertrophic spinalis cervicis muscle, that is not commonly involved in CD.This highlights the use of MRI for muscle selection in treatment refractory CD cases. A 45-year-old cervical dystonia (CD) patient with retrocollis, right sided torticollis and left sided laterocollis responded insufficiently to botulinum toxin treatment. By ultrasound, the right longissimus capitis muscle appeared hypertrophic, otherwise no abnormalities were noted. Repeated ultrasound-guided injections of the right sided splenius capitis, longissimus capitis and obliquus capitis inferior muscles partially improved the torticollis component, while the laterocollis component showed only marginal response to injections into the left trapezius, semispinalis and levator scapulae muscles. No effect on the retrocollis was reported. Magnetic resonance imaging (MRI) of the neck then revealed an untypical prominent variant of the spinalis cervicis muscle on the left side . The typ4"}
+{"text": "Fistulizing perianal disease is a debilitating complication present in nearly half of all patients diagnosed with Crohn\u2019s disease. The majority of anal fistulas arising in these patients are complex. Treatment can be challenging with therapy often requiring both medical and surgical interventions with differing levels of symptomatic relief. Fecal diversion is an option after medical and surgical modalities have been exhausted but demonstrates limited efficacy. Complex perianal fistulizing Crohn\u2019s disease is inherently morbid and can be difficult to manage. We present a case of a young male with Crohn\u2019s, severe malnutrition and multiple perianal abscess with extensive fistula tracts up to his back; a planned fecal diversion was instituted to control sepsis and allow for wound healing and optimize medical therapy. Crohn\u2019s disease (CD) is a chronic inflammatory bowel disease that can occur throughout the entire gastrointestinal tract. Anal fistulae are a complication of CD secondary to anal crypt gland infection leading to abscess formation and an epithelized tract that communicates between the anorectal lumen and the perineal or buttock skin. . The cumA 22-year-old male with a past medical history of hidradenitis suppurativa (HS), malnutrition and recently diagnosed CD presented to our tertiary academic center with extensive trans-sphincteric, supra-sphincteric and extra-sphincteric perianal fistulas. He had fistulizing disease with multiple external openings, atypical locations and perianal abscesses that required several incision and drainage procedures and seton placements prior to presentation at outside institutions. On examination, these openings extended to his mid-back in addition to the perineum. We initially treated him by obtaining source control (drainage of abscess), draining setons and subcutaneous fistulotomies . After hIn the 8 months following his index surgery, the patient was readmitted on several occasions due to his extensive fistulizing perianal CD. A reluctance to undergo fecal diversion, issues with treatment compliance, loss of follow up and insurance authorizations contributed to the challenges in managing these complex anal fistulas that would eventually require multiple courses of antibiotics. Multispecialty care was guided by infectious disease consultations, use of biologics , interventional radiology drainage, bowel regimen, pain management, surgical nutrition and physical and occupational therapy. The patient eventually agreed to a laparoscopic loop sigmoid colostomy after further incision and drainage of his perianal abscess, subcutaneous fistulotomy and seton placement.At the 3-month follow up, the patient was no longer on biologic therapy but endorsed only minor improvement in symptoms. Abdomino-perineal resection had been discussed as a potential future surgical option and the patient remains currently on Ustekinumab therapy.CD patients frequently require surgical intervention despite recent advancements in biologics . PatientThe combination of noncutting setons and medical management has demonstrated complete or partial healing in two-thirds of patients . As our A combination of surgical and medical treatment can yield complete fistula remission in 62% of patients as compared with 43% with monotherapy . Critica"}
+{"text": "Premenopausal period is characterized by cognitive and mood disorders in women . Resveratrol  is a phytoestrogen present in the skin of a range of foods including red grapes, blueberries and peanuts. Resveratrol can act through multiple mechanisms, including binding and activation of estrogen receptors (ER), to increase nitric oxide bioavailability and thereby facilitate the endothelium-dependent vasodilatation necessary for adequate cerebral perfusion . Some evidences indicate that resveratrol can improve cognitive processes and emotional state .The aim of the present study was to compare the efficacy the combined treatmnet of SSRIs  plus resveratrol (50 mg twice per day) for 6 months therapy on the affective profile of premenopausal woman with clinically confirmed Major Depressive Disorder (MDD)For the assessment of affective profile in premenopausal women (35-45 years) with clinically confirmed MDD, we used the different tests: Montgomery-Asberg Depression Rating Scale (MADRS) and Shihan Anxiety Scale .After 6 months of SSRIs plus resveratrol therapy, MADRS Scale showed more significant improvement of the depressive symptoms in premenopausal women with clinically confirmed MDD compared to the SSRIs treatment alone . Moreover, these patients demonstrated a significantl low anxiety state using ShARS Scale.Thus, our pilot clinical study clearly demonstrated that co-treatment with SSRIs plus resveratrol (50 mg twice per day) was able to enhance the therapeutic effects of SSRIs on the affective-related symptoms in premenopausal women. We need to create new approaches to treat the premenopausal women with MDD using a combination of SSRIs with resveratrol.None Declared"}
+{"text": "Significant Influencing Factors and Effective Interventions of Mobile Phone Addiction - Volume II\u201d. This Research Topic encompasses both empirical research and meta-analysis studies. Empirical studies allow for the discovery of new insights, while meta-analysis enables the formulation of more robust conclusions based on a synthesis of multiple research findings. Meta-analyses in our Research Topic have extensively synthesized previous research findings regarding the impact of self-esteem, self-control, social support , and academic burnout  on and exercise  mobile phone addiction. Our Research Topic has made notable advancements in understanding the causes of mobile phone addiction, as well as the practical implications for addressing this issue through effective interventions.The issue of mobile phone addiction has garnered significant attention among researchers over the past two decades. Expanding on our previous work, we have successfully completed the Research Topic titled \u201cDing et al.), emotional factors such as anxiety and depression , loneliness , and academic burnout , cognitive factors such as automatic thoughts , as well as executive dysfunction , have all been confirmed to have significant predictive effects on mobile phone addiction. From an environmental perspective, the family is an important environmental micro-system that influences mobile phone addiction , family cohesion and adaptability , and parenting style of encouraging autonomy  have all been found to be closely associated with mobile phone addiction. Moreover, based on comprehensive research findings, environmental factors not only predict mobile phone addiction through the mediation of individual factors, but also the predictive effect of environmental factors on mobile phone addiction varies depending on certain individual factors. In other words, mobile phone addiction is a complex outcome resulting from the joint influence of external environmental factors and internal individual factors.Our Research Topic contributes to a comprehensive understanding of influencing factors from both individual and environmental perspectives. Regarding individual factors, according to the Interaction of Person-Affect-Cognition-Execution model . Another meta-analysis systematically summarizes and compares the intervention effects of different types of exercise on Internet addiction . These studies not only inspire further research on internet addiction/mobile phone addiction but also offer empirical support and practical recommendations for future educational practices. Indeed, there are numerous other efficacious intervention approaches to address internet addiction and mobile phone addiction, including cognitive-behavioral therapy (Kim et al., Our Research Topic delves deeper into intervention methods and their effectiveness. One study examines the direct and indirect effects of physical exercise on Internet addiction (In summarizing our two Research Topics, it is evident that they hold significant theoretical and practical implications. However, they also present several areas that merit further investigation by future researchers. Firstly, our Research Topics did not comprehensively explore the complex interactions between multiple environmental systems and various individual factors. To achieve research results of greater ecological validity, it is crucial to consider the combined effects of these factors. Secondly, our Research Topics lacked studies simultaneously analyze and compare the effects of certain influencing factors on different types of internet addiction/mobile phone addiction. Different types of internet addiction/mobile phone addiction exhibit distinct behavioral characteristics (Liu et al., QL: Writing\u2014original draft, Writing\u2014review and editing. ZZ: Writing\u2014review and editing. CE: Writing\u2014review and editing."}
+{"text": "Accurate determination of intravascular volume status is challenging in acutely ill patients. Favorable patient outcome is vital to correctly identify intravascular volume depletion and avoid systemic venous congestion. Most of the conventional means of hemodynamic monitoring in the acute healthcare setting are geared toward addressing the cardiac output and maintaining an optimum mean arterial pressure. While assessing and maintaining cardiac output in an acutely ill patient is very important, a venous congestion cascade is often overlooked, which can negatively affect the intraabdominal end organs. The prospect of using point-of-care ultrasound (POCUS) to determine systemic venous congestion could be a potentially handy tool for clinicians. Venous excess ultrasound score (VExUS) has also been utilized by clinicians as a semi-quantitative assessment tool to assess fluid status. This review aims to discuss the potential role of POCUS and VExUS scores in determining systemic venous congestion through a narrative review of recently published literature. The current focus in managing critically ill patients relies on maintaining mean arterial pressure, thereby addressing cardiac output and systemic vascular resistance. Clinicians have challenges in accurately assessing and managing systemic venous congestion to avoid its deleterious effects on vital organ perfusion. Optimal fluid management is vital for acutely ill patients to avoid the negative effects of both insufficient and aggressive fluid therapy Figure  1]..1].Some of the current tools that help measure the intravascular volume include laboratory parameters such as brain natriuretic peptide (BNP), chest imaging, pre-load assessment with inferior vena cava (IVC) diameter, and central venous pressure (CVP), among others. However, several clinical factors might influence these measures and lead to inaccurate assessment of systemic venous congestion.With rapidly growing interest in point-of-care ultrasound (POCUS), acute care providers have been leaning towards bedside parameters of hemodynamic assessment and fluid responsiveness. Venous excess ultrasound score (VExUS) has also been utilized by clinicians as a semi-quantitative assessment tool to assess the fluid status and mainly predict acute kidney injury (AKI) in acutely ill patients due to cardiac causes. Current literature regarding POCUS parameters and systemic venous congestion assessment is still a relatively new field. We aim to revisit the concept of systemic venous congestion, mention conventionally used parameters for intravascular volume assessment, and discuss the potential role of POCUS and VExUS scores in determining systemic venous congestion.Systemic venous congestionMaintaining a stable cardiac output is essential for organ perfusion, achieved through the interplay of mean arterial pressure and peripheral venous resistance. The venous structure is a reservoir accommodating approximately two-thirds of blood volume at rest . The cliImportance of understanding venous congestionVenous congestion decreases arteriovenous gradient, ultimately affecting organ perfusion ,7. A dysCurrently available indices for volume assessment and their limitationsClinicians have traditionally depended on physiological parameters such as heart rate and blood pressure for volume assessment, but these parameters have been proven to be unreliable for guiding fluid replacement therapy ..34].Literature reviewTo find the appropriate article on the use of POCUS for detecting systemic venous congestion, we conducted a thorough search on PubMed, Google Scholar, and the Cochrane database. Our keyword search terms were \"(systemic venous congestion) AND (point of care ultrasound OR venous excess ultrasound).\"\u00a0Table Beaubien-Souligny et al.  conducteA case study by Singh et al.  describeTorres-Arrese et al.  conducteUpon admission, during discharge, and for 90 days of follow-up, ultrasounds were conducted to assess multiple organs, including the lungs, IVC, and various veins such as hepatic, portal, intra-renal, and femoral, using pulsed-wave Doppler technology. The experts used the VExUS to determine a score for systemic congestion based on the dilatation of the IVC and the pulsed-wave Doppler morphology of the hepatic, portal, and intra-renal veins. The results of specific tests, such as the intra-renal monophasic pattern, as well as a portal pulsatility greater than 50% and a VExUS score of 3 indicating severe congestion, can predict the likelihood of death during hospitalization. During a follow-up visit, it was found that an IVC measurement above 2 cm and a monophasic pattern in the kidney were strong indicators of potential re-admission related to AHF. Based on the information provided, it can be concluded that having a VExUS score of 3 upon admission may indicate a higher likelihood of death during admission, death related to heart failure, and early re-admission. However, this finding is similar to other ultrasound evaluations that are easier to perform. As this is a pilot study, it is imperative to note that only four expert sonographers were chosen to conduct the examination, which may limit the reproducibility of the findings. Nevertheless, it is clear that ultrasound imaging is an essential tool for predicting mortality and hospital re-admission in AHF patients by detecting systemic venous congestion.Bhardwaj et al.  conducteTwelve patients with ADHF were included in a case series by Argaiz et al. . EligiblA group of patients who underwent outpatient and inpatient right heart catheterization were examined with VExUS right before the catheterization procedure . InternaFuture research directionsStudies have shown that POCUS may be useful in assessing systemic venous congestion, but further research is needed to fully explore its potential. To improve early recognition and intervention, we recommend investigating the sensitivity and specificity of POCUS in detecting subtle changes that indicate early systemic venous congestion. These changes include variations in CVP, hepatic vein flow patterns, and renal venous Doppler indices. By conducting such research, we can potentially prevent disease progression and reduce morbidity and mortality. Incorporating POCUS with artificial intelligence algorithms could potentially enhance diagnostic precision, simplify workflow, and facilitate remote monitoring of patients suffering from systemic venous congestion, particularly in areas with limited resources. One way to track the progression or resolution of systemic venous congestion over time is through serial POCUS examinations. Conducting longitudinal studies can provide valuable information about the natural history of the condition, as well as how patients respond to treatment and potential indicators of clinical deterioration.Identifying the volume status of critically ill patients through systemic venous congestion is crucial, yet this approach is unfortunately underutilized. POCUS is a useful and versatile tool for evaluating systemic venous congestion. It provides non-invasive, real-time imaging that helps clinicians make prompt and accurate decisions. The evidence presented in this review supports the use of POCUS in the early detection of systemic venous congestion. Clinicians can use POCUS to identify signs of venous congestion before they become clinically apparent by evaluating parameters such as CVP, hepatic vein flow patterns, and renal venous Doppler indices. Early recognition of conditions is crucial to prevent disease progression and complications. POCUS has shown promise in evaluating systemic venous congestion, but additional research is imperative. Prospective studies must investigate the impact of POCUS on patient outcomes, and there must be an effort to standardize POCUS training and establish best practices."}
+{"text": "Plants inhabit complex environments that often encompass a myriad of abiotic and biotic stressors. Abiotic stressors, such as extreme temperatures, drought, soil salinity, high light, and flooding can profoundly influence the way pathogens and pests interact with plants. Abiotic stressors frequently serve as predisposing factors, exerting profound effects on a plant\u2019s physiological and biochemical processes. These alterations often create conditions that are conducive to the development of diseases. For instance, prolonged exposure to high temperatures or drought can substantially compromise a plant\u2019s natural defense mechanisms, rendering it more susceptible to fungal infections or insect infestations . ConversChai et\u00a0al. have shed light on the impact of temperature and relative humidity on the inoculum levels of Pseudomonas amygdali pv. lachrymans , [causal agent of angular leaf spot in cucumbers (Cucumis melo)]. Their findings paint a vivid picture of how environmental factors come into play, as high humidity and low temperatures create an environment conducive to the release and survival of pathogenic spores. These revelations underscore the critical role of environmental conditions in shaping pathogen infection dynamics and suggest a promising avenue for disease control\u2014manipulating air temperature and humidity to mitigate disease spread.The current Research Topic delves deeply into a collection of studies that meticulously examine the influence of abiotic stressors on plant-pathogen interactions. These investigations not only unveil the intricate mechanisms underlying plant-pathogen interactions but also offer invaluable mechanistic insights into strategies for safeguarding plants against pathogens within complex environmental conditions. In a notable contribution, Shahzad et\u00a0al. have offered a compelling demonstration of how the shoot dieback associated with Huanglongbing (HLB) in \u2018Hamlin\u2019 sweet orange (Citrus sinensis) can be traced back to hypoxia stress. As the disease progresses, hypoxia is triggered, unleashing a cascade of detrimental effects. This includes the generation of excessive reactive oxygen species (ROS) that exacerbate oxidative stress, leading to cell death and ultimately resulting in shoot dieback. The authors have also elucidated the pivotal roles of plant hormones including abscisic acid, salicylic acid, and auxins in influencing infection dynamics and disease severity.On another front, Zhang et\u00a0al. delved into the intricate mechanism of action of the anti-fungal compound phenazine-1-carboxamide (PCN) against Rhizoctonia solani AG1IA, [causal agent of sheath blight in rice (Oryza sativa)]. Employing an integrated approach that combined transcriptomic and metabolomic analyses, the authors shed light on the remarkable mechanisms through which PCN inhibits pathogen survival inside the host plant. PCN was revealed to disrupt the very integrity of the fungal cell wall and membrane, thereby hindering the R. solani\u2019s survival and proliferation. Additionally, PCN affected crucial metabolic pathways of the pathogen, including purine metabolism, ABC transporters, arachidonic acid metabolism, and phenylpropanoid biosynthesis, decreased the extracellular pH, thereby inhibiting fungal growth and invasion. Moreover, its effects extended to dampening fungal superoxide dismutase (SOD) activity, thereby impairing the pathogen\u2019s antioxidant defense mechanisms. This multifaceted assault orchestrated by PCN exemplifies the intricate and multifarious ways in which anti-fungal compounds can subvert fungal infections.One of the most effective strategies employed to safeguard plants against fungal infections involves the application of anti-fungal compounds. However, it is of paramount importance to ascertain whether the efficacy of these anti-fungal compounds endures under extreme environmental conditions. This necessitates a profound understanding of the mechanisms by which these compounds operate. Adamik et\u00a0al. have adeptly comprehended the complexity of combined stresses underscoring the importance of unraveling both the shared and unique responses to combined stresses. Their insights provide a remarkable understanding of the multifaceted nature of combined stresses and highlight ways for the development of superior protective strategies for plants when confronted with complex combined stresses. The authors further emphasize the need to prioritize experimental studies conducted under field or near-field conditions. This emphasis on field studies is paramount to gaining a deeper understanding of how plants adapt and respond to a multitude of stressors. It bridges the gap between controlled laboratory studies and the dynamic, complex realities faced by plants in their natural habitats.By delving into these complex interactions between plants, pathogens and the environment researchers can develop more effective strategies for managing plant health. Notably, The knowledge of combined stress induced responses and the interaction between the different stressors will empower us to implement targeted interventions, whether through breeding programs to enhance stress tolerance or by employing sustainable agricultural practices that mitigate the impact of both abiotic and biotic stressors on plants. In essence, recognizing and exploring the intricate interplay of these stressors is the key to ensuring the robust health and productivity of plants, thereby safeguarding our food supply and the overall stability of ecosystems.PP: Writing \u2013 original draft, Writing \u2013 review & editing. AG: Writing \u2013 review & editing. NE-S: Writing \u2013 review & editing."}
+{"text": "The incidence of hypothermia and frostbite is increasing given larger numbers of people experiencing homelessness (PEH) across the country. Cold injuries create functional deficits that compound comorbidities of people who already experience disproportionate disability burdens. We collaborated with PEH to identify modifiable cold injury hazards, understand prevention knowledge and first aid techniques, and develop prevention strategies.We conducted 12 interviews with PEH with and without lived experience of cold injury. Interviews covered domains of risk factors/hazards, utility of existing educational materials, novel strategies, and acceptable stakeholders for dissemination. Interviews were transcribed and coded by two analysts using both deductive and inductive approaches.Participants varied in the type  and chronicity of homelessness. Six themes emerged: i) PEH are engaged in prevention, ii) there is a need for improved awareness around synergistic risks , iii) existing materials are not sufficiently contextually specific, iv) a narrowly focused prevention and dissemination strategy will not suffice, v) prevention strategies need to be framed within the realities of living homeless, and vi) respect and kindness are integral to successful uptake (Table 1).Insightful perspectives shared by PEH provided key strategies for cold injury prevention. Prevention strategies must fit into the reality of homelessness, be respectfully delivered, and need to be a collective community effort where voices of PEH are valued.Themes and specific perspectives uncovered by this study can help clinicians, community service providers, and public health practitioners develop cold injury prevention strategies alongside people with lived experience of homelessness."}
+{"text": "Artificial Intelligence (AI) has recently gained significant attention and broader recognition due to its vital role in various sectors, most notably the health sector , selected preoperative clinical features (ultrasound features and stress elastography) were utilized to construct an AI-based model that refines the assessment of benign and malignant breast lumps. The model achieved a specificity of 0.92, surpassing other models. Thus, this model has the potential to enhance preoperative detection of benign and malignant breast tumors and reduce unnecessary breast biopsies.In the inaugural paper on the Research Topic  trained with radiomic features derived from breast magnetic resonance imaging (MRI) to predict improvements in centrally diagnosed ductal carcinoma in situ (DCIS) following surgical resection through needle biopsy (CNB). The experimental results illustrate that this approach attains remarkable accuracy and serves as a useful tool for predicting histological improvements in DCIS.Gong et al. performed a meta-analysis evaluating the diagnostic power of radiomics for predicting axillary lymph node metastasis (ALNM) and sentinel lymph node metastasis (SLNM) in breast cancer. The meta-analysis included thirty studies involving 5,611 patients, and the results demonstrated that radiomics exhibits exceptional diagnostic performance in predicting ALNM and SLNM in breast cancer.Bansal et al. assessed Thermalytix, a novel machine learning technique to enhance breast thermography, as an adjunct in breast disease assessment. The study results display acceptable sensitivity and specificity in the use of mammography, establishing it as the standard across the patient population and particularly in women with dense breast tissue.Zhang et al. a multi-parameter MRI model incorporating ensemble learning to explore the predictive performance of ALNM in preoperatively invasive breast cancer. The results of this study demonstrated that this model can provide clinicians with extensive preoperative information about axillary breast cancer, assisting in accurate clinical decision-making.Xu et al. developed a radiograph based on grayscale ultrasound (USA) for the preoperative prediction of lymphatic vessel invasion (LVI) in patients with pathologically confirmed invasive breast carcinoma (IDC) T1. The results showed satisfactory preoperative prediction of LVI in pT1 IDC patients.Ji et al. performed a bibliometric analysis on research trends related to tumor DNA associated with breast cancer from 2012 to 2021. This study explored the value of ctDNA in breast cancer using bibliographic analysis, providing a comprehensive and intuitive understanding of the topic and revealing research trends over the past decade.Recently, circulating tumor DNAs (ctDNAs) have become a focus for scientists in relation to personalized treatment, early detection, diagnosis, and accurate prognosis of breast cancer. Consequently, Dihge et al. developed an artificial neural network algorithm for non-invasive lymph node staging as a decision support system to facilitate the potential omission of axillary surgery in breast cancer patients at low risk of lymph node metastasis. The algorithm provides healthcare decision support and facilitates the preoperative identification of patients who may be good candidates to avoid surgical staging of the axillary region.Ding et al. identified a novel immunosuppressive tumor microenvironment subtype of triple-negative breast cancer with high PD-L1 expression and potential resistance to ICH treatment. These results provide novel insights for understanding the molecular mechanisms underlying resistance to ICH therapy and for developing suitable immunotherapeutic strategies for patients with distinct molecular characteristics.Chen et al. proposed a deep learning model based on C2FTrans to diagnose breast masses using mammographic density. The model could readily distinguish between benign and malignant mass lesions in the breast on mammography images, potentially serving as an auxiliary diagnostic tool for radiologists in the future.Liu et al. developed a learning-based EfficientNetV2 model for identifying and diagnosing malignant structural distortions in mammography. The model improves the overall accuracy of mammography in detecting malignant structural distortions.Zhou et al. examined the QOL of breast cancer patients using both traditional and modern anchor-based methods to determine a minimal clinically important difference (MCID). When assessing the QOL of patients with breast cancer, MCID values calculated using different methods were found to be relatively similar. Anchor-based methods render the results of the MCID more clinically interpretable by introducing clinical variables. Clinicians and researchers can select the appropriate method according to their research preferences.The measurement of the quality of life (QOL) of patients with breast cancer assists in assessing the therapeutic efficacy of medical interventions and informs clinical decisions. To this end, Zarean Shahraki et al. predicted a time-related survival probability for breast cancer patients over 30 years of age with various molecular subtypes, who were diagnosed with invasive breast cancer between 1991 and 2021. In this retrospective analysis of 3,580 patients, a random forest learning algorithm identified tumor status, age at diagnosis, and lymph node status as the best set of variables for predicting breast cancer survival probability.Xu et al. developed an Integrated Clinical Radiological model (ICR) to investigate the feasibility of predicting progression-free survival (PFS) in patients with breast cancer using a positron emission tomography/18F-fluorodeoxyglucose computed tomography (FDG PET/CT) radiographic signature and clinical parameters. The model independently predicted PFS in patients with breast cancer, outperforming both the clinical model alone and the RAD index.Wu et al. proposed a novel multiregion dose-gradient-based multistacking classifier framework incorporating Bayesian optimisation parameter tuning for accurate prediction of symptomatic RD2+ in patients with breast cancer undergoing radiotherapy. This approach represents a substantial improvement over conventional models, allowing early identification of patients at risk of radiation-induced toxicity and providing a highly accurate prediction of symptomatic RD2+ in patients with breast cancer.Murtas et al. developed a clinical radiographic model based on features extracted from digital breast tomosynthesis (DBT) images and clinical factors that could aid in differentiating between benign and malignant breast lesions. The study's results suggest that this model can be considered a support tool for radiologists in the diagnosis of breast tumors, particularly during initial screenings.Sun et al. investigated the utility of radiometric features based on T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), and ADC maps in identifying TP53 mutations in triple-negative breast cancer. The results showed that radiometric features combined with a Support Vector Machine learning algorithm can achieve better predictive performance than other conventional models.Saha et al. carried out a natural language processing (NLP) scope assessment of radiological reports related to breast cancer. The study's results showed that NLP applications can automate routine tasks, allowing physicians to focus on more complex cases or tasks, and enable consistent quality control measures for routine mammograms and breast cancer treatment.Wang et al. evaluated the capability of ultrasound imaging-based integrated radiomics to differentiate between fibroadenomas (FAs) and pure mucinous carcinomas (P-MCs). The study retrospectively enrolled 170 patients with either FA or P-MC (120 in the training group and 50 in the testing group) with clear pathological confirmation. Four hundred and sixty-four radiomic features were extracted from conventional ultrasound images (CUS), and radiomics scores (RadScores) were constructed. The results indicated that the Clin + CUS + RadScore model could effectively differentiate between FA and P-MC, thus enhancing radiologists' confidence and supporting clinical decision-making.Sultana et al. investigated the potential role of serum cfDNA levels as an early diagnostic marker for breast cancer using UV spectroscopy, fluorescence, and real-time qPCR assays. They proposed a sequential combination of NanoDrop, Quantus, and RT-qPCR methods for the preliminary assessment of total circulating cfDNA, which is both cost-effective and comprehensive. The findings of the study demonstrated that RT-qPCR combined with fluorescence measurement could identify a statistically significant difference in cfDNA levels between patients with breast cancer and healthy controls.To et al. proposed an automated method leveraging the power of deep learning techniques. In this method, the DUV-WSI image was divided into small patches, and features were extracted using a pretrained CNN. A gradient boosting tree was then trained on these features for patch-level classification. An ensemble learning method combined patch-level classification results and regional importance to determine the margin status. The proposed method outperformed standard deep learning classification methods on DUV breast surgery samples. It can be used to enhance classification performance and more effectively identify cancerous areas.The Research Topic contributed immensely for development of the novel frameworks, methods, approaches, and tools that provide efficient diagnosis of breast cancer.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Surgical procedures on the shoulder pose distinctive challenges in managing pain during the perioperative period, underscoring the importance of exploring innovative anesthesia techniques. This comprehensive review article delves into integrating dexmedetomidine, an alpha-2 adrenergic agonist, within interscalene brachial plexus blocks for shoulder surgery. The review initiates by underscoring the pivotal role of effective anesthesia in shoulder surgery and elucidates the rationale behind investigating dexmedetomidine as an adjunct. It meticulously examines the anatomy and physiology of the brachial plexus, emphasizing its critical significance in shoulder surgery. Furthermore, the article expounds on dexmedetomidine's mechanisms of action and pharmacokinetics, encompassing its safety profile and potential side effects. The conventional interscalene brachial plexus block techniques, along with their limitations and challenges, are discussed, laying the foundation for the integration of dexmedetomidine. The review subsequently delves into exploring the role of dexmedetomidine in regional anesthesia, covering previous studies, mechanisms of action, and the potential advantages of incorporating it into nerve blocks. The review's core concentrates on the practical application of dexmedetomidine-enhanced interscalene brachial plexus blocks. This includes discussions on administration techniques, dosage guidelines, and compelling evidence supporting its utilization. Clinical scenarios where this approach proves most advantageous are thoroughly explored, comparing its effectiveness with traditional techniques in terms of pain control and patient outcomes. A comprehensive examination of relevant clinical trials and case studies highlights the evidence supporting its efficacy. The review also underscores safety considerations associated with dexmedetomidine. It proposes strategies for mitigating risks to ensure patient safety. Insights into future directions and research are provided, encompassing ongoing studies, areas necessitating further investigation, and potential refinements in technique. Finally, the article summarizes key findings, emphasizing the practicality of dexmedetomidine-enhanced interscalene brachial plexus blocks in shoulder surgery and its far-reaching implications for clinical practice and patient care. Advancements in shoulder surgery have positioned it as a vital component of orthopedic practice, addressing a spectrum of conditions like rotator cuff tears, labral injuries, and osteoarthritis. The intricate mobility of the shoulder joint, integral to daily activities, underscores the impact of shoulder pathology on patients' quality of life, often necessitating surgical interventions for pain relief and functional restoration .Orthopedic surgeons employ diverse techniques to address shoulder issues, including arthroscopy, open surgery, and joint replacement. While surgical proficiency is crucial for success, the choice of anesthetic management holds equal importance in ensuring patient comfort, optimizing surgical conditions, and minimizing postoperative pain. This review explores the evolving landscape of anesthesia in shoulder surgery, focusing on the use of dexmedetomidine-enhanced interscalene brachial plexus block-an emerging technique with the potential to revolutionize the perioperative experience for shoulder surgery patients ,3.Effective anesthesia is fundamental for safe and successful surgical procedures, particularly in shoulder surgery where intraoperative collaboration with the patient is often essential. Unlike many other orthopedic surgeries, shoulder procedures frequently require active patient participation to assess joint mobility, stability, and overall function. This poses unique challenges for anesthesia providers who must ensure pain control and patient comfort without compromising the patient's involvement in the surgical process -6.Postoperative pain management is of paramount importance in shoulder surgery due to the intricate anatomy and rich innervation of the shoulder, which can lead to significant pain if not adequately addressed. In recent years, regional anesthesia techniques, particularly the interscalene brachial plexus block, have gained prominence for providing targeted analgesia to the shoulder and upper extremities while allowing patient consciousness and interaction with the surgeon during the procedure ,7.Dexmedetomidine, a highly selective alpha-2 adrenergic agonist, has emerged as a potential adjuvant to traditional interscalene brachial plexus block. Its sedative and analgesic properties, combined with a favorable side-effect profile, make it an attractive option for enhancing the quality and duration of analgesia provided by the block. Dexmedetomidine's ability to induce conscious sedation without respiratory depression is particularly valuable in maintaining intraoperative collaboration, a critical aspect of shoulder surgery .This comprehensive review aims to examine the current state of dexmedetomidine-enhanced interscalene brachial plexus block in shoulder surgery. The exploration will cover anatomical and physiological considerations, mechanisms of action, administration techniques, clinical applications, safety profiles, and potential future directions in this evolving field. The review will logically progress, starting with the significance of shoulder surgery, the role of anesthesia, and the rationale for considering dexmedetomidine-enhanced interscalene brachial plexus block. It will then delve into various aspects of this technique, concluding with a comprehensive assessment of its potential to enhance the field of shoulder surgery anesthesia.Anatomy and physiologyOverview of the Brachial PlexusTo comprehend the role of dexmedetomidine-enhanced interscalene brachial plexus block in shoulder surgery, it is imperative to grasp the anatomy and physiology of the brachial plexus. The brachial plexus is a complex network of nerves originating from the cervical and upper thoracic spinal nerve roots (C5-T1) and is responsible for innervating the upper extremities. This intricate neural structure is essential for motor and sensory function in the shoulder, arm, and hand . The braInnervation of the Shoulder RegionSuprascapular nerve: The suprascapular nerve, originating from the superior trunk of the brachial plexus (composed of nerve roots C5-C6), plays a crucial role in the innervation of certain shoulder muscles. It provides motor innervation to the supraspinatus and infraspinatus muscles. The supraspinatus muscle contributes to shoulder abduction during the initial phase of this movement, while the infraspinatus muscle aids in the external rotation of the shoulder joint. These muscles are vital for shoulder stability and rotator cuff function .Axillary nerve: The axillary nerve arises from the posterior cord of the brachial plexus (composed of nerve roots C5-C6). It primarily innervates the deltoid muscle, which is responsible for shoulder abduction. The deltoid muscle allows the arm to be lifted from the body's side. Damage to the axillary nerve can result in weakness or dysfunction of the deltoid muscle, leading to difficulty raising the arm .Lateral and medial pectoral nerves: While not exclusively shoulder muscles, the pectoralis major muscles receive motor innervation from the lateral and medial pectoral nerves, respectively. These nerves originate from the lateral and medial cords of the brachial plexus. Although the primary function of the pectoralis major is related to the chest, these muscles also contribute to certain shoulder movements and stability. For example, they play a role in activities that involve adduction and internal rotation of the arm .Long thoracic nerve: The long thoracic nerve originates from the nerve roots of C5-C7. It innervates the serratus anterior muscle. The serratus anterior muscle is crucial for maintaining the scapula (shoulder blade) against the thoracic wall. This function is vital for normal shoulder movement and stability, especially during overhead arm movement activities. Damage to the long thoracic nerve can result in a condition known as \"winged scapula,\" which can impair shoulder function and stability .Role of the Brachial Plexus in Shoulder SurgeryThe brachial plexus plays a pivotal role in shoulder surgery, as it houses the nerves responsible for both motor and sensory functions in the shoulder and upper limb. During surgical procedures on the shoulder, such as rotator cuff repairs, labral repairs, or joint replacements, it is essential to provide effective anesthesia that renders the shoulder region insensate to pain. This ensures patient comfort and allows the surgeon to manipulate the joint and assess its function without causing distress to the patient .The interscalene brachial plexus block has emerged as a favored technique for achieving regional anesthesia in shoulder surgery. By precisely targeting the brachial plexus at the level of the interscalene groove in the neck, this block can provide complete sensory blockade to the shoulder, arm, and hand. Importantly, the block's mechanism facilitates anesthesia from the distal portion of the limb to the clavicle and the midshaft of the humerus. Furthermore, motor function remains preserved, allowing patients to actively participate in the surgical process when required . UnderstDexmedetomidine: mechanism of action and pharmacologyDexmedetomidineDexmedetomidine is a relatively recent addition to the armamentarium of anesthetic agents, gaining recognition for its unique properties and versatility in clinical practice. It belongs to the class of alpha-2 adrenergic agonists, and its pharmacological characteristics make it well-suited for various applications, including sedation, analgesia, and adjunctive therapy in regional anesthesia .Mechanism of Action of DexmedetomidineSedation and anxiolysis: Dexmedetomidine's mechanism of action primarily involves its selective activation of alpha-2 adrenergic receptors in the central nervous system, particularly in the locus coeruleus. This activation reduces the release of norepinephrine, resulting in a calming and sedative effect. Patients who receive dexmedetomidine often experience reduced anxiety and increased cooperation, which can be particularly beneficial in regional anesthesia procedures where patient comfort and cooperation are essential. The sedative and anxiolytic properties of dexmedetomidine contribute to a more relaxed and less apprehensive patient experience during the procedure .Analgesia: Dexmedetomidine, recognized for its analgesic properties, operates through a multifaceted mechanism to relieve pain. In the realm of regional anesthesia, it can augment the effectiveness of local anesthetics. Operating at the spinal cord level, dexmedetomidine modulates pain signaling pathways, thereby diminishing pain perception. This attribute is particularly advantageous in objectively extending the duration of analgesia facilitated by regional blocks. Numerous research studies have explored the potential of dexmedetomidine as a perineural adjunct, focusing on its impact on the mean/median duration of the prolongation of effect and the objective assessment of analgesic quality, often measured through pain scores. The findings of these investigations collectively contribute to a comprehensive understanding of the efficacy of dexmedetomidine in reducing the requirement for rescue analgesia in the postoperative period .Sympatholysis: Dexmedetomidine exhibits a significant sympatholytic effect, attributed to the activation of alpha-2 receptors, resulting in reduced sympathetic outflow from the central nervous system. This action leads to a decrease in heart rate and blood pressure. While this reduction in sympathetic tone can offer advantages in specific patient populations, such as those with hypertension or cardiovascular comorbidities, it necessitates vigilant monitoring of hemodynamic parameters. Anesthesiologists and healthcare providers must be prepared to manage potential hemodynamic changes, including bradycardia and hypotension, especially during dexmedetomidine bolus administration or high-dose infusions .Preservation of respiratory drive: Dexmedetomidine typically preserves respiratory drive, unlike some sedative agents. This property makes it a safer choice for patients requiring conscious sedation during procedures, as it reduces the risk of respiratory depression. This is particularly relevant in regional anesthesia, where maintaining spontaneous respiration is crucial, especially when patients must actively participate in the surgical process .Pharmacokinetics and PharmacodynamicsDexmedetomidine is administered intravenously and exhibits a rapid onset of action, typically within minutes of administration. Its pharmacokinetic properties include a relatively short half-life of approximately 2 hours, facilitating precise control over sedation levels and allowing for rapid recovery once the infusion is discontinued . PharmacSafety Profile and Side EffectsHypotension and bradycardia: Dexmedetomidine's primary mechanism of action involves its selective activation of alpha-2 adrenergic receptors in the central nervous system, which leads to reduced sympathetic outflow. While this property contributes to its analgesic and anxiolytic effects, it can also significantly decrease blood pressure and heart rate, particularly when dexmedetomidine is administered as a bolus or at higher infusion rates . MaintaiSedation-related issues: Dexmedetomidine's sedative and anxiolytic properties, while advantageous in promoting patient comfort and cooperation, can also pose risks. Excessive sedation, especially when dexmedetomidine is administered at high doses or rapidly, can lead to respiratory depression. This concerns patients with compromised respiratory function, such as those with chronic obstructive pulmonary disease (COPD) or sleep apnea . CarefulNausea and vomiting: Nausea and vomiting are potential side effects of dexmedetomidine administration. Some patients may experience these symptoms during or after the procedure. Nausea and vomiting can be uncomfortable for patients and may necessitate the administration of antiemetic medications to alleviate these side effects . The risDelayed recovery: Dexmedetomidine has a relatively short half-life compared to other sedative agents, which generally facilitates a faster recovery. However, in some cases, prolonged sedation may occur, resulting in a longer time to complete recovery. This can impact the patient's ability to mobilize and achieve discharge criteria, potentially affecting the overall length of the hospital stay or time spent in the recovery area . HealthcInterscalene brachial plexus blockInterscalene Brachial Plexus BlockThe interscalene brachial plexus block is a well-established regional analgesia and shoulder surgery technique. It involves the precise placement of local anesthetics near the brachial plexus as it passes through the interscalene groove between the neck's anterior and middle scalene muscles. This block is favored for shoulder surgery because it can achieve targeted shoulder, arm, and hand anesthesia while preserving motor function . The bloTraditional Techniques and Agents UsedTraditionally, the interscalene brachial plexus block has been accomplished using local anesthetics, such as bupivacaine or ropivacaine. These agents provide effective anesthesia by blocking nerve conduction in the brachial plexus, resulting in sensory loss and muscle relaxation. Opioids, such as fentanyl or morphine, are sometimes added to the local anesthetic mixture to enhance postoperative pain relief . TechniqLimitations and Challenges of Traditional ApproachesMotor function preservation: One of the primary challenges with traditional approaches to interscalene brachial plexus blocks is achieving the delicate balance between sensory anesthesia and motor function preservation. While the primary goal is to provide effective pain relief, inadvertent motor blockade can occur, resulting in motor weakness. This limitation can be especially problematic for procedures requiring patient cooperation and active participation, such as certain types of shoulder surgery . SurgeonDuration of analgesia: Traditional local anesthetics used in interscalene brachial plexus blocks may provide adequate analgesia during the surgery, but their duration of action can be limited. Patients frequently experience a decrease in the effectiveness of the block in the hours following surgery. As a result, many patients require additional analgesia, often in the form of systemic opioids, to manage postoperative pain . The relHemodynamic effects: Traditional approaches to interscalene brachial plexus blocks involve the administration of a relatively high volume of local anesthetic in the interscalene groove. This can lead to systemic absorption of the local anesthetic, which, in turn, can result in transient hemodynamic changes, including hypotension. Hypotension can be of particular concern in patients with preexisting cardiovascular conditions or hemodynamically unstable patients . ManaginRisk of systemic toxicity: One of the most significant concerns with traditional interscalene brachial plexus blocks is the risk of local anesthetic systemic toxicity (LAST). LAST can occur when high doses of local anesthetic are administered or when the local anesthetic is rapidly absorbed into the systemic circulation . LAST caDexmedetomidine in regional anesthesiaDexmedetomidine in Regional AnesthesiaProlonged analgesia: Multiple studies have consistently demonstrated that adding dexmedetomidine to local nerve block anesthetics significantly prolongs analgesia duration. This effect is particularly notable in peripheral nerve blocks, where dexmedetomidine enhances the action of the local anesthetic agent. This prolongation's precise mechanism involves dexmedetomidine's local and systemic effects . DexmedeReduced local anesthetic volume: The use of dexmedetomidine as an adjunct to local anesthetics allows for a reduction in the volume of local anesthetic required to achieve effective anesthesia. This reduction in local anesthetic volume is advantageous for several reasons; one is mitigating the risk of local anesthetic systemic toxicity (LAST) . MinimizImproved postoperative pain control: Dexmedetomidine has consistently shown promise in improving postoperative pain control when used as an adjuvant in regional anesthesia. Patients who receive dexmedetomidine-enhanced blocks frequently report lower pain scores in the immediate postoperative period, translating to enhanced postoperative comfort . AdditioSedative and anxiolytic effects: Dexmedetomidine's sedative and anxiolytic properties are valuable in the context of regional anesthesia procedures. Patients often experience reduced anxiety and a calmer perioperative experience when dexmedetomidine is included in their anesthesia regimen. This is especially relevant in procedures where patients remain conscious and cooperative during surgery, such as interscalene brachial plexus blocks for shoulder surgery . DexmedeHemodynamic stability: Dexmedetomidine's sympatholytic effects are particularly important in patients with cardiovascular comorbidities undergoing regional anesthesia. These effects contribute to hemodynamic stability during procedures, helping to maintain normal heart rate and blood pressure . PatientMechanisms of Dexmedetomidine's Action in Regional AnesthesiaPresynaptic inhibition: Dexmedetomidine's primary mechanism of action in regional anesthesia involves presynaptic inhibition. When administered locally, dexmedetomidine acts on presynaptic nerve endings by binding to alpha-2 adrenergic receptors. This binding inhibits the release of norepinephrine, a neurotransmitter responsible for transmitting pain signals along the nerves . By reduPeripheral actions: Dexmedetomidine's direct actions on peripheral nerves are another important aspect of its mechanism in regional anesthesia. At the site of the nerve block, dexmedetomidine interacts with nerve endings, modulating nociceptive signaling locally. This direct effect is particularly relevant in enhancing the precision and efficacy of the block . DexmedeAlpha-2 agonist effects: Dexmedetomidine's selective activation of alpha-2 adrenergic receptors in the central nervous system plays a pivotal role in its mechanism of action during regional anesthesia. These effects are particularly beneficial for patient comfort and cooperation during surgical procedures .Sedation: Dexmedetomidine's sedative properties promote a state of calm and relaxation without inducing deep unconsciousness. Patients often remain conscious and responsive but experience reduced anxiety and discomfort. This level of sedation ensures patients are comfortable and cooperative during the regional anesthesia procedure. This is especially relevant for procedures like interscalene brachial plexus blocks where patient interaction may be required .Anxiolysis: Dexmedetomidine's anxiolytic effects are crucial for alleviating anxiety and apprehension in patients undergoing regional anesthesia. These effects contribute to a more pleasant perioperative experience and help reduce the psychological stress associated with surgery .Reduced sympathetic tone: The activation of alpha-2 adrenergic receptors by dexmedetomidine leads to a decrease in sympathetic tone, resulting in lowered heart rate and blood pressure. This hemodynamic stability is valuable during regional anesthesia procedures, as it minimizes the risk of hemodynamic fluctuations and ensures patient safety .Benefits and Potential Advantages of Using Dexmedetomidine in Nerve BlocksProlonged analgesia: One of the primary benefits of incorporating dexmedetomidine into nerve blocks is its ability to extend the analgesia duration significantly. When administered locally, dexmedetomidine acts directly on adrenergic receptors in nerve endings, leading to prolonged pain relief in the targeted area. This prolonged analgesic effect is particularly advantageous for postoperative pain management as it reduces the need for frequent reinjections of local anesthetics or systemic opioids . In inteReduced local anesthetic requirements: Dexmedetomidine's ability to enhance the action of local anesthetics has the added benefit of allowing for the use of smaller volumes of these agents. By using lower volumes of local anesthetics, there is a reduced risk of local anesthetic systemic toxicity (LAST), a potentially severe complication associated with nerve blocks . ReducinImproved patient comfort: Dexmedetomidine's sedative and anxiolytic effects are crucial in promoting improved patient comfort during regional anesthesia procedures. Patients undergoing shoulder surgery can experience significant anxiety and discomfort, especially when fully awake during the procedure. Dexmedetomidine's sedative properties can alleviate anxiety and provide a calming effect, making the perioperative experience more pleasant . AdditioMinimized opioid consumption: Dexmedetomidine's opioid-sparing effect is another notable advantage. By reducing the need for systemic opioids, patients are less likely to experience opioid-related side effects, including respiratory depression, nausea, vomiting, and constipation. This is particularly important in shoulder surgery, where the respiratory status and comfort of the patient are critical postoperatively .\u00a0MinimizDexmedetomidine-enhanced interscalene brachial plexus blockTechniques for Administering Dexmedetomidine with Interscalene Brachial Plexus BlockCo-administration with local anesthetic: Co-administering dexmedetomidine with the local anesthetic mixture is a well-established technique for enhancing interscalene brachial plexus blocks. Dexmedetomidine is added to the local anesthetic solution, delivering both agents directly to the target nerves during the block procedure. This approach offers several advantages . CombiniBolus or infusion: The choice between administering dexmedetomidine as a bolus dose or as an infusion during the interscalene block depends on specific clinical considerations and surgical requirements .Bolus administration: Dexmedetomidine can be given as a bolus dose for rapid onset of its effects. This is particularly beneficial when immediate sedation and analgesia are needed, such as during the initial stages of the procedure. The bolus dose is typically administered as a single injection, allowing swift action .Infusion: Alternatively, dexmedetomidine can be administered as an infusion during the block procedure. This approach involves delivering dexmedetomidine gradually and continuously over time. Infusions are especially useful for longer-duration surgeries, providing a sustained effect. The infusion rate can be adjusted to achieve and maintain the desired level of sedation and analgesia throughout the procedure .Single or multiple injection points: Deciding whether to inject dexmedetomidine at a single point or multiple points along the brachial plexus is contingent on the complexity of the surgery and the necessity for a comprehensive blockade .Single injection point: In certain cases, a single injection point may suffice to achieve the required sensory blockade for the surgical site. This approach simplifies the procedure by minimizing the number of needle insertions. It is often suitable for less complex shoulder surgeries where a targeted blockade can adequately control pain .Multiple injection points: For more extensive surgeries or when a broader blockade is essential, multiple injection points along the brachial plexus may be used. Distributing dexmedetomidine and the local anesthetic across multiple sites allows for a more comprehensive and widespread block. This is particularly advantageous for surgeries that involve multiple nerves and require extensive pain control .Ultrasound guidance: Incorporating ultrasound guidance is indispensable when administering dexmedetomidine-enhanced interscalene brachial plexus blocks. Ultrasound technology provides real-time visualization of the targeted area's nerves, blood vessels, and surrounding structures . UtiliziDosage and Administration GuidelinesDexmedetomidine concentration: Dexmedetomidine is available in various concentrations, typically ranging from 0.1 to 1.0 mcg/mL. The choice of dexmedetomidine concentration is a critical consideration in administering interscalene blocks. The selected concentration can significantly impact the total volume of solution administered and influence the onset and duration of the block . HealthcTotal dexmedetomidine dose: The dose of dexmedetomidine administered for interscalene blocks typically falls within a range of 0.25 to 1.0 mcg/kg. The specific dose chosen depends on several factors, including the patient's age, weight, and the anticipated duration of the surgical procedure . Higher Rate of infusion: When dexmedetomidine is administered as an infusion, the typical infusion rate ranges from 0.2 to 0.7 mcg/kg/hour. The infusion rate is a critical parameter that requires careful adjustment to achieve the desired level of sedation and analgesia. Continuous monitoring of the patient's sedation level, vital signs, and response to the infusion is essential for effective titration. The infusion rate can be increased or decreased as needed to maintain the desired depth of sedation while avoiding excessive sedation or adverse effects such as hemodynamic instability. Healthcare providers should be attentive to changes in patient status and adapt the infusion rate accordingly to ensure that the patient remains comfortable and cooperative throughout the procedure .Local anesthetic volume: An important safety consideration in dexmedetomidine-enhanced interscalene blocks is the volume of local anesthetic used in combination with dexmedetomidine. To minimize the risk of systemic toxicity, the volume of local anesthetic should be reduced compared to traditional techniques. The specific reduction in local anesthetic volume should be determined based on the type and concentration of the local anesthetic chosen. By using smaller volumes, clinicians can achieve the desired sensory blockade while minimizing the risk of systemic absorption and toxicity. Ensuring that the volume of local anesthetic remains within safe limits is a fundamental aspect of patient safety in dexmedetomidine-enhanced interscalene brachial plexus blocks, and adherence to established guidelines and best practices is paramount .Evidence Supporting the Use of DexmedetomidineProlonged analgesia: Numerous studies have provided strong evidence that dexmedetomidine enhances the duration of analgesia provided by interscalene brachial plexus blocks. Dexmedetomidine's alpha-2 adrenergic agonist properties extend the effect of local anesthetics, resulting in longer-lasting pain relief compared to traditional blocks using local anesthetics alone. This extended analgesia is especially valuable in shoulder surgery, where postoperative pain can be significant .Improved postoperative pain control: Clinical trials consistently demonstrate that patients who receive dexmedetomidine-enhanced blocks report improved postoperative pain control. These patients experience reduced pain intensity, translating to decreased opioid consumption in the early postoperative period. This effect contributes to a more comfortable patient recovery experience and reduces the reliance on opioids, thereby minimizing opioid-related side effects .Enhanced patient comfort: Dexmedetomidine's sedative and anxiolytic effects are well-documented and significantly enhance patient comfort during shoulder surgery. Patients receiving dexmedetomidine often report feeling calmer and less anxious, which fosters a cooperative and positive surgical environment. This is particularly important in shoulder surgery, where patient cooperation may be required for intraoperative adjustments and feedback .Reduced opioid use and side effects: The opioid-sparing effect of dexmedetomidine is a key advantage. Studies consistently show reduced opioid requirements in patients who receive dexmedetomidine-enhanced blocks. Reducing opioid use helps mitigate opioid-related side effects, such as respiratory depression, nausea, and constipation. By minimizing these complications, dexmedetomidine contributes to a safer and more comfortable postoperative course .Potential for same-day discharge: Dexmedetomidine-enhanced blocks have the potential to enable same-day discharge for select patients undergoing shoulder surgery. This is due to extended analgesia, reduced opioid requirements, and the absence of prolonged sedation or motor impairment. Same-day discharge protocols can be particularly advantageous for patients and healthcare systems by reducing hospital stays and associated costs while allowing patients to recover in their homes .Clinical applications and efficacyThe Clinical Scenarios Where Dexmedetomidine-Enhanced Interscalene Brachial Plexus Block is Most BeneficialShoulder arthroscopy: Dexmedetomidine-enhanced blocks benefit patients undergoing shoulder arthroscopy procedures, such as rotator cuff or labral repairs. These minimally invasive surgeries often require precise patient cooperation, as intraoperative adjustments and feedback are essential. Dexmedetomidine provides profound analgesia while preserving motor function, enabling patients to participate in the surgical process actively. This enhances patient comfort and ensures optimal cooperation during the procedure, contributing to its success .Joint replacement: Patients undergoing shoulder replacement surgeries, which may be more extensive and associated with significant postoperative pain, can benefit significantly from dexmedetomidine-enhanced blocks. Dexmedetomidine's ability to provide extended and robust pain relief in the early postoperative period is particularly valuable. It may expedite the rehabilitation process by allowing patients to engage in early mobilization and physical therapy, ultimately leading to improved shoulder function and faster recovery .Same-day surgery: Dexmedetomidine is a valuable option for same-day discharge protocols, where patients undergo shoulder surgery and are discharged on the same day. Its potential to provide effective analgesia and sedation without the need for prolonged hospital stays contributes to the cost-effectiveness of these procedures. Patients can recover comfortably at home while benefiting from the extended analgesic effects of dexmedetomidine, promoting patient satisfaction and healthcare resource optimization .High-risk patients: Patients with preexisting cardiovascular conditions or those at risk for opioid-related complications, such as respiratory depression, may particularly benefit from dexmedetomidine-enhanced blocks. Dexmedetomidine's opioid-sparing effect reduces the need for systemic opioids, minimizing the risks associated with opioid use in these high-risk populations. This approach aligns to enhance patient safety and optimize outcomes in vulnerable patient groups .Patient preferences: Patient preferences are significant in anesthesia decisions. Some individuals may prefer regional anesthesia techniques incorporating dexmedetomidine due to the associated anxiolysis and perceived comfort during the procedure. The calming and sedative effects of dexmedetomidine can alleviate patient anxiety and contribute to a positive surgical experience .Comparative Analysis with Traditional Techniques in Terms of Pain Control and Patient OutcomesPain control: Dexmedetomidine-enhanced blocks consistently demonstrate superior pain control compared to traditional blocks using local anesthetics alone. Dexmedetomidine's alpha-2 adrenergic agonist properties extend the duration and intensity of analgesia, leading to longer-lasting and more robust pain relief. Patients who receive dexmedetomidine-enhanced blocks often report reduced postoperative pain levels, translating to decreased opioid requirements and improved comfort during the early recovery phase .Motor function preservation: One of the notable advantages of dexmedetomidine is its ability to preserve motor function. Patients undergoing shoulder surgery frequently require intact motor function for various reasons, such as intraoperative positioning adjustments or active participation in physical therapy. Dexmedetomidine allows for precise sensory blockade while maintaining motor function, enabling patients to cooperate with surgeons and rehabilitation teams. In contrast, traditional blocks may result in varying degrees of motor weakness, potentially limiting patients' ability to actively engage in their care .Patient satisfaction: Dexmedetomidine's sedative and anxiolytic effects significantly increase patient satisfaction during the procedure. These properties help reduce patient anxiety and apprehension, promoting a more comfortable and cooperative surgical environment. Patients who receive dexmedetomidine-enhanced blocks often report feeling calmer and more at ease during surgery, which can positively impact their overall perception of the surgical experience .Early rehabilitation: Enhanced pain control and preserved motor function provided by dexmedetomidine may facilitate earlier postoperative rehabilitation. Patients are more likely to engage in early mobilization and physical therapy when they experience less pain and maintain motor function. This can lead to improved shoulder function, quicker recovery, and potentially shorter hospital stays or outpatient recovery periods .Reduced opioid use: Dexmedetomidine's opioid-sparing effect is a significant benefit, especially in the context of shoulder surgery. Patients receiving dexmedetomidine-enhanced blocks typically require fewer opioids for pain management, reducing the risk of opioid-related side effects such as respiratory depression, nausea, and constipation. This can lead to a more comfortable postoperative course and minimize the need for opioid reversal agents or interventions .Clinical Trials and Case StudiesExtended duration of analgesia: Clinical trials consistently demonstrate that the supplementation of dexmedetomidine in regional anesthesia prolongs the duration of analgesia when compared to traditional blocks. This extended pain relief is especially evident in the studies of shoulder arthroscopy and joint replacement procedures. Dexmedetomidine's ability to enhance the duration of pain control provides patients with prolonged relief in the critical immediate postoperative period, reducing discomfort and improving overall surgical experience .Improved pain scores: Patients receiving dexmedetomidine-enhanced blocks frequently report lower pain scores in the immediate postoperative period. These improved pain scores not only reflect enhanced comfort for patients but also signify the efficacy of dexmedetomidine in providing effective analgesia. Reduced pain intensity in the early postoperative phase contributes to a smoother recovery process and improved patient satisfaction .Reduced opioid consumption: Clinical trials consistently reveal reduced opioid consumption in patients receiving dexmedetomidine-enhanced blocks. This reduction in opioid requirements indicates the potential of dexmedetomidine to mitigate opioid-related side effects and complications. By minimizing opioid use, patients experience fewer adverse effects, such as nausea, vomiting, and respiratory depression, contributing to safer and more comfortable postoperative care .Patient satisfaction: Case studies often highlight individual patient experiences that underscore the advantages of dexmedetomidine in regional anesthesia for shoulder surgery. These case reports showcase reduced anxiety, enhanced patient cooperation during the procedure, and overall patient satisfaction. Dexmedetomidine's anxiolytic properties and ability to provide a calm and cooperative surgical environment contribute to a positive patient experience .Safety profile: An essential aspect of clinical trials and case studies is the evaluation of safety parameters associated with dexmedetomidine administration. This includes monitoring hemodynamic stability and assessing the occurrence of adverse events. Dexmedetomidine's safety profile is generally favorable when administered judiciously and closely monitored. Clinical studies provide valuable insights into the balance between achieving the desired sedation and analgesia and maintaining hemodynamic stability, helping healthcare providers make informed decisions about its use .Safety and side effectsPotential Side Effects and Complications Associated with Dexmedetomidine-Enhanced BlocksHemodynamic instability: Dexmedetomidine's alpha-2 adrenergic agonist properties can lead to hemodynamic instability, particularly during bolus administration or high-dose infusions. These effects may manifest as bradycardia (slow heart rate) and hypotension (low blood pressure). While these effects are generally well-tolerated and manageable, they can be of concern in patients with preexisting cardiovascular conditions, such as coronary artery disease or heart block. Careful dosing and continuous monitoring are essential to promptly address hemodynamic changes .Sedation and respiratory depression: Dexmedetomidine is renowned for providing sedation without causing respiratory depression, making it a valuable choice for anesthesia. However, high doses or rapid dexmedetomidine infusions can result in excessive sedation, potentially leading to respiratory depression. This is particularly relevant in patients with compromised respiratory function, such as chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea. Close monitoring of sedation levels and respiratory parameters is crucial to prevent and manage these effects .Delayed recovery: Prolonged sedation and residual effects of dexmedetomidine may lead to delayed recovery, affecting the patient's ability to mobilize and discharge from the healthcare facility promptly. While the extended analgesic effects of dexmedetomidine can be advantageous in pain management, careful planning and monitoring are necessary to ensure that patients are sufficiently alert and responsive for safe postoperative recovery .Local anesthetic toxicity: Co-administration of dexmedetomidine with local anesthetics may increase the total dose of medication delivered to the patient. This raises the risk of local anesthetic systemic toxicity (LAST), a rare but serious complication. LAST can manifest as neurologic symptoms, cardiovascular disturbances, or seizures and requires immediate treatment. Anesthesia providers should exercise caution and adhere to safe dosing practices to minimize the risk of LAST .Nausea and vomiting: Some patients may experience nausea and vomiting as a side effect of dexmedetomidine. While these symptoms are generally mild, they can be uncomfortable and may necessitate additional antiemetic medications. Preventive measures, such as administering prophylactic antiemetics, can help reduce the incidence of postoperative nausea and vomiting .Over-sedation: Dexmedetomidine's sedative properties, while desirable for providing patient comfort, can lead to excessive sedation if administered inappropriately or if the patient is particularly sensitive to its effects. Careful titration and monitoring are essential to maintain the desired level of sedation while avoiding over-sedation .Allergic reactions: Although rare, allergic reactions to dexmedetomidine or other medication components can occur. These reactions may manifest as skin rashes, itching, swelling, or, in severe cases, anaphylaxis. Immediate recognition and prompt treatment of allergic reactions are critical to ensure patient safety .Strategies for Mitigating Risks and Ensuring Patient SafetyIndividualized patient assessment: A thorough preoperative assessment is critical to identify patient-specific factors that may influence the use of dexmedetomidine. This assessment should encompass the patient's medical history, comorbidities, medication regimen, and allergies or sensitivities. Identifying high-risk patients, such as those with cardiovascular disease or respiratory conditions, is essential to tailor the anesthesia plan accordingly .Dosing considerations: Dexmedetomidine dosing should be customized based on the patient's characteristics and the surgical context. Patients at higher risk for hemodynamic instability may benefit from lower initial bolus doses and slower infusion rates. Careful consideration of the appropriate dosage ensures that the desired level of sedation and analgesia is achieved without excessive effects .Hemodynamic monitoring: Continuous blood pressure and heart rate monitoring is crucial throughout the procedure, especially during dexmedetomidine administration. Monitoring allows for the early detection of hemodynamic changes and provides an opportunity for timely intervention. Healthcare providers should be prepared to manage potential episodes of bradycardia or hypotension .Respiratory monitoring: Respiratory parameters, including oxygen saturation, end-tidal carbon dioxide (ETCO2), and respiratory rate, should be closely monitored to detect signs of respiratory depression. This is particularly important in patients with preexisting respiratory conditions or those receiving high doses of dexmedetomidine. Prompt recognition of respiratory issues is essential for patient safety .Local anesthetic dosing: When dexmedetomidine is combined with local anesthetics, the volume of local anesthetic should be carefully considered to minimize the risk of local anesthetic systemic toxicity (LAST). Reducing the volume while maintaining effective analgesia can help mitigate the risk of this potential complication .Careful titration: Dexmedetomidine dosing should be titrated carefully to achieve the desired level of sedation and analgesia while avoiding excessive sedation. Close monitoring of the patient's sedation level, responsiveness, and vital signs is essential to strike the right balance .Antiemetic prophylaxis: Prophylactic administration of antiemetic medications can help reduce the risk of postoperative nausea and vomiting, which may occur as a side effect of dexmedetomidine. This can enhance patient comfort and satisfaction during recovery .Patient education: Patients should be informed about the potential side effects of dexmedetomidine and the importance of close monitoring during the procedure. Open communication between patients and healthcare providers ensures that concerns or discomfort are promptly addressed .Reversal agents: Anesthesia providers should be prepared to administer alpha-2 adrenergic receptor antagonists, such as atipamezole if excessive sedation or hemodynamic instability occurs. Having reversal agents readily available can help rapidly reverse the effects of dexmedetomidine if needed .Continuous monitoring post-procedure: Monitoring of patients should continue into the postoperative period to ensure that they are recovering appropriately. Vital signs and comfort levels should be closely observed, and any signs of complications should be addressed promptly .Future directions and researchOngoing Research and Emerging Trends in the Use of Dexmedetomidine in Anesthesia for Shoulder SurgeryExpanded applications: Research explores the expanded applications of dexmedetomidine-enhanced blocks in a broader range of shoulder surgeries. This includes procedures beyond the typical scope of shoulder arthroscopy and joint replacement, such as revisions, complex reconstructions, and arthroplasties. Investigating the feasibility and benefits of dexmedetomidine in these diverse surgical scenarios will provide insights into its versatility and potential to enhance patient outcomes in a wide array of shoulder-related interventions.Optimized dosing regimens: Ongoing studies are dedicated to determining the most effective and safe dosing regimens of dexmedetomidine for specific patient populations and surgical procedures. This includes investigations into the ideal concentration of dexmedetomidine, infusion rates, and bolus dosing strategies. The goal is to achieve the optimal balance between providing adequate sedation and analgesia while minimizing the risk of adverse effects. Tailoring dexmedetomidine dosing to the unique requirements of different patient profiles and surgical contexts is central to these efforts.Patient-centered outcomes: The emphasis on patient-centered outcomes is gaining prominence in dexmedetomidine research. Studies are increasingly focusing on measuring outcomes that matter most to patients, such as overall satisfaction with their anesthesia experience, quality of postoperative recovery, and long-term shoulder function. Assessing the holistic impact of dexmedetomidine-enhanced blocks goes beyond pain relief and sedation, providing a more comprehensive understanding of how this technique affects the lives and well-being of patients over time.Combination therapies: Research is actively exploring the potential synergy of dexmedetomidine with other agents, including non-opioid analgesics and adjuvants. The aim is to optimize pain control while minimizing opioid consumption further. By combining dexmedetomidine with complementary medications or techniques, researchers hope to create multimodal analgesic approaches that maximize the benefits of each component while reducing the reliance on opioids. This approach aligns with the broader goal of reducing opioid-related complications and improving postoperative recovery.Comparison to alternative techniques: Emerging trends involve direct comparisons of dexmedetomidine-enhanced blocks with alternative regional anesthesia techniques used in shoulder surgery. This comparative research allows clinicians to make evidence-based decisions regarding the anesthesia approach. Dexmedetomidine's effectiveness and safety profile are assessed about other methods, such as continuous catheter-based infusions and intravenous opioid-sparing regimens. Comparative studies aim to provide a nuanced understanding of the advantages and limitations of each technique, facilitating informed clinical decision-making.Areas Where Further Investigation is NeededLong-term outcomes: The need for studies assessing long-term functional and pain outcomes remains paramount. While existing research has demonstrated the immediate benefits of dexmedetomidine-enhanced blocks, long-term follow-up is essential to understand how these interventions impact patients' quality of life, shoulder function, and pain relief beyond the immediate postoperative period. Longitudinal studies can provide insights into the durability of the analgesic effects and the potential for sustained improvements in patient outcomes. Comparing these long-term outcomes with patients who underwent traditional techniques will also help establish the enduring advantages of dexmedetomidine-enhanced blocks.Patient selection criteria: Research efforts should focus on further refining patient selection criteria. Identifying which patients are most likely to benefit from dexmedetomidine-enhanced blocks is crucial for optimizing the use of this technique. Factors such as age, comorbidities, and the specific type of shoulder surgery should be considered when developing evidence-based guidelines for patient selection. Understanding the patient characteristics that predict the greatest benefit and safety from dexmedetomidine administration will help tailor its use to those who gain the most.Safety and monitoring protocols: Continuous refinement of safety and monitoring protocols is imperative. As clinical experience with dexmedetomidine-enhanced blocks expands, there is an ongoing need to develop and enhance monitoring techniques that allow for the early detection and intervention of potential adverse effects. The optimization of safety protocols should involve real-time monitoring of vital signs, sedation levels, and adverse events to minimize complications and ensure patient safety. The development of standardized monitoring guidelines specific to this technique will further improve patient care.Cost-effectiveness analysis: Evaluating the cost-effectiveness of dexmedetomidine-enhanced blocks is essential for healthcare institutions and policymakers. Studies should not only consider the direct costs of dexmedetomidine administration but also factor in the potential cost savings associated with reduced hospital stays, decreased opioid-related expenses, and accelerated recovery protocols. A comprehensive cost-effectiveness analysis will provide valuable insights into the economic implications of adopting this technique on a broader scale.Comparative effectiveness: Comparative studies should be conducted to assess the effectiveness and safety of dexmedetomidine-enhanced blocks about other adjuvants or regional anesthesia techniques used in shoulder surgery. Comparative research can help clinicians make informed decisions about the choice of anesthesia technique by providing a comprehensive understanding of the benefits and limitations of each approach. Comparative effectiveness studies should encompass various surgical procedures and patient populations to yield robust and generalizable findings.Potential Refinements or Innovations in TechniquePrecision medicine: Precision medicine involves tailoring dexmedetomidine dosing and administration to individual patient characteristics. This includes genetics, age, weight, comorbidities, and pharmacogenomics. By leveraging genetic information, clinicians can optimize dosing regimens to maximize the effectiveness of dexmedetomidine while minimizing the risk of adverse effects. For example, genetic variations may influence the metabolism and response to dexmedetomidine, allowing for tailored treatment plans that enhance patient outcomes.Advanced delivery systems: Innovative delivery systems like PCRA devices offer patients greater autonomy over their pain management. With PCRA, patients can self-administer dexmedetomidine on demand within predefined safety limits, allowing them to titrate their infusion postoperatively. This approach empowers patients and enhances their ability to manage pain effectively while minimizing the risk of over-sedation or excessive drug administration.Pharmacokinetic modeling: Using pharmacokinetic modeling and simulation tools provides an opportunity to predict and individualize each patient's ideal dexmedetomidine dosing regimen. These models consider patient-specific factors such as age, weight, and surgical complexity, allowing for precise adjustments to optimize sedation and analgesia. Such modeling can help strike the delicate balance between achieving the desired clinical effects and preventing unwanted side effects, contributing to safer and more effective anesthesia.Telemedicine and remote monitoring: Telemedicine and remote monitoring technologies can revolutionize postoperative care for patients receiving dexmedetomidine-enhanced blocks. Real-time data on patient comfort, vital signs, and side effects can be continuously transmitted to healthcare providers, enabling immediate intervention if complications or discomfort arise. Telemedicine also facilitates early recognition of adverse events, potentially reducing the severity and consequences of complications.Enhanced safety algorithms: Developing advanced safety algorithms and decision-support systems is crucial for patient safety. These systems can integrate real-time data from patient monitoring devices, such as continuous blood pressure and heart rate monitoring, and use algorithms to identify trends or anomalies. Early warnings and alerts can be generated when potential complications are detected, prompting healthcare providers to intervene promptly. This proactive approach enhances patient safety by preventing or mitigating adverse events.In conclusion, incorporating dexmedetomidine into interscalene brachial plexus blocks for shoulder surgery significantly advances regional anesthesia. This comprehensive review has highlighted this approach's advantages, including extended analgesia, improved pain management, reduced opioid reliance, enhanced patient comfort, and preserved motor function. While acknowledging the need for meticulous patient selection, monitoring, and dosing considerations to mitigate potential risks, the utility of dexmedetomidine-enhanced blocks in clinical practice is undeniable. As we look to the future, ongoing research and collaboration among healthcare professionals are poised to refine techniques, optimize dosing strategies, and enhance patient outcomes. Dexmedetomidine has the potential to reshape the landscape of shoulder surgery anesthesia, ushering in a new era of improved pain control, patient satisfaction, and overall surgical experience."}
+{"text": "Dear Editor,Technology in Cancer Research & Treatment, Wang et al review the genetic and clinical characteristics of myeloproliferative neoplasms (MPN) with dual driver mutations suggesting that such patients have suboptimal responses with conventional treatments that require more customized therapeutic approaches. The incidence of such cases may be significantly underestimated in this review and can be largely attributed to the mutation detection methodology employed.Recently published in  Co-existence of classical and functional, noncanonical driver mutations of the same gene have been frequently reported in JAK2 exon 14, CALR exon 9, and MPL exon 10.35 Even dual noncanonical mutations have been described.Several techniques are available for the routine detection of MPN driver mutations and include Sanger sequencing, allele-specific PCR, high-resolution melt analysis, fragment length analysis, and next-generation sequencing (NGS), each with its own methodological limitations of sensitivity and specificity and also clinical applicability. In the last few years NGS has become increasingly employed in routine molecular diagnostic laboratories and while lacking in sensitivity to targeted allele-specific real-time polymerase chain reaction, has the advantage of detecting  single nucleotide polymorphisms (SNPs), benign variants and a considerable number of noncanonical mutations in these driver genes. While bioinformatics pipelines are able to filter out SNPs and benign variants, each noncanonical mutation requires either in silico or in vitro functional characterization to affirm pathogenicity. It must also be acknowledged that the presence of a particular driver mutation, alone or in combination with another, does not entirely account for the clinical course of MPN patients: the germline host makeup, bone marrow micro-environmental factors, and acquisition of further somatic mutations in myeloid malignancy-associated genes can be responsible for modifying disease progression and outcome. Biologically, it is currently unknown whether if each driver mutation exists in a single or distinct clone impacts on clinical outcomes. Single-cell sequencing, a new approach not widely adopted in routine molecular diagnostics, has demonstrated further molecular complexity of MPN including intralineage clonal evolution.Given the increasing evidence that MPN patients with concurrent driver mutations have an inferior clinical outcome, detection of the second noncanonical  mutation now appears entirely warranted for appropriate treatment decisions.Coincident with this increasing appreciation of the dual driver MPN entity is the consequence of diagnostic algorithms and mutation detection technologies. The major time and cost benefits of NGS are the ability to sequence multiple targets  simultaneously on a unified technological platform therefore considerably reducing the requirement for a diagnostic algorithm that has multiple steps involving different methodological platforms."}
+{"text": "Integrating cervical cancer screening into routine Human Immunodeficiency Virus (HIV) care has been endorsed as an effective strategy for increasing uptake of cervical cancer screening, facilitating early detection and treatment of pre-cancerous lesions among HIV-infected women. In Uganda, this strategy has not been implemented yet in most HIV clinics. Assessing acceptability of this intervention among HIV-infected women is of great relevance to inform implementation. We assessed acceptability of integration of cervical cancer screening into routine HIV care, associated factors and perceptions among HIV-infected women enrolled in the HIV clinic at Mbarara Regional Referral Hospital.p-value <0.05. Thematic analysis utilizing inductive coding was applied to analyse qualitative data.A mixed methods study utilizing explanatory sequential approach was conducted among 327 eligible HIV-infected women. Acceptability of integration of cervical cancer screening into routine HIV care was measured based on Theoretical Framework of Acceptability. Quantitative data was collected using\u00a0a\u00a0pre-tested questionnaire. We conducted focus group discussions to explore perceptions regarding the intervention among purposively selected HIV-infected women. Modified Poisson regression with robust variance analysis was utilized to determine factors associated with acceptability of the intervention. Statistical significance was determined at The majority of HIV-infected women (64.5%) accepted integration of cervical cancer screening into routine HIV care. Religion, perceived risk of developing cervical cancer and ever screened for cervical cancer were statistically significantly associated with acceptability of integration of cervical cancer screening into routine HIV care. Perceived benefits of the proposed intervention were: convenience to seek for cervical cancer screening, motivation to undergo cervical cancer screening, improved archiving of cervical cancer screening results, confidentiality of HIV patient information, and preference to interact with HIV clinic health workers. Shame to expose their privacy to HIV clinic health workers and increased waiting time were the only perceived challenges of the integrated strategy.Study findings highlight the need to take advantage of this acceptability to prioritize implementation of integration of cervical cancer screening into routine HIV care. HIV-infected women should be reassured of confidentiality and reduced waiting time to increase uptake of integrated cervical cancer screening and HIV services among HIV-infected women along the continuum of HIV care and treatment services. Globally, cervical cancer is the fourth most frequently diagnosed cancer and fourth leading cause of cancer death in women with an estimated 570,000 incident cases and 311,000 deaths . In low Human Immunodeficiency Virus (HIV) has been associated with high vulnerability of developing cervical cancer, a great public health challenge. Since 1989, research studies have reported an increased incidence of cervical cancer among HIV-infected women . HIV-infIntegration of cervical cancer screening into routine HIV care has been endorsed as an effective strategy to increase uptake of cervical cancer screening, achieve early detection and treatment of pre-cancerous lesions among HIV-infected women in Sub Saharan Africa where cervical cancer burden parallels that of HIV , 15\u201322. HIV-infected women enrolled in the HIV clinic are either referred or voluntarily undergo cervical cancer screening conducted by health workers in the cervical cancer screening department at Mbarara Regional Referral Hospital. Despite establishing referral or client-initiated cervical cancer screening system at Mbarara Regional Referral Hospital for the last 10 years, only 11.3% of HIV-infected women enrolled in the HIV clinic at Mbarara Regional Referral Hospital had undergone cervical cancer screening by September 30, 2019. HIV-infected women miss cervical cancer screening opportunities for early detection of pre-cancerous cervical lesions at enrolment and during subsequent annual intervals despite their frequent visits to HIV clinics for medical reviews, viral load monitoring, and monthly Anti\u2013Retroviral Treatment (ART) refills. Such missed opportunities increase risk of presenting late with advanced cervical cancer and poor prognosis among this vulnerable population. Implementation of integration of cervical cancer screening into routine HIV care is expected to increase uptake of cervical cancer screening services at enrolment and during subsequent annual HIV clinic visits among HIV-infected women enrolled in the HIV clinic at Mbarara Regional Referral Hospital compared to currently practiced referral or client-initiated cervical cancer screening system. We assessed acceptability of integration of cervical cancer screening into routine HIV care, associated factors and perceptions among HIV-infected women enrolled in the HIV clinic at Mbarara Regional Referral Hospital.The study was conducted in the HIV clinic at Mbarara Regional Referral Hospital in Mbarara District, South Western Uganda. Cervical cancer is the leading gynaecological cancer at Mbarara Regional Referral Hospital . With a Mixed methods study design utilizing explanatory sequential approach was used to assess acceptability of integration of cervical cancer screening into routine HIV care, associated factors and perceptions among HIV-infected women. Using explanatory sequential approach, the quantitative phase of the study was first conducted followed by analysis of data. HIV-infected women were then selected based on generated quantitative results of acceptability of integration of cervical cancer screening into routine HIV care; to participate in qualitative investigations.This study was conducted among HIV-infected women receiving HIV care and treatment services from the HIV clinic at Mbarara Regional Referral Hospital. Only HIV-infected women aged 18 and above who turned up for ART refills at the HIV clinic on interview dates were included in the study. HIV-infected women aged 18 and above who turned up for ART refills on unscheduled dates were excluded based on electronic appointment lists generated for the respective appointment dates. HIV-infected women who turned up on unscheduled dates were excluded because they were not on the appointment list from which study respondents were systematically selected to participate in the study.The dependent variable for this study was acceptability of integration of cervical cancer screening into routine HIV care. The Theoretical Framework of Acceptability was adapted to measure acceptability of integration of cervical cancer screening into routine HIV care. The Theoretical Framework of Acceptability was proposed as a multi-component framework and systematic approach to assess intervention acceptability across prospective, concurrent, and retrospective temporal perspectives . QuestioInformation on sociodemographic characteristics, awareness of cervical cancer, knowledge of risk factors of cervical cancer, knowledge of symptoms of cervical cancer, cervical cancer screening awareness, uptake of cervical cancer screening, and perceived risk of cervical cancer was obtained. Sociodemographic characteristics included age, marital status, highest education level, religion, area of residence, number of living biological children, and duration of HIV disease.To assess knowledge of risk factors and symptoms of cervical cancer, participants were requested to select from response options \u201c1. Yes\u201d \u201c2. No\u201d for each item. A correct answer was awarded \u201c1\u201d whereas a wrong answer was awarded \u201c0\u201d.\u00a0According to the African Women Awareness of CANcer tool, codes to response options were assigned without any meaning. So, out of two options, if the participant selected an appropriate answer, one received an award of \"1\" for the item because it was the correct answer. If the participant selected an inappropriate answer,\u00a0one received an award of \"0\" for the item because it was the wrong answer. A summated score was obtained for variables: knowledge of risk factors and knowledge of signs and symptoms of cervical cancer.Knowledge of risk factors of cervical cancer was categorised into two categories: \u201c1. Poor Knowledge\u201d and \u201c2. Good Knowledge\u201d; based on the mean score\u00a0as evidenced in recent published studies , 28. \u201c1.Knowledge of signs and symptoms of cervical cancer was also categorised into two categories: \u201c1. Poor Knowledge\u201d and \u201c2. Good Knowledge\u201d; based on the mean score as\u00a0demonstrated in recent published studies , 28. \u201c1.For the quantitative component, sample size was calculated using sample size estimation formula , 30. TheQuantitative data were collected using administered questionnaires. The pre-coded questionnaire was pre-tested at Kawaala Health Centre IV to check for suitability of various aspects such as translations, skip procedures, filtering questions and modifications were made thereafter. The questionnaire was translated into Runyankole/Rukiiga. Selection and recruitment of experienced research assistants was based on competence, quantitative data collection skills and qualifications. Research assistants received training on how to administer study questions before data collection. After meeting selected participants to take part in the study, research assistants introduced themselves and explained the purpose of the study. Eligible participants provided written informed consent before the interview was conducted. Each questionnaire was completed within 15 - 20 minutes. During data collection, questionnaires were reviewed on completion of each interview so that corrections are made in addition to checking for completeness before departure of participants. Supervision was conducted to ensure compliance throughout the study.Data capture screens with in-built checks for consistency, logical flow, range and accuracy of data were designed in EpiData version 3.0\u00a0for data entry. Data were cleaned and stored daily. Double-entry of data was done to check for any errors. Stored data was backed up on different flash discs. Questionnaires were kept securely throughout the study and thereafter.Linear regression analysis was the recommended method of modelling since the dependent variable, acceptability of integration of cervical cancer screening into routine HIV care, was a continuous variable. Summated scores of acceptability of integration of cervical cancer screening into routine HIV care were converted into percentages. The regression modelling predicting acceptability of integration of cervical cancer screening into routine HIV care from all independent variables was conducted. Residuals were generated followed by testing assumptions of linear regression: normality of residuals and homogeneity of variance. Linear regression analysis was not utilised for this study because both assumptions of normality and homogeneity of variance of residuals were violated.th percentile of the highest possible summated score of 35 from seven constructs of Theoretical Framework of Acceptability. The 75th percentile was recommended as the cut-off value based on a published study which utilised likert-type scale responses assessing constructs to measure composite dependent variable  \u2026\u201d HIV-infected women in the\u00a0majority of focus group discussions argued that delivering cervical cancer screening comprehensively with other routine HIV care services during scheduled HIV clinic visits would be very time consuming hence increasing waiting time at the HIV clinic. With increased numbers of HIV-infected women enrolled into HIV care at the HIV clinic, participants were worried of potential delay at the HIV clinic attributed to integration of cervical cancer screening into routine HIV care.This study assessed\u00a0acceptability of integration of cervical cancer screening into routine HIV care, associated factors and perceptions among HIV-infected women enrolled in the HIV clinic at Mbarara Regional Referral Hospital. Analysis of data showed that 64.5% of HIV-infected women enrolled in the HIV clinic at Mbarara Regional Referral Hospital accepted integration of cervical cancer screening into routine HIV care. This study finding is lower than acceptance among HIV-infected women to undergo cervical cancer screening procedure reported at 87.6% after incorporating Visual Inspection with\u00a0Acetic acid\u00a0into the routine clinical services offered at Family AIDS Care and Education Services clinics in Kisumu, Kenya .Acceptability of the proposed intervention at 64.5% is lower than cervical cancer screening acceptance of 79.8% among HIV-infected women at the HIV treatment centre, Nigerian Institute of Medical Research (NIMR), Lagos, Nigeria who participated in the study assessing acceptability of integration of cervical cancer screening into HIV care . This coResults of multivariable regression analysis indicated that religion, perceived risk of developing cervical cancer and ever screened for cervical cancer were statistically significantly associated with acceptability of integration of cervical cancer screening into routine HIV care among HIV-infected women. Despite the fact that Muslims accepted integration of cervical cancer screening into routine HIV care compared to Protestants, a study conducted among HIV-infected women reported that religion was not significantly associated with acceptability of integration of cervical cancer screening into routine HIV care . AdditioHIV-infected women with \u201cMuch Above Average\u201d perceived risk of developing cervical cancer accepted integration of cervical cancer screening into routine HIV care. This study finding highly correlates with findings from the systematic review conducted in Ethiopia where perceived susceptibility to acquiring cervical cancer  was significantly associated with cervical cancer screening acceptability among HIV-positive women . HoweverIt was also found out HIV-infected women who had not undergone cervical cancer screening were less likely to accept integration of cervical cancer screening into routine HIV care compared to HIV-infected women who had undergone cervical cancer screening. A study conducted among HIV-infected women at the HIV treatment centre, Nigerian Institute of Medical Research, Lagos, Nigeria reported that ever screened for cervical cancer was not significantly associated with acceptability of integration of cervical cancer screening into routine HIV care . HIV-infPerceived benefits of the proposed intervention were: convenience to seek for cervical cancer screening, motivation to undergo cervical cancer screening, improved archiving of cervical cancer screening results, confidentiality of HIV patient information, and preference to interact with HIV clinic health workers. In all FGDs, HIV-infected women acknowledged that integration of cervical cancer screening into routine HIV care would grant them an opportunity to receive both cervical cancer screening in addition to HIV services conveniently from the HIV clinic compared to currently practiced referral or client-initiated cervical cancer screening. This study finding is in agreement with findings from other studies which reported that convenience of seeking for integrated HIV and cervical cancer screening services from one point without forgetting an added advantage of one off relief of anxiety was attributed to the integrated strategy compared to stand alone screening services , 24. TheHIV-infected women in all FGDs reported that integration of cervical cancer screening would motivate HIV infected women to undergo cervical cancer screening services. Furthermore, HIV-infected women in the\u00a0majority of FGDs alleged that integration of cervical cancer screening into routine HIV care would inspire HIV-infected women, targeted recipients for the proposed intervention, to comply and adhere to recommended annual cervical cancer screening. Researchers, community members, health care providers and policy makers were also optimistic that intervention would improve uptake of initial and annual cervical cancer screening among HIV-infected women , 15\u201324. HIV-infected women in the\u00a0majority of FGDs claimed that the proposed intervention would promote confidentiality of HIV status and any other health related information due to interaction with only health workers and fellow HIV-infected women. This study finding was also reported in a study conducted in Uganda where women reported that the integrated model would promote confidentiality of HIV and any other health related information due to being accessed and confined to limited teams of health care practitioners in\u00a0HIV clinics . In mostShame to expose their privacy to HIV clinic health workers and increased waiting time were the only perceived challenges of integration of cervical cancer screening into routine HIV care among HIV-infected women. HIV-infected women in only \u201cVery Unacceptable and Unacceptable\u201d FGD reported that they would prefer undergoing cervical cancer screening conducted by health workers at the cervical cancer screening unit of Mbarara Regional Referral Hospital as opposed to HIV clinic health workers. Based on a study conducted in Uganda, discomfort and invasion of privacy expressed by HIV-infected women due to genital illnesses, menstrual periods, and fear to expose their private parts was one of the challenges to undergo cervical cancer screening integrated into routine HIV services at Mildmay Uganda . HIV-infHIV-infected women in the\u00a0majority of the FGDs argued that delivering cervical cancer screening comprehensively with other routine HIV care services during scheduled HIV clinic visits would be very time consuming hence increasing waiting time at the HIV clinic. This study finding was consistent with findings from other studies where long waiting time was cited as one of the potential challenges HIV-infected women would have to endure through to undergo cervical cancer screening integrated into comprehensive HIV services , 24, 37.The mixed methods study design using explanatory sequential approach increased rigor and internal validity of the study. Utilisation of systematic sampling method for selection of HIV-infected women to participate in the quantitative phase of the study was an added strength to the conduct of the study. However, the Theoretical Framework of Acceptability adapted to measure acceptability of integration of cervical cancer screening into routine HIV care had not yet been validated among Ugandan populations. HIV-infected women who turned up on unscheduled dates were excluded from participating in the study; increasing potential for information bias. Furthermore, this study was conducted in only one HIV clinic in the entire country due to limited funding; hence affecting generalisability of study findings to all HIV-infected women in Uganda.Study findings highlight the need to take advantage of this acceptability to prioritize implementation of integration of cervical cancer screening into routine HIV care. Ministry of Health should prioritise implementation of integration of cervical cancer screening into routine HIV care to increase uptake of cervical cancer screening among HIV-infected women along the continuum of HIV care and treatment services. Health workers delivering HIV care and treatment services should endeavour to conduct intensified health education and awareness about increased risk of developing cervical cancer among HIV-infected women. HIV-infected women should be reassured of reduced waiting time, confidentiality and optimisation of privacy by HIV clinic health workers during provision of integrated HIV care and cervical cancer screening services. Furthermore, a nationally representative study should be conducted to assess acceptability of integration of cervical cancer screening into routine HIV care, associated factors, and perceptions among HIV-infected women enrolled in HIV clinics in Uganda."}
+{"text": "Cancer cells that remain viable despite treatment constitute a persister condition that is implicated in residual diseases and a source from which resistant clones and relapses can emerge. Unlike resistant cells that are capable of cycling under therapy, persister cancer cells stay viable but assume a quiescent or non-proliferating state that is reversible upon treatment discontinuation. A source of persisters that has been under extensive study is drug-tolerant persisters, a small cancer cell population that can withstand the selection pressure of cytotoxic treatment and have been attributed to failure in achieving complete response. It is well recognized that many targeted therapeutic agents possess cytostatic effects that suppress growth without directly inducing cell death. While representing favorable responses, treatment-mediated cytostatic conditions require continual maintenance and intrinsically confer an obligate persister population throughout therapy. However, few efforts have focused on understanding the properties of such cytostatic persisters and exploring their therapeutic potentials.A recent study  from ourThese initial findings prompted us to investigate the general effects of oncogenic AKT signaling on non-proliferating cells. To do that, we undertook a bottom-up approach and devised a platform amendable for engineering cell signaling in cytostatic states using three-dimensional culture of quiescent mammary organoids. Quantitative proteomic analysis showed that hyperactive AKT signaling alters the homeostatic control in cytostatic state and promotes an oxidative and proteotoxic environment. Screening a small set of pharmacologic agents that further perturb redox and proteostasis identified an efficacy of proteasome inhibitors in inducing apoptosis in the cytostatic persister cancer cells with selectivity over quiescent normal cells. Mechanistically, this induction of apoptosis is dependent on p70S6K, redox, and ASK1 [+, Her2+, and triple negative), epithelial tissue origins , and drug-mediated cytostatic conditions (CDK4/6 and EGFR/Her2 inhibitors). Furthermore, tumor spheroids and xenograft models of lung and breast cancer showed that targeting cytostatic persisters could significantly reduce and delay cancer recurrence after treatment discontinuation.Notably, this targeting approach shows efficacy in cytostatic persisters harboring PTEN/PI3K pathway mutations independent of breast cancer subtypes (ERFindings from this study have shed light into the cellular controls in cytostatic persisters and highlighted that treatment-mediated cytostatic condition before resistance emerges is a viable targeting venue to reduce cancer recurrence. This study also raised insights into the complexity and challenges of targeting persister cancer cells in therapy. Investigating oncogenic AKT signaling under cytostatic conditions has suggested a different homeostatic environment between cytostatic and drug-tolerant persisters despite similar non-proliferating status, which may contribute to the distinct approaches for targeting. Inhibiting the pro-survival oncogenic AKT signals have broad efficacy in targeting drug-tolerant persisters , 8. We sThe synthetic-lethal approach for targeting is dependent on the effects of specific oncogenic signaling on the cytostatic state homeostasis, suggesting that distinct approaches may be necessary for targeting cytostatic persisters harboring different oncogenic alterations. This notion emphasizes a value of identifying sustained oncogenic signals and their effects in cytostatic persisters, which could facilitate the development of targeting strategies. More broadly, given the pharmacokinetic limitations and the dose-dependent cytostatic and cytotoxic effects of many cancer therapeutic agents, we anticipate that heterogeneous persister populations are inevitable in treatment. The distinct vulnerabilities of cytostatic and drug-tolerant persisters imply that administering multiple targeted regimens would be necessary to effectively deplete the persister reservoirs in patients under cancer treatments."}
+{"text": "Cognitive impairment is a well-recognized key feature of schizophrenia. However, these cognitive impairments may be worsened by alcohol consumption. Up to 80% of patients with alcohol use disorders (AUD) display cognitive impairments. Screening for those impairments with a full neuropsychological assessment may be difficult. The Brief Evaluation Alcohol-Related Neuropsychological Impairments (BEARNI) is a specific tool for screening those impairments easy to implement in in clinical practice . To our knowledge, no previous studies have assessed the alcohol-related cognitive impairments using the BEARNI test in schizophrenia patients.The objective of the study was to compare BEARNI mean scores between a group of schizophrenia patients with alcohol use disorders and a group of schizophrenia patients without alcohol use disorder.39 patients with schizophrenia and AUD (SCZ/AUD +)  and 49 patients with schizophrenia without AUD (SCZ/AUD-)  consecutively included in the study, were assessed using the BEARNI test. All patients met DSM-5 criteria for schizophrenia and AUD. Demographic and clinical variables were also collected, using the Alcohol Use Disorders Identification Test (AUDIT) and the Positive and Negative Syndrome Scale (PANSS). The primary endpoint of the study was the difference in BEARNI cognitive mean scores between the SCZ/AUD+ and SCZ/AUD- groups.There was no difference between the two groups regarding demographic variables or PANSS mean scores . The AUDIT mean score was higher in the group of patients SCZ/AUD+ . Total BEARNI and cognitive BEARNI mean scores were significantly lower in the group of patients SCZ/AUD+ compared to the group of patients SCZ/AUD- . The mean subscores of delayed verbal memory, alphabetical ordination, and alternating verbal fluency subtests were also significantly lower in the group of patients SCZ/+ group .The present study found cognitive impairments using BEARNI test in schizophrenia patients with AUD compared to their counterparts without AUD. Screening alcohol related cognitive impairments using BEARNI could be easier in patients in schizophrenia patients with AUD than usual neurocognitive assessmentsNone Declared"}
+{"text": "Cancer diagnosis, prognosis, and treatment stand as pivotal factors in enhancing patient outcomes. Recent advances in AI, deep learning, and genomics are reshaping cancer research . The intResearch in this domain has spotlighted predictive modeling and cancer biomarkers, demonstrating the application of machine learning in predicting malignancy and metastasis across various cancers, including lung and colorectal cancers . FurtherMachine learning and whole-evidence analysis have facilitated comprehensive evaluation in cancer research. Studies focusing on lung cancer screening and hepatocellular carcinoma prognosis have enhanced screening and prognostic accuracy . AdditioThe investigation of cancer stem cells and their involvement in tumorigenesis has gained significant attention. Studies in this field have delved into the exploration of prognostic long non-coding RNAs (lncRNAs) and the development of deep learning models for early cancer diagnosis. These efforts underscore the critical importance of integrating both physical and genomic markers in treatment planning .Huang et al. pioneered a novel approach integrating low-rank matrix completion for missing value imputation. Their work not only enhanced the accuracy of intratumor heterogeneity analysis but also laid a foundation for precise interpretations within the intricate landscape of cancer biology.In a stride toward addressing technical challenges in single-cell RNA-Seq data analysis, Zhou et al. illuminated the significance of an immune-related prognostic signature in predicting the clinical outcomes and tumor immunity of stomach adenocarcinomas (STAD). Their findings underscored the pivotal role of immune cell infiltration, unveiling distinctive clusters of \u201chot\u201d and \u201ccold\u201d tumors with divergent clinical trajectories, while identifying key genes, such as PEG10, DKK1, and RGS1, as critical prognostic markers.A pivotal study by Chuang et al. delved into the genetic nuances of diabetic retinopathy, shedding light on the influence of genetic variants of the lncRNA LINC00673 on disease susceptibility. Their exploration unveiled associations between specific LINC00673 single nucleotide polymorphisms (SNPs) and the development of non-proliferative diabetic retinopathy (NPDR), providing crucial insights into the genetic underpinnings of this complex ocular condition.Genes exert a significant impact not only on cancer but also on the development of various other diseases. Hsieh and Li harnessed the potential of image recognition techniques to rectify data imbalances in genetic disease research, spotlighting the transformative role of Synthetic Minority Oversampling Technique (SMOTE) in restoring data integrity within human biobanks. Their study streamlined data processing and facilitated more robust analysis and interpretation of genetic datasets.In parallel, In summary, these groundbreaking studies demonstrate the transformative potential of integrating physical and genomic markers into intelligent therapy systems, fortified by cutting-edge computational technologies. By fostering a collaborative and interdisciplinary approach that promotes scientific excellence, societal inclusivity, and ethical healthcare practices, we pave the way for a future where personalized medicine is not just a vision but a tangible reality accessible to all."}
+{"text": "Drosophila revealed two different mechanisms to regulate synapse formation. In photoreceptor neurons, autophagosome formation in synaptogenic filopodia destabilizes presumptive synaptic contacts and thereby restricts incorrect synaptic partnerships. In dorsal cluster neurons, autophagy is actively suppressed to keep mature synapses stable during axonal branching. These findings indicate that different neuron types can require activation or suppression of synaptic autophagy during the same developmental period to ensure proper synapse formation and brain connectivity.A recent characterization of the role of autophagy in two different neuron types during brain development in  Atg5 or Atg7. This seminal work revealed that functional neurons develop in the absence of autophagy, but are at increased risk for adult-onset degeneration. However, subsequent studies revealed that autophagy-deficient neurons, although functional, exhibit hallmarks of neurodevelopmental defects. Loss of autophagy during mouse brain development leads to increased spine density due to defective pruning after synapse formation, a hallmark of neurodevelopmental autism spectrum disorders. Conversely, in worms and flies, loss of neuronal autophagy can lead to reduced synapse formation. These findings suggest developmental roles for autophagy at the level of synapses, yet there is currently no coherent picture about a single, shared mechanism by which autophagy functions during brain development and synapse formation.The role of macroautophagy/autophagy in the brain was initially characterized in mice with neuron-specific loss of the core autophagy genes Our labs have recently studied the role of neuronal autophagy during fly brain development in two different neuronal cell types. Loss of autophagy in photoreceptor neurons leads to a stabilization of synaptogenic filopodia, which in turn leads to increased synapse formation, similar to what has been suggested for spine stabilization in mice . Importasuppression of autophagy. The signaling mechanism underlying this suppression requires Egfr  function, which had previously been shown to function in DCN axon branching during early axon development. The new study now revealed an independent second, later role for Egfr signaling in axonal branches during synapse formation. However, loss of Egfr signaling does not affect the initial trafficking of presynaptic proteins to synaptogenic filopodia at the time synaptogenesis commences in these branches. Instead, Egfr function is specifically required to stabilize newly formed presynaptic active zones by preventing their turnover through membrane degradation . Correspondingly, a reduction of endomembrane degradation through Presynaptic active zones form concomitantly with the elaborate axonal branch morphogenesis of DCN axons. A role for synapse formation in axonal and dendritic branching is well known as \u201csynaptotropic growth\u201d. During synaptotropic growth synapse formation stabilizes branches and provides a local basis for new probabilistic branch formation. Correspondingly, suppression of autophagy during DCN synapse formation secondarily leads to branch destabilization and a deterioration of the stereotypic axonal branching pattern . The conWe conclude that autophagy can restrict synapse formation through different mechanisms in two different neuron types of the fly visual system during the development of synaptic connectivity. In the non-branched axon terminals of photoreceptor neurons autophagy is actively induced at the tips of synaptogenic filopodia to restrict synapse formation and partner choice; in the highly branched axons of DCNs autophagy is actively suppressed to allow synaptotropic growth of an axonal branching pattern. Furthermore, the autophagic cargo in photoreceptor filopodia include the presynaptic seeding factors Liprin-a and RhoGAP100F/Syd-1, but not the mature active zone marker Brp ; by contThe observation that activation versus suppression of autophagy can be required in two different neuron types in the same brain region and during the same critical window of brain development may also affect how we view brain-wide autophagic up- or downregulation as a therapeutic opportunity. If neighboring neurons employ opposite autophagic regulation to develop proper synaptic connectivity, then levels of autophagy must be controlled at the level of individual neurons to ensure normal development.In summary, we have identified two very different neuron types in the fly visual system that employ the spatial and temporal regulation of autophagy for the fine-tuning of synaptic connectivity through selective restriction of synapse formation, albeit through different mechanisms. In both cases cell type-specific modulation of presynaptic autophagy during synapse formation represents a quantitative contribution to brain wiring that is selectable at the level of animal behavior. Based on the diversity of autophagy-dependent synapse development in the few neuron types analyzed thus far, we speculate that more cell-specific roles of autophagy will emerge as more neuron types are investigated during brain development."}
+{"text": "Atmospheric heavy metal pollution presents a severe threat to public health and environmental stability. Transition metal catalysts have emerged as a potent solution for the selective capture and removal of these pollutants. This review provides a comprehensive summary of current advancements in the field, emphasizing the efficiency and specificity of nanostructured transition metals, including manganese, iron, cobalt, nickel, copper, and zinc. Looking forward, we delve into the prospective trajectory of catalyst development, underscoring the need for materials with enhanced stability, regenerability, and environmental compatibility. We project that advancements in computational materials science, nanotechnology, and green chemistry will be pivotal in discovering innovative catalysts that are economically and environmentally sustainable. The integration of smart technologies for real-time monitoring and adaptive control is anticipated to revolutionize heavy metal remediation, ensuring efficient and responsive pollution abatement strategies in the face of evolving industrial scenarios and regulatory landscapes. Atmospheric heavy metal pollution, a critical public health concern, has intensified with industrialization, emitting toxic elements like arsenic and lead . IndustrThese metals undergo atmospheric transformations, influencing their environmental persistence and human bioaccumulation, with significant health impacts . They coHeterogeneous catalysis with transition metals has become a key approach for removing atmospheric heavy metals, supported by advancements in catalyst design for improved specificity and cost effectiveness . ResearcTransition metals are exceptionally well suited as catalysts for highly selective capture and removal of atmospheric heavy metals. The variable oxidation states, coordination modes and tunable active sites of transition metals like iron, manganese, cobalt, nickel, copper and zinc facilitate specific binding with heavy metal contaminants . The nanThis review discusses recent advances in emerging transition metal catalytic systems for atmospheric heavy metal removal. The sources, toxicity and environmental impacts of key heavy metal pollutants are first outlined. Progress in the rational design and development of nanostructured transition metal catalysts using synthesis strategies to optimize selective removal performance is then reviewed. Key mechanisms including adsorption, reduction, photocatalytic degradation and vapor-phase catalytic oxidation are examined. Finally, current challenges and future prospects for transition metal catalysts as solutions for real-world atmospheric heavy metal abatement are discussed.Transition metal nanoparticles (NPs) supported over porous materials have been widely explored as promising catalysts for adsorptive removal and reduction in atmospheric heavy metals. Nanostructuring enhances reactive surface area and metal dispersion while supports like silica and activated carbon provide stability and prevent aggregation . By modu2) with sizes of 10\u201330 nm via a microemulsion technique  (MOF-2)) which showed excellent As(III) and As(V) removal capacity from simulated flue gas . The thi0 vapor under visible light [0 to Hg2+, which was captured in the MOF pores, preventing volatilization.Semiconductor MOFs containing photoactive metal clusters like Ti, Fe, and Zr can generate reactive oxygen species under light irradiation to oxidize toxic heavy metals. MIL-125-NH2, a Ti-based MOF, was able to completely oxidize harmful Hgle light . The phoMOFs selectivity for target heavy metals can be improved through rational functionalization of the organic linkers. Amino-functionalized MOFs are promising for capturing acidic oxoanions of toxic metals like Cr(VI) and As(V). Li et al. synthesized an ethylenediamine-modulated MOF which showed excellent Cr(VI) removal capacity of 199 mg/g . The amiIn summary, MOFs offer a versatile platform for atmospheric heavy metal capture through highly porous structures, tunable functionality and photocatalytic activity. Further development of visible light responsive, durable MOFs through modular synthesis and advanced characterization will drive progress in atmospheric heavy metal remediation.Porous coordination polymers (PCPs), also known as metal\u2013organic polyhedra (MOPs), have attracted interest as selective sorbents for separating toxic heavy metals like mercury and arsenic from flue gas streams. PCPs consist of multimetallic nodes bridged by organic ligands to create crystalline porous architectures . The tun2+ compared to lower adsorption of Pb2+, Cd2+ and Zn2+. This high Hg2+ selectivity was attributed to complementary interactions between the pore size and the ionic diameter. The porous coordination polymers for heavy metal removal are given in The ultrafine micropores (<2 nm) and open metal sites in PCPs promote capture of heavy metal ions and particles. Yuan et al. synthesized a series of PCPs with pore sizes ranging from 0.5 to 2.5 nm and demonstrated size selective adsorption of metal ions . The PCPIncorporating coordinatively unsaturated metal sites in PCPs facilitates strong binding with heavy metals. Zhang et al. synthesized an aluminum methylphosphonate PCP containing open Al(III) sites which demonstrated a remarkable arsenic adsorption capacity of 1025 mg/g . XPS and0 and photoreduction of Cr(VI) under UV irradiation [0 was oxidized to HgO while Cr(VI) was reduced to less toxic Cr(III) species by photoexcited electrons. The local coordination environment around the Ti(IV) sites facilitated the photocatalytic activity.The reactive open metal sites in PCPs also enable redox transformations of toxic metals like Hg(II) and Cr(VI). A Ti(IV)-based PCP synthesized by Boorboor et al. exhibited selective oxidation of Hgadiation . XPS anaOverall, precise modulation of pores sizes, functional groups, and metal binding sites make PCPs promising selective sorbents for removing toxic heavy metal contaminants from industrial flue gas emissions. Future development of durable PCPs with optimized pore structures and active sites will help advance practical heavy metal remediation applications.Metal oxides are a versatile class of catalysts that have shown immense potential for removing toxic heavy metals from industrial flue gas emissions. Redox-active transition metal oxides, especially manganese, iron, cobalt, nickel, copper and zinc oxides, exhibit favorable properties like high stability, good adsorptivity, and multiple oxidation states that facilitate catalytic abatement of atmospheric heavy metals .Nanostructuring enhances the performance of metal oxide catalysts by providing increased reactive surface area, surface defects, and nanoscale interactions that augment heavy metal adsorption and catalytic activity . Common Metal oxides demonstrate excellent adsorption capacity for heavy metals due to surface hydroxyl groups, oxygen vacancies, and labile lattice oxygen that can trap metal ions and particles . Nanosiz2, ZnO and \u03b1-Fe2O3 catalyze the photooxidation of toxic metals upon band gap excitation under UV or solar irradiation [0 and As(III) into less volatile higher oxidation states that are readily captured [2O3 nanoparticles prepared using a sol\u2013gel method achieved a 98% photooxidation of Hg0 to HgO, enabling flue gas purification [Semiconducting metal oxides like TiOadiation . Photoexcaptured . For exafication .The variable oxidation states of transition metals like Cu, Fe and Co in metal oxides facilitate catalytic reduction in toxic metals like Hg(II), Cr(VI) and As(V) . Redox cOverall, metal oxide catalysts present versatile, high-performance platforms for removing heavy metals from industrial flue gas emissions through combinations of adsorption, photooxidation and redox catalytic mechanisms. Advances in morphology and interface engineering, visible light harvesting, and multi-functional composite fabrication offer exciting opportunities to leverage these mechanisms for efficient atmospheric heavy metal abatement.Bimetallic catalysts comprised of coupled transition metals have emerged as promising materials for removing airborne heavy metal contaminants. The synergistic effects between the constituent metals in bimetallic nanoparticles and porous materials augment their adsorption capacity, redox activity and stability compared to their monometallic counterparts . Strateg0 while Cu provided abundant binding sites. The combined effect significantly exceeded their individual performances.Bimetallic catalysts often demonstrate increased heavy metal adsorption capacity owing to the combination of favorable properties from the two metals. Pd-Cu bimetallic nanoparticles supported on multiwalled carbon nanotubes showed excellent capture of elemental mercury, achieving a 96% removal from simulated flue gas . The Pd 0 which was then oxidized by interfacial Cu(II) sites [0.Incorporating two transition metals with different reduction potentials generates bifunctional sites that can catalyze sequential conversion of heavy metals between multiple oxidation states. Fe-Cu bimetallic nanoparticles synthesized by Liu et al. displayed cooperative redox activity where Fe(III) centers first adsorbed gaseous HgI) sites . This tw0 under visible light irradiation [0 oxidation.The distinct electronic structures of constituent metals in bimetallic catalysts allow modulating band alignment, charge transfer and surface reactivity. Au-Ag bimetallic nanoclusters exhibited plasmon-enhanced photocatalytic oxidation of Hgadiation . The Ag In summary, bimetallic catalysts present opportunities to strategically couple the unique properties of transition metals to develop multifunctional materials with synergistically enhanced activity, selectivity and lifespan for removing harmful atmospheric heavy metals.Zeolites are crystalline aluminosilicate materials comprised of intersecting channels and cavities that make them promising catalysts for capturing airborne heavy metal pollutants. The porous structure, high surface area, and ion exchange capacity of zeolites facilitate adsorption of heavy metal ions and particles . FunctioThe microporous channels and cavities in zeolites promote physical adsorption and trapment of heavy metal contaminants. Zeolite Y with a faujasite structure demonstrated high capacity adsorption of 215 mg/g for Cd(II) ions owing to the porous supercages . EnhanciThe aluminosilicate framework of zeolites contains abundant charge balancing cations that can be readily exchanged with heavy metal ions. Zeolite NaY exhibited reversible ion exchange with Pb(II) and Cd(II), enabling cyclic heavy metal removal from simulated flue gas . The cat0 [0 to HgO along with high thermal stability, achieving near complete mercury removal [Incorporating redox-active transition metals like Fe, Ti and Ce introduces reactive sites in zeolites that chemisorb and catalytically oxidize elemental metals like Hg0 . Fe-exch removal .Graphene and graphene oxide (GO) are emerging support materials for metal and metal oxide nanocatalysts owing to their high surface area, thermal/chemical stability, and mechanical durability . GraphenGraphene is an ideal support for dispersing metal and metal oxide nanocatalysts while preventing aggregation and leaching during high-temperature operation . Ni nano3O4 nanoparticles grown on graphene nanosheets exhibited potent low-temperature catalytic oxidation of Hg0 to HgO [3O4-graphene interface to boost Hg0 oxidation kinetics.The high conductivity of graphene facilitates electron transfer to supported catalysts, improving redox conversion of absorbed heavy metals. CO0 to HgO . GraphenOxygen functional groups in GO enable selective coordination with heavy metal ions, while restoration of conjugation in reduced GO improves electron mobility . Thiol-fIn summary, graphene-based materials present versatile supports to augment metal/metal oxide nanocatalysts for atmospheric heavy metal removal through carrier, binding site and electron transfer effects.Understanding the kinetics of heavy metal adsorption on MOFs is fundamental to the design of efficient removal processes. Kinetic studies shed light on the rate at which heavy metal ions are immobilized on the MOF surface, impacting overall removal efficiency.In this section, key aspects of kinetics and modeling applied to MOFs photocatalysis for removing heavy metal ions, organic pollutants and microbes from water are reviewed. The discussion illustrates the multifaceted reaction networks involved and highlights recent efforts to develop integrated kinetics models incorporating coupled adsorption, interfacial transfer, light absorption, contaminant degradation and mass transport effects that influence overall treatment rates and efficiencies.Langmuir\u2013Hinshelwood model: The Langmuir\u2013Hinshelwood model is a widely used kinetic model that describes the adsorption and reaction kinetics of surface-catalyzed reactions. Recent advancements in Langmuir\u2013Hinshelwood modeling for MOFs have focused on integrating factors such as photonic efficiency, active site availability, intermediates, and competitive adsorption between multiple contaminants. These refinements enhance the model\u2019s accuracy in describing the kinetics of heavy metal adsorption on MOF surfaces .Pseudo-first-order model: The pseudo-first-order kinetic model is a simplified approach used to describe the kinetics of adsorption reactions. It assumes that the rate of adsorption is directly proportional to the concentration of the adsorbate on the surface. Recent studies applying the pseudo-first-order model have explored its applicability to heavy metal adsorption on MOFs. These investigations have provided insights into the initial stages of adsorption and the factors that influence it, such as temperature and initial concentration .Pseudo-second-order model: The pseudo-second-order kinetic model is an alternative approach for modeling adsorption kinetics. It suggests that the rate of adsorption is related to the square of the concentration of the adsorbate on the surface. Recent developments in the pseudo-second-order model have extended its application to heavy metal adsorption on MOFs. This model accounts for the interactions between heavy metal ions and MOF surfaces and provides insights into the kinetics of adsorption processes, including factors like dosage and initial concentration .Elovich model: The Elovich model is a kinetic model commonly used to describe chemisorption processes. It considers the exponential decrease in adsorption rate over time. Recent studies have applied the Elovich model to investigate the kinetics of heavy metal adsorption on MOFs. This model has been refined to account for factors influencing the rate of adsorption, including temperature and the presence of intermediates .Intraparticle diffusion model: The intraparticle diffusion model focuses on the diffusion of adsorbate molecules within the adsorbent particles. It considers the role of particle size in affecting adsorption kinetics. Recent research has incorporated intraparticle diffusion effects into kinetic models for heavy metal adsorption on MOFs. These studies have provided insights into how particle size influences the rate of adsorption and overall removal efficiency .Chick\u2013Watson model: The Chick\u2013Watson model is commonly applied to describe the kinetics of microbial inactivation through photocatalysis. It considers the reduction in microbe concentration over time. Recent advancements in the Chick\u2013Watson model have focused on its application to MOFs-based photocatalytic disinfection. This model has been adapted to describe multi-step damage processes, shedding light on the kinetics of microbe inactivation .Hom model: The Hom model is an empirical approach used to model the kinetics of microbial inactivation during photocatalysis. It relates the reduction in microbe concentration to reaction time. Recent research has applied the Hom model to investigate the kinetics of microbial inactivation using MOFs-based photocatalysis. This model has been adapted to consider factors such as photonic utilization efficiency and transport effects that influence disinfection rates . The kinThe application of transition metal catalysts for atmospheric heavy metal removal has made significant strides in recent years. As we evaluate the innovations and advances in this field, it becomes apparent that conducting a comprehensive Life Cycle Assessment (LCA) is indispensable. LCA, a systematic evaluation of the environmental impacts associated with a product, process, or technology throughout its entire life cycle, offers a holistic perspective on the sustainability of transition metal catalysts for heavy metal removal .Advancements in LCA methodologies: One of the pivotal advancements lies in the refinement and diversification of LCA methodologies tailored to this niche. Researchers are increasingly adopting hybrid and consequential LCA approaches, allowing for a more accurate assessment of the cradle-to-grave environmental implications of heavy metal removal processes. These approaches enable the integration of local environmental factors, temporal dynamics, and indirect consequences into the evaluation, resulting in a more comprehensive understanding of the technology\u2019s sustainability .Materials selection and sourcing: LCA has played a crucial role in optimizing the selection and sourcing of materials used in transition metal catalysts. Evaluations encompass aspects such as the extraction of raw materials, the energy-intensive production of catalysts, and the management of waste streams generated during the life cycle. As a result, researchers are better equipped to identify environmentally favorable materials and minimize the ecological footprint of catalyst production .Energy efficiency and emission reduction: Transition metal catalysts are continually evolving to enhance energy efficiency and reduce emissions during heavy metal removal. LCA studies have been instrumental in quantifying the environmental benefits of these innovations. The assessment of energy consumption, greenhouse gas emissions, and other pollutants provides valuable insights into the catalyst\u2019s ecological performance and guides further research into sustainable design .End-of-life considerations: The disposal and recycling of transition metal catalysts have gained prominence within the context of LCA. Understanding the fate of catalysts at the end of their life cycle, including potential reclamation and recycling processes, is vital. LCA has facilitated a more complete evaluation of the environmental implications associated with the disposal of catalysts, thereby promoting strategies for sustainable end-of-life management.Socioeconomic and health impacts: Beyond environmental considerations, recent LCA studies have increasingly incorporated socioeconomic and health impacts into the assessment framework. Researchers are examining the potential effects of heavy metal removal processes on local communities and workers, as well as the broader societal implications. This holistic approach ensures that the assessment extends beyond environmental boundaries to encompass the broader spectrum of sustainability.In summary, the integration of Life Cycle Assessment into the evaluation of transition metal catalysts for atmospheric heavy metal removal marks a pivotal advancement in this field. LCA provides a multidimensional view of the technology\u2019s sustainability, encompassing environmental, socioeconomic, and health aspects. As innovation continues to drive this field forward, LCA remains an invaluable tool for guiding research and development efforts towards more sustainable, efficient, and responsible heavy metal removal technologies. The key impact metrics for life cycle assessment of transition metal catalysts are given in The deployment of transition metal catalysts for atmospheric heavy metal removal brings forth several complex challenges that necessitate careful consideration as we move forward. These encompass environmental, societal, and technological dimensions, demanding innovative solutions for sustainable progress.Environmental challenges: The environmental challenges are paramount, as they directly relate to the core goal of mitigating heavy metal pollution. While transition metal catalysts offer substantial promise, their production and deployment must be carefully managed to minimize ecological impacts. Issues such as the environmental footprint of catalyst manufacturing, energy consumption, and greenhouse gas emissions during operation require vigilant attention. Furthermore, the potential release of nanoscale catalyst particles into the environment demands rigorous study to ensure long-term ecological safety.Societal and health concerns: Transition metal catalysts for heavy metal removal often operate in urban and industrial settings. Consequently, the health and safety of nearby communities and workers emerge as vital considerations. Ensuring that these technologies do not inadvertently introduce health risks or disproportionately affect vulnerable populations is of paramount importance. Assessing potential socioeconomic disparities and addressing them proactively is a challenge that the field must confront.Scaling up and integration: Transitioning from laboratory-scale experimentation to real-world application remains a significant challenge. Scaling up catalyst production, maintaining performance consistency, and integrating these technologies into existing industrial processes require innovative engineering solutions. Addressing issues like catalyst stability under varying conditions, efficient mass transport, and reactor design are paramount to success.Long-term stability: The durability and stability of transition metal catalysts in harsh environmental conditions are essential for sustained heavy metal removal. Overcoming issues related to catalyst degradation and ensuring long-term functionality pose notable technological hurdles. Strategies involving materials engineering and advanced coatings are being explored to enhance catalyst longevity.Resource availability: Many transition metal catalysts rely on critical or scarce elements for their functionality. Ensuring a stable supply of these materials is crucial. The development of alternative catalysts with reduced reliance on rare resources or the implementation of effective recycling and reclamation strategies is essential for long-term viability.Outlook for Transition Metal Catalysts:The future of transition metal catalysts in the context of atmospheric heavy metal removal is poised at the cusp of transformative advancements. As we navigate towards more sustainable and efficient environmental remediation technologies, several key development trajectories are anticipated to shape the evolution of these catalysts.Material Innovation and Synthesis:Future research is expected to focus on the discovery and synthesis of novel materials with enhanced catalytic properties. The use of high-throughput computational screening and machine learning will accelerate the identification of catalysts with superior adsorption capacities, selectivity, and stability. Green synthesis routes, employing biological or recycled feedstocks, are projected to gain traction, minimizing the environmental impact associated with catalyst production.Catalyst Architecture and Nano-engineering:Advancements in nanotechnology will enable the precise engineering of catalysts at the atomic level, controlling their morphology, surface properties, and porosity. Such nano-engineered catalysts will exhibit higher efficiencies and targeted action, ensuring the rapid and selective removal of heavy metals from complex atmospheric matrices.Stability and Regeneration:Ensuring the long-term stability of catalysts under operational conditions remains a critical objective. Research will likely advance towards the development of self-healing and regenerative catalyst systems that maintain their activity over extended periods, reducing the need for replacement and minimizing waste generation.Integration with Sensing and Monitoring Technologies:The convergence of catalysis with sensor technology will lead to the advent of intelligent remediation systems. These systems will dynamically adjust to fluctuating pollution levels, optimizing heavy metal capture in real time and providing continuous monitoring to ensure compliance with environmental regulations.Scalability and Process Integration:Translating benchtop innovations to industrial-scale applications will be a significant focus. Addressing the challenges of catalyst scalability, including manufacturing and deployment costs, will be key to their widespread adoption. Modular and adaptable catalyst designs will facilitate seamless integration into existing industrial infrastructures.Holistic Environmental Impact Assessments:Life Cycle Assessments (LCAs) will become integral in evaluating the environmental footprint of catalysts throughout their lifecycle. Emphasis on the sustainable procurement of raw materials, energy efficient production processes, and end-of-life recycling or disposal will guide the development of environmentally benign catalyst systems.Policy-Driven Catalyst Development:Evolving environmental policies and regulations will continue to drive the innovation of transition metal catalysts. Catalyst development will increasingly align with regulatory frameworks aimed at mitigating heavy metal pollution, fostering the creation of compliant and future-proof technologies.In the foreseeable future, transition metal catalysts will likely emerge as more than mere agents for pollution mitigation; they will become integral components of a broader ecosystem aimed at fostering sustainable industrial practices and promoting public health and environmental conservation. The progressive integration of these catalysts into global efforts to combat atmospheric pollution will exemplify the harmonious intersection of science, technology, and policy, crafting a cleaner and safer environment.In conclusion, our review synthesizes the significant strides made in employing transition metal catalysts for the remediation of atmospheric heavy metals, delineating their operational mechanisms, efficiency, and current technological standing. As we peer into the future, we envision a landscape where the development of transition metal catalysts is propelled by breakthroughs in material science, with a pronounced emphasis on sustainability and environmental stewardship. The advent of smart remediation systems, powered by the confluence of catalytic technology and IoT, is set to provide adaptive and precise pollution control. Furthermore, the adoption of green synthesis approaches and life cycle assessments will ensure that catalyst production aligns with global sustainability targets. The challenges of scalability and integration with existing infrastructures will necessitate a collaborative effort across scientific disciplines and industries. By embracing these future directions, transition metal catalysts will not only continue to mitigate the perils of heavy metal pollution, but also pave the way for a cleaner, safer, and more sustainable future."}
+{"text": "Fueled by support from the National Cancer Institute\u2019s \u201cCancer Moonshot\u201d program, the past few years have witnessed a renewed interest in the canine spontaneous cancer model as an invaluable resource in translational oncology research. Increasingly, there is awareness that pet dogs with cancer provide an accessible bridge to improving the efficiency of cancer drug discovery and clinical therapeutic development. Canine tumors share many biological, genetic, and histologic features with their human tumor counterparts, and most importantly, retain the complexities of naturally occurring drug resistance, metastasis, and tumor-host immune interactions, all of which are difficult to recapitulate in induced or genetically engineered murine tumor models. The utility of canine models has been particularly apparent in sarcoma research, where the increased incidence of sarcomas in dogs as compared to people has facilitated comparative research resulting in treatment advances benefitting both species. Although there is an increasing awareness of the advantages in using spontaneous canine sarcoma models for research, these models remain underutilized, in part due to a lack of more permanent institutional and cross-institutional infrastructure to support partnerships between veterinary and human clinician-scientists. In this review, we provide an updated overview of historical and current applications of spontaneously occurring canine tumor models in sarcoma research, with particular attention to knowledge gaps, limitations, and growth opportunities within these applications. Furthermore, we propose considerations for working within existing veterinary translational and comparative oncology research infrastructures to maximize the benefit of partnerships between veterinary and human biomedical researchers within and across institutions to improve the utility and application of spontaneous canine sarcomas in translational oncology research. Sarcomas are a heterogeneous group of neoplasms which arise from mesenchymal cells within tissues derived from the embryonic mesoderm. Sarcomas are rare in people and account for only about 1% of all cancers, though pediatric patients are disproportionately burdened by this tumor type as sarcomas represent greater than 20% of pediatric solid tumors  is the most common primary malignant bone tumor in both dogs and people , 8. HoweAppendicular OS arising from the metaphysis of long bones is the most common and best researched form in both people and dogs and has a remarkably similar clinical presentation in both species, including a similar bimodal age distribution , 13\u201315. The molecular landscape of canine OS has been relatively well characterized compared with other canine sarcomas. Comparative genomic analysis of OS from dogs and people consistently identifies striking similarities between these tumors, with one study finding them indistinguishable by global gene expression signature . The genWhile further exploration is warranted (and ongoing), the genetic similarities between the canine and human tumors suggest rich opportunities for utilization of canine OS models in the development of new prognostication methods and personalized, targeted therapeutics. Indeed, comparison of the genetic signatures of canine and human OS have led to identification of a pair of genes (CXCL8 and SLC1A3) for which high expression in human tumors was linked with poorer clinical outcome . The cliAngiosarcoma (AS) refers to a group of sarcomas which exhibit differentiation toward vascular or lymphatic endothelial cells. These are among the rarest of the sarcoma types in humans, comprising less than 1% of all soft tissue sarcomas . The incThe clinical presentations of AS and HSA are similar with both tumors diagnosed predominantly in older patients , 47. HowAS and HSA exhibit similarly aggressive biologic behavior with highly infiltrative and invasive patterns of local growth and a high risk of metastasis contributing to the poor clinical outcomes seen in both species , 48\u201350. The cellular origins of both AS and HSA remain incompletely understood, but recent genomic profiling of canine HSA has driven paradigm shifts regarding the histogenesis of this tumor. Though classically thought of as arising from transformed endothelial cells, these data suggest a pluripotent bone marrow progenitor cell of origin for HSA , 68. WhiIn canine patients, multiple histologic subtypes of sarcomas arising from cutaneous and subcutaneous connective tissues are grouped under a shared grading system and are referred to collectively as soft tissue sarcomas (STS) , 76. DesWhile the general histologic features are similar between canine STS and human sSTS the distribution of histologic subtypes varies between these species. In dogs, fibrosarcoma, peripheral nerve sheath tumors, and perivascular wall tumors are most common among STS for which subtype is reported. In contrast, liposarcoma and undifferentiated pleomorphic sarcoma are the most commonly reported sSTS in people , 80. As Molecular characterization of canine STS represents an area where increased focus could overcome challenges posed by differences in current classification and nomenclature schemes to facilitate inclusion of these tumors in translational studies. For example, dermatofibrosarcoma protuberans in people is characterized by a pathognomonic COL1A1-PDGFB gene fusion , and thoThe genetic landscape of human malignant peripheral nerve sheath tumors (MPNST) reveals recurrent themes of Ras/Raf pathway activation and impairment of DNA repair and P53 regulation resulting from mutations in NF1 , BRAF and CDKN2A/B \u201391. LimiLiposarcoma is an uncommonly reported STS subtype in dogs, but one for which histologic classification closely parallels human classification. Several immunohistochemical studies in canine liposarcoma demonstrate some similarities with the human disease, including overexpression of MDM2 in well-differentiated and de-differentiated variants. However these studies fail to provide evidence for other histotype-characteristic genetic alterations used in the diagnosis of myxoid and pleomorphic liposarcoma variants in people , 96. Morc-kit gene are implicated in the pathogenesis of many GIST and contribute to remarkable sensitivity of these tumors to tyrosine kinase inhibitors  and leiomyosarcomas) and rhabdomyosarcoma, require further investigation but may also have potential applications as models for human disease. GIST and leiomyosarcoma are primary gastrointestinal sarcomas which account for only around 1% of GI malignancies in people , 98 but hibitors . As withine GIST . LimitedRhabdomyosarcoma refers to a group of malignant mesenchymal neoplasms which exhibit varying degrees of skeletal muscle differentiation. These neoplasms are rare in the veterinary literature, though this apparent low prevalence may be partially due to diagnostic challenges posed by the extreme variation in phenotype, age of presentation, and cellular morphology in these tumors . In peopin vivo biological complexity of human tumors.The conception and implementation of co-clinical trials approaches in translational oncology research has significantly expanded over the last decade. This expansion has been driven by technological advances which continue to provide an ever-increasing understanding of the mutational landscape and key genetic drivers of human cancer types. Our expanded understanding of this genetic complexity has led to an increasingly granular stratification of patients with a common cancer histology into diverse molecular subtypes. Personalized medicine through tailored therapeutic approaches targeting each individual patient\u2019s actionable molecular drivers will no doubt led to additional clinical advances. However, the breadth and depth of these advances, and the time it takes to achieve them, continues to hinge entirely on effective pre-clinical modeling of the in vivo models allow an almost exact recapitulation of treatment protocols for human clinical trial cancer patients in their GEMM or PDX counterpart. This type of mirrored approach can inform strategies and biomarkers for patient stratification, lead to the identification of mechanisms of de novo and acquired drug resistance, and rapidly evaluate drug combinations that overcome this resistance. For certain tumor types, the success of this approach has surmounted increasing cynicism of the basic and clinical oncology research communities around small animal pre-clinical cancer models. Still, these models are not without inherent challenges and disadvantages. PDX models require the use of immunodeficient mice, thus failing to recapitulate tumor-immune interactions and evolution and precluding investigation of anti-metastatic or immunomodulatory therapies. GEMMs alleviate some of these issues via de novo tumor development in the presence of an intact immune system, subsequent establishment of a microenvironment with tumor-host interactions, and in some models, spontaneous metastasis, but GEMMs can be limited in the number of concurrent mutations, limiting their ability to fully recapitulate the molecular heterogeneity of human tumors  accessibility and feasibility of obtaining, expanding, and utilizing patient-derived xenograft (PDX) mouse models, and 2) insightful development and refinement of compelling genetically engineered mouse models (GEMMs) of human cancers. These pre-clinical n tumors , 113.Spurred from these challenges is an increasingly renewed interest in employing a similar comparative dog-human co-clinical approach Table\u00a01.Thus, enhancing engagement and collaboration between academic physician-veterinarian research teams and the pharmaceutical industry is something that must be increasingly addressed in the comparative sarcoma research community. One potential solution to this pressure point is the National Cancer Institute\u2019s (NCI) Cancer Therapy Evaluation Program (CTEP). The long-established NCI Comparative Oncology Trials Consortium (COTC) could work internally with the NCI Division of Cancer Treatment and Diagnosis to develop a secondary function wherein COTC could enter into collaborative agreements with pharmaceutical companies similar to those of CTEP. This could allow COTC, perhaps through CTEP's already established \u201cNon-clinical Use Request\u201d avenue, to supply academic investigators of human-canine veterinary cancer center consortium institutions (e.g. The V Foundation Canine Oncology Research Consortium \u2013 CORC) with investigator brochure canine pharmacokinetic and toxicity data and the desired investigational agent or active pharmaceutical ingredient for compounding.Despite these challenges, co-clinical trial designs in dogs with spontaneous sarcomas can still significantly aid in pharmacokinetic and pharmacodynamic based vetting of pre-clinical therapies Figure\u00a02A prime example of the type of \u201chigh-risk high-reward\u201d investigations that may best leverage dogs with spontaneous sarcoma is metastasis biology research in osteosarcoma. Metastasis accounts for greater than 90% of all cancer-related mortality , and in Stephen Paget\u2019s 1889 \u201cseed and soil\u201d hypothesis on metastatic organotropism continues to foresee one of the most intensive areas of cancer research over the last two decades \u2013130. Deshttps://caninecommons.cancer.gov/#/home), a centralized, open access repository of clinical and genomic data from spontaneous canine cancers, and by private biotechnology companies such as nanoString\u00ae who have made significant investments in canine comparative oncology research (https://www.precinctnetwork.org/). Through an NIH-hosted workshop, these groups of comparative oncology investigators could provide a list of prioritized canine targets for which antibody reagents are needed. Subsequently, working through the channels of the Comparative Oncology Program or Canine Cancer Immunotherapy Network, NCI could produce a Small Business Innovation Research (SBIR) request for proposals for companies to produce these antibody reagents. Once produced, competitive supplemental funding could then be provided to NCI PRECINCT members who submit detailed proposals for validating the specificity and functionality of these antibodies in a variety of immune assays.While remarkable clinical and biological similarities of human and canine OS have been previously demonstrated, increasing knowledge of the genomic complexity in human OS obtained through investigations leveraging technological advances is beginning to widen the gap between these parallel patient populations. If not addressed, this widening gap in the molecular understanding of human vs. canine OS could undermine the predictability of the canine model for testing novel preclinical candidates more so than in studies focused on the fundamental biology of sarcoma progression and metastasis. However, work on addressing this knowledge gap has already begun through establishment of the NCI\u2019s Integrated Canine Data Commons . Additional opportunities in areas such as advanced molecular imaging, cross disciplinary training in human molecular pathology and human investigative new drug trial design would allow veterinary clinician scientists to bring these skills back to our patients and better inform comparative oncology trial design and laboratory correlative studies to maximize extraction of data from these trials and increase their impact on clinical sarcoma patient management.Continued efforts in diversification of our cancer research workforce training infrastructure is an indispensable prerequisite for enhancing the quantity and quality of comparative sarcoma research. To be successful in this approach, the next generation of cancer researchers must include veterinary biomedical scientists with training backgrounds in medical, surgical, and radiation oncology, pharmacology, pathology, and immunology Figure\u00a01Sustaining and bolstering cross-veterinary and -medical institutional support in the form of expanded financial and faculty training investment into specialized and clinically relevant comparative and translational biomedical research fellowship training programs for veterinary scientists would provide more than just a pipeline of well-trained, diverse clinician scientists to foster co-clinical trial approaches in large animal models. Specifically, these fellowship programs would be separate from the already successfully established, and in some cases National Institutes of Health training grant funded, DVM-PhD and post-DVM residency/PhD programs established at veterinary schools across the USA. Instead, these fellowships could more closely mirror MD post-residency clinical fellowships programs, which often contain a multi-year research intensive component and in many cases lead the trainee to pursue further post-doctoral research following fellowship completion. In veterinary medicine, establishment of these fellowship programs would serve to further develop and fortify a more integrated veterinary and medical oncology research landscape from its current partially siloed state, into one that effectively blends and aligns the comparative oncology trials work of veterinary clinicians and scientists with their human colleague counterparts. Veterinary clinicians and scientists completing these fellowships would likely emerge with strong established collaborations with their human oncology research counterparts, a key benefit that circumvents an otherwise not infrequent barrier for junior veterinary clinician scientist faculty looking to establish independent comparative oncology research programs.Similar to their medical counterparts, veterinary clinician-scientists are invaluable members of increasingly necessary multi-disciplinary cancer research teams. If and when these types of translational research fellowships are established, recruiting, retaining, and growing the number of clinically trained veterinarians entering into these programs would in part require a paradigm shift in how veterinary medical institutions themselves value these post-DVM trainees. Based on the latest American Veterinary Medical Association (AVMA) compensation report, veterinarians entering academic residency or PhD programs immediately after graduation would likely receive 40-50% of the starting salary of their fellow classmates entering into private clinical practice despite comparably high educational loan burdens. When considering post-residency DVMs entering PhD or the fellowship programs proposed here, this compensation gap exponentially widens. Post-residency academic fellowship programs that provide compensation at the NIH-specified post-doctoral stipend levels, regardless of whether or not the program holds, or the individual successfully competes for, an NIH institutional training grant, would provide the necessary institutional commitment needed to broaden the veterinary clinician-scientist pipeline.V foundation for Cancer Research), and 4) inclusion of members of both groups in monthly grant progress and update meetings of these consortia. Additionally, non-profit groups such as Ethos Discovery, the Osteosarcoma Institute, and Make It Better (MIB) Agents are fully invested in engaging academic investigators, leveraging their collaborative networks, and raising funds to support both human and canine sarcoma research.There exists already a strengthening network of key academic, government, and non-profit stakeholders with an expanding intellectual and financial investment in comparative sarcoma research. For example, opportunities are already arising to share ideas and data from members of canine clinical trials and comparative oncology research consortia such as the Comparative Oncology Trials Consortium, the Consortium for Canine Comparative Oncology (c3o) between Duke Cancer Institute and North Carolina State University College of Veterinary Medicine, and NCI PRECINCT (which was created through the aforementioned NCI Cancer Moonshot funding opportunities), with that of their human counterparts such as the Children\u2019s Oncology Group Osteosarcoma Biology and Bone Tumor Steering Committees. These collaborative opportunities occur through 1) focused comparative oncology scientific sessions at national meetings, 2) joint national meetings between canine and human cancer moonshot grant awardees, 3) funding opportunities requiring veterinary and medical scientist co-PI submissions (Although clear gaps in the comparative molecular characterization of the canine sarcoma types reviewed herein remain, these temporary limitations should not preclude the cancer research community\u2019s embracement of these valuable translational models. Leveraging dogs with spontaneous sarcomas in co-clinical trial approaches will undoubtedly provide a valuable and complementary source of high predictive value data to inform clinical practice, and ultimately, improve both human and canine sarcoma patient outcomes. Fully realizing the potential of this comparative approach requires fortifying veterinary and human medical oncology research partnerships alongside continued and enhanced investment in training the next generation of diverse, cross-disciplinary cancer researchers.MK, LH, LA, AM, ML and DR all drafted and edited the manuscript. MK and DR generated the figures and table. All authors contributed to the article and approved the submitted version."}
+{"text": "Minimal (or measurable) residual disease (MRD) negativity has emerged as one of the most important prognostic tools in multiple myeloma (MM) and is associated with significant improvements in progression-free survival (PFS) and overall survival . Much ofMRD negativity is associated with improved outcomes for older adults with MM . Table 1Older adults with MM have traditionally had inferior outcomes compared to younger patients . A signiThe ideal treatment for older adults should be highly effective, safe and with no enduring toxicity. Moreover, it should aim to minimize treatment burden, ideally with a finite duration, while improving patient quality of life. Even low-grade symptoms such as protracted fatigue from continuous immunomodulatory drugs can have a major impact on quality of life. The ideal treatment strategy should target not only specific disease characteristics but also patient specific characteristics, including frailty. A precise evaluation of disease response should allow for treatment titration including dose escalation, dose de-escalation or treatment discontinuation altogether.MRD testing represents one of the most powerful prognostic tools in MM, offering the potential for a more precise approach to treatment. This approach applies across the entire spectrum of treatment options, including bispecific and CAR-T therapies. Moreover, insights from clinical trials suggest that treatments with a higher likelihood of achieving MRD negativity, along with agents adding only modest or minimal toxicity , shouldFor instance, in an older adult receiving daratumumab\u2013lenalidomide\u2013dexamethasone therapy, achieving MRD negativity, especially sustained MRD negativity with a complete response, could prompt de-escalation of one of the agents or even therapy discontinuation, particularly if the current treatment is symptomatically burdensome. During this off-treatment phase, close monitoring would be essential, and if MRD resurgence occurs, therapy could be re-initiated, either with dara-len-dex or an alternative regimen. Proper tailoring using MRD testing should enhance quality of life, reduce treatment burden, and minimize the ongoing risk of treatment-related toxicity.Despite its potential value, numerous key unanswered questions remain regarding the role of MRD testing in older adults with MM. We need further evidence to demonstrate that tailoring treatment based on MRD results improves patient outcomes, including quality of life among older adults. This evidence generation is necessary not only for fit older adults but also for the frail patient population. Among the frail group, low-intensity continuous treatments are often used, typically yielding low rates of MRD negativity. Thus, given the already high rates of toxicity among frail patients, thoughtful consideration and data are required to justify treatment escalation with potentially more potent agents to achieve higher rates of MRD negativity, while balancing the impact of treatment modification on the risk of treatment-related toxicity and quality of life.Designing clinical trials involving older adults with MM to demonstrate the utility of MRD testing will pose unique challenges. It will be crucial to ensure that the eligibility criteria of these trials accurately reflect the real-world diversity of these patients, encompassing variations in comorbidities and functional status. Adequate sample sizes in these designed trials will also be essential to detect meaningful differences in MRD status and outcomes among older adults. Lastly, as MRD assessments often require long-term follow-up to assess their impact on patient outcomes, strategies to reduce attrition and maintain consistent follow-up over longer periods will be important. Ultimately, overcoming the challenges of designing trials in older adults, particularly to demonstrate the utility of MRD testing, demands a multidisciplinary approach involving geriatric specialists, oncologists, statisticians, and patient advocates. Striking a balance between scientific rigor and the unique needs and characteristics of real-world older adult patients is essential for obtaining clinically relevant results.\u22125 vs 10\u22126) also remains to be defined and may differ for fit older adults who may require dose escalation for MRD positivity versus among frail older adults where dose de-escalation is being considered for MRD negativity. Lastly, given that the risk of progression is dynamic, the role and feasibility of repeat bone marrow aspiration measurements for MRD testing in the context of dynamic frailty status [Additional challenges in MRD testing for older adults with MM include determining the optimal timing for MRD measurement. Unlike transplant-eligible patients with defined treatment blocks , many current treatment regimens for older adults are continuous, making it unclear when the ideal time for MRD assessment would be. This needs to be further analyzed with respect to the intended use of the MRD result. Discontinuation likely requires the establishment of durable MRD negativity while dose intensification may require more frequent testing at time points where an intervention would be re-planned. The optimal threshold 10\u2212 vs 10\u22126 In summary, MRD testing stands as an exciting advancement in the field of MM, offering valuable insights into prognosis for older adults with MM. Additionally, while data remains somewhat limited, in specific scenarios such as discontinuing maintenance therapy, especially for patients encountering treatment-related toxicity, MRD-negative results could serve as a valuable tool in treatment decision-making. As emerging data continue to evolve, MRD testing holds the potential to help us fine-tune treatment strategies, optimizing both under- and over-treatment for the diverse population of older adults with MM."}
+{"text": "Apathy and goal-oriented behaviors are key dimensions of late-life depression (LLD) and are iteratively associated with cognitive decline in most neuropsychiatric disorders. However, scales and criteria remains insufficient to provide robust individual biomarkers that could foster personalized therapeutic approaches. Therefore, dimensional and digital phenotyping offer new possibilities of stratifying LLD population. This presentation will show our recent results of functional connectivity cerebral networks associated with multidimensional paper-and-pen measures of apathy, including the default mode and the cingulo-opercular networks. We will also show how dimensional reduction  of 3 days actimetry measures are associated with both FC and inflammatory measures (diffusion and multicompartment indices such as free water and neurite orientation dispersion), providing arguments for different pathophysiological mechanisms underlying goal-oriented behaviors and reinforcing actimetry as a good candidate for individual biomarker of cognitive decline in LLD. Finally, machine learning approaches using combination of different, yet correlated, indices of actimetry will be presented and discussed with their corresponding classifying accuracies . Altogether, this presentation aims at bridging the gap between cerebral imaging and digital phenotyping to enhance personalized medicine in the field of old-age psychiatry and cognitive decline prevention.None Declared"}
+{"text": "Mops condylurus bats in Kenya, indicating the virus is well-tolerated. Our findings indicate M. condylurus bats may be a reservoir host for Bombali virus. Increased surveillance of these bats will be important to reduce potential virus spread. We found similar mild perivascular inflammation in lungs of Bombali virus\u2013positive and \u2013negative  Despite extensive research since the first documented human Ebola virus (EBOV) disease outbreak in 1976, animal species involved and mechanisms by which ebolaviruses spillover to humans remains enigmatic. Bats have been implicated as reservoir hosts , the sixth and most recent ebolavirus identified. First reported in M. condylurus bats; the BOMV-negative bats were used as negative controls  as described previously  support bats as a chronic subclinical BOMV reservoir with the potential for infection and sporadic virus excretion. However, the small number of samples, absence of recovery of infectious virus, and lack of longitudinal data make interpretation of our results difficult. As for all wildlife-borne ebolaviruses, no direct evidence currently exists regarding the transmission route of BOMV between susceptible hosts. Our findings suggest the mode of transmission involves activation of replication in either macrophages or other cells and virus dispersal through saliva droplets or feces. The identification of BOMV infection in lungs and occasional virus presence in intestines further supports this hypothesis (M. condylurus bats and an absence of substantial concurrent pathologic findings. Our results support M. condylurus bats as reservoir hosts for ebolaviruses and highlight the importance of bat surveillance to understand and mitigate potential emerging disease risks.In summary, we showed EBOV-VP40 immunolabeling, acting as a cross-reactive surrogate for BOMV antigen, in pulmonary macrophages of wild BOMV RT-PCR\u2013positive Mops condylurus bats naturally infected with Bombali virus, Kenya. Additional information for no substantial histopathologic changes in"}
+{"text": "Daucus carota L.), resulting in reduced crop yields and quality. Drought stress induces a range of physiological and biochemical changes in carrots, including reduced germination, hindered cell elongation, wilting, and disrupted photosynthetic efficiency, ultimately leading to stunted growth and decreased root development. Recent research has focused on understanding the molecular mechanisms underlying carrot's response to drought stress, identifying key genes and transcription factors involved in drought tolerance. Transcriptomic and proteomic analyses have provided insights into the regulatory networks and signaling pathways involved in drought stress adaptation. Among biochemical processes, water scarcity alters carrot\u00a0antioxidant levels, osmolytes, and hormones. This review provides an overview of the effects of drought stress on carrots and highlights recent advances in drought stress-related studies on this crop. Some recent advances in understanding the effects of drought stress on carrots and developing strategies for drought stress mitigation are crucial for ensuring sustainable carrot production in the face of changing climate conditions. However, understanding the mechanisms underlying the plant's response to drought stress is essential for developing strategies to improve its tolerance to water scarcity and ensure food security in regions affected by drought.Drought stress is a significant environmental factor that adversely affects the growth and development of\u00a0carrot ( Daucus carota L. is an important vegetable, grown in a cool climate and globally used for its edible taproot  enhanced the physio-biochemical stress response of carrot plants  and total phenolics exhibit higher levels of accumulation   and proline dehydrogenase genes (PDH) are involved in drought stress tolerance in carrot cultivars. Furthermore, proline dehydrogenase is the first enzyme involved in the proline oxidation pathway and they are associated with cellular homeostasis. The same study also described the role of catalase (CAT) and proline transporter genes (PRT) under drought stress in carrot plants, these genes are involved in the transportation of proline among organs and cells  and 20.058 SNPs (single nucleotide polymorphisms) in carrots  involved in different processes in carrot plants including stress tolerance  might also be beneficial. There is still\u00a0a significant research gap in understanding drought effects and its mechanisms in carrot crop and developing tolerant carrot cultivars. Therefore, it is needed to incorporate both\u00a0conventional and modern techniques to acquire fruitful results."}
+{"text": "The overall health care costs for managing patients with community-acquired pneumonia (CAP) in U.S. hospitals is burdensome.While pharmacy costs comprise only a minor proportion of these costs,hospital length of stay (LOS) is the greatest contributor. Infections due to antimicrobial-resistant pathogens are also associated with increased overall health care cost. Therefore, strategies that aim to minimize antimicrobial resistance and reduce hospital LOS may have the greatest impact in reducing overall health care costs in managing patients with CAP.To evaluate how antimicrobial resistance can impact healthcare costs associated with CAP and review strategies to minimize the risk of resistance development while promoting appropriate antimicrobial therapy (including optimized dosing) and decreasing hospital LOS.Antimicrobial resistance can increase the risk of clinical failure and result in higher overall health care costs. Further development of antimicrobial resistance during therapy should, therefore, be minimized.This can be achieved through optimized antimicrobial dosing strategies\u2014using a higher dose of concentration-dependent agents or prolonged infusion of time-dependent agents\u2014that increase the probability of attaining pharmacokinetic-pharmacodynamic targets for eradication of the pathogen and hence successful clinical outcomes. Decreasing LOS must be a priority when attempting to reduce hospital costs. Active intravenous-to-oral switch therapy has been shown to effectively reduce LOS. Appropriate short-course regimens may also offer the opportunity for effective treatment while reducing or eliminating unnecessary antimicrobial exposure that not only reduces the potential for drug-related adverse events, but may also minimize the selection of resistant organisms.Clinical failure and antimicrobial resistance can significantly increase the cost of managing patients with CAP, primarily by increasingLOS. Therefore, strategies should be employed to minimize the risk of resistance development and reduce LOS. These include early appropriate therapy, optimized dosing based on pharmacodynamic principles, and efficient IV-to-PO switch therapy when appropriate."}
+{"text": "Patients' willingness to pay (WTP) is a subject of interest, particularly in these times of consumer-directed health care and benefit designs that involve multiple copayment tiers. Since tiered copayment products have been found to reduce premium costs, the continued proliferation of tiered copayment benefits can be expected."}
+{"text": "Infectious diseases of plants, animals and humans pose a serious threat to global health and seriously impact ecosystem stability and agriculture, including food security. In recent years, more serious damage by fungal diseases infecting plants and/or humans, and increased resistance of disease-associated fungi and bacteria to antimicrobial drugs have been reported. In this Special Issue (SI) \u201cOmics Research of Pathogenic Microorganisms\u201d, nine research groups have submitted a total of ten papers where they present and discuss results and insights on ecology, evolution and virulence of disease-associated microbes, host responses and an evaluation of two popular platforms to diagnose and monitor pathogenic microbes in complex microbiome samples. This SI highlights current -omics approaches and software tools that are widely used to study disease-associated microbes, from in vitro cultures to metagenomic samples and host\u2013pathogen interactions. The main insights from the contributions to this SI are summarised below.Lara and colleagues predicted metabolic interactions between bacteria associated with urinary tract infections (UTIs) and showed that a common dietary metabolite may influence population sizes of specific UTI-associated bacteria .Escherichia coli bacteria, clonal interference and mutator phenotypes greatly influenced the rise of resistance to a \u03b2-lactam antibiotic [Interactions between bacterial clonal lineages were also one aspect of the study by Ruelens and de Visser, who showed that in vitro, in small populations of tibiotic  in theseSalmonella serotype Derby (S. Derby) and discovered 35 genes that may influence acid stress resistance in S. Derby, including CRISPR-Cas system genes. They validated, via in vitro bioassays, that two predicted operons including two CRISPR-Cas genes contributed to acid tolerance and virulence of S. Derby [Next to antibiotic resistance, acid stress resistance is of considerable relevance to pathogenicity. Gu and colleagues used genomics to predict genes of interest to acid stress resistance of clinical Salmonella enterica (S. Typhi) from Bangladesh for CRISPR-Cas sequence-derived biomarkers associated with antibiotic resistance of endemic isolates [In addition to the abovementioned study by Gu and colleagues, bacterial CRISPR-Cas genes have been reported by diverse research groups to be associated with antibiotic resistance and virulence. Tanmoy and colleagues investigated genomes and metadata of clinical typhoid isolates . Tanmoy isolates  and compisolates .Bacterial epidemiology, especially the sequencing of taxonomically informative ribosomal 16S rRNA gene sequences, greatly benefits from reliable sequencing platforms that can be used in-house, to facilitate the rapid and reliable typing of bacteria present in metagenomic samples. Heikema and colleagues compared Illumina short-read sequencing- and nanopore long-read sequencing platforms for 16S profiling. The authors used Oxford Nanopore sequencing technology (ONT) which has gained popularity for in-house sequencing at various labs. Heikema and colleagues came across potential pitfalls in standard ONT analysis pipelines and recommended validations to further improve reliable applications of long-read sequencing via ONT platforms .Monilinia brown rot fungi that cause economically relevant diseases in stone fruits. They improved the resulting gene models using proteome and transcriptome data and listed 134 genes predicted to encode candidate virulence factors. Vilanova and colleagues assayed five predicted virulence factors and showed that three of these induced necrosis in plant leaf assays, neatly validating their -omics approach to predict fungal virulence factors [Long-read sequencing was employed by Vilanova and colleagues to obtain high-quality genomes of  factors .Amyloodinium parasites infecting the economically relevant fish seabass, to identify candidate virulence factors. Using their data as input in a virulence database, they focused on seven candidate virulence factors of which two were analysed in greater detail. Their transcriptome data provided a reference database for further study of Amyloodinium parasite biology [Two other studies in this SI used transcriptome analysis to study pathogenic microbes and host responses to clinical bacteria. Byadgi and colleagues used transcriptomics of protozoan  biology .Campylobacter jejuni bacteria and an isogenic cas9 gene deletion mutant. The authors identify several DNA damage, inflammatory and cell death pathways that were induced during infection by wild-type C. jejuni, but not during infection by the cas9 gene deletion mutant, corroborating previous work that C. jejuni Cas9 has a role in the virulence of highly virulent C. jejuni strains [Finally, Saha and colleagues used transcriptomics to unravel in vitro changes in gene expression of epithelial cells during the first 4 h of infection by highly virulent, clinical  strains .This SI touches upon the diverse, highly relevant applications of -omics technologies to the study of pathogenic microbes and host\u2013pathogen interactions. The editor hopes that the reports of this SI may further inspire scientists who are considering including -omics approaches in their research."}
+{"text": "Coordinated and harmonic (synchronous) ventricular electrical activation isessential for better left ventricular systolic function. Intraventricularconduction abnormalities, such as left bundle branch block due to artificialcardiac pacing, lead to electromechanical \u201cdyssynchronopathy\u201d with deleteriousstructural and clinical consequences. The aim of this review was to describe andimprove the understanding of all the processes connecting the several mechanismsinvolved in the development of artificially induced ventricular dyssynchrony bycardiac pacing, most known as pacing-induced cardiomyopathy (PiCM). The chroniceffect of abnormal impulse conduction and nonphysiological ectopic activation byartificial cardiac pacing is suspected to affect metabolism and myocardialperfusion, triggering regional differences in the activation/contractionprocesses that cause electrical and structural remodeling due to damage,inflammation, and fibrosis of the cardiac tissue. The effect of artificialcardiac pacing on ventricular function and structure can be multifactorial, andbiological factors underlying PiCM could affect the time and probability ofdeveloping the condition. PiCM has not been included in the traditionalclassification of cardiomyopathies, which can hinder detection. This articlereviews the available evidence for pacing-induced cardiovascular disease, thecurrent understanding of its pathophysiology, and reinforces the adverse effectsof right ventricular pacing, especially right ventricular pacing burden(commonly measured in percentage) and its repercussion on ventricularcontraction (reflected by the impact on left ventricular systolic function).These effects might be the main defining criteria and determining mechanisms ofthe pathophysiology and the clinical repercussion seen on patients. According to Kaye etal.16][.Definition 3: a reduction in LVEF \u2265 10% irrespective ofbaseline LVEF. This definition is relevant as it has been used in previouspublications17][.14][. This cutoff point wasrecently reviewed in the current European Society of CardiologyGuidelines31][ attributed to the \u201cinflammatory\u201d (andtoxic?) process triggered by ectopic electrical activation of themyocyte34][.\u201cConventional\u201d RV pacing  causes myocardial activation almost in reverse tothat which occurs in intrinsic physiological antegrade conduction using theHis-Purkinje system. It causes delayed and abnormal ventricular myocardialactivation  associated with nonphysiological ventricularcontraction vs. 632 with single-chamberventricular rate-modulated (VVIR) pacing29][. RV PiCM is usually defined as LV systolic dysfunctionresulting from electrical and mechanical dyssynchrony caused by RV pacing. RV PiCMis common and occurs in 10-20% of patients exposed to frequent RVpacing46][.Although the follow-up period in the previous cohort was the longest49][. Paced QRS duration \u2265 163 ms was the mostimportant predictor of HF admission17]. ynchrony[61].62][.A systematic review aiming to compile available data included randomized andobservational studies comparing HBP or CRT 67]) and another using RV pacing (successful in 137 of 433patients [32%])Based on these results, can we state that PPS can prevent PiCM and should beroutinely recommended at least on an individualized basis? It could be argued thatthe success of physiological pacing is in part related to the use ofelectrophysiological parameters when performing this technique, which allows properidentification of the target region. Although this procedure is more complex andimplies a potential rise in costs, we propose this debate because we believe thatPiCM is secondary to artificially induced myocardial dyssynchrony by RV pacing. Whywould a patient with preserved physiological pacing of the ventricular syncytium develop 68][.In the context of AF, the Left Ventricular-Based Cardiac Stimulation Post AV NodalAblation Evaluation (or PAVE) study randomized 184 patients undergoing ablation ofthe AV node to receive CRT vs. PPS are needed to consolidate HBP as an initial strategyfor reducing PiCM. Several factors should be considered, including implant-relatedcomplications such as higher capture thresholds and undersensing and tool costs(dedicated leads and sheaths). In addition, some post-implantation factors are ofgreat influence, such as increased battery depletion and premature generatorreplacement (due to higher energy drain), among others. These aspects need to betested in a randomized, controlled setting before PPS can be widely used. There arecurrently several clinical trials comparing PPS vs. RV pacing and,more ambitiously, PPS vs. CRT. The results will demonstrate thetrue value of physiological artificial activation within the context of ACP and thepossibility of significantly reducing PiCM incidence.However, in addition to current studies, further robust clinical trials comparing RVpacing Artificially induced myocardial dyssynchrony by RV pacing leading to PiCM is arecently acknowledged condition. Its potential genesis occurs after RV pacinginitiation  and is probably associated with factors thatare prone to this condition (underlying heart disease or phenotype). It is caused byartificial ventricular dyssynchrony due to artificial electrical cardiac activationof the myocardium only. Its impact on ventricular function and association witharrhythmia and congestive HF should be considered. Therefore, sentinel biomarkerscould be used in the future to identify, prior to implantation, individuals who havea natural tendency to develop artificially induced dyssynchrony. In addition, strictclinical follow-up with evaluation of cardiac function and structure should beperformed periodically . Correction involves using biventricular cardiac pacing or the newphysiological alternatives, via PPS (direct His bundle or left bundle activation),to minimize ventricular dyssynchrony."}
+{"text": "Facial vascularized composite allotransplantation (FVCA) is an emerging field of reconstructive surgery that represents a dogmatic shift in the surgical treatment of patients with severe facial disfigurements. While conventional reconstructive strategies were previously considered the goldstandard for patients with devastating facial trauma, FVCA has demonstrated promising short- and long-term outcomes. Yet, there remain several obstacles that complicate the integration of FVCA procedures into the standard workflow for facial trauma patients. Artificial intelligence (AI) has been shown to provide targeted and resource-effective solutions for persisting clinical challenges in various specialties. However, there is a paucity of studies elucidating the combination of FVCA and AI to overcome such hurdles. Here, we delineate the application possibilities of AI in the field of FVCA and discuss the use of AI technology for FVCA outcome simulation, diagnosis and prediction of rejection episodes, and malignancy screening. This line of research may serve as a fundament for future studies linking these two revolutionary biotechnologies. Facial vascularized composite allotransplantation (FVCA) is a surgical procedure that involves transplanting composite tissue to patients with devastating and irreversible (mid-)facial defects \u20134. FVCA While various basic science and translational projects are underway to solve these issues, there is a scarcity of studies elucidating the integration of artificial intelligence (AI) into the field of FVCA. AI refers to computer systems that can learn, infer, synthesize, and perceive information similar to human cognition. AI is commonly established on large data sets that serve as training models to produce mathematical and computational programs; these computational designs are often based on machine learning (ML) and its subsets including deep learning (DL), and neural networks, among other computational methods . More imHerein, we aim to shed light on the application possibilities of AI systems in FVCA and discuss future research directions. This scoping review may provide a fundament to leverage the innovation of FVCA and the limitless learning capacities of AI.Over the past decades, preoperative surgical outcome simulation has become a vital component of comprehensive perioperative patient management . PreoperA 2020 study by Bashiri-Bawil et al. trained an AI-based computer model to visualize postoperative rhinoplasty results using 400 patient images  and 87 facial landmarks. In a testing set of 20 patients, this approach resulted in an accuracy level of >80% . SimilarHowever, such concepts cannot be directly transferred to FVCA, since preoperative outcome simulation needs to integrate the donor's and patient's facial features at the same time. Subsequently, reliable predictions can only be made once the donor is identified. Automated facial landmark recognition systems such as Emotrics  or 3D VECTRA could be used for quick and precise facial measurements , 20. FolThe potential advantages of AI are substantial, particularly for intricate procedures such as FVCA. The degree to which preoperative planning can be detailed and meticulously executed largely predicts the potential success of the outcome.Precision and real-time feedback are essential pillars of contemporary surgical practice. These elements are considerably amplified with the integration of AI into intraoperative image-guidance systems . These aDuring FVCA, the precise fitting of the donor tissue onto the recipient's facial structure is paramount for the success of the procedure , 27. AI Real-time feedback plays a significant role during surgery, a role that might be efficiently fulfilled by AI-integrated intraoperative imaging systems. These systems provide surgeons with real-time data, enabling immediate adjustments to their surgical approach, which can prove invaluable during complex procedures like FVCA . More prDespite distinct advancements in the perioperative patient management including more patient-specific risk profiles, novel biomarkers, and targeted immunosuppressants, allograft rejection persists as a major burden in transplant surgery still affecting more than 15% of solid organ transplant (SOT) patients , 35. MorIn SOT, ML and DNN  have been successfully investigated to identify risk patients for transplant rejection. Thongprayoon et al. performed ML consensus cluster analysis for 22,687 Black kidney transplant recipients identifying four distinct clusters. Interestingly, the authors found that the risk for transplant rejection was significantly increased in highly sensitized recipients of deceased donor kidney retransplants and young recipients with hypertension . In liveAcross the different vascularized composite allograft (VCA) surgery subtypes, 85% of VCA patients experience at least one rejection episode one year post transplantation with more than 50% of cases reporting multiple rejection episodes . Such epCancer represents a widely recognized complication of both SOT and VCA, since there is a two to four-fold elevated risk of malignancies following organ transplant. Remarkably, transplant recipients are at a 100-fold higher risk for developing skin cancer . While tAI technology  has been shown to provide a versatile and precise screening platform for diverse cancer entities and detect mammographic abnormalities with comparable accuracy to radiologists and reduce radiologist workloads \u201370. Yi eFollowing FVCA, one transplant recipient patient was diagnosed with basal cell carcinoma of the native facial skin six years post-transplant, while another FVCA patient presented with a B cell lymphoma which was treated with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone . DespiteFVCA has emerged as a novel and versatile reconstructive technique to provide adequate therapy for patients with devastating facial wounds and trauma , 87. Whi"}
+{"text": "Dystonia syndromes are diverse movement disorders characterized by disabling, painful, and sustained involuntary muscle contraction.Various neurosurgical interventions have been trialled for the treatment of dystonia, including peripheral denervation, intrathecal baclofen infusion, and ablating the basal ganglia or thalamus. However, deep brain stimulation (DBS) primarily targeting the globus pallidus internus (GPi) and the subthalamic nucleus (STN) has evolved as a covetable option with the ability to provide personalized, reversible, and titratable neuromodulation. The available literature has recently been reviewedIn the current edition of the Arquivos de Neuro-Psiquiatria, Listik et al.Similarly, intraoperative target selection has been further refined by studies employing stimulation-outcome mapping in large cohorts. Elias et al.Insights into outcome variation in DBS therapy have also come from the functional magnetic resonance imaging literature. Loh et al. demonstrate that optimal DBS programming engages a functional network resulting in sensorimotor cortex deactivation in 15 cervical dystonia patients with GPi-DBS.There is growing scientific evidence demonstrating the safety and efficacy of DBS for the treatment of medically refractory dystonia, however, optimal patient and surgical target selection remains unclear. Here multiple examples are presented that demonstrate how advances in neuroimaging are contributing to the understanding of DBS therapy in dystonia. These advances may lead to improved patient and target selection and DBS programming."}
+{"text": "We present the first documented case of a fistula between the treated zone and the appendix after RFA in a patient with HCC. Contrast-enhanced CT and MRI revealed a subcapsular hepatic nodule with image findings of HCC located adjacent to the ascending colon and cecum. An ultrasound-guided core needle biopsy was subsequently performed to distinguish between hepatic metastasis and HCC. Post-RFA imaging identified a low-attenuating ablated area adjacent to an air-filled appendix. The patient later experienced complications, including increased liver enzymes and an abscess at the ablation site. Imaging revealed a fistulous tract between the RFA zone and the appendix. Over the following months, the patient underwent conservative treatment involving intravenous antibiotics and repeated percutaneous drainage, exhibiting eventual symptom relief and an absence of the fistulous tract upon subsequent imaging. This case highlights the rare complications that can arise during RFA due to peculiar anatomical variations, such as a subhepatic appendix, resulting from midgut malrotation and previous surgery. It is imperative for operators to be cognizant of potential anatomical variations when considering RFA treatment, ensuring comprehensive pre-procedural imaging and post-procedure monitoring. This case also emphasizes the potential viability of nonoperative management in complex scenarios in which surgical interventions pose significant risks."}
+{"text": "Rates of late allograft loss have improved slowly in the last decades. Well described traditional risk factors that influence allograft survival include cardiovascular events, rejection, infections and post-transplant neoplasia. Here, we critically evaluate the influence of several non-immunological, non-traditional risk factors and describe their impact on allograft survival and cardiovascular health of kidney transplant recipients. We assessed the following risk factors: arterial stiffness, persistent arteriovenous access, mineral bone disease, immunosuppressive drugs residual levels variability, hypomagnesemia, glomerular pathological alterations not included in Banff criteria, persistent inflammation and metabolic acidosis. Recent high-level evidence confirms the superiority of transplantation in reducing all-cause mortality for most patients with end-stage kidney disease . In the We searched three databases: Medline, EMBASE and Cochrane Library, and included studies from January 2000 to December 2022 with the following terms: \u201ckidney graft survival\u201d, \u201ckidney graft loss\u201d, \u201cfailed kidney transplant\u201d, \u201cchronic allograft nephropathy\u201d, \u201crisk factors\u201d, \u201cchronic kidney disease progression\u201d.Late allograft failure is a heterogenous background picture of several multifactorial pathogenic entities that all contribute to kidney dysfunction in transplant patients. Naesens et al. elegantly described data derived from failing grafts: Importantly, one quarter of biopsies exhibit more than one coexisting disease, and almost one third of patients with lost allograft had no specific diagnosis on the last biopsy performed but highlighted the important prognostic capacity of the extent of chronic damage . ConsequRecent efforts have focused on better characterization of allograft loss and described a more complex picture of the multifactorial pathogenic processes. A study conducted by Mayrdorfer et al. examining 303 death-censored graft losses among 1642 transplant recipients discriminated primary failure causes (responsible for more than 50% persistent estimated glomerular filtration rate decrease) from secondary failure causes (contribution to less than 50% estimated glomerular filtration rate decline) and analyzed data in a time-dependent manner. Late allograft failure was mainly attributed to intercurrent medical events, defined as cardiovascular events or infections conducting to prominent decline in renal function, and representing almost 40% of late graft failures. Moreover, antibody-mediated rejection met increasing frequencies with time as a primary failure cause (48.6% of graft failures at more than 10 years from transplant intervention) while T-cell mediated rejection had a sharp decline with transplant vintage. Interestingly, calcineurin-inhibitors toxicity was isolated in only two cases as a primary cause, but it was described as the most frequent secondary cause responsible for graft loss (64 of 240 late graft failures). The authors once again highlighted the multifactorial etiology of transplant failure .The ability to predict the evolution of the transplanted kidney is of great significance and has been the center of some valuable research. Search of prognostic factors begins even before implantation with evaluation of donor quality. Preimplantation histology may provide important clues but clinical decisions of implanting or discarding the kidney based on this data have shown conflicting results. In a recent large multinational study, discarded kidneys due to biopsy alterations could have been offered to patients with improved survival and quality of life. Data shows 70% of implanted similar grafts matched with the refused grafts due to biopsy were functioning at 10 years .Prediction models can be computed by means of artificial intelligence and deep learning models to predict evolution of estimated glomerular filtration rate after kidney transplantation. Raynaud et al. identified, after performing multinomial regression models, seven significant determinants of progression: donor age, estimated glomerular filtration rate, proteinuria, graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation and circulating anti-HLA donor specific antibodies. Resulting computed trajectories were significantly associated with progression to allograft loss .Other techniques proved good forecast capability utilizing sequence-to-sequence modelling in order to create a machine learning algorithm-based prediction model that is based on inputting repeated estimated glomerular filtration rate measurements .Recently, an interesting dynamic prediction tool that incorporates histological, immunological and clinical parameters together with repeated measurements of graft function was validated in multiple cohorts and proved superior prediction performance of allograft survival compared to other similar systems. Individualized parameters that altered survival were estimated glomerular filtration rate, proteinuria, delay between transplant and evaluation, Banff categories , mean fluorescence intensity of anti-HLA donor specific antibodies and repeated measurements of eGFR. The iBox system has proved good prediction ability of graft survival and it has been validated as a valuable endpoint in clinical trials in transplantation ,15.Cardiovascular disease has recently gained well-deserved attention since it represents the main driver of comorbidity and mortality in kidney transplant recipients. Pregnant emphasis was attributed to defining and addressing traditional cardiovascular risk factors in improving survival outcomes in this population. Management of these associated relevant comorbidities have been reviewed elsewhere and they do not meet the purpose of this paper  16,17].,17.16,17The association between increased values of arterial stiffness and eGFR decline has been noted in the general chronic kidney disease (CKD) population and suggests that the resulting hemodynamic stress insults the kidney by means of endothelial dysfunction and microvascular ischemia. Chronic inflammation, oxidative stress and overactivation of the renin\u2013angiotensin systems may represent other possible mechanistic underpinnings . Aortic Continuous functioning arteriovenous fistula after kidney transplantation has the potential to worsen the maladaptive remodeling changes in the cardiovascular system and alter kidney function. A meta-analysis addressing the impact of ligating the arteriovenous fistula showed that patients undergoing access occlusion had better cardiac morphological parameters and better kidney allograft function .Furthermore, patency at 5 years was only 61% and arteriovenous fistula-related complications were frequently reaching about 30% of patients. On the other hand, preservation of the vascular access may provide the advantage of an optimal backup strategy if transition to dialysis is needed. Consequently, decisions should be individualized on several parameters, mainly based on renal and cardiac functions and on selecting complications-prone profile of patients .After kidney transplantation, particularly older patients find themselves at an increased risk for pathological fractures. The fractures appear multifactorial in nature  and are associated with unfavorable outcomes, such as subsequent graft loss or mortality. It remains unclear whether only the high end of mineral bone disease spectrum (fractures) is linked to allograft survival decline or if other biologic entities contribute as well .Persistent mineral abnormalities after kidney transplantation mainly include hypercalcemia and hypophosphatemia. Previous severe hyperparathyroidism and high levels of circulating PTH and FGF-23 are established risk factors for altered mineral metabolism post-transplantation. However, impact on outcomes is unclear. As they may not contribute directly to allograft loss and rapid eGFR decline, they are the main drivers of vascular calcifications affecting graft vessels and, interestingly, of tubulointerstitial calcifications on allograft biopsies ,31.Cinacalcet has proven its ability to correct persistent hyperparathyroidism after kidney transplantation and the associated metabolic derangements but without impact on bone mineral density or allograft survival . Data frBiphosphonate therapy in kidney transplant recipients has the clear benefit of improving bone mineral density. Recent studies have proven low rates of adynamic bone disease, strengthening the safety profile of this medication. However, there is no clear data on rates of fractures and there are no benefits or harms related to renal function evolution in kidney transplant recipients .Assessment of pre-transplantation profile of mineral bone disease phenotype may predict survival and high-risk patients. In a cohort of more than 11,000 patients, recipients that exhibited higher levels of pre-transplant serum alkaline phosphatase (>120/U/L) were subject to increased post-transplant mortality. No association was found between circulating PTH or calcium and post-transplant evolution .The negative correlation between graft survival and vitamin D deficiency has been described in an observational manner . InsuffiCurrent therapeutic armamentarium provides means to effectively correct mineral abnormalities in kidney transplant recipients. However, impact of described treatments on graft survival have been insufficiently studied and proved no significant benefits.Excessive immunosuppression contributes to significant complications linked to allograft loss; infections, malignancy and polyoma virus nephropathy account for about one third of graft losses . BecauseInterestingly, another tool available for the evaluation of drug exposure is the time in therapeutic range\u2014addresses the interval of time that a patient is exposed to correct predefined range of values of immunosuppression. Patients with high variability and time in therapeutic range < 40% were at increased risk of de novo donor-specific antibodies and at an estimated four times greater risk of graft loss by 5 years .Hypomagnesemia represents one of the most frequent electrolyte disturbances post-transplantation . SeveralMagnesium deficit exhibits diabetogenic effects and it represents a proven independent risk factor for post-transplant diabetes mellitus ,49. ReceReports on mortality are conflicting and derived from observational retrospective studies. There have been signals of the possible interaction between hypomagnesemia and graft dysfunction . RecentlMagnesium metabolism, however, is important and may have implications in long-term outcomes as it interferes with glycemic alterations, endothelial dysfunction and cardiovascular abnormalities. In addition, correction is cumbersome and magnesium levels may not reflect true stores. No significant trials regarding supplementation and the associated impact on graft function have been conducted .Overall, due to conflicting results and the presence of many confounders, such as the use of CNI, nutritional status, measurement issues, other additional studies addressing this problem will evaluate true impact.The kidney transplant biopsy interpretation is submitted to a well described and standardized score system\u2014Banff classification. Diagnostic entities are established by pathologists after grading several acute and chronic lesions . HoweverDenic et al. conducted a study with repeated biopsies in well-functioning transplant recipients at 5 years post-implantation. Three parameters previously linked to unfavorable graft outcomes were examined: glomerular volume, global glomerulosclerosis and ischemic appearance of glomeruli. All three parameters combine successfully predicted death-censored graft failure at 5 years. Moreover, glomerular ischemia is significantly associated with allograft loss, even after adjustment for Banff scores .Moreover, other recent data highlight the impact of early subclinical inflammation detected on surveillance biopsies on allograft survival. Patients with subclinical inflammation and tubulitis were exposed to a higher hazard of acute rejection and death-censored allograft loss .Implantation of the kidney allograft is often realized in uremic patients exhibiting a state of inflammatory milieu. Moreover, inflammation is enhanced by perioperative events and induced by other stressors. For example, brain death is linked to increased cytokine excretion and ischemia-reperfusion injury can lead to delayed graft function. All forms of rejection are responsible for elevated markers of inflammation, and viral infections could be a source of enhanced cytokine production leading to overreactive innate immunity . AtherosThe persistent inflammatory state is multifactorial and contributes to graft dysfunction by several mechanisms: triggering chronic hypoxia, extracellular matrix deposition and extending graft fibrosis . FurtherMetabolic acidosis identifies as one of the most common complications in kidney transplant recipients. The fall of bicarbonate and pH levels with a decrease in serum partial pressure of carbonic dioxide occurs mainly when the glomerular filtration rate falls under 30 mL/min in patients with chronic kidney disease. This threshold is higher in kidney transplant recipients, showing that metabolic acidosis may occur at higher GFRs in these patients ,64. The Data on allograft survival are pointing to metabolic acidosis as a risk factor for graft dysfunction in the long term. Park et al. conducted a study that showed that low TCO2 concentrations 3 months after transplant are associated with an increased risk of graft loss and death-censored graft failure . FurtherThus, these associations require the application of therapeutic measures to correct acidosis. From this point of view, the data are limited, with most studies focusing on alkali therapy. If supplementation with sodium bicarbonate is effective in patients witch chronic kidney disease, the data in kidney transplant recipients are limited. Schulte at al. evaluated the effect of sodium bicarbonate in kidney transplant recipients with chronic metabolic acidosis. Treatment with sodium bicarbonate was associated with an increased risk of graft failure with no changes in mortality. Authors speculated that the interference with gastric acid pH of oral bicarbonate intake may lead to altered absorption of mycophenolate mofetil. Consequently, patients may be exposed to lower plasma concentrations of mycophenolic acid . The recLong-term survival of kidney allografts is altered mainly by cardiovascular disease, malignancy and infections. However, in order to maximize survival, other relevant pathogenic entities need to be addressed. Care of kidney transplant patients is complex and needs to be centered also on many potential risk factors that can influence long-term survival, consisting of the following: metabolic derangements such as hypomagnesemia, metabolic acidosis and mineral bone disease after transplantation, cardiovascular disease manifesting as arterial stiffness, immunosuppressive drug metabolism and non-adherence, persistent inflammation and glomerular changes not highlighted by Banff criteria. ."}
+{"text": "A 72-year-old man presented with painful enlargement of the scrotum and weight loss. Physical examination revealed that the right testicle and epididymis were hardened and tender. Hematology and chest radiography results were normal. Pelvic computed tomography (CT) revealed bilateral hydrocele and an irregular right testicle and epididymis with peripheral contrast enhancement and central necrotic hypodense portions . Radical,Genitourinary tuberculosis is the second most common form of extrapulmonary tuberculosis after lymph node involvement; however, tuberculous orchiepididymitis is rare. Ultrasound may show focal or diffuse areas of hypoechogenicity in the testicle and epididymis, with increased surrounding vascularity on color Doppler imaging, and a hydrocele. CT usually shows irregular testicular masses with heterogeneous or peripheral contrast enhancement, and a hydrocele, with or without calcification"}
+{"text": "More than 8 million people contract typhoid annually, resulting in about 100\u2009000 deaths. Despite associated sociopsychological and economic fallouts,,The most frequent co-endemic acute undifferentiated febrile illnesses are flaviviral illnesses, scrub typhus, malaria, leptospirosis and acute viral hepatitis.Several actionable insights emerge from these gaps that are relevant to future diagnostic test development and evaluations. First, investigators must aim to integrate clinical and laboratory results in diagnostic test evaluations. Clinicians are aware that the diagnosis of acute fever requires a combination of several clinical, physiological and contextual parameters. Systematic assessments of the discriminative power of various tests are important to determine the true added value of rapid tests. Second, researchers should use modelling approaches to identify algorithms worth evaluating in trial settings. Models can inform the incremental value and post-test probabilities of rapid diagnostic tests within clinical algorithms based on pretest accuracies of combinations of clinical signs. To improve testing algorithms for multiple pathogens, the global health community needs renewed data mining efforts to inform modelling approaches. Third, implementers should tailor diagnostic test interventions to the needs and preferences of end-users. Guidelines cannot be translated into interventions unless contextualized to specific practice settings. Qualitative studies should therefore be undertaken in high-burden settings to understand drivers of test use and physician-patient preferences to avoid translation failures. Fourth, funders should incentivize diagnostic research. As new infectious challenges emerge, it is important that funding focus does not shift away from this common cause of illness and death.The recent World Health Assembly resolution on strengthening diagnostics capacity"}
+{"text": "In this issue of the Journal, Guadamuz et al.  considerCancer care delivery research typically aspires to execute intervention studies targeting modifiable clinical and practice-level factors in the care delivery environment , but GuaThe built environment  may particularly predict chronic disease , with hoEarlier research indicated that profit and affluence predict for-profit hospitals\u2019 locations, thus intentionally marginalizing Medicaid and uninsured patients ,25. MoreMultilevel policies may beget care access benefitting cancer prevention and survivorship, but enhanced facility proximity and care reimbursement, although necessary, is likely insufficient for optimizing care for patients residing in low area-level socioeconomic status locales. Health-care organizations and their care teams may create and sustain care equity threats. Workforce conditions, such as unfavorable patient to clinician ratios  potentiaWe encourage hypothesis testing that considers relationships between the built environment, practice norms , and cancer treatment initiation and survival. How might we design studies to test these relationships? Cancer care delivery espouses advancing beyond traditional randomized clinical trial paradigms  to embrace pragmatic trial methods that prioritize external validity and the relevance of community practice . MoreoveGuadamuz et al.  reveal a"}
+{"text": "On November 7, 2022, dengue virus (DENV), which is not endemic in the continental United States , MCESD, and Arizona Department of Health Services locally acquired mosquitoborne disease response plan, MCDPH and MCESD activated an incident command office on November 10. MCDPH took the following actions: 1) prioritized prospective investigations of health care provider and laboratory reports of DENV and suspected arboviral visits queried from the National Syndromic Surveillance Program's BioSense Platform (BioSense)Aedes aegypti mosquitoes and breeding sites; mosquitoes collected in a professional BG-Sentinel mosquito trapAfter discussions with CDC\u2019s Dengue Branch and Florida Public Health (Coordinated surveillance and response activities identified the first locally acquired human DENV infections in Maricopa County, Arizona. Established partnerships and preexisting plans were essential to mounting a rapid, coordinated response to nonendemic arboviral transmission. MCDPH and MCESD will enhance future surveillance activities to identify and prevent autochthonous DENV transmission, including additional mosquito trap placement around patient residences and public mosquito exposure prevention education."}
+{"text": "These on-site sanitation systems, a positivestep toward improved household WASH services, are used by 43% of theglobal population, mainly comprising low- and middle-income countries(LMICs).3 There is an urgent need to expand decentralized(non-sewered system) surveillance as LMICs are currently being overlookedin pandemic prevention as it is currently focused on SARS-CoV-2 wastewaterfrom centralized (sewered) systems.The availabilityand accessibilityof water, sanitation, and hygiene (WASH) services are key in preventingdisease transmission.Wastewater surveillanceof centralized systems presents a vastlydistinct set of challenges compared with fecal sludge surveillance.For example, sewers also contain gray water and sometimes stormwater,and wastewater is commonly sampled as a composite volume over a 24h period, whereas fecal sludge is most commonly grab sampled. Broadeningthe focus of non-sewered sanitation surveillance (NSSS) should accommodatefecal sludge analysis to support globally relevant public health strategies.4 Unfortunately, interest in fecal sludge researchhas been largely limited to a small group of researchers funded bya few core donors. The pandemic has renewed the focus of both scienceand policy. Surveillance of pathogens in fecal sludge may need tobe adapted and could include Vibrio cholerae or poliovirus;however, this should be determined by assessing localized needs. Thepotential of the public health impact in LMICs can be amplified byusing fecal sludge data in addition to clinical data in multipathogendisease surveillance and continuous local monitoring for early warningsof a pandemic.Even before the COVID-19 pandemic, fecal sludge was used as a valuablesource of information for understanding community health.5 but possibly more complex in the Southern Africansanitation field with five decades of human waste research.6 With no formal global network, internationalnonprofit institutions can fill this role by bringing together academicresearch partners and public health officials for interdisciplinaryand collaborative research and increased awareness of NSSS. Such partnershipscan enable these settings to innovatively adapt academic or healthcarelaboratory operations while maintaining high-quality data and alsopromote peer-reviewed literature originating from resource-limitedlaboratory settings.Research partnerships are required to progressfrom individualclinical patient samples  to pooled community samples in terms of fecalsludge. The importance of research partnerships is not new,Timelier and better-quality global epidemiologicaldata sets arerequired for better pandemic preparedness in the future. There isa need in LMICs for the different, but unique, value of NSSS comparedto that of wastewater surveillance, built-in capacity at local laboratoriesthat can include fecal sludge as part of continuous multipathogendisease surveillance, and long-term global research collaborationsfocused on creating systems with data-driven approaches. Challengeswill remain, including importation and lengthy delays in suppliesand equipment (such as polymerase chain reaction primers and probesthat are not manufactured in many LMICs), repurposing existing LMIClaboratory spaces for fecal sludge samples, and limited LMIC accessto biosafety level 3 and 4 laboratories for sample processing, therebylimiting pathogen target lists. We recommend that LMICs navigate throughthese barriers to ensure that fecal sludge surveillance benefits publichealth, generates local policy-relevant information for future pandemicprevention and control, and holistically supports global WASH services."}
+{"text": "Recently, an empiric Cone-beam Computed Tomography (CBCT)-guided transarterial embolization (TAE) technique has been investigated for lower gastrointestinal bleeding (LGIB). Although this empirical strategy reduced the rate of rebleeding in hemodynamically unstable patients compared to a \u2018wait and see\u2019 strategy, the specified technique is challenging and time-consuming.We present two methods to perform a prompt empiric TAE in LGIB when catheter angiography is negative. Based on the pre-procedural Computed Tomography Angiography bleeding site and using vessel detection and navigation software tools that are integrated in contemporary angiosuites, the culprit bleeding artery could be targeted with only one selective intraprocedural CBCT acquisition.The proposed techniques are promising to reduce procedure time and facilitate the implementation of empiric CBCT-guided TAE in clinical practice when angiography is negative. Empirical transarterial embolization (TAE) is a well-known strategy in interventional radiology (IR). In upper gastrointestinal bleeding, when primary endoscopic hemostasis has failed, endoscopy-directed empiric TAE of the left gastric or gastroduodenal artery is recommended if angiography is negative  and vasopressor requirements upon arrival, subsequent inferior mesenteric Digital Subtraction Angiography (DSA) and CBCT angiography  failed to demonstrate active bleeding. Because of hemodynamic instability and risk of bleeding recurrence, an empirical TAE (illustrated in Fig.\u00a038y old female patient with history of a lateral pancreatojejunostomy after pancreatic trauma was admitted because of recurrent RBPA and one-time hematemesis. Initial upper gastrointestinal endoscopy and CTA could not identify an active bleeding focus. However, because of progressive hemodynamic instability, the patient was transferred the following day to our tertiary referral hospital. A new CTA now did reveal an active bleeding proximally in the Roux-en Y jejunal loop and the patient was immediately transferred to the angiosuite. Nevertheless, superior mesenteric DSA and CBCT failed to identify a bleeding focus. Regarding inaccessibility for endoscopy, empirical TAE (illustrated in Fig.\u00a0Recent guidelines emphasize the importance of CTA and TAE in the management of active or hemodynamically unstable LGIB (Triantafyllou et al. The use of vessel detection and navigation software could be promising to reduce procedure time and facilitate the implementation of empirical TAE in clinical practice. However, safety and efficacy of this approach should be verified on a larger scale."}
+{"text": "Pseudomonas aeruginosa. Fungal infections in MEO are also likely but extremely rare. And conventional microbiology tests is difficult to diagnose.Most of malignant external otitis (MEO) cases reported in the literature are attributed to Aspergillus by metagenomic Next-Generation Sequencing (mNGS) and recovered after comprehensive treatment including operation and voriconazole. The antifungal treatment was delayed due to repeated cultures of secretions being negative and pathological examination showed granulation tissue proliferation with extensive neutrophil infiltration.Two patients were diagnosed with Fungal malignant external otitis (FMEO) due to mNGS might be helpful for patients suspected with FMEO, especially when conventional microbiology tests were negative. Pseudomonas aeruginosa , previously diagnosed otitis externa not responsive to therapy.Aspergillus is also frequently isolated from external auditory canal smears and diagnosis of FMEO should be based on histopathologic confirmation on deep tissue biopsy  for the publication of any potentially identifiable images or data included in this article. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.QW: patient management, data collection, and writing original draft. RH and YZ: patient management and data collection. WZ: review and modify the article. HJ: review and modify the article. All authors contributed to the article and approved the submitted version."}
+{"text": "Orcinus orca) to quantify patterns of fine-scale foraging movements and their relationships with demography. We reveal striking interpopulation differences in patterns of individual foraging behavior. Females from the endangered Southern Resident (SRKW) population captured less prey and spent less time pursuing prey than SRKW males or Northern Resident (NRKW) females, whereas NRKW females captured more prey than NRKW males. The presence of a calf (\u22643 years) reduced the number of prey captured by adult females from both populations, but disproportionately so for SRKW. SRKW adult males with a living mother captured more prey than those whose mother had died, whereas the opposite was true for NRKW adult males. Across populations, males foraged in deeper areas than females, and SRKW captured prey deeper than NRKW. These population-level differences in patterns of individual foraging behavior challenge the existing paradigm that females are the disproportionate foragers in gregarious resident killer whales, and demonstrate considerable variation in the foraging strategies across populations of an apex marine predator experiencing different environmental stressors.In cooperative species, human-induced rapid environmental change may threaten cost\u2013benefit tradeoffs of group behavioral strategies that evolved in past environments. Capacity for behavioral flexibility can increase population viability in novel environments. Whether the partitioning of individual responsibilities within social groups is fixed or flexible across populations is poorly understood, despite its relevance for predicting responses to global change at the population and species levels and designing successful conservation programs. We leveraged bio-logging data from two populations of fish-eating killer whales ( Rapid environmental change may disrupt cost\u2013benefit tradeoffs of foraging strategies in cooperative species, yet whether populations differ in the partitioning of individual responsibilities within social groups is poorly understood. By combining fine-scale movement and sound data from bio-logging tags and demographic data from long-term population censuses, we reveal opposite patterns of individual foraging behavior between killer whale populations with divergent population trajectories, demonstrating variation in the partitioning of foraging responsibilities in an apex marine predator. Orcinus orca , primarily Chinook (O. tshawytscha) and to a lesser extent chum (O. keta) and coho . We also collected prey remains using fine-meshed dip nets  in MATLAB v R2016b  to calibrate sound and movement data based on sensor characteristics and tag orientation on the whale  and the marmap R package  and Fisheries and Oceans Canada (NRKW) to assign demographic variables. These databases contain extensive maternal familial relationships established through field observations and genetic testing  in R v.3.6.3  using thFor the model examining the relationship between the presence of a living mother and the number of prey capture dives by adult males model h, , we addiWe were unable to use available salmon abundance indices due to 1) spatial incongruency between the salmon stocks/regions where these abundance data were sampled and the prey consumed by NRKW and SRKW during our study period and location, 2) issues with sporadic coverage and the degree to which effort had been accounted for in some of the existing salmon indices, and 3) reliability issues with applying widely used salmon data from the Albion Test Fishery situated on the Fraser River e.g., , becauseWe analyzed 186.8 h of dive data from 52 Dtag deployments  or maximizing energy obtained from foraging (optimizing) . For SRKThe finding that adult SRKW males captured more prey if their mother was alive highlights the opposite patterns of foraging behavior we observed for adult males between the two populations. Males require more energy due to their larger size , and theIt is worth considering an alternative, nonmutually exclusive hypothesis related to the role of group leadership by post-reproductive females to explain the increased prey capture by SRKW males with living mothers. Given that post-reproductive females typically lead groups  and thatDifferences in prey abundance and availability between populations could have contributed to the differences in foraging strategies we document here. However, we could not use existing indices of salmon abundance in our analyses because these metrics do not address spatiotemporal uncertainty in the distributions of Chinook salmon returning along one of two paths to the Fraser River. The nuances of migration paths taken are directly related to accurately estimating salmon availability for each population, yet data at this fine-scale spatiotemporal resolution are not currently available. We suggest that future research should elucidate the complex relationships between 1) environmental factors including location, prey distributions, and availability, 2) the behavioral context of the animal at the time of tagging, and 3) differential population-level impacts of anthropogenic pressures, including impacts from tagging and vessel presence, on foraging behavior e.g., , 2021b. This study revealed considerable differences in sex-based and demographic patterns of individual foraging strategies, demonstrating that these strategies are not fixed across two ecologically similar populations of a gregarious marine predator. The total number of prey capture dives and proportion of time capturing prey was female biased in the growing NRKW population, and male biased in the endangered SRKW population. The presence of a calf reduced female foraging activity across populations, but disproportionately so for SRKW females. Adult SRKW males with a living mother exhibited increased foraging behavior, possibly as a compensation strategy to offset their pod\u2019s caloric deficits and/or as an outcome of matriarch-led navigation to areas that promote greater prey capture by their adult sons. Interpopulation differences in individual roles within social groups may have arisen with the loss of key individuals as populations shrink, or may provide small, unbalanced populations experiencing environmental stressors the necessary flexibility to respond to novel and unpredictable environments caused by human-induced rapid environmental change. Indeed, interpopulation variation in individual roles may be an important evolutionary strategy for promoting resilience in the face of change.arad002_suppl_Supplementary_MaterialClick here for additional data file."}
+{"text": "To the Editor: Fetal alcohol syndrome (FAS) is characterized by a range of structural birth defects, including facial dysmorphia, central nervous system growth deficits , and prenatal/postnatal growth restriction, which correlate with the magnitude of prenatal alcohol exposure .Due to the development of grossly observable alcohol-induced phenotypes consistent with clinical presentations of FAS, mouse models have become a powerful resource for investigating the development of alcohol-induced dysgenesis . TherefoWe first employed geometric morphometric analyses  to contrFurthermore, our analyses revealed that alcohol-induced changes predominantly centered on the lower portions of the face, including the mandible (lower jaw), maxilla (upper jaw), and positioning of the ear . As in cTo validate our observations, we examined offspring for alterations in established measures of alcohol-induced craniofacial defects . ConsistFinally, we conducted a dose-response analysis, contrasting offspring snout-occipital distance and body weight\u2013normalized brain weights with the parental average daily ethanol dose (g/kg). We identified a significant correlation between both measurements and parental alcohol dose for male offspring across the PatExp and DuelExp treatments . In contIn 1981, the US Surgeon General issued a public health advisory warning that alcohol use by women during pregnancy could cause birth defects. Since this time, maternal alcohol use during pregnancy has remained the sole explanation for alcohol-related birth defects. In contrast, paternal drinking and lifestyle choices remain unexamined. Using a physiologically relevant mouse model, our studies are the first to our knowledge to demonstrate that male drinking is a plausible yet completely unexamined factor in the development of alcohol-related craniofacial abnormalities and growth deficiencies. Our study demonstrates the critical need to target both parents in prepregnancy alcohol messaging and to expand epidemiological studies to measure the contributions of paternal alcohol use on children\u2019s health."}
+{"text": "Cell-to-cell communication is a critical process that ensures interaction between adjacent and distant cells to maintain cellular homeostasis in normal physiology and pathophysiological conditions. Two adjacent cells communicate to transfer ions and small molecules via Gap junctions, small selective ion channels. Distant cells establish long-range communication via endocrine/paracrine secretions, extracellular vesicles (EVs) and tunneling nanotubes (TNTs) , that membrane-bound exosomes attached to the plasma membrane of brain endothelial cells (BEC), participate in TNT formation between the cells, and facilitate in vitro blood brain barrier (BBB) genesis. Research has also shown that exosomes released by BECs transfer specific cargo to recipient brain cells (Banks et al., Mentor and Fisher suggested TNT-mediated trans-permeability between BEC cells. Recently another study has shown that thrombospondin-1-containing exosomes released from breast cancer cells promote biogenesis of TNTs (Mahadik and Patwardhan, Another issue is the interplay between exosomes and TNTs to harness synergistic effect on intercellular communication. In this context, the work of In conclusion, the synergistic interplay between exosomes and TNTs in long-range intercellular transfer is rapidly evolving as a promising area of cellular communication. Several important questions have been raised by recent advancements in this emerging field of research. What molecular mechanisms govern their on-demand biogenesis in response to cellular toxicities to rescue pathologies? How are exosomes selectively incorporated into TNTs? Do specific pathophysiological conditions enhance or restrict biogenesis of these intercellular conduits and their functionality? Addressing these questions could provide valuable insights into intercellular communications and their complexities, and will open up new avenues for therapeutic intervention.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Managed care pharmacists utilize clinical guidelines to assist themin identifying acceptable treatment and management of chronic diseases. For thepast several months, an expert panel representing the National Asthma Education andPrevention Program (NAEPP) has discussed updated asthma guidelines, which couldchange future medication management of patients with asthma.To identify new guidelines for asthma control.Taking control of asthma is a foremost objective in managed care, asnew guidelines are debated, and asthma disease management programs identifymore effective models of asthma disease management. Within an effective asthmadisease management program, managed care practitioners, including but not limitedto physicians and pharmacists, must have a thorough understanding of the mostrecent clinical guidelines as well as current knowledge of the current consensusamong opinion leaders regarding asthma treatment and management. This ongoingeducation is critical in order to allow managed care practitioners to perform theirrole and function within their organizations. With the advent of changing asthmapractice guidelines and processes, managed care practitioners need current informationto recognize and apply guidelines-based asthma control.Appropriate asthma treatment requires adherence to currentmanagement guidelines. Approximately one third of asthmatics will not respondto standard asthma treatment and may even worsen while on therapy. Monitoring,close tracking, and regular evaluation of asthma patients at every health careprovider visit is a strategy that can be utilized to generate improved asthma control."}
+{"text": "Prosthetic aortic valve dehiscence is an uncommon complication of prosthetic valve endocarditis that may occur in patients who have undergone aortic valve replacement (AVR). The concurrent presence of aortic root pseudoaneurysm may further complicate the clinical presentation through the external compression of coronary arteries. Thus, patients may present with clinical features of coronary ischemia. Echocardiogram and coronary angiography are useful in establishing diagnosis. Treatment involves a multidisciplinary approach involving cardiologists, infectious disease specialists, and cardiothoracic surgeons. The authors of this study discuss a 51-year-old male who presented with anginal chest pain and was found to have a new left bundle branch block, elevated troponins, and left main coronary artery compression complicating aortic root aneurysm. He ended up requiring a re-do AVR, repair of the pseudoaneurysm, and coronary artery bypass graft. Prosthetic aortic valve infection with dehiscence is a major complication in patients with prior valve replacements . This coA 51-year-old male was referred from an outside facility on account of dyspnea, anginal chest discomfort and elevated troponins. His medical history was significant for intravenous (IV) drug use, hepatitis C, and multiple cerebrovascular accidents (CVAs) that necessitated patent foramen ovale closure. His cardiac history was significant for infective endocarditis-related valve dysfunctions status-post bio-prosthetic aortic valve replacement (AVR) and mitral valve repair with an annuloplasty ring.His vital signs included a blood pressure of 130/74 millimeters of Mercury, a pulse rate of 86 beats/minute, and a temperature of 98.6 degrees Fahrenheit. Examination findings were notable for crackles on lung auscultation. Initial lab results showed an elevated high-sensitivity troponin I level of 327 picogram per milliliter (pg/ml) (reference range 3-58 pg/ml). Rapid plasma reagin was negative. Computed tomography (CT) of the lungs suggested pulmonary septic emboli. Electrocardiogram (ECG) showed sinus rhythm and a new left bundle branch block (LBBB) that was not present on an ECG obtained three months earlier. Both ECGs are shown in Figures The cardiology service was consulted. A transthoracic echocardiogram (TTE) was performed and showed an abnormal prosthetic aortic valve function with rocking motion, prosthesis stenosis with peri-valvular regurgitation, pseudo-aneurysm of the aortic root, and ejection fraction of 25%. A transesophageal echocardiogram (TEE) was pursued and showed prosthesis stenosis, high sense of aortic valve more than 180 degrees detached with severe perivalvular regurgitation, and sewing ring dehiscence in the prosthetic aortic valve. It also showed a 4.7 cm by 4.3 cm aortic root pseudoaneurysm communicating with the aortic sinus  was subsequently performed and showed external compression of the left main coronary artery (LMCA) and proximal left circumflex artery from the pseudoaneurysm as shown in Figure The aortic root pseudoaneurysm was believed to be the cause of the external pressure on the LMCA as demonstrated in the coronary angiogram; coronary artery bypass graft (CABG) was thus not planned initially. The plan, however, changed during the aneurysmal repair when the patient developed elevated pulmonary artery (PA) pressure and a visibly distended heart. CABG with saphenous vein graft to the left anterior descending artery was therefore performed. PA pressure normalized after the CABG. The dehiscent aortic valve is shown in Figure Unlike an atherosclerotic disease, external compression of the LMCA is a much less common cause of coronary ischemia. Etiologies include pulmonary artery in the setting of primary pulmonary hypertension, perivalvular abscess of the aortic valve, aneurysm of the aortic root, and left ventricular aneurysm -4. PatieProsthetic valve endocarditis (PVE) can result in valve dehiscence and mycotic aortic root aneurysm . The incThe diagnosis is usually made using echocardiography. It is important to remember that a negative TEE does not rule out the presence of vegetation. Large vegetation is a later event and the detection of smaller vegetation by a transesophageal echocardiogram (TEE) can be challenging due to the shadowing effect and reflection of the prosthetic material . MoreoveThe current case faced a distinctive complication involving compression of the left main coronary artery and proximal left circumflex artery by the aortic root pseudoaneurysm. ECG showed LBBB which was concerning for acute coronary syndrome necessitating coronary angiogram. LHC will usually show the area of external compression of the LMCA like in our patient. Surgical treatment of the aneurysms relieves the mechanical compression of the coronary arteries. Surgical management for PVE is not without challenges with some series reporting mortality rates of 20-60% and infection recurrence rate of about 7% . Long-teAortic root aneurysm causing external compression of LCA is an important but unusual cause of myocardial ischemia. Patients may be asymptomatic or present with chest pain and dyspnea. Management requires a multi-disciplinary approach. Since the clinical presentation is varied, clinicians need to be aware of the various presentations and challenge of variation in anatomic structure observed in management of such patients. Therefore, this is an important differential diagnosis to consider in the right clinical scenario: patients with PVE and aneurysmal aortic root, especially those with minimal to no atherosclerotic risk factors."}
+{"text": "We also found that youth-reported positive parenting buffered against the association between childhood stress and decreased hippocampal volumes  such that youth who experienced high levels of childhood stress and who reported increased levels of positive parenting did not exhibit smaller hippocampal volumes. Our work identifies positive parenting as a resilience factor buffering youth against the deleterious impact of stressful childhood experiences on problem behaviors and brain development. These findings underscore the importance of centering youth perspectives of stress and parenting practices to better understand neurobiology, mechanisms of resilience, and psychological well-being.Childhood stress has a deleterious impact on youth behavior and brain development. Resilience factors such as positive parenting (e.g. expressions of warmth and support) may buffer youth against the negative impacts of stress. We sought to determine whether positive parenting buffers against the negative impact of childhood stress on youth behavior and brain structure and to investigate differences between youth-reported parenting and caregiver-reported parenting. Cross-sectional behavioral and neuroimaging data were analyzed from 482 youth  who participated in an ongoing research initiative, the Healthy Brain Network (HBN). Regression models found that youth-reported positive parenting buffered against the association between childhood stress and youth behavioral problems ( Childhood stress (e.g. the death of a loved one or illness) can have a negative impact on mental health and well-being; it is therefore critical to investigate resilience factors that might protect against stress. We consider positive (i.e. warm and supportive) parenting as a buffer against the impacts of childhood stress on youth behavior problems and corticolimbic structure. Youth perceptions of positive parenting moderated the association between childhood stress and (i) youth behavioral problems and (ii) hippocampal volumes. No significant associations emerged from interactions with caregiver-reported positive parenting or amygdala volumes. We conclude that positive parenting may function as a key resilience factor protecting youth from the deleterious impact of stressful experiences and that youth perspectives are critical to understanding how life stress shapes neurodevelopment and behavior.Stress in childhood and adolescence can significantly compromise mental health and well-being . A growiResilience factors such as relationships with caregivers can significantly protect against the many deleterious developmental outcomes associated with childhood stress, with more positive caregiver\u2013child connections being associated with better adjustment and fewer problem behaviors among youth , 13. Varslower amygdala growth over time for youth experiencing high levels of positive parenting and high stress, accelerated amygdala growth for youth experiencing high levels of positive parenting and less stress, and no significant effects of stress and parenting on hippocampal volumes  and typically focus on stressful contexts (i.e. socioeconomic disadvantage) and not the actual experience of stress . We were particularly interested in investigating differences between youth versus caregiver perceptions of positive parenting, predicting stronger interactive effects for youth reports of positive parenting compared with caregiver reports.\u03b1 > 0.7, as detailed in our Data from 482 participants  between the ages of 10\u201317 years with T1-weighted structural images were analyzed from the ongoing Healthy Brain Network (HBN) research initiative , a checklist measuring family-, community-, and school-based stressors . Due to Youth report and caregiver report of positive parenting were measured using the positive parenting subscale from the Alabama Parenting Questionnaire (APQ) . For eacYouth behavioral functioning was operationalized by the Youth Self-Report (YSR) Total Raw Score. The YSR is a well-validated and widely used 112-item instrument for problem behaviors across the internalizing and externalizing spectrums among children aged 11\u201318 .High-resolution T1-weighted anatomical MRI scans were collected from four sites in the New York City area. We performed standard-processing approaches from FreeSurfer (version 7.1) and excluded participants with low-quality images and high-motion scans . Regression models examined the interactions of stress and parenting in predicting youth behavioral problems and included sex, age, and scanning site as covariates. We fit linear mixed-effects models (LMEMs) for each brain region of interest  due to potential variations in research sites and scanners. LMEMs included a random effect of the imaging site and sex, age, and estimated total intracranial volume as covariates. We ran separate models testing interactions between negative life events and a) youth-reported positive parenting and b) caregiver-reported positive parenting for each brain region of interest. For significant interaction terms, we conducted simple slope analyses . Across models, we tested for differences between any significant and nonsignificant interaction terms (see N = 226)   anerms see  and psycerms see . We ran pproach) .Descriptive statistics are found in Table \u03b2 = 0.14, Praw < 0.001, Pcorrected = 0.017) and a significant main effect of positive parenting . We also found a significant interaction between negative life events and positive parenting . Simple slope analyses indicated that the association between negative life events and behavioral problems was significant at lower  and average  levels of positive parenting, but not at high levels of positive parenting. There was no relation between stress and behavioral problems when youth were exposed to the highest levels of positive parenting, suggesting a buffering effect. We considered a similar model examining the interaction between stress and positive parenting on behavioral problems using caregivers as the informant of positive parenting. We found no buffering effect of positive parenting against the association between stress and behavioral problems using the caregiver report measure of positive parenting. Models without interaction terms and caregiver report measures of behavioral problems and negative life stress can be found in the We first considered the moderating effect of youth-reported positive parenting on the association between negative life events and youth-reported behavioral problems Fig. . Results\u03b2 = \u22120.07, Praw = 0.029, Pcorrected = 0.042) on the total hippocampal volume. As predicted, there was a significant interaction between youth-reported positive parenting and stress . There was no effect of youth-reported negative life events on hippocampal volumes for participants reporting above-average positive parenting. This finding underscores the stress-buffering role of positive parenting given that reports of negative life events had a negative association with hippocampal volumes only in the presence of below-average and average levels of positive parenting, and not in the presence of above-average positive parenting. Sensitivity analyses testing left and right hippocampal volumes individually can be found in the We next considered the moderating effect of youth-reported positive parenting on the association between negative life events in childhood and hippocampal volumes  on total hippocampal volume. We tested differences between interaction terms for our two models   on total amygdala volume. There were also no interactive effects between negative life events and youth-reported positive parenting on total amygdala volume .There was not a significant main effect of negative life events (N = 226). In this subsample, adding the presence of a mental health diagnosis was not significantly associated with the total hippocampal volume.We constructed additional models to determine the robustness of our effects see . These aWe ran additional analyses examining associations with several markers of socioeconomic status given connections between socioeconomic status and hippocampal volumes. Results indicated that the potentially comorbid and stressful experience of the socioeconomic environment did not account for observed effects of negative life events and positive parenting on youth behavioral problems and hippocampal volumes see . To accoWe found three major results: (i) negative life events and youth perceptions of positive parenting are associated with behavioral problems, (ii) negative life events are significantly associated with smaller hippocampal volumes, and (iii) positive parenting moderates this association such that youth who reported high levels of positive parenting did not show smaller hippocampal volumes even with increasing levels of stress. Only youth perspectives of positive parenting interacted with childhood stress (measured through negative life events) to predict hippocampal volumes; caregiver report of positive parenting was not related to neurobiology as either a main effect or in an interaction with stress. Such findings underscore the importance of including youth as reporters of their own experiences to better understand consequences for neurodevelopment and behavior . We did Our results underscore well-replicated connections between exposure to childhood stress and smaller volumes in the hippocampus , 32. ThePositive parenting can provide youth with a stable environment to learn social skills, feel supported, and practice cognitive and behavioral regulation. Other work examining interactive effects between childhood stress and parenting on brain volumes has not found evidence of a buffering effect of parenting, instead suggesting that warm and supportive parenting was a compounding positive force in the context of low stress . In contThe protective effect of parenting against the deleterious neurobiological impacts of stress may function through modulating biological and socioemotional processes such as hypothalamic\u2013pituitary\u2013adrenal (HPA) axis responsiveness, cortisol reactivity, and self-regulation. Longitudinal work has found that parenting influences HPA axis and cortisol reactivity, which in turn impacts hippocampal volume during development . In addir = 0.22) between youth and caregiver reports of positive parenting in this sample aligns with previous work establishing small to moderate correlations between youth and caregiver reports of behavioral and emotional functioning , suggesting that the observed interaction between childhood stress and youth-reported positive parenting on hippocampal volumes in our larger sample is not explained by comorbid psychopathology. Similarly, we considered associations with various operationalizations of socioeconomic status considering that socioeconomic disadvantage can be an experience of stress that has been associated with altered corticolimbic structure  for consistency in findings (We note several limitations that could serve as important directions for future research. First, we report significant associations that are small in magnitude, with effect size estimates indicating that childhood stress at below-average parenting explains 0.06% of the variance in youth behavioral problems; similarly, childhood stress at below-average parenting explains 0.02% of the variance in total hippocampal volumes. Youth behavioral problems and total hippocampal volumes were also not significantly associated in our supplemental analyses. Of note, we did find a significant association between youth behavioral problems and left hippocampal volumes (detailed in our findings  and apprfindings .Our findings have implications for understanding the impact of childhood stress as well as the factors that buffer youth against the noxious consequences of stress. Given the critical role of the hippocampus in memory and goal-directed behavior, alterations in this structure may create vulnerabilities for later negative outcomes. While additional research is needed to clarify complex relations between stress, parenting, and the brain, our data provide insight into how environmental forces may interact to influence neurobiology.pgad145_Supplementary_DataClick here for additional data file."}
+{"text": "Spectroscopy imaging machine learning for crop stress.\u201d By exploring these cutting-edge research findings we can gain valuable insights into the application of these technologies to enhance agricultural resilience productivity.Crop stress poses a huge challenge to food security necessitating innovative approaches for early detection monitoring management of stress. In recent years the integration of spectroscopy imaging machine learning techniques has emerged as a promising avenue for detecting various types of crop stress. This editorial work introduces recent publications within the field included in the Research Topic \u201cXiao et\u00a0al. focused on the use of visible and near-infrared spectroscopy combined with deep learning to estimate leaf nitrogen concentration in cotton leaves. The study employed random frog, weighted partial least squares regression and saliency map to select characteristic wavelengths. The models based on convolutional neural network showed excellent performance for both qualitative and quantitative prediction of leaf nitrogen. These findings highlight the potential of deep learning and visible and near-infrared spectroscopy within accurate and real-time assessment of cotton leaf nitrogen content, enabling farmers to make applicable fertilization decisionsWu et\u00a0al. employed an unmanned aerial vehicle (UAV) to obtain multispectral images of a rice canopy and analyzed the response of multispectral reflectance features and physiological parameters including net photosynthetic rate (Pn), plant height (PH), and SPAD to different nitrogen treatments or leakage conditions at various growth stages of the crop. The study extensively analyzed the correlation between vegetation indices (VIs), texture indices (TIs), and Pn based on UAV multispectral images. The techniques and findings presented in this paper provide valuable insights within field-scale photosynthetic monitoring in rice cultivation and improve stress detection and yield prediction.Choudhury et\u00a0al. introduces two innovative algorithms, namely VisStressPredic and HyperStressPropagateNet, to predict the onset and propagation of drought stress in plants using camera-captured image sequences in visible light and hyperspectral modalities. The algorithms analyze visible light sequences at discrete intervals and utilize a deep neural network and hyperspectral images to propagate stress over time, which demonstrate a strong correlation between soil water content and the percentage of stressed plants. These algorithms are evaluated on a dataset of cotton plant image sequences and offer valuable support for studying abiotic stresses in diverse plant species, promoting sustainable agricultural practices.Hu X. et\u00a0al. propose a novel approach called Class-Attention-based Lesion Proposal Convolutional Neural Network (CALP-CNN), utilizing a class response map to locate the main lesion object and identify discriminative lesion details in visual light images. Through a cascade architecture, CALP-CNN effectively handles complex background interference and misclassification of similar diseases. Experimental results on a self-built dataset demonstrate CALP-CNN achieves good classification performance and outperforms the existing fine-grained image recognition methods, highlighting its efficacy in field identification of strawberry diseases.Hu Y. et\u00a0al. presents an enhanced encoder-decoder framework based on DeepLab v3+ analysis of images to accurately identify crops with diverse planting patterns. The network utilizes ShuffleNet v2 as the backbone for feature extraction and incorporates a convolutional block attention mechanism to fuse attention features across channels and spatial dimensions. The enhanced network achieves significant improvements and requires fewer parameters and computational operations compared to other networks. This study demonstrates the effectiveness of Deep-agriNet in identifying crops with different planting scales, making it a valuable tool for crop identification in various regions and countries.The combination of spectroscopy, imaging, and machine learning has a high potential for improving crop stress analysis and management. By utilizing these technologies, we can enhance our understanding of crop stress dynamics, develop precise and targeted stress detection methods, and improve decision-making processes for farmers. Ongoing research, technological advancements, and collaborative efforts are necessary to unlock the full potential of spectroscopy, imaging, and machine learning in mitigating crop stress and ensuring global food security.The\u00a0author\u00a0confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "A 60-year-old male patient underwent coronary angiography for acute myocardial infarction. Angiograms revealed significant multivessel disease and an abnormal branch arising from the proximal right coronary artery and extending backwards, likely to the right lung A. Both iIsolated DOPA is a rare vascular malformation that may remain undiagnosed until advanced age, often manifesting with nonspecific symptoms such as recurrent bronchopneumonia, haemoptysis, and dyspnea.,Lack of a connection between the main and affected branch PA, resulting from the involution of the ventral sixth aortic arch, led to the erroneous definition of unilateral pulmonary artery agenesis.\u2022Chest radiograph may provide relevant clues to the diagnosis of DOPA.\u2022CTPA is the method of choice for noninvasive diagnostic confirmation.\u2022Key diagnostic findings are a well-formed but hypoplastic pulmonary artery and a ductal diverticulum on the aortic arch or the base of an epiaortic vessel.Interestingly, DOPA could be suspected by jointly considering the anomalies detected by coronary angiography and chest radiograph. Despite not providing direct visualization of DOPA, these diagnostic modalities could offer subtle but important clues to this rare malformation, ultimately confirmed by CTPA."}
+{"text": "Gastrointestinal cancers represent a major challenge to public health. Pancreatic cancer is the most lethal cancer among all gastrointestinal cancers. Most patients cannot meet the criteria of resection at diagnosis, indicating these patients will have dismal prognosis.Neoadjuvant chemotherapy helps some patients regain the opportunity of radical resection. An optimal regimen of chemotherapy is one that maximizes the anti-tumor efficacy while maintaining a relatively manageable safety profile. The development of surgical procedures further improves the outcomes of these patients.Combination therapies in a multidisciplinary manner that involves modified chemotherapy regimen, radical resection, and intestine auto-transplantation may provide the currently best possible care to patients with locally advanced pancreatic cancer. Gastrointestinal cancers account for around 25.8% of newly diagnosed cancers annually. Among them, pancreatic cancer is the most lethal cancer, with a 5-year overall survival rate of only around 12%. There are more than 495,700 new cases of pancreatic cancer each year [Liang and colleagues proposed a modified FOLFIRINOX regimen, consisting of 85% oxaliplatin, 75% irinotecan, and zero fluorouracil bolus . This moThe modified FOLFIRINOX regimen was also applied as a neoadjuvant treatment to borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) for downstaging and creating surgical opportunity. According to the LAPACT trial that applied gemcitabine plus nab-paclitaxel to LAPC, the neoadjuvant induction therapy achieved a 15% conversion rate of radical resection . The medThe expanded surgical resections after neoadjuvant therapy are critical to the improvement of the radical resection rate in LAPC. For LAPC involving the pancreatic body/tail and the celiac trunk, radical resection can be achieved by the modified Appleby procedure . This group is one of the leading groups that focus on intestine auto-transplantation and liver cancer surgery , 8. As fLiang\u2019s integrated treatment strategy by combining modified FOLFIRINOX with sequential radical resection has established an excellent model of multimodal treatment against pancreatic cancer, and extended criteria of surgical resectability, which would benefit more pancreatic cancer patients at locally advanced stages. The success of this strategy implies that for pancreatic cancer patients, especially those who cannot meet the resectability criteria, the combination of modified chemotherapy and surgical intervention would provide an increased survival benefit. Furthermore, the interim analysis of a prospective phase 3 clinical trial  conducted by Liang\u2019s group , compariIn summary, gastrointestinal cancers represent a major challenge to public health. Most patients cannot meet the criteria of resection at diagnosis, indicating these patients will have dismal prognosis. Neoadjuvant chemotherapy helps some patients regain the opportunity of radical resection. The development of surgical procedures further improves the outcomes of these patients. Combination therapies in a multidisciplinary manner that involves modified FOLFIRINOX regimen, radical resection plus intestine auto-transplantation, targeted therapy and immunotherapy may provide the best possible care to patients with LAPC.The modified FOLFIRINOX regimen is currently an optimal treatment option for pancreatic cancer patients. Combination of the modified FOLFIRINOX regimen, radical resection, and intestine auto-transplantation provides the currently best possible survival benefit for those who have otherwise lost the opportunity of surgery. The addition of immunotherapy, targeted therapy, and radiotherapy may further increase the efficacy of the combination therapy."}
+{"text": "How adult tissue-specific stem cells with indicated markers contact the adjacent lineage with indicated markers is of significance to be studied. Novel methods bring future findings. Recent advances in lineage tracing, synthetic receptor systems, proximity labeling, and transcriptomics have enabled easier and more accurate cell behavior visualization and qualitative and quantitative analysis of cell-cell interactions than ever before. These technological innovations have prompted researchers to re-evaluate previous experimental results, providing increasingly compelling experimental results for understanding the mechanisms of cell-cell interactions. This review aimed to describe the recent methodological advances of dual enzyme lineage tracing system, the synthetic receptor system, proximity labeling, single-cell RNA sequencing and spatial transcriptomics in the study of adult tissue-specific stem cells interactions. An enhanced understanding of the mechanisms of adult tissue-specific stem cells interaction is important for tissue regeneration and maintenance of homeostasis in organisms.Adult tissue-specific stem cells play a dominant role in tissue homeostasis and regeneration. Various   Adult tissue-specific stem cells interactions can be viewed as communication modalities that play a central role in regulating cell behavior and function .In this paper, we first discuss the methods for studying adult tissue-specific stem cells interactions in two directions: bioinformatics analysis and visualization analysis. Specifically, these techniques or methods include lineage tracing, synthetic receptor systems, proximity labeling, and transcriptome analysis. In addition, there are few systematic descriptions of the mechanisms of stem cell interactions. Therefore, this paper also combs the biological understanding of adult tissue-specific stem cells interactions. We do not provide a summary assessment of all relevant literature, and references throughout the text tend to be more illuminating examples. Based on the latest literatures, stems cells referred in this review focus on adult tissue-specific stem cells.in vivo single-cell analysis because of its efficiency and spatiotemporal specificity  during long bone formation is clearly illustrated  to regenerate the bronchoalveolar junction region after an injury has been demonstrated using dual-recombinase-activated lineage tracing (DeaLT) system, reiterating previous findings . Applyinustrated . It has ustrated . In lungustrated . Updatedustrated .Based on the Cre: Dre dual recombinase reporter system, Lingjuan We also note the contribution of optogenetic genetic engineering to the content of our work, which is widely used to study and control cells and has been previously described . OptogenInspired by the natural cell-signaling paradigm, researchers have implemented artificially designed synthetic receptor systems to manipulate signal translation to control cellular functions, including artificially tunable cellular sensing and subsequent transcriptional responses . The devThe synNotch receptor system, which detects cell-cell contact, was developed during the development of synthetic receptor systems . The synDrosophila model  genetically engineered to be expressed in decoy cells to transfer the markers to prey cells . This laThe FucoID protocol installs the glycosyltransferase directly onto the decoy cell without gene expression on the cell membrane . This enProtocols using photocatalysts have greater temporal control and remote manipulation than enzymatic proximity-labeling systems . These pin situ studies of cellular interactions in animal models  act as alveolar adult tissue-specific stem cells in response to injury . AT2 celin vivo  triggers EphB2 signaling attenuation in adjacent radial neural stem cells (rNSCs) through direct cell contact, leading to rNSC activation and the generation of new neurons . Conversin vitro . TranscrInteractions between immune cells and stem cells have also been reported. The fate of intestinal stem cells (ISC) is regulated by adhesion signals from immune cells . BindingThe paracrine effects of stem cells are also influenced by the cell-cell contact between stem cells and other cells. For example, the immunomodulatory effects of MSCs are enhanced upon contact with pro-inflammatory macrophages . AdditioMoreover, immune cell function is affected by intercellular contact between stem cells and immune cells. This may be due to the secretion of cytokines that affect stem cells . There aStem cells can also regulate immune cell functions through paracrine and intercellular contacts . TGF-\u03b2 Min situ.\u201dIn bone marrow tissue, bone marrow regeneration after radiation clearance is inseparable from the transfer of mitochondria from hematopoietic stem cells to bone marrow mesenchymal stromal cells through intercellular contacts . HematopMechanical signals include both the structure and properties of the ECM and forces generated by the cell through various connections . This inDrosophila, the proliferation and differentiation of all stem cells that ectopically express Piezo are promoted by a mechanism that is inseparable from calcium signaling (Mechanically gated Piezo1 channels are expressed in both neural stem cells and astrocytes and regulate adult neurogenesis . In Drosignaling . Piezo1 ignaling . Furtherignaling . During ignaling . When thignaling . Adult mignaling . The NotWnt and Src-YAP signaling cooperate to drive intestinal regeneration . Additiovice versa in favor of endocrine cell fate (Physical signaling with tunable properties that act immediately and locally is an object of interest to regulate the differentiation of stem cells into specific lineages . The ECMell fate . MSCs arell fate . Smallerell fate . The intell fate . Moreoveell fate . The intell fate .Indeed, numerous researchers have shed a light on how mechanical information affects cell behavior. We are currently studying the mechanisms underlying stem cell interactions to improve the application of stem cells in regenerative medicine. To systematically and precisely elucidate these mechanisms, technologies with higher spatial and temporal resolutions, more realistic simulations of the stem cell microenvironment, and more specific stem cell population differentiation and tracing are required. This demand has led to many powerful technologies that elucidate the mechanisms of stem cell interactions. We discuss how lineage tracing, synthetic receptors, proximity labeling and transcriptome data analysis tools can be applied in the study of CCI. The techniques presented in this paper include but are not limited to using stem cells as research models, and using non-stem cells as research models has complementary and reference significance. In addition, we note some other techniques. For example, SPEAC-seq based on CRISPR-Cas9 with microfluidic microarrays to identify cell signaling pathways . It provThe study of stem cell interactions is in a rapidly evolving stage, especially in the context of rapid iterative updates in biotechnology. Although, the biological understanding of stem cell interactions sorted out in this paper is not sufficient to elaborate a comprehensive picture of stem cell behavior during mammalian development or injury repair, it contributes to a complete description of stem cell interaction mechanisms in the future."}
+{"text": "Cerebrovascular injuries resulting from frontobasal head trauma represent a range of imaging and clinical presentations. Severe cerebrovascular injuries such as vessel transection commonly present with profound neurological deficits and are often easily identified with routine imaging. However, small intimal injuries and dissections may be challenging to detect and may be clinically silent or masked by additional injuries in the setting of polytrauma. The onset of symptoms and complications from cerebrovascular injuries may be delayed from the time of initial presentation, and failure to recognize and diagnose these injuries may result in devastating outcomes if management is delayed. In this case report, we present a case of frontobasal craniofacial trauma that resulted in an anterior cranial fossa dural arteriovenous fistula (ACF-dAVF) and supraclinioid segment internal carotid artery (ICA) pseudoaneurysm.\u00a0 Vascular injuries have been identified in 8.5% of skull base fractures in some case series, particularly when the sella turcica-sphenoid sinus complex and the petrous carotid canal are involved ,2. ResulDural arteriovenous fistulas (dAVF) are uncommon vascular lesions with abnormal connections between arteries and leptomeningeal veins or a dural venous sinus\u00a0. They maTraumatic intracranial aneurysms represent fewer than 1% of all intracranial aneurysms . AlthougA 45-year-old male presented with extensive frontobasal and craniofacial injury after an all-terrain vehicle (ATV) rollover. Initial trauma computed tomography (CT) scans depicted bilateral naso-orbito-ethmoid complex fractures with fracture planes extending to the bilateral sphenoid sinus walls. Multi-compartmental intracranial hemorrhage, including subarachnoid hemorrhage and hemorrhagic contusions with basifrontal predominance, were also present. Subsequent CT angiography (CTA) of the neck revealed vessel wall irregularities and non-flow limiting stenosis involving the left supraclinoid ICA, and prominent cortical veins along the right ACF Figures , 2. The Cerebrovascular injury from blunt trauma can be subtle and difficult to detect at initial presentation. It can be stratified using a five-point scale Biffl cerebrovascular arterial injury grading scale\u00a0based on the severity of vessel injury from mild intimal injury (Grade I) to vessel transection (Grade V) Table  11]. Gr. Gr11]. In this case, the patient developed an ACF-dAVF within three days of the initial encounter, which is to our knowledge the first case report of a patient presenting with this condition within one month of the initial injury. In ACF-dAVFs, the cribriform plate is commonly the fistula point, in which afferent arterial supply arises from the distal ophthalmic artery and both anterior and posterior ethmoidal arteries, and venous drainage occurs through frontal cortical veins into the superior frontal sinus or posteriorly into the cavernous sinus or basal vein of Rosenthal ,15. In tTraumatic intracranial aneurysms may be true or false aneurysms. True aneurysms have preserved adventitia and partially disrupted and damaged intima, internal elastic lamina, and media, whereas false aneurysms/pseudoaneurysms result from disruption of all arterial wall layers and are contained by adjacent hematoma and perivascular connective tissues . In partThis report is a description of a rare case of ACF-dAVF and ICA pseudoaneurysm that developed in the days following significant frontobasal craniofacial trauma as an opportunity to discuss the clinical presentation and associated imaging findings of these lesions, and to provide a better understanding of the pathogenesis and management of these and related post-traumatic cerebrovascular injuries and complications."}
+{"text": "Scar pregnancy is a rare and potentially life-threatening condition that occurs when an embryo implants and grows within a previous cesarean section scar or other uterine scars. This unique form of ectopic pregnancy poses significant diagnostic and management challenges for healthcare providers. Scar pregnancies are associated with an increased risk of uterine rupture, massive hemorrhage, and other complications, underscoring the importance of early detection and appropriate management strategies . Scar pr"}
+{"text": "Discoid lupus erythematosus (DLE) is a chronic variant of cutaneous lupus erythematous developing on sun-exposed areas in multi-morphic forms making diagnosis challenging. Clinical suspicion and prompt treatment are necessary to avoid permanent disfigurement, progression to systemic involvement and poor quality of life. We report a case of delayed DLE diagnosis in a 45-year-old man who presented with a new skin lesion mimicking the early stages of mycosis fungoides that prompted further investigation. Histopathological examination confirmed DLE and appropriate treatment was initiated. However, the atypical clinical presentation led to disseminated DLE and refractory disease control, resulting in scarring and cosmetic disfigurement. Lupus erythematosus (LE) is an autoimmune disease existing on a spectrum of cutaneous and systemic manifestations. Discoid lupus erythematosus (DLE) is the most common variant of chronic cutaneous LE that can present in a variety of morphologies . UnderstA 45-year-old male presented with a new erythematous plaque on the left upper chest after an initial diagnosis of photodermatitis due to the presence of erythematous patches and plaques on the scalp . The newA 4-millimeter punch biopsy from lesional skin showed an orthokeratotic and mildly atrophic epidermis with extensive vacuolar degeneration of the basal layer. There was a dense superficial dermal lichenoid-type of lymphocytic inflammatory infiltrate with scattered melanophages and presence of colloid bodies . Marked Histopathological findings coupled with serological findings were corroborative of DLE and thus the patient was started on short-term oral steroids with prednisolone (20\u00a0mg daily), oral hydroxychloroquine (HCQ)  and high-potency topical steroid clobetasol propionate. Treatment included photoprotection recommendations.At a 6-week follow-up, new cutaneous lesions appeared on the back  and the Patient\u2019s systemic evaluation was negative to date. The patient is under regular follow-up with dermatology and rheumatology.DLE renders difficulty in clinical suspicion and definitive diagnosis as skin lesions resemble common dermatoses. It can lead to permanent disfigurement with hair loss, dyspigmentation and scarring if not treated early or adequately controlled. The chronic nature of the disease imposes a psychological burden and high morbidity on patients, often requiring psychosocial support , 4. Diag"}
+{"text": "Neural oscillatory activity has emerged as a central Research Topic in neuroscience  and phase . Despite their conceptually clear-cut operationalization, analyses of these parameters are confronted with an inherent problem: For which frequency range should these parameters be calculated and how should this range be determined? Initially, a priori-defined frequency ranges centered on a prominent power peak were linked to behaviorally relevant functions , has the potential to overcome the above-mentioned limitations. Computation of PF allows definition of recording-specific frequency peaks based on the empirical data, which can be used to compare individuals and/or experimental conditions. Additionally, when paired with novel tools correcting for aperiodic signal components  and discrete perception . Correlation analyses revealed no systematic connection between individual alpha PF and the latency of neural markers of visual processing. These findings indicate that individual alpha PF does not systematically shift early sensory processing in time.Two of the four contributions to this Research Topic examine the link between individual alpha PF and visual processing. Strang et al. assessed if individual alpha-band PFs over occipitoparietal  and sensorimotor  areas are linked to autism spectrum disorders. EEG recordings of neurotypical participants during motor execution and movement observation revealed that individuals with slower sensorimotor PFs exhibited higher autism-spectrum traits. This finding adds important information about potential biomarkers, since research so far largely focused on the classical alpha rhythm. The work by Sponheim et al. recorded individual alpha-band PFs with MEG during rest and visual processing in participants with psychotic psychopathology, their biological siblings, and healthy controls. Alpha PF varied widely across participants and remained temporally stable across multiple months. Moreover, slowed alpha PF was linked to longer visual percept duration in participants with psychopathology, as well as to lower IQ estimates and higher symptom severity. This study shows how fundamental research can inspire a directed functional assessment of neural markers as indicators of clinical symptom severity.Two other contributions studied the link between PFs and trait variables related to neuropsychiatric disorders. The systematic and hypothesis-driven analysis of PF holds the potential to provide exciting and novel roles of neural oscillatory activity. It promises to strengthen the analysis of oscillatory power and phase by providing an empirically-informed frame of reference instead of rigid a priori defined frequency definitions. We hope that this Research Topic has increased the visibility of PF in the neuroscientific audience and motivated future research.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Cell, Gungabeesoon and colleagues1 demonstrated that a specific subpopulation of neutrophils, characterized by a distinct Sellhi (CD62Lhi) phenotype with an interferon gene signature, acutely accumulates in tumors during successful immunotherapy and is associated with better treatment outcome. These findings enhance our understanding of the neutrophil heterogeneity within the tumor context and highlight their potential in cancer immunotherapy.In a recent study published in Traditionally, neutrophil infiltration of tumor tissue has been primarily associated with tumor progression. However, the remarkable heterogeneity of neutrophils allows them to play multiple roles in this process. In addition to their typical pro-angiogenic and immunosuppressive functions, neutrophils can also have protective roles, such as direct cancer cell killing or stimulation of adaptive immune responses. Importantly, various anti-cancer therapies directly or indirectly (by modulation of tumor microenvironment), impact neutrophil responses and activity. Nevertheless, some immunotherapies fail to induce clinical responses in certain patients, prompting extensive efforts to understand the underlying mechanisms.1 analyzed neutrophil phenotypes expanded after successful immunotherapy. These cells had been previously overlooked in single-cell transcriptomic research due to unintended elimination during standard preparation of the sample. The authors observed that therapy-induced neutrophils expressed high levels of Sell transcripts, encoding the protein Selectin L . These neutrophils exhibited a more immature phenotype (CD101lo), associated with increased cytotoxicity and upregulated expression of genes responsible for regulation of neutrophil degranulation, suggesting their potential immunostimulatory activity. This aligns with prior observations indicating anti-tumoral properties of immature neutrophil populations.2Sellhi neutrophils also exhibited a distinct interferon (IFN) signature, including interferon regulatory factor 1 (IRF1), a crucial driver of their anti-tumor phenotype, and appeared to be essential for the successful therapy , was sustained in tumors after treatment, even as Sellhi neutrophils increased. SiglecFhi neutrophils were previously shown to have pro-tumorigenic properties.5 Here the authors showed that these neutrophils were characterized by multiple gene signatures that support their pro-tumorigenic roles, including expression of genes that promote tumor proliferation, remodeling of extracellular matrix, angiogenesis, suppression of antitumor immunity, and recruitment of myeloid cells, and thus reported to be responsible for metastasizing, sustained in tumors after treatment. Therefore, this study suggests that therapies should aim not only to expand anti-tumor neutrophils, but also to eliminate pro-tumor counterparts. Further human studies will be needed however to understand the dynamics of these populations in a relevant clinical setting following therapy. Human studies should also allow evaluating whether the abundance of these neutrophil populations predict progression and outcome in human cancers.The authors also noted that another population of neutrophils, Single-cell transcriptomics has revolutionized our understanding of neutrophil biology by unraveling the phenotypical and functional diversity of neutrophil subsets across various organs. The pursuit of selective strategies to therapeutically enhance beneficial neutrophil populations while concurrently eliminating tumor-supporting neutrophils remains a compelling approach in immunotherapy. Rather than complete depletion of neutrophils, successful immunotherapy should focus on modulating the tumor microenvironment to favor anti-cancer repolarization of neutrophils. This approach holds the potential to establish an effective strategy for achieving optimal anti-tumor responses and enhancing the outcomes of cancer patients."}
+{"text": "Dear colleagues,Pediatric minimally invasive surgery (MIS) epitomizes a dynamic and continuously evolving field that encompasses a broad range of procedures. From fetoscopic interventions in the prenatal population to robotic-assisted bariatric surgeries in overweight adolescents, the spectrum of techniques and patients encountered in pediatric MIS reflects its inherent intricacy and the fascination it inspires.In the context of this particular Special Issue, our primary objective revolved around an extensive exploration of the expansive landscape of pediatric MIS. This comprehensive investigation encompassed a wide range of relevant aspects, including well-established procedures, pioneering and audacious concepts\u2014even those yielding unfavorable outcomes, breakthrough technological advancements, potential hazards and challenges, contentious procedures, and invaluable insights drawn from our counterparts in the realms of general, thoracic, and visceral surgery.Our intention was to transcend a simple retrospective appraisal by eschewing the common narrative of \u201cwhat has been accomplished thus far?\u201d. Instead, our aim was to assemble a compendium of reports from pioneering colleagues from diverse medical disciplines. These individuals have forged innovatively ahead, propelling developments in minimally invasive surgical interventions in order to enhance the welfare of pediatric patients.We are pleased to say that our endeavors have borne fruit, and we believe that we have achieved our objective.To improve the wellbeing of pediatric patients even before their birth, Thomas Kohl delves into the study of fetal surgery, offering insights into both established and emerging minimally invasive approaches. Expanding upon this, Susanne Eva Brunner provides an exhaustive review comparing bimanual techniques and procedures in fetal surgery with single-instrument interventions. Additionally, Lidya-Olgu Durmaz sheds light on the use of minimally invasive techniques in fetal surgery for the treatment of gastroschisis.Regarding infants and congenital malformations, Anne-Sophie Holler describes the endoscopic magnetic-assisted anastomosing technique, specifically designed for the repair of esophageal atresia. Additionally, Julia K\u00fcppers presents an innovative approach termed \u201cendoscopic percutaneous rectal anoplasty\u201d, which has garnered considerable attention from the esteemed Alberto Pena, a prominent authority on anorectal malformation repair, prompting subsequent scholarly discourse. In a closely related context, Ulrike Metzger provides valuable insights into a recently modified approach involving transanal endoscopic-assisted pull-through colectomy targeted toward pediatric patients afflicted by high intestinal aganglionosis. These developments in pediatric surgical interventions offer promising avenues for improved outcomes and enhanced patient care.When it comes to general pediatric surgical procedures, this comprehensive compilation includes many notable contributions. Hanna Noemi Stundner Ladenhauf presents a meticulous evaluation of the minimally invasive approach in managing traumatic pancreatic ruptures, shedding light on its efficacy and potential benefits. Armin-Johannes Michel provides a detailed account of the thoracoscope-guided pericostal suture technique, showcasing its efficacy as a robust fixation method for closing congenital diaphragmatic hernias. The state-of-the-art of advancements in the field of minimally invasive repair of pectus excavatum (MIRPE) is expertly detailed by Frank-Martin Haecker, as he reveals the current developments and techniques employed in this realm. In a similar vein, Christian Tomuschat delves into the boundaries and limitations encountered in laparoscopic partial splenectomy, providing valuable insights into the challenges associated with this minimally invasive procedure.The domain of pediatric surgery encompasses not only general procedures but also extends to minimally invasive urological interventions. In this context, Frank-Martin Haecker contributes valuable insights by reporting on the combined antegrade and retrograde endoscopic injection technique into the bladder neck employed in children with neurogenic bladder disorders. Furthermore, Christian Kruppa presents a fascinating approach to vesicoscopic cross-trigonal ureteral reimplantation, specifically addressing vesicoureteral reflux. This innovative technique offers a compelling avenue for the treatment and resolution of this condition. These advancements in minimally invasive urological procedures within pediatric surgery hold great promise for enhanced patient outcomes and an improved quality of care.Mareike Grosshauser contributes an insightful examination of interdisciplinary knowledge transfer within the study of minimally invasive pediatric surgery. Similarly, Tatjana Tamara K\u00f6nig delves into the topic of telementoring in the context of minimally invasive esophageal atresia repair, shedding light on the potential benefits and implications of this approach. Expanding our understanding, Andrea Schmedding presents a comprehensive nationwide assessment of the current landscape surrounding laparoscopic pediatric inguinal hernia surgery, drawing upon an extensive dataset. Furthermore, Ma\u0142gorzata Sobol offers a unique perspective by focusing on the parental experience of minimally invasive surgery, specifically examining the role of parents\u2019 time perspective as a predictive factor for their child\u2019s postsurgical pain and emergence delirium, and the potential manifestation of post-traumatic stress disorder in parents.The integration of robotic-assisted surgery will be pivotal element in the future landscape of minimally invasive pediatric surgical procedures. Ewan Brownlee and Mark Slack delve into this paradigm-shifting subject, offering an insightful report on the novel Versius surgical robotic system developed by Cambridge Medical (CMR), exploring its potential utility within the pediatric population. In a related investigation, Marit Kayser presents an evaluation of the Versius system for pediatric surgery, employing inanimate models that simulate small infants and, thus, providing valuable insights into its feasibility and effectiveness. Within the pages of this publication, we also encounter a groundbreaking contribution by J\u00fcrgen Holzer, who provide the world\u2019s inaugural account of a pediatric pyeloplasty performed using the Senhance\u00ae robotic system. This pioneering achievement marks a significant milestone in the application of robotic technology in the pediatric surgical domain. Additionally, Elisabeth Ammer explores the phenomenon of \u201crobotic anxiety\u201d and elucidate parents\u2019 perception of robot-assisted pediatric surgery and its impact on their children. This investigation sheds light on the psychological aspects and human factors associated with the adoption of robotic systems in pediatric surgical contexts. Finally, Thomas Krebs offers a comprehensive review encompassing diverse aspects of robotic-assisted pediatric surgery. Our collective insights and synthesis of existing knowledge serve to enrich our understanding and foster advancements in this rapidly evolving field.Nevertheless, the possibilities of minimally invasive pediatric surgery transcend the traditional boundaries of abdominal and thoracic procedures. Within the field of pediatric orthopedics and orthopedic trauma, Karsten Krohn unveils a pioneering technique involving the dual pre-bending of an intramedullary nail to treat diametaphyseal fractures of the distal radius in children. This innovative approach not only renders the procedure and osteosynthesis less invasive but also holds promise for improved patient outcomes. Moreover, the use of resorbable implants presents an intriguing possibility for circumventing the need for subsequent explantation surgeries; this is an area explored by Christoph Roeder. Through a pilot study, he investigates the application of biodegradable intramedullary nailing, specifically for forearm fractures in the pediatric population. His findings shed light on the feasibility and potential benefits of this approach, paving the way for future advancements in pediatric orthopedic interventions. Similarly, Pascal Heye contributes to this line of inquiry by delving into the utilization of resorbable implants for osteosynthesis in pediatric cases. His research further expands our understanding of this evolving field, exploring possibilities for enhanced treatment modalities and improved patient outcomes. Furthermore, Mathis Wegner presents his insights into a minimally invasive orthosis designed to address a fixed equinus deformity following a modified transverse Vulpius procedure. This novel orthosis holds promise in rectifying this deformity while minimizing invasiveness, thus offering potential benefits to pediatric patients.These contributions to the knowledge of minimally invasive pediatric surgery collectively underscore the constant pursuit of innovative techniques and advancements aimed at optimizing patient care and improving long-term outcomes.This remarkable collection merits great attention, as it encompasses 27 pioneering works by surgeons who fearlessly expand the horizons of minimally invasive pediatric surgery.We thank all the contributors, and congratulate them on their excellent work.Best regards from Sankt Gallen, Switzerland and Kiel, Germany.Thomas Franz Krebs and Robert Bergholz."}
+{"text": "Injection drug use using nonsterile equipment can lead to transmission of viral, bacterial, and fungal infections. Frontline healthcare workers (HCW) are at high risk for substance use disorder due to unprecedented job stress and access to injectable controlled substances. The Tennessee Department of Health (TDH) developed a collaborative investigative process to determine the risk of bloodborne pathogen (BBP) transmission from licensed HCWs engaging in drug diversion. This program recommends public health action and provides consultation to improve drug diversion programs.In 2019 TDH formed a drug diversion investigation team (DDIT) consisting of pharmacists, epidemiologists and medical directors from the HAI and HIV/STI/Viral Hepatitis programs. The DDIT responds to notification by the Health-Related Boards (HRB) of a licensed HCW under investigation for diversion of injectable products. The DDIT interviews the investigator and meets the facility drug diversion program to review drug diversion policies and processes. Based on the suspected method(s) and, if known, the individual\u2019s Hepatitis B/C and HIV status, recommendations are made regarding the need for patient notification and testing.From 2020\u20132022 the DDIT received notification of 49 licensed HCWs under investigation for diversion of injectable products. Patient notification and testing was recommended in seven facilities for CDC Category A infection control breaches; in two cases, later HCW testing negated the need for further action. Among the 34 facilities queried, only five (14.7%) had existing policies for for-cause BBP testing. Other recommendations to improve diversion programs include infection prevention participation and releasing \u201cnot eligible for rehire\u201d status to other facilities.The TDH DDIT facilitates communication with HRB on reported cases of injectable drug diversion. Joint investigations with facilities raise awareness of the risk of BBP transmission and improve facility diversion programs. Tennessee facilities are adding for-cause BBP testing to their investigation procedures. The TDH DDIT model receives mostly positive responses from facility and health system drug diversion teams and may be considered by other public health jurisdictions.All Authors: No reported disclosures"}
+{"text": "Breast cancer is the most common cancer worldwide, and advanced breast cancer with metastases is incurable mainly with currently available therapies. Therefore, it is essential to understand molecular characteristics during the progression of breast carcinogenesis. Here, we report a dataset of whole genomes from the human mammary epithelial cell system derived from a reduction mammoplasty specimen. This system comprises pre-stasis 184D cells, considered normal, and seven cell lines along cancer progression series that are immortalized or additionally acquired anchorage-independent growth. Our analysis of the whole-genome sequencing (WGS) data indicates that those seven cancer progression series cells have somatic mutations whose number ranges from 8,393 to 39,564  compared to 184D cells. These WGS data and our mutation analysis will provide helpful information to identify driver mutations and elucidate molecular mechanisms for breast carcinogenesis. They were clonally selected to yield seven HMEC lines ([Breast cancer is the most common cancer diagnosed among women in the United States (excluding skin cancers). It is the second leading cause of cancer death among women after lung cancer . It is cigenesis   to isolate gDNA from HMEC cultures. The quantity of the extracted gDNA was analyzed with an ND-1000 spectrophotometer . For WGS library construction, we used the TruSeq DNA library Prep Kit  according to the manufacturer\u2019s instructions. For WGS, paired-end sequencing was performed on the Illumina HiSeq X Ten sequencing instrument, yielding ~150-bp short sequencing reads.Raw sequence reads were aligned to the human reference genome 19 using Burrows Wheelers Aligner , and duphttps://kobic.re.kr/kona) and Sequence Read Archive  public database with the accession number PRJKA220370 and PRJNA913438.The whole-genome data are available in the Korean Nucleotide Archive . Then, we performed the driver mutation analysis using the IntOGen cancer mutation browser  and obseIn this study, we generated WGS data and analyzed mutation profiles in the HMEC cancer progression series because genetic mutations are one of the most significant factors in determining breast cancer progression and therapeutic management . We hope"}
+{"text": "Rhinella marina) that is particularly successful in human-altered landscapes. There have been numerous investigations of the cane toad diet, but most of these studies identified prey items at lower taxonomic resolutions . We used higher resolution for prey identification and multiple dietary measures of prey consumption to assess the ecological role of cane toads in the urban landscape of southwest Florida. Prey taxa commonly considered urban pests dominated the diet of cane toads inhabiting golf course communities, and there were differences in prey consumed during the wet and dry seasons of this region. We provided a better understanding of the potential relationships between cane toads and their prey in the urban environment.Urban ecosystems provide habitat to many species, including invasive species such as the cane toad (Rhinella marina) inhabiting urbanized areas in southwest Florida to provide high taxonomic resolution of prey items, contrast toad diets between sampling seasons and sexes, and assess this invasive species\u2019 ecological role in the urban landscape. A pest control agency collected cane toads from two golf course communities in Naples, Florida, USA during November\u2013December 2018 (early dry season) and June\u2013July 2019 (early wet season), and faunal stomach contents were quantified from a random subsample of 240 adult toads . Yellow-banded millipedes (Anadenobolus monilicornis), big-headed ants (Pheidole spp.), and hunting billbugs (Sphenophorus venatus vestitus) were the most frequently consumed prey items and had the highest total numbers and/or volume with corresponding highest indices of relative importance. There was considerable overlap in the seasonal prey importance values for each golf course community and little if any difference in the importance values between toad sexes in each community. Nonetheless, big-headed ants were the most important prey in both communities during the wet season, while yellow-banded millipedes were the most important dry season prey in one community and hunting billbugs the most important in the other. Despite limited spatiotemporal sampling effort, our results indicated that cane toad was consuming arthropod taxa considered pests in the urban ecosystem. Further studies are needed to investigate the potential effects of human activities and environmental variability on the cane toad diet and to determine whether cane toads act as a biological control for pest populations.We investigated the diet of cane toads ( Rhinella marina) is one such invasive species that has demonstrated an affinity to human habitation [Urban areas are often seen as ecologically inferior to their natural area counterparts; however, in the age of rapid urbanization, these developed areas have nonetheless become complex ecosystems inhabited by many species with their own adaptations to the novel urban conditions ,2. An adbitation ,10,11,12The cane toad is a large, toxic amphibian with a native range from southern Texas, USA and western Mexico, through Central America, and into central Brazil . This NeKnowledge of a species\u2019 diet is crucial to understanding its interactions with other species and, in some cases, function in the urban ecosystems it may inhabit ,25. DextAnaxyrus terrestris). Rossi [There have been three diet studies for cane toads in Florida, all of which were conducted in urban ecosystems. Krakauer  characte). Rossi  focused The purpose of our study was to examine the dietary composition of cane toads inhabiting residential golf course communities in southwest Florida. The objectives were to provide fine-scale taxonomic resolution of prey items, contrast cane toad diets between sampling seasons and sexes, and assess this invasive species\u2019 ecological role in the urban landscape.Our study was located in Naples, Collier County on the southwest coast of Florida, USA . Herein,A licensed pest control agency was contracted by the golf course communities to remove cane toads from their respective properties. Toads were collected by hand between 22:00 and 01:00 during November\u2013December 2018 (early dry season) and June\u2013July 2019 (early wet season). Captured toads were kept in ventilated buckets and later euthanized via cooling then freezing . We selet-test.For toad sexes, differences in SUL between seasonal collections in the golf course communities were analyzed with Welch\u2019s ANOVA and Games\u2013Howell post hoc tests using the Real Statistics Data Analysis Tools add-in  for MicrPercent frequency of occurrence (%F), number (%N), and volume (%V) of cane toad prey taxa were determined byi with equationA percent index of relative importance  was calCompound indices such as IRI reduce potential bias associated with the component diet measures ,53. ExamMultivariate analyses were performed on cane toad dietary compositions using PRIMER v6 software . AmbiguoR is an absolute measure of the separation between two or more groups, typically ranging between 0 (no separation of groups) and 1  was used to contrast diet composition between sampling seasons, allowing for differences between toad sexes, and between sexes allowing for differences between seasons. The ANOSIM statistic aration; ). Unlikeificant; ). Two-wap = 0.002) among seasonal sampling events with smaller females collected during the early dry season in golf course Community A , big-headed ants (Pheidole spp.), and hunting billbugs (Sphenophorus venatus vestitus) were the most frequently consumed prey items and had the highest total numbers and/or volume with corresponding highest indices of relative importance (combined IRI of 74%) for all taxonomic categories.A total of 13,961 prey items in 180 taxonomic categories  was identified from the stomachs of 239 cane toads . One of Labidura riparia) were also frequently consumed (62% F) during this season, but their lower contributions to prey volume and number resulted in lower relative importance (16% IRI). In contrast, yellow-banded millipedes were the dominant dry season prey  in golf course Community B with much lower contributions to the diet measures by hunting billbugs and a corresponding low relative importance (7% IRI). Big-headed ants were the most important early wet season prey in both golf course communities (49% IRI), owing to the high frequency of occurrence and the highest contributions to number of prey items but with relatively low-volume contributions. Yellow-banded millipedes in both communities and lepidopterans, primarily caterpillars, in Community B were also frequently consumed during the wet season and both taxa had the highest prey volume contributions but much lower numbers and corresponding relative importance. Additionally, Cuban May beetles (Phyllophaga bruneri) and scavenger scarab beetles (Hybosorus illigeri) were only consumed during the wet season in both communities.After resolving ambiguous taxonomic categories, there were 109 unique prey taxa , and 14 of these unambiguous taxa had an IRI > 1% for at least one of the seasonal cane toad collections in either of the golf course communities  in prey importance value percentages between sampling seasons. The low R value indicated moderate overlap with some separation in prey compositions. The SIMPER routine identified hunting billbugs as contributing the most to the seasonal diet dissimilarity in Community A with a much greater mean importance value percentage for this prey item in the early dry season (Camponotus floridanus) had higher mean percentages during the early wet season. Other distinctive prey items only consumed in the wet season included uneven billbugs  and Cuban May beetles. The average similarity value for prey taxa consumed in the early dry season (26.4%) was higher than that of the early wet season (18.9%), but these relatively low similarity values also indicate considerable variability in prey consumed by toads during each season.For golf course Community A, there was a significant difference  in prey importance value percentages between toad sexes in golf course Community A; however, the very low R value indicated strongly overlapping importance value compositions with little difference between sexes. Nonetheless, hunting billbugs were identified by the SIMPER routine as contributing the most to the dietary dissimilarity between toad sexes and males exhibited a greater mean Importance value percentage for this prey item  in prey importance value percentages between sampling seasons and the low R value indicated moderate overlap with some differences in prey compositions. The SIMPER routine identified yellow-banded millipedes as contributing the most to the seasonal dissimilarity in Community B and this prey item had a substantially greater mean importance value percentage during the early dry season (Asiomorpha coarctata), and shore earwigs also had higher importance value percentages during the early dry season but contributed less to the seasonal dissimilarity. Big-headed ants and lepidopterans had higher mean importance value percentages during the early wet season. Other prey items with distinctive wet season differences included Cuban May beetles, scavenger scarab beetles, darkling beetles (Platydema), and rover ants (Brachymyrmex). Average similarities were higher in the early dry season (23.5%) compared to the early wet season (11.5%), but dietary variability was indicated by the relatively low values.For golf course Community B, there was a significant difference  in prey importance value percentages between toad sexes in golf course Community B. The negligible R value indicated dietary compositions were barely separable with little if any differences in prey importance values between sexes. Furthermore, the borderline statistical significance should be interpreted cautiously owing to the relatively high number of replicates/permutations and their influence on significance levels. The SIMPER routine indicated some minor dietary differences by sex . Ideally, dietary investigations should employ at least one metric measuring amount (frequency and number), and one measuring the bulk of food items present in each sample [In addition to prey resolution, the choice of diet metrics may have influenced previous interpretations of cane toad diet. Most studies reported one or two diet metrics for prey taxa, such as frequency and/or number, and only a few measured the bulk (volume or mass) of food items . Only Pah sample . Reportih sample . As demoDespite individual variability and overlapping dietary compositions, cane toads exhibited significant seasonal differences in prey consumption in southwest Florida. Big-headed ants were the most important prey in both golf course communities during the early wet season and contributed the most to the differences for this season in both communities. Florida carpenter ants were also important wet-season prey in Community A. For regions with seasonal patterns of precipitation, cane toads ingested higher numbers of ants during the wet season in a coastal village of the Philippines  and withPrey compositions during the early dry season differed significantly from those in the early wet season for both golf course communities, but the importance of dry-season prey types also differed between communities. Hunting billbugs were the most important dry-season prey in Community A, while yellow-banded millipedes were more important in Community B, and both prey items contributed the most to the seasonal differences in the respective communities. The golf course communities in our study were relatively proximal to one another  so location does not appear to be a factor; however, different human activities may be affecting arthropod ecology, or our perception as such, within each community . HuntingYellow-banded millipedes, hunting billbug weevils, and bigheaded ants were the most important prey items for cane toads collected from golf course communities in southwest Florida. These arthropods are considered urban pests, but further studies are needed to determine whether cane toads provide any beneficial service with respect to the consumption of these nuisance taxa in the urban ecosystem. Our higher resolution for prey identification provided a better understanding of potential predator\u2013prey relationships and their inferred use of habitats in the anthropogenically altered landscape. Furthermore, using multiple dietary metrics revealed size bias with the prey , and applying compound indices provided a balance for interpretations of prey importance. There were significant seasonal differences in prey importance for cane toads, possibly related to the behavior of toads and the ants consumed during the wet season, and a locational difference in dry season prey importance that could have resulted from pest management practices in the golf course communities or unintentional bias during toad collections. We recognize the limited spatiotemporal scope of sampling effort in the current study and suggest a more rigorous, multiannual sampling design to address the potential effects of human activities and environmental variability on cane toad diet in urban ecosystems."}
+{"text": "Wound healing is a complex and coordinated biological process easily influenced by various internal and external factors. Hydrogels have immense practical importance in wound nursing because of their environmental moisturising, pain-relieving, and cooling effects. As photo-crosslinkable biomaterials, gelatine methacryloyl (GelMA) hydrogels exhibit substantial potential for tissue repair and reconstruction because of their tunable and beneficial properties. GelMA hydrogels have been extensively investigated as scaffolds for cell growth and drug release in various biomedical applications. They also hold great significance in wound healing because of their similarity to the components of the extracellular matrix of the skin and their favourable physicochemical properties. These hydrogels can promote wound healing and tissue remodelling by reducing inflammation, facilitating vascularisation, and supporting cell growth. In this study, we reviewed the applications of GelMA hydrogels in wound healing, including skin tissue engineering, wound dressing, and transdermal drug delivery. We aim to inspire further exploration of their potential for wound healing. The skin is a multifunctional barrier organ that protects internal organs from potential environmental hazards . The proGelMA is a synthesised biomacromolecule with excellent biocompatibility and formability; it was first reported to be synthesised by Bulcke et al., in 2000 . Since tin situ photo-crosslinking properties make GelMA hydrogels particularly suitable for application in irregular wounds  and hydroxyl (\u2013OH) groups on the side chains of gelatine are substituted by the methylacryloyl group . GelMA-dHAMMA hydrogels were found to promote fibroblast proliferation and \u03b1-smooth muscle actin expression. GelMA-dHAMMA has also been shown to promote wound collagen deposition and angiogenesis and accelerate tissue healing in rabbit full-thickness skin tissue defects  are competitive candidates because of their excellent biological characteristics .in vivo vascularisation. In a previous study, epidermal stem cell\u2013derived EVs loaded with VH298 were encapsulated in GelMA hydrogels to enhance the angiogenic ability of diabetic wounds. GelMA hydrogels were shown to be convenient and adaptable delivery carriers for the sustained release of VH298-EVs, effectively promoting wound healing by locally improving blood supply and angiogenesis by increasing the HIF-1a level  delivery (Microneedles are one of the transdermal drug delivery techniques that usually release loaded drugs directly into the deep layer of the skin through tiny holes formed by puncture . Hydrogedelivery . The micIn conclusion, GelMA hydrogels have been widely used in many applications, ranging from wound dressings to 3D printing skin tissue engineering. They provide an ideal multistratified anisotropic scaffold for the growth of various cells such as fibroblasts, endothelial cells, and keratinocytes. They can also be used to prepare personalised multifunctional dressings by combining small molecules, metal nanoparticles, and cellular EVs via physical binding or chemical reactions. Therefore, the application prospects of GelMA hydrogels for wound healing are significant. However, the biosafety of GelMA-based hydrogels remains a major obstacle to their clinical applications. The release of unreacted methacryloyl monomers after photo-crosslinking is a potential risk. Furthermore, photo-crosslinking under UV radiation may damage cellular DNA . Additio"}
+{"text": "Impairments in cognitive and executive function of presumed cerebral microvascular origin are important and recently recognized neuropathological manifestations of vascular contributions to cognitive impairment and dementia (VCID) , 2. It hStudying WM continues to pose unique methodological and diagnostic challenges for aging research. WM is highly enriched in auto-fluorescent pigments that make rigorous immunohistochemical (IHC) approaches for mechanistic and diagnostic studies extremely challenging. Although astrocytes may degenerate in overt WM infarcts, the vulnerable glial subtypes in diffuse microvascular WM lesions remain essentially unknown. Admittedly, glial lineages are complex and relatively few specific markers are available. Furthermore, the expression of glial markers can change dramatically in regions of WM injury leading to nonspecific false positive staining . In addiTo provide rigorous access to human WM lesions, we recently developed a unique rapid autopsy brain procurement protocol using specimens donated by participants in the Adult Changes in Thought (ACT) study, a prospective, population-based study of aging and incident dementia among men and women in Seattle, Washington . This prA unique opportunity afforded by this rapid autopsy brain procurement protocol is access to fresh tissue samples for direct analysis of human penetrating microvessels. We have developed novel protocols to preserve these vessels for a wide range of physiological and molecular studies performed within 24 hours after procurement. Although cerebral microvascular disease is a common manifestation of aging, prior human and murine vascular and morphological studies were limited mostly to the middle cerebral artery and pial microvessels, and findings were extrapolated to WM penetrating microvessels. Moreover, despite growing interest in WM injury and MRI-defined WM hyperintensities in VCID and AD, vascular studies mostly lacked histopathological, neuroimaging or mechanistic correlation.We established the feasibility to study human penetrating WM arterioles in initial studies of aged human microvascular lesions with low ADNC . We founThe molecular mechanisms that mediate enhanced dysfunction of WM parenchymal arterioles when vascular dysfunction and ADNC coincide remain elusive. Analysis of human WM lesions and WM parenchymal arterioles , 7, as wTaken together WM injury and WM hyperintensities of presumed microvascular origin are of growing interest to aging and VCID researchers. A growing body of evidence supports that microvascular brain injury is accompanied by oxidative stress, astrogliosis, changes in the extracellular matrix , and quantitative MRI-defined abnormalities in prefrontal WM that involve disrupted integrity of axons and myelin. Mechanistic studies are needed to further define contributions of microvascular dysfunction to WM injury, particularly as it relates to the identities of the cell types and molecular signatures that could be harnessed to diagnostically discriminate among VCID, AD or mixed vascular/ADNC."}
+{"text": "Cancer is the second most common fatal disease leading to death worldwide. Metastatic growth in distant organs is the main reason for increased cancer mortality . Cancer in vivo mouse models targeting cancer stem cells and their signaling pathways  which are effective in treating pancreatic cancer. The article focuses on the mode of action of bioactive plant metabolites from TCM against various signaling pathways such as Wnt and Notch, which regulate cancer stem cells in pancreatic cancer. Zhang et al. explain the inhibition of cancer stem cell signaling pathways involved in epithelial to mesenchymal transition, migration, metastasis and apoptosis of pancreatic cancer cells by the plant metabolites.The exploration of plant derived drugs as potential therapeutic interventions against cancer stem cells and metastasis is an exciting area of research that complement existing cancer therapies and improve patient outcomes. Koklesova et al. describes how nanoparticles specifically designed to target cancer stem cells in tumor, serve as carriers for targeted delivery of plant-based drugs. Several Nano-drugs developed to target and treat the different types of cancer and their subsequent CSCs are discussed. Plant metabolite-based nanoparticles are modified to specifically target cancer stem cells, which helps in reducing the risk of tumor recurrence and the manifestation of metastases. Zhao et al. describe the anti-metastatic effect of thymoquinone in pancreatic cancer and its sensitivity to gemcitabine by regulating collagen. In pancreatic cancer cells, thymoquinone promotes apoptosis, inhibits tumor cell migration, invasion and metastasis, and sensitizes pancreatic cancer cells to gemcitabine. Furthermore, the study shows that thymoquinone stimulates cellular matrix production via TGF\u03b2/Smad pathways.Targeted therapies for the heterogeneous population of cancer tumors and multidrug resistance associated with cancer stem cells are still not effectively established. The review article by Mazurakova et al.). In the systemic review article, Mazurakova et al. detail the effect of flavonoids on breast cancer stem cells to combat therapy resistance and cancer proliferation. The accumulation of breast cancer stem cells (BCSCs) after chemotherapy, prevents further effective treatment of breast cancer patients. Therefore, it is also postulated that eradication of BCSCs in combination with standard cytotoxic drugs and flavonoids specifically targeting CSCs in breast cancer tumor is essential for successful treatment.Studies show that flavonoids have an anticancer effect against various types of cancer. Flavonoids can induce apoptosis and autophagic cell death of breast cancer cells, inhibit cancer proliferation and overcome drug resistance of cancer tumors (This Research Topic provides new data and detailed reviews on plant-derived compounds that target cancer stem cells and inhibit metastasis through various mechanisms of action by modulating self-renewal pathways, suppressing EMT, affecting the tumor microenvironment and disrupting signaling pathways essential for cancer cell migration, invasion and survival. Thus, plant metabolites are promising for developing innovative therapeutic strategies against cancer stem cells and metastasis. Prospective research is inevitable to successfully translate research findings into clinical trials by addressing challenges such as safety, bioavailability, formulation and standardization of herbal medicines. These findings and reviews demonstrate how phytomedicines targeting cancer stem cells significantly reduce metastasis and subsequent mortality. These prospective and innovative findings, if clinically established, are promising and can pave the way to new vistas for cancer therapy."}
+{"text": "Advances and Challenges of Non-Invasive Brain Stimulation in Age-Related Neurodegenerative Diseases\u201d, highlighting the significance of aging as a risk factor for neurodegenerative diseases, the limited effectiveness of current treatments and the potential of non-invasive brain stimulation.This editorial summarizes the contributions of the Frontiers Research Topic \u201cAging is a major risk factor for neurodegenerative diseases. Neuronal losses during aging can lead to cognitive decline, particularly when combined with accumulation of toxic proteins. Treatment options for these conditions are limited. Noninvasive brain stimulation (NiBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial current stimulation (TCS), can modulate brain networks and enhance cognitive functions in both healthy individuals and neurodegenerative patients. The effects of NiBS can persist even after the stimulation ends. However, a comprehensive understanding of its biological mechanisms and clinical applications is still lacking, which poses challenges. This topic aims to explore NiBS as an innovative therapeutic tool, specifically discussing its advances and challenges in treating age-related neurodegeneration.He et al. promoted that spinal cord stimulation (SCS) is a promising treatment for disorders of consciousness (DoC). This study analyzed 66 DoC patients who received SCS treatment to investigate the association between postoperative cerebrospinal fluid (CSF) protein levels and consciousness improvement. Patients with permanent electrodes had higher CSF protein levels than those with temporary percutaneous electrodes. Moreover, elevated CSF protein levels were linked to reduced sagittal diameter and poor outcomes at 3 months. The findings propose that reducing the influence of electrode pads on anatomical changes may improve treatment outcomes. CSF protein levels could serve as potential biomarkers of postoperative outcomes and deserve further exploration.A study conducted by Ni et al.) evaluated the effects of various repetitive TMS (rTMS) stimulation procedures on upper limb function and brain functional network characteristics in stroke patients. The study involved 36 stroke patients who were assigned to either receive 1 Hz stimulation in the contralesional hemisphere and 10 Hz stimulation in the affected hemisphere, or solely 10 Hz stimulation in the affected hemisphere. The results demonstrated that rTMS treatment improved upper limb motor function, enhanced brain network connections, and reduced activation of isolated brain areas. Depending on the specific brain network states, optimal rTMS treatment plans could be suggested for precise rehabilitation.Another study  explores the effects of continuous theta burst stimulation (cTBS) on enhancing language abilities in patients with aphasia. The researchers focused on targeting the right posterior superior temporal gyrus (pSTG), a region acknowledged for its critical role in semantic processing. This article presents findings from a randomized controlled trial involving 34 aphasic patients who underwent either cTBS or sham stimulation, followed by speech and language therapy. The study aimed to uncover whether cTBS applied to the right pSTG could promote language recovery and elucidate the underlying brain mechanisms. The results showed promising effects of cTBS, manifesting as improved language performance and modulation of brain activity and connectivity in specific regions. Overall, this research offers valuable insights into potential therapeutic interventions for language rehabilitation in individuals with aphasia.Another study  investigates the effects of brain stimulation on two different age groups: middle-aged adults (40\u201360 years) and older adults (65 years and above). The researchers aimed to understand how tDCS impacts behavior and brain function differently in these two groups. Additionally, behavioral assessments and neurophysiological measurements were performed. This research provides valuable insights into age-specific brain stimulation effects and its potential applications for cognitive enhancement.One article  explores the potential therapeutic effects of two brain stimulation techniques, median nerve stimulation (MNS) and rTMS, on patients with prolonged disorders of consciousness (pDOC). In a rigorously conducted trial, 75 eligible patients with pDOC were randomly assigned to one of three groups: (1) rTMS + sham-MNS; (2) MNS + sham-rTMS; or (3) MNS + rTMS. The primary outcome was the change in the Coma Recovery Scale-Revised (CRS-R) score after treatment. Findings showed that the combined MNS + rTMS intervention yielded significantly greater improvements in Glasgow Coma Scale (GCS) scores and somatosensory evoked potentials, compared to the other two groups. This research offers valuable insights into the potential benefits of combining brain stimulation modalities to enhance consciousness recovery in patients with pDOC.Another article  and elderly adults (65\u201380 years). They aimed to measure the impact of stimulation on motor skills and cortex responsiveness. The study revealed significant age-related differences, indicating that ccPAS enhances action performance and corticomotor excitability more effectively in young adults compared to elderly adults. These findings offer valuable insights into the age-specific effects of brain stimulation and its potential applications for cognitive enhancement. By delving into this research, the researcher can gain deeper understanding of how brain stimulation techniques may differ in their outcomes based on age, contributing to advancements in neurostimulation and its implications for age-related cognitive functions.In a study conducted by Naparstek et al.) presents a comprehensive review of the potential uses of transcutaneous vagus nerve stimulation (tVNS), a non-invasive neuromodulation technique, in the context of cognitive aging. The authors have compiled a thorough review and provided valuable commentary on the existing literature, shedding light on the effectiveness of tVNS in enhancing various cognitive functions in older adults. Through this review, researchers can uncover the promising applications of tVNS for memory, attention, and executive functions in the aging population. This review not only synthesizes the current knowledge on tVNS but also suggests pathways for future research, offering new insights into innovative therapeutic approaches for addressing age-related cognitive decline.Another study (YG: Writing\u2014original draft. WW: Writing\u2014review and editing. JZ: Writing\u2014review and editing."}
+{"text": "This cross-sectional study compares clinician and artificial intelligence (AI) chatbot responses to patient vignettes used to identify bias in medical decisions. This study aimed to evaluate AI chatbot responses to clinical questions previously tested in large samples of clinicians to examine established biases in medicine related to gender, race and ethnicity, and socioeconomic status (SES) through published vignettes.Artificial intelligence (AI) chatbots transformed how we access information provided by large language models. However, AI models may carry inherent bias, often mirroring the systematic inequalities present in our society.STROBE) reporting guideline. This study was deemed exempt from the institutional review board at Stanford University. Informed consent was waived because the study did not involve human participants. We selected 19 clinical vignettes in cardiology, emergency medicine, rheumatology, and dermatology. A full list of references can be found in the eReferences in This cross-sectional study followed the Strengthening the Reporting of Observational Studies in Epidemiology (The 4In this cross-sectional study, we observed that AI chatbots provided different recommendations based on a patient\u2019s gender, race and ethnicity, and SES in certain clinical scenarios. We found both overlapping and unique differences in responses among the AI chatbots and between the AI chatbots and physicians. The presence of bias among clinicians and clinical risk algorithms has historically caused disparities in clinical care and led to poorer health outcomes for some marginalized populations. While AI chatbots have shown proficiency in various medical tasks, including passing the United States Medical Licensing Examination, interpreting laboratory tests, and answering patient questions, neither chatbot is approved for medical applications.5 Differences in AI chatbot recommendations have not been fully explored, and their impact is unclear. These differences may be shown to propagate or counter biases that clinicians have, the impact of AI-based tools on health disparities may vary in different clinical situations. However, these tools are being adopted by patients and clinicians, making further research especially urgent.Limitations include a small number of vignettes tested and different assessment scales used per vignette following the original studies\u2019 approaches. Although AI chatbots are promising tools in medicine, our findings underscore the need for careful application of early adoption. Prior studies have suggested that using AI in medicine could contribute to treatment inequities in marginalized racial and ethnic groups."}
+{"text": "Endoscopic ultrasound (EUS) has entered its golden age. The benefits of providing refined diagnosis and advanced therapeutic procedures by EUS are numerous and widely appreciated by clinicians worldwide \u20133.Just 20 years ago, EUS diagnosis was based mainly on radial mechanical echoendoscopes with no electronic image enhancement functions . On the Since then, EUS has gone through years of exciting and unrelenting scientific and technologic advancements. The biggest improvements were introduced by image enhancement techniques with ultrasound contrast agents and elastography allowing better detection and characterization of the lesions of interest.Frontiers in Medicine about advancements in the EUS diagnosis of pancreatobiliary diseases, image enhanced EUS for the diagnosis of gallbladder lesions is presented. Differential diagnosis between benign and malignant gallbladder tumors can be challenging in order to select the candidates for surgery. Contrast-enhanced harmonic EUS (CH-EUS) has been previously reported to be useful for the diagnosis of gallbladder tumors  and accuracy (90%) . Data inThe usefulness of liquid-based cytology to increase the diagnostic yield of EUS-guided tissue acquisition is also discussed. Several techniques have been used in this regard, including fine needle biopsy with histology needles, rapid onsite cytopathology evaluation, and guidance by CH-EUS. A recent meta-analysis showed a pooled diagnostic sensitivity of 85% with CH-EUS-fine needle aspiration and 75% with standard EUS- fine needle aspiration . HoweverEUS is also a great tool for pancreatic cancer screening in conjunction with magnetic resonance imaging . InteresFinally yet importantly, bibliometric analysis of EUS publications is presented. Compared to previous EUS literature scans , an updaPF wrote the editorial. MT and YY reviewed the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version."}
+{"text": "They validated their initial findings by targeted metabolomic analyses in two different cohorts with similarly increased cardiovascular risk, from the United States (n\u2009=\u20092149) and Europe (n\u2009=\u2009833) undergoing cardiac evaluation. This follow-up analysis strengthened their original findings by revealing that the association of erythritol not only remained significant but was independent of age, sex, and other established risk factors. This suggests the additional operation of other than metabolic mechanisms. Indeed both in vitro and in vivo studies in human whole blood and mice revealed an erythritol-elicited increase in platelet adhesion and clot formation (Fig. 1 Their subsequent pilot study showed that a single dose of 30\u2009g erythritol results in prolonged excessive plasma erythritol elevation for over 48\u2009h. The recorded concentrations remained well above the threshold, which increased platelet reactivity and thrombocyte reactivity in vitro,1 suggesting a prolonged thrombotic risk arising from exogenous erythritol.Abnormal vascular function and coagulation represent other central drivers of cardiovascular disease onset and development.3 At present, controlled trials did not detect detrimental effects of erythritol ingestion in healthy humans,5 but specific trials on vascular function and coagulation in healthy and diseased humans are lacking.While these studies support a novel conceptual framework of erythritol-induced promotion of thrombus formation leading to excess cardiovascular risk, several limitations need to be addressed. There is not only a lack of standardization of erythritol measurements but also of the preanalytical conditions. The observed prolonged elevation of erythritol upon dietary intake raises the question of whether simple overnight fasting conditions suffice for the interpretation of baseline concentrations; moreover, the kinetics of erythritol elimination might substantially differ between healthy and metabolically compromised people. Importantly, their in vitro procedures raised the platelet concentrations creating artificial experimental conditions. Also, the mice experiments showing enhanced clot formation upon erythritol injection do not necessarily mirror thrombosis risk in humans. Thus, a direct analysis of platelet activation in humans upon erythritol might better reflect real-life conditions. Further questions arise: to what extent do different conditions affect the relative contributions of exogenous versus endogenous sources to the total circulating erythritol concentration, particularly could people with increased cardiovascular risk produce more erythritol? One might speculate that altered hepatic metabolism in humans with type 2 diabetes, who are at higher risk of fatty liver disease, might at least contribute to the described effects. Of note, epidemiological and cohort studies cannot exclude reverse causality because people with an unfavorable metabolic profile are more prone to consume sugar-free meals to avoid weight gain or hyperglycemia, even before cardiovascular disease diagnosis.Taken together, Witkowski and colleagues shed light on one of the widely-used non-nutritive sweeteners and provide novel evidence for the potentially deleterious effects of erythritol on platelet function. At the same time, these findings raise new questions calling for sufficiently powered double-blind, randomized controlled trials addressing the safety as well as mechanistic studies examining the Janus-head-like features of erythritol. Importantly, the evidence derived from the current study should already suffice for the authorities to re-evaluate their policy statements regarding the cardiovascular and metabolic risks of artificial sweeteners."}
+{"text": "Advanced Materials (2023) 10.1002/adma.202306834Owing to the absence of appropriate helical templates, circularly polarized organic ultralong room temperature phosphorescence with a high dissymmetry factor remains a formidable challenge in contemporary research. A team of Qiang Zhao and Yanqing Lu proposes an effective tactic to enable the high dissymmetry factor by employing a circularly polarized phosphorescent system composed of meticulously designed phosphorescent polymers and self-assembled chiral helical superstructures. Specifically, multiple interactions among polymer chains can strictly restrict molecular motions of phosphorescent molecules, thereby inhibiting the non-radiative relaxation pathways and resulting in the emission decay time of 735 ms. The self-organized periodic helical superstructures serve as an ideal medium for enhancing chirality, giving rise to the attained dissymmetry factor of 1.49 and surpassing previous records by two orders of magnitude. The creatively explored system displays remarkable photo-thermal stability and demonstrates the potential applications of photoprogramming photonics. These findings would create a brilliant outlook of the optical multiplexing-based information encryption, and establish the intimate connection between circularly polarized phosphorescent materials and the evolving field of optical information technologies toward the cutting-edge photonic applications and beyond."}
+{"text": "Popular press coverage of the Medicare Part D coverage gap is based largely on research conducted using retrospective analyses of administrative claims data. These datasets are incomplete because they lack information about methods of obtaining medication that are commonly used by seniors, including free samples, generic drug discount programs, over-the-counter substitution, and patient assistance programs. As a result, evidence about the effects of 100% cost sharing on seniors is limited and suboptimal. Although the current deficit of information about the coverage gap is not entirely unexpected because the Medicare Part D program is relatively new, reliance on claims-based analyses to inform questions that claims data cannot possibly address accurately has tended to mislead and politicize rather than produce constructive policy guidance. Numerous important health policy questions remain unaddressed. These questions are becoming especially important as optimal approaches to providing health care to seniors are the subject of an increasingly vigorous debate."}
+{"text": "Parents frequently purchase and inquire about smartwatch devices to monitor child behaviors and functioning. This pilot study examined the feasibility and accuracy of using smartwatch monitoring for the prediction of disruptive behaviors.N\u2009=\u200910) aged 7\u201310 years hospitalized for the treatment of disruptive behaviors. The study team completed continuous behavioral phenotyping during study participation. The machine learning protocol examined severe behavioral outbursts  for preparing the training data. Supervised machine learning methods were trained with cross-validation to predict three behavior states\u2014calm, playful, and disruptive.The study enrolled children (The participants had a 90% adherence rate for per protocol smartwatch use. Decision trees derived conditional dependencies of heart rate, sleep, and motor activity to predict behavior. A cross-validation demonstrated 80.89% accuracy of predicting the child's behavior state using these conditional dependencies.This study demonstrated the feasibility of 7-day continuous smartwatch monitoring for children with severe disruptive behaviors. A machine learning approach characterized predictive biomarkers of impending disruptive behaviors. Future validation studies will examine smartwatch physiological biomarkers to enhance behavioral interventions, increase parental engagement in treatment, and demonstrate target engagement in clinical trials of pharmacological agents for young children. Evidence-based interventions such as parent\u2013child interaction therapy (PCIT) reduce behavioral and emotional symptoms in children by improving parent\u2013child relationships through the implementation of specific rules taught over a multiweek period  the effectiveness of PCIT is contingent upon parents making a concerted effort to remember the rules imparted by a provider in engaging with their children and (2) families from rural areas and under-represented populations are less likely to have access to and utilize evidence-based therapies when it is available , there is an opportunity to improve access and effectiveness of behavioral interventions in children and adolescents, including PCIT. Smartwatches measure individual functioning in real time and provide opportunities to identify point-of-care smartwatch biomarkers in young children that can provide prompts for parents of child's impending behavioral outbursts. Accessible digital tools may have the promise of increasing parental engagement for improved outcomes.The growth in children's smartwatch market  is largely driven by parental interest to track their child's functioning  aged 7\u201310 years were enrolled in this IRB-approved study conducted during May 2020 through December 2020. Registered nurses (RNs) of the Mayo Clinic Child and Adolescent Psychiatry inpatient unit continuously assessed and annotated behavior for 24 hours daily during hospitalization , heart rate (beats per minute), and sleep (including duration and sequence of sleep stages) data through the Garmin Connect mobile application. The smartwatch minute-level data were aggregated and collected through Fitabase. Each participant and family had an abbreviated PCIT training intervention during hospitalization.Calm  indicated that the child was sedentary while performing routine activities such as reading, lying down, watching movie, talking/interacting with others, or doing their daily homework. Playful  indicated that the child was engaged in a nondisruptive activity of elevated heart rate such as exercising , playing a sport , or playing with other children .Inpatient RNs annotated behavior states as either calm, playful, or disruptive using the behavior code described in Disruptive (behavior codes 9\u201311) indicated that the child showed uncontrolled aggression/behavior  warranting intensive behavioral interventions, time-outs, or restraint for safety. For each of the calm, playful, and disruptive phenotypic annotations on a given day, the corresponding average heart rate in the preceding 60 minutes and the durations of sleep stages from the previous night were captured with the smartwatches (see ches see .Decision trees were trained to use heart rate (60-minute average) and sleep data to predict calm, playful, or impending disruptive behaviors  across the three behavior phenotypes. The Garmin vivosmart4 smartwatch provides three levels of intensity of motor activity . Notably, when participants were characterized as calm, there was no difference (p\u2009>\u20090.8) between the mean heart rate during the 60-minute calm period and the overall resting heart rate . However, the durations of REM, light, and deep sleep stages were different between participants who exhibited disruptive behavior versus those who did not  if the duration of light sleep exceeded 4 hours, and there were no significant associations with the total sleep duration or duration of awake, deep, and REM sleep.The Garmin vivosmart4 watch provides the duration and sequence of sleep stages   with an accuracy of 80.89%.Prior research has demonstrated parental acceptance -approved features  are becoming ubiquitous across all ages for wellness monitoring and improved health-related outcomes. Cardiology practice has adopted the use of smartwatch devices for monitoring and assessment of remote cardiac monitoring  are underway to establish benchmarks and the utility of wearable devices for monitoring, decision support, augmented interventions, and predictive models. Valid and accessible digital biomarkers will have great utility for future pharmacological trials for young children.This study has limitations. First, an inpatient monitoring study did not present specific behavioral triggers in outpatient settings . Biomarker thresholds and accuracies of predicted behavior states may vary between patients based on parents' perception of what constitutes disruptive behavior versus nearly homogeneous annotations of disruptive behavior marked by trained nurses. Second, only one smartwatch brand was used and additional studies with trackers from other vendors  are needed. Third, the study used data from hours with complete measurements, hence the impact of time gaps in measurements is yet to be understood.Fourth, it is possible that more computationally intensive algorithms may outperform prediction performance of decision trees with larger sample sizes and duration of observation. Fifth, although the study psychiatrists and medical records did not identify any medication-related side effects in the sample, the potential impact of concurrent psychotropic medications on physiological measures (including sleep disturbances) is unknown as it is highly possible that the threshold of biomarkers varies with time and improves behavior states.Therefore, larger studies with longer duration of observation and treatment modalities are needed to further develop and refine time-series algorithms to predict impending disruptive behavior in children. Finally, digital biomarkers derived in this study need validation in an outpatient setting to guide the development of a technology-enhanced version of behavioral interventions such as PCIT.There is a critical societal need to better understand and leverage scalable remote technologies to foster healthy parenting practices within the framework of traditional evidence-based behavioral therapies such as PCIT. This feasibility study demonstrates the capability to introduce precision target-based  technologies using smartwatch-derived biomarkers to improve effectiveness of psychosocial interventions in young children by predicting disruptive behavior in children before manifestation. Such biomarkers when successful could be utilized in delivering precision care to children and families through remote care capabilities\u2014thereby addressing barriers to accessing specialty pediatric behavior clinics."}
+{"text": "Acculturation refers to the process of change that occurs when people of different cultural backgrounds are in enduring first-hand contact  intersect to impact acculturation experiences in educational settings.While some papers focus on specific demographic groups, there is room for more research that considers Longitudinal studies could provide insights into how acculturation attitudes and experiences evolve over time, especially in relation to educational outcomes.Most of the papers employ cross-sectional designs. Comparative studies could provide insights into how cultural and national contexts influence acculturation processes in education.The papers focus on various geographical contexts. how educational policies impact acculturation processes. Future research could explore the role of policies in facilitating or hindering acculturation in schools.While the papers discuss individual and group experiences, there is a gap in the examination of technology in acculturation within educational settings remains underexplored. Research could focus on how digital platforms and online education impact acculturation experiences.In an increasingly digital world, the role of In summary, while the current Research Topic provides valuable insights into the relationship between acculturation and education, it also opens up multiple avenues for further exploration. These new directions could significantly enrich the academic discourse and have practical implications for educators, policymakers, and researchers alike.EM: Conceptualization, Writing\u2014original draft. NL: Writing\u2014review & editing. CW: Writing\u2014review & editing. DB: Writing\u2014review & editing."}
+{"text": "Behavioral  and emotional  problems were showed to be associated with the prenatal environment. Changes in placental DNA methylation was identified as a relevant potential mechanism of such association.We aimed to explore the associations between placental DNA methylation and child behavior in order to explore pathways that could link prenatal exposures to child behavior.Data including 441 children of 3 years of age from the EDEN mother-child cohort. Child behavior assessed using the Strengths and Difficulties Questionnaire (SDQ). Both hypotheses-driven and exploratory analyses (including epigenome-wide association studies (EWAS) and differentially methylated regions (DMR) analyses) were conducted. The analyses were adjusted for confounding and technical factors and estimated placental cell composition. All the p-values were corrected using a false discovery rate (FDR) procedure for multiple tests.cg26703534 (AHRR), was significantly associated with emotional problems (pFDR = 0.03). In the exploratory analyses, cg09126090 (pFDR = 0.04) and cg10305789  were significantly associated with peer-relationship problems and 33 DMRs were significantly associated with at least one of the SDQ subscales. Placental DNA methylation showed more associations with internalizing than externalizing symptoms, especially among girls. DMRs tented to include highly methylated CpGs.In the hypothesis-driven analysis, This study investigated for the first time the associations between placental DNA methylation and internalizing and externalizing symptoms in preschoolers. Further analyses, such as consortium meta-analyses would be necessary to confirm and extend our results.None Declared"}
+{"text": "This could be due to the primary surgical oncologist informed by MD-PALS members being able to better identify key EOL issues surrounding the patient and hence better equipped to conduct a quality GOC discussion during a surgical admission.We established a multidisciplinary palliative surgical intervention (MD-PALS) team comprising healthcare providers of various subspecialties involved in the care of these patients. We then performed a single-centre prospective cohort study recruiting advanced cancer patients who received palliative interventions, comparing the outcomes of those cared for under the newly established MD-PALS team and those who received usual care.6 Future research should delve deeper into investigating and validating the other potential benefits of MD-PALS teams. Robust and rigorous studies will be essential in refining team structures and processes, ensuring the model is optimized to cater to the unique needs of palliative surgical oncology patients.Our study highlights the positive impact of multidisciplinary specialist providers\u2019 involvement in the care of palliative surgical oncology patients, leading to enhanced GOC discussions. MD-PALS teams hold the potential to become the cornerstone of a \u2018Community of Practice\u2019, fostering interdisciplinary collaboration and seamless communication between team members, patients, and their families, ensuring the comprehensive and holistic management of the multifaceted challenges faced by these patients."}
+{"text": "This editorial reports from seven international working groups from the US and Europe as follow-up of the Eight Kraepelin Symposium in Munich, LMU, recruiting former and recently recruited ones. It covers basic research investigating the consequences of genetic and environmental factors on psychosis in the translation in preventing psychosis in children of parents with severe mental illness. Secondary prevention aims to avoid further episodes having foci on translation of new mechanisms targeting family communication, patterns of cannabis use or targeting cognitive biases in metacognitive training. Translation in later phases of psychoses refer to translating the knowledge, its evidence and meta-analysis. Novel foci include psychoeducational groups for close relatives of patients with borderline personality disorder and lifestyle behaviors combined with metabolic disturbances in a transdiagnostic psychiatric sample. Recently, metacognitive training gained importance being an important addition to family therapy and cognitive behavioral therapy. Strategies that proved their effectiveness are to be implemented in standard treatment as well as strategies implemented to train professionals in effective crisis and family management.In the nineteenth century, Emil Krapelin  pioneereThis special supplement related to the Eighth Kraepelin Symposium\u2014Translation in Psychiatry and Psychotherapy\u2014A Life-long Necessity  covers tTranslation from mechanism to mental health practices covers basic research in psychological targets in trauma and its translation in mental health practices . TranslaThe vulnerability\u2013stress-coping model (2\u20133.5) is our conceptual framework guiding psychoeducational and family therapy focusing on the interaction between biological vulnerability, protective personal and environmental factors Garosi et al. and the real world FACE-SZ cohort  investigWright et al.  investigBighelli et al.  investigNovel foci include psychoeducational groups for close relatives of patients with borderline personality (BPD). Pitschel-Walz et al.  evaluateIn summary, the vulnerability-stress-coping model provides valuable targets for treatment stressing psychoeducation, family therapy and cognitive behavioral therapy (CBT) and recently MCT proved their effectiveness in meta-analysis. Psychoeducation, communication, and problem-solving skills are the main tools for relapse prevention. Novel trends refer to pioneering psychoeducational groups in borderline personality disorder, cannabis patterns in first episodes and predictive capability for weight gain during treatment in a transdiagnostic sample.Primary intervention is to focus on psychological targets in trauma in children of parents with PHSMI and there should be visiting and complex community programs, residential treatments and online help. Further research, as well as more training for professionals on effective crisis and family management seems necessary."}
+{"text": "Case reports are vital components of scientific literature, providing essential insights into rare or unique medical conditions, diagnostic dilemmas, and therapeutic challenges . There hClinical case reports correspond to articles with the lowest level of evidence on the hierarchy of various research study types . HoweverMedical literature is often dominated by observational studies involving larger patient cohorts, leaving rare and unusual cases underrepresented. Case reports fill this gap by presenting detailed accounts of such unique situations that can be useful for other clinicians . Within The diverse range of respiratory diseases often presents diagnostic challenges due to overlapping clinical features. Case reports detailing unique diagnostic dilemmas and the strategies used to resolve them offer valuable learning opportunities for healthcare professionals . By sharCase reports can provide early evidence of the effectiveness of novel therapies or management strategies for different conditions . In instPneumocystis jiroveceii pneumonia, which exhibited a positive response to endobronchial Watanabe spigot and blood coagulation factor XIII supplementation . In the same way, others atipical respiratory infection are exposed in this Research Topic. Sun et al. described a chronic respiratory condition due to Fusobacterium nucleatum in pleural effusion associated with squamous cell carcinoma. Similarly, Yuan et al. presented a case with Actinomyces graevenitzii, Zhang et al. illustrated an abnormal Streptococcus pneumoniae thoracic image presentation, Peng et al. showed a hypervirulent Klebsiella pneumonia, and Liu and Gao described an infection with Chlamydia psittaci in severe pneumonia cases. All these cases had a positive clinical resolution after identification of the pathogen by molecular sequencing. Unfortunately, molecular diagnostics by next-generation sequencing is not a procedure accessible at the most respiratory centers in the world. In this context, these published cases are important to propose management of rare infection cases in respiratory field.For example, in this Research Topic, we present unusual cases that can provide valuable insights for clinicians facing similar challenges in their practice. One of the cases reported highlights a refractory pneumothorax secondary to human immunodeficiency virus -associated Zuccatosta et al.). The absence of cartilaginous support involvement allowed for successful bronchoscopic treatment, resulting in complete and permanent resolution of the stenosis . Other rare conditions are described in the biliobronchial fistula after cholecystectomy surgery case , a Kartagener s\u00edndrome with DNAH9 mutation case , an anomalous systemic arterial supply to the left lower lung lobe , an epithelioid hemangioendothelioma in main bronchus , and tracheal lobular capillary hemangioma . These reports offer important clinical knowledge and potential solutions for managing complex respiratory conditions.Another intriguing cases involved abnormalities in the thoracic anatomy. A post-COVID-19 tracheal stenosis with fibrotic bridges, leading to significant respiratory distress (Finally, this type of evidence serve as powerful teaching tools, especially in medical education . They prDespite representing the lowest level of evidence, clinical case reports continue to be among the most significant sources of knowledge in the biomedical field. They offer valuable insights into unusual disease presentations and the benefits of employing unconventional approaches in treatment . MoreoveRT-C: Writing \u2013 original draft, Writing \u2013 review & editing. ST: Writing \u2013 original draft, Writing \u2013 review & editing."}
+{"text": "Pseudomonas aeruginosa PAO1 biofilm cell clusters. These P. aeruginosa cell clusters are in vitro models of the chronic P. aeruginosa infections found in adult cystic fibrosis patients, which display resistance to antibiotic treatments, leading to exacerbated morbidity and mortality. This resistance has been partially attributed to periphery sequestration, where antibiotics are unable to penetrate biofilm cell clusters. The underlying physical phenomena driving this periphery sequestration have not been definitively established. This paper introduces mathematical models to account for two proposed physical phenomena driving periphery sequestration: biofilm matrix attachment and volume-exclusion due to variable biofilm porosity. An antibiotic accumulation model which incorporated these phenomena was able to better fit observed periphery sequestration data compared to previous models.A spatiotemporal model for antibiotic accumulation in bacterial biofilm microcolonies which leverages heterogenous porosity and attachment site profiles replicated the periphery sequestration phenomena reported in prior experimental studies on  To solve the time-dependent governing equations for dynamic concentration profiles, the method-of-lines technique was incorporated into the same solver system. Additionally, a variable liquid-interface concentration boundary replaced the constant concentration BC for this dynamic solver due to the observed dynamic BC in the literature data. Relative antibiotic concentrations were inferred from Tseng et al using WebPlotDigitizer (To solve the steady-state form of governing equations used in this paper for equilibrium concentration profiles, a finite-differences solver based on spatial discretization along with the Newton-Raphson technique for the resulting set of non-linear equations was implemented in python in the SPYDER IDE, with code available on Github (igitizer .Supplement 1"}
+{"text": "Purpose: Competency assessment standards for Critical Care Ultrasonography (CCUS) for Graduate Medical Education (GME) trainees in pulmonary/critical care medicine (PCCM) fellowship programs are lacking. We sought to answer the following research questions: How are PCCM fellows and teaching faculty assessed for CCUS competency? Which CCUS teaching methods are perceived as most effective by program directors (PDs) and fellows. Methods: Cross-sectional, nationwide, electronic survey of PCCM PDs and fellows in accredited GME training programs. Results: PDs and fellows both reported the highest rates of fellow competence to use CCUS for invasive procedural guidance, but lower rates for assessment of deep vein thrombosis and abdominal organs. 54% and 90% of PDs reported never assessing fellows or teaching faculty for CCUS competency, respectively. PDs and fellows perceived hands-on workshops and directly supervised CCUS exams as more effective learning methods than unsupervised CCUS archival with subsequent review and self-directed learning. Conclusions: There is substantial variation in CCUS competency assessment among PCCM fellows and teaching faculty nationwide. The majority of training programs do not formally assess fellows or teaching faculty for CCUS competence. Guidelines are needed to formulate standardized competency assessment tools for PCCM fellowship programs.  Goal-directed critical care ultrasound (CCUS) has become a necessary skill set for clinicians managing critically ill patients. The Accreditation Council for Graduate Medical Education (ACGME) includes CCUS among the core procedural requirements specifically for trainees in anesthesia and emergency medicine residencies Previous surveys of pulmonary and critical care medicine program directors demonstrated a heavy emphasis on informal bedside teaching of ultrasonography skills despite low reported levels of CCUS competency among faculty (i.e. PCCM attendings that routinely work and train fellows in the workplace setting) Better understanding of these gaps will allow for more transparency among pulmonary-critical care fellowship training programs regarding CCUS competency assessment of fellows and faculty, and allow for better standardization among programs nationwide. Our objectives were to investigate perceptions and methods utilized by fellows and teaching faculty in U.S. training programs to achieve and assess competency in CCUS.This study was approved by the New York University Grossman School of Medicine (NYUGSOM) Institutional Review Board (s18-00282). We conducted two cross-sectional surveys on CCUS competency from September to December of 2018: a survey of ACGME-accredited PCCM fellowship program directors or their designees, and a survey of PCCM fellows in ACGME-accredited programs. Surveys were designed through an iterative process of development that incorporated feedback from three groups at our institution: faculty experts in CCUS, PCCM fellowship program key clinical faculty, and senior PCCM fellows. The surveys were distributed via email to 148 PCCM fellowship program directors in the U.S. and Canada by the Association of Pulmonary and Critical Care Medicine Program Directors (APCCMPD). We asked PDs or their designee to complete the online PD survey, and forward a link to a second online survey to their fellows. We sent follow-up emails once a month for two months. The PD survey asked questions regarding methods used to teach CCUS to their fellows and their perceived effectiveness, perceived CCUS competency of their fellows and their teaching faculty that work with their fellows, and methods used to assess CCUS competency of their fellows and teaching faculty (see Appendix A for full PD survey). The Fellows survey asked questions regarding methods used to learn CCUS and their perceived effectiveness, their performance numbers of CCUS examinations, their perceived CCUS competency, and methods of CCUS competency assessment used by their programs (see Appendix B for full Fellows survey). Both surveys captured basic demographic information about respondents and training programs. Survey responses were anonymous and no personally identifiable information was collected. Survey study data was collected and managed using REDCap\u00ae (Research Electronic Data Capture) electronic data capture tools hosted at NYU Grossman School of Medicine Forty program directors completed the PD survey ; the total number of fellows that received survey invitations is unknown and a response rate cannot be definitively calculated but we estimated a response rate of 18%. Program and fellow demographics are described in Table 1. The vast majority were combined PCCM fellowship programs , academic , and moderately sized . Responding fellows represented a spectrum of training years .The majority of PDs thought the vast majority (76-100%) of their faculty were competent to perform US-guided vascular access (62%) and US-guided drainage catheter placement (64%). The majority of PDs (59%) felt that the majority or vast majority (51%-100%) were competent in lung/pleural US. However, only a minority of PDs believed that the majority or vast majority (51%-100%) of their faculty were competent in goal-directed cardiac echo (36% of PDs), abdominal/kidney US (23%), and lower extremity DVT studies (18%).We also performed a sub-analysis to explore if PD\u2019s perception of faculty CCUS competence correlated with their perception of fellow CCUS competence and the strength of that correlation. Spearman\u2019s rank correlation was computed to assess the relationship between PD\u2019s perception of faculty competence and fellow competence for the 5 different CCUS examinations. There was a statistically significant positive correlation for goal-directed echo, r(38) = [0.436], p=0.006; and DVT studies, r(38) = [0.624], p <0.001. It was not statistically significant for US-guided vascular access (p=0.05), US-guided drainage catheter placement (p=0.271), or lung/pleural US (p=0.089).Methods of teaching and learning CCUS and their perceived effectiveness are documented in Table 2. Utilized methods of teaching CCUS (PD survey) and methods of learning CCUS (Fellow survey) were similar for the two surveys--local lecture-based teaching , directly supervised bedside CCUS exams with feedback , local hands-on workshops , and self-directed learning . Slightly lesser use included regional/national courses , case-based didactics , and unsupervised archival of images with subsequent review for teaching . PD and Fellow perceptions of usefulness for these different teaching/learning methods were similar. Percentage of PDs and Fellows that perceived the different teaching/learning methods as \u201cvery\u201d or \u201cextremely useful\u201d on 5-point Likert scale were: hands-on local workshops , directly supervised bedside CCUS exams with feedback , regional/national courses , local lectures , local case-based conferences ; unsupervised CCUS with archival of images and subsequent review  and self-directed learning  were rated as less useful.Number of each CCUS examination performed by fellows over their fellowship is displayed in Figure 1. Percentage of fellows performing greater than 20 examinations varied by specific CCUS examination type: 90% for US-guided vascular access, 68% for US-guided drainage catheter placement, 69% for goal-directed echocardiography, 66% for lung/pleural US, 33% for abdominal US, and 19% for DVT studies.Program Director and Fellow Surveys: Methods of Assessing Fellow and Faculty CCUS Competency Methods of assessing fellows for CCUS competency are detailed in Table 3. The majority of PDs (54%) report never formally assessing fellows for CCUS competency, and the majority of fellows (67%) also reported never receiving formal competency assessment. Of the programs that do assess their fellows for CCUS competency, the most used method was global assessment by expert faculty . Half of PDs who engage in fellow CCUS assessments reported using formal review of archived real patient images, practical exam on real patients, and use of a standardized assessment tool. However, fellows report all methods other than global assessment by faculty to be used in the minority of their programs. Of the programs that do assess their fellows for CCUS competency, the specific CCUS exams being tested varied: procedural guidance 61% use on PD survey and 46% use on fellow survey; goal-directed Echo 78% and 62% respectively; lung/pleural US 67% and 59%; abdominal/kidney US 33% and 38%, and lower extremity DVT study 50% and 35% respectively.Ninety percent of PDs reported never assessing their teaching faculty for competence in performing CCUS examinations, and 8% did so only pre-employment. Given the very low prevalence of faculty competency assessment in general, data on methods of assessing faculty competence or specific examinations being assessed were deemed too small to draw conclusions and thus not reported.Regarding the documentation of CCUS competency, only 28% of PDs and 7% of fellows reported having a requirement for completion of a designated number of CCUS examinations prior to fellowship graduation, and only a small minority utilize an electronic portfolio to save their clips and images (18% per PDs and 6% per fellows).etails the percentage of fellows at a given fellowship program who attain competency to independently perform basic CCUS examinations by the end of fellowship training, as well as percentage of teaching pulmonary and/or critical care faculty at a given institution currently competent to perform these same CCUS exams. The percentage of PDs that believed the vast majority (76-100%) of their fellows attain competence varied by the specific CCUS examination type\u2014very high perceived percentage of competence for vascular access and drainage catheter placement (97% of PDs for both), moderately perceived percentage of competence for lung/pleural US (71%), and lesser perceived percentage of competence for goal-directed echocardiography (47%), lower extremity DVT study (37%), and abdominal/kidney US (26%). Fellows\u2019 perceptions generally agreed with PD competency perceptions for vascular access and drainage catheter placement, with fellows agreeing or strongly agreeing in their competence , as well as for lung/pleural exam (86% agreement with competence) and lesser perceived competence in DVT studies (50%) and abdominal/kidney US (44%). However, fellows perceived their competence higher for goal-directed echo (77% agree or strongly agree with competence) compared with PD perceptions. Breaking down fellow perceived competency by year of training, all years reported high perceived competency in US-guided vascular access  and US-guided drainage catheter placement . A stepwise pattern of increasing perceived competency was seen for goal-directed Echo  and lung/pleural US . However, rates of competence by year remained relatively flat/plateaued regardless of year of training for abdominal US  and DVT study . CCUS is a complex skill that combines cognitive knowledge along with psychomotor image acquisition skills and affective attitudes, and has become essential in daily practice for intensivists at the bedside Prior surveys of PCCM faculty and trainees have demonstrated heterogeneous institutional practices and methodologies to assess competency Interestingly, these levels of perceived competence were mirrored by fellow-reported experience with the different CCUS examinations, as most fellows reported greater experience with US-guided placement of vascular access devices or drainage catheters , goal-directed echocardiography and lung/pleura assessment but less abdominal and DVT ultrasound experience. About half of fellows reported performing fewer than 10 abdominal or DVT ultrasounds. ACCP/SRLF expert consensus guidelines do not specify the number of each US examination type recommended for CCUS competence A survey of 67 surgical critical care fellowship program directors reported the following exams as \u201cvery important\u201d\u2014FAST exam (75%), central venous access (80%), transthoracic echo (47%), DVT study (3%), and abdominal US for biliary pathology (1.5%) Regarding CCUS competency assessment, we found in this study 54% of PDs and 67% of fellows reported that their programs never conduct formal competency assessments for CCUS. Among the programs that reported conducting formal assessments, a global assessment by expert faculty was the most common method cited by both PDs and fellows. Among those programs that do formally assess their fellows, the majority do not test specifically for competency in DVT studies or abdominal ultrasound. Additionally, there is a lack of use of archival review with feedback as well as development of ultrasound portfolios. Prior studies have documented the issue of poor faculty competence in CCUS as a barrier to training Given the lack of formal assessment of CCUS competency of faculty, it is uncertain what information or data PDs used to answer our survey questions on faculty competence\u2013 institutional delineation of privileges, direct observation, gestalt, or other. Of note, we saw a correlation with PD perception of faculty CCUS competency with their perception of fellow CCUS competency for goal-directed echo (moderate correlation) and DVT studies (strong correlation). This is of uncertain significance, as it could reflect causality , or could represent PD\u2019s inability to differentiate fellow from faculty competence due to lack of tangible metrics for the latter. Future studies to better understand the relationship between fellow and teaching faculty CCUS competency are warranted. PDs and fellows agreed on preferred methodologies for learning CCUS. Both groups reported that regional/national ultrasound courses, hands-on institutional workshops and directly supervised bedside CCUS exams were their most preferred approaches to learning CCUS, reinforcing concepts of learning through active processes. Regional CCUS courses including hands-on workshops with expert faculty have been found to be feasible and efficient in providing much needed hands-on training in CCUS Unsupervised CCUS exams, self-directed learning and lecture-based teaching were the least favored approaches to CCUS education. Brady et al. had determined through their 20-item survey of PCCM program directors that the most common method of learning CCUS was in fact unsupervised, independent bedside learning Our survey has several strengths and limitations. Unlike previous studies, our survey included perceptions of both program directors and fellows and found a general agreement on most topics. Our findings on the perceptions of program directors with respect to the competency of clinical teaching faculty to perform CCUS have not been described previously. The major limitation of our study was the small sample size compared to all PCCM training programs which could introduce selection bias and limit the overall generalizability to all current practices. However, the consistent data from both fellows and faculty does help with overall validity of the themes that emerged from the results, and the heterogeneous distribution of academic and affiliated hospitals improves the generalizability of the findings. However, given the small sample size of this study, we would caution that the results should be viewed as intriguing but ultimately hypothesis-generating and in need of future targeted studies to expand upon this work. Also, as this is a cross-sectional survey, there could be recall biases from the PD or fellow respondents. As stated above, it is uncertain what information PDs used particularly for faculty competence given the overall lack of faculty assessment. We also relied on PDs to forward a survey link to their fellows, introducing another element of potential sampling bias to fellow responses as there was a potential gatekeeper deciding to forward or not the survey to their fellows. Thus the assumption we made is that the responding PDs and fellows likely represent the same training programs, and thus the aggregate data is representative of the same training programs. This assumption is bolstered by the Demographic information detailed in Table 1 which shows very similar PD and Fellow survey demographics . However, as the data collected were anonymous, we expect the fellows to have been truthful and accurate in their responses. Lastly, given the anonymous nature of the data collection, we were able only to carry out analyses in aggregate, but unable to carry out detailed analyses of associations between PD and fellow responses from the same program.Our survey lays a foundation for future directions in the applicability and training of CCUS in clinical practice. Our exploratory analysis suggests that program director and fellow perspectives on CCUS competency overlap substantially; future surveys of PDs only might therefore be sufficient. It is also currently unknown how the COVID-19 pandemic may have impacted CCUS training despite high utilization of CCUS in intensive care units. This may help further improve our teaching practices and develop methodologies using advanced tools such as portable ultrasounds with remote access capabilities in the setting of contact precautions, virtual training and feedback sessions. It is currently unknown if CCUS training methodologies differ between CCM only programs vs PCCM programs and country-wide, survey-based studies are needed to include more CCM only programs.Our study highlights substantial heterogeneity in the CCUS teaching and competency assessment methods among ACGME-accredited PCCM programs in the United States. We found the perceptions of PDs and fellows were in general agreement with high levels of perceived competency to perform CCUS-guided procedures and lung/pleura assessment but deficiencies in the competent performance and interpretation of abdominal and lower extremity diagnostic venous ultrasonography. We also found that the majority and vast majority of programs do not assess their fellows and teaching faculty respectively for competence in CCUS, highlighting a major area of programmatic and curricular need. Our survey also demonstrates that active learning through regional and local hands-on workshops and directly supervised bedside CCUS exams were perceived as extremely useful, whereas, unsupervised CCUS exam, self-directed learning and lecture-based learning were perceived as less useful by both PDs and fellows. These findings suggest that further studies and guidelines are needed to formulate standardized competency assessment tools across all PCCM/CCM fellowship programs. MHA had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. MHA and DP contributed substantially to the study design, data analysis and interpretation. MHA, HD and DP contributed substantially to the writing of the manuscript. The authors have no relevant conflicts of interest to disclose.Appendix AAppendix A"}
+{"text": "Biological events occurring in the human brain are elegantly tuned to impart diverse emotions and elaborate behavioral patterns. The role of signaling pathways often changes during the progression of CNS disorders, and there is remarkable spatial heterogeneity in cell types and molecular expression profiles over the brain. Therefore, a full temporal and spatial illustration of the pathological progression of CNS disorders would benefit the development of novel therapeutic strategies. In this Research Topic, 6 articles, including high-quality original research articles and comprehensive reviews, discuss the spatiotemporal regulation patterns of CNS disorders and emerging techniques in this field.Zou et al. explored the cell type-specific modulatory roles of dopamine receptor D1 (D1R)- and D2R-expressing medium spiny neurons in the nucleus accumbens shell in TLE. They found that cell-type-specific inhibition of either D1R-MSN or D2R-MSN alleviated TLE seizures by reducing the number of secondarily generalized seizures and improving seizure stages, without altering the onset time of focal seizures. The data of the aforementioned study along with other studies suggest that different brain areas and cell populations participate in seizure initiation, propagation and termination, thereby highlighting the necessity of demonstrating the spatial heterogeneity of pathological mechanisms of epilepsy.Temporal lobe epilepsy (TLE) is the most prevalent focal seizure, which is highly likely to progress to generalized seizures. Here, Zhou and Zhang. discussed the cell type-specific role of oligodendrocytes in various CNS disorders and delineated the contribution of myelin to neuronal activity. Interestingly, neuronal excitability can also affect myelin functions. The authors overviewed the potential strategies for myelin regeneration through the precise modulation of neuronal activity.Similarly, Yi et al. reviewed the temporal regulation of key biological events that occur during neurodevelopment after experiencing febrile seizures. Febrile seizures are quite common during early childhood (-4%)   and receLai et al. examined the molecular mechanisms involved in the treatment of chronic pain using sinomenine, an active ingredient in the natural plant \u2018sinomenium acutum (Thunb.) Rehd. Et Wils\u2019, while focusing on its regulatory roles in distinct immune cell subpopulations. Sinomenine can regulate the interaction among different immune cells, immune cells and neurons and glial cells and neurons to confer immunosuppressive effects.The aforementioned studies dissect pathological mechanisms of CNS disorders from a spatiotemporal perspective. Similar research approaches can also be used to study the pharmacological mechanisms of drugs and other functional compounds. Wong et al. proposed a novel electrochemical localized oxygen scavenging system (eLOS) to induce hypoxia in vitro with spatiotemporal precision. Focal hypoxia is very common in multiple diseases such as ischemic stroke, cardiac arrest and dementia; however, the currently available experimental model of spatially restricted ischemia is limited. Using the eLOS platform, Wong et al. successfully induced axon-restricted hypoxic stress in human cortical neurons and found that localized axonal hypoxic stress induced neuronal death even when the somas remain in the normoxic culturing condition. These findings indicate the potential of the eLOS platform in studying cellular and subcellular changes in white matter after an injury and other hypoxic insults.Studies focusing on the spatiotemporal pathological mechanism of CNS disorders will benefit from the newly developed techniques providing spatiotemporal information. Ya et al. illustrated working principles and provided examples of the application of cutting-edge spatially resolved transcriptomic technologies in studying CNS disorders. The rapid development of these technologies will eventually provide a deeper understanding of the molecular mechanisms underlying CNS disorders.Furthermore, Overall, it has become inevitable to elucidate the pathological progression of CNS in high spatiotemporal resolution. We hope that this Research Topic will help readers understand CNS disorders from a highly spatiotemporally precise perspective."}
+{"text": "We thank Drs. Sutt and Fraser for their insightful commentary on our publication. They open an important debate on tracheostomy timing and outcomes of interest.We concur that for decades, research has focused on \u201ctraditional\u201d outcomes such as mortality and length of stay (LOS). Additionally, focus on tracheostomy-specific outcomes including swallowing, and communication may aid efforts to improve recovery after intensive care unit (ICU) discharge.Our analysis of\u2009>\u200917,000 critically ill patients with severe stroke attempted to clarify whether tracheostomy timing is an important piece of the stroke management puzzle .We found that early tracheostomy does not impact neurological outcome (mRS). This was reflected in the SETPOINT2 trial, where 75% of patients in each group experienced poor neurological outcome  despite active rehabilitation efforts (~\u200970% of patients were discharged to rehabilitation facilities) [We recognise that, strictly speaking, the timing of tracheostomy should not substantially impact neurological outcome. Studies often inadequately separate early and late groups . The phEvidence on patient-centric outcomes in this population is limited. Our work humbly sought to quell decades of debate on the impact of tracheostomy timing on mortality, neurological outcome (mRS), and LOS, in patients with severe stroke. Given our findings, we commend future efforts to protocolise reporting of additional patient-centred outcomes such as speech , swallowing   and psyc"}
+{"text": "Editorial on the Research TopicUrothelial carcinoma of renal pelvis and ureter, prognosis and recent advancesUrothelial carcinoma of the renal pelvis and ureter is a prevalent malignancy primarily affecting the elderly population . Its incZhanghuang et al.). The study revealed that non-UTUC deaths accounted for the majority of mortality among patients with localized disease. This highlights the importance of considering non-cancer causes in the management of UTUC survivors. Moreover, UTUC was found to be the leading cause of death in patients with regional and distant stages, emphasizing the need for improved therapeutic strategies targeting advanced disease while considering the increased risk of death from non-cancer causes  survivors has provided valuable insights into mortality patterns. By utilizing the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, a large cohort of UTUC patients was examined  and cancer-specific survival (CSS) in renal pelvic urothelial carcinoma (RPUC) patients. Using data from the SEER database, the study compared radical nephroureterectomy (NU) and inadvertent radical nephrectomy (RN). The results underscored the significance of accurate diagnosis and appropriate surgical intervention in RPUC patients. The study concluded that RN could lead to worse oncological outcomes compared to NU, emphasizing the importance of precise surgical planning and execution.Wu et al.).Another study emphasized the importance of distinguishing between radical nephroureterectomy (NU) and inadvertent radical nephrectomy (RN) in patients with renal pelvis urothelial carcinoma (RPUC). A retrospective analysis of data from the SEER database revealed that patients who underwent RN experienced worse overall survival (OS) compared to those who received NU. Furthermore, the study highlighted that the negative impact of RN on OS was more significant in patients with tumors larger than 4.2\u2005cm . While no significant differences were observed in surgical outcomes between the two approaches, the study identified various predictive factors associated with adverse oncological outcomes. Age over 70, positive lymph node metastasis, upper ureter tumor location, and male sex were identified as potential risk factors. Additionally, higher surgical volume showed trends toward favorable outcomes in terms of overall survival and cancer-specific survival.A study utilizing data from the Taiwan nationwide upper urinary tract urothelial carcinoma (UTUC) collaboration database evaluated the outcomes of transperitoneal hand-assisted laparoscopic nephroureterectomy (TP-HALNU) and transperitoneal pure laparoscopic nephroureterectomy (TP-LNU) . The findings indicate that patients who received chemotherapy (CT) combined with NU exhibited improved overall survival (OS) compared to those who received CT alone. This benefit was observed in both nonmetastatic and metastatic UTUC. The study emphasizes the potential advantages of NU in prolonging survival outcomes for patients with advanced-stage UTUC.A multicenter retrospective cohort study addressed the role of nephroureterectomy (NU) in stage IV upper tract urothelial carcinoma (UTUC)  was shown to have a negative impact on overall survival (OS), particularly in patients with larger tumors. Furthermore, while the choice between surgical approaches may not significantly influence outcomes, other factors such as patient age, lymph node metastasis, tumor location, and surgical volume should be considered for prognostic evaluation. Finally, the role of nephroureterectomy (NU) in stage IV UTUC demonstrates potential benefits in terms of overall survival (OS) for both nonmetastatic and metastatic cases. These findings underscore the importance of precise diagnosis and treatment among patients with UTUC."}
+{"text": "Three years since the onset of COVID-19, pandemic-related trends in child sexual abuse (CSA) remain poorly understood. Common administrative surveillance metrics may have underestimated abuse during the pandemic, given youths\u2019 limited access to mandatory reporters. Research using anonymous service-use data showed increased violence-related online help-seeking but overlooked youth-specific help-seeking for CSA during COVID-19. Understanding pandemic-related trends in CSA can inform abuse detection practices and mental health service provision for youth victims.The purpose of this study was to harness anonymous help-seeking data from the National Sexual Assault Online Hotline (NSAOH) to glean insights about CSA occurrence in the United States during the COVID-19 pandemic.We used an archival sample of victims who contacted NSAOH from 2016 to 2021 . We examined differences in the proportion of youth and adult victims contacting NSAOH during the first COVID-19 year (March 2020 to February 2021) compared to the prior year . Further, we compared key characteristics of hotline interactions among youth victims during the first COVID-19 year to the prior year (n=5913). Using joinpoint regression analysis, we examined linear trends in the number of monthly sampled youth and adult victims (excluding victims of unknown age) from 2016 to 2021 who discussed any victimization event  and who discussed recent events .Most youth victims were abused by family members prior to  and after  the onset of COVID-19. The number of youth victims contacting NSAOH spiked in March 2020 and peaked in November 2020 for all youth  and those discussing recent events . We observed a decline in youth victims into spring 2021 for all youth  and those discussing recent events . The number of adult victims discussing any victimization event increased steadily from January 2018 through May 2021  and then declined . Trends were stable for adults discussing recent events.This study extends the use of hotline data to understand the implications of the pandemic on CSA. We observed increased youth help-seeking through the NSAOH coinciding with the onset of COVID-19. Trends persisted when limiting analyses to recent victimization events, suggesting increased help-seeking reflected increased CSA during COVID-19. These findings underscore the utility of anonymous online services for youth currently experiencing abuse. Further, the findings support calls for increased youth mental health services and efforts to incorporate online chat into youth-targeted services. As we approach a postpandemic world, understanding trends in child maltreatment during COVID-19 remains vital for informing practices to detect abuse and ameliorate the effects of trauma. Evidence of pandemic-related trends in child maltreatment is conflicting, resulting in part from limitations of traditional surveillance strategies. Apparent declines in child maltreatment reflected in emergency room visits  may be aWhile youths\u2019 perspectives are often assessed through self-report survey methodologies, indicators of online help-seeking are potentially valuable. Prior to the pandemic, youth actively sought help for experiences of abuse via online and text-based hotlines ,8, whichRecent work has explored trends in violence-related online help-seeking during the pandemic. Google searches related to child maltreatment increased during the pandemic ,12 but mA study of multinational child helplines  lacked cAmid these challenges, research on pandemic-related child maltreatment has largely overlooked child sexual abuse (CSA). However, concerns about victims\u2019 physical and social isolation and accessibility to perpetrators during stay-at-home orders  are partWe advance knowledge by addressing limitations of previous work on 3 fronts. First, we examine online help-seeking for sexual violence among youth victims specifically. Second, we incorporate 5 years of observations (2016-2021), providing a broader picture of help-seeking patterns across the pre- and postpandemic onset time periods. Third, we delineate recent events to distinguish violence that occurred during the pandemic.The NSAOH is a US-based online hotline providing 24/7 anonymous crisis intervention services via desktop and mobile internet chat. RAINN , an anti\u2013sexual violence organization in the United States, created and has operated NSAOH since 2006 to serve victims of sexual violence.Data collection via an in-depth online assessment  serves an integral role in hotline operations to identify areas for service improvement and staff training. Directly following the first chat session of their shift, staff record session information, such as event characteristics and topics discussed. Because information is not requested for the purpose of completing the assessment, data are often considered unknown . Staff receive instructions for assessment completion both within the assessment and through supplemental training.Data in this study represent a sample of all hotline chats in which the visitor discussed an experience of sexual or other interpersonal violence  between January 2016 and December 2021 . Additional information about hotline procedures, the organizational context, and sample inclusion criteria are available in Data used in this study were originally collected as part of ongoing internal program evaluation; thus, informed consent was not required. Analysis of this archival data for the purposes of generating generalizable knowledge of online hotline users and sexual violence experiences was deemed exempt by the Advarra institutional review board under category 4 of the Revised Common Rule.We examined differences in the proportion of youth  and adult (aged 18 years and older) victims during the first COVID-19 year (March 2020 through February 2021) compared to the year prior , with victims of unknown age excluded . Among youth (n=5913), we compared perpetrator type (family vs nonfamily), perpetrator living status (currently living with vs not currently living with the victim), event timeframe , and event frequency (repeated abuse vs single occurrence) during the first COVID-19 year compared to the year prior. These analyses used the chi-squared test with pairwise exclusion of missing data; analyses used SPSS .To contextualize trends in youth help-seeking, we used Joinpoint  to examine linear trends in the number of monthly sampled victims by age group from 2016 to 2021 among all youth and adult victims . Among youth, we noted statistically significant but small shifts in the proportion of chats that involved family-perpetrated assaults , perpetrators currently living with the victim , recent assaults , and repeated assaults . Inflection points reveal variability in the strength or direction (or both) of trends in the number of victims by age in our sample . Prior tThis study is the first, to our knowledge, to reveal increases in youth help-seeking for sexual violence coinciding with the onset of COVID-19. These increases peaked in November 2020 and were present for all youth victims and for youth victims discussing recent events. Although the number of adult victims increased, this trend was more gradual, preceded the onset of COVID-19, and was not present for those discussing recent events. Our finding that trends were sustained for recent events suggests an increase in youth affected by sexual violence during the pandemic rather than increased help-seeking among all victims for current and past events due to limited alternative support options.While our findings seemingly conflict with declines in abuse-related hospital visits and official reports ,2, evideMost youth who contacted the NSAOH\u2014both prior to and during the pandemic\u2014discussed repeated experiences of violence perpetrated by family members or someone else living with them. During the pandemic, we observed small proportional increases in youths\u2019 chats that featured these characteristics, consistent with elevated violence driven by victims\u2019 increased accessibility to perpetrators in the home amid limited contact with trusted adults . Future work should examine to what extent increased youth help-seeking reflected increased frequency and severity of ongoing violence predating the pandemic or cases of violence that began during the pandemic.The number of chats from youth began to decrease after November 2020. This decline could relate to youth having a greater ability to avoid perpetrators or opportunities to disclose to alternative sources of support as schools reopened in the summer and fall of 2020. However, because reopening policies were variable across the United States, driven by state and local government, this trend should be interpreted with caution.While reported trends were transitory, the effects of sexual abuse are not. Our findings reflect increased help-seeking by youth during the pandemic, an indication of rising demand for mental health services to treat trauma and its sequelae among youth. Given the national shortage of child mental health providers that predates COVID-19 , there iJoinpoint regression analysis allowed us to identify changes in the linear trend of victims\u2019 hotline use from 2016 to 2021. While we interpreted the reason for some of these changes, their causes cannot be definitively ascertained from our analysis. We could not differentiate repeat hotline users from new users, which would help delineate new cases of abuse. Our data collection protocol prioritized the delivery of victim-centered services. We did not solicit information from visitors for assessment purposes, resulting in some missing data and limited demographic information. Future work could incorporate anonymous collection of demographics prior to service provision to enhance the utility of hotline data as a surveillance indicator of child maltreatment. Understanding the interplay of hotline supply and demand will also be useful because changes in staff availability  could affect the accessibility and use of services.Our study demonstrates the utility of anonymous online hotline data as a complementary surveillance indicator for child maltreatment that is transferrable to other public health priority areas . Increased help-seeking amid decreased safety at home also speaks to the utility of online support options for youth experiencing abuse. Preparing for future public health emergencies necessitates consideration of additional online communication options that allow youth to privately disclose abuse to trusted adults. Future work should explore how to safely incorporate these communication options into existing services, such as online schooling or telemedicine platforms."}
+{"text": "Remyelination biology and the therapeutic potential of restoring myelin sheaths to prevent neurodegeneration and disability in multiple sclerosis (MS) has made considerable gains over the past decade with many regeneration strategies undergoing tested in MS clinical trials. Animal models used to investigate oligodendroglial responses and regeneration of myelin vary considerably in the mechanism of demyelination, involvement of inflammatory cells, neurodegeneration and capacity for remyelination. The investigation of remyelination in the context of aging and an inflammatory environment are of considerable interest for the potential translation to progressive multiple sclerosis. Here we review how remyelination is assessed in mouse models of demyelination, differences and advantages of these models, therapeutic strategies that have emerged and current pro-remyelination clinical trials. Multiple sclerosis (MS) is a chronic demyelinating, inflammatory and neurodegenerative disease of the central nervous system (CNS). Remyelination is a regenerative process by which oligodendrocytes restore myelin sheaths to demyelinated axons. Evidence from animal models indicate that remyelination can restore neuronal conduction , 1981, pRemyelination is robust in many animal models that have been used to study remyelination, which is somewhat discordant with the heterogeneous patterns of oligodendrocyte loss, demyelination and remyelination in human pathology-based studies of MS tissue . The mecThe inflammatory environment can modulate oligodendroglial properties including oligodendroglial survival, migration, differentiation, axon engagement and remyelination . AdvanceIn animal models, aging influences oligodendroglial properties  and prog14C has been used to investigate the age of oligodendroglia within MS lesions and this study indicated limited production of new oligodendrocytes within shadow plaques that may have undergone remyelination suggesting that mature surviving oligodendrocytes contribute to subsequent remyelination in human MS lesions (14C) prior to differentiation despite rodent studies indicating that OPCs can directly differentiate into mature oligodendrocytes without cell division  is an endogenous lysophospholipid that can be used to generate a focal demyelinating lesion by injection into white matter tracts and demyelination results through disruption of oligodendroglial cell membranes  leading In the lysolecithin model, myelin  and extrEthidium bromide, a DNA-intercalating agent, injected into white matter tracts creates a focal demyelinating lesion with a larger area of demyelination compared to lysolecithin . EthidiuCombining X-irradiation with ethidium bromide injection has allowed for the investigation of transplanted progenitor cells in a lesion environment devoid of endogenous remyelination potential . NeonataAged animals exhibit slower remyelination after lysolecithin and ethidium bromide injection  and agedCuprizone, bis-cyclohexanone-oxaldihydrazone, was first used as an animal model of demyelination in the 1960s . CuprizoMyelin loss occurs after several weeks of cuprizone ingestion and peaks at 4\u20135\u2009weeks . One of Manipulation of astrocyte and microglial responses after cuprizone-mediated demyelination can influence remyelination. Ablation of astrocytes after chronic cuprizone treatment results in improved oligodendrocyte density, remyelination and motor functional outcomes . AstrocyThe role of T cells in cuprizone-mediated demyelination is unclear. T cells are present in cuprizone ingestion  and CD8 Toxin models have greatly facilitated the investigation of pathways involved in oligodendroglial proliferation, recruitment, differentiation and remyelination. Promising mechanisms that are under investigation in clinical trials for remyelination in MS that have emerged from investigation of remyelination in focal and systemic toxin models include LINGO-1 antagonism , Nogo-A The major advantages of toxin models are the robust remyelination response with stereotyped kinetics, separation of the demyelinating process from the regenerative process, minimal axonal degeneration, and decline of remyelination with aging that have allowed for discovery of targets that accelerate repair in an aged environment. While focal toxin models have these advantages, the short demyelinating insult and robust remyelination response are limitations. Diffuse CNS demyelination and white matter injury induced by cuprizone ingestion offers the advantage of an environment with prolonged oligodendroglial loss, neuronal stress and subsequent neurodegeneration, which may allow for the investigation of pathways that prevent neuronal degeneration and allow for the ability to assess motor  and physExperimental autoimmune encephalomyelitis (EAE) models are one of the most commonly used models to investigate the immunopathogenesis of MS . Immuniz35\u201355 peptide    and tranpt-mGFP) ,D. Signipt-mGFP) . Despitept-mGFP) , pharmacpt-mGFP)  and K-oppt-mGFP)  were abluprizone . Immunizl course . Remyelil course . The relon phase  and whet35-55 EAE does not resemble the clinical course of relapsing remitting or progressive MS. The high degree of neurodegeneration and minimal remyelination after the acute EAE phase represent challenges for the utilization of these models in assessing remyelination strategies.Active immunization models have many features that differ from human MS pathobiology and clinical course. The robust inflammatory response and resulting secondary demyelination, early neurodegeneration , sparingEncephalitogenic T cells from CNS antigen immunized mice or myelin-specific T cells isolated from T cell receptor transgenic lines can be used to induce neuroinflammatory disease upon adoptive transfer into naive hosts . A majorAdoptive transfer of myelin-reactive Th17 cells after acute cuprizone ingestion has been used as a model to investigate oligodendroglial responses in the setting of T cell mediated inflammation  and has Gfap-tTA) with tetracycline response element (TRE) upstream of IFN-\u03b3 sequence (TRE-IFN-\u03b3) in a double transgenic line allows for temporal regulation of CNS IFN-\u03b3 expression upon removal of doxycycline  have been used to investigate demyelination and remyelination. Initial studies of transgenic mice with targeted expression of IFN-\u03b3 from the myelin basic protein (MBP) promotor  and gliaycycline . CNS IFNlination . Prolonglination  suggestiPlp-CreER\u2122) with a diphtheria toxin subunit A (DTA) floxed stop reporter line (ROSA26-eGFP-DTA) results in oligodendrocyte apoptosis upon exposure to tamoxifen  results in oligodendrocyte death, widespread demyelination, microglia and macrophage reactivity, axonal damage and incomplete remyelination (Loss of function of transcription factor myelin gene regulatory factor (MYRF) that induces expression of mature myelin genes  in maturlination . Subsequlination . While tChronic encephalomyelitis viral mouse models share pathogenic features similar to MS  and may Theiler\u2019s murine encephalomyelitis virus (TMEV) is a single-stranded RNA picornavirus that causes flaccid myelitis in mice  and can Mouse hepatitis virus (MHV) is a positive-strand RNA virus with neurotropic strains that can be used to induce a chronic demyelinating disease through intracranial or intranasal inoculation of susceptible mouse strains. An acute encephalomyelitis phase is followed by a secondary phase of demyelination and remyelination . MHV-spein vitro have been used to identify pathways with remyelination potential (High-throughput screens that evaluate the ability of compounds to promote oligodendrocyte differentiation otential . Many paotential .Assessment of remyelination in MS clinical trials has been challenging, with few validated clinical tools to assess remyelination in humans . MeasureAnimal models of MS with demonstrated remyelination capacity vary considerable in their mechanisms of demyelination, inflammatory infiltrates, degree of ongoing inflammatory activity, axonal loss and neurodegeneration and extent of remyelination. Focal toxin models offer the advantage of stereotyped remyelination after a short single demyelinating insult which has allowed for the investigation of factors that promote or inhibit this robust reparative response. A prolonged demyelinating insult predominated by corpus callosum and cortical demyelination and subsequent neurodegeneration and motor decline can be modelled with chronic cuprizone exposure and may share some features of the neurodegenerative process in progressive MS. Both cuprizone and EAE models induce inflammatory subsets of glia that are found in MS tissue and further investigation of how these subsets of glia contribute to ongoing inflammatory activity and promote or inhibit repair may offer insight into potential mechanisms to modulate remyelination in inflammatory settings. While no single animal model recapitulates the pathobiology of MS, considerations of the limitations and advantages of each model should be taken into account when investigating remyelination and translating animal model findings to human MS.DP and EH contributed to writing the manuscript. EF contributed to researching and generating the clinical trial table. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Carotid web (CaW) and carotid free-floating thrombus (CFFT) are rare yet critical causes of ischemic stroke in young adults.A 54-year-old woman presented with a fluctuating right sensory-motor faciobrachial syndrome. A brain MRI scan revealed multiple small recent asynchronous cortico-subcortical ischemic foci in the vascular territory of the left internal carotid artery. A CT angiography identified a CFFT in the left internal carotid artery arising from an underlying CaW. The patient was treated with excellent clinical outcomes with carotid artery stenting and dual antiplatelet therapy.We provide a structured pathophysiological rationale connecting CaW and CFFT and highlight pivotal therapeutic implications. Further studies are needed to investigate this relationship and guide assessment and treatment. Etiological diagnosis of stroke in young adults is a challenging and critical aspect of neurovascular care. Indeed, patients affected by such devastating occurrences have an inherently longer time after the index event and can thus benefit most from adequate secondary prevention strategies . UnfortuCarotid web (CaW) and carotid free-floating thrombus (CFFT) are well-known yet often neglected causes of ischemic stroke in young adults. CaW defines a localized carotid intimal fibromuscular dysplasia presenting as a shelf\u00adlike projection into the lumen of the proximal internal carotid artery , 4. ConvHereby, we describe a case of ischemic stroke due to a CFFT originating from a contiguous CaW. We illustrate the diagnostic and therapeutic implications of these two rare conditions, as well as their possible pathophysiological relationship.A 54-year-old woman presented to the emergency department with a two-day history of fluctuating right sensory-motor faciobrachial syndrome. The patient was an active smoker without further major cardiovascular risk factors. Specifically, she had a normal body mass index and no medical history of hypertension, dyslipidemia, diabetes, neurological or cardiovascular events. Additionally, she was not using estrogen-containing oral contraceptives and her family history was unremarkable for cerebrovascular events. Neurological examination on admission revealed a right inferior facial palsy NIHSS\u2009=\u20092). Brain CT scan and blood tests were normal. A minor stroke was suspected, therefore, the patient initiated dual antiplatelet therapy (DAPT) and was admitted to our Stroke Unit. A brain MRI scan revealed multiple small recent asynchronous cortico-subcortical ischemic foci in the left middle cerebral artery and a subacute/chronic ischemic lesion in the left head of the caudate nucleus, a territory of the recurrent artery of Heubner Fig.\u00a0. Continu. Brain CWe report the case of an otherwise healthy young woman who presented with multi-embolic strokes caused by a CFFT stemming from an underlying CaW. The co-occurrence of these two conditions has been reported anecdotally, and the presence of thrombus superimposition on CaW was suggested to be a contributing factor to stroke recurrence \u201310. HoweRadiological differentials for CaW encompass atherosclerotic plaque with plaque rupture, carotid artery dissection, and fibromuscular dysplasia (FMD). However, the regular morphology of the filling defect, lack of calcium deposits and signs of intramural hemorrhage make atherosclerotic plaque unlikely in our patient. Furthermore, neither CTA nor DSA revealed the presence of an intimal flap, and no other stenotic segments were identified in our imaging studies, reducing the probability of carotid artery dissection and FMD.CTA has shown superior diagnostic accuracy compared to carotid US in diagnosing CaW . It is tAs a secondary prevention, our patient was successfully treated with CAS and transitory DAPT. Evidence of the best management is currently lacking in the literature. Indeed, secondary prevention strategies for CaW and CFFT are based on small case series and expert consensus, as no specific guidelines or clinical trials have been designed to date. Concerning CaW prevention, current strategies aim to avoid long-term complications arising from the high stroke recurrence rates. Although chronic pharmacologic management with anti-platelet agents would fall within current guidelines  also antWe described a case of CFFT and CaW co-occurrence focusing on their possible pathophysiological connection as well as diagnostic and therapeutic implications. Meticulous evaluation of non-invasive or invasive vascular imaging tests aiming to detect an underlying CaW in unexplained CFTT should be required. Carotid artery stenting and, eventually, thrombectomy might be a safe and effective secondary prevention strategy to kill two birds with one stone unless underlying thrombophilic conditions requiring anticoagulation therapy are present. Future studies are needed to estimate the frequency and understand the underpinning biologics of the co-occurrence of these two conditions in order to inform assessment and treatment."}
+{"text": "Since organizational psychology is a broad and evolving discipline, the topic editors are pleased to announce sixteen articles that highlight new insights into how leadership, collective intelligence, intellectual capital, innovation, job performance, satisfaction advance the tradition, nature, and research methods of organizational psychology. The articles showcase a global perspective of new insights in organizational psychology from Asia, Europe, Middle East, Africa, North America, and Oceania. The authors explored new insights in organizational psychology through conceptual analysis, qualitative and empirical research, a brief research report, and a systematic review.There is a continual focus to expand and provide new insights on leadership theory and research (Lord et al., van Niekerk highlights the importance of psychosocial factors and elevated stress levels that limit a flourishing multi-cultural environment, stakeholder engagement and leader-follower relationships. The author recommends that organizations should promote a multi-cultural team to counteract elevated stress and to better manage psychosocial factors in an organization. Zhao et al. extend the literature on authoritarian leadership by providing a new perspective for authoritarian leadership practice. In comparison to previous research studies, the authors findings indicate authoritarian leadership generates positive employee wellbeing and creativity. Haar and de Jong explored the dark side of leadership personality to provide new insights on how the dark side of leadership could benefit an organization's performance rather than decreasing organizational performance. Latent transition analysis is introduced by Zyberaj et al. for helping organizational psychology researchers to analyze longitudinal data through an applied example utilizing psychological capital and leader-member exchange. The author findings indicates psychological capital is more likely to occur when leader-member exchange is high rather than low. Therefore, high leader-member exchange works hand-in-hand with high psychological capital.Janssens et al. extends the collective intelligence literature and research through a conceptual analysis on the dynamic granular tensions between the needs of the environment with the collective team behaviors over time. The authors explored various methods to help organizational psychology researchers unpack micro-level team behavior. Senawi and Osmadi research study findings reveal that relational capital plays a significant role with intellectual capital for improving property tax reassessment activities. Overall, the attitudes of local government officials must align with relational capital and intellectual capital for successful property tax reassessment performance.Fan et al. research study findings extend self-determination theory to reveal employees' perceptions on organizational support has positive and profound effects on employees' proactive innovative behavior through the satisfaction of basic psychological needs such as autonomy, competence, and relatedness. Liu and Zhang focuses on employees' paradox mindset on innovative performance through role breadth self-efficacy. Employees with a paradox mindset intentionally make innovative things happen through their own actions. Moreover, role breadth self-efficacy and individual ambidexterity play an important role in understanding how employees manage a paradox mindset and innovative performance. Song et al. provide new insights on how employees should manage innovation performance under time pressure. The authors research study findings indicate time pressure significantly improves innovation performance. Therefore, employees operating under time pressures should receive significant leadership support for improving innovative performance.From a new Chinese perspective, Xu et al. investigated the interdependence of psychological capital, social capital and human capital, including the three capital's impact on job performance. The authors study findings discovered new insights on configuration and casual asymmetry from psychological capital, social capital and human capital that affect job performance. Consequently, Xu et al. challenged previous studies' symmetrical regression relationship findings and extended the relationship among psychological capital, social capital and human capital within intelligent career theory. Moreover, high psychological capital plays a key role in high job performance. Sanclemente et al. explored inconsistencies from previous research studies that predict workers' health levels in linear models. The authors research study focused on differences among service sub sectors through linear and non-linear relationships within task complexity, job autonomy, user contacts, time pressure, and psychological and physical symptoms of employees. Overall, Sanclemente et al. research study findings on non-linear relationships indicate medium levels of task complexity from job demands should not exceed greatly to mitigate increased negative impacts to foster service sector employees' physical and psychological well-being in job satisfaction and performance.Levitats et al. provides new insights on unexplored contexts of emotional intelligence in the literature. Specifically, the authors explore the role played by emotionally intelligence in an organization's culture combined with supervisors' emotionally intelligent behaviors. The two-study research findings reveal process links between emotionally intelligent values and practices, and job demands between supervisor emotional intelligence behaviors that affect employee exhaustion and engagement. Chen Y. et al. systematic review provides deeper understanding on the relationship between pay for performance and job performance by highlighting the research studies that examine pay for performance and job performance in real work settings. The results of the systematic review complements the positive effects of pay for performance and job performance in work settings through contextual performance and task performance. In addition, the authors introduce two mediating variables namely, intrinsic motivation and pressure that integrates the positive and negative effects of pay for performance and job performance into one framework.L\u00f3pez-Cabrera et al. research study is to explore potential factors that promote job satisfaction between volunteers and regular paid staff in non-profit organizations. The research study contributes to new understandings of the mechanism that promotes greater satisfaction from volunteer workers vs. regular paid staff through role ambiguity, role conflict and job performance. Chen C. et al. research study provides new insights on positive outcomes of customer incivility that could trigger employees' customer service behavior to challenge and extend the literature stream's focus on negative outcomes and customer incivility. The authors provide a more comprehensive understanding how customer incivility influences employees' behavior and the implications for revenge behavior and customer service behavior and performance in the work environment. Uzum et al. combine crab barrel syndrome and social comparison theory as a new approach for identifying precursors of crab barrel syndrome. The authors' research study findings indicate through social comparison theory that type A personality precedes crab barrel syndrome, especially when the work environment is highly competitive. Consequently, job performance for type A personalities requires strengthening the employee's self-esteem with group support to decrease crab barrel syndrome.The aim of In conclusion, the articles in this Research Topic provide examples of new insights that we find relevant and thought provoking for progressing further research into organizational psychology scholarship from multiple perspectives.MT: Writing\u2014original draft. DT: Writing\u2014review and editing. GG: Writing\u2014review and editing."}
+{"text": "Impairments in decision-making processes are believed to play an important role in both substance use disorders and behavioral addictions. Clinical and pre-clinical experimental testing provide complimentary insights on the psychobiological mechanisms of decision-making. The IOWA Gambling Task (IGT) assesses decision-making under ambiguity and risk, in which individuals are faced with four card choices associated with varying monetary reinforcer/loss contingencies. The rat Gambling Task is a pre-clinical version using palatable reinforcers as wins and timeouts mimicking losses. However, studies with interspecies comparisons in these tasks are lacking, but important to facilitate translation of information that may help unravel the complex processes of decision-making and generate clinical advances.This study explores decision-making strategies among humans and rats performing the IGT and rGT.A total of 270 young human adults performed a computerized version of the IGT, and 72 adult outbread male Lister Hooded rats performed the rGT. Performance was assessed and explored by normative scoring approaches and subgroup formations based on individual choices.Results showed that most humans and rats learned to favor the advantageous choices, but the overall level of performance differed considerably. Humans displayed both exploration and learning as the task progressed, while rats showed relatively consistent pronounced preferences for the advantageous choices throughout the task. Nevertheless, variability in individual choice preferences during end performance were evident in both species.Results are discussed in relation to procedural differences impacting performance and potential to study different aspects of decision-making. This is a first attempt to provide formal evaluation of similarities and differences regarding decision-making processes in the IGT and rGT from an explorative perspective.None Declared"}
+{"text": "Brain 2022).Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder affecting 1-2% of the population worldwide. Recent large-scale whole-exome sequencing (WES) studies identified hundreds of rare, highly penetrant genetic variations associated with ASD. Many of these genetic variations underlie particular genetic syndromes characterized by a variety of congenital anomalies in addition to the core ASD symptoms. Recently, we reported about certain ultrasonography fetal anomalies (UFAs) associated with later development of ASD  who have both fetal ultrasound and WES data. We used an integrative in-house bioinformatics pipeline specifically designated to identify gene-disrupting variants (GDVs) in a panel of >1200 genes associated with ASD according to SFARI gene database. Then, we compared the prevalence of GDVs in these genes between children with and without UFAs. Finally, we applied the Gene Analytics tool to disrupted genes in children with specific fetal anomalies to identify biological pathways associated with both ASD and these fetal anomalies.children with UFAs were more likely to carry GDVs in ASD genes than their counterparts even after adjustment to the sex differences between the groups , and this association was the most prominent with GDVs in the most notable ASD genes . Also, the study shows higher prevalence of children with GDVs in most anatomical systems, with UFAs in fetal size  and the head&brain  being the most prominent . In addition, children with UFAs had significantly more co-occurring mutations, and the number of mutations in a single fetus was significantly correlated with the number of UFAs .Overall, 115 ASD children were included in this study, of which 49 (42.6%) of them had UFAs in their ultrasound scans . Children with and without UFAs did not differ in their sociodemographic and clinical characteristics except for a significantly lower proportion of males in the UFA group . Notably, Image:Image 2:Our findings suggest distinct genetic mechanisms for ASD subtypes that are characterized by unique UFAs. These findings may form a basis for future prenatal screening approaches for ASD using both ultrasound and genetic testing. Our findings suggest distinct genetic mechanisms for ASD subtypes that arecharacterized by unique UFAs. These findings may form a basis for future prenatal screening approaches for ASD using both ultrasound and genetic testing.None Declared"}
+{"text": "Proteome stability  is critical for proper cellular functionality and consequently organismal health and it is ensured by an extensive compartment-specific network of machineries known as the proteostasis network (PN) . Key comDeclined proteasome functionality is a hallmark of aging and a major risk factor for the development of many age-related diseases such as neurodegenerative disorders and cardiomyopathies . On the Drosophila experimental in vivo model we previously reported that flies exposed to therapeutic PIs  display similar adverse effects with multiple myeloma patients treated with PIs, including both neurotoxicity and cardiac dysfunction [By exploiting the function . Recentlfunction ; these mfunction . Interesfunction ). In supfunction .Taken together, our findings provide mechanistic explanations for the heart-related adverse effects of therapeutic PIs, suggesting that proteasome dysfunction in the heart results in cardiotoxicity and systemic complications due to proteome instability, mitochondria disruption, redox imbalance and metabolic deregulation. Moreover, our therapeutically relevant finding that co-administration of autophagy inducers  exert beneficial effects on heart functionality, provide preclinical insights for alleviating PIs-induced cardiac adverse effects and thus preventing anti-tumor therapy discontinuation."}
+{"text": "The ATTRv patient underwent heart transplantation because of progressive heart failure. Within the next two years, progressive myopathic symptoms and extracardiac tracer uptake on 99mTc-DPD planar scintigraphy were documented, attributable to ATTR amyloid myopathy. Interstitial amyloid deposits were confirmed by muscle biopsy in both patients, with a particularly high amyloid burden in the adipose tissue. This case report highlights the frequent concomitant presence of cardiac ATTR amyloidosis and ATTR amyloid myopathy. ATTR amyloid myopathy may precede cardiac manifestation in ATTRwt or occur after heart transplantation in ATTRv. Due to the high diagnostic accuracy of 99mTc-DPD scintigraphy for detecting ATTR amyloid myopathy and the emergence of novel therapeutics, it is important to increase the awareness of its presence.We identified two patients with transthyretin (ATTR) amyloid myopathy . Myopathy was the initial manifestation in ATTRwt, whereas it followed neuropathy and cardiomyopathy in ATTRv. The ATTRwt patient showed muscular tracer uptake on  This was particularly pronounced in ATTRwt and ATTR-Val122Ile and could be confirmed histologically as ATTR amyloid myopathy in a small subset of patients with Perugini grade 3 on 99mTc-DPD scans.7ATTR amyloid myopathy, which is characterized by intramuscular interstitial amyloid deposits leading to weakness in the upper and/or lower extremities may contribute significantly to morbidity.We herein describe two cases of ATTR amyloidosis (ATTRv and ATTRwt) with clinical, imaging, and histological evidence of ATTR amyloid myopathy, which is probably often underappreciated and underrecognized in routine clinical practice Table .Table 1C99mTc-DPD whole-body planar imaging . There was no family history of amyloidosis. The patient\u2019s medical records were remarkable for bilateral carpal tunnel syndrome ten years and decompression for lumbar vertebral stenosis two years before diagnosis of ATTRv amyloidosis. Neurological examination at the time of diagnosis of ATTRv amyloidosis in 2015 revealed fatigue, paresthesia of the feet, and loss of Achilles tendon reflexes. Dyspnea, bilateral lower leg edema, muscle cramps, mild proximal muscle weakness, upper extremity paresthesia, and numbness in the upper and lower extremities developed over the following 1.5 years. In addition to heart failure treatment, the ATTR tetramer stabilizer tafamidis was started in 2017 when this substance was first available in Austria. Three years after the initial diagnosis, the patient underwent heart transplantation due to progressive heart failure. Tafamidis, which was paused perioperatively, was restarted seven weeks thereafter. On routine follow-up 12 and 19 months after successful heart transplantation, no evidence for recurrent cardiac amyloidosis was found on endomyocardial biopsy and 99mTc-DPD planar scintigraphy  showed minor abnormalities with a mixed pattern of mild neurogenic and myogenic changes.Serum creatine kinase (CK) levels were within the normal range.Figure Reticular deposits of homogeneous eosinophilic material, representing amyloid, were mainly observed in the perimysial adipose tissue. Interstitial deposition of amyloid was also found in endomysium of skeletal muscle. Interestingly, the ATTR amyloid load was greater in the surrounding adipose tissue than in skeletal muscle. Immunohistochemistry showed amyloid deposits immunoreactive for transthyretin Figure E-G.99mTc-DPD scintigraphy and cardiac magnetic resonance imaging. No pathogenic mutation could be detected and treatment with tafamidis was initiated in 2019. 99mTc-DPD whole-body planar imaging  after diagnosis of ATTRwt amyloidosis showing significant ATTR amyloid deposition  initially presented with bilateral lower leg edema, vertigo, numbness in the pretibial area, lower extremity muscle weakness and muscle cramps. The latter had already started 1-2 years before and was initially considered as side effect of statin use. In the absence of monoclonal proteins, diagnosis of cardiac ATTR amyloidosis was obtained by A low-grade sensorimotor axonal polyneuropathy of lower extremities was revealed in 2019. Myopathic changes in the left gluteal muscle could be detected one year later by EMG.CK levels were within the normal range.Figure Hematoxylin and eosin staining showed slight variation of fiber size and increase of endomysial connective tissue. Necrotic fibers were not seen, although few regenerating fibers were present. Single atrophic fibers were vacuolated and contained amorphous sarcoplasmic deposits suspicious of amyloid. These amorphous deposits were clearly identified as green birefringent amyloid deposits on Congo red staining and were immunoreactive for transthyretin Figure A-D.TTR gene have been described to date, characterized by a wide phenotypic heterogeneity.2 The ATTR-Val40Ile variant, which was diagnosed in patient 8 A similar course was seen in patient 99mTc-DPD planar scintigraphy 19 months after heart transplantation revealed pronounced muscular tracer uptake in the shoulder and gluteal regions in the absence of cardiac tracer uptake in the transplanted heart. At the same time the patient complained of progressive muscle weakness and muscle cramps. Biopsy from the deltoid muscle confirmed significant ATTR amyloid deposition. As there was no evidence of progression of the previously diagnosed neuropathy in the follow-up examinations, it seems likely that the patient's complaints were due to increased amyloid deposits in the peripheral muscles after heart transplantation.In ATTRv more than 140 mutations in the 9One possible explanation for the development and clinical presentation of amyloid myopathy could be that ATTRv amyloid binds to pre-existing ATTRv amyloid deposits with high affinity. Therefore, after heart transplantation and release of ATTR amyloid cardiomyopathy, ATTRv amyloid may preferably deposit on pre-existing, formerly subclinical, ATTRv amyloid deposits in skeletal muscle, causing posttransplant amyloid myopathy in our patient. Similarly, it was reported that amyloid cardiomyopathy may develop after liver transplantation in ATTRv patients, due to binding of wild-type transthyretins, produced by the transplanted liver, on pre-existing ATTRv amyloid deposits in the myocardium.7 In this study bone uptake on 99mTc-DPD scintigraphy increased over the 3 h imaging period, whereas cardiac uptake and soft-tissue uptake (mainly muscle) decreased over time. This seems to be contradictory to the Perugini grading system, which is based on the reciprocal and relative decrease in bone uptake on planar imaging. The authors postulated that bone uptake particularly in patients with Perugini grade 3 on 99mTc-DPD scans may be obscured by tracer uptake in overlying skeletal muscles. Extensive soft-tissue uptake may even obscure visualization of cardiac tracer uptake on planar imaging.7 Conversely, it is conceivable that extensive cardiac tracer uptake may obscure visualization of muscular tracer uptake. It must therefore be considered that in our patient amyloid myopathy was already present before heart transplantation but was not noticed due to this phenomenon. However, increasing muscular complaints suggest an increase in amyloid load after heart transplantation.Hutt et al reported that most patients with cardiac ATTR amyloidosis, especially ATTRwt and ATTR-Val122Ile variant showed muscular tracer uptake on bone scintigraphy.Despite clinical improvement of muscular complaints under gene silencing therapy, a scintigraphic follow-up examination in November 2021 (40 months after heart transplantation) still showed a marked increase in muscular tracer uptake in shoulder and gluteal regions. Whether prolonging the duration of therapy will ultimately result in regression of muscular amyloid deposits remains to be seen.6Patient 2 (ATTRwt) complained about lower extremity muscle weakness and muscle cramps, which already started 1-2 years before cardiac manifestation. This was primarily attributed to a side effect of statin therapy. However, it is more likely that these complaints were already due to the subsequently confirmed amyloid myopathy. This is in concurrence with previous reports indicating that amyloid myopathy may precede cardiac manifestation in ATTRwt.It must be noted that ATTR amyloid myopathy is often difficult to distinguish from neuropathy in routine clinical practice. This is particularly because symptoms attributed to amyloid myopathy, such as weakness and cramps, are similar to symptoms of neuropathy, CK levels are mostly within the normal range and changes in EMG are often not very pronounced. This is due to interstitial amyloid localisation, whereas muscle fiber necrosis and muscle fiber alterations, causing changes in CK levels and EMG, are rarely present. Consequently, ATTR amyloid myopathy is likely to be frequently overlooked or mistaken as neuropathy.99mTc-DPD scintigraphy may ultimately be the more important diagnostic screening tool for diagnosis of ATTR amyloid myopathy than biopsy in future, given the current literature.7Histologically remarkable in this case report is the pronounced amyloid deposition in the adipose tissue in both patients, especially in patient 99mTc-labeled-pyrophosphat (99mTc-PYP) was minimal when assessed by qualitative and quantitative metrics. Thus, they conclude that the properties of 99mTc-PYP may be different from 99mTc-DPD in terms of non-cardiac uptake and that 99mTc-PYP cannot be used to image extracardiac ATTR deposition.10In a previous retrospective analysis of 57 patients with cardiac ATTR amyloidosis, Sperry et al noted that skeletal muscle uptake of 99mTc-DPD scintigraphy with high accuracy. As already shown in previous studies, myopathy can precede cardiac manifestation in ATTRwt amyloidosis.6 To date, amyloid myopathy has not been reported in the ATTR-Val40Ile variant and must be recognized as an important contributor to morbidity in these patients. In concurrence with previous reports, our findings from patient 1 (ATTRv) show that neuropathy and cardiomyopathy may precede the initial manifestation of myopathy.6 Whether this also applies to other patients with the ATTR-Val40Ile variant will be subject of future studies.In summary, muscular ATTR deposits can be visualized by 99mTc-DPD scintigraphy enables non-invasive diagnosis of ATTR amyloid myopathy with high accuracy, while invasive muscular biopsy is no longer obligatory. Due to the broad availability of 99mTc-DPD scintigraphy and the emergence of novel therapeutics it is of utmost importance to increase the awareness for the frequent concomitant occurrence of ATTR amyloid cardiomyopathy and myopathy, expanding the clinical spectrum of ATTR amyloidosis.Conclusively, we think that ATTR amyloid myopathy is still underappreciated and underrecognized, because accurate diagnosis in the past seemed difficult to achieve in routine clinical practice. As shown in this case report,"}
+{"text": "Emotion regulation is crucial in individuals' cognitive ability to manage and express their emotions effectively. This Research Topic delves into the neural processes and reactions associated with emotion regulation using various neurophysiological techniques, including electroencephalogram (EEG), event-related potentials (ERPs), functional magnetic resonance imaging (fMRI), and transcranial electrical stimulation (tES). Furthermore, it investigates the impact of different stimulus types, aesthetic preferences, and mindfulness practices on emotion regulation. The findings contribute to a comprehensive understanding of emotion regulation strategies and provide insights for potential therapeutic interventions.Yang et al.) has proposed distinct roles for the P100, N170, and P250 neural generators. These generators are involved in encoding comprehensive frames of reference, maintaining structural cohesion, and adapting to internal representations of emotional expressions.Within this context, EEG and event-related potentials are valuable tools for investigating the neural processes and reactions related to emotion regulation. A piece of research  component was examined using the mismatch negativity (MMN) in a group of young and middle-aged adults. They employed a modified oddball paradigm to compare responses to standard tones under fearful and neutral facial expressions. The results demonstrated that when exposed to fearful facial expressions, the amplitude of the N1 in response to classic techniques was smaller than in neutral facial expressions.In a study by Additionally, the amplitude was more negative in young adults than middle-aged adults. These findings suggest that the perception of negative emotions visually facilitates the processing of auditory features and enhances acoustic change detection in middle-aged adults. However, this effect cannot compensate for the age-related decline in MMN amplitude.Jamieson et al.).Emotions are interconnected with our social interactions as we navigate the social realm by interpreting and choosing between conflicting emotional cues. The effective face-word Stroop (AFWS) is an experimental method that can help uncover the fundamental neural processes that support crucial social and emotional abilities. Regarding the timing, location, and sequence of control processes involved in responding to emotional conflicts during the AFWS, a study determined that conflict control processes occur within the components of Visually evoked potentials (\u00c5sli and \u00d8vervoll) discovered that the interaction between emotional expressions and model gender influences the magnitude of startle responses. Specifically, greater startle responses were observed when participants viewed angry faces displayed by male models and happy expressions displayed by female models. Another study investigating emotional stimuli in individuals with spinal cord injury  proposed an integrated explanation for emotional conflict resolution during response activation tasks. This study emphasized the influence of emotional arousal and primed approach or avoidance motivation. Furthermore, they discussed the role of arousal in individuals with spinal cord lesions, providing insights into the typical mechanisms involved in emotional conflict control. Understanding emotional conflict control is crucial for adaptive behavior and may have implications for therapeutic interventions.On the other hand, the role of other internal variables has also been addressed. A study utilizing electromyography . Moreover, a study conducted with patients suffering from mild traumatic brain injury examined negative frontal alpha asymmetry using EEG data and found greater right-sided frontal activity than healthy controls .Focusing on the clinical population, results from a study suggested that individuals with Authentic pride (AP) demonstrated greater success in down-regulating negative emotions through cognitive reappraisal, both in daily life and experimental settings, compared to individuals with hubristic pride . The amplitudes of the N400 brain wave component were correlated with participants' level of negative affect during the pre-contemplation stage. Another study revealed that post-error adjustments varied depending on the specific task context.Cognitive appraisal and associated emotional processes were also examined in motivational interviewing  augmented mindfulness, suggesting that regular physical exercise before meditation can enhance early-stage mindfulness. Neurocognitive research indicates that physical exercise (such as aerobic exercises or yoga) and mindfulness impact similar pathways involved in stress regulation and cognitive control, supporting the idea of synergistic effects between physical exercise and mindfulness. Studies focusing on the psychophysiological impact of physical exercise have shown that it can lead to short-term neurocognitive changes that facilitate cognitive control and the attainment of mindful awareness.Mindfulness is another topic covered in this context. Despite the known benefits of mindfulness for mental health, drop-out rates among mindfulness practitioners can occur due to factors such as chronic stress, cognitive reactivity, and pathology. To address this issue, K\u00fc\u00e7\u00fckta\u015f and St. Jacques, the influence of visual perspective on the emotional aspects of autobiographical memory (AM) retrieval was examined. The review concluded that the impact of visual perspective depends on the emotional nature connected to the event.Lastly, in a review conducted by By investigating the neural correlates and strategies associated with emotion regulation, this research paper aims to advance our understanding of how individuals skillfully handle and display their emotions in various contexts. The multimodal approach provides valuable insights into the underlying processes involved in emotion regulation and informs potential interventions for improving emotional wellbeing and adaptive behavior.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Background: Nonprescription antibiotic use includes taking an antibiotic without medical guidance . Nonprescription use contributes to antimicrobial resistance, adverse drug reactions, interactions, and superinfections such as Clostridioides difficile colitis. Qualitative studies exploring perspectives regarding nonprescription use among Hispanic patients are lacking. We used the Kilbourne Framework for Advancing Health Disparities Research to identify factors influencing Hispanic patients\u2019 nonprescription use and to organize our findings. Methods: Our study includes Hispanic primary-care clinic patients with different types of health coverage in the Houston metroplex who endorsed nonprescription use in a previous quantitative survey. Semistructured interviews explored the factors promoting nonprescription use in Hispanic adults. Interviews were conducted remotely, in English or Spanish, between May 2020 and October 2021. We used inductive coding and thematic analysis to identify the factors and motives for nonprescription use. Results: Of the 35 Hispanic participants surveyed, 69% were female and between the ages of 27 and 66. All participants had some form of healthcare coverage . Participants reported obtaining antibiotics from their own leftover prescriptions and through trusted persons , buying them under the counter in US markets, and purchasing them without a prescription outside the United States. Thematic analysis revealed the factors contributing to nonprescription use . Themes included beliefs that the \u2018doctor visit was unnecessary,\u2019 \u2018limited direct access to healthcare\u2019 in the United States , \u2018more open indirect access to healthcare\u2019 abroad and under the counter in the United States, and communication difficulties . Figure 2 shows representative quotes across thematic domains. Participants expressed having confidence in medical recommendations from pharmacists and trusted community members in their social networks. Conclusions: Antibiotic stewardship interventions that include pharmacist-driven patient education regarding appropriate antibiotic use may decrease nonprescription antibiotic use in Hispanic communities. Additionally, improving access to care while addressing communication barriers and cultural competency in clinics may improve primary care delivery and reduce potentially unsafe antibiotic use.Disclosure: None"}
+{"text": "Multiple myeloma generally occurs in older adults, with the clonal proliferation of plasma cells and accumulation of monoclonal protein resulting in a broad range of clinical manifestations and complications, including hypercalcemia, renal dysfunction, anaemia, and bone destruction (termed CRAB features). A 64-year-old man with no history of malignancy presented with an enlarging precordial lump occurring three years post-sternotomy for uneventful coronary artery bypass grafting surgery. Initial investigations showed anaemia and impaired renal function. Multimodal imaging performed for further evaluation showcases the radio-pathological features which can be encountered in haematological malignancy. Subsequent percutaneous biopsy confirmed an underlying plasma cell neoplasm, and a diagnosis of multiple myeloma was achieved. The prompt resolution of the lesions upon the initiation of treatment highlights the importance of early diagnosis and treatment."}
+{"text": "Aedes aegypti\u2013a primary vector of dengue, Zika, and chikungunya viruses. We then validated the use of our approach to generate experimental microcosms colonized by standardized lab- and field-derived bacterial communities. Our results overall reveal minimal effects of cryopreservation on the recovery of both lab- and field-derived bacteria when directly compared with isolation from non-cryopreserved fresh material. Our results also reveal improved reproducibility of bacterial communities in replicate microcosms generated using cryopreserved stocks over fresh material. Communities in replicate microcosms further captured the majority of total bacterial diversity present in both lab- and field-based larval environments, although the relative richness of recovered taxa as compared to non-recovered taxa was substantially lower in microcosms containing field-derived bacteria. Altogether, these results provide a critical next step toward the standardization of mosquito studies to include larval rearing environments colonized by defined microbial communities. They also lay the foundation for long-term studies of mosquito-microbe interactions and the identification and manipulation of taxa with potential to reduce mosquito vectorial capacity.Mosquitoes develop in a wide range of aquatic habitats containing highly diverse and variable bacterial communities that shape both larval and adult traits, including the capacity of adult females of some mosquito species to transmit disease-causing organisms to humans. However, while most mosquito studies control for host genotype and environmental conditions, the impact of microbiota variation on phenotypic outcomes of mosquitoes is often unaccounted for. The inability to conduct reproducible intra- and inter-laboratory studies of mosquito-microbiota interactions has also greatly limited our ability to identify microbial targets for mosquito-borne disease control. Here, we developed an approach to isolate and cryopreserve bacterial communities derived from lab and field-based larval rearing environments of the yellow fever mosquito  i) facilitate the study of mosquito traits of interest  in the absence of confounding effects of microbiota variation, and (ii) enable reproducible intra- and inter-laboratory studies of mosquito-microbiota interactions to identify microbial targets for disease control. Our results are also of broad interest to researchers in the fields of microbial ecology and host-microbe interactions because they demonstrate how tools commonly used to study microbiota assembly and function in mammals can be leveraged in other systems.Mosquitoes develop in the presence of diverse bacterial communities that shape their ability to transmit disease-causing pathogens. However, our current understanding of mosquito-microbiota interactions is largely based on studies of individuals colonized by low-diversity communities of bacteria that are not commonly associated with mosquitoes in the laboratory or field. In this study, we developed an approach to isolate and cryopreserve microbiota from mosquito larval rearing environments in the lab and field. We then demonstrated the successful use of this approach to produce experimental microcosms colonized by standardized microbial communities. Our results are of critical significance to the field of vector biology because they will directly ( The community of bacteria (hereafter referred to as \u2018microbiota\u2019) present in the aquatic environments where mosquito larvae develop can have profound impacts on mosquito biology by modulating larval growth and development and, consequently, adult survival, reproduction, and the competency of adult female mosquitoes to transmit human pathogens (reviewed in ). HoweveAedes aegypti and Culex quinquefasciatus mosquitoes that serve as primary vectors of arboviral infections and filariasis in humans   .We initially sought to develop an approach to isolate and cryopreserve microbiota from conventional larval rearing pans in the laboratory for recapitulation in experimental microcosms. Multiplex sequencing of 16S rRNA gene amplicons for the resulting rearing pan- and microcosm-derived water samples generated a total of 2,669,979 quality-filtered reads with a median sequencing depth of 44,707 reads per sample . An unusi.e., those with a maximum relative abundance \u22641% in rearing pans), with significantly fewer rare ASVs being recovered in experimental microcosms generated using cryopreserved stocks of lower cell densities , even at 5 days post-incubation  between any of the microcosms we generated  of reads from these samples were assigned to ASVs belonging to one of eight bacterial families within the following phyla/classes: Alphaproteobacteria , Betaproteobacteria (Comamonadaceae), Gammaproteobacteria , and Bacteroidetes  . A totalcubation . Howeverenerated .4, 105)  . Differences in beta diversity, measured as average Bray-Curtis dissimilarity, were also overall higher between rearing pans and unprocessed controls than between rearing pans and experimental microcosms generated using material from cryopreserved stocks, regardless of cell density  . Further= 0.001) , post-ho density .i.e., decreased in abundance) in response to cryopreservation .Finally, we performed ALDEx2 tests to identify rearing pan ASVs that significantly changed in relative abundance in response to cryopreservation and/or re-culturing under conventional mosquito rearing conditions Figs  and S4. ion Figs  and S4. Next we sought to validate the use of cryopreservation approaches developed above to generate experimental microcosms colonized by microbiota derived from a naturally occurring mosquito larval habitat in the field. Multiplex sequencing of 16S rRNA gene amplicons for the resulting habitat- and microcosm-derived water samples generated a total of 2,111,045 quality-filtered reads with a median sequencing depth of 43,541 reads per sample , with raP = 0.426).As expected, we identified a substantially higher diversity of bacteria (993 ASVs) across the field-derived water samples as compared to those derived from conventional larval rearing pans in the laboratory, with ~42% of reads being assigned to ASVs belonging to the eight bacterial families dominating communities in rearing pans and the remaining ~58% being assigned to ASVs belonging to one of 306 other families within 187 bacterial orders and 34 phyla/classes . A substP > 0.05).ALDEx2 tests identified a total of 110 of the 993 ASVs found in the habitat water samples we sequenced showing significantly different relative abundances in experimental microcosms, but only 12 of these ASVs, representing <6% of all habitat water sequences, were specifically negatively affected in response to cryopreservation Figs  and S7. While our isolation and cryopreservation approaches resulted in the loss of some lab- and field-derived bacterial taxa and concurrent changes in the total alpha and beta diversity of microbiota within experimental microcosms as compared to the larval rearing pans and habitat water we originally sampled, we observed little variation among the bacterial communities present within replicate microcosms generated using the same cryopreserved stock, with the only exceptions being those generated using stocks of lower cell densities . On averMosquitoes live in close association with bacteria and other microorganisms that shape their ability to transmit pathogens . Howeveri) decouple the effects of sample processing and the cell density of cryopreserved stocks on the recovery and persistence of bacteria in microcosms from those of larvae, which are known to shape water pH, nutrient levels, and even bacterial metabolism [ii) better reflect natural microbiota exposure and acquisition processes in the field, whereby larvae hatch from eggs laid directly into (or adjacent to) water containing established bacterial communities [Ae. aegypti revealed a bacterial community comprised of ~100 unique bacterial taxa and dominated by members of the Proteobacteria, Bacteroidetes, and Firmicutes, consistent with sequencing studies of other laboratory colonies of mosquitoes [Paenarthrobacter, which were significantly reduced or absent in experimental microcosms and may represent taxa that are not readily amenable to centrifugation and/or cryopreservation using our methodology.In this study, we first developed an approach to isolate and cryopreserve microbiota from conventional larval rearing pans in the laboratory for recapitulation in experimental microcosms. We intentionally conducted our experiments in the absence of any larvae in order to:  detected in laboratory rearing pans and commonly detected in field-collected mosquitoes \u201349,60\u201365The cell density of cryopreserved stocks also had a much larger impact on the recovery and persistence of field-derived taxa, with microcosms generated using stocks of lower cell densities exhibiting more variable bacterial communities that were overall lower in complexity that communities in microcosms generated using stocks of higher cell densities. This is consistent with results showing that small sampling volumes from aquatic and other high-complexity environments like soil often fail to adequately capture bacterial diversity \u201377, owine.g., immediately after a rainfall). Defined diets that support mosquito growth and development could also be developed to improve the reproducibility of field bacterial diversity between replicate microcosms, including the maintenance of rare taxa important for community assembly and stability [Overall, experimental microcosms generated using cryopreserved stocks containing lab-derived microbiota exhibited levels of reproducibility that were the same or better than those present under conventional rearing conditions in the laboratory, highlighting the value of our approach for intra-and inter-lab studies of mosquitoes in the presence of standardized microbial communities. Similar levels of reproducibility could also be replicated in microcosms generated using cryopreserved stocks of field-derived microbiota, although reproducibility significantly decreased with decreasing inoculum size\u2013consistent with our previous observation that variability among the bacterial communities present within replicate microcosms was significantly higher in those generated using cryopreserved stocks of lower cell densities. Future studies are warranted to establish best practices for field habitat sampling, though our results at minimum suggest that higher-volume samples are preferable, and that sampling should be avoided in situations where bacterial density is expected to be low . Unmodified bacteria that naturally inhibit pathogen colonization or mosquito fitness could also be disseminated to mosquito populations. The identification of suitable microbial candidates for pathogen or mosquito control will require a comprehensive understanding of the factors that influence the acquisition, maintenance, and transmission of mosquito microbiota and the mechanisms that underlie how individual microbial species and assemblages impact mosquito vectorial capacity. However, the dearth of tools to manipulate mosquito microbiota, including microbiota derived from naturally occurring mosquito habitats in the field, has greatly slowed progress in this area. In this way, the results reported here not only provide a critical first step toward the standardization of microbial inputs in mosquito studies, but also provide a critical first step toward the identification of taxonomic and functional profiles of bacteria associated with phenotypic traits of interest in mosquitoes. For example, a defined microbiota could be universally adopted by the community to conduct vector competence assays in the absence of confounding effects due to microbiota variation. Libraries of cryopreserved microbiota could also be screened to identify bacteria that improve or reduce mosquito fitness and/or pathogen susceptibility, or to predict the success of individual microbial candidates under variable microbial conditions. Similarly, the results reported here strongly support that our methods could immediately be leveraged to expand studies of mosquito-microbiota interactions to include microbial genotypes derived from the field, and thereby conduct lab-based mosquito experiments with field-relevant microbiota.Owing to their ability to impact numerous components of mosquito vectorial capacity, there is a growing interest in exploiting microbes for mosquito-borne disease control. For example, bacteria that naturally colonize the mosquito gut could be genetically modified to produce effector molecules that alter the mosquito\u2019s ability to become infected with and transmit pathogens, or that reduce mosquito fecundity or lifespan (S1 TableAsterisks (*) indicate samples that were removed from the dataset prior to downstream analyses.(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 FigReads from each water library were sampled starting at 1 sequence per step and increased in increments of 100 until the total number of reads per sample was reached. Lines are colored by sample source . Time of sampling of experimental microcosms is designated by line type .(TIF)Click here for additional data file.S2 FigP < 0.05).Proportion of rare (left) and abundant (right) ASVs found in at least one larval rearing pan that were detected in experimental microcosms containing unprocessed water or sterile water plus material from a given cryopreserved stock. An ASV was considered \u201crare\u201d if it had a maximum relative abundance \u22641% across the four larval rearing pans we sampled, while ASVs with a minimum relative abundance >1% were considered \u201cabundant\u201d. Asterisks (*) indicate significant differences between experimental microcosms generated using cryopreserved stocks relative to unprocessed controls as determined by paired Fisher\u2019s exact tests with Bonferroni correction ((TIF)Click here for additional data file.S3 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in samples from larval rearing pans. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across rearing pan samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing unprocessed water and experimental microcosms containing sterile water plus material from cryopreserved stocks see .(TIF)Click here for additional data file.S4 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in samples from larval rearing pans. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across rearing pan samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing sterile water plus material from cryopreserved stocks and experimental microcosms containing unprocessed water see .(TIF)Click here for additional data file.S5 FigReads from each water library were sampled starting at 1 sequence per step and increased in increments of 100 until the total number of reads per sample was reached. Lines are colored by sample source . Time of sampling of experimental microcosms is designated by line type .(TIF)Click here for additional data file.S6 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in habitat water samples. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across habitat water samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing unprocessed habitat water and experimental microcosms containing sterile water plus material from cryopreserved stocks see .(TIF)Click here for additional data file.S7 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in habitat water samples. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across habitat water samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing sterile water plus material from cryopreserved stocks and experimental microcosms containing unprocessed water see .(TIF)Click here for additional data file."}
+{"text": "Simulation is a key component of surgical training, enabling trainees to develop their skills in a safe environment. With simulators broadly grouped into physical models and virtual-reality (VR) simulators, it is important to evaluate the comparative effectiveness of the simulator types in terms of validity as well as cost. The review aims to compare the benefits and drawbacks of novel VR and physical simulators within the broader themes of endourology, laparoscopic and robotic operations, and other urological procedures.Key benefits of bench models include their comparatively lower cost, easy access and provision of haptic feedback, whereas VR simulators are generally self-sufficient, reusable and enable skills of haemostasis to be practised. The advent of perfused 3D printed simulators across a range of urological procedures may replace cadavers as the traditional gold-standard simulation modality.Although possessing differing strengths and downsides, VR and physical simulators when used together can have an additive effect due to skill transferability across the platforms. Further comparative studies are required to directly quantify the differences between physical models and VR simulators in terms of performance metrics and cost-effectiveness. There is lack of validated VR simulators for open and reconstructive procedures. Simulation is an integral part of surgical training enabling trainees to hone their technical skills away from actual patients until they achieve a safe level of competency . This isEndourological procedures include ureteroscopy, cystoscopy and transurethral resections of the bladder and prostate. The SIMULATE international prospective trial  examined3D model simulators have been recently developed in the field of cystoscopy such as the \u2018FlexBlad\u2019  and \u2018Bla\u25aa\u25aa] examining simulation training in transurethral resection and laser vaporisation procedures of the prostate. The review findings pointed towards VR simulators uniquely possessing data capture and performance evaluation features but that alongside their typically poor haptic feedback, their simulation of bleeding is generally poor for TURP and laser vaporisation. Physical simulators such as bench-top tissue and food-based models also inadequately simulate bleeding for these procedures and carry hygiene risks, but are lower cost and beneficial in that they use real instruments. In the context of laser-based procedures, cadavers demonstrate content validity for holmium laser AEEP training [The European Section of Uro-Technology (ESUT) undertook a systematic review \u25aa\u25aa examintraining  with suptraining , VR simutraining \u25aa,16 and PCNL is another endourological procedure for which simulators have been validated. One study used participant ratings and performance data to compare three simulators ; a porciAlthough cadavers are considered the gold-standard simulation modality, artificial perfusion of cadavers is limited by high cost, positive viral profiles and difficulty clearing the vascular tree. One low-cost, nonbiohazardous physical model for robot-assisted partial nephrectomy (RAPN)  directlyLive animal models such as porcine models pose ethical challenges not associated with other simulators. One study  aimed toVR simulation performance for robot-assisted radical prostatectomy (RARP) has crucially been shown to correlate with live surgical performance in the real operative environment thereby increasing its validity as a training modality. One study  of 20 suWith VR, simulation is moving beyond just basic isolated skills training to full procedural simulation. This has been demonstrated for RARP  with supFor laparoscopic pyeloplasty, various physical simulators exist with advantages over VR simulators such as significantly lower cost and easy access whilst maintaining anatomical realism. As with aforementioned procedures, 3D printed models for pyeloplasty have been produced  demonstrFor the management of urological emergencies such as priapism and testicular torsion, there is an absence of validated VR simulators to develop the skills necessary for the therapeutic interventions these conditions require. There is therefore a reliance on physical simulators to facilitate skill acquisition and these have been incorporated effectively into training curricula. For example, a urological emergency simulation curriculum was devised for military surgeons  utilisinFor penile fracture repair, the first validated simulation model was recently created , based oReconstructive urology is another field in which validated VR training is absent. Instead high-fidelity, 3D-printed penile models have been produced for the simulation of plaque incision and graft (PIG) as indicated for the treatment of Peyronie's disease , achieviTo conclude, physical models are generally superior with regard to cost-effectiveness, the provision of haptic feedback and ease of access, while VR simulators are self-sufficient, reusable and avoid the ethical and infection concerns associated with animal models. Although cadavers have long been considered the gold-standard simulation modality, these may soon be superseded by the advent of highly realistic, perfused 3D printed models capable of procedural simulation incorporating anatomical variation and intraoperative complications  at a subThe authors received no source of funding and have no conflicts of interest.None.Baldev Chahal, Abdullatif Aydin and Kamran Ahmed have no conflicts of interest or financial ties to disclose."}
+{"text": "Watermelon stomach, also known as gastric antral vascular ectasia (GAVE), is a rarely seen cause of acute upper gastrointestinal bleeding or chronic iron deficient anemia, revealed when gastroscopy is performed. GAVE affects predominantly women of advanced aged and is usually associated with certain underlying co-morbidities including liver cirrhosis, autoimmune diseases and chronic kidney disease. Based on the above, we report the case of a 75-year-old woman under hemodialysis for six consecutive years due to end-stage renal disease attributable to hypertensive nephrosclerosis. The patient also suffered from chronic ischemic heart disease, severe peripheral artery disease and an unidentified connective tissue-disease characterized by high levels of anti-nuclear antibodies and clinical symptoms restrained in flares of non-erosive polyarthritis. Six months prior, she developed hyporesponsiveness to recombinant human erythropoietin (rEPO) due to iron deficiency despite the administration of the appropriate dose of intravenous iron as well as the exclusion of other co-existing causes of resistance, namely inadequate hemodialysis, inflammation, malnutrition, severe hyperparathyroidism and underlying hematologic disorders. Surprisingly, the patient experienced a sudden episode of severe upper gastrointestinal bleeding characterized by hemodynamic instability, hemoglobin fall and melena that required blood transfusions. Once hemodynamic stabilization was achieved, an upper endoscopic exam was performed showing the pathognomonic extensive vascular ectasias and patchy erythematosus lesions at the distal antrum. Thus, GAVE should be considered in the differential diagnosis of chronic kidney disease patients who present not only with acute blood loss but also with resistance to rEPO due to inadequate iron stores."}
+{"text": "Many cattle and sheep do not produce enough colostrum for their offspring.Prepartum nutrient intake is an accessible strategy for producers to influence colostrum production.Greater prepartum starch intake can influence colostrum composition and increase colostrum yield for beef cattle and ewes.Colostrogenesis is sensitive to fat intake, dependent on the dietary fatty acid composition: greater linoleic acid intake often increases colostrum antibody concentration.Colostral bioactive compounds are frequently altered by a prepartum diet without changes in overall colostrum composition. Prepartum nutrient intake could be strategically used to maximize beneficial compounds for the newborn.IgG), macronutrients, and bioactive compounds that promote physiological maturation and support the immune system  or protein (MP) intake, or dietary components such as starch, neutral detergent fiber (NDF), or fat.Most research evaluating how prepartum nutrient intake affects colostrum production has mainly focused on global nutrient under- or over-provision prior to parturition. Imposing mid to late-gestation nutrient restriction reduced first-milking colostrum yield  in beef cattle  without NE]). This is additionally complicated by using either empirical or mechanistic models to predict energy requirements and dietary sufficiency and which coefficients of energetic efficiency are used for the conversion of ME to NE for pregnancy or maintenance. Thus, utilization of either system can impose a bias on colostrum production responses between studies. Research evaluating carbohydrate consumption prior to parturition is shown in Carbohydrates proportionally contribute the greatest amount of dietary energy in ruminant rations and, as such, relative starch and NDF substitutions have consequences for dietary energy intake that often confound colostrum production responses. Furthermore, studies that manipulate dietary starch and NDF content to achieve specific energy intakes differ in which energy partition they target  and MP intake not always being balanced across treatments  increased colostrum yield by 80% in Simmental-Angus crossbred beef cattle . These cIn accordance with beef cattle, increasing dietary starch and energy intake in sheep consistently increased colostrum yield . Bancher1 and total IgG concentrations in colostrum ; thus, this factor should be considered when comparing colostral IgG concentrations between studies using different dietary starch sources. Nonetheless, IgG concentration in first-milking colostrum collected within 1 to 12 h after calving has been reduced by greater dietary starch inclusion or ME intake precalving  while suppressing the synthesis of de novo FA relative to cows fed a ration that targets 125% or 150% predicted ME requirements prior to calving  are substantial but transient and, as such, presumed negligible relative to pregnancy and maintenance requirements. Regardless, numerous studies .Models that evaluate the sufficiency of prepartum shown in  have evashown in  and 2. Wiso-nitrogenous and iso-energetic rations; Apart from substituting sunflower meal for cottonseed meal as a protein source wherein the authors observed that greater sunflower meal increases first-milking colostrum yield  increases colostrum yield . HoweverAs with colostrum yield, colostrum IgG concentration, as measured by radial immunodiffusion  or estimThere are limited data regarding how prepartum protein intake affects colostrum macronutrient composition and yield in cattle. That said, from what is available, colostral fat, protein, and lactose concentrations are unaffected , nor areComparatively, colostrum protein concentration has been reported to increase with protein supplementation in some studies with ewes , but notRations typically have 2%DM dietary fat and, generally, dietary fat should not exceed 6% to 7%DM to avoid detrimental impacts on ruminal fermentation. However, greater dietary fat provision can also improve ration palatability, control dust and fines, and alleviate heat stress due to its lesser heat increment respective to proteins and carbohydrates. Increasing prepartum dietary fat intake can concurrently increase energy intake without providing excessive dietary starch. Consequently, prepartum fat intake may have utility for prepartum rations and studies in cattle  and ewesLate-gestation fat inclusion rate and source have not been shown to affect first-milking colostrum production in dairy cattle, either when NE concentration was maintained  or when \u0251-linolenic) in late-gestation rations could be beneficial for increasing ewe colostrum yield. Currently, it is unclear why this response occurs.First-milking colostrum yield in ewes appears to be more responsive to dietary fat content than cattle, but results across studies remain inconsistent. Some authors have found that specific fat sources  can decrease first-milking half-udder colostrum yield collected within an hour  and betwInterestingly, colostral IgG concentration, as measured by ELISA or estimated using Brix, appears to be responsive to dietary fat inclusion and source in both dairy  and beefAlthough fewer data are available for ewes, their colostral IgG concentration does not appear to respond to fat intake and source as in cattle . Though,Colostral macronutrient concentrations are usually unaltered by dietary fat content and source for cattle . NotablyThe colostral FA profile is the most reported bioactive component among research evaluating prepartum dietary fat intake and source. For both cattle and sheep, colostrum FA composition ubiquitously varies across all reported studies when the dietary fat inclusion rate or source is altered in such a way that coincides with dietary FA intake and maternal plasma FA profile. With respect to other bioactive components and micronutrients, Prepartum nutrient intake has the capacity to influence colostrogenesis in bovine and ovine species and impact colostrum yield and composition. Although ewes are generally more sensitive to ration composition than cattle, there is evidence to suggest that prepartum nutrition can be used strategically to promote colostrum production in both species. Dietary starch and fat content and source appear to exert influence on colostrum IgG concentration, with data indicating that starch:NDF substitutions affects colostrum yield in beef but not dairy cattle. Current data suggest that cattle are irresponsive to dietary protein content, whereas ewe colostrum production responds to dietary protein source and intake. Further work needs to differentiate between carbohydrate, protein, and fat sources, accounting for total IgG and macronutrient yield, to characterize mammogenic capacity under differing nutritional regimens, particularly in relation to the feeding duration and timing of supplementation relative to the onset of colostrogenesis. In addition, there is a need to detail the colostral bioactive profiles, as this constituent often responds to prepartum nutrient intake without changes in the gross composition of colostrum. Colostral bioactive components are inherently important for neonatal development and, as such, prepartum nutrient intake might be used strategically to benefit the offspring."}
+{"text": "Psychiatric disorders are complex clinical conditions with large heterogeneity and overlap in symptoms, genetic liability and brain imaging abnormalities. Building on a dimensional conceptualization of mental health, previous studies have reported genetic overlap between psychiatric disorders and population-level mental health, and between psychiatric disorders and brain functional connectivity. Here, in 30,701 participants aged 45\u201382 from the UK Biobank we map the genetic associations between self-reported mental health and resting-state fMRI-based measures of brain network function. Multivariate Omnibus Statistical Test revealed 10 genetic loci associated with population-level mental symptoms. Next, conjunctional FDR identified 23 shared genetic variants between these symptom profiles and fMRI-based brain network measures. Functional annotation implicated genes involved in brain structure and function, in particular related to synaptic processes such as axonal growth (e.g. NGFR and RHOA). These findings provide further genetic evidence of an association between brain function and mental health traits in the population.The online version contains supplementary material available at 10.1186/s12888-023-04905-7. Psychiatric disorders are complex, with a polygenic architecture, and large degree of overlapping symptoms and risk factors. Both imaging and genetics studies have shown numerous but small associations between brain phenotypes, psychiatric disorders, and genetics, such as schizophrenia (SCZ) \u20133, bipolWe have recently deployed a multivariate analysis to study the genetic architecture of brain functional connectivity, revealing genetic variants associated with functional brain connectivity as well as variance in brain activity over time . The resPrevious studies have shown widespread phenotypic and genetic overlap between psychiatric disorders \u201318. In aHere, we aimed to uncover the genetic architecture of mental symptoms and identify shared genetic loci with neurobiological processes related to brain function. Using multivariate analysis , we geneWe utilized data from the UK Biobank  with perThe processing pipeline for imaging data used for the multivariate GWAS is described in Roelfs et al. . In shorIn this study we applied MOSTest to the phenotypic data from the ICA decomposition described in Roelfs et al. . MOSTestIn order to quantify the degree of genetic overlap and identify shared genetic loci between the mental health profiles and the imaging features we deployed the pleiotropy-informed conjunctional false discovery rate (conjFDR) through the pleioFDR toolbox . We usedADH1B and ADH5 (chromosome 4) and CRHR1 (chromosome 17).MOSTest revealed 10 significant (P\u2009<\u20095e-8) loci across the 13 previously identified profiles of mental health  , bipolarNext, we explored the genetic overlap between the mental health profiles and the psychiatric disorders through the conjunctional false discovery rate (conjFDR) , 36 whicWe then calculated the number of shared genetic loci between the multivariate genome-wide association statistics for mental health profiles and the two multivariate measures of the brain functional connectome using conjFDR. The GWAS summary statistics from our previous study of brain function . In shorIn this study we identified a number of loci associated with multivariate genome-wide association statistics for mental health profiles and found overlapping loci with the measures of brain function and psychiatric disorders. Using MOSTest we were able to leverage the phenotypic overlap between different mental health profiles to identify new loci associated with a multivariate measure of mental health. Genes associated with these loci showed regional expression in different parts of the brain .Our analysis using conjFDR revealed a number of shared loci and genes between the multivariate genome-wide association statistics and the psychiatric disorders. This demonstrates the shared genetics between psychiatric symptoms regardless of clinical diagnosis, emphasizes the utility of using population-level phenotypes to investigate variance in mental health profiles, and highlights the advantage in leveraging pleiotropy between complex phenotypes to boost discovery. We found shared genes with all but two case-control GWAS , which also had the two smallest sample sizes, which may reflect insufficient power to detect an effect , or may We also identified a number of overlapping loci between mental health profiles and fMRI measures of brain function, including 18 shared loci with functional connectivity and 5 shared loci with node variance. The higher number of shared loci for functional connectivity might be partially explained by the number of phenotypes in each composite measure. While the functional connectivity GWAS comprises 210 measures, i.e. partial correlations between 21 brain nodes, the node variance GWAS encompasses only the temporal variance in each node. It is possible that the number of phenotypes included in the multivariate analysis can affect the discovery . Both thThe two conjunctional analyses with fMRI measures and the multivariate genome-wide association statistics for mental health each showed a number of overlapping loci. Not all shared loci were unique, this can be partially explained by the definition of the brain networks in our analyses. The functional connectivity and the node variance measures use the same 21 nodes, and, ultimately, the two measures reflect different properties of the same time series. We found that the number of overlapping loci between the multivariate genome-wide association statistics for mental health and the brain functional connectome was generally larger than findings from our previous study highlighting shared genetic loci between psychiatric disorders and the brain functional connectome. This may partly be due to the larger sample size of the multivariate measure of mental health, but it could also reflect that the multivariate genome-wide association statistics capture genetic variance more generally related to the brain functional connectome. We found little direct overlap between loci of these two GWAS\u2019 separately, which highlights the discovery boost advantage of using conjFDR in phenotypes with generally low heritability.The main implication from our findings is that we can identify shared genetic variants between a multifactorial measure of mental health in an undiagnosed population sample and fMRI-based measures of brain functional connectivity. Several limitations should be considered. First, the data were obtained from a middle-aged and older White British population, which limits the generalizability of the findings. Further, the mental health questionnaires are self-administered, so the data is vulnerable to various response and self-selection biases . We exclIn conclusion, our multivariate GWAS on 13 mental health symptom profiles showed a number of shared genetic loci with two fMRI-measures reflecting brain function and connectivity. This research shows that genetic overlap between mental health symptom profiles and brain functional connectivity can be linked to, among other processes, axonal growth regulation (through NGFR and RHOA) and regulation of MECP2 transcription factors (through MEF2C). This provides further genetic evidence of an association between brain function and mental health traits in the population.Below is the link to the electronic supplementary material.Supplementary Material 1: Supplementary Figures and Tables"}
+{"text": "Editorial on the Research TopicMolecular pathogenesis and novel treatments for inherited cardiomyopathiesInherited cardiomyopathies have diverse genetic etiologies, but together are major contributors to cardiac disease that affect patients of all ages, typically with early onset in childhood or adolescence. While inherited cardiomyopathies are currently classified according to functional and morphologic features, finer resolution of these categories has been made possible with the aid of modern genetics. However, despite the identification of many disease-causing variants, effective therapies for the majority of inherited cardiomyopathies remains scarce. In this issue, a collection of original research and review articles unveil and summarize the pathogenic mechanisms and gene expression signatures of various inherited cardiomyopathies as well as novel and extant therapeutic strategies in treating selected subsets of inherited cardiomyopathies.Hilal et al. which discusses in detail how mutations in RAS genes underlie phenotypically diverse cardiomyopathies in addition to distinct systemic syndromology. Notably, one must cautiously distinguish cardiomyocyte-intrinsic from extrinsic effects of RAS hyperactivation. While several in vitro studies demonstrated that ectopic RAS activation results in cardiomyocyte hypertrophy, cardiomyocyte-specific expression of gain-of-function RAS variants did not result in HCM despite cardiomyocyte hypertrophy seen in neonatal mice carrying the same germline mutation in the RAS gene , represents a major co-morbidity of genetic hemochromatosis as well as secondary iron overload. A recent clinical trial demonstrated that amlodipine and chelation combination therapy significantly lowers intracardiomyocyte iron deposition. Mechanistically, amlodipine appears to block the L-type calcium channel, which otherwise provides a major route for iron entry into the cardiomyocyte. Over the past decades, the identification of genes in which pathogenic variants are associated with inherited cardiomyopathies has raised expectations for new therapies. Advances in genomic editing technology hold promise for directly targeting pathogenic variants, and have the potential for shifting the paradigm for treatment in genetic medicine. Other approaches harnessing natural genetic modifying mechanisms that suppress the penetrance of pathogenic variants may also be useful. While the incomplete penetrance of inherited cardiomyopathies often complicates the genetic evaluations of families with cardiomyopathies, the observation that many mutation carriers remain disease free in fact provides paradoxical hope that disease-modifying therapeutics may be achievable. Future omics studies comparing transcriptome and proteome between clinically active and silent mutation carriers may thus uncover novel therapeutic approaches to delaying disease onset. In parallel, development of additional genetic animal models that approximate human cardiomyopathies will enable rigorous mechanistic studies that potentiate development of therapeutic agents."}
+{"text": "Structural valve deterioration is commonly defined as an intrinsic permanent change of the bioprosthesis due to leaflet calcification, thickening, pannus formation, tear, or disruption. The resulting deterioration leads to stenosis and/or intra-prosthetic regurgitation. Here we present the case of a 75-year-old patient who underwent aortic valve replacement with a bioprosthetic valve. Predischarge transthoracic echocardiography revealed an aortic prosthesis with normal gradients. Three years later, the patient reported exertional dyspnea. Transthoracic echocardiography was performed and showed a high transvalvular pressure gradient of 80 mmhg with restricted mobility of the leaflet caused by subprosthetic tissue. Redo aortic valve replacement was planned and surgical resection was performed showing pannus ingrowth in both aortic and ventricular side of the bioprosthesis."}
+{"text": "We also do not understand how suicide and suicidal ideation changed for different Hispanic immigrant populations since 2015, coinciding with a rise in anti-immigrant political sentiment and policymaking. Without action to either improve public health surveillance or leverage existing data sources with immigration status information to better understand the burden of suicide death and suicide risks among Hispanic immigrants, we may fail to prevent unnecessary loss of life.,,Anti-immigrant attitudes are not a new phenomenon in the U.S.,A key example of these policies was the administration's highly publicized public charge rule changes, which built upon the public charge standard developed through the Illegal Immigration Reform and Immigrant Responsibility Act.,Unfavorable immigration policy has been linked to greater perceived health problems among adults and children.,Despite these risks, deportation fears and the chilling effects of anti-immigrant attitudes and policies likely discouraged enrollment into health insurance programs ,Avoiding care while facing discrimination or psychological trauma can be problematic for suicide prevention. Discrimination is a risk factor for mental health problems among Hispanic persons.In response, public health researchers have an opportunity to increase their understanding of the burden of suicide among Hispanic immigrant populations in relation to the rise of anti-immigrant sentiment. This remains a challenging task when national mental health and suicide statistics do not take immigration status into account, when commonly available data sources restrict access to information about visa status, and when data from the Centers for Disease Control and Prevention do not distinguish between immigrants and U.S.-born Hispanics.Many researchers have attempted to account for immigration status in their studies\u2015cutting across multiple disciplines\u2015although these attempts have been discordant, resulting in different definitions and experiences of unauthorized legal status.Specific actions can be taken while being mindful of stigma-related implementation concerns. First, rather than actively seeking information from Hispanic immigrants, we can prioritize efforts to report deceased immigrants\u2019 citizenship status on either the U.S. Standard Certificate of Death or equivalent state-level forms. Specifically, citizenship status, available by contacting Citizenship and Immigration Services, could feasibly be collected by the medical certifier or funeral director when collecting demographic data required for the death certificate. This information would then be reported into state violent death report systems, which already aggregate deidentified information on country of birth and other sensitive characteristics for suicide decedents.Second, additional initiatives could include collecting citizenship information for immigrants participating in large health surveys. Previous studies suggest that unauthorized immigrants are interested in and willing to discuss legal status in research. To ease the impact of the deportation-related concerns on unauthorized immigrant participation, surveyors should build rapport before presenting legal status questionsThird, the research community can use existing data in creative ways to better understand suicide-related risks experienced by Hispanic immigrants. Data sources collecting citizenship or country of birth information, such as the National Health Interview Survey or Hispanic Community Health/Study of Latinos, respectively, can be used to estimate the relationships between immigration status and important suicide risk factors for Hispanic populations since 2015. Existing data sources can also give us guidance on how to estimate the impact of recent immigration policies on suicide risk factors such as mental health outcomes.We do not fully understand the burden of suicide or recent changes in suicidal ideation among Hispanic immigrant populations in the U.S. However, we hypothesize that increasingly acrimonious immigration attitudes and policies likely worsened suicide-related outcomes for many Hispanic immigrants, authorized and unauthorized. The coronavirus disease 2019 (COVID-19) pandemic is likely intensifying suicide-related risks, given the harmful impacts the pandemic has imposed on Hispanic communities."}
+{"text": "The United States Department of Health and Human Services (HHS) pledged $90 million to help reduce health disparities with data-driven solutions. The funds are being distributed to 1400 community health centers, serving over 30 million Americans. Given these developments, our piece examines the reasons behind the delayed adoption of big data for healthcare equity, recent efforts embracing big data tools, and methods to maximize potential without overburdening physicians. We additionally propose a public database for anonymized patient data, introducing diverse metrics and equitable data collection strategies, providing valuable insights for policymakers and health systems to better serve communities. This sum is planned to be distributed to 1400 community health centers (CHCs) serving over 30 million Americans1. Specifically, this pledge will allow health centers to expand analytics and reporting capabilities to enhance healthcare services while supporting patient-level UDS+ data submissions to collect more precise data on health disparities2. We herein propose a national public database featuring voluntarily self-disclosed and deidentified patient data to increase the granularity of health disparities metrics, and propose how this project can incorporate diverse metrics and equitable data collection procedures.In April 2022, Health and Human Services (HHS) pledged 90 million USD to the American Rescue Plan Uniform Data System Patient-Level Submission (ARP-UDS+) funding award in support of new data-driven efforts for Health Resources and Services Administration (HRSA) Health Center Programs to identify and reduce health disparities3. The NHQR is a comprehensive review of American healthcare comparing health outcomes across both state and national levels4. This report revealed that, although communities of color have enjoyed increased healthcare access since 2000, racial inequity persisted in 2021 due to lack of focused interventions addressing disparities3. While CHCs disproportionately serve marginalized populations, their lack of granular data collection is likely leading to underestimations of health disparities in areas requiring the greatest resource support4.Big data has already been proposed to promote health equity at the federal level. For instance, in 2021, the Agency for Healthcare Research and Quality (AHRQ) released the National Healthcare Quality and Disparities Report (NHQR)4. For instance, the Community Health Needs Assessment (CHNA) in the Patient Protection and Affordable Care Act (ACA) requires CHCs to investigate the biggest health-related challenges in their communities and outline solutions5. However, CHNAs often lack subjective data like medical trust and are only collected periodically, producing an unnecessary lag time between when systemic health issues arise and when healthcare providers can identify and respond to them.Big data has impacted patient care for decades by helping health insurance companies incentivize preventative care among patients and physicians, ultimately decreasing the use of costly acute care and improving care equity4. This platform can also be used to monitor medications while empowering CHCs to pinpoint and respond to systemic issues more quickly. Although the database may be skewed towards higher-income individuals with more time to self-report, the resource can help compare assess healthcare quality without overburdening physicians, ultimately improving equity interventions.Given these challenges with current healthcare metrics, the Centers for Medicare and Medicaid Services (CMS) should develop a national database like the CDC\u2019s Vaccine Adverse Event Reporting System (VAERS), which collects self-reported issues with vaccine reactions, to regularly collect self-reported data on symptoms, diseases, adverse reactions, medical trust, and perceptions of health equity through metrics like transportation time or food insecurity6. These metrics were only introduced to eight of these measurements, and that only in 20226. HEDIS also does not stratify metrics by other determinants of health like food insecurity or employment status6. Metrics for further development could also include language access, transportation barriers, and health literacy.Although the data would be self-reported, the requested data should include many new metrics. For instance, the National Committee for Quality Assurance (NCQA) Healthcare Effectiveness Data and Information Set (HEDIS), the basis for many equity measurement systems, HEDIS was inaugurated in 1991 and continued for 31 years without race or ethnicity included in its nearly one hundred performance measures7. CHCs can also assess the readability of patient education materials and track the effectiveness of health literacy interventions like counseling, visual aids, staff training on health literacy communication, and simplified language in educational pamphlets through validated health literacy screening tools like REALM-SF (Rapid Estimate of Adult Literacy in Medicine - Short Form)8. REALM-SF examines abilities to read aloud medical terminology and is available free for download on the National Center for Education Statistics (NCES) website9.Healthcare organizations can better understand language barriers by offering patient surveys after each visit. Depending on the extent of the issue, Community Health Centers (CHCs) can then adopt interpreter services and track its effectiveness through surveys. To address transportation barriers, patients can opt to disclose transportation service use and reasons for missed appointments. CHCs can then partner with transportation providers like Uber WAV (Wheelchair Accessible Vehicles) and Uber Health to improve patient accessibility and cover for deficiencies in available wheelchair-accessible vehicles11.To ensure that the system captures data from marginalized populations, we propose CHCs invest in technology infrastructure and staff training to prepare for more comprehensive data collection by, for instance, leveraging telehealth services to provide care management while streamlining data collection through remote patient monitoring and automated post-checkup surveys. Then, outside partnerships with research organizations can help CHCs analyze this data and devise tailored solutions through partnerships with relevant nonprofits like the National Partnership for Women and Families, which has developed best practices for patient engagement in healthcare, and Leapfrog, which helps analyze data to promote healthcare safety and qualityFurthermore, to promote interoperability with electronic health records, we suggest following the technical standards developed by organizations such as the Office of the National Coordinator for Health Information Technology (ONC) and the Health Level Seven International (HL7) organization. These standards ensure that data can be exchanged seamlessly between different healthcare systems while safeguarding self-reported data. We also recommend consulting with the ONC\u2019s Trusted Exchange Framework and Common Agreement (TEFCA) to help establish policies for securely exchanging health information across organizations.However, marginalized groups must be involved in the design of this database. They could provide input on how to create a user-friendly interface with icons instead of words on buttons to accommodate those with low literacy or limited technological proficiency. The database should also collect data on the widest possible range of demographic factors; provide technical support through online tutorials or help desks staffed by technical support personnel; establish robust privacy policies like strict data access controls, encryption protocols, and other technical safeguards; and implement data quality controls, like automated data validation checks; and seamlessly deliver the data to researchers and policymakers through data dashboards.As big data revolutionizes the world, we must not forget its potential impact on improving health outcomes and disparities. By investing funds into health centers and hospitals for patient-driven reporting and data collection on race and ethnicity and developing minimum standards for health equity metrics collection and reporting across states, public discourse and media then draw on subsequent patient data analyses to bring greater attention to regional and national healthcare inequities, leading lawmakers to prioritize health equity initiatives and healthcare systems to have a clearer picture of the communities they serve.Further information on research design is available in the Reporting Summary"}
+{"text": "In recent years, the advancement in biotechnology has enabled much improvement in quality and outcomes of medicine. These innovations have also drawn great attention in dental research fields. Regenerative medicine such as tissue (bone and tooth) engineering has been a hot topic in oral and craniofacial research for a few decades. Cells, signaling molecules and scaffold materials are three key components of tissue engineering approaches. Almost everyday new bioengineering approaches are proposed and tested for various diseases and treatment in dentistry.Liu et al.). EVs secreted by human gingival MSCs (hGMSC-derived EVs) were shown to promote osteogenesis and neovascularization in vitro and in vivo . The roles of stem cell-derived EVs and non-stem cell-derived EVs in bone tissue regeneration  are reviewed . Engineering modified EVs may play important roles in future cell free EV-based bone tissue engineering therapies.Stem cells such as mesenchymal stem cells (MSCs) are multipotent and may differentiate into different cell types for tissue repair and regeneration. However technical issues including phenotype consistency, host immune response and potential tumorigenicity are still not completely resolved. Extracellular vesicles (EVs) originate from cellular endosomes and contain bioactive molecules to target cells by paracrine. It is known that these EVs are one of the major mediators of stem cells leading to their biological effects. MSC-derived EVs (MSC-EVs), instead of MSCs, may be potentially used in tissue repair and regeneration. The current status and future therapeutic applications of MCS-EVs in oral and craniofacial tissue regeneration are discussed in a review . Similarly, nanofibrous scaffold material can be modified to provide better coordinated regenerative endodontic treatment when pulp connective-tissue, dentin formation, revascularization and reinnervation need to be well orchestrated . Silk fibroin nanoparticles were coated with genetically engineered cell membrane overexpressing toll-like receptor 4 and loaded with minocycline hydrochloride. These biomimetic nanoparticles demonstrated excellent targeted antibacterial and immunoregulatory effects in vitro and in vivo (ligature-induced periodontitis mouse model) .A new generation of scaffold materials has been developed for tissue engineering. A multifunctional structurally optimized hydrogel scaffold was designed by integrating polyvinyl alcohol, gelatin, and sodium alginate with aspirin and nano-hydroxyapatite (nHAP). The osteogenic of nHAP and anti-inflammatory function of aspirin were successfully synergized . Targeted delivery of antitumor drugs has been recognized as a promising therapeutic modality to improve treatment efficacy, reduce toxic side effects and inhibit tumor recurrence. A controlled-release of an anti-tumor drug (apatinib) from supramolecular nanovalve-modified mesoporous silica was designed for targeted inhibition of osteosarcoma . This in vitro study showed efficient release of antitumor drug and promising results for future osteosarcoma treatment. Enamel white spot lesions do not have effective yet conservative treatment methods. Synergistic remineralization of enamel white spot lesions was achieved by using mesoporous bioactive glasses loaded with amorphous calcium phosphate, which implies great potential for clinical application .Other advancements in oral disease therapies are also made in recent years. Eldecalcitol, a novel active vitamin D3 analog, was shown to be effective on preventing alveolar bone loss in diabetes-associated periodontitis . Understanding the composition and differences between supragingival plaque biofilm microbes on the surface of fixed prostheses and natural crowns can provide patients with targeted guidance to focus on oral hygiene habits, reduce the risk of periodontal diseases and improve the success rate of fixed prostheses.The microbial composition and structural diversity of supragingival plaque on the surface of fixed prostheses were found to differ from that of normal natural crowns, with relatively high levels of periodontally related pathogens and higher microbial metabolism. The microflora on the surface of all-ceramic crowns was more similar to that of natural crowns than to that of porcelain-fused-to-metal crowns . Through the use of AM technology, personalized implant treatment for individual patients can be achieved.In addition to biotechnology, digital technology has also been applied in oral disease treatment, such as implant therapy. Additive manufacturing (AM) can enable the direct fabrication of customized physical objects with complex shapes, based on computer-aided designs. The applications of AM technologies in oral implantology, including implant surgery and restorative products, was reviewed (With the quick advancement of therapeutic approaches, biotechnology, and bioactive materials, it will not be too long before precision and personalized dentistry become reality."}
+{"text": "Background: Older people living in residential aged care facilities frequently experience medicines-related harm. Evidence regarding the perception and practices towards reducing these harms may facilitate the development of customised educational programs for pharmacists providing services in RACFs.Objective: To explore Australian pharmacists\u2019 opinions and practices towards reducing the risk of medicines-related harm in aged care residents.Methods: An online survey was developed based on a literature review, expert opinion, and feedback from pharmacists providing services in RACFs. A web link for the survey was shared via professional pharmacy organisations and social media groups with Australian pharmacists providing services in RACFs.Results: A total of 209 pharmacists participated in the survey. Of these, 76% (n = 158) were residential medication management review embedded pharmacists, and 24% (n = 51) were supply pharmacists for RACFs. Most pharmacists believed that medicines-related harm is common in residents , yet few agreed that pharmacists have enough time to participate in medicines-related harm reduction services . There was a high level of agreement regarding the key risk factors  and potential strategies  for reducing medicines-related harm in residents.Conclusion: Pharmacists agreed that older residents often experience medicines-related harm, but they did not frequently participate in medicines-related harm reduction services. Initiatives to engage pharmacists in team-based harm reduction services and educate aged care staff regarding safe medication management may improve residents\u2019 safety and health outcomes. Medicines play an integral role in disease management, yet can be associated with significant problems, especially in vulnerable older people . Older pPharmacists are recognised as experts in pharmacotherapy and could potentially prevent medicines-related harm in older people . A pharmPrevious studies in Australian RACFs focused on determining pharmacists\u2019 views towards antibiotic prescribing  and moniA cross-sectional national survey was conducted between February 2022 and August 2022. Pharmacists across Australia providing clinical or supply services to RACFs were the target population.An initial draft of the survey was generated based on a literature review, expert opinion, and feedback collected from pharmacists providing services to RACFs. The survey comprised questions on demographics, pharmacists\u2019 extent of agreement with statements regarding medicines-related issues and practice considerations, and perceptions towards risk factors for medicines-related harm and potential strategies for reducing medicines-related harm in aged care residents. Question types included Likert scales and free-text boxes. The face and content validity of the draft questionnaire was determined through a pilot sample of 10 registered pharmacists. Based on feedback, the questionnaire was reviewed to ensure it was easy to understand and complete. It was designed to be completed within 15\u00a0min.\u00ae was shared with pharmacists via Australian pharmacy organisations , Pharmacy Daily (an online publication), and social media groups . An information sheet was on the cover page of the survey to provide general information to the potential study participant, including eligibility such as providing any type of services to RACFs. Completion of the survey was deemed as implied consent. We opted for the \u201cOff\u201d setting under multiple responses in SurveyMonkey\u00ae portal, which prevents the survey from being taken multiple times from the same device. Further, we added an additional note \u201cIf you have already taken this survey, then you do not need to submit it again\u201d on the cover page of the survey to prevent multiple responses from the same pharmacist. All participants who completed the survey were entered in a draw to receive one of two AUD$100 gift cards. All returned questionnaires were reviewed for eligibility and completion.In 2020, the total number of RACFs in Australia was 3,300 . An assuU test for non-parametric numerical variables, were used to compare responses between the RMMR/embedded and supply pharmacists. Many supply pharmacists also provide services as RMMR pharmacist after receiving case-related training and accreditation from the Australian Association of Consultant Pharmacists. The purpose of comparing these groups was to assess the differences in their perceptions and practices towards reducing medicines-related harm among aged care residents. A p-value of <0.05 was used as the level of significance in all analyses.Data analysis was carried out using SPSS  and Microsoft Office Excel 2019. The mean \u00b1 standard deviation was used to present normally distributed continuous data. Ordinal or skewed data were presented using the median [interquartile range (IQR)], and frequency (percentage) was used to report categorical variables. The study questionnaire was comprised of four main sections: Perception (13 items), Practices (6 items), Risk Factors (11 items) and Strategies (7 items), and a 5-point Likert scale (1 = Strongly disagree to 5 = Strongly agree) was used. Inferential statistics, such as a chi-square test for categorical and Mann-Whitney Approval was obtained from the Tasmanian Human Research Ethics Committee (Reference: H0026755). We followed the reporting guidelines of the STROBE  statement for observational studies .From February to August 2022, 209 pharmacists completed the survey. One hundred and forty-six were RMMR pharmacists and twelve were embedded pharmacists within RACFs; we combined these groups as their roles are relatively similar and distinct from supply pharmacists. The demographics of the pharmacists are detailed in n = 174, 83%) and only half believed that safe medication management is usually practiced in RACFs . Almost all pharmacists agreed regarding the risk factors for medicines-related harm in aged care residents, such as polypharmacy, PIMs, dementia, recent drug changes, shortage of aged care staff, transitions of care, renal impairment, and specific drug use . A minority of respondents agreed that antibiotics  and antipsychotics  are usually prescribed in appropriate circumstances in older residents.n = 199, 95%). Most pharmacists also agreed that RMMRs prevent medicines-related harm , although only 62% of the RMMR/embedded pharmacists believed that their recommendations during RMMRs were typically accepted by general practitioners. Most pharmacists, particularly within the RMMR/embedded pharmacist group, agreed that aged care management personnel consider pharmacists\u2019 suggestions for reducing medicines-related harm in residents , but few agreed that pharmacists have enough time to participate in medicines-related harm reduction services .As with risk factors, the pharmacists displayed high agreement regarding potential strategies  for reducing medicines-related harm in aged care residents. Enhancing collaboration between pharmacists and aged care staff was acknowledged by almost all pharmacists as a key strategy to reduce this harm in older residents ; this was lower for supply pharmacists (29%) relative to the RMMR/embedded pharmacists (60%). Also, a significantly lower proportion of the supply pharmacists reported that they were familiar with medication appropriateness tools  and routinely utilised these tools. Overall, very few supply pharmacists participated in harm reduction services, reported adverse drug reactions to the Australian Therapeutic Goods Administration, and utilised tools to predict the risk of medicines-related harm. There was a large difference in the proportions of supply and RMMR/embedded pharmacists  who agreed that supply pharmacists detect medicines-related harms whilst supplying medicines. Most pharmacists indicated that they routinely recommend deprescribing interventions ; this was lower for supply pharmacists (47%) relative to the RMMR/embedded pharmacists (92%).Only half of the pharmacists indicated that they routinely participate in harm reduction services (The role of pharmacists in aged care is evolving globally and may be critical in reducing the incidence of medicines-related injury in aged care residents . KnowingMost pharmacists agreed that medicines-related harm is highly prevalent in residents. Aged care residents take many medicines for their multiple morbidities, and it is a responsibility of all stakeholders involved in managing older residents to ensure the safe medication management . All staPharmacists believed that older residents frequently experience medicines-related harm due to factors such as polypharmacy, PIMs, anticholinergic drug use and multi-morbidity. They believed increased collaboration between pharmacists and aged care staff would reduce these harms. The 2021 Australian Aged Care Royal Commission report recommended increased communication and collaboration between aged care staff and other healthcare professionals, such as general practitioners and pharmacists providing services in RACFs . In New Relatively few pharmacists in our study agreed that antibiotics and antipsychotics are frequently prescribed in appropriate circumstances in Australian aged care residents. The RedUSe intervention, comprising multidisciplinary case review, provision of education to the staff, and audit and feedback, has recently been introduced in RACFs to reduce inappropriate antipsychotic prescribing . AntibioMost RMMR/embedded pharmacists believed that supply pharmacists do not usually identify medicines-related injury whilst supplying medicines. Many supply pharmacists in our study were not familiar with tools, such as the Beers criteria and anticholinergic drug burden scale, to predict the risk of medicines-related harm in aged care residents. In addition, very few supply pharmacists regularly utilised these tools or routinely engaged in harm reduction services. Similarly, a Malaysian study reported that only 27% of community pharmacists were familiar with Beers criteria and 17% frequently used this tool in practice . Educativia supplying medicines and consultancy, and these roles are executed remotely or in a visiting capacity (In Australia, pharmacists usually provide services in RACFs capacity . There icapacity . Embeddecapacity . In 2023capacity . A recencapacity .This study is the first of its kind that explored the perceptions and practices of Australian pharmacists providing services in RACFs towards reducing the risk of medicines-related injury in residents. One of the key study limitations was that the recommended sample size was not reached, indicating that these findings may not be representative of the entire group of Australian pharmacists providing services for aged care residents.Pharmacists agreed that aged care residents frequently experience medicines-related harm, but their involvement in medicines-related harm reduction services was relatively limited. Initiatives to engage pharmacists in harm reduction services and educate aged care staff regarding safe medication management may improve residents\u2019 health outcomes. Medicines use in aged care residents can be optimised by the presence of embedded pharmacists in a team environment, provision of education to aged care personnel, and collaborative medication reviews with general practitioners. Ideally, supply pharmacists would also play a greater role in accepting responsibility for the risks posed by the medicines they provide to RACFs. Future research is needed to assess the impact of educating aged care staff about safe medication management on residents\u2019 health outcomes."}
+{"text": "Elevated peripheral inflammation is common in psychosis. Impairments in general cognition were linked to elevated C-reactive protein (CRP) and other inflammatory markers in patients with psychotic disorders. Whether there is a subgroup of persons with elevated peripheral inflammation demonstrating deficits in specific cognitive domains remains unclear. While molecular underpinnings of altered inflammation in psychosis are hypothesized, genetic contributions to relationships of psychosis, inflammation, and cognition have not been clarified. Thirteen peripheral inflammatory markers and 17 neurobehavioral tasks were quantified in a subset of participants  from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Principal component analysis resulted in 5 inflammation factors across inflammatory markers. Three latent cognitive domains  were characterized based on the neurobehavioral battery. Hierarchical clustering identified a psychosis subgroup with elevated inflammation and worse cognitive performance. Genetic predispositions to schizophrenia and cognition were explored in relation to inflammation. Among persons with psychosis, higher inflammation indices were associated with impairments of Inhibitory Control and Visual Sensorimotor function. Greater deficits in Inhibitory Control were observed in a high inflammation patient subgroup. Consistent with previous studies, global genetic correlations of schizophrenia, CRP, and cognition were observed. Significant bivariate local genetic correlations of CRP with schizophrenia or cognition across 22 loci with several genes in 1 locus on chromosome 3 suggested pleiotropic mechanisms for inflammatory relationships with cognition and psychosis. Specific neurobehavioral domains may be more sensitive to inflammation dysregulation in psychosis as compared to general cognitive function, particularly performance on tasks requiring ongoing behavioral monitoring and control. These, along with evidence of genetic correlations of CRP, psychosis, and cognition, provide further supporting evidence that inflammation dysregulation is an important underlying mechanistic contributor to the disruption of cognition in psychosis. Targeting this dysregulation may be an avenue for novel therapeutics to improve cognitive outcomes in these patients.None Declared"}
+{"text": "Migraine is a primary headache disorder recognized by the World Health Organization as one of the most poorly understood and debilitating neurological conditions impacting global disability. Chronic pain disorders are more frequently diagnosed among cisgender women than men, suggesting that female sex hormones could be responsible for mediating chronic pain, including migraine and/or that androgens can be protective. This review discusses the major gonadal hormones, estrogens, progesterone, and testosterone in the context of molecular mechanisms by which they play a role in migraine pathophysiology. In addition, the literature to date describing roles of minor sex hormones including prolactin, luteinizing hormone, follicular stimulating hormone, and gonadotropin releasing hormone in migraine are presented. Because transgender and gender non-conforming (trans*) individuals are an underserved patient population in which gender-affirming sex hormone replacement therapy (HRT) is often medically necessary to align biological sex with gender identity, results from cisgender patient populations are discussed in the context of these major and minor sex hormones on migraine incidence and management in trans* patients. Migraine headaches are diagnosed based upon attack frequency and aura. When headache symptoms are present for at least three months, episodic migraine is defined as 0\u201314 headache days per month while chronic migraine requires 15 or more headache days . The phy1.2.Cortical spreading depression is defined as the spreading of a slowly propagating wave of cellular depolarization and inhibition within neuronal and glial cells across the cerebral cortex. A large change in the concentration gradient between extracellular potassium and intracellular sodium/calcium ions produces a depression of electrocortical signals that travels anteriorly at a rate of 3\u20136\u2005mm/min , 6. In aPreliminary research on the possible involvement of CGRP in migraine found that patients experienced elevated CGRP levels during the interictal phase when headache symptoms were absent ; furtherGiven that trigeminovascular neurons have intrinsic projections to the cerebrovascular system, cortical hyperexcitability induced within central neurons activates and amplifies the underlying vascular processes that sustain migraine headache. The current neurovascular understanding of migraine suggests that neurological processes are necessary to alter trigeminal activity . Clinica1.3.Migraine is more commonly diagnosed with a higher rate of disability in cisgender  women than men , 21. AltResearch on sex differences usually refers to the hormonal differences between female sex hormones  and male sex hormones , but the correlation between migraine and menstrual sex hormone fluctuations reveals that the physiological concentration as well as the type of sex hormone is critical for headache pain. The human menstrual cycle typically lasts 28 days and is divided into two stages: the follicular and luteal phase. In the follicular phase, progesterone levels remain low while estradiol steadily increases. Ovulation then triggers a sharp decline in estradiol simultaneous with rising progesterone levels; when progesterone peaks halfway through the luteal phase, estradiol remains slightly elevated until both hormones drop back down to baseline , Figure\u00a0Sex hormones are lipid signaling messengers that can enact long-lasting effects on neurovascular structure and function. To provide more comprehensive treatment for cisgender women/men and to expand the much-needed area of research on chronic conditions within transgender/gender non-conforming (shortened to trans* as a gender-inclusive umbrella term) patients who receive gender-affirming sex hormone replacement therapy (HRT), a comprehensive analysis on the impact of hormonal fluctuations in migraine-related pathological processes and on nociceptive processing is required. This review will first examine pre-existing, chronic pain-related health disparities among trans* patients to determine current healthcare needs regarding pain management and migraine headache. The medical necessity of gender-affirming treatment and current barriers to healthcare access will then be integrated to emphasize that gender affirmation is critical to reestablish important health measures\u2014such as patient self-efficacy and trust in the healthcare system\u2014that will grant trans* patients with the necessary skills needed to improve pain outcomes. Due to the significant knowledge gap between gender-affirming care and physical health disparities, research on sex hormone activity in migraine pathology will be summarized through cisgender patient data as it pertains to ovarian HRT (estrogen/progesterone) and androgen HRT (testosterone). Further gaps in knowledge and future research directions will be identified as needed to improve healthcare practice and to continue gender-affirming healthcare for LGBTQ\u2009+\u2009patients.2.2.1.When explicitly examining sex differences in primary headache, cisgender women report a higher migraine prevalence of 18% compared to 6% among men , whereas2.2.Estrogen is categorized as a \u201cfemale\u201d sex hormone synthesized within the ovaries to induce female sexual maturity; however, this simplification fails to consider the role of estrogen in male physiology as well as on other biological systems in cisgender women. Estrogen incorporates three hormones that have different functions based on the stage of female reproduction: estradiol is the main hormone that is sustained over a woman's lifespan while estrone and estriol are weaker forms that become dominant during menopause and pregnancy, respectively . EstrogeThe high prevalence of disabling migraine features among cisgender women implies that fluctuating levels of estrogen are critical for migraine development, but assumptions based on female physiology and the effects of hormonal signaling currently restrain the understanding of migraine to a system primed for estrogen. The difference in prevalence between migraine with aura during high estrogen and migraine without aura during estrogen withdrawal suggests that in addition to promoting migraine mechanisms, higher levels of estrogen increase CSD susceptibility and encourage significant headache-related disability through neurovascular dysfunction. Headache studies conducted using animal models demonstrated that female mice have intrinsically lower CSD thresholds than male mice , but wheGiven that CSD could be an initiating mechanism of migraine in patients, increased CSD susceptibility from female hormones indicates that estrogen has a critical role in triggering migraine wherein higher hormonal concentrations correlate to worse pain outcomes. However, clinical data from both cisgender and trans* patients differentiate the effectiveness of estrogen on male and female physiology. The introduction of estradiol to male physiology enables rapid CSD and central sensitization induction since low levels of pre-existing estrogen are insufficient to dominate testosterone activity, but for patients with female physiology, the developmental role of estrogen for sexual reproduction could require hormones that exceed healthy estradiol concentrations to propagate migraine mechanisms. During Tanner stage IV which occurs after puberty onset, patients with female physiology report estradiol levels between 15 and 85\u2005pg/ml while male patients report a maximum of 38\u2005pg/ml. In adulthood, female patients experience fluctuating levels of estradiol within the range of 15\u2013350\u2005pg/ml that varies according to the menstrual cycle ; during B receptors from the G-protein-coupled receptor attached to potassium ion channels; this suppression of neuronal hyperpolarization lowers activation thresholds because hyperpolarization is necessary to return neuronal activity back to baseline  pathway contains several metabolites vital to regulating excitatory and inhibitory signaling in the central nervous system. Kynurenic acid (KYNA) is a competitive antagonist that binds to the glycine site of the GluN1 subunit of NMDA receptors while other metabolites\u2014such as quinolinic acid (QUINA) and xanthurenic acid (XA)\u2014increase cortical excitability as orthosteric agonists that bind to the GluN2A-D subunit of NMDA receptors. QUINA and XA also activate type-2 metabotropic glutamate receptors . MigrainCentral sensitization consists of two critical components: cortical hyperexcitability facilitated through increased glutamate expression and enhanced synaptic efficiency through long-term potentiation; therefore, revealing the contributions of estrogen signaling on both aspects will improve headache pain relief. Clinical studies on migraine sex differences reported that in addition to elevated CGRP, cisgender women also experience fluctuating CGRP expressions within the central and peripheral nervous systems that correspond to estradiol concentrations across the menstrual cycle . EvidencEstradiol signaling seems to have a minimal role in directly perpetuating cerebral vasodilation since a significant portion of endothelial dysfunction and oxidative stress is proportional to the sensitized strength of trigeminal neurotransmission. However, research on the vascular contributions to migraine with sex hormones is still needed to elucidate the full impact of estrogen. In a study that compared plasma concentrations of nitric oxide among cisgender women with either menstrual migraine, non-menstrual migraine, or non-headache controls, enhanced activation of the nitric oxide pathway during the luteal phase leads to increased nitric oxide synthesis that aligns with reports of oxidative stress markers peaking during the late follicular and early luteal phases . EstrogeEstrogen-mediated disruptions in essential biomolecules bolster the efficiency of trigeminal neurotransmission at the cost of regulatory processes that are necessary to prevent excessive cortical hyperexcitability and cerebral vasodilation; therefore, since migraineurs demonstrate higher levels of serotonin (5-HT) during the ictal phase of headache but lower levels during the interictal phase, estrogen could influence the synthesis of neurotransmitters like serotonin . AlthougIn addition to generating intermediate metabolites that destabilize excitatory and inhibitory cortical signaling, the KYN pathway also reduces serum 5-HT levels in migraineurs by metabolizing the amino acid tryptophan into KYN metabolites at the expense of serotonin synthesis. Michael et al.  demonstrAn overview of the current understanding of estrogen signaling on neurovascular migraine mechanisms is summarized in 2.3.Although estrogen hormones are incredibly efficient at accumulating dysfunction within the trigeminovascular system, the role of fluctuating progestin hormones with estradiol signaling could clarify gaps in understanding between migraine headache, hormonal states, and pain symptomology. Progesterone has two receptors: progesterone receptor alpha (PR\u03b1) and progesterone receptor beta (PR\u03b2). Although murine models demonstrate higher expressions of one receptor isoform over the other, human cells contain equivalent amounts of PR\u03b1 and PR\u03b2, which suggests that the PR\u03b1-PR\u03b2 heterodimer is the dominant molecular species for humans . Therefo2.4A receptor activity within neurons of the trigeminal nucleus caudalis  gene on chromosome 5 encodes three different isoforms: long (PRL-L), intermediate, and short (PRL-S), but only PRL-L and PRL-S will be considered since unlike humans and rats, mice lack intermediate PRL receptors . PRL-L ae models .Prolactin-induced sensitization imitates estradiol neurogenic inflammation by proliferating CGRP release from sensory neurons via the excessive activation of sensitized TRP channels. Although sensory neurons lack PRL, application of TRP channel activators to cultured female sensory neurons pretreated with prolactin resulted in amplified trigeminal neurotransmission due to enhanced calcium ion influx. Within male physiology, prolactin sensitization might require abnormally high concentrations to further support estrogen-mediated sensitization since males have lower PRL-L and PRL-S expressions in the dorsal root ganglion . PRL-S sWhen prolactin is considered alongside androgen and ovarian hormones, pronociceptive headache states fueled by estrogen can recruit prolactin-induced sensitization to further advance chronic pain since estrogen increases PRL receptor expression. Conversely, testosterone suppresses PRL expression to mitigate central sensitization, but since the molecular pathway defining this androgen-mediated phenomenon has yet to be explored, only coinciding interactions between estrogen and prolactin will be discussed. High concentrations of endogenous estrogen within female migraineurs correlate to an increase in PRL receptor mRNA in dorsal root ganglion neurons; however, because equal expressions of PRL-S and PRL-L were retained in both sexes regardless of estradiol concentrations, estrogen upregulation of PRL expression occurs independently from receptor isoform translation . ApplicaCRE mice to deduce sex differences in migraine. Prior to experimentation, murine models expressed KORCRE neurons in the dorsomedial/ventromedial hypothalamic nuclei and ARC as well as within tyrosine-hydroxylase-positive cells that were quantified as 80% for female and 70% for male mice. In response to RS, enhanced serum prolactin produced allodynia from latent sensitization in both male and female mice, although females experienced an intrinsically greater increase. When the KOR antagonist nor-binaltorphimine dihydrochloride was applied to the right ARC, serum prolactin was reduced likely due to the synchronized TIDA network  axis and reduced efficacy of the kappa-opioid receptor (KOR) system to alleviate trigeminal nociception. Previous clinical studies reported that stress activates the hypothalamus of migraineurs to increase cortisol levels, resulting in a positive correlation between stress-induced priming and chronic headache frequency. Since stress increases prolactin and the endogenous KOR agonist dynorphin, central sensitization could decrease the analgesic efficiency of the KOR signaling pathway such that chronic stress would hinder endogenous recovery from headache . Watanab network . Combinehibition , 81. Furhibition . Howeverhibition . Therefohibition . The mec2.6.2.Luteinizing (LH) and follicle-stimulating (FSH) hormones are synthesized from gonadotropin cells in the anterior pituitary to amplify estrogen synthesis during the menstrual cycle . Several2.6.3.Although the majority of gender-affirming healthcare focuses on medical interventions for trans* adults, trans* youth who wish to postpone the puberty of their assigned sex might receive puberty blockers\u2014which are gonadotropin-releasing hormone (GnRH) agonists such as goserelin, leuprolide, and histrelin\u2014to delay the development of secondary sex characteristics and prevent gender dysphoria\u2014which is defined in the DSM-5 as the \u201cpsychological distress that results from an incongruence between one's sex assigned at birth and one's gender identity\u201d , 89. SexGnRH is synthesized within hypothalamic neurons to regulate LH and FSH concentrations throughout the menstrual cycle; the activation of GnRH G-protein-coupled type I receptors on gonadotrophin cells in the anterior pituitary generates GnRH pulse frequencies wherein low pulses stimulate FSH and high pulses promote LH. Although female migraineurs demonstrated normal FSH/LH levels, dysfunction of the hypothalamic-pituitary-adrenal axis could cause abnormal GnRH pulse frequencies. Research demonstrated that persistent GnRH stimulation produces elevated LH:FSH ratios\u2014amplifying the ovarian synthesis of androgen hormones\u2014while minimal stimulation and abnormal GnRH serum levels were associated with hypothalamic amenorrhea . Despite3.Despite the growing number of trans* patients, healthcare practices have yet to move beyond the perspective that this patient population only engages with the healthcare system to receive gender-affirming medical treatment. Research examining pre-existing health disparities among LGBTQ\u2009+\u2009patients has been recognized as a crucial gap in knowledge ; howeverWhile the exact number of trans* individuals with migraine is unknown, there are an estimated 1.4 million transgender adults  and 39 million individuals with migraine in the United States . Based oAlthough this risk of headache could be detrimental for the physical and mental wellbeing of an already vulnerable population, transgender men and gender non-conforming individuals who receive androgen HRT might experience some relief from migraine. Yalinay Dikmen et al.  investigFrom the available evidence, estrogen HRT is associated with an increased risk for acquired migraine in transgender women while testosterone HRT could potentially provide some pain relief for transgender men with a pre-existing primary headache disorder. Although data from cisgender migraineurs has supported the role of estrogen in promoting migraine mechanisms, gaps in knowledge remain on the minimum physiological concentration of estrogen required to propagate chronic pain states; given that migraine has been observed during states of estrogen withdrawal  and elevation , determining physiological hormone concentrations can clarify the association of sex hormones and migraine symptoms. Consenting trans* patients represent the ideal clinical population to investigate this theory as the natural diversity in gender identity and use of gender-affirming hormones allows researchers to clarify the issue of sex hormone functionality without subjecting cisgender patients to potential unwanted side effects. These individuals are also ideal in furthering progress for LGBTQ\u2009+\u2009health outcomes beyond mental health disorders and sexual diseases because current debates regarding the legality of gender-affirming care already establish the immediate need for improved LGBTQ\u2009+\u2009healthcare and better understanding on the long-term effects of HRT. Treatment of headache for cisgender patients can also be improved through trans* data by reframing the consideration of health with gender identity; notably, by replacing binary sex as a health factor with measures of serum sex hormone levels, mechanisms involved in chronic pain pathology can improve the accuracy of disease diagnosis and treatment as well as support pain outcomes hindered by sexist gender stereotypes.4.Despite limited data in trans* individuals with migraine, cisgender data suggests that femininizing estradiol HRT increases the risk for acquired headache and chronic pain while masculinizing testosterone HRT is associated with improved pain relief for patients with a pre-existing headache disorder. Future studies are needed to directly evaluate the risk between gender-affirming HRT and migraine. Ovarian hormones like estrogen and progesterone promote migraine headache via CSD and central sensitization within the trigeminal nociceptive network through reactive species, CGRP, and an imbalance of excitatory/inhibitory neurotransmission while androgens like testosterone attempt to reduce excessive cortical hyperexcitability by bolstering neuroprotective and analgesic qualities. When the effects of sex hormones in cisgender and trans* patients are examined together, rapid sex hormone fluctuations create vulnerabilities through which heightened estrogen induces pronociceptive states and reduced testosterone fails to adequately establish trigeminal neuroprotection. Since many trans* individuals begin HRT when patients are already well into adulthood, pubertal hormones likely establish migraine susceptibility that can be aggravated further by estrogen HRT, thus putting transgender women at the most risk. Susceptibility could be curtailed through pubertal suppression and treatment with puberty blockers, but the same limitations currently impacting adult gender-affirming care also affect trans* youth, maybe even more so due to debates on parental rights to oversee the healthcare decisions of their children. Given the changing landscape of trans* patients seeking gender-affirming healthcare, more investigation into sex hormones on migraine pathology is warranted to determine the impact of gender-affirming HRT and potential chronic pain risk.Research on LGBTQ\u2009+\u2009healthcare has largely focused on educating medical providers about the appropriate terminology to improve interpersonal interactions between patients and providers , 99. How"}
+{"text": "Antibiotic resistance stands as one of the most significant public health challenges in recent decades. FEM proteins are responsible for the synthesisof pentaglycine cross-bridge, a primary constituent of bacterial peptidoglycan polymer crosslinking during cell wall biosynthesis. Since they are necessaryfor bacterial survival and antibiotic resistance, they were considered as significant antibacterial targets. We report herein, the virtual screening andselection of FDA-approved drugs and their potent similar molecules as FEM protein inhibitors and analyzed for inhibiting affinity and their ADMET pharmacokineticproperties. This data provide a foundation for the development and optimization of structurally innovative antimicrobial drugs. Staphylococcus aureus causes a wide spectrum of common ailments that can be acquired from the community and in hospitals. Due tolower responsiveness to commercially available drugs, the rise of Methicillin-resistant Staphylococcus aureus (MRSA) clinical isolateshas increased and evolved into various multi-drug resistant strains making the treatment difficult. The foreign expression of altered PBP2a performs the host PBPfunction and governs the strategy of \u03b2-lactam antibiotic resistance in methicillin-resistant S. aureus (MRSA)amino]-3-methylpyridin-2-yl]benzoic acid (PubChem ID: 90080139) against FemX with highest binding energy of -137.66 among all by forming a Pi-sulfur and Pi-alkylinteraction with TYR320, 377 and MET196. The whole complex has involved many hydrogen bonding with several residues listed in active site amino acids of theFemX receptor .In addiinvitro evaluations.For the first time this manuscript reported the FemB inhibitors from FDA approved drug molecules, which can be possibly repurposed.An overview of selected chemical molecules and clinical features with pharmacokinetic properties were analyzed using the pkCSM webserver and labeled ininvitro results. In this work, we virtually examined a library of FDA-authorized drugs from ZINC15 and DrugBank databases againstS. aureus FEM proteins. Three lead molecules were shortlisted based on their docking scores and prioritized based on their minimum bindingenergy and active interactions with the FEM proteins. In this study, we also evaluated the molecules solubility and toxicity properties.The limited therapeutic spectrum against MRSA necessitates an urgent development of antibiotics and medications to enhance the current antibiotic efficacyand drugs to enhance the existing antibiotic efficacy. We report the optimal binding features of structure-based FDA-approved drugs repurposed to treat MRSApathogenic infections. It helps to cross the emergence by following certain time limit management in collaboration with certain existingThe authors declare that they have no known competing interests (or) personal relationships that could have appeared to influence the work reported in thismanuscript. The research leading to these results received funding from the DST-SERB-ECR grant under file no: ECR/2017/003381."}
+{"text": "Pain generator-based lumbar spinal decompression surgery is the backbone of modern spine care. In contrast to traditional image-based medical necessity criteria for spinal surgery, assessing the severity of neural element encroachment, instability, and deformity, staged management of common painful degenerative lumbar spine conditions is likely to be more durable and cost-effective. Targeting validated pain generators can be accomplished with simplified decompression procedures associated with lower perioperative complications and long-term revision rates. In this perspective article, the authors summarize the current concepts of successful management of spinal stenosis patients with modern transforaminal endoscopic and translaminar minimally invasive spinal surgery techniques. They represent the consensus statements of 14 international surgeon societies, who have worked in collaborative teams in an open peer-review model based on a systematic review of the existing literature and grading the strength of its clinical evidence. The authors found that personalized clinical care protocols for lumbar spinal stenosis rooted in validated pain generators can successfully treat most patients with sciatica-type back and leg pain including those who fail to meet traditional image-based medical necessity criteria for surgery since nearly half of the surgically treated pain generators are not shown on the preoperative MRI scan. Common pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte and cyst, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte. The position of the key opinion authors of the perspective article is that further clinical research will continue to validate pain generator-based treatment protocols for lumbar spinal stenosis. The endoscopic technology platform enables spine surgeons to directly visualize pain generators, forming the basis for more simplified targeted surgical pain management therapies. Limitations of this care model are dictated by appropriate patient selection and mastering the learning curve of modern MIS procedures. Decompensated deformity and instability will likely continue to be treated with open corrective surgery. Vertically integrated outpatient spine care programs are the most suitable setting for executing such pain generator-focused programs. Lumbar spinal stenosis (LSS) is defined as a narrowing of the lumbar spinal canal caused by age-related degeneration of the spinal motion segment. It causes encroachment of neural elements and may contribute to back and leg pain. It is a leading cause of disability from lack of mobility due to neurogenic claudication worldwide . Spinal Spondylolisthesis  and decoIn this review perspective article, the authors take a fresh, consensus look at the available evidence including their own professional expertise and experiences on using minimally invasive and endoscopic lumbar decompression techniques in a more targeted and personalized care model. 14 professional societies reviewed recent articles on the topic and through their related committees and subcommittees express their professional position. This perspective paper is coordinated by the Interamerican Society For Minimally Invasive Spine Surgery\u2013La Sociedad Interamericana de Cirug\u00eda de Columna M\u00ednimamente Invasiva (SICCMI) and the Spine Subcommittee of the Society For Brain Mapping & Therapeutics (SBMT), and endorsed by the International Society For Minimal Intervention In Spinal Surgery (ISMISS), the Korean Minimally Invasive Spine Society (KOMISS), the Minimally Invasive Surgery Section of the Chinese Orthopaedic Association (COA-MIS SECTION), The Colombian Spine Society, the Bolivian Spine Association, the Iberolatinoamerican Spine Society\u2013La Sociedad Iberolatinoamericana de Columna (SILACO), the Mexican Association of Spinal Surgeons\u2013Associacion Mexicana de Cirujanos de Columna (AMCICO), the Federation of Latinamerican Neurosurgical Societies\u2013Federaci\u00f3n Latino-Americana de Sociedades de Neurocirug\u00eda (FLANC), the Latin American Society of Neurosurgeons of USA & Canada (SLANC), the Brazilian Spine Society\u2013Sociedade Brasiliiera de Columna (SBC), the Brazilian Society For Thoracic Surgery\u2014Sociedade Brasileira de Cirurgia Tor\u00e1cica (SBCT), and the International Intradiscal Therapy Society (IITS).The annual incidence of adult spine disease is estimated at 266 million people globally . The higIn the 2010 Global Burden of Disease (GBD) Study ,23, LBP Most contemporary medical necessity criteria for spinal decompression are based on analyzing advanced imaging studies such as MRI or CT. Using these image-based criteria reserves decompression surgery only for patients with progressive disease ,38,39,40Whoever does not fit these medical necessity criteria is often committed to repetitive cycles of spinal injections, physical therapy, and non-steroidal anti-inflammatory treatments. Those who are so disabled that they cannot even participate in these programs in a meaningful way or have poorly controlled co-morbidities which preclude medical management often cannot get much help. An exemplary summary of traditional Review Clinical Guidelines For Spinal Stenosis affecting coverage decisions is shown in In this perspective paper, SICCMI, in collaboration with 12 other international surgeons\u2019 societies, is confronting the increased scrutiny on the appropriateness of spine care spending by payers, government, and patients in an attempt to deliver on simplified, innovative, less costly, more effective, and more durable treatments for common degenerative and painful spine conditions associated with lower complication and revision rates. Resolution to these problems is needed to meet the increasing demand by the aging baby-boomer population for such simplified treatments.The treatment of the painful degenerative disease process of the spinal motion segment with traditional open spine surgery is dictated by the application of MRI and CT image criteria of spinal stenosis, instability, and deformity. The clinical decision-making for surgery focuses on treating the end-stage of the disease, leaving many patients without timely treatment or no treatment at all. With the backdrop of recent clinical studies describing the limited utility of the lumbar MRI scan and its reporting suffering from relatively low sensitivity and specificity to diagnose the painful spine condition , key opiTraditional open spine surgery in the lumbar spine includes laminectomy. A translaminar decompression is performed by removing the posterior spinal elements, including the spinous process, the lamina, and part of the bilateral facet joints. The benefit of lumbar decompression for symptomatic herniated disc and spinal stenosis has been demonstrated in several prospective randomized clinical trials, including the original study by Weber , the MaiMinimally invasive surgery (MIS) for the treatment of common degenerative conditions of the spine is increasingly practiced. It encompasses a portfolio of surgical techniques that are aimed to alleviate patients\u2019 pain via reduced surgical access resulting in less blood loss and reduced peri- and postoperative problems including pain, nausea, and vomiting. The introduction of tubular retractors and microsurgical dissection techniques simplified the very nature of spine surgery by transforming it through the implementation of less burdensome and more simplified protocols. Over the last 40 years, open spine surgery has established a track record that is interpreted by most patients, employers, and payers as aggressive and too costly due to high out-of-work complications and reoperation rates.Quality of life and cost-effectiveness of minimally invasive surgery (MIS) for spinal stenosis in patients with degenerative lumbar spondylolisthesis (DLS) has been calculated relative to failed medical management and compared to the cost-effectiveness of hip and knee arthroplasty for matched cohorts of patients with osteoarthritis . IncremeSelect pain generators in the lumbar spine are not diagnosed on routine lumbar MRI scan . A recenCommon pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte, and many others examples, as shown in One example is highlighted by the INTRACEPT prospective, open-label, 1:1 randomized controlled trial. This trial tests the efficacy of basivertebral nerve (BVN) ablation technology compared to a standard care control treatment of vertebrogenic chronic low back pain . ConceptThe authors take the position that direct visualization and treatment of pain generators is the foundation for surgical pain management of the lumbar spine. Spinal endoscopy enables the surgeon to diagnose and treat the painful condition during the same operation ,66,67,68Objective measurements of the foraminal or lateral canal dimensions are rarely given. Surgical stenosis classifications use measurable parameters such as height and width of the posterior disc, lateral recess, or neuroforamen to stratify patients for the most appropriate MIS approach and technique . The lacTreating pain generators involves identifying those structural problems in the lumbar spine that cause the majority of the patient\u2019s symptoms as implicated in the symptoms by history and physical examination or by advanced imaging studies such as MRI or CT scan. Most patients have unilateral or mono-segmental radiculopathy symptoms. When confirmed with diagnostic selective nerve root blocks, these clinical observations highlight that many structural changes in a degenerative spine are multilevel but may not be painful, even if the MRI or CT scan suggests a similar degree of stenosis as within the symptomatic spinal motion segment. For example, exiting and traversing nerve root pain syndromes may or may not exist within the same lumbar motion segment simultaneously. However, when they do, the surgeon can easily be confused with patients whose MRI suggests multilevel disease. Identifying the correct source level of axial facet joint pain in multilevel degeneration may even be more difficult without a radicular component. The staged management concept is the central element of the clinical spine care model. It implies treating validated symptomatic pain generators and ignoring all degenerative changes or injuries that do not hurt.While it is easier to rely on MRI-based criteria of compression, instability, and deformity when deducting a plan of surgical care\u2014certainly within the mainstream of traditionally trained surgeons, and perhaps a coincidence between the radiologist\u2019s confirmation of compressive pathology and the surgical plan of care invites less scrutiny during the health insurance preauthorization process for surgery\u2014identifying the predominant pain generator can be a daunting task. Recommending a targeted surgical treatment plan to a patient in pain is as much of an art as it is a science and relies heavily on judgment and clinical experience. Less aggressive treatment recommendations are often sufficient to substantially reduce pain, all while ignoring traditional decompression and lumbar fusion criteria.What to treat and, more importantly, what to ignore requires attention to detail and utilization of preoperative diagnostic tools of high positive predictive value. For the endoscopic spine surgeon, the plan of care is derived from identifying those pain generators that impair the patient the most. Minimizing the risk-taking and maximizing the benefit, all while managing patients\u2019 expectations about the desired outcome, are the key to achieving high patient satisfaction . The staA new subspecialty is emerging: \u201cSurgical Pain Management.\u201d The term implies a blend of diagnostic and patient management strategies employed by interventional pain physicians comprised of physiatrists, anesthesiologists, and spine surgeons consisting of orthopedic and neurosurgeons. This new emerging subspeciality is a grassroots development driven by enthusiast physicians who invested their careers into a more personalized approach to spine care. Thus, surgical pain management integrates needle-based non-visualized interventions into MIS and endoscopic surgical procedures by tailoring the treatment based on the individual patient\u2019s symptoms and the functional context when the spine care is delivered. Examples of this development include the integration of radiofrequency and laser into endoscopic surgeries. The continued use of rule-based medical necessity criteria for lumbar spine care seems increasingly inappropriate. It invites the delivery of costly, ineffective therapies and treatments which ultimately do not lower the societal burden of spine care. Ignoring individual pain generators stemming from the underlying disease causing cumulative disability does not address the root cause and precludes the patient from definitive care or leads to patient entrapment in repetitive yet ineffective treatment cycles. In the opinion of the KOL authors of this lead perspective article in the JPM special issue \u201cThe Path To Personalized Pain Management,\u201d the staged approach to surgical pain management is poised to lower disability and the direct and indirect costs with all of its hidden unintended consequences of repetitive treatments. Its implementation has the potential for diminishing the burden of failed medical pain management and opioid addiction, delayed returned to work, and disrupted social reintegration. While the authors do not suggest abandoning traditional open spine surgery, we propose integrating staged surgical pain management of directly visualized pain generators early in the disease process into existing spine care programs.The authors of this perspective paper arrived at the consensus statement on the indications for surgical treatment for symptomatic lumbar spinal stenosis based on validated pain generators rather than traditional image-based medical necessity criteria. This approach to treating patients with claudication and sciatica-type low back and leg symptoms represents the authors\u2019 views and their respective surgeon societies. The most published individuals on this team of authors are accomplished and passionate endoscopic spinal surgeons. In experienced hands, approximately 80% of patients with painful degenerative spine conditions may be treated successfully with a targeted outpatient MIS or endoscopic decompression procedure ,82,83. WJudiciously and skillfully executed modern targeted MIS surgeries can provide more cost-effective and less burdensome spine care with shorter treatment cycles as the underlying structural correlate for the patient\u2019s pain is treated causally. Lateral recess and foraminal stenosis are the most common clinically relevant indications for primary surgery and revision surgery after decompression in the lumbar spine. The personalized clinical protocols for treating lumbar spinal stenosis based on validated pain generators are a break with traditional population management protocols that employ image-based medical necessity criteria for intervention since nearly half of the surgically treated pain generators are not shown on the preoperative MRI scan. Common pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte. It is the authors position, that further clinical research will continue to validate pain generator-based treatment protocols for lumbar spinal stenosis. The endoscopic technology platform enables spine surgeons to directly visualize pain generators, forming the basis for more simplified targeted surgical pain management therapies. Clinical judgment of appropriate patient selection and mastering the learning curve of modern MIS procedures will likely lead to a broadening of the accepted indications for such a pain generator-based approach to patient care. Limitations of this care model are dictated by decompensated deformity and instability, for which open corrective surgery will likely continue to be the treatment of choice. Vertically integrated outpatient spine care programs are probably the most suitable setting for executing such a pain generator focused program since physicians who have complete custody of their patients can minimize protocol breaches by other providers who are not invested in the personalized care model proposed by the authors."}
+{"text": "Epidemics in the Pacific Islands noted flu-like symptoms and complications following human ZIKV infection. However, after a severe outbreak in 2015, Latin American studies reported fetal birth defects with maternal infection but reports in other developing countries where outbreaks occurred were not fully characterized. This study aims to review current reports on birth outcomes associated with maternal ZIKV infection .Zika Virus became an emerging health threat in the early 21This narrative review evaluated birth outcomes of Zika positive pregnant women. Research articles were found using Google Scholar, PubMed, and MEDLINE. The inclusion criteria were publication between 2012 to 2022, availability as full text in English, categorization as original research, meta-analyses or case reports. Exclusion criteria were studies that were part of a book chapter or encyclopedia and studies that cited results from developed nations. The articles were studied and 20 methodologically sound studies were selected for review, and the data was classified in themes based on birth outcomes.18 studies reported that infants born to some laboratory-confirmed zika-positive mothers had abnormal birth outcomes after delivery including microcephaly, stillbirth, neurological abnormalities and hearing loss. Maternal ZIKV infection is associated with an increased risk of abnormal birth outcomes in newborns in developing countries. In the countries of studies that did not report abnormal outcomes there may have been a protective factor from previous maternal Dengue Virus (DENV) infection adding protection for their infants.Overall, there appears a difference in birth outcomes of infants born to mothers infected with ZIKV, however more research is needed on environmental factors and prior arboviral infection as additional factors contributing to these outcomes.All Authors: No reported disclosures"}
+{"text": "Spinal cord injury (SCI) disrupts the structural and functional connectivity between the higher center and the spinal cord, resulting in severe motor, sensory, and autonomic dysfunction with a variety of complications. The pathophysiology of SCI is complicated and multifaceted, and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after SCI. Combinatory strategies targeting multiple aspects of SCI pathology have achieved greater beneficial effects than individual therapy alone. Although many problems and challenges remain, the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat SCI. In this review, we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following SCI at both the acute and chronic stages. In addition, we analyze the current status, remaining problems, and realistic challenges towards clinical translation. Finally, we consider the future of SCI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice. Going forward, clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeutic benefit in humans with SCI. Spinal cord injury (SCI) leads to long-term dysfunction and lifelong disability. There are hundreds of thousands of new patients suffering an SCI each year worldwide, and ninety percent of these SCIs are caused by traumatic events, including traffic accidents, falling, sports injuries, violence, etc. . SCI intThe pathophysiology of SCI involves primary injury and secondary injury. The primary injury is caused by acute mechanical trauma and results in vascular disruption, blood\u2013spinal cord barrier rupture, cell death , and interruption of neural fiber tracts in the spinal cord. The secondary injury references the consecutive pathological events triggered by the primary injury, such as hemorrhage, excitotoxicity, neuroinflammation, demyelination, astrogliosis and extracellular matrix (ECM) remodeling, which aggravate tissue damage, and compromise neuroplasticity . The curIn this review, we provide an overview of recent advances and challenges in SCI research and treatment. We summarize the recent progress regarding interventions after SCI in preclinical rodent and non-human primate models as well as in the clinical settings. We then discuss the current status and challenges with respect to clinical translation, prospect the future of SCI repair, and we highlight combinatory approaches and multidisciplinary cooperation are imperative to optimize clinical outcomes after SCI. This review provides an update of current strategies following SCI and provide researchers with new insights to develop more effective and targeted interventions to facilitate clinically meaningful recovery after SCI.The originally narrow concept of regeneration referred to the regrowth of transected axons across the lesion core to form functional synapses with their original pre-injury targets after SCI. The broad definition of regeneration now encompasses multiple forms of axon growth, including long-distance axon regrowth, compensatory sprouting of injured and spared supraspinal axons as well as propriospinal neurons, synapse remodeling, and circuit reorganization  Fig. 1)Fig. 1). Axon outgrowth is driven by the growth cone, a motile structure located at the tip of the growing axon. Growth cone motility and axon growth are determined by the neuronal cytoskeleton, which includes microtubule and actin filament (F-actin) . MicrotuCytoskeletal dynamics and rearrangements are mainly modulated by two intracellular signaling pathways: glycogen synthase kinase 3\u03b2 (GSK3\u03b2) and Rho GTPases. GSK3\u03b2 is downstream of PI3K signaling and is inactivated through serine-9 phosphorylation within its amino-terminal region upon activation of the PI3K pathway. GSK3\u03b2 has been shown to be a crucial negative regulator of microtubule dynamics by phosphorylating multiple microtubule binding proteins (MBPs), such as collapsin response mediator protein 2 (CRMP-2), adenomatous polyposis coli (APC), and microtubule-associated protein-1B (MAP1B) . InhibitEnhancing cytoskeletal dynamics in the growth cone supports axon growth, whereas aberrant cytoskeletal dynamics following injury represents a major obstacle to axon regeneration. Therefore, manipulations targeting cytoskeletal dynamics may be potential strategies to induce axon regeneration of adult neurons following injury.Socs3 in adult retinal ganglion cells magnified JAK/STAT signaling, thereby inducing axon regeneration after optic nerve injury  axons in the mouse spinal cord (Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is involved in regulating axon regeneration and cell survival. JAK is activated by growth factors and cytokines ) and then phosphorylates STATs, which transduce the signals to the nucleus and promote transcription of regeneration-associated genes (RAGs). Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of the JAK/STAT pathway. Ablation of e injury . Activatnal cord .Pten promotes mTOR activation and positively modulates regeneration of facial nerve and CST axons  pathway plays a crucial role in regulating fundamental cell processes, including cell growth and metabolism, gene transcription, protein synthesis, and cytoskeletal remodeling . mTOR fuST axons . Activatneration .dlk-1 is sufficient to enhance regrowth capacity of injured axons in C. elegans , a highly conserved mitogen-activated protein kinase kinase kinase (MAP3K), plays a vital role in injury response, apoptosis, axon transport, and regeneration following injury both in the peripheral nervous system (PNS) and in the central nervous system (CNS) . Upon ax elegans . Germina elegans .Klfs), Sox11, Stat3, cAMP-response element binding protein (Creb), and hypoxia inducible factor-1a (Hif-1a) , which initiate pro-regenerative transcriptional programs and enable the reacquisition of regenerative potential. Previous studies have identified multiple pro-regenerative TFs, such as Kr\u00fcppel-like factors ((Hif-1a) . ManipulEpigenetic modifications, which include histone acetylation, DNA demethylation and hydroxymethylation, as well as modification of non-coding RNAs, facilitate access to gene regulatory regions by TFs, thus enabling active transcription of genomic regions and RAG expression. Epigenetic modifications play a key role in embryonic and adult neurogenesis . In receIt is difficult to achieve frank regeneration of injured axons beyond the lesion site in the adult mammalian CNS. Apart from limited intrinsic regenerative competence, multiple extrinsic barriers contribute to the axon regeneration failure. Among these, myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) represent the major inhibitors to axon regeneration following SCI. Nogo A, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) are three prototypical myelin-associated inhibitory molecules that exert inhibition on axon regeneration after injury in the adult CNS. These MAIs initiate intracellular Rho and ROCK signaling pathways through multiple receptors  and eventually lead to growth cone collapse and prevent neurite extension . CSPGs aSpinal cord injury interrupts the connectivity of the spinal cord and leads to devastating neurological deficits. In addition, concomitant complications, including respiratory and urinary infections, gastrointestinal disorders, muscle atrophy, and chronic pain exacerbate clinical outcomes. Numerous novel approaches have been emerged to ameliorate SCI outcomes that can be divided into two parts: (i) relieving secondary damage via neuroprotection and (ii) fostering neuroplasticity and axon regeneration by triggering intrinsic regenerative mechanisms, ameliorating the extrinsic environment, and applying cell transplantation and neuromodulation technologies . Each ofThe primary mechanical injury to the spinal cord triggers a cascade of complex biological processes, termed the secondary injury, which cause further damage to the spared tissue and exacerbate neurological impairment and regeneration failure. Therefore, interventions that confer neuroprotection during the acute phase are crucial to suppress the spread of the secondary injury and to protect the spinal cord tissue from further damage. Several strategies have been deployed to attenuate the secondary damage. Pharmacological agents like methylprednisolone, minocycline, and cyclosporine A have been used to in patients with SCI to suppress secondary damage . HoweverIn recent years, a large number of novel neuroprotective approaches have emerged designed to counteract the progression of secondary injury. These therapies have demonstrated neuroprotective effects in preclinical studies and provide new perspectives for the treatment of clinical SCI. Oxidative stress following SCI leads to excess release of reactive oxygen species (ROS), which exacerbates secondary injury and results in axon degeneration and permanent neurological dysfunction. Antioxidant enzymes encapsulated in biodegradable nanoparticles have been shown to significantly reduce ROS activity and neuronal cell apoptosis, attenuate mitochondrial dysfunction, and improve locomotor recovery following severe contusive SCI in rats . In a moOveractivation of microglia after SCI exacerbates the inflammatory response and results in loss of neurons, gliosis, and synaptic damage. Inhibition of microglia proliferation by oral administration of the CSF1R inhibitor, GW2580, reduced neuroinflammation and improved locomotor function in mice and non-human primates following lateral spinal cord hemisection . MicroglWhile self-repair spontaneously occurs after injury in the adult mammalian PNS, mature neurons in the CNS fail to regain regenerative competence after SCI. Axon regeneration failure is mostly attributed to the poor intrinsic growth competence of the adult CNS neurons. Axon growth capacity sharply declines with age and is switched off upon maturation. However, over the last few decades, accumulating evidence suggests that axon regeneration and remodeling of neural circuits are possible via pharmacological, molecular, or genetic manipulations in the adult mammalian CNS . SubstanMicrotubule destabilization and actin disassembly following SCI lead to growth cone collapse and retraction bulb formation. The reformation of a growth cone-like structure from severed axon stumps is the first step in axon regeneration. Most manipulations aiming to augment axon regenerative ability eventually converge on cytoskeletal dynamics and remodeling within the growth cone.Rhoa knockdown was shown to enhance axon regeneration and reduce apoptosis, cavity formation, and astrogliosis in a rat compression SCI model , which is mainly produced in the mitochondria. SCI-induced mitochondrial dysfunction and energy deficits exacerbate axon regeneration failure. Syntaphilin (Snph) is a static anchor protein that holds axonal mitochondria stationary on microtubules via its microtubule-binding domain. Enhancing mitochondrial transport by  in mice . The mit in mice .Intracellular signaling pathways, such as mTOR, JAK/STAT/SOCS3 and DLK regulate neuronal survival and axon growth. Accumulating evidence suggests that manipulating these pathways could enhance intrinsic growth competence and neuroplasticity after SCI.Socs3 triggered collateral sprouting of intact CST axons to the denervated spinal cord after unilateral pyramidotomy. Moreover, co-deletion of Pten and Socs3 further enhanced CST sprouting with significant restoration of skilled locomotion function, suggesting the reformation of functional circuits mediated by sprouting axons  concentration by extruding Cl\u2212 from the cytosol. KCC2 has important roles in synaptic inhibition as well as in neuronal development and plasticity  directly modulate transcription of RAGs and initiate the switch from the resting state to the robust regrowth state in damaged neurons. TFs have been shown to be an important determinant controlling axon growth potential in the mature CNS. Over the past decades, researchers have identified several candidate TFs that potentiate the regenerative capacity of injured axons after SCI.Klf6 or Klf7 promoted sprouting and regeneration of CST axons in adult mice  promoted histone 3 Lys 9 acetylation (H3K9ac) following peripheral injury, and nal cord . Recent nal cord . These rnal cord . This stIn addition to limited intrinsic growth ability, the hostile microenvironment is another obstacle to axon regeneration after SCI. Indeed, extrinsic growth-inhibitory factors and the deficiency of neurotrophic factors further hamper neuroplasticity and axon regeneration. Therefore, removing inhibitory molecules and augmenting neurotrophic support contribute to render a more permissive environment and promote functional recovery following SCI.The presence of inhibitory factors  surrounding the lesion site appears to be the major environmental obstacle to axon growth that prevents the injured axons from real regeneration. Removal of extrinsic inhibitory components by enzymatic degradation, receptor blocking, or antibody neutralization has demonstrated positive effects on axon regeneration and neurological restoration.Chabc gene expression was shown to promote recovery of skilled reaching and ladder walking performance as well as sensory axon conduction following cervical contusion injury in adult rats  to specifically modulate PTP\u03c3 released the inhibitory effect of CSPGs on axon growth and markedly fostered functional recovery of sensory, locomotor, and urinary systems after contusive SCI in rats . InhibitAttenuating MAI-mediated inhibition can be achieved by antibody neutralization, receptor antagonists, and genetic inhibition. Anti-Nogo A treatment ameliorated lower urinary tract dysfunction and restored bladder function in rats with severe SCI . The firLotus overexpression has been proved to enhance axon regeneration of the raphespinal tract and reticulospinal tract fibers, suppress axonal dieback of CST fibers, and promote motor recovery in a mouse contusive SCI model  into neurons and oligodendrocytes, and transplantation of Lingo-1 shRNA-treated NSPCs facilitated locomotor recovery in mice with contusive SCI  are a family of proteins that direct neuronal survival, synaptic function, and axonal growth within the adult nervous system . NFs areBdnf vector into the lesion significantly enhanced sprouting of 5-HT+ axons and increased their synaptic connections with phrenic motor neurons (PhMNs), and contributed to recovery of diaphragm function following cervical SCI  is a secreted protein that fosters neuron survival and synaptic plasticity. Delivery of BDNF mRNA with cationic polymers resulted in improved motor function recovery in a mouse model of contusive SCI . Intraspical SCI . Retrogrical SCI . Sustainical SCI . In addiical SCI . Insulin pathway . Igf-1 o in mice . Subcuta in mice . In addi in mice . Vascula in mice . VEGF wa in mice .The substantial loss of neurons and oligodendrocytes following SCI leads to disruption of neural network and signal transduction. Cell transplantation exhibits multitherapeutic capacities, such as replacement of damaged tissue, formation of relay neural circuits, immunomodulation, neuroprotection, and myelin regeneration, thus emerging as a more promising intervention to promote functional improvement following SCI . A varieNeural stem cells/neural progenitor cells (NSCs/NPCs) are self-renewing cells and can differentiate into specific neurons or glial cells to replace damaged spinal cord tissue. Implantation of NPCs/NSCs has shown great therapeutic potential in axon regeneration and functional restoration after SCI in rodents and primates . The obsMSCs are ideal candidate for cell-based therapies. MSCs raise no ethical concerns and can be acquired from diverse tissue sources like bone marrow, placenta, umbilical cord, and adipose tissue. Therefore, MSC transplantation is one of the most promising candidates for SCI repair. The therapeutic effects MSC transplantation after SCI are primarily due to their paracrine activity and trophic support: MSC-secreted factors modulate the immune response and induce neuroprotection, angiogenesis, and fiber regeneration in the injured spinal cord . In the SCs are another potential candidate for transplantation in patients with SCI. SCs have been shown to promote spinal cord repair through multiple mechanisms; they myelinate axons, reduce tissue injury, enhance neuroprotection, and maintain axonal plasticity. SCs are easily acquired from autologous nerve, thus alleviating the risk of immune rejections and avoiding the need for immunosuppression. SCs have demonstrated potential therapeutic effects in rodent SCI models, and their safety and potential efficacy have also been confirmed in clinical trials. A phase I clinical trial in humans with subacute SCI suggested that autologous human Schwann cell (ahSC) transplantation injected into the epicenter of the spinal lesion was safe and feasible. No serious adverse events or neurological complications were detected within in one year after transplantation . AnotherLike ahSCs, iPSCs derived from somatic cells avoid ethical concerns and immune rejection, and they can be reprogrammed to NPCs/NSCs, supporting human iPSC-derived NSC/NPC transplantation as a viable approach to treat SCI. Transplantation of human iPSC-derived NSCs facilitated axon growth and functional neural circuit reconstruction as well as motor function restoration after cervical spinal cord hemisection in rats . SimilarCollectively, the multiple observed therapeutic benefits associated with cell transplantation makes cell-based therapy an attractive approach that could substantially improve outcomes for patients with SCI. However, some remaining issues may limit their clinical practice, including ethical controversy, cell source, intervention time, uncontrolled cell proliferation, and long-term safety. Continued efforts to resolve these issues and concerns could make cell transplantation a feasible clinical option.The descending motor pathways are severely interrupted after SCI. Although the spinal neural circuits below the injury level remain intact, the absence of supraspinal descending commands leads to the circuits functionally dormant and loss of motor function. Neuromodulation is a bioengineering approach that utilizes electrical or magnetic stimulation, pharmacological agents, optogenetics, and chemogenetics to modulate neuronal activity. Neuromodulation has been successfully applied in a variety of neurological diseases. Neuromodulatory technologies applied for SCI aim to reactivate the spinal intrinsic motor circuits below the lesion and ultimately restore the basic motor function and/or voluntary movements. These neuromodulatory inventions primarily include spinal cord stimulation, brain stimulation, and brain\u2013machine interface.Spinal cord stimulation is emerging as a potential therapy to alleviate neurological deficits and promote functional recovery following SCI. Epidural electrical stimulation (EES), transcutaneous spinal cord stimulation (tcSCS) and intraspinal microstimulation (ISMS) are the three forms of spinal cord stimulation that designed to facilitate functional restoration after SCI.Epidural electrical stimulation (EES) applied to the lumbosacral spinal segments has been shown to substantially restore locomotion and motor control after SCI both in preclinical and clinical studies. Paralyzed rats treated with EES were able to perform continuous stepping, walking, and even climbing staircases . Co-deliContinuous EES may abolish proprioceptive information in humans and restrict locomotion recovery. In contrast, spatiotemporal EES enhanced the active control of motor neurons while preserving the interaction between antagonistic muscles to ensure coordination and stability of lower limb movement . SpatiottcSCS is another well-developed form of spinal cord stimulation and has been demonstrated to restore motor, sensory, and autonomic function when used alone or combined with other interventions . tcSCS iPrevious studies have indicated that even clinically complete SCI spares some descending nerve fibers, but they are dormant and insufficient to trigger movement. Brain stimulation has been used to engage the residual motor circuits to restore voluntary limb movement after SCI. The brain stimulation strategies mainly include deep brain stimulation (DBS), transcranial direct current stimulation (tDCS), and transcranial magnetic stimulation (TMS).DBS is a well-established technique that activates neural activity of the target brain region via implanted electrode. Motor cortex electrical stimulation was shown to promote CST axon sprouting, and the combination of motor cortex stimulation and transcutaneous spinal direct stimulation (tsDCS) further augmented CST axon plasticity and restored forelimb motor function after rat spinal cord contusion . This coBrain\u2013machine interface (BMI) has emerged as a novel technique that combines engineering, computer science, and neurophysiology to restore sensorimotor functions in patients with severe neurological disability . BMI recA participant with quadriplegia from cervical SCI regained cortical control of dexterous hand movements using BMI. The participant\u2019s forearm muscles were reactivated and controlled by the intracortically recorded signals, ultimately enabling complete functional movement task like grasping, manipulating, and releasing objects . An indiThe wireless brain\u2013spine interface was employed to directly link the intended motor states decoded from leg motor cortex activity to spatiotemporal EES over the lumbosacral segment to re-establish voluntary control of leg activity. This approach alleviated gait deficits and enabled weight-bearing locomotion on a treadmill and overground in rhesus monkeys with unilateral corticospinal tract lesion during the first week post-injury . As obseNeuromodulation therapies have achieved unexpected efficacy in restoring locomotion and volitional control in both SCI animal models and individuals with SCI. Therefore, these neuromodulatory technologies might be the most promising approach to achieve meaningful functional recovery following SCI.Individual treatments are insufficient to restore meaningful locomotion due to the complex pathological responses after SCI. Therefore, combinatory approaches targeting diverse aspects of SCI pathology are warranted to facilitate functional recovery in humans with SCI. Biomaterials serve as physical and structural supports to guide axon outgrowth and have been widely applied in the treatment of SCI. Meanwhile, biomaterials act as a key component of combinatorial approaches, as they provide temporary storage substrates for the long-term release of drugs, bioactive molecules, and transplanted cells to modulate inflammation, neural plasticity, axon regeneration, and cell survival .Combined delivery of multiple growth factors and chemokines released from hydrogel depots elicited robust propriospinal axon regrowth after complete SCI in both mice and rats. The regenerating propriospinal axons formed synapse-like contacts with neurons below the lesion site and restored electrophysiological conduction across lesions . The supLycium barbarum oligosaccharide (LBO) promoted microglia towards M2 polarization. Combination of LBO, nasal mucosa-derived mesenchymal stem cells, and fibronectin hydrogel synergistically enhanced the M2 polarization of microglia and promoted axon remyelination and recovery of hind limb movement after complete spinal cord transection in rats  was shown to promote functional recovery in rodent models of SCI, and its safety and feasibility were confirmed in preliminary phase I/IIa clinical trial. However, the phase 3 clinical trial failed to show significant benefit of G-CSF in the primary end point . A few oAlthough encouraging results have been achieved in SCI animal models, interventions that are effective preclinically demonstrate little efficacy to produce functional improvements when translated into clinical trials. Therefore, the beneficial outcomes from rodent models are not always reproduced in clinical practice. One possible reason is the limitation of rodent models for predicting efficacy in human SCI. The anatomy and size of the spinal cord vary greatly between rodents and primates. For instance, the anatomical characteristics and function of descending pathways involved in motor control  demonstrates pronounced interspecies differences between rodents and primates. In rodents, the CST fibers mostly travel in the dorsal columns of the spinal cord, and no direct connections exist between CST fibers and the cervical motoneurons. By contrast, in humans and non-human primates, the CST fibers are mainly located in the lateral columns and have developed direct connections with motoneurons . In addiFuture clinical trials for the treatment of SCI should be designed after considering several factors that may influence outcomes. Accumulating more data and comprehensive preclinical testing is essential before initiating clinical trials to minimize the risk of patients experiencing adverse effects or undergoing futile treatment. Moreover, the lack of reproducibility and robustness in preclinical experiments is another major issue contributing to the failure of clinical translation . Thus, iIndividual therapeutic interventions are inadequate to resolve the multifaceted pathological processes that occur after SCI and to promote spinal cord repair. Multi-targeted, combinatorial approaches are expected to maximize therapeutic effect. However, this becomes more complicated because many aspects must be taken into account when different strategies are combined. For instance, the optimal temporal window of treatment and whether the treatments are safe, tolerable, and feasible in combination must be determined to identify the most effective synergistic strategies. To optimize combinatorial strategies, determine analytical frameworks and achieve clinically relevant recovery in patients with SCI, it is therefore essential to enhance collaboration and communication between basic researchers and clinicians.Spinal cord injury interrupts the descending motor pathways and ascending sensory fibers within the spinal cord, leading to multi-system dysfunction and permanent disability. To alleviate the devastating effects of SCI, researchers have developed a variety of novel therapeutic approaches in recent years, some of which have shown promising therapeutic efficacy in preclinical studies and are progressing to clinical trials. This review summarizes the recent progress of preclinical and clinical strategies in SCI treatment and discusses the challenges and prospects for spinal cord repair.Despite encouraging results in preclinical experiments, many interventions have failed to translate to clinical application. This translational failure is partially due to the complex and multifaceted features of SCI pathology. Hence, a better understanding of the pathological processes following SCI and thorough investigation of intrinsic and extrinsic mechanisms controlling axon growth are urgently warranted to develop novel strategies to achieve greater beneficial outcomes. Notably, most individual therapeutic strategies targeting a single pathophysiological mechanism are insufficient to achieve relevant efficacy, resulting in clinical translation failure. Combinatorial strategies that act on multiple pathological processes of SCI have been shown to be more effective than individual treatments alone. Therefore, combinatorial approaches are more promising to wok synergistically to overcome multiple regeneration barriers and foster neural repair in patients with SCI. Furthermore, multidisciplinary collaboration and conversations are essential to ensure the accuracy of therapeutic design and predictive analysis.Neuronal regeneration or the formation of relay neural circuits after SCI is not necessarily accompanied by associated functional improvement. Rehabilitation training could augment the adaptive plasticity of residual pathways and is expected to trigger reorganization and integration of neural circuitry to promote longer-lasting functional readouts. Together with appropriate rehabilitation, combinatorial strategies might further enhance recovery of neurological function in clinical SCI. Furthermore, it is vital to select appropriate animal models for preclinical studies, and potential strategies should be extensively investigated preclinically in diverse SCI animal models to validate their therapeutic effects. Pronounced species divergence exists between primates and rodents or carnivores, and non-human primate models are particularly relevant for designing interventions and validating their therapeutic potential before translated to clinical application. In the future, further investigation is warranted to identify the neural regenerative mechanisms of functional recovery after SCI, especially in non-human primate models, as they are more similar to those in humans. These studies might be crucial to develop novel therapeutic interventions targeting particular neural circuits to improve function restoration."}
+{"text": "Lacrimal gland enlargement can be a feature of thyroid eye disease (TED). Unilateral or asymmetric lacrimal gland enlargement is poorly described and may impede diagnosis. We present the histological and clinical findings of four patients with asymmetric lacrimal gland enlargement.A retrospective case note review was performed for patients over two tertiary orbital clinics  presenting with an asymmetrical lacrimal gland enlargement with a background of TED that underwent biopsy to exclude alternate diagnoses. Baseline data was collected for each patient and histopathological images and reports were reviewed.All four patients were hyperthyroid at time of lacrimal gland biopsy. Biopsy demonstrated nonspecific, lymphoid aggregates, typically of B cell type, with no diagnostic findings to support lymphocyte clonality or IgG4-related disease. One biopsy specimen demonstrated evidence of some fibrosis.Asymmetrical lacrimal gland enlargement can occur as part of the TED spectrum but may require biopsy to exclude alternate pathology. Histology demonstrates a non-specific lymphocytic infiltrate. Thyroid eye disease (TED) is the commonest cause of orbital inflammation in adults. It can result in expansion and fibrosis of the extraocular muscles and orbital fat . RadioloThe purpose of this study is to report on the histopathological findings of lacrimal gland biopsies in patients with asymmetric lacrimal gland enlargement.A retrospective review of clinical case notes was performed for all patients presenting to two units  between the years 2013 to 2020. Inclusion criteria included patients with known thyroid dysfunction, upper eyelid retraction and/or lid lag in keeping with thyroid eye disease, clinical and/or radiological findings of lacrimal gland enlargement, magnetic resonance imaging (MRI) of the orbits and subsequent lacrimal gland biopsy and serological investigations (eg serum immunoglobulin subclasses) to exclude concurrent disease.Baseline data for each patient was collected including age, sex, ocular comorbidity, laterality, ophthalmic findings, and histopathological findings. Clinical Activity Score (CAS) was obtained for the patient\u2019s initial presentation. The CAS evaluates inflammatory signs and symptoms that are often characteristic of active TED.Ethical approval for this study was not required as per the Human Research Authority (HRA) online decision-making tool. Informed consent was provided by each patient for the procedure and use of clinical information.Four patients were identified through case note review Table . The meaThree of the four patients presented with upper lid retraction. All four patients had inactive disease. Other common presentation features included lid lag and proptosis. MRI had been requested as routine baseline imaging of the orbital contents.All patients were biochemically hyperthyroid and demonstrated asymmetrical lacrimal gland enlargement on MRI (Fig.\u00a0Histopathological analysis of lacrimal gland biopsy specimens showed nonspecific chronic inflammation composed largely of B lymphocytes in all four cases Figs.\u00a0,\u00a03,\u00a04. OLacrimal gland enlargement is a common finding in TED and particularly in the active stage of the disease , 6, 7. ARadiological findings may assist the decision-making regarding biopsy of the lacrimal gland. Epithelial neoplasms predominantly involve the orbital lobe whilst inflammatory and lymphoproliferative lesions tend to involve both the orbital and palpebral lobes . LymphopPreviously reported lacrimal gland histopathological findings in TED have also shown nonspecific inflammatory cell infiltration with and without fibrosis , 13, 14.These nonspecific histological changes, to some extent, diagnoses thyroid eye disease by exclusion, given the lack of a specific histopathological marker, although there remains the possibility of other concurrent, non-specific, diseases such as idiopathic dacryoadenitis that tend to present unilaterally.All four patients in the present study were hyperthyroid which contrasts with previous studies which have shown asymmetric TED clinical presentations predominantly in euthyroid or hypothyroid disease states , 18, 19.There are several limitations to this study. Firstly, the retrospective and non-comparative design limit inferences that can be drawn. Secondly, a standard set of immunohistochemical testing was not undertaken due to the retrospective and multi-centre nature of the study. Finally, we have included a small number of patients, although this may reflect the relatively uncommon nature of TED-related, asymmetric lacrimal gland enlargement.This study confirms that those patients with lacrimal gland enlargement presumed secondary to TED typically show nonspecific chronic inflammatory changes on histopathological analysis. Lacrimal gland biopsy is prudent given concurrent malignant or inflammatory disease is possible with asymmetrical enlargement although radiological imaging modalities of the lacrimal gland show promise in diagnosing active TED."}
+{"text": "Brain structural and functional alterations have been consistently proposed to be involved in the neurobiological underpinnings of aging and neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease. Given that pathological perturbations of the central nervous system are often intertwined with brain connectivity alteration, it is becoming increasingly accepted that connectome reorganization plays a key role in determining cognitive or motor disability. The advances in connectome-wide association studies (CWAS) have the potential to allow for the identification of novel neural correlates of neurodegeneration at the whole-brain scale, elucidating how brain-network topology can shape neural responses to neurodegenerative damage.This Research Topic aims to encourage the proposal of state-of-the-art methodologies related to CWAS techniques and their applications to neurodegenerative disorders. A total of five studies collected in this topic mainly cover (1) advanced statistical methods to avoid multiple covariates in analyzing brain connectivity; (2) a data-driven CWAS design to clarify and validate brain network findings associated with aging in a large sample of subjects; (3) a virtual analytical approach to describe brain disconnectome reorganization while avoiding the issue of artifacts that are prone to occur in the presence of white matter hyperintensity; (4) advanced dynamic connectivity measurements as novel brain imaging markers to discriminate AD patients at different stages; and (5) the brain structural covariance network analysis and related novel statistical model to unravel pathological progression of AD. In what follows, we summarized the highlights the methodologies and applications in aging and related neurodegeneration of each article.Smith et al. proposed a subject-level regression model to consider multiple covariates, including parcel-wise geographic/homotopic distance and region or network belongings, to move away from reliance on localization assumptions underlying FC comparisons. The key point is to keep each individual's FC in its own geometry, without morphing to a common template. This could be extraordinarily useful when the extent and location of lesions to brain regions varies across subjects. Additionally, the authors demonstrated high repeatability of this model achieved in individual space with test-retest individual scans.Functional connectivity (FC) comparison across individuals can be challenging in CWAS due to complex covariates in inter-subject variations. Du et al. applied a priori-driven independent component analysis, named NeuroMark, on 6,300 healthy adult with an age range of 49\u201373 years from UK Biobank project. They highlighted multiple significant joint between-network FC changes related to aging occurred in default mode and sub-cortical networks. This spatial diversity of brain network reorganization revealed by CWAS may shed new light on mechanism underlying aging-related brain changes.How aging affects functional networks of the brain in both within-network and between-network connectivity is unclear. To comprehensively explore this effect, Li et al. addressed the focal effect when analyzing brain structural network. To avoid potential confounds of white matter hyperintensity (WMH) in CWAS, the authors proposed a virtual lesion approach to estimate brain connectivity changes in aging. Specifically, WMH frequency maps across age ranges  were used to generate virtual lesion masks for each decade as regions of avoidance in white matter tractography. They quantitatively described the spatial disconnectome evolving patterns in cortical and subcortical areas, which might underlie cognitive and sensorimotor deficits seen in aging. The advancement of this virtual lesion approach can further help identify brain disconnectome features contributing to dementia risk.Another study conducted by Penalba-S\u00e1nchez et al. compared multiple FC measurements  and evaluated their corresponding network segregation and integration in mild cognitive impairment and AD. The authors unexpectedly observed an increase in late stage AD and a slight decrease of FC in early MCI, and explained the potential underlying cognitive mechanism. Understanding the dynamic and non-linear nature of FC might be crucial for unraveling the unclear neuropathological factors affecting behavior symptoms along the trajectory of AD.Emerging evidence has supported that abnormal brain structural or functional connectivity could have been observed 10\u201320 years prior to the onset of clinical symptoms of AD. Aiming to clarify inconsistent brain FC findings in early stage of AD, the study conducted by Xiao et al. applied SCN analysis using T1-weighted MR images from a longitudinal cohort to examine whether and how earlier brain atrophy patterns impact the progressive changes of gray matter atrophy in AD patients over time. After establishing regular structural connectivity by Pearson correlation and causal structural connectivity by Granger causal analysis, they used a new approach named gray matter based spatial statistics to measure the gray matter volume at the core of the cortical plate, aiming to alleviate partial volume effect and inter-subject variability. High discrimination accuracy based on SCN connectivity features suggests that SCN approach may help identify the unique pathological progression of AD and other types of neurodegeneration.Unlike structural connectivity, which is classically represented by the connection strength of white matter tracts on individual level, brain structural covariance network (SCN) analysis highlights synchronized gray matter atrophy undergoing neurological pathological processes across brain regions on population level. In sum, the collective findings represented in these articles reflect the rapidly expanding development of the CWAS field. One could further expect a rising body of brain network analytical tools and statistical models updated in this emerging area, providing new avenues for identification of brain network markers related to aging and neurodegenerative disorders. However, whether and to what degree the brain network construction procedures  affects robustness of findings in neurodegeneration is still in dispute. Therefore, before further translating into clinical applications such as individual auxiliary diagnosis and treatment decision-making, we must be cautious whether the reliability and validity performance of these CWAS approaches has been fully reported and validated in large-sample and multi-center brain imaging data.CY: Writing\u2014original draft. TW: Writing\u2014review & editing. AF: Writing\u2014review & editing."}
+{"text": "This review article delves into the intricate and evolving relationship between coronary microvascular dysfunction (CMD) and takotsubo cardiomyopathy (TCM), two intriguing cardiovascular conditions increasingly recognised for their potential interplay. We examine their characteristics, shared pathophysiological mechanisms, diagnostic challenges, and management strategies. Emerging evidence suggests a link between microvascular dysfunction and the development of TCM, leading to a deeper exploration of their connection. Accurate diagnosis of both conditions becomes essential, as microvascular dysfunction may modify TCM outcomes. We underscore the significance of understanding this connection for improved patient care, emphasising the need for tailored interventions when CMD and TCM coexist. Collaborative research and heightened clinical awareness are advocated to advance our comprehension of this relationship. Through interdisciplinary efforts, we aim to refine diagnostic precision, develop targeted therapies, and enhance patient outcomes in cardiovascular medicine. Medical interest has surged toward two distinct yet captivating cardiovascular conditions: coronary microvascular dysfunction (CMD) and takotsubo cardiomyopathy (TCM). While initially perceived as separate entities, recent research hints at a potentially intricate link between these conditions. This article delves into this complex interplay between CMD and TCM, probing their shared pathophysiological mechanisms, clinical presentations, diagnostic challenges, and treatment implications -3.Coronary microvascular dysfunction encompasses a spectrum of disorders characterised by anomalies in the microvasculature's structure and function within the coronary circulation. Unlike traditional coronary artery disease, which affects large epicardial vessels, CMD involves dysfunction in the smaller arterioles and capillaries that regulate myocardial blood flow. Despite the absence of significant obstructive coronary artery disease, CMD leads to angina-like symptoms, myocardial ischemia, and abnormal stress test results. The elusive nature of CMD and its limited diagnostic tools pose challenges in diagnosis, rendering understanding its underlying mechanisms and clinical significance increasingly pivotal ,5.In contrast, TCM, or \"broken heart syndrome,\" manifests as transient left ventricular dysfunction mimicking acute myocardial infarction. Chest pain, electrocardiographic changes, and elevated cardiac biomarkers typify this condition. Often arising from emotional or physical stressors, TCM's hallmark is the unique apical ballooning pattern evident in cardiac imaging. While initially viewed as reversible with a favourable prognosis, recent research illuminates potential severe complications and enduring consequences ,7.The realisation of a possible connection between CMD and TCM carries profound ramifications for both clinical practice and research. Evidence suggests that patients with TCM often exhibit microvascular dysfunction, hinting at an underlying link between these conditions. Understanding this association could offer insights into the triggers and pathogenesis of TCM. Furthermore, discerning the relationship between CMD and TCM stands to shape therapeutic strategies and enhance patient outcomes ,9.This review comprehensively explores the evolving relationship between CMD and TCM. We offer a holistic perspective on their shared pathophysiological mechanisms, clinical manifestations, diagnostic hurdles, and therapeutic implications by delving into the crossroads of these two distinct yet potentially intertwined conditions. Through a critical analysis of existing research, clinical observations, and theoretical models, our synthesis aims to provide healthcare professionals, researchers, and clinicians with an exhaustive resource. This resource illuminates conceivable connections between CMD and TCM, emphasising the importance of recognising and addressing this association in clinical practice. Our in-depth examination of CMD and TCM's complexities strives to advance medical understanding, enhance patient care, and formulate precise strategies for managing these captivating cardiovascular conditions.Coronary microvascular dysfunction (CMD)Definition and Pathophysiology of CMDCoronary microvascular dysfunction encompasses a spectrum of disorders characterised by intricate abnormalities within the smaller coronary vessels, including arterioles and capillaries. In contrast to traditional coronary artery disease, which primarily affects the larger epicardial vessels, CMD homes in on the delicate microcirculation. To comprehensively understand CMD's pathophysiology, it's crucial to explore the underlying mechanisms that have been identified. Endothelial dysfunction stands at the forefront of CMD's pathophysiology, playing a pivotal role in impairing the functionality of the microvasculature. This dysfunction is intricately linked to the imbalance of vasoactive factors and nitric oxide availability, ultimately affecting the vascular tone and endothelium-dependent vasodilation . MoreoveClinical Presentation and Diagnostic ChallengesThe clinical presentation of CMD\u00a0closely mirrors that of obstructive coronary artery disease, making it challenging to distinguish between the two based solely on symptoms. Patients with CMD often report chest pain, dyspnea (shortness of breath), and exercise intolerance, commonly associated with traditional coronary artery disease. This similarity in symptoms can lead to confusion in diagnosis, mainly when relying solely on clinical presentation .One of the critical diagnostic challenges in CMD lies in the limitations of conventional diagnostic tests, such as angiography. Unlike obstructive coronary artery disease, CMD does not involve significant narrowing or stenosis of the larger coronary arteries, typically visualised through angiography. This absence of visually apparent coronary stenosis can lead to underdiagnosis or misdiagnosis, as these tests may not capture the microvascular abnormalities characteristic of CMD .Furthermore, the need for well-defined diagnostic criteria and standardised assessments for CMD exacerbates the difficulty in identifying the condition accurately. The absence of universally accepted guidelines to diagnose CMD makes it challenging for healthcare practitioners to consistently recognise and differentiate it from other cardiac conditions. This lack of standardised criteria also hampers research efforts and makes it difficult to compare findings across studies .The confluence of overlapping symptoms, along with the limited sensitivity of existing diagnostic tests, contributes to a significant underrecognition and underdiagnosis of CMD. This diagnostic shortfall is consequential, potentially resulting in treatment delays and impacting patient outcomes. An appreciable aspect to consider is the percentage of undetected cases due to these challenges. Additionally, it is pertinent to discuss the sensitivity and specificity of the employed diagnostic tests and the symptoms associated with CMD. As the landscape of CMD research evolves, the need becomes apparent to establish standardised diagnostic criteria and innovative diagnostic techniques. By addressing this pressing need, the accurate identification and effective management of this intricate condition can be significantly improved .Underlying Causes and Risk FactorsCoronary microvascular dysfunction is a complex condition influenced by various underlying causes and risk factors extending beyond traditional cardiovascular risk factors. While hypertension, diabetes, and dyslipidemia are recognised as conventional contributors to CMD, a growing body of evidence highlights the significance of non-traditional risk factors in its development .Psychosocial stress emerges as a potent contributor to CMD. Chronic stress triggers the release of stress hormones, leading to endothelial dysfunction and impaired vasomotor responses in the coronary microvasculature. This can result in reduced myocardial blood flow regulation and contribute to the manifestation of CMD symptoms .Hormonal imbalances play a role in CMD pathogenesis, particularly in women. Oestrogen, for instance, exerts protective effects on endothelial function, and its decline during menopause might contribute to microvascular dysfunction. Hormonal fluctuations during the menstrual cycle also influence vasomotor responses, potentially impacting coronary microcirculation .Systemic inflammation is increasingly recognised as a critical player in CMD. Chronic inflammation contributes to endothelial dysfunction, oxidative stress, and impaired nitric oxide bioavailability. Inflammatory cytokines can directly affect coronary microvascular function, altering vasodilation responses and contributing to CMD .Endothelial dysfunction, a hallmark feature of CMD, is a common link between these risk factors. It disrupts the delicate balance between vasodilation and vasoconstriction, impairing coronary blood flow regulation. Endothelial dysfunction contributes to the microvascular abnormalities observed in CMD and lays the groundwork for developing ischemic symptoms ,20.Available Diagnostic Techniques for CMDCoronary flow reserve measurements using Doppler ultrasound: Doppler ultrasound measures blood flow velocities within the coronary arteries during rest and stress. The coronary flow reserve is assessed by calculating the ratio of flow velocities before and after vasodilation. Reduced coronary flow reserve indicates microvascular dysfunction and impaired vasodilatory capacity, which can contribute to myocardial ischemia ,22.Positron emission tomography (PET): Positron emission tomography imaging quantitatively assesses myocardial blood flow at rest and during stress, usually induced by pharmacological agents or exercise. The comparison of these flow measurements provides insights into the functionality of the microvasculature. Positron emission tomography can help identify regions of reduced perfusion and abnormalities in microvascular function, contributing to the diagnosis of CMD ,24.Cardiac MRI: Cardiac MRI offers non-invasive visualisation of the myocardium and surrounding structures. Techniques like myocardial perfusion imaging provide information about blood flow distribution, aiding in identifying microvascular dysfunction. Cardiac MRI can help evaluate myocardial oxygen supply-demand balance and detect ischemic regions without obstructive coronary artery disease ,26.Invasive coronary reactivity testing: Invasive procedures involving the administration of vasoactive agents within the coronary arteries allow for direct assessment of microvascular function. Endothelial-dependent and independent vasodilatory responses are measured, providing insights into microvascular dysfunction. However, the invasiveness of this approach limits its routine clinical use ,28.Despite the availability of these diagnostic techniques, challenges persist in interpreting results and establishing definitive diagnostic criteria. The lack of standardised protocols and reference values makes establishing universally accepted thresholds for diagnosing CMD difficult. Variability in patient populations, equipment, and procedural protocols further complicates result interpretation. Overcoming these challenges requires collaborative efforts among researchers and clinicians to establish consensus guidelines and refine the diagnostic approach for CMD, ultimately enhancing its recognition and management .Current Treatment Strategies for CMDLifestyle modifications: Lifestyle interventions stand as the cornerstone of CMD management. Encouraging patients to adopt a heart-healthy lifestyle is paramount. This includes regular physical exercise tailored to individual capabilities, as exercise has been shown to enhance endothelial function and improve microvascular health. Furthermore, weight management plays a pivotal role, as excess body weight can contribute to metabolic disturbances and exacerbate microvascular dysfunction. Smoking cessation is of utmost importance, given that smoking damages endothelial cells and worsens microvascular health. Additionally, addressing psychosocial stressors through stress reduction techniques, mindfulness, and psychological counselling can contribute to overall well-being and potentially mitigate the impact of stress on microvascular function ,31.Pharmacological interventions: Pharmacotherapy for CMD aims to alleviate symptoms, enhance microvascular function, and target underlying risk factors. Endothelial function-enhancing agents, such as angiotensin-converting enzyme (ACE) inhibitors and statins, promise to improve endothelial health and promote vasodilation. Vasodilators, such as calcium channel blockers and nitric oxide donors, can help alleviate microvascular constriction and enhance coronary blood flow. Additionally, anti-inflammatory agents are being explored due to their potential role in reducing vascular inflammation and improving microvascular function ,33.Patient education and psychosocial support: Patient education is integral to holistic CMD management. Empowering patients with knowledge about their condition, its underlying mechanisms, and the significance of lifestyle modifications fosters active participation in their care. Moreover, addressing psychosocial stressors, including anxiety and depression, is essential, as these factors can exacerbate microvascular dysfunction. Psychological support and counselling can help patients cope with CMD\u2019s emotional and psychological impact, promoting a holistic approach to well-being ,35.Takotsubo cardiomyopathy (TCM)Definition and Characteristic Features of TCMTakotsubo cardiomyopathy, often called \"broken heart syndrome,\" is a unique and transient condition characterised by acute left ventricular dysfunction, typically presenting with symptoms resembling acute myocardial infarction. The hallmark feature of TCM is the distinctive ventricular ballooning observed during cardiac imaging, which resembles a Japanese octopus trap known as \"takotsubo.\" Left ventricular dysfunction typically involves the apex but can also affect other heart segments .Proposed Mechanisms for TCM DevelopmentThe precise mechanisms driving the development of TCM\u00a0remain a subject of continuous investigation and exploration. Multiple hypotheses have emerged, each offering insights into the intricate cascade of events that culminate in this unique cardiac phenomenon. These mechanisms include but are not limited to, surge-induced myocardial stunning, microvascular dysfunction, coronary artery vasospasm, and neurogenic influences .Catecholamine surge-induced myocardial stunning: One of the prominent theories centres around the significant role of the autonomic nervous system's response to stress. A sudden and excessive release of stress hormones, particularly catecholamines such as adrenaline, is thought to trigger a surge-induced myocardial stunning. This stunning effect results in transient myocardial dysfunction, marked by impaired contractility and ventricular ballooning .Microvascular dysfunction: Another hypothesis emphasises the role of microvascular dysfunction in TCM development. Under the influence of stress hormones, there is potential for the small coronary vessels, including arterioles and capillaries, to undergo dysregulation. Microvascular dysfunction disrupts normal blood flow regulation, leading to inadequate myocardial oxygen supply. This compromised perfusion contributes to myocardial stunning and the characteristic ventricular ballooning observed in TCM cases .Coronary artery vasospasm: The involvement of coronary artery vasospasm is also proposed as a mechanism for TCM initiation. Stress-induced alterations in vasomotor tone could trigger transient spasms in the coronary arteries, leading to reduced blood flow to the heart muscle. This diminished blood supply can result in myocardial dysfunction, with the apical region particularly susceptible due to its anatomical characteristics .Neurogenic influences: Neurogenic factors, including the brain-heart connection, have gained attention as potential contributors to TCM development. Emotional stressors can stimulate the autonomic nervous system, leading to altered heart rate variability, sympathetic nervous system activation, and hormonal fluctuations. This complex interplay between the brain and the heart might contribute to the intricate pathophysiology of TCM .Clinical Presentation and Diagnostic Criteria for TCMTakotsubo cardiomyopathy is characterised by a distinctive clinical presentation and diagnostic criteria that differentiate it from other cardiovascular conditions. The hallmark symptom is the sudden onset of chest pain, often accompanied by dyspnea, palpitations, and a feeling of impending doom. This presentation can closely mimic acute coronary syndrome, particularly ST-segment elevation myocardial infarction (STEMI), leading to initial diagnostic challenges .Diagnostic criteria for TCM have evolved to aid in accurate differentiation from other cardiac pathologies. Transient left ventricular dysfunction is a central feature of TCM, with echocardiography and cardiac MRI serving as crucial tools for its visualisation. Coronary angiography reveals the absence of significant coronary artery stenosis or plaque rupture, further supporting the diagnosis. This differentiation is paramount, as TCM is managed differently from acute coronary syndromes .Also, diagnostic criteria exclude other conditions that might mimic TCM's presentation. Pheochromocytoma, a rare tumour causing excess catecholamine release, and myocarditis, inflammation of the heart muscle, should be ruled out due to their potential to induce similar stress-related myocardial dysfunction .Cardiac imaging, particularly echocardiography and cardiac MRI is indispensable in confirming the diagnosis. Echocardiography unveils the hallmark feature of TCM, the unique apical ballooning pattern, which distinguishes it from other cardiac pathologies. Cardiac MRI further enhances diagnostic accuracy by providing detailed insights into myocardial tissue characteristics and perfusion patterns, facilitating the differentiation of TCM from other conditions presenting with similar symptoms .Differentiating TCM from Acute Coronary SyndromeDistinguishing TCM\u00a0from acute coronary syndrome (ACS) is paramount due to their shared clinical presentations, which often include chest pain, dyspnea, and electrocardiographic changes. One crucial distinction is the absence of culprit coronary lesions on angiography in TCM cases. Unlike ACS, where obstructive coronary artery disease is typically evident, TCM patients display normal or near-normal coronary arteries. This disparity emphasises the need for comprehensive angiographic evaluation to exclude coronary artery obstruction and confirm the absence of significant stenosis .Furthermore, TCM patients tend to exhibit less pronounced elevations in cardiac biomarkers, such as troponin levels, when compared to the more typical ACS cases. While troponin elevation is a hallmark of myocardial injury, the extent of elevation in TCM is often milder than observed in ACS, further aiding differentiation. However, it is essential to note that a certain degree of troponin elevation can still be present in TCM cases, underscoring the importance of integrating multiple diagnostic criteria .Cardiac imaging is an invaluable tool in the differentiation process, particularly echocardiography and cardiac MRI. The characteristic apical ballooning pattern observed during imaging is a hallmark of TCM. This distinctive morphology, resembling the shape of a Japanese octopus trap (takotsubo), is a strong differentiator from ACS. Imaging findings directly visualise ventricular dysfunction and shape abnormalities, providing critical insights into the diagnosis .Management and Prognosis of TCMTakotsubo cardiomyopathy management encompasses a multi-faceted approach focused on supportive care to stabilise hemodynamics, address complications, and alleviate symptoms. Given the acute nature of TCM, patients often require vigilant monitoring in a specialised cardiac care setting. Stabilising hemodynamics involves carefully managing fluid balance, blood pressure, and heart rate to ensure optimal cardiac function. Efforts to maintain adequate perfusion and oxygenation are crucial, and interventions like supplemental oxygen and intravenous medications might be employed as necessary .Furthermore, addressing potential complications is of paramount importance in the management of TCM. Patients with TCM are at risk of developing heart failure due to transient left ventricular dysfunction. Standard heart failure therapies, including diuretics and beta-blockers, may be considered to manage volume overload and control heart rate. Arrhythmias, such as atrial fibrillation or ventricular tachycardia, might occur in the acute phase and necessitate appropriate treatment to restore a stable cardiac rhythm. Additionally, systemic embolism, particularly involving the left ventricular clot or thrombus formation, is a potential complication that requires attention to prevent embolic events .Most TCM cases exhibit a favourable prognosis with the spontaneous recovery of left ventricular function within weeks to months. Serial cardiac imaging, such as echocardiography or cardiac MRI, is valuable for monitoring the improvement in ventricular function over time. The heart's remarkable ability to heal and return to normal functioning underscores the transient nature of TCM. However, vigilance remains essential, as some cases might experience a protracted recovery period or recurrent episodes .Lifestyle modifications and addressing psychosocial factors play a crucial role in the long-term prognosis of TCM patients. Encouraging patients to adopt heart-healthy habits, including maintaining a balanced diet, engaging in regular physical activity, and avoiding tobacco and excessive alcohol consumption, contributes to overall cardiovascular well-being. Addressing underlying stressors and providing psychological support is equally important, as emotional triggers often precede TCM episodes. Comprehensive care extends beyond the acute phase to mitigate the potential triggers for recurrent episodes and optimise long-term cardiac health .The interplay between CMD and TCMReview of Studies Suggesting a Connection between CMD and TCMRecent years have witnessed a burgeoning body of research that unveils the captivating prospect of a multifaceted interplay between CMD\u00a0and TCM. This intriguing association has emerged through meticulously scrutinising diverse studies, including case reports and retrospective analyses. These inquiries have illuminated instances where TCM manifested in individuals previously displaying indications of underlying microvascular dysfunction. These preliminary observations have ignited curiosity within the medical community, suggesting a compelling nexus between CMD and TCM's pathogenesis .Numerous case reports have documented instances in which individuals diagnosed with CMD, an ailment marked by coronary microvasculature irregularities, subsequently encountered episodes of TCM. These cases potentially offer insights into a shared physiological connection that warrants closer investigation. Likewise, retrospective patient data analyses have unveiled a suggestive pattern that a subset of TCM cases might be heralded by documented or suspected CMD, implying a temporal relationship deserving thorough exploration .While these revelations prompt inquiries into potential mechanisms and implications, they also underline the need to consider additional research methodologies. Could microvascular dysfunction contribute to or even initiate TCM's development? Could CMD influence the trajectory or prognosis of TCM episodes? Rooted in these clinically observed correlations, these queries beckon a deeper understanding of the shared pathophysiological underpinnings that might underscore this intriguing association .The studies discussed undoubtedly build a compelling case for the connection between CMD and TCM. Nevertheless, they simultaneously serve as a launchpad for broader research endeavours. The implications of such an interrelationship could resonate profoundly, impacting diagnostic precision, risk evaluation, and therapeutic strategies. Hence, the clarion call for further investigation into these intricate dynamics transcends academic curiosity. It promises to advance comprehension of these enigmatic cardiovascular conditions and, by extension, elevate patient care in a substantive and impactful manner -57.Shared Pathophysiological MechanismsEndothelial dysfunction: A central component in both CMD and TCM, endothelial dysfunction refers to the impaired function of the endothelium, the inner lining of blood vessels. In CMD, compromised endothelial function reduces vasodilation and impairs blood flow regulation within the coronary microvasculature. Similarly, endothelial dysfunction could hinder normal coronary blood flow responses in TCM, potentially contributing to the transient myocardial dysfunction observed during TCM episodes .Oxidative stress: Elevated oxidative stress, characterised by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defences, is a common denominator in CMD and TCM. In CMD, oxidative stress can lead to endothelial dysfunction and structural alterations in the microvasculature, further impairing blood flow regulation. Takotsubo cardiomyopathy episodes, often triggered by stress, can trigger a surge in oxidative stress, which may contribute to myocardial injury and contractile dysfunction .Neurohormonal pathways: Dysregulation of neurohormonal pathways, particularly the autonomic nervous system's response to stress, plays a pivotal role in both conditions. Excessive release of stress hormones, such as adrenaline, can lead to vasoconstriction, increased heart rate, and myocardial oxygen demand. In individuals with pre-existing CMD, this heightened neurohormonal response could trigger the myocardium towards the transient dysfunction observed in TCM .Abnormal microvascular function and autonomic responses: Aberrant microvascular function, a hallmark of CMD, contributes to impaired myocardial perfusion and ischemia. In the context of TCM, microvascular dysfunction could exacerbate the myocardial stunning observed during TCM episodes. Furthermore, abnormal autonomic nervous system responses, including sympathetic overactivity, could influence both conditions, affecting coronary blood flow and myocardial contractility .Potential Role of Microvascular Dysfunction in Triggering TCMMicrovascular dysfunction is a compelling candidate for triggering TCM\u00a0in specific vulnerable individuals. Coronary microvascular dysfunction, marked by compromised vasodilation and impaired myocardial perfusion in the microcirculation, could set the stage for a cascade of events contributing to the initiation of TCM. The intricate link between these conditions is grounded in the notion that microvascular dysfunction might make the myocardium susceptible to the profound physiological responses of stress-induced catecholamine release .In individuals with CMD, the altered microvascular tone and reduced perfusion capacity might weaken the myocardium's resilience against the surge of stress hormones, particularly adrenaline. Stress-induced catecholamines have been implicated in TCM as potential triggers, initiating a sequence of cardiac events that lead to the distinctive features of this condition. The heightened vulnerability created by microvascular dysfunction could predispose the myocardium to stress-induced myocardial stunning, whereby the heart's contractility becomes impaired and its ability to pump blood effectively diminishes. This state of myocardial dysfunction, combined with the surge of catecholamines, could culminate in the hallmark ventricular ballooning pattern observed in TCM, particularly affecting the apex of the heart .Unravelling the intricate connection between microvascular dysfunction and TCM could provide valuable insights into the complex mechanisms governing the onset of TCM. By understanding how microvascular dysfunction amplifies the effects of stress hormones on the heart, researchers and clinicians can develop a more nuanced understanding of the factors contributing to TCM development. This comprehension, in turn, could inform targeted therapeutic approaches that address microvascular dysfunction and stress hormone responses, potentially mitigating the risk of TCM episodes in susceptible individuals .Impact of CMD on the Prognosis and Outcomes of TCMEmerging evidence underscores the potential significance of CMD\u00a0in shaping the clinical course of TCM. Research suggests that pre-existing CMD in individuals experiencing TCM could influence disease severity and subsequent clinical outcomes. This interaction between CMD and TCM holds implications for risk stratification and the development of tailored management strategies .In the context of TCM episodes, individuals with underlying CMD may exhibit more pronounced left ventricular dysfunction. The compromised microvascular function observed in CMD might render the myocardium vulnerable to the stress-induced catecholamine surge that characterises TCM. Consequently, the acute myocardial stunning and contractile impairment associated with TCM might manifest more severely in those with microvascular dysfunction. This could contribute to a heightened likelihood of complications, including heart failure and arrhythmias, impacting the overall prognosis .Recognising CMD as a potential modifier of TCM outcomes is crucial for risk assessment and management decisions. Risk stratification becomes more nuanced when CMD coexists with TCM, as these individuals might warrant closer monitoring and intensive interventions to mitigate the heightened risk of adverse events. Tailored management strategies could involve a more proactive approach to managing cardiac function, optimising fluid balance, and instituting preventative measures against potential complications. Such individualised management aligns with the complex interplay between CMD and TCM, addressing the unique vulnerabilities presented by their coexistence .Incorporating the potential impact of CMD into the risk assessment and management of TCM provides a broader perspective on the factors influencing disease progression and outcomes. As understanding this interaction evolves, healthcare practitioners can better tailor their approach to patient care, ensuring that individuals with CMD and TCM receive a comprehensive evaluation and strategic interventions that optimise their clinical trajectory .Theoretical Models Explaining the Relationship between CMD and TCMExploring the intricate relationship between CMD and TCM has given rise to several theoretical models to unravel the underlying mechanisms that potentially connect these conditions. These models provide valuable insights into the complex interplay between CMD and TCM, shedding light on possible pathways that link these distinct cardiovascular entities .The \"two-hit hypothesis\": This model postulates that CMD is the first \"hit,\" rendering the myocardium more vulnerable to subsequent stressors, such as catecholamine release triggered by emotional or physical stress. In this scenario, microvascular dysfunction could act as a priming factor, altering myocardial responsiveness and making it more susceptible to the detrimental effects of stress hormones. This susceptibility could lead to myocardial stunning and the unique contractile abnormalities observed in TCM. The \"two-hit hypothesis\" suggests that CMD sets the stage for the development of TCM by modifying the myocardium's response to stressors .The \"common substrate hypothesis\": According to this model, CMD and TCM share underlying mechanisms that make them mutually predisposing conditions. These shared mechanisms could include abnormalities in neurohormonal signalling, endothelial dysfunction, and impaired autonomic regulation. Factors that contribute to CMD, such as chronic stress or metabolic disturbances, could also create an environment conducive to the development of TCM under the right circumstances. The common substrate hypothesis underscores the potential interconnectedness of CMD and TCM, proposing that they arise from an everyday pathophysiological basis . ExploriClinical assessment and diagnostic challengesChallenges in Diagnosing CMD and TCM IndividuallyDiagnosing CMD\u00a0and TCM\u00a0as distinct cardiovascular conditions presents significant diagnostic challenges due to their unique complexities .Coronary microvascular dysfunction's subtle presentation and diagnostic complexity: Coronary microvascular dysfunction's inconspicuous and often asymptomatic nature adds to the difficulty of its identification. Unlike typical angina associated with traditional coronary artery disease, CMD often displays vague symptoms or remains entirely asymptomatic. Recognizing CMD becomes particularly challenging as patients may lack characteristic chest pain, leading to delayed diagnosis or overlooking the condition. Moreover, the absence of well-defined diagnostic criteria for CMD further compounds accurate detection .Diverse diagnostic criteria complicate CMD identification: The absence of universally agreed-upon diagnostic criteria for CMD contributes significantly to the diagnostic predicament. Varied definitions and diagnostic approaches across different medical contexts hinder establishing a consistent identification method. This lack of standardized criteria can lead to underdiagnosis or misclassification, impeding the implementation of appropriate management strategies .Takotsubo cardiomyopathy's resemblance to ACS\u00a0and diagnostic confusion: Takotsubo cardiomyopathy's clinical presentation resembles ACS\u00a0with symptoms like chest pain, electrocardiographic changes similar to\u00a0STEMI, and elevated cardiac biomarkers, which can cause diagnostic confusion. The overlap between TCM and ACS can result in healthcare providers selecting ACS treatment strategies without considering the possibility of TCM. Consequently, TCM patients might receive interventions like invasive coronary procedures or antithrombotic therapy that might not suit their condition .Implications of misdiagnosis: Misdiagnosing CMD and TCM can lead to inappropriate treatment plans and interventions. Mistakenly categorizing CMD patients as having non-cardiac causes for their symptoms could delay proper management, potentially exacerbating underlying microvascular dysfunction. Similarly, misidentifying TCM as ACS might expose patients to unnecessary invasive procedures and therapies, subjecting them to undue risks and potential complications .Overlapping Clinical Features and Diagnostic DilemmasThe convergence of clinical features between CMD and TCM\u00a0challenges their accurate diagnosis. Patients with both CMD and TCM may present with overlapping symptoms, including angina-like chest pain, breathlessness, and abnormal results in stress tests. The shared clinical presentation of these conditions accentuates the complexity of discerning one from the other. The diagnostic dilemma arises because these symptoms are common in various cardiac disorders, making it arduous to attribute them to CMD or TCM solely based on clinical presentation .In times of diagnostic uncertainty, the importance of employing precise diagnostic tools becomes evident. These tools must go beyond identifying symptoms and delve into each condition's underlying mechanisms and structural abnormalities. While symptoms might be the initial presentation, accurate differentiation necessitates comprehensive imaging techniques and functional assessments that illuminate the distinct pathophysiological underpinnings of CMD and TCM. This not only aids in pinpointing the correct diagnosis but also forms the foundation for developing targeted management strategies .Appropriate management hinges on accurate diagnosis, especially given the potential impact of shared symptoms on patient outcomes. The pursuit of enhanced diagnostic precision has driven the exploration of advanced imaging modalities such as cardiac MRI, which can delineate the myocardial microstructure and function, aiding in differentiating CMD from TCM. Moreover, non-invasive functional assessments like coronary flow reserve measurements using Doppler ultrasound offer insights into microvascular function and help discern between these conditions. The development and validation of these diagnostic tools are pivotal in overcoming the challenges posed by overlapping clinical features and ensuring optimal patient care .Novel Imaging and Diagnostic Techniques to Assess CMD and TCMThe continuous evolution of imaging and diagnostic technologies has paved the way for innovative methods of assessing CMD and TCM. These advancements offer promising avenues to enhance our understanding and diagnostic capabilities for these conditions .Cardiac MRI with contrast-enhanced perfusion imaging: Cardiac MRI\u00a0has emerged as a powerful tool for evaluating microvascular dysfunction in CMD. Utilising contrast-enhanced perfusion imaging, cardiac MRI allows for a non-invasive assessment of myocardial blood flow and perfusion patterns. This technique helps identify regions of impaired microvascular function and provides valuable insights into the subtler aspects of CMD. Moreover, cardiac MRI's ability to visualise the unique apical ballooning pattern associated with TCM aids in distinguishing it from other conditions with similar clinical presentations .Invasive techniques for microvascular assessment: Invasive techniques, such as coronary reactivity testing and Doppler ultrasound, are increasingly recognised for their potential in assessing microvascular function. Coronary reactivity testing involves administering pharmacological agents to induce controlled vasodilation and measuring the coronary blood flow response. This approach allows for the direct evaluation of microvascular reactivity and provides valuable information about the functional state of the microvasculature. Similarly, Doppler ultrasound offers insights into blood flow velocities within the microcirculation, aiding in identifying abnormalities in blood flow regulation .These novel techniques promise to improve the accuracy and specificity of diagnosing CMD and TCM. By enabling the direct assessment of microvascular function and subtle myocardial changes, these imaging and diagnostic methods enhance our ability to differentiate between these conditions and guide targeted treatment strategies. As these technologies continue to evolve, they are likely to play an increasingly significant role in the clinical management of CMD and TCM, facilitating earlier diagnosis and more personalised patient care .Importance of Accurate Diagnosis for Appropriate ManagementAccurate diagnosis is a cornerstone for effectively managing CMD\u00a0and TCM. The ramifications of misdiagnosis reverberate across patient outcomes, potentially causing profound harm. A misdiagnosed CMD might lead to inappropriate therapeutic interventions that neglect its unique pathophysiology, thereby failing to mitigate underlying microvascular dysfunction. This mismanagement could perpetuate the progression of microvascular impairment, contributing to a cascade of adverse cardiovascular events. Similarly, inaccurately managed TCM could translate into inadequate care for a condition that requires distinct attention. This misalignment in management could impede the natural recovery process and exacerbate the associated symptoms and complications .A comprehensive diagnostic approach is thus paramount to tailoring treatment strategies precisely to the specific condition at hand. Recognising CMD and TCM individually and understanding their potential coexistence inform appropriate therapeutic decisions. Accurate diagnosis empowers healthcare professionals to provide targeted interventions that address the intricate mechanisms driving each condition. Such precision ensures that interventions are aligned with the underlying pathophysiology, optimising the chances of positive patient outcomes. Through an accurate and holistic diagnostic approach, clinicians can circumvent the pitfalls of misdiagnosis, avoid unnecessary interventions, and significantly enhance patient well-being by offering the most fitting and efficacious treatments .Management strategiesConventional Treatment Approaches for CMDManaging CMD entails a comprehensive and multifaceted strategy that focuses on addressing the underlying risk factors contributing to microvascular dysfunction and improving the health and function of the microvasculature itself. This approach aims to alleviate symptoms, improve myocardial perfusion, and enhance cardiovascular health .Lifestyle modifications: A cornerstone of CMD management is empowering patients to adopt healthy lifestyle practices. Encouraging individuals to embrace a heart-healthy diet is crucial, emphasising the consumption of nutrient-rich foods such as fruits, vegetables, whole grains, lean proteins, and healthy fats while minimising processed foods, sugary drinks, and excessive sodium intake. This dietary approach supports blood pressure control, lipid management, and weight maintenance, ultimately promoting better microvascular health .Regular exercise: Physical activity improves endothelial function, enhances microvascular dilation, and increases cardiac fitness. Tailored exercise programmes that combine aerobic activities, strength training, and flexibility exercises can improve blood flow regulation and oxygen delivery to the myocardium. Regular exercise also positively impacts systemic factors such as blood pressure, lipid levels, and glucose metabolism, which are crucial in mitigating microvascular dysfunction .Stress reduction: Stress reduction techniques are pivotal in CMD management. Chronic stress can contribute to endothelial dysfunction and exacerbate microvascular abnormalities. Incorporating relaxation techniques such as deep breathing, meditation, and yoga can help mitigate the effects of stress on the cardiovascular system. Stress reduction also involves addressing psychosocial factors and adopting strategies to manage daily stressors effectively .Smoking cessation: Smoking significantly contributes to endothelial dysfunction and microvascular damage. Encouraging individuals to quit smoking is paramount to improving microvascular health and reducing the risk of cardiovascular events. Smoking cessation interventions, including counselling and pharmacotherapy, can significantly enhance endothelial function .Pharmacological interventions: Pharmacotherapy often addresses associated risk factors and enhances microvascular function. Angiotensin-converting enzyme (ACE) inhibitors manage hypertension and improve endothelial function by reducing vascular resistance. Statins are beneficial for managing dyslipidemia and mitigating inflammation, which can contribute to microvascular dysfunction. Antiplatelet agents, such as aspirin, may be prescribed to reduce the risk of thrombotic events and improve microvascular flow .Current Management Strategies for TCMMonitoring and assessment: Continuous monitoring of hemodynamics, fluid balance, and cardiac biomarkers is paramount to evaluating the extent of ventricular dysfunction, assessing fluid status, and tracking improvements. Regular blood pressure, heart rate, and oxygen saturation assessments help gauge the patient's cardiovascular stability and guide adjustments in medical management .Fluid management: Optimal fluid management is crucial to maintaining an appropriate balance while preventing fluid overload or depletion. Careful monitoring of urine output and central venous pressure aids in tailoring fluid administration, especially in the acute phase. Diuretics may be used judiciously to manage fluid retention and oedema .Complication prevention: Preventing complications is a cornerstone of TCM management. Standard heart failure therapies, including angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics, might be considered in patients with significant ventricular dysfunction. These medications aim to alleviate symptoms, stabilise hemodynamics, and enhance cardiac function .Spontaneous recovery: One of the remarkable aspects of TCM is its tendency towards spontaneous recovery. Most TCM cases exhibit gradual improvement in left ventricular function over time. This recovery is a testament to the transient nature of the condition, although the timeline varies between individuals. Regular echocardiographic assessments are essential to monitor improvements and guide the adjustment of medical therapy .Long-term follow-up and psychological support: Although TCM cases typically show favourable outcomes, long-term follow-up is recommended to ensure sustained recovery and identify any potential recurrence. Psychological support is an integral component of TCM management, as the emotional stress that triggers TCM can leave a lasting impact on patients. Addressing the psychosocial aspects through counselling and support groups can aid emotional healing .Special Considerations When CMD and TCM CoexistWhen confronted with cases where both CMD\u00a0and TCM\u00a0coexist within an individual, an intricate treatment approach is imperative. The convergence of these conditions necessitates a holistic strategy that navigates the complexities of both CMD and TCM, acknowledging their potential interrelation. Central to this approach is recognising the profound impact that microvascular dysfunction, a hallmark of CMD, can exert on the outcomes of TCM .A critical step in managing such cases is meticulously evaluating individual patient characteristics. This evaluation extends beyond the confines of CMD and TCM, encompassing the patient's broader medical history, comorbidities, and risk factors. These factors play a pivotal role in shaping the optimal treatment path. Comprehensive risk assessment guides the selection of therapies, ensuring that interventions are tailored to address the unique nuances of both conditions while considering potential interactions and complications .The personalised approach in this context acknowledges the intricate interplay between CMD and TCM. Rather than viewing these conditions in isolation, healthcare practitioners should perceive them as interconnected components of the patient's cardiovascular landscape. Tailoring interventions to this interplay enhances patient care, yielding a more effective treatment regimen. This personalised strategy may encompass lifestyle modifications, pharmacological interventions, and psychological support, all seamlessly integrated to address both CMD and TCM harmoniously .By adopting this holistic and personalised treatment paradigm, healthcare professionals optimise patient management in cases where CMD and TCM coexist. This approach reflects a nuanced understanding of their potential relationship, emphasising the need to acknowledge the complex interplay between these conditions for the most effective and comprehensive patient care .Potential Future Therapies Targeting Both CMD and TCMImproving microvascular function: Emerging research suggests that interventions designed to enhance microvascular function could hold significant promise for both CMD and TCM. Therapies focused on endothelial health and vasodilation might alleviate the microvascular dysfunction common to both conditions, potentially preventing the cascade of events that lead to TCM. By improving coronary blood flow regulation, these interventions could mitigate the susceptibility of CMD patients to TCM episodes triggered by stressors .Mitigating the effects of stress hormones: Given the role of stress hormones, particularly adrenaline, in triggering TCM, future therapies could aim to modulate the effects of these hormones on the cardiovascular system. Developing agents that buffer the impact of stress-induced catecholamines might prevent or attenuate the myocardial stunning characteristic of TCM. These interventions could safeguard individuals with CMD, who might be at higher risk of developing TCM due to underlying microvascular dysfunction .Modulating neurohormonal pathways: Neurohormonal imbalances are implicated in both CMD and TCM, suggesting that therapies targeting these pathways could benefit both conditions. Agents that influence autonomic nervous system responses, regulate sympathetic activation, and modulate the release of stress hormones could provide a comprehensive approach to managing the intricate relationship between CMD and TCM. By restoring balance to these pathways, such interventions improve microvascular function and reduce susceptibility to TCM .Collaborative efforts between cardiology subfields: The convergence of CMD and TCM highlights the importance of collaboration among various cardiology subfields. Cardiologists specialising in microvascular disorders and those focused on TCM could work synergistically to develop targeted interventions. A collaborative approach could involve integrating expertise in vascular health, heart failure management, and neurohormonal regulation, resulting in therapies that effectively address the shared pathophysiological mechanisms underlying CMD and TCM .Future directions and research implicationsAreas for Further Research into the CMD-TCM RelationshipThe intricate connection between CMD and TCM\u00a0remains an area for further exploration. Research should delve deeper into understanding the underlying mechanisms that link these conditions, such as the role of shared neurohormonal pathways and their impact on microvascular function. Prospective studies could investigate whether CMD predisposes individuals to TCM and how CMD might modify TCM outcomes. Longitudinal studies assessing the prevalence of TCM in patients with documented CMD could help elucidate the temporal relationship between the two conditions.Novel Treatment Avenues Based on Understanding the LinkThe evolving understanding of the potential interplay between CMD and TCM could lead to novel treatment approaches that simultaneously target both conditions. Strategies focusing on improving microvascular function, addressing endothelial dysfunction, and modulating the impact of stress hormones hold promise in preventing or mitigating TCM episodes in susceptible individuals. Exploring the potential synergies between therapies used for CMD and TCM could yield innovative interventions that improve patient outcomes.Importance of Collaborative Research Between Cardiology DisciplinesGiven the potential overlap between CMD and TCM, collaborative research efforts among various cardiology disciplines are paramount. Cardiologists specialising in microvascular disorders and those focused on TCM should work together to uncover shared mechanisms, define diagnostic criteria, and develop comprehensive management strategies. A multidisciplinary approach integrating expertise from diverse fields, including cardiology, endocrinology, and psychology, can offer a more comprehensive understanding of the complex relationship between these conditions.In conclusion, this comprehensive review has illuminated the intricate relationship between\u00a0CMD\u00a0and\u00a0TCM, shedding light on their potential interconnection. Through thoroughly exploring their distinct characteristics, shared pathophysiological mechanisms, diagnostic challenges, and management strategies, we have unveiled the intriguing possibility that microvascular dysfunction may contribute to the development and outcomes of TCM. This understanding has significant implications for patient care, underscoring the importance of accurate diagnosis and tailored interventions, particularly in cases where CMD and TCM coexist. As we navigate the evolving landscape of cardiovascular medicine, we advocate for ongoing collaborative research efforts and heightened clinical awareness to unravel the complexities of this relationship. By doing so, we strive to enhance diagnostic precision, refine therapeutic approaches, and ultimately improve the well-being and outcomes of individuals affected by these fascinating cardiovascular conditions."}
+{"text": "Accurate assessment of gender identity and biological sex in dermatology research is crucial since their conflation or poor demarcation undermines patient respect and study accuracy. Clearer guidance is needed for health care researchers, particularly in light of the notable disparities in skin disease rates, skincare practices, literature representation, and the persistent underrepresentation of transgender and nonbinary patients. Although gender identity is a social determinant of health, its assessment in health care research is inadequate. We highlight the intricacy of gender and biological sex in dermatology research, revealing the need for more robust protocols for their assessment. We begin by evaluating the current protocols used to make such assessments, demonstrating lack of consensus. Next, we evaluate the relationships between biological sex and gender identity and how these impact skin health. We then examine the inadequate representation of gender minorities\u2014including those who identify as transgender or gender nonbinary\u2014in academic literature and how this disparity compromises the applicability of evidence-based medicine to all. Finally, we consider the importance of physician communication about gender identity.The articles analyzed in this study emphasize the importance of transparency when delineating differences between biological sex and gender identity. In addition, researchers should be coached on techniques to extinguish investigators\u2019 biases. The models and tools for discerning gender identity and biological sex are shown in Note that the results obtained from the above methods were analyzed in conjunction with other questionnaires to assess correlations between the factors affecting overall population health ,2,4. GenQuestionnairesStanford Gender-Related Variables for Health Research (GVHR) Bem Sex-Role Inventory (BSRI) ,2BSRI: short form ,2GENESIS-PRAXY (Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond-Premature Acute Coronary Syndrome) Guidelines and recommendationsSex and Gender Equity in Research (SAGER) guidelines Sex-gender variable: methodological recommendations for increasing scientific value of clinical studies Cisgender (gender identity corresponds to sex assigned at birth) males and females exhibit different rates of various skin diseases . IncreasGender-affirming therapies may induce drastic skin changes. Hormone therapies increase the risk of acne vulgaris, androgenetic alopecia, excessive sebum production, melasma, and hirsutism . DermatoResearchers believe numerous factors contribute to skin differences between gender identities . TransmaGender minority populations also face health care barriers from noninclusive treatment eligibility models. For instance, despite the increased prevalence of acne vulgaris in transgender populations, iPledge medication guidelines for isotretinoin use sex assigned at birth and require contraception to remain eligible .Although increasing female participation in clinical trials is widely supported, data on gender minority participation is nonexistent. Additionally, the risks of some conditions fluctuate depending on the stage of gender-affirming therapies. Although existing data sets may not use inclusive models of gender identity assessment, there is value in their implementation given the prospect of large-scale observational studies and meta-analyses in which these variables could be better assessed. As gender minority populations grow, these inclusive models will help physicians support all patients while ensuring that salient trends and health impacts are captured by research analyses.About 28% of transgender individuals delay seeking preventative care because of mistreatment by health care workers; thus, inclusive language is important to build trust in these communities . MedicalMisgendering patients can have profound effects on patients\u2019 health and safety and can damage the patient-provider relationship . As ideaRobust methodologies exist to eliminate subjectivity and maximize data accuracy and utility. Current approaches to distinguishing gender identity and biological sex are inadequate and threaten the applicability of research findings to many patients. Conflating sex and gender neglects the unique dermatologic health impacts of these attributes and contributes to the underrepresentation of gender minority populations in medical literature. While more research is needed to address these issues, communication training for physicians and other health care providers could be improved. The language used must respect patients\u2019 identities while maintaining objectivity in clinical research."}
+{"text": "Major educational goals of Infectious Diseases (ID) are to recruit more trainees into ID and promote good antimicrobial decision-making. National survey research  revealed that ID curricula that deemphasize memorization are associated with greater odds of trainees entering the field of ID. As ID electives are not required during medical school, preclinical ID courses could represent the last dedicated opportunity for students to gain exposure to the field and acquire key clinical skills for antimicrobial selection. Yet little is known about how students experience preclinical ID courses. We aimed to explore how students experience and engage with these courses to better understand how best to augment their learning and interest in ID.We conducted individual interviews with a purposeful sample of medical students who took the preclinical ID course during three curricular years (2019-2021). Our semi-structured interviews explored students' challenges in learning ID, as well as the motivations, learning principles, and strategies guiding that learning. We generated a codebook through an iterative, inductive process using Dedoose to code interviews and facilitate analysis. We confirmed and refined major themes over 19 interviews.Establishing Relevance, Organized Study, Relating Ideas, Multi-Modal Learning, Socially Constructed Learning, and Active Engagement with Material) that support student learning, deployed through four main strategies  .Students face unique challenges learning ID but are motivated to succeed by both intrinsic and extrinsic factors (Table 1). We identified six core learning principles (Our results build on prior research indicating that students learning ID benefit from incorporation of educational principles and strategies that move beyond rote memorization to encourage active engagement and self-reflection. We found that students preference deep, strategic learning methods propelled by intrinsic motivation, despite external pressures. Our findings have implications for optimizing ID education and ultimately increasing interest in the field.All Authors: No reported disclosures"}
+{"text": "A perceived increase in weekly quality control (QC) failures prompted the development of an electronic monitoring system for quality assurance of antibiotic susceptibility testing.Antibiotic susceptibility testing (AST) procedures are sensitive to variations in testing conditions. Our diagnostic laboratory is compliant with recommendations set out in Clinical and Laboratory Standards Institute (CLSI) M100 . The trends in cefepime zone sizes against P. aeruginosa ATCC 27853 also prompted an internal review and these improved when antibiotic disk dispensers were consolidated to improve disk utilization .Persistent recurrent borderline results reflected on the monitoring system sparked the implementation of systematic investigations into QC failures; a replacement program for QC strains; and standardization of incubation timings and desiccant usage. Using new American Type Culture Collection (ATCC) reference strains reduced the percentage of QC antibiotic-organism data which failed or were borderline, and led to greater consistency in testing . Visual presentation of QC data triggered greater reflection. For instance, recurrent failures of ertapenem disks against Systemic monitoring of QC trends is low cost and highlights issues which were previously not apparent. Standardization of practices and a systematic troubleshooting process have improved the quality of our disk diffusion susceptibility testing.All Authors: No reported disclosures"}
+{"text": "Coronary vasospasm is a known complication after coronary artery bypass grafting surgery but has rarely been described in non-coronary cardiac operations. We report the case of a 51-year-old male with nonischemic cardiomyopathy and paroxysmal atrial fibrillation. He presented with severe mitral and tricuspid regurgitation and was taken for mitral valve replacement, tricuspid valve repair, and Maze procedure. Postoperative emergent coronary angiography demonstrated diffuse coronary vasospasm. Injection of intracoronary nitroglycerin led to clinical and angiographic improvement. This demonstrates the possibility of coronary vasospasm following mitral valve replacement and effective treatment with intracoronary administration of vasodilating agents. Coronary vasospasm is a known and feared complication following coronary artery bypass grafting surgery that has rarely been described in non-coronary cardiac operations . IatrogeWe describe herein the case of a 51-year-old African American male with hypertension, paroxysmal atrial fibrillation, stage III chronic kidney disease, and nonischemic cardiomyopathy presenting with progressive shortness of breath and bilateral lower extremity edema. Echocardiogram demonstrated severe mitral regurgitation with asymmetric systolic restriction (Carpentier Type IIIc) and moderate-to-severe tricuspid regurgitation Figure . Right hCardiopulmonary bypass (CPB) was initiated with Del Nido cardioplegia. The mitral valve was replaced with 33mm St. Jude Biocor Porcine bioprosthetic, tricuspid valve repair was performed with Edwards MC3 30mm annuloplasty ring, LAA was ligated with AtriCure 50mm AtriClip, and Cox-Maze IV was completed with a cryoprobe. The transesophageal echocardiogram showed a well-seated mitral valve prosthesis with a peak gradient of 5 mmHg, a mean gradient of 2 mmHg, and no paravalvular leak Figure . IntraveCoronary vasospasm is a known and feared complication after coronary artery bypass grafting surgery but has rarely been described in non-coronary cardiac operations. Iatrogenic causes of ST-segment changes, hemodynamic instability, or difficulty weaning from CPB must be considered after valvular surgery and anti-arrhythmia procedures. Left circumflex artery injury or occlusion during mitral valve surgery and right coronary artery injuries during tricuspid valve operations are well described ,3. HowevH\u00a0Shafei et al.  reportedUnlike most of the cases above, our patient developed ST segment changes while still in the operating room. The decision to pursue coronary angiography rather than reopening and performing a bypass graft is not trivial, but neither is the exercise of attempting a graft to the obtuse marginal branches. We must also consider the potential injury from cryoablation used during the CMP. Direct ablation of the coronary arteries may lead to significant obstruction or total occlusion. There is also a theoretical risk of indirect injury from cryolesions penetrating too deeply or pericoronary edema following the procedure.\u00a0If technical considerations have been ruled out as a source of coronary injury, systemic administration of vasodilators is an appropriate next step. If this fails to address the issue, then in the appropriate patient, transportation to the coronary catheterization laboratory can provide further information via emergent coronary angiography with the potential to deliver intracoronary vasodilators and perform other advanced interventions. This capability does require a close working relationship between the surgical, anesthesia, and interventional teams within the hospital system. The availability of interventional cardiology allowed us to avoid a bypass graft that likely would have failed in the short term and not addressed the underlying pathology.\u00a0Diffuse coronary vasospasm is a rare and potentially devastating complication following noncoronary cardiac surgery that should be considered in the setting of ECG changes and hemodynamic instability. As demonstrated by this case and the others cited, coronary spasms may present intraoperatively, shortly after the patient arrival to the intensive care unit, or in the first days after noncoronary surgery. Consideration of this pathology in the event of new ECG changes and hemodynamic changes will allow for timely diagnosis and treatment."}
+{"text": "Neurotrauma and Repair: from Peripheral to Central Nerve Injury\u201d brought together a diverse group of 58 authors, fostering interdisciplinary collaboration and offering new insights into the multifaceted landscape of neurotrauma research.Neurotrauma, encompassing traumatic brain injury (TBI), peripheral nerve injury (PNI), and spinal cord injury (SCI), continues to be a major global public health concern. The complex pathophysiological mechanisms and lifelong neurological deficits associated with neurotrauma emphasize the urgent need for effective clinical interventions. The Research Topic \u201cThis collaborative effort yielded a body of work that has garnered significant attention within the scientific community, underscoring the importance of the research contributions and the demand for advances in neurotrauma understanding and treatment.Effects of a Neurokinin-1 Receptor Antagonist in the Acute Phase after Thoracic Spinal Cord Injury in a Rat Model\u201d delves into the potential therapeutic effects of neurokinin-1 receptor antagonists on neuroinflammation and edema following SCI . While the study suggests limited impact on reducing edema, it demonstrates a notable reduction in T-lymphocyte invasion and apoptotic cell numbers with the treatment. Additionally, it suggests a trend toward reduced fibrinogen leakage, endothelial and microglial activation, chondroitin sulfate glycosaminoglycan deposition, and astrogliosis. Although general locomotion recovery remained modest, CatWalk gait analysis revealed early improvements in several parameters. This research showcases the intricate and multifaceted nature of SCI and the potential of neurokinin-1 receptor antagonists in mitigating some aspects of neurogenic inflammation.\u201cMuscle-Derived Stem Cell Exosomes with Overexpressed miR-214 Promote the Regeneration and Repair of Rat Sciatic Nerve after Crush Injury,\u201d researchers explore the regenerative potential of muscle-derived stem cell exosomes enriched with miR-214 . The study demonstrates the ability of these exosomes to promote the proliferation and migration of Schwann cells, enhance the expression of neurotrophic factors, and facilitate axon extension in dorsal root ganglion neurons. By targeting PTEN and activating the JAK2/STAT3 pathway, these exosomes hold promise for promoting nerve regeneration in the context of sciatic nerve crush injuries. This research not only contributes to our understanding of neural repair mechanisms but also offers a potential avenue for therapeutic intervention.In \u201cPartially Brain Effects of Injection of Human Umbilical Cord Mesenchymal Stem Cells at Injury Sites in a Mouse Model of Thoracic Spinal Cord Contusion\u201d takes an intriguing angle, investigating the consequences of SCI on the brain . This study explores the potential therapeutic mechanisms of human umbilical cord mesenchymal stem cell injection at the injury site. It highlights the intricate interactions between the spinal cord and the brain, underscoring the interconnectedness of neural systems. This research raises important questions about the broader neurological effects of spinal cord injuries and offers insights into potential therapeutic interventions that could extend beyond the immediate injury site.\u201cA Closed-Body Preclinical Model to Investigate Blast-Induced Spinal Cord Injury\u201d introduces an innovative preclinical model for studying blast-induced spinal cord injuries . These injuries are particularly relevant in military contexts, where exposure to blast overpressure can result in significant spinal trauma. This research enhances our understanding of blast dynamics and their effects on the spinal cord, providing valuable insights into the complexities of these injuries. By investigating markers of traumatic axonal injury and neuroinflammation, this study sets the stage for future research into minimally invasive treatment approaches.\u201cHuntingtin-Associated Protein 1 Ameliorates Neurological Function Rehabilitation by Facilitating Neurite Elongation,\u201d researchers explore the role of Huntingtin-associated protein 1 (HAP1) in promoting neurological function recovery . By activating the TrkA-MAPK signaling pathway, HAP1 demonstrates its potential to enhance neurite elongation and improve outcomes in SCI. This study not only advances our understanding of the molecular mechanisms underlying neural repair but also suggests a promising avenue for therapeutic intervention.In \u201cDifferential Effects on TDP-43, Piezo-2, Tight-Junction Proteins in Various Brain Regions Following Repetitive Low-Intensity Blast Overpressure\u201d delves into the often-overlooked issue of mild traumatic brain injuries caused by repetitive low-intensity blast overpressure . This research highlights the varied effects of such exposures on critical proteins in different brain regions, underscoring the structural and anatomical heterogeneity of the brain. The findings emphasize the need for a comprehensive understanding of neurotrauma's diverse impacts, especially in military and combat-related contexts.\u201cA Cutting-Edge Strategy for Spinal Cord Injury Treatment: Resident Cellular Transdifferentiation,\u201d the authors explore a cutting-edge strategy for SCI treatment\u2014resident cellular transdifferentiation . This innovative approach involves reprogramming mature somatic cells into functional neurons, offering new hope for post-traumatic spinal cord repair and functional improvement. While the mechanisms and induced neuronal subtypes are not yet fully understood, this review provides a comprehensive analysis of the current state of research in this exciting field.In the review article \u201cThese contributions collectively advance our understanding of neurotrauma and offer new insights into potential pathways for treatment. While challenges remain, this collaborative effort signifies progress in the field, underscoring our shared commitment to alleviating the burden of neurotrauma for individuals worldwide. As we reflect on these achievements, we acknowledge the road ahead, filled with challenges and opportunities. Neurotrauma research continues to evolve, driven by a global community of researchers dedicated to translating insights into tangible treatments. Together, we embark on a journey that promises to bring healing and recovery to those affected by neurotrauma, one breakthrough at a time.AY: Writing\u2014original draft."}
+{"text": "The mesentery is a broad fan-shaped fold of peritoneum that suspends the loops of small intestine from the posterior abdominal wall. Although primary neoplasms arising in the mesentery are rare, the mesentery is a major avenue for the dissemination of tumours, which can spread through hematogenous, lymphatic, direct or peritoneal seeding. Imaging helps in the diagnosis of these tumours and aids in directing appropriate treatment by assessing their size, extent and relationship with adjacent structures. The aim of this article is to describe the spectrum of imaging findings of the various mesenteric lesions using ultrasound and CT.Evaluation of the mesentery is often neglected during routine ultrasound (US) because of inadequate training and unfamiliarity with the common US features encountered with mesenteric disease. CT plays an essential role in the diagnosis of mesenteric disease. Knowledge of imaging characteristics of various mesenteric lesions helps in timely diagnosis and management. The mesentery is a broad, fan-shaped fold of peritoneum that suspends the loops of small intestine from the posterior abdominal wall. Secondary involvement of the mesentery from tumours elsewhere is much more common than primary mesenteric neoplasms such as desmoid tumour, inflammatory myofibroblastic tumour (IMFT), and others. Most patients with mesenteric lesions present with non-specific symptoms of abdominal pain, tenderness, palpable abdominal swelling, abdominal distension and weight loss. These symptoms are shared by pathologies of other abdominal organs and it is therefore very difficult to identify mesenteric lesions clinically.Some mesenteric diseases present with distinctive imaging findings while others have similar findings, thereby complicating their differential diagnosis. Understanding the characteristic radiological patterns on ultrasound (USG) and CT offers valuable insights for differential diagnoses of mesenteric lesions and their treatment.Primary mesenteric solid neoplasms are rare and the majority of them are benign.1 On USG, this tumour appears as a well-defined or ill-defined mass with heterogenous echotexture and internal vascularity. On CT, it appears as a well-defined or ill-defined mass showing heterogenous enhancement usually in the portal venous phase and it may infiltrate the adjacent organs.2 The MRI appearance of desmoid tumours depends on the relative proportion of cellular, myxoid and fibrous components.The most common soft tissue lesion in the mesentery is a desmoid tumour. It usually occurs in patients with familial adenomatous polyposis (FAP) or Gardner syndrome. Trauma or surgery serves as a predisposing factor for the development of desmoid tumours.3 Inflammatory myofibroblastic tumour appears as a hypo or iso-attenuating mass compared with skeletal muscle depending on the amount of myxoid or collagenous stroma, respectively. Dense central calcification may be noticed. They demonstrate various contrast enhancement patterns including early peripheral enhancement because of vascular tissue , associated soft tissue component and thick irregular septations. Liposarcomas are rare malignant tumours of the mesentery. Liposarcomas are divided into five types histopathologically: well-differentiated, myxoid, pleomorphic, round cell and de-differentiated liposarcoma. Well-differentiated liposarcomas have mixed fatty and soft tissue components while de-differentiated liposarcomas have clearly separated soft tissue and fatty components. Myxoid liposarcomas have fluid density on CT with mixed soft tissue and fatty components. Pleomorphic and round cell liposarcomas have soft tissue components only, with no identifiable fatty component on imaging.5Three patterns of mesenteric involvement have been described for Castleman disease, namely a solitary non-invasive mass (most common), a dominant infiltrative mass with associated lymphadenopathy and matted lymphadenopathy without a dominant mass. These tumours show early, homogenous and intense enhancement . Tumours6  is seen as one or more irregular fibrotic soft tissue mesenteric masses10 They show variable attenuation depending on their contents  and may insinuate between the mesenteric vessels  on USG and as a unilocular or multilocular cyst with enhancement of the wall or septations on contrast enhanced CT. vessels .11These appear as thin-walled anechoic unilocular cysts with posterior acoustic enhancement on USG and unilocular fluid attenuation lesions with no discernible wall on CT.2 They occur because of entrapment of fluid (secreted by the ovaries during ovulation) between peritoneal adhesions.7 They are seen as a fluid attenuation multilocular cystic lesion, multiple unilocular thin-walled cysts or unilocular cystic mass on CT with enhancing but non-calcified septa, which often surround the ovaries. On USG, they appear as unilocular or multilocular cystic lesions, which may be anechoic or may display contents of variable echogenicity  and demonstrate homogeneous enhancement following contrast administration . Other findings observed in cases of abdominal tuberculosis include mesenteric nodularity, fat stranding, peritoneal thickening, localised collections, free fluid, clumping of bowel loops, bowel wall thickening and solid organ involvement in the form of hepatomegaly, splenomegaly, liver and splenic granulomas.Tropheryma whipplei. On imaging, small bowel wall thickening associated with enlarged mesenteric lymph nodes demonstrating hypoattenuating centres because of fat deposition can be seen. Diagnosis is made by small intestinal mucosal biopsy.16It is an infectious condition caused by Gram-positive bacterium, Actinomyces israelii is an anaerobic Gram-positive bacterium and is a normal inhabitant of the oral cavity, gastrointestinal tract and female genital tract. It spreads to involve the mesentery when a mucosal breach is present such as inflammation, surgery, trauma or intrauterine contraceptive device (IUCD) use.17 On imaging, an ill-defined heterogeneously enhancing soft tissue mass infiltrating the mesentery and adjacent organs can be seen. Septic embolism leading to hepatic, renal and splenic abscesses can occur.2 Diagnosis is made based on aggressive imaging features and subtle clinical symptoms in predisposed individuals. Biopsy should be performed in indeterminate imaging findings, which reveal sulphur granules representing bacterial colonies.18These usually occur because of intraperitoneal rupture of liver or splenic hydatid cysts . HydatidMesenteric changes in inflammatory bowel disease include mesenteric fibrofatty proliferation, mesenteric lymphadenopathy, fat stranding , abscess19 (Findings in acute mesenteric ischaemia related to superior mesenteric artery (SMA) thrombosis include dilated bowel loops with paper-thin walls, pneumatosis intestinalis, air within mesenteric vessels, mesenteric fat stranding and free fluid on CECT19 .On USG, tangled serpentine vessels can be seen, which show pulsatile waveforms on spectral doppler while on CECT, tangled serpentine vessels can be seen with early opacification of venous channels in the arterial phase. Direct communication between branches of the SMA and superior mesenteric vein (SMV) can be visualised on volume rendering technique (VRT) images.20 Evaluation of lesions is limited on USG because of operator-dependence, obscuration of the mass in the presence of a gaseous abdomen and obese patients, and inadequate visualisation of the extent of large mesenteric lesions. Contrast enhanced CT is the primary workhorse for evaluation of mesenteric lesions. It helps in determining the origin of the lesions, providing thoughtful differential diagnosis of masses, for selecting the site of biopsy, determining the extent of pathology and accessibility for resectability of lesion. CT, however, has several limitations including poor soft tissue contrast resolution, exposure to ionising radiation and contrast reactions. MRI can be used as the next step in characterising mesenteric lesions. It has higher soft tissue contrast resolution and helps in characterising fluid content of cysts as serous, mucinous, chylous or haemorrhagic and the soft tissue component of solid lesions. Fluoro-deoxyglucose (FDG) positron emission tomography (PET) CT is presently used to detect lymph nodes and distant metastases in mesenteric tumours and also for response assessment to chemotherapy.Ultrasound is the primary imaging modality in the evaluation of mesenteric lesions. It helps in characterising mesenteric lesions as solid or cystic. Ultrasound guided percutaneous biopsy offers real time assessment of the needle tract to avoid vascular injury while performing biopsy.21Management of mesenteric lesions depends on symptoms and imaging findings. Mesenteric lesions detected incidentally on imaging need classification as benign or malignant. Definite diagnosis of a few pathologies such as mesenteric panniculitis, lymphoma, desmoid tumour in patients with FAP and benign cystic lesions can be made on imaging. However, lesions with indeterminate imaging findings need to be biopsied to rule out malignancy. Imaging helps in determining the site for percutaneous biopsy in such tumours. Lesions that are inaccessible to percutaneous biopsy or show indeterminate histopathology findings on percutaneous biopsy require surgical biopsy to confirm the diagnosis.Once confirmed by biopsy, management of the mesenteric lesions depends on the histopathology. Lymphomas and desmoid tumours are managed conservatively with chemotherapy and hormonal therapy or imatinib, respectively. Well-circumscribed lesions located in the periphery of the mesentery can be resected completely, without sacrificing significant bowel length or major mesenteric vessels. Infiltrative mesenteric lesions, located in the root of mesentery are usually managed conservatively because of involvement of major vessels and the need for sacrificing a major portion of bowel, which may lead to small bowel syndrome. Well-defined malignant tumours and symptomatic benign tumours are treated surgically. The goal of surgery is R0 resection , while R1 resection followed by adjuvant chemoradiotherapy can also be performed. Well-defined asymptomatic benign lesions can be followed up and resection is performed when they become large or cause symptoms. Symptomatic infiltrative benign or malignant lesions can be managed by debulking surgery to reduce tumour load and prevent complications such as bowel obstruction or mesenteric ischemia.Although histopathology is the gold standard for diagnosis of mesenteric lesions, imaging plays an important role in diagnosis of mesenteric neoplasms, detection of complications and in deciding appropriate treatment options. Ultrasound is inadequate for optimal visualisation of mesenteric neoplasms and in detecting their relation with other structures because of shadowing from bowel gas, calcification or inadequate penetration of sound beams in obese patients. CT is an excellent imaging modality in the characterisation of mesenteric lesions, detecting their extent and relations with surrounding structures, which is useful for surgical planning. However, CT too has several limitations and other imaging modalities such as MRI and FDG-PET can be helpful in further characterisation of mesenteric lesions."}
+{"text": "This report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old woman had difficulty extending her left-thumb interphalangeal joint several weeks after a palpation-guided local corticosteroid injection. Passive motions remained intact without sensory abnormalities. Ultrasound examination showed hyperechoic tissues at the site of the extensor pollicis longus (EPL) tendon at the wrist level and an atrophic EPL muscle stump at the forearm level. Dynamic imaging demonstrated no motion in the EPL muscle during passive thumb flexion/extension. The diagnosis of complete EPL rupture, possibly due to inadvertent intratendinous corticosteroid injection, was therefore confirmed. This report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old female complained of difficulty in extending the left thumb for several months. The medical history comprised radial wrist pain after a contusion injury one year ago, for which corticosteroid injection under palpation guidance had also been performed, with gradual symptom relief. The physical examination revealed loss of the active extension of the left-thumb interphalangeal joint with normal passive motions . Other fThe posterior interosseous nerve (PIN) remained bilaterally intact based on dynamic tracking from the level of the supinator tunnel to the dorsal wrist . Moving Finger drop can ensue due to neurological and orthopedic causes . In caseStatic ultrasound examination can serve as a helpful tool for scrutinizing tendon injury, whereas dynamic imaging can be employed to validate motion problems. The most common sonographic finding of tendon rupture is loss of fiber continuity with the formation of a retracted stump. The absence of normal tendon gliding during passive motion further confirms the diagnosis . In chroOne of the important etiologies of spontaneous EPL tendon rupture is intratendinous corticosteroid injection. Other causes include distal radial fracture, repetitive friction against metal implants, and contusions . Local cNeedless to say, ultrasound is a preferred tool for guiding the needle, in order to avoid unwanted intratendinous corticosteroid injection ,17. Peri"}
+{"text": "This case highlights the importance of having constrictive pericarditis (CP) as a differential diagnosis in unexplained sign and symptoms of right-sided heart failure. This case portrays challenges in diagnosing CP caused by certain rheumatologic diseases despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis. Constrictive pericarditis (CP) is a rare condition that often presents with non-specific symptoms and is often misdiagnosed. CP is characterized by a rigid pericardium that restricts the heart, resulting in signs and symptoms of diastolic heart failure. It occurs as a late sequela of pericardial inflammation caused by prior infection or radiation, inflammatory diseases and rarely, connective tissue disorders. We present a case of new-onset right-sided heart failure caused by constrictive pericarditis in a patient with diffuse systemic sclerosis (SSc). This case highlights the importance of having CP in our differential diagnosis in patients with unexplained sign and symptoms of right-sided heart failure and increased systemic venous pressure. This is crucial since CP secondary to SSc is largely curable and failure to diagnosis has devastating consequences. This case portrays the challenges in diagnosing pericardial diseases caused by certain rheumatologic diseases and that despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis.A 27-year-old female with a seven-year history of diffuse systemic scleroderma complicated by recurrent pericarditis and severe Raynaud\u2019s disease resulting in gangrene and amputation of the upper and lower extremity digits presented to the hospital with two weeks of progressive shortness of breath, early satiety, fatigue, abdominal distention, and lower extremity pain and edema. The physical examination was notable for the presence of jugular vein distention with positive hepatojugular reflux, right upper quadrant tenderness, ascites and 3+ lower extremity edema to the thighs. Her heart rate was 108 beats per minute; other vital signs were within normal limits. EKG showed sinus tachycardia with nonspecific ST-T wave changes. Chest x-ray showed a moderate right-sided pleural effusion with right basilar airspace opacity and a cardio mediastinal silhouette. Transthoracic echocardiogram demonstrated a normal left ventricular ejection fraction, mildly reduced right ventricular function, mild pulmonary hypertension with an estimated mean pulmonary artery pressure of 40 mmHg, and no significant valvular abnormalities. Abdominal ultrasound redemonstrated ascites and was also notable for hepatomegaly and a hyperechoic pancreatic mass.Initially the patient\u2019s ascites was attributed to intrinsic hepatic disease and she was started on diuretics. However, her renal function deteriorated, halting diuresis while further diagnostic evaluation was pursued. The patient continued to have abdominal distension and shortness of breath which prompted a cardiovascular evaluation with a right heart catheterization. Mild pulmonary arterial hypertension was noted with elevated mean pulmonary arterial pressure (mPAP) of 28 mmHg. Due to the discrepancy between the mildly elevated cardiac filling pressures and significant anasarca on physical examination, a repeat hemodynamic assessment was pursued. The patient underwent right and left heart catheterization which discovered near equalization of the diastolic filling pressures, raising suspicion for pericardial tamponade constrictive physiology . In addiAs most diagnostic imaging studies were contraindicated due to the patient\u2019s impaired renal function, a cardiac MRI without contrast was obtained to evaluate for possible pericardial disease. Cardiac MRI showed an abnormally thick pericardium (4\u20135 mm) and evidence of significant pericardial adhesion with a small dependent pericardial effusion. The ventricles were cone shaped and a septal bounce was seen during diastole. In addition, free breathing CINE imaging demonstrated ventricular interdependence. These findings were consistent with pericardial constriction.After extensive discussion between cardiology, rheumatology, nephrology and cardiothoracic surgery, the primary team agreed that surgical intervention was the best option to improve this patient\u2019s quality of life and disease prognosis. Subsequently, she underwent successful pericardiectomy with complete resolution of her symptoms. The pathology report revealed extensive dense fibrosis in the pericardium that was likely secondary to patient\u2019s known collagen vascular disease.Cardiac involvement in both limited and diffuse SSc has been recognized over the years as one of the most rare and feared complications due to poor prognosis . CardiacThe noteworthy pathophysiology involved in presentation of this condition is unique in that there is recurrent coronary microvascular ischemia and myocardial inflammation which leads to ischemic necrosis, reperfusion damage, and myocardial fibrosis . This adHowever, constrictive physiology can complicate virtually any condition associated with pericardial effusion . The nonCertain serologic tests for patients with systemic sclerosis can provide useful information about specific organ involvement, including cardiac manifestations. Studies have shown that patients with SSc with myocarditis had cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) and antiproteinase 3 (PR3) antibody positivity . FurtherOverall, due to the high prevalence of cardiac involvement in patients with SSc, it becomes imperative to do a thorough history taking and examination of this population. Prompt recognition and management of constrictive pericarditis can alleviate symptoms such as volume overload, drastically transform these patients\u2019 quality of life, improve prognosis, and decrease mortality.This case portrays the challenges in diagnosing pericardial diseases caused by certain rheumatologic diseases and that despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis.To be able to recognize rare but very specific findings of a constrictive pericarditis physiology.To understand the role of Multidisciplinary approach to benefit the patient\u2019s quality of life.A patient presenting with an odd case of Constrictive Pericarditis due to Systemic Sclerosis."}
+{"text": "A hallmark of retroviral replication is stable integration of the viral genome in the host cell DNA. This characteristic makes retroviral-derived vector particles attractive vehicles for gene therapy. However, retroviral integration is not a random process. Lentiviruses preferentially integrate in the body of active transcription units, while gammaretroviruses, including Moloney Murine Leukemia Virus (MLV), favour transcription start sites and CpG islands. In clinical trials using gammaretroviral vectors for gene therapy, leukemogenesis has been associated with integration of vectors near oncogene transcription start sites. We found that the bromodomain and extra-terminal (BET) proteins  interact with MLV integrase and direct integration towards transcription start regions. BET proteins specifically bind and co-localize with the gammaretrovirus integrase protein in the nucleus of the cell. The interaction is gammaretroviral-specific and mediated by the integrase C-terminal domain and the BET extraterminal (ET) domain as determined by co-immunoprecipitation assays and in an Alphascreen assay using recombinant proteins. Interfering with chromatin interaction of BET proteins via specific bromodomain inhibitors JQ1 and l-BET decreases MLV virus replication and MLV vector transduction 5-to 10-fold, while HIV vector transduction is not affected. Analysis of viral DNA intermediates by quantitative PCR revealed a block at the integration step. In addition, bromodomain inhibitors do not have an effect on the late steps of viral replication. MLV integration site distribution analysis revealed a strong correlation with the BET protein chromatin binding profile. Finally, expression of an artificial fusion protein that merges the BET integrase binding domain with the chromatin interaction domain of the lentiviral targeting factor LEDGF/p75, retargets MLV integration into the body of actively transcribed genes, paralleling the Human Immunodeficiency Virus (HIV) integration pattern. Our results explain the molecular mechanism behind gammaretroviral integration site targeting and suggest methods for engineering gammaretroviral vectors with a safer integration site profile."}
+{"text": "Next-generation DNA sequencing has dramatically affected cancer genomics efforts in several important ways. Although whole genome sequencing remains an analytical challenge, such efforts are yielding data that elucidate the myriad ways in which a genome can be influenced by single point mutations, focused insertions or deletions, and large structural alterations. In addition to cataloguing somatic alterations, various correlation analyses are indicating the genes whose alterations most profoundly determine patient outcomes, patient responses to therapeutics and other important aspects of disease biology. We have recently begun exploring how the digital nature of next-generation sequencing reads allows important information about tumor cell genomic heterogeneity to be inferred, revealing the earliest mutations and how the composition of the tumor cell mass changes over time under the influence of stressors such as chemotherapy."}
+{"text": "To study the role of hypotension and associated injuries in increasing the chances of secondary amputation in lower limb with vascular injuries.This study was conducted in the Department of cardiovascular and thoracic surgery( CVTS ), Sher-i- Kashmir Institute of Medical Sciences, ( SKIMS ) Srinagar Kashmir India and comprised all patients sustaining vascular injury due to different causes like road traffic accident, fire arm and blast injuries or falling from height during the last five years. Following admission to our Department, the patients were divided into two groups. The first group with associated injuries was hemodynamically unstable during vascular repair or in post-operative period and the second group had no associated injuries and was hemodynamically stable during vascular repair and in post-operative period.During the past five years, 95 patients were operated for lower limb vascular injury in our department. Of these 25 patients had associated multi-organ injuries and were hemodynamically unstable and needed intensive care monitoring after surgical intervention. Additionally, 10 patients died due to associated multiple organ injuries, 10 needed amputation due to recurrent thrombosis of their anastomosis, and in five patients limb salvage was achieved. Seventy patients who had isolated limb vascular injuries with no associated injuries or hypotension were hemodynamically stable and were kept in low dependency unit after vascular repair. Only Four patients from this group needed amputation for thrombosis of the anastomosis.Patients with shock and related injuries face significant rate of amputation. These patients whether with multi-organ injuries or isolated vascular injuries need judicious treatment for hypovolumic shock during surgical intervention and in post-operative period. Injury to the popliteal vessels has been recognized as one of the most limb-threatening peripheral vascular injuries so far as vascular trauma has been studied. The popliteal artery is a true end artery with a tenuous collateral supply. The popliteal vein provides the bulk of lower limb and foot drainage. This explains why injury to these vessels is so dangerous. Management of these multiply injured patients can be very challenging and restoring perfusion to an ischemic extremity needs to be accomplished within 6\u20138 hours, if limb is to be salvaged. Clean and sharp cut in the artery closed by primary repair behave differently than an arterial repair with RSV(Reverse saphenous vein graft) graft which needs multiple Fogarty catheterization for retrieval of thrombus. Extensive tissue damage increases chances of compartment syndrome (CS). Post\u2013operative infection and CS are most important causes for amputation. Conventionally there are hard and soft signs of vascular injury. Hard signs which warrant immediate intervention include i) external arterial bleeding, ii) rapidly expanding hematoma, iii) palpable thrill, and audible bruit, iv) signs of acute limb ischemia. Soft signs of vascular injury warrant urgent evaluation in the form color Doppler/angiography. The successful management of vascular injury includes two goals: i) treating the life-threatening problems by fluid resuscitation, control of bleeding and ensuring adequate oxygenation; ii) repairing the injured vessel and save the limb. Arterial repairs include: reverse saphenous vein graft, primary repair, PTFE( polytetrafluroethylene) graft, ligation, and vein patch. CS leads to tissue necrosis, permanent functional impairment, or severe renal failure and death. The general consensus is that intra-compartmental pressures (ICPs) greater than 30mm Hg require intervention. During the first and second world wars, important knowledge had been gained both in diagnosis and treatment of vascular injuries, but vascular reconstructive methods were mainly introduced during the Korean and Vietnam wars with tremendous progress , 2.The studied population included patients with sustained vascular injury due to different causes like road traffic accident, fire arm and blast injuries or falling from height and admitted to our center during the past five years. The patients were divided into two groups of hemodynamically unstable and stable patients during vascular rep air or in post-operative period and notes were taken of their other associated injuries. Severity of injury was assessed by MESS (mangled extremity severity score). All hemodynamically unstable patients during and after surgery, had multiple organ injury and needed intensive care monitoring. However, hemodynamically stable patients were managed in a low dependency unit after vascular repair, and had predominantly isolated lower extremity injury or associated minor injuries. All patients operated for lower limb vascular injury were followed for post-operative outcome with respect to patency of the anastomosis and adequate blood flow for viability of the limb. Distal blood flow was assessed by clinical examination followed by Doppler study to confirm doubtful clinical examination. All patients who needed primary or secondary amputation with MESS score equal to or greater than 7 were excluded from the study. The study included only patients with MESS score of <6 and confirmed to have good vascularity on table by clinical as well as by vascular Doppler examination. Hemodynamic parameters and blood gas analysis were checked during and after operation. Post-operative blood gases and electrolytes were determined four hourly in patients who needed intensive care monitoring. Other associated injuries were taken care of by respective departments including general surgery, plastic surgery, neurosurgery and by critical care specialists.0 double arm prolene. As for associated injuries, the patients referred to other specialties. Hemodynamic parameters, blood gas and electrolytes were checked during the operation.After initial resuscitation and assessment, patients with confirmed arterial injury were operated under general anesthesia immediately following basic work-up. Patients with multi-organ injury were directly shifted to the tertiary care hospital from the spot of injury. Forty patients with isolated limb injury were referred after skeletal fixation by an orthopedist. Exposure was made through an incision in the aspect of knee, approximately central to site of injury. After controlling the affected arterial segment, medial proximal and distal embolectomy was performed, and backflow and inflow were assessed. Arterial repair was done either by primary end-to-end anastomosis or by reverse sephanous vein (RSV) graft. RSV was always taken from contralateral large saphenous vein. Suture material used for anastomosis was always 6During five past years, 95 patients, 87 males and 8 females, aged from 18 to 45 years were operated in our department, for lower limb vascular injury. Younger patients sustained vascular injuries mostly due to motorcycle and fire arm accidents, while older patients received vascular injuries either due to blast injury or fall from height. Following surgical intervention, 25 patients with associated multi-organ injuries needed intensive care monitoring. Of these, 10 patients died due to associated multiple organ injuries, and 10 had amputation due to recurrent thrombosis of their anastomosis, and in five patients limb salvage was achieved, but their functional outcome was not as good as those who never had hypotension during surgical intervention or in post-operative period. After vascular repair, 70 patients with isolated limb vascular damage and no associated injuries were kept in low dependency unit. Patients with isolated limb vascular injury and managed in low dependency unit after surgical intervention never had prolonged hypotension, either during vascular repair or in post-operative period and four patients from this group needed amputation for thrombosis of the anastomosis. One of these patients died due to infectious complications followed by DIC even after amputation. In remaining three, one patient had atherosclerosis, one had hypercoagulabe state for protein C deficiency, and the third patient had no apparent sign of thrombosis of anastomosis.Advances in hemorrhage control, wound care, orthopedic and vascular surgery during Iraq and Afghanistan war have allowed greater attention to shift toward limb salvage efforts. They also suggest that hypotension may result in muscle damage at even lower compartment pressures . PatientPatients with vascular and multi organ injuries ,active hemorrhage and shock have a poor prognosis and demand more urgent management than do patients with isolated limb injuries in which perfusion and blood pressure remains optimal. Shock is associated with a significant rate of amputation. These patients, whether with multi-organ or isolated vascular injuries, need judicious treatment for hypovolumic shock during surgical intervention and post-operative period."}
+{"text": "The question whether neural activity follows a rate code or a temporal code is still an unsolved issue in neuroscience. Recent theoretical works have suggested that realistic models of spike-timing-dependent-plasticity (STDP) in recurrent networks could resolve this issue because they observed a seemingly unique relation between the neural code and the resulting pattern of synaptic connections . In partWe have disproved both assumptions. In particular, here we show that already simple STDP models can easily grow bidirectional connections for a temporal code based on spike synchronization unless synchronization is extremely precise (see  for dispThus, both rate coding and temporal coding based on coarse synaptic synchronization can account for the bidirectional connectivity observed, for example, in visual cortex . However"}
+{"text": "Prostatic stromal hyperplasia with atypia (PSHA) is a rare histologic finding diagnosed incidentally on prostate biopsies, transurethral resection specimens, and radical prostatectomy specimens. PSHA has a bizarre histologic appearance and these lesions often raise concern for sarcoma; however, their clinical course is indolent and does not include extraprostatic progression. We discuss a case of PHSA discovered on prostate biopsy performed for an abnormal digital rectal examination and review the literature on this rare pathologic finding. Prostatic stromal hyperplasia with atypia (PSHA) is a rare histologic finding diagnosed incidentally in specimens from transrectal ultrasound (TRUS-) guided needle biopsy of the prostate, transurethral resection of prostate (TURP), radical prostatectomy, and simple prostatectomy . BecauseA 55-year-old man underwent a 10-core TRUS biopsy for a grossly abnormal digital rectal exam. Histologic examination  revealed PSHA is characterized by one or more ill-defined, uncircumscribed, and hyperplastic stromal nodules infiltrating around benign acini . ImmunohPSHA does not generally present as a symptomatic lesion in and of itself, though symptomatic cases have been reported . In all  This finding has been referred to by a variety of names including: atypical stromal hyperplasia, symplastic leiomyoma, and pseudoneoplastic lesion of the prostate gland. PSHA was previously grouped with low malignant potential findings such as phyllodes tumor and low-grade sarcoma as stromal tumors of unknown malignant potential (STUMP); however, given the univerally benign course of PSHA, this may constitute a misnomer. The current nomenclature emphasizes the expected indolent clinical course with treatment focused on the original disease of interest ."}
+{"text": "To understand the impact of integrative medicine (IM) therapies on patients receiving care at BraveNet practice-based research network (PBRN) via longitudinal collection of patient-reported outcomes. Previously, the BraveNet PBRN conducted a cross-sectional study including over 4,000 patients receiving clinical care at the 9 IM clinics, which comprise the Bravewell Clinical Network and BraveNet PBRN. This effort provided important information about patients receiving care at these IM clinics as well as the type of medical condition and IM treatments patients were receiving.The current pilot study extends the prior study by collecting patient-reported outcomes every 6 weeks for 6 months from patients receiving various types of IM services . Patients are asked to complete demographics, substance use, exercise habits, Perceived Stress Scale, Arizona Integrated Health Outcomes, and Patient Related Outcomes Measurement Information System-29  measures. Questions examining the patients\u2019 prior IM history, perceived benefits of IM treatments, and satisfaction with IM clinic are also included. Medical records are reviewed to obtain billing and healthcare utilization information. While electronic questionnaires are completed using the REDCap (Research Electronic Data Capture) system, patients may also complete the questionnaires via paper format.The Penny George Institute for Health and Healing  has been successfully piloting this project and 200 participants are enrolled to date. Additional BraveNet PBRN sites are joining the pilot study and expanded results of the entire pilot study will be presented.Practice-based research and patient-reported outcome measures will be key factors in demonstrating the effectiveness of IM interventions in the treatment of many clinical conditions. Multicenter participation provides increased enrollment and allows for generalizability of results from which future randomized controlled trials may be developed."}
+{"text": "Gene expression profiling has been widely used to study molecular signatures of many diseases and to develop molecular diagnostics for disease prediction. Gene selection, as an important step for improved diagnostics, screens tens of thousands of genes and identifies a small subset that discriminates between disease types. A two-step gene selection method is proposed to identify informative gene subsets for accurate classification of multiclass phenotypes. In the first step, individually discriminatory genes (IDGs) are identified by using one-dimensional weighted Fisher criterion (wFC). In the second step, jointly discriminatory genes (JDGs) are selected by sequential search methods, based on their joint class separability measured by multidimensional weighted Fisher criterion (wFC). The performance of the selected gene subsets for multiclass prediction is evaluated by artificial neural networks (ANNs) and/or support vector machines (SVMs). By applying the proposed IDG/JDG approach to two microarray studies, that is, small round blue cell tumors (SRBCTs) and muscular dystrophies (MDs), we successfully identified a much smaller yet efficient set of JDGs for diagnosing SRBCTs and MDs with high prediction accuracies . These experimental results demonstrated that the two-step gene selection method is able to identify a subset of highly discriminative genes for improved multiclass prediction."}
+{"text": "Pain responses can be suppressed by heterotopic continuous noxious conditioning, e.g. continuous noxious cold stimulation.These diffuse noxious inhibitory controls (DNIC) may be abnormal in migraine . DNIC eWe examined in healthy volunteers blood oxygenation level dependent (BOLD) responses in prefrontal cortex to repeated continuous noxious cold stimulation. The relationships between those responses and degree of inhibition of laser-induced pain during heterotopic cold stimulation were analyzed.Our results show that cold-induced BOLD response in anterior cingulate, orbitofrontal and lateral prefrontal cortices predict cold-induced heterotopic analgesia and attenuation of cerebral BOLD responses to laser stimulation. Prefrontal responses to the onset of cold stimulation were strongly related to the subsequent DNIC effect.We conclude that early responses to noxious conditioning are important for prediction of the analgesic DNIC effect. We hypothesize that this predictive effect of frontal cortices may be abnormal in chronic migraine."}
+{"text": "Rapid and efficient selection of emotionally salient or goal-relevant environmental stimuli is crucial for flexible and adaptive behaviors. Emotional events rapidly and automatically capture attention by activating subcortical neural structures Ohman, . BehavioWith regard to the interaction of emotion and attention, there are unsolved and controversial issues. For example, to what extent does emotional stimulus processing depend on attentional resource availability? Previous studies have shown conflicting results, probably due to several factors, including attentional load allocated to competing tasks. Some studies have demonstrated that emotional faces evoke amygdalar responses even when attention is diverted to other stimuli, suggesting that some types of emotional perception occur outside of top-down directed attention  and two ignore-faces conditions (easy and difficult digit/letter-matching tasks). The behavioral data suggested that the experimental design successfully controlled the attentional load and perceptual properties of emotional stimuli  presented foveally or peripherally in the visual field. Their study resulted in two main findings. First, amygdalar activity was strongly suppressed during high attentional loads, which suggests that emotional information processing might be suspended when attention-demanding cognitive tasks are performed simultaneously. Although this finding is not new (Pessoa, Morawetz et al.  directly Pessoa, , this waIn summary, Morawetz et al.  provided"}
+{"text": "Examining process rates alone may obscure the microbial physiological mechanisms that underlie climate-induced changes in soil C cycling, leading to contradictory patterns among different studies. For instance, in a large-scale survey of soil protease activities from climate manipulations, drier and warmer conditions resulted in lower extracellular enzyme activities (EEA) compared to ambient conditions (Brzostek et al., In this issue, Steinweg et al.  examine These findings challenge our existing knowledge about the mechanisms driving EEA in soils. In the laboratory, EEA increases linearly with temperature over the narrow temperature range observed here (German et al., The work of Steinweg and colleagues is an example of how shifts in gross process rates emerge from multiple interacting microbial mechanisms. However, these physiological feedbacks are often not incorporated into biogeochemical models. For instance, despite ample evidence that soil microbes shift allocation to enzyme production depending upon resource availability, EEA is often modeled simply as a function of the microbial biomass pool size. This approach may be valid in some ecosystems under steady state conditions or during the growing season (Kivlin and Treseder, Shifts in intracellular C allocation may also affect element cycling at the ecosystem scale if the stoichiometric requirements of the microbial biomass are altered. Steinweg and colleagues found that enzyme ratios varied with season, indicating higher microbial C vs. N demand in the winter. They suggest that changes in enzyme stoichiometry may reflect increased microbial maintenance cost during freeze-thaw cycles, which impose a high C cost on the microbial biomass. Shifts in biomass C:N have also been observed in response to altered substrate stoichiometry (Fanin et al., Based on the findings of Steinweg et al.  many of While Steinweg et al.  focus onMultiple processes will have large consequences for soil C storage in future climates, including climate controls on enzyme production and turnover, and tradeoffs in microbial allocation to growth, respiration, and resource acquisition. Yet, because all of these processes interact, the effects of climate change on soil C pools and fluxes can be extremely variable. As Steinweg and colleagues demonstrate, measuring mass-specific microbial responses is the first step toward improving our understanding of microbial physiological responses to altered climate regimes. However, studies that simultaneously examine the links among these mechanisms will be necessary to predict when tradeoffs in microbial C allocation occur and their long-term effects on soil C storage. By viewing ecosystem responses to temperature and precipitation through the lens of microbial physiology, we may arrive at a more mechanistic understanding of soil feedbacks on climate change."}
+{"text": "Globally, forests store ~45% of carbon sequestered terrestrially, contribute more to the terrestrial sink per area than any other land cover type, and assimilate an important portion of anthropogenic emissions Bonan, . ForestsThe justification for physiological research on drought-induced tree mortality is often stated as a need to improve the predictive capability of vegetation models through incorporation of mortality mechanisms  must be simulated across the Earth. Dynamic global vegetation models (DGVMs) coupled with general circulation models are a common tool for simulating vegetation response to climate change , derived from tree-ring records and predictable from regional climate, is highly correlated with forest mortality in the southwest USA  improved experimentation to distinguish physiological causes from symptoms, (2) continued model development based on existing knowledge and emerging discovery, (3) improved model validation against both experimental results and regional-scale mortality observations, and (4) high-resolution measurement of forest composition at large scales. While ecologists studying tree mortality have favored investigating physiological mechanism, measuring species composition and mortality at high resolution across regions is crucial for providing baseline observations to constrain model predictions. Without improved input on current forest conditions, even accurate models of forest mortality cannot generate useful predictions of change."}
+{"text": "Age-related macular degeneration (AMD) is the most common cause of legal blindness among the elderly in developed countries. The prevalence of advanced forms of AMD is increasing; it is expected to rise by 50% by the year 2020 in the United States. Early identification of AMD susceptibility and implementation of preventive measures are important management strategies. Antibodies against vascular endothelial growth factor (VEGF) have become the treatment of choice in patients with choroidal neovascularization (CNV); however, substantial improvement of vision occurs only in approximately one-third of patients. Early diagnosis and treatment of CNV may increase the success rate of treatment.Standard diagnostic modalities including fundus angiography and optical coherence tomography can detect CNV in clinical stages when vision is affected. In a novel approach, Takeda and coworkers evaluated the role of an eosinophil/mast cell chemokine receptor, CCR3, in CNV. They studied CCR3 expression among patients with AMD and previously untreated surgically excised CNV membranes, donor eyes of age-matched non-AMD controls, atrophic AMD, uveal melanoma, and surgically excised epiretinal membranes. Additionally, in vivo CCR3 bioimaging was performed in transgenic mice with spontaneous CNV using intravenous quantum-dot labeled CCR3 antibody fragments followed by fundus fluorescent imaging which demonstrated hyperfluorescent signals in regions of the fundus that were silent on standard fluorescein angiography. These hyperfluorescent dots were subsequently confirmed to be CNVs using histologic examination. The investigators showed that CCR3 was specifically expressed in the endothelial cells of all human CNV membranes but not in other conditions. Interestingly, they found that CCR3 neutralization was superior to VEGF blockade in suppressing laser-induced CNV in mice. Considering emerging safety concerns about continual blockade of VEGF, which is constitutively expressed in the normal adult human retina and needed for retinal health, a treatment strategy based on more specific targeting of CNV would be desirable.These findings suggest that CCR3 targeting may be a viable strategy for early detection and treatment of CNV, and might be superior to the current standard of care. CCR3 bioimaging would probably be most useful in eyes at high risk for CNV such as multiple large drusen or sound fellow eyes of patients with clinically evident CNV; it can also serve as a useful tool for differentiating lesions mimicking CNV."}
+{"text": "Background. Aberrant right hepatic duct (ARHD) draining intocystic duct (CD) is relatively rare but clinically importantbecause of its susceptibility to injuries during cholecystectomy. These injuries are often-times missed or diagnosed late and as aresult can develop serious complications. Methods. Fourconsecutive patients diagnosed with ARHD draining into CD wereidentified for inclusion. Results. The mean age of patients was42.5 years. The diagnosis in one of the patient was incidentalduring a routine endoscopic retrograde cholangiopancreatography(ERCP). Other three patients were diagnosed post-cholecystectomy-one presented with suspected intra-operative biliary injury, onewith persistent bile leak and another with recurrent cholangitis. Inadequate filling of the segment of liver on ERCP with dilationof intrahepatic ducts in the corresponding segment on imaging waspresent in two patients with complete obstruction of ARHD whichwas managed surgically. In another patient, the partiallyobstructed ARHD was managed by endoscopic therapy. Conclusion. ARHD draining into the CD can have varied clinical manifestations. In appropriate clinical settings, it should be suspected inpatients with persistence of bile leak early aftercholecystectomy, segmental dilation of intrahepatic-bile ducts onimaging and paucity of intrahepatic filling in a segment of liveron ERCP. Bile duct injury is an uncommon complication following cholecystectomy. With the increasing use of laparoscopic cholecystectomy (LC), there has been an associated increase in the incidence of bile duct injuries . Early s Therefore, the knowledge of various biliary anomalies and their early identification may further assist in decreasing the rate of biliary tract injuries. Here we present a case-series on various presentations and management of a rare anomaly of biliary tree.A 55-year-old woman presented 3 days postcholecystectomy (LC) with upper abdominal pain. HIDA scan revealed a bile leak. ERCP with minimal contrast injection revealed a leak from cystic stump; therefore a 10 F biliary stent was placed. Six weeks later a repeat ERCP revealed no leak from the cystic duct stump. However, large branch of the right intrahepatic duct was filled through the cystic duct stump . MinimalA 38-year-old Caucasian woman was referred to our hospital for recurrent episodes of gram-negative bacteremia. On presentation she was asymptomatic. Her past surgical history was significant for complicated cholecystectomy requiring conversion from laparoscopic to open technique six years earlier when she was 28 weeks pregnant. The surgical report described normal common and cystic ducts and described bile staining within the hilum where a drain was placed. After a few days drainage stopped and drain was removed. She was found to have minimally abnormal LFT's during a routine blood workup, a year after the surgery. Ultrasound at that time demonstrated dilated biliary tree in a segment of the right lobe of the liver and an ERCP revealed a questionable cystic dilation of distal common bile duct (CBD), for which sphincterotomy was performed. She had recurrent episodes of fever in the subsequent years and blood cultures persistently grew Klebsiella species. Computerized tomography (CT) scan  and MRCPA 27-year-old healthy young woman with history of generalized fatigue presented for further evaluation of abnormal liver biochemistries. Her alkaline phosphatase levels had nearly increased 3 times the upper limits of normal. The most recent LFT revealed elevation of aspartate aminotransferases (AST) (104\u2009U/L) and alanine aminotransferases (ALT) (234\u2009U/L), which were reported as normal two years ago. An abdominal ultrasound showed no focal lesions. MRCP was performed which did not reveal any abnormal findings. Clinical examination was normal. In view of strong clinical suspicion of sclerosing cholangitis, ERCP was performed which revealed diffuse multifocal strictures with beading of intrahepatic ducts bilaterally, suspicious for primary sclerosing cholangitis. An aberrant branch of right hepatic duct draining into CBD with cystic duct originating from the aberrant branch was noted on ERCP .A 50-year-old woman presented with symptomatic cholelithiasis. Elective LC was attempted at an outside facility. Intraoperative cholangiogram (IOC) was interpreted as-right intrahepatic ducts filling without opacification of mid-CBD and CHD. Surgery was aborted in view of suspicion of bile duct injury. Two JP (Jackson-Pratt) drains were placed and she was referred to our center. ERCP performed at our center revealed cystic duct remnant leak and staples were noted close to CBD. There was inadequate filling of intrahepatic ducts in a segment of right hepatic lobe . SphinctAberrant right hepatic duct (ARHD) is branch providing biliary drainage to variable portion of right hepatic lobe and drains directly into the extrahepatic biliary tree. ARHD is a common bile tract anomaly with the incidence of 4.6%\u20138.4% and it frequently drains into common hepatic duct, CBD or even left hepatic duct . HoweverIOC during LC has been utilized to identify anatomic variants of biliary tract, even though it's routine use is debatable . While sPersistent bile leak may be an initial presentation of injury to the ARHD during cholecystectomy . These pLess frequently, patients with ARHD injury can present in the postoperative period weeks to months later, with cholestatic pattern of abnormality on LFT's, if the aberrant duct is blocked. In addition, these patients can also present with episodes of cholangitis in the obstructed segment of biliary tree as was the case with our second case. A high index of suspicion is required to look for these complications. Segmental dilation of intrahepatic ducts may be revealed on a CT-scan. These patients will require cholangiography (PTC or ERCP) to define the anatomy of biliary tree. Scantiness of intrahepatic filling on ERCP with dilation of intrahepatic branches in the same sector on radiologic imaging should be a useful clue to the diagnosis of obstruction of aberrant branch of bile duct. PTC can be performed when intrahepatic ducts are dilated; sometimes both the procedures may be required to obtain the diagnosis  as was tUsually, the initial management of patients presenting with a bile leak after LC is decompression of biliary tree by placing a stent with or without sphincterotomy or placement of naso-biliary drain or percutaneous drain . If an aThe diagnosis of aberrant right hepatic duct draining into cystic duct can be incidental during ERCP or MRCP if performed before surgery, as in our third patient. In these situations, the knowledge of aberrant anatomy of biliary track would be important for a surgeon to avoid any inadvertent complications if they undergo cholecystectomy or any other biliary surgery. In addition, the safe approach to avoid injury to aberrant bile-ducts during cholecystectomy is adhering to the gallbladder itself, identifying the triangle of Calot and using the \u201ccritical view of safety (CVS)\u201d, as described by Strasberg, before dividing the cystic structures. CVS involves 3 steps: (i) clearing triangle of Callot of fat and fibrous tissue, (ii) separation of lowest part of GB from liver bed, (iii) only 2 structures (cystic artery and cystic duct) should be seen entering GB .  In summary, we present a varied clinical presentation and management of a relatively rare but clinically significant anatomic variation of bile duct anatomy. Aberrant bile-duct injury is often missed as subtle signs of injury remain unrecognized both by surgeons as well as by gastroenterologists. Aberrant bile duct injury after cholecystectomy should be strongly suspected in following situations: (i) paucity of intrahepatic filling in a segment of liver on ERCP; (ii) abnormal LFTs with segmental dilation of intrahepatic-bile ducts on abdominal CT-scan or ultrasound."}
+{"text": "They provide a broad overview of the important advances that such mechanistic studies in Drosophila have made to our understanding of the age-related decline in muscle mass and strength, immune response, stress resistance, sexual behavior, and cognitive function. Walton and Pizzitelli (Caenorhabditis elegans. The authors dissect molecular and cellular mechanisms through which the spatiotemporal dynamics of unsaturated fatty acids regulates longevity by modulating the Nuclear Hormone Receptor signaling and maintaining the integrity of various organellar membranes. They also explore the mechanistic links between hydrolysis of neutral lipids and several longevity-defining processes, discuss how lipid-derived signaling molecules impact signaling networks central to longevity assurance, and outline the essential roles of mitochondrial membrane lipids in longevity regulation via multiple cellular pathways. Postnikoff and Harkness (Aging of multicellular and unicellular eukaryotic organisms is a highly complex biological phenomenon that affects a plethora of processes within cells. This wide array of longevity-defining cellular processes\u2014which are governed by an evolutionarily conserved signaling network\u2014includes oxidative metabolism and protein synthesis in mitochondria, lipid, and carbohydrate metabolism, NADzzitelli  demonstrzzitelli  explore zzitelli  provide Harkness  offer usHarkness  outline Harkness  provide Harkness  summarizHarkness  provide"}
+{"text": "Luminescent colloidal quantum dots (QDs) possess numerous advantages as fluorophores in biological applications. However, a principal challenge is how to retain the desirable optical properties of quantum dots in aqueous media while maintaining biocompatibility. Because QD photophysical properties are directly related to surface states, it is critical to control the surface chemistry that renders QDs biocompatible while maintaining electronic passivation. For more than a decade, investigators have used diverse strategies for altering the QD surface. This review summarizes the most successful approaches for preparing biocompatible QDs using various chemical ligands. These applications require an appropriate fluorescent probe having specific chemical and optical properties. Organic and genetically-encoded fluorophores generally have narrow absorption, broad emission, and are vulnerable to continuous irradiation by the excitation source which limits their usefulness in some applications such as multiplexed measurements, long-term imaging, and single molecule imaging, among others ..83].4.2.n-alcanoic acids  (PE-PEG) was the attached to SiO2-OTMS-coated QDs through hydrophobic interactions [2 and PE-PEG showed similar brightness over pH 1\u201314. They also evaluated the cellular toxicity of these nanoparticles with and without embedded QDs and found that the toxicity is purely due to the exposure of bare nanoparticles, indicating QDs were adequately protected within the silica spheres with no appreciable leaching of heavy metals [Gao\u2019s group  found thractions . As Figuy metals .5.To enable the use of QDs in a wider range of biological applications, all of the preceding methods require a route for attaching biomolecules stably onto the QD surface. A suitable ligand candidate should allow attachment of a diversity of biomolecules including nucleic acids, proteins , polysaccharides, and peptides. Biomolecules are commonly conjugated to the QD surface through the following approaches : (1) cov6.in vivo diagnostics and treatments.Biocompatible QDs are typically generated through either an organic synthetic route requiring subsequent ligand exchange or encapsulation, or a more direct aqueous synthetic route where the nanocrystals are inherently water-soluble. There are nearly countless variations of these methods reported in the literature where each protocol carries its own inherent advantages and disadvantages and must be considered in light of the eventual application. A ligand exchange procedure that uses small charged molecules can maintain minimal hydrodynamic diameters, but they are usually more susceptible to aggregation in biological buffers or solutions of high ionic strength. These compact capping ligands often fail to maintain suitably high luminescence without additional processing. Methods that improve the density of ligands on the QD surface while ensuring a strong binding interaction appear to have the most promise. Polymer and silica coatings are better able to isolate QDs from solution which results in improved colloidal stability, limited non-specific binding, and high QY. However, these characteristics are often achieved at the expense of compact size which can impede cellular mobility  and limi"}
+{"text": "In trial design, decisions are made about which intervention components/processes to standardise and which remain flexible to maximise utility and/or effectiveness. The intervention-context-system fit for complex interventions impacts on trial recruitment, delivery and outcomes. Survey vignettes and discrete choice experiments are quantitative researcher led approaches which focus on a few measurable attributes. Our aim was to explore the utility of qualitative vignettes as a methodological tool allowing service users/providers to contribute to intervention design.A case series of four acceptability and feasibility studies  with service users and providers. Data were collected at different pre-trial stages: i) vignettes of studies in a systematic review of incentives for breastfeeding and smoking cessation in pregnancy, subsequently modified following emergent qualitative analysis; ii) emergent vignettes in the last of up to 8 serial qualitative interviews investigating infant feeding behaviour, following a systematic review showing poor generalizability of effective interventions in the UK context; iii) intervention vignettes of an effective intervention (groups for weight management) to refine the design for a new population (women treated for breast cancer) and iv) emergent intervention vignettes explored at a second interview with obese older adults.Illustrations of how qualitative vignettes can complement quantitative design tools will be presented.Carefully constructed qualitative vignettes combining known effective and emergent promising intervention aspects can optimise trial design. When talking service users and providers through a potential intervention, different perspectives emerge compared with responses to closed or more abstract questions."}
+{"text": "Eating disorders (ED) are chronic, deadly illnesses and especially for adults with anorexia nervosa, existing treatments have limited proven efficacy. Growing knowledge about the neural underpinnings to ED provides an avenue for more targeted, brain directed interventions. Brain stimulation techniques, such as Transcranial Magnetic Stimulation (TMS), transcranial Direct Current Stimulation (tDCS), Vagus Nerve Stimulation (VNS) and Deep Brain Stimulation (DBS) have the ability to directly alter neural activity within the brain. Such methods are being used extensively within both research and clinical settings to treat movement disorders such as Parkinson's and a range of psychiatric illnesses including depression. Findings within such disorders, relevant animal models and more recent research within ED populations have led to a strong rationale for the use of brain stimulation in ED. This paper systematically reviews this literature, identifying deficits in the current knowledge in an attempt to help guide future research and clinical practice within the imminent field of brain directed interventions for ED.Understanding and Treating Eating Pathology stream of the 2013 ANZAED Conference.This abstract was presented in the"}
+{"text": "Biomedical imaging is a rapidly growing field to provide a state-of-the-art tool for preclinical biomedical research and clinical applications, in view of its ability to noninvasively reveal subtle structural variations of biological tissues and visualize in vivo physiological and pathological processes at the cellular and molecular levels. Mathematical methods are involved with imaging theories, models, and reconstruction algorithms in biomedical imaging. X-ray computed tomography (CT) was a successful application of mathematical method in medical imaging. The CT mathematical model can be reduced to a Radon transform. The inverse transform of Radon transform is invented by Radon in 1917. Magnetic resonance imaging (MRI) is a versatile medical imaging modality. MRI can provide more diagnostic information than any of the existing imaging techniques. It does not involve the use of ionizing radiation, hence free from associated harmful effects. Inverse Fast Fourier Transform (IFFT) is a standard method of image reconstruction in MRI from uniformly sampled K-space data. From nonuniform K-space data, iterative algorithms can improve image quality of image reconstruction for MRI. In the optical molecular imaging, the radiative transport equation (RTE) is the fundamental equation to describe photon propagation in biological tissues. The forward solution predicts photon propagation in the optical molecular imaging. The inverse solution can reconstruct molecular probe distribution in a small animal for providing unique insights into disease pathogenesis, drug development, and responses of therapy. The solutions for RTE usually involve analytical methods, Monte Carlo (MC) method, diffusion approximation (DA) method, simplified spherical harmonics method, and some numerical methods.In this special issue, each paper was reviewed by at least two reviewers and revised according to review comments. This special issue covered most of common biomedical imaging models and various image processing methods, such as registration, segmentation, and so forth, were involved. For Positron Emission Tomography (PET) imaging model, two attenuation correction methods based on X-rays CT (CTAC method) and segmentation of emission images (SE-AC method) were simulated with Monte Carlo method and compared. For synchrotron Micro-CT imaging model, a semiautomatic segmentation algorithm for extracting the complete structure of acini has been proposed. For ultrasound imaging model, a common carotid artery segmentation scheme based on active shape model can get better result and promote the translation of carotid 3D US to clinical care for the monitoring of the atherosclerotic disease progression and regression. For MRI model, a mesh-deformation constraints based image registration algorithm was carefully investigated. Also the development of image segmentation for intracranial aneurysms and rotation covariant image processing method for biomedical applications are summarized. Furthermore, in order to accelerate the parallel imaging, a sparse constrained reconstruction approach with variable splitting methods was proposed and verified: total variation (TV)-minimization interior tomography algorithm, dynamic and robust blind watermarking scheme to resist against common distortions, modified global and modified linear contrast stretching techniques for identification of various stages and species of malaria, a 3D surface-based deformable model as guidance for nonrigid 3D medical image registration and fusion, mathematical or computational modeling for oncogene inactivation, a group factor analysis model for neuroimaging applications by assigning separate factor patterns to control and patient groups yielding more reasonable factor scores and patterns, different MISO Volterra methods to model simulated ultrasound contrast agents signals, an automated process that determines whether an aortic object in a slice is a candidate for aortic dissection or PAU based on contrast enhanced CT data, image-based computational techniques to quantify the severity and directionality of individual scratches and scrapes, combination of genetic algorithm and closed loop to obtain optimal ternary command which maximized the contrast to tissue ratio, and magnetoacoustic tomography with magnetic induction (MAT-MI) for generating electrical conductivity images of biological tissues with high spatial resolution. An acceleration strategy for fluorescence molecular tomography (FMT) with early photons is proposed using graphics processing units (GPUs). The fluorescence molecular tomography (FMT) with early photons can efficiently improve the spatial resolution and fidelity of the reconstructed results. An efficient compressed sensing-based algorithm is proposed for CT image reconstruction from few-view data to suppress the streak artifact. The compressed sensing (CS) algorithm shows the potential to accurately recover images from highly undersampled data. The discriminant analysis techniques are discussed using MRI to identify the correlative pattern of brain changes for differentiating parkinsonian syndromes. A hybrid multiscale and multilevel image fusion algorithm for green fluorescent protein (GFP) image and phase contrast image of Arabidopsis cell is proposed. This algorithm uses different fusion strategies for different detailed subbands, which include neighborhood consistency measurement (NCM) that can adaptively find balance between color background and gray structure. A detrended fluctuation analysis (DFA) method is applied to image analysis to investigate the characteristic of different type of simulated and lymphoma image. A method is presented to estimate the tilt and decentration of intraocular lens (IOL) more accurately. The Bayesian hierarchical model for the analysis of categorical longitudinal data is investigated from sedation measurement for MRI and CT. In vivo MRI of local drug delivery is discussed to visualize and quantify the time resolved distribution of MRI contrast agents.These papers represent an insightful observation into the state of the art, as well as future topics in this biomedical imaging field. We hope that this special issue would attract a wide attention of the peers.Wenxiang CongKumar DurairajPeng Feng"}
+{"text": "Although the advent of MRI impacted significantly our presurgical investigation, ictal semiology with interictal and ictal EEG has clearly retained its roles in localizing epileptogenesis. MRI-identified lesions considered epileptogenic on semiological and electroencephalographic grounds have increased the likelihood of resective surgery effectiveness whereas a nonlesional MRI would diminish this probability. Ictal propagation and the interplay between its source and destination have emerged as a significant component of seizure evaluation over the past 30 years. Epilepsy and Functional Anatomy of the Human Brain [Ictal semiology and EEG dominated our localization of intractable epileptogenesis prior to the introduction of MRI. Dr. John Girvin and I each attempted to outdo the other in obtaining patient and observer descriptions of the patients' seizures, guided by the most comprehensive observations and perceptions documented by Wilder Penfield and Herbert Jasper in an Brain . SeizureIn addition to Penfield's identification for a semiological pattern as representing temporal lobe epilepsy and subsequent description of mesial temporal ictal semiology , subsequThe works of International League against Epilepsy Commissions on Epileptic Seizure Classification and Terminology have, in sequential fashion, clarified our clinical analyses. The 1981 ILAE Commission classified partial  seizures into simple partial (consciousness preserved) and complex partial (consciousness impaired). This division has encountered clinical and heuristic limitations as it depends upon evaluating an entity\u2014consciousness\u2014that can neither be defined nor assessed. Gloor  discusseCombined with ictal semiology, ictal and interictal EEG were the principal tools before the mid-1980s to localize epileptogenesis in virtually all patients whose intractable focal epilepsies required resective surgery for alleviation. Focal temporal interictal spikes, if predominant over one temporal lobe, lateralised temporal lobe seizure origin in over 90% of patients [For many years, nasopharyngeal or sphenoidal EEG leads supplemented the Ten Twenty EEG electrode system to better record anterior-mesial temporal EEG activity, especially spikes. As illustrated by F. A. Gibbs and E. L. Gibbs , the antOur group at Western/University Hospital was the first to formally study and describe the morphology of scalp-recorded focal seizures-temporal and extratemporal . Recognisubdural electrodes. Inserted as imbedded in silicon strips through burr holes to avoid a craniotomy during the patient's evaluation, these electrodes record directly from the cortical surface. Moreover, they may extend to mesial and inferior cortical surfaces, areas remote from scalp electrodes. For patients with temporal lobe epilepsy, SDE provides more precise and sensitive ictal and interictal recording from the mesial temporal regions. In 1979, Dr. John Girvin and Mr. Dan Jones, EEG technologist, designed Commercially manufactured subdural electrodes were not available in the early 1980s, resulting in some other epilepsy centres purchasing our in-house-manufactured electrodes. Design and manufacture of SDE at UH without any complication continued by Dan Jones and Frank Bihari for over 20 years. Figures However, in 2004 London Health Sciences Centre chose to make use of commercially produced electrodes, though at a significantly greater cost. Our centre was the first to routinely employ subdural electrodes (SDE), and they continue today as a major part of evaluation of about 50% of our patients ultimately operated upon. We studied 27 consecutive patients whose temporal lobe epilepsy clinically implicated both temporal lobes from ictal semiology, scalp EEG, and imaging features. We found that the side of SDE-recorded seizures correlated with that containing most scalp spikes and most scalp-recorded seizures in most but not all patients, confirming the value of both EEG and SDE .Although unable to detect small cortical epileptogenic lesions, plain skull X-rays had disclosed several cranial and intracranial abnormalities of lateralising value. Cranial erosion on skull roentgenography could have resulted from a previous wide fracture or from a subdural or subarachnoid cyst; one or more asymmetrical cranial features may have indicated cerebral hemiatrophy, compatible with accompanying epileptogenesis; intracerebral calcification may have represented tumours or congenital lesions. Pneumoencephalography disclosed displaced or deformed ventricles from tumours, abscesses, hematoma, and other lesions. Cerebral arteriography helped localize expanding lesions but proved less helpful in the study of atrophic lesions . A major advance in evaluating patients for temporal lobe surgery was the advent of MRI. Imaging afforded by MRI discloses focal structural abnormalities underlying intractable epilepsy that may remain undetected by earlier neuroimaging methods . SubsequThree common epileptogenic lesions are particularly well displayed by MRI: mesial temporal sclerosis, cortical dysplasia (CD), and benign tumours such as dysembryoplastic neuroepithelial tumours (DNETs) and gangliogliomas (GGL). Rhythmic epileptiform discharges (REDs) may characterize the scalp EEGs of those with focal CD ; abundanThe presence or absence of mesial temporal sclerosis (MTS) became far better displayed by MRI than any previous imaging modality. This greatly facilitated, with EEG, an assessment as to whether one or both temporal lobes are epileptogenic. In the latter instance, assessment of their relative epileptogenicities may influence a surgical decision. In some patients, MRI and EEG (via REDs) have demonstrated both MTS and CD with comparable epileptogenicity in each, termed \u201cdual pathology\u201d , 19. OriThe appearance of dual pathology in some patients augmented our awareness of seizure propagation and its influence on semiology. Thus, ictal symptoms and signs may signify the site of seizure spread rather than origin. Both normal cerebral connectivity and neuronal pathways developed in the process of epileptogenesis likely participate in seizure spread. For example, occipital seizures may propagate to the mesial temporal region via the \u201cventral stream,\u201d a multisynaptic pathway that terminates primarily in the amygdala but also in the parahippocampal area . Munari personal communication). However, often a full temporal lobectomy has been performed . Surgical approach and technique have not measurably changed over the years.Three approaches to the mesial temporal region have been described: sylvian fissure, middle temporal gyrus, and inferior temporal pole . Our surThat a substantial left temporal lobectomy will significantly impair verbal memory has become increasingly realized over the past decades creating a distinction between left and right temporal epilepsy in terms of surgical candidature , 25. Con"}
+{"text": "This study is the first to use quantitative perfusion CMR to evaluate regional differences in myocardial blood flow (MBF) in patients with left bundle branch block (LBBB).LBBB is often associated with underlying CAD but its presence can limit the diagnostic accuracy of non-invasive imaging tests. In particular, there is a high incidence of false-positive results with exercise SPECT due to apparent septal perfusion defects. The use of vasodilator stress has reduced but not eliminated this problem. Several hypotheses have been postulated to explain the cause of such perfusion defects, and these include early activation of the septum, leading to shortened diastole and reduced blood flow; partial volume effects caused by impaired septal thickening; and increased septal intra-myocardial pressure during diastole, resulting in reduced flow reserve. A number of small studies using PET or early quantitative SPECT techniques have evaluated regional differences in MBF in patients with LBBB, but the results have been conflicting and have shown either no regional differences or a relative but not absolute reduction in septal perfusion. This study re-evaluates the unresolved question of septal perfusion in LBBB using quantitative perfusion CMR.9 patients with LBBB and no significant CAD underwent adenosine stress/rest perfusion CMR at 1.5T and X-ray coronary angiography. Absence of CAD was defined as luminal stenosis <40% on quantitative coronary angiography in all major vessels. Mid-ventricular perfusion data were segmented into 3 regions for each patient: septal, adjacent (anterior-inferior) and lateral. MBF and myocardial perfusion reserve (MPR) were then determined for the septal and lateral regions by Fermi function deconvolution.Resting MBF was similar in both septal and lateral regions in all patients  ."}
+{"text": "Coincident expression of otherwise unrelated inborn errors of metabolism may occur as a result of large deletions of multiple gene, referred to as the contiguous gene deletion syndrome. We describe two male infants who presented with failure to thrive and raised urinary glycerol levels, leading diagnosis of glycerol kinase deficiency, congenital adrenal hypoplasia and myopathy.These clinical diagnoses, suggest Xp21 contiguous gene deletion syndrome.The two male infants currently 48 months and 3 months old, presented with failure to thrive at 10 months and 1 month of age respectively. On evaluation for metabolic causes of poor weight gain, urine organic acids showed high levels of glycerol. Further results revealed pseudo-hypertriglyceridemia which raised the suspicion of glycerol kinase deficiency. Both infants were persistently hyponatremic and hyperkalemic, and the synacthen test showed a suboptimal cortisol peaks. Plasma renin was high with low aldosterone indicating mineralocorticoid defiency.The older male infant who presented at 10 months of age also had significant developmental delay with muscular weakness and markedly raised creatinine kinase.He was confirmed to have Duchene Muscular Dystrophy.Both the infants were started on steroid and salt replacement and monogen feeds containing medium chain triglycerides. Their weight improved with normalization of sodium & potassium levels. The above spectrum of clinical & biochemical features is consistent with a diagnosis of Xp21 contiguous gene deletion syndrome. Although rare, raised urinary glycerol and serum triglycerides leads to suspicion and allows early recognition of this condition, where prompt treatment can prevent life-threatening adrenal crises."}
+{"text": "Dilated cardiomyopathy (DCM) occurring due to an unknown etiology or genetic predisposition is termed as idiopathic dilated cardiomyopathy (iDCM), although iDCM may also result from viral exposure. However, the incidence of myocardial inflammation and its relation to left ventricular (LV) function in iDCM remains unknown.Cardiovascular magnetic resonance (CMR) imaging allows for the visualization of myocardial inflammation using early Gadolinium enhancement (EGE). We applied EGE imaging in the setting of clinically suspected iDCM to determine both the incidence and relation of myocardial inflammation to LV function.26 patients  were referred to us for the assessment of iDCM following a clinical suspicion of iDCM, based upon the following criteria: ejection fraction below 45%; invasive exclusion of significant coronary artery disease using a cutoff of 50% stenosis; stable clinical course for at least 3-months prior to the CMR study; exclusion of myocarditis within the past 12 months; as well as exclusion of comorbidities which may otherwise account for patient presentation including valvular heart disease.Standard CMR imaging procedures for the assessment of LV function and EGE were utilized. EGE images were acquired before and early after (over 4 minutes) Gd-DTPA 0.1ml/kgBW contrast injection using T1-weighted images.LV function was assessed by manually tracing endo- and epicardial contours. Myocardial signal intensity was normalized to skeletal muscle, generating a ratio that had to be greater than or equal to 4 to be considered positive for EGE.Eighteen patients (69%) presented with EGE and a significantly increased EGE ratio . The ratio of EGE correlated with LVEDVI  and LVESVI , LVSVI , and LVEF . Patients with elevated EGE had significantly dilated left ventricles and globally reduced ventricular function: LVEDVI  and LVESVI  were increased, while LVSVI  and LVEF  were reduced (Figure Using CMR-based EGE as a surrogate marker of myocardial inflammation, we provide first evidence for a high incidence of inflammation in patients with clinically suspected iDCM. The extent of myocardial enhancement was directly related to reduced ventricular function. CMR-based assessment of myocardial inflammation may be utilized as a biomarker for patient prognosis and guide medical therapy to target those patients in whom there is active myocardial inflammation."}
+{"text": "This case report illustrates two unusual cases of parapharyngeal schwannomas mimicking carotid body tumors in terms of characteristic vascular displacement. Carotid body tumors classically cause splaying of internal and external carotid arteries demonstrating the Lyre sign on imaging. Also interestingly, both of these cases were seen in younger ages and include cervical sympathetic chain schwannoma and vagal schwannoma. However, these schwannomas revealed hypovascularity on imaging studies allowing differentiation from hypervascular carotid body tumors. Preoperative distinction between carotid body tumors and schwannomas is very important. Carotid body tumors, cervical sympathetic chain schwannomas, and vagal schwannomas have common location in neck that is the retrostyloid compartment of parapharyngeal space \u20133. AmongAn 18-year-old female was referred to the otolaryngology department with a swelling on the left side of the neck since 4 months. On examination, nonpulsatile mass near angle of the left mandible was seen. Cranial nerve examination was normal. Doppler ultrasonography revealed hypoechoic mass in the left carotid space showing mild peripheral vascularity . ComputeA 17-year-old female came with history of painless swelling on the left side of the neck and change in voice since 2 months. On examination, there was nontender swelling noted posterior to the angle of the left mandible. USG neck revealed hypoechoic mass on the left parapharyngeal space showing mild vascularity on the Doppler study . On CT sVagal schwannomas, carotid body tumours and cervical sympathetic chain schwannomas are the most common tumours of the retrostyloid parapharyngeal space , 2. CaroSchwannomas or neurilemomas, are derived from schwann cells. They are common in middle age with female preponderance \u20133. In thPreoperative diagnosis is very important in these retrostyloid parapharyngeal masses as management of carotid body tumors varies from surgery to radiation to observation, while complete surgical excision is the therapy of choice in vagal and cervical sympathetic schwannomas . Also, rBoth of the described tumors displayed splaying of external and internal carotid arteries on CT contrast study, MRI, and DSA which was also confirmed at surgery. However both of these tumors demonstrated mild vascularity on the Doppler USG, CT, and DSA.Although characteristic vascular displacement, that is, splaying of carotid bifurcation helps to distinguish carotid body tumor from other retrostyloid parapharyngeal masses, similar vascular displacement can be seen in vagal and cervical sympathetic chain schwannomas. So, this imaging pitfall should be taken into account while considering differential diagnosis of retrostyloid parapharyngeal tumors.Both of these tumors showed hypovascularity, hence favor schwannomas rather than carotid body tumors. Internal vascularity and enhancement characteristics of the tumor should be given more importance while differentiating schwannomas from carotid body tumors. Hence enhancement pattern is the imaging pearl in differentiating carotid body tumors from schwannomas."}
+{"text": "Drug addiction is a serious public health problem that consists of a compulsive drive to take drugs despite repeated severe adverse consequences . FactorsThe accumulated evidence supports the view that a large number of substance users suffer from significant neuropsychological impairments . NeuroimBefore elaborating the idea of drug-induced cognitive changes in patients addicted to illicit drugs, it is important to briefly discuss the influence of potential premorbid deficits on the cognitive performance of some drugs abusers . For exaThe prefrontal cortex (PFC) and the striatum participate in integrated functions that are modulated by glutamate  and dopaPathological changes in the orbitofrontal cortex (OFC) might also be involved in the manifestation of addiction-related behaviors because it is relevant to outcomes related to primary reinforcers . OFC neuImpaired self-control plays a fundamental role in drug-taking behaviors in addictive states . ImpulsiThe available evidence does support the thesis that impulsivity is a vulnerability marker for substance abuse , 12. SevInterestingly, abnormalities have been identified in frontal networks that subsume poor self-regulation and impulse control in cocaine dependency. Specifically, cocaine users were reported to show stronger connectivity within the perigenual anterior cingulate cortex (ACC) social processing/\u201cmentalizing\u201d network . This stAttention represents a number of intimate mechanisms that facilitate the filtering, selection, and processing of information . In subsPoor cognitive performance in areas of risk-taking and decision making may influence the degree to which illicit drug users engage in risky behaviors with consequent negative health consequences. Deficits in tests of decision making have been found in patients who suffer from marijuana , 50, cocIn summary, drug addiction is marked by mild, yet pervasive, cognitive disruptions that may cause the negative progression of the clinical course, threaten sustained abstinence , or incr"}
+{"text": "The letter by Mullier8C intervals,The inhibition of pre-hepatic/hepatic CYP3A4 metabolism of amiodarone alters both plasma and cardiac substrate:metabolite ratios. It therefore reduces alterations of PR and QTC by inhibiting the rapid component of delayed rectifier K+ current (Ikr), leading to significant QT prolongation in healthy subjects and in patients with dilated or hypertensive cardiomyopathy,The interaction of grapefruit juice with amiodarone is more complicated than previously thought. Naringenin, the naringin (the predominant flavonoid in grapefruit juice) aglycone, has recently been reported to prolong QTEven though cases of QT prolongation and torsades de pointes with amiodarone are rare, a case has been reported of a female patient who presented with marked QT prolongation associated with ventricular arrhythmias including torsades de pointes, requiring electrical cardioversion after amiodarone administration, after she had been drinking large quantities of among others grapefruit juice."}
+{"text": "Chronic heart failure (CHF) is the leading cause of hospitalization and death in industrialized countries. CHF is frequently associated with humoral and metabolic disturbances, including reduced bioavailability of the important signalling molecule nitric oxide (NO), which has vasodilating properties. Several studies reported high plasma levels of asymmetrical NG, NG-dimethyl-L-arginine (ADMA), an endogenous inhibitor of NO production, in CHF, contributing to endothelial dysfunction. The Dynamic Vessel Analyzer (DVA) enables dynamic analyses of retinal vessels. NO is a mediator of retinal vasodilator response to flicker light. Reduced response of retinal arterioles to flicker light may be an attractive technique to non-invasively assess endothelial dysfunction. The aim of the study was to test the hypothesis that retinal vessel response to flicker light is reduced in patients with CHF and correlates inversely with serum ADMA levels.16 patients with non-ischemic cardiomyopathy and 22 healthy volunteers were included. Retinal arteriolar flicker response as percent change from baseline and serum ADMA level were measured.Retinal arteriolar flicker response was significantly reduced in CHF patients compared to the healthy control group . ADMA levels tended to be higher in CHF patients . Noteworthy, we observed a highly significant inverse correlation between retinal arteriolar flicker response and ADMA levels .Our findings suggest that analysis of retinal vessels could be an attractive non-invasive method to quantify endothelial dysfunction in CHF."}
+{"text": "Candida is the most common human fungal pathogen and the cause of invasive candidiasis, the fourth leading cause of nosocomial bloodstream infection in the United States with an estimated annual cost of \u223cUS$2 billion and mortality that exceeds 40% despite administration of antifungal therapy in modern intensive care unit facilities Candida yeast cells intravenously and mimics skin-derived bloodstream human candidiasis, has been successfully employed to study fungal and host factors that regulate susceptibility to the infection Candida expresses a variety of virulence factors that contribute to its pathogenesis and could be exploited for development of vaccines and targeted therapeutic strategies. Firstly, Candida albicans filaments' virulence factors, including secreted aspartyl proteases and phospholipases, are thought to be important for Candida invasion in infected organs and, probably, for mediating fungus-induced tissue immunopathology Candida is able to efficiently adhere to and invade epithelial and endothelial cells via induced endocytosis and active penetration; both adhesion and invasion facilitate Candida dissemination Candida to form biofilms on implanted medical devices such as central venous catheters, which are a frequent portal of entry for invasive infection in humans Candida factors that promote its adhesion and invasion, the agglutinin-like sequence (Als) family has attracted significant attention; Als3 in particular, a C. albicans\u2013specific virulence factor, was recently shown to mediate brain-specific Candida endothelial invasion and tissue penetration vps51\u0394/\u0394 C. albicans mutant was shown to be responsible for its increased ability to invade brain endothelial cells in vitro and traffic to the brain in vivo via binding to the gp96 heat shock protein, which is expressed specifically on brain endothelium Candida tissue burden C. albicans virulence factor is its ability to transition between unicellular yeast cells and filamentous growth during infection; in fact, it is the interchange between these morphotypes that is critical for pathogenesis, as strains locked either in the yeast or the filamentous forms have attenuated virulence in vivo albicans Candida species such as Candida glabrata, which is an important cause of invasive candidiasis in humans even though it does not form hyphae. Strikingly, the ability of C. albicans to form filaments in vivo is tissue-specific Candida growth in mice such as the liver and spleen prevent Candida filamentation, whereas hyphal formation is abundant in the kidney, the target organ of murine disseminated candidiasis, where Candida proliferation is inexorable Candida filamentation could lead to the discovery of novel therapeutic interventions.Moreover, a fundamental Candida immune response is fungal recognition by the innate immune system. Over the past decade there has been an explosion in our understanding of how soluble and membrane-bound pattern recognition receptors (PRRs) recognize various pathogen-associated molecular patterns (PAMPs) of Candida yeast and filamentous forms  in modulating downstream anti-Candida immune responses. In addition, more studies are needed to understand how Candida influences its recognition in vivo by employing immune evasion strategies; for example, \u03b2-glucan exposure on the Candida surface occurs in infected mouse tissues only late after infection The challenge for future research will be to define how Candida experimental strains impedes on drawing definite conclusions about the in vivo role of certain PRRs, as apparently discrepant results have been reported for some TLRs and CLRs with different fungal strains Candida strains in mammals could potentially be ameliorated by employing non-vertebrate  and/or mini-vertebrate model hosts  that have evolutionarily conserved innate immune pathways , and could allow for facile and inexpensive high-throughput screening of greater numbers of Candida strains C. albicans is the most common agent of human invasive candidiasis, research performed until now has predominantly focused on the recognition of this species, and much less is known about the interaction of other Candida species with the immune system. It is expected that research aiming to gain more insight on the recognition of emerging non-albicans Candida species will represent an important area of research in the coming years.In addition, the notable diversity in PAMP structure among various Candida killing Candida ingestion is followed by assembly of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex at the phagosomal membrane and oxidative burst, which leads to generation of candidacidal reactive oxygen species and K+-influx\u2013induced activation of neutrophil candidacidal granular proteases Candida yeast-to-hyphae conversion, a process dependent on the oxidative burst Candida yeasts and hyphae and appear important for anti-Candida host defense in vivo Neutrophils are indispensable for host defense against invasive candidiasis, and neutropenia is a well-recognized risk factor for development of and adverse outcome after infection in humans Nonetheless, neutrophils have differential effects in invasive candidiasis in vivo depending on the phase of the infection in mice. Specifically, early neutrophil presence after infection is protective, whereas neutrophil presence late after infection is pathogenic Candida phagocytosis and secretion of a variety of pro-inflammatory cytokines and chemokines that orchestrate the antifungal innate immune response Candida compared to neutrophils; the lack of macrophage myeloperoxidase and extracellular trap formation may, at least in part, account for this deficit Candida effects in mice; yet, the importance of Candida-induced nitric oxide formation in human phagocytes is unclear Candida infection. In addition, future studies should aim to shed light on the relative role of recruited versus resident monocytes/macrophages in host defense against invasive candidiasis.Besides neutrophils, monocytes/macrophages are key phagocytic cells for protection against invasive candidiasis, as their depletion in mice leads to increased mortality Candida challenge, monocytes were recently shown to also confer protection following systemic Candida re-infection via functional reprogramming that involves the dectin-1/Raf-1 non-canonical signaling pathway and results in enhanced cytokine production Intriguingly, besides the protective role of monocytes/macrophages in host defense against primary Candida yeast and hyphal forms and respond differentially to the Candida morphotypes by priming the production of distinct cytokines + dendritic cells were recently shown to activate invariant natural killer T cells to mediate innate immune responses against fungi (including Candida) via dectin-1- and MyD88-dependent mechanisms without apparent requirement for fungal lipid antigen presentation Candida effects after systemic infection Candida-specific CD4+ T cells after systemic infection of mice vaccinated with the Als-derived peptide pALS Candida immunity could lead to the design of effective vaccination and immunomodulatory strategies against invasive and mucosal candidiasis in patients.The role of other hematopoietic cells in host defense against invasive candidiasis merits further investigation. For example, dendritic cells are able to phagocytize Candida killing capacity of human myeloperoxidase-deficient phagocytes, invasive candidiasis occurs in patients with myeloperoxidase deficiency, the most common inherited phagocytic disorder In agreement with the requirement of innate immunity for effective host defense in the mouse model of invasive candidiasis, certain innate immune factors have been associated with protection against the infection in humans Candida immunity in humans \u2212/\u2212Card9 and \u2212/\u2212dectin-1 mice are both susceptible to invasive candidiasis Click here for additional data file."}
+{"text": "Unfortunately, at present, degenerative retinal diseases such as retinitis pigmentosa remains untreatable. Patients with these conditions suffer progressive visual decline resulting from continuing loss of photoreceptor cells and outer nuclear layers. However, stem cell therapy is a promising approach to restore visual function in eyes with degenerative retinal diseases such as retinitis pigmentosa. Animal studies have established that pluripotent stem cells when placed in the mouse retinitis pigmentosa models have the potential not only to survive, but also to differentiate, organize into and function as photoreceptor cells. Furthermore, there is early evidence that these transplanted cells provide improved visual function. These groundbreaking studies provide proof of concept that stem cell therapy is a viable method of visual rehabilitation among eyes with retinitis pigmentosa. Further studies are required to optimize these techniques in human application. This review focuses on stem cell therapy as a new approach for vision restitution in retinitis pigmentosa. At present, degenerative retinal diseases such as retinitis pigmentosa (RP) and dry type age related macular degeneration (AMD) remain untreatable. Patients with these conditions suffer progressive visual decline resulting from continuing loss of photoreceptor cells and outer nuclear layers. Both disorders are characterized by the progressive dysfunction and death of the light sensing photoreceptors of the retina and other supportive cells. Because of the limited regenerative capacity of the mammalian retina, retinal progenitor cell are being developed to serve as \u201cspare parts\u201d for lost photoreceptor cells. Advances in molecular biology have identified innovative approaches that, for the first time, provide hope for permanent visual rehabilitation. Stem cell therapy can potentially replace lost photoreceptor and retinal pigment epithelial cell and subsequently restore visual function in eyes with degenerative retinal disorders .A potential target disease for stem cell therapy is retinitis pigmentosa (RP). RP is the most commonly inheritable eye disease that causes progressive loss of photoreceptor cells resulting in gradual visual decline. While the onset of RP may occur during infancy, the first symptoms are usually observed in early adulthood, beginning with nyctalopia or night blindness followed by loss of peripheral vision and eventually, as the central photoreceptors in the macula are damaged, loss of fine central vision. Morphologically, these retinas are characterized by centripetal proliferation of bone spicule-like pigmentation, attenuation of retinal blood vessels and optic nerve pallor . At leasTransplantation of progenitor stem cells that can be stimulated to become replacement photoreceptors and supportive outer retina cells can theoretically lead to treatments that restore visual function . RecentlTwo types of stem cells may be utilized to produce retinal progenitor cells. Firstly, Embryonic stem (ESC) and secondly, induced pluripotent stem (IPS) cells. Both types of cells are pluripotent and capable of becoming any cell type. ESC\u2019s are derived from embryos while IPS cells are obtained from a variety of adult tissues such as skin, bone marrow, teeth. IPS cells, if successfully implanted and optimized, can potentially provide an unlimited supply of stem cells for transplantation. Cell replacement is one approach for restoration of vision in RP. Because visual loss usually occurs when the outer retinal photoreceptor layer is lost, therapeutic timing should be at this stage of disease. Singh and colleagues have demonstrated using a murine model of severe human retinitis pigmentosa, that at a stage when no host rod cells are remaining, transplanted rod precursors can reestablish an anatomically distinct and appropriately polarized outer nuclear layer. In their study, restoration of a trilaminar retinal organization was restored to RD1 hosts with only two retinal layers before treatment. The introduced rod precursors continued to develop in the host niche to become mature rods complete with light-sensitive outer segments and connections to host neurons downstream. Visual function was also restored. These findings indicated that stem cell therapy may reinstate a light-sensitive cell layer de novo and restore structurally damaged visual circuits. In this model, total photoreceptor layer reconstruction is one approach to further develop cell-based strategies for retinal repair .ESC\u2019s have been shown to generate functional photoreceptor cells restoring light response of photoreceptor-deficient mice, but there is concern over the risk for tumor formation using ESC. Li and colleagues successfully cultured Nestin(+)Sox2(+)Pax6(+) multipotent retinal stem cells (RSCs) from the adult mouse retina. These ESC\u2019s are capable of producing functional photoreceptor cells that restore light response of photoreceptor-deficient RD1 mutant mice. After several cycles of expansion using growth factors, cultured RSCs still maintained proliferation and differentiation potential .Under optimized differentiation conditions, ESC\u2019s can differentiate into all the major retinal cell types found in the adult retina such as photoreceptor cells under optimized differentiation conditions. Following transplantation into the subretinal space of slowly degenerating RD7 mutant eyes, RSC-derived photoreceptor cells were shown to integrate into the retina, and develop into cells morphologically resembling endogenous photoreceptors and forming synapses with resident retinal neurons. When transplanted into eyes of photoreceptor-deficient RD1 mutant mice, an RP model, RSC-derived photoreceptors can partially restore light response, indicating functionality. In animal studies, no evidence for tumor development was found . Along similar lines, autologous IPS cells are being developed for stem cell transplantation. This lack of immunogenicity confers an important advantage. Because IPS cells are autologous or derived from the same organism, they do not incite immunological reaction nor require use of immunosuppressive medication . Li and colleagues recently transplanted human IPS cell-derived retinal pigment epithelium (RPE) cells into the subretinal spaces of mouse models with the Rpe65rd12 /Rpe65rd12 form of RP. A healthy adult provided skin fibroblasts cultured with lentivirus-delivered genes encoding transcription factors OCT4, SOX2, KLF4, and MYC. Antibody staining of markers  and a teratoma assay demonstrated pluripotency of the hiPS cells. Culturing in differentiation medium guided their fate to RPE. By 12 weeks, from 30% to 50% of the surfaces of 12-well dishes were coated with RPE with characteristic hexagonal shapes, perinuclear melanin granules, and microvilli [The target mice had albinism, which provided a white contrast against which the transplanted pigmented cells would be visible. The mice also had severe combined immune deficiency to prevent graft-vs-host disease. An injection of 1000 hiPS-derived RPE cells was administered into the subretinal space in the right eyes of 34 mice at two days following birth. The mice were sacrificed at six months, shortly before they would have died from severe combined immune deficiency .Successful development into RPE cells was indicated by: 1) microscopic confirmation of pigmented hiPS-derived RPE admixed into the native, albino RPE; 2) quantitative polymerase chain reaction detection of markers of human fetal RPE and IPS-derived RPE; 3) positive staining for rhodopsin indicating that the hiPS-derived RPE cells phagocytosed photoreceptors. Furthermore, in some mice, electroretinogram (ERG) response to measure neuronal function, demonstrated a small but significant improvement of mean \u03b2-wave peak difference between treated and control eyes of 13.7 \u03bcV P = 0.0246). Furthermore, no tumor growth was observed [. FurtherThe use of retinal progenitor sheet transplantation is another promising approach. Seller and Aramant demonstrated that when freshly dissected sheets of fetal-derived retinal progenitor cells are mixed with RPE and transplanted subretinally, improvements of visual acuity are observed among animals and humans. Visual improvement in this model is attributed to restoration of synaptic connections between transplant and host when transplant processes proliferate into the inner plexiform layer of the host retina and presumably form synapses. One drawback of widespread use of this method is limited supply of fetal donor tissue .Future areas for stem cell development include methods for optimizing stem cell production and delivery. The use of specific extracellular matrix can stimulate the development of human pluripotent stem cells into transient organized neuroepithelum with rapid differentiation into retinal progenitor cells . Garit-HPreviously, RP was considered a devastating and untreatable condition. These pioneering animal studies provide hopeful evidence for the hypothesis that stem cell therapy is a viable means for visual rehabilitation of RP patients. What is now known is that stem cell therapy can potentially replace degenerate photoreceptors and outer retinal cells. When placed in the appropriate tissue niche, these stem cells not only survive but differentiate into critical retinal cells, develop a retina-like organizational structure and exhibit functional characteristics of full-fledged photoreceptors and outer retinal cells. Further studies are needed to optimize techniques and validate these findings before proceeding to human trials. Conflicts of Interest: None declared."}
+{"text": "Bone plays metabolic roles through osteocalcin(OC) when it is released into the systemic circulation in uncarboxylated form. Identified novel metabolic roles of OC include increasing insulin secretion and sensitivity, energy expenditure, reduction of fat mass and mitochondrial proliferation and functional enhancement. The onset of puberty can be influenced metabolic factors. This study was aimed to determine serum OC levels in girls with central precocious puberty(CPP) and to investigate the effects of OC on the onset of puberty.Serum OC levels of girls CPP (n=30) and their age-matched controls (n=30) were measured. GnRH stimulation test was performed in CPP group. Bone age was determined in all subjects.Serum OC levels were significantly higher in CPP group compared with control group . Serum OC levels were correlated with peak LH levels during GnRH stimulation test , bone age  and bone age advance , but not related to age, height, weight and BMI.Serum OC seems to be associated with the onset of puberty leaving casual relations unresolved."}
+{"text": "To report a case of central serous chorioretinopathy after solar eclipse viewing.A middle-age man developed a sudden-onset unilateral scotoma after viewing a partial solar eclipse in Hong Kong. Fundus examination, fluorescein angiography, and optical coherence tomography showed features compatible with central serous chorioretinopathy. The patient was managed conservatively and reevaluated periodically. Serial optical coherence tomographic evaluations demonstrated an initial increase in the amount of subretinal fluid which spontaneously resolved 10 weeks after the onset of symptoms.This case demonstrates the possibility of development of central serous chorioretinopathy following solar eclipse viewing. Retinopathy following viewing of a solar eclipse without the use of safe eyewear has been well-documented in the literature. The usual lesion consists of mild foveal changes due to photochemical damage to the retina. Patients usually present with reduced visual acuity and a central scotoma. Classical findings on fundus examination include a yellow-white spot in the fovea surrounded by granular changes in the retinal pigment epithelium (RPE). Fundus fluorescein angiography (FA) may reveal a small central foveal window defect. Optical coherence tomography (OCT) may also demonstrate hypo- or hyperreflective lesions in the outer retina and RPE.4Central serous chorioretinopathy (CSCR) is an entity characterized by neurosensory retinal detachment with or without RPE detachment. Previous studies have reported the association of CSCR with various risk factors such as psychological stress, type A personality, pregnancy, untreated hypertension, use of corticosteroids, and psychopharmacologic medications.7Herein, we describe a rare case of CSCR after viewing a solar eclipse. To our knowledge, the association between CSCR and solar eclipse viewing has not been reported in the literature.A 44-year-old Caucasian man with good past health and unremarkable ophthalmic history presented with an acute-onset relative scotoma in his left eye after viewing a partial solar eclipse in Hong Kong on July 22, 2009.The patient was reassessed six weeks later and he still complained of a persistent central scotoma. Nonetheless, visual acuity remained stable. Fundus examination of the left eye showed an increase in subretinal fluid. OCT demonstrated an increase in the serous neurosensory retinal detachment . Ten weeTo the best of our knowledge, this is the first report describing acute CSCR after direct solar eclipse gazing. Unprotected sun-gazing, particularly during an episode of solar eclipse, is a well-known cause of solar retinopathy.Clinical features of CSCR include accumulation of subretinal fluid, neurosensory retinal and RPE detachment, and leakage with angiographic evidence of RPE hyperpermeability.The exact pathogenetic mechanism of CSCR in our case remains unclear. We hypothesize that intense sunlight was preferentially absorbed by melanosomes in the RPE, causing localized RPE damage and thus resulting in CSCR."}
+{"text": "In addition, no change in intracerebral incubation period was observed following active rumen digestion of unbound hamster HY TME prions and HY TME prions bound to a silty clay loam soil. These results demonstrate that both unbound and soil-bound prions readily survive rumen digestion without a reduction in infectivity, further supporting the potential for soil-mediated transmission of chronic wasting disease (CWD) and scrapie in the environment.Before prion uptake and infection can occur in the lower gastrointestinal system, ingested prions are subjected to anaerobic digestion in the rumen of cervids and bovids. The susceptibility of soil-bound prions to rumen digestion has not been evaluated previously. In this study, prions from infectious brain homogenates as well as prions bound to a range of soils and soil minerals were subjected to in vitro rumen digestion, and changes in PrP levels were measured via western blot. Binding to clay appeared to protect noninfectious hamster PrP Sc, a misfolded isoform of a normal cellular prion protein (PrPc) found in all susceptible species Sc exhibits resistance to proteolysis and inactivation, increased hydrophobicity, and a propensity for aggregation Sc can seed conversion of PrPc to PrPSc (\u2018replicate\u2019) and thereby initiate prion propagation and, presumably, disease infection Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases that afflict ruminants, including cattle , sheep and goats (scrapie), and deer, elk, and moose (chronic wasting disease or CWD), as well as humans (Creutzfeld-Jakob disease or CJD) Natural transmission of CWD and scrapie occurs primarily or exclusively through ingestion or inhalation of prion-contaminated material shed from infected hosts or present in mortalities Sc survives the digestive processes in the rumen and lower gastrointestinal system. Results from previous in vitro studies of PrPSc fate in rumen digestion have been varied. Scherbel and colleagues observed a near-complete loss of 263 K hamster PrPSc, as detected by western blot, following rumen digestion Sc in scrapie-infected sheep brain homogenates following exposure to rumen and other alimentary fluids Sc was detected post-digestion when precipitation and proteinase-K digestion were used prior to western blotting. An additional limited study found no evidence of scrapie PrPSc digestion in rumen fluids Sc.Prions are orally infectious Sc (both CWD-elk and hamster) has been shown previously Ingestion of prion-contaminated soil has been implicated as a likely mechanism of natural CWD and scrapie transmission Sc levels were measured by western blotting. Intracerebral hamster bioassay was also employed to measure changes in infectious titer. The results demonstrate the strong resistance of both unbound and soil-bound prions to rumen digestion, which further supports the efficacy of soil-bound prion ingestion as a natural route of disease transmission in ruminants.Adsorption of prions to soil may alter prion resistance to host degradation, thus potentially altering their oral infectivity and transmissibility. The objective of this research was to evaluate and compare the ability of rumen digestion to degrade unbound prions as well as prions bound to a range of soils and soil minerals. In vitro anaerobic digestion assays seeded by bovine rumen fluid were conducted, and the resultant PrPAll procedures involved in animal bioassay were approved by the Creighton University Institutional Animal Care and Use Committee and complied with the Guide for the Care and Use of Laboratory Animals. Collection procedures for rumen fluid from cannulated dairy cows was approved by the University of Nebraska-Lincoln Institutional Animal Care and Use Committee.++ or Mg++  using strain-dedicated Tenbroeck tissue grinders .Prion-infected brain tissue was collected without prior buffer profusion from golden Syrian hamsters infected with the hyper (HY) strain of transmissible mink encephalopathy (TME) as previously described Sc/PrPc and uninfected PrPc from brain homogenates were sorbed to a range of soils as described previously 2, Sigma Aldrich, St. Louis, MO) were used and have been described previously HY TME PrP2, 10% H2, and 5% CO2. Rumen fluid was diluted 1\u223610 or 1\u22365 in McDougall's buffer  with soluble carbohydrates . There was no difference in immunoblot results between 1\u223610 and 1\u22365 rumen\u2236buffer dilutions (data not shown).Standard in vitro rumen digestion assay methods were followed Resazurin dye  was used as an indicator of redox state and does not affect in vitro digestion Sc in digested and undigested samples was accomplished using SDS-PAGE/Western blotting as described previously without modification Detection of PrPIntracerebral inoculations of male golden Syrian hamsters  were conducted as described previously Two-tailed student's T-tests assuming unequal variances were performed using Microsoft Excel to determine statistical significance as noted. P values less than 0.05 were considered statistically significant.An in vitro digestion assay was employed to simulate rumen digestion of prion-contaminated material. Standard methods, including standard rumen fluid sampling procedures and substrate and buffer compositions, were used Sc from brain homogenate was not significantly reduced in actively digested samples compared to inactive and buffer controls .Unbound HY TME PrPSc following in vitro rumen digestion, but somewhat inconsistent with Scherbel et al. Sc degradation during active digestion in the absence of detergents. Methodological differences such as rumen fluid seed or western blotting techniques may be responsible for the observed differences. For instance, we collected rumen fluid from a live, cannulated dairy cow while Scherbel et al. collected fluid from a slaughtered beef bull.These results are consistent with the result of Nicholson and colleagues Sc was sorbed to a range of soils and soil minerals and exposed to in vitro rumen digestion. Consistent with the unbound results, HY PrPSc bound to silty clay loam (SCL) soil was not reduced following active rumen digestion (Sc bound to SCL soil demonstrated similar resistance to digestion (data not shown). Increased detection of PrPSc bound to bentonite clay (2)  and not a direct effect on PrPSc.To determine the effect of soil on the susceptibility of prions to rumen digestion, PrPabnormal , the lowSc was not detected on sand samples actively digested .HY TME bound to sandy loam (SL) soil and sand was susceptible to rumen digestion , and PrPdigested , lane 4.c from uninfected hamster brain homogenate  (data not shown). Since there is a well-established relationship between HY TME infectious titer and incubation period Sc levels before and after digestion in unbound and SCL soil-bound PrPSc (Hamsters were inoculated with unbound and SCL-bound HY TME prions subjected to either active or inactive (pre-autoclaved) in vitro rumen digestion. The incubation periods of hamsters inoculated with inactive or active samples were equal . The incnd PrPSc .Sc replication efficiency Also consistent with previous results, the mean incubation time of SCL soil-bound HY TME was significantly longer (13 d) than unbound HY TME  [27]. ThSc resistance to in vitro rumen digestion Sc abundance  To initiate infection via absorption across the lower gastrointestinal epithelium, orally ingested prions must survive passage through the rumen bundance , and conbundance . MoreoveSc resistance to digestion with respect to soil type, where, in contrast to the other soils and minerals, PrPSc levels bound to sand and sandy loam soil were reduced following digestion (2 is not significantly different than unbound prions (data not shown). Based on the established relationship between PMCA replication efficiency and infectious titer We did observe variance in PrPigestion . VariancA number of factors must be considered in extending the present results. First, the results were obtained using in vitro digestion, which is a simulation of in vivo processes with limitations Sc, it may alter PrPSc uptake efficiency, which would not be detected by immunoblot or intracerebral bioassay. Thus, study of soil-bound prions in, for example, the gut-loop system employed by Dagleish and Jeffery Finally, unbound and soil-bound prions surviving rumen passage will be exposed to stomach and intestinal digestion before uptake. These two processes are less complex than rumen digestion, and previous results indicate unbound prions are resistant to both Figure S1Sc without proteinase-K treatment.Rumen digestion of unbound HYTME PrP(DOCX)Click here for additional data file.Table S1PrP Adsorption to Soil and Soil Minerals.(DOCX)Click here for additional data file."}
+{"text": "Escherichia coli sepsis in baboons strongly induces procoagulant responses and affects the integrity of the lung. These effects are diminished by the treatment with compstatin, a C3 convertase complement inhibitor [Pulmonary fibrosis is a major and common medical condition, characterized by progressive scaring and decline in lung function. Persistent inflammation and acute lung injury in response to sepsis are potential triggers of the fibrotic response. Recently, we have reported that nhibitor .E. coli sepsis triggered metabolic and signaling pathways related to lung remodeling and fibrosis, and whether complement inhibition could attenuate these pathways.Here we used the baboon model described  in conjuE. coli challenge. Immunochemical and biochemical analysis reveals enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Compstatin treatment decreases sepsis-induced expression of extracellular matrix genes, including eight collagen genes. Sirius Red and immunofluorescence staining for procollagens 1 and 3 confirms the collagen deposition in the lung. Ingenuity\u00ae pathway analysis of transcriptomics data shows that compstatin treatment reduces sepsis-induced expression of genes involved in fibroblast transformation and connective tissue production, cell chemotaxis, migration and proliferation (see Table Microarray gene expression analysis shows that sepsis augments several fibrotic gene clusters in the lung as early as 24 hours post Our data demonstrate that bacterial sepsis initiates pulmonary collagen deposition, and complement inhibition effectively attenuates the fibrotic response. This suggests that complement inhibitors could be used for prevention of sepsis-induced pulmonary fibrosis."}
+{"text": "Endogenous retroviruses (ERVs) have much lower mutation rates than exogenous retroviruses (XRVs), therefore they are an important tool in analysing the long-term evolutionary history of retroviruses. Their transmission patterns also act as useful markers when studying host phylogenetics.[Oryctolagus cuniculus) [Lepus europeaus) [Microcebus murinus) [Cheirogaelus medius) [gamma- and beta- retroviruses, which are present in many vertebrate species The aim of this project is to look for and characterise further examples of primate ERVs and therefore gain insight into the evolutionary history of retroviruses and their primate hosts. This will involve data mining of primate genomes for previously unknown ERVs as well as PCR based screening of genera for which genome sequences are not available. Preliminary work suggests that prosimian primate genomes contain previously unclassified endogenous lentiviruses, so PCR-based screening will be used with DNA samples from lemurs, bushbabies and lorises to sequence and characterise these viruses.Recently, the first examples of endogenous lentivirus were characterised. The earliest was rabbit endogenous lentivirus type K in the European rabbit pol), group-specific antigen (gag) and envelope (env) genes of representative XRVs from all known retroviral genera were used to identify regions of the host genome which are highly similar to retroviral genes. We have validated this method by successfully searching the human genome for known ERV insertions. Regions of interest are then extracted and analysed in detail.The bioinformatics analysis component of this project used Exonerate  to perfopol gene  on sampM. murinus genome sequence identified 3542 ERV-like regions. This included 256 regions of less than 10,000 base pairs which incorporated gag, pol and env-like sequences in the correct orientation. The subset of pol genes which were within these 256 proviruses appear to be closely related to known gamma- and beta-retroviruses from other species.Bioinformatics analysis of the low-coverage Varecia variegata, Eulemur rufus and Mirza coquereli; the loris Perodictus potto and the bushbaby Galago moholi, although these insertions are yet to be further characterised.Preliminary laboratory work has shown previously uncharacterised lentiviral insertions in several species of lemur - murinus genome. Preliminary laboratory results suggest that there are undescribed endogenous lentiviruses in further prosimian primate species. Methodology has been established which can be used to screen further species for proviral insertions and to explore these in detail.Multiple potential ERV sequences have been found in the M."}
+{"text": "Entropy is an elusive and somehow non-intuitive concept. Nevertheless, entropy governs spontaneous thermodynamic processes as important contribution to Gibbs Free Energy. Information theory defines Shannon entropy as a measure for uncertainty. In the context of protein binding the inherent link between flexibility, thus conformational entropy, and substrate specificity is discussed. Substrate promiscuity of proteases is quantified as cleavage entropy correlating local binding site flexibility directly with substrate readout. Caspases are examined as example protease family, where active site dynamics play a major role in mediating substrate specificity. Direct comparison of entropy in substrate data allows highlighting previously unexpected similarities in substrate recognition in proteases. Promiscuous binding to several protease targets demonstrates the emerging importance of quantitative studies on binding specificity. Shannon entropy applied to probability densities is used to rationalize ordering or disordering by binding processes. We have developed a data-driven method to reconstruct probability densities from discrete sampling by computer simulations. Application to solvent degrees of freedom leads to excellent correlation with experimental data."}
+{"text": "Bisphenol A (BPA) is a chemical widely used to make polycarbonate plastics and epoxy resins lining food and beverage containers. A number of in vitro and in vivo studies have demonstrated that BPA has an estrogenic effect by binding to the nuclear estrogen receptor, and early BPA exposure could in induce early puberty. However, effects of human exposure to BPA on pubertal onset and the association of gonadotropin levels have not been fully evaluated. We aimed to study whether serum bisphenol A levels are associated with central precocious puberty (CPP) in Korean children.A total of 103 girls  were enrolled. Pubertal staging, anthropometry, bone maturation were assessed. Gonadotropin releasing hormone-stimulation test were conducted to determine the basal and peak levels of luteinizing hormone (LH). Serum bisphenol A levels were analysed by gas chromatography/mass spectrometry method. Geometric mean serum BPA levels were higher in CPP girls than in controls . In partial correlation analysis controlling for age and body mass index, serum BPA level showed significant positive correlation with bone age , fat mass , waist circumference , basal LH levels , and peak LH levels . Bone age, height, basal/peak LH levels and prevalence of CPP increased significantly with increasing tertile of serum BPA. Increased risk of CPP [Odds ratio] was observed across increasing serum BPA tertile  after adjusting for age and BMI.Serum BPA level was higher in CPP girls compared with controls, and higher serum BPA level was associated with increased risk of CPP. Prospective studies are needed to determine potential causal links between BPA exposure and CPP."}
+{"text": "We present a case of myocardial infarction in a 19 year old female with cystic fibrosis who had a heart and lung transplant performed at the age of four years old. She presented atypically with a one day history of severe, intermittent, central, sharp chest pain, radiating to her back and down her left arm. A coronary angiogram showed proximal stenosis of the left anterior descending artery and right coronary artery. She was treated with percutaneous coronary intervention, involving drug eluting stents to the left anterior descending artery (LAD) and the right coronary artery (RCA). In this study we discuss the pathophysiology, investigations and treatment of cardiac transplant vasculopathy. Although complete reversal of LAD and RCA stenosis was achieved, routine follow-up with coronary angiography and careful control of cardiac risk factors will be important to identify and reduce future restenosis and adverse cardiac events. Heart and lung transplantation in children with cystic fibrosis (CF) and end-stage lung disease are now rarely performed, with bilateral sequential lung transplantation (BSLT) being the preferred procedure . AlthougA 19 year old female with CF who had a heart and lung transplantation in 1997 presented to the Emergency Department (ED) with a one day history of severe, intermittent, central, sharp chest pain, radiating to her back and down her left arm. This was associated with intermittent paraesthesia, pallor and coldness in her left hand. The chest pain was worse on deep inspiration but was not positional or exacerbated by movement. Over the previous four weeks she had been having a productive cough with a reduced exercise tolerance but no chest pain.9/L), creatinine (138 \u03bcmol/L) and urea (12.8 \u03bcmol/L).On examination there was no swelling, pallor or erythema of her left arm/hand and no chest wall tenderness. She was well perfused with a regular pulse and a stable blood pressure. No murmur or added heart sound was present and vesicular breath sounds were heard on auscultation. A chest radiograph showed no acute changes and an initial electrocardiogram (ECG) taken in the ED showed a sinus tachycardia with no ST or T wave changes. Initial blood tests were normal apart from an elevated white cell count  was 10,801. A computed tomography pulmonary angiogram (CTPA) the following day showed no pulmonary embolus (PE) and no vascular abnormalities. A coronary multi-slice computed tomography (MSCT) was not performed as it is not used as an investigation of acute MI in inpatients at St James\u2019s University Hospital.Later that day the patient was reviewed by a cardiology registrar who performed a bedside echocardiogram. This demonstrated moderate left ventricular impairment due to extensive apical akinesis and anterior/antero-septal hypokinesis with an ejection fraction of 42%. No valvular dysfunction was identified. That evening the patient received percutaneous coronary intervention (PCI) which illustrated a 95% proximal stenosis of the left anterior descending artery (LAD), normal left circumflex artery (LCx) and 80-95% proximal stenosis of the right coronary artery (RCA) Figure\u00a0. Drug elCardiac transplant vasculopathy (CTV) is a rapidly progressive form of atherosclerosis involving thickening of the intima, leading to stenosis of coronary artery grafts and subsequent myocardial ischaemia . It is gThe development of CTV is thought to be due to a combination of an immune-mediated process and non-immunologic risk factors resulting in endothelial injury and subsequent fibroelastic proliferation of the intima . Risk faThe diagnosis of CTV is particularly challenging as it rarely presents with typical angina, despite 10-30% of patients with heart transplants having partial reinnervation . HoweverIn many transplant centres, patients with heart transplants receive annual coronary angiography. However, due to the diffuse nature of CTV, angiography may underestimate the severity of disease or miss it completely . The patThe gold standard investigation of CTV is intravascular ultrasound (IVUS) which has the ability to assess the amount of intimal thickness and identify vessel wall morphology . A studyA number of non-invasive radiological modalities (e.g. dobutamine stress echocardiography (DSE), myocardial perfusion imaging (MPI) and multislice computed tomography (CT) coronary angiography) have also been utilized to assist in the diagnosis of CTV, with variable degrees of sensitivity and specificity . A pilotThe most effective treatment of CTV is prevention and modification of risk factors using antihypertensive agents , statins (e.g. pravastatin) and strict diabetic control. Coronary artery bypass grafting is rarely an option in CTV due to the diffuse nature of the disease process and the limited availability of donor hearts makes re-transplantation unlikely. In patients with heart transplants presenting with chest pain  or features of congestive heart failure, if the ECG or echocardiogram show ischaemic changes or wall motion abnormalities, acute coronary syndrome should be suspected and patients should be treated accordingly with antiplatelet agents and PCI .A systematic review of six small, retrospective, nonrandomised studies comparing the use of bare-metal stents (BMS) with drug-eluting stents (DES) in the treatment of CTV (328 lesions treated with BMS and 287 lesions treated with DES) showed that DES were associated with a lower restenosis rate at 6\u201312 months, but in only half of the six studies were the differences statistically significant . There wA recent retrospective nonrandomised study involving 34 patients receiving a total of 46 stents (27 DES vs 19 BMS) is the first to suggest a clinical benefit  with DES compared to BMS in the treatment of CTV . RandomiMaintenance immunosuppression following heart transplantation usually consists of a triple therapy of corticosteroids , a calcineurin inhibitor (CNI) (cyclosporine or tacrolimus) and an antiproliferative agent . AzathioTacrolimus and cyclosporine have failed to demonstrate prevention of CTV after heart transplantation and there appears to be little difference between these CNIs in terms of long-term development of CTV . HoweverIn terms of CTV prevention, the optimum maintenance immunosupression regime is unclear and a long-term randomised trial is required to determine this. The maintenance immunosupression regime following heart and lung transplantation for the patient in this case consisted of tacrolimus and prednisolone without the use of an antiproliferative agent. There was no change in the maintenance immunosupression regime post MI.MI must be considered in young patients with CF and a heart and lung transplant with atypical chest pain. Although complete reversal of LAD and RCA stenosis was achieved in this case with the use of PCI and DES, routine follow-up with coronary angiography and careful control of cardiac risk factors will be important to identify and reduce future restenosis and adverse cardiac events.Written informed consent was obtained from the patient for publication of this case report and any accompanying images.BMS: Bare-metal stents; BSLT: Bilateral sequential lung transplantation; CF: Cystic fibrosis; CFRD: Cystic fibrosis related diabetes; CMV: Cytomegalovirus; CNI: Calcineurin inhibitor; CTV: Cardiac transplant vasculopathy; DES: Drug eluting stents; DSE: Dobutamine stress echocardiography; ECG: Electrocardiogram; ED: Emergency Department; CTPA: Computed tomography pulmonary angiogram; IVUS: Intravascular ultrasound; LAD: Left anterior descending artery; LCx: Left circumflex artery; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PE: Pulmonary embolus; RCA: Right coronary artery; MPI: Myocardial perfusion imaging; CT: Computed tomography.The authors declare that they have no competing interests.JE and DP were both involved in the management of the case. JE wrote the case report with assistance from DP. Both authors read and approved the final manuscript."}
+{"text": "The patient with a history of bone pain and muscle weakness, was thought to have oncogenic osteomalacia as a result of biochemical investigations and directed to Nuclear Medicine Department for a whole-body bone scintigraphy and 111In-octreotide scintigraphy. There was no focal pathologic tracer uptake, but generalized marked increase in skeletal uptake on bone scintigraphy. Octreotide scintigraphy showed accumulation of octreotide in the region of the left lobe of the thyroid gland in the neck. Thereafter, parathyroid scintigraphy was performed with technetium-99m labeled metroxy-isobutyl-isonitryl (99mTc-MIB) and MIBI scan demonstrated radiotracer uptake at the same location with octreotide scintigraphy. The patient underwent left inferior parathyroidectomy and histopathology confirmed a parathyroid adenoma. Somatostatin receptor positive parathyroid adenoma may show octreotide uptake. Octreotide scintigraphy may be promising and indicate a possibility of using somatostatin analogues for the medical treatment of somatostatin receptor positiveConflict of interest:None declared. HowevA 48-year-old woman was presented to our department with history of bone pain, muscle weakness. Biochemical investigations showed hypophosphatemia ; increased alkaline phosphatase ; normocalcaemia  supporting hypocalcaemic onkogenic osteomalacia.Whole body bone scintigraphy was performed after intravenous administration of 20 mCi (740 MBq) of methyleno-diphosphonate labeled with technetium-99m (Tc- 99m MDP). Bone scan showed metabolic bone disorder featured by the following characteristics: Prominent tracer uptake in the calvarium, mandible, spine, rib, and bilateral femora; intense uptake at the costochondral junctures and faint kidney visualization . BesidesParathyroid adenoma is part of a spectrum of parathyroid proliferative disorder that includes parathyroid hyperplasia, parathyroid adenoma and parathyroid carcinoma . Eighty Patients with primary hyperparathyroidism may present clinical evidence of elevated serum calcium levels which include non-specific symptoms such as fatigue, pain and weakness as well as polydipsia, polyuria, and nephrolithiasis . SonograSome studies also have suggested a role for somatostatin analogues in the medical treatment of hyperparathyroidism ,12,13. FIn conclusion, when a focal uptake was observed in the region of the thyroid gland on octreotide scintigraphy, the presence of parathyroid adenoma should also be considered. Parathyroid tumors expressing somatostatin receptors may show octreotide uptake and octreotide scan may be promising and indicate a possibility of using somatostatin analogues for medical treatment of somatostatin receptor positive parathyroid tumors in some situations which surgery is not possible and parathyroid tumor recurrence."}
+{"text": "Dear Editor,Atrial fibrillation (AF) is one of the most frequent complications after cardiac surgery. It occurs in approximately 20% to 35% of patients after coronary artery bypass graft (CABG) surgery and in more than 50% of patients after valve surgery . AF afteAlthough many of potential risk factors for development of post-operative AF have previously been demonstrated in cardiac surgery patients ; the resRegarding the relatively high prevalence of opium abuse among patients undergoing cardiac surgery and considering its potential role in prediction of AF after cardiac surgery, anesthesiologists and cardiac surgeons should provide better preventive measures when planning surgery in opium addict patients. Since most of the studies performed in this field were retrospective, with inherent limitations, future prospective studies are needed to confirm this association."}
+{"text": "In the traditional view on brain activity dynamics, the cognitive flow of information wanders through multiple stable states driven by task-dependent inputs -3. This It has been recently proposed that such transient states are basically shaped by anatomical connectivity and transitions between them occur even in the absence of external stimuli : Noise eA different metaphor of transient brain dynamics was proposed by Rabinovich and colleagues . In suchIn this work we develop an empirical criterion to discern whether observable neural ensemble activity can be originated by non-autonomous yet deterministic dynamical systems or rather by stochastic fluctuations between temporally attracting states. Towards this goal, we used in vivo multiple single-unit recording in rodent frontal cortex during a decision making task. Effective dynamics of neural activity is first empirically reconstructed in nonlinear state spaces . Then, tUnderlying dynamics of recorded ensemble activity is probably driven by a slowly drifting, non-autonomous dynamical system containing low-order nonlinear interactions."}
+{"text": "Colorectal cancers are the third most common type of cancers globally, affecting both sexes . As of nNine normal and 25 tumoral colon tissue sections (3mm diameter x 10 \u00b5m thick) embedded in the form of paraffinized tissue microarray, stabilized in an agarose matrix were analyzed directly by IR imaging. To avoid chemical deparaffinization, a modified Extended Multiplicative Signal Correction (EMSC) method[EMSC permitted mathematical correction of the spectral interferences originating from paraffin and agarose. K-means classification allowed to identify and to distinguish important histological features of the colonic tissues such as crypts, lamina propria, tumor, etc. When compared to HPS stained images, after whole slide image analyzed with crop and score Calopix module from TRIBVN or through pathologist control, color-coded spectral images not only reveal features representative of the biochemical make up of the tissues, but also highlight additional features like intra-tumoral heterogeneity and tumor-associated stroma, which are difficult to discern by conventional histopathology. The LDA prediction model was promising since an average sensitivity of 91 % was achieved in the identification and prediction of tumoral tissues.IR imaging allowed differentiating and detecting normal and tumoral colon tissue features based on their intrinsic biochemical information. This chemical-free approach on paraffinized tissue biopsies combined with multivariate statistical image analysis opens a new avenue for numerical spectral histopathology and appears as a promising tool for colon cancer diagnosis. Further work to improve the model and to predict tumors in blind samples is ongoing."}
+{"text": "The regulation of gene expression plays a pivotal role in complex phenotypes, and epigenetic mechanisms such as DNA methylation are essential to this process. The availability of next-generation sequencing technologies allows us to study epigenetic variation at an unprecedented level of resolution. Even so, our understanding of the underlying sources of epigenetic variability remains limited. Twin studies have played an essential role in estimating phenotypic heritability, and these now offer an opportunity to study epigenetic variation as a dynamic quantitative trait. High monozygotic twin discordance rates for common diseases suggest that unexplained environmental or epigenetic factors could be involved. Recent genome-wide epigenetic studies in disease-discordant monozygotic twins emphasize the power of this design to successfully identify epigenetic changes associated with complex traits. We describe how large-scale epigenetic studies of twins can improve our understanding of how genetic, environmental and stochastic factors impact upon epigenetics, and how such studies can provide a comprehensive understanding of how epigenetic variation affects complex traits. The term epigenetics was originally introduced to describe how interactions between genetics and environment can give rise to phenotypes during development de novo methylation and the maintenance of methylation patterns during replication Epigenetic mechanisms are present in many taxa, but DNA methylation has been most extensively studied in mammals where it appears to be restricted to the cytosine base, and especially in the context of CpG dinucleotides. CpG dinucleotides are cytosine\u2013phosphate\u2013guanine sequences that typically cluster in genomic regions referred to as CpG islands (CGI), which are often located in gene promoters and exhibit low levels of DNA methylation. However, DNA methylation in mammals can also occur outside the CpG context, and this has been reported for example in embryonic stem cells H19 locus control imprinting and gene expression at the maternally imprinted and transcriptionally-silenced insulin-like growth factor II (IGF2) locus and at the paternally imprinted and silenced H19 region de novo DNA methylation has also been suggested  twins are traditionally regarded as genetically identical, therefore any phenotypic differences within MZ twin pairs are classically attributed to environmental factors. However, epigenetic variants can also associate with phenotypic differences, and the identification and interpretation of such associations is currently an important area of research. Epigenetic studies of disease-discordant MZ twins, who are completely matched for genetics, age, sex, cohort effects, maternal influences and common environment, and are closely matched for other environmental factors, should be considerably more powerful in detecting disease-related epigenetic differences than epigenetic studies of unrelated disease cases and controls with different life-histories. In the following sections we consider the value of twin studies in epigenetics and discuss recent findings highlighting the possibility that epigenetic variation can be transmitted through generations and impact upon common diseases.Heritability is the proportion of the phenotypic variance in the population that is attributed to genetic variation. Heritability estimates are traditionally obtained by comparing the extent of similarity between relatives in classical twin studies, twin-adoption studies, sib/half-sib studies, and transgenerational family studies. Each has weaknesses, but for most traits twin studies are generally regarded as the most reliable because they are unbiased by age effects and offer the ability to separate common environment from genetic effects post hoc in twins who differed most in lifestyle. However, the study was cross-sectional instead of longitudinal, potentially obscuring comparison of individual variability; furthermore, comparing epigenetic patterns in fast-growing children and adults might not be generalizable to the aging process. To this end, a recent longitudinal study of twin epigenetic heritability assayed DNA methylation patterns in the promoters of three genes in 46 MZ and 45 DZ twin pairs sampled at 5 and 10 years of age Several studies have examined DNA methylation patterns in twins. Early work focused on X-chromosome inactivation patterns in females \u2013 where one X chromosome is inactivated at random and the silent state of the inactive X-chromosome is maintained by DNA methylation IGF2) gene and the paternally imprinted H19 region, estimating high epigenetic heritability in those regions using multiple tissues from 182 newborn MZ and DZ twins Substantive evidence for epigenetic heritability has been obtained from further studies of age-matched twins using larger samples Overall, these findings confirm that DNA methylation is a heritable trait on a genome-wide basis, but also highlight the importance of taking age into account when studying epigenetic processes. Furthermore, the results are consistent with recent population-based findings of quantitative trait loci (QTL) for DNA methylation DNA methylation patterns can be affected by genetic variation, environmental changes, heritable and non-heritable changes in other epigenetic processes , and stochastic changes over time. All these factors can contribute to DNA methylation heritability estimates, which are therefore time-, tissue-, locus- and population-specific. There are three further important aspects of epigenetic heritability. First, does twin epigenetic heritability reflect stability in methylation transmission during mitosis and meiosis? Second, does epigenetic variation contribute to phenotype heritability? Finally, how do epigenetic heritability findings relate to time-dependent methylation changes?In mammals, maintenance DNA methyltransferases and histone methyltransferases ensure propagation of epigenetic marks through mitotic cell divisions with high fidelity  in two discordant or concordant pairs of schizophrenic twins; this study found greater methylation differences between discordant MZ twins than in unrelated cases Recently, several epigenetic studies of MZ discordant twins have examined differences in DNA methylation profiles, aiming to identify differentially methylated regions (DMRs) in human disease The power of discordant MZ twin studies to detect DMRs will depend on a number of factors, including the effect size of the epigenetic change on the phenotype, the similarity of methylation profiles between MZ twins, sample size, and the sensitivity and coverage of the methylation assay. An estimate of the power of the discordant MZ twin design for a specific microarray methylation assay There are several aspects of epigenetic studies where twins present novel opportunities to understand the biology and the mechanisms underlying complex traits. We suggest a few examples.http://www.muther.ac.uk/), which aims to assay gene expression variation in multiple tissues in twins and to identify regulatory genetic variants, can be linked with epigenetic data to explore the tissue specificity and functional consequences of epigenetic variation in twins. This project is being extended to RNA sequencing (via the EUroBATS project), and this will also allow differential allelic expression to be explored. Allele-specific expression (ASE) patterns are relatively common and are under strict genetic control Twin resources such as the MuTHER (multiple tissue human expression resource) project  affect epigenetics. ARTs include IVF and related technologies http://www.twinsuk.ac.uk/) aims to discover methylated genes responsible for discordance of ten common traits and diseases. The study is using MeDIP-seq on blood samples to assay epigenomic differences in 5000 adult UK twins aged 16\u201385, discordant and concordant for a wide variety of diseases and environments. Next-generation sequencing, although currently at significant cost, has the potential to prove powerful in detecting disease-related methylation differences at a high level of resolution in a sample of this size. Another ongoing large-scale prospective study consists of a cohort of Australian newborn twins http://www.euengage.org/), where MeCAP-seq is being performed by sample pooling across multiple traits in discordant twins.A recent large-scale study (EpiTwin \u2013 Two further areas that can benefit from the epigenetic differences observed in MZ twins are forensic science and medical transplantation. Although twins are no more likely to be criminals than the general population, one in 250 people are MZ twins and legal cases involving MZ twins are high-profile. For example, the genetic identity of MZ twins can allow twins to provide each other with alibis in criminal cases. Differences in epigenetic profiles between MZ twins, if consistently replicated, could in future lead to closing this loophole. In transplantation there are reports of occasional graft failures in identical twins. Studying subtle differences in twin epigenetic profiles could improve transplantation outcomes, where small epigenetic changes of immune-related genes in the host or in transplanted organs could affect transplant success The study of epigenetic profiles in twins offers an excellent opportunity to understand the causes and consequences of epigenetic variation. Twin epigenetic heritability estimates tell us about the genetic control of DNA methylation variability and the stability of methylation patterns during cell division. The contribution of epigenetic variants to complex phenotypes can be assessed using disease-discordant MZ twins who are otherwise matched for genetics, age, sex, cohort effects, maternal effects and a common environment. These twin designs are considerably more powerful discovery tools than studies on singletons. In the near future, large-scale epigenetic studies in twins across different ages, tissues, and diseases will improve our understanding of the etiology and mechanisms of a wide range of common complex traits and diseases."}
+{"text": "Vaccination strategies capable of eliciting neutralizing antibody responses to HIV remain elusive despite extensive efforts. Alternative antibody functions offer opportunities for protection without necessarily achieving broad neutralization breadth. Viral immune exclusion through aggregation has been proposed as an alternative protection pathway, but mechanisms for studying this phenomenon at the scale necessary for clinical trials have not been explored.Concentrated fluorescent virions of two colors, suspended in hydroxyethylcellulose (HEC) gel, which has been formulated to simulate the diffusion characteristics of cervical mucus, are imaged over time. Mean squared displacement and incidence of colocalized viral particles are determined. The addition of monoclonal antibodies of various specificities and isotypes affects these parameters is explored. Immunoglobulin isolated from HIV-1 positive individuals was examined as well. Correlative scanning electron micrographs of the same preparations were performed to confirm the nature of suspected aggregates.Multimeric antibodies, rather than monomeric isoforms, selectively hinder the diffusion characteristics of colocalized virions, more so than non-aggregated virions. The incidence of colocalized virions is also increased in a concentration dependent manner. Excessive antibody or virus concentration is seen to obviate aggregate formation. These results are seen in both monoclonal antibody experiments alongside polyclonal patient IgA isolated from breast milk and IgM from serum.Virus aggregation has been demonstrated as a feasible effector function of HIV-1 specific antibody preparations. This assay platform is amenable to adaptation for medium to high throughput sample screening and low sample size. Monoclonal antibodies as well as patient samples are able to induce similar behaviors. Measurement of viral aggregation as a corollary of vaccine efficacy is deserving of further exploration in a clinical setting."}
+{"text": "The resulting adducts were fully characterized by spectroscopic and analytical methods; they constitute interesting substrates for further organic transformations.The chemical behaviour of various alkyl-substituted, acyclic conjugated bisallenes in reactions involving polar intermediates and/or transition states has been investigated on a broad scale for the first time. The reactions studied include lithiation, reaction of the thus formed organolithium salts with various electrophiles , oxidation to cyclopentenones and epoxides, hydrohalogenation , halogenation (Br"}
+{"text": "X-linked hypohidrotic ectodermal dyplasia (XLHED) is the most common form of ectodermal dysplasia. It often presents with ocular symptoms, already in early childhood. Multiple ophthalmological tests are available, but in early childhood only tests of lower invasiveness can be applied. We have evaluated tear film tests and ocular surface staining as screening methods in pediatric patients with signs of ectodermal dysplasia. These tests may also be used in adults with confirmed XLHED to determine the severity of ocular surface disease.Twelve children and 14 adults with XLHED were subjected to a panel of tests including the ocular surface disease index (OSDI), non-invasive measurement of tear film break-up time (NIBUT), osmolarity, Schirmer test, lissamine green staining, fluorescein staining, meibography and infrared thermography. Sensitivity and specificity were determined for single tests and selected test combinations. For adults with XLHED, OSDI, NIBUT and osmolarity were the best single routine tests . Their combination increased the sensitivity to 92.8%. Meibography yielded optimal results (100% sensitivity and specificity). Infrared thermography revealed a typical pattern for XLHED. In children with XLHED, NIBUT or OSDI were the most convincing single tests , combination of which increased the sensitivity to 100%. More invasive tests such as meibography and infrared thermography led to good results if they were tolerated.Tear film tests can help to establish an early diagnosis in individuals with suspected XLHED, even before genetic test results are available. Meibomian gland disorder and resulting hyperevaporative dry eye are typical features of XLHED. Once the diagnosis is made, tear film tests are an important instrument to establish an effective therapy of dry eye disease."}
+{"text": "Spinal cord injury (SCI) causes chronic peripheral sensitization of nociceptors and persistent generation of spontaneous action potentials (SA) in peripheral branches and the somata of hyperexcitable nociceptors within dorsal root ganglia (DRG). Here it is proposed that SCI triggers in numerous nociceptors a persistent hyperfunctional state  that originally evolved as an adaptive response to compensate for loss of sensory terminals after severe but survivable peripheral injury. In this hypothesis, nociceptor somata monitor the status of their own receptive field and the rest of the body by integrating signals received by their peripheral and central branches and the soma itself. A nociceptor switches into a potentially permanent hyperfunctional state when central neural, glial, and inflammatory signal combinations are detected that indicate extensive peripheral injury. Similar signal combinations are produced by SCI and disseminated widely to uninjured as well as injured nociceptors. This paper focuses on the uninjured nociceptors that are altered by SCI. Enhanced activity generated in below-level nociceptors promotes below-level central sensitization, somatic and autonomic hyperreflexia, and visceral dysfunction. If sufficient ascending fibers survive, enhanced activity in below-level nociceptors contributes to below-level pain. Nociceptor activity generated above the injury level contributes to at- and above-level sensitization and pain (evoked and spontaneous). Thus, SCI triggers a potent nociceptor state that may have been adaptive (from an evolutionary perspective) after severe peripheral injury but is maladaptive after SCI. Evidence that hyperfunctional nociceptors make large contributions to behavioral hypersensitivity after SCI suggests that nociceptor-specific ion channels required for nociceptor SA and hypersensitivity offer promising targets for treating chronic pain and hyperreflexia after SCI. My focus is on the many uninjured nociceptors that are chronically altered by SCI and positioned to help drive below-level and at-level pain.Neuropathic pain in general and spinal cord injury (SCI) pain in particular are usually viewed as maladaptive consequences of neural injury , sprout new branches within the dorsal horn after SCI, which potentially could lead to more extensive nociceptive input to dorsal horn neurons  3 days to 8 months after SCI compared to what has been reported (0\u201320%) for dissociated small DRG neurons sampled from rats with peripheral neuropathy   under these quite different conditions  can be triggered in nociceptors by a combination of events after SCI that mimic patterns of signals used by nociceptors to recognize particularly severe e Figure . I then Long-lasting changes in intrinsic functional properties of primary sensory neurons are likely to depend upon changes in gene expression in these neurons  to the nociceptor's own branches. This includes immediate injury discharge and both positive injury signals , and negative injury signals  transported from damaged axons to the nucleus , which are unlikely to have axons projecting close enough to the lesion to experience axotomy or other forms of direct damage     are conveyed directly to cells within the DRG after peripheral injury/inflammation and after SCI Figure . Periphe2)  that avoids apparent tissue inflammation produce behavioral hypersensitivity for at least 1 month afterwards, which is accompanied by Nav1.8 upregulation and is dependent upon Nav1.8 expression, suggesting a key role for intrinsically altered nociceptors  continuing release of extrinsic signals, such as inflammatory mediators, that continuously refresh the hyperfunctional state, (2) positive feedback loops between nociceptor activity and inflammatory and retrograde synaptic effects, and (3) switching of the nociceptor into a potentially permanent intrinsic hyperfunctional state that remains after the extrinsic induction signals fade (\u201cnociceptor memory\u201d). First, widespread inflammation may persist chronically after SCI . Somata of nociceptors identified thus far in vertebrates, molluscs, and annelids are often located centrally, distant from their peripheral receptive fields, which ensures that these cells can survive sublethal injury that destroys their peripheral branches. In the mollusc, Why haven't chronic, somally expressed HSA states in nociceptors been reported previously in mammalian models of long-lasting pain? Few chronic studies have tested somal excitability in nociceptors, or recorded under conditions where nociceptor SA generated in the DRG could be distinguished from SA generated peripherally. Moreover, most studies of dissociated nociceptors have examined ionic currents under voltage clamp, without testing for somal hyperexcitability or SA. In addition, common models of long-lasting pain, including models based on cutaneous injection of inflammogens, surgical incision models (which produce relatively little inflammation or nerve damage), and various nerve injury models may not mimic adequately severe peripheral injuries that involve extensive amounts of tissue destruction  combined with prolonged inflammation\u2014i.e., the traumatic conditions most likely to result in chronic pain in humans. Thus, while standard pain models produce many sensitizing effects on nociceptors  and other hyperfunctional alterations in nociceptors contribute significantly to human at- and below level pain, as well as to hyperreflexia and visceral problems after SCI, pharmacological agents that selectively target nociceptor hyperexcitability should be clinically useful. A number of genes important for excitability are preferentially expressed in nociceptors, raising the possibility that blocking their function could ameliorate some of the suffering caused by SCI while producing minimal side effects. Indeed, preliminary results show that SA in dissociated nociceptors depends upon nociceptor-specific Nav1.8 channels, and indicate that knocking down the expression of these channels can attenuate behavioral hypersensitivity after SCI (Yang et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Daphnia magna) \u2013 bacterium (Pasteuria ramosa) system typifies such specificity and high virulence. We studied the North American host Daphnia dentifera and its natural parasite Pasteuria ramosa, and also found strong genetic specificity for infection success and high virulence. These results suggest that Pasteuria could promote Red Queen dynamics with D. dentifera populations as well. However, the Red Queen might be undermined in this system by selection from a more common yeast parasite (Metschnikowia bicuspidata). Resistance to the yeast did not correlate with resistance to Pasteuria among host genotypes, suggesting that selection by Metschnikowia should proceed relatively independently of selection by Pasteuria.The Red Queen hypothesis can explain the maintenance of host and parasite diversity. However, the Red Queen requires genetic specificity for infection risk  and strongly virulent effects of infection on host fitness. A European crustacean ( R0 when all else is equal, Genetic specificity between hosts and their parasites shapes the ecology and evolution of infectious disease Daphnia magna and its sterilizing bacterial parasite Pasteuria ramosa exemplify genetic specificity Pasteuria \u2013 the physical attachment of spores to the host oesophageal wall Pasteuria inflicts high virulence on infected hosts through sterilization Pasteuria epidemics can become large D. magna-Pasteuria system The European freshwater crustacean Pasteuria could maintain genetic diversity in other susceptible host species. Therefore, Pasteuria could act as a general catalyst of Red Queen-driven coevolution in freshwater systems. To test this possibility, we looked for genetic specificity for infection with Pasteuria in a natural North American host, Daphnia dentifera, using an established experimental design Pasteuria castrates its European D. magna hosts: Pasteuria's specificity and virulence effects are general, the European Daphnia \u2013 Pasteuria story may apply more broadly.These results suggest that D. dentifera populations, epidemics of the yeast Metschnikowia bicuspidata are usually larger and more frequent than Pasteuria epidemics Metschnikowia does not, however, exhibit genetic specificity with D. dentiferaPasteuria may not necessarily resist Metschnikowia. Such parasite-specific resistance  and five Pasteuria isolates  all originated from Midland Lake, Greene County, Indiana, USA. The five Pasteuria isolates were taken from five different infected hosts in 2010  and were propagated by feeding homogenized, infected hosts to a single host genotype (H119). These isolates likely consist of a mix of Pasteuria clones and represent ecologically relevant sub-populations of Pasteuria . We used only this lab-based culture because Metschnikowia isolated from different lakes and in different years show no genetic variation in infectivity or virulence on D. dentiferaD. dentifera (which is not a protected or endangered species), but permission was obtained for access to lakes.The experiments used host and parasite cultures and previously established laboratory protocols. The six clonal genotypes of Pasteuria isolates, one Metschnikowia isolate, and a sham-exposure control), replicated 15 times, for a total of 630 experimental units. Four of the Pasteuria replicates were lost due to accidental death after treatment exposure. Maternal lines consisted of individual Daphnia kept under favourable conditions (20\u00b0C and 16\u22368 hour light/dark) in 40 mL of medium . Experimental animals consisted of second clutch offspring of third-generation maternal lines and were also kept in 40 mL of medium and fed ample food. In the parasite exposure treatments, each neonate (<24 hour old) received a high dose of spores  produced by gently crushing and diluting infected hosts. These doses aimed to yield similar infection levels among parasite species (based on pilot data). Sham controls received 100 \u03bcL of a Daphnia solution (50 uninfected hosts ground in 10 ml nanopure water). Replicates were fed lower food  during exposure to increase spore uptake by hosts 6Ankistrodesmus algal cells) again. Hosts were checked daily for reproduction and mortality for 25 days. Medium was refreshed every 2\u20133 days.The experimental design involved a factorial manipulation of these hosts and parasites. We crossed the six host genotypes with seven parasite treatments (five http://www.r-project.org). We analysed infection risk  by testing the fixed effects of host genotype and parasite species using data from only parasite-exposed hosts (not sham-exposed hosts). We tested for genetic specificity of Pasteuria infection using the fixed effects of host genotype and parasite isolate. Both Generalized Linear Models (GLM) were estimated with a binomial error distribution, and significance of each treatment was evaluated with deviance tests . However, in previous Daphnia-parasite studies, genotype is fitted as a fixed effect, a random effect or both (e.g. Metschnikowia and Pasteuria (averaged over the five isolates) for each host genotype using a Spearman rank correlation.All analyses were performed using the statistical package R . Fecundity was analysed by testing the fixed effects of infection status (infected or not), host genotype, and parasite species. Both host survival and r were analysed by testing the fixed effects of host infection status (infected or not) and parasite species. All of these tests used data from parasite-exposed hosts only; for r, the means of data from each infection category and parasite species for each host genotype were used.We examined the fitness consequences of infection by the two parasites using three metrics: production of host offspring (fecundity), host survival, and the instantaneous rate of host population growth, Metschnikowia's capacity to disrupt Red Queen dynamics between D. dentifera and Pasteuria should be reduced if the host pays an activation cost of resistance to Metschnikowia  We looked for evidence of an activation cost of resistance to Metschnikowia by comparing host fecundity, survival, and r in controls (sham-exposures) with hosts that were exposed to parasites but did not suffer infection .Fecundity across treatments was examined using a GLM fit with a quasipoisson error distribution (used due to over-dispersion of the fecundity data), and survival analyses used Cox's proportional hazards. Measures of Pasteuria) and between parasite species. Infection risk from Pasteuria depended on the specific combination of host and parasite genotypes . As expected based on prior studies, host genotype strongly influenced infection risk from Metschnikowia . There was, however, no correlation between a genotype's risk of infection by Metschnikowia and its overall risk of infection by Pasteuria  depended on both infection status and parasite species: infection with either parasite reduced r, but Pasteuria infections reduced r more than Metschnikowia infections. Thus, Pasteuria was more virulent . Thus, there was no evidence for a fitness cost of mobilising resistance mechanisms against Metschnikowia  to a lesser extent than Pasteuria  should reduce host population densities, even during small epidemics Due to differences in specificity and virulence, these two parasites may exert different ecological impacts on host populations. Theory suggests that specificity can reduce invasion success of parasites; i.e., they will have a lower reproductive ratio Pasteuria and Metschnikowia could either amplify or dampen Red Queen oscillations. A negative correlation would indicate antagonistic pleiotropy, where resistance to Pasteuria would come at a cost to resistance to MetschnikowiaMetschnikowia and Pasteuria suggests evolution of D. dentifera in response to the two parasites should proceed relatively independently. Thus, we do not expect Metschnikowia epidemics to amplify or dampen Red Queen dynamics between D. dentifera and Pasteuria.Correlations between host resistance to Pasteuria could promote genetic diversity in multiple host species through host-parasite coevolution. Pasteuria exhibits strong genetic specificity and high virulence with its North American host, D. dentifera, just as it does with its European host, D. magna. Can Pasteuria then promote host diversity in North American lakes? We cannot yet fully answer that question with these or other data, but the D. dentifera-Pasteuria system in isolation certainly contains several of the essential ingredients of the Red Queen. Still, it seems likely that the larger epidemics of the more common Metschnikowia yeast may mean that parasite-mediated selection in D. dentifera is driven primarily by Metschnikowia, making Red Queen dynamics relatively rare. This possibility further highlights the need to consider other co-occurring parasites when exploring host-parasite coevolution.In conclusion,"}
+{"text": "Cardiogenic shock is very uncommon in healthy people. The differential diagnosis for patients with acute heart failure in previously healthy hearts includes acute myocardial infarction and myocarditis. However, many drugs can also depress myocardial function. Propofol and fentanyl are frequently used during different medical procedures. The cardiovascular depressive effect of both drugs has been well established, but the development of cardiogenic shock is very rare when these agents are used.After a minor surgical intervention, a 32-year-old Caucasian woman with no significant medical history went into sudden hemodynamic deterioration due to acute heart failure. An urgent echocardiogram showed severe biventricular dysfunction and an estimated left ventricular ejection fraction of 20%. Extracorporeal life support and mechanical ventilation were required. Five days later her ventricular function had fully recovered, which allowed the progressive withdrawal of medical treatment. Prior to her hospital discharge, cardiac MRI showed neither edema nor pathological deposits on the delayed contrast enhancement sequences. At her six-month follow-up examination, the patient was asymptomatic and did not require treatment.Although there are many causes of cardiogenic shock, the presence of abrupt hemodynamic deterioration and the absence of a clear cause could be related to the use of propofol and fentanyl. Cardiogenic shock is the most serious form of presentation of heart failure (HF). The anticipation of hemodynamic deterioration and multiple organ failure in these patients is very important in terms of survival. The outcome for patients with refractory acute cardiogenic shock remains disproportionately poor. Technological advances in recent years have enabled the development of new treatments, such as extracorporeal life support (ELS). ELS is a variation of cardiopulmonary bypass which could improve the outcomes of patients in cardiogenic shock . AlthougWe report the case of a 32-year-old Caucasian woman who experienced sudden, severe hemodynamic deterioration after undergoing a minor surgical procedure. Her medical history was unremarkable except for a vaginal delivery two years before. She underwent surgery to remove a Bartholin cyst, and no infection in the gland was found. The operation was performed while the patient was under sedation and being given an analgesic. Spontaneous breathing was maintained by infusing a propofol bolus 1 mg/kg) and fentanyl 100 \u03bcg intravenously. During surgery, the patient remained hemodynamically stable. She has nausea and vomiting in the early post-operative period, which were treated with intravenous ondansetron 4 mg). A few minutes later the patient went into sudden hemodynamic deterioration, with sinus tachycardia (113 regular beats/minute) and hypotension (50/30 mmHg). Pulse oximetry showed that her oxygen saturation level had decreased to 80% despite oxygen supplementation through a face mask (fraction of inspired oxygen 40%). In this clinical situation, we treated her with intravenous dopamine and dobutamine, as well as with mechanical ventilation because of global respiratory failure . The electrocardiogram showed sinus tachycardia. Signs of HF were found on her chest X-ray, and urgent transthoracic echocardiography (TTE) revealed severe biventricular dysfunction with global hypokinesia and a LVEF estimated to be 35%. Coronary angiography showed no coronary lesions, and an intra-aortic balloon pump was inserted for counterpulsation. Repeat TTE revealed a LVEF of 20% with a dilated left ventricle  showing severe left ventricular dysfunction during the acute phase.Click here for fileShort-axis view showing severe left ventricular dysfunction. Transthoracic echocardiography  showing severe left ventricular dysfunction during the acute phase.Click here for fileApical four-chamber view after total recovery of left ventricular function. Transthoracic echocardiography  showing total recovery of left ventricular function before discharge.Click here for fileShort-axis view after total recovery of left ventricular function. Transthoracic echocardiography  showing total recovery of left ventricular function before discharge.Click here for file"}
+{"text": "Cellular and molecular regulation of the immune system is exquisitely controlled in the brain and is disrupted in neoplasia. Despite accumulation of immune cells in the tumor microenvironment, glioblastoma (GBM) growth persists while the mechanisms suppressing immune function remain largely unknown. Myeloid derived suppressor cells (MDSCs) are a heterogeneous class of immune cells responsible for immunomodulation through the suppression of cytotoxic T-cells. These populations are elevated in the peripheral blood of GBM patients, but their roles within the GBM microenvironment are uncharacterized. Through immunofluorescence analysis, we identified MDSCs within human GBM specimens, suggesting an immunosuppressive phenotype marked by arginase 1 (Arg1) staining. We have also observed co-localization between MDSCs and GBM cancer stem cells (CSCs) in both human tissues and mouse xenografts, leading to the hypothesis that CSCs recruit MDSCs to the tumor microenvironment, promote their survival, and that MDSCs are responsible for the immune-evasive properties of CSCs Fig. . Intracr"}
+{"text": "Hypertrophic cardiomyopathy (HCM) is most common in patients under 40 years and is associated with early sudden death, but HCM is increasingly recognized in elderly patients. We sought to characterize and identify features unique to elderly HCM patients when compared with youthful patients using CMR.Cine CMR and late gadolinium enhancement (LGE) imaging were performed in 902 HCM patients, including 202 young , and 143 elderly patients .Elderly HCM patients had a lower proportion of males . They had significantly lower left ventricular (LV) mass  and lower maximal LV wall thickness . The most common maximal thickness segment in the elderly patients was in the basal anterior septum . Elderly patients were also more likely to have the thickest segment located within the septum . Elderly patients were far less likely to have massive hypertrophy  .Elderly HCM patients had a smaller LV cavity size, with lower LV end-diastolic volume  and smaller LV end-diastolic dimension . The elderly patients had similar LV ejection fraction (LVEF)  and similar rates of depressed (<60%) LVEF .The prevalence of LGE (a marker of fibrosis) was similar in both groups . When present, both LGE mass  and percentage of LV with LGE  were similar.Substantial amounts of late gadolinium enhancement are compatible with normal longevity in many patients with hypertrophic cardiomyopathy. Presence of LGE may thus have different prognostic significance across the vast spectrum of HCM. This has potential implications for using LGE as a risk stratification tool for sudden death in HCM.Nil."}
+{"text": "Successful scientific investigations at CAM institutions are often hampered by limited research infrastructure. Enhancing the clinical trial capabilities of our chiropractic research center was one goal of 2 NIH/NCCAM developmental center grants.Web applications were enhanced and customized based on individual project needs and trial team requests. Templates were built to support quick development and standard functionality of project web applications. We also developed standardized processes to effectively provide project-specific participant management, data collection, staff training, and quality control.Web applications included: the Centralized Participant Database System and Project/Users Permissions System to securely capture participant contact information and control personnel access to web modules; a real-time participant tracking report to monitor recruitment and participant flow; a role-specific Reminder System to track outstanding activities requiring personnel follow-up; and double key-entry verification on web data used for an adaptive treatment allocation algorithm. Templates of these tools can be incorporated into any new trial\u2019s web application. Study protocol templates facilitate timely, accurate translation of research proposals into detailed protocols for IRB applications, DSMC review and training. A revised training plan included role-specific training logs for tracking training objective completion and a thorough certification process for key protocols to ensure accurate and consistent performance. Quality control templates support the informed consent process and fidelity of trial interventions and outcomes assessment. We implemented these enhanced resources in 5 clinical trials. To date, our team has completed 3378 phone screens, conducted 1439 first and 473 second in-person screening visits, enrolled 394 participants, and followed 315 through trial end. The study protocol templates have been used in two additional clinical trials currently undergoing IRB review.We expanded our capacity to support multiple, diverse trials with complex methodologies. This is a successful example of a CAM institution successfully leveraging research grant funding to enhance research infrastructure."}
+{"text": "Synapses in neuron networks filter incoming spikes with a wide variety of time constants, affecting the stability of various collective dynamics , the selHere, we addressed this issue working out a unified framework in which from small to large synaptic time scales the same approximated theoretical description holds for the firing rate dynamics of spiking neuron networks. Starting from single-neuron stochastic dynamics, we derived a set of ordinary differential equations for the population emission rate relying on the spectral expansion of the associated Fokker-Planck equation, eventually extending to the colored noise case a previous derivation obtained under white noise hypothesis . The resMoreover, such perturbative approach allowed to avoid the analytical difficulties of dealing with multi-dimensional Fokker-Planck equations with discontinuous boundary conditions. A simplification which helped in highlighting as main result that networks of neurons with non-instantaneous synapses can, under fairly broad assumptions, be described by equivalent networks with suitable distributions of transmission delays. A formal analogy valid from simple VIF models to more realistic point-like simplifications like LIF or EIF neurons."}
+{"text": "Late gadolinium enhancement (LGE) is excellent for identifying focal lesions in the myocardium , but diffuse homogeneous abnormalities are not readily detectable. Quantitative measurement of the myocardial extracellular volume (ECV) fraction using MRI has recently been validated histologically, and implemented for parametric imaging in patients. We hypothesized that quantification of ECV using ECV imaging could detect focal lesions detected by LGE, and diffuse homogenous disturbances in the myocardial extracellular volume fraction which are not detectable by LGE. The objective of the study was to examine the diagnostic utility of ECV MRI for detecting myocardial tissue abnormalities compared to LGE.Consecutive patients referred for clinical cardiac MRI evaluation of known or suspected heart disease were prospectively enrolled . MRI was undertaken at 1.5T using a Modified Look-Locker Inversion recovery (MOLLI) sequence before and 15 minutes after an intravenous bolus of a gadolinium-based extracellular contrast agent . Maps of the extracellular volume fraction (ECV images) were generated using MOLLI-derived T1-mapping before and after contrast, calibrated to hematocrit from a venous blood sample. Motion correction and co-registration was performed offline using an automated dedicated algorithm. ECV images were interpreted quantitatively and the results were compared to clinical assessment of LGE images. Increased myocardial ECV was determined by quantitative comparison to established normal values where the 95% confidence limits are 20-32%.Out of 32 patients, 10 had focal lesions . All lesions identified by increased ECV were also identified by blinded clinical read of LGE images (100% agreement). Among patients with normal LGE findings (n=22), two patients (9%) had diffusely increased myocardial ECV . The figure shows examples of LGE and ECV images in a normal finding, a focal lesion and a case with diffusely increased ECV.Our initial findings suggest that ECV and LGE imaging have excellent diagnostic agreement for identifying focal myocardial findings such as those seen in myocardial infarction and non-ischemic heart disease. The ability of ECV imaging to quantify and detect diffuse abnormalities in myocardial ECV increased the number of diagnostic findings compared to LGE in 9% of cases with otherwise normal LGE. Further studies in larger populations are warranted to explore the diagnostic and prognostic benefits of ECV imaging in assessment of diffuse pathologies of the myocardial extracellular space.The study has been funded in part by a grant (PI: Dr. Ugander) from the Swedish Society for Medical Research."}
+{"text": "Central statistical monitoring (CSM) can identify trial misconduct, and help to prioritise on-site visits and additional training. Key risk indicators (KRIs) focus CSM on variables most likely to affect study reliability or patient safety. We developed the use of robust minimum covariance determinant (MCD) distances to detect outlying centres in the context of KRI analyses.Initially, a summary statistic (e.g. mean) describing the KRI is calculated for each centre and robust MCD-based distances are calculated by the FAST-MCD algorithm . For each KRI, robust estimates of the multivariate location Robust MCD distances offer a flexible approach for analysing both univariate and multivariate KRIs and can be implemented in standard statistical software."}
+{"text": "Major trauma is the leading causing of death in young adults across the globe. Themortality from traumatic cardiac arrest remains high but survival with good neurologicaloutcome from cardiopulmonary arrest following major trauma has now been reported. Rapid,effective intervention is required to address potential reversible causes of traumaticcardiac arrest if the victim is to survive. There is no standard treatment algorithm fortraumatic cardiac arrest. We present a simple algorithm to manage the major traumapatient in actual or near cardiac arrest.We reviewed current pre-hospital clinical practice and the published literature on majortrauma management. An algorithm was developed and used regularly by London\u2019s AirAmbulance pre-hospital physician/paramedic trauma team.The algorithm addresses the need treat potential reversible causes of traumatic cardiacarrest. This includes immediate resuscitative thoracotomy in cases of penetrating chestor abdominal trauma resulting in cardiac arrest, airway management, optimisingoxygenation, reversal of hypovolaemia using intravenous/intraosseous fluid replacementand chest decompression to exclude tension pneumothorax.A standard approach to traumatic cardiac arrest is feasible. Use of a treatmentalgorithm can rapidly, simultaneously address reversible causes of traumatic cardiacarrest and has the potential to save lives."}
+{"text": "MDLcompress. We apply this tool to explore the relationship between miRNAs, single nucleotide polymorphisms (SNPs), and breast cancer. Our new algorithm outperforms other grammar-based coding methods, such as DNA Sequitur, while retaining a two-part code that highlights biologically significant phrases. The deep recursion of MDLcompress, together with its explicit two-part coding, enables it to identify biologically meaningful sequence without needlessly restrictive priors. The ability to quantify cost in bits for phrases in the MDL model allows prediction of regions where SNPs may have the most impact on biological activity. MDLcompress improves on our previous algorithm in execution time through an innovative data structure, and in specificity of motif detection (compression) through improved heuristics. An MDLcompress analysis of 144 over expressed genes from the breast cancer cell line BT474 has identified novel motifs, including potential microRNA (miRNA) binding sites that are candidates for experimental validation.We describe initial results of miRNA sequence analysis with the optimal symbol compression ratio (OSCR) algorithm and recast this grammar inference algorithm as an improved minimum description length (MDL) learning tool:"}
+{"text": "Optical coherence tomography (OCT) has enhanced our understanding of changes in different ocular layers when axial myopia progresses and the globe is stretched. These findings consist of dehiscence of retinal layers known as retinoschisis, paravascular inner retinal cleavage, cysts and lamellar holes, peripapillary intrachoroidal cavitation, tractional internal limiting membrane detachment, macular holes (lamellar and full thickness), posterior retinal detachment, and choroidal neovascular membranes. In this review, recent observations regarding retinal changes in highly myopic eyes explored by OCT are described to highlight structural findings that cannot be diagnosed by simple ophthalmoscopy. Pathologic or high myopia is defined as a refractive error of \u22126.00 diopters (D) or greater and an axial length exceeding 26 mm.2Optical coherence tomography (OCT) has recently made it possible to explore changes in ocular layers as axial myopia progresses and the globe is stretched. These findings consist of dehiscence of retinal layers known as retinoschisis, paravascular inner retinal cysts and lamellar holes, peripapillary intrachoroidal cavitation , tractional internal limiting membrane detachment, macular holes (lamellar and full thickness), posterior retinal detachment and choroidal neovascular membranes.In this review, we describe retinal changes in highly myopic eyes according to findings observed by OCT.The early stages of myopic retinal changes can easily be underestimated by biomicroscopy, angiography or ultrasonography, and therefore remain undiagnosed. Recently, OCT with its fine cross-sectional imagery of retinal structures has greatly facilitated the evaluation of posterior vitreoretinal anatomy in eyes with high myopia. It can also reveal otherwise undetectable retinal changes in asymptomatic patients. The OCT ophthalmoscope produces longitudinal retinal B-scans and coronal C-scans.B-scan produces cross-sectional images of retinal morphology which bears strong resemblance to histology. OCT C-scans are represented as 2-dimensional transverse slices at any given depth through the retina, thereby enabling visualization of the lateral extent of different structures. OCT C-scans are associated pixel-to-pixel points with simultaneously confocal images used to identify the exact position of lesions on the posterior pole. With en face OCT, localization and relation of retinal lesions can be precisely defined, especially in myopic eyes. En face OCT provides accurate imaging of retinal abnormalities in high myopia and allows width measurement and point-to-point localization of changes.Myopic posterior staphyloma, with its outward globe bulge, results in a deep concave B-scan OCT and distorted retinal structures. Because of the smaller base curvature of the horizontal section and larger base curvature of vertical section, macular structures can be defined more easily by vertical sections . Remarkably, the incidence of internal limiting membrane (ILM) detachment and macular retinoschisis was significantly higher in eyes with paravascular lamellar holes than those with other paravascular abnormalities. Paravascular lamellar holes were associated with ILM detachment in 44% and with macular retinoschisis in 20% of eyes. More than 80% of eyes with macular retinoschisis had paravascular lamellar holes.Tractional ILM detachment was reported in 2.4%\u20136% of highly myopic persons.In a study by Bando et alThe prevalence of myopic foveoschisis (MFS) ranges from 9% to 34% in highly myopic eyes with posterior staphylomas.23MFS tends to occur in eyes with severe myopic retinopathy.25Half of patients with MFS have been reported to develop retinal detachment or macular holes within two or more years of follow-up.26Choroidal neovascular membrane (CNV) is considered to be the most important sight-threatening complication of high myopia. Myopic CNV has been classified into active, scar and atrophic stages.In the scar stage, only the surface of the neovascular tuft shows high reflectivity and the tissue underneath is markedly attenuated. Overlying retinal layers are not disarranged or disorganized, cystic changes are also absent.In the atrophic stage, the CNV becomes flat and chorioretinal atrophy around the regressed CNV is highly reflective.29Macular holes always exist at the edge of a pigmented lesion suggestive of an old CNV. Therefore periodic OCT examinations for evaluation of macular holes or macular retinoschisis, even in patients in atrophic stages, are recommended. The retina in the area of chorioretinal atrophy around the CNV is very thin regardless of coexisting macular retinoschisis, but the retina at the edge of CNV in myopic eyes with large chorioretinal atrophy (larger than 1 disc diameter) has been reported to be significantly thinner in eyes with chorioretinal atrophy smaller than 1 disc diameter around the CNV.28Posterior retinal detachment is another consequence of ocular expansion and posterior staphyloma in high myopic eyes. Full thickness macular hole and tractional maculopathy may accompany this finding and may be its contributor .Macular hole formation in myopic eyes has multiple etiologies. Expansion of the globe, tractional components and growth of neovascular membranes through clefts in the posterior pole may create partial thickness and/ or full-thickness macular holes. In asymptomatic myopic persons, macular holes were detected in 6.26% of cases.Pathologic myopia is accompanied by thinning and stretching of the globe. With increasing age and myopia, these changes further progress.Individuals with high myopia are subject to various retinal pathologies including posterior pole and peripapillary lesions. Because of extreme retinal thinning and chorioretinal changes in these persons, simple fundus examination may miss subtle retinal pathologies. OCT is an accurate tool which can localize such anatomical changes. It seems to be the paraclinical test of choice for highly myopic eyes."}
+{"text": "Cancer cells have altered metabolism, with an increased rate of glucose uptake, increased glycolysis, and due to the Warburg phenomenon, increased production of biomass (amino acids and nucleic acids) as metabolic byproducts. Association of these metabolic changes with breast cancer subtype and tumor gene expression has not been evaluated, nor is it well understood what biological processes and characteristics are most important in driving altered metabolic state in breast cancer.Thirty-four breast tumors and six samples of cancer-adjacent normal tissue were analyzed by liquid and gas chromatography (LC/GC) mass spectrometry (MS) to determine the expression of 379 metabolites. The same tissues were also used to perform gene expression microarrays and the resulting gene expression profiles were used to identify tumor subtype. These data combined with clinical tumor characteristics were evaluated in association with metabolic phenotype. To complement these analyses of human tissues, in vitro assays using human breast cancer cells alone and in coculture with cancer-associated fibroblasts (CAFs) were performed to study glucose uptake and utilization.Unsupervised cluster analysis on all metabolites resulted in two main clusters, with differences in the prevalence of aggressive tumor subtypes in each cluster. Characteristic of the Warburg phenomenon, four groups of metabolites showed differential levels between the two tumor clusters: amino acids, sugars, nucleic acids, and citric acid (TCA) cycle metabolites. Normal breast tissue samples were similar to less aggressive tumors with low biomass production and decreased levels of glycolysis/TCA byproducts. Parallel to these results in human tissues, glucose uptake was increased in basal-like breast cancer cells when they were cocultured with fibroblasts, but less aggressive luminal-fibroblast cultures did not show increased glucose uptake. Rather, in luminal cocultures, the fibroblasts appeared to suppress glucose uptake. Glucose utilization (oxidation and glycogen synthesis) was also higher in basal-like mono- and cocultures compared to luminal cultures. Consistent with these findings that the stroma influences metabolic phenotype, tumors that had active wound response gene expression had the more aggressive, Warburg-like metabolic profile.We observed distinct metabolic profiles associated with more aggressive breast cancer tumors. Based both on the observed patterns of glucose uptake and utilization in cocultures, and on the association between wound response activation and metabolic profile, these metabolic signatures appear to be influenced by multiple factors, including the stroma. These data suggest that integration of genomic and metabolic data provide insights for better understanding a Warburg effect in human breast cancer that may be regulated by the stroma."}
+{"text": "Visual hallucinations (VH) represent one of the core features in discriminating dementia with Lewy bodies (DLB) from Alzheimer\u2019s Disease (AD). Previous studies reported that in DLB patients functional alterations of the parieto-occipital regions were correlated with the presence of VH. The aim of our study was to assess whether morphological changes in specific cortical regions of DLB could be related to the presence and severity of VH. We performed a cortical thickness analysis on magnetic resonance imaging data in a cohort including 18 DLB patients, 15 AD patients and 14 healthy control subjects. Relatively to DLB group, correlation analysis between the cortical thickness and the Neuropsychiatric Inventory (NPI) hallucination item scores was also performed. Cortical thickness was reduced bilaterally in DLB compared to controls in the pericalcarine and lingual gyri, cuneus, precuneus, superior parietal gyrus. Cortical thinning was found bilaterally in AD compared to controls in temporal cortex including the superior and middle temporal gyrus, part of inferior temporal cortex, temporal pole and insula. Inferior parietal and supramarginal gyri were also affected bilaterally in AD as compared to controls. The comparison between DLB and AD evidenced cortical thinning in DLB group in the right posterior regions including superior parietal gyrus, precuneus, cuneus, pericalcarine and lingual gyri. Furthermore, the correlation analysis between cortical thickness and NPI hallucination item scores showed that the structural alteration in the dorsal visual regions including superior parietal gyrus and precuneus closely correlated with the occurrence and severity of VH. We suggest that structural changes in key regions of the dorsal visual network may play a crucial role in the physiopathology of VH in DLB patients. Dementia with Lewy bodies (DLB) is the second most common form of dementia in the elderly after Alzheimer\u2019s Disease (AD). Despite the precise nosological relationship between DLB and AD remains uncertain, persistent visual hallucinations (VH) along with fluctuations in cognitive function and parkinsonism represent the core feature in discriminating DLB from AD and other dementias The physiopathology underlying VH in DLB is not well understood. Causative models for complex VH have suggested that the origin of this deficit may be related to a range of pathological alterations affecting both the dorsal visual stream, specialized for visuo-spatial attention and location, and the ventral visual stream, designated to object recognition In this context, structural Magnetic Resonance Imaging (MRI) could be a powerful tool to investigate the aetiology of core symptoms in DLB. To date, several studies by using voxel-based morphometry (VBM) found widespread cortical sites of grey matter atrophy in DLB patients compared to healthy controls Cortical thickness approach allows to perform cortical parcellation and to measure with great reliability the pathological thinning of the cortical grey matter. By measuring a real physical quantity that is much easier to interpret and to localize in comparison to the three-dimensional VBM, cortical thickness methods provide a better localization of structural changes because the smoothing procedure is performed on a two-dimensional manifold which reduces morphological artefacts due to ageing and pathological processes Despite the potential advantage of cortical thickness analysis, to date this approach has not been applied to DLB patients.In the present study, we performed cortical thickness analysis to verify the presence of cortical grey matter damage related to VH in DLB patients. To this aim, firstly, we compared DLB patients respect to healthy controls. Subsequently, we included a comparison against AD groups to exclude possible pathologic alterations arising as a result of a dementia process per se and not specific to DLB pathology. Finally, relatively to DLB group, we performed a correlation analysis between the cortical thickness and the Neuropsychiatric Inventory (NPI) hallucination item scores to highlight the cortical regions which were effectively related to the occurrence and severity of VH.The study was approved by the Institutional and Ethics Committee of the University \u201cG. d\u2019Annunzio\u201d Chieti-Pescara (ID#157801). All procedures were conducted according to the Declaration of Helsinki and subsequent revisions All patients underwent MRI scan within six months before the inclusion in the study and dopaminergic presynaptic ligand ioflupane SPECT (DAT scan).Global tests of cognition included Clinical Dementia Rating (CDR), Mini Mental State Examination (MMSE), Dementia Rating scale-2 (DRS-2) Exclusion criteria were uncontrolled hypertension, myocardial ischemia, peripheral vascular disease and chronic kidney.1-Weighted Turbo Field-Echo sequence  was carried out. Participants with images characterized by motion artefacts were excluded from the analysis.All acquisitions were carried out with a Philips Achieva 3 T scanner  equipped with 8-channel receiver coil. After scout and reference sequences, a 3-dimensional T1-weighted image was estimated at each vertex across the brain surface using Freesurfer software package (http://surfer.nmr.mgh.harvard.edu). This method has been previously described in detail by Fischl and Dale Cortical thickness on TCortical brain regions affected by cortical thinning were classified by using the Desikan-Killiany Atlas integrated in FreeSurfer.SPSS version 14.0 was used for statistical analysis. Analysis of variance (ANOVA) among groups and Tukey\u2019s HSD post-hoc test was performed on demographic and clinical data. Chi-squared test was carried out for gender.For each hemisphere, comparison among groups was performed by using general linear model (GLM), including cortical thickness as dependent factor and group  as independent factor. MMSE, CAF and UPDRS scores were included as covariates.https://surfer.nmr.mgh.harvard.edu/fswiki/FsgdFormat).FreeSurfer processing stream was used to assess the pairwise differences among groups  was used to individuate statistically significant regions where NPI hallucination item scores and thickness were correlated. MMSE, CAF, UPDRS scores were included as nuisance factors.In DLB group, QDEC . Next, SPSS version 14.0 was used for statistical computation and MMSE, CAF and UPDRS scores were included as nuisance factors.To perform partial correlations between NPI hallucination item scores and mean cortical thickness values in the posterior regions which were affected significantly in DLB in comparison with AD, the mean cortical thickness values were extracted from each region of interest (defined by Desikan-Killiany Atlas) by using \u201caparcstats2table\u201d command line,  in cortical thickness between DLB and age-matched healthy controls. Cortical thickness was reduced in the posterior regions of DLB. Specifically, pericalcarine, lingual gyri, cuneus precuneus and superior parietal gyrus were affected bilaterally. panel B shows regional differences (corrected p<0.05) in cortical thickness between DLB and AD. Cortical thickness was reduced in DLB compared to AD in the right posterior regions including superior parietal gyrus, precuneus, cuneus, pericalcarine and lingual gyri.With the present MRI study, we have evidenced that DLB patients are characterized by marked cortical thinning in posterior regions when compared with AD and age-matched healthy controls.Posterior cortical regions play a critical role in the visual information processing, and their damage was related to recurrent VH in DLB patients Consistently with neuroimaging Although previous studies reported abnormalities related to VH in DLB or Parkinson\u2019s Disease (PD) patients compared to control groups Additionally, despite both the dorsal and ventral attention networks were affected in DLB as compared to controls and AD, the correlation analysis between cortical thickness and NPI hallucination item scores, suggested a greater involvement of the dorsal attention regions including superior parietal gyrus and precuneus in the occurrence and severity of VH in DLB.The superior parietal region is implicated in visuo-spatial working memory Precuneus acts in concert with the parietal regions, elaborating information about motor imagery and more abstract mental imagery tasks Despite impairment of dorsal stream is well defined in DLB patients, the ventral stream resulted to be affected in both AD and DLB as compared to controls. However a different distribution of grey matter loss along the ventral pathway was found in DLB and AD. Specifically, cortical thinning in lingual and pericalcarine giri was observed in DLB, whereas a marked and diffuse cortical thinning was found in the mesial temporal cortex in AD. This latter structural alteration could be linked to greater memory impairment affecting AD patients and it is in accordance with previous morphometric studies According to previous reports from our group Different models have suggested a central role of posterior regions in manifestation of VH"}
+{"text": "Client-owned pet dogs represent exceptional translational models for advancement of Cancer Research, as they reflects the complex heterogeneity observed in human cancer. We have recently shown that a genetic vaccine targeting dog telomerase (dTERT) and based on Ad/DNA-EGT technology can induce strong cell-mediated immune responses against this tumor antigen and increase overall survival of dogs affected by B-cell lymphosarcoma (LSA) in comparison with historical controls when combined with COP chemotherapy regimen. Here, we have conducted a double arm clinical trial with an extended number of LSA patients, measured the antigen-specific immune response and evaluated potential toxic effects of the immunotherapy along with a follow up of patients survival for three years and half. The immune response was measured by ELISPOT. The expression of dTERT was quantified by quantitative PCR. Changes in hematological parameters, local/systemic toxicity or organic dysfunction and fever were monitored over time during the treatment. dTERT-specific cell mediated immune responses were induced in almost all treated animals. No adverse effects were observed in any dog patient that underwent treatment. The overall survival time of vaccine/COP treated dogs was significantly increased over the COP-only treated cohort . There was a significant association between dTERT expression levels in LSA cells and overall survival (OS) among vaccinated patients. In conclusion, Ad/DNA-EGT-based cancer vaccine against dTERT in combination with COP chemotherapy is safe and significantly prolongs the survival of LSA canine patients. These data confirm the therapeutic efficacy of dTERT vaccine and support the evaluation of this approach for other cancer types as well as the translation of this approach to human clinical trials."}
+{"text": "Optimizing productivity and growth of recombinant Chinese hamster ovary (CHO) cells requires insight and intervention in regulatory processes. This is to some extent accomplished by several 'omics' approaches. However, many questions remain unanswered and bioprocess development is therefore still partially empirical. In this regard, the analysis of DNA methylation as one of the earliest cellular regulatory levels is increasingly gaining importance. This epigenetic process is known to influence transcriptional events when it occurs at specific genomic regions with high CpG frequencies, called CpG islands (CGIs). Being methylated, CGIs attract proteins with methyl-DNA binding domains (MBD proteins) that in turn can interact with chromatin modifying complexes, thereby leading to a transcriptionally inactive state of the associated gene . In CHO Based on the genomic and transcriptomic information available for CHO cells ,5, 21,992+, MAPK and Wnt signalling systems were comprised within the latter group and showed a large coverage by differentially methylated components. 48 hours upon butyrate addition the number of differential methylations decreased by about 90 %. COBRA analysis of the Wnt responsive myc proto-oncogene protein-like gene showed clearly detectable cleavage products  24 hours upon butyrate addition, that completely vanished another 24 hours later (Figure Butyrate treated CHO DP-12 cultures stopped proliferating and decreasing viabilities could be detected 24 hours upon addition of the SCFA Figure . Simultar Figure , confirmOur first genome-wide screening for differential DNA methylation in CHO cells shows that the epigenetic response upon butyrate treatment seems to be highly dynamic and reversible. This was confirmed by applying the bisulfite-based single-gene method COBRA to analyze a region of the myc proto-oncogene protein-like gene. Furthermore, detection of differential methylation before butyrate addition indicates that heterogeneity in DNA methylation occurs even if cells originated from the same preculture and were treated identically. This occurrence of differentially methylated genes in parallel cultivations strongly fosters the hypothesis that the culture history influences final process outcomes . It unde"}
+{"text": "Sensory cortex often undergoes population activity fluctuations due to attentional modulations and arousal changes, but activity fluctuations can also be generated intrinsically. The mechanisms that underlie these spontaneous activity fluctuations are unknown, in particular whether they arise from common inputs or more active neuronal processes. We measured the activity of tens of V1 neurons simultaneously in monkeys stimulated with oriented visual stimuli, and found that the tuning curves (TCs) of orientation selective neurons spontaneously underwent shifts and multiplicative scalings proportional to population activity while their widths remained constant Based on this observed TC activity dependence, we constructed a precise statistical model featuring Poisson-like firing, shifts and gain modulation. The model not only accounted for neuronal co-variability but also approached the performance of state-of-art decoding methods. Surprisingly, we found that decoding performance on sensory stimuli increased with population activity, despite the fact that the stimulus was identical. Therefore, spontaneous population activity fluctuations display highly non-random features, boosting TCs by shifts and multiplicative factors that gate information processing.We found that TCs are shifted and scaled by a multiplicative factor proportional to mean population activity Figure . The amoThe observed boosting properties of TCs motivated us to build a statistical model with Poisson-like neurons that includes a multiplicative scaling factor (PS). We observed that the effect of population activity on TCs is not purely multiplicative, and we introduced therefore a shift (PSS). Our models approached the performance of state-of-art decoding techniques  and provided higher accuracy than other tested decoders based on population vector and independent Poisson neurons. Experimental methods are as in ."}
+{"text": "Diverse therapeutic strategies for food allergy are under investigation including food allergen-specific and non-specific approaches. Allergen-specific approaches include immunotherapy with native food allergens, immunotherapy with mutated recombinant allergens, and diets containing extensively heated milk or egg. Native allergen immunotherapy can be administered via oral, sublingual, subcutaneous, or epicutaneous route. Oral immunotherapy trials with native food allergens such as milk, peanut, or egg reported that approximately 50-75% of the treated subjects reached and tolerated the maintenance dose. Failure of desensitization occurred in about 10-20% of the treated subjects and might be associated with the most severe and likely permanent food allergy phenotype, as opposed to the successful desensitization and tolerance that might be associated with a transient clinical phenotype and higher chances of spontaneous resolution of food allergy. Food allergens can be altered to decrease their allergenicity and lower the risk of acute adverse reactions. Immunotherapy with mutated recombinant peanut proteins, which have decreased IgE-binding activity, co-administered within heat-killed E.coli to generate maximum immune response had a strong protective effect in the mouse model of peanut anaphylaxis. This vaccine is being currently evaluated in the phase I clinical trials in adults with peanut allergy. Heating and processing changes food protein conformation and affects how food proteins are digested and transported via the gut barrier. Extensively heated (baked) milk and egg are tolerated by approximately 70% of the milk or egg allergic children. Diets containing extensively heated (baked) milk and egg represent an alternative approach to food oral immunotherapy and are already changing the paradigm of strict dietary avoidance for food-allergic patients."}
+{"text": "We construct a state-and-transition model for mammals in tropical savannas in northern Australia to synthesize ecological knowledge and understand mammalian declines. We aimed to validate the existence of alternative mammal assemblage states similar to those in arid Australian grasslands, and to speculate on transition triggers. Based on the arid grassland model, we hypothesized that assemblages are partitioned across rainfall gradients and between substrates. We also predicted that assemblages typical of arid regions in boom periods would be prevalent in savannas with higher and more regular rainfall. Data from eight mammal surveys from the Kimberley region, Western Australia (1994 to 2011) were collated. Survey sites were partitioned across rainfall zones and habitats. Data allowed us to identify three assemblage states: State 0:- low numbers of mammals, State II:- dominated by omnivorous rodents and State III:- dominated by rodents and larger marsupials. Unlike arid grasslands, assemblage dominance by insectivorous dasyurids (State I) did not occur in savannas. Mammal assemblages were partitioned across rainfall zones and between substrates as predicted, but\u2014unlike arid regions\u2014were not related strongly to yearly rainfall. Mammal assemblage composition showed high regional stability, probably related to high annual rainfall and predictable wet season resource pulses. As a consequence, we speculate that perpetually booming assemblages in savannas allow top-down control of the ecosystem, with suppression of introduced cats by the dingo, the region's top predator. Under conditions of low or erratic productivity, imposed increasingly by intense fire regimes and introduced herbivore grazing, dingoes may not limit impacts of cats on native mammals. These interacting factors may explain contemporary declines of savanna mammals as well as historical declines in arid Australia. The cat-ecosystem productivity hypothesis raised here differs from the already-articulated cat-habitat structure hypothesis for mammal declines, and we suggest approaches for explicit testing of transition triggers for competing hypotheses. The processes that drive fluctuations in population size and community composition have long been a source of fascination for ecologists, and gaining a general understanding of their identity and effects remains an enduring goal. Although some emphasis has been placed on the influence of intrinsic factors, such as social interactions, in driving species' dynamics In many systems, the interplay between bottom-up and top-down forces can lead to the existence of alternative states that are characterized by different dominant species or species-groups State-and-transition models were initially developed to assist in managing non-equilibrial rangeland systems Here, we apply state-and-transition modelling to synthesize knowledge about native mammal assemblages in the Kimberley region of northern Australia and explore factors that might drive them. This region is of considerable conservation concern: populations of many mammal species are declining across the northern Australian savannas, conceivably towards irreversible regional or total extinctions. Worldwide, about a quarter of all mammal species are threatened with extinction; about 38% of land mammals suffer from habitat loss associated with diversion of natural resources to benefit humans, and 16% are at risk from hunting or harvesting Although mammal declines elsewhere in Australia have received considerable attention Sminthopsis macroura, Pseudomys desertor, Rattus villosissimus, Mus musculus) and functional groups (particularly insectivorous dasyurids and omnivorous rodents).We use a recently described model from central Australia There are two key differences between central Australian arid grassland assemblages and those of the Kimberley's tropical savannas: (1) The former are now largely devoid of medium-sized mammals (e.g. peramelids) whereas all medium-sized mammals persist in the tropical savannas, albeit in most cases, with greatly reduced ranges It is important that state-and-transition models be testable annual rainfall,rocky versus non-rocky savannas, andthe abundance and representation of particular species and taxonomic or functional groups.Because of the importance of antecedent rainfall in driving patterns of mammalian abundance and composition through time, we predicted also that inter-annual differences in rainfall would lead to shifts between states. Rainfall, and thus productivity, is predictable in the Kimberley but not in central Australia, where erratic rainfall drives ephemeral pulses of productivity. In consequence, we predicted further that Kimberley mammal assemblages would be more stable and exist in higher states than those in central Australia. We use our results to generate hypotheses about the key factors that prompt shifts between assemblage states and hence further our understanding of the threats to the Kimberley mammal faunas. These hypotheses also can be extended to, and tested in, other tropical savanna areas.4 grasses dominating the ground layer The Kimberley region is in the far north west of Australia and represents the Western Australian component of Torresian  habitats. It has a tropical monsoonal climate with rain falling mostly during the summer from November to April. Annual rainfall ranges from 1400 mm on the far north coast to <400 mm along the semi-arid southern boundary . AlthougTo classify mammal assemblage states, we collated data from 229 survey sites in savanna across all the major Kimberley bioregions All survey data presented here consist of one-off site surveys. Where repeat site surveys occurred, we maintained temporal independence by choosing just one survey at random to represent that site. As different rainfall regions and savanna habitats provide the potential conditions needed to drive different states and transitions, we considered this space-for-time approach to be appropriate.This study makes use of data from eight separate mammal fauna surveys with differing methodologies and trap effort per site . DespiteAnalyses were performed on individual species and also on pre-defined functional groups , terrestrial omnivorous rodents (Muridae), arboreal rodents, large marsupials (>150 g) including dasyurid predators, bandicoots (peramelids), possums , and small macropods (macropodids <2000 g)). We compared species and taxonomic/functional groups in terms of their abundance, measured here as percentage trap success  for each survey. We tested for potential under-estimation of small dasyurids among surveys by separately analyzing trap records from pitfall traps based on the rationale that pitfall traps are the most effective method for estimating the abundance of small dasyurids in arid grassland surveys The hypothesis that species and mammal groups differ in abundance among rainfall zones and between rocky and non-rocky savannas was tested using Kruskal-Wallis tests. This non-parametric test was chosen due to inequality of sample sizes and non-normality of the survey data, which had many zero values. The effect of fluctuations in annual rainfall within rainfall zones/savanna types  was tested using regressions of trap success over previous wet season rainfall. Differences among mammal assemblages across rainfall zones and savanna habitats were explored using Bray Curtis ordinations, with the Sorensen dissimilarity distance used to calculate separation between surveys. A non-parametric multi-response permutation procedure (MRPP) was used to test for differences among predefined rainfall zone and savanna habitat (rocky and non-rocky) groups. We used PC-ORD 4 for ordinations and MINITAB 14 for all statistical analyses.Zyzomys argurus, Pseudomys nanus, Rattus tunneyi and P. delicatulus. The next most prominent group comprised large dasyurid predators , with 0.95% trap success. Small insectivorous dasyurids were relatively rare and yielded a total trap success of only 0.09%. Other groups represented in the surveys included bandicoots (0.58%) and arboreal rodents (0.43%). The low trap success rate for macropods and possums (<0.2%) probably reflects ineffective sampling rather than low numbers as these animals are not often trapped even where locally numerous.After removal of data from sites sampled more than once, we recorded a total of 5138 mammals from 71,016 trap nights (mean trap success 7.24%) . The larCanis lupus dingo and feral cats Felis catus were abundant. Dingoes were frequently observed and recorded in the high and medium rainfall zones during surveys . Similarly, cats are present throughout the Kimberley Although not recorded by trapping, dingoes P. delicatulus, P. nanus) were more numerous in low rainfall zones and non-rocky savannas, while others  were most abundant in high rainfall rocky savannas  showed variable responses to rainfall and habitat. Some rodent species , the bandicoot Isoodon auratus and arboreal rodents occurred only in surveys in the high rainfall zone , including rodents and small dasyurids, were captured using pitfall traps irrespective of rainfall zone . RodentsIn individual surveys, 17% of sites had no mammals (State 0), 2% were dominated by insectivorous dasyurids (State I), 37% were dominated by omnivorous rodents (State II) and 44% had a significant component of large mammals in addition to omnivorous rodents (State III). Surveys yielding zero mammals (State 0) were unusual in high (8% of surveys) and medium (0%) rainfall rocky savannas but more common in non-rocky savannas  and in low rainfall rocky savannas (32%). Small dasyurids (State I) dominated assemblages in 1% of high rainfall rocky savannas, and in 5% and 10% of rocky and non-rocky sites in the low rainfall zone. Rodents dominated assemblages (State II) in medium rainfall non-rocky (73%), low rainfall rocky (63%) and low rainfall non-rocky (71%) savannas. State II assemblages were also common in medium rainfall rocky (25%) and high rainfall non-rocky savannas (38%), but less so (6%) in high rainfall rocky savannas. State III assemblages with large CWR mammals (>150 g) were restricted to high rainfall or rocky savannas, with 84% and 75% of surveys yielding these assemblages in high and medium rainfall rocky savannas, and 40% in high rainfall non-rocky savannas.Z. argurus and P. desertor and on non-rocky substrates (sand plains and open non-rocky savannas) by P. nanus, P. delicatulus and R. tunneyi. These species differ from their arid zone counterparts where State II assemblages are dominated by Notomys alexis and Pseudomys hermannsburgensis (Letnic and Dickman 2010). Finally, surveys in the high rainfall zone conformed to State III arid zone assemblages, with rodents and marsupial groups including predatory dasyurids dominating. State III assemblages were dominated by rodents  and the large dasyurid predator Dasyurus hallucatus on rocky substrates. State III assemblages also included bandicoots (Isoodon macrourus and I. auratus), arboreal rodents (Mesembriomys macrurus and Conilurus penicillatus) and infrequently trapped possums (e.g. Wyulda squamicaudata) and small macropods . The latter groups, comprising CWR mammals, have become extinct since European settlement in central Australian grasslands This study confirms the existence of alternative assemblage states for mammals in tropical savannas of the Kimberley region. A proposed model depicting these states is shown in Sminthopsis macroura, S. virginiae, Planigale ingrami, P. maculata and Pseudantechinus ningbing occurred throughout Kimberley. However, they never occurred at high abundance, nor were they ever more common than other mammal groups. In contrast, arid assemblages are often dominated by small dasyurids (i.e. State I) A key difference between the arid zone assemblages described by Letnic and Dickman D. hallucatus, P. tapoafata), bandicoots and arboreal rodents have generally been restricted to high rainfall savannas in the Kimberley and Top End regions since the 1980s The assemblages described here correspond closely with previous reports on mammals in the Kimberley savannas Key transition triggers for changes in mammal assemblage state in central Australian grasslands are rainfall events that drive ephemeral pulses of primary production, and wildfires, drought, grazing by introduced herbivores and predation by introduced predators (cats and foxes) D. hallucatus) Despite the predictability of these patterns, assemblage states were not fixed; for example, State II assemblages sometimes occurred in the high rainfall zone and State III assemblages in the medium rainfall zone. Several other studies have also documented changes in assemblage states at particular sites over time High regional stability among assemblages of Kimberley savanna mammals in response to inter-annual differences in rainfall suggests that transitions there are governed differently from those in central Australian grasslands. Because savanna productivity is generally relatively high due to higher rainfall than in more arid regions, factors that effect downward state transitions may assume more importance in driving assemblage changes. Such factors operating in the savannas may also explain the relatively low abundance of mammals in most Kimberley assemblages relative to those in the arid grasslands during periods of population irruption Predation by introduced cats and foxes drives mammal assemblages towards lower states in arid regions Of the predators in the Kimberley savannas, dingoes are most likely to have a top-predator role and to influence mammal assemblage states. Ecological theory and many empirical observations show that where resource pulses are regular, as in the Kimberley relative to the arid zone, predators often maintain higher and more stable populations and can then exert strong regulatory effects on prey If dingoes act as \u2018biodiversity regulators\u2019 As in the conceptual model for arid Australian assemblages, fire regimes and introduced herbivores have major influences on assemblages of savanna mammals Arid zone mammals typically occur as State 0 or State I assemblages for long periods until shifted up by large but infrequent flooding rains The cat-ecosystem productivity hypothesis posited here, and depicted in"}
+{"text": "It has been previously shown that loss of consciousness is associated with a breakdown of dominating fronto-parietal feedback connectivity as assessed by electroencephalogram (EEG) recordings. Structure and strength of network connectivity may change over time. Aim of the current study is to investigate cortico-cortical connectivity at different time intervals during consciousness and unconsciousness. For this purpose, EEG symbolic transfer entropy (STEn) was calculated to indicate cortico-cortical information transfer at different transfer times.The study was performed in 15 male volunteers. 29-channel EEG was recorded during consciousness and propofol-induced unconsciousness. EEG data were analyzed by STEn, which quantifies intensity and directionality of the mutual information flow between two EEG channels. STEn was computed over fronto-parietal channel pair combinations  to analyze changes of intercortical directional connectivity. Feedback  and feedforward  connectivity was calculated for transfer times from 25 ms to 250 ms in 5 ms steps. Transfer times leading to maximum directed interaction were identified to detect changes of cortical information transfer  induced by unconsciousness (p<0.05).The current analyses show that fronto-parietal connectivity is a non-static phenomenon. Maximum detected interaction occurs at decreased transfer times during propofol-induced unconsciousness . Strength of maximum feedback interaction decreases during unconsciousness (p\u200a=\u200a0.026), while no effect of propofol was observed on feedforward interaction. During both consciousness and unconsciousness, intensity of fronto-parietal interaction fluctuates with increasing transfer times.Non-stationarity of directional connectivity may play a functional role for cortical network communication as it shows characteristic changes during propofol-induced unconsciousness. Altered states of consciousness are associated with changes in directional (effective) and functional connectivity within a fronto-parietal network. This is observed as a common phenomenon during anesthesia, vegetative states and sleep Recent studies show that functional connectivity of cerebral areas is not a static phenomenon, but shows spontaneous fluctuations over time However, so far, fluctuations of neuronal network connectivity have been shown for functional connectivity as measured by functional magnetic resonance imaging (fMRI). The current study evaluates whether directional cortical connectivity as measured by electroencephalogram (EEG) may also show fluctuations, but in the range of milliseconds Fifteen healthy male volunteers  participated after approval by the university's ethics committee  and informed written consent. The study was conducted in the department of anesthesiology of the Technische Universit\u00e4t M\u00fcnchen, Germany. Standard monitoring parameters and 29-channel EEG  were continuously recorded with a sampling rate of 5 kHz using BrainAmp  electroencephalographic amplifier and BrainVision Recorder  data acquisition software. Propofol was administered by a target controlled infusion pump . Subjects received propofol in stepwise increasing concentrations until loss of consciousness occurred, which was defined clinically when subjects stopped following the investigator's instruction to squeeze his hand. TCI concentration at this point was maintained for 10 minutes to allow equilibration. EEG was recorded without drug application  and during propofol-induced unconsciousness (10 minutes). Basic artifact detection  and average reference were performed on EEG recordings.In existing EEG data of propofol-induced unconsciousness we applied EEG analysis within the framework of an information-theoretic approach allowing a model-free exploration of directed interactions between frontal (process X) and parietal (process Y) electrodes. For this purpose, EEG symbolic transfer entropy (STEn) was calculated For calculation, STEn analyzes consecutive sequences For frontal (x) and parietal (y) EEG this indicates feedforward parietal \u2192 frontal projections between parietal and frontal electrodes . STEn was computed over fronto-parietal channel pair combinations at consciousness and propofol-induced unconsciousness using one artifact free EEG signal of 10 s length for each subject . Acording to the signal length criterion Values of STEn may indicate spurious interdependencies in the EEG caused by spectral changes. To address this question, surrogates from the electroencephalographic signals were derived by maintaining the spectral amplitudes  and randomising the phase  non-parametric STEn showed consistent results even in different setups, e.g. embedding parameters, electrode montage Further studies with different anesthetics and altered states of consciousness are required to clarify some open points. Unconsciousness was induced by propofol. Therefore, it remains an open question, whether the detected results are a propofol-specific phenomenon or reflect characteristics of unconsciousness in general. The small number of subjects and low spatial resolution of the fronto-parietal network analyzed in EEG represent further limitations. Method inherent issues can not be fully excluded. Estimation of transfer times as performed in the present analysis may also include intrinsic prediction within one area In conclusion, our results indicate that cortical information transfer is not a static process but fluctuates periodically. Fluctuations of directional connectivity seem to reflect an intrinsic phenomenon of the brain to energetically optimize cortical communication. Characteristically, fluctuations are changed during propofol-induced unconsciousness towards faster information transfer. At the same time, the amount of parieto-frontal feedforward projections is not reduced during unconsciousness, while fronto-parietal feedback interactions are reduced. Both the inhibition of feedback connectivity and the altered fluctuation of information transfer during propofol administration are proposed as functional correlates of loss of consciousness."}
+{"text": "Quality of Life (QoL) data from oncology trials may have missing data which cannot be assumed to be missing completely at random (MCAR) . IgnorinWe searched MEDLINE (2002-2012) to identify oncology trials reporting longitudinal analysis of QOL data. The appropriateness of the analysis was reviewed and trials reporting QOL as primary/secondary endpoint were assessed for reporting quality using the CONSORT extension for PROs .69 RCTs reporting longitudinal QOL analyses were identified. 29 (42%) use an analysis to account for the nature of the missing data. Methods varied widely, eg pattern-mixture models, conditional linear models, QTWiST, joint longitudinal models, generalised estimating equations, selection models and Markov models. Fourteen papers used more than one method check the robustness of their results.In order for QOL data to adequately inform clinical decision-making the correct analysis needs to be performed. Statistical methods ignoring the missing data were found to over-estimate QOL but it was rare for the significance of QOL differences between treatments to change. A strategy for appropriate analysis of QOL data will be presented using case studies to highlight where ignoring informative missing data could alter the conclusions regarding treatment differences."}
+{"text": "Progressive increase of temperatures as well as longer seasonal drought periods revealed by climate studies correspond to fast environmental changes that forest species face with their actual genetic background. Natural selective processes cannot develop an adaptive response within this time frame. Thus the capability of forest tree species to adapt to the new environments will depend on their genetic background, but also rely on their phenotypic plasticity. Several reports have shown the involvement of epigenetic modifiers as the basis of the phenotypic plasticity, and in particular to the adaptation to abiotic stresses. DNA methylation (methylation of cytosine residues)is one the most important epigenetic modification in eukaryotes. Itis involved in specific biological processes such as gene transcription regulation, gene silencing, mobile element control or genome imprinting.Therefore, there is a great interest in analyzing cytosine methylation levels and distribution within the genome.HpaII and MspI are isoschizomers that are frequently used to detect cytosine methylation. HpaII cannot cleave if one or both cytosines are fully methylated (in both strands), whereas MspI cleaves C5mCGG but not 5mCCGG sequences). For each sample, MSAP analysis is performed using both EcoRI/HpaII and EcoRI/MspI digested samples. Comparative analysis between EcoRI/HpaII and EcoRI/MspI fragment patterns allows the identification of two types of polymorphisms: (1) \u201cMethylation-insensitive polymorphisms\u201d that are associated with genetic variability and will show common EcoRI/HpaII and EcoRI/MspI profiles among samples; and (2) \u201cMethylation-sensitive polymorphisms\u201d that are associated with epigenetic variability and detected as amplified fragments differing in their presence or absence or in their intensity between EcoRI/HpaII and EcoRI/MspI patterns of the same sample. Thus, full methylation of the internal cytosine at the assayed CCGG sites will be associated with fragments detected in EcoRI/MspI pattern which are absent or less intense in EcoRI/HpaII profile. Hemi-methylation of the external cytosine will be associated with fragments observed in EcoRI/HpaII pattern which are absent in EcoRI/MspI profile.In order to analyze methylation-sensitive anonymous CCGG restriction sites we used MSAP technique (Methylation-Sensitive Amplified Polymorphism), an AFLP-based technique for the analysis of cytosine methylation. The technique is based on the use of isoschizomers that show differential cleavage sensitivity to cytosine methylation. Fagus sp.) and gymnosperm (Pinus sp.) species.We have optimized DNA methylation analysis for two forest tree species, including both angiosperm (Pinus pinea L. a specie which is characterized by a low genetic variability and high level of phenotypic plasticity. Representative populations spanning the whole distribution of this specie within Spanish geography were chosen for this study, including coastal and interior populations. MSAP patterns from vegetative propagated trees were compared among and within populations. Percentage of methylation-sensitive polymorphisms was calculated and selective markers were identified.The set-up of the MSAP technology has allowed study intra-specific variability of DNA methylation in Fagus sylvatica L. in response to water deficit we analyzed two populations of beech from Spain and Sweden which differ in the response to water stress. Patterns of DNA methylation clearly differed between populations. Although the rate of DNA methylation was similar between irrigated and non-irrigated trees in each polpulation after AMOVA, some specific MSAPs associated with water stress response were identified.To test a possible role of DNA methylation in the plasticity of"}
+{"text": "DNase I hypersensitivity (DHS) combined with next generation sequencing (DNase-seq) is an efficient way of observing, in a single experiment, the genome-wide chromatin effects associated with the binding of multiple transcription factors. Using quantitative contrasts of DHS before and after estrogen and androgen stimulation in breast and prostate cancer cell lines, we have shown that differential DHS can accurately predict hormone induced transcription factor binding. Despite its effectiveness, the DHS assay can vary significantly depending on the experimental parameters. To increase the robustness of this assay, we have systematically evaluated two major parameters, digestion level and fragment size. We found that while there is a broad range of suitable digestion level, over-digestion dramatically decreases the efficiency of detecting DHS regions. More interestingly, we found that different fragment sizes capture distinct chromatin elements, and thus represent different chromatin structures. We were able to classify different combinations of estrogen receptor coregulators that resulted in different local chromatin structures."}
+{"text": "Aging is worldwide recognized as a dominant risk factor for most forms of cardiovascular disease -3. HowevIn adult and elderly humans, high levels of physical activity preserve the protective role of preinfarction angina against in-hospital mortality and cardiogenic shock after myocardial infarction. More recent data indicate that higher levels of physical activity performed before primary coronary angioplasty may independently predict the reduction of early and late cardiac mortality in older infarcted patients . Accordi"}
+{"text": "Mitotic chromosome motions have recently been correlated with electrostatic forces, but a lingering \"molecular cell biology\" paradigm persists, proposing binding and release proteins or molecular geometries for force generation.Pole-facing kinetochore plates manifest positive charges and interact with negatively charged microtubule ends providing the motive force for poleward chromosome motions by classical electrostatics. This conceptual scheme explains dynamic tracking/coupling of kinetochores to microtubules and the simultaneous depolymerization of kinetochore microtubules as poleward force is generated.We question here why cells would prefer complex molecular mechanisms to move chromosomes when direct electrostatic interactions between known bound charge distributions can accomplish the same task much more simply. Molecular mechanisms underlying mitosis, particularly those associated with directed chromosome movement during the cell cycle, have been pursued intensely over the past two decades with no clear picture emerging--or is there? Recent experiments identify positively charged kinetochore-associated molecules  that likely interact with negatively charged microtubule ends to generate electrostatic-dependent poleward forces that drive chromosome motion . This coIndeed, current thought on mitotic motions is shifting from a molecular to a more electrostatics-based framework -3, and psic] attempted to explain chromosome motions by nanoscale electrostatics and unnecessary sophistry...\" [Perhaps the most surprising part of this story is the untimely resistance to classical electrostatics by the cell biology community. For example, critiques including \"...groundless speculations in which the authors [stry...\" , and reqstry...\"  suggest stry...\" ,2, and istry...\"  and redustry...\" .To gain perspective on this subject, it may be instructive to consider the problem of cell division in an evolutionary context, and more specifically in an ancestral cell that lacked \"modern\" molecular machinery. Clearly, cells have been dividing since the origin of life, and the mechanisms underlying this fundamental process in modern cells are likely derived from some ancestral state--just like other cellular processes  were likely derived from ancestral, catalytic RNAs that were later supplemented with supporting proteins. In a simple cell, all chromosome movements during mitosis are readily explained by electrostatic interactions between core components of the system , without the requirement for supplemental protein machinery -6. Why tOur current bottleneck in understanding mitotic chromosome movements seems reminiscent of another challenging question in our imperfect scientific history, namely the self-imposed constraints of ancient Greek astronomers in trying to explain geocentric planetary motions with perfect circles. Indeed, layers of epicycles were incorporated into an increasingly complex scheme of integrated circles that was \"understood\" by only the best natural philosophers of the time. It took ~2,000 years of scientific work by Brahe, Galileo, Kepler and Newton to achieve the simplicity of a modern theory based on a different conceptual scheme, i.e., elliptical orbits in a heliocentric solar system.Twenty years ago, Guenter Albrecht-Buehler lamented the view of many cell biologists that \"molecular analysis of cellular functions\" is the only acceptable approach to cell biology , yet thiThe authors declare that they have no competing interests.DHS made intellectual contributions and drafted the manuscript. LJG conceived the study. All authors read and approved the final manuscript."}
+{"text": "We conducted a qualitative study to gain insight into the high retention rate and variable outcomes achieved in the 3-year PODOSA (Prevention of Diabetes and Obesity in South Asians) family-based cluster randomised controlled trial of a dietitian-delivered lifestyle modification intervention.We interviewed 21 trial participants and family volunteers following trial completion. Purposive sampling ensured representation of the diversity within the trial population. Data were thematically analysed. Findings were shared with trial dietiticans once the trial had closed.Many participants were aware of their family history of diabetes and attracted by the availability of information and monitoring. Offering home or clinic-based interventions, communication in the participant's chosen language(s) and excellent relationships between participants and dieticians contributed to retention. Adaptations in food choices were accommodated by participants, although community and faith based considerations made consistent adherence challenging. Participants found increasing their level of physical activity difficult given other demands, including long working hours, physically demanding employment and domestic commitments.Undertaking qualitative research allowed in-depth insight into participation, retention and adherence in the PODOSA trial. The main benefit participants sought was information regarding diabetes. Home-based interventions and continuity in dieticians were included in trial design, but it was not anticipated that these relationships would contribute so greatly to retention. Adaptations in food choices were not felt to be an extra burden upon participants but were made more difficult due to cultural considerations. Increasing levels of physical activity were felt to be an additional burden, again augmented by cultural considerations."}
+{"text": "Rodent models of heterotopic cardiac transplantation are important for gaining a better understanding of heart allograft rejection. This study compared a working heart (WkHt) transplant model, which have developed by our laboratory, with the traditional non-working heart (Non-WkHt) model using cardiac MRI (CMRI) and pathological evaluation. Our results indicate that the physiological hemodynamic loading significantly impacts graft immune cell infiltration and myocardial function. Our WkHt transplant model with intact pulmonary circulation, retains hemodynamic loading close to that of native heart, and is thus more appropriate for both functional and immunological studies, especially for developing the clinically relevant CMRI techniques for comprehensive evaluation of the heart graft.The traditional heterotopic heart transplantation rodent model ,2 lacks WkHt model: En bloc of graft heart and lung was transplanted into the recipient abdomen. Graft aorta and superior vena cava (SVC) were anastomosed with recipient abdominal aorta and inferior vena cava (IVC), respectively.,4 Non-WkAlthough isograft hearts from both models had strong heart beats and normal ECG, they exhibited very different cardiac functions revealed by CMRI Fig.. The WkHOur results indicate that hemodymamic loading significantly impacts the graft status. The WkHt transplant model, with intact pulmonary circulation, retains physiological conditions close to that of the native heart, and therefore is more appropriate for functional and immunological studies, especially for developing the clinically relevant CMRI techniques for comprehensive evaluation of the heart graft.This study is supported by grants from the National Institutes of Health (P41EB001977 and R01HL-081349)."}
+{"text": "Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFOX) is a common chemotherapeutic regimen for advanced colorectal cancer. Here, we present a case of interstitial lung disease associated with FOLFOX therapy.A 74-year-old man with a history of metastatic colorectal cancer was admitted with a four week history of progressive dyspnoea and evidence of severe respiratory failure. He had recently completed six cycles of FOLFOX chemotherapy in the months prior to presentation. Investigations did not reveal convincing evidence of infection or pulmonary embolism. CT chest demonstrated widespread pulmonary infiltrates and interlobular septal thickening. The patient was commenced on both broad spectrum antibiotic therapy and high dose corticosteroid treatment however his respiratory failure continued to progress. The patient died four days after admission due to progressive respiratory failure. Subsequent post-mortem examination demonstrated evidence of diffuse alveolar damage without evidence of tumour infiltration, infection or pulmonary embolism.Although infrequent, pulmonary toxicity can occur in association with FOLFOX therapy. Cessation of therapy and prompt initiation of corticosteroids may improve outcomes. Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFOX) is an effective chemotherapeutic regimen for advanced colorectal cancer, improving survival with acceptable tolerability and side effect profile.A 74-year-old man with a history of metastatic colorectal cancer was admitted with a four week history of progressive dyspnoea and haemoptysis. He had undergone a right hemicolectomy three and a half years previously for a Duke\u2019s A colorectal cancer. Three years post resection, a large single liver metastasis was identified with no other evidence of metastatic disease on PET scanning. CT examination of the chest at the time demonstrated only mild emphysematous changes .The patient was commenced on FOLFOX chemotherapy  and underwent six cycles from October to December 2008. A re-staging CT scan in January 2009 demonstrated progressive malignant disease with multiple new metastases within the liver. Chest imaging at this time revealed bilateral peripheral subpleural reticular changes and interlobular septal thickening without evidence of overt lung metastases . No chanThe patient subsequently presented in early February 2009 with four weeks of worsening dyspnoea and haemoptysis. His Creactive protein level was moderately elevated although white cell count and differential were normal. Arterial blood gases demonstrated severe type I respiratory failure. CT pulmonary angiogram excluded pulmonary embolism but demonstrated new patchy infiltrates with interlobular septal thickening . Sputum He was commenced on empirical broad spectrum antibiotics and high dose intravenous corticosteroid therapy. His respiratory failure worsened and after discussion with both the patient and his family, mechanical ventilation was not administered. The patient died four days after admission from progressive respiratory failure.Post-mortem examination did not demonstrate evidence of an infective aetiology on staining and culture of fresh specimens. There was also no evidence of emboli, thrombus or malignant infiltration within the lungs. Histological examination demonstrated widespread generalised changes within both lungs, with oedema, intra-alveolar haemorrhage and fibrin deposition along with interstitial and intraluminal fibroblastic proliferation without mature fibrosis. These findings were consistent with diffuse alveolar damage.Diffuse alveolar damage (DAD) is a common histopathological finding in patients with ARDS and is commonly associated with infections (both respiratory and systemic). It is more frequently seen in immunocompromised patients. Although drug reactions are a relatively uncommon cause of DAD, chemotherapeutic agents are overrepresented as potential precipitants. Mortality following histologically proven DAD obtained from surgical lung biopsy has been reported to be greater than 50%.7et al. demonstrated improved response rate, median time to progression and overall survival in patients with advanced colorectal cancer treated with FOLFOX in comparison to a regimen utilising Irinotecan instead of Oxaliplatin.17Oxaliplatin, in combination with 5-fluorouracil and leucovorin (FOLFOX) has been shown to be an effective regimen for the treatment of advanced colorectal cancer.Although pulmonary toxicity from FOLFOX appears to be an uncommon and apparently idiosyncratic effect of therapy, this case highlights the importance of clinicians being aware of this potentially fatal complication and the importance of regular follow-up.Given the temporal relationship between the use of FOLFOX and the onset of radiological changes and clinical symptoms, we believe that FOLFOX is the likely precipitant in this case. Whilst this appears to be an uncommon adverse effect, early recognition may allow prompt cessation of FOLFOX therapy and initiation of systemic corticosteroids, and this has the potential to improve outcomes for such patients."}
+{"text": "Batrachochytrium dendrobatidis - Bd) are major drivers of amphibian declines worldwide. Habitat loss regulates host-pathogen interactions by altering biotic and abiotic factors directly linked to both host and pathogen fitness. Therefore, studies investigating the links between natural vegetation and chytridiomycosis require integrative approaches to control for the multitude of possible interactions of biological and environmental variables in spatial epidemiology. In this study, we quantified Bd infection dynamics across a gradient of natural vegetation and microclimates, looking for causal associations between vegetation cover, multiple microclimatic variables, and pathogen prevalence and infection intensity. To minimize the effects of host diversity in our analyses, we sampled amphibian populations in the Adirondack Mountains of New York State, a region with relatively high single-host dominance. We sampled permanent ponds for anurans, focusing on populations of the habitat generalist frog Lithobates clamitans, and recorded various biotic and abiotic factors that potentially affect host-pathogen interactions: natural vegetation, canopy density, water temperature, and host population and community attributes. We screened for important explanatory variables of Bd infections and used path analyses to statistically test for the strength of cascading effects linking vegetation cover, microclimate, and Bd parameters. We found that canopy density, natural vegetation, and daily average water temperature were the best predictors of Bd. High canopy density resulted in lower water temperature, which in turn predicted higher Bd prevalence and infection intensity. Our results confirm that microclimatic shifts arising from changes in natural vegetation play an important role in Bd spatial epidemiology, with areas of closed canopy favoring Bd. Given increasing rates of anthropogenic habitat modification and the resulting declines in temperate and tropical frogs, understanding how vegetation cover and disease interact is critical for predicting Bd spread and developing appropriate management tools for wild populations.Habitat loss and chytridiomycosis (a disease caused by the chytrid fungus  Anthropogenically driven habitat change has important implications for host-pathogen interactions, because even slight changes in environmental conditions can modify numerous biotic and abiotic factors that influence these interactions Batrachochytrium dendrobatidis (Bd), for instance, is more prevalent and occurs at higher infection intensities in pristine tropical forests compared to disturbed habitats Bd-induced amphibian declines Shifts in microclimate and changes in host community structure across gradients of habitat alteration play important roles in amphibian epidemiology Bd, thus limiting pathogen growth and persistence Bd persistence in these environments From the host's perspective, immune responses usually decrease as a result of the multiple effects of habitat alteration Bd  in populations of the common Green Frog (Lithobates clamitans) across a gradient of natural vegetation and microclimate. We sampled frogs in the southern Adirondack Park, New York State, a region with relatively low amphibian diversity and high dominance of this habitat generalist host Bd in amphibians and (ii) test for causal associations linking vegetation cover and microclimate with both Bd prevalence and infection intensity. Combined, these goals may elucidate whether vegetation and microclimate modulate disease risk in temperate amphibian populations affected by anthropogenic habitat change.Here, we examined the infection dynamics of Bd is enzootic and widespread in the northeastern U.S. Bd growth in this region Lithobates clamitans, Ranidae), the locally dominant amphibian host species. Green Frogs breed in permanent ponds during the boreal spring and summer, and typically spend most of the time at the shallow banks of water bodies \u22121. We recorded body weight (g) for each captured individual and screened post-metamorphic frogs with sterile swabs to quantify Bd prevalence and infection intensity (average of 16.6 L. clamitans per site). We tested samples for Bd in singlicate using Taqman qPCR Bd in each sample. This protocol maximizes amplification efficiencies by diluting extracts to reduce inhibition in environmental samples. For calculations of Bd prevalence, we categorized individuals as Bd-positive when their qPCR showed an infection load of greater than or equal to one g.e. Bd prevalence as the percentage of infected individuals and Bd infection intensity as average number of g.e. per population.We sampled anuran populations in the Adirondack Park of the State of New York . This region is heavily forested with elements representative of temperate and boreal forests \u22121) as a proxy for host population density. We specifically chose this study system because of its relatively low species diversity and high single host species dominance. These community attributes allow us to test hypothesis about the roles of microclimate in disease dynamics without the potential effects of complex host community structure. Nonetheless, we recorded host community diversity , and we reported the model with the highest goodness-of-fit for each run. We also used CAR to test for associations of natural vegetation with host population  and community attributes .To control for the effects of spatial autocorrelation among ponds, we analyzed our data using conditional autoregressions (CAR). We used CAR to test the relationship of each explanatory variable with Bd infection parameters. Because canopy density may be a better proxy for microclimate than our actual temperature records from a single data logger per pond, we tested an alternative path diagram in which canopy density directly affected Bd infection parameters. We compared goodness-of-fit among models using Expected Cross-validation Index (ECVI), an AIC-based index. We conducted CAR using Spatial Analysis in Macroecology v4.0 We used path analyses to statistically test for the strength of unidirectional cascading effects linking natural vegetation, canopy density, water temperature, and Bd at all study sites with mean prevalence of 24.25%\u00b116.41 SD and mean infection intensities of 29.36\u00b1151.60 SD, reaching a maximum load of 1063.23 g.e. in our focal species without observed mortalities. Canopy density was the best predictor of Bd prevalence in L. clamitans , maximum daily average temp. , minimum daily average temp. ], and natural vegetation . We found no significant relationships between Bd prevalence and average body weight, capture rate, elevation, host community diversity, or overall host community biomass.We detected Bd infection intensity. Canopy density best predicted Bd infection intensities , maximum daily average temp. , minimum daily average temp. ], natural vegetation , average body weight , and capture rate  were also significant predictors of Bd infection intensity in L. clamitans. Similar to prevalence, we found no direct associations of Bd infection intensity with elevation, host community diversity, or overall host community biomass.We found similar results for Bd prevalence and infection intensity, our model selection identified three key environmental factors: canopy density, natural vegetation, and daily average water temperature  and infection intensity  underscores the dominance of the focal species across this landscape . The amount of natural vegetation surrounding our sampling ponds did not significantly predict host population and community attributes; namely host average body weight , host capture rate , overall host community biomass , species richness , and host diversity .The high evenness and low diversity among our sampling ponds . Although these species may help maintain Bd throughout the cold months, it is unlikely that they have a strong effect on disease dynamics later in the season, because they spend long periods of time away from water bodies Bd growth Bd infections in the wild Bd prevalence and infection intensity in temperate amphibian populations by modulating shade and associated microclimatic patterns, and that host community structure plays at most a minor role in our study system.The effects of habitat loss and forest fragmentation on host-pathogen interactions are varied Bd prevalence and infection intensity were environmental variables associated with vegetation cover and microclimate  in Pennsylvania showed that the proportion of leaf-litter and vegetation in the pond substrate correlated positively with Bd prevalence and infection intensity Bd transmission by providing substrates for Bd growth. Alternatively, leaf-litter may be an indicator of canopy cover and total degree of shade, which are potentially the true drivers of higher Bd levels in natural forest habitats. Similarly, in Costa Rica and Australia, localities with little to no canopy cover may provide amphibians with a refuge from Bd-induced extinction Bd year round (above 69%) Bd infections by environmental factors is a general phenomenon, and that these environmental controls linking natural vegetation to Bd dynamics are similar in tropical and temperate amphibian communities.The best predictors of mate see . The amontensity . A studyBd growth and persistence in both host and the environment, and (ii) by changing host's ability to fight and clear Bd through thermoregulation. The growth rate of Bd in the laboratory is strongly temperature-dependent, with an optimum climatic envelope ranging between 17\u201325\u00b0C and reduced persistence at temperatures above 28\u00b0C Bd growth may have been limited during some periods in our highest-temperature ponds. In fact, in four of our ponds 40.85\u00b114.42% SD of water temperature records were above 25\u00b0C during the study period. Our data closely match the association between Bd infections and temperature found by Raffel et al. Bd infection intensities and prevalence at sites with average water temperatures above 23\u00b0C. In the State of Maine, USA, Bd infections were lower during the peak of the summer than in spring and fall, presumably because water temperatures often exceeded the optimal temperature range for Bd growth Bd-infected frogs were largely absent from sites where spring water exceeded 25\u00b0C Bd strain showed that pathogen growth in vitro is hampered by short exposures  to high temperatures that would typically be available to frogs at basking sites Bd infections Bd infection and transmission in open habitats Bd loads Bd infection intensity and frog survival were unrelated to water temperature Microclimate can affect amphibian disease risk in two ways by (i) regulating Bd system are larger than the effects imposed by density-dependent forces that typically predict prevalence and infection intensity in other temperate amphibians Bd infection intensity, potentially indicating density-dependent controls; however, this effect was marginal and capture rate was not a significant predictor of Bd when considered together with environmental factors in model selection. The potential effect of density on Bd was not linked to forest cover because we did not detect a significant effect of natural vegetation on host capture rate. Pathogen build-up to lethal infection intensities is more likely to occur in dense populations, under conditions that promote continuous reinfection of the hosts Our results indicate that the small-scale effects of vegetation and microclimate on our host-Bd susceptibility Bd prevalence and infection intensities. One potential explanation is that disease risk drops with age in response to host-acquired immunity, as repeated exposure to a given pathogen increases host resistance Bd infection intensity when considered independently, this parameter became a weak predictor when considering other environmental variables in the analysis. This weak effect of host body weight on Bd infection coupled with the fact that vegetation cover had no influence on host capture rate is an indication that, in our study system, habitat change has a larger influence on pathogen fitness than on host fitness. This result suggests that our focal species is highly resistant to Bd regardless of microclimate and vegetation. In fact, L. clamitans persists with a local Bd strain in the laboratory within optimal Bd grow temperatures Earlier studies in both tropical and temperate zones have found ontogenetic differences in Bd infections in both temperate and tropical systems Bd epidemics Bd resistance or tolerance could be a useful tool for assisted reintroductions in the wild Bd is most prevalent. With the high rate of anthropogenic modification to temperate and tropical forests, understanding how vegetation cover and disease interact is critical for predicting Bd spread and developing appropriate management tools for wild populations. Our results indicate that species-specific in situ management strategies will need to consider fine-scale microclimatic factors to safeguard Bd-susceptible species with narrow geographic distributions We have shown that disturbances to natural forest habitats reduce Table S1Model selection for environmental and biological variables influencing Batrachochytrium dendrobatidis (Bd) prevalence and infection intensity in populations of Lithobates clamitans in the Adirondack region, New York, USA.(DOCX)Click here for additional data file."}
+{"text": "This study intends to develop a physiologic thumbprint for nonconvulsive seizures (NCSz) after acute brain injury. Abnormal electrographic brain activity including NCSz is common after acute brain injury and is associated with poor outcome. Mechanisms underlying this phenomenon are poorly understood but in animals periods of inadequate perfusion during seizures have been documented. In the present study we hope to gain better understanding of the relationship between abnormal electrographic patterns and brain homeostasis in patients with subarachnoid hemorrhage (SAH).2), regional cerebral blood flow (rCBF), and intracranial pressure monitoring; 69% (n = 36) also with intracortical EEG . Each minute of EEG  was categorized separately into non-ictal, on the ictal-interictal continuum (including periodic discharges at 2 Hz or faster), or seizures. We identified seizure onsets on ICE recordings and extracted the physiologic monitoring data 30 minutes pre and post seizure onset. Physiologic profiles based on standard error of the means plots were generated using high-frequency time series physiologic measurements and interpreted by visual analysis.Between June 2006 and June 2010, 51 poor-grade SAH patients underwent multimodality monitoring with microdialysis, brain oxygen tension  of patients with ICE recordings . NCSz were preceded by an increase in rCBF starting 15 minutes prior to onset of depth NCSz that stayed elevated throughout the observation period. Heart rate, mean arterial, intracranial, and cerebral perfusion pressures were elevated surrounding NCSZ. There was a small transient drop in PbtOThese findings confirm in comatose human beings that NCSz detected by ICE are associated with hyperemia, increased metabolism, and possibly brain tissue hypoxia, which serve as surrogates for secondary brain injury. Future research should implement novel approaches for ICU time-series data analysis, evaluate surface seizures, and utilize other surrogates of brain metabolism such as microdialysis."}
+{"text": "Groin infections resulting in arterial bleeding due to bacterial vessel destruction are a severe challenge in vascular surgery. Patients with them most often present as emergencies and therefore need individualized reconstruction solutions.Case 1 is a 67-year-old man with infectious bleeding after an autologous reconstruction of the femoral bifurcation with greater saphenous vein due to infection of a bovine pericard patch after thrombendarterectomy. Case 2 is a 35-year-old male drug addict and had severe femoral bleeding and infection after repeated intravenous and intra-arterial substance abuse. Both patients were treated with an autologous obturator bypass of the superficial femoral vein. We review the current literature and highlight our therapeutic concept of this clinical entity.Treatment should include systemic antibiotic medication, surgical control of the infectious site, revascularization and soft tissue repair. An extra-anatomical obturator bypass with autologous superficial femoral vein should be considered as the safest revascularization procedure in infections caused by highly pathogenic bacteria. Severe groin infections with inguinal blood vessel destruction may be caused by intravenous substance abuse, radiation scars, transfemoral interventions and, most commonly, infection of prosthetic vascular implants (incidence 2% to 18%). ComplicStaphylococcus aureus (MRSA) superinfection of an inguinal lymphatic fistula. For surgical control of bleeding, orthotopic revascularization with iliacofemoral and iliacoprofundal greater saphenous vein interposition and resection of the xenogenic patch material was performed, accompanied by systemic MRSA-specific antibiotic treatment. Three weeks later rebleeding occurred due to an infectious arterial pseudoaneurysm. Intra-operative findings revealed complete erosion of the profundal venous graft anastomosis  or severe claudication-7. Witho% or seveThe obturator bypass, with primary patency rates of up to 76% after 2 years, has proven to be feasible in a few small clinical series with a considerable risk of late prosthetic graft infection remaining,3,4,9-11Streptococcus in this report. With proven susceptibility of several native and prosthetic materials to MRSA and rising clinical incidence, femoral vein obturator bypass is the safest revascularization procedure with the best long-term results[To the best of our best knowledge, investigators of only one clinical series have reported the use of obturator bypass fashioned from autologous superficial femoral vein at infection sites. We ther results.Pseudomonas aeruginosa and Group B Streptococcus. It should be considered the primary treatment option by vascular surgeons confronted with this problem, especially in young patients.The extra-anatomic obturator bypass with femoral vein is a safe and feasible revascularization procedure in patients with severe groin infections and highly pathogenic bacteria such as MRSA, Written informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests and did not receive any payment from industrial partners.RK, CB, CT and AB performed surgery on the patients and were responsible for postoperative intensive medicine care. UL performed vascular graft infection studies in mice and was a major contributor in writing the manuscript. All authors read and approved the final manuscript."}
+{"text": "This case study followed one adolescent patient who underwent bilateral deep brain stimulation of the centromedian parafascicular complex (CM-Pf) for debilitating, treatment refractory Tourette's syndrome for a period of 1.5 years. Neurocognitive testing showed no significant changes between baseline and follow-up assessments. Psychiatric assessment revealed positive outcomes in overall adaptive functioning and reduction in psychotropic medication load in this patient. Furthermore, despite significant baseline psychiatric comorbidity, this patient reported no suicidal ideation following electrode implantation. Deep brain stimulation is increasingly being used in children and adolescents. This case reports on the positive neurologic and neuropsychiatric outcome of an adolescent male with bilateral CM-Pf stimulation. Tourette syndrome (TS) is a chronic, childhood onset neuropsychiatric disorder, which occurs in approximately one percent of the general population, consists of motor tics and at least one vocal tic lasting longer than one year . Tic symHigh-frequency (above 100\u2009Hz) deep brain stimulation (DBS) is being increasingly used as an efficacious treatment modality in patients with severe TS complicated by behavioral and psychiatric comorbidity that is refractory to first and second line treatment . Here, wA 17-year-old left-handed male with severe Tourette's syndrome, attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD) was evaluated by pediatric neuropsychology and child psychiatry prior to the date of electrode implantation for DBS for treatment of refractory tic symptoms. The patient was treated with bilateral centromedian parafascicular complex (CM-Pf) stimulation and was followed for 1.5 years. Preoperative neuropsychometric testing was noteworthy for borderline general intellectual functioning and commensurate academic achievement . CognitiPreoperative psychiatric evaluation demonstrated severe psychosocial impairment related to treatment refractory Tourette's syndrome. Social impairment was associated with significant amounts of missed school and anxiety related to tics. Attempts to garner employment were hampered with being overwhelmed by his neurologic symptoms. Past psychiatric history was significant for three prior psychiatric hospitalizations, all occurring within the context of managing a complicated psychotropic medication regimen, and treatment approach for comorbid psychiatric conditions . InpatiePostoperative neuropsychometric testing revealed general cognitive functioning that had remained stable across time . The patPostoperative psychiatric evaluation was noteworthy for significant functional and psychosocial gains. No concerns for suicidal or self-injurious thoughts or actions were noted. The patient's psychotropic medication load was also significantly reduced . ImproveThis case report focused on the neurocognitive and psychosocial outcomes in an adolescent male who had received DBS for severe refractory Tourette's syndrome followed for 1.5 years. This patient demonstrated no significant changes in his follow-up psychometric testing and reported significant improvement in psychosocial functioning postoperatively. He was able to decrease his psychotropic medication load during follow-up psychiatric assessments and did not report any suicidal ideation throughout the course of treatment. DBS is being increasingly used for treatment-refractory TS in adults and is an important emerging treatment modality of treatment-refractory TS within the pediatric population . Thus faCase reports documenting long-term treatment outcomes in both adults and adolescents with severe refractory TS using DBS have yielded mixed results with regards to improved psychosocial functioning and overall quality of life. Stimulation of the globus pallidus internus (GPi) was shown to be beneficial in one adolescent boy with severe TS and comorbid OCD and anxiety but had little therapeutic benefit in another patient with similar tic severity, but lacking comorbid psychiatric conditions , 7. AckeIn a larger prospective cohort study, Porta and colleagues documented improvement in tic symptoms, as well as improvement in neuropsychiatric symptoms without cognitive decline in a 24-month followup of 15/18 patients who underwent bilateral thalamic stimulation [Given the ongoing need for awareness of cognitive and psychiatric outcomes in adolescent patients who have undergone DBS treatment, we specifically focused on the neurocognitive and psychosocial outcomes in an adolescent male who had received DBS for severe refractory TS . This ca"}
+{"text": "Acute variceal bleeding continues to be associated with significant mortality. Current standard of care combines hemodynamic stabilization, antibiotic prophylaxis, pharmacological agents, and endoscopic treatment. Rescue therapies using balloon tamponade or transjugular intrahepatic portosystemic shunt are implemented when first-line therapy fails. Rescue therapies have many limitations and are contraindicated in some cases. Placement of fully covered self-expandable metallic stent is a promising therapeutic technique that can be used to control bleeding in cases of refractory esophageal bleeding as an alternative to balloon tamponade. These stents can be left in place for as long as two weeks, allowing for improvement in liver function and institution of a more definitive treatment. Acute variceal bleeding continues to be associated with significant mortality. Recently published randomized controlled trials have shown that mortality from acute variceal bleeding has decreased over the past two decades from 42% to 15%, but this figure is still remarkably high [Balloon tamponade (BT) using Sengstaken-Blakemore tube used to be the primary therapy prior to the availability of endoscopic methods. Sengstaken-Blakemore tube, was first described in 1950 , is a muSurgical management for bleeding esophageal varices falls into two categories: shunt and nonshunt procedures. Nonshunt procedures include esophageal transection and gastroesophageal devascularization. Shunt procedure is classified into selective shunts such as splenorenal shunts, partial shunts such as calibrated small-diameter portacaval shunts, and nonselective shunts such as portacaval shunts. Surgical procedures are used less frequently in the era of advanced endoscopic therapy, TIPS, and liver transplant. However, surgical intervention remains an important and effective treatment modality in selected patients . Distal TIPS is an intrahepatic shunt that is placed using a percutaneous approach. It connects the hepatic vein and intrahepatic branch of portal vein using an expandable metallic stent with a diameter of 8 to 12\u2009mm. TIPS was introduced as an alternative to surgery in the 1990s and has replaced surgical shunts in most centers . CurrentThe previously listed limitations of the current rescue therapies have led to the continued search for other methods as rescue therapy for refractory esophageal variceal bleeding.Self-expandable metal stents (SEMSs) are increasingly used in treatment of esophageal obstruction, stricture, leak, perforation, and tracheoesophageal fistula . AnecdotThe initial pilot study by Hubmann et al. in 2006 reported the use of SEMS in 20 patients with massive ongoing esophageal variceal bleeding . All patHubmann et al. published their extended series of 39 patients with massive ongoing esophageal variceal bleeding despite prior use of endoscopic or pharmacological therapy . ResultsWright et al. reported their experience using the SX-Ella Danis stent in ten patients with variceal bleeding and contraindications to TIPS insertion or balloon tamponade . The patDech\u00eane et al. recently reported their experience using SEMS  in 8 patients with refractory esophageal variceal bleeding events . One patStandard fully covered SEMSs have also been used successfully for the management of esophageal tears caused by Sengstaken-Blakemore tube or banding. These applications further confirm the important role of SEMS in the successful management of iatrogenic esophageal injuries , 26, 27.Limited data suggests that specially designed SEMS (SX-Ella Danis stent) can effectively stop refractory bleeding from esophageal varices . This stStent placement requires appropriate training and expertise. Gastric varices will not be adequately compressed by the stent and persistent variceal bleeding after stent placement should raise the suspicion for presence of bleeding gastric varices. Appropriate precautions to prevent aspiration are needed since the stent is positioned at the gastroesophageal junction. Distal stent migration into the stomach was observed frequently but was not associated with apparent complications. Stent-related compression of the left main bronchus was reported in one patient and was treated successfully with stent removal , 28. No Current rescue therapies for bleeding esophageal varices are effective in stopping the bleeding in the majority of patients . In some"}
+{"text": "Pragmatic trials of treatment pathways can require patient awareness of treatment allocation in order to better represent clinical reality, for example when concordance with a treatment has an important effect on outcome. Conversely, masking of treating clinicians to allocation group can be impossible when full clinical assessment requires knowledge of the current treatments, resources do not permit separate teams for treatment and assessment or when such duplication of clinician contact might affect an outcome such as patient experience.The LiGHT trial is a 718 subject multi-centre 6-year NIHR-funded study of two treatment pathways for glaucoma with outcome measures of health related quality of life and cost effectiveness. We aimed to minimise variation in aspects of clinical behaviour that might introduce bias by affecting either of these outcomes.Custom-written decision support software permits real-time decision-making using analysis of multiple clinical measures made by masked observers: optic disc analysis, visual field assessment and intra-ocular pressure measurements. Treatment targets are objectively defined according to disease severity criteria. Target attainment accounts for known measurement uncertainties.A treatment algorithm based on robust, published criteria determines clinical decisions that influence cost or patient experience .Where objective criteria for clinical decisions exist, it is possible to balance the competing demands of reducing bias with protocol-driven escalation criteria with a pragmatic \u2018real-world\u2019 approach to therapeutic choices permitting variation in clinical practice, in a manner acceptable to clinicians recruiting into an unmasked pragmatic trial."}
+{"text": "Picea rubens) populations at high elevation sites in Southern Appalachians to anthropogenic sulfate depositions. Red spruce seedlings are more sensitive to drought and cold stresses elicited by exposure to anthropogenic sulphate air pollution, than old trees. Genetic variation in seedlings and young trees was significantly reduced in heavily polluted stands. Several candidate genes involved in cold acclimation and calcium metabolism demonstrated signatures of selection corresponding with sulfate pollution levels. SNP allele frequencies at one gene involved in calcium metabolism demonstrated directional selection in response to anthropogenic sulfate deposition in red spruce growing at severely polluted high elevation sites, which corresponds well with the putative role of this gene in adaptation to acidification stress. Unlike range-wide experimental designs (e.g. the popular FST outlier test) and nucleotide diversity-based association studies, our within-population testing approach disentangled the confounding effects of geographic variation and demography from the genetic effects of recent selection.Rapid environmental changes, such as anthropogenic air pollution, can create significant evolutionary pressures on populations, species and ecosystems. Evolutionary processes occurring in natural populations at very short time scales, especially in response to human-induced environmental changes, are not well understood. Confounding effects of geographic variation and demography cannot be easily separated from signatures of recent selection in natural populations. We investigated the genetic response of declining red spruce ("}
+{"text": "The goal of enhanced nutrition in critically ill patients is to improve outcome by reducing lean tissue wasting. However, such effect has not been proven. This study aimed to assess the effect of early administration of parenteral nutrition (PN) on muscle volume and composition by repeated quantitative computer tomography (qCT).We performed a preplanned substudy of a randomized controlled trial (EPaNIC) that compared early initiation of PN when enteral nutrition was insufficient (early PN) with tolerating a pronounced nutritional deficit for 1 week in the ICU (late PN) [Critical illness evoked substantial loss of femoral muscle volume in 1 week, irrespective of the nutritional regimen. Early PN reduced the quality of the muscle tissue, as reflected by the attenuation, revealing increased intramuscular water/lipid content. Early PN also increased the volume of adipose tissue islets within the femoral muscle compartment. These changes in skeletal muscle integrity correlated with caloric intake. In the abdominal muscle compartments, changes were similar, albeit smaller. Femoral and abdominal subcutaneous adipose tissue compartments were unaffected by disease and nutritional strategy.Early PN did not prevent the pronounced wasting of skeletal muscle observed over the first week of critical illness. Moreover, early PN increased the amount of adipose tissue within the muscle compartments."}
+{"text": "Varanus komodoensis). The growth of 400 individual Komodo dragons was measured in a capture-mark-recapture study at ten sites on four islands in eastern Indonesia, from 2002 to 2010. Generalized Additive Mixed Models (GAMMs) and information-theoretic methods were used to examine how growth rates varied with size, age and sex, and across and within islands in relation to site-specific prey availability, lizard population density and inbreeding coefficients. Growth trajectories differed significantly with size and between sexes, indicating different energy allocation tactics and overall costs associated with reproduction. This leads to disparities in maximum body sizes and longevity. Spatial variation in growth was strongly supported by a curvilinear density-dependent growth model with highest growth rates occurring at intermediate population densities. Sex-specific trade-offs in growth underpin key differences in Komodo dragon life-history including evidence for high costs of reproduction in females. Further, inverse density-dependent growth may have profound effects on individual and population level processes that influence the demography of this species.Somatic growth patterns represent a major component of organismal fitness and may vary among sexes and populations due to genetic and environmental processes leading to profound differences in life-history and demography. This study considered the ontogenic, sex-specific and spatial dynamics of somatic growth patterns in ten populations of the world\u2019s largest lizard the Komodo dragon ( Somatic growth patterns represent a major component of an organism\u2019s life-history Sex-specific growth variation must occur to result in sexual size dimorphism (SSD), reflecting different tactics and requirements for energy acquisition and investment between maximum female and male body size Across a species distribution growth rates influencing life history and demography can vary considerably due to an interaction between genetic and environmental regulation Several issues have hindered understanding of the causes of individual growth rate variation in animals, and particularly ectotherms that experience indeterminant growth. First, most growth rate models do not accommodate potential polyphasic growth Varanus komodoensis; 300 cm snout-vent-length and 87 kg body mass). Data were collected from marked individuals from 2002\u20132010, with the aim to evaluate individual, sex-specific and spatial patterns in somatic growth. It was assumed that several energy allocation trade-offs may alter investment in growth in Komodo dragons during life-history changes including distinct transitions in habitat use, sex related growth differences pre- and post-maturation, and aging, that may occur in long-lived apex predators such as this, which have very low mortality due to predation . Each of these phenomena could result in polyphasic growth trajectories involving growth \u201clags\u201d and \u201cspurts\u201d across ontogeny. As this sort of pattern may not be possible to model with the use of standard growth models such as the von Bertalanffy growth function  in this species  was addressed. Such pronounced SSD must entail different tactics and requirements for energy acquisition and investment The final aim considered spatial variation; looking at differences in ecological, demographic and genetic factors on the islands that may account for differences in growth patterns among sites. Dragon body size varies dramatically between islands, with the presence of dwarf and giant forms in part suggesting spatial variation in growth. For Komodo dragons potential variation in growth could be mediated by differences in prey availability Rusa timorensis), feral pig (Sus scrofa) and water buffalo  The Komodo dragon is endemic to five islands in eastern Indonesia, with four island populations in Komodo National Park and several fragmented populations on Flores 2 Komodo Island); Loh Baru (Lba), Loh Buaya (Lbu), Loh Dasami (Lda) and Loh Tongker (Lto) ; and one site on each of the islands of Gili Motang  and Nusa Kode . Only two of 1062 marked Komodo dragons moved between any of the sites during the course of the study  and hence the ten sites are considered discrete closed populations.To evaluate growth patterns in Komodo dragons, a capture-mark-recapture (CMR) study was undertaken at ten sites on four islands in Komodo National Park , eastern Indonesia , during Dragons were captured in a trapping grid at each site using aluminium box traps and noose poles, and were uniquely marked with passive integrated transponder (PIT) tags . Further details of the capture program are outlined elsewhere Absolute growth rates were calculated from growth records for each individual sampled using snout-vent-length as the dependent variable, and included negative and zero growth rates because animals can shrink in size due to senescence or in response to extreme resource limitation A two-stage statistical modelling approach was used to model somatic growth Size-specific growth rates were modelled as a function of snout-vent-length using a GAMM t- and F-ratio tests The mgcv package Size frequency distributions were constructed for all male and female lizards using the SVL obtained at the first capture event. Using sex-specific age-at-size equations we predicted the mean age for each individual at first capture. To evaluate if male and female size and predicted age distributions differed significantly we performed Kolmogorov-Smirnov tests in program R is) (see methods below for determination of site estimates for each covariate). The four candidate models, including a null model, were fitted again using a GAMM approach in the mgcv package w), considering the strength of evidence that the candidate model is the best model for the data Four competing models were conceived involving three putative covariates; population density, prey availability, and level of inbreeding  Faecal counts were conducted annually from 2003\u20132010 (i.e. late dry season) at each site, with faeces of Timor deer and water buffalo counted within circular plots on 150 m transects in each site. Hand-held GPS  units were used to locate transect line starting points, and ungulate faeces were counted within 30 sample plots placed at 5 m intervals along each transect. Between 20 and 41 transects were randomly positioned and orientated at each site, providing a total of 308 transects with a total length of 45.50 km. Faecal counts of both species show positive relationships with actual density estimates derived from distance sampling V. komodoensis genetic microsatellite data sampled from eight sites is) were calculated using Genetix 4.01 is values to a frequency distribution of fixation indices obtained after 10,000 permutations of alleles.Estimates of site-specific inbreeding coefficients were obtained predominantly from previously analysed This Research was authorized under successive collaborative research memorandums of understanding (MOU), first (2002\u20132007) between Zoological Society of San Diego, The Nature Conservancy and the Indonesian Department of Forest Protection and Nature Conservation (PHKA), and second (2008\u20132015) under MOUs between the Komodo Survival Program and PHKA. Animal experimental ethics committee approval was obtained from the University of Melbourne (under Permit 0911162.1).Growth measurements were obtained from 400 individually marked Komodo dragons refer to  capturedThe estimated size-specific growth function for Komodo dragons was polyphasic with highest growth rate at the juvenile stage , and incComparing the estimated size-specific growth curves of both sexes  however,The estimated size-at-age growth curves indicate that males and females are of similar size until \u223c7 years , after wThe estimated age-specific growth function  indicateMale and female lizards exhibited significantly different frequency distributions in body size with males exhibiting substantially larger body sizes than females  exhibited: distinct sex-based differences in growth trajectories, suggesting altered energy allocation tactics with different life-stages; and spatial variability in growth rates, due to population density-dependent processes.Somatic growth dynamics of individuals and populations can have profound consequences for fitness, life-history and demography In species with indeterminate growth, where females have higher energy costs for reproduction, they must allocate nearly all energy investment from growth to reproduction after maturity ; whereas males may typically invest considerably less to ensure reproductive success increases with body size The largest females tend to be in poor body condition  due to extended periods of fasting whilst nest-guarding. Males in comparison appear to live longer presumably aided by lower reproductive costs and an absence of predation conferring higher male survival. A consequence of these sex related differences appears to be large differences in the age of maturity and also maximum longevity estimates . Female Significant variation in mean growth rates was evident among sites and islands . SupportWith size-specific growth variation among sites and islands, it would be worthwhile to detect specific habitats with distinct environmental or genetic differences in dragon growth trajectories that underpin life-history traits such as maximum body size, longevity and vital rates. Vast geographic variation in phenotypic traits are recognised in various intra- and inter-specific studies of sea turtles Our study shows that across ontogeny somatic growth of Komodo dragons is polyphasic in males, yet not in females, as a consequence of differences in energy allocation tactics regarding the onset of reproduction, which also result in an extreme contrast in longevity between sexes. This vast difference in life-span likely has a significant effect on population sex ratios, which in turn could be increasing sexual size dimorphism (SSD) within this species. In future it would be interesting to compare how SSD may vary between populations in regards to demographics and environmental quality Figure S1Mean growth year index as a predictor for growth rate in Komodo dragons. Year index was one covariate in the fitted generalized additive mixed model (GAMM). Dotted lines represent the 95% confidence interval for the fitted values.(TIF)Click here for additional data file.Figure S2Spatial variation in growth rates in Komodo dragons. Mean growth rates (cm SVL/yr) for each site indicate spatial variation in growth among sites and islands. Error bars are standard errors of site mean growth rates.(TIF)Click here for additional data file.Methods S1(DOCX)Click here for additional data file.Methods S2Methods & Results.(DOCX)Click here for additional data file.Table S1(DOCX)Click here for additional data file.Table S2(DOCX)Click here for additional data file."}
+{"text": "Dear Editor,The study named \u201cThe role of myocardial perfusion gated SPECT study in women with coronary artery disease\u201d reveals some current and important issues in diagnosing myocardial ischemia in women . BecauseOn the other hand the evaluation criterion for diagnosing ischemia seems controversial in the study. The question is that: \u201cDo the left ventricular (LV) wall motion abnormality and decreased systolic thickening at the segment with reduced perfusion in gated SPECT study necessarily show true ischemia as it is expressed in the study?This approach considers that wall motion abnormality and perfusion defects occur exactly at the same time in CAD stages, but as it is known, wall motion abnormalities follow quite a bit later after the perfusion defects appear. Myocardial hypoperfusion is first seen in ischemic cascade, and followed by decrease in metabolic activity, relaxation impairment (diastolic dysfunction), reduction in contractility (systolic dysfunction), global LV dysfunction, ECG changes and angina pectoris, respectively . So, theMore importantly, because the imaging begins 30-60 minutes after the radiopharmaceutical injection, stress\u2013gated images with Tc-99m MIBI show stress perfusion at the time of injection, but LV function  at the time of acquisition. Snapper et al. demonstrated that the combination of a perfusion defect with normal wall motion and thickening in the same segment on stress-gated MIBI images was associated with a high positive predictive value (96%) for detecting ischemia. They concluded that the diagnosis of ischemia could be made confidently in patients with normal wall thickening in a segment with perfusion defect. The lack of wall thickening was found less specific, because only 40% of the cases with perfusion defects and wall motion abnormalities showed reversibility on rest perfusion imaging . Thus, tFinally, the criterion mentioned in the study could be entirely true and supporting if all the subjects had been shown to have reversible defect (ischemia), but some patients are reported to have myocardial infarction. So the criterion might include myocardial scar in patients with fix defect (particularly when the presence of metabolic activation on the defect related with hibernation was excluded). In the routine evaluation of gated SPECT studies, wall motion abnormality and/or systolic thickening at the same segment with fixed defect primarily indicates myocardial scar. So, the inclusion criterion that the authors used in the study constitutes a great limitation for drawing true conclusions about ischemia and/or infarct without making some comparisons between post-stress and rest end-systolic and end-diastolic volumes or measuring LVEF differences together with the wall motion abnormalities.The evaluation criteria to differentiate ischemia, infarct and soft tissue attenuation artifacts in stress-rest gated SPECT imaging may be simply summarized as below:1. Normal perfusion with no wall motion abnormality or TID: Normal2. Normal perfusion with wall motion abnormality or TID: Stunning (and/or multivessel disease?).3. Reversible ischemia with no wall motion abnormality, TID or reduced LVEF in stress-gated images: Ischemia.4. Reversible ischemia with wall motion abnormality, TID or reduced LVEF in stress-gated images: Severe ischemia with increased cardiac event rate.5. Fixed defect with normal wall motion or wall thickening: Soft tissue attenuation artifact.6. Fixed defect with wall motion or wall thickening abnormality: Myocardial scar."}
+{"text": "Cryopreservation and transplantation of ovarian tissue is one option for re-establishing ovarian function, but optimal conditions for graft sustainment and follicular survival are still considered experimental. The present study aims to analyze the effect of FSH treatment on the resting follicle pool in fresh and cryopreserved primate ovarian tissues following xenografting.Ovarian tissues from adult marmosets were grafted freshly or following cryopreservation to ovarectomized nude mice treated with FSH 25 IU twice daily post transplantation or left untreated as controls. Grafts were retrieved 2 or 4 weeks after transplantation to evaluate the number and morphological appearance of follicles.Early start of FSH treatment within 1 week following transplantation partly prevents primordial follicle loss in fresh and frozen-thawed tissues, whereas after a 3 weeks time interval this effect is present only in fresh tissues. A similar positive effect of early, but not later FSH treatment on primary follicles is seen in fresh tissues compared to only marginal effects in frozen-thawed tissues. The percentage of morphologically normal follicles is generally increased in FSH treated tissues, whereas the percentage of primary follicles over all primordial and primary follicles is increased by FSH only in freshly-grafted tissues.FSH treatment alleviates depletion of the resting follicle pool and promotes normal follicular morphology both in freshly and frozen-thawed grafted tissues. In previously cryopreserved tissues, applying to most of the tissues intended for clinical use in fertility preservation attempts, its positive effect on primordial follicle numbers and potential graft sustainment is dependent on an early start of treatment within one week of transplantation. Increasing cancer survival rates and awareness of fertility as a quality of life issue in long-term cancer survivors have fuelled the growing demand for fertility preservation in recent years . In femain vitro study has confirmed equal effectiveness of human recombinant FSH compared to marmoset FSH on the marmoset FSH receptor . Grafting duration has no influence on mean primordial follicle numbers  compared to untreated tissues  but not at 4 weeks  and frozen-thawed (29.9+/\u22122.9%) ovarian tissues. In freshly grafted tissues, these proportions decrease significantly after transplantation and then remain stable over time , but not FSH-treated tissues (p=0.411; Figure\u2009The size of the resting follicle pool determines the ovarian reserve of an individual and correlates with graft sustainment after restoration of fertility by ovarian tissue cryopreservation and transplantation. Assessment of ovarian reserve following ovarian tissue transplantation is challenging when using established markers and indicates high variability between patients . Besidesnd week of transplantation. In freshly but not in frozen-thawed grafted tissues, a positive effect of FSH treatment on primordial follicle number was also observed if the start of treatment was postponed to 3 weeks post transplantation. As we have previously documented in the marmoset [in vitro co-culture system had previously been described for other non-human primates [Enhanced follicular depletion through FSH effects during ovarian stimulation has anecdotally been reported in the human , but conmarmoset , and othmarmoset ,33,34, cprimates . In humaprimates , thus enprimates , and forprimates , suggestWhen started after a prolonged grafting period of frozen tissues, FSH negatively influences primordial follicle numbers that are already low and most likely at this point reflect manifestation of preceding tissue damages due to cryopreservation. Since primary follicle numbers are increased in these tissues, the reduction in the primordial follicle pool may additionally mirror the beginning of follicular recruitment becoming apparent in already low primordial follicle numbers. However in fresh tissues, baseline values of follicle numbers are higher also after a prolonged grafting period, and FSH treatment following early or at a later point in time after transplantation prevents primordial follicle loss. This is in agreement with viability studies on fresh and frozen ovarian tissue resulting in significantly reduced viability when applying a slow-freezing protocol .per se on follicle pool dynamics and primary follicle activation in adult and prepubertal ovarian tissues [Proportional analysis of primary and primordial follicle number can indicate initiation of follicular growth, and for xenografted human ovarian tissue the influence of cryopreservation  and timi tissues . This co tissues . As the FSH treatment alleviates depletion of the resting follicle pool and promotes normal follicular morphology both in freshly and frozen-thawed grafted tissues. In previously cryopreserved tissues, applying to most of the tissues intended for clinical use in fertility preservation attempts, its positive effect on primordial follicle numbers and potential graft sustainment is dependent on an early start of treatment within one week of transplantation. Whereas in fresh tissues FSH treatment following xenografting results in a higher percentage of primary over all un-advanced follicles, this appears to be largely independent of FSH in frozen-thawed tissues.All authors declare that they have no competing interests.VVS and BS designed the study, analyzed and interpreted the results and drafted the manuscript. RC performed the experiments and analyzed the results. EN and LK participated in the study design, helped in the acquisition of funding and critically reviewed the manuscript. RO helped to perform statistical analysis and with the drafting of the manuscript. All authors read and approved the final manuscript."}
+{"text": "Duchenne muscular dystrophy (DMD) is a severe, progressive muscle-wasting disorder, while Becker muscular dystrophy (BMD) is milder muscle disease . Both arThe exon skipping approach uses antisense oligonucleotides (AONs) to induce skipping of targeted exons during pre-mRNA splicing, with the aim of reading frame restoration, converting of the severe DMD into the milder BMD phenotype . This apAfter promising results in cultured cells and animal models where AON treatment allowed in dystrophin restoration (reviewed in ), a firsTowards systemic application, studies in animal models revealed that dystrophic muscles facilitated uptake of 2OMePS AONs and that subcutaneous delivery was feasible . In a suIn parallel, preclinical studies to further optimise treatment regimens are in progress as well as clinical trials for additional exons for exon 44 skipping . Trials are planned for exon 45 and 53 skipping .The mutation specificity of the approach poses challenges to drug development regulations. A concerted effort of academic researchers, industry, regulators and patients is needed to adapt regulations to enable application of these personalised medicine approaches to rare diseases."}
+{"text": "Olfactory dysfunction develops in many neurodegenerative diseases, and is an early feature of the most common neurodegenerative disorder, Alzheimer's disease (AD).Here we compared olfactory function prospectively in cohorts of patents with PCA and typical AD (tAD). Neuroanatomical associations of odour identification were assessed using voxel-based morphometry (VBM). We hypothesised that PCA would be associated with olfactory impairment qualitatively similar to tAD, but less severe ; and that deficits of odour identification in both syndromes correlate with grey matter loss in anteromedial temporal and inferior frontal lobes.6\u201310Fifteen patients fulfilling consensus criteria for PCA,supplementary table S1). Further details about the behavioural assessments are in online supplementary material.All subjects had a comprehensive general neuropsychological assessment which corroborated the clinical impression in both disease groups (see online supplementary table S2) before identifying it; and target-foil choices were name-picture combinations rather than odour names alone, to maximise available response cues. Group differences were assessed using analysis of variance (ANOVA) or \u03c72 tests (Stata V.12.1), adjusting for cognitive severity, verbal processing measures, age and gender.Olfactory processing was assessed using the 40-item, four-alternative-forced-choice University of Pennsylvania Smell Identification Test (UPSIT: British version).http://www.fil.ion.ucl.ac.uk/spm) following previously described procedures . Linear regression was used to examine voxel-wise associations between regional grey matter volume and odour identification performance (age-normed and gender-normed percentile score) across the combined patient cohort, within the PCA subgroup, and between syndromic subgroups, incorporating syndromic group, mini-mental state examination (MMSE) score and total intracranial volume as covariates. Statistical parametric maps were assessed thresholded over the whole brain volume and after multiple-comparisons correction over small volumes of interest  specified in our prior anatomical hypotheses.Twelve patients with PCA and eight patients with tAD had T1-weighted volumetric magnetic resonance (MR) brain images acquired on a 3.0T Siemens Trio scanner. VBM was performed using SPM8 . Based on published UPSIT norms,supplementary table S1). An error analysis of individual odour items in the identification test revealed a qualitatively similar profile of errors across all groups (see online supplementary figure S2).For both patient groups, mean odour categorisation and identification raw scores were significantly lower than the HC group . Across the combined patient cohort, performance on the odour identification task was positively associated with regional grey matter volume in right entorhinal cortex and parahippocampal gyrus . At a more lenient threshold (p<0.001 uncorrected over the whole brain volume), additional associations were present in more distributed, predominantly right-sided cerebral areas, including hippocampus, posterior inferior temporal gyrus/sulcus, temporo-parieto-occipital junction and premotor cortex (see online supplementary table S3). Similar grey matter associations of odour identification performance were identified for the PCA subgroup alone . Direct comparison between the PCA and tAD subgroups revealed no significant between-group differences in regional grey matter correlations of olfactory performance.Statistical parametric maps of significant regional grey matter associations of odour identification performance are displayed in Here we have demonstrated deficits of odour identification and categorisation in patients with PCA relative to HCs. A similar proportion around 30%) of patients with PCA and tAD in this study had an absolute deficit of odour identification referenced to published age and gender norms and taking account of associated cognitive impairment. Olfactory impairment was similar quantitatively and qualitatively in the PCA and tAD groups. To the extent that PCA manifests underlying AD, the findings imply that olfactory impairment is a hallmark of AD pathology. It is noteworthy that only a minority of patients in both phenotypical groups here reported olfactory symptoms, suggesting that in many cases olfactory impairment is \u2018subclinical\u2019. Mean corrected odour identification scores were higher than categorisation scores in the HC and PCA groups: this unexpected finding might hold clues to the cognitive organisation of olfactory knowledge or the cognitive strategies engaged by these tests, and would warrant further study in larger populations. Odour identification tasks tend to be cognitively demanding and therefore potentially susceptible to executive and attentional deficits that accompany AD.0% of pat13The deficit of odour identification identified here was associated with regional grey matter volume in a cerebral network focussed on the right anteromedial temporal lobe. The most robust neuroanatomical associations occurred in parahippocampal gyrus and entorhinal cortex: areas linked to odour identification in healthy human subjects.This study has several limitations that suggest directions for future work. We did not assess perceptual encoding of odours: it will be important to compare associative and perceptual olfactory functions directly, to assess the extent to which these different factors contribute to olfactory impairment in AD. The patient groups studied here were relatively small: there is a need to extend the work to larger patient cohorts spanning other AD phenotypes  and in direct comparison with other neurodegenerative pathologies."}
+{"text": "After publication of our work , we notiThe authors declare no competing interests.JL and DM designed research; JL carried out phylogenetic analyses, and JL and DM wrote the manuscript. Both authors read and approved the final version."}
+{"text": "Microscopic Colitis (MC) is characterized by chronic watery diarrhea, grossly normal appearing colonic mucosa during conventional white light endoscopy, and biopsy showing microscopic inflammation. We report a case of collagenous colitis with gross endoscopic findings. A 71-year-old female with past medical history of coronary artery disease, carotid artery disease, hypertension, and diabetes mellitus type 2 was being evaluated for recurrent intermittent diarrhea. Patient denied any abdominal pain, weight loss, or any blood in stool. Patient was not on any medications and lab work was within normal limits. Colonoscopy was required to further evaluate patient's diarrhea. Colonoscopy revealed multiple scattered segments throughout the colon with increased nodularity and loss of vascular markings in the hepatic flexure, descending colon and cecum Figures . These fMicroscopic examination showed lymphocytic colitis with marked thickening of the superficial collagen table consistent with collagenous colitis. The submucosal collagen was dense and paucicellular with several entrapped lymphocytes and capillaries (red arrow). The lamina propria displays an increase in eosinophils, plasma cells, and lymphocytes (black arrow) .Microscopic Colitis (MC) is characterized by chronic watery diarrhea, grossly normal appearing colonic mucosa during conventional white light endoscopy, and biopsy showing microscopic inflammation. It accounts for 4%\u201313% of patients evaluated for chronic diarrhea and divided into lymphocytic and collagenous colitis . CertainAlthough identical clinically, both types of colitis have distinct microscopic findings. Lymphocytic colitis is characterized by intraepithelial lymphocytosis  while collagenous colitis is diagnosed by thickening of subepithelial collagen layer of more than 10 micrometer [By definition colonic mucosa has a normal appearance in MC. Yet distinct endoscopic findings, particularly for collagenous colitis, have been described in the literature. These findings include alteration of mucosal vascular pattern, mucosal abnormalities such as red spots, increased mucosal nodularity, or textural alteration, and pseudomembranes . Recent advance in endoscopy may enhance the ability to detect MC. A newly developed post processing light filters such as i-Scan  helps to enhance the visualization of mucosal pattern and vascular architecture. Chromoendoscopy using indigocarmine dye sprays may show a mosaic pattern of mucosa in lymphocytic colitis and a nodular, grooved pattern in collagenous colitis . These nMicroscopic Colitis is traditionally known to have normal colonic mucosa on endoscopy. Recent advance in endoscopic techniques has shown that various mucosal abnormalities such as alteration of mucosal vascular pattern and increased mucosal nodularity are associated with MC. These newer techniques will allow us to get targeted biopsy, which will increase the yield of endoscopic diagnosis of MC."}
+{"text": "Borrelia burgdorferi infection. Little has been published in the medical literature about patients with chronic Lyme disease or their relationships with healthcare providers. The objective of this study was to gain insights into the health beliefs and experiences of patients with chronic Lyme disease.Chronic Lyme disease is a term that describes a constellation of persistent symptoms in patients who may or may not have serologic evidence of This was a qualitative, descriptive study in which face-to-face in-depth interviews were conducted with patients who were diagnosed with or self-identify as having chronic Lyme disease. Patients were recruited through Connecticut-based Lyme disease mailing lists and support groups. A coding structure was developed using an iterative process. Transcribed interviews were coded using Atlas.ti software and analyzed for emergent topics and themes. Interviews were conducted until thematic saturation was achieved.A total of 12 interviews were conducted. Four major themes emerged. Patients reported: (1) diminished health status associated with chronic Lyme disease; (2) concerns about persistence of symptoms ; (3) two divergent types of physician-patient relationships ; and (4) seeking and receiving unconventional care .Our findings show that patients report a marked decrease in health status associated with chronic Lyme disease and are often unsatisfied with care in conventional settings. Negative experiences with providers were associated with reports of dismissive, patronizing, or condescending attitudes. Positive experiences were associated with providers reported to be attentive, optimistic, and supportive. Patient-centered approaches that acknowledge suffering and focus on continuity of care and symptomatic relief may result in increased patient satisfaction."}
+{"text": "Increasing the use of pharmacotherapies for alcohol dependence has the potential to improve patient outcomes and reduce health-care costs by reducing hospital admissions. This randomized controlled trial (RCT) evaluated the cost-effectiveness of tailored mailed feedback on general practitioner (GP) prescribing for alcohol dependence and alcohol-related hospital admissions. General practitioners (N = 115) in 10 communities randomized to the experimental arm of the Alcohol Action in Rural Communities (AARC) project received tailored mailed feedback on their prescribing of acamprosate and naltrexone. Segmented regression analysis examined the impact of the intervention relative to GPs\u2019 prescribing and inpatient hospital admissions for alcohol dependence in those communities. Incremental cost-effectiveness ratios were estimated to compare costs per additional prescription written and costs per inpatient admission averted. Trend analysis showed GPs significantly increased their prescribing of acamprosate  and significantly decreased their prescribing of naltrexone . Rates of alcohol-related inpatient admissions for alcohol dependence decreased significantly in the experimental group compared with the control group . Similar to evidence showing SBI can improve patient outcomes, this study showed mailed tailored feedback to GPs achieved cost-effective increases in their prescribing of acamprosate, with a subsequent and plausibly causal reduction in inpatient hospital admissions for alcohol dependence. Demonstrating the capacity of brief intervention in primary-care settings to reduce demand for tertiary care services appears to be a promising direction for the SBI field. A large-scale RCT of the cost benefit of tailored feedback to GPs appears warranted."}
+{"text": "We used ecologic niche modeling of outbreaks and sporadic cases of filovirus-associated hemorrhagic fever (HF) to provide a large-scale perspective on the geographic and ecologic distributions of Ebola and Marburg viruses. We predicted that filovirus would occur across the Afrotropics: Ebola HF in the humid rain forests of central and western Africa, and Marburg HF in the drier and more open areas of central and eastern Africa. Most of the predicted geographic extent of Ebola HF has been observed; Marburg HF has the potential to occur farther south and east. Ecologic conditions appropriate for Ebola HF are also present in Southeast Asia and the Philippines, where Ebola Reston is hypothesized to be distributed. This first large-scale ecologic analysis provides a framework for a more informed search for taxa that could constitute the natural reservoir for this virus family. Mononegavirales, family Filoviridae) are unknown potential reservoirs, including bats, rodents, arthropods, and plants   to the nearest 0.001\u00b0. Although assigned geographic coordinates may not fix the exposure point precisely, they represent our best guess as to its position and are likely to be representative of the coarse-scale ecologic conditions. Distributional data for filovirus-associated HF occurrences in hominids were accumulated from the literature . Occurrehttp://www.lifemapper.org/desktopgarp/). In general, GARP focuses on modeling ecologic niches (the conjunction of ecologic conditions wherein a species can maintain populations without immigration) Ecologic niches and potential geographic distributions were modeled by using the Genetic Algorithm for Rule-set Prediction (GARP) (Occurrence points are divided evenly into training (for model building) and test  datasets. GARP works in an iterative process of rule selection, evaluation, testing, and incorporation or rejection: a method is chosen from a set of possibilities  and applied to the training data to develop or evolve a rule. Predictive accuracy is evaluated on the basis of the test data. Rules may evolve in ways that mimic DNA evolution . Change in predictive accuracy between iterations is used to evaluate whether particular rules should be incorporated into the model; the algorithm runs 1,000 iterations or until convergence. Model quality was evaluated through independent test dataset reserved prior to modeling; a chi-square test was used to compare observed success in predicting the distribution of test points with that expected under a random model .http://edcdaac.usgs.gov/gtopo30/hydro/), and climate characteristics, including daily temperature range; mean annual precipitation; maximum, minimum, and mean annual temperatures; solar radiation; frost days; wet days; and vapor pressure . These coverages are worldwide and provide a consistent view of ecologic variation across regions studied. GARP\u2019s predictive ability has been tested under diverse circumstances . The resulting dataset represents unique combinations of environments and predictions; its attributes table provides the model prediction for all environmental combinations to permit visualization of ecologic variation. We also compared ecologic conditions inside and outside of the modeled Ebola HF distribution within 11 regularly spaced circular windows (radius 50 km); comparisons were summarized through Mann-Whitney U-statistics, permitting a nonparametric visualization of the strength of association of each ecologic dimension  with the range limit.-7). Although subsequent modeling was done without subsetting to maximize occurrence data, these preliminary results nonetheless indicated excellent predictivity of our distributional hypoptheses. The geographic distribution of filovirus disease spreads generally across the humid Afrotropics A. OutlieFiloviridae in general , a complementary distributional area was predicted D. Marbur Sequential omission of Ebola virus species from analyses provided a view of ecologic similarity of species  Inspection of niche models of Ebola HF occurrences (Marburg HF excluded) in ecologic space  provided Distributional limits are complex results of multiple causal agents. A species is seldom limited on all sides by a single factor; rather, distributional limits are the combined result of many such factors. Inspection of the ecologic dimensions coincident with modeled geographic limits of Ebola HF occurrences  showed s Given the mysterious origin of Ebola Reston virus  A. ProjecThe ecologic niche characteristics reconstructed for filovirus species disease outbreaks coincided closely with phylogenetic patterns in the group  , GARP predictions will be overly large. Jackknife manipulations (systematic omission of ecologic dimensions to assess sensitivity to coverage density) can, to some degree, help in assessing sensitivity to coverage completeness Detailed understanding of the geography and ecology of filovirus HF outbreaks represents an underexplored avenue of investigation regarding natural transmission cycles of filoviruses. We assembled available information regarding filovirus HF outbreaks and used various analytical tools to arrive at a detailed understanding of geography and ecology of filovirus disease occurrences. Consequently, we can now assemble criteria by which potential reservoir taxa might be judged. If one assumes a fair degree of host specificity in this host-parasite system, patterns of codistribution and cophylogeny can be expected. Hence, criteria include the following: 1) African Ebola virus reservoirs would be distributed principally in evergreen broadleaf forest; 2) the main focus of the geographic distribution of the reservoir(s) would be in the Congo Basin; 3) a disjunct  distributional area would be present in West Africa; 4) a related taxon in eastern Africa would range in more arid habitats; 5) the reservoir would belong to a clade more broadly distributed across Africa and Southeast Asia. Assessment of potential reservoir taxa by using these criteria has begun , with the idea of eventually testing hypotheses of host associations through ecologic niche comparison methods"}
+{"text": "Most pathogenesis studies focus on pathogen virulence attributes that mediate host colonization, toxicity, or immune evasion. Some studies focus on how pathogens employ active mechanisms to acquire essential nutrients such as iron and vitamins from the host by producing siderophores or avidins. In order to prevent pathogen nutrient acquisition, host cells employ a process called nutritional immunity to sequester these nutrients, particularly iron, from invading pathogens How and where do intracellular pathogens obtain sufficient amounts of energy and nutrients to support their replication? Pathogens may either parasitize existing energy stores or manipulate the host cell to create usable energy and anabolic precursor metabolites. Several recent studies have identified the host AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) kinases as two important regulators of cellular metabolism whose activities are often altered during infection. However, the AMPK/mTOR pathway also regulates autophagy, which can destroy cytosolic pathogens. While the evasion of autophagy by pathogens is well appreciated, recent work suggests that both the AMPK/mTOR pathway and autophagy itself can provide intracellular metabolites that support intracellular pathogen replication.During times of limited nutrient availability, intracellular ATP levels fall, with a corresponding increase in AMP levels. Within eukaryotic cells the increased AMP\u2236ATP ratio induces AMPK activity, which in turn initiates a series of signaling events that stimulate energy and nutrient acquisition In order to achieve optimal levels of proliferation, many pathogens must manipulate activity of AMPK and mTOR. Interestingly, several viral pathogens have evolved strategies that allow for the induction of both AMPK and mTOR activity. For example, infection with human cytomegalovirus (HCMV) increases both AMPK and mTOR activity Simian virus 40 (SV40) infection also stimulates both AMPK and mTOR activity. SV40 small T antigen is both necessary and sufficient for AMPK activation Mycobacterium tuberculosis and Chlamydia trachomatis utilize fatty acids derived from lipid droplets Enveloped viruses require host lipids to generate the virion membrane. Activated mTOR stimulates fatty acid and lipid synthesis, and therefore could prove beneficial for virus assembly. In fact, host lipid metabolism is essential for the hepatitis C virus (HCV) life cycle and is highly regulated during infection AMPK activation also inhibits the replication of several arboviruses, including Rift Valley fever virus (RVFV) Leishmania donovani amastigotes (the parasitic form that grows inside macrophages) preferentially generate energy through fatty acid oxidation and amino acid catabolism L. donovani acquires fatty acids and amino acids from the infected host cell. Consistent with this finding, transcriptomic analysis of macrophages infected with the related parasite Leishmania major suggests that infected cells increase glucose transport, glycolysis, and starch degradation Leishmania alters host metabolic processes, a reasonable hypothesis is that intracellular Leishmania activates AMPK to benefit parasite replication. Activated AMPK could stimulate increased glucose utilization and autophagy, thus creating elevated levels of anabolic precursor pools for parasite growth. Parasite replication requires the Leishmania protein GP63, which cleaves and inactivates mTOR to reduce type I interferon production, thus AMPK activation could further benefit parasite replication by inhibiting mTOR It takes a lot of energy to make hundreds, thousands, or potentially millions of new parasites, bacteria, or viruses. It seems logical that intracellular pathogens that undergo significant intracellular growth would activate AMPK due to the energetic demands placed on the infected cell. Activation of AMPK could provide several benefits for intracellular pathogens. The increased glucose uptake, glycolysis, and fatty acid breakdown would increase available intracellular energy and nutrient pools needed for pathogen replication. For example, Francisella tularensis growth is impaired in autophagy-deficient host cells. Bacterial growth was restored in autophagy-deficient cells by supplying the infected cells with excess pyruvate or amino acids. Since F. tularensis replicates within the cytosol of host cells, our results suggest that intracellular F. tularensis uses autophagy to increase cytosolic nutrient pools that support bacterial growth F. tularensis avoids engulfment by classical autophagosomes Autophagy is an essential cellular process that recycles cellular constituents from macromolecular complexes under conditions of nutrient stress. As discussed above, autophagy is positively regulated by AMPK and negatively regulated by mTOR. However, autophagy also functions as a host defense mechanism that destroys intracellular pathogens through a process termed xenophagy. While generally viewed as detrimental for intracellular pathogens, some bacteria and viruses use autophagosomes as a replicative niche AMPK and mTOR are critical regulators of host cell metabolism making them logical targets for manipulation by invading pathogens. The energetic burden of the host cell to create hundreds or more pathogens should deplete cellular ATP levels, thus activating AMPK. AMPK induction stimulates host processes to produce energy and nutrients that the pathogen could then steal from the host. This idea suggests AMPK activation may be a common theme among infection by successful intracellular pathogens. On the other hand, mTOR signaling stimulates protein and lipid synthesis, which could be beneficial for many viral pathogens; whereas mTOR modulation is likely less important for free-living bacteria pathogens and parasites that supply their own biosynthetic and translation machinery. Identifying what nutrient sources are required for intracellular growth and how host metabolic signaling is manipulated by infection is being investigated in viral pathogenesis, yet remains poorly understood in bacterial and parasitic pathogenesis.Manipulating host metabolism is an attractive approach to controlling infection as targeting the host rather than the pathogen should considerably reduce the ability of pathogens to develop drug resistance. Several drugs already in clinical use target the AMPK or mTOR kinases to treat diseases such as cancer and diabetes. The studies described above suggest that these drugs may have additional uses in treating infections with intracellular pathogens. As our understanding of pathogen manipulation of host metabolism grows, it may also be possible to develop inhibitors of specific host metabolic pathways hijacked by intracellular pathogens. Identifying the essential nutrients required for intracellular pathogen proliferation and the host pathways manipulated to acquire these nutrients will be a significant step in understanding the requirements for viral, bacterial, and parasitic pathogenesis and identifying new targets for novel therapeutics."}
+{"text": "Poecilia parae, a colour polymorphic fish, exhibit five distinct phenotypes: drab-coloured (immaculata), striped (parae), structural-coloured (blue) and carotenoid-based red and yellow morphs. Previous work indicates that immaculata males employ a sneaker strategy, whereas the red and yellow morphs exploit female preferences for carotenoid-based colours. Mating strategies favouring the maintenance of the other morphs remain to be determined. Here, we report the role of agonistic male-male interactions in influencing female mating preferences and male mating success, and in facilitating the evolution of AMSs.Intense competition for access to females can lead to males exploiting different components of sexual selection, and result in the evolution of alternative mating strategies (AMSs). Males of P. parae morphs during indirect and direct interactions with sexually receptive females. Two morphs, parae and yellow, use aggression to enhance their mating success  by 1) directly monopolizing access to females, and 2) modifying female preferences after winning agonistic encounters. Conversely, we found that the success of the drab-coloured immaculata morph, which specializes in a sneak copulation strategy, relies in its ability to circumvent both male aggression and female choice when facing all but yellow males.Our study reveals variation in aggressiveness among Strong directional selection is expected to deplete genetic variation, yet many species show striking genetically-based polymorphisms. Most studies evoke frequency dependent selection to explain the persistence of such variation. Consistent with a growing body of evidence, our findings suggest that a complex form of balancing selection may alternatively explain the evolution and maintenance of AMSs in a colour polymorphic fish. In particular, this study demonstrates that intrasexual competition results in phenotypically distinct males exhibiting clear differences in their levels of aggression to exclude potential sexual rivals. By being dominant, the more aggressive males are able to circumvent female mating preferences for attractive males, whereas another male type incorporates subordinate behaviours that allow them to circumvent male aggression and female mating preferences. Together, these and previous results indicate that exploiting different aspects of social interactions may allow males to evolve distinct mating strategies and thus the long term maintenance of polymorphisms within populations. Intense sexual selection can lead to competing males evolving alternative ways to obtain fertilizations, thereby enhancing their reproductive success . In geneUta stansburiana), males have evolved AMSs  and the relative fitness of each strategy fluctuates depending on the frequency of the competing strategies from one generation to the next )A and MB representing total proportion of time spent with male A or B, respectively, positive values of this index (MA - MB) would indicate a preference for male A and negative values a preference for male B. To determine whether there was a switch in female mating preferences after observing male-male interactions, we subtracted the post-male competition preference score from the pre-male competition preference score . We determined if females switched or enhanced their mate preferences between trials using a paired t-test. Preference scores were arcsine transformed to meet the assumptions of parametric tests  into two categories: aggressions received and initiated. Both categories (aggressions received and initiated) were analysed using Kruskal-Wallis non-parametric ANOVAs. To determine which morphs were attacked less and attacked more, we ran multiple comparisons of mean ranks. We also performed Kruskal-Wallis non-parametric ANOVAs and multiple comparisons of mean ranks to analyse aggressions received and initiated during the open aquarium experiments. To compare whether there were differences in the number of attacks performed by males during direct and indirect interactions with females, we used a Mann-Whitney test. Finally, the difference in number of gained or lost copulations to the competitors was analysed with Wilcoxon matched pair tests. All data sets were tested for normality and analysed with STATISTICAJLHG conceived the study, carried out the experiments, analysed the results and drafted the manuscript in partial fulfilment of a doctoral degree at Syracuse University, New York (USA). JACU contributed to the study design, supervised the study, edited and revised the manuscript critically. Both authors have read and approved the final manuscript.This file includes: Table A1 with additional information of the standard body lengths (mm) of males used during the experiments. Table A2 presents a brief description of aggressive behaviours commonly displayed by males of Poecilia parae. Figure A1 presents a simplified view of the experimental settings.Click here for file"}
+{"text": "In this article, we review studies of astrocytic-neuronal interactions and their effects on the activity of oxytocin (OXT) neurons within the magnocellular hypothalamo-neurohypophysial system. Previous work over several decades has shown that withdrawal of astrocyte processes increases OXT neuron excitability in the hypothalamic supraoptic nucleus (SON) during lactation. However, chronically disabling astrocyte withdrawal does not significantly affect the functioning of OXT neurons during suckling. Nevertheless, acute changes in a cytoskeletal element of astrocytes, glial fibrillary acidic protein (GFAP), occur in concert with changes in OXT neuronal activity during suckling. Here, we compare these changes in GFAP and related proteins with chronic changes that persist throughout lactation. During lactation, a decrease in GFAP levels accompanies retraction of astrocyte processes surrounding OXT neurons in the SON, resulting from high extracellular levels of OXT. During the initial stage of suckling, acute increases in OXT levels further strengthen this GFAP reduction and facilitate the retraction of astrocyte processes. This change, in turn, facilitates burst discharges of OXT neurons and leads to a transient increase in excitatory neurochemicals. This transient neurochemical surge acts to reverse GFAP expression and results in postburst inhibition of OXT neurons. The acute changes in astrocyte GFAP levels seen during suckling likely recur periodically, accompanied by rhythmic changes in glutamate metabolism, water transport, gliotransmitter release, and spatial relationships between astrocytes and OXT neurons. In the neurohypophysis, astrocyte retraction and reversal with accompanying GFAP plasticity also likely occur during lactation and suckling, which facilitates OXT release coordinated with its action in the SON. These studies of the dynamic interactions that occur between astrocytes and OXT neurons mediated by GFAP extend our understanding of astrocyte functions within the central nervous system."}
+{"text": "The emergence of spontaneous bursting events in developing neuronal networks likely depends on the evolving network connectivity. Theoretical models have shown that hierarchical network structures embedding clusters of strongly inter-connected neurons are optimal for initiating and sustaining spontaneous activity . It is cTo test this we chronically manipulated activity-dependent structural plasticity by inhibition of protein kinase C (PKC) in developing networks of cortical neurons in vitro. Previous studies showed that PKC inhibition in developing cerebellum promotes dendritic outgrowth and arborization of Purkinje cells and impairs pruning of climbing fibers. We found that developmental inhibition of PKC in cortical cell cultures increased dendritic outgrowth, impaired neurite fasciculation and clustering and abolished network pruning. This resulted in more homogeneous and potentially better connected networks fig. . As a re"}
+{"text": "This study investigated procedural errors made during root canal preparation using stainless steel and nickel-titanium (NiTi) instruments by undergraduate students, using two diagnostic imaging methods.n=20; group 1: K-Flexofile, group 2: K3, and group 3: BioRace). The root canals were filled with gutta-percha and AH Plus. Periapical radiographs and cone beam computed tomography (CBCT) images were obtained to detect procedural errors made by undergraduate students during root canal preparation. Two examiners evaluated the presence or absence of fractured instruments, perforations and canal transportations. The agreement between observers was assessed using the kappa coefficient. The Kolmogorov-Smirnov, Fisher exact, ANOVA and Tukey tests were used for statistical analysis. The level of significance was set at 5%.Sixty human molars were divided into three groups (There were no significant differences in detecting procedural errors between two- and three-dimensional diagnostic imaging methods. There were no significant differences in procedural errors between stainless steel and NiTi instruments. Mean preparation time was recorded in minutes, and results were significantly different between the three groups. NiTi instruments had the lowest mean preparation time.Both periapical radiographs and CBCT identified procedural errors, however, three-dimensional images offered more diagnostic resources. The frequency of procedural errors was low for any of the endodontic instruments despite being used by inexperienced operators. Centralizing ability and apical transportation were not influenced by mechanical motion or type of instrument used. Hartmann et al. . Further research should investigate new concepts and technologies that raise opportunities for discussion, reflection and changes in the scientific world.The frequency of procedural errors  during the preparation of canals of maxillary and mandibular molars using stainless steel and NiTi instruments was low regardless of diagnostic imaging method when used by inexperienced operators."}
+{"text": "Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also develop defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but, to date, has not been reported in patients with Cartilage-hair hypoplasia.To describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency and evaluate treatment options.In a retrospective, observational study, we collected clinical data on 21 patients with CHH in order to identify and further characterize individuals with granulomatous inflammation.Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) developed epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti Tumor necrosis factor alpha monoclonal antibody therapy in 3 of these patients led to significant regression of granulomas. However, one treated patient developed fatal progressive multifocal leukoencephalopathy due to the JC polyomavirus. In two patients, immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas.To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although Tumor necrosis factor alpha antagonists may effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients."}
+{"text": "DNA methylation may play a role in the etiology of neuropsychiatric disorders through abnormal genomic methylation patterns regulating genes involved in brain development or physiology. In this study we explored the DNA methylation profile of depression in the prefrontal cortex because converging evidence from brain imaging and postmortem studies has implicated this region in depression neuropathology.et al., doi: 10.4161/epi.6.11.17876). Overall, these data represent relatively unbiased coverage of the genome, including CpG-rich domains such as CpG islands and repetitive elements.In order to better understand both the wild type genomic DNA methylation patterns and aberrant methylation events occurring in disease states we profiled DNA methylation patterns in human postmortem brains of 12 depressed and non-psychiatric controls using the methylation mapping and paired-end sequencing (Methyl-MAPS) method. Methyl-MAPS is an enzymatic-base method that can delineate the methylation status of greater than 80% of CpG sites genome-wide  across all RefSeq annotated genes, but significant variations were detected proximal to the TSS (referred to as \u201cCpG island shores\u201d). We observed statistically significant methylation loss in CpG island shores in depressed cases compared to controls. These findings were replicated in purified neuronal cell populations. Using an independent sample of depressed cases and matched non-psychiatric controls, we isolated neuronal nuclei from the dorsal prefrontal cortex of 11 depressed cases and 11 controls. Due to limited quantities of neuronal DNA typically obtained from isolation of nuclei using fluorescence-activated cell sorting, we used the Illumina HumanMethylation450 BeadChip. DNA methylation differences in CpG island shores revealed that, of the CpG dinucleotides with significant methylation differences, >95% showed loss of methylation in depressed brains. The underlying mechanism involved in the loss of methylation in depression psychopathology is unclear. However, the global 5-hydroxymethylcytosine levels in neuronal DNA from the same sample specimens also showed a loss of hydroxymethylation in depressed brains compared to controls. Although these data were not statistically significant, they revealed an important trend in loss of hydroxymethylation and the possible mechanism for DNA demethylation in brains of depressed patients. Gene ontology analysis of genes with significant methylation differences (primarily loss of methylation) in depressed vs. controls identified a number of cellular functions. Of note, the fourth most significant gene set identified was involved in programmed cell death and 74% of the genes in this set were associated with neuronal cell death. These changes in methylation dynamics suggest a possible mechanism linking neuronal cell death associated with oxidative stress and inflammation in the depressed brain."}
+{"text": "This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics, and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.Poly(ADP-ribose) polymerase (Parp) is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose) chains (known as PARylation). Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis, and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on  Breast cancer is an epidemic afflicting approximately one out of every nine women  and gemcitabine showed improved overall survival  of varying degrees of homology , all of whom use NAD+ as a substrate to catalyze the addition of ADP-ribose moieties onto target proteins  locus  glycohydrolase (known as Parg). Parg catabolizes ADP-ribose polymers synthesized by Parp-1. This enzymatic activity has been demonstrated to impair Parp-mediated chromatin remodeling In addition to histone H1 removal, Parp-1 configures chromatin through modification of proteins involved in remodeling and organizing chromatin structure. PARylation generally results in protein activation, but can also result in functional suppression of chromatin remodelers. For example, PARylation is inhibitory to the function of the repressive remodeling complex Iswi , together with histone deacetylases (Hdacs), results in a repressive complex, inactivating the transcription of genes involved in cardiomyocyte differentiation through deacetylation of histones .Finally, we propose that Parg represents an attractive therapeutic target Figure . The undParp-1 is an important activator of transcription and probably plays an important role in promoting transcription of tumor suppress genes. Therefore, we postulate Parp inhibitors may actually have pro-oncogenic effects on some cell populations. But, what is the impact of inhibiting Parg on these same processes? While the overall impact of Parg on gene regulation remains unclear at this time, it has been shown that Parg can block Parp-1 mediated chromatin remodeling and transcriptional activation in specific circumstances. Therefore, we speculate Parg inhibition might heighten the effects of PARylation, thus promoting the transcription of tumor suppressor genes. Further, in cancer cells having defects in the PARylation pathway such as aberrantly dePARylated Ctcf, Parg inhibition might serve to correct these deficiencies.in vivo (Marienfeld et al., in vitro data showing growth inhibitory activity of Parg inhibition or knockdown in multiple types of cancer (Fauzee et al., Supporting these rationale for Parg inhibition being a novel approach for anti-cancer therapy are several reports indicating Parg inhibition has potent anti-tumor effects against cholangiocarinoma The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Acute liver failure related to hepatitis B infection may occur after acute HBV infection or during an exacerbation (flare) of a chronic HBV infection. The condition is associated with a very high morbidity and mortality rate.We present the diagnosis and management difficulties of a four-case series admitted to our clinic during the last year, with severe acute liver failure, with encephalopathy that required medical management, intensive care and organ support, including artificial extracorporeal liver support.In the presence of acute liver failure and serological evidence of hepatitis B viral infection, differentiating between acute infection and exacerbation (flare) of chronic infections remains a challenge. Mortality rates remain high inspite of recent medical advance."}
+{"text": "NATbox: Network Analysis Toolbox in the language R that houses a battery of BSL algorithms in conjunction with suitable statistical tools for modelling FRs in the form of acyclic networks from gene expression profiles and their subsequent analysis.There has been recent interest in capturing the functional relationships (FRs) from high-throughput assays using suitable computational techniques. FRs elucidate the working of genes in concert as a system as opposed to independent entities hence may provide preliminary insights into biological pathways and signalling mechanisms. Bayesian structure learning (BSL) techniques and its extensions have been used successfully for modelling FRs from expression profiles. Such techniques are especially useful in discovering undocumented FRs, investigating non-canonical signalling mechanisms and cross-talk between pathways. The objective of the present study is to develop a graphical user interface (GUI), i) impute missing observations in the given data (ii) model FRs and network structure from gene expression profiles using a battery of BSL algorithms and identify robust dependencies using a bootstrap procedure, (iii) present the FRs in the form of acyclic graphs for visualization and investigate its topological properties using network analysis metrics, (iv) retrieve FRs of interest from published literature. Subsequently, use these FRs as structural priors in BSL (v) enhance scalability of BSL across high-dimensional data by parallelizing the bootstrap routines.NATbox is a menu-driven open-source GUI implemented in the R statistical language for modelling and analysis of FRs from gene expression profiles. It provides options to (http://bioinformatics.ualr.edu/natboxWiki/index.php/Main_Page.NATbox provides a menu-driven GUI for modelling and analysis of FRs from gene expression profiles. By incorporating readily available functions from existing R-packages, it minimizes redundancy and improves reproducibility, transparency and sustainability, characteristic of open-source environments. NATbox is especially suited for interdisciplinary researchers and biologists with minimal programming experience and would like to use systems biology approaches without delving into the algorithmic aspects. The GUI provides appropriate parameter recommendations for the various menu options including default parameter choices for the user. NATbox can also prove to be a useful demonstration and teaching tool in graduate and undergraduate course in systems biology. It has been tested successfully under Windows and Linux operating systems. The source code along with installation instructions and accompanying tutorial can be found at  Classical biological experiments have focused on understanding changes in the expression of single genes across distinct biological states. Such differential gene expression analyses while useful may not provide sufficient insight into their interactions or functional relationships (FRs). Understanding FRs is crucial as genes work in concert as a system as opposed to independent entities. On a related note, phenotype formation is mediated by pathways comprising of complex interactions between several genes as opposed to a single gene. Recent development of high-throughput assays in conjunction with sophisticated computational tools has enabled modelling such interactions and gain system-level understanding.Several commercial and non-commercial software packages have been developed in the past for modelling gene interactions. Ontology-based packages ,2 that rBayesian structure learning (BSL) techniques  have beehttp://bioinformatics.ualr.edu/natboxWiki/index.php/Main_Page.Several open-source packages are available for BSL and can be used to model gene networks -13. Howei) determine missing values in a given data using the functions LLSimpute, also implemented in the R-package pcamethods [ii) Learn acyclic network structure using BSL routines from the R-package deal [dynamicGraph [iii) identify what the author term as 1st order network structure using a resampling procedure and (iv) reconstruct coherent sub-regulatory networks using an extended version of the algorithm CODENSE [Prior to a detailed description of NATbox functionalities, we briefly review those of a closely related package BNArray  which waamethods  (ii) Leaage deal . SubsequmicGraph  (iii) id CODENSE . In the The comparisons are also enclosed under Table i. GUI: NATbox provides a convenient menu-driven graphical user interface (GUI) developed using Tcl/Tk for modelling and analysis of gene expression networks. This has to be contrasted with BNArray [ BNArray , which iii. Input/output: The input data in NATbox is assumed to be in tab-delimited text format, similar to that of BNArray. In NATbox, the rows of the input file represent independent experiments whereas the columns represent the names of the genes. However, in BNArray the rows represent the genes of interest and the columns represent their expression across experiments. Unlike NATbox, BNArray does not specify whether the experiments need to be independent or dependent.iii. Missing values: Gene expression profiles often have missing values. For instance, in microarray data such missing values are common and may be attributed to experimental artefact, improper hybridization and non-specific binding of the probes. It is prudent to use suitable statistical techniques to accommodate such data sets rather than discard them. NATbox provides an option to determine missing values using nearest-neighbour averaging approach (menu: File), impute.knn (R-package impute) which has been found to perform well for high-dimensional data sets [LLSImpute) [pcamethods).ata sets . BNArraySImpute)  algorithiv. Functional relationships: NATbox provides the option to model functional relationships using a battery of Bayesian structure learning techniques from the R-package (bnlearn) [menu: Bayesian Networks). It is important to note that they model the network structure solely from the joint probability distribution in the absence of explicit temporal information. The tab-delimited input data should be in the form of a matrix where the columns represents the number of genes, and rows the number of repeated (independent) experiments. Each element in the matrix represents the expression value of that gene in a given experiment.bnlearn)   : GS is b\u2022 Incremental Association Markov Blanket Algorithm (IAMB) : IAMB is\u2022 Fast Incremental Association Markov Blanket Algorithm (Fast-IAMB) : Fast-IA\u2022 Interleaved Incremental Association Markov Blanket Algorithm (Inter-IAMB) : Inter-I\u2022 Max-Min Parents Children Algorithm (MMPC) : MMPC ismutual information, mutual information for Gaussian distributed data, fast mutual information, Pearson's \u03c72, Akaike information criterion) as well as numerical/continuous distributions  are provided. NATbox also provides an interface to the search and score algorithm  from bnlearn. HC searches the model space and retrieves the best model using a scoring criterion which is also provided. Several choices of scoring criterion are provided for categorical/discrete  and numerical/continuous distributions (Gaussian posterior density). Each BSL technique works under implicit assumptions and may result in spurious conclusions when these assumptions are violated. NATbox provides a battery of BSL techniques to alleviate such concerns. For instance, constraint-based techniques can be affected by sample sizes and are sensitive to initial results of the conditional independence tests. Search and score algorithms can result in local optima, hence may benefit from multiple random restarts unlike constraint-based approaches.Several choices of conditional independence tests for categorical/discrete  are deemed robust. Bootstrap procedures can be computationally demanding for high-dimensional data sets. Search and score techniques such as hill-climbing implicitly require several random restarts during the confidence estimation. NATbox provides an option to parallelize bootstrapping across multiprocessor or multi-core processor by invoking the appropriate routines from the R-package SNOW (Simple Network Of Workstations) [nfidence  of an edtations) . Such patations)  is shown\u03b8 > 0.8) on the acyclic graph learned from the given data, Fig. dynamicGraph [The results of the bootstrap are written onto a tab-delimited file. An option is also provided for highlighting the robust FRs (micGraph  for visuwhitelisting (include) and blacklisting (exclude) FRs. Such priors impose constraints on the network structure which implicitly rely on prior knowledge and needs to be chosen prudently in order to avoid bias during learning. However, a proper choice can alleviate uncertainty and improve accuracy of the conclusions. A text retrieval interface is provided for identifying structural priors and can be useful for investigating well-established signalling mechanisms.In addition, NATbox GUI also provides options for incorporating  structural priors in BSL by vi. Network analysis metrics: BSL techniques are useful in inferring the cause-effect relationships and network structure from the gene expression profiles. However, they provide no insight into the network's topological properties. NATbox incorporates social network analysis metrics and motif finder from the package (igraph) [menu: Network Analysis Metrics) for investigating the topological properties of the networks generated using BSL techniques. Such metrics can be especially useful in investigating large networks. The input is assumed to be a binary adjacency matrix of the network constructed using BSL with ones and zeros representing the presence/absence of an edge respectively. Since BSL results in directed acyclic graphs, the corresponding binary adjacency matrix need not be symmetric. The centrality measures  along with their respective parameter options are provided for the user. A detailed discussion of these centrality measures are deferred to [igraph [igraph package incorporated into NATBox also provides option to save the acyclic network in formats compatible with Cytoscape [(igraph)  under . The user has the option to input the (a) pairs of gene names (co-occurrence) of interest through the GUI or (b) upload a two-column matrix of FRs of interest or those identified as robust by the bootstrap procedure. For well-documented studies, an integrated approach that incorporates the results from the Text Retrieval  in justifying the choice of whitelisted (include) and/or blacklisted (edges) in BSL. The Text Retrieval results are in html format, with a list of PUBMED identifiers hyper-linking to the respective abstracts/articles in PUBMED. The results of text retrieval on gene expression data from [ata from  is showni) expand the choice of structure learning algorithms including dynamic bayesian networks (ii) improve statistical inference of the network features (ii) parallelization of the implemented routines across multi-core and multi-processor machines of BSL functions as well as bootstrapping (iii) provide a web-interface so as to obviate the need for local installation of the toolbox (iv) enhance text retrieval so as to accommodate advanced text mining approaches.Modelling and analysis of gene expression networks is an area of active research. Several tools have been proposed in the literature for the same. Recently, Bayesian structure learning (BSL) techniques in conjunction with high throughput assays were used successfully to capture functional relationships. Existing packages may demand the user to have considerable programming expertise. NATbox provides a convenient menu-driven GUI along with appropriate parameter recommendations including default parameter choices for modelling and analysis of gene expression networks. It incorporates diverse functionalities from existing R-packages. This in turn encourages transparency and reproducibility, characteristic of open-source environment. NATbox can also be used as a teaching and demonstration tool for graduate courses in systems biology. Immediate future enhancements to the toolbox include (The authors declare that they have no competing interests.bnlearn package and was involved in trouble shooting the Bayesian structure learning routines. RN wrote the manuscript.SSC and MAB implemented the toolbox under RN's guidance. MS developed the"}
+{"text": "Patients after fractures become more and more immobile. Necessary stimuli decrease further. It comes to progressive deconditioning, whereby the vicious circle is complete, because it results in decreasing muscle cross-sectional area as well as bone strength. Accordingly, therapy concepts have to focus on maintenance and increasing muscle force and power. An established method is intensive resistance exercise training aimed to hypertrophy. Also the training program must ensure that forces reach the minimal effective strain and leads to bone remodelling. High-load resistance exercises effectively increase muscle and bone at the same time.Bone and muscle are dynamic tissues. Muscle adapts to stimuli above thresholds (energetic emptying > exhaustion). Wolff\u2019s law states that structural bone adaptation is driven by the experienced bone strains. Osteocytes within our bones regulate bone formation and degradation in response to mechanical stimuli. The largest strains emerge from muscle contractions. A lot of diseases are associated with secondary muscle weakness (sarcopenia) and reduced bone density (osteoporosis). Both deficits cause an increase in fall incidence. About every 4"}
+{"text": "Yersinia pestis, are highly variable in their response to plague ranging from near deterministic extinction  to a low probability of extinction despite persistent infection . Much of the work to understand this variability has focused on specific host characteristics, such as population size and resistance, and their role in determining plague dynamics. Here, however, we advance the idea that the relative importance of alternative transmission routes may vary causing shifts from epizootic to enzootic dynamics. We present a model that incorporates host and flea ecology with multiple transmission hypotheses to study how transmission shifts determine population responses to plague. Our results suggest enzootic persistence relies on infection of an off-host flea reservoir and epizootics rely on transiently maintained flea infection loads through repeated infectious feeds by fleas. In either case, early-phase transmission by fleas  has been observed in laboratory studies, and we show that it is capable of driving plague dynamics at the population level. Sensitivity analysis of model parameters revealed that host characteristics  vary in importance depending on transmission dynamics, suggesting that host ecology may scale differently through different transmission routes enabling prediction of population responses in a more robust way than using either host characteristics or transmission shifts alone.Host populations for the plague bacterium,  Yersinia pestis, remains a public health concern because of its high virulence in multiple mammal species, including humans, and its role in past pandemics in humans. Despite its historical importance and the continued threat of human cases, plague is primarily a disease of rodents and their fleas. Consequently, humans are at greatest risk of exposure to Y. pestis during plague epizootics when rodent hosts die in large numbers increasing potential exposures to sick or dead animals and infectious fleas Plague, caused by the bacterium However, rodent species show high variability in their population-level response to plague infection, and the mechanisms that determine outbreak conditions are not fully understood. The variability in host response can be compartmentalized into two classes: either enzootic  or epizootic . This classification enables predictions that can be based on observable intra-population dynamics rather than invoking landscape-level maintenance mechanisms involving the interaction of plague dynamics in multiple species Rhombomys opimus) in Kazakhstan, show high levels of prolonged resistance , rarely survive plague infection Previous research on plague dynamics depended on observation of host characteristics to differentiate between epizootic and enzootic populations. For example, enzootic hosts, such as great gerbils  allows for the maintenance of infection levels in fleas and increases infectious duration for early-phase transmission Y. pestis has survived in carcasses and soil for several days under both field and laboratory conditions Experimentally studying transmission routes in natural systems is nearly impossible, but laboratory experiments have identified effective transmission routes that could also affect population responses to plague infection. In particular, early-phase transmission by un-blocked fleas  has been shown to be a viable alternative to blocked-flea transmission in several flea species under laboratory conditions Y. pestis dynamics that incorporates three routes of plague transmission: 1) the booster-feed infection cycle; 2) the build-up of infectious, questing fleas; and 3) contact with carcass-derived material. We parameterize the model for an epizootic host, the black-tailed prairie dog, and for an enzootic host, the California ground squirrel (Spermophilus beecheyi). We sequentially remove or reduce each transmission route to understand how the influence of each route may vary between characteristic epizootic and enzootic hosts. We also use sensitivity analysis of model parameters to quantify the importance of transmission routes across a broader range of species and to explore how previously identified host characteristics interact with transmission to improve prediction of plague dynamics.In order to simultaneously consider how multiple transmission routes interact to determine plague dynamics, we present a general model of We developed an ordinary differential equation (ODE) model consisting of both host and flea submodels  causing fleas to transition to EP stage 2 , while the infectious, questing flea reservoir increases almost throughout . InfectiSystematic removal of transmission routes helped provide a clearer picture of each in plague dynamics, especially for epizootic behavior . For thea, was positively correlated with enzootic probability but had little effect on extinction probability. Increasing transmission efficiency from EP2, L\u03b2, increased extinction probability as did an increase in the transition rate between EP1 and EP2 for fleas taking non-infectious blood meals, E\u03b8.Our multi-parameter sensitivity analysis was consistent with the relative importance of transmission routes described above and revealed that model results were sensitive to parameters influential to both the booster-feed infection cycle and the infectious, questing flea reservoir ; Fig. 3.\u03d5, and shorter host exposure periods . However, increased host resistance, p, and increased host carry capacity, K, served to decrease epizootic behavior. In contrast, enzootic probability was increased by increasing host carrying capacity and declined with higher rates of resistance loss, shorter host exposure periods, and decreasing host connectance . Sensitivities that are not reported were not significant.Population responses to plague infection were also sensitive to several host parameters in the model . Among tOur model produced characteristic enzootic and epizootic behaviors, and model behaviors for our specific parameterizations were consistent with empirical observations of plague activity in the hosts they were based on, black-tailed prairie dogs and California ground squirrels. The agreement with natural systems highlights our ability to reliably compare the shifting roles of transmission routes in creating each dynamic. In particular, the booster-feed infection cycle is primarily responsible for epizootic behavior. While laboratory experiments have demonstrated that the booster feed infection cycle results in the maintenance of infection levels in fleas B; Our sensitivity analysis supports the role of shifting transmission dynamics in determining plague dynamics in the host population. We found that epizootic behavior  was strongly affected by flea characteristics that determine both the strength and turnover rate of the booster-feed infection cycle, while enzootic potential was strongly influenced by flea questing efficiency adding support to the involvement of a flea reservoir in the maintenance of plague at the population level While the flea reservoir may be important in connecting spatially distinct groups of hosts, we also hypothesize that questing fleas may act as a bridge in enzootics, connecting temporally separated pools of susceptible hosts generated from a resistant refuge. This endogenously derived temporal bridge contrasts with more traditionally hypothesized exogenous sources of re-infection. Bat rabies virus may display a similar endogenous bridging mechanism by entering a quiescent state during host hibernation, thus creating a bridge between birth pulses that refresh the susceptible pool Most of the previous research on the variability in population responses to plague infection has focused on host traits, and our sensitivity analysis confirmed some of these observations, particularly the importance of host resistance and population size as observed in Asian great gerbils However, while our analysis confirms previous observations on the role of host characteristics in determining disease dynamics, it is important to note that these traits do not act independently of transmission routes to determine population response and thus, the effects of host traits may depend on the specific transmission routes operating. For example, we found that increasing host carrying capacity generally increased enzootic potential in our sensitivity analysis. However, our specific results for prairie dogs and California ground squirrels exhibited the opposite of the expected responses with black-tailed prairie dogs having larger population sizes but higher probabilities of extinction. Here, knowledge of transmission shifts may be more informative. Specifically, the importance of booster-feeds in epizootics, a transmission route that relies on continued contact between hosts and fleas, may create a situation where increasing host abundance leads to large epizootic potential that cannot be maintained. This is in contrast to enzootic hosts where an endogenous bridging mechanism like infectious, questing fleas overcomes issues of host limitation. The maintenance of infection potential in a flea reservoir may also alter the traditionally hypothesized role of resistance in promoting enzootics. In this case, resistance may primarily be important in avoiding epizootics and becomes important in promoting enzootics only when infectious, questing fleas dominate transmission. Thus, host and flea characteristics may scale up through transmission routes allowing for more robust predictions than when considering either host or flea characteristics alone.Figure S1Flow chart for the host sub model. The three transmission routes included in the model are highlighted: booster-feed infection cycle (blue), infectious, questing flea reservoir (green), and infectious carcasses (orange).(TIF)Click here for additional data file.Figure S2Flow chart for the flea submodel. The relationship between the booster-feed infection cycle (blue) and infectious flea reservoir (green) is highlighted.(TIF)Click here for additional data file.Table S1Alternate flea parameter values. Parameter values for the prairie dog flea O. tuberculata cynomuris. Other flea species are provided for comparison.(DOC)Click here for additional data file.Text S1Alternate flea submodel which prevents the buildup of infectious, questing fleas.(DOC)Click here for additional data file.Text S2Parameter fitting and estimation.(DOC)Click here for additional data file.Text S3Detailed prairie dog and California ground squirrel model outputs.(DOC)Click here for additional data file."}
+{"text": "Urobatis halleri, as a model species. First, we examined the effects of temperature  on vertebral elemental incorporation . Second, we tested the relationship between water and subsequent vertebral elemental composition by manipulating dissolved barium concentrations . We also evaluated the influence of natural variation in growth rate on elemental incorporation for both experiments. Finally, we examined the accuracy of classifying individuals to known environmental histories (temperature and barium treatments) using vertebral elemental composition. Temperature had strong, negative effects on the uptake of magnesium (DMg) and barium (DBa) and positively influenced manganese (DMn) incorporation. Temperature-dependent responses were not observed for lithium and strontium. Vertebral Ba/Ca was positively correlated with ambient Ba/Ca. Partition coefficients (DBa) revealed increased discrimination of barium in response to increased dissolved barium concentrations. There were no significant relationships between elemental incorporation and somatic growth or vertebral precipitation rates for any elements except Zn. Relationships between somatic growth rate and DZn were, however, inconsistent and inconclusive. Variation in the vertebral elemental signatures of U. halleri reliably distinguished individual rays from each treatment based on temperature (85%) and Ba exposure (96%) history. These results support the assumption that vertebral elemental composition reflects the environmental conditions during deposition and validates the use of vertebral elemental signatures as natural markers in an elasmobranch. Vertebral elemental analysis is a promising tool for the study of elasmobranch population structure, movement, and habitat use.Differences in the chemical composition of calcified skeletal structures  have proven useful for reconstructing the environmental history of many marine species. However, the extent to which ambient environmental conditions can be inferred from the elemental signatures within the vertebrae of elasmobranchs  has not been evaluated. To assess the relationship between water and vertebral elemental composition, we conducted two laboratory studies using round stingrays,  The trace and minor elemental composition of biomineralized structures can provide insight into the environmental conditions in which the elements were deposited. Elemental assays of coral skeletons and foraminifera tests, for example, have been commonly applied as surrogates of past climatic or oceanographic conditions  \u20133. RecenThe most widespread and expanding application of elemental markers in biomineralized structures has occurred using the otoliths of fishes ,5. OtoliThe elemental composition of biogenic calcified structures is not a simple reflection of environmental conditions. A variety of physiological barriers and processes are encountered as elements are taken up from the water through the gills or intestine, transferred through the blood plasma, and eventually incorporated into biomineralized structures . PhysiolSharks, skates, and rays (elasmobranchs) are cartilaginous fishes that lack otoliths. Elasmobranch skeletons are composed of mineralized cartilage, an impure (non-stochiometric) form of carbonated calcium phosphate (hydroxyapatite) . Like thChemical analyses of elasmobranch vertebrae to date have been predominately directed toward age validation ,27 and dUrobatis halleri, as a model species. We manipulated environmental concentrations of barium (Ba) to determine the extent to which vertebral elemental ratios reflect the ambient environment. Finally, we evaluated the utility of these elemental markers to distinguish the environmental history experienced by individual rays using multivariate classification models. These experiments allowed us to test the following hypotheses: (i) elemental incorporation in vertebrae is mediated by water temperature; (ii) vertebral Ba to calcium ratios (Ba/Ca) reflects water Ba/Ca; (iii) growth rate does not significantly influence vertebral elemental composition; and (iv) vertebral elemental markers can distinguish individuals based on differences in environmental history. This investigation represents the first attempt to evaluate the utility of vertebral chemistry as potential records of environmental history in elasmobranchs.Key assumptions regarding vertebral elemental incorporation in relation to the physical and chemical environment must be evaluated before broader ecological questions and hypotheses can be addressed using naturally occurring elemental markers in elasmobranchs. We quantified the effects of temperature and growth rate on vertebral elemental incorporation through controlled laboratory studies using the round stingray, This investigation was conducted with a permit from the California Department of Fish and Game (803099-01) and in strict accordance with guidelines established by the American Fisheries Society and National Institutes of Health for the use of fishes in research. Experimental protocol was approved by Oregon State University\u2019s Institutional Animal Care and Use Committee (3783).Urobatis halleri, is a benthic, live-bearing elasmobranch that occurs in estuaries and nearshore coastal soft bottom habitats from Panama to Eureka, California, USA ) experiment.Correlations (r) between partition coefficients (DThe number (n) of round rays  included in growth rate estimates, observed range of individual somatic growth rates (mm disc width month-1), and vertebral precipitation rates (\u03bcm radius month-1) are reported for each treatment. Significant p-values are indicated by bold font.(PDF)Click here for additional data file."}
+{"text": "Vascular injury represents less than 1% of all injuries, but deserves special attention because of its severe complications. Amputation or retention of a painful functionless limb is the most untoward result of severe vascular injury or inadequate treatmet. Thus, vascular injury needs a judicious and multidimensional approach.This retrospective study was done to asess the outcome of minor modifications of the methodology of extremity fasciotomy by making it liberal with respect to incision and definition.Out of 55 patients in 2008, 45 patients (Group A) had either no fasciotomy or limited primary fasciotomy, 10 patients (Group B) had primary liberal fasciotomy. Another group from 2008 onwards had undergone primary liberal fasciotomy in all the 45 patients (Group C).In group A, we had 5 amputations and one death. In group B, there were no amputations or deaths and from group C, we had one amputation and no deaths.Blunt and distal traumatic vascular injury of the extremities and its repair should always combined with primary liberal fasciotomy, which although increases manageable morbidity, avoids disability . Vascular injury represents less than 1% of all injuries, but deserves special attention because of their severe complications. Amputation or retention of a painful functionless limb is the most untoward result of severe vascular injury or inadequate treatment, so vascular injury needs a judicious and multidimensional approach. Patients with pain out of proportion to injury, pain upon passive stretching, sensory changes, weakness or parasthesia after vascular repair indicate vascular compromise due to compartment syndrome and need immediate fasciotomy. Popliteal artery injuries continue to result in maximum limb loss, possibility due to use of limited fasciotomy.This study was done to assess the outcome of minor modifications of the methodology of extremity fasciotomy by making it liberal with respect to incision and definition.We studied 55 patients in 2008 with firearm or splinter vascular injuries of extremities; 45 patients (Group A) underwent different methods of vascular repair either without primary fasciotomy or with limited fasciotomy. Only 10 patients (Group B) had liberal primary fasciotomy. After 2008 to date, we treated 45 patients (Group C) with different types of vascular injuries, by different reparatory methods all of which received primary liberal fasciotomy.Assessment included emergency work-up: clinical examination, CBC, KFT, ECG, chest x-ray, USG abdomen, color flow Doppler, blood grouping and cross-matching; only 6 patients were subjected to pre-operative angiography.Vascular repair was done by primary end-to-end anastomosis or reverse sephanous vein graft either without fasciotomy or with varied limits of fasciotomy.Limited fasciotomy included superficial incision with inadequately cut deep fascia, isolated compartment fasciotomy, inadequate length of fasciotomy not passing across proximal and distal joints. Liberal fasciotomy included cutting through skin, deep fascia as well as outer covering of underlying exposed muscles (epimysium), till muscle pouts out. Oozing blood from muscle indicates adequate blood flow through the repaired vessel as well as adequacy of fasciotomy, thus it has therapeutic as well as diagnostic importance. Checking muscle viability with low voltage electric cautery stimulation. Confirming muscle viability helps in adequate debridement to prevent infective complications of dead tissue.We use S-shaped incision both at elbow and popliteal fossa, closure of this incision does not cause any constricting effect, while in case of liberal primary fasciotomy, the same incision is extended. The repaired vessel is loosely covered either by surrounding fat or muscle to prevent desiccation of the vessel. Curved fasciotomy incisions decompress the maximum area of the extremity and avoids superficial venous injury.Ensure muscle pouting along fasciotomy wound. All-compartmental fasciotomy is better than isolated-compartment fasciotomy. Dressings should not be tight. Avoid entrapment of adventitia in the anastomotic suture line.Passing a Fogarty catheter damages endothelium and increases tendency of thrombosis, thus anticoagulation is recommended.From group A, we had 5 amputations and one death (death due to infective complications of gangrene followed by DIC - despite that the limb was amputated); from group B we had no complications and from group C one amputation and no deaths were recorded; 12 patients from group A needed either extension of fasciotomy or secondary fasciotomy.Most of the patients with liberal primary fasciotomy need care by a plastic surgeon. But 25% patients were discharged and referred to their respective primary health care centers for regular dressings and admitted subsequently for split-thickness skin grafting with favorable results.All those patients with primary liberal fasciotomy even with borderline muscle viability at the time of primary vascular repair had the least amputation rate. There was no significant increase in infection rate. Soaked dressings were changed regularly. One significant complication with primary liberal fasciotomy was pain which needed short interval analgesics. Also changing dressings in these patients was time consuming and significantly painful which demanded extra patience by patient as well as attending resident. These patients have long lasting paresthesia at graft site with varied presentation. Patients in high dependency units with no or limited fasciotomy obscured signs of compartment syndrome due to liberal use of analgesics. Delayed or revised fasciotomy in these patients helped to a very limited extent, and in the long run gave a functionally disabled limb with chronic pain in saved limbs.Delayed fasciotomy, revision fasciotomy and disability due to amputation/vegetative limb or chronic limb parasthesia all have a very strong psychological impact in contrast to less morbidity associated with primary liberal fasciotomy.In patients with primary liberal fasiotomy crossing knee and ankle in lower limb, elbow and wrist in upper limb with cutting some fibers of reticulum at ankle or wrist appreciably improved blood flow. Any vascular injury associated with blunt trauma limb, fracture, venous injury, longer duration of ischemia; below knee/elbow vascular repair needed primary liberal fasciotomy whether the patient had a tense compartment at the time of vascular repair or not.Extensive soakage from fasciotomy wound needs frequent change of dressings, which is painful and cumbersome for patient. Frequent analgesics make patients apprehensive. Painful postural changes and difficulty in assuming comfortable postures effects sleep. Longer hospital stay is uncomfortable.Compartment syndrome is a surgical emergency characterized by raised pressure in an unyielding osteofascial compartment caused by trauma, revascularization, myocyte edema after ischemia-reperfusion injury, or resuscitation -4. The cBlunt and distal traumatic vascular injury of extremities and its repair should be combined with primary liberal fasciotomy, which may although increase manageable morbidity, will avoid lifelong disability. No fasciotomy can be acceptable when chances of compartment syndrome are absolutely nil; however, limited fasciotomy is absolutely discouraged in favor of primary liberal fasciotomy."}
+{"text": "The autonomic nervous system (ANS) and innate immunity are intimately linked. Heart rate variability (HRV) analysis is a widely employed method to assess cardiac ANS activity, and changes in HRV indices may correlate with inflammatory markers. Here, we investigated whether baseline HRV predicts the innate immune response. Second, we investigated whether the magnitude of the inflammatory response correlated with HRV alterations.Escherichia coli O:113). Of these, 12 healthy volunteers were administered LPS again 2 weeks later. HRV was determined at baseline (just prior to LPS administration) and hourly thereafter until 8 hours post LPS. Plasma cytokine levels were determined at various time points.Forty healthy volunteers received a single intravenous bolus of 2 ng/kg endotoxin (lipopolysaccharide (LPS), derived from Baseline HRV indices did not correlate with the magnitude of the LPS-induced inflammatory response. Despite large alterations in HRV following LPS administration, the extent of the inflammatory response did not correlate with the magnitude of HRV changes. In subjects that were administered LPS twice, inflammatory cytokines were markedly attenuated following the second LPS administration, while LPS-induced HRV alterations were similar. See Figure HRV indices do not predict the innate immune response in a standardized model of systemic inflammation. The innate immune response results in HRV changes; however, no correlations with inflammatory cytokines were observed. These findings suggest that cardiac ANS activity may not reflect ANS outflow to other organs involved in the innate immune response. Furthermore, the magnitude of endotoxemia-related HRV changes does not reflect the extent of the inflammatory response."}
+{"text": "An asymptomatic issueless young staff nurse underwent pre-employment health screening and USG abdomen showed multiple hypodense lesions in liver. Further screening with whole body positron emission tomography-computed tomography (PET-CT) scan showed significantly FDG avid mass involving most of the right lobe of liver with multiple large FDG avid lymph nodal metastases. Unsuspected focal abnormal, FDG avid, hyperdense mural nodule was seen in uterus, which is the site of primary. With the advent of sophisticated medical instrumentation in the diagnostic workup for malignancies, detailed investigations fail to reveal the primary site of origin for a subset of patients with metastatic carcinoma. This is often referred to as Carcinoma of Unknown Primary (CUP) or occult primary malignancy.The exact incidence of CUP in the United States is not precisely known, but it is definitely underreported. Its actual incidence is most probably between 2 and 6%. In 15\u201325Clinical presentation of cancer of unknown primary origin is extremely variable and depends on the extent and type of organ involvement. Investigations are usually guided by any positive findings on initial evaluation. Patients have early dissemination of their cancer without symptoms at the primary site. The symptoms often depend on the site of metastases, like ascites may be the initial presentation in a patient with a GI or an ovarian malignancy, etc.The patient was an issueless, 32-year-old staff nurse undergoing pre-employment health checkup. USG abdomen showed a large heterogenous lobulated mass with predominant hypoechogenicity suggestive of possible atypical hemangioma or possible evolving abscess. Magnetic resonance imaging (MRI) of abdomen showed a large heterogenous enhancing hypodense lesion with altered signal intensity with a large exophytic component in the right lobe of liver suggestive of possible hepatic adenoma/atypical hemangioma/possible neoplasm. Fine needle aspiration cytology (FNAC) followed by trucut biopsy was suggestive of possible metastatic rhabdomyosarcoma.18F FDG (Fluoro Deoxyglucose) intravenously in euglycemic status. After 1 hour, the patient was imaged. Images showed large hypodense, significantly FDG avid, non-enhancing mass involving most of the right lobe of liver [Standard Uptake Value (SUV) max 30 g/ml]. Multiple large FDG avid, left axillary, porta hepatic, celiac and retropancreatic lymph nodal metastases were also present. Portal vein was seen encased by the tumor at porta hepatis. Inferior venacava was obstructed below the liver and collateralized via azygos and hemiazygous system. [Whole body positron emission tomography-computed tomography (PET-CT) scan was done using 8 mCi on  system. . Inferio system. .The patient underwent further pelvic USG and was biopsy proven. The patient was started on chemotherapy and is doing well for the past 6 months. Follow-up CT of abdomen showed recession in size of liver metastases.Rhabdomyosarcoma is primarily a disease affecting children; it rarely affects adults. Common sites of involvement are the head and neck 28%), extremities 24%), and genitourinary tract (18%).8%, extre Uterine %, and geMost uterine sarcomas fall into the category of leiomyosarcoma, endometrial stromal sarcoma, or undifferentiated sarcoma.5 MetastaRhabdomyosarcoma is subdivided into three general types histologically as follows.Embryonal rhabdomyosarcoma: This usually occurs in head and neck locations with small round or oval tumor cells and a finely granular eosinophilic cytoplasm. Well-differentiated tumors demonstrate elongated, strap-shaped or tadpole-shaped rhabdomyoblasts.Alveolar rhabdomyosarcoma is the next variety comprising relatively small, poorly differentiated round and oval cells aggregated into irregular clusters or nests separated by fibrous septa. An occasional variant, referred to as the botryoid type, shows a diffuse myxoid or mucoid matrix with thinly scattered primitive mesenchymal cells. The characteristic feature of this type is a peripheral zone of increased cellularity, sometimes known as the \u201ccambium layer.\u201dPleomorphic rhabdomyosarcoma shows randomly arranged eosinophilic cells with considerable variation in cell size and shape, as well as variation in nuclear size and shape. The pleomorphic cells are often admixed with small, primitive mesenchymal cells. This tumor is often so undifferentiated that the identification of the cell of origin is difficult or impossible. Positive immunostains for desmin and myoglobin are helpful as in our case.Regardless of the histologic subtype, special stains are often quite useful for differentiating rhabdomyosarcoma from other neoplasms. The trichrome stain is especially useful because it colors rhabdomyoblasts bright red while myofilaments and cross-striations have fuchsinophilic properties, also highlighted by PTAH (deep purple color). Myxoid stroma may be positive for hyaluronidase with acid mucopolysaccharide staining, although many other tumors also have positive stroma with these stains. The most418F FDG PET-CT is an important screening tool for the evaluation of unknown primaries as well as for staging and follow-up of several malignancies.[In patients with metastatic disease, prognosis is poor with a 5-year event-free survival rate of less than 30%. 18F FDG gnancies.8 FDG PETOur patient was unique, as she was a young asymptomatic lady presenting with multiple large liver and nodal secondaries, which is relatively an uncommon site for metastases. The patient had no previous history of menorrhagia or metrorrhagia as usually expected in uterine rhabdomyosarcomas. Incidentally detected mural nodule in uterus helped in finding the site of hidden primary malignancy."}
+{"text": "We compared the difference in left atrial tissue remodeling (LATR) pre-ablation and post-ablation lesion characteristics between three methods for electrical isolation of pulmonary veins  routinely done to treat paroxysmal atrial fibrillation (PAF).Patients presenting with PAF who qualified for a cryo, PVAC or SRF ablation were prospectively followed. DE-MRI of the left atrium (LA) was performed prior to and three months post procedure. The degree of LATR is reported as a percentage of the total LA area.37 patients  were included in this study. Six patients underwent an ablation using PVAC catheter, SRF catheter was used in 14 patients, and 17 patients underwent a cryoballoon ablation. Pre-ablation LATR was comparable in all three cohorts (Figure From our preliminary results, PVAC ablation appears to result in lesser scar formation as compared to Cryo and SRF ablation. The greater recurrence in patients with low scar post-ablation suggests the need to implement an adequate ablation strategy that results in greater scar to maximize successful outcomes. DE-MRI is an appropriate method to compare lesion formation induced by different ablations strategies.None."}
+{"text": "Two variants with evidence of association with higher endometrial cancer grade (p-trend<10\u20136) have been selected for validation in independent sample sets. These SNPs are located in or near genes not previously reported to be involved in cancer aetiology or prognosis and, if confirmed, would represent novel gene targets. Neither of these SNPs fall into the top 1500 SNPs prioritised for validation of association with risk. Results to date suggest that genetic alleles associated with prognostic features, such as cancer grade, may be distinct from those associated with predisposition. GWAS analysis of tumour prognostic features is thus likely to improve understanding of biological pathways influencing outcome for endometrial cancer patients.Endometrial cancer is the most commonly diagnosed gynaecological cancer. Although endometrioid endometrial cancer (80% of cases) generally carries a good prognosis, some patients with this tumour subtype relapse within two years. Identifying genetic variants associated with prognosis could inform clinical decision-making for management at diagnosis, and inform development of chemotherapeutic agents targeting aggressive disease. Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in cancer susceptibility. Presently there are limited published studies using GWAS data to identify single nucleotide polymorphisms (SNPs) associated with tumour prognostic indicators, such as grade. We used case data from an endometrial cancer case-control GWAS to assess association of SNPs with endometrial cancer grade. Genome-wide genotyping of 1285 Australian and British women with endometrioid endometrial cancer and reporting Caucasian ethnicity was performed using the Illumina 610K BeadChip. After applying quality control measures, data on 583,366 SNPs for 1220 cases with grade information were used in the analysis. PLINK software was used to assess SNP association with grade , adjusting for study group . Fifty-seven SNPs were found to be significant at <10"}
+{"text": "Reduced muscle strength- commonly characterized by decreased handgrip strength compared to population norms- is associated with numerous untoward outcomes. Preoperative handgrip strength is a potentially attractive real-time, non-invasive, cheap and easy-to-perform \"bedside\" assessment tool. Using systematic review procedure, we investigated whether preoperative handgrip strength was associated with postoperative outcomes in adults undergoing surgery.PRISMA and MOOSE consensus guidelines for reporting systematic reviews were followed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials (1980-2010) were systematically searched by two independent reviewers. The selection criteria were limited to include studies of preoperative handgrip strength in human adults undergoing non-emergency, cardiac and non-cardiac surgery. Study procedural quality was analysed using the Newcastle-Ottawa Quality Assessment score. The outcomes assessed were postoperative morbidity, mortality and hospital stay.Nineteen clinical studies  comprising 2194 patients were identified between1980-2010. Impaired handgrip strength and postoperative morbidity were defined inconsistently between studies. Only 2 studies explicitly ensured investigators collecting postoperative outcomes data were blinded to preoperative handgrip strength test results. The heterogeneity of study design used and the diversity of surgical procedures precluded formal meta-analysis. Despite the moderate quality of these observational studies, lower handgrip strength was associated with increased morbidity (n = 10 studies), mortality (n = 2/5 studies) and length of hospital stay (n = 3/7 studies).Impaired preoperative handgrip strength may be associated with poorer postoperative outcomes, but further work exploring its predictive power is warranted using prospectively acquired, objectively defined measures of postoperative morbidity. A substantial minority of patients sustain an excess of postoperative complications  and acceThe systematic review was undertaken in accordance with the PRISMA  Preferr.Two of the authors (P.S. and M.A.H.) searched the electronic databases MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials independently using the following population search terms: 'postoperative complications' OR 'perioperative complications' OR 'surgical complications' OR 'surgical outcome'. These search results were combined with 'handgrip dynamometry' OR 'hand grip dynamometry' OR 'hand grip strength' OR 'handgrip strength' OR 'maximal voluntary contraction' in the title or abstract text using the Boolean search operator 'AND'. . The references of retrieved articles were hand searched for any relevant articles not identified in the original search. The study selection criteria were limited to include only studies reported in the English language and those involving human adults undergoing surgery (including cardiac and transplant surgery). Each abstract was screened to identify studies that had assessed handgrip strength prior to surgery. Studies were excluded if postoperative outcomes focussed on upper limb neuromuscular functional outcomes alone.The data were extracted on to a standardized data entry form by each reviewer. Differences between the reviewers were resolved by re-examination of the original manuscript until consensus was obtained. Data extracted for comparison included year of publication, primary author, total number of subjects, mean patient age, proportion of male subjects and co-morbidity (where reported). The method of quantifying or qualifying handgrip strength was recorded.The specific outcomes sought in each article were: (i) mortality, (ii) postoperative morbidity, categorized according to the Post Operative Morbidity Survey, (iii) length of hospital stay . PrimaryThe procedural quality of each trial was assessed using several criteria, although no studies were excluded on the basis of these assessments. The quality of studies was scored according to the Newcastle-Ottawa Quality Assessment Scale  Additio, on a scNineteen studies were identified that compared postoperative outcomes in relation to handgrip strength Table , comprisThe majority of studies measured handgrip strength pre-operatively Table . Eleven Variable definitions for impaired handgrip strength have been used across studies Table . StudiesTable Tables Table Contrary to large population studies, our systematic review of the relationship between preoperative handgrip strength and postoperative outcome did not find compelling data to support the hypothesis that the results of studies in the general population translate to perioperative medicine. The majority of studies were considered to be of reasonable quality. Despite these quality scores, many studies contained important potential confounding factors which varied markedly between studies. A range of different instruments have been employed to measure grip strength, with other corroborative assessments of strength being frequently absent. Due to the substantial variation in the way in which each specified outcome had been defined between studies, plus the lack of analyses testing any one particular association, it was not possible to perform meta-analyses of results or formally test the heterogeneity (consistency) between studies. This marked heterogeneity between studies limits any definitive conclusions for the perioperative environment and renders this preoperative assessment largely unexplored. Nevertheless, several of these studies - albeit with the limitations as discussed above - suggest the role for preoperative handgrip strength assessment should be explored further.Large epidemiological studies have shown that perioperative morbidity is associated with dramatic differences in post-discharge life expectancy across different operations and health systems . The cosThere are also compelling basic biological reasons for establishing the role of handgrip strength in preoperative assessment. Cardiopulmonary reserve is a long-established predictor of cardiovascular and all-cause mortality, in both asymptomatic individuals and patients with cardiovascular disease . CardiacOne limitation of this systematic review is that no original study data were retrieved, although given the heterogeneity of both study design and the surgical populations in question this would have been unlikely to alter the main conclusions. Because only published reports were examined , a formal assessment of publication bias was not undertaken. It remains possible that not all relevant studies may have been identified since unpublished studies were not sought. There is very little perioperative demographic data provided in these studies, including cardiovascular risk and the identification of higher risk patients. Standards of postoperative care were not reported or apparently standardized. Since no interventions were conducted based on preoperative handgrip strength assessment, the studies only provide associative conclusions.This systematic review has generated two significant clinical implications. Firstly, given the compelling general population data that predicts longevity, there is clearly a need for the further prospective assessment of whether preoperative handgrip strength can help stratify risk of adverse postoperative outcomes. Second, these studies demonstrate that handgrip strength is a feasible, pragmatic, real-time bedside tool that may enhance preoperative risk stratification.Impaired preoperative handgrip strength may be associated with increased postoperative morbidity, mortality and prolonged hospital stay following surgery. Given the robust predictive power of this inexpensive, objective bedside test beyond the perioperative population, further studies of its' role in predicting postoperative outcomes appear to be warranted provided prospective, objectively defined measures of morbidity are employed.The authors declare that they have no competing interests.All authors contributed to Study design, Conduct of study, Data analysis and Manuscript preparation.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2253/12/1/prepubChecklist of items demonstrating adherence to PRIMSA systematic review guidelines.Click here for fileNewcastle Ottowa Scale.Click here for file"}
+{"text": "Petromyzon marinus). This dataset allows the exploration of early vertebrate evolution because the lamprey lineage split from that of other vertebrates before the emergence of hinged jaws, the defining feature of jawed vertebrates . Additionally, lamprey axons are not ensheathed by myelin  is particularly relevant because MBP is an abundant structural myelin constituent essential for myelination in the central nervous system (CNS). The fact that MBP had not been traced in species more ancient than gnathostomata   Figure . The fun) Figure . MBP andOther presumed myelin proteins traced in the lamprey genome are not functionally related to myelin at all, despite an equivalent gene ontology (GO) term. For example, MYT1L (myelin transcription factor-1-like), a neuronal transcription factor , PMP22 , MAL (myelin and lymphocyte protein), and PLP (proteolipid protein) were previously noted to be evolutionarily older than vertebrates (Mazumder et al., Taken together, the lamprey genome does not provide reason to consider that myelin may have evolved in non-jawed vertebrates. More generally, conclusions from genomic datasets on cellular structures come with the danger of misinterpretations if not carefully considered in conjunction with morphological analyses (Bullock et al.,"}
+{"text": "Transplantation therapy for diabetes is limited by unavailability of donor organs and outcomes complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation (embryonic day 28 (E28)) engraft long-term in non-immune, suppressed diabetic rats or rhesus macaques. Morphologically, similar cells originating from adult porcine islets of Langerhans (islets) engraft in non-immune-suppressed rats or rhesus macaques previously transplanted with E28 pig pancreatic primordia. Our data are consistent with induction of tolerance to an endocrine cell component of porcine islets induced by previous transplantation of embryonic pig pancreas, a novel finding we designate organogenetic tolerance. The potential exists for its use to enable the use of pigs as islet cell donors for humans with no immune suppression requirement. J. Transplantation, why transplantation of embryonic pancreatic primordia to replace endocrine pancreas function is advantageous relative to transplantation of either pluripotent embryonic stem (ES) cells, or of terminally differentiated (adult) organs [We have reviewed previously, for ) organs : (1) unlTransplantation of human embryonic pancreas in human hosts has been contemplated . HoweverCells originating from E28 pig pancreatic primordia transplanted in mesentery engraft similarly in non-immune-suppressed STZ-diabetic rhesus macaques , 8. GlucIn lieu of increasing the numbers of transplanted primordia or transplant surgeries in diabetic rhesus macaques, we embarked on a series of experiments to determine whether porcine islets, a more easily obtainable and possibly more robust source of insulin-producing cells, could be substituted for animals in which embryonic pig pancreas already had been engrafted. To this end, we implanted adult porcine islets beneath the capsule of one kidney of rats or macaques, that several weeks earlier had been transplanted with E28 pig pancreatic primordia in mesentery. We employed the renal subcapsular site for islet implantation so that we could differentiate engrafted porcine tissue originating from the islets from tissue originating from prior mesenteric E28 pig pancreatic transplants, that never engraft in host kidney , 8. In t Figures Neither cells that stain for insulin nor cells to which the probe for porcine proinsulin mRNA binds are present in contralateral (nonimplanted) kidneys of STZ diabetic rats  or macaqTo provide additional evidence that cells in the kidneys of islet-implanted rats or macaques previously transplanted with E28 pig pancreatic primordia in mesentery are of porcine origin, we demonstrated using fluorescent in situ hybridization, that the cells contain pig X chromosomes , 8. ShowMultiple organs were excised from a STZ-diabetic macaque transplanted with E28 pig pancreatic primordia in mesentery and subsequently with porcine islets in the renal subcapsular space of one kidney. Tissues were homogenized individually and total RNA was purified. RT-PCR was performed using primers specific for pig or monkey proinsulin mRNA. Products were separated by electrophoresis on 3% agarose gels and their identities confirmed by sequencing in the Washington University Core Protein and Nucleic Acid Chemistry Laboratory [To ascertain whether cells originating from kidney-implanted porcine islets function in rats or rhesus macaques, we determined whether the glucose tolerance of STZ-diabetic animals normalized partially by prior transplantation of E28 pig pancreatic primordia in mesentery was rendered normal by subsequent islet implantation, and measured glucose-stimulated insulin release from islet-implanted kidneys in vitro. Rats were rendered fully glucose tolerant by subsequent implantation of porcine islets in one kidney . The gluAs illustrated in a representative of 3 experiments using weight-matched tissue, no insulin could be detected at time 0 in supernatants from the implanted macaque kidney . HoweverCells containing endocrine granules in an expanded renal subcapsular space were identified in electron micrographs of kidneys from rats implanted with porcine islets following transplantation of E28 pig pancreatic primordia in mesentery .  FigureThe shortage of human pancreas donor organs imposes severe restrictions on the use of allotransplantation to treat diabetes mellitus \u201322. WhenThe severity of humoral rejection effectively precludes the use of pigs as whole pancreas organ donors for humans. However, because they are vascularized by the host posttransplantation, islets like other cell transplants are not subject to humoral rejection. Porcine islets are rejected within two weeks of transplantation in non-immune suppressed non-human primates , 16\u201318. Xenotransplantation of embryonic pig pancreatic primordia in lieu of mature pig organs or porcine islets couples the wide availability of pig organs with the immunological advantages inherent in transplanting cellular embryonic tissue, circumventing humoral rejection and obviating the need for host immune suppression . HoweverCells from porcine islets do not survive afterimplantation in rat or macaque kidneys without prior transplantation of E28 pig pancreatic primordia transplantation in mesentery , 8. WholSchroeder et al.  define tEngraftment of pancreatic progenitors transplanted across a xenogeneic barrier to non-immune-suppressed immune-sufficient hosts has been reported twice previously. Eloy et al. described normalization of glucose posttransplantation of E15, but not E18 embryonic chick pancreas into liver of non-immune-suppressed STZ-diabetic rats . AbrahamHost immune suppression is required for successful engraftment of embryonic pig pancreas in rodents  or non-hInterestingly, GALT may have served similarly to prevent an immune response to insulin-producing cells scattered originally in the gut epithelium of primitive vertebrates , 32 and Harada et al. have proposed a similar coopting of oral tolerance to explain the muted immune response in vivo and by cells from mesenteric lymph nodes in vitro to a colon carcinoma of BALB/c origin or a human CD80-transfected DBA/2 mastocytoma injected into the subserosal space of cecum in BALB/c mice relative to tumors injected subcutaneously . One way to confirm a causative link between gut immunity and our ability to transplant E28 pig pancreatic primordia and porcine islets in non-immune-suppressed hosts would be to \u201cbreak\u201d the established oral tolerance , using gIn any case, we have demonstrated in two species , 8, a no"}
+{"text": "Natural Killer (NK) cells contribute to the control of cancer through immunosurveillance and may influence phenotypic sculpting of cancer through immunoediting. NK cells may also contribute to the control of hematological malignancies such as acute myeloid leukemia (AML) following allogeneic stem cell transplantation. However, no studies have shown direct clinical evidence that supports immunoediting by NK cells in AML at presentation, or whether activating ligand expression at diagnosis serves as a prognostic indicator of survival. We now show that at diagnosis, expression of NK cell ligands on AML blast populations is heterogeneous. Furthermore, expression of multiple activating ligands is associated with favorable cytogenetics and improved leukemia-free survival. In analyses of paired diagnostic and relapse samples, AML blasts exhibiting lower expression of activating ligands were selectively increased at relapse, indicating that NK cell-mediated blast immunoediting occurred prior to AML escape. Therapeutically, NK cell activating ligands could be upregulated on AML by in vitro treatment with bortezomib that enhanced NK cell-mediated cytotoxicity. Thus, diagnostic analyses of the expression of NK cell activating ligands in AML could be used to design therapeutic approaches for specific patients, and agents that stimulate NK cell function by restoring NK cell ligand expression may be appropriate to eliminate minimal residual disease and reduce risk of relapse."}
+{"text": "Disseminated metastatic breast cancer needs aggressive treatment due to its reduced response to anticancer treatment and hence low survival and quality of life. Although in theory a combination drug therapy has advantages over single-agent therapy, no appreciable survival enhancement is generally reported whereas increased toxicity is frequently seen in combination treatment especially in chemotherapy. Currently used combination treatments in metastatic breast cancer will be discussed with their challenges leading to the introduction of novel combination anticancer drug delivery systems that aim to overcome these challenges. Widely studied drug delivery systems such as liposomes, dendrimers, polymeric nanoparticles, and water-soluble polymers can concurrently carry multiple anticancer drugs in one platform. These carriers can provide improved target specificity achieved by passive and/or active targeting mechanisms. Breast cancer is the most common cancer in females and the second most common cause of death in women in the United States . MetastaFor better therapeutic effectiveness combination anticancer treatment has long been adopted in clinics. The general rationale for employing combination therapy is twofold. First, when multiple drugs with different molecular targets are applied, the cancer adaptation process such as cancer cell mutations can be delayed. Second, when multiple drugs target the same cellular pathway they could function synergistically for higher therapeutic efficacy and higher target selectivity. Currently available combination regimens for metastatic breast cancer in clinics are limited to administrating a physical mixture of two or more anticancer agents. The clinically used combination regimens in the US can be broadly classified based on their mechanisms of action Figures  includinSmall molecule chemotherapeutic agents can be given singly or in combination . ToxicitStreptomyces bacteria, are a class of drugs widely used and studied in cancer chemotherapy. Mechanisms of action of anthracyclines are (1) to inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells, (2) to inhibit topoisomerase II, preventing the relaxing of supercoiled DNA, and thus blocking DNA transcription and replication, and (3) to create iron-mediated free oxygen radicals that damage the DNA and cell membranes. Anthracyclines-based combination chemotherapy has shown improved anticancer activity than anthracyclines alone. For example, doxorubicin has achieved response rate of 40\u201350% as single agent while 60\u201370% in combination [With response rates of up to 60% in previously untreated patients with metastatic breast cancer anthracycline-based regimens are one of the most widely used first-line chemotherapies. Because of this advantage patients relapsing more than 12 months after anthracycline-based treatment may be reinduced with anthracycline-based combination chemotherapy . Anthracbination . These rbination . The combination . These rbination , 24. JoeTaxanes are another class of chemotherapy agents originally derived from natural sources then synthetically derivatized including paclitaxel (Taxol) and docetaxel (Taxotere). The mechanism of action of taxanes is to disrupt microtubule function. Microtubules are essential to cell division, and taxanes stabilize GDP-bound tubulin in the microtubule, thereby inhibiting the process of cell division. Therefore taxanes also can be classified as mitotic inhibitors. However due to their poor water-solubility, taxanes encounter difficulties in pharmaceutical formulation and this often results in reduced bioavailability.Different mechanisms of action of anthracyclines and taxanes provide the rationale of combination therapy of these two classes of drugs. Taxanes and anthracyclines typically do not produce overlapping toxicities with existing therapies. Bria et al. reported improved time to progression and overall survival from doxorubicin with paclitaxel (or docetaxel) therapy compared to anthracycline-based combination therapy (FAC or AC). Although greater hematologic toxicity (such as neutropenia) occurs from taxane containing regimen (74%) than the anthracycline regimen (63%)  the overTaxane with nonanthracycline combinations is another highly effective regimen and is particularly useful in patients with rapidly progressive visceral metastases, who were previously treated with an anthracycline. In this regimen, capecitabine and gemcitabine are drugs of choices as nonanthracycline drugs for combination with taxanes (docetaxel or paclitaxel). Albain et al. reported the combination of gemcitabine and paclitaxel regimen to be superior to paclitaxel alone with longer time to progression (6 versus 4 months) and better response rate (41% versus 26%). However toxicity of this combination was higher with increased neutropenia (61% versus 22%), fatigue (19% versus 13%), and neuropathy (24% versus 22%) .Increased use of anthracyclines and taxanes in adjuvant (given in addition to main treatment) and neoadjuvant (given before the main treatment) settings limits the treatment options for patients upon relapse. Multidrug resistance (MDR) is a major limitation of conventional chemotherapy . This isAs discussed above most combination therapies with small molecule chemotherapeutic agents present improved clinical benefits including enhanced response rate and prolonged overall survival, progression-free survival, relapse-free survival, and/or time to progression. However, with additive efficacy the adverse effects from each agent are compounded resulting in patients' suffering from more treatment-related toxicity. The nonspecific nature of small molecule chemotherapeutics accounts for much of the toxicity due to nonselective biodistribution in healthy tissues concurrently with tumor accumulation. Additionally exposure to multiple conventional chemotherapeutic agents reduces response rate due to increased efflux of these drugs out of the cells mediated by the overexpression of MDR related efflux pumps or transporters . TherefoSmall molecule chemotherapeutic agents lack cancer cell-specific targeting ability and also affect the fast-dividing normal cells of the body . Therefore, the major adverse effects from these chemotherapeutic agents are nonspecific toxicities including anemia, nausea, vomiting, and hair loss. Biologic agents are advantageous to chemotherapy in their ability to actively target-specific receptors. Conventional chemotherapy does not discriminate effectively between tumor cells and rapidly dividing normal cells thus leading to nonspecific adverse effects. In contrast, target-specific anticancer therapies interfere with molecular targets that have an important role in tumor growth or progression distinct from normal cells. Also some of these agents act as inhibitors to MDR-related proteins thereby increasing the response rate . OverallMonoclonal antibodies are monospecific antibodies made by identical immune cells as clones of a unique parent cell. Due to their nature monoclonal antibodies can be designed to bind to specific substances hence they are widely used for target specific detection or purification . ApproxiBevacizumab, a monoclonal antibody against VEGFR, acts as an inhibitor of angiogenesis. VEGF is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from preexisting vasculature). Since angiogenesis is the essential way of providing nutrition to tumors and a fundamental step in the transition of tumors from a dormant state to a malignant one, it serves as important target for anticancer therapy. As monotherapy in metastatic breast cancer, it has only modest activity (response rate of 9%) . HoweverCetuximab is a monoclonal antibody that targets overexpressed EGFR in various cancers . EGFR isMonoclonal antibodies as biologic anticancer agents have shown reduced toxicity while having modest activities. The low response rates due to drug resistance can explain such modest activities. TRZ resistance is developed in about 70% of TRZ-treated breast cancer patients in early treatment period  and onlyLapatinib is a small molecule dual tyrosine kinase receptor inhibitor of EGFR and HER2 that, like TRZ, has demonstrated a significant improvement in overall survival when added to the treatment of HER2-positive metastatic breast cancer . The benAnother strategy for targeting VEGF and tumor angiogenesis is the use of small molecule tyrosine kinase receptor inhibitors that target the VEGF receptor (VEGFR), including sunitinib, sorafenib, axitinib, and pazopanib. Gianni et al. reported improved response rate of 72% with the docetaxel plus sunitinib combination compared to 11% with sunitinib monotherapy. Most common side effects of sunitinib are anorexia, fatigue, mucositis, diarrhea, and nausea. However, the combination was well tolerated and did not significantly worsen the toxicity associated with the chemotherapy alone . Although these agents, alone or in combination with chemotherapy and/or other biologics, hold great promise, to date they have failed to demonstrate significant activity in metastatic breast cancer , 55. MosP = 0.02) of patients receiving olaparib, gemcitabine, and carboplatin compared to that of placebo and chemotherapy groups [Poly(adenosine diphosphate-ribose) polymerase (PARP) is a DNA-binding protein involved in detection and repair of DNA strand breaks . PARP iny groups .Although not many of the regimens are clinically approved, the concept of combination of two or more target-specific biologic agents is promising . The ratCmax\u2061 were not significantly different in comparing the combination with lapatinib alone. AUC24 and Cmax of TRZ were not significantly different when comparing the combination to trastuzumab alone [Beneficial therapeutic effectiveness from combination treatment is promising when considering theoretically nonoverlapping mechanisms of action of each anticancer agent. However, current combination treatments in metastatic breast cancer are far from perfect with moderate enhanced efficacy but additive toxicity as described above. Commonly these anticancer agents are administered together as a physical mixture of each agent without pharmacokinetic modification. These agents (free drugs) therefore distribute are eliminated independently of each other. As a result the additive effects are seen not only in anticancer activity but concurrently in adverse effects. Combining molecularly targeted agents is an improved strategy, but brings added complications including patient compliance issue. For example, in HER2 targeted combination therapy with TRZ and lapatinib, these two agents have two different routes of administration. TRZ is given intravenously weekly while lapatinib is administered daily as an oral formulation. Due to two different ways of administration with different schedules it is challenging to manage proper pharmacokinetic and pharmacodynamic profiles and virtually impossible to achieve uniform temporal and spatial codelivery. Storniolo et al. reported the results of a pharmacokinetic study of coadministration of TRZ and lapatinib to 27 patients. Serial blood samples were collected over a 24-hour period after ingestion of the lapatinib dose and/or the initiation of the 0.5-hour TRZ infusion. They reported that lapatinib area under the plasma drug concentration versus time curve within a 24-hour period after dosing and ab alone . HoweverThe challenges discussed above have driven researchers to investigate novel approaches by incorporating nanotechnology with combination anticancer treatment. The promising hypothesis is that by delivering two of more drugs simultaneously using a carrier-mediated drug delivery system the combination system can generate synergistic anticancer effects and reduce individual drug related toxicity. However this area of delivering multiple drugs with a single vehicle remains largely unexplored while most research efforts focus on single agent delivery systems. Therefore, here we will review carrier-mediated drug delivery systems containing multiple anticancer agents for cancer treatment in general not limited to metastatic breast cancer. Carrier-mediated drug delivery systems can offer many advantages over delivery of physical mixture of multiple drugs. The advantages include (1) prolonged drug circulation half-life mediated by the carrier, (2) reduced nonspecific uptake, (3) increased accumulation at the tumor site through passive enhanced permeation and retention (EPR) effect and/or active targeting by incorporation of targeting ligands , (4) preLiposomes are spherical vesicles composed of one or more lipid bilayers with a drug containing aqueous core . LiposomAnother unique liposomal system is a polymer-caged nanobin PCN,  developeAttaching targeting ligands such as antibodies and peptides to a drug carrier is a widely applied strategy drastically increasing carrier accumulation in the desired cells, tissues, and organs. Several such targeted liposomes have been developed for combination drug delivery applications . Wu et aAs with any carrier-mediated codelivery system, determination of the optimal dose as the relative ratio of multiple drugs is a complex aspect in liposome-based combination drug delivery system. Mayer et al. reported precise control over combinatorial drug dosing in liposomes . The comDendrimers are well-established three-dimensional, branched polymers that have been thoroughly investigated as controlled and targeted drug delivery systems. The structure of dendrimers can be defined by an initiator core and layers of branched repeating units  with functional end groups on the outmost layer . DendrimPolymeric nanoparticles are submicron-sized aggregate structures (3\u2013200\u2009nm) that are prepared using random or block copolymers. Polymeric nanoparticles are widely used as drug delivery carriers where the active drug may be physically encapsulated or covalently bound to the polymer matrix depending upon the method of preparation. Several polymeric nanoparticle systems have been explored specifically for combination drug delivery in cancer using both passive and active targeting strategies . For exaIn general it has been shown that polymeric nanoparticles, compared to liposomes, have greater stability, controlled size distribution, more tunable physicochemical properties, sustained and more controllable drug-release profiles, and higher loading capacity for poorly water-soluble drugs. While majority of the nanoparticle systems described above have demonstrated synergistic therapeutic efficacy in both in vitro and in vivo models some of these studies specifically illustrate that synergistic therapeutic effect is primarily due to the ability to administer two drugs in a tunable mass ratio with predictable spatial and temporal drug release profiles. For example Sengupta et al. developed a hybrid polymeric micelle  comprisiPolymer-drug conjugates are drug delivery systems in which a drug is covalently bound to a water-soluble polymeric carrier, normally via a biodegradable linker. Such nanoconstructs were first proposed in the 1970s , develop N-(2-hydroxypropyl)methacrylamide (HPMA) is one example of biocompatible, non-immunogenic, non-toxic water-soluble copolymers that can be tailor-made for specific combination drug delivery needs . The uniOthers have explored modifications of the PEG backbone to conjugate a combination of chemotherapeutic agents. While unmodified PEG can only conjugate two drug molecules per chain (one on each end), Pasut et al. developed a PEG with a dendritic structure on one end that allowed coupling of upto 8 nitric oxide (NO) and one epirubicin (EPI) molecule per chain , 100. InOur research group has recently proposed a novel carrier-mediated combination drug delivery system for HER2 overexpressing metastatic breast cancer . We synthttp://www.celator.ca/) has developed a methodical approach to assess different drug ratios within their liposomal technology resulting in the development of different liposomal formulations that are now being assessed in phase II clinical trials, namely, CPX-1 (irinotecan: floxuridine) and CPX-351 (cytarabine: daunorubicin). Such an approach needs to be extended to other combination delivery systems such as dendrimers or polymer-drug conjugates. Determination of the kinetics of release of each drug in a multidrug combination system will be also necessary to determine the optimum ratio as one drug may affect the release profile of the other drug and thereby affect activity. Finally clinical development of these combination products is extremely challenging, due to developmental costs of designing such complex systems. However, these combination drug delivery system-based therapeutics are likely to be perceived by pharmaceutical companies as novel opportunities to extend the patent lives compared to current blockbuster drugs.The presence of two or more therapeutic agents on a single carrier platform offers new therapeutic possibilities but at the same time poses many new challenges. In order to identify an appropriate drug combination, it is necessary to perform thorough biological evaluation which must be supported by a profound understanding of the molecular mechanisms involved. Another critical aspect is the determination of the optimal mass ratio of each component within a combination drug delivery system. This requires systematic research investigating the impact of different drug ratios on the biological activity of the combination delivery systems. Recently a Canadian pharmaceutical company Celator ("}
+{"text": "Tension-type headache (TTH) is the most prevalent headache among adults and is associated with impaired functional and psychosocial quality of life. Further analysis of eventual pathophysiology and comorbidities is needed. Temporomandibular Disorders (TMD) and TTH are frequently coexisting disorders and both characterized by increased pericranial tenderness. In a specialised tertiary headache centre more than half of the patients were also diagnosed with TMD but their eventual causality is yet unknown. Likewise is the relationship between tenderness, sleep quality and oral health in TTH patients also unknown. Our aim was to characterize the relationship between pericranial tenderness, sleep quality and oral health in TTH patients in comparison with healthy controls.The survey included 58 consecutive patients with frequent, episodic TTH or chronic TTH from a tertiary Headache Center and 58 healthy controls. Questionnaires regarding The Research Diagnostic Criteria for Temporomandibular Disorders (RDC), Oral Health Impact profile and Sleep/tiredness/snoring were completed.TTH-patients were significantly more affected in the RDC-Screening by increased characteristic pain intensity (CPI) regarding self reported temporomandibular pain (TMP) (p<0.001), decreased quality of life , and the total sleep score (p<0.001) compared to healthy controls).TTH patients are severely affected by TMP; demonstrate impaired sleep quality and oral health function and may reflect common underlying pathophysiological mechanisms."}
+{"text": "Complex patients present with numerous risk factors and disease states. Clinical uses of biomarkers include diagnosis , risk stratification (assessing future risk of adverse outcomes or monitoring risk of adverse events), screening, and guiding therapy. Plasma natriuretic peptide are released from the heart in response to volume overload, as well as serving as markers of elevated filling pressures, a finding that in many cases would otherwise only be detectable with invasive testing. Therefore, the use of natriuretic peptides is an important adjunct to echocardiography in many circumstances. Just as BNP levels can be considered the arbitrator of CHF, cardiac troponins (TnI/TnT) are decisive for myocardial necrosis. The introduction of novel assays with even higher clinical sensitivity, detecting troponin levels at nanogram quantities, suggest even earlier diagnosis of acute myocardial infarction and identification of patients at substantial risk post-infarction. NGAL is one of the earliest and most robustly induced genes and proteins in the kidney after ischemic or nephrotoxic injury. Elevations are detectable within hours of acute kidney injury (AKI); whereas corresponding creatinine elevations lag 1 to 3 days behind."}
+{"text": "This manuscript describes the NIH Human Microbiome Project, including a brief review of human microbiome research, a history of the project, and a comprehensive overview of the consortium's recent collection of publications analyzing the human microbiome. The Human Microbiome Project (HMP) Pioneering medical microbiologists applied these approaches, finding far more microbial diversity than expected even in well-studied body site habitats http://commonfund.nih.gov/hmp/) To coordinate these efforts relating the microbiome to human health, the NIH Common Fund launched the HMP as a community resource program  unique to the study of the microbiome Any study of human populations must put both subject protection and study design first, and the HMP was no exception. Power calculations for microbiome studies in human cohorts are particularly challenging, as they must simultaneously address assay types , depth of sequencing, taxon detection, and fold abundance changes in clades, genes, or pathways of interest http://hmpdacc.org) hosts all available HMP data and many tools, focusing the tremendous quantity of raw data through lenses such as SitePainter Finally, quality data generation from appropriately designed microbiome studies enables a variety of subsequent computational analyses . While wThe HMP was designed in part to address a key question about our microbial selves: do all humans have an identifiable \u201ccore\" microbiome of shared components comparable to our shared genome A potentially more universal \u201ccore\" human microbiome emerged during the consideration of microbial genes and pathways carried throughout communities' metagenomes. While microbial organisms varied among subjects as described above, metabolic pathways necessary for human-associated microbial life were consistently present, forming a functional \u201ccore\" to the microbiome at all body sites Data from individuals without overt signs of disease serve as an excellent reference for disease-associated microbiome studies, while also providing a comprehensive baseline for comparison of Western populations with disparate geographic, ethnic, and genetic cohorts The HMP has thus greatly advanced our knowledge of the microbes in a healthy adult reference population, and provided much-needed infrastructure in terms of reference genomes, laboratory protocols, computational methods, and ELSI considerations"}
+{"text": "Although very late stent thrombosis (VLST) after drug-eluting stent (DES) implantation remains a major concern, the precise mechanisms have not been clarified. An association between late acquired incomplete stent apposition (ISA) and VLST of DES has been suggested by several intravascular ultrasound studies demonstrating very high prevalence of ISA in the setting of VLST. To clarify the pathological mechanisms of VLST, we investigated vascular responses of coronary arteries of VLST cases after DES implantation. Drug-eluting stents (DESs) have dramatically reduced angiographic restenosis and clinical need for repeat revascularization procedures , 2. Howe The pathological findings from patients who died of late DES thrombosis have demonstrated that delayed arterial healing characterized by incomplete reendothelialization is an important underlying factor . The patAlthough a correlation has been observed between uncovered DES struts and LST, in our pathological studies of Japanese patients, considerable number of cases showed neointimal coverage with reendothelialization of a great deal of the DES struts, especially in simple lesions beyond 1 year . Thus, e Late ISA has been observed on follow-up intravascular ultrasound (IVUS) in patients who received sirolimus-eluting stents (SESs) . Althoug Thus, late ISA by focal positive vessel remodeling caused by medial necrosis may be responsible for LST and/or VLST after DES implantation. Peri-stent contrast staining (PSS) was defined as contrast staining outside the stent contour extending to \u226520% of stent diameter measured by quantitative coronary angiography. PSS found within 12 months after SES implantation appeared to be associated with subsequent VLST . PSS couRecent studies have identified immune cells and mediators at work in atheroma, implicating inflammatory mechanisms in disease development . As prevThus, DES can induce atherosclerotic and thrombogenic lesions with a significantly higher incidence and earlier than with BMS.  LST may be more frequently related to incomplete healing and/or inadequate neointimal coverage with poor re-endothelialization. However, in the cases of VLST, several pathological studies have suggested a causal relationship between the inflammatory responses to the durable polymer and VLST, provoking late ISA and accelerated atherosclerosis followed by neointimal disruption. Histopathologic differences  among DES platforms have been observed; this may reflect unique responses to the specific polymer/drug. Thus, until novel DES using superbly biocompatible and/or biodegradable polymers becomes available, we still need to be cautious and carefully keep surveying these devices."}
+{"text": "Isolated granulomatous noncaseating pancreatitis is a rare condition exceptionally described in human population. We demonstrate a case of the a 71-years-old female patient suffering from recent diabetes mellitus, generalized atherosclerosis and hypertension who died due to pulmonary embolism and terminal bronchopneumonia. Lipomatosis of pancreatic tissue was observed during the postmortem examination. Histological examination of pancreatic tissue discovered multiple small noncaseating epithelioid cell and giant cell granulomas, partly replacing the islets of Langerhans. To our knowledge, our case represents the first description of noninfectious granulomatous pancreatitis associated with acute manifested insulin-dependent diabetes mellitus. Noncaseating granulomatous inflammation confined to the pancreas has been only exceptionally described in human patients. Infections like tuberculosis and syphilis, exogenous noxes, autoimmunity, and systemic granulomatous diseases are the most frequent causes of granuloma formation within the pancreatic tissue . AbdominA 71-year-old obese woman was admitted with the recent onset of diabetes mellitus manifested as hyperglycaemic ketoacidotic precoma. The past medical history was unremarkable. Recently, arterial hypertension was discovered. Her body weight was 110\u2009kg, BMI 38. The plasma glucose level ranged from 3.1 to 15.1\u2009mmol/L. The patient was treated with intensified insulin regime. The status of the patient was complicated by intermittent fever and several antibiotics were repeatedly administered. Terminally, clinical signs of septic shock and multiorgan failure appeared and the patient died. Postmortem examination performed 11 hours after death discovered signs of septic shock with activation of spleen pulp and terminal bronchopneumonia. Thromboemboli were found in several peripheral branches of the pulmonary artery. Hypertrophy of the heart (545\u2009g), predominantly of the left ventricle, was also observed. The pancreas showed a macroscopically lobular arrangement and lipomatosis; other macroscopic changes were not visible. Lungs, thoracic lymph nodes, and other organs did not show any changes corresponding with tuberculous process or sarcoidosis.\u03bcm-thick sections were stained with haematoxylin and eosin and by immunohistochemical methods using N-Histofine Immunohistochemical staining reagent  and 3-3\u2032diaminobenzidine as a chromogen to visualize the reaction. The list of antibodies, including manufacturers and the dilutions used, is introduced in Five representative tissue samples of pancreatic tissue taken from head, body, and tail were fixed with 10% formalin and routinely embedded in paraffin. Five-Microscopic examination of pancreatic tissue discovered an increased amount of lipomatous tissue within the pancreatic lobules. Irregular inflammatory infiltrates of a variable density composed predominantly of small lymphocytes and sparse neutrophilic and eosinophilic granulocytes were also observed (\u03bcm) noncaseating epithelioid granulomas with giant cells, without Schaumann bodies, were present within the pancreatic lobules  and pancreatic hormones  verified the original microscopic finding of absence of islets of Langerhans . The majority of patients were presented by the obstructive jaundice, weight loss, and abdominal pain. Other autoimmune disorders, like sclerosing cholangitis or interstitial pneumonia, can appear in patients with AP. Histologically, AP is characterized by dense lymphoplasmacytic infiltrates and secondary fibrosis within the pancreatic tissue. Inflammation frequently displays a patchy collar arrangement around both small and large interlobular ducts and periphlebitis and obliterative phlebitis is invariably observed . It seemDiabetes mellitus in adults is predominantly of type 2. Much less frequently, type 1 diabetes and latent autoimmune diabetes (LADA) can appear in adult patients . DiabeteOur recent finding suggests that granulomatous pancreatitis is a possible underlying cause of diabetes mellitus and urges the microscopic examination of pancreatic tissue obtained during the post mortem examination of patients who died with signs and symptoms of recently manifested diabetes mellitus."}
+{"text": "Burden of obesity has increased significantly in the United States over last few decades. Association of obesity with insulin resistance and related cardiometabolic problems is well established. Traditionally, adipose tissue in visceral fat depot has been considered a major culprit in development of insulin resistance. However, growing body of the literature has suggested that adipose tissue in subcutaneous fat depot, not only due to larger volume but also due to inherent functional characteristics, can have significant impact on development of insulin resistance. There are significant differences in functional characteristics of subcutaneous abdominal/truncal versus gluteofemoral depots. Decreased capacity for adipocyte differentiation and angiogenesis along with adipocyte hypertrophy can trigger vicious cycle of inflammation in subcutaneous adipose tissue and subsequent ectopic fat deposition. It is important to shift focus from fat content to functional heterogeneity in adipose tissue depots to better understand the relative role of subcutaneous adipose tissue in metabolic complications of obesity. Therapeutic lifestyle change continues to be the most important intervention in clinical practice at any level of increased adiposity. Future pharmaceutical interventions aimed at improving adipose tissue function in various subcutaneous depots have potential to help maintain adequate insulin sensitivity and reduce risk for development of insulin resistance complications. Prevalence of obesity has been increasing in the US. In 1960s, prevalence of obesity was approximately 13% , 3. ObesHowever, we have to consider clinical paradoxes along the spectrum of obesity, insulin resistance and metabolic complications. Metabolically healthy but obese (MHO) phenotype exhibits higher insulin sensitivity, absence of hypertension, and favorable lipid, inflammation, hormonal and liver enzyme profile. On the basis of epidemiological and clinical studies, prevalence of MHO phenotype varies from 10%\u201340% . The extExcessive insulin resistance and related metabolic abnormalities can be due to differential distribution of adipose tissue and/or adipose tissue dysfunction. Anatomically adipose tissues can be divided into truncal region or peripheral region. Truncal adipose tissue includes subcutaneous fat in thoracic and abdominal region and also intrathoracic and intraabdominal fat depots . PeripheVague in 1947 described two patterns of adipose tissue distribution\u2014android (upper body) and gynoid (lower body)\u2014and suggested that android obesity was associated with diabetes, coronary artery disease, gout, and uric acid renal stones . Later oVisceral fat has increased metabolic activity, both lipogenesis and lipolysis, compared to other fat depots. Free fatty acids, product of lipolysis, can directly enter liver via portal circulation and lead to increased lipid synthesis, gluconeogenesis, and insulin resistance resulting in hyperlipidemia, glucose intolerance, hypertension, and ultimately atherosclerosis . Excess We have examined the relationships between generalized and regional adiposity and insulin sensitivity in a group of nondiabetic men with varying degree of obesity . We concSimple explanation for stronger relationship between subcutaneous adipose tissue and insulin sensitivity comes from larger volume of subcutaneous adipose tissue mass. The subcutaneous abdominal fat mass is approximately twice more than intraperitoneal fat mass and total subcutaneous truncal fat mass can be 4-5 times larger than intraperitoneal fat mass , 23, 26.\u03baB stress pathway were upregulated suggesting stimulation of inflammatory mediators. Lundgren et al. [Inflammation in adipose tissue has been identified as a mediator of systemic insulin resistance. This has been suggested by presence of macrophage in the form of crown-like structures (CLSs) in adipose tissue. Apovian et al.  examinedn et al.  examinedn et al. . This isn et al.  reportedn et al. , 35. Recent work on angiogenesis in adipose tissue has provided important insights into potential mechanisms of heterogeneity in the systemic metabolic impact of specific adipose tissue compartments. Gealekman et al.  reportedIn contrast to abdominal subcutaneous adipose tissue, larger subcutaneous thigh fat mass has a protective effect. The Health, Aging, and Body Composition Study  reported\u03baB pathway. The resultant effects are downregulation of cellular insulin signaling, recruitment of additional macrophages through monocyte chemoattractant protein 1, propagation of inflammation by interleukins and tumor necrosis factor alpha, and tissue matrix remodeling through matrix metalloproteinase-9 [Finally, it is worth putting truncal/abdominal subcutaneous adipose tissue characteristics all together to explain their emerging role in insulin resistance . Increaseinase-9 . These iConclusion. There is enough evidence in the literature for association between obesity and insulin resistance. Many investigators have proposed that visceral adipose tissue is a major contributor to insulin resistance. Our previous studies, in concordance with those of other investigators, suggest that subcutaneous truncal adipose tissue has significant impact on development of insulin resistance. Thus, adipose tissue distribution and function in different body compartments can be heterogeneous and can differentially contribute to insulin resistance. Changing focus from visceral adipose tissue mass as a sole contributor to insulin resistance to functional heterogeneity in adipose tissue depots can help better understand relationship of adiposity and insulin resistance. Therapeutic lifestyle change, including physical activity and weight loss, continues to be the most important intervention at any level of adiposity. One can envision that better understanding of adipose tissue function in various depots will help identify much needed additional and more effective therapeutic modalities to improve adipose tissue function and maintain adequate systemic glucose and lipid metabolism to reduce risk for morbidity and mortality associated with insulin resistance."}
+{"text": "Since the introduction of recombinant human growth hormone (GH) in in the mid-1980s, supplies are almost limitless and predictably GH usage has escalated dramatically. There have been more than 150,000 children treated with GH worldwide with a wide variety of growth disorders.Adverse events (AE) with all forms of drug therapy are markedly under-reported, considerably underestimating the incidence of the AE. This under-reporting occurs even when the AE is serious and has a possible or probable association with GH therapy. Careful audit of the frequency of reporting of severe AE to other drugs with a possible or probable association with treatment is only 14%. Furthermore missing data is very common and adds to the difficulty in interpreting AE.Important conditions (adverse events) possibly linked to GH treatment are fortunately rare. There are several major limitations to accurately assessing the prevalence and risk of rare adverse events. Firstly, extremely large datasets are required found in large databases such KIGS and NCGS each with >50,000 enrolled patients. Secondly, accurate risk assessment of the possible adverse event in an untreated population that matches the GH treated population has rarely been determined.Important potential adverse events that have received considerable attention will be addressed. These include; tumour recurrence, new malignancies including leukaemia, diabetes mellitus, benign intracranial hypertension and slipped upper femoral epiphyses. The physiological rationale and the risk of these conditions during GH treatment will be addressed.Serum IGF-I monitoring to prevent elevated levels that may further increase the risk of adverse events is recommended. The potential adverse consequences of sustained elevated serum IGF-I levels will be discussed. In addition, monitoring IGF-I helps to monitor compliance of GH therapy in children with GH deficiency."}
+{"text": "Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory pathological left ventricle (LV) hypertrophy due to sarcomere dysfunction. In an important proportion of patients with HCM, the site and extent of cardiac hypertrophy results in severe obstruction to LV outflow tract (LVOT), contributing to disabling symptoms and increasing the risk of sudden cardiac death (SCD). In patients with progressive and/or refractory symptoms despite optimal pharmacological treatment, invasive therapies that diminish or abolish LVOT obstruction relieve heart failure-related symptoms, improve quality of life and could be associated with long-term survival similar to that observed in the general population. The gold standard in this respect is surgical septal myectomy, which might be supplementary associated with a reduction in SCD. Percutaneous techniques, particularly alcohol septal ablation (ASA) and more recently radiofrequency (RF) septal ablation, can achieve LVOT gradient reduction and symptomatic benefit in a large proportion of HOCM patients at the cost of a supposedly limited septal myocardial necrosis and a 10-20% risk of chronic atrioventricular block. After an initial period of enthusiasm, standard DDD pacing failed to show in randomized trials significant LVOT gradient reductions and objective improvement in exercise capacity. However, case reports and recent small pilot studies suggested that atrial synchronous LV or biventricular (biV) pacing significantly reduce LVOT obstruction and improve symptoms (acutely as well as long-term) in a large proportion of severely symptomatic HOCM patients not suitable to other gradient reduction therapies. Moreover, biV/LV pacing in HOCM seems to be associated with significant LV reverse remodelling. Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory LV hypertrophy mainly due to sarcomere dysfunction. Prevalence of the disorder in the general population is estimated to be 0.2% . A subseMedical therapy is at least partially effective in the majority of HOCM patients  and consIn severely symptomatic HOCM patients despite optimal medical treatment and with significant resting or provocable LVOT obstruction (with gradient \u226530 mm Hg at rest or \u226550 mm Hg during exercise) non-pharmacologic treatment is indicated  even in less symptomatic HOCM patients , with a  even in In the overwhelming majority of HOCM patients LV/biV pacing is acutely more effective for gradient reduction than standard RVA pacing: eight out of nine in one study  and all In contrast to studies with DDD RVA pacing, LV/biV pacing showed that the reduction in LVOT gradient induced a progressive and significant reduction in LV mass (reverse remodelling) . The thiDuring long term LV/biV pacing in HOCM there was no SCD/syncope in patients with CRT-P ,38. In tThe small number of patients included in studies with LV/biV pacing in HOCM as well as the fact that all of them are observational and uncontrolled  requires caution in interpreting the results. However, the differences observed in comparison with standard DDD RVA pacing warrants further research. Considering the relatively large number of HOCM patients submitted to cardioverter-defibrillator implantation for primary or secondary prevention, data for such analysis should be readily available.In selected patients with HOCM, LV/biV pacing is feasible and usually the best configuration for gradient reduction. Overall, LV/biV pacing in patients with HOCM significantly and progressively improves functional capacity and quality of life. It may also induce LV reverse remodelling."}
+{"text": "Microbial cells are highly complex and heterogeneous systems. In general, cell populations contain subgroups of cells which exhibit differences in growth rate as well as resistance to stress and drug treatment In the past 20 years a new form of microscopy, atomic force microscopy (AFM), has revolutionized the way researchers probe the microbial cell surface. Instead of using an incident beam, AFM measures the minute forces acting between a sharp tip and the sample AFM is much more than a surface-imaging tool in that it also measures the localization and mechanical properties of the individual cell surface molecules. In this modality, known as single-molecule force spectroscopy, the cantilever deflection is recorded as a function of the vertical displacement of the scanner (as the sample is pushed towards the tip and it retracts) Lactobacillus rhamnosus GG, Lactococcus lactis, and Lactobacillus plantarumL. rhamnosus GG had a rough surface morphology decorated with 15 nanometer\u2013high wave-like structures, attributed to the production of extracellular polysaccharides involved in host adhesion L. lactis showed 25 nanometer\u2013wide striations documenting peptidoglycan cables running parallel to the short cell axis, thus supporting the classical model for peptidoglycan organization Bacillus subtilisL. plantarum documented a highly polarized surface morphology  that was correlated with a heterogeneous distribution of teichoic acids There has been rapid progress in recent years using AFM for imaging microbial surfaces under physiological conditions. In structural biology, AFM has provided fascinating insights into the supramolecular architecture of membrane proteins, thereby complementing data obtained by electron and X-ray crystallography Bacillus thuringiensis flagella involved in cell motility Aspergillus fumigatusCorynebacterium glutamicumStaphylococcus aureus was observed during growth, revealing ring-like and honeycomb structures at 20 nanometers resolution Bacillus atrophaeus spores revealed germination-induced alterations in spore coat architecture and disassembly of rodlet structures Candida albicans and macrophages Remarkably, high-resolution imaging has allowed researchers to observe cell surface structures to a resolution of a few nanometers. Observed structures include Escherichia coli cells AFM imaging thus opens up unprecedented possibilities for studying the structural details of the surface of microbial pathogens without drying, staining, or fixation. As conventional AFM imaging is limited by a rather poor temporal resolution, an important challenge is to increase the speed of AFM to study fast dynamic biological processes Shewanella oneidensis bacteria C. albicans with AFM tips terminated with specific antibodies triggered the formation and propagation of adhesion nanodomains on the cell surface While AFM imaging lacks biochemical specificity, single-molecule force spectroscopy with functionalized AFM tips makes it possible to map the distribution of specific molecules on living cells. The method involves scanning the cell surface with a tip bearing cognate ligands while measuring specific receptor-ligand forces E. coli fimbrial adhesive protein FimH which strengthen under external mechanical force C. albicans revealed sawtooth patterns with multiple force peaks, corresponding to the force-induced unfolding of hydrophobic tandem repeats engaged in cell adhesion  and respond to force . Knowing these molecular properties is critical to our understanding of cell surface functions.Many challenges remain to be addressed. As we have already discussed, further developments in high-speed AFMs"}
+{"text": "There is no consensus on optimal use of radiotherapy following radical prostatectomy. The purpose of this study was to describe opinions of urologists and radiation oncologists regarding adjuvant and salvage radiotherapy following radical prostatectomy.Urologists and genitourinary radiation oncologists were solicited to participate in an online survey. Respondent characteristics included demographics, training, practice setting, patient volume/experience, and access to radiotherapy. Participant practice patterns and attitudes towards use of adjuvant and salvage radiotherapy in standardized clinical scenarios were assessed.One hundred and forty-six staff physicians participated in the survey (104 urologists and 42 genitourinary radiation oncologists). Overall, high Gleason score , positive surgical margin , and extraprostatic tumour extension  conferred an increased probability of recommending adjuvant radiotherapy. Radiation oncologists were more likely to recommend adjuvant radiotherapy across all clinical scenarios . Major differences were found for patients with Gleason 6 and isolated positive surgical margin (radiotherapy selected by 21% of urologists vs. 70% of radiation oncologists), and patients with extraprostatic extension and negative surgical margins (radiotherapy selected by 18% of urologist vs. 57% of radiation oncologists).Urologists and radiation oncologists frequently disagree about recommendation for post-prostatectomy adjuvant radiotherapy. Since clinical equipoise exists between adjuvant versus early salvage post-operative radiotherapy, support of clinical trials comparing these approaches is strongly encouraged. Approximately 40% of patients diagnosed with prostate cancer will be treated with radical prostatectomy and approximately 15-35% will develop a detectible serum prostate-specific antigen (PSA) following surgery . A positTraditionally, clinicians may have been more likely to treat patients with androgen deprivation if clinicopathologic features were associated with high risk of systemic disease  and more likely to treat patients with adjuvant or salvage radiotherapy if features were associated with high risk of isolated localized disease  . HoweverWhile indications for pelvic radiotherapy may have changed, questions remain about the timing of treatment. Adjuvant radiotherapy is offered to patients prior to PSA recurrence while salvage radiotherapy reserves treatment, and its associated side effects, for men with proven biochemical recurrence. Randomized trials of adjuvant radiotherapy versus observation reveal a reduction in biochemical recurrence  and prolonged survival (SWOG 8794) while observational studies suggest salvage radiotherapy versus observation reduces progression and prolongs survival ,20. The th, 2011. Institutional ethics approval was obtained for this survey from the Ottawa Hospital Research Ethics Board prior to study commencement.In October 2011, Canadian Urological Association (CUA) members and genitourinary radiation oncologists from the Canadian Association of Radiation Oncology (CARO) were invited to participate in an online survey. CUA members were contacted through the CUA listserv and radiation oncologist emails were available through the CARO member directory. A second request was made one month following the original invitation. E-mail recipients were provided with a hyperlink to an online survey that populated a secure database. The survey was closed on November 7Participants were asked to provide demographic information including age, geographic location of practice, specialty (urology or radiation oncology), practice type (academic or community), years in practice, sub-specialty training, number of prostate cancer patients assessed per year, and access to radiotherapy.Respondents were asked to rate how various clinical and pathologic variables independently influenced their recommendation for adjuvant and salvage radiotherapy via Likert items. Clinical variables included patient age, urinary continence, and erectile function. Pathologic variables included extraprostatic tumour extension, seminal vesicle tumour invasion, lymph node metastases, pre- and post-operative PSA concentrations, Gleason score, pathologic stage, and surgical margin status. Respondents were provided with a standardized case scenario of a healthy 60 year old male 3-months post radical prostatectomy with an undetectable PSA. They were asked to recommend for or against adjuvant radiotherapy for this patient given varied Gleason score, pathologic stage, and surgical margin status.adjuvant radiotherapy after radical prostatectomy in the provided clinical scenario. A-priori independent variables for the clinical scenario model were Gleason grade, tumour stage, surgical margin status, and medical specialty. P-values < 0.05 were considered statistically significant.Survey responses were summarized with frequencies and percentages. Associations between clinician/patient characteristics and choice of adjuvant radiotherapy were calculated using logistic regression. Log binomial regression was used to calculate relative risks (RR) using the proc genmod procedure in SAS. RR are presented with 95% confidence intervals (CI). Candidate predictor variables included clinician characteristics  and pathologic factors . Each predictor variable was assessed as a categorical variable. The primary outcome was the respondent\u2019s decision to recommend From 586 listed emails, 146 (25%) staff physicians participated in the survey and were included in the analysis. 104 (22%) of solicited urologists and 42 (40%) of solicited genitourinary radiation oncologists completed the survey. The majority of radiation oncologists  and approximately half of urologists  indicated they practiced in an academic institution. Sub-specialty training in genitourinary oncology was reported in 51 (35%) respondents. The mean number of years in practice was 14 years (SD 10.3). Full demographic characteristics are presented in A majority of urologists  and radiation oncologists  reported that recent randomized trials have changed the way they manage patients after radical prostatectomy. When asked their opinion regarding the value of adding androgen deprivation therapy (ADT) to adjuvant or salvage radiotherapy, 29 (35%) urologists and 13 (32%) radiation oncologists reported believing it is likely beneficial and 44 (52%) urologists and 22 (55%) radiation oncologist would recommend it to high risk patients. A large proportion of urologists  and radiation oncologists  believed more research is required to evaluate the benefit and harm of ADT when used in conjunction with radiotherapy following prostatectomy. The influence of clinical and pathologic factors on the recommendation for adjuvant or salvage radiotherapy is presented in Large differences were identified in the opinions of radiation oncologists and urologists regarding recommendations for adjuvant radiotherapy when pathologic variables were placed in the context of a standardized clinical scenario . SeventyOverall, radiation oncologists were 48% more likely to recommend adjuvant radiotherapy compared to urologists . Of the remaining clinical factors evaluated, only physician age had a significant impact on the recommendation for adjuvant radiotherapy with older physicians being less likely to recommend radiotherapy . Practice setting, access to radiotherapy, and genitourinary oncology fellowship training did not strongly influence the probability of recommending radiotherapy .Pathologic variables  were associated with the recommendation for adjuvant radiotherapy . A GleasTo adjust for potential confounders, multivariable analysis was performed to determine the independent associations between each predictor variable and the recommendation for adjuvant radiotherapy . PatholoThis survey explored the practice patterns and opinions of two different specialty groups involved in the management of patients with prostate cancer, urologists and radiation oncologists, and identified factors that influence recommendations for post-operative radiotherapy. For every pathological variable examined, radiation oncologists were more likely to recommend adjuvant radiotherapy than were urologists with a mean absolute difference of 27% and relative difference of 48%. There were clinical scenarios where urologists and radiation oncologists agreed; specifically, both commonly recommended adjuvant radiotherapy in patients with extraprostatic tumour extension and a positive surgical margin, high Gleason score and a positive surgical margin, or seminal vesicle invasion. Conversely, there was lack of consensus for patients with low Gleason score and an isolated positive surgical margin, and for patients with extraprostatic extension and negative surgical margin. The influence of medical specialty on treatment recommendations was striking and is a trend that has been previously observed amongst urologists and radiation oncologists when selecting primary treatment of prostate cancer .Standardized scenarios in the survey represented patients that would have met inclusion criteria for entry into SWOG 8794 . The SWOExamining each variable independently, a large proportion of physicians surveyed were more likely to recommend adjuvant post-operative radiotherapy in patients with extraprostatic disease, high Gleason score, seminal vesicle invasion, and positive surgical margins. It is interesting to note that surgical margin status appeared to influence urologists much more than radiation oncologists (RR 1.6 vs. 1.08). Taken as a whole, these results indicate a departure from the dogmatic approach of avoiding radiotherapy in patients with high risk of metastases  . FactorsAmong post-operative patients who develop a detectable serum PSA, the survey identified several factors that influence the likelihood of physicians recommending salvage radiotherapy. In addition to the pathological and clinical characteristics identified for adjuvant radiotherapy, post-operative PSA kinetics strongly influenced physician opinion. Physicians were more likely to recommend radiotherapy when there was a prolonged duration between prostatectomy and detection of post-operative PSA and when the PSA doubling time was long. This finding is somewhat surprising and illustrates a misconception amongst physicians surveyed regarding the value of salvage radiotherapy for long and short PSA doubling times (PSADT). Although observational studies have reported a better prognosis for men with PSADT > 10 months, the absolute benefit of salvage radiotherapy is in fact greater in men with rapid PSADT ,20. TherA limitation of the current literature is a lack of randomized comparison of adjuvant and salvage radiotherapy. Adjuvant radiotherapy (prior to PSA recurrence) may be better than salvage radiotherapy (when PSA becomes detectible) for several reasons. Firstly, recurrences are predominantly local in the absence of seminal vesicle invasion or lymph node metastases, therefore early local treatment may prevent metastases . FurtherIdentification of patients likely to benefit from post-operative radiotherapy is important since this intervention is associated with harm . ComplicThis survey has limitations. We are unable to determine the true response rate since email lists were used and the activity of the email accounts could not be determined. While a wide distribution of clinician age, practice setting, and sub-specialty training was observed in the respondents, information about non-respondents was not available to assess potential biases. This survey included primarily Canadian physicians, and practice patterns may be different in other health care settings. Finally, this survey draws data from responses to realistic but fictional patient scenarios and thus cannot control for variations in respondent interpretation.The results of this survey reveal some consensus and some salient differences in the opinions of physicians regarding post-radical prostatectomy radiotherapy. Most notably, there was a large difference in the proportion of urologists and radiation oncologists who recommended radiotherapy for patients with low Gleason scores and isolated positive margins or extraprostatic extension. Since clinical equipoise exists between adjuvant and early salvage post-operative radiotherapy, support of clinical trials comparing these two approaches is strongly encouraged."}
+{"text": "Cuculus canorus) is a generalist brood parasite that lays its eggs in the nest of many different passerine birds, but each female tends to specialize on one particular host species giving rise to highly specialized host races. The different host species show large variation in their ability to invest in the parasitic offspring, presenting an opportunity for female cuckoos to bias offspring sex ratio in relation to host species quality. Here, we investigate host-race specific sex allocation controlling for maternal identity in the common cuckoo. We found no evidence of any significant relationship between host race and sex ratio in one sympatric population harbouring three different host races, or in a total of five geographically separated populations. There was also no significant association between host quality, as determined by species-specific female host body mass, and cuckoo sex ratio. Finally, we found no significant relationship between individual cuckoo maternal quality, as determined by her egg volume, and sex ratio within each host race. We conclude that the generalist brood-parasitic common cuckoo show no significant sex-ratio bias in relation to host race and discuss this finding in light of gene flow and host adaptations.Sex allocation theory and empirical evidence both suggest that natural selection should favour maternal control of offspring sex ratio in relation to their ability to invest in the offspring. Generalist parasites constitute a particularly interesting group to test this theory as different females commonly utilize different host species showing large variation in provisioning ability. The common cuckoo ( Fisher In birds, females are the heterogametic sex and the sex determining division in avian meiosis occurs prior to ovulation and fertilization, providing the females with an unusual direct opportunity to modify offspring sex ratio Cuculus canorus) therefore constitutes a particular interesting species for investigating sex allocation. The common cuckoo is highly polygynous with ca. half of all males siring offspring with more than one female and is sexually size dimorphic The avian brood-parasitic common cuckoo (Molothrus ater) A few previous studies have not revealed any significant relationship between host species and sex ratio in the common cuckoo or the brood-parasitic brown-headed cowbird  was drawn by puncturing either the brachical or femoral vein. Permits for working with cuckoos and their hosts and collect DNA samples was received in each country; permits were issued by the Ministry of Environment and Water in Bulgaria; the Municipal Office in Hodonin (3C2KA/2003) in the Czech Republic; the Southeast Finland Regional Environment Centre in Finland; the Middle-Danube-Valley Inspectorate for Environmental Protection (31873), Nature Conservation and Water in Hungary; and the Regional Ethical Committee in Wroc\u0142aw and the Faculty of Biology (KWB.0118.1-2003), University of Wroc\u0142aw in Poland.Milaria calandra), great reed warblers  and marsh warblers  was collected in the surroundings of Zlatia, north-western Bulgaria A. scirpaceus) in Luzice, Czech Republic where also great reed warblers, marsh warblers and sedge warblers (A. schoenobaenus) are parsitized Phoenicurus phoenicurus) Data on three sympatrically breeding cuckoo host races parasitizing corn buntings . All loci were amplified by polymerase chain reaction (PCR) on a GeneAmp PCR System 9700  and run on a 3130XL Genetic Analyser . The sex marker and microsatellites were scored in Genemapper v. 3.7 , and the mitochondrial sequence data were assembled and manually checked in Geneious v. 4.7.6 We used the CHD1-M5 primer in combination with P8 for molecular sex determination Many cuckoo nestlings were collected within the same geographic area and could be either full- or halfsiblings, and hence potentially represent a problem of pseudoreplication. We therefore analysed a genetic dataset on 13 microsatellite markers . Furthermore, there were no significant differences in sex ratio between any pair of the five host races pooled across the different geographic localities , or between sympatric and allopatric populations, including host species as a random effect to control for host race identity .In order to analyze the effect of host species quality we included species-specific host female body mass In this study, we investigated host-specific sex ratio in the generalist brood-parasitic common cuckoo. We hypothesized that sex ratio of cuckoo offspring should vary in relation to host species quality in accordance with predictions from sex allocation theory. However, we found no evidence of any significant relationship between host race and sex ratio in one sympatric population harbouring three different host races, or in a total of five different geographically separated populations. Hence, our results corroborate the few previous studies on avian brood parasites According to theory, female cuckoos have both the ability and opportunity to increase their own fitness by selectively producing the rarer sex. Firstly, avian females have an unusual direct opportunity to modify offspring sex ratio because the sex determining division in avian meiosis occurs prior to ovulation and fertilization The traditional Trivers-Willard hypothesis rests on three assumptions. Firstly, parental condition must be associated with offspring condition; secondly, any difference in offspring condition must persist into adulthood; and thirdly, condition must differentially affect the mating success of one sex more than the other sensu Trivers and Willard The occurrence of genetic differentiation and assortative mating may explain why females show no evidence of sex ratio bias in relation to host quality. If males commonly mate within their own host race, males from large host races will not compete directly with males from smaller host races, and therefore not achieve a higher reproductive success than their sisters. Hence, natural selection will not select for a male-biased sex ratio sensu Trivers-Willard may be counteracted by the selection for smaller females in cuckoos. This could also explain the lack of any relationship between sex ratio and female quality, as determined by cuckoo egg volume, within each host race. It is also possible that egg volume does not capture maternal quality in the way we expect, and that other measures like investment in hormones and anti-oxidants in the oocyte would be more suitable A comparative study on the family Cuculidae suggests that sexual size dimorphism has more likely evolved via coevolution than sexual selection in this taxa We conclude that the generalist brood-parasitic common cuckoo show no evidence of sex-ratio bias in relation to host race, host race quality or individual maternal quality."}
+{"text": "Aging is accompanied by substantial changes in brain function, including functional reorganization of large-scale brain networks. Such differences in network architecture have been reported both at rest and during cognitive task performance, but an open question is whether these age-related differences show task-dependent effects or represent only task-independent changes attributable to a common factor . To address this question, we used graph theoretic analysis to construct weighted cortical functional networks from hemodynamic  responses in 12 younger and 12 older adults during a speech perception task performed in both quiet and noisy listening conditions. Functional networks were constructed for each subject and listening condition based on inter-regional correlations of the fMRI signal among 66 cortical regions, and network measures of global and local efficiency were computed. Across listening conditions, older adult networks showed significantly decreased global  efficiency relative to younger adults after normalizing measures to surrogate random networks. Although listening condition produced no main effects on whole-cortex network organization, a significant age group x listening condition interaction was observed. Additionally, an exploratory analysis of regional effects uncovered age-related declines in both global and local efficiency concentrated exclusively in auditory areas , further suggestive of specificity to the speech perception tasks. Global efficiency also correlated positively with mean cortical thickness across all subjects, establishing gross cortical atrophy as a task-independent contributor to age-related differences in functional organization. Together, our findings provide evidence of age-related disruptions in cortical functional network organization during speech perception tasks, and suggest that although task-independent effects such as cortical atrophy clearly underlie age-related changes in cortical functional organization, age-related differences also demonstrate sensitivity to task domains. Aging is characterized by marked declines in sensory and cognitive functions In recent years, graph theoretic analysis has offered a powerful data-driven framework to explore the topological organization of brain networks These functional differences are underlain by neuroanatomical changes across the lifespan. Such changes include widespread atrophy of both subcortical and cortical grey matter structures Given these pervasive, co-occurring functional and neuroanatomial changes, the question also arises whether age-related effects on brain functional organization are independent of cognitive domains , or show task specificity. Recently, Wang et al. examined changes in functional networks of younger and older adults obtained via fMRI during memory encoding and retrieval tasks involving visually presented words and pictures To address these questions, we employed functional MRI to investigate age-related differences in large-scale cortical networks associated with speech perception tasks. In the scanner experiment, we tested 12 younger and 12 older adults' abilities to recognize spoken word stimuli and match them to objects on a screen  in both a quiet listening condition and in loud multi-talker background noise regional measures) and also averaged across all nodes in each network  to describe the overall network topology. We compared both regional and whole-cortex measures across age groups and task conditions, after normalizing the graph measures to values in surrogate random networks. Additionally, to test for a relationship between age-related changes in functional network properties and neuroanatomical characteristics, we examined the relationship between whole-cortex network measures and mean cortical thickness.In the present analysis, we applied graph theoretic analysis to construct weighted cortical functional networks for each subject and listening condition based upon interregional correlations of the fMRI signal among 66 cortical regions. Graph measures describing the efficiency of global and local information transfer were computed within each individual network node  of older adults coupled with age-related increases in cognitive areas in prefrontal and posterior parietal cortex, changes believed to underlie a compensatory mechanism for reduced sensory abilities in aging To foreshadow the results, we found significant age-related decreases in global  network efficiency, agreeing with previous studies of age effects on large-scale brain networks globE) and local (locE) efficiency were computed and averaged across all cortical regions to quantify the efficiency of global and local information transfer within the networks.  by assigning connections based on the inter-regional correlation of fMRI responses between 66 cortical regions specified in the Desikan-Killiany atlas . Both younger and older adults possessed small-world network topologies characterized by es e.g., . RelativTo test these differences statistically, summary measures of osts see . HencefoConceivably, observed differences in brain functional connectivity could be related to head motion in the scanner Next, we tested for effects of subject group and listening condition on network measures within individual cortical regions. We applied a single p-value cutoff of 0.05 (uncorrected for multiple comparisons) to establish significance for regional effects; thus, our results at the regional level must be regarded as exploratory. Additionally, we found several areas that showed main effects of listening condition on the network measures see . The noiWe also observed regions showing an interaction effect between subject group and task condition see . For , ssubjects .As anticipated, older adults had significantly reduced mean cortical thickness relative to younger adults  despite normal peripheral hearing abilities Interestingly, we observed a different pattern of results in these residual data relative to the original results see , S2. ForThe performance effect analysis also revealed a different pattern of results for the regional network measures . As in tyrus see . ListeniIn this study, we applied a weighted graph theoretic analysis to assess cortical functional organization in younger and older adults during performance of a speech perception task in both quiet and noisy listening conditions. We found that older adult cortical networks possessed significantly reduced global  efficiency relative to younger adults after normalizing graph measures to values in randomized networks. Most importantly, a significant group x listening condition interaction effect for This report adds to a body of research linking cognitive aging to disrupted organization of communication pathways encompassing the entire cerebral cortex Importantly, the age-related disruptions observed for whole-cortex network properties were underlain by regional changes concentrated in auditory areas of the lateral temporal cortex. Older adults possessed decreased global and local efficiency within bilateral superior and middle temporal cortex. The superior temporal cortices constitute key auditory regions responsible for low-level acoustic analysis; thus, declines in efficient information transfer involving these regions could affect mapping of inputs from the peripheral auditory system onto acoustical representations Additionally, we observed regions that exhibited main effects of listening condition (quiet vs. noisy) on either global or local efficiency. Several of these regions overlapped the default-mode network, including bilateral posterior parietal and right parahippocampal cortex We also found several cortical areas showing significant group x listening condition interaction effects on the regional network measures. Group x condition interaction effects were observed in left primary auditory cortex, right middle temporal cortex, and in default-mode areas within posterior parietal cortex. Thus, in addition to task-dependent age-related differences on whole-cortex network structure, the two listening conditions evoked differential effects on network organization between younger and older adults at the regional level.In addition, group x condition interaction effects on Based on findings of consistent age-related differences in activation patterns and functional network topology across memory encoding and recognition tasks, Grady et al. and Wang et al. argued that age-related changes in brain network organization derive from a common, domain-general factor Declining cognitive performance is a central aspect of aging. Even though the older participants in our study possessed normal peripheral hearing abilities, their speech perception performance  was significantly worse than that of younger adults under the increased sensory/cognitive demands of the noisy listening environment Ultimately, the effects of reduced cognitive performance on cortical functional organization in aging remains an area for further investigation. However, the significant age-related effects at both the whole-cortex and regional levels in this residual analysis suggest that task performance is not the only important factor driving the results observed in this study. These types of complementary analyses may prove useful in future studies to help disentangle the various behavioral, anatomical, and physiological factors influencing functional organization of the cortex in both aging research and comparative neuroimaging studies in general.Looking across all subjects, we found a significant positive correlation between mean cortical thickness and It is also worth noting some important limitations of our study. First, similar to previous studies This study provides evidence of age-related disruptions in large-scale cortical functional organization during performance of a speech perception task. Although the observed age-related differences in whole-cortex network topology partly corroborated previous studies of resting-state connectivity All subjects in this experiment gave informed written consent prior to inclusion in the study and were compensated monetarily for their participation. All research was conducted under the approval of the Northwestern University Institutional Review Board, and thus adhered to the ethical standards outlined in the 1964 Declaration of Helsinki.In this study, we employed functional magnetic resonance imaging (fMRI) to examine characteristics of cortical functional networks related to speech perception in noise (SPIN) performance in younger (19\u201327 years) and older (63\u201375 years) adults We recruited twelve younger ; 8 females) and twelve older ; 6 females) adults with no reported neurological deficits for participation in the study.Speech stimuli consisted of a set of twenty target words obtained from In the scanner experiment, subjects were presented with one-word speech stimuli via headphones . During each stimulus presentation, subjects were shown three images on a screen, including an image matching the target word and two distracters, and used a response box to select the image corresponding to the target word. For instance, in one trial, subjects heard the word \u201cwitch\u201d in the presence of background noise, and had to select between images of a witch and two other objects from the list of stimuli. Stimuli were presented in 12-second blocks consisting of three individual stimuli (each corresponding to the same listening condition), limiting response times to four seconds per stimulus. In total, the fMRI experiment consisted of 60 stimulus blocks per condition as well as 30 null blocks during which no stimuli were presented, with all blocks presented in pseudorandomized order.*-weighted functional images were acquired using a susceptibility-weighted EPI pulse sequence , with 24 slices acquired per scan in an interleaved measurement . Functional image acquisition occurred directly after each 12-second stimulus block and lasted two seconds in duration, resulting in a 14-second repetition time (TR). The sparse functional image acquisition (long TR) ensured there was no scanner noise during stimulus presentation MR imaging data were acquired on a Siemens 3T Trio machine at the Center for Advanced MRI at Northwestern University. T1-weighted, high-resolution anatomical images were acquired axially . During the speech perception experiment, T2We pre-processed MRI data using AFNI V) were extracted containing the functional data from the stimulus blocks corresponding to the listening condition of interest, and pair-wise, zero time-lag Pearson's correlations were calculated between nodes such thati and j, where R) containing the pair-wise correlations of the fMRI responses between each pair of cortical regions for each listening condition.Next, using FreeSurfer's automated cortical parcellation G by assigning undirected, weighted connections (edges) between nodes whose absolute pair-wise correlation exceeded a pre-specified cost threshold, cr. This resulted in a weighted adjacency matrix (W), such that ij\u200a=\u200aW|ijR| if ij|\u2265rc|R or ij\u200a=\u200a0W if ij|<rc|R. The cost thresholds (cr) were specified separately for each subject in order to generate networks with fixed costs . This approach facilitated comparison of network properties by ensuring that each individual network contained the same number of nodes and edges. To ensure that results were not dependent on any particular network cost, we constructed networks over a cost range from 0.10 to 0.40 at increments of 0.02.Subsequently, we defined weighted cortical graphs netL) and cluster coefficient (netC) to quantify small-world network properties i, the global efficiency (glob(i)E) quantifies the efficiency of parallel information transfer between that node and the network at large:N is the total number of nodes in the network and ijL is the shortest weighted path linking nodes i and j. Shortest paths are calculated as Watts & Strogatz originally proposed the characteristic path length (i (loc(i)E) defines the efficiency of information transfer within the subgraph iG of nodes directly connected to node i:ik equals the number of nodes directly neighboring node i. This measure represents the speed of processing within the immediate functional vicinity of a node, with high local efficiency indicating efficient local functional organization globE and locE) may then be obtained by averaging the values across all individual nodes. Small-world networks possess globE approaching (but slightly less than) that of comparable random networks .The local efficiency of an individual node We compared the cost-averaged network measures  and local (locE) efficiency for cortical networks after regressing out performance (task accuracy) effects. Error bars indicate the standard error of the mean. (JPG)Click here for additional data file.Figure S2Aging and listening condition effects on whole-cortex network measures after regressing out performance (task accuracy) effects. Summary values of (JPG)Click here for additional data file.Methods S1(DOC)Click here for additional data file.Table S1(DOC)Click here for additional data file.Table S2(DOC)Click here for additional data file."}
+{"text": "Caenorhabditis elegans (C. elegans) to high-throughput genomic, proteomic and drug screening approaches make this organism an attractive choice for identifying new therapeutic compounds for these disorders and for understanding their mechanism of action. Indeed, a diverse set of informative C. elegans ND models have been developed manifesting abnormal behavioural or pathological phenotypes that partially recapitulate the salient cellular, molecular and pathological aspects of several distinct human NDs processes. Recent studies have identified dnajc5 encoding cysteine-string protein \u03b1 (CSP\u03b1) as the disease-causing gene of a rare autosomal dominant human ND known as adult-onset neuronal ceroid lipofuscinosis (ANCL). The null animal models of CSP are characterised by impaired neurotransmission, pre-synaptic neurodegeneration and premature mortality. Simple model organisms may therefore shed light on potential therapeutic approaches for ANCL and other NDs.Debilitating neurodegenerative disorders (NDs) including Alzheimer\u2019s disease, Parkinson\u2019s disease, and polyglutamine diseases are a major public health challenge in increasingly aging societies. Currently approved therapeutics are successful in slowing the progression of NDs but not in reversing or preventing the symptoms of NDs. The simplicity and amenability of the nematode C. elegans ND models to uncover potential therapeutic interventions that target shared pathogenic pathways. We tested parameters such as locomotion and lifespan which act as a measure of neurological and neuromuscular function, and viability upon drug treatment in C. elegans.In this study, we are integrating multiple well-defined C. elegans null mutant model of ANCL, but also ameliorates the mobility defect and short lifespan of a distinct worm tauopathy model based on transgenic expression of mutant human tau. We are currently investigating how ethosuximide might exert its neuroprotective properties. We found that ethosuximide has no obvious aggregation-suppressing effect and suppression of proteotoxicity by ethosuximide is independent of the low voltage activated T-type calcium channel, the principal therapeutic target of ethosuximide in controlling generalised absence epilepsy.Using locomotion behaviour and lifespan as phenotypic readouts, we uncovered the anticonvulsant ethosuximide as a promising candidate drug that not only rescues the short lifespan of a Overall, our data provide good evidence that anti-epileptic ethosuximide is efficacious in several worm ND models. Further investigation of its precise mode of action and validation in vertebrate systems is required to gauge the effectiveness of this compound as early leads for drug discovery. These findings should encourage further screening and characterisation of other neuroprotective compounds, and ultimately may assist in accelerating the clinical evaluation and development of drugs to combat protein conformational disorders in general."}
+{"text": "Analysis of MZvangl2 mutants revealed that PCP is not required for cilia formation but is required for the posterior tilting and posterior positioning of motile cilia. To determine whether cilia were required to establish cell polarity, we generated MZift88 mutants where ciliogenesis is completely abolished. MZift88 mutants have normal C&E movements, suggesting that cilia are not directly required for PCP mediated morphogenetic movements. However, we have observed defects in PCP-controlled OCD occurring during gastrulation. Remarkably, these divisions occur prior to cilia formation, suggesting a cilia-independent role for IFT proteins in cell divisions. We are currently determining whether IFT88 regulates all OCD or just those that are PCP-controlled.Polycystic kidney disease (PKD) is characterized by dilated collecting tubules causing fluid filled cysts and enlarged kidneys. Dilated tubules can result from disrupted convergence and extension (C&E) movements and defects in oriented cell divisions (OCD). Planar cell polarity (PCP) signalling has been implicated in PKD since defects in C&E and OCD are both characteristic of disrupted PCP. Surprisingly, genetic studies of mutations causing PKD predominantly affect proteins that localize near cilia and basal bodies. The functional relationship between cilia and PCP signalling in the context of PKD is still poorly understood. Previous studies of PCP effector proteins suggested that PCP signalling was required for cilia formation. However, these proteins are not specific to PCP signalling and are shared with other Wnt pathways. To determine the role of a core and specific PCP regulator on ciliogenesis, we examined maternal-zygotic (MZ)"}
+{"text": "Tonight at a classical dance recitalsymbolizing the eternal quest of the soul-force for GodI too raised for myself some questionsAs I saw the dancer adopt body twistedbeautifully gymnastic postureslike a question mark put before me- who am I?Am I the inquisitive streetwalker listening at pavementsto snake charmers\u2019 aphrodisiac calls,watching indolently as the fast cycling roguewhirling past knocks her off, squeezes her breasts,makes offand leaves me to pacify her smothered adolescence.Or am I the automatonThat hangs on to footboards and breezes past in fast trainsevery morning and eveningthe only sensation left in me being in my handsholding on for dear life, and in my lipswolf whistling as I swirl past platforms.Or just the nimble fingerstyping away at jet-speed,taking down bosses\u2019 notes, thumbing across wads of money,hand shakingwith prospective customers.Or just tongues, tongues and more tongueswith mounds and mounds of sugar and ghee and adulterated oilspouring it all into unknowing earsfurthering business prospectsfeeding everyone around in slow poison dosesand fattening on pure ghee, purity of expression, conscience.So that I can decorate my drawing room with costly paintings andupholsterywatch expensive dance recitalsand answer question marks once in a while.Ajai R. Singh"}
+{"text": "ATRX are clinically characterised by severe cognitive disabilities and muscular hypotonia, thus dramatically compromising their independent locomotory ability.The growth of muscle tissue and its regeneration from injury is crucially dependent on a self-renewing population of muscle progenitor cells called satellite cells. Activated satellite cells give rise to a rapidly expanding population of myoblasts that increase muscle mass by differentiating into new or adding into pre-existing muscle fibers. Patients with mutations in the chromatin remodeling gene Myf5-Cre mice with mice harbouring the Atrx floxed conditional knockout allele (herein referred to as Atrx cKO). Body mass of Atrx cKO and control littermates were measured along with general morphometric analysis of select hindlimb muscles at 3-weeks, 5-weeks, and greater than 8-weeks of age. Methods of analysis included single muscle fiber preparations from the extensor digitorum longus (EDL) and soleus muscles as well as RNA expression analysis from the EDL and soleus muscles. Primary myoblasts were also cultured from dissociated muscle tissue from the hindlimbs and analyzed via immuno-fluorescent microscopy. Neuromuscular acuity and endurance was assessed in Atrx cKO and control littermates by the roto-rod apparatus. Muscle strength was assessed by utilizing a digital grip strength measuring apparatus.We generated a skeletal muscle specific knockout mouse model by interbreeding Atrx cKO mice presented with telltale characteristics of weaker musculature, exemplified by spinal kyphosis and reduced body mass at 3-weeks of age. Satellite cell derived myoblasts from Atrx cKO mice were incapable of rapid expansion in culture but were fully capable of terminally differentiating. Atrx cKO myoblasts displayed delayed cell cycle progression through mid-late S-phase and rampant signs of genomic instability characterised by fragmented nuclei, \u03b3-H2AX foci, and telomeric aberrations. Despite inefficient myoblast proliferative capacity, Atrx cKO animals were able to re-establish normal body mass by adulthood. Muscular fitness and function in Atrx cKO mice was also age dependent, as younger 3-week old Atrx cKO mice had a reduced capacity to stay on the roto-rod and poorer gripping strength. However, differences in grip strength of adult Atrx cKO mice were almost indistinguishable from their control littermates. Data regarding pathways mediating the hypertrophic compensatory adaptation in Atrx cKO mice will also be presented.Inefficient expansion of activated satellite cells in Atrx cKO mice results in delayed muscle development up to 3-weeks of age, when myonuclear accretion reaches its plateau. Reduced muscle mass at 3-weeks of age also correlated with poorer performance in physical tasks that require muscular force, endurance, and coordination. Compensatory mechanisms are triggered after 3-weeks of age in Atrx cKO mice that allow for the eventual recovery of body mass and muscle functionality in adults."}
+{"text": "Objective: The report herein presents a case of a 49-year-old woman with left breast cancer who presented seeking immediate autologous reconstruction. Surgical history included an abdominal hysterectomy and an abdominal contouring procedure. This is a first description of a deep inferior epigastric perforator flap after abdominal wall manipulation of this magnitude. Methods: Computed tomographic angiography identified patent medial row perforators. Doppler confirmed the location of the perforators. The flap was designed with the inferior incision at the previous lower abdominal scar. Laser-assisted indocyanine green imaging confirmed adequate flap perfusion on the basis of a single left deep inferior epigastric perforator. Results: The flap was harvested on one perforator and anastomosed to the internal mammary system. The postoperative course was complicated by venous anastomosis kinking, requiring revision, but otherwise unremarkable. Conclusion: Computed tomographic angiography confirmed presence of perforators, communication with the deep inferior epigastric system, and location acceptable for flap design. Laser-assisted indocyanine green angiography facilitated perforator selection and provided intraoperative assessment of flap perfusion. Utilization of these modalities allowed safe completion of an operation considered contraindicated by conventional algorithms and highlights their role in complex perforator flap reconstruction. Deep inferior epigastric perforator (DIEP) flaps have been reported in patients with vertical and short transverse abdominal scars after intra-abdominal surgery.3Clearly, as the body of experience grows, microsurgeons are becoming more aggressive in their surgical efforts. We seek to do so while maintaining patient safety and increasing procedural reliability. The objective of this report was to propose that advanced imaging modalities might permit perforator-based reconstruction in patients previously thought to be ineligible because of prior surgery.A 49-year-old woman with left breast cancer  was seen in consultation seeking immediate autologous breast reconstruction. Review of her surgical history revealed an abdominal contouring procedure performed by another surgeon approximately 6 years prior to presentation. This surgery included resection of skin and fat of the lower abdomen and elevation of an adipocutaneous flap above level of umbilicus. A hysterectomy was performed at the time by a vertical fascial incision. The umbilicus was translocated. Of note, the rectus fascia was not plicated.Physical examination revealed moderate sized breasts with grade 2 ptosis. Abdominal scars included a low transverse incision from hip to hip and a periumbilical scar. Adequate abdominal soft tissue for bilateral reconstruction was present, whereas medial thigh and gluteal donor sites were deemed insufficient .Preoperative evaluation included a computed tomographic angiography. Bilateral deep inferior epigastric artery perforators were identified. These perforators were located approximately 4 cm caudal and lateral to the umbilicus on either side. The right-sided perforator measured 1 mm in diameter, and the left-sided perforator measured 2 mm. Both perforators were traceable to their origin from the deep inferior epigastric artery .The mastectomy specimen weighed 942 g. The flap was centered on the radiographically identified perforators. The lower portion of the abdominal incision incorporated the previous transverse scar, and the flap dissection proceeded cephalad, allowing identification of the perforators on each side. At this point, given the prior surgery and stretching of the upper abdominal wall soft tissue, in addition to standard clinical signs, laser-assisted indocyanine green (ICG) fluorescence imaging was used to assess flap perfusion. The right-sided perforators were temporarily clamped, ICG was injected, and the SPY Elite system  was used to obtain the images.The abdominal flap demonstrated perfusion in zones 1, 2, and 3, based on the single left-sided medial row deep inferior epigastric artery perforator . The flaThe early postoperative course was complicated by venous congestion 2 hours after surgery. Exploration revealed a kink at the coupled venous anastomosis. The venous anastomosis was revised, and the remainder of the patient's course was unremarkable  and 6.,1Cases of DIEP flaps in patients with vertical abdominal scars have been reported in the literature.4In 2010, Jandali et alIn April 2012, Mahajan et alThe use of computed tomographic angiography to guide surgical planning for perforator-based reconstructing has been well described.The introduction of laser-assisted ICG angiographyConventional \u201cabdominoplasty\u201d may have different interpretations and executions by different surgeons, with varying degrees of cephalad undermining and perforator preservation. This variability and resultant perceived flap unreliability has rendered perforator-based reconstructions after extensive abdominal wall procedures \u201ccontraindicated.\u201d However, as perforator-sparing techniques are progressively used and engrained across various disciplines of plastic surgery, specifically in abdominal wall procedures, should the need arise, the opportunity to use these perforators in free tissue reconstruction need not be discounted. We suspect that, in this case, the perforators superior to the umbilicus were not injured during the patient's initial procedure despite noted dissection above this level. The case presented illustrates the utility of advanced imaging modalities in delineating surgically altered vascular anatomy and physiology.The combination of preoperative computed tomographic angiography for anatomic assessment and intraoperative laser-assisted ICG angiography for perfusion assessment may allow extension of perforator-based reconstruction in scenarios previously considered contraindicated."}
+{"text": "Fragment-based methods are quite popular in 2D QSAR/QSPR studies. In the advanced versions of these approaches for developing highly predictive models, one have to generate a huge set of descriptors that in turn requires well-designed algorithms and high-quality parallelism. To overcome these problems we developed the software for tagged generation of fragmental descriptors.One of the most perspective programming paradigms is functional programming. Programs in pure functional languages are easy to parallelize, tend to be faultless, more clear, easy extensible . DespiteUsing this software we processed several structure-activity/property databases containing hundreds of compounds and generated the sets of more than 500 000 fragmental descriptors in each case. Then for each database 100 most correlated with activity/property descriptors were selected using stagewise MLR. Based on selected descriptors the predictive models were developed using artificial neural networks (ANN) and Random Forest algorithms. Comparison with other fragmental descriptors generation software showed better predictive ability of our models."}
+{"text": "Neural stem cells (NSCs) possess the ability to self-renew and to differentiate into the three major cell types found in the central nervous system (CNS). Recent studies have shown that epigenetic gene regulation events such as DNA methylation and histone modification play important roles in regulating NSC fate specification. In this context, we have previously shown that the histone deacetylase inhibitor valproic acid (VPA) enhances neuronal differentiation of NSCs. Perhaps because these patterns of NSC differentiation are exquisitely controlled during normal embryonic development, restoration of damaged neural networks in the injured adult CNS is severely limited. Here, using a mouse model of spinal cord injury(SCI), we examined the effectiveness of NSC transplantation and differentiation control by VPA administration.NSCs were transplanted into the SCI epicenter 7 days after injury. Non-transplanted control and transplanted mice were then intraperitoneally administered VPA or saline daily, for 7 days, whereafter we monitored their hindlimb motor function using the open field locomotor scale for 6 weeks. We next analyzed the migration, morphology, neuronal marker expression and viability of these cells after co-administration with VPA. We examined extensively the roles of the neurons responsible for reconstruction of broken neuronal networks using two neuronal tracers, immunoelectron microscopy, and two cell-ablation methods.We show that transplanting NSCs and administering VPA enhances the functional recovery of their hindlimbs. Neuronal differentiation of transplanted NSCs was promoted in VPA-treated mice. Anterograde corticospinal tract tracing revealed that transplant-derived neurons partially reconstructed the broken neuronal circuits, most likely in a 'relay' manner. Ablation of the transplanted cells abolished the recovery of hindlimb motor function, indicating that transplanted cells contributed directly to the improvement of motor function.These data raise the possibility that epigenetic regulation in transplanted neural stem cells can be exploited to provide treatment for SCI."}
+{"text": "The authors discuss this unexpected finding with regard to increased cellular NO utilisation and distal airway mucous barriers to NO diffusion.The well-executed study by Sisson et al.  demonstrOx in CF , 3. ContAn alternative explanation involves NO synthetase (NOS) and arginase activity in airway epithelial cells. Both enzymes compete for L-arginine as substrate and imbalances in activity levels are believed to be important in the pathogenesis of airway inflammation and hyperreactivity . Arginasx after VCPT may be an increase in arginase activity through oscillatory mechanical stimulation of lung epithelial cells. Several studies in animal and cell models have demonstrated that specific patterns of mechanical stimulation can induce vascular endothelial arginase expression and activity. For instance, oscillatory shear stress induced stronger arginase activation than application of unidirectional shear force in porcine [ in vitro study showed that cyclic stretching of vascular smooth muscle cells upregulated arginase mRNA expression and enzyme activity whilst inhibiting NOS [A possible mechanism to explain Sisson et al.'s  surprisi porcine  and ApoE porcine . An in vting NOS . The VCPting NOS  study pr"}
+{"text": "Peritubular contractile cells within the testis and epididymis surround seminiferous tubules and the epididymal duct. These cells are crucial for the transport of sperm which only acquire motility and fertilizing capacity during transit from the testis to the distal epididymal duct. cGMP contributes to regulate smooth muscle cell function ,2. The rIsolated epididymal duct segments and seminiferous tubules were studied by organ bath and time-lapse video microscopy to assess sperm transport and contractile activity. In all parts of the epididymis, regular contractions which elicited transport of sperm could be observed. Contraction frequency was reduced after the addition of cGMP-elevating agents sildenafil, nitric oxide (NO) or atrial natriuretic peptide (ANP) . In semiWestern blotting, immunohistochemistry and RT-PCR using laser-dissected contractile cells confirmed expression of the corresponding cGMP pathway components. PDE5 activity was assessed using a cGMP-ELISA and sildenafil dose-dependently increased cGMP.In a rat model of chronic sildenafil treatment, PDE5 expression, contractility and sperm transport remained unaltered.Video microscopy allows to visualize contractile activity and sperm transport in seminiferous tubules and the epididymal duct. Distinct patterns of spontaneous contractile activity are observed in both organs. In the epididymis, regular spontaneous and peristaltic contractions elicit movement of sperm and contractile frequency is reduced by increasing cGMP. In contrast, seminiferous tubules, show an irregular contractile activity of smaller amplitude without clear peristalsis. Our results suggest that this irregular activity can be characterized by a spectrum of frequencies generated by Fourier analysis and that increasing cGMP slows down spontaneous contractile activity as indicated by a shift towards lower frequencies."}
+{"text": "Fulminant myocarditis (FM) represents a crucial cardiac pathology with extensive hemodynamic compromise occurring in a previously healthy patient. Early death occurs because of acute cardiac decompensation from inflammation, necrosis, and myocytolysis. Nevertheless, in this situation implantation of an extracorporeal circulatory support system may ensure cardiac recovery. We herein report our experience using a biventricular Levitronix CentriMag system for bridge to recovery. Fulminant myocarditis (FM) represents a crucial cardiac pathology characterized by rapid and extensive hemodynamic compromise occurring in a previously healthy patient . In caseA 49-year-old previously healthy woman presented to a local emergency department because of recurrent fatigue, dyspnoea, and chest pain within the last three weeks. She described a \u201cflu-like\u201d upper respiratory infection for the past month that progressively worsened to these specific symptoms. The echocardiographic evaluation showed ejection fraction (EF) about 10% with biventricular failure. Despite pathologic ECG and highly elevated cardiac troponin, urgent cardiac catheterization detected only mild coronary sclerosis. During this procedure she progressed to circulatory collapse with the need for highly inotropic support and mechanical ventilation. For higher level of care the lady was transferred to our institution. Due to rapid aggravation of her condition while admission at our ICU, we initiated intraaortic balloon pump (IABP) implantation via the right femoral artery and venoarterial Extracorporeal Membrane Oxygenation (ECMO) implantation through the right femoral vein and right axillary artery. Despite maximum hemodynamic support, the heart showed no evidence of recovery. Furthermore the lady progressed to multiple organ failure including highly elevated lactate level, acute renal failure, and hepatic insufficiency. Our Heart Team decided on urgent biventricular CentriMag  implantation to decompress and support both ventricles. Through a median sternotomy the right atrium and aorta were cannulated and the patient was transferred from ECMO to cardiopulmonary bypass (CPB). A left ventricular 23\u2009F cannula and a 22\u2009F right atrial p-VAD cannula were placed for biventricular outflow into the CentriMag pumps. The left apex cannulation was chosen for maximum flow and complete left ventricular decompression. For return flow to pulmonary and systemic circulation the pulmonary artery and the ascending aorta were anastomosed with two 18\u2009F sealed inflow cannulas. The patient was then weaned from CPB to BVAD support. The ECMO cannulas were removed and the femoral vessels repaired. With moderate inotropic support the patient was administrated to our ICU . IntraveThe postinterventional course was complicated by renal failure and neurologic morbidity necessitating continuous dialysis and tracheotomy. Left and right ventricular functions were daily assessed by transesophageal echocardiogram (TEE), while contractility and aortic valve opening were studied. Recovery of left ventricular contractility began on postimplantation day seven. We considered BVAD explantation when full recovery of biventricular contractility and aortic valve opening were observed. Weaning started on hospital on day 21, with the patient's condition and cardiac function improving to an ejection fraction (EF) of 50% in sinus rhythm. The CentriMag BVAD was removed nine days later without the need for additional CPB. Transesophageal control echocardiogram showed an EF >60% and sufficient right ventricular function. Ten days later she was discharged to rehabilitation in a stable condition.The patient had signs of FM on histological findings with foci myocyte necrosis and lymphocytic infiltration with interstitial oedema. In spite of serologic studies and viral genome research on myocardial biopsies, including in situ hybridization and polymerase chain reaction, pathogenic agents were not identified.FM is clinically characterized by distinct onset of cardiac symptoms in otherwise healthy patients after nonspecific flu-like symptoms rapidly resulting in severe ventricular dysfunction and cardiogenic shock. Most of these patients with acute fulminant myocarditis are stabilized with heart failure management  and recover within a few weeks . HoweverFor our case percutaneous cannulation and emergency implementation of ECMO was initially the therapy of choice due to her life-threatening condition, maybe as a bridge to decision. With cardiac nonrecovery evident and progressive endorgan dysfunction, support was escalated to biventricular nonpulsatile CentriMag assist device implantation. Arguments in favour of BVAD shortterm support are better unloading of both ventricles, a primary condition for recovery from fulminant myocarditis, and avoidance of significant morbidities associated with prolonged ECMO support . Successful treatment of fulminant myocarditis with severe hemodynamic compromise and end organ failure is possible with early CentriMag biventricular assist device implantation. In most cases it facilitates completely cardiac recovery."}
+{"text": "Hundreds of diverse genetic loci have been linked to autism spectrum disorders (ASDs), making large-scale analysis essential for understanding the molecular events underlying the pathogenesis of these disorders. Our laboratory first released the autism database AutDB in 2007 as a bioinformatics tool for systematic curation of all known ASD candidate genes -3. AutDBTo curate the PIN module, our researchers utilize a multi-level annotation model to systematically search, collect and extract information entirely from published, peer-reviewed scientific literature. Although we initially consult public molecular interaction databases (HPRD and BioGRID) and commercial molecular interaction software , every interaction is manually extracted and verified by evaluating the primary reference articles from PubMed. Our manual curation has proved critical for accurate annotation, because these references were the second largest source of references for the initial PIN dataset, providing more interactions than both HPRD and Pathway Studio. Each ASD gene entry within the PIN module is presented as a multi-level display, with interactive graphical and tabular views of its corresponding interactome.The initial PIN dataset includes interactomes for 86 ASD candidate genes, with a total of 1,311 direct protein interactions garnered from 533 unique primary references. These interactomes are composed of 6 interaction types and 13 species, documented by 402 distinct pieces of evidence. Our researchers will expand and maintain the data content of the PIN module with systematic updates.We have created an integrated bioinformatics tool that can be used for the large-scale analysis of the biological relationships among ASD candidate genes. Such network analysis is envisioned to provide a framework for identifying the key molecular pathways underlying ASD pathogenesis, potentially leading to the development of novel drug therapies."}
+{"text": "We investigated the occurrence of goal-directed motivational change in the form of apathy in patients with frontotemporal dementia (FTD), particularly those with behavioral variant social and executive deficits (bvFTD). Standardized behavioral inventory was employed to survey and compare apathy ratings from patients and caregivers. In cases of bvFTD, apathy ratings were further related to measures of social cognition, executive function, and atrophy on brain MRI. Results indicated that caregivers rated bvFTD patients as having significantly elevated apathy scores though patient self-ratings were normal. Caregiver and self-ratings of FTD samples with progressive nonfluent aphasia and semantic dementia did not differ from healthy controls and their informants. In the bvFTD sample, caregiver apathy scores were not correlated with general cognitive screening or depression scores, but were significantly correlated with social cognition and executive function measures. Voxel-based morphometry revealed that apathy ratings in bvFTD were related to prominent atrophy in the right caudate , the right temporo-parietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum- anterior insula region. Findings suggest that bvFTD is associated with a significant breakdown in goal-directed motivated behavior involving disruption of cortical-basal ganglia circuits that is also related to social and executive function deficits."}
+{"text": "Lesion-symptom mapping studies are based upon the assumption that behavioral impairments are directly related to structural brain damage. Given what is known about the relationship between perfusion deficits and impairment in acute stroke, attributing specific behavioral impairments to localized brain damage leaves much room for speculation, as impairments could also reflect abnormal neurovascular function in brain regions that appear structurally intact on traditional CT and MRI scans. Compared to acute stroke, the understanding of cerebral perfusion in chronic stroke is far less clear. Utilizing arterial spin labeling (ASL) MRI, we examined perfusion in 17 patients with chronic left hemisphere stroke. The results revealed a decrease in left hemisphere perfusion, primarily in peri-infarct tissue. There was also a strong relationship between increased infarct size and decreased perfusion. These findings have implications for lesion-symptom mapping studies as well as research that relies on functional MRI to study chronic stroke."}
+{"text": "Chimera states are spatio-temporal patterns of synchrony and disorder observed in homogeneous oscillatory media with nonlocal coupling. They are characterized by coexistence of distinct spatial regions with regular synchronized and irregular incoherent motion. Initially discovered for phase oscillators, chimera states have been also found in systems of nonlocally coupled discrete maps , time-coWe demonstrate the existence of chimera states for neural oscillators . In detaSurprisingly, we find that for increasing coupling strength classical chimera states undergo transitions from one to multiple domains of incoherence. Then patches of synchronized dynamics appear within the incoherent domain giving rise to a multi-chimera state. We find that, depending on the coupling strength and range, different multi-chimeras arise in a transition from classical chimera states. The additional spatial modulation is due to strong coupling interaction and thus cannot be observed in simple phase-oscillator models."}
+{"text": "Even if better clinical outcomes have been achieved with the implantation of newer generation continuous-flow left ventricular assist devices (LVADs), infection complications are still a major risk for these patients in long-term follow-up.We present a case of a 56-year-old male with dilated cardiomyopathy who was urgently implanted with left ventricular assist device HeartMate II. During the entire postoperative period, we observed repeated life-threatening septic complications. Clinical signs of infection disappeared after prolonged treatment with broad-spectrum antibiotics and patient was discharged to outpatient monitoring. During the entire duration of circulatory support, no LVAD suction events were detected, pump power consumption remained in the normal range and the patient was listed for heart transplantation. Patient was two month rehospitalized due to worsening of his status. Hemoglobinuria, an increase of inflammatory markers, and alteration in hepatic and renal function were detected. TEE imaging showed no obstructive formation in inflow or outflow cannulas; only velocities were decreased. The LV was severely dilated and the aortic valve was opening at each contraction. Patient was initially considered for systemic thrombolysis, but this urgent status was finally solved with explantation of the LVAD and subsequent heart transplantation. Massive obstruction with thrombus-like formation was found in the outflow cannula. Histopathologic examination and microbiologic culturing of the mass showed extensive fungal growth (Aspergillus species). During the postoperative period, patient was aggressively treated with antifungal therapy. He was discharged 8 weeks after the transplantation.We believe that clinical decision-making in patients with signs of ongoing sepsis and end-organ dysfunction together with any signs of LVAD malfunction should be very straightforward in terms of device exchange or explantation."}
+{"text": "Congenital muscular torticollis (CMT), also known as fibromatosis colli, is recognized as unilateral contracture and shortening of the sternocleidomastoid (SCM) muscle due to muscle atrophy and interstitial fibrosis, causing ipsilateral head tilt and turn Do, . Its freThis 31-year-old woman exhibited a fixed left head tilt and turn with minor limitation of cervical range of motion since childhood. Her forceps-assisted birth by vaginal delivery was not associated with perinatal injuries. During childhood, she reported persistent head tilt to the left. She had headaches and back pain presumably from compensatory efforts at straightening her neck posture. There was no sensory trick or abnormal posturing of other body segments. Palpation of her neck musculature revealed a non-tender, taut fiber within the left SCM. She had limitation of right head tilt  into the affected SCM but experienced substantial relief of their torticollis and associated pain following partial myectomy of the anterior belly of the SCM muscle. Biopsy in both cases demonstrated fibrous transformation of skeletal muscle fibers Figures , pathognCMT is a rare cause of pseudodystonia expressed as torticollis, whose recognition is important in order to avoid ineffective and potentially harmful antidystonic treatments. CMT is usually recognized in neonates as a circumscribed palpable mass confined to the SCM, affected unilaterally, which may gradually disappear between 4 and 8 months of age or be associated with other orthopedic abnormalities such as hip dysplasia or lower extremity abnormalities (Morrison and MacEwen, Although isolated successes have been reported with chemodenervation (Bouchard et al., Besides CMT, other causes of pseudodystonic torticollis include focal myopathies, rotational atlantoaxial subluxation, posterior fossa tumors, congenital Klippel\u2013Feil anomaly, syringomyelia, trochlear nerve palsy, and vestibular torticollis."}
+{"text": "Objective: The aim of this work was to review de literature about the role of mesenchymal stem cells in bone regenerative procedures in oral implantology, specifically, in the time require to promote bone regeneration.Study Design: A bibliographic search was carried out in PUBMED with a combination of different key words. Animal and human studies that assessed histomorphometrically the influence of mesenchymal stem cells on bone regeneration procedures in oral implantology surgeries were examined.Reults:- Alveolar regeneration: Different controlled histomorphometric animal studies showed that bone regeneration is faster using stem cells seeded in scaffolds than using scaffolds or platelet rich plasma alone. Human studies revealed that stem cells increase bone regeneration.- Maxillary sinus lift: Controlled studies in animals and in humans showed higher bone regeneration applying stem cells compared with controls.- Periimplantary bone regeneration and alveolar distraction: Studies in animals showed higher regeneration when stem cells are used. In humans, no evidence of applying mesenchymal stem cells in these regeneration procedures was found.Conclusion: Stem cells may promote bone regeneration and be useful in bone regenerative procedures in oral implantology, but no firm conclusions can be drawn from the rather limited clinical studies so far performed. Key words:Mesenchymal stem cells, bone regeneration, dental implants, oral surgery, tissue engineering. Embryonic stem cells are derived from blastocysts  and are Surgical bone regeneration procedures such as guided bone regeneration or maxillary sinus augmentation, are well established , but metThe aim of this work was to review de literature about the role on MSC in bone regenerative procedures in oral implantology, specifically, in the time require to promote bone regeneration.A bibliographic search in PUBMED with a combination of different key words: mesenchymal stem cells, bone regeneration, dental implants, tissue engineering, dental pulp stem cells, periodontal ligament stem cells, apical papilla stem cells, deciduous teeth stem cells, oral implantology, oral surgery. Moreover, the references of the articles were also assessed. English articles published until 2011 were evaluated. Animal and human studies that assessed the influence of MSC on bone regeneration procedures in oral implantology surgeries were examined. Studies about alveolar bone regeneration, maxillary sinus lift, periimplantary bone regeneration and alveolar distraction were identified.-Inclusion criteriaDue to the number of studies performed no strict inclusion criteria could be performed. Only studies that used MSC to performed bone regeneration where histologic or histomorfometric analysis was performed were included. The studies should specify the moment where the analysis was carried out.\u2022Clinical Human studies: Clinical trials, case-controls and case series were included. Case reports were excluded.\u2022 Animal studies: Controlled studies were included. Non-controlled studies were excluded.When we applied these inclusion criteria, 26 articles were specifically analyzed. Data about study design, bone regeneration surgery performed and time of histologic -histomorfometric study was carefully taken in account. Different MSC sources, scaffolds and growth factors were used in the reviewed articles so no differences between studies could be performed in this sense.Tissue engineering is an emerging interdisciplinary field, which applies principles of life sciences and engineering towards the development of biological substitutes that restore, maintain and improve the function of damaged and/or lost tissues . In tiss-Alveolar bone regeneration\u2022Animal studiesDifferent studies have compared bone regeneration using MSC and PRP. Yamada et al.  in 10 mmMylonas et al.  applied Other studies exposed that MSC can also accelerate bone formation in alveolar shockets ,27, in 1Clinical human studiesMeijer et al.  implante-Maxillary sinus lift \u2022Animal studiesControlled studies in animals using MSC to increase bone regeneration in maxillary sinus lifts have been performed. Pieri et al.  in a spl\u2022Clinical human studiesClinical case series studies using MSC with different biomaterials have been performed. Shayesteh et al.  performeGronshor et al.  in a conVery recently the first controlled clinical trial using engineered bone stem cells in maxillary sinus elevation has been performed. Rickert et al.  executed-Periimplantary bone regeneration\u2022Animal studiesAnimal studies have evaluated MSC combined with PRP in order to enhance periimplantary bone regeneration. Yamada et al.  regeneraDifferent studies have evaluated the regeneration potential of stem cells harvested from different sources. Ito et al.  compared-Alveolar distraction\u2022Animal studiesQi et al.  evaluateControlled animal studies reveal that stem cells combined with PRP accelerate bone regeneration in oral implantology surgeries. This combination has shown higher capacity than PRP alone to promote bone regeneration. Controlled, long-term follow up clinical human studies have not been performed, but so far, no serious complications related to stem cells grafting (like systemic inflammatory response) have been reported. There is only one very recently clinical trial performing maxillary sinus lift using stem cells seeded on a xenograft showing similar morphometric results than autografts with xenograft. The interesting results of this clinical work as well as those of previous animal studies, indicate that stem cells may promote bone regeneration and be useful in human oral implantology. Many different scaffolds are used; for this reason and the heterogeneity between studies, no big conclusions can be performed yet. More clinical controlled studies applying stem cells are necessary to validate in humans, the favorable results observed in animals."}
+{"text": "Cu+ is significantly more bactericidal than Cu2+ due to its ability to freely penetrate bacterial membranes and inactivate intracellular iron-sulfur clusters. Copper ions can also catalyze reactive oxygen species (ROS) generation, which may further contribute to their toxicity. Transporters, chaperones, redox proteins, receptors and transcription factors and even siderophores affect copper accumulation and distribution in both pathogenic microbes and their human hosts. This review will briefly cover evidence for copper as a mammalian antibacterial effector, the possible reasons for this toxicity, and pathogenic resistance mechanisms directed against it.Recent findings suggest that both host and pathogen manipulate copper content in infected host niches during infections. In this review, we summarize recent developments that implicate copper resistance as an important determinant of bacterial fitness at the host-pathogen interface. An essential mammalian nutrient, copper cycles between copper (I) (Cu Copper is both an essential mammalian micronutrient and a potent antibacterial agent. The Smith Papyrus, an ancient Egyptian medical text dated at 2400 BC, is the earliest medicinal archive to recommend copper sulfate to sterilize water and treat infections ] Liochev, .\u22129 s before reacting with organic molecules in vivo ]:Hydroxyl radicals are extremely reactive, cannot be scavenged by enzymatic reaction, and have a diffusion controlled half-life of ~10Hydrogen peroxide can in turn participate in reaction 1 and may further propagate radical formation.Escherichia coli mutant with multiple copper efflux deficiencies to hydrogen peroxide  oxidation by macrophage-like THP-1 cells was found to be ATP7A-dependent, suggesting metal catalyzed oxidation by secreted copper ions .Phagosomal copper may add to, and perhaps synergize with, the diverse cellular microbial killing strategies described since Elie Metchnikoff's pioneering work on phagocytosis Gordon, . These sM. tuberculosis upregulates genes encoding copper efflux-associated P1B-type ATPases during macrophage infection  exhibit higher growth than concomitant rectal isolates in a medium containing an inhibitory concentration of copper  may reduce the outer membrane's copper permeability , copper sequestration (CusF and siderophores), and copper oxidation (mixed copper oxidases and superoxide dismutase mimics). For the sake of brevity, the following sections primarily discuss Cu2+ detection and resistance proteins that have been described in E. coli  transcriptionally activates both plasmid- and chromosomally-encoded copper homeostatic systems in response to intracellular Cu+ sensing through CueR, a MerR-family metalloregulatory transcriptional activator  located at the dimer interface   system confers copper-tolerance under moderate to high copper levels in oxic conditions  proton antiporter family, CusB belongs to the membrane fusion protein family which anchor into the cytoplasmic membrane with a long periplasm-spanning domain, and CusC is an outermembrane protein with homology to the TolC-stress response protein  studies of the closely related E. coli, the periplasmic chaperone CusF binds copper, ultimately delivering it to CusCBA for export  such as methanobactin and phytochelatin  from copper toxicity, suggesting that yersiniabactin's iron uptake function does not contribute to this phenotype. Copper oxidation state selectivity among microbial small molecules is also observed in pyoverdin and pyochelin, two major siderophore types expressed by P. aeruginosa . Cu+ is more toxic than Cu2+ when applied under anoxic conditions, as demonstrated by Macomber and Imlay . CueO is structurally similar to the large, cross-Kingdom family of MCOs [including ascorbate oxidase and the ferroxidases Fet3 and ceruloplasmin  pathway with copper-bound active sites   and (7)]:+ concentrations while increasing oxidized\u2014and less toxic\u2014Cu2+ ion concentrations. Periplasmic Cu,Zn-SOD may similarly protect against copper stress, although there are distinctive pathogenic advantages to deploying a non-protein catalyst such as copper-yersiniabactin in the phagosomal microenvironment  that help resist copper toxicity. SOD activity may promote bacterial survival in several pathologically important host niches and its connection with copper suggests new insights into host defense mechanisms that are critical to infection pathogenesis.Copper-yersiniabactin confined within the phagolysosome may thus greatly diminish concentrations of superoxide (a reductant), while maintaining or increasing production of hydrogen peroxide (an oxidant). This may have the effect of minimizing reduced CuMuch remains to be understood about the mechanisms by which mammalian hosts deploy copper to resist infection, and how pathogenic bacteria respond to these strategies. ATP7A's emerging role in direct antibacterial immunity warrants its detailed study in mammalian cells that encounter bacterial pathogens. Cell type, pathogen, and regulatory activity may result in unforeseen interactions between copper and other innate immune effector molecules. Possible cooperation with mammalian copper absorption and trafficking may suggest routes by which copper-based immunity could be therapeutically supported. Both basic and translational research efforts will be necessary to understand these details.E. coli binds copper during humans infections  (Grass et al., in vivo and in environmental settings will be necessary to optimize antimicrobial uses of copper.Copper's inherent toxicity has renewed interest in its use as an antimicrobial. Three hundred different copper and copper alloy surfaces are registered with the U.S. Environmental Protection Agency as antimicrobials and trials are underway to determine whether copper treated surfaces can significantly reduce nosocomial infections (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Next generation sequencing platforms and high-throughput genotyping assays have remarkably expedited the pace of development of genomic tools and resources for several crops. Complementing the technological developments, conceptual shifts have also been witnessed in designing experimental populations. Availability of second generation mapping populations encompassing multiple alleles, multiple traits, and extensive recombination events is radically changing the phenomenon of classical QTL mapping. Additionally, the rising molecular breeding approaches like marker assisted recurrent selection (MARS) that are able to harness several QTLs are of particular importance in obtaining a \u201cdesigned\u201d genotype carrying the most desirable combinations of favourable alleles. Furthermore, rapid generation of genome-wide marker data coupled with easy access to precise and accurate phenotypic screens enable large-scale exploitation of LD not only to discover novel QTLs via whole genome association scans but also to practise genomic estimated breeding value (GEBV)-based selection of genotypes. Given refinements being experienced in analytical methods and software tools, the multiparent populations will be the resource of choice to undertake genome wide association studies (GWAS), multiparent MARS, and genomic selection (GS). With this, it is envisioned that these high-throughput and high-power molecular breeding methods would greatly assist in exploiting the enormous potential underlying breeding by design approach to facilitate accelerated crop improvement. IntUnlike regular breeding programmes, the major objective of phenotyping in GS is to predict GEBVs rather than selection of genotypes , 107. PrBy its nature, GS focuses on genetic improvement of QTs rather than understanding their genetic basis , 115. Inin silico and Peleman and van der Voort [Ideotypes or ideal plant types are known to plant breeder, since 1968 when Donald  defined er Voort  describein silico designing of a superior genotype through combining desirable loci (https://www.integratedbreeding.net/ib-tools/breeding-decision). The concept of breeding by design includes (i) locating genes/QTLs associated with important traits (ii) exploring the allelic variation at these loci and the estimation of phenotypic effects of these allelic variants (iii) choosing desirable recombinants by targeting marker/haplotype-defined genomic fragments , 118. ReAvailability of highly saturated genetic maps and populations like ILs has facilitated fine mapping of various QTLs . FurtherOnce genetic loci influencing the expression of the trait have been mapped precisely, allelic variants at all these loci can be mined along with their relative contribution to complex traits, and highly resolved marker haplotypes could be recovered for several agriculturally important traits . With thMoreover, precise phenotyping or phenomics is one of the major bottlenecks in capitalizing the full potential of breeding by design concept . TherefoRapidly decreasing genotyping and sequencing costs are dramatically changing the scenario of genomics-assisted breeding. For instance, a shift has been seen from biparental to multiparental populations, and, with the help of various NGS-based sequencing platforms, a detailed genetic analysis of these complex mapping resources would likely to be feasible. Moreover, extensive recombination and multiallelic nature of these lines make them an excellent platform for practising multiparent MARS and GS. More importantly, the development of such public resources like MAGIC and NAM would strengthen the community-based research approach . Additionally, by virtue of eliminating need for any prior QTL information, MARS and GS schemes would save time, money, and energy that is required for finding significant gene-trait relationships. Still, realization of immense potential of all these approaches would greatly rely on throughput, precision, and cost effectiveness of phenotyping techniques. Though, precise phenotyping has always been a potent limiting factor in genetic analysis of QTs, efforts are underway to meet the growing demands for accurate and HTP screening against various biotic/abiotic stresses. It is envisaged that parallel developments in the next-generation phenotyping systems would help in making GS a practical reality in case of plant species as well. Therefore, rising molecular breeding methods like MARS or GS would enable harnessing unexplored genetic variation to a greater extent, thereby facilitating speedy development of superior cultivars."}
+{"text": "Alcohol use and tobacco smoke exposure are frequently correlated, with many individuals smoking and/or experiencing secondhand smoke (SHS) exposure while drinking . Unfortunately, most medical school curricula do not adequately address the topic of screening and brief intervention (SBI) for tobacco use, SHS exposure, and/or problematic drinking. The aim of this study was to assess the effectiveness of a three-part educational intervention for health-professions schools to address the consequences of SHS exposure and develop SBI skills in medical students. Because information regarding the effects of smoking and SHS can be effectively communicated via self-directed online lectures, we developed an online training module including a videotaped lecture series with accompanying PowerPoint slides. To help students develop diagnostic skills related to SHS and other substance exposure, 10 standardized patient cases were included for instruction and testing. Finally, a clinical-instruction DVD provided examples of how practitioners can implement motivational-interviewing strategies in behavior change counseling related to tobacco use, with or without co-occurring alcohol use. Participants in the educational intervention, compared with controls (no intervention), scored significantly higher on the SHS Competency Exam. In addition, 100% of students who received the intervention reported plans to screen for SHS exposure. This educational intervention may be a valuable addition to medical and health professional school curricula while requiring minimal faculty time and effort."}
+{"text": "Literary data suggest apparently ambiguous interaction between menopausal status and obesity-associated breast cancer risk based on the principle of the carcinogenic capacity of estrogen. Before menopause, breast cancer incidence is relatively low and adiposity is erroneously regarded as a protective factor against this tumor conferred by the obesity associated defective estrogen-synthesis. By contrast, in postmenopausal cases, obesity presents a strong risk factor for breast cancer being mistakenly attributed to the presumed excessive estrogen-production of their adipose-tissue mass. Obesity is associated with dysmetabolism and endangers the healthy equilibrium of sexual hormone-production and regular menstrual cycles in women, which are the prerequisites not only for reproductive capacity but also for somatic health. At the same time, literary data support that anovulatory infertility is a very strong risk for breast cancer in young women either with or without obesity. In the majority of premenopausal women, obesity associated insulin resistance is moderate and may be counteracted by their preserved circulatory estrogen level. Consequently, it is not obesity but rather the still sufficient estrogen-level, which may be protective against breast cancer in young adult females. In obese older women, never using hormone replacement therapy (HRT) the breast cancer risk is high, which is associated with their continuous estrogen loss and increasing insulin-resistance. By contrast, obese postmenopausal women using HRT, have a decreased risk for breast cancer as the protective effect of estrogen-substitution may counteract to their obesity associated systemic alterations. The revealed inverse correlation between circulatory estrogen-level and breast cancer risk in obese women should advance our understanding of breast cancer etiology and promotes primary prevention measures. New patents recommend various methods for the prevention and treatment of obesity-related systemic disorders and the associated breast cancer.  Many studies support an apparently Janus-faced ambiguous interaction between obesity and breast cancer risk depending on the menopausal status of patients -3. In yoNevertheless, several authors could find confusing and disturbing associations between obesity and breast cancer risk in postmenopausal women. Obese postmenopausal women, who had never used hormone replacement therapy (HRT) exhibited fairly high breast cancer risk . By contIn premenopausal cases, the results of clinical studies justify that obesity induces mild or moderate decrease in circulating estrogen levels reflected by their inclination to anovulatory infertility and long or irregular menstrual cycles . Based oEven larger studies, which equivocally strengthen the protective effect of obesity for premenopausal breast cancer risk, confess that the responsible mechanisms are completely obscure. Evidences, provided by clinical endocrinological studies regarding correlations between defective hormonal status of obese women and decreased breast cancer incidence, are inconsistent or fairly contradictory . ConsideObesity is a well-known cancer risk factor associated with different grades of insulin resistance and a disturbance of male to female circulating sexual steroid levels , 20. HypThe aim of the present study is to clarify the realistic correlations between breast cancer risk and obesity-associated hormonal alterations during the whole life of women. Moreover, this study tries to reveal the sources of the misleading clinical and epidemiologic results suggesting the breast cancer protective effect of obesity in the young. These associations are examined in an analytical review based on the results of prospective, case-control and meta-analytic studies.1). The main stream of obesity related alterations is a self-generating, progressive insulin resistance in thorough interplay with the dysmetabolism and inflammation of adipose tissue mass and with an imbalance of sexual steroid production in the endocrine organs.Clinical and experimental evidences prove that obesity, particularly visceral fatty tissue deposition leads to insulin resistance, associated with diverse immunologic, metabolic and hormonal alterations mediating breast cancer risk  is a defect of insulin-mediated cellular glucose uptake, which may elicit many disorders in the gene regulation of cellular metabolism, growth, differentiation and mitotic activity. The progression of this disorder predisposes patients to a variety of diseases, such as metabolic syndrome, type-2 diabetes, cardiovascular lesions and malignancies at different sites .in the first, compensated phase of insulin resistance maintains serum glucose level within the normal range by means of an increased secretory capacity of insular \u03b2-cells . Insulindevelops in the second, partially uncompensated phase of insulin resistance when the enhanced insulin synthesis of pancreatic islet cells is not enough to maintain euglycemia. This is a quartet of elevated fasting glucose, high serum triglyceride, low HDL cholesterol level and hypertension, being characteristic of viscerally obese patients . Each ofHyperglycemia is advantageous for the unrestrained DNA synthesis of tumor cells. It provokes deliberation of free radicals causing derangements in both DNA and enzymes having important role in repair mechanisms [chanisms , 33. Higchanisms . A prospchanisms .Dyslipidemia is a complex disturbance of the lipid metabolism associated with insulin resistance and hyperinsulinemia [ulinemia . Serum lulinemia , 38. Resulinemia .Hypertension usually shows close positive correlation with obesity, insulin resistance and hyperinsulinemia [ulinemia , 41. Eleulinemia , 42. Theulinemia . In postulinemia .Metabolic syndrome is associated with both increased breast cancer risk and high mortality rates in postmenopausal cases , 46. Timis the uncompensated phase of insulin resistance when the secretory capacity of insular \u03b2-cells becomes exhausted and the decreased serum insulin level results in hyperglycemia. The disrupted glucose homeostasis, the excessive formation of free radicals and the protein glycation depress the activities of the antioxidant scavengers and enzymes. These noxious processes cause serious damages in all biological structures even at a molecular level , 48. Thehyperandrogenism and anovulatory infertility through several pathways as insulin is a potent regulator of sexual steroid production in the endocrine organs [ovarian androgen production at the expense of reduced estrogen synthesis [Obesity related insulin resistance and excessive insulin synthesis in women may contribute to e organs . Hyperinynthesis . High inynthesis . Therapeynthesis , 59. A rynthesis .adrenal androgen synthesis as well by means of increased adrenal sensitivity to adrenocorticotropin. At the same time, high insulin level may favor the luteinizing hormone(LH) secretion of pituitary. Increased LH level also stimulates androgen biosynthesis by the activation of adrenal gland and ovarian theca cells [Hyperinsulinemia promotes ca cells , 62. Accca cells . In centca cells , 65.Insulin resistance, hyperinsulinemia and excessive IGF-I activity mediate defective estrogen synthesis by counteraction to aromatase enzyme gene expression at cellular level. The aromatase enzyme complex catalyzes the conversion of androgens to estrogens in a wide variety of tissues. In premenopausal women, the ovaries are the principle sources of estradiol; by contrast, in postmenopausal women when the ovaries cease to produce estrogen, it is synthesized in a number of extragonadal sites . These sIn premenopausal insulin resistant women with type-2 diabetes, the ovaries exhibit decreased capacity to convert androgen to estrogen, probably due to a reduction of ovarian aromatase activity . ConversEstrogens decrease low grade inflammatory reactions and may in parallel reduce the glucocorticoid responses. Low estrogen levels after menopause allow the predominance of glucocorticoids and the manifestation of the metabolic syndrome. These observations suggest that the disturbed equilibrium between sex hormones and glucocorticoids may be a critical element in the manifestation of metabolic syndrome-related pathologies .Visceral adipose tissue has important functions in energy homeostasis, metabolic equilibrium, immune responses and in the regulation of cell proliferation. Secretion of signaling molecules; adipokines regulates the cellular microenvironment both locally and systemically -73.The chronic low grade inflammation associated with obesity is an important player in tumor development and progression. Increased IGF-I level may mediate the inflammation of adipose tissue via its effects on immunologically active cells including macrophages and T cells . IGF-I madipocytokines; such as leptin, adiponectin resistin, ghrelin etc. [Adipokines include unique products of fatty tissue known as lin etc. . Leptin lin etc. . High lelin etc. . Converslin etc. . The ballin etc. .Proinflammatory cytokines  produced in excessive adipose tissue mass increase nitric oxide (NO) production, a substrate for reactive oxygen species (ROS). Accumulation of cytokines and ROS further contribute to insulin resistance resulting in elevated circulating glucose and free fatty acid levels. All signaling molecules of fatty tissue including cytokines, hormones and growth factors are involved in the regulation of the proliferation, invasion and metastatic spread of tumor cells . ProinflOut of several hormones affecting body mass and adipose tissue deposition, estrogens promote, maintain and control the ideal distribution of body fat . These sEstrogen regulates the metabolism, differentiation, growth and cell kinetic mechanisms of adipocytes. In healthy premenopausal women central adipocytes show higher insulin sensitivity and exhibit a higher turnover rate despite similar fat content as compared with male cases . ConversObesity and overweight are important concomitants of insulin resistance and they are strongly associated with disturbed equilibrium of male to female sexual hormone concentrations in women . HealthyHealthy premenopausal women are typically protected from cardiovascular diseases and hypertension as compared with men and this has been hypothesized to be because of the protective effects of estrogens. Conversely, obese, diabetic young women, and postmenopausal cases may lose this protected state as their bioavailable estradiol levels are strongly reduced .Estrogen may have crucial role in the maintenance of normal serum lipid levels. Postmenopausal women have higher total cholesterol, LDL cholesterol and triglyceride levels, whereas lower HDL cholesterol levels as compared with premenopausal cases. These changes may be regarded as a shift toward a more atherogenic lipid profile in estrogen deficient milieu . PostmenEstradiol has cardiovascular protective impact by its anti-hypertensive activity as well. Estrogens can downregulate components of the renin-angiotensin system (RAS) and reduce the expression and activity of angiotensin I-converting enzyme , 95. EstClinical and experimental studies support that estradiol has also antioxidant activities , 99 thatpancreatic islet cells [Estrogens have beneficial effects on the energy metabolism and glucose homeostasis by means of several pathways . Estrogeet cells . Estrogeet cells . EstrogeIn the liver, estrogen regulates insulin sensitivity by the balanced activation of glycogen synthase and glycolytic enzymes to maintain the equilibrium of glycogen synthesis and glycogenolysis. In ER-\u03b1 knockout mice, hepatic insulin resistance was associated with decreased glucose uptake in skeletal muscles [ muscles .In the peripheral tissues, ERs advantageously modulate the insulin stimulated glucose uptake through regulation of the phosphorylation of insulin receptor protein. In hyperinsulinemia, high concentrations of estradiol can inhibit the excessive insulin signaling in adipocytes [ipocytes , which mERs have crucial roles in cellular glucose uptake by regulation of intracellular glucose transporters (GLUTs) and enhancing both GLUT4 expression and translocation . In humaEstrogens and ER signals have pivotal role in the regulation of growth hormone (GH) activity by means of modulation of its secretion and cellular GH receptor function. Estrogens play a major and positive role in the regulation of GH-IGF-I axis in both genders , which mPostmenopausal hormone replacement therapy (HRT) reduced abdominal obesity, insulin resistance, new-onset diabetes, hyperlipidemia, blood pressure, adhesion molecules and procoagulant factors in women without diabetes and reduced insulin resistance and fasting glucose in women with diabetes .Low grade systemic inflammation may be associated with estrogen deficient states, namely menopause and ovariectomy. At early stages of estrogen deficiency estrogen administration decreased the inflammation associated risk of developing cardiovascular disease . NeverthPhytoestrogens may advantageously influence the level of adipokines in insulin resistant women. In postmenopausal cases, diet, physical exercise and daily oral intake of soy isoflavones had a beneficial lowering effect on serum leptin, and TNF-\u03b1 levels and showed a significant increase in mean serum levels of adiponectin . EpidemiEstrogen advantageously regulates serum levels of available growth factors. In clinical studies estradiol lowered, whereas testosteron increased total IGF-I level and estradiol specifically suppressed unbound, free IGF-I level . CrosstaThe presumed synergistic contribution of ERs and GFRs to cancer development and progression would be a permanent danger without contraregulatory impact. Inhibition of growth factor signaling in apparently ER-negative breast cancer cells successfully restored ER expression suggesting a dynamic, inverse relationship between the two receptor systems . Moreoveobese premenopausal women, peripheral, subcutaneous adiposity is typical and there is a lower incidence of obesity associated dysmetabolism. By contrast, in obesepostmenopausal cases, circulating levels of estrogen are dramatically decreased and adipose tissue distribution becomes more male-like. Predominance of visceral adiposity and the associated metabolic and hormonal disorders mean high risk for obesity related diseases, included breast cancer [Fat deposition is thoroughly affected by male to female sexual steroid level . Circulat cancer .The most important data characterizing the grade of obesity are body mass index (BMI) and weight in kilogram , 5, 118 Some authors reported on the value of WC, HC and WHC ratio in the prediction of premenopausal breast cancer occurrence , 122. CoMagnetic resonance imaging (MRI) was used to quantify separately the mass of visceral and subcutaneous abdominal fat depositions in obese adolescent girls . Mass ofIn conclusion, neither BMI nor circumference measurement may exactly separate the metabolically indifferent, subcutaneous fat and the dangerous visceral fat, which may partially explain the controversial correlations between obesity grade and breast cancer risk.Circulating female sexual steroid levels and fertility continuously decrease during the life of women. The ability to conceive is at its peak in young women under 30 years of age with a continuous decline from the fourth decade, which suggests decreasing fertility even in the premenopausal phase . Menopau1).In premenopausal women, the good equilibrium of sex steroid synthesis defines health and reproductive capacity, whereas good, symptom-free adaptation to the estrogen deficient environment is a prerequisite of postmenopausal health. Changes in the hormonal equilibrium during women\u2019s lives strongly influence the obesity associated breast cancer risk  the coexistence of anovulatory infertility and insulin resistance represents common risk for the cancers of highly hormone dependent breast, endometrium and ovary , 148. MoHyperprolactinemia is also associated with cycle disorders, reproductive dysfunction and hyperandrogenism in women, however, it may be sharply discerned from PCOS and other disorders related to androgen excess. An increased overall cancer risk was found in hyperprolactinemia patients but further investigations are necessary to confirm these results . Data ofHow can we explain the increased prevalence of breast, endometrial and ovarian cancers in women with fertility disorders, even without obesity? In premenopausal cases, slight or moderate decrease in circulating female sexual steroid levels may be enough to block the delicate mechanism of ovulation. At the same time, a slightly estrogen deficient milieu confers preferential cancer risk for the female organ triad having high estrogen demand , 136.In women, multiparity and risk for malignancies at several sites exhibit an inverse relationship -157. HigNulliparity may be associated with ovulatory disorders in the majority of cases and there are studies, which equivocally exhibited increased prevalence of breast cancer in nulliparous women , 162. Fuin vitro fertilization (IVF) in anovulatory cases [Possible role of fertility medications in the increased risk of breast cancer has been hypothesized. However, large studies were not able to find any associated risk of breast cancer after ovulation provocation and ry cases . Moreovery cases . Recentlry cases . Howeverry cases . These rIn postmenopausal estrogen deficient, obese cases the regional distribution of fat deposition near uniformly affects the visceral region in close correlation with their high breast cancer risk .Obese postmenopausal women never using HRT are obviously insulin resistant. Moreover, ageing after menopause is a further factor increasing the cancer risk as it is associated with a continuous estrogen loss and parallel advancing insulin resistance [sistance . In old obese HRT user postmenopausal women, the incidence of breast cancer is equivocally reduced [In  reduced . The pro reduced . In HRT  reduced  yields f reduced  and by i reduced . All theA great challenge is to explain the beneficial anticancer impact of HRT in obese postmenopausal women based on the misbelief that they have excessive circulatory estrogen level. To solve this contradiction, some authors assumed that mediators other than estrogen, such as insulin and insulin-like growth factors might confer the obesity associated breast cancer risk after menopause . Oral contraceptive (OC) use replaces the natural menstrual cycle with relatively steady levels and fluctuations of artificial sex hormones.Recent epidemiological studies have confirmed that combined oral contraceptives provide substantial protection against endometrial and ovarian cancer in the endangered anovulatory women , 169. EfIn PCOS cases, treated with OCs, the volume of cystic ovaries is reduced, ovarian testosterone secretion is decreased and there are favorable effects on carbohydrate and lipid metabolism as well . A recenUse of HRT has highly controversial associations with breast cancer risk. Till now, the carcinogenic capacity of postmenopausal estrogen therapy was a prevailing concept [ concept . By cont concept , 172. ReIn 2011, the WHI Randomized Controlled Trial strengthened that the estrogen treatment in women with prior hysterectomy resulted in a significantly lower risk for breast cancer than in untreated controls . Breast Today, increasing numbers of evidence from the clinical trials suggest that unopposed estrogen as hormone treatment does not increase the risk of breast cancer, and may even reduce it. The earlier concepts regarding the breast cancer risk of hormone replacement therapy are completely changing -178.HRT decreases the accumulation of central fatty tissue in obese postmenopausal women and provides them long term metabolic and health benefits , 167. HR environmental estrogens (xenoestrogens) occurs through diet, household products and cosmetics, but concentrations of single compounds in breast tissue are generally lower than needed for assayable estrogenic responses [Exposure to esponses . ExposurEndocrine disruptors (EDs) are environmental chemicals that are able to bind hormonal receptors. These compounds may disrupt the endocrine regulation of reproduction and adaptive mechanisms and promote the development of endocrine disorders. Since several EDs have a structure similar to that of endogenous steroid hormones such as estrogens, they have an affinity for steroid hormone receptors and may alter the normal hormone-mediated reactions [eactions . EnvironPoor natural light exposure mediates deleterious metabolic and hormonal alterations by excessive melatonin secretion; such as insulin resistance, deficiencies of estrogen, thyroxin and vitamin D [itamin D . Long teBefore the introduction of antiestrogens, high dose estrogen was successfully administered as endocrine therapy for postmenopausal women with advanced breast cancer. Nowadays, the ambiguous, unreliable therapeutic effects and high toxicity of antiestrogens suggest the necessity of finding new strategies for breast cancer treatment . RecentlPhytoestrogen containing health supplement compositions are recommended by some patents for the prevention or treatment of postmenopausal breast cancer and for the alleviation of menopausal symptoms [symptoms . Soybeansymptoms . A recensymptoms .Obesity-associated hormonal disorders confer breast cancer risk during the whole life of women without any ambiguous interaction between obesity and menopausal status. Erroneous results regarding the breast cancer protective effect of obesity in young women derive mainly from the deceivingly lower tumor incidence among them. Further misleading factor may be that hormonal disorders related to anovulatory infertility are strong cancer risk factors for the breast both in obese and non-obese young women. Low incidence rate of breast cancer in young obese women may be a very important misleading finding. In the majority of premenopausal obese cases a predominantly subcutaneous adipose tissue deposition results in milder insulin resistance being counteracted by their preserved hormonal cycle. Consequently, in obese premenopausal women their circulatory estrogen level confers protective effect against breast cancer rather than obesity.Tumor cell kinetics may also provide an explanation for the low breast cancer incidence rate in obese premenopausal cases. A long term exposition to harmful environmental and systemic factors is necessary for cancer initiation; moreover the tumor growth from the initiation to clinically diagnosable size takes further several years. This double delay of clinical appearance of breast cancers may frequently result in a postmenopausal tumor, though it was initiated in the premenopausal period. Anovulatory infertility and the associated hormonal defects seem to be stronger breast cancer risk factors than adiposity alone and these alterations are not rare even among control cases with normal weight. Studies on obesity-related breast cancer risk disregarded the random occurrence of these hormonal alterations both among obese cases and lean controls. Moreover, oral contraceptive use is fairly widespread among premenopausal women, which may reverse the mild hormonal defects and attenuates their cancer risk either in obese or in lean cases. Strict selection of healthy, lean control women for obesity associated breast cancer studies and taking into account the OC use among obese cases and controls will justify the health advantage of normal body weight over obesity.Recognition of the inverse correlation between circulatory estrogen-level and breast cancer risk in obese women should advance our understanding of breast cancer etiology. Moreover, it would promote primary cancer prevention measures and the introduction of causal cancer therapy.2 and 3). Circulatory endogenous estrogen was blamed to provoke cancer initiation and promotion in the highly hormone responsive female organs, however, this misbelief yielded fairly controversial results in the clinical and experimental fields of medicine. Nowadays, overwhelming literary data suggest that estrogens have advantageous impact on dysmetabolism and hyperandrogenism, which are essential sources of tumor development.Changing concepts concerning breast cancer etiology provide completely new strategies against mammary tumors (Tables Recent patents disclose oral contraceptive and metformin derivative treatment possibilities for breast cancer prevention and therapy. Moreover, a new invention provides special estrogen derivatives being metabolically more advantageous for the treatment of PCOS than oral contraceptives. As anovulatory disorders in young women are strong risk factors for breast cancer, insulin resistance screening of asymptomatic occult cases in the population and their hormone treatment would be effective primary breast cancer prevention.In postmenopausal cases, obesity, metabolic syndrome, type-2 diabetes and hysterectomy are strong risk factors for mammary malignancies. Hormone replacement therapy in these endangered cases would be advantageous preventive measure.The present practices of breast cancer therapy have fairly controversial results. Worldwide administration of antiestrogen compounds for breast cancer treatment yielded thorough disappointment. Antiestrogens are cytostatic agents blocking the most important regulatory mechanisms associated with estrogen receptors. They do not have only toxic effects but also strong carcinogenic capacity. Recently, scientists in some centers confess, that one armed estrogen treatment is rather cancer protective than carcinogenic. Certain patents disclose the beneficial effects of phytoestrogens in breast cancer prevention and therapy. Moreover, publications on the high dose estrogen treatment of advanced breast cancer cases are regularly returning and the results are fairly encouraging. Today, we are on the route to regard estrogens as beneficial anti-cancer drugs rather than carcinogenic agents."}
+{"text": "To describe uncommon association between central retinal artery obstruction and dominant macular drusen in two young female patients. First patient, a 22-year-old female was presented with right central artery obstruction associated with bilateral dominant macular drusen. Systemic evaluation disclosed the presence of mitral valve regurge. Second patient, a 34-year-old female with a previous history of right central retinal artery obstruction diagnosed elsewhere. Fundus exam showed bilateral dominant macular drusen and her systemic evaluation revealed severe rheumatic valve stenosis, moderate aortic regurge with moderate to severe tricuspid regurge and she underwent mitral valve replacement. To the best of our knowledge, the association between central retinal artery obstruction and dominant macular drusen was not previously reported. Occlusive disorders of the retinal circulation are among the most dramatic problems encountered by the ophthalmologists because of their rapid onset, their potentially profound effects on vision, and their strong association with life-threatening systemic diseases.The causes of retinal arterial occlusion in young adult patients often differ from those found in older adults.8We report herein, two cases of right central retinal artery occlusion associated with bilateral dominant macular drusen in young adult females with cardiac valve diseases.A 22-year-old female presented with sudden loss of vision in her right eye for 10 hours duration with past ocular history of intermittent visual obscurations in both eyes for the last 3 years. Details of ocular examination can be seen in Diagnosis: right central retinal artery occlusion; Management: immediate paracentesis, ocular massage in conjunctions with Carbogen and Diamox.Investigation: The following were within normal limits:Physical examinations, CBC, ESR, Electrolytes, Hgb electrophoresis, PT, PTT, protein electrophoresis, central plasma viscosity, lipid profile, plasma homocysteine, blood sugar, C proteins, antiphospholipid antibodies, plasma fibrinogen, lipoprotein A, abnormal factor V leiden, antithrombin III deficiency, protein S and C deficiency. revealed a delay in retinal arterial filling with prolong arteriovenous transit time with ground glass appearance in the right eye and sharply demarcated hyper fluorescent spots in the temporal aspect of macular in both eyes.Intravenous fluorescein angiography Cardiac evaluation was performed by a cardiologist and her carotid doppler was within normal and echocardiography showed mild mitral regurge. The patient was treated with Aspirin.A 34-year-old female referred with diagnosis of right retinal arterial occlusion presented with history of decreased vision in her right eye for 1 year after an attack of cerebrovascular accident with left side weakness. Surgical and medical history revealed diagnosis of heart valvular disease and she underwent mitral valve replacement three years ago and using warfarin and digoxin. Details of ocular examination can be seen in Diagnosis: old recanalized right central artery occlusions with bilateral macular drusen.Investigation: Systemic evaluation by her Cardiologist showed rheumatic mitral valve stenosis, moderate aortic regurgitations with moderate to severe tricuspid regurge status post mitral valve replacement. revealed to some extent a delay in arterial filling with prolong arteriovenous transit time in right eye and hyper fluorescent spots macular area of both eyes.Intravenous fluorescein angiography Dominant macular drusen (Doyne honey comb dystrophy) is an autosomal dominant disorder, which mimics drusen seen in age-related macular degeneration. This disorder occurs in younger patients at 20 to 30 years of age and the extent of the drusen is variable, with most cases limited to the posterior pole. Affected patients may later develop choroidal neovascularization. It may be relevant that drusen like deposits can be seen in some renal disorders that involve basement membrane abnormalities, such as Alport's syndrome and membranoproliferative glumerulonephritis Type II.910Further literature review showed no reports of association of dominant macular drusen with other systemic disorders, particularly cardiac valvular disorders. Our cases revealed a trait of young adult females with bilateral dominat macular drusen, each of them presented with right central artery occlusion secondary to cardiac valvular disease. This association is based on observations which could be coincidental findings. And to the best of our knowledge these associations have not been reported previously."}
+{"text": "Unexpected drug efficacy or resistance is poorly understood in cancers because of the lack of systematic analyses of drug response profiles in cancer tissues of various genotypic backgrounds. The recent development of high-throughput technologies has allowed massive screening of chemicals and drugs against panels of heterogeneous cancer cell lines. In parallel, multi-level omics datasets, including genome-wide genetic alterations, gene expression and protein regulation, have been generated from diverse sets of cancer cell lines, thus providing a surrogate system, known as cancer cell line modeling, that can represent cancer diversity. Taken together, recent efforts with cancer cell line modeling have enabled a systematic understanding of the causal factors of varied drug responses in cancers. These large-scale association studies could potentially predict and optimize target windows for drug treatment in cancer patients. The present review provides an overview of the major types of cell line-based large datasets and their applications in cancer studies. Moreover, this review discusses recent integrated approaches that use multi-level datasets to discover synergistic drug combination or repositioning for cancer treatment. IntroductionLarge-scale datasets from cell line panelsSystematic analysis of multi-level omics and chemical screening dataPerspectives1.in vivo anticancer drug responses or optimize target treatment windows in clinical trials.Cancer cells exhibit varied responses to anticancer agents . Fast hiin vitro cell line modeling in translational cancer studies.The goals of this review are to survey the major types of cell line-based high-throughput datasets and highlight their applications in the systematic modeling of selective drug responses in cancer samples. This review focuses on several representative types of large datasets, including genotyping, gene and protein regulation, and chemical screening from well-defined cancer cell line panels. The major analytical efforts conducted with these representative datasets will be described, together with systematic approaches to integrate the multi-level omics and drug data. We expect that the present review will provide clear insights into the future impact of 2.Several cancer cell line panels have been organized to perform large-scale chemical screening and multi-level omics data profiling. For example, the National Cancer Institute (NCI) developed a panel of 60 well-characterized cancer cell lines from diverse tumor types for the purpose of chemical screening against heterogeneous cancer subtypes . This paMore recently, the sizes of cell line panels for chemical screening and omics data generation have greatly increased. For example, GlaxoSmithKline (GSK) released various genomic profiling datasets from a panel of >300 cancer cell lines that comprised 24 different cancer lineages  7). In . In 7). Genotypic variation among cancer cells is the major cause of inconsistency in anticancer drug responses. The prospect of targeted cancer therapies relies mainly on extensive information on the genetic variations observed in diverse cancer types. Recent efforts based on high-throughput PCR and sequencing technologies have generated reliable annotations of genome-wide genetic alterations in large cancer cell line and tissue sample collections ,9. For eIn addition to somatic mutations in coding regions, SNPs and copy number alterations in cancer cells have been proven to be of significant importance for understanding of cancer progression and therapies. For example, cancer subtype-specific SNP markers or CNA exhibited powerful predictions regarding drug responses, clinical prognostics and oncogenic factor identification ,12. In 2Gene expression analysis in cancers has provided considerable information on diagnostic or prognostic marker signatures and potential drug targets. DNA microarray experiments have generated substantial transcriptome-wide gene expression profile information in various cancer samples. A DNA microarray dataset of the NCI60 cell lines was initially generated to explore the expression of approximately 8,000 unique genes  18). Th. Th18). Cancer transcriptome expression profiles were also generated for the GSK and CCLE cell lines. The GSK dataset includes gene expression data for >300 cell lines, each in triplicate, thus providing a robust statistical analysis  Table I. This daAlthough large-scale gene expression studies have yielded useful information for cancer biomarker identification and targeted cancer therapy development, high-throughput protein expression and activation level screening are required in order to better understand cellular signaling in the contexts of tumorigenesis and drug response. Reverse-phase protein array (RPPA) technologies, which are based on sample spot arrays for specific antibody reactions, allow fast, quantitative measurements of protein expression or phosphorylation in a large cancer sample panel . More thhttp://dtp.nci.nih.gov/index.html). This is the largest dataset for studies of structure-activity relationships between anticancer agents and diverse cancer subtypes. The COMPARE program is a useful tool with which to search for compounds with similar patterns of cellular sensitivity in the NCI60 panel  is another exciting project that has extended ideas about cell line modeling to human cancer tissue samples. An increasingly large collection of clinical cancer samples are directly used to generate multi-level omics data, thus revealing a comprehensive landscape of genetic alterations and transcriptional regulation in each cancer subtype . A recendatasets . TogetheTogether with systematic cell line modeling using large omics datasets, RNAi screening data were recently generated to identify the target genes associated with changes in cancer phenotypes. For example, a kinome-based shRNA screening study was performed to determine the mechanism of resistance against BRAF inhibitors in colon cancers that harbored an activating mutation in the BRAF oncogene . Feedbac"}
+{"text": "Detection of a novel Gammaretrovirus, Xenotropic Murine leukaemia virus-Related Virus (XMRV) has been reported in peripheral blood mononuclear cells of patients with chronic fatigue syndrome, and in prostate cancer tissue. As Multiple Sclerosis (MS) is a disease with retroviral association (human endogenous retroviruses (HERVs)), we investigated whether XMRV could be contributing to MS aetiology by testing a well defined cohort of Danish MS patients for the presence of XMRV sequences.We have analysed DNA samples isolated from peripheral blood mononuclear cells (PBMCs) from 50 Danish patients with clinically well-characterized MS for evidence of the presence of XMRV gag or env sequences by PCR, using concomitant amplification of the cellular GAPDH gene as control.In this study, which included relevant positive and negative isolation controls and PCR controls, we failed to detect XMRV sequences in PBMCs from Danish MS patients.There is no apparent association between XMRV infection and MS in Denmark."}
+{"text": "Septic shock is one of the major causes of death in children and is characterized by a massive inflammatory response. To present date, no studies have been performed to assess the impact of such an \u2018inflammatory hit\u2019 on aortic wall structure and myocardial performance.This study shows that despite adequately preserved systolic biventricular function, frequently reduced aortic elasticity may indicate aortic wall pathology, being associated with biventricular hypertrophy and concomitant delayed biventricular relaxation in pediatric patients after septic shock.Septic shock is one of the major causes of death in children and is characterized by a massive inflammatory response. To present date, no studies have been performed to assess the impact of such an \u2018inflammatory hit\u2019 on aortic wall structure and myocardial performance. The objectives of the current study were therefore to prospectively assess aortic elasticity and biventricular systolic and diastolic function in a group of pediatric patients after meningococcal septic shock by using MRI.Eighteen pediatric meningococcal septic shock survivors  treated with at least 2 inotropic and vasoconstrictive agents for 48 hours or longer and 18 for age and gender matched controls were prospectively studied. Routine MRI was used to assess aortic pulse wave velocity (PWV) and systolic and diastolic biventricular function. Independent-samples-t-test and Pearson-correlation-coefficient were used for statistical analysis.Sepsis patients showed reduced aortic elasticity vs. controls . Systolic biventricular function was preserved , whereas biventricular mass was increased . Also, delayed biventricular relaxation was found after sepsis: peak filling rates corrected for end-diastolic-volume (PFREDV) across the mitral and tricuspid valve were significantly reduced . Increased PWV in aortic arch and descending aorta were associated with increased LV mass  and delayed LV relaxation parameters.Despite adequately preserved systolic biventricular function, reduced aortic elasticity in pediatric patients after septic shock may indicate aortic wall pathology, being associated with biventricular hypertrophy and concomitant delayed biventricular relaxation. Long-term prognosis after septic shock may therefore be adversely affected considering the cumulative effects of cardiovascular disease during a lifetime.No disclosures."}
+{"text": "While monkeys perform a task alternating between behavioral adaptation --relying on feedback monitoring and memory of previous choices-- and repetition of previous actions, firing rates in dorsal Anterior Cingulate Cortex (dACC) modulate with cognitive control levels . FurtherWe used spike-train metrics  to decodWe found that timing sensitivity could improve behavioral adaptation vs. repetition classification of single unit spike trains. Optimal decoding occurred when accounting for spike times at a resolution <= 200 ms. Furthermore, spike-train metrics decoding of unitary discharges was related to the monkeys' response time. A downstream neural decoder could exploit this temporal information through coincidence detection determined by synaptic and membrane time constants. In addition, when decoding two units jointly, we found that each pair had a specific optimal distinction degree between spikes coming from the two different neurons. In a realistic neural decoder, the tuning of this distinction degree might occur through non-linear dendritic integration.To further investigate the computational properties of temporal decoding in the context of decision-making, we are implementing a recurrent spiking neural network with connectivity leading to attractor dynamics. In this framework, each decision is mapped to a state in which a corresponding neural subpopulation shows elevated activity, as observed experimentally in dlPFC . In addiThe spatiotemporal structure of spike trains appears to be relevant in this cognitive task. This opens the possibility for pattern matching-based decoding of dACC activity, potentially leading to adapted behavioral response."}
+{"text": "Tightly controlled extracellular matrix (ECM) homeostasis and remodeling is critical for normal organ homeostasis, wound healing and tissue repair. However, excessive or uncontrolled ECM deposition contributes to aberrant homeostasis of tissue microenvironment in various inflammatory diseases and tumors. Matricellular proteins are a set of structurally unrelated ECM proteins that do not exert a primary role in tissue architecture but have regulatory roles in embryonic development, tissue injury, inflammation and tumor progression. Two recent studies demonstrated that matricellular proteins in the ECM surrounding dormant tumor cells may determine the fate of tumor cells to remain quiescent or undergo metastatic outgrowth. The identification of matricellular proteins in regulating ECM homeostasis and remodeling specific organ niches during tumor dormancy may provide potential novel extracellular targets for the development of therapeutic interventions against tumor dormancy.Many cancer patients who have undergone surgical resection of their primary tumors suffer from metastatic relapse several months, years or even decades later. Current evidence supports the idea that tumor cells can be disseminated at an early stage of tumor progression. The disseminated tumor cells (DTCs) exist in a quiescent state at a hostile site, but may switch from quiescence to proliferative metastatic growth in a permissive and supportive microenvironment. Increasing data suggest that tumor dormancy can be regarded as a protracted asymptomatic stage during which tumor cells either remain in a quiescent state or their proliferation is balanced by cell death due to immunosurveillance or insufficient angiogenesis  and periostin (POSTN), play crucial roles in regulating DTC dormancy. TSP-1 is enriched in the basement membrane of mature microvessel stalks and maintains DTCs in a dormant state; however, TSP-1 levels are markedly decreased at the sprouting neovascular tips of newly forming vessels. Interestingly, they also found an increased distribution of matricellular proteins, such as POSTN, tenascin-C and SPARC, together with fibronectin and TGF-\u03b21, around these growing tips. The authors further provided evidence that high POSTN and active TGF-\u03b21 expression surrounding neovascular tip cells enables DTCs to exit from dormancy and triggers metastatic relapse  proteins, mainly including thrombospondins (TSPs), OPN, tenascins, SPARC, POSTN and CCNs, which do not exert a primary role in tissue architecture but regulate similar biological functions in response to external stimuli during embryonic development, tissue injury, inflammation and tumor progression  to maintain quiescence, whereas the perivascular niche accommodates more activated HSCs. Quiescent HSCs reside preferentially at the endosteal region where bone-lining osteoblasts and their secreted proteins are critical components of HSC niches. Interestingly, bone marrow microenvironment is also a critical reservoir for DTCs. When metastasizing to the bone, DTCs take shelter in HSC niches in bone marrow and adopt similar mechanisms to those used by HSCs for homing to bone marrow. That is to say, DTCs may occupy and remodel preexisting physiological HSC niches to help them survive and subsequently grow and metastasize (Wan et al., How do matricellular proteins maintain dormant tumor cells in a quiescent state or reactivate them to metastatic outgrowth? As a class of structurally unrelated ECM proteins, matricellular proteins serve as links between the ECM and cells to regulate cell-cell and cell-matrix interactions, and their functions are highly dependent upon the cues from local microenvironment. These matricellular proteins are often needed for ECM remodeling during embryonic development and their expressions are highly induced at sites of injury, inflammation or tumors within the adult organism. An excessive or uncontrolled matricellular proteins\u2019 function contributes to aberrant remodeling and homeostasis of tissue microenvironment in various inflammatory diseases and tumors. Matricellular protein knockout mice are often viable, but typically exhibit abnormal responses to mechanical stress, wound healing, inflammation and tumor metastasis. POSTN, for example, can directly interact with collagen I, fibronectin and Notch1 via its EMI domain and interact with tenascin-C and BMP-1 via its FAS1 domains (Norris et al., The work by Ghajar et al. and Boyerinas et al. greatly expanded our understanding of the roles of tissue microenvironmental cues in regulating tumor dormancy and subsequent metastatic growth. The identification of matricellular proteins in regulating ECM homeostasis and remodeling specific organ niches during tumor dormancy provides useful extracellular targets for the development of therapeutic interventions to induce or maintain DTCs in a dormant state, or alternatively to activate and then eradicate dormant DTCs."}
+{"text": "The majority of neural encoding models employed today consist of a linear feature-selection stage followed by a static memoryless nonlinearity generating the neuronal rate of response. Although such linear-nonlinear (LN) models have been proven useful in characterizing computation in many neurons (see  and refeHere we investigate nonlinear-nonlinear neuron models that combine both biophysics and dendritic computation. Specifically, we consider models in which the nonlinear dendritic processing of input stimuli is described by a Volterra series  and the"}
+{"text": "To the Editor: Factor et al. recently reported the results of a population-based, case-control study regarding risk factors for pediatric invasive group A streptococcal (GAS) infection  were unlikely to have received NSAIDs in the 2 weeks before their interview should be surprising. A more informative case-control study would have matched case-patients with similar-aged children who had febrile infections not caused by GAS infection; both groups of children would have been equally likely to have received analgesic and antipyretic medications. Furthermore, population-based data suggest that most patients with invasive GAS infection are hospitalized (Prospective studies have failed to define a causal link between NSAIDs and invasive GAS infections (Although NSAIDs may neither alter the risk of developing an invasive GAS infection nor accelerate an established infection, these drugs can mollify the signs and symptoms of streptococcal infection, possibly delaying appropriate management and treatment ("}
+{"text": "Sir,A 60-years-old male presented to us with complaint of fever and cough with expectoration for last one month and pus discharging sinus on anterolateral aspect of right side chest wall for last one week. There was no history of hemoptysis, chest pain, dyspnoea or any previous swelling on chest wall at the site of discharging sinus. There was no previous history of tuberculosis or any anti-tubercular drugs (ATT) intake. Also there was no past history of intercostal tube drain (ICD) insertion or any history suggestive of pleural effusion. On respiratory system examination, crepts were present in bilateral lung fields. Examination of cardiovascular system and gastrointestinal system was absolutely normal.In laboratory investigation, ESR was raised while complete blood count (CBC), renal function test, liver function test were within normal limit. Smear and culture of sputum was positive for acid fast bacilli. Pus from discharging sinus failed to reveal any growth of pyogenic or fungal organism on staining as well as culture. CECT of -thorax was performed after injecting dye in the discharging sinus which revealed the presence of bronchopleurocutaneous fistula. Frontal CT scout view demonstrates extensive fibrocavitatory changes in both lungs more on right side with right sided mediastinal shift. It also revealed volume loss of right lung associated with extensive pleural thickening and blunting of CPA. Infant feeding tube was used for injecting dye in fistula. Axial chest CT demonstrates movement of dye injected in subcutaneous fistula along posterior pleural space into cavity in posterior segment of right upper lobe. From the cavity dye entered in draining segmental bronchus, thus confirming the presence of bronchopleurocutaneous fistula . There wPatient was diagnosed as a case of pulmonary tuberculosis with bronchopleurocutaneous fistula. Patient was put on antitubercular drugs. Patient responded well and the fistula healed.Bronchopleurocutaneous fistula is a pathological communication between bronchus, pleural space and skin. It usually develops due to pulmonary operations, perforating chest trauma, empyema, lung abscess, pneumonia or massive pulmonary infarction.\u20133 Occasi4"}
+{"text": "Implementation of an evidence-based care bundle in critically ill patients has been shown to improve outcome. Use of care bundles to reduce ventilator-associated pneumonia and other ICU complications has been increasing in critical care practice.We conducted a prospective audit on implementation of a care bundle after audit approval. We collected data for 101 patient days from all patients admitted to Hull Royal Infirmary ICU during the month of November 2011. We collected information regarding stress ulcer prophylaxis, deep vein thrombosis (DVT) prophylaxis, ventilator care bundle, blood glucose control, daily assessment of need for a central line, sedation score assessment and delirium score assessment at least twice a day.All patients received stress ulcer prophylaxis. At least 95% of patients received DVT prophylaxis, adequate blood glucose control and appropriate sedation need assessment. There was further scope for improvement in areas of sedation hold practice and assessing daily need for a central line. Poor clinical practice was identified in delirium score assessment and head elevation to reduce VAP. See Table It is very challenging to implement care bundles despite evidence showing that they improve outcome. A recent study suggests that doing a daily quality rounds checklist (QRC) will improve long-term compliance, thereby reducing potential complications for intensive care patients . We have"}
+{"text": "Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that carries a high burden of morbidity and mortality. Immune system dysfunction has been undisputedly demonstrated to underlie SSc pathogenesis. In particular, pDCs not only circulate in very high number in SSc patients but also secrete high concentrations of specific chemokines that directly drive various features of SSc, including endothelial dysfunction and fibroblast activation.Plasmacytoid dendritic cells (pDCs) were isolated from whole blood of early diffuse SSc, late diffuse SSc, limited SSc patients or healthy controls. The genome-wide profiling of microRNAs (miRNA) was performed on pDC total RNA by using the Illumina miRNA Profiling Array. Genes targeted by differentially expressed miRNAs were identified thanks to a combination of Miranda, Mirtar and MirPath prediction algorithms.On the quest to decipher why pDCs appear so abundantly in SSc and their activity is deregulated, miRNA profiling was performed. miRNA screening demonstrated that seven miRNAs were significantly over- and two were under-expressed in pDCs from patients with early diffuse SSc compared to late diffuse disease, limited SSc or healthy controls and this profile perfectly correlated with pDC abundance in the different disease stages. According to Miranda, Mirtar and MirPath prediction algorithms, this set of 9 miRNAs is predicted to influence a vast number of target genes, mostly involved in three molecular pathways: 1) leukocyte apoptosis, 2) epidermal growth factor EGFR (ErbB) signaling and 3) WNT signaling. Interestingly, the emergence of the leukocyte apoptosis pathway might provide a preliminary hint on why pDCs are expanded early in SSc. On the other side, ErbB and WNT signaling are ultimately involved in immune response regulation and often linked to the malfunctioning of the immune system in SSc.Altogether these unique observations suggest that SSc-associated miRNAs could strongly impact on cellular pathways involved in SSc pathology, and therefore they would provide an important target for disease prediction and therapeutic approaches."}
+{"text": "Local populations of sensory cortical cells exhibit a diverse range of activity patterns. However, classical approaches have neither fully accounted for nor characterized this heterogeneity, especially in response to natural stimuli. First, classical single cell recordings suffered from sampling bias and favored highly responsive cells . Second,We analyzed data sets from two recording sessions in anaesthetized cats viewing natural movies. To quantitatively measure the difference between model predictions and the recording, we used the earth mover's distance  to quant"}
+{"text": "Chemical inducers such as 5-azacytidine (AzaC) and 5'-iodo-2'deoxyuridine (lUdR) have been used to discover and characterize endogenous retroviruses from rodent and avian speciecs, for example KBALB mouse cells. We found that induction conditions that have been optimized for mouse cells were not successful in inducing retrovirus from cell lines of other species, including nonhuman primates. Therefore, we developed a step-wise strategy based upon identification of critical parameters for endogenous retrovirus induction in mouse cells for optimizing induction conditions for non-murine cells. Using this approach, we have determined optimum conditions for investigating inducible endogenous retroviruses from Vero cells, which are of African green monkey (AGM) origin, a species that has never been reported to produce endogenous retroviruses .Based upon a step-wise induction strategy , Vero cegag, pol, and env regions related to endogenous SERV and BaEV sequences previously reported in the AGM DNA. Biological studies showed no evidence of replication-competent particles using several target cell lines. Similarly, an RT activity could be induced from a dog cell line, which is another species with no evidence of retrovirus isolation. This is currently under investigation for further characterization.The results demonstrated that endogenous retrovirus particles could be induced from Vero cells under optimized cell growth and drug treatment conditions. Molecular analysis indicated that the particles contained The induction of retrovirus particles from Vero cells was low and detected in cell-free supernatant only by using a highly sensitive PCR-based RT assay and virus-specific PCR assays. Further investigations of various emerging virus detection technologies used for novel virus discovery has demonstrated that induced viral RNAs could be detected in drug-treated cells using high throughput 454-massively parallel or deep sequencing: investigations with virus microarrays and long range PCR with mass spectrometry are ongoing. The results support that the combination of chemical induction strategy with sensitive broad virus detection technologies may be used for the discovery of novel endogenous retroviruses."}
+{"text": "Vision loss degrades the quality of life of aged individuals. The major cause in industrialized countries is age-related macular degeneration (AMD), a blinding eye disease due to death of photoreceptors in the macula, a specialized retinal region responsible for high acuity vision. Photoreceptor death in AMD is thought to follow damage to the retinal pigment epithelium (RPE) , a monolRobust mTOR activation in the context of OXPHOS deficiency is counterintuitive because mTOR integrates trophic factor and nutrient availability signals to regulate cell growth and proliferation , and poiOXPHOS deficiency leads eventually to RPE atrophy, which is seen more commonly in AMD than RPE hypertrophy. Our findings suggest that RPE hypertrophy may be present at earlier stages of AMD. Indeed, ocular coherence tomography imaging demonstrated thickened macular RPE more frequently in early AMD eyes than in advanced AMD or control eyes . RPE hypertrophy may be less prominent in advanced AMD because drusen and diminished transport through aged Bruch's basement membrane  may restIntriguingly, pharmacological inhibition of mTORC1 with rapamycin blunted RPE dedifferentiation and hypertrophy and preserved photoreceptor numbers and function for both the metabolic and oxidative stress models . Rapamyc"}
+{"text": "In order to generate more accurate consensus sequences from ESTs, tools are needed to reduce or eliminate errors from de novo assemblies.Expressed Sequence Tags (ESTs) have played significant roles in gene discovery and gene functional analysis, especially for non-model organisms. For organisms with no full genome sequences available, ESTs are normally assembled into longer consensus sequences for further downstream analysis. However current We present iAssembler, a pipeline that can assemble large-scale ESTs into consensus sequences with significantly higher accuracy than current existing assemblers. iAssembler employs MIRA and CAP3 assemblers to generate initial assemblies, followed by identifying and correcting two common types of transcriptome assembly errors: 1) ESTs from different transcripts  are incorrectly assembled into same contigs; and 2) ESTs from same transcripts fail to be assembled together. iAssembler can be used to assemble ESTs generated using the traditional Sanger method and/or the Roche-454 massive parallel pyrosequencing technology.de novo EST assembly programs using both Roche-454 and Sanger EST datasets. It demonstrated that iAssembler generated significantly more accurate consensus sequences than other assembly programs.We compared performances of iAssembler and several other  We demonstrate the utility and performance of this program by performing assemblies on different EST datasets with different sets of parameters.iAssembler is implemented in Perl and can be executed under either 32-bit or 64-bit Linux systems with Bioperl  installede novo assemblies of EST sequences. As shown in Figure iAssembler employs an iterative assembly strategy and automated assembly error corrections to deliver highly accurate The unique feature of iAssembler is its ability to detect and automatically correct all possible assembly errors. Following initial assemblies by MIRA and CAP3, all-versus-all pairwise sequence alignments of resulting unigenes are performed using the NCBI megablast program. Unigenes whose overlapped sequence length and identity, and overhang length meet user-defined cutoffs are identified as type II assembly errors, i.e., sequences from same transcripts fail to be assembled together. The megablast assembler then utilizes the pairwise sequence alignment information to join the unigenes into new contigs. Next, the type I error corrector module maps individual EST members to their corresponding contigs using megablast. ESTs that have sequence similarities to their corresponding contigs less than and/or overhang lengths larger than the corresponding user-defined cutoffs are identified as type I assembly errors, i.e., two different transcripts are incorrectly assembled together. These misassembled ESTs are then extracted by the type I error corrector and together with unigenes derived from the current round of assembly and error correction, are used as the input sequences in the next round of assembly and error correction Figure .The iterative assembly strategy employed by iAssembler can result in loss of accuracy in final unigene base calling since later assemblies are performed on unigenes generated from previous assemblies, instead of ESTs; thus during assemblies by CAP3 and megablast assemblers, the information of depth of coverage by individual EST members at each unigene position will be lost and thus not used in base calling of assembled sequences. This will cause significant number of wrongly called bases in unigenes. iAssembler provides a unigene base error correction module Figure  which reFollowing corrections of type I and II assembly and unigene base calling errors, iAssembler reevaluates the resulting unigenes and identifies and corrects new assembly and base calling errors. The error identification and correction steps will be iterated until no new errors can be identified or corrected.It is worth noting that not all identified assembly errors can be corrected by iAssembler. A simple such example is illustrated in Figure iAssembler is designed to generate highly accurate assemblies of EST sequences by performing iterative assembly strategy and automated error detection and correction. The three assemblers in iAssembler, MIRA, CAP3 and megablast assemblers, are all base on the overlap-layout-consensus strategy thus iAssembler is applicable for ESTs with relative long sequences, such as those generated using Sanger and/or Roche-454 platforms.The workflow of iAssembler is shown in Figure Cleaned EST sequences are first supplied to iAssembler with appropriate user-defined parameters. iAssembler first employs MIRA to assemble EST sequences, followed by assembling the resulting MIRA unigenes using CAP3. These two open source assemblers were chosen because we have observed that MIRA is efficient in handling large-scale and relatively short Roche-454 reads while CAP3 can complement MIRA by correcting certain type II assembly errors. Following initial assemblies by MIRA and CAP3, type II assembly errors (unigenes belonging to same transcripts) are then identified by performing all-versus-all pairwise sequence alignments of the resulting unigenes using the NCBI megablast program. iAssembler then utilizes the pair-wise alignment information to assemble these unigenes into new contigs using the megablast assembler module. Next, iAssembler identifies type I assembly errors by aligning individual EST members to their corresponding unigenes. The misassembled ESTs, whose alignments to their corresponding unigenes do not satisfy cutoffs of user-specified parameters such as minimum percent identity or maximum overhang, were then extracted and used in the next round of assembly and error correction. Finally, unigene base calling errors are corrected based on alignment information of individual ESTs to their corresponding unigenes contained in the SAM output file. iAssembler iterates through error identification and correction steps until no new errors can be identified or corrected.The main output of iAssembler includes 1) the final assembled unigene sequence file in FASTA format, 2) a text file summarizing the statistics of alignments of ESTs against their corresponding unigenes, which provides necessary information to assess the quality of the assembly, and 3) a file containing detailed alignment information of individual EST sequences against their corresponding unigenes in SAM format. SAM format is a generic alignment format for storing read alignments against reference sequences  and has E. coli genome sequences, which resulted in a total of 246,993 olive ESTs with an average length of 196 bp and 362,445 tomato ESTs with an average length of 579 bp. EST assemblies were performed using a single CPU on a server with six Quad-core 2.93 GHz Intel Xeon processor and 64 GB of RAM. The following parameters were used for all the tested assembly programs, if applicable: minimum overlap length of 40 bp, minimum overlap percent identity of 97%, and maximum overhang length of 30 bp. Detailed commands and parameters used for these assemblers are listed in Table We compared the performance of iAssembler to that of several commonly used EST assembly programs including MIRA, CAP3, TGICL, Phrap, and Newbler. An olive EST dataset generated using the Roche-454 platform as described in Alagna et al.  and a toAs shown in Table We then tested performances of these assemblers using another set of parameters: minimum overlap length of 50 bp, minimum overlap percent identity of 95%, and maximum overhang length of 20 bp. The results also indicated that iAssembler generated much higher quality of assemblies than other assembly programs we investigated  using the megablast program with a minimum percent identity of 99 and a word size of 20. Only ESTs aligned to Arabidopsis cDNAs in their entire length were kept and the final collection contained 394,298 ESTs. These ESTs were assembled de novo using the six assemblers with the following parameters: minimum overlap length of 40 bp, minimum overlap percent identity of 97%, and maximum overhang length of 10 bp : LinuxProgramming language: PerlOther requirements: Bioperl version 1.006 or higherThird-party tools: BLAST, CAP3 and MIRA. These tools are already integrated into the iAssembler package.License: NoneAny restrictions to use by non-academics: noneZF conceived the general idea of this project and provided the guidance on the whole study. YZ developed the software and performed comparison with other assemblers. JG and LZ helped with design and evaluation of the software. ZF, YZ, and JG wrote the manuscript. All authors have read and approved the manuscript.Examples of common EST assembly errors. The file provides several examples of common EST assembly errors.Click here for filePerformances of EST assembly programs. The file provides evaluation results on performances of several EST assembly programs.Click here for file"}
+{"text": "Tropheus sp., a Lake Tanganyika endemic with rich geographical colour pattern variation, in which the strength of sexual isolation varies between populations. We conducted two-way mate choice experiments to compare behaviour of males of a red-bodied morph (population Moliro) towards females from their own population with behaviour towards females from four allopatric populations at different stages of phylogenetic and phenotypic divergence. Males courted same-population females significantly more intensely than females of other populations, and reduced their heteromorphic courtship efforts both with increasing genetic and increasing phenotypic distinctness of the females. In particular, females of a closely related red-bodied population received significantly more courtship than either genetically distinct, similarly coloured females (\u2018Kirschfleck\u2019 morph) or genetically related, differently coloured females (\u2018yellow-blotch\u2019 morph), both of which were courted similarly. Genetically and phenotypically distinct females (Tropheus polli) were not courted at all. Consistent with previous female-choice experiments, female courtship activity also decreased with increasing genetic distance from the males\u2019 population. Given successful experimental and natural introgression between colour morphs and the pervasive allopatry of related variants, we consider it unlikely that assortative preferences of both sexes were driven by direct selection during periods of secondary contact or, in turn, drove colour pattern differentiation in allopatry. Rather, we suggest that sexual isolation evolved as by-product of allopatric divergence.Whether premating isolation is achieved by male-specific, female-specific or sex-independent assortative preferences often depends on the underlying evolutionary processes. Here we test mate preferences of males presented with females of different allopatric colour variants of the cichlid fish  Assortative and conspecific mate preferences play an important role in maintaining reproductive isolation between species or among morphs within a species . It has Tropheus comprises another cichlid species complex with rich allopatric colour pattern variation  dates back to approximately 1.5 million years ago  on the extent of phenotypic and genetic differentiation , 2012. WIn the previous mate choice experiments, females were offered a two-way choice between a homomorphic and a heteromorphic male, and interactions of females with the males were scored in categories representing aggression and mate preference. Although designed as female choice experiments, both male and female preferences could have contributed to the observed patterns, for instance because the intensity of male courtship apparently influences female preferences in within-population interactions (Tropheus sp. \u2018red\u2019 (Tropheus moorii (T. moorii), a genetically distinct population with a red \u2018Kirschfleck\u2019 (cherry-blotch) colour pattern  equipped with internal box filters, heaters and hollow bricks and illuminated with overhead white light in a 12:12 h light:dark cycle.Tropheus by Experimental setup was analogous to the female-choice design developed for n = 15 males) were given a choice of one female from the Moliro population  and one female from one of the four other populations , resulting in four experiments with the four different heteromorphic populations. Heteromorphic stimulus females were from Ndole , Chiseketi , a location north of Mabilibili  and a location south of Isonga . Logistic constraints limited the numbers of stimulus females that could be used in the experiments. Males of the Moliro population  with package glmmADMB.To account for the repeated use of individual males and females, we employed generalized linear mixed models (GLMM) with male and female identities as crossed random factors. As male behaviour towards homomorphic females did not differ between experiments (see Results), data from all four experiments were combined to build models testing for morph-dependent differences in male and female behaviour. As the response variables were tallies of events, models were fitted with negative binomial error distributions  and log link functions, and included total observation time as offset. Analyses were conducted in R v. 2.15.0  aggressive and courtship behaviour of males towards homomorphic females was independent of the morph of the alternative stimulus female, (ii) males behaved differently towards homomorphic and heteromorphic females in the contexts of both courtship and aggression, and addressed significantly more courtship and significantly less aggression to homomorphic females, and (iii) the intensity of male heteromorphic courtship, but not of aggression, depended on the females\u2019 population, as genetically and phenotypically similar females received significantly more courtship than females of genetically and/or phenotypically distant populations. Females from genetically distant populations also showed reduced courtship activity towards Moliro males, but an opposite trend in the allocation of aggression, which they only displayed in homomorphic encounters. Aggression between males and females reflects competition for feeding territories , and mayTropheus, which demonstrated that discrimination against foreign populations is not universal and amongst other possible factors dependent on the similarity between the involved morphs  and previously , genetically related females with distinct colour pattern (Chiseketi) and genetically distinct but similarly coloured females (\u2018Kirschfleck\u2019). Males did not differentiate in their courtship rates between the latter two heteromorphic populations (Chiseketi and \u2018Kirschfleck\u2019), whereas they displayed significantly more courtship quivers to the genetically and phenotypically similar population (Ndole), and significantly less courtship towards the genetically and phenotypically distinct T. polli. Apparently, male discrimination was influenced not only by colour pattern differences but also by divergence in other, for example olfactory or acoustic, cues , which did not discriminate between homo- and heteromorphic males in laboratory two-way female choice tests against a bluish morph , and hence the maximum divergence between populations, dates to approximately 1.5 Ma , the time span within which sexual isolation evolved among Tropheus populations fits well with the haplochromine model.Overall, mate choice data of la flies  and haplTropheus populations at their various stages of phylogenetic and phenotypic divergence has the potential to improve our general understanding of how allopatric populations evolve premating isolation on their way to speciation.In conclusion, males of the Moliro population discriminate between females of different populations, and even vary their courtship behaviour between females of the same population and a phenotypically and genetically similar population. Discrimination among populations appears to increase with both, genetic distance and colour pattern dissimilarity. On the basis of current evidence, we consider it likely that assortative mate preferences evolved in both sexes as a by-product of allopatric divergence under natural or social selection. Experiments testing the effects of learning and sensory environments on mate choice are warranted to address the mechanisms underlying sexual isolation within this species complex. Understanding assortative mate preferences among"}
+{"text": "Rubiaceae (coffee), Violaceae (violet), Cucurbitaceae (cucurbit), Fabaceae (bean) and recently Solanaceae (potato family), but it is very likely that cyclotides are more widely distributed since their predicted number in Rubiaceae alone is ~50.000. Additionally, the pharmacological validation of plants used in traditional medicines may trigger the discovery of novel uterotonic compounds [Drug discovery from natural products is still one of the biggest sources of novel lead compounds. In particular, plant cyclotides, disulfide-rich peptides comprising three conserved disulfide bonds in a knotted arrangement, known as cyclic cystine knot motif, and a head-to-tail cyclization, have been extensively investigated over the last four decades for their use as scaffolds in drug development. However, their distribution among flowering plants still remains limited to few species of the families of ompounds .de novo sequencing and automated database identification. The aqueous extracts and semipure peptide fractions have been tested further in a collagen gel contractility assay model and showed varying ability to induce contractions in human myometrial smooth muscle cells.Based on the use of plants in traditional Nigerian medicine during pregnancy and childbirth, we analyzed several plants from different families to evaluate their uterotonic properties at cellular level and to identify cyclotides as active molecules. Using a MALDI-TOF/TOF-based screening protocol we were able to identify many novel cyclotide-containing species which was confirmed by manual In conclusion, our results underpin earlier suggestions that cyclotides are one of the largest peptide classes within plants, covering a large chemical space based on their high sequence diversity. The evaluation of contractile properties of plants used in traditional medicines offers new starting points for the discovery and development of peptide-based uterotonic drug leads."}
+{"text": "Arterial embolism with lower limb ischemia is a rare manifestation of paraneoplastic hypercoagulability in cancer patients. We report a unique case of fatal thromboembolism involving both circulations associated with a poorly differentiated neuroendocrine tumor of the lung with rapid progress despite high doses of unfractioned heparin and review the current literature on anticoagulative regimen in tumour patients.  Limb ischemia due to arterial embolism in cancer patients has been reported for phaeochromocytoma, malignant melanoma, angiosarcoma, or cardiac tumour patients \u20133. SinglVascular tumour invasion, metastatic spread, and fragmentation of cardiac masses need to be distinguished from paraneoplastic effects like catecholamine associated vasospasm, protein precipitation, and hypercoagulability . The latEmbolism suggestive of Trousseau syndrome may occur as initial symptom resulting in tumour diagnosis, as complication alongside disease progression or may be triggered by specific chemotherapy agents , 12. ThrHere we report the unique case of a patient diagnosed with a multilocular metastasized neuroendocrine tumour (NET) of the lung suffering from progressive arterial embolisms in both circulations leading to bilateral lower limb ischemia, pulmonary embolism, stroke, and finally death five weeks after the initial bout of chemotherapy despite high doses of unfractioned heparin.A 58-year-old Caucasian male was admitted to the Oncology Department with polyuria and weight loss of seven kilos in the last two weeks. Risk factors were arterial hypertension and cigarette smoking. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) with hyponatremia was noticed and tumour search detected metastatic liver disease and enlarged hilar lymph nodes. Blood analysis revealed elevated levels for neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin-fragment (Cyfra), and liver biopsy specified metastases of a small cellular, poorly differentiated neuroendocrine tumour (NET). Further staging via FDG PET disclosed the primary tumour near the left lung hilus with positive mediastinal and hilar lymph nodes, diffuse osseous filiarisation, and a sole metastasis in the right adrenal gland. Oncology board consensus decision was made for palliative chemotherapy with cisplatin and etoposid  as common for dedifferentiated NET.Two weeks after the initial bout of chemotherapy the patient presented in the Surgical Department with incomplete ischemia of the left lower limb. Immediate interventional recanalization failed and open embolectomy of the tibiofibular trunk with consecutive venous patch plasty was performed. Histological examination of the embolus showed no malignancy. Three days later reischemia of the same leg occurred and the operative procedure was repeated. Search for embolic origin by CT-scan disclosed clinically inapparent pulmonary embolism in three lobes. Mural thrombus of the infrarenal aorta with perifocal aortic wall calcifications appeared identical to the initial staging CT . All tumAgain four days later, transfemoral and pedal embolectomy with multilocular patch plasties of all native crural arteries as ultima ratio due to complete ischemia had to be performed. Decision was made for major amputation as symptoms recurred again two days later. After clinical signs of ischemia of the contralateral limb and respiratory impairment, all parties agreed upon the best supportive care concept. The patient died three days later after an additional stroke with left-sided hemiplegia. Autopsy revealed right-sided heart failure due to new severe pulmonary embolism as cause of death, as well as heavy thrombotic alterations of all major arterial vessels .To our best knowledge this is the first case with fulminant arterial embolisms involving the lung, brain, and both legs within a two-week period despite high doses of unfractioned heparins as paraneoplastic symptoms of a multilocular metastasized NET.Initially, calcifications of the infrarenal aorta with intraluminal thrombus were suggested as origin of embolism and protective stenting was discussed but not conducted due to the rapid chain of events Figures  and 2. RConclusively, paraneoplastic or chemotherapy-triggered hypercoagulability remains as possible explanations for generalized thromboembolic disease.Paraneoplastic syndromes occur in about 10% of malignant diseases and are defined as symptom complexes that cannot be readily explained by either the local or distant spread of cancer cells or specific secretory products . ConstitCisplatin, as part of the chemotherapeutic regimen among other substances such as thalidomide, is known to trigger thromboembolism in cancer patients with different nonrelated tumour entities \u201321. The 9/litre as the patient worsened rapidly.Some authors have reported secondary heparin-induced thrombocytopenia (HIT) of type II in cancer patients suggesting a higher incidence due to bone marrow infiltration , 25. HITIn terms of which anticoagulant drug to administer in paraneoplastic embolism, low-molecular-weight heparin (LMWH) seems to be superior compared to unfractioned heparin (UFH) and vitamin K antagonists. This assumption is mainly supported by studies with patients suffering from deep vein thrombosis , 28. RegLower limb ischemia in tumour patients is a severe paraneoplastic complication and might be the first clinical sign in a fast chain of overwhelming thromboembolic events. Tumours of neural crest origin seem to bear a high risk of hypercoagulation. Adequate surgical intervention and sufficient anticoagulation are the only treatment options and may be still too late. Further substantial research on anticoagulative treatment in tumour patients suffering from severe thromboembolic complications is needed."}
+{"text": "Effort thrombosis refers to axillary-subclavian vein thrombosis associated with strenuous and repetitive activity of the upper extremities. Spontaneous thrombosis of upper extremity veins, subsequently termed the Paget-Schroetter syndrome, is relatively rare.A 26 -year-old woman presented with progressive left arm swelling that had started one week before admission. Her past medical history was unremarkable for trauma to the shoulder or arm, venous catheter insertion or intravenous drug usage. She was otherwise healthy and did not report any personal or family history of hematological disorders and denied using oral contraceptives. On further questioning, the patient gave a history of knitting daily, at continuous stretches of 4\u20136 hours. Physical examination revealed nonpitting edema involving the entire left upper extremity. The left upper limb showed normal arterial pulses and there was no neurological deficit or bony injury. A color Doppler and duplex ultrasound scan of the left upper limb showed acute deep vein thrombosis involving the left axillary and subclavian veins.Blood was taken for factor V Leiden-factor II (G20210A) mutations and antinuclear antibody concentrations, all of which were normal. The coagulation profile revealed activated partial thromboplastin time and prothrombin time within normal range. Anticoagulation was then started with heparin and continued with warfarin. As an outpatient, she completed 8 weeks of anticoagulation therapy. A repeat ultrasound examination showed that the thrombus had resolved completely and the left subclavian vein appeared intact. After having excluded other possible predisposing factors for upper limb deep vein thrombosis, we concluded that our patient`s thrombosis was primarily prolonged knitting induced.The upper limb is an uncommon site for deep vein thrombosis. Primary axillary-subclavian vein thrombosis is, however, well described and is also called Paget-Schroetter syndrome.6In 1894, von Schroetter was the first to identify vascular trauma from muscle strain as a potential etiologic factor. It is believed that retroversion, hyperabduction and extension of the arm involved with these activities impose undue strain on the subclavian vein leading to microtrauma of the endothelium and activation of the coagulation cascade. Substantial evidence now supports the role of anatomical abnormalities involving the thoracic outlet in the pathogenesis of effort thrombosis.7Effort thrombosis of the upper extremity has been described in athletes involved in a wide variety of sports, including ball games, combatant sport and heavy athletics, games with rackets or clubs, push-up exercise and aquatic sports.Hand knitting might be a potential risk for upper limb thrombosis. Effort thrombosis should be suspected in women who perform repeated hand knitting and present with symptoms characteristic of effort thrombosis."}
+{"text": "Leptospira infection or icterohemorrhagic disease (LIR) are not rare entities. Our study introduces a patient infected with LIR following repeated professional underwater dives.Because of disturbances in visual acuity, the patient initially turned to the services of the Timi\u015foara Ophthalmological Clinic in 2011, and was later sent to the Infectious Diseases Clinic of Timi\u015foara, showing low grade fever, moderate hepatosplenomegaly, discreet subicteric sclera and a severely increasing deterioration of visual acuity.Direct ophthalmoscopy revealed disseminated bilateral chorioretinitis foci. The Infectious Diseases Clinic Laboratory confirmed hematological and serological diagnosis of LIR.The ocular chorioretinal determination of LIR is not frequent. In such situations, inoculation particularities along with evolving clinical and biological characteristics invite the clinician to extend the area of investigation."}
+{"text": "Genome-wide association studies (GWAS) have achieved great success in identifying common genetics variants associated with increased risk for developing breast cancer. More recently, advances in next-generation sequencing (NGS) have made possible identification of mutations associated with breast cancer. However, to date, the information generated by GWAS and NGS has not been maximally leveraged and integrated with gene expression data to identify biomarkers associated with the most aggressive subset of breast cancer: the triple-negative breast cancer (TNBC). Here we present results from an integrative genomics approach that combines GWAS and sequence information with gene expression data to identify functionally related genes and biological pathways enriched for expression-associated genetic loci and mutations associated with TNBC using publicly available data.We used publicly available data derived from 60 GWAS involving over 400,000 cases and over 400,000 cancer-free controls to identify SNPs and associated genes with increased risk of developing breast cancer. Specifically, we first identified SNPs in population-based human cohorts that are associated with the expression of genes in TNBC. Mutations and associated genes were identified by mining publicly available RNA-Seq and whole exome/ genome sequencing data derived from 104 TNBC patients. Gene expression data were from 124 TNBC tumors and 142 cancer-free controls. We performed supervised and unsupervised analysis on gene expression data from genes containing genetic variants and mutations to identify functionally related genes. Additionally, we performed pathway prediction and network modeling using Ingenuity. For each predicted pathway and network, we counted the number of SNPs and mutation events by direct enumeration.We identified 600 SNPs mapped to 205 genes, and 250 genes with mutations that included inserts, deletions (Indels) and copy number variants. Hierarchical clustering revealed functional relationships and similarity in patterns of expression profiles between SNP-containing genes and genes containing mutations. We identified multi-gene biological pathways enriched for SNPs and mutations. Many of the pathways identified have been proposed as important candidate pathways for TNBC, including the p53, NFkB, apoptosis, BRCA, DNA repair and DNA mismatch repair pathways.The results provide convincing evidence that integrating GWAS and sequence information with gene expression data provides a unified and powerful approach for biomarker discovery in TNBC. Furthermore, the results provide insights about the broader context in which genetic variants and mutations operate in TNBC."}
+{"text": "A new study provides information on another possible mechanistic pathway by revealing that cadmium impairs NAT-dependent carcinogen metabolism as demonstrated by altered biotransformation of environmental aromatic amines (AAs) N-acetyltransferases, are metabolic enzymes known to play a major role in the biotransformation of exogenous chemicals including AAs, many of which are known or suspected human carcinogens.Cadmium accumulates in body tissues and causes disease of the lungs, kidneys, liver, testes, prostate, and bladder. It also is thought to potentiate the carcinogenicity of many common workplace chemicals. NATs, or arylamine In the current study the authors exposed purified NAT enzymes to cadmium and found the exposure led to rapid and irreversible functional impairment\u2014removing the cadmium could not restore enzyme activities. They also exposed lung epithelial cells and laboratory mice to cadmium, then assessed NAT acetylation activity in the cells and mouse tissue samples. Biologically relevant concentrations of cadmium similar to those found in the lung tissue of heavy smokers impaired the NAT-dependent acetylation of carcinogenic AAs in lung epithelial cells, and NAT activity was strongly impaired in multiple tissues of mice exposed to cadmium.These findings indicate acute cadmium exposure can alter the metabolism of carcinogenic AAs through impairment of the NAT-dependent pathway, with potentially important toxicologic effects\u2014especially considering AAs are commonly found in cigarette smoke along with cadmium. The authors recommend further studies to address whether chronic cadmium exposure leads to similar effects."}
+{"text": "The disruption of mother-infant interactions can have life-long detrimental consequences for offspring and mothers. Recently, science has begun to emphasize translational research including preclinical and neurobiological research that may have direct implications for clinical populations and issues (see Figure"}
+{"text": "Nowadays, the use of cardiopulmonary bypass (CPB) followed by systemic hypothermia is common in cardiac surgery procedures. CPB causes a systemic inflammatory response syndrome (SIRS) that is markedly expressed in congenital caridiosurgical surgery programe resulting with deleterious consequences. Those effects are mediated through cytokines and others mediators of acute inflammatory response in circulation, which may lead to low cardiac output syndrome, multiorgan failure and lethal outcome after surgical total correction of congenital heart disease. The best method for SIRS prevention remains unclear, although some authors suggest perioperative use of corticosteroids. The study sough to evaluate the impact of perioperative corticosteroids on SIRS extent as well as clinical outcomes following total correction of congenital heart disease.The study was conducted as prospective randomized controlled trial. We enrolled 60 patients who were scheduled for total correction of congenital heart disease.In this study we examine the effects of corticosteroids in different doses and different time. Patients were divided into three groups with respect to perioperative corticosteroids administration regime.More favorable clinical outcomes as well as laboratory findings were obtained in group of patients receiving high doses of corticosteroids. The best clinical outcome was observed in group receiving (30mg/kg metilprednisolon after induction in anesthesia), where we found the shortest ICU stay , the lowest requirements for inotropic support , the shortest ventilation time .Our study presumably described that perioperative corticosteroids provide more favorable outcomes in group of patients who undergo total correction of congenital disease. However, further prospective multicentric randomized trials are required with aim to elucidate optimal timing and dosing regimens of perioperative corticosteroids."}
+{"text": "Astatotilapia latifasciata (Figure Haplochromis obliquidens. This species was described as Haplochromis latifasciatus [Astatotilapia [Haplochromis \"zebra obliquidens\" in the aquarium trade. Astatotilapia latifasciata has been reported to occur in Lake Nawampasa a small satellite lake of the much larger Lake Kyoga, and in Lake Kyoga located north of Lake Victoria in Uganda [After the publication of our work , we detea Figure , was errasciatus  and lateotilapia . Our misn Uganda ."}
+{"text": "Vancomycin-resistant Enterococci (VRE) is one of the most important hospital pathogens.The aim of the study was to evaluate the VRE colonization in patients hospitalized at the Hematology Intensive Care Unit and associated risk factors.Enterococci were isolated by standard microbiological methods. Isolate sensitivity was tested by disk-diffusion test using the 30\u03bcg/ml (BBL) Vancomycin plates according to CLSI standard.Prospective cohort study involved 70 patients hospitalized at the Intensive Care Unit (ICU), Clinic for Hematology, during three months. Demographic data and data risk factors for VRE colonization during present and previous hospitalization (within 6 months) were recorded for each patient using the questionnaire. Feces or rectal swab was collected for culture from patients on admission and at discharge in case when VRE was not isolated on admission. The Upon admission, 7% of patients were already colonized with VRE. The rate of VRE colonization during present hospitalization was 41.5%. Univariate logistic regression demonstrated statistical significant differences of acute myeloid leukemia (AML) diagnosis , length of present stay , use of aminoglycosides , and pip/tazobactam  in present hospitalization, duration of use of carbapenem  and pip/tazobactam  in present hospitalization between the VRE-colonized and non-colonized patients. AML, use of carbapenem in previous hospitalization and duration of use of piperacillin/tazobactam in present hospitalization were independent risk factors of VRE-colonized patients according to multivariate logistic regression.VRE colonization rate was high among patients admitted to hematology ICU. Rational use of antibiotics and an active surveillance may be helpful preventive measures for development of bacterial resistance to antimicrobial agents.None declared"}
+{"text": "Dendroctonus ponderasae Hopkins) and its associated pathogenic fungi  in western North America has resulted in the loss of more than 13 million hectares of pines since 1999 in British Columbia alone [Pinus contorta Dougl. ex Loud. var. latifolia) in British Columbia. However, since 2006 MPB has spread into northern Alberta, where lodgepole pine hybridizes with jack pine (Pinus banksiana Lamb.) [G. clavigera differ, and that water deficit affects these responses.The ongoing outbreak of mountain pine beetle  two year old lodgepole and jack pine seedlings in growth rooms, and (2) ca. sixty year old lodgepole x jack pine hybrids in naturally regenerated, thinned stands. Soil relative water content was monitored using time-domain reflectometry. Seedlings were subjected to watering or water deficit for one week prior to wounding or wounding plus Tree physiological status was evaluated by measuring gas exchange and stomatal conductance using a LiCor 6400, stem hydraulic conductivity using a low-pressure flow meter and safranin dye xylem perfusion, and HPLC. Defense responses were assessed by lesion measurements histochemistry, and qRT-PCR.Stomatal conductance and photosynthesis significantly decreased under water deficit for both lodgepole and jack pine seedlings, but seedling hydraulic conductivity was not affected. The mild water deficit applied to the mature trees reduced stomatal conductance and photosynthesis, but not significantly.G. clavigera-induced lesions developed more slowly in jack pine than lodgepole pine seedlings. Stem hydraulic conductivity decreased in inoculated lodgepole but not jack pine seedlings, likely because of greater tracheid occlusion caused by increased fungal growth and/or resin production in lodgepole pine [G. clavigera in the co-evolved lodgepole pine host than in the new jack pine host, and (2) defense responses are slowed by water limitation.Stem lesions are a means of killing and compartmentalizing invading organisms . G. clavole pine . Water dole pine , with loole pine . Accordiaquaporin and five DREB genes, families associated with water stress responses. Although the mild water deficit did not significantly alter expression of these genes, expression of one aquaporin and one DREB decreased in response to G. clavigera inoculation. We then profiled five chitinase and four terpene synthase defense-associated genes. Expression of two chitinases was significantly induced by water deficit but not G. clavigera. Expression of other chitinases significantly increased in response to fungalinoculation, but the response was attenuated by water deficit. Expression of one terpene synthase significantly increased with fungal inoculation, but this response was also attenuated under water deficit. In contrast, water deficit increased constitutive expression of another terpene synthase. Higher constitutive expression of the monoterpene synthase under mild water stress suggests a pre-emptive defense via higher biosynthesis of volatile monoterpenes. Microarray and qRT-PCR analyses of the lodgepole and jack pine seedling experiment are underway.We then examined the effect of water deficit on transcript abundance corresponding to genes classically associated with drought and defense responses. We conducted qRT-PCR transcript abundance profiling of secondary phloem from mature lodgepole x jack pine hybrids. We first profiled four Our analyses suggest that defense responses of jack pine differ from those of lodgepole pine. Molecular analyses are underway to further characterize these differences. Both constitutive and induced defense responses are modulated in pines by water deficit, and this response appears to be gene-specific. This study shows evidence of cross talk between the water stress and defense responses of pine trees."}
+{"text": "Brain stem arteriovenous malformations (AVMs) are rare and their clinical management is controversial. A location in highly eloquent areas and a greater risk of radionecrosis are both serious issues for radiosurgery of this entity. We report a case of a pontine AVM treated successfully with gamma knife therapy. At 3 years angiographic follow-up, imaging demonstrated complete thrombosis and there were no new neurological deficits, and at 7 years clinical follow-up, the patient continued to be neurologically stable. Although all treatments carry risk of neurological compromise, gamma knife therapy may offer the best treatment option for brain stem AVMs as seen in the case presented herein. This case illustrates a rare case of holo-pontine AVM tolerating gamma radiation with complete angiographical response and minimal neurological sequalae. Arteriovenous malformations (AVM) are congenital vascular malformations with direct arterial to venous connections without an intervening capillary network Doppman . The abrThe main diagnostic tools for these pathologic entities are magnetic resonance imaging (MRI), CT angiogram, and angiography , where single treatment of a pontine AVM with overlapping isodoses led to complete obliteration without any new neurological deficit.Any treatment of brain stem AVMs offers considerable risk for neurological compromise. Radiosurgery in highly selected cases may offer a treatment option with reasonable risks."}
+{"text": "Overproduction of insulin and associated hypoglycemia are hallmark features of this disease. Diagnosis can be made through demonstration of hypoglycemia and elevated plasma levels of insulin or C-Peptide. Metastatic disease can be detected through computerized tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT. Somatostatin receptor scintigraphy can be used not only to document metastatic disease but also as a predictive marker of the benefit from therapy with radiolabeled somatostatin analog. Unresectable metastatic insulinomas may present as a major therapeutic challenge for the treating physician. When feasible, resection is the mainstay of treatment. Prevention of hypoglycemia is a crucial goal of therapy for unresectable/metastatic tumors. Diazoxide, hydrochlorothiazide, glucagon, and intravenous glucose infusions have been used for glycemic control yielding temporary and inconsistent results. Sandostatin and its long-acting depot forms have occasionally been used in the treatment of Octreoscan-positive insulinomas. Herein, we report a case of metastatic insulinoma with very difficult glycemic control successfully treated with the radiolabeled somatostatin analog lutetium ( Insulinoma is a rare pancreatic neuroendocrine tumor . OverproThe treatment of unresectable metastatic insulinoma is associated with prolonged hospitalization for intravenous glucose infusion. The management of recurrent hypoglycemia also encompasses the administration of diazoxide, hydrochlorothiazide, and glucagon.Sandostatin and its long-acting depot form (Sandostatin LAR) are an adjunct therapy to neuroendocrine tumors. There are a few reports of glycemic control in patients with insulinoma treated with radio labeled somatostatin analogs , 5.The m-TOR inhibitor everolimus has been used to control hypoglycemia in this group of patients \u20137. Moreo177LU).Herein, we report a case of metastatic insulinoma successfully treated with the radiolabeled somatostatin analog lutetium . Computerized tomography (CT) scan of the abdomen was performed confirming the sonographic findings. The patient underwent a liver biopsy. Histopathology and immunohistochemistry results were consistent with low-grade neuroendocrine neoplasia (positive stain for chromogranin A) . InsulinThe patient received continuous intravenous glucose because of recurrent episodes of hypoglycemia throughout the hospital stay . GlucagoOctreoscan was performed showing a high uptake in focal areas of the liver, left lower quadrant of the abdomen, and cervicothoracic area .177LU) 8 weeks apart beginning on hospital day 56. By the second administration of the radiopharmaceutical, Octreoscan SPECT/CT had already shown objective metabolic and radiologic response to treatment  has been successfully tested in the treatment of gastroenteropancreatic neuroendocrine tumors [Radiolabeled somatostatin analog lutetium  did show clear evidence of objective response in line with other reports.After results of Octreoscan became available, we decided to use radiolabeled somatostatin analog because of previous reports of glycemic control and objective responses. Glucose levels steadily improved, as shown in 177LU) may represent an option for glycemic and systemic disease control, as shown in the case presented here.In summary, unresectable metastatic insulinomas may present as a major therapeutic challenge for the treating physician. For Octreoscan-positive tumors, radiolabeled somatostatin analog lutetium ("}
+{"text": "Pulse wave velocity (PWV) is an indirect measure of vascular stiffness. Higher PWV is a recognised cardiovascular risk marker. Magnetic resonance imaging (MRI) is a non-invasive method of assessing PWV. Assessing maternal influences on offspring PWV is important as reduced fetal nutrient supply and impaired early development are linked with an increased risk of cardiovascular disease in adulthood. In multiparous women, changes in the uterine spiral arteries arising during previous pregnancies result in increased fetal nutrient supply. Rat studies have shown that changes in maternal fatty acid intake in pregnancy are associated with increased offspring arterial stiffness. Some studies of human adults suggest omega-3 fish oils reduce arterial stiffness. The objective of the study was to measure vascular stiffness using MRI, and examine maternal influences on vascular structure in children aged 9 years.Aortic PWV was assessed in 125 children aged 9 years  using velocity-encoded MRI as part of a study of developmental influences on cardiovascular structure and function. Maternal diet had been assessed in early and late pregnancy, and the child's diet at age 9 years, using administered food frequency questionnaires.PWV values fell within previously reported childhood ranges. Childhood aortic PWV was lower in offspring of multiparous mothers . Higher maternal oily fish intake in pregnancy was associated with lower childhood aortic PWV , but there was no association with the child\u2019s current fish intake.MRI measurements of childhood aortic PWV indicate that the mother\u2019s parity, and normal variations in maternal oily fish intake in pregnancy, may alter vascular development in utero - changing arterial structure and function with long-term consequences for cardiovascular risk in later life.This work was supported by funding from the British Heart Foundation and the National Institute for Health Research ."}
+{"text": "Introduction. The mechanisms underlying the association between insulin resistance and intrahepatic lipid (IHL) accumulation are not completely understood. We sought to determine whether this association was explained by differences in fasting non-esterified fatty acid (NEFA) levels and/or NEFA suppression after oral glucose loading. Materials and Methods. We performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial  who underwent oral glucose tolerance testing with glucose, insulin, and NEFA levels measured over two hours. IHL was quantified with magnetic resonance spectroscopy. Insulin sensitivity was measured with the oral glucose insulin sensitivity (OGIS) model, the leptin: adiponectin ratio (LAR), and the homeostasis model assessment (HOMA). Results. Measures of insulin sensitivity were not associated with fasting NEFA levels, but OGIS was strongly associated with NEFA suppression at 30 minutes and strongly inversely associated with IHL. Moreover, LAR was strongly inversely associated with NEFA suppression and strongly associated with IHL. This latter association  was explained by reduced NEFA suppression (P = 0.24 after adjustment). Conclusions. Impaired postprandial NEFA suppression, but not fasting NEFA, contributes to the strong and well-established association between whole body insulin resistance and liver fat accumulation. Excess intrahepatic lipid (IHL) accumulation  is an important component of the spectrum of metabolic derangements associated with central obesity and insulin resistance . StudiesNEFA suppression is impaired in type 2 diabetes  and NAFLThe rationale and design for the Hertfordshire Physical Activity Trial ISRCTN 60986572) have been described previously 8], and o"}
+{"text": "The spiking state is thought to be maintained by a positive feedback loop between a nonspecific, calcium-sensitive cationic current (ICAN) carried by canonical transient receptor potential (TRPC) channels and heightened intracellular calcium levels sustained during sufficiently fast spiking. Bistable persistent spiking (PSB) has been observed across layers and cell types in mEC and has been implicated in working memory and grid cell function, so cholinergic modulation of TRPC channels represents a potentially fundamental mechanism shaping the spiking output of mEC neurons. However, spiking of mEC neurons during navigation and goal directed behavior in vivo is strongly theta modulated (4-12 Hz), and it is not known how the PSB mechanism may interact with theta oscillations. In the present study we evaluated the effect of muscarinic modulation on input-output processing of mEC neurons to tonic, slowly varying, and oscillatory inputs. First, we investigated the frequency to injected current (FI) relationship using step and ramp current injection protocols in the presence of the muscarinic agonist carbachol (CCh). FI measures made following suprathreshold pre-pulse current injections exhibited higher spike frequencies than when measured following subthreshold pre-pulses, illustrating a spike-history dependence of the FI relationship. The instantaneous spike frequency measured during a range of current steps showed a positive slope for most PSB neurons, indicating that ICAN acts as a reverse spike frequency adaptation mechanism. In response to linearly increasing ramp current stimuli, mEC neurons showed a steep acceleration followed by a plateau of spike frequency. Spike frequency hysteresis during decreasing ramp stimuli demonstrated significant adaptation for higher input levels, but spiking was often maintained at lower levels of injected current. Next, using different combinations of theta frequency sinewave current injections and DC holding currents, we were able to generate a range of spiking patterns where spikes were elicited on different proportions of theta cycles and at different phases of the theta input. With muscarinic activation, spiking was elicited on a higher proportion of theta cycles and at earlier phases of the oscillatory input for lower levels of tonic current input. A subset of recorded neurons exhibitted repeated sequences of intrinsic phase precessing spiking behavior. Similar to the plateau in spike rate observed with ramp stimuli, in response to stimuli composed of sinewaves superimposed on ramps, spiking phase rapidly advanced and maintained an 'early-phase plateau' as DC current continued to increase. Taken together, we demonstrate that muscarinic modulation of TRPC channels determines the gain of the frequency to injected current relationship of mEC neurons, interacts with adaptation mechanisms to generate spike history dependencies of spike rate including hysteresis, and shapes the distribution of spiking phases relative to oscillatory input. We propose that increasing activation of ICAN by spike-triggered calcium influx as an animal enters a firing field may provide a cellular mechanism contributing to theta phase precession of mEC grid cells.In the presence of muscarinic cholinergic modulation"}
+{"text": "To the Editor: Rift Valley fever (RVF) virus causes severe disease, abortion, and death in domestic animals  in Africa and the Arabian Peninsula. Humans are infected by mosquitoes, which maintain epizootic transmission, or through exposure to infected animal tissue. Although human disease may be mild, sometimes severe retinitis, meningoencephalitis, or hemorrhagic fever syndromes may develop in patients. In Africa, epizootics and associated human epidemics usually follow heavy rainfall  and Kenya (1997), which suggests that the virus was imported through infected mosquitoes or livestock from East Africa  and the Department of Defense Global Emerging Infections Surveillance and Response System (DoD-GEIS) monitor the satellite-derived normalized difference vegetation index (NDVI), which reflects recent rainfall and other ecologic and climatic factors \u2013 panel A Satellite-derived rainfall estimates show that widespread rainfall occurred over most of western Saudi Arabia and Yemen from mid-April to mid-June 2005 (No human cases of RVF have been reported in Saudi Arabia and Yemen since the 2000 outbreak, but in September 2004 the Saudi Ministry of Agriculture reported that 5 RVF-seropositive sheep had been identified during routine surveillance in Jizan where most infected persons were exposed during the outbreak in 2000 (Since RVF virus can be maintained in mosquito eggs for extended periods and transmitted under favorable conditions ("}
+{"text": "Zosterisessor ophiocephalus), thornback ray (Raja clavata), and scorpionfish (Scorpaena scrofa) were studied. At least four caseinolytic proteases bands were observed in zymogram of each enzyme preparation. These proteolytic preparations were successfully used in the deproteinization of shrimp wastes for chitin extraction. Furthermore, a trypsin was purified from the pyloric ceca of Pacific cod  using chromatographic methods. The cod trypsin was successfully applied to catalyze dipeptide synthesis using series of \u201cinverse substrates.\u201d A Mackerel trypsin was also purified from defatted viscera by supercritical carbon dioxide, and its biochemical properties were studied.Sea products are valuable resources of natural substances such as lipids, polysaccharides, enzymes, vitamins, and proteins. In this issue, a variety of fish proteases  have been characterized and sometimes purified. Many of these enzymes display potentially interesting new biochemical properties for industrial applications. Their potential adequacy for biotechnological applications such as chitin extraction was demonstrated. Biochemical characteristics of crude alkaline protease extracts from the viscera of goby . Sea products proteins digestion using bacterial proteases generated protein hydrolysates displaying interesting biochemical properties and antioxidant activity. Antioxidative activities and biochemical properties of protein hydrolysates with different hydrolysis degrees, prepared from cuttlefish  using an Alcalase and This issue highlights the potential of sea products as valuable resources of bioactive peptides and proteins such as hydrolytic enzymes, lectins, and antioxidants. These resources might be of great interest for industrial biotechnological processes using safe and natural materials such as peptides or enzymes. Dicer is an RNase III enzyme with two catalytic subunits, which catalyzes the cleavage of double-stranded RNA to small interfering RNAs and micro-RNAs, which are mainly involved in invasive nucleic acid defense and endogenous genes regulation. In addition, Dicer is thought to be involved in defense mechanism against foreign nucleic acids such as viruses. A paper focused on the recent progress of Dicer-related research and discussed potential RNA interference pathways in aquatic species. Dicer is abundantly expressed in embryos, indicating the importance of the protein in early embryonic development. Nabil MiledNabil MiledMoncef NasriMoncef NasriHideki KishimuraHideki KishimuraFaouzi Ben RebahFaouzi Ben Rebah"}
+{"text": "University course processes have recently changed with student enrolments increasing, ultimately placing new demands on student placements within the healthcare setting. In response to the changing university curriculum and in line with the Victorian Department of Health, Clinical Placement Networks and Health Workforce Australia, Northern Health (NH) Podiatry department identified a unique opportunity in provision of clinical placement education.NH developed an innovative and exciting approach to the management and delivery of podiatry student clinical placements in order to increase capacity. Recruitment to a new Podiatry Clinical Educator (CE) position allowed implementation of strategies to significantly increase capacity, ensure provision of high quality, evidenced based and safe clinical education whilst supporting podiatrists and students.To increase student capacity with limited resources, NH created a Podiatry CE position. This facilitated developments including; 2:1 Model of Supervision with peer learning and incorporating a focus on student feedback and reflection, integrating simulation into traditional clinical education, evidenced based tutorials and support to podiatrists and students.Preliminary evaluation findings show significant increase in capacity with high student and podiatrist satisfaction. Results of student placement evaluations will be presented including perspectives on simulation, peer learning and specific podiatrist professional experiences.With a Podiatry CE position and great team functioning; strategies implemented allow consistent provision of efficient, high quality, evidence based podiatry student clinical placements enabling increased capacity."}
+{"text": "Prosthodontists can serve as productive members of the craniofacial team and can help coordinate multidisciplinary treatment of patients with congenital anomalies. Often there are few, if any, evidence-based criteria to assist them in developing \u201ccorrect\u201d clinical protocols. When syndromes involve hypodontia, oligodontia, or anodontia, coordinating prosthetic treatment through phases of three-dimensional growth and development can be daunting.Early implant intervention with anodontia patients is acceptable in some treatment centers. Correcting previously untreated adolescent oligodontia can be extremely challenging and removal of strategic teeth with immediate implant placement is surely controversial. Understanding the morbidity of grafting in these patients and the questionable long-term survival of overdenture abutment teeth will lend to an active discussion of the advocated aggressive therapeutic approach."}
+{"text": "Neuronal death and subsequent denervation of target areas is a major feature of several neurological conditions such as brain trauma, ischemia or neurodegeneration. The denervation-induced axonal loss results in reorganization of the dendritic tree of denervated neurons. Dendritic reorganization of denervated neurons has been previously studied using entorhinal cortex lesion (ECL).ECL leads to shortening and loss of dendritic segments in the denervated outer molecular layer of the dentate gyrus . HoweverTo perform comparative electrotonic analysis we used computer simulations in anatomically and biophysically realistic compartmental models of 3D-reconstructed healthy and denervated granule cells. Our results show that somatofugal and somatopetal voltage attenuation due to passive cable properties was strongly reduced in denervated granule cells. In line with these predictions, the attenuation of simulated backpropagating action potentials and forward propagating EPSPs was significantly reduced in dendrites of denervated neurons. In addition, simulations of somatic and dendritic frequency-current (f-I) curves revealed increased excitability in deafferentated granule cells.Taken together, our results indicate that unless counterbalanced by a compensatory adjustment of passive and/or active membrane properties, the plastic remodeling of dendrites following lesion of entorhinal cortex inputs to granule cells will boost their electrotonic compactness and excitability."}
+{"text": "Mammalian gene regulation is often mediated by distal enhancer elements. Despite this, mechanistic investigations of correlated expression have thus far been focused on proximal promoter regions, mainly because distal enhancers are not known for a vast majority of genes. However, distal enhancers of co-regulated genes are likely to have correlated activity.cis) and from different chromosomes, after accounting for HS autocorrelation affecting cis-pairs. Using non-parametric tests and controlling for dependencies, highly correlated pairs are compared with background pairs for: enrichment of co-occurring binding motifs; for correlated gene expression across the 15 cell samples sourced for HS data; for shared gene function; for evidence of interactions between shared enhancer-binding transcription factors (TFs) and chromatin-modifying enzymes; and for Hi-C evidence of pair co-localization. The relationship between correlated enhancers now established, we conclude by scaling this pairs perspective to the building and validating of an enhancer network.Using P300-bound regions as putative enhancers  and usinWe find that correlated enhancers tend to share common TF-binding motifs, and that several chromatin modification enzymes preferentially interact with these TFs. We show that we can predict correlated enhancers with 73% accuracy based only on the presence of shared motifs for specific TFs. Also, genes near correlated enhancers have correlated expression and share common function. Correlated enhancers coincide with spatially proximal genomic regions assayed by Hi-C in two different cell types. Finally we construct an enhancer network based on shared motifs and correlated activity, and show its high overlap with biological processes and pathways.Overall, our analysis suggests that functionally linked genes may be co-regulated by distal enhancers whose activities are regulated by common sets of TFs and mediated by both 3D chromatin structure as well as chromatin modification enzymes. Our work represents the first investigation of enhancer networks based on correlated activity across multiple cell types."}
+{"text": "Nocardia infections; ganciclovir, valganciclovir, or acyclovir for cytomegalovirus related complications in at-risk recipients; and lamivudine for prevention of progressive liver disease in HBsAg positive recipients. Viral load monitoring and pre-emptive treatment is used for BK virus infection. Infection with new organisms has recently been reported, mostly due to inadvertent transmission via the donor organ.Infections are the leading cause of hospitalization in transplant recipients. The increased risk of new onset diabetes after transplantation, cardiovascular disease, post-transplant lymphoproliferative disorders adversely affects allograft outcomes. Risk is determined by epidemiologic exposure, immunosuppressive therapy and prophylaxis. The predictable sequence of appearance of infections helps in making management decisions. High likelihood of infections with unusual and multiple organisms necessitates aggressive use of imaging techniques and invasive procedures. Serologic tests depend upon antibody response and are unreliable. Nucleic acid based assays are sensitive, rapid, and allow detection of subclinical infection and assessment of response to therapy. Preventive steps include screening of donors and recipients and vaccination. All indicated vaccines should be administered before transplantation. Inactivated vaccines can be administered after transplantation but produce weak and transient antibody response. Boosters may be required once antibody titers wane. Post-transplant chemoprophylaxis includes cotrimoxazole for preventing urinary tract infections, pneumocystis and  Optimal use of immunosuppressive drugs in a renal transplant recipient (RTR) requires a careful balancing act. Availability of potent and specific immunosuppressive agents has reduced the incidence of acute rejection to about 10\u201315% in most centers. However, despite refinements in diagnostic techniques and discovery of new anti-microbial drugs, the risk of infection amongst transplant recipients has not come down. showed iInfection risk is even greater in the pediatric transplant population. Data from the North American Pediatric Renal Transplant Cooperative study show that 38\u201342% patients transplanted between 1987 and 2002 required hospitalization for infections. Infection was the primary cause of hospitalization in the first 2 years after transplantation, exceeding that for rejection. Cl55 Cl5455In conclusion, infections remain a major problem in the transplant population. They are a main cause of death with functioning graft, and cause a number of other complications that increase morbidity. Molecular diagnostic techniques have allowed earlier identification and better monitoring of infections. Prophylactic strategies include vaccination and targeted post-transplant chemoprophylaxis. Use of drugs carries the risk of late and resistant infections. A high index of suspicion and early and aggressive use of diagnostic techniques are essential for accurate diagnosis and improved outcomes."}
+{"text": "WebGimm is a free cluster analysis web-service, and an open source general purpose clustering web-server infrastructure designed to facilitate easy deployment of integrated cluster analysis servers based on clustering and functional annotation algorithms implemented in R. Integrated functional analyses and interactive browsing of both, clustering structure and functional annotations provides a complete analytical environment for cluster analysis and interpretation of results. The Java Web Start client-based interface is modeled after the familiar cluster/treeview packages making its use intuitive to a wide array of biomedical researchers. For biomedical researchers, WebGimm provides an avenue to access state of the art clustering procedures. For Bioinformatics methods developers, WebGimm offers a convenient avenue to deploy their newly developed clustering methods. WebGimm server, software and manuals can be freely accessed at  Identifying groups of co-expressed genes through cluster analysis has been successfully used to elucidate affected biological pathways and postulate transcriptional regulatory mechanisms. Methods for co-expression analysis of gene expression data have been extensively researched, and numerous clustering algorithms have been developed. New clustering algorithms often have been implemented as stand-alone computer programs, R packages, or both . NumerouThe rationale for developing WebGimm is two-fold. First, sophisticated and better performing clustering methods are likely to be used more often if they are accessible through a streamlined and familiar interface requiring only minimal computational resources and no local installation. Second, an integrated web-based cluster/treeview-like platform that also incorporates functional enrichment analysis will further improve the utility of even simple hierarchical clustering procedures. We aimed to combine the \"wrapper\" model to facilitate access to clustering algorithms implemented in R, with the web-server model of deployment that obviates any local software installation.cluster/treeview package. The version of the software deployed on our server implements multiple infinite mixture model based clustering procedures [k-means clustering). In addition, functional analysis using the CLEAN framework and FTreeView browser [To achieve these goals, we developed WebGimm, an open source general purpose clustering web-server infrastructure designed to facilitate the easy deployment of integrated cluster analysis servers based on clustering algorithms implemented in R. The design of our Java Web Start (JWS) client was modeled after the familiar ocedures ,8-11 as  browser  are inteWebGimm is an open source general purpose clustering web-server infrastructure designed to facilitate the easy deployment of integrated cluster analysis servers based on clustering algorithms implemented in R. The system consists of a Java GUI client deployed using the Java Web Start (JWS), and the server-side infrastructure designed around Java-based WebGimm server and multiple computing R servers. The server architecture is shown in Figure Rserve infrastructure http://www.rforge.net/Rserve/. R servers perform all computational tasks associated with cluster analysis and functional enrichment analysis by executing an R script with parameters supplied by the WebGimm server. R servers provide clients with feedback about the progress being made and also send a notification once the computation completes. Jobs are assigned to the servers in a round-robin fashion to evenly distribute the load among a \"farm\" of R servers.The design of the Java client is modeled after the familiar cluster/treeview package. The client's function is to pass user-specified analysis parameters and data to the server for analysis, and to facilitate viewing and downloading of analysis results. The server facilitates simple data centering and scaling, executing various clustering algorithms, performing functional enrichment analysis using CLEAN and viewing results of functionally annotated clustering results using Functional TreeView (FTreeView) . The Webk-means clustering). In addition to providing a convenient tool for using GIMM, the integrated functional analysis and FTreeView browser provide a strong incentive to use the tool even when applying simple clustering procedures. The simplicity of deployment and the interface allows anybody with only conceptual understanding of cluster analysis to start using it with little effort.WebGimm serves as an integrated platform for cluster analysis, functional annotation of clustering results, and for exploring analytical results using the (FTreeView). The version of the software deployed on our server implements Gaussian Infinite Mixture Model (GIMM) based clustering procedures ,8-10 as Figure The WebGimm infrastructure also provides a convenient way to implement and distribute newly developed clustering procedures. The complete code for client and server-side software, as well as instructions for deploying the server, can be downloaded from the support web site. By making simple modifications to the client GUI and the backend R scripts, Bioinformatics developers can deploy their own methods on their own servers in a way that is accessible to users without technical Bioinformatics expertise. Such deployment will likely increase the impact of their procedures, while allowing biomedical researchers to easily test state of the art analytical procedures and choose the one producing most meaningful results for their dataset at hand. Furthermore, separating the computational infrastructure from the user interface allows for a straightforward adoption of advanced computational paradigms. For example, the recent implementation of the hierarchical clustering using CUDA general purpose programming tools for NVIDIA Graphical Processing Units achieved 48-fold speed-up over typical desktop CPU using traditional sequential algorithm . ImplemeProject name: WebGimmhttp://ClusterAnalysis.orgProject home page: Operating system: platform independent client , Linux-based web-server, platform-independent R packagesProgramming language: Java, C++, MySQL, ROther requirements: NoneLicense: The tool is available online free of charge, and code is available based on GNU GPL.Any restrictions to use by non-academics: NoneCLEAN: Clustering Enrichment Analysis; DAVID: Database for Annotation, Visualization and Integrated Discovery; GIMM: Gaussian Infinite Mixture Model; JWS: Java Web Start.'The authors declare that they have no competing interests.VJ developed the complete server infrastructure and the JWS client. MM conceived and led the development of the software and the web-server. JF developed the server-side R scripts for performing cluster analysis and functional analysis. ZH develops and maintains the c++ GIMM code, VJ and MM wrote the paper. All authors read and approved the final manuscript."}
+{"text": "Female genital tuberculosis remains as a major cause of tubal obstruction leadingto infertility, especially in developing countries. The global prevalence of genital tuberculosis has increased during the past two decades due to increasing acquired immunodeficiencysyndrome. Genital tuberculosis (TB) is commonly asymptomatic and it is diagnosed duringinfertility investigations. Despite of recent advances in imaging tools such as computed tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasongraphy, hysterosalpinography has been considered as the standard screening test for evaluation of tubal infertilityand as a valuable tool for diagnosis of female genital tuberculosis. Tuberculosis gives rise tovarious appearances on hysterosalpingography (HSG) from non-specific changes to specificfindings. The present pictorial review illustrates and describes specific and non-specific radiographic features of female genital tuberculosis in two parts. Part I presents specific findings oftuberculosis related to tubes such as \"beaded tube\", \"golf club tube\", \"pipestem tube\", \"cobblestone tube\" and the \"leopard skin tube\". Part II will describe adverse effects of tuberculosison structure of endometrium and radiological specific findings, such as \"T-shaped\" tuberculosis uterus, \"pseudo-unicornuate \"uterus, \"collar-stud abscess\" and \"dwarfed\" uterus withlymphatic intravasation and occluded tubes which have not been encountered in the majorityof non-tuberculosis cases. Female genital tuberculosis (FGTB) is one formof extrapulmonary manifestations of tuberculosisand includes 5% of all female pelvic infections, 2. It iThe reported prevalence of genital tuberculosis hasshown a descending trend in developed countries, butrecently, its rate has started to increase again due toco-infection with human immunodeficiency virus(HIV) and the development of drug resistants trains ofMycobacterium tuberculosis -6. PrimaDiagnosis of genital TB may be difficult becausemajority of cases are asymptomatic; furthermore, inhigh prevalence-countries, culture facilities for mycobacterium and histopathologic diagnosisare limited-11. In tThis part of pictorial review illustrates and describes endometrial changes following genital tuberculosis detected by HSG. Tubal tuberculosis is disseminated to the endometrium in approximately 50% of cases  and persThe pathognomonic findings for tuberculosisinclude specific and non-specific features. Specificradiographic features are \"collar-stud abscess\",\"T-shaped\" uterus and unicornuate uterus-likeappearance (the \"pseudounicornuate\" uterus). Otheruterine changes due to tuberculosis known as nonspecific features include endometritis, synechiae,distortion of uterine contour, and venous and lymphatic intravasations , 15.Uterine manifestations in tuberculosis may varyfrom mild endometritis to severe scarring and deformity leading to total obliteration of the uterinecavity  16). In. In16). Later with progression of TB, caseation and ulceration of endometrium occur, and intrauterine scarring may result in synechiae and intrauterineadhesions. In this stage, the uterine cavity is usually normal in size, but irregularity of uterine contour, filling defects, lack of uterine contractilityand tubal patency may be seen .With progression of disease, irregularity ofuterine contour and filling defects may resultin a denticulate cavity  18, 19), 1918, 1A dwarfed uterus which is characterized witha small and shrived uterus with irregularity anddisproportion between uterine cavity and cervix,while trifoliate shaped uterus are other presentations of uterine tuberculosis  (17).After long duration of infection, extensive destruction of endometrium and myometriumfollowed by fibrosis and complete obliteration of the uterine cavity may occur as the\"Netter syndrome\" (21). Hysterosalpingographic characteristic of Netters syndrome iscalled \"glove\u2019s finger\" consisted of a cervical canal and a small part of the uterus  (21). Other radiographic findings of tubercular affection of the uterus include theformation of a \"collar-stud abscess\", whichis pathognomonic for tuberculosis (14).This feature should be differentiated fromintracavitary changes due to necrosis in anadjacent uterine leiomyoma. A collar-studabscess classically has a narrow neck with abroader base which is away from the endometrial cavity.The venous and lymphatic intravasation inuterine and adnexal vessels is acomplicateddisorder which occurs due to progressive destruction and ulceration of endometrium.Themost important cause of intravasation is the entry of contrast medium to the venous andlymphatic canals through unprotected ves-sels. Although this feature is not specific fortuberculosis, it can be detected by HSGs performed early in the menstrual cycle, shortlyafter endometrial instrumentation or pathological deficiency of endometrium . It isaIn hysterosalpingography filling of multiple,parallel beaded channels are seen.Contrast in thin delicate lymphatics are differentiated from blood vessels by their narrower caliber and reduced draining of contrast.  Cervical tuberculosis is rare due to the nature of stratified squamous epithelium of theectocervix which causes to be resistance tobacterial penetration - 26. TheIn the cervix, the tuberculous lesion can beulcerative or proliferative. In the ulcerativeform, the ulcers have wavy borders, clean cutedges and a yellow base. The proliferative lesion has papillary formations which may bepedunculated or sessile.On HSG, caseous ulceration of the mucosaproduces ragged irregular contours and diverticular outpouching with a feathery appearance . The other various featuressuch as adhesions, distortion and a serratedendocervical canal have also seen in somecases.There are useful differential diagnostic criteria suggested by Klein et al.  for diag Calcified lymph nodes or smaller irregularcalcifications in the adnexal area.Obstruction of the fallopian tube in the zoneof transition between the isthmus and the ampulla.Multiple constrictions along the course ofthe fallopian tube.Endometrial adhesion and/or deformity orobliteration of the endometrial cavity in theabsence of curettage or of surgical terminationof pregnancy.Uterine tuberculosis may show a range of mildto severe endometritis, restricted to superficiallayers of endometrium or endometrial ulcer leading to progressive destruction, obliteration anddeformity of the uterus in the late stages.Some of the hysterosalpingographic findings ofuterine tuberculosis, such as \"T-shaped\" tuberculosis uterus, \"pseudounicornuate\" uterus, \"collarstud abscess\" and \"dwarfed\" uterus with lymphatic intravasation and occluded tubes, are specificfor female genital tuberculosis and have not beenencountered in the majority of non-tuberculosiscases. Diagnosis of these radiographic characteristics is reliable evidence of genital tuberculosisand iscrucial in the infertility workup in order tomake a proper decision."}
+{"text": "Platelet-derived growth factor (PDGF) has ample evidence to support its importance in pulmonary fibrosis. Expression of PDGF in the lungs of IPF patients as well as in BAL samples from animal models of lung fibrosis support its involvement during disease development. Vascular endothelial growth factor (VEGF) being a key regulator of angiogenesis and its receptors have been shown to be involved in the pathogenesis of pulmonary sarcoidosis and fibrosis. The hypothesis under investigation is that receptor tyrosine kinase inhibitors (e.g. Sutent) will slow both the fibrotic processes associated with PDGF signaling and the angiogenic processes regulated by VEGF. We tested two RTKi compounds from Pfizer\u2019s internal portfolio (SU-11248 (Sutent), SU-14813) in the bleomycin-induced pulmonary fibrosis mouse model. Prophylactic as well as therapeutic dosing protocols were conducted. Endpoints included histology, body weights, wet lung weights, lung HO-Pro levels and tissue and serum samples for biomarker and lung exposure analyses. Statistically significant reductions in histological changes were demonstrated in lungs treated with both RTK inhibitors in both percentage of total collagen and inflammatory collagen present. RTK inhibitors demonstrated a statistically significant reduction in both wet lung weight and lung HO-Pro content when dosed prophylactically and therapeutically compared to controls. We have demonstrated that broad-spectrum RTK inhibition is efficacious in inhibiting established pulmonary fibrosis in the bleomycin-induced mouse model. Sutent and other broad spectrum RTKis may provide therapeutic benefit to IPF patients by slowing both the fibrotic and angiogenic processes regulated by tyrosine kinases."}
+{"text": "The National Cancer Institute (NCI) supports a Cancer Centers Program (CCP) including 66 NCI-designated cancer centers. Several CCPs have associations with Integrative Medicine Programs (IMPs). However, limited information is available regarding cancer-CAM research and collaborations between them. An inventory by NCI\u2019s Office of Cancer Complementary and Alternative Medicine (OCCAM) was conducted to learn about CAM related services and resources at NCI\u2019s CCPs and IMPs, including members of the Consortium of Academic Health Centers for Integrative Medicine (CAHCIM).Sixty-six NCI-designated cancer centers of the CCP and 41 IMPs were eligible to participate in a brief inventory about clinical services, education, and research. This project examines the CCP-IMP cancer research results of this inventory.Most CCPs and IMPs indicated collaborating with each other and also working independently. CCPs conducted more independent research (38%) than IMPs (28%). Types of research collaborations included mainly clinical research . International collaborations were higher among CCPs (27%) compared to IMPs (11%). Both CCPs and IMPs reported NIH as their major source of funding . About 70% of CCPs and IMPs reported having CAM research experts in their centers. When asked if their institutions would find an NCI training on cancer CAM research grants beneficial, both CCP (85%) and IMP (94%) respondents were interested in such training and considered it to be beneficial.This inventory shows that research collaborations between CCPs and IMPs are ongoing. However, additional in depth details are needed. Research training on cancer CAM grants can be beneficial in fostering research collaborations and in advancing cancer CAM research among CCPs and IMPs."}
+{"text": "Diabetic peripheral neuropathy (DPN) affects the sensory, motor, and autonomic nervous system. The biomechanical changes resulting from DPN may translate to increased plantar pressures in the foot, which contributes to the pathogenesis and development of foot ulcers. This review aims to investigate the existing biomechanical literature associated with gait, dynamic electromyography and plantar pressure of patients with DPN.Electronic databases  were searched for papers reporting observational studies on patients with DPN in gait, dynamic electromyography or plantar pressure. Exclusion criteria were papers investigating children, interventional studies or studies published prior to 2000.Twenty-five papers met the inclusion criteria and were reviewed. Overall there were disparities between studies due to methodological differences in reporting such as the disease duration and degree of neuropathy of participants. DPN subjects walked slower, with smaller stride length and reduced knee extension and active ankle plantar/dorsiflexion compared to healthy and diabetes controls. Dynamic electromyography studies suggested an early activation of lateral gastrocnemius, whilst findings in the tibialis anterior and vastus lateralis muscles were inconsistent. Markedly elevated forefoot peak plantar pressures (PPP) were observed in those with a history of ulceration.This review suggests marked biomechanical  variation in DPN patients compared to controls. Studies investigating kinematic (description of movement) variables of the foot are lacking and further studies are needed. It is recommended that future DPN biomechanical studies should document the duration and degree of DPN."}
+{"text": "Ostracism\u2014being ignored and excluded\u2014causes distress and threatens psychological needs ? We will review the emerging research on vicarious ostracism, highlighting the neural correlates of this phenomenon. Finally, we posit future research questions to strengthen the theoretical understanding of vicarious ostracism from social cognitive and evolutionary psychological perspectives.Empathy research suggests that individuals vicariously experience others' pain. Most of this research has focused on vicarious physical pain, but might observers also experience vicarious We are aware of nine experimental studies demonstrating vicarious ostracism. These studies find that observers recognize an ostracized individual's distress and also feel ostracized themselves  and anterior insula (AI), two brain regions activated by directly experiencing ostracism  popular? When participants are eliminated, they are openly rejected . Schadenfreude research has found feelings of dislike, anger, or resentment can lead to perceived deservingness and pleasure at another's misfortune, both in self-reports and neurological measures (Weiner, Williams  argues a Weiner, . If ostr"}
+{"text": "The aim of this study was to assess the clinical implications of reversed ophthalmic artery flow (ROAF) for stroke risk and outcomes in subjects with unilateral severe cervical carotid stenosis/occlusion.We investigated 128 subjects (101 with acute stroke and 27 without), selected from a large hospital patients base , identified with unilateral high-grade cervical carotid stenosis/occlusion by using duplex ultrasonography and brain magnetic resonance imaging. All clinical characteristics were compared for stroke risk between acute stroke and nonstroke groups. Patients with acute stroke were divided into 4 subgroups according to ophthalmic artery flow direction and intracranial stenosis severity, and stroke outcomes were evaluated.The acute stroke group had significantly higher percentages of ROAF , carotid occlusion , and severe intracranial stenosis . However, multivariate analysis demonstrated that intracranial stenosis was the only significant risk factor . Analysis of functional outcomes among the 4 subgroups of patients with stroke showed significant trends (p \u200a=\u200a 0.018 to 0.001) for better stroke outcomes from ROAF and mild or no intracranial stenosis. ROAF improved 10\u201320% stroke outcomes, as compared to forward ophthalmic artery flow, among the patients with stroke and the same degree of severities of intracranial stenosis.Patients with acute stroke and severe unilateral cervical carotid stenosis/occlusion significantly have high incidence of intracranial stenosis and ROAF. Intracranial stenosis is a major stroke risk indicator as well as a predictor for worse stroke outcomes, and ROAF may provide partial compensation for improving stroke outcomes. Extracranial severe carotid stenosis or occlusion is a well-known pathogenic factor for ischemic stroke. The risk of stroke increases in patients with concurrent severe stenosis of extra- and intracranial vessels To address this question, we selected patients with acute ischemic stroke and unilateral high-grade cervical carotid stenosis/occlusion and evaluated clinical functional outcomes in the presence of ROAF and intracranial stenosis. We hypothesized that intracranial stenosis would be a predictor for stroke risk and poor stroke outcomes and that the presence of ROAF would provide compensation for improving stroke outcomes in patients with ischemic stroke and severe unilateral cervical carotid stenosis/occlusion.This retrospective cohort study was carried out within the certificated Neurovascular Ultrasound Laboratory in Tri-Service General Hospital, Taipei, Taiwan. Written consent was given by every subject before the examination. The study was approved by the hospital's Institutional Review Board for Human Studies. Between January 1, 2005 and July 31, 2012, 3 certified sonographers screened 14,701 consecutive subjects for carotid stenosis  or occlusion (100%) of the cervical segment of the ICA. They underwent a detailed neurological examination and provided clinical history based on a structured checklist Head MRI  was performed to differentiate stroke type when clinically indicated. The 128 selected patients underwent cranial MRI with multiple modalities, including fluid-attenuated inversion recovery, diffusion-weighted imaging, and three-dimensional time-of-flight magnetic resonance angiography, to differentiate stroke pattern and type if appropriate. The grade of intracranial vascular stenosis was classified into 2 groups: normal to mild stenosis (\u226450%) or moderate stenosis to occlusion (>50%), as described in previous reports Continuous variables were calculated as mean \u00b1 standard deviation. Categorical variables were expressed as numbers and percentages. Categorical or continuous variables were patient age, gender, vascular risk factors, ROAF, and cervical and intracranial stenosis. Odds ratios (ORs) were used to estimate multivariate relative risks, and 95% confidence intervals (CIs) were evaluated with age-adjusted logistic regression analyses. The multivariate logistic regression with a forward selection model was performed to identify significantly independent contribution factors for acute stroke. Attributable risk difference was calculated between the acute stroke and non-stroke groups for investigating the risk of ROAF in patients with acute stroke and severe intracranial stenosis. Fisher's exact tests for categorical variables and Mantel\u2013Haenszel extension tests for trend analyses were conducted for stroke outcome evaluation to assess the compensation effect of ROAF on intracranial stenosis severity. Statistical analyses were performed with SPSS version 19 . Values were considered statistically significant at p<0.05.Out of 14,701 consecutive subjects, only 128 met the study criteria. Among them, 27 subjects had not experienced strokes and had no evidence of stroke as assessed clinically and with brain MRI, and these subjects were considered as the non-stroke group. The remaining 101 subjects had experienced acute ischemic strokes, including 58 with first-ever onset and 43 with recurrent strokes. There were no statistically significant differences in clinical characteristics after age-adjusted univariate analysis between the 2 subgroups, and they were hence collectively considered as the acute stroke group. Statistical analysis revealed that acute stroke group was younger  than the non-stroke group. The reason may be that the lack of symptoms in the non-stroke group delayed their decision to screen for the risk of carotid stenosis. To further determine acute stroke risk factors in patients with unilateral high-grade cervical carotid stenosis/occlusion, we compared clinical characteristics between the non-stroke and acute stroke groups with age-adjusted univariate logistic analysis. Among the 81 patients with intracranial stenosis , 80 had ipsilateral severe intracranial stenosis/occlusion in the anterior circulation, and 33 patients had other concomitant critical lesions in the contralateral anterior or posterior circulation. However, no difference of ROAF occurrence was observed between patients with ipsilateral severe intracranial stenosis/occlusion in the anterior circulation and those with multiple severe intracranial stenoses at other locations.To evaluate the roles of individual risk factors in predisposition to acute stroke in patients with unilateral high-grade cervical carotid stenosis/occlusion, we performed multivariate analyses with a forward selection model . The comWe employed logistical regression analysis to explore the role of severe intracranial stenosis in ROAF occurrence. To evaluate the relationship between OA flow direction and intracranial stenosis severity in the context of stroke outcomes, 4 acute stroke subgroups were analyzed by Fisher's exact tests for categorical variables and Mantel\u2013Haenszel extension tests for trend analyses. However, regardless of blood flow direction of OA, the patients with intracranial stenosis had worse stroke outcomes than those without. This study demonstrated that intracranial stenosis was the major risk factor for the development of acute stroke in patients with severe unilateral cervical carotid stenosis/occlusion. Patients with acute ischemic stroke and concurrent severe cervical carotid stenosis/occlusion and intracranial stenosis had a higher rate of ROAF and worse stroke outcomes compared to those with extracranial severe carotid stenosis alone. However, ROAF partially compensated for cerebral insufficiency and was associated with improved stroke outcome.Angiographic and pathologic evidence has previously demonstrated racial differences in the distribution of cervicocerebral atherosclerosis In The strengths of this study are that the included patients were strictly selected using CCDU and brain MR angiography data from a large patient pool , and the patients with ischemic stroke all had the large artery atherosclerosis stroke type. However, the novel findings and potential implications of ROAF are limited by the lack of conventional digital subtraction angiography, which is the gold standard for confirming the diagnosis of extra- and intracranial stenosis and for imaging the cerebral collateral vessels. In addition, some medications in patients with ischemic stroke have been linked to better collateral circulation Our study found that patients with acute ischemic stroke and unilateral severe cervical carotid stenosis/occlusion had a significantly higher occurrence of severe intracranial stenosis and ROAF. Regardless of blood flow direction of OA, the patients with severe intracranial stenosis have worse stroke outcomes as compared to those without. ROAF may act as a secondary collateral when brain tissues receive insufficient blood supply from the primary collaterals, thereby providing patients a valuable, but limited, compensation for partial improvement of stroke outcomes. The results of this study revealed an important implication for clinical practice. It suggested that patients with ischemic stroke should undergo advanced brain imagining and cerebral hemodynamic evaluation when they were detected with unilateral severe cervical carotid stenosis/occlusion and ROAF by CCDU. Early identification of the intracranial pathological vascular lesions and hemodynamic compromise are essential for determining optimal therapeutic strategies for improving stroke outcomes."}
+{"text": "Mitochondria is known as powerhouse of cell because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. In addition to supplying cellular energy, mitochondria are involved in a range of other processes, such as signaling, cellular differentiation, cell growth, and cell death. Transcription and replication of mitochondrial DNA (mtDNA) are important steps in mitochondrial biogenesis and mitochondrial transcription factor A (Tfam) is essential for mtDNA transcription and replication. However, the functional significance of mitochondria has not been established in osteoclastic bone resorption.There is accumulating evidence that osteoclasts, the primary cells responsible for bone resorption, are involved in bone and joint destruction in rheumatoid arthritis. Bone resorption is highly regulated by mature osteoclast function as well as osteoclastogenesis. The life span of mature osteoclasts is relatively short both fl/fl mice with cathepsin K-Cre transgenic mice, in which the Cre recombinase gene is knocked into the cathepsin K locus and specifically expressed in mature osteoclasts. The in vivo effects of Tfam deficiency on bone metabolism were examined by histological and histomorphometric analysis. The survival and bone-resorbing activity of Tfam cKO osteoclasts were determined by in vitro survival assay and pit formation assay, respectively.To address this question, we generated osteoclast-specific Tfam conditional knock-out (cKO) mice by mating TfamThe expression level of Tfam, mtDNA copy number, and cellular ATP level were markedly reduced in osteoclasts derived from Tfam cKO mice. The body size of Tfam cKO mice was smaller than that of the control mice, although trabecular bone volume remained unchanged by Tfam deficiency. However, histological sections of proximal tibia and lumbar spine of Tfam cKO mice showed significantly decreased osteoclast number. Interestingly, Tfam cKO osteoclasts exhibited increased bone-resorbing activity in spite of their pro-apoptotic tendency.This study demonstrates that Tfam cKO osteoclasts exhibited increased bone resorption with accelerated apoptosis, indicating that there may be an inverse correlation between osteoclast survival vs bone resorption. Further investigation of mitochondria in bone-resorbing osteoclasts will give us new insights into the molecular mechanism regulating bone homeostasis."}
+{"text": "In this study, we used high-dimensional pattern regression methods based on structural  and functional  brain data to identify cross-sectional imaging biomarkers of cognitive performance in cognitively normal older adults from the Baltimore Longitudinal Study of Aging (BLSA). We focused on specific components of executive and memory domains known to decline with aging, including manipulation, semantic retrieval, long-term memory (LTM), and short-term memory (STM). For each imaging modality, brain regions associated with each cognitive domain were generated by adaptive regional clustering. A relevance vector machine was adopted to model the nonlinear continuous relationship between brain regions and cognitive performance, with cross-validation to select the most informative brain regions (using recursive feature elimination) as imaging biomarkers and optimize model parameters. Predicted cognitive scores using our regression algorithm based on the resulting brain regions correlated well with actual performance. Also, regression models obtained using combined GM, WM, and PET imaging modalities outperformed models based on single modalities. Imaging biomarkers related to memory performance included the orbito-frontal and medial temporal cortical regions with LTM showing stronger correlation with the temporal lobe than STM. Brain regions predicting executive performance included orbito-frontal, and occipito-temporal areas. The PET modality had higher contribution to most cognitive domains except manipulation, which had higher WM contribution from the superior longitudinal fasciculus and the genu of the corpus callosum. These findings based on machine-learning methods demonstrate the importance of combining structural and functional imaging data in understanding complex cognitive mechanisms and also their potential usage as biomarkers that predict cognitive status.  Aging is associated with declines in neurocognitive functions often characterized by degeneration of brain tissue, changes in brain function, and accelerated cognitive decline, particularly in clinical cases such as Alzheimer's disease (AD). However, despite the connection with neural changes, diagnosis of clinical cognitive impairment to date still primarily depends on cognitive changes measured by neuropsychological assessments. Neuroimaging studies have shown that structural and functional brain changes often precede clinical symptoms of cognitive impairment , which ra priori. As such, characterizations of brain changes in normal or clinical aging have had specific and limited scopes within each study and have been relatively unwieldy in the context of the multi-faceted nature of the issue.Finding specific brain regions involved in a cognitive process has been a recurrent goal in functional neuroimaging in the last two decades -5. In thTo overcome the limitations of univariate and ROI-based approaches, machine learning-based pattern analysis methods have been widely adopted to automatically derive distinctive brain regions related to a hypothesis or a given study objective . The maja priori hypotheses  water. The images were obtained on a GE 4096 scanner, during a resting state scan with eyes open [Details of our image acquisition parameters have been described in . Brieflyyes open . After tAll MR images used in this study were pre-processed using a mass-preserving shape transformation method . Gray ma15O] PET-CBF image pre-processing included normalization for global activity, removal of extraneous signal scatter by thresholding the image intensity at 80% of the gray matter mean, and removal of activity in the skull, nasal sinuses, and cerebellum. PET-CBF images were rigidly registered to the corresponding participants\u2019 MR image then deformed to the same template space based on the spatial normalization transformation parameters determined from the MRI. After registration, PET-CBF images were smoothed using a 12mm Gaussian filter. PET-CBF alone, and one using both MRI and PET. To evaluate model performances, we examined the MSEs and correlation coefficients indexing the strength of agreement between the actual cognitive scores and scores predicted by the models. Since MSEs and correlation coefficients are not normally distributed, differences in cognitive score predictions between models were statistically compared using non-parametric random permutation testing [For step 3 of each cognitive domain, a summary map of brain region contributions to cognitive score prediction was obtained by averaging the spatial difference maps from all leave-k-out cases. To facilitate comparison of contribution maps across the optimized models using single or combined imaging modalities, we then normalized the contribution levels to a range from 0 to 1, indexing lowest to highest predictive contributions respectively. The predicted cognitive scores were also based on averaged optimal predicted scores across all leave-k-out cases for each cognitive domain. Overall, we performed three RVR computations for each of the four cognitive domains: one RVR using MRI (white and gray matter structure) alone, one using [ testing , which wThe study was approved by the local Institutional Review Board of the University of Pennsylvania and the National Institute on Aging. Written informed consent was obtained from all participants at each visit. MSEs were used to describe the performance of machine learning-based regression models  top. As For visualization, We additionally evaluated whether the detected imaging biomarkers were more effective predictors of cognitive performance than another important factor related to cognitive decline, age. For comparison, The top panels of As shown in Several brain regions predicting LTM were also involved in STM . SpecifiFor semantic retrieval, predictive brain regions included left occipital-temporal, bilateral inferior frontal, insula, medial and lateral orbitofrontal areas, as well as right superior longitudinal fasciculus and periventricular areas . MaximumFor manipulation, predictive contributions were observed in the right inferior frontal, and insula regions, left precentral and middle frontal regions, bilateral anterior cingulate and temporal areas, as well as the left uncinate fasciculus and genu of the corpus callosum . MaximumTo validate the performance of our multi-modality pattern regression method, we also applied conventional GLM analysis with the same cognitive components. The GLM analyses revealed positive correlations between GM/WM/PET and cognitive performance, as shown in The GLM analysis also showed that manipulation was significantly associated with WM volumes across several regions. Similarly, the majority of brain regions detected by multi-modality pattern regression were from structural MRI, especially WM, which had the highest contribution to manipulation performance . HoweverWe highlight that GLM maps indicate the directions of associations separately between each imaging modality and each cognitive domain. By contrast, the contribution maps obtained from pattern regression shows the combined power of multi-modality imaging with no sign of association. Thus, the combined associations are less restricted and show simultaneous contributions across imaging modalities that could be due to a positive brain-behavior association in one modality but a negative association in another. In addition, direct comparison of the contributions across modalities is not meaningful with the GLM maps but relatively straightforward with the contribution indices used in our pattern regression method.This study applied a multi-modality pattern regression method to investigate the brain imaging biomarkers related to memory and executive functions. Combined regression models for LTM, STM and semantic retrieval had similar prediction power, with regression rates of 0.41, 0.45 and 0.46 respectively . AlthougOur finding that LTM and STM involved middle and medial frontal regions, along with temporal regions and the hippocampus and amygdala (for LTM) is consistent with the existing literature on brain regions involved in episodic memory. Episodic memory tasks generally involve accessing the representations of the test items including contextual information about when and where the items were encountered. Many studies have shown that the hippocampus is an important region that forms and stores such item-context associations , superior longitudinal fasciculus and genu were associated with semantic retrieval and manipulation performance, with the maximum contribution from white-matter images. Other studies have similarly found that these white-matter regions show structural declines with age that are associated with poorer performance in tests of executive function and working memory -57. ThesThis present study focused on modeling the continuous cross-sectional distribution of cognitive performance across individuals instead of individual longitudinal performance changes over time. It is plausible that longitudinal data may capture distinct important regional contributions toward cognitive performance ,58. We nWe investigated the utility of multi-modality high-dimensional pattern regression for detecting imaging-based biomarkers of cognitive ability in a cohort of cognitively normal older adults. Our findings show that this machine learning-based pattern regression method is able to detect specific brain regions associated with different cognitive processes, while simultaneously assessing the contribution of different imaging modalities. Moreover, the combination of PET and MRI was better than each modality alone. Critically, our results suggest that functional imaging provided slightly better predictive ability than structural MRIs for memory functions, but WM modality outperformed PET when predicting executive functions. The predicted cognitive scores using our methodology could be used to identify individuals with risk of future cognitive decline from baseline images, such as in the case of when the predicted score deviate from the normal range. Future studies will evaluate imaging biomarkers of additional aspects of memory and executive function as well as the predictive ability with respect to longitudinal performance."}
+{"text": "Heterotopic transplantation of pluripotent stem cells (PSCs) produces growths known as teratomas (Greek word for monstrous), which consist of a heterogeneous amalgamation of fetal-like tissues. Engraftment of even a few undifferentiated cells is potentially sufficient for teratoma formation. Such an event would have far reaching consequences for the future of this field. Current differentiation protocols produce cultures with unknown degrees of purity and are therefore potentially hazardous. We provide here a succinct overview of current methods and outline challenges for the removal of residual teratoma-initiating cells.OCT4 promoter controls HSV1 thymidine kinase expression, allowing for selective ablation of undifferentiated PSCs upon treatment with of Ganciclovir [Retrospective and prospective approaches for teratoma depletion have been the subject of significant investigation. Retrospective removal includes standard oncologic treatments of formed tumors via radiation, chemotherapy, and surgery . To avoiciclovir . UnfortuProspective depletion of teratoma-initiating cells is advantageous to retrospective removal as such methods prevent initial tumor formation. Two main strategies of prospective removal include treatment with agents specifically cytotoxic to undifferentiated cells and mechanical separation. The first was extensively developed by the lab of Dr. Andre Choo, who produced the cytotoxic antibody mAb 84 which targets PODXL, a protein abundantly expressed by PSCs .Non-cytotoxic cell separation has emerged as a central approach for depletion of teratoma-initiating cells. This method relies on tagging undifferentiated cells either by inducing reporter gene expression or through reversible labeling of surface antigens. Labeled cells are then removed through fluorescence- or magnetic-activated cell sorting (FACS or MACS). Although tagging PSC-specific surface antigens is considered safer than introducing gene reporters , this goA major advantage to utilizing surface markers for prospective separation is that this method relies on the intrinsic properties of the cells and therefore can be applied to all PSC lines and differentiation conditions. A typical protocol may entail removing cells expressing a tailored combination of surface markers such as SSEA-5 and/or CD9 and/or CD90 . Such a In summary, we propose that prospective removal is superior to retrospective approaches since the latter may result in anatomical damage and also risks malignant and/or metastastic transformation. As such, retrospective removal should always be considered a backup rather than first line. We also believe that clinical utilization of PSC derivatives should rely on combination of prospective approaches to provide the highest level of safety. One example is to utilize PSC-specific antibodies for cell separation followed by a subsequent cytotoxic antibody incubation step . Ultimat"}
+{"text": "Dear editor,Aortocaval Fistula (ACF) is a rare condition of an Abdominal Aorta Aneurysm (AAA). ACF caused by perforation of atherosclerotic infrarenal aortic aneurysm into the adjacent IVC, iliac vein, or left renal vein. Its inciA 63-year-old man presented to Emergency Department with sudden left flank pain.Abdominal physical examination revealed palpable mass, tenderness and self-guarding in left flank area without rebound tenderness. All peripheral pulses were present.Sonography of abdomen displayed infrarenal AAA with 63mm diameter. CT-images demonstrated infrarenal aortic aneurysm with fistula to IVC arising from aneurysm lumen that penetrated to retroaortic renal vein situated beneath the aneurysm .At laparotomy No hematoma or active bleeding existed in peritoneal space. Followed by controlling blood flow of aneurysm neck, distal common iliac arteries were clamped. Therefore, renal veins became noticeable posterior the aorta. IVC was dilated excessively 4 cm and trill was palpable on aneurysmal site. Further investigations revealed that exact site of fistula at the entrance of left renal vein to IVC.IVC was repaired and renal vein was ligated and aneurysm repaired using 20 tubular Dacron graft. There are several causes for ACF including spontaneous rupture of atherosclerotic aneurysm directly into adjacent IVC, penetratEarly diagnosis of ACF prior to surgery is vital and also difficult due to rarity of complication and non-specificity of the signs and symptoms. Standard signs of ACF as a result of aneurysmal disease, include acute abdominal pain, hypotension, and pulsatile abdominal mass. However Specific treatment for ACF is operative transaortic closure of fistula and placement of prosthetic graft or endovascular repair of fistula."}
+{"text": "Dear Editor,We enjoyed reading the excellent article by Yilmaz and colleagues on noninvasive assessment of liver fibrosis using aspartate transaminase to platelet ratio index (APRI) in adult patients with chronic liver disease (CLD) . They peA drawback for using APRI is that its performance is not reliable in women, younger patients and in those with non-vertically-transmitted hepatitis C virus infection . Alterna"}
+{"text": "With the recognition of early trauma coagulopathy, trauma resuscitation has recently shifted towards early and aggressive transfusion of platelets (PLTs). However, the clinical benefits of this strategy remain controversial. This systematic review examined the impact of an aggressive approach (higher PLT:RBC ratios) compared to restrictive PLT transfusions (lower PLT:RBC ratios) in the acute phase of trauma resuscitation.We systematically searched Medline, Embase, Web of Science, Biosis, Cochrane Central and Scopus to identify relevant randomized controlled trials (RCTs) and observational studies comparing the effect of two or more different PLT:RBC ratios in trauma resuscitation. We excluded studies using whole blood or systematically addressing the use of hemostatic products. Two independent reviewers selected the studies, extracted data using a standardized form, and assessed the risk of bias using the Newcastle-Ottawa scale and a checklist of key methodological elements . Disagreements were solved by consensus or a third party. The primary outcome was mortality. Secondary outcomes were multiple organ failure (MOF), lung injury and sepsis. A meta-analysis using random effects models was planned.n = 4,230 patients). No RCT was identified. All studies were considered to be at low risk of bias and addressed confoundings through multivariate regression or propensity scores. Four studies  reported a decrease in mortality with higher PLT:RBC ratios in patients requiring massive transfusion and one study observed no mortality difference  in nonmassively transfused patients. Two studies reported on the implementation of a massive transfusion protocol with higher PLT:RBC ratios; only one revealed a survival benefit (n = 211). Of the three studies accounting for survival bias, two demonstrated a survival benefit . Among two studies reporting on the secondary outcomes (n = 854), one observed an increase in MOF with higher PLT:RBC ratios. Clinical heterogeneity between studies and methodological limitations precluded the use of a meta-analysis.From 6,123 citations, seven observational studies were included (There is insufficient evidence to strongly support the use of a specific PLT:RBC ratio for acute trauma resuscitation, especially considering survival bias and nonmassively transfused patients. RCTs examining both safety and efficacy of liberal PLT transfusions are warranted."}
+{"text": "To describe a consensus-based case review development process that applies eligibility and diagnostic criteria for diverse clinical trials of chiropractic care for chronic pain conditions.A multidisciplinary team of investigators and clinical research staff provide iterative feedback to develop case review processes for application across complex clinical trials involving biomechanical testing and/or spinal manipulation. Investigative team members design eligibility criteria and operational definitions consistent with the specific aims of the trial. These parameters are codified in study protocols and programmed into secure, web-based data collection systems that record eligibility decisions. The clinical team develops study-specific procedures, documentation templates, and flow-charts for conducting meetings. Research records are uploaded onto a web server for panel members to view during the meeting.Our case review panel consists of research clinicians, project managers, study coordinators and the senior clinician who convene twice weekly to discuss participants who remain eligible following completion of baseline visits. The research clinician who performed the eligibility examination begins case review with an oral presentation of the case and leads the case review panel through a discussion of safety and compliance issues, eligibility concerns, diagnosis determination, and clinical precautions. Panel members provide clinical recommendations and determine final eligibility status by consensus vote. The senior clinician determines eligibility only in cases where consensus (80%) is not reached. Through this process, our research clinic presented 534 cases, excluded 174 participants, and allocated 291 into two phase II clinical trials and six feasibility studies over a three year period.Our case review process utilizes the combined scientific and clinical experience of panel members for consistent eligibility determination, thereby reducing selection bias and ensuring that participants are appropriate candidates for study procedures. The consensus building process creates a collegial environment that enhances clinical trial management and fosters rigorous clinical research."}
+{"text": "Avian malaria is an important cause of the decline of endemic Hawaiian honeycreepers. Because of the complexity of this disease system we used a computer model of avian malaria in forest birds to evaluate how two proposed conservation strategies: 1) reduction of habitat for mosquito larvae and 2) establishment of a low-elevation, malaria-tolerant honeycreeper (Hawaii Amakihi) to mid-elevation forests would affect native Hawaiian honeycreeper populations. We evaluated these approaches in mid-elevation forests, where malaria transmission is seasonal and control strategies are more likely to work. Our model suggests the potential benefit of larval habitat reduction depends on the level of malaria transmission, abundance of larval cavities, and the ability to substantially reduce these cavities. Permanent reduction in larval habitat of >80% may be needed to control abundance of infectious mosquitoes and benefit bird populations. Establishment of malaria-tolerant Amakihi in mid-elevation forests increases Amakihi abundance, creates a larger disease reservoir, and increases the abundance of infectious mosquitoes which may negatively impact other honeycreepers. For mid-elevation sites where bird populations are severely affected by avian malaria, malaria-tolerant Amakihi had little impact on other honeycreepers. Both management strategies may benefit native Hawaiian honeycreepers, but benefits depend on specific forest characteristics, the amount of reduction in larval habitat that can be achieved, and how malaria transmission is affected by temperature. Plasmodium relictum) and its vector, the Southern House Mosquito (Culex quinquefasciatus), are considered primary contributors to population declines of native Hawaiian forest birds More than one-third of all U.S. listed bird species occur in Hawaii, and 71 Hawaiian birds have gone extinct since humans colonized the islands Temporal and spatial dynamics of malaria in Hawaii are driven by seasonal, annual, and elevational weather patterns To reduce future population impacts and potential species extinctions, conservation strategies that reduce the impact of avian malaria on Hawaiian honeycreepers are essential. However, conservation strategies to preserve future populations of Hawaiian birds can be controversial if focused strictly on habitat improvement Sus scrofa) feed on native tree ferns (Cibotium glacum) creating cavities that fill with rainwater. These cavities are an important and ideal habitat for mosquito larvae, especially in mid-elevation forests Common methods for reducing mosquito abundance include reduction of larval habitat, insecticides that increase larval or adult mortality rates, and the introduction of predators on mosquitoes Hemignathus virens) found in low-elevation forests may have developed malaria-tolerance compared to conspecific birds at mid- and high- elevations Although most of the native Hawaiian forest birds are highly susceptible to avian malaria Ecological models can provide an indispensable tool for exploring the consequences of alternative management strategies All necessary access and collection permits for this study were obtained from the State of Hawaii, Department of Land and Natural Resources and Hawaii Volcanoes National Park.2 study sites with mosquito larval habitat  larval mosquito habitat and associated larval mosquitoes  were in Himatione sanguinea sanguinea), and Iiwi (Vestiaria coccinea). The model also includes the Japanese White-eye (Zosterops japonicus) to represent introduced species, which typically have lower prevalence and intensity of infection with malaria Our simulation model Mosquitoes and all bird species are divided into immature and adult stages. Adult mosquitoes are subdivided into susceptible, latent, and infectious disease stages. Native juvenile (susceptible when hatched) and adult birds are subdivided into susceptible, acutely infected, and recovered stages. Acutely infected birds have a high parasitemia Mosquito dynamics are driven by rainfall and temperature 2, and no mosquito larvae. Simulations were then conducted for a 24 year period (1980\u20132003) using historical weather conditions (see above). Mosquito dynamics typically became stable within a few years regardless of the initial densities or elevation We modeled the potential impact of reducing larval habitat for two study sites where pig-created cavities provide an important habitat for mosquitoes (Cooper and Waiakea). We modeled the potential impact of Amakihi establishment at all four study sites. Initial conditions for our simulations used predicted bird densities in the absence of malaria To assess the potential effects of different weather patterns caused by variation in elevation and topography across the Hawaiian landscape, we modeled both conservation strategies under five climate scenarios derived from our baseline climate (1980\u20132003) data at study site Cooper . Three dIn mid-elevation forests with feral pigs, our model predicts that density of adult and infectious mosquitoes change in proportion to the carrying capacity for larval mosquitoes and in response to climate . For bas2. Once this threshold was reached, further reductions produced dramatic increases in honeycreeper populations. These simulated population increases were accompanied by large increases in the percentage of susceptible and large decreases in the percentage of chronically-infected individuals  is an important driver of mosquito dynamics, but density of infectious mosquitoes is the primary driver of malaria transmission to susceptible Hawaiian birds.Weather patterns interact with the larval habitat reduction needed to enhance bird populations . Effecti2 after establishment of malaria-tolerant Amakihi. Presence of malaria-tolerant Amakihi in mid-elevation forests increased the predicted density of Amakihi by >900 birds/km2 at Cooper and Waiakea, while Apapane and Iiwi were not additionally affected  in mid-elevation forests, but the density of infectious mosquitoes increased by 25% at Cooper, 26% at Waiakea, and 303% at Crater. At Pu'u, the density of infectious mosquitoes was <1/kmaffected  because affected . At Pu'uaffected . The pre2 threshold, indicating that less tolerant Amakihi populations at these sites were limited by malaria. In these simulations the proportion of chronically-infected Amakihi exceeded 85\u201389%, indicating high rates of disease transmission.Predicted changes in malaria-tolerant Amakihi depended on the density of infectious mosquitoes . ClimatePredicted Apapane and Iiwi population responses to malaria-tolerant Amakihi depended on the density of infectious mosquitoes. Apapane and Iiwi densities were generally unaffected in forests where malaria transmission was either very low (Pu'u) or high (Waiakea and Cooper). At high transmission sites, malaria infection had already reached a high level so further increasing the reservoir of chronically-infected birds had little effect. At low transmission sites, predicted Amakihi density was not affected because there was little malaria impact and bird communities in these forests were unaffected. Apapane and Iiwi populations declined in forests where the density of infectious mosquitoes was below the threshold needed to enhance native bird populations . In these forests small increases in density of infectious mosquitoes increased rates of disease transmission which benefited malaria-tolerant Amakihi, but were detrimental to susceptible Apapane and Iiwi.Avian malaria has a significant population impact on susceptible Hawaiian honeycreepers and disease transmission by mosquito vectors is likely a primary factor contributing to the decline and restricted distribution of native Hawaiian forest birds 2) before mosquito control benefits mid-elevation honeycreepers. For infectious mosquito densities above this threshold, most surviving birds are predicted to be chronically-infected with malaria, and therefore a disease reservoir for susceptible birds. Although both rainfall and temperature affect the relationship between larval habitat and malaria transmission, model results indicate that the density of infectious mosquitoes was the key factor influencing transmission and bird abundance . Above this threshold, an increase in the density of infectious mosquitoes from malaria-tolerant Amakihi does not significantly increase the impact of avian malaria on bird populations (Our model indicates malaria-tolerant Amakihi could increase the abundance of infectious mosquitoes in some mid-elevation forests and therefore decrease densities of more susceptible honeycreepers. The negative impact of malaria-tolerant Amakihi on other honeycreepers should be highest at sites where density of infectious mosquitoes is below a predicted threshold of 300/kmulations . OverallWhether translocation of Amakihi would succeed depends on many factors In Hawaii, malaria infection patterns are driven by the effects of temperature and rainfall on mosquito dynamics across an elevational gradient, seasonal weather patterns, and availability of larval habitat Even low densities of infectious mosquitoes appear sufficient to produce high rates of malaria infection in native Hawaiian birds. In part, these high rates of malaria transmission likely result from favorable climatic conditions, abundant larval mosquito habitat, and efficient transmission of the malaria parasite between mosquito vectors and avian hosts. Native birds that survive malaria infection acquire immunity, but also become an effective reservoir for malaria transmission to mosquitoes and then to susceptible Hawaiian birds. Reducing the amount of larval habitat for mosquitoes by feral pig management or other alternatives provides one potential strategy to help control malaria impacts and would likely be most beneficial in mid-elevation forests. Establishment of malaria-tolerant Amakihi to mid-elevation forests benefits Amakihi populations, but could negatively impact other honeycreepers depending on the larval habitat and malaria transmission. Our evaluation uses an ecological model that provides a simplified representation of the Hawaiian forest bird malaria system which appears to provide realistic, but somewhat uncertain predictions of mosquito, bird, and malaria patterns in Hawaii"}
+{"text": "The eyedrop form of rebamipide was approved in Japan for use in the treatment of dry eye diseases, because it up-regulates mucin secretion and production. Others reported that rebamipide, a gastroprotective drug, could not only increase gastric mucus production but also suppressed gastric mucosal inflammation and that it was dominantly distributed in mucosal tissues. In this study we investigated whether rebamipide has anti- inflammatory effects in the ocular surface.We used ELISA and quantitative RT-PCR assay to examine the effects of rebamipide on polyI:C-induced cytokine expression by primary human conjunctival epithelial cells. We studied the effects of rebamipide on ocular surface inflammation in our murine experimental allergic conjunctivitis (EAC) model. Moreover, we also observed their condition of allergic conjunctivitis when we treated the dry eye patients accompanied with allergic conjunctivitis using rebamipide.Rebamipide could suppress polyI:C-induced cytokine mRNA expression and the production of CXCL10, CXCL11, RANTES, MCP-1, and IL-6 in human conjunctival epithelial cells. The topical administration of rebamipide suppressed conjunctival allergic eosinophil infiltration in our EAC model. Furthermore, the allergic conjunctivitis which accompanied by dry eye patients treated with rebamipide tended to be better.The topical application of rebamipide on the ocular surface might suppress ocular surface inflammation by suppressing the production of cytokines by ocular surface epithelial cells."}
+{"text": "Long-lasting insecticidal nets (LLINs) and indoor residual sprays (IRS) have decimated malaria transmission by killing indoor-feeding mosquitoes. However, complete elimination of malaria transmission with these proven methods is confounded by vectors that evade pesticide contact by feeding outdoors.For any assumed level of indoor coverage and personal protective efficacy with insecticidal products, process-explicit malaria transmission models suggest that insecticides that repel mosquitoes will achieve less impact upon transmission than those that kill them outright. Here such models are extended to explore how outdoor use of products containing either contact toxins or spatial repellents might augment or attenuate impact of high indoor coverage of LLINs relying primarily upon contact toxicity.LLIN impact could be dramatically enhanced by high coverage with spatial repellents conferring near-complete personal protection, but only if combined indoor use of both measures can be avoided where vectors persist that prefer feeding indoors upon humans. While very high levels of coverage and efficacy will be required for spatial repellents to substantially augment the impact of LLINs or IRS, these ambitious targets may well be at least as practically achievable as the lower requirements for equivalent impact using contact insecticides.Vapour-phase repellents may be more acceptable, practical and effective than contact insecticides for preventing outdoor malaria transmission because they need not be applied to skin or clothing and may protect multiple occupants of spaces outside of treatable structures such as nets or houses. Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) have dramatically reduced malaria transmission by indoor-feeding (endophagic) mosquito populations in recent years -4. HowevWhile mosquitocidal vaccines  and drugHowever, it is crucial to clearly distinguish between alternative modes of action of vector control products and assess their potential comparative value for preventing malaria. Pesticide products either deter insects away from protected houses, sleeping spaces and humans, or they kill those that make physical contact with them . While rh,\u03a9) compared with that predicted under baseline conditions  where neither measure was in place:Existing models of the interaction between contrasting deterrent and toxic properties ,18 assumh,0,\u03a9) or as a community-wide average, reflecting the coverage-weighted mean of such non-users and users of one or both measures  [This term was calculated for unprotected individuals lacking either of these measures  . For simAnopheles gambiae, which rarely uses cattle as alternative non-human hosts, and zoophagic Anopheles arabiensis, which does where they are available. These relative exposure outcomes (\u03c8) were predicted as a function of the mean proportion of malaria transmission exposure of a non-user of any measure which occurs indoors (\u03c0i) [\u0394) or pre-feed mortality  of mosquitoes attacking users of the product [In all cases, coverage levels of 80% were assumed for both the indoor and outdoor protection measures, consistent with current global targets for LLINs and IRS , and twoors (\u03c0i) ,25,26 an product . By comp product . TherefoLLINs depend upon high proportions of human exposure occurring indoors to achieve maximum impact upon malaria transmission Figure . Note thi), spatial repellents applied outdoors consistently supplement the impact of indoor toxins  because mosquitoes diverted from outdoor repellent users may subsequently attack those protected indoors by lethal LLINs  and vectors rarely feed upon non-human blood sources , Syngenta (SJM), Pinnacle Development (SJM) and SC Johnson (SJM).Both authors formulated the research questions and developed the conceptual basis of the model. GFK drafted the model formulation and manuscript, which was then critiqued and edited by SJM. All authors have read and approved the final version of the manuscript.Figure S1. Purely community-level impact of products for outdoor malaria prevention expressed in terms of the mean relative risk of exposure experienced by non-users of any protective measure.Click here for fileFigure S2. Additional incremental community-level impact of outdoor contact toxins or repellents that are exclusively used outdoors or used both indoors and outdoors when combined with indoor LLINs with contact toxins, compared with their direct impact as stand-alone intervention strategies.Click here for fileFigure S3. Progressive community-level impact upon a completely outdoor transmission system of products with increasing efficacy of personal protection achieved by either repelling or killing attacking mosquitoes before they feed upon human users.Click here for fileSupplemental methods S4. Detailed model description.Click here for file"}
+{"text": "To identify whether axillary US is less accurate in invasive lobular breast cancer than in ductal breast cancer.Randomised cohorts of screening and symptomatic patients were retrospectively identified from histology records of 2010/11. Axillary US of 65 patients with primary breast cancers (BC) from each group of invasive lobular cancer (ILC) and invasive ductal cancer (IDC) were reviewed. Preoperative US-guided needle biopsy sampling was performed on abnormal lymph nodes (LN).See Tables The previous literature on this topic is inconclusive. Some authors have suggested axillary ultrasound in ILC may be less accurate than in IDC, with a higher false-negative axillary assessment rate. Another study concluded that axillary US accuracy rates in ILC were comparable with previous published studies of IDC, used FNA in all cases. We specifically compared accuracy rates of preoperative axillary staging between ILC and IDC in own institution, with 14G needle biopsy as the procedure of choice to sample abnormal nodes. We found that there is no statistical difference in accuracy in US axillary staging between ILC and IDC."}
+{"text": "P301S) mice develop tau filamentous inclusions and axonopathy in retinal ganglion neurons (RGCs), in the absence of neuronal loss or alterations in the outer retina. Moreover, we showed that tauP301S transgenic retinal explants do not respond to neurotrophic stimuli in vitro. Here, we investigated the impact of tau pathology on RGC physiology in living animals and neurotrophin signaling pathways in vivo. In anesthetized 5-month old wild type (WT) and tauP301S mice, we measured RGCs activity using pattern electroretinogram (pERG), which selectively detects RGC response upon pattern light stimuli exposure. In transgenic tauP301S mice the amplitude of both P1 positive and N2 negative components of pERG at saturating contrast and spatial frequency was significantly smaller than WT values. Furthermore, retinal acuity was significantly reduced in tauP301S mice. Using uniform flickers of light (flash ERG), we measured the activity of the outer retina and found that outer retina response was preserved in tauP301S mice. Neurotrophins, and especially brain-derived neurotrophic factor (BDNF), are important modulators of neuronal survival and function in the brain and in the visual system. We therefore investigated the BDNF signaling pathway and found that BDNF signalling was altered in tauP301S transgenic retinas. Our results indicate that, in the tauP301S mouse, tau pathology specifically impairs the activity of RGCs, without affecting the outer retina function and is associated with BDNF signalling alterations. Given the role of BDNF in synaptic plasticity, these data suggest that mild levels of tau pathology are sufficient to trigger significant neuronal dysfunction possibly through alteration of neurotrophic signalling. Funded by a grant of Compagnia di San Paolo awarded to LG.Intracellular inclusions made of microtubule-associated tau protein are a defining pathological hallmark of tauopathies, which include Alzheimer disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17. Altered levels of tau protein have been detected in the retina and optic nerve of patients with glaucoma, suggesting that retina degeneration and tauopathies share similar pathogenic mechanisms. We have recently demonstrated that P301S mutant human tau (tau"}
+{"text": "The insect olfactory system is capable of classifying odorants by encoding and processing the neural representations of chemical stimuli. Odors are transformed into a neuronal representation by a number of receptor classes, each of which encodes a certain combination of chemical features. Those representations resemble a multivariate representation of the stimulus space . The inschannel correlation). In previous work, we demonstrated how lateral inhibition in an olfaction-inspired network reduced channel correlation [Olfactory receptors typically have broad receptive fields, and the odor spectra of individual receptor classes overlap. From the viewpoint of multivariate data processing, overlapping receptive fields cause correlation between input variables  ,5. After"}
+{"text": "Intrinsic foot muscle weakness has been implicated in a range of foot deformities and disorders. However, to establish a relationship between intrinsic muscle weakness and foot pathology, an objective measure of intrinsic muscle strength is needed. The aim of this review was to provide an overview of the anatomy and role of intrinsic foot muscles, implications of intrinsic weakness and evaluate the different methods used to measure intrinsic foot muscle strength.Literature was sourced from database searches of MEDLINE, PubMed, SCOPUS, Cochrane Library, PEDro and CINAHL up to June 2012.There is no widely accepted method of measuring intrinsic foot muscle strength. Methods to estimate toe flexor muscle strength include the paper grip test, plantar pressure, toe dynamometry, and the intrinsic positive test. Hand-held dynamometry has excellent interrater and intrarater reliability and limits toe curling, which is an action hypothesised to activate extrinsic toe flexor muscles. However, it is unclear whether any method can actually isolate intrinsic muscle strength. Also most methods measure only toe flexor strength and other actions such as toe extension and abduction have not been adequately assessed. Indirect methods to investigate intrinsic muscle structure and performance include CT, ultrasonography, MRI, EMG, and muscle biopsy. Indirect methods often discriminate between intrinsic and extrinsic muscles, but lack the ability to measure muscle force.There are many challenges to accurately measure intrinsic muscle strength in isolation. Most studies have measured toe flexor strength as a surrogate measure of intrinsic muscle strength. Hand-held dynamometry appears to be a promising method of estimating intrinsic muscle strength. However, the contribution of extrinsic muscles cannot be excluded from toe flexor strength measurement. Future research should clarify the relative contribution of intrinsic and extrinsic muscles during intrinsic foot muscle strength testing. Intrinsic foot muscles contribute to the support of the medial longitudinal arch,2 and arThe electronic databases MEDLINE, PubMed, SCOPUS, Cochrane Library and CINAHL were searched between 21 May and 21 June 2012 to locate scientific articles on intrinsic foot muscles and muscle strength measurement. The main search terms and number of articles retrieved are listed in Table\u2009Fifty three research articles were identified that related to intrinsic foot muscles and strength measurement. Articles had to meet certain criteria for inclusion. The inclusion criteria were as follows.(i) Research related to the role of intrinsic foot muscles(ii) Research related to the anatomy of intrinsic foot muscles(iii) Research describing the measurement of intrinsic muscles and toe muscle strength or weakness. Papers relating to the intrinsic foot muscle strength were considered initially, but it became apparent that few papers existed. Therefore the search was broadened to include articles relating to the measurement of toe muscles(iv) Publication in peer-reviewed journals(v) Full-text English language articlesplantar aponeurosis and includes the abductor hallucis, flexor digitorum brevis, and the abductor digiti minimi[quadratus plantae and the lumbricals. The third layer consists of adductor hallucis transverse, adductor hallucis oblique, flexor hallucis brevis and flexor digiti minimi brevis. The deepest layer consists of the three plantar interossei. All the plantar intrinsic muscles are innervated by the medial and lateral plantar branches of the tibial nerve[The plantar and dorsal intrinsic muscles of the foot have both their origin and insertion within the foot,27. Intrti minimi. The secextensor hallucis brevis and extensor digitorum brevis. The deep layer consists of the dorsal interossei muscles. The extensor hallucis brevis and extensor digitorum brevis is innervated by the deep fibular nerve while the dorsal interossei are innervated by the lateral plantar nerve with the first and second dorsal interossei also receiving part of their innervation from the deep fibular nerve[extensor hallucis brevis and extensor digitorum brevis during walking varied significantly between participants, with some participants demonstrating no activation of extensor digitorum brevis during gait[. The extensor hallucis brevis and extensor digitorum brevis muscles are now widely used in tissue grafts, such as the island flap to cover soft tissue defects in the distal leg and ankle regions[The dorsal intrinsic muscles of the foot can be divided into two layers. The mosar nerve. The dorar nerve. Early Eing gait. The ext regions. Therefoquadratus plantae disproves this hypothesis. The medial and lateral attachment sites of the quadratus plantae muscle into the calcaneus is unique to humans[quadratus plantae is unique to the foot as there is no analogous muscle in the hand[. Since the flexor digitorum longus tendon enters the foot from the medial side and pulls the toes medially[quadratus plantae allows the toes to flex in the sagittal plane by redirecting the pull of the flexor digitorum longus. This is a necessary development for bipedal ambulation[It has been hypothesised that during human evolution, toe flexor force and function are gradually diminishing and therefore plantar intrinsic muscles are becoming largely redundant in the foot. In simio humans and quadthe hand. Since tmedially, one thebulation. Therefoabductor digiti minimi, abductor hallucis, flexor digitorum brevis, dorsal interossei and lumbrical muscles were all active during the stance phase of gait and continued until toe off[flexor hallucis brevis  and flexor digitorum brevis muscles are able to exert forces approximately 36% and 13% of body weight during the propulsive phase of walking[et al.[A number of studies reveal that intrinsic foot muscles are active as a group during walking,4,36. A  walking. However walking or have  walking. Mann ang[et al. and Goldg[et al. postulatg[et al.,40. Therabductor hallucis, flexor digitorum brevis and the quadratus plantae muscles during relaxed standing with a significant increase in activity with increased postural demands[et al.[The role of intrinsic muscles in the support of the medial longitudinal arch has been investigated in both standing-5 and wa demands. Reeser s[et al. suggestes[et al.. The lacs[et al.. TherefoThe next section will review the influence of intrinsic muscle weakness in the development of pes cavus in Charcot-Marie-Tooth disease, lesser toe deformities, hallux valgus and heel pain.Charcot-Marie-Tooth disease (CMT) is a peripheral neuropathy, where anatomically distal muscles including the intrinsic muscles are preferentially affected. WeaknesMuscle imbalances between the intrinsic and extrinsic foot muscles have been proposed as the possible cause for lesser toe deformity,11,46. Cextensor digitorum longus and brevis are balanced by the flexors forces produced by long and short toe flexors[et al.[et al.[In an unaffected foot, the strong extension forces at the MTP joint by the  flexors. However flexors. The fins[et al. support s[et al.,46, rupts[et al.. These as[et al. in partil.[et al. reportedbunion, describes a foot deformity characterised by lateral deviation of the great toe at the MTP joint away from the midline of the body[abductor hallucis compared to the adductor hallucis transverse and adductor hallucis oblique[abductor hallucis muscle in patients with symptomatic hallux valgus deformity[Hallux valgus, or the body. One pros oblique,13. Whens oblique. This thet al.[The role of the intrinsic muscle weakness in the development of plantar heel pain, or plantar fasciitis, is unclear. One theory proposed by Allen and Gross describeet al. of partiet al.. The atret al.. Hence, The next section will review the \u2018direct\u2019 and \u2018indirect\u2019 methods of measuring intrinsic muscle strength. The subheading \u2018direct methods of assessing intrinsic/extrinsic muscle strength\u2019 reviews the methods that can directly measure a unit of force or power. However, these \u2018direct\u2019 methods actually measure toe flexion strength which is a combination of intrinsic and extrinsic muscle strength. The subheading \u2018indirect methods of assessing intrinsic muscle strength\u2019 reviews methods that are unable to directly measure force but provide information regarding intrinsic muscle structure and activity.The direct methods reported in the literature include a variety of clinical tests,19,49,50Toe dynamometry is an objective tool used to measure toe flexor strength. Different methods of using toe dynamometry have been reported including hand-held dynamometry, fixed dThe different types of toe dynamometers allow testing of different actions of the toes. The procedure used to measure toe flexor strength with hand-held dynamometry involves the dynamometer being positioned beneath the interphalangeal joint of the hallux to measure either greater toe strength or interphalangeal joints two to five, for lesser toe strength. As suchinterossei and lumbrical muscles, Garth and Miller[interossei and lumbrical muscles can be electrically stimulated to produce flexion at the MTP joint and extension at the interphalangeal joint[interossei and lumbrical in the hand and foot, flexion at the MTP joint and extension interphalangeal joint are likely actions of intrinsic foot muscles. Therefore, hand-held dynamometry might activate intrinsic muscles more effectively than other types of toe dynamometry because it promotes flexion at the MTP joint and extension at the interphalangeal joint.The different types of toe dynamometry may activate intrinsic muscles to varying degrees because each model promotes different actions of the toes. Cuff-based fixed dynamometry, the modified hand grip tester and fixed dynamometry all allow flexion at the MTP joint, but do not provide a way to limit excessive flexion at the interphalangeal joints. A toe curling action can occur during toe flexor testing, an action which is hypothesised to activate the long (extrinsic) toe flexors. Based od Miller postulatd Miller. Studiesal joint. Based oAnother important consideration when measuring intrinsic muscle strength is the position of the ankle. Spink and co-workers hypothesThe Paper Grip Test involves the participant attempting to hold a standard piece of paper, like a business card, underneath the hallux or lesser toes while the examiner attempts to pull the card away,15. The et al.[There are a limited number of validation studies of the Paper Grip test as a measure of intrinsic muscle strength. De Win et al. conducteet al.. Furtheret al.. TherefoPlantar pressure sensors can assess the force beneath the toes. Plantar pressure measurement is generally available in two different forms: (1) in-shoe systems such as Novel Pedar\u00ae, TekScan F-Scan\u00ae, RS-Scan Insole\u00ae, IVB Biofoot \u00ae and; (2)The validity of using plantar pressures to determine intrinsic muscle strength is questionable because the contribution of the extrinsic muscles during the pressure measurement is unknown. Electromyography performed during Paper Grip Test has revealed that some extrinsic toe flexor muscles, particularly the long toe flexors muscles and ankle plantar flexor muscles were active. TherefoThe Intrinsic Positive Test is a qualitative test designed to assess intrinsic muscle function of the lesser toes. The tesThe indirect methods that will be reviewed are: Magnetic resonance imaging (MRI); computerised tomography (CT); ultrasonography; electromyography (EMG) and muscle biopsy. Indirect methods are generally used to estimate muscle structure -24,55-57Magnetic resonance imaging (MRI) is the method of choice for detecting soft tissue structure and abnormalities,59. It het al.[MRI has been used in three main ways to assess intrinsic muscle atrophy: (1) qualitative observation of muscle atrophy,7; (2) fet al. has alsoThe significant limitation of qualitative observations of muscle atrophy and using the five point scale to assess intrinsic muscle atrophy is that conclusions are based on a selected image, which may not be representative of the entire muscle. The MR images of intrinsic foot muscles can be taken in the coronal,7, transThe total volume of intrinsic foot muscles can be calculated by multiplying the total cross sectional area of the muscle, determined from MRI, by the distance between the sections, which is the gap between each MRI slice,57,60. Tet al.[MRI can also be used to estimate physiological cross-sectional area (PCSA) of intrinsic muscles. PCSA haet al. has showet al. and suggAn important advance in MRI is the fast-cine phase contrast (or dynamic MRI), which allows images to be acquired while the participant performs an action. Dynamicet al.[et al.[Computerised tomography (CT) is an imaging technique that uses ionising radiation to generate three dimensional images of musculoskeletal structures. CT scanet al. and Muell.[et al. performel.[et al.. Furtherl.[et al..dorsal interosseus muscle, adductor hallucis muscle, and the first lumbrical muscle[abductor hallucis[abductor digiti minimi[flexor hallucis brevis[quadratus plantae[extensor digitorum brevis[et al.[abductor hallucis muscles.Ultrasonography is a technique that uses mechanically produced longitudinal sound waves to create an image. Ultrasol muscle. More re hallucis,61,69, aum brevis. StudiesUltrasonography has two main limitations; low spatial resolution of the image, and theet al.[Electromyography (EMG) has been assessed by non-invasive surface electrodes and invasive intramuscular electrodes. Surfaceet al. recordedet al.. Therefoabductor hallucis, flexor digitorum brevis, dorsal interossei and quadratus plantae during standing task with increasing postural difficulty. The study revealed increased EMG signal amplitude in all muscles with increasing postural demands of the task, as assessed by deviation of the centre of pressure[Intramuscular EMG involves needle electrodes placed directly in the muscle. Most intramuscular EMG studies of intrinsic foot muscles insert needle electrodes into individual muscle bellies-5,28. Hopressure. The limpressure. Therefoet al.[abductor hallucis muscles in participants with symptomatic hallux valgus and reported histological abnormalities including muscle fibres atrophy, lipid laden fibres and ultrastructural changes in the mitochondria. However, the limitation of muscle biopsies is that findings may not be representative of the whole muscle belly[Muscle biopsy can be used to detect changes in muscle histology and ultrastructure. Biopsy et al. performele belly. TherefoThere is no gold standard method to measure intrinsic muscle strength in the foot. At present methods of measuring intrinsic muscle strength can be categorised as direct and indirect methods. Direct methods are able to quantify,15-19,50However, hand-held dynamometry has some barriers to accurately measure intrinsic muscle strength. First, it is currently unknown which intrinsic muscles are active during the hand-held dynamometry test. Second, it is unclear what action should be performed by the toes to best activate the individual intrinsic muscles during the dynamometry test. Garth and Miller hypothesIndirect methods such as imaging modalities-24,55-57This review suggests that at present, there is no adequately validated method of measuring intrinsic muscle strength. The main challenges are that no direct method can isolate intrinsic muscle strength from extrinsic muscle strength, and indirect methods cannot quantify muscle force. Future research in this field would benefit from using a combination of indirect and direct methods to measure intrinsic muscle force, because both measures have their strengths and limitations. For instance, a study comparing muscle architectural information from MRI, muscle modelling estimates of muscle force and muscle activation data from EMG, with the findings of direct methods such as hand held dynamometry would disentangle each method\u2019s limitation. Also indwelling EMG during hand-held dynamometry would enable both intrinsic and extrinsic muscle activity patterns to be compared, although this approach has numerous practical and analytical considerations to overcome. Nevertheless, a strong correlation would validate the findings of direct methods used to measure intrinsic muscle strength.An accurate and reliable measure of intrinsic muscle strength will enable prospective studies to address the causal relationship questions between intrinsic muscle weakness and foot/toe deformity in conditions like Charcot-Marie-Tooth disease,7, diabeIn conclusion, measuring intrinsic muscle strength poses many challenges. Most studies have focussed on toe flexor strength as a surrogate measure of intrinsic muscle strength, while other actions of toe muscles have not been assessed. Hand-held dynamometry represents a promising method of estimating intrinsic muscle strength. However, the contribution of extrinsic muscles cannot be excluded from toe flexor strength measurement. Future research should clarify the relative contribution of intrinsic and extrinsic muscles during intrinsic foot muscle strength testing.The authors declare that they have no competing interests.AS searched the literature, analysed the articles and drafted the review. JB, CH and KR conceptualised and edited the review. All authors read and approved the final manuscript."}
+{"text": "Mesorhizobium metallidurans STM 2683T and Mesorhizobium sp. strain STM 4661 were isolated from nodules of the metallicolous legume Anthyllis vulneraria from distant mining spoils. They tolerate unusually high Zinc and Cadmium concentrations as compared to other mesorhizobia. This work aims to study the gene expression profiles associated with Zinc or Cadmium exposure and to identify genes involved in metal tolerance in these two metallicolous Mesorhizobium strains of interest for mine phytostabilization purposes.Mezorhizobium strains were sequenced and used to map RNAseq data obtained after Zinc or Cadmium stresses. Comparative genomics and transcriptomics allowed the rapid discovery of metal-specific or/and strain-specific genes. Respectively 1.05%  and 0.97%  predicted Coding DNA Sequences (CDS) for STM 2683 and STM 4661 were significantly differentially expressed upon metal exposure. Among these, a significant number of CDS involved in transport  and sequestration  were identified. Thirteen CDS presented homologs in both strains and were differentially regulated by Zinc and/or Cadmium. For instance, several PIB-type ATPases and genes likely to participate in metal sequestration were identified. Among the conserved CDS that showed differential regulation in the two isolates, we also found znuABC homologs encoding for a high affinity ABC-type Zinc import system probably involved in Zinc homeostasis. Additionally, global analyses suggested that both metals also repressed significantly the translational machinery.The draft genomes of the two Mesorhizobium strains. Very few of them were involved in the non-specific metal response, indicating that the approach was well suited for identifying genes that specifically respond to Zinc and Cadmium. Among significantly up-regulated genes, several encode metal efflux and sequestration systems which can be considered as the most widely represented mechanisms of rhizobial metal tolerance. Downstream functional studies will increase successful phytostabilization strategies by selecting appropriate metallicolous rhizobial partners.The comparative RNAseq-based approach revealed a relatively low number of genes significantly regulated in the two  Such a phytostabilization approach is nevertheless challenging since it requires metallicolous plants able to grow in soils where nutrients are most often dramatically scarce. Legume/rhizobia symbioses which transform atmospheric dinitrogen into organic nitrogen is of ecological interest here as it can improve natural soil fertility and thereby allow the colonization of other plant species and the installation of a plant cover ..Strains,Click here for filePrimers used for quantitative PCR assays.Click here for file"}
+{"text": "Propionic acidaemia (PA) results from deficiency of Propionyl CoA carboxylase, the commonest form presenting in the neonatal period. Despite best current management, PA is associated with severe neurological sequelae, in particular movement disorders resulting from basal ganglia infarction, although the pathogenesis remains poorly understood. The role of liver transplantation remains controversial but may confer some neuro-protection. The present study utilises quantitative magnetic resonance spectroscopy (MRS) to investigate brain metabolite alterations in propionic acidaemia during metabolic stability and acute encephalopathic episodes.Quantitative MRS was used to evaluate brain metabolites in eight children with neonatal onset propionic acidaemia, with six elective studies acquired during metabolic stability and five studies during acute encephalopathic episodes. MRS studies were acquired concurrently with clinically indicated MR imaging studies at 1.5 Tesla. LCModel software was used to provide metabolite quantification. Comparison was made with a dataset of MRS metabolite concentrations from a cohort of children with normal appearing MR imaging.MRI findings confirm the vulnerability of basal ganglia to infarction during acute encephalopathy. We identified statistically significant decreases in basal ganglia glutamate+glutamine and N-Acetylaspartate, and increase in lactate, during encephalopathic episodes. In white matter lactate was significantly elevated but other metabolites not significantly altered. Metabolite data from two children who had received liver transplantation were not significantly different from the comparator group.The metabolite alterations seen in propionic acidaemia in the basal ganglia during acute encephalopathy reflect loss of viable neurons, and a switch to anaerobic respiration. The decrease in glutamine + glutamate supports the hypothesis that they are consumed to replenish a compromised Krebs cycle and that this is a marker of compromised aerobic respiration within brain tissue. Thus there is a need for improved brain protective strategies during acute metabolic decompensations. MRS provides a non-invasive tool for which could be employed to evaluate novel treatments aimed at restoring basal ganglia homeostasis. The results from the liver transplantation sub-group supports the hypothesis that liver transplantation provides systemic metabolic stability by providing a hepatic pool of functional propionyl CoA carboxylase, thus preventing further acute decompensations which are associated with the risk of brain infarction. Propionic acidaemia  results from deficiency of the biotin-dependent mitochondrial enzyme propionyl CoA carboxylase. The commonest and most severe form of PA presents in the neonatal period with acute metabolic acidosis, hyperammonaemia and progressive encephalopathy. Despite optimal management, later neurologic sequelae are a major cause of morbidity, and include neurodevelopmental delay, episodic acute encephalopathy, and movement disorders due to a propensity to basal ganglia infarction . The maiThe pathogenesis of the neurological insult remains poorly understood. Neurological damage may occur secondary to hyperammonaemia; alternatively inhibition of the mitochondrial Krebs cycle and electron transfer chain by accumulating metabolites may lead to a \"bioenergetic stroke\" . Based oin vivo changes in regional metabolites within the brain, and could be specifically employed to monitor directly alterations in brain energy metabolites including glutamine, glutamate and lactate. Previous MRS reports have demonstrated elevated glutamine+glutamate (Glx) in the basal ganglia of metabolically stable PA patients [Magnetic resonance spectroscopy (MRS) is a non-invasive technique capable of probing patients , while lpatients .The present study utilises quantitative MRS to investigate brain metabolite alterations both during metabolic stability and acute encephalopathic episodes, confirming the basal ganglia as a particular target and demonstrating novel insights in to alterations in neurotransmitter metabolites in particular glutamine and glutamate.Eight children  with propionic acidaemia were studied (median age (range) at first MRS, 36 7-190) months) . During these episodes all children required ventilatory support and continuous veno-venous haemofiltration (CVVH), and only one episode was associated with significant persistent hyperammonaemia. During these episodes three children received intravenous sodium benzoate and two received sodium phenylbutyrate.MRS studies were performed concurrently with clinically indicated MRI scans at 1.5 Tesla  facilitated by general anaesthesia as needed. Five studies from three children were acquired during severe acute episodes requiring intensive care support. Six studies from six children were acquired with elective outpatient MRI studies undertaken during metabolic stability and before any severe acute episode had occurred.MRS was acquired using point resolved spectroscopy (PRESS) technique  with 2 cm-sided voxels located in the left basal ganglia and right parieto-occipital white matter. Voxels were placed in standard positions guided by T1 and T2 weighted image sequences in coronal, sagittal and axial planes. Spectra were quality-assessed to ensure appropriate voxel localisation, shimming and water suppression. Raw data were processed using LCModel [Comparison was made with MRS metabolite data from a cohort of children with normal appearing MRI and similar age profile who had undergone MRI/MRS for investigation of various suspected neurodegenerative and neurocognitive conditions  age 4.7(0.5-16.7) years; basal ganglia n = 63, 4.1(0.5-16.7) years).Mean spectra were generated for each cohort for basal ganglia and white matter from LCModel fitted spectra after baseline subtraction. Spectra were compared by qualitative visual inspection.Metabolite concentrations for each region were compared between groups by Mann Whitney nonparametric U test (SPSS Statistics 17.0), with the p-value determined by the exact 2-tailed significance, with significance level set at p < 0.05.The basal ganglia appeared normal in all children (n = 6) prior to any severe acute episode beyond the neonatal period. MRI obtained during severe acute episodes demonstrated abnormal signal in the basal ganglia variably including the caudate heads, putamen and globus pallidi and in some cases there was also evidence of acute changes in the dentate nuclei and cerebral cortex. One child demonstrated evidence of previous basal ganglia infarction relating to a previous acute encephalopathic episode, with cystic degeneration of caudate, putamen and globus pallidus. Interestingly the hippocampi appeared atrophic in seven cases. Cerebral volume loss was most marked in children with preceding severe acute episodes. The two children who had liver transplantation had normal appearing basal ganglia, cortex and white matter on MRI undertaken more than 10 years post-transplant, with one showing probable temporal mesial sclerosis.Analysis of mean spectra figure  and meanMRS studies undertaken during metabolic stability before any severe acute episodes beyond the neonatal period demonstrated decreased Glx in basal ganglia compared to the normal MRI comparator group but a trend to increase in white matter. Glutamine alone was significantly decreased in basal ganglia during metabolic stability. Mean lactate was not elevated, although two cases had reliably detected lactate in basal ganglia. There was no significant decrease in the total N-acetylaspartate and N-acetylaspartylglutamate (tNAA) in this group.myo-inositol, and no propionic acid was detected in the propionic acidaemia cohort.MRS studies acquired during severe acute episodes demonstrated significantly decreased tNAA, Glx and creatine, and significantly elevated lactate, in the basal ganglia compared to both the normal MRI comparator group and to the metabolically stable propionic acidaemia cohort. In white matter lactate was significantly elevated but other metabolites were not significantly altered. . There were no significant differences between groups in brain Separate analysis of brain metabolites from the two children post-liver transplant demonstrated normal basal ganglia tNAA and slightly decreased Glx. tNAA was elevated in white matter and total choline decreased.The data presented represent the largest series of children with the severe neonatal form of propionic acidaemia to be investigated with MRS, and is to our knowledge the first to study children during severe acute encephalopathic episodes. The selective vulnerability of the basal ganglia in PA is well established, and our data provide further insight in to processes occurring within the basal ganglia. MRI results found that basal ganglia appeared normal in children who had not had a severe acute encephalopathic episode beyond the neonatal period, as similarly reported in glutaric aciduria , but werDecreased tNAA is seen in many pathologies, and is thought to reflect loss of viable neurons  includinThe alterations seen in glutamine and glutamate in basal ganglia are of particular note. Glx was significantly decreased during severe acute episodes, with a smaller (non-significant) decrease noted in basal ganglia in studies acquired during metabolic stability. The ratio of Glx/tNAA was lower in the propionic acidaemia cohort than in cohorts of children with other defined inherited metabolic disorders including a cohort with confirmed respiratory chain disorders, while the Glx/NAA ratio was elevated in a cohort with the urea cycle disorder argininosuccinic aciduria . This suggests that the alterations seen in Glx here were not simply a reflection of neuronal loss represented by lower tNAA.Although the spectral signals from glutamine and glutamate overlap, there is increasing evidence that they can be differentiated in the analysis of cohorts even at 1.5Tesla using software such as LCModel. Such evidence includes Montecarlo simulations of normal brain spectra fitted with LCModel , compariA previous MRS study reported elevated basal ganglia Glx in three metabolically stable propionic acidaemia patients who had normal ammonia and near-normal glutamine and glutamate in plasma and cerebrospinal fluid leading the authors to suggest differential mechanisms regulating brain parenchymal metabolism . HoweverThe administration of the alternative pathway drugs used to control hyperammonaemia depletes plasma glutamine and glycine and may contribute to the decreased brain Glx seen. Furthermore, all children were haemofiltered during severe acute episodes which may further deplete glutamine due to its high sieving coefficient . HoweverThe acute decrease seen in Glx supports the hypothesis that they are consumed to replenish a depleted Krebs cycle , and thaThere is a need for brain protective strategies during acute metabolic decompensations, with potential methods including brain cooling, adequate energy provision, and anaplerotic therapies. MRS could provide a tool to monitor the effect of dietary supplements aimed at increasing glutamine levels, specifically monitoring metabolite levels within the target-organ of interest, namely the brain.The two children who had liver transplant have had no severe acute encephalopathic episodes beyond the neonatal period, and have normal appearing basal ganglia on MRI. MRS demonstrated normal/high tNAA reflecting the absence of major neuronal loss and correlating with their good neurocognitive status, and no reliably detected lactate. The small numbers preclude statistical significance, but Glx was slightly increased in white matter but decreased in basal ganglia compared to the comparator group. These results support the hypothesis that liver transplantation provides systemic metabolic stability by providing a hepatic pool of functional propionyl CoA carboxylase, thus preventing further acute metabolic decompensations which are associated with the risk of brain infarction.The data presented here have yielded some interesting observations, however further prospective data collection and analysis could overcome some of the specific limitations of the present work. In particular, use of higher field strength MRI scanners (3Tesla and above) would provide more robust differentiation of the metabolites of interest, notably glutamine and glutamate. Serial data collection in specific patients could also confirm the alterations in brain metabolites seen before, during and after metabolic decompensations. Finally analysis of a larger cohort of post-liver transplant patients as well as longer follow up with serial studies will provide stronger evidence for the therapeutic value of liver transplantation in PA.in vivo brain metabolic derangements, and can feasibly be employed in children with acute encephalopathy. In propionic acidaemia the use of MRS in conjunction with MRI has confirmed the basal ganglia as a particularly vulnerable target and has demonstrated novel insights in to alterations in neurotransmitter metabolites. Evaluation of patients in long-term follow up after liver transplantation demonstrates the potential for good neurological outcome and near-normal brain metabolism. MRS provides a tool to directly evaluate the tissue-level effects of novel treatment strategies including anaplerotic therapies.We have demonstrated that quantitative MRS is able to offer insight in to The authors declare that they have no competing interests.JED carried out data analysis and collated clinical data and drafted the manuscript.NPD, MW, YS assisted with data processing including software development.AC, PJM and JHW provided clinical management for subjects, assisted with patient recruitment and critically appraised the manuscript.PG and ACP conceived of the study and participated in its design.All authors read and approved the final manuscript."}
+{"text": "Implementation of alcohol screening and brief intervention (SBI) is a prevention priority. The Veterans Affairs (VA) Healthcare System uses a clinical reminder (CR) in the electronic medical record to prompt and document results of screening and trigger a subsequent CR for BI when screening is positive. Although screening rates are over 90%, marked variability in screening quality has been documented. Four researchers observed clinician interactions with CRs during alcohol screening at nine primary care clinics in the northwest US to identify barriers and facilitators to using CRs to implement quality screening. Observers took handwritten notes, which were transcribed and analyzed qualitatively using an a priori coding template adapted during analyses. We observed 58 support staff  caring for 166 patients. Alcohol screening prompted by the CR was often uncomfortable and of low quality. Clinicians often offered disclaimers prior to screening or made adjustments to how questions were presented, with some citing the sensitive nature of the questions. Verbal screening typically did not include asking questions verbatim. There was substantial variability in methods of conducting screening across clinics, with some using the CR to facilitate in-person screening by interview and others entering patient responses into the CR after completion of a paper-based screen. Although the CR was designed to trigger a subsequent CR for BI when positive, some clinics used paper encounter forms for this. Findings suggest that VA CRs have important limitations as a method of facilitating effective, high-quality alcohol screening. Barriers observed reflect a combination of limitations of CR technology , ways the CR was implemented, clinical workflow, complexity of patient needs, and alcohol-related stigma. Future research should address these barriers to effectively implement recommended care."}
+{"text": "The pressure flow model of phloem transport envisaged by M\u00fcnch  has gain The pressure flow model of phloem transport M\u00fcnch,  has gainP) for a given viscosity (\u03b7), predicts that variation in flow path geometries of STs , will alter their hydraulic conductances (Lo and see Equation 2) and hence impact axial volume flow rates (Rv) through them.Experimental observations provide persuasive support for phloem sap moving through STs by bulk flow  by variations in sieve pore radii  provided by plasmodesmata interconnecting these cells.Phloem unloading rates are regulated by hydraulic conductances (Equation 2) of the unloading pathway rather than the axial hydrostatic pressure differential Equation 1). In this context, the latter is comparable between a source and an array of sinks irrespective of their rates of phloem unloading  of symplasmic unloading pathways linking SEs with phloem parenchyma cells in the release phloem Figure .Key elements of the high-pressure manifold model of phloem transport articulated by Fisher  and captOur analysis of the high-pressure manifold model of phloem transport primarily rests on evaluating the extent to which the model is consistent with known properties of resource flow through the phloem. Of necessity much of this analysis will focus on phloem transport in herbaceous plants where most experimental studies have been undertaken. However, with appropriate caveats, the analysis is extended to phloem transport in trees.Bulk flow in the M\u00fcnch model is conceived to be restricted to STs alone in which substantial hydrostatic pressure gradients develop from their source to sink ends. In contrast, the high-pressure manifold model  trees during the photoperiod  and stem (transport) lengths that accounts for phloem translocation by M\u00fcnch pressure flow in plant heights spanning several orders of magnitude  exceed the potential capacity of phloem loading, phloem sap concentrations of sugars, accompanied by ST hydrostatic pressures, decline until a new equilibrium between loading and unloading rates are reached. This condition could cause a pronounced axial gradient in ST hydrostatic pressure from source to sink to develop. The corollary is sink limitation whereby the potential capacity for phloem loading of sugars exceeds that of phloem unloading. For this condition, any increase in rates of phloem unloading is met by a commensurate increase in phloem loading. This condition would sustain high phloem sap sugar concentrations and hence ST hydrostatic pressures throughout the system.There are no direct measures of rates of phloem loading and unloading. However, there is considerable indirect evidence suggesting that potential capacities of leaf photosynthesis arranged in series with phloem loading exceed those of phloem unloading into expanding and storage sinks. For instance, under optimal environmental conditions for leaf photosynthesis, increasing sink/source ratios by experimentally attenuating sugar export from a portion of leaves  results in elevated rates of sugar export from the untreated leaves of trees  expressed on a cross-sectional area basis i.e., \u03c0r2) would vary directly with sieve pore radius raised to the second power. However, across a cohort of test species, estimates of phloem transport velocities were found to exhibit an inverse rather than the predicted direct relationship with their estimated ST hydraulic conductivities  in STs  plants whose STs do not seal upon severance, allowing phloem transport to continue. Hence rates of phloem transport can be estimated by measuring quantities  of phloem sap exuded from cut surfaces across specified times. The estimated transport rates can be expressed as ST fluxes based on measures of their cross-sectional areas through which axial transport takes place  surgical removal of phloem cross-sectional area in stems was found to exert little influence over axial flow rates in both woody plants  or storage  organs. In particular, under high source/sink ratios, net resource flows occur from transport phloem of petioles, stems and roots into storage pools of their ground tissues in which transport phloem is embedded. A striking example of this phenomenon is accumulation of sucrose in storage parenchyma cells of sugarcane stems to concentrations that match those of the phloem sap Patrick, . Thus, cPhloem unloading may be arbitrarily divided into SE unloading and post-SE unloading which extends from phloem parenchyma cells to cellular sites of resource utilization or storage in non-vascular cells. For the purposes of evaluating the high-pressure manifold model of phloem transport, the primary focus is on SE unloading wherein resources reach the phloem parenchyma cells. However, some consideration, where relevant, will be given to post-SE unloading.A central tenant of the high-pressure manifold model is that hydraulic conductances of the symplasmic unloading pathways, from SEs of release phloem, impose a major constraint over bulk flow of resources through the source-path-sink system Figure . This diThe most definitive experimental approach to mapping phloem-unloading pathways has been through the use of membrane-impermeant fluorochromes introduced into phloem sap as membrane-permeant esters or as tags linked to transgenically-expressed foreign molecules under the control of companion cell specific promoters.Axial delivery pathways into apical meristems comprise protophloem SEs giving way to strands of provascular cells more proximal to the apical dome. Distribution of membrane-impermeant fluorochromes, imported through the phloem, have identified putative symplasmic unloading pathways extending from terminal ends of protophloem SEs through provascular stands to reach meristematic cells in root apices of monocots  predicts that any symplasmic bulk flow of phloem sap exiting from SE/CC complexes will encounter considerable hydraulic resistances and hence a proportionate reduction in hydrostatic pressure upon entering recipient cells. These predictions are consistent with the presence of large (1.0 MPa) differences in hydrostatic pressures between release phloem SEs and cortical/epidermal cells of root tips measured directly using aphid stylet micromanometry and pressure probe respectively Table . Similar\u22121 into a developing wheat grain across a set of microchannel radii (see Table Rv \u2013 Equation 1) from which microchannel numbers supporting the observed volume flow rate were derived. From these data, microchannel numbers per plasmodesmata were estimated assuming that a single row of microchannels occupy 50% of the sleeve cross-section. Microchannel numbers per plasmodesma then allow determination of plasmodesmatal numbers required to support the observed volume flow rate  of a solute i are described by Fick's First Law of diffusion as:D is the diffusion coefficient of solute i; A is the cross-sectional area (r = \u03c0r2) of the diffusional pathway; \u0394C is the concentration difference of solute i between either end of the diffusive pathway; \u0394x is the length of the diffusive pathway.Since SE/CC complexes and vascular parenchyma cells share identical apoplasmic water potentials, turgor differentials arise from intracellular osmotic differentials and, as a result, concentration differences of phloem sap constituents. Hence diffusion must be a component of phloem unloading and the issue of the relative contributions of symplasmic phloem unloading by diffusion and bulk flow becomes one of degree. Diffusion rates  and bulk flow (Equation 1) in SE unloading, published sucrose concentrations in SEs  with that of 14C-sucrose along elongating pea epicotyls, independent of their differing symplasmic concentration gradients, suggests symplasmic unloading of these disparate solutes is primarily by bulk flow rather than diffusion  and Ficks First Law of diffusion Equation 3). That is, rates of these two processes are proportional to the radius of the conducting pipe raised to the fourth and second powers respectively. Thus, control of pipe radius can exert a four-fold greater control over rates of bulk flow compared to diffusion. This translates into an operational system whereby modest changes in microchannel dimensions can elicit substantial impacts on bulk flow rates of solute unloading from release phloem as illustrated in Tables . That isIn addition to optimizing control over phloem unloading (see above), bulk flow also avoids a dependence upon a very high level of co-ordination of unloading between individual solute species to avoid compromising phloem transport as outlined in the following scenario. If symplasmic unloading were to occur primarily by diffusion, then a mechanism must be present to ensure exit rates of each solute species and water from release phloem SEs match their rates of replenishment by axial transport. This is not a trivial requirement as diffusion rate of each solute moving through the same unloading pathway geometry depends not only on their concentration differences between SEs and vascular parenchyma cells but also on their individual diffusion coefficients (see Equation 3). Moreover phloem-imported water will diffuse at rates dictated by water potential differences between SE-CCs and vascular parenchyma cells. In these circumstances it would be very problematic for axial rates of each solute and water transported into, to match those of their diffusional exit from, release phloem SEs. As a consequence, regulation of ST hydrostatic pressures of release phloem could be compromised. This problem does not apply if SE unloading were to occur by bulk flow since solutes and solvent are transported at identical fluxes .Rv and see Equation 1) and cortical cell turgor points to hydraulic conductances of plasmodesmata, located along the symplasmic unloading pathway, exerting a major regulatory influence over radial fluxes of water and hence solutes travelling from SEs to cortical cells. This explanation also accounts for transport behaviors in developing seeds whereby coat cell turgors were found to be invariant across a three-fold range of seed growth rates exhibited between French bean cultivars  and densities, formed during their development at various cellular interfaces located along phloem unloading pathways set upper limits for symplasmic hydraulic conductances. For example, inferred from Stoke's radii of the permeating molecules, these data yield conservative estimates of plasmodesmal microchannel radii for phloem and non-phloem domains that extend over a two-fold range (see Section Is Symplasmic Sieve Element Unloading Dominated by Bulk Flow?). In relative terms, these radii translate into a 16-fold range of hydraulic conductances. Second, plasmodesmal gating (open versus closed), mediated by callose deposition/hydrolysis around plasmodesmal neck regions, has been demonstrated to play a key role in regulating transmission of macromolecular signals orchestrating cell development (Burch-Smith and Zambryski, Conductance for symplasmic movement between two adjacent cells is a function of their averaged conductance of plasmodesmata summed over the density of plasmodesmata located in their shared wall. Plasmodesmal densities are under both positional and developmental control (Burch-Smith and Zambryski, Within meristematic sinks, plant hormones regulate rates of cell division and hence sink demand. This hormone function is linked with their ability to directly act on transport processes delivering resources to hormone-enriched sites Patrick, . Fully-eFor expansion/storage sinks, some insights into the regulatory mechanisms integrating sink demand with plasmodesmal control of resource flow along phloem unloading pathways has been obtained from observations of developing seeds. Phloem unloading pathways in developing seeds universally contain a symplasmic discontinuity at, or proximal to, their maternal and filial interfaces at which phloem-imported resources are released to, and retrieved from, the seed apoplasmic space (Zhang et al., Crop biomass yield potential is the harvested yield per plant of any cultivar raised under optimal environmental conditions for its development in the absence of any limitation imposed by abiotic or biotic stresses (Evans and Fischer, The elements carbon, hydrogen and oxygen account for ca 90% of crop biomass yield. These elements reach the harvested units as phloem-imported sugars that form the major osmotica generating ST hydrostatic pressures propelling bulk flow from source to sink. The preceding analysis of the high-pressure manifold model of phloem transport identified hydraulic conductances of plasmodesmata, located at the sink-end of phloem pathways, as key regulators of bulk flow rates from source to sink and for partitioning of flow rates between competing sinks Figure . This shZea mays ADP-glucosepyrophosphorylase, under control of an endosperm-specific promoter, in pre-storage grains of wheat (Smidansky et al., The pre-storage phase of harvestable organ development is photoassimilate limited as demonstrated by positive responses of harvestable organ numbers to elevated source/sink ratios (Ruan et al., The storage phase filling rates are characteristically sink-limited (Borr\u00e1s et al., Overall, the above circumstantial evidence indicates that opportunities may well exist to improve crop biomass yield through manipulating resource transport informed by the high-pressure manifold model of phloem transport.Reviewing current knowledge of phloem transport leads to a strong circumstantial case being made for the high-pressure manifold model of phloem transport. This is considered sufficient to warrant further study of the model. Initially, most effort could be directed to increasing knowledge of the plasmodesmal sub-structures and how these influence resource flow through their plasmodesmal microchannels. In particular, it is crucial to obtain direct evidence that hydraulic conductances of plasmodesmata, linking SEs with surrounding phloem parenchyma cells, support SE unloading of phloem sap by bulk flow. This enterprise could be informed by the exciting findings emerging from investigations of water flows through nanotubes showing that, with radii of several nm, flow velocities exceed those predicted by the Hagen-Poiseuille law by four to five orders of magnitude (Majumber et al., This paper is dedicated to the memory of Donald Fisher, a modest, but passionate, plant scientist. Don's contributions to advancing our conceptual knowledge of phloem transport biology were substantial, unyielding in their rigor and trail blazing in their impact on the field.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The present investigation compared parenting practices in a sample of preschoolers whose mothers reported smoking during pregnancy versus those who did not.A sample of n = 216, 3.0- to 5.11-year-old children, participants in an ongoing longitudinal study, was separated into those reportedly exposed to smoking in utero and those who were not. Parenting practices were compared between the two groups, using T-tests and exact logistic regressions. Multiple linear regressions and multivariate logistic regressions were used to examine the association between smoking status and parenting, controlling for variables also known to be associated with parenting practices.Current study findings suggest that smoking during pregnancy is associated with harsh parenting practices.Study results highlight the possible role of parenting in disruptive outcomes well-known in toddlers exposed to nicotine in utero and have implications for targeting early interventions in these populations. An association between prenatal cigarette exposure and disruptive behavior in childhood has been reported in the empirical literature from multiple independent investigations . HoweverNumerous individual and psychosocial differences have been found between mothers that smoke during pregnancy and mothers that do not. Such differences have included the findings of more antisocial character traits in smoking mothers and a higher likelihood of selecting mates with these traits . MothersThe above mentioned personal and psychosocial features of pregnancy smokers may themselves contribute to poor parenting skills. To further complicate the challenges of parenting in this population, the child of a pregnancy smoker may also be more difficult to parent than the child of a non-smoker on the basis of biological risk factors. For example, while the mechanism remains unclear, smoking while pregnant has been associated with increased negativity in toddlers measured as rebelliousness, risk taking, and impulsivity, behaviors often found in children with disruptive disorders . Brook eTo better understand the relationship between smoking in pregnancy and early child behavioral problems, further examination of parenting among pregnancy smokers compared to non-smokers is now warranted. There is a dearth of published studies that specifically inform this issue. While most prior investigations have focused on prenatal smoking and risk for disruptive behavior outcomes in the child, parenting constructs were also examined in some of these studies. These available study findings have suggested that mothers who smoked showed less parental nurturing, as well as poor behavioral management and dyadic communication skills , 23, 24.Additional studies have examined parenting among pregnancy smokers at multiple stages of development, from neonates  to adolePreschool age children (n = 306) between the ages of 3.0 and 5.11 and their caregivers were recruited from pediatricians\u2019 offices, daycares, and preschools in the St. Louis metropolitan area using the Preschool Feelings Checklist (PFC) , a briefThe PAPA is an interviewer-based diagnostic assessment with established test-retest reliability designed for use in children ages 3 to 6 . The PAPThe CAPA is an interviewer-based, structured psychiatric interview for children with collection of data on symptom onset, frequency, intensity and duration according to DSM-IV, III-R or ICD-10 criteria. Modules such as substance use (tobacco), can be used separately, and test-retest reliability for diagnoses range from k = 0.55 (conduct disorder) to k = 1.0 (substance abuse) . MothersThe HBQ-P is a 140-item reliable and valid parent informant measure that produces dimensional ratings of 4- to 8-year-old children\u2019s functioning in the domains of emotional and behavioral symptomotology, impairment, adaptive social functioning, and physical health using a 3-point Likert scale with a 20-minute completion time .Parenting practices based on self-report were examined in mothers who smoked versus those who did not smoke cigarettes during pregnancy in a sample of n = 306 children enrolled in an ongoing longitudinal investigation of preschoolers. T-tests and exact logistic regressions were used to compare the differences for parenting variables between mothers who smoked and those who did not. Mann-Whitney U tests were used to compare two smoking categories. Multiple linear regressions and multivariate logistic regressions were used to examine the association between smoking status and parenting variables (frequency or intensity) controlling for confounding variables.Of the n = 306 preschoolers from the longitudinal investigation, n = 216 participants had data available on both parenting and smoking exposure. Demographic characteristics of study participants included in this analysis are shown in T-tests and exact logistic regressions revealed that mothers who did not smoke during pregnancy were significantly less likely than mothers who smoked to: (1) give verbal dispraises   ; (2) ever leave bruises ; (3) verbally reject .A multiple linear regression controlling for demographic differences including total family income, baseline education of the biological mother, ethnicity, and several variables known to impact parenting including alcohol during pregnancy and HBQ-P externalizing scores were controlled and included as covariates shown below. In this analysis, as depicted in Smoking during pregnancy was also significantly associated with leaving marks or bruises (intensity)  . SmokingThe current study findings suggest specific parenting differences in those mothers that smoked during pregnancy compared to those who did not. Pregnancy smokers demonstrated harsher parenting in several specific domains than parents who did not smoke during pregnancy. These differences remained significant even after other factors known to be associated with poor parenting such as low SES, alcohol use, and child\u2019s externalizing behavior scores were accounted for in the analysis. Parenting behaviors among pregnancy smokers remain under-investigated. Current findings suggesting increased levels of harsh parenting in pregnancy smokers extend the extant literature associating pregnancy smoking exposure to child disruptive outcomes. These findings point to modifiable risk factors in pregnancy smokers to ameliorate child disruptive outcomes. While further studies are warranted to elaborate on the mechanisms that drive this association, study results suggest that parenting should be an important target for dyads exposed prenatally to cigarettes. Other studies have suggested treatment intervention to be less effective in children prenatally exposed to cigarettes, warranting further understanding and need for targeted treatment . RegardlStudy limitations include a relatively small sample size of pregnancy smokers that were from a longitudinal investigation on depression. Other potential limitations were no bioassay confirmation of smoking measurements and no maternal personality assessment. Additionally, current study findings show less Caucasian and more African American mothers in the group of pregnancy smokers versus non-smokers, making the findings less generalizable to the population. This is also important as multiple smoking investigations find Caucasians to be the ethnic group making up the large majority of pregnancy smokers. Further investigations of such ethnic differences are warranted.Finally, our reliance on self-reported parenting in the absence of observational parenting measures is a limitation due to the possibility of bias towards appropriate, socially acceptable responses and shared method variance with the same reporter providing information on both predictor and outcome . HoweverThe present investigation compared parenting practices in preschoolers whose mothers reported smoking during pregnancy versus those who did not. Current study findings suggest that smoking during pregnancy is associated with harsh parenting practices. While the current investigation is preliminary and limited by a small sample size, study findings inform the need for larger investigations that specifically examine parenting of younger children among pregnancy smokers, taking into account key variables such as maternal personality characteristics and other related substance use. Future investigations could inform how to improve parenting skills to minimize disruptive behaviors in young children of pregnancy smokers at greatest risk for harsh parenting. Such studies would help identify those most likely to benefit from targeted parenting interventions to optimize public health resources."}
+{"text": "Direct implantation of isolated myoblasts, cardiomyocytes, and bone-marrow-derived cells has shown prospect for improved cardiac performance in several animal models and patients suffering from heart failure. However, direct implantation of cultured cells can lead to major cell loss by leakage and cell death, inappropriate integration and proliferation, and cardiac arrhythmia. To resolve these problems an approach using 3-dimensional tissue-engineered cell constructs has been investigated. Cell engineering technology has enabled scaffold-free sheet development including generation of communication between cell graft and host tissue, creation of organized microvascular network, and relatively long-term survival after  Cardiac repair by cell therapy offers hope to improve performance of diseased heart by reconstituting or maintaining cardiac specific tissue . First sNevertheless, the hypothesis that cardiac function in heart failure can benefit from cell therapy has gained extensive attention and preliminary clinical trials have been launched \u201314. MiyaOne of the crucial issues in cell therapy for heart failure has been the cell delivery route. Injection of the cells has been the most typical method in clinical feasibility studies . The celIn addition, arrhythmogenicity of intramyocardial myoblast transplantation has aroused debate. Episodes of ventricular tachycardia and fibrillation have been noted after several feasibility studies. Due to small number of patients in nonrandomized series and the arrhythmogenic nature of the heart disease itself, direct causality is difficult to conclude. In an early study of Menasch\u00e9 et al., 4 out of 10 patients experienced sustained ventricular tachycardia , and in Another approach for cell delivery as opposed to injection involves tissue-engineered constructs. The main advantage of this technology over standard cell implantation lies on the preservation of microcellular communication and matrix, which is lost upon trypsin treatment in the typical procedure of cell preparation. Epicardial deposition of cell sheets might be a solution to prevent significant cell loss and arrhythmia after cell transplantation . Memon eCurrent tissue engineering methods allow us to reconstruct myocardial tissue grafts for clinical applications, though human fetal and neonatal cardiomyocytes are difficult to obtain. Therefore, several classes of stem cells are being investigated as a potential cell source. Despite their attractive potential to differentiate into various cell types, several issues remain, including difficulties in obtaining and amplifying the cells and the lack of understanding of the mechanisms for differentiation and proliferation. Consequently, the clinical cell sheet transplantation has mainly focused on utilization of myoblasts.bcl2 was shown to enhance the efficacy of sheet transplantation therapy in acute myocardial infarction [bcl2 improved myoblast sheet transplantation therapy also in chronic myocardial infarction model [Memon et al.,  reportedfarction . Moreoveon model .Dilated cardiomyopathy (DCM) is characterized by global myocardial remodeling, which mainly consists of myocardial fibrosis associated with changes in the cytoskeletal and sarcolemmal proteins in cardiomyocytes, leading to a reduction in the number and function of these cells . ConsequHoashi et al.,  showed tPreclinical studies in impaired porcine heart using single monolayer skeletal muscle cell sheet demonstrated improved cardiac performance accompanied with increased myocardial perfusion and viable myocardial tissue .Further, Miyahara et al., used mesenchymal stem cells (MSCs) derived from adipose tissue in a rat myocardial infarction model . MSC sheDifficulties still exist in the outcome of cell therapy, as it is challenging to control the cell growth and localization of the grafted cells and to deliver a cell sheet patch that significantly aids the function of the damaged myocardium. To overcome these problems research has begun on fabricating three-dimensional cardiac grafts composed of multilayered cell sheets. Several methods have been studied with reconstructed tissues based on biodegradable scaffolds, such as poly(lactic-co-glycolic acid) and gelatin or extracellular matrix components , 49.In native cardiac tissue the cell density is considerably high, cells being tightly interconnected with gap junctions facilitating electrical communication. The use of scaffolds can lead to abnormal tissue development, electrical communication caused by insufficient cell-to-cell connections, inflammatory responses, and fibrous tissue formation. Alternatively, fabrication of scaffold-free cell sheets requires means of cell detachment from the culture surface that will preserve cell morphology, orientation within the scaffold, and adhesion to surrounding cells and the extracellular matrix. One way to achieve such detachment is to covalently employ a temperature-responsive polymer on cell culture surface. Poly(N-isopropylacrylamide) (PIPAAm) is a hydrophobic polymer at temperatures above 32\u00b0C which\u2014after grafting to cell culture dishes\u2014allows cell adhesion and proliferation . At temp\u03bcm. These sheets, however, were subject to necrosis due to limited oxygen supply. The same method was then used to create prevascularized sheets composed of cardiomyocytes, endothelial cells, and fibroblasts. These sheets effectively integrated with the coronary circulation after implantation and evaded necrosis. Furthermore, Itabashi et al., fabricated cardiomyocyte sheets using polymerized fibrin-coated culture dishes [Stevens et al., and Itabashi et al., described other methods for creating scaffold-free sheets. Stevens et al., created embryonic stem cell-derived cardiomyocyte sheets utilizing Teflon-coated low-attachment tissue culture dishes combined with rotating orbital shaker . The diae dishes . This meIn addition to cell-to-cell communication, the layers need to establish a connection with each other and with the host tissue. Using a multielectrode extracellular recording system, Haraguchi et al., demonstrated that the electrical coupling between 2 sheets starts approximately 34 minutes after initial layering and is completed by about 46 minutes. They also showed small molecule exchange through gap junctions and presence of connexin-43 within 30 minutes of layering .When Shimizu et al., implanted a 4-layered neonatal rat cardiomyocyte sheet into the subcutaneous space of nude rats, synchronous beating  and survMiyagawa and colleagues showed that neonatal cardiomyocyte sheets fabricated on temperature-responsive culture dishes attached to the infarcted myocardium and led to an improvement in cardiac performance and improved vascular density . The impAnother study demonstrated a similar electrical integration between a neonatal myocyte sheet and the host myocardium without serious arrhythmia . Furtherin vitro rely on diffusion. In order to reconstruct thicker and metabolically active tissue grafts sufficient blood supply network has to be created.Heart is a metabolically active organ that requires virtually constant oxygen supply in order to function in a normal fashion. The major limitation of the multilayered cell grafts is insufficient circulation causing hypoxia, nutrient insufficiency, and accumulation of waste products. Cells in living tissues receive oxygen supply through a capillary network, whereas the cultured cell aggregates in vitro in tissue-engineered constructs before transplantation. Levenberg et al., demonstrated the induction of endothelial vessel networks in engineered skeletal muscle tissue constructs using a 3D culture system consisting of myoblasts, embryonic fibroblasts, and endothelial cells coseeded on porous, biodegradable polymer scaffolds [in vitro bone coculture model with human MSCs, human umbilical vein endothelial cells (HUVECs) [One strategy could be to generate capillary-like networks caffolds . Similar(HUVECs) , 62, and(HUVECs) . As the Sasagawa et al., developed a novel cell sheet stacking manipulation technique to create multilayered cell sheets from human skeletal muscle myoblasts . They pl\u03bcm thick [\u03bcm thick. In order to progress the human cell sheet applications the greater thickness of the construct would be of great advantage. Sekiya et al., investigated the relationship between the number of transplanted cell layers and cardiac function. They found a significant improvement of cardiac function, induction of angiogenesis, more elastic fibers, and less fibrosis with implantation of 3- and 5- layered myoblast sheets compared to single layer [A single myoblast layer is about 45\u2009\u03bcm thick . Accordile layer .Shimizu et al., showed that the 1-, 2-, and 3-layer constructs transplanted into the dorsal subcutaneous tissue of nude rats thoroughly survived without necrosis . Howeverin vitro and increased blood perfusion in vivo by using a coculture of fibroblasts and human smooth muscle cells [One way to enhance the cell sheet graft survival is to promote angiogenesis. Enhanced angiogenesis and functional improvement were achieved by using cocultured cell sheets with fibroblasts and endothelial progenitor cells . Anotherle cells . In addile cells . Stimulation of angiogenesis has also been shown in single cell-type cell sheets. Miyagawa et al., demonstrated that human HGF gene transfection enhanced the cellular cardiomyoplasty likely by stimulating angiogenesis, restoring the impaired extracellular matrix, and promoting the integration of the dissociated grafted myocytes . Zakharoin vitro and in vivo models and demonstrated that cardiac cell sheets express VEGF, Cox-2, and Tie-2 and exhibit endothelial cell organisation and microvessel formation [in vivo. Expression of these proangiogenic genes was further induced by preventing graft apoptosis with antiapoptotic gene therapy [To understand the molecular mechanisms of cell sheet angiogenesis Sekiya et al., studied both ormation . Kitabay therapy . Moreove therapy . Memon e therapy . Finally therapy . In thisDifficulties in reproducibility in cell injection therapy, including low survival and function of the cells, have led to search for more robust methods. Engineering of 3D cell constructs has currently been under extensive investigation. Preassembled cell constructs might provide effective tools for the future cell therapy research. Establishment of programmable materials used in the cell engineering technology has enabled the creation of scaffold-free cell sheets in a rather simple and inexpensive method. The main aspects of cell sheet construction that must be met for successful regenerative therapy are dynamic, electrical, and histological integration. Increased cell-to-cell communication and survival in cell sheets warrant further attention. The reviewed studies demonstrate the existing potential to produce viable, functional myocardial tissue implantable constructs well beyond the current diffusion-limited thickness regime."}
+{"text": "Thus, targeting IAP proteins represents a promising molecular targeted strategy to overcome apoptosis resistance in childhood leukemia, which warrants further exploitation.Inhibitor of Apoptosis (IAP) proteins are a family of proteins with antiapoptotic functions that contribute to the evasion of apoptosis, a form of programed cell death. IAP proteins are expressed at high levels in a variety of human cancers including childhood acute leukemia. This elevated expression has been associated with unfavorable prognosis and poor outcome. Therefore, IAP proteins are currently exploited as therapeutic targets for cancer drug discovery. Consequently, small-molecule inhibitors or antisense oligonucleotides directed against IAP proteins have been developed over the last years. Indeed, IAP antagonists proved to exhibit  Cancer cells have typically acquired the ability to evade apoptosis, a form of programed cell death . In addic and second mitochondria-derived activator of caspases (Smac)  pathway and the mitochondrial (intrinsic) pathway . Signal s (Smac) . Smac fas (Smac) . By comptivation .The family of IAP proteins comprises eight human analogs . Among tExpression levels of IAP proteins are elevated in a variety of human malignancies including pediatric leukemia, which may be caused by genetic events as well as by transcriptional or posttranscriptional mechanisms. It is important to note that aberrant expression of IAP proteins was described to correlate with adverse patients\u2019 outcome, suggesting that IAP proteins bear a prognostic impact.The prognostic significance of XIAP has been studied in childhood acute myeloid leukemia (AML). XIAP has been associated with adverse prognosis in pediatric leukemia by independent studies showing a correlation of high mRNA and protein expression levels of XIAP and several unfavorable prognostic parameters including high-risk groups for cytogenetics, immature morphology, poor treatment response to induction chemotherapy, and reduced relapse-free survival , 9. ThesIn childhood ALL, a large study comprising the analysis of 222 patients showed that high expression levels of ML-IAP mRNA correlated with a favorable rather than an unfavorable prognosis . In addide novo AML  or a locked antisense oligonucleotide was reported to induce apoptosis in leukemia cell lines and also potentiated the chemotherapeutic antileukemic effects \u201327. In aIAP proteins are promising novel targets for molecular targeted therapy in childhood leukemia. Agents antagonizing IAP proteins, including small-molecule inhibitors and antisense oligonucleotides, have been shown to trigger apoptotic and non-apoptotic cell death alone or in combination in preclinical studies in pediatric leukemia. Currently, IAP antagonists are under evaluation in early clinical trials in adult leukemia. Thus, IAP-targeting treatment strategies warrant further clinical investigation in childhood leukemia.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The authors present the endoscopic intranasal orbital decompression, one of the surgical techniques used for orbital decompression. It can be applied for various indications. The most common indications are: maxillo-facial trauma, orbital haemorrhage, subperiorbital abscess as the complication of sinusitis, optic neuropathy, thyroid-associated orbitopathy (Graves\u2019 orbitopathy). The authors conclude that the endoscopic transnasal orbital decompression is a valuable and safe operational technique for patients requiring orbital decompression."}
+{"text": "Physiologic (flexible) pes planus (flatfoot) is a descriptive term for feet that have a visually lowered medial longitudinal arch often in association with rearfoot eversion . ReporteA systematic review of randomised, quasi-randomised or controlled clinical trials comparing rigid or semi-rigid functional foot orthoses with: no orthoses or any other approach to managing symptomatic flexible pes planus in the adult. Relevant data bases were searched from inception to October 2011 with studies meeting the predetermined inclusion criteria retrieved and screened by two independent reviewers. No restrictions were placed on type of foot orthoses or alternative interventions. Included studies were independently assessed by two reviewers with risk of bias determined by the Cochrane criteria. Where feasible, meta-analysis will be undertaken.A narrative summary will be presented of the results with outcome measures to include: pain, gait changes , dynamic foot function or static foot posture changes.A determination of the current level/s of evidence for the use of foot orthoses in the adult with symptomatic pes planus."}
+{"text": "Tau inclusions composed of tau fibrils are one of the key hallmarks of Alzheimer\u2019s disease and other tauopathies. Studies from transgenic animal models and human AD pathological cases suggest that tau inclusions spread from the transentorhinal cortex to mono and transynaptically connected regions of the hippocampus and neocortical regions. This study examines cell-to-cell propagation of pathological tau in cell culture and in vivo animal models.To study transfer between donor and recipient cells, donor primary neurons isolated from human tau expressing mice (line rTg4510) were co-cultured in microfluidic(MF) chambers with recipients that were either GFP expressing tau knockout, or wildtype neurons (model one). In another model (model two) in which more aggregates were formed, fluorescently tagged pro-aggregating domains of tau (RD) were expressed in neurons using lentivirus; mCherry was used to label the recipient cell population. Immunofluorescence (IF) and live imaging were performed to examine transfer of tau between donor and recipient neurons. To further increase tau aggregate formation (model three), brain-derived tau filaments or full length recombinant tau were used as seeds to induce endogenous tau templating, and the effect on propagation was monitored. To gain insight into possible mechanism of tau transfer between entorhinal cortex (EC) and mono-synaptically connected hippocampal cells, immuno-electron microscopy (IEM) was used to examine tau distribution in donor and recipient cells.1. In both models one and two, endogenously produced tau transferred from donor to recipient cells. Live imaging and IF revealed that donor tau was localized, and accumulated into synapses derived from recipient cells.2. In model three, exogenous aggregated tau was taken up and induced templating of endogenous full-length tau or RD. These tau aggregates transferred from donor to recipient cells in MFs.3. Tissue IEM showed human tau in pre-synaptic terminals derived from EC neurons that express tau transgene, and in post-synaptic compartments derived from recipient granule cell dendrites in the hippocampus.in vitro and in vivo models. Future studies will elucidate the relevance of synaptic accumulation and the mechanism by which propagation occurs.Our data demonstrates that endogenous produced, physiologically relevant tau, aggregates derived from tau fragments and tau generated by templating transferred between neurons in culture. Current data implicates synapses as a point of accumulation for tau during propagation"}
+{"text": "Effective improvement in sorghum crop development necessitates a genomics-based approach to identify functional genes and QTLs. Sequenced in 2009, a comprehensive annotation of the sorghum genome and the development of functional genomics resources is key to enable the discovery and deployment of regulatory and metabolic genes and gene networks for crop improvement.Sorghum bicolor exons and UTRs. The genechip contains 1,026,373 probes covering 149,182 exons  across the Sorghum bicolor nuclear, chloroplast, and mitochondrial genomes. Specific probesets were also included for putative non-coding RNAs that may play a role in gene regulation , and confirmed functional small RNAs in related species (maize and sugarcane) were also included in our array design. We generated expression data for 78 samples with a combination of four different tissue types , two dissected stem tissues (pith and rind) and six diverse genotypes, which included 6 public sorghum lines  representing grain, sweet, forage, and high biomass ideotypes.This study utilizes the first commercially available whole-transcriptome sorghum microarray (Sorgh-WTa520972F) to identify tissue and genotype-specific expression patterns for all identified Here we present a summary of the microarray dataset, including analysis of tissue-specific gene expression profiles and associated expression profiles of relevant metabolic pathways. With an aim to enable identification and functional characterization of genes in sorghum, this expression atlas presents a new and valuable resource to the research community. Its unique and advanced ability to grow in regions of low and variable rainfall highlight its potential to impact agricultural productivity in widespread water-limited environments [\u0394]Ct) [\u0394]Ct) . Gene exhttp://affymetrix.com).The transcriptome dataset supporting the results of this article is available through NCBI's Gene Expression Omnibus (GEO) under accession number GSE49879, and the Sorghum Genome Array is available through Affymetrix . Common: genes expressed in all 78 tissue types .Click here for fileGene Ontology classifications in the biological processes category identified using the AgriGO Singular Enrichment Analysis (SEA).Click here for fileIdentification of stably expressed genes.Click here for fileList of small RNAs  included in microarray design.Click here for fileNumber of tissue-specific small RNAs across sorghum ideotypes. AR2400: biomass sorghum; Fremont: sweet sorghum; PI152611: forage sorghum; Common: number of genes in common among all three ideotypes.Click here for fileExpression of select sucrose metabolizing enzyme/transporter genes.Click here for fileExpression of select phenylpropanoid-monolignol biosynthesis pathway genes.Click here for file"}
+{"text": "Approximately one third of patients treated with cardiac resynchronization therapy do not derive any detectable benefit. In these patients, acute invasive hemodynamic evaluation can be used for therapy optimization. This report describes the use of systematic invasive hemodynamic measurements for clinical decision making in a patient who experienced severe ventricular arrhythmias and clinical deterioration following a biventricular upgrade. Cardiac resynchronization therapy (CRT) has been established as an effective treatment for heart failure patients with severe left ventricular (LV) systolic impairment and electrical dyssynchrony . UnfortuA 65-year-old male patient with non-ischemic dilated cardiomyopathy, left ventricular ejection fraction of 20%, intra-ventricular conduction delay with a QRS duration of 148 ms, and NYHA class 3 was scheduled for upgrade of an implantable cardioverter defibrillator (ICD) to a cardiac resynchronization therapy - defibrillation (CRT-D) system. The ICD had previously been implanted for primary prevention. Echocardiography prior to the BiV upgrade demonstrated myocardial scarring of the LV lateral wall and showed no evidence of mechanical dyssynchrony. Unfavorable coronary venous anatomy required epicardial LV lead placement in the lateral position via minimal lateral thoracotomy. Four weeks later, the patient was admitted with multiple ICD discharges due to incessant ventricular tachycardia (VT) . He was An invasive hemodynamic pacing study was performed to evaluate the hemodynamic effect of conventional BiV pacing and to explore whether LV endocardial pacing could effectuate hemodynamic improvement. For this purpose, a temporary pacing electrode and a RADI pressure wire were positioned within the LV cavity, another temporary pacing electrode was placed in the right atrium . The RADNeither LV, RV or BiV pacing with the implanted system nor LV endocardial pacing at different sites improved LVdP/dtmax as compared to baseline . FurtherPatient selection plays an important role in CRT response. According to the ESC heart failure guidelines available at the time of device implantation, our patient had a class I indication for CRT . HoweverThe presence of myocardial scar at the area targeted by the LV lead is an important determinant of CRT response . Lead poIn a small percentage of patients, CRT may potentiate ventricular tachyarrhythmias. The exact mechanisms of proarrhythmia remain largely unclear but our findings suggest that pacing in the region of myocardial scar may facilitate its development. This conception is supported by the morphology of the VT which suggested a lateral exit site close to the LV epicardial pacing lead. A suggested underlying mechanism is a potential increase in local myocardial oxygen demand by pacing, precipitating ischemia in the peri-infarct zone and making it vulnerable to re-entry ,9. The cThis case report illustrates the potential contribution of acute invasive hemodynamic evaluation to clinical decision making in CRT. Acute hemodynamic testing may also be considered as a step-up approach to justify implantation of a LV endocardial lead and to guide lead positioning optimization. Finally, this case underlines the importance of considering the possibility of CRT related proarrhythmia, whenever CRT treated patients develop new ventricular tachyarrhythmia's."}
+{"text": "Nitric oxide (NO) is a potent biological mediator and plays an important role in cardiovascular homeostasis. Here it activates the soluble guanylyl cyclase (sGC) that synthesizes cGMP. The intracellular second messenger cGMP regulates vascular tone, vascular permeability, modulates inflammation and platelet reactivity. In platelets cGMP activates platelet inhibitory pathways via PKG and thereby inhibits platelet activation. Many cardiovascular diseases e.g. pulmonary arterial hypertension (PAH), are associated to a defective NO signalling. Therefore agents that stimulate the sGC are interesting therapeutic tools for the treatment of several cardiovascular diseases.Riociguat (Bay 63-2561) stimulates the sGC NO-independently without the risk of nitrate tolerance. Clinical Phase II and III studies determined the efficacy and tolerability in pulmonary hypertension patients. Riociguat was well tolerated and also significantly improved exercise capacity and hemodynamic parameters. To further analyse the effects of riociguat on platelet activation we tested the inhibitory effects on functions in isolated platelets and whole blood to elucidate additional applications of riociguat and to estimate adverse effects such as increased bleeding tendencies.In order to study the effects of riociguat on platelet sGC activity we monitored the VASP phosphorylation and cyclic nucleotides in washed platelets. Already low therapeutically relevant doses of 0.1 \u00b5M riociguat increased cGMP levels and VASP phosphorylation significantly. Consistent to these findings ADP induced platelet activation in washed platelets, as shown by platelet shape change, aggregation and integrin activation, was significantly impaired using low doses of riociguat. Additionally adhesion on collagen under shear conditions is significantly reduced in platelet riched plasma. In contrast to that one hundred times higher concentrations of riociguat were needed to obtain a significant increase of VASP phosphorylation as well as a significant inhibition of ADP induced aggregation in whole blood.Our results indicate that riociguat treatment will not lead to an increased bleeding tendency in pulmonary hypertension patients. Additional possible applications of riociguat, where targeting platelet function is beneficial, might be achieved using higher doses of riociguat."}
+{"text": "People who have extremely high-arched feet or pes cavus often suffer from substantial foot pain. Custom-made foot orthoses have been shown to be an effective treatment option, but their specificity is unclear. It is generally thought that one of the primary functions of custom foot orthoses is redistribution of abnormal plantar pressures. This study sought to identify variables associated with pain relief after custom foot orthoses intervention.\u00ae in-shoe plantar pressure data from a randomised controlled trial of 154 participants with painful pes cavus were retrospectively re-analysed at baseline and three month post orthoses intervention. The participants were randomised to a treatment group prescribed custom-made foot orthoses or a control group given sham orthoses.Demographic, physical characteristics and Pedarp=0.03). Our final model predicted 73% of the variance in pain relief from custom foot orthoses and consisted of initial pain level, BMI, foot alignment, and changes in both Dynamic Plantar Loading Index and pressure-time integral. Results indicate that a primary function of effective orthotic therapy is redistribution of abnormal plantar pressures.No relationship between change in pressure magnitude and change in symptoms was found in either group. While redistribution of plantar pressure, measured with the Dynamic Plantar Loading Index, had a significant effect on pain relief (This study provides the mechanism by which custom-made foot orthoses reduce pain and disability in patients with painful pes cavus. The proposed model may assist in better designing and assessing orthotic therapy for pain relief in patients with a variety of painful foot disorders."}
+{"text": "Environmental Health Perspectives (EHP) established the Paper of the Year in 2008  mouse as an epigenetic biosensor to demonstrate that genistein, the major phytoestrogen in soy, increases DNA methylation of the Agouti gene, resulting in population-level decreased incidence of adult-onset obesity, diabetes, and cancer. At the inception of this study, epidemiological data suggested that increased dietary genistein plays a role in decreased incidence of cancer in Asians compared with Westerners. Thus, they hypothesized that early dietary exposures, including genistein, might be linked to adult health status via epigenetic mechanisms. These authors demonstrated that maternal dietary genistein supplementation of mice during gestation at levels comparable to humans consuming high soy diets shifted the coat color of heterozygous viable yellow agouti (Avy/a) offspring toward pseudoagouti. This phenotypic change was significantly associated with increased methylation of six cytosine\u2013guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. A significant finding was that genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from adult-onset obesity.in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome. They also established the framework for future studies by showing that both genistein and methyl donors, such as folic acid, betaine, and choline, counteract DNA hypomethylation caused by bisphenol A, an endocrine-active agent used to make polycarbonate plastic. Their results showed that simple dietary changes can protect against the deleterious effects of environmental toxicants on the fetal epigenome (pigenome .EHP congratulates Dolinoy and colleagues for their contribution to the environmental health science literature. In addition to demonstrating that single-nucleotide polymorphisms can affect environmentally responsive genes, they demonstrated that early nutritionally and environmentally induced epigenetic modifications may be an alternative mechanism underlying individual susceptibilities to environmental agents."}
+{"text": "Insecticide Treated Nets (ITNs) remain an important tool for sustained malaria control and play an integral part in malaria elimination strategies. As malaria incidence decreases in holodemic areas, however, proactive and regular use of ITNs may simultaneously decline if risk perception diminishes.In Summer 2012, we conducted a cross-sectional survey of three communities in Vanuatu: i) where malaria has been locally eliminated (Aneityum), ii) where malaria remains present but with rapidly declining incidence (Ambae), and iii) an urban area where malaria transmission may or may not occur (Efate). Respondents were asked a battery of questions regarding knowledge of malaria, ITN possession and use, and compliance with other anti-malaria interventions. Information on basic demographics, education levels, dietary habits and household economic activities were also recorded.Residents of Aneityum  reported near universal use of ITNs, but uneven knowledge of malaria, particularly in younger individuals born around the time of malaria elimination. Residents in the other communities reported less consistent, though high levels of ITN use despite past individual malaria diagnoses.Results indicate that achieving sustained high levels of ITN use in near- and post-elimination contexts is possible, but that maintaining awareness could present a long-term challenge to prevent reintroduction and recrudensence. Sustained local community cooperation will be essential to maintaining elimination efforts worldwide."}
+{"text": "Implantable cardioverter defibrillator (ICD) is the currently accepted treatment for prevention of sudden cardiac death (SCD). Left ventricular ejection fraction is the only useful tool currently available to risk stratify patients at risk of SCD. Several other parameters have been studied for further risk stratification of SCD. Selection of appropriate subjects will improve the efficacy of treatment and also avoid unwanted ICD implantations in low risk patients. Role of QRS duration, QT dispersion, signal-averaged ECG, heart rate variability, ambulatory ECG monitoring, heart rate turbulence, T wave alternans, baroreceptor sensitivity and heart rate recovery have been investigated to identify patients at higher risk of arrhythmia and sudden cardiac death. However, none of these non-invasive tests could reliably stratify patients at risk of sudden cardiac death .Fragmented QRS complex (fQRS) has been identified as one of the non-invasive markers of mortality and sudden cardiac death . fQRS haIn this issue of the journal Apiyasawat et al  have repThus based on the available data in the literature, fQRS cannot be reliably used for risk stratification of SCD currently. More understanding is needed on the relation between fQRS, scar burden and arrhythmia inducibility  before i"}
+{"text": "Myocardial PVM may be used to assess peak velocities and the times to those peaks (TTP) in order to characterise healthy and pathological regional heart motion . HoweverAn efficient navigator-gated spiral trajectory PVM sequence  was used to scan basal, mid-ventricular and apical short-axis slices in ten healthy volunteers on two separate occasions. Retrospective cardiac gating was implemented, allowing analysis of all major velocity peaks throughout the cardiac cycle, including atrial systole. The reproducibility of peak velocities and their TTP values was assessed by Bland Altman analysis. Analysis of TTP vales was repeated after normalisation to a fixed systolic and diastolic length.Reproducibility data are shown in Table High temporal resolution myocardial PVM with retrospective cardiac gating is a highly reproducible technique for measuring all peak velocities in the cardiac cycle, including those in atrial systole. Absolute and normalised systolic TTP values have comparable reproducibility. However the reproducibility of diastolic TTP values is improved following normalisation to a fixed systolic and diastolic length. This is particularly apparent for the late diastolic peak representing atrial systole.The authors acknowledge the support of Heart Research UK, Imperial College London and NIHR Royal Brompton Cardiovascular Biomedical Research Unit."}
+{"text": "Many drugs are characterized by polypharmacological mechanisms of action. Thus, prospective drug discovery studies often start by testing large compound libraries in multiple and diverse High-Throughput Screening (HTS) assays. These large heterogeneous data collections pose numerous computational challenges concerning processing, curation, and analysis of untreated output files generated by plate readers. We have developed the freely-accessible HTS Navigator software to enable and facilitate the processing and analysis of polypharmacological HTS data. We report on the capabilities of Navigator and present several case studies where we employed cheminformatics approaches embedded within the Navigator to curate and analyze large datasets of compounds tested toward different panels of targets. Examples include libraries of compounds tested for their inhibition potencies across several CYP450; or for their inhibition of multiple protein kinases; or their binding profiles against multiple GPCRs. We show how to quickly identify and highlight compounds with unique mono- and dual- selectivity for certain targets in the curated HTS matrix. We discuss the problem of experimental variability in HTS data and its consequences for molecular modeling and emphasize the synergistic potential of different cheminformatics approaches to detect both false-positive and false-negative compounds using neighborhood analysis and target baseline correction factors. Finally, we describe the Chemical\u2212Biological Read-Across (CBRA) approach  also imp"}
+{"text": "Migraine attacks originate in the meninges which are densely innervated by trigeminal nerve fibers. Stimulated endothelial cells of dural blood vessels secrete nitric oxide, where neuropeptides are released from trigeminal nerve fibers. This, in turn, leads to meningeal Plasma Protein Extravasation (PPE), serving as an established indicator for migraine attacks in animal models. In our mouse migraine model, we sensitized mice against the 5-HT2B receptor agonist meta-chlorphenylpiperazine (mCPP). Mice kept under hypoxic conditions for four weeks displayed significantly elevated PPEs in the dura mater upon mCPP injection. Tissue accumulation of the tracer Evans Blue was measured to quantify the extent of the PPE. In this study, several histological tracers were employed to identify the part of the vasculature where PPE occurs and the cellular mechanism associated with it. Injections of BSA-FITC  verified the mCPP induced PPE in the dura mater. After leaving the blood vessels, the tracer was incorporated into perivascular, CD68-positive macrophages. With electron microscopic studies using the tracer HRP (horse radish peroxidase) we demonstrated that the PPE is associated with increased transcytotic transport. After 5-HT2B receptor activation, HRP escapes from capillaries and venules of hypoxic mice via an increased transcytotic transport in the endothelium. The hypoxic treatment itself increases transcytosis in arterioles, which may be indicative of a proinflammatory state of the endothelium. HRP was also detectable in intercellular clefts, but was always retained at tight junctions In summary, we demonstrated that in mice hypoxic treatment induces dural PPE via increased transcytotis at arterioles and that this is elevated to capillaries and venules after mCPP-injection."}
+{"text": "Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal infarction, lower limb ischaemia, and even acute myocardial infarction (MI), via embolisation to the coronary arteries. We present a case of acute MI, cardiogenic shock, and cardiac arrest caused not by this mechanism, but by embolisation of thrombotic material to the aortic root with transient complete occlusion of the left main stem (LMS) coronary artery. During percutaneous coronary intervention to treat this occlusion the thrombus became lodged at the aortic bifurcation causing lower limb ischaemia. Despite successful treatment of this via bilateral groin exploration and thromboembolectomy the patient became increasingly acidotic and an abdominal and pelvic CT scan was performed. This revealed the source of the thrombus to be the patient's congested and compressed pelvic veins which were the result of a large, previously undiagnosed ovarian malignancy with metastatic spread. Although very unusual we feel this case highlights an important differential in the diagnosis of anterolateral MI and images similar to those presented here are previously unreported in the literature. Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal infarction, lower limb ischaemia, and even acute myocardial infarction (MI), via embolisation to the coronary arteries. We present a case of acute MI, cardiogenic shock, and cardiac arrest caused not by this mechanism, but by embolisation of thrombotic material to the aortic root with transient complete occlusion of the left main stem (LMS) coronary artery.A 57-year-old woman presented acutely to the primary percutaneous coronary intervention (PCI) service at our institution with a history of indigestion-type symptoms for several hours followed by acute shortness of breath, back, and chest pain. She was previously fit and well with no personal or family history of cardiac disease. Her electrocardiogram (ECG) showed typical changes of anterolateral ST elevation myocardial infarction (STEMI) and she was transferred immediately to the catheterisation lab. The patient was haemodynamically unstable with signs of cardiogenic shock; femoral arterial and venous sheaths were inserted on arrival. Initial coronary angiography revealed a large irregular mass in the aortic root  causing 1) branch consistent with microembolisation. These findings were confirmed on transoesophageal echo (TOE) which also demonstrated anterior wall akinesis (as expected) and a patent foramen ovale with a small left-to-right shunt. However, an angiogram of the distal aorta revealed occlusion of the left common iliac artery with compromised lower limb circulation evident both angiographically , aortic root thrombus, or possible dissection. On return of cardiac output (within minutes) a repeat aortogram via the coronary guide-catheter was performed . Surprisphically  and clinAt this stage a vascular surgery opinion was sought and the decision made to perform urgent open groin exploration with thromboembolectomies bilaterally in the cardiac cath-lab. The patient remained critically unwell and required an intra-aortic balloon pump as well as increasing inotropic support to augment cardiac output. Successful catheter trawl proximally and distally restored lower limb perfusion and embolic material was sent for emergent histology, whilst four-compartment calf fasciotomies were performed to prevent the development of subsequent compartment syndrome. Despite this acute management the patient's clinical state continued to deteriorate with worsening metabolic acidosis, rising lactate levels, and falling blood glucose.An urgent CT scan was undertaken to exclude significant mesenteric ischaemia, however, this revealed the presence of a huge ovarian tumour with pelvic venous congestion, thrombus, and evidence of widespread metastatic spread or \u201comental cake\u201d. There was no evidence of bowel, renal or liver ischaemia however the patient continued to deteriorate and ITU support was sadly withdrawn after consultation with the patients' family and clinical team. Blood tests taken prior to deterioration did not reveal any evidence of thrombophilia although routine clotting parameters were deranged due to the patient's poor clinical state. A postmortem examination reinforced the clinical and radiological findings Figures  and 5 anAlthough a sad and thankfully rare case, we feel this paper illustrates an important differential in the cause of acute myocardial infarction. Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal, or renal infarction, and lower limb ischaemia. Paradoxical embolism to the coronary arteries has been previously proposed as a cause of MI  and bothTo our knowledge this is the first report of a venous thromboembolism causing complete coronary artery occlusion and subsequent iliac obstruction after entering the arterial circulation via PFO. As such this is a novel condition which highlights many learning points in terms of diagnosis and management, not least the importance of multidisciplinary team working between surgical, radiological, cardiological, and anaesthetic colleagues."}
+{"text": "Macropus and Wallabia) exhibit more expansive areas of high radiodensity in the distal tibia than arboreal  or terrestrial quadrupeds , which may reflect the former carrying body weight only through the hind limbs. Arboreal quadrupeds exhibit smallest areas of high radiodensity, though they differ non-significantly from terrestrial quadrupeds. This could indicate slightly more compliant gaits by arboreal quadrupeds compared to terrestrial quadrupeds. The observed radiodensity patterns in marsupial tibiae, though their statistical differences disappear when controlling for phylogeny, corroborate previously documented patterns in primates and xenarthrans, potentially reflecting inferred limb use during habitual activities such as locomotion. Despite the complex nature of factors contributing to joint loads, broad observance of these patterns across joints and across a variety of taxa suggests that subchondral radiodensity can be used as a unifying form-function principle within Mammalia.Joint surfaces of limb bones are loaded in compression by reaction forces generated from body weight and musculotendon complexes bridging them. In general, joints of eutherian mammals have regions of high radiodensity subchondral bone that are better at resisting compressive forces than low radiodensity subchondral bone. Identifying similar form-function relationships between subchondral radiodensity distribution and joint load distribution within the marsupial postcranium, in addition to providing a richer understanding of marsupial functional morphology, can serve as a phylogenetic control in evaluating analogous relationships within eutherian mammals. Where commonalities are established across phylogenetic borders, unifying principles in mammalian physiology, morphology, and behavior can be identified. Here, we assess subchondral radiodensity patterns in distal tibiae of several marsupial taxa characterized by different habitual activities . Computed tomography scanning, maximum intensity projection maps, and pixel counting were used to quantify radiodensity in 41 distal tibiae of bipedal (5 species), arboreal quadrupedal (4 species), and terrestrial quadrupedal (5 species) marsupials. Bipeds ( Dendrolagus; Dendrolagus), in that the former are able to decouple speed and cost of transport Eutherian and metatherian  lineages diverged approximately 160 million years ago Eutherian mammals and marsupials Compressive strength of subchondral bone is determined by mineral content and porosity Primates and xenarthrans exhibit subchondral radiodensity patterns that corroborate theoretical expectations of limb loading according to their habitual activity patterns . Human distal radii exhibit lower weight-bearing (compressive) loads compared to suspensory and quadrupedal primates, as would be expected since human forelimbs no longer have an active weight-bearing role in locomotion Mammalia. In order to achieve these aims, we test two predictions. First, bipedal marsupials should exhibit significantly more expansive high radiodensity area in the distal tibia compared to quadrupedal marsupials because of the unique mechanics of their hopping gait, and because they carry body weight only through the hind limbs rather than all four limbs . Second, high radiodensity area in distal tibiae of terrestrial quadrupedal marsupials should exceed high radiodensity area in distal tibiae of arboreal quadrupedal marsupials because the latter may systematically adopt a more compliant gait, and/or systematically use more compliant arboreal substrates . If observed relationships between high radiodensity patterns and limb use in marsupials are consistent with previously documented relationships in eutherian mammals , it would be reasonable to elevate these relationships to unifying form-function principles throughout Mammalia.The goals of this study are two-fold. First, we aim to document whether a form-function relationship exists in radiodensity patterns in subchondral bone of marsupial distal tibiae. Second, we evaluate whether radiodensity patterns of subchondral bone exhibit a unifying form-function principle within The study sample consists of data derived from 41 marsupial tibiae housed in collections curated at the: Australian Museum (AM), Australian National Wildlife Collection (ANWC), Queensland Museum (QM), and Tasmanian Museum (TM)  maps from the standard reconstructions and fitted them to 3D renderings of distal tibiae generated from the bone reconstructions Following field observations and locomotor descriptions Ratio distributions for gait groups did not differ significantly from normal distributions according to a series of Kolmogorov-Smirnov Tests (p>0.05). Thus, we applied a series of one-way ANOVAs in order to statistically evaluate observed differences between gait group means . Gait grphytools package In our sample, some marsupial taxa representing gait groups are also closely related . In order to tease apart the extent to which observed gait group differences may have reflected phylogeny and function, we performed a second set of ANOVAs in which we accounted for phylogenetic effects (pANOVAs). We constructed a phylogenetic tree with known divergence dates  for taxaDendrolagus) has a comparatively low mean ratio of 0.017 (n\u200a=\u200a2). When accounting for phylogeny, the comparison of species means eliminates statistical significance  again has a comparatively low mean ratio of 0.300 (n\u200a=\u200a2) compared to other macropods. When accounting for phylogeny, the comparison of species means eliminates statistical significance , the ankle was observed to be the greatest contributor to whole limb work and power over a range of accelerations and decelerations The distinctiveness of distal tibiae of bipedal marsupials corroborates findings of others who have noted distinctiveness of the calcaneus of bipedal marsupials It was unexpected that mean radiodensity ratios of arboreal and terrestrial quadruped marsupials did not differ significantly. Arboreal quadrupedal primates exhibit gait compliancy compared to terrestrial quadrupedal primates, and thus limbs of the former experience lower peak vertical components of SRFs A second potential explanation for the unexpected non-significant difference between arboreal and terrestrial marsupial quadrupeds could be related to the application of such rigid gait and substrate use categories in the first place. There are a wealth of primate observational data on locomotor activities and substrate use Vombatus and Lasiorhinus) and non-fossorial terrestrial quadrupeds  would facilitate another potentially interesting comparison within marsupials. Wombats are described as emphasizing forelimbs during digging, while their hind limbs are primarily relegated to clearing accumulated sediment Expanding samples of fossorial , the observed trend exhibited by bipedal and quadrupedal marsupials adds to the accumulating evidence suggesting that the relationship between relative area of maximum radiodensity and joint compressive loads in limbs may be a unifying form-function principle amongst eutherian and metatherian mammals. By demonstrating how behavior influences morphology in a variety of mammals, these unifying principles support the existence of form-function signals in skeletal tissues that often elude comparative functional anatomists.Table S1Specimen information and raw data used in analyses.(XLS)Click here for additional data file.Table S2Nexus tree file used in the pANOVA. The phylogenetic tree with known divergence dates for taxa in the sample is based on recent molecular studies of marsupials (NEX)Click here for additional data file."}
+{"text": "Osteonecrosis after craniofacial radiation (ORN), osteomyelitis and bisphosphonates related necrosis of the jaw (BRONJ) are the predominant bone diseases in Cranio- and Maxillofacial surgery. Although various hypothesis for the pathophysiological mechanisms including infection, altered vascularisation or remodelling exist, the treatment is still a challenge for clinicians. As the classical pharmacological or surgical treatment protocols have only limited success, stem cells might be a promising treatment option, indicated by recently published data. In maxillofacial surgery clinicians face three diseases of the jaws predominantly: osteonecrosis after craniofacial radiation (ORN), osteomyelitis and bisphosphonates related necrosis of the jaw (BRONJ). Numerous reports exist suggesting various pathological mechanisms and treatment modalities for these diseases ,2. Altho"}
+{"text": "Transcranial direct current stimulation (tDCS) is a promising tool for cognitive enhancement and neurorehabilitation in clinical disorders in both cognitive and clinical domains . Here we suggest the potential role of tDCS in modulating cortical excitation/inhibition (E/I) balance and thereby inducing improvements. We suggest that part of the mechanism of action of tDCS can be explained by non-invasive modulations of the E/I balance. Cognitive enhancement is a popular topic in the neuroscience community. Non-invasive neuromodulation methods, such as transcranial direct current stimulation (tDCS) can either increase  or decrease  cortical excitability  studies have shown that anodal tDCS reduces local concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), whereas cathodal tDCS reduces excitatory glutamate levels  receptors and brain-derived neurotrophic factor (BDNF) in the synaptic potentiation of the motor cortex after anodal tDCS  balance, measured by ratios of glutamate/GABA, may provide more meaningful interpretations of individual cognitive performance and deficits than glutamate or GABA alone. GABA and glutamate contribute in a complementary fashion to high-level prefrontal cognitive performance in healthy adults  and transcranial alternating current stimulation (tACS) is currently unknown and requires further exploration.Roi Cohen Kadosh filed a patent for an apparatus for improving and/or maintaining numerical ability."}
+{"text": "RPE65) gene. Tremendous challenges still lie ahead to extrapolate these studies to other retinal disease-causing genes, as human gene augmentation studies require testing in animal models for each individual gene and sufficiently large patient cohorts for clinical trials remain to be identified through cost-effective mutation screening protocols.Retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to be incurable. In the last two decades genetic studies have shed light on the molecular causes of several of these diseases, which has opened new avenues to develop therapeutic approaches. The mammalian eye has been at the forefront of therapeutic trials based on gene augmentation in humans with Leber congenital amaurosis, an early-onset recessive retinal dystrophy, due to mutations in the retinal pigment epithelium-specific protein 65 kDa (Pharmacological approaches to antagonize retinal degeneration are also under development, including modulation of the immune system."}
+{"text": "While the effects of hypoxia on stem cells have been examined under in vivo hypoxia on a recently characterized population of pluripotent stem cells known as very small embryonic-like stem cells (VSELs) by whole-genome expression profiling and measuring peripheral blood stem cell chemokine levels.We investigated the effects of We found that exposure to hypoxia in mice mobilized VSELs from the bone marrow to peripheral blood, and induced a distinct genome-wide transcriptional signature. Applying a computationally-intensive methodology, we identified a hypoxia-induced gene interaction network that was functionally enriched in a diverse array of programs including organ-specific development, stress response, and wound repair. Topographic analysis of the network highlighted a number of densely connected hubs that may represent key controllers of stem cell response during hypoxia and, therefore, serve as putative targets for altering the pathophysiologic consequences of hypoxic burden.A brief exposure to hypoxia recruits pluripotent stem cells to the peripheral circulation and actives diverse transcriptional programs that are orchestrated by a selective number of key genes. Hypoxia is a pathophysiologic condition commonly seen in lung diseases and in many other disorders such as tissue ischemia and cancer . In the et al isolated a homogenous population of rare, small stem cells from adult murine BM mononuclear cells that expressed embryonic lineage markers, and were thus named very small embryonic-like stem cells (VSELs) .Click here for fileGene product interaction network of differentially expressed genes in VSELs. This file contains two figures depicting a gene product interaction network of differentially expressed genes in VSELs after in vivo exposure to hypoxia. Panel (A) highlights up and downregulated genes (red and green respectively). This network has 424 genes (nodes) and 604 connections (edges). Note that each connection represents a known direct interaction between two gene products. Panel (B) demonstrates that the topology of this network is scale-free because it follows a power law distribution. Nk, degree distribution; k, nodal connectivity.Click here for file"}
+{"text": "The great importance of cytological examination in diagnostic procedures of thyroid gland pathological lesions is widely known. Unfortunately, cytology as a diagnostic method presents many limitations due to possible presence of elements abnormal for thyroid gland physiology and histology. Especially difficult in cytological diagnosis appear: among non-neoplastic lesions - dyshormonogenetic and amyloid goiter and Riedel disease and among neoplastic lesions - rare microscopic variants of tumours, neoplasms arising from ectopic tissues and nonepithelial tumours."}
+{"text": "Human monoclonal antibodies have been characterized recently that potently neutralize HIV-1 isolates across all clades. These exciting new antibodies (PGT series) were derived from direct functional screening of B cells from IAVI protocol G donors (Theraclone/Monogram) and are unusually potent with binding predicted to be to novel glycan-dependent epitopes on Env.Structures of these new PGT antibodies are being determined by x-ray crystallography and electron microscopy with further characterization using binding and mutagenesis assays.The crystal and EM structures so far have been elucidated for many of these antibodies. Work on the others are in progress, focusing on Fab complexes with glycans, gp120 core and fragment constructs, as well as Env trimers.Structural characterization and biochemical analysis of these antibodies have uncovered novel specificities to new glycan-dependent epitopes and reveal further mechanisms for viral neutralization. These new epitopes provide additional insights for neutralization of HIV-1 and how antibodies can bind and penetrate the glycan shield, a novel framework for structure-assisted vaccine design.This study was supported by the International AIDS Vaccine Initiative (IAVI), Ragon Institute of MGH, MIT and Harvard, and NIH AI84817."}
+{"text": "Self-organized criticality refers to the spontaneous emergence of self-similar dynamics in complex systems poised between order and randomness. The presence of self-organized critical dynamics in the brain is theoretically appealing and is supported by recent neurophysiological studies. Despite this, the neurobiological determinants of these dynamics have not been previously sought. Here, we systematically examined the influence of such determinants in hierarchically modular networks of leaky integrate-and-fire neurons with spike-timing-dependent synaptic plasticity and axonal conduction delays. We characterized emergent dynamics in our networks by distributions of active neuronal ensemble modules  and rigorously assessed these distributions for power-law scaling. We found that spike-timing-dependent synaptic plasticity enabled a rapid phase transition from random subcritical dynamics to ordered supercritical dynamics. Importantly, modular connectivity and low wiring cost broadened this transition, and enabled a regime indicative of self-organized criticality. The regime only occurred when modular connectivity, low wiring cost and synaptic plasticity were simultaneously present, and the regime was most evident when between-module connection density scaled as a power-law. The regime was robust to variations in other neurobiologically relevant parameters and favored systems with low external drive and strong internal interactions. Increases in system size and connectivity facilitated internal interactions, permitting reductions in external drive and facilitating convergence of postsynaptic-response magnitude and synaptic-plasticity learning rate parameter values towards neurobiologically realistic levels. We hence infer a novel association between self-organized critical neuronal dynamics and several neurobiologically realistic features of structural connectivity. The central role of these features in our model may reflect their importance for neuronal information processing. The intricate relationship between structural brain connectivity and functional brain activity is an important and intriguing research area. Brain structure  is thought to strongly influence and constrain brain function . Concurrently, brain function is thought to gradually reshape brain structure, through processes such as activity-dependent plasticity . In this study, we examined the relationship between brain structure and function in a biologically realistic mathematical model. More specifically, we considered the relationship between realistic features of brain structure, such as self-similar organization of specialized brain regions at multiple spatial scales  and realistic features of brain activity, such as self-similar complex dynamics poised between order and randomness . We found a direct association between these structural and functional features in our model. This association only occurred in the presence of activity-dependent plasticity, and may reflect the importance of the corresponding structural and functional features in neuronal information processing. The temporal and spatial statistics of EEG, ECoG, MEG and fMRI signals likewise show power-law scaling Self-organized criticality is increasingly postulated to underlie the organization of brain activity Brain dynamics are thought to be strongly influenced by neuroanatomical connectivity The presence of an intuitive association between self-similar brain structure  and self-similar brain dynamics , has not been previously examined. The relationship between brain structure and dynamics is reciprocal: while the structure strongly constrains the dynamics, the dynamics continuously modify the structure through mechanisms such as activity-dependent synaptic depression A number of modeling studies recently reported self-organized critical avalanche dynamics in neuronal networks with nontrivial topology and activity-dependent plasticity The fundamental organizational unit of our network model is a densely connected 100-neuron module The studied leaky integrate-and-fire neuron evolves according toormation .For a postsynaptic neuron Synaptic weights changed at every spike of a neuron incident to the synapse, according to a spike-timing-dependent plasticity (STDP) rule . The STDibutions . The uniParameter values of the model were adapted from the Thivierge and Cisek Each network comprised l levels . The denff rates . SynapseThe wiring cost associated with each scaling function was computed by estimating the number of synapses in each hierarchical level for that function, equating the cost of each synapse with the number of its hierarchical level  to other meaningful changes in neurobiologically relevant parameters, such as changes in external current, changes in conduction delays, changes in the postsynaptic response, presence of neuronal inhibition, changes in the STDP rule and changes in network size . Theoretvity see , but begweakened , top, buweakened , bottom.in vivo each neuron is thought to have thousands of synapses. We compensated for the small number of connections in our model by setting the postsynaptic-response magnitude of each neuron to a value which could theoretically exceed the neuron spike threshold and by using an instantaneous STDP learning rate that substantially exceeds empirically observed values  and self-similarity of dynamics . We now discuss the mechanisms behind this association, and the implication of our findings for empirical research.We found that despite seemingly stable neuronal activity, spike-timing-dependent plasticity enabled coherent within- and between-module neuronal activity. Furthermore, we showed that two variations of the STDP rule produced distinct weight distributions, but enabled a broad critical regime on conducive network topologies. In contrast, fixed or randomly altered synaptic weights were associated with subcritical dynamics and negligible module spike rates. STDP may facilitate coherent within-module activity by intermittently potentiating and depressing synapses between reciprocally connected neurons. In small networks, simulations showed that intermittent synaptic potentiation and depression was associated with pairwise neuronal synchrony, fluctuations of synaptic weights and continuous reversal of phase differences between reciprocally connected pairs of neurons (results not shown). In our networks, within-module weights were potentiated during module spikes, and depressed between module spikes . These aRecent studies have shown the importance of short-term synaptic depression in self-organized critical dynamics in networks of spiking neurons, but have not concurrently considered the effects of STDP Modular networks with low wiring cost showed a broad critical regime. Modular networks with high wiring cost showed a narrow critical regime, possibly due to high numbers of costly long-range connections, which enabled a rapid onset of globally synchronous, supercritical dynamics. Lattice networks with low wiring cost showed a narrowed critical regime due to uncoordinated inhibition and a consequent loss of coherent ensemble dynamics. Modularity and low wiring cost were hence simultaneously required for self-organized criticality to emerge. This simultaneous requirement is notable, as both properties are thought to be ubiquitously present in neuroanatomical organization.In an early comprehensive exposition, Jensen We found that inhibitory neurons in our model did not explicitly enable a broad critical regime. In contrast, recent network simulations of simple stochastic neurons by Benayoun et al. Our findings may be used to generate empirically testable hypotheses of the relationship between anatomical connectivity and emergent network dynamics. For instance, we hypothesize that self-organized critical dynamics in dissociated neuronal cultures emerge on a low-cost modular neuroanatomical connectivity. Recent studies show that dissociated neuronal cultures self-organize towards a critical state, via subcritical and supercritical states Our findings may hence be used to explicitly compare structure and dynamics of dissociated neuronal cultures, throughout this period of self-organization. A recent study found that functional activity patterns of dissociated neuronal cultures constitute a small-world network A clear limitation of our study is the oversimplified symmetric hierarchical organization and the relatively small size of our model. Substantial increases in the number of modules, and in the number of neurons within modules, are required to make realistic inferences about neuronal dynamics at larger scales. The study hence sets the groundwork for simulations of large networks of spiking neurons and for characterization of spatiotemporal activity patterns emergent on these networks. Such simulations may be conducted on increasingly detailed maps of large-scale anatomical connectivity in healthy subjects Studies of neuronal dynamics often employ numerical integration schemes (such as the Euler method), and manually store all previous spike times to compute synaptic currents. An advantage of the integrate-and-fire neuron model is the ability to integrate subthreshold activity exactly and incorporate effects of all previous spikes without the need for explicit summation at each step Despite growing empirical evidence for self-organized criticality, several important studies argue against this evidence, by either noting the potential for spurious reports of power-law scaling, or by attributing such scaling to simpler mechanisms, such as diffusive processes In conclusion, we show an association between modularity, low cost of wiring, synaptic plasticity and self-organized criticality in a neurobiologically realistic model of neuronal activity. Our findings theoretically reinforce the reciprocal relationship between connectivity and dynamics on multiple spatial scales.Text S1Supporting information code.(PDF)Click here for additional data file.Text S2Supporting information code.(TXT)Click here for additional data file.Text S3Supporting information code.(TXT)Click here for additional data file.Text S4Supporting information code.(TXT)Click here for additional data file.Text S5Supporting information code.(TXT)Click here for additional data file.Text S6Supporting information code.(TXT)Click here for additional data file.Text S7Supporting information code.(TXT)Click here for additional data file.Text S8Supporting information code.(TXT)Click here for additional data file.Text S9Supporting information code.(TXT)Click here for additional data file.Text S10Supporting information code.(TXT)Click here for additional data file.Text S11Supporting information code.(TXT)Click here for additional data file.Text S12Supporting information code.(TXT)Click here for additional data file.Text S13Supporting information code.(TXT)Click here for additional data file.Text S14Supporting information code.(TXT)Click here for additional data file.Text S15Supporting information code.(TXT)Click here for additional data file.Text S16Supporting information code.(TXT)Click here for additional data file.Text S17Supporting information code.(TXT)Click here for additional data file."}
+{"text": "The role of cortical feedback in thalamo-cortical processing loop have been extensively investigated over the last decades. In general, these studies focused on cortical feedback exerted over lateral geniculate nucleus (LGN) principal cells, only in several cases the effects of cortical inactivation were investigated simultaneously in both thalamic relay cells and perigeniculate nucleus (PGN) inhibitory neurons. In the previous study  we showeTo identify network mechanisms underlying such functional changes we conducted a modelling study in NEURON on several networks of point neurons with varied model parameters, such as membrane properties, synaptic weights and axonal delays. We considered five network topologies of the retino-geniculo-cortical pathway -6.All models were robust against changes of axonal delays except for delay between LGN feed-forward interneuron and principal cell when this connection was present. In all such cases the models were found to be very sensitive to this delay. To reproduce the experimental results  the mode"}
+{"text": "Pulmonary tumor thrombotic microangiopathy is a rare complication of malignant diseases. The diagnosis is extremely difficult and is most often performed after death. Invariably, patients develop acute pulmonary hypertension causing right heart failure, shortness of breath and death in a few days. We describe the clinical and radiological findings of a patient who presented with this complication.A 28-year-old Caucasian woman with a previous history of pelvic tumor resection two months previously, suggestive of metastatic adenocarcinoma, presented with intense shortness of breath. A computed tomography scan showed signs of acute cor pulmonale and diffuse nodular opacities associated with a tree-in-bud pattern disseminated through her lungs, suggestive of bronchiolitis. Our patient's condition worsened and she underwent a surgical biopsy. Pathologic analysis of the biopsied specimens revealed pulmonary tumor thrombotic microangiopathy. Our patient's tumor evolved from a gastric origin (Krukenberg tumor). She underwent progressive clinical deterioration and died less than 24 hours after the biopsy. None of the cases described previously in the literature had diffuse centrilobular nodular opacities associated with a tree-in-bud pattern disseminated through the lungs, as in our case.Pulmonary tumor thrombotic microangiopathy should be considered in cancer patients with rapidly progressing dyspnea, chest computed tomography findings compatible with pulmonary hypertension and typical findings of inflammatory bronchiolitis. Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare complication of malignant diseases. The diagnosis is extremely difficult and is most often performed after death . InvariaA 28-year-old Caucasian woman presented to our hospital with a previous history of abnormal vaginal bleeding and abdominal pain that had begun four months prior to her initial presentation. A transvaginal ultrasound was performed at that time and demonstrated solid lesions in her left adnexal region, confirmed two weeks later with magnetic resonance imaging. She then underwent an exploratory laparotomy with a bilateral anexectomia. A pathological examination diagnosed a solid poorly differentiated adenocarcinoma, with signet ring cells diffusely infiltrating the ovaries and fallopian tubes bilaterally, compatible with a metastatic pelvic tumor of probable gastric origin, traditionally known as a Krukenberg tumor. After surgery, during the staging and treatment planning, our patient presented to our Emergency Room complaining of dry cough and shortness of breath of recent onset, with intense and progressive worsening. She had no other complaints and no fever. On examination, she was in generally poor condition, malnourished, dehydrated, with tachycardia and dyspnea; pulmonary auscultation revealed decreased breath sounds and mild wheezing in both lungs. Her leukocyte count showed no signs of infection; a blood test revealed the presence of mild anemia and a chest X-ray showed no abnormalities. Due to clinical suspicion of a pulmonary thromboembolism, our patient underwent a computed tomography (CT) scan of her chest, pelvis and thighs. Although the angiographic phase did not present any signs of pulmonary thromboembolism, the CT scan showed signs of acute cor pulmonale characterized by increased right heart chamber dimensions, slight interventricular septum deviation and a right ventricular to left ventricular ratio greater than 1.5 Figures , 4 and 5Laboratory investigations were remarkable for microcytic anemia  and a strongly positive D dimer (1100 ng/mL). Her arterial blood gas examination breathing room air showed hypoxia with respiratory alkalosis . Our patient was admitted with a presumptive diagnosis of pulmonary thromboembolic disease.PTTM is a rare complication of malignancies commonly detected after death. It was first described by von Herbay and colleagues as a diffuse intimal myofibroblast proliferation that causes pulmonary hypertension, leading to cardiopulmonary failure and death . This diDistinguishing between the clinical presentation of lymphatic and microvascular disease can be challenging, and many authors do not distinguish between these two. Soares and colleagues evaluated a series of 222 patients who had undergone autopsy, including 19 with microvascular pulmonary arterial embolism and 44 with lymphangitic carcinomatosis . AlthougOn histopathological investigation, pulmonary tumor thrombotic microangiopathy is characterized by widespread fibrocellular intimal hyperplasia of small pulmonary arteries, also called carcinomatous endarteritis induced by tumor microemboli . DiffuseNone of the cases described previously in the literature had diffuse centrilobular nodular opacities associated with a tree-in-bud pattern disseminated through the lungs, as in our case.PTTM should be considered in cancer patients with a rapidly progressing dyspnea, chest CT compatible with pulmonary hypertension and typical findings of inflammatory bronchiolitis.Written informed consent was obtained from our patient's next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.All the authors contributed to the writing of the paper. The original manuscript was written by MFA and AB, and the final version by MDG. RC and JLG contributed the CT images and additional references. All authors read and approved the final manuscript"}
+{"text": "Ungulates exert a strong influence on the composition and diversity of vegetation communities. However, little is known about how ungulate browsing pressure interacts with episodic disturbances such as fire and stand thinning. We assessed shrub responses to variable browsing pressure by cattle and elk in fuels treated  and non-fuels treated forest sites in northeastern Oregon, US. Seven treatment paddocks were established at each site; three with cattle exclusion and low, moderate and high elk browsing pressure, three with elk exclusion and low, moderate and high cattle browsing pressure, and one with both cattle and elk exclusion. The height, cover and number of stems of each shrub species were recorded at multiple plots within each paddock at the time of establishment and six years later. Changes in shrub species composition over the six year period were explored using multivariate analyses. Generalized Linear Mixed Models were used to determine the effect of browsing pressure on the change in shrub diversity and evenness. Vegetation composition in un-browsed paddocks changed more strongly and in different trajectories than in browsed paddocks at sites that were not fuels treated. In fuels treated sites, changes in composition were minimal for un-browsed paddocks. Shrub diversity and evenness decreased strongly in un-browsed paddocks relative to paddocks with low, moderate and high browsing pressure at non-fuels treated sites, but not at fuels treated sites. These results suggest that in the combined absence of fire, mechanical thinning and ungulate browsing, shrub diversity is reduced due to increased dominance by certain shrub species which are otherwise suppressed by ungulates and/or fuels removal. Accordingly, ungulate browsing, even at low intensities, can be used to suppress dominant shrub species and maintain diversity in the absence of episodic disturbance events. Both livestock and wild ungulates commonly occupy high elevation pastures during the summer months in many parts of the globe. In the western United States, most ranchers bring their livestock to high elevation summer pastures that are located within public forest lands Considerable research has been conducted on the separate impacts of fires Odocoileus virginianus) led to loss of preferred woody species which in turn resulted in increased abundance of less palatable understory plants such as sedges Both episodic disturbances The response of vegetation diversity to ungulates can also vary depending on browsing frequency and intensity We measured the compositional and diversity responses of native forest shrubs  to variable browsing pressure over several years from dominant ungulate herbivores, cattle and elk, at sites where fuel loads were mechanically removed and followed by prescribed fire, and at sites with no history of fire or fuels removal for 40 years (referred to fuels treated and non-fuels treated respectively from here on). We hypothesized that vegetation responses to browsing would vary between fuels treated and non-fuels treated sites, and that the greatest level of diversity would be achieved at moderate levels of browsing pressure, particularly at non-fuels treated sites where shrub cover and dominance is high.Research was conducted under approval and guidance by an Institutional Animal Care and Use Committee (IACUC 92-F-0004), as required by the United States Animal Welfare Act of 1985, following the IACUC protocol for conducting cattle, elk, and mule deer research in our study area. Permission to perform the study was given by the USDA Forest Service Pacific Northwest Research Station.Our study was carried out within the Starkey Experimental Forest and Range (SEFR) in the Blue Mountains Ecological Province of northeast Oregon , approxiPseudotsuga menziesii) and grand fir (Abies grandis) Conditions at SEFR are typical of montane forest types of interior western North America Pinus ponderosa), western larch , lodgepole pine (Pinus contorta), and Englemann spruce (Picea engelmannii). Common understory grass and grass-like species include Idaho fescue (Festuca idahoensis), elk sedge (Carex geyeri), pinegrass , western fescue , Kentucky bluegrass (Poa pratensis), and annual bromes (Bromus spp.). Common forbs include lupine (Lupinus spp.), strawberry (Fragaria spp.), tall annual willowherb (Epilobium paniculatum), and western yarrow (Achillea millefolium). Common shrub species include bearberry (Arctostaphylos uva-ursi), big huckleberry (Vaccinium membranaceum), grouse huckleberry (Vaccinium scoparium), rose (Rosa spp), snowberry , shinyleaf spiraea (Spiraea betulifolia lucida), twinflower , sticky currant (Ribes viscosissimum), prickly currant (Ribes lacustre), raspberry (Rubus spp.), Saskatoon serviceberry , black hawthorn (Crataegus douglasii), snowbrush (Ceanothus velutinus), willow , oceanspray (Holodiscus discolor), wax currant (Ribes cereum var. cereum), orange honeysuckle (Lonicera ciliosa), Scouler's willow , elderberry (Sambucus spp.), mountain ash (Sorbus scopulina), black cottonwood , and boxleaf myrtle (Paxistima myrsinites).In addition to Douglas-fir and grand fir, other canopy tree species present in these stands include ponderosa pine (Fuels reduction treatments were applied to grand fir and Douglas-fir stands (between 10 and 50 ha in size) in SEFR between 2000\u20132003 Stands were mechanically thinned with a feller-buncher to reduce fuel loadings to <35 tons/ha, compatible with fuel loads considered unlikely to carry stand-replacement fires Following fuels reduction treatment, exclosures ranging in size from five to seven hectares were established at five mixed Douglas-fir and grand-fir forest sites in the SEFR: Half Moon (HM), Louis Spring (LS), Bally Camp (BC), Doug Prairie (DP), and Bee Dee (BD) . Three . The othThe exclosures were established at each site by constructing a fence eight feet in height that excluded all ungulates , but allowed for other wildlife to pass under, over, or through. The exclosures were constructed in the year following the fuels treatments. The size and shape of each exclosure varied with site conditions, including topography, slope, forest structure, and the shape of the forest patch to minimize site variation within and among exclosures. The ungulate exclosures were divided into seven, roughly equal-sized paddocks  in which seven different levels of cattle and elk herbivory treatments were randomly assigned and implemented . The levBrowsing intensity for each treatment level was defined in terms of the number of days per ha that elk and cattle use Douglas-fir and grand fir habitat types in the interior northwestern United States, broken down into three levels of forage utilization: high\u201445% utilization; moderate\u201430% utilization; and low\u201415% utilization. These levels typify the range of grazing and browsing use established for cattle on summer ranges in Douglas-fir and grand fir habitat types on public lands like those at SEFR Stocking density  for each type of ungulate was then calculated using standard forage allocation procedures The calculated stocking densities were then refined so that the final number of cattle days per ha and elk days per ha for each treatment level corresponded to what was logistically feasible to implement with the tractable animals. Moreover, the number of animals must be compatible with each ungulate's group behavior for foraging and the need to complete the trials in as few days as possible to minimize changes in forage availability and phenology. Consequently, we used 4 elk and 6\u20138 cattle per trial to most efficiently approximate the calculated stocking densities. The diets of elk and cattle tend to converge during late summer in grand fir and Douglas-fir forests 2 plots (4\u00d710 m) were systematically established in each paddock. Due to differences in paddock size and layout, the number of plots per paddock varied (from 12\u201318), though the percent of each paddock sampled remains similar (7\u20139%). Plot locations were determined using real-time differential global positioning system placed in a geographic information system (GIS). Plots were located 15 m apart along transect lines, with each transect line spaced 15 m apart from one another within each paddock. Edges of paddocks were excluded from sampling with a 5 m buffer, and a random starting point was used to determine the starting point of each transect (ranged from 5\u201310 m from the outer edge of exclosure).Permanent 40 mdiversity function in the vegan package The absolute and relative cover of shrub species were estimated using the line-intercept method, with transects running along the center of each 4\u00d710 m plot. Within each 4\u00d710 m plot, all shrub stems \u22651 m in height were identified, counted, and their height measured to the nearest cm. Due to their high abundances, stems <1 m in height were identified, enumerated, and their height and cover measured in a smaller 2\u00d710 m plot through the center of each permanent 4\u00d710 m plot. Shrub abundances were adjusted by dividing the number of stems by the area of the sampling plot area prior to analyses. Sampling occurred in July just before implementation of the browsing treatments, and again in July, after six years of the browsing treatment. Shrub diversity and evenness were calculated for each plot using all species with Simpson index using the The overstory has a strong influence on understory vegetation dynamics in western coniferous forests metaMDS function in the R package vegan Multivariate analyses were carried out to compare the relative changes in shrub species composition  across un-browsed paddocks and paddocks under differing levels of browsing pressure by elk and cattle separately. A Non-metric Multidimensional Scaling was conducted using the glmmPQL function of the MASS package plot function in R Because of the nested structure of our sampling design, ungulate treatment effects on vegetation structure were assessed with Generalized Linear Mixed Models GLMM;  with theInitial mean shrub cover and height were higher at paddocks within non-fuels treated sites than paddocks within fuels treated sites . Mean shAt non-fuels treated sites, the change in shrub composition was much greater at un-browsed paddocks compared to browsed paddocks, regardless of browsing intensity or ungulate type . The comIn contrast, un-browsed paddocks showed minimal change in shrub composition at fuels treated sites . The amoShrub species diversity and evenness were strongly affected by the interaction between fuels treatment and browsing at all three levels  indicatiIn non-fuels treated sites, shrub species diversity and evenness generally did not change over the study period in browsed paddocks regardless of ungulate type or browsing pressure . HoweverOur results demonstrate that ungulates have an important role in maintaining plant diversity in western forest ecosystems in the absence of episodic disturbance events such as fire and/or mechanical fuels removal. This finding agrees with Rambo and Faeth Episodic disturbances provide new growth that is often highly preferred by ungulates While we hypothesized that diversity would be highest at moderately browsed paddocks, shrub diversity was consistently higher at all three levels of browsing pressure compared to ungulate exclusion, and no differences were observed among paddocks under different levels of browsing pressure. This suggests that relatively little browsing, 8 and 10 days per hectare annually for elk and cattle respectively, is needed to suppress dominant shrub species and maintain shrub diversity in this ecosystem. Furthermore, diversity is not reduced under higher levels of browsing pressure, of up to 32 and 30 days per hectare annually for elk and cattle respectively. It has been suggested that reduced diversity occurs once browse-tolerant species become dominant Furthermore, because we conducted our browsing treatments towards the end of the summer when the diet of elk and cattle converge, we cannot conclude from our findings that perennial understory vegetation in western conifer forest is insensitive to browsing pressure or ungulate type. Cattle and elk may have different effects on shrub dominance and diversity patterns at the beginning of the growing season, particularly with high browsing pressure. Accordingly, browsing effects at different times of the year need to be determined to assess how much browsing pressure is required to maintain diversity when herbivory occurs during the spring, early summer, late summer/fall, or a combination of the three with some browsing in each season. The latest scenario is the most realistic since elk and other wild ungulates are likely to visit these sites several times over the growing season.Our findings have important implications for both livestock and wild ungulate management in dry forests of the western United States. First, management decisions to modify ungulate densities on the landscape will result in changes in abundance of different shrub species that could be based on a priori designs to meet vegetation management objectives for other resources, such as the desire to increase abundance of certain shrubs as habitat for wildlife. Second, while specific shrub responses may vary by type of ungulate and by the background site conditions in which herbivory occurs, either cattle or elk can be used to maintain shrub diversity in the absence of episodic disturbances. Consequently, management decisions that alter ungulate browsing patterns should take into consideration other current forest management activities and disturbances that may alter inter-specific interactions, such as prescribed burning and fuels removal. These considerations are particularly important to sustaining biodiversity in seasonally arid and fire-prone forest ecosystems of the Western United States where natural and human-induced disturbances exert strong control on vegetation."}
+{"text": "Stroke after internal jugular venous cannulation typically leads to acute carotid or vertebral arteries injury and cerebral ischemia. We report the first case of delayed posterior cerebral infarction following loss of guide wire after left internal jugular venous cannulation in a 46-year-old woman with a history of inflammatory bowel disease. Our observation highlights that loss of an intravascular guide wire can be a cause of ischemic stroke in patients undergoing central venous catheterization. Inadequate placement of a jugular venous catheter is a well-known complication, with serious and immediate secondary complications including stroke. Acute complications are usually associated with injury to contiguous structures , leading0) to segment V3 with no signs of arterial dissection (A 46-year-old woman with a history of inflammatory bowel disease was admitted for recurrence of severe active colitis and treated by intravenous corticosteroids. Left internal jugular venous cannulation was performed for total parenteral nutrition using the Seldinger technique. During catheterization, the patient suddenly experienced transient dizziness and blurred vision. No further problems were observed after withdrawing the catheter. The anaesthetist did not report any inattention during the procedure. Five days after hospital discharge, the patient presented sudden onset of difficult swallowing. Neurological examination revealed left hemiataxia with hypermetria, left Horner's sign, right deviation of the uvula indicating left palatal palsy, and hypoesthesia of the left hemiface. General examination revealed left cervical subcutaneous hematoma with no hemodynamic impairment . Brain mssection . A lost ssection . Cervicassection , and totssection . The guiCases of acute stroke caused by vertebral intimal damage with thrombosis leading to posterior cerebral infarction during internal jugular venous cannulation have been previously reported \u20139, althoIn conclusion, our observation highlights that stroke after catheter placement is scarce but constitutes a major and potentially fatal complication of a benign condition."}
+{"text": "Three techniques for the treatment of intractable pancreatic fistula: percutaneous transfistulous pancreatic duct drainage (PTPD), percutaneous transfistulous pancreatojejunostomy (PTPJ), and percutaneous transfistulous pancreatic duct embolization (PTPE) are presented as treatment options for intractable pancreatic fistula. PTPD is effective for most cases of intractable fistula that communicate with the main pancreatic duct. However, PTPD itself is not enough in some specific cases. PTPJ and PTPE are applicable in such cases. Pancreatic fistula (PF) remains a significant problem in the management of pancreatectomy. Despite decreased morbidity and mortality rates after pancreatic resection, PF remains a common and potentially lethal complication after pancreatectomy. Its reported incidence varies from 6 to 38% \u20137. If PFPF also sometimes becomes a significant problem in severe acute pancreatitis. Pseudocysts and postnecrotic collections of the pancreas are treated by percutaneous drainage if they are large and likely to aggravate the patients' condition. Approximately 65\u201390% of patients recover from this disease by percutaneous drainage alone . HoweverTechniques of percutaneous transfistulous drainage of the main pancreatic duct (percutaneous transfistulous pancreatic duct drainage: PTPD) for intractable PF cases are presented. Furthermore, percutaneous transfistulous pancreatojejunostomy (PTPJ) and percutaneous transfistulous pancreatic duct embolization (PTPE) are also presented as advanced techniques of PTPD.This technique is useful for major PF in which the main pancreatic duct is visualized in fistulography , 14. AnyWhen intractable PF is developed after pancreatoduodenectomy, abscess around the pancreatojejunostomy is drained percutaneously at first. Then, drainage catheters are inserted into the pancreatic duct (PTPD procedure) and jejunum, respectively. A guidewire is inserted into the jejunum via percutaneous transfistulous route through the drainage tube. The guidewire, grasped by a basket catheter inserted from the percutaneous transhepatic biliary drainage (PTBD) route under fluoroscopy, is led externally via the PTBD outlet Figures . FinallyLarge postnecrotic collection can be formed owing to disruption of the main pancreatic duct in some severe necrotizing acute pancreatitis Figures . In suchPF represents clinically relevant complications with life-threatening consequences  after pancreatic resection and in acute necrotizing pancreatitis. PTPD, PTPJ, and PTPE are presented as treatment options for intractable PF. Visualization of the main pancreatic duct during fistulography indicates that the PF is intractable.The conventional treatment strategy for PF consists of establishing adequate external drainage, treating infection, providing nutritional support, and reducing pancreatic juice secretion by parenteral nutrition or octreotide. With effective drainage, most of the PF can be cured by conservative treatment. However, the management of intractable PF cases has not been standardized and remains challenging. The management of intractable PF is individualized. Several procedures have been reported, including endoscopic drainage, percutaneous intervention , and surTranspapillary stents can bypass the high resistance of the sphincter of Oddi, ductal strictures, and calculi, thereby reducing the intraductal pressure that is the driving force behind the fistula. Endoscopic pancreatic sphincterotomy is also recommended for the treatment of PF after DP . HoweverIn necrotizing pancreatitis, disruption of main pancreatic duct appears to be associated with the most severe form of necrosis , 20. Uom"}
+{"text": "Pancreatic cancer shows a characteristic tissue structure called desmoplasia, which consists of dense fibrotic stroma surrounding cancer cells. Interactions between pancreatic cancer cells and stromal cells promote invasive growth of cancer cells and establish a specific microenvironment such as hypoxia which further aggravates the malignant behavior of cancer cells. Pancreatic stellate cells (PSCs) play a pivotal role in the development of fibrosis within the pancreatic cancer tissue, and also affect cancer cell function. PSCs induce epithelial-mesenchymal transition and cancer stem cell (CSC)-related phenotypes in pancreatic cancer cells by activating multiple signaling pathways. In addition, pancreatic cancer cells and PSCs recruit myeloid-derived suppressor cells which attenuate the immune reaction against pancreatic cancer cells. As a result, pancreatic cancer cells become refractory against conventional therapies. The formation of the CSC-niche by stromal cells facilitates postoperative recurrence, re-growth of therapy-resistant tumors and distant metastasis. Conventional therapies targeting cancer cells alone have failed to conquer pancreatic cancer, but targeting the stromal cells and immune cells in animal experiments has provided evidence of improved therapeutic responses. A combination of novel strategies altering stromal cell functions could contribute to improving the pancreatic cancer prognosis. The prognosis of pancreatic cancer remains poor despite diagnostic and therapeutic improvements. A sensitive early detection screening method has not yet become available, and clinical symptoms such as obstructive jaundice or back pain are signs of advanced disease. Most patients are not eligible for curative surgery, due to the local invasion and distant metastasis Hidalgo, . ChemothKras, inactivating mutations of tumor suppressor p16, p53, and Smad4  reside within pancreatic parenchyma and remain in a quiescent state in normal pancreas. Quiescent PSCs contain vitamin A droplets in the cytoplasm  than CD10\u2212 PSCs, whose siRNA-based knockdown attenuated the invasive capacity of the pancreatic cancer cells . EMT is characterized by the loss of epithelial phenotypes and gain of mesenchymal phenotypes, increased cellular migration and invasion, which is an indispensable process for the initiation of metastasis  are the counterpart of the normal stem cells  was correlated with the presence of a fibrotic focus in pancreatic cancer tissue, suggesting desmoplasia provides a hypoxic condition within the tumor  or granulocytic MDSC (CD11b+CD15+)] have been reported  and mutant p53 (inactivating mutation R172H) in the pancreas, recapitulating human pancreatic cancer including prominent desmoplasia  in pancreas (Chang et al., PSCs interact with another type of immune cells, which also promote the growth of pancreatic cancer. Mast cells trigger type I hypersensitivity in various diseases such as bronchial asthma and urticaria (Beunk et al., As summarized in this review, tumor-stromal interaction has pivotal role in pancreatic cancer progression. Interventions directed to the desmoplasia-inducing signaling pathways revealed favorable effects, such as the inhibition of Shh pathway or CTGF pathway in mouse model (Olive et al., Targeting immune cells could be an alternative approach to modify the tumor microenvironment. Restoring the immune reaction could be performed by several agents, such as ATRA or IL-12 in mouse model, which exhibited therapeutic effects (Kerkar et al., Pancreatic cancer is a deadly disease and its establishment proceeds silently. Stromal reaction and escape from immune surveillance are perpetuating systemic changes. The involvement of stromal cell activation and immunosuppression enable cancer cells to remain in a favorable niche, leading to distant metastasis and therapy resistance. A schematic view of the cancer cell-stromal cell interaction is shown in Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "TP63, TERT-CLPTMIL and 8q24.21, to be highly associated with disease risk. Whole transcriptome sequencing (RNA-Seq) is a revolutionary tool for generating a large amount of qualitative and quantitative information, thus helping to explore known and novel transcripts, splicing forms and fusion genes.Bladder cancer is the 9th most common cancer worldwide and the 13th most common cancer-related cause of death. Bladder cancer frequently recurs after the removal of primary carcinomas. This recurrence leads to repeated surgeries and long-term treatment and surveillance, making it the most expensive type of cancer to treat. Genetic factors and environmental factors such as cigarette smoking and occupational exposure to aromatic amines are linked to bladder cancer risk. Genome-wide association studies (GWAS) for bladder cancer have identified multiple genetic variants within genes and regions, including To understand the genetic and genomic landscape of the GWAS susceptibility regions, we investigated and characterized the entire transcriptome of normal and tumor bladder tissue samples by using powerful massively parallel RNA sequencing. We used an Illumina HiSeq 2000 instrument to sequence six paired samples of normal and tumor bladder tissues. For each of the samples, we generated 50 Gb of 100-bp reads to represent the whole transcriptome.Using the Bowtie/TopHat and Samtools packages, we successfully aligned approximately 80% of the total sequence reads against the human genome reference sequence (build 19). Our analysis sought to identify alternative splicing forms, novel exons, non-coding transcripts and chimeric fusion events. Total levels of mRNA in normal and tumor samples were evaluated by Cufflinks analysis based on the Ensembl transcripts database. Multiple splicing isoforms were identified for some of the GWAS susceptibility genes, and some of these isoforms were differentially expressed between the tumor and normal samples. We found that novel transcripts and non-coding RNAs corresponding to gene desert regions such as 8q24 were abundantly expressed. Our next step will focus on validation of these differentially expressed genes and novel transcripts by using quantitative RT-PCR on independent samples.Using RNA-Seq, we explored transcripts corresponding to candidate regions identified by bladder cancer GWAS. Some of these transcripts demonstrated splicing variability and differential levels of expression between normal and tumor tissue samples, which might be of importance for bladder cancer."}
+{"text": "Pseudomonas, type III secretion systems (T3SS) and T3 effectors do not appear central to pathogenesis of pectobacteria. Indeed, recent genomic analysis of several Pectobacterium species including the emerging pathogen Pectobacterium wasabiae has shown that many strains lack the entire T3SS as well as the T3 effectors. Instead, this analysis has indicated the presence of novel virulence determinants. Resistance to broad host range pectobacteria is complex and does not appear to involve single resistance genes. Instead, activation of plant innate immunity systems including both SA  and JA (jasmonic acid)/ET (ethylene)-mediated defenses appears to play a central role in attenuation of Pectobacterium virulence. These defenses are triggered by detection of pathogen-associated molecular patterns (PAMPs) or recognition of modified-self such as damage-associated molecular patterns (DAMPs) and result in enhancement of basal immunity . In particular plant cell wall fragments released by the action of the degradative enzymes secreted by pectobacteria are major players in enhanced immunity toward these pathogens. Most notably bacterial pectin-degrading enzymes release oligogalacturonide (OG) fragments recognized as DAMPs activating innate immune responses. Recent progress in understanding OG recognition and signaling allows novel genetic screens for OG-insensitive mutants and will provide new insights into plant defense strategies against necrotrophs such as pectobacteria.Soft rot pectobacteria are broad host range enterobacterial pathogens that cause disease on a variety of plant species including the major crop potato. Pectobacteria are aggressive necrotrophs that harbor a large arsenal of plant cell wall-degrading enzymes as their primary virulence determinants. These enzymes together with additional virulence factors are employed to macerate the host tissue and promote host cell death to provide nutrients for the pathogens. In contrast to (hemi)biotrophs such as  Pseudomonas syringae and Xanthomonas spp. that rely on living plant cells for nutrient acquisition at least until later stages of infection. Their lifestyle is largely dependent on their ability to avoid and suppress plant defense responses most notably by secretion of effector proteins enabling them to obtain nutrients and multiply within living plant tissue , conserved structures such as the bacterial flagellin essential for the microbial lifestyle . The resPectobacterium and Dickeya are classical and well-studied examples of necrotrophic plant pathogenic bacteria. Their taxonomical classification has been revised several times in recent years. They were first characterized in the early 20th century , i.e., wasabi , P. wasabiae WPP163 (accession: CP001790.1), P. wasabiae SCC3193  and a polyketide phytotoxin  to virulence of the bacterium. T4SS machineries translocate DNA and/or proteins across the bacterial cell wall into bacterial or eukaryotic cells  but absent from genomes of other Pectobacterium species. These islands contain uncharacterized genes but also genes encoding for example a second type VI secretion (T6SS) machinery and a bacterial microcompartment of unknown function. T6SS is a common protein secretion system in Gram-negative bacteria and it has been reported to function in interactions with animals, plants and other bacteria  and EF-Tu receptor (EFR), that recognizes one of the most abundant and conserved proteins of bacteria, Ef-Tu (Pseudomonas and necrotrophic Pectobacterium trigger PTI responses through the recognition of flagellin (Inducible plant innate immunity responses are comprised of two separate lines of defense that are distinguished by the type of pathogen-derived molecules (elicitors) recognized. The first has an equivalent in animals and is triggered after the perception of a group of conserved, or general, pathogen-derived molecules, called PAMPs/MAMPs that can be present in both pathogenic and non-pathogenic microorganisms . Well-cha, Ef-Tu . Recognilagellin . Furtherlagellin .Pseudomonas syringae usually express 15\u201330 effectors depending on the strain , that controls several ABA- and JA-regulated genes resulted in decreased tolerance to necrotrophic pathogens but also to water deficit and salt stress  overlapping at least partly with those induced by PAMPs including oxidative burst, cell wall strengthening, production of phytoalexins and proteinase inhibitors as well as hormone biosynthesis  are involved in OG sensing. WAK1 and WAK2 have been shown to bind to pectin in vitro  and WAK1in vitro . The in x dimers . The eggx dimers . Even shWAK1 is up-regulated by OGs  OGs and also compared the expression changes between OG-PTI and Flg22-PTI . Furthermore, NO was found to contribute to OG-induced immunity against B. cinerea. Whether this applies to Pectobacterium remains to be demonstrated.Interestingly, recent studies indicate participation of NO in OG-PTI . It was Figure 1, PTI appears central to plant defense against broad host range bacterial necrotrophs like Pectobacterium. ETI, which is highly efficient against (hemi)biotrophs such as Pseudomonas is not an effective strategy to combat necrotroph infection, as ETI relies on localized cell death to trigger the downstream defense responses. Necrotrophs like Pectobacterium employ induction of cell death as part of their virulence strategy, thus ETI would rather enhance than prevent the infection. Indeed Pectobacterium species have a very limited arsenal of T3 effectors and those few that have been studied  appear to promote infection by causing cell death. Consequently, plant immune responses are triggered by recognition of conserved pathogen-associated molecular patterns (PAMPs) such as flagella or damage-associated molecular patterns (DAMPs) such as OGs released by the action of PCWDEs by respective pattern recognition receptors. While the PTI induced by PAMP recognition is a common response to both biotrophs and necrotrophs, DAMPs are more typical to necrotrophic interactions. Consequently, Pectobacterium strives to attenuate PTI particularly in the early phase of infection by tight control of PCWDE production minimizing DAMP generation. PAMP and DAMP recognition events trigger partly overlapping defense responses including induction of defense gene expression and synthesis of various defensive compounds such as phytoalexins, defensins, and PR-proteins \u2013 resulting in PTI. Indeed prior induction of either response will enhance plant resistance to Pectobacterium. Elucidating the molecular details of these two partially redundant signal networks is essential for our understanding of the plant-necrotroph interactions and can take advantage of the rapidly developing genomic techniques including transcriptional profiling and RNA sequencing combined with the powerful genetic screens available in Arabidopsis for mutants altered in their PTI responses. In particular elucidation of the less well-characterized OG-induced PTI deserves further studies including correlation of the chain length of the OG elicitor to a particular response at specific stages of infection and defining the downstream components that are most significant for bacterial resistance. Such studies would be crucial for providing new insights into plant defense strategies against necrotrophs. Further genome level analysis would also help to elucidate the interactions of Pectobacterium with other plant associated microbes, as well as their insect vectors.In summary, see The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Inhibiting transport of virions within the female reproductive tract is an attractive mechanism for transmission prevention. The mucosal environment varies with menstrual cycle and concurrent bacterial vaginosis (BV). Previous studies of transport within mucosal samples have focused on cervico-vaginal samples in exclusion. Severe BV corresponds to increased incidence of female-to-male HIV-1 transmission although the mechanism remains unclear.We have established a cohort of HIV +ve and \u2013ve women to be longitudinally studied for correlates of inhibited transport phenotypes. Cervical and cervico-vaginal mucus samples  are collected, along with mucosal antibodies, vaginal smears, hormone levels, viral load, T cell monitoring panels as well as medical and behavioral history. Viral transport assays employ a diverse panel of viral isolates, testing clade specific effects. As of this interim analysis, over 60 study subjects have been recruited and repeat sampling is beginning.The hormone profile demarcating menstrual cycle phase correlates strongly with particle movement. In CVM, the nature of viral interactions with their environment changes; lowest progesterone to estradiol ratio corresponds with hindered diffusion. Non-reactive similarly sized PEGylated beads have freely diffusive behavior throughout the menstrual cycle. Cycle classification into follicular, mid-cycle and luteal periods demonstrates that CVM in the luteal phase is, unexpectedly, most permissive to viral transport. Severe BV has modest effects on pH of CVM and no effect on CM. This is reflected in viral transport characteristics whereby the magnitude and nature of movement is invariant during severe BV relative to healthy flora.It is unlikely that the mechanisms of increased transmission with BV are related to virus diffusing more freely within mucus. Correlates of hindered diffusion are not restricted to adaptive immune responses. This study begins to reveal the significance of immune correlates and hormone profiles on HIV-1 transmission mechanisms and transport in the female reproductive tract."}
+{"text": "Ovis aries) to construct a linkage map for bighorn sheep, Ovis canadensis. We then assessed variability in genomic structure and recombination rates between bighorn sheep populations and sheep species.The construction of genetic linkage maps in free-living populations is a promising tool for the study of evolution. However, such maps are rare because it is difficult to develop both wild pedigrees and corresponding sets of molecular markers that are sufficiently large. We took advantage of two long-term field studies of pedigreed individuals and genomic resources originally developed for domestic sheep , resulting in an autosomal female map of 3166 cM and an autosomal male map of 2831 cM. Despite differing genome-wide patterns of heterochiasmy between the sheep species, sexual dimorphism in recombination rates was correlated between orthologous intervals.Ovis species. However, domestication may have played a role in altering patterns of heterochiasmy. Finally, we found that interval-specific patterns of sexual dimorphism were preserved among closely related Ovis species, possibly due to the conserved position of these intervals relative to the centromeres and telomeres. This study exemplifies how transferring genomic resources from domesticated species to close wild relative can benefit evolutionary ecologists while providing insights into the evolution of genomic structure and recombination rates of domesticated species.We have developed a first-generation bighorn sheep linkage map that will facilitate future studies of the genetic architecture of trait variation in this species. While domestication has been hypothesized to be responsible for the elevated mean recombination rate observed in domestic sheep, our results suggest that it is a characteristic of  The construction of genetic linkage maps in model organisms and domesticated species enables studies of the genetic architecture of trait variation and genome evolution. However, such resources for free-living populations of non-model species are still rare because it is difficult to acquire large enough pedigrees and associated sets of molecular markers ,2. The uOvis canadensis), a mountain ungulate inhabiting western North America )We constructed a first-generation bighorn sheep linkage map using DNA from two wild pedigreed population and genomic resources originally developed for domestic sheep. Since bighorn sheep and domestic sheep genomes are very similar, future efforts to increase marker density in specific chromosomal regions should be relatively straightforward. This could be achieved using bighorn sheep single nucleotide polymorphism (SNP) markers recently discovered using the OvineSNP50 Beadchip , additioThe main reason for developing genomic resources in bighorn sheep is to allow studies of complex trait genetic architecture and evolution under natural settings. In the NBR population, genomic resources will enable investigations into the genetic basis of fitness, inbreeding depression and genetic rescue . In RM, Ovis species while the unusual male-biased heterochiasmy might have been a consequence of domestication. Finally, we have demonstrated that interval-specific patterns of sexual dimorphism could be conserved among closely related species, possibly due to the position of these intervals relative to centromeres and telomeres.While resources developed for domestic sheep are obviously highly useful to bighorn sheep research, genomic research in bighorn sheep can also yield valuable information through comparisons with domestic sheep in return. For example, we have demonstrated how linkage mapping in bighorn sheep can be used to infer ancestral marker order in domestic sheep. Also, by comparing the domestic sheep map with the map of a close wild relative, we were able to determine that the elevated recombination rates observed in domestic sheep were likely a characteristic of The NBR population was established by transplanting four rams and eight potentially pregnant ewes from Banff National Park  in 1922 . The popThe RM population is native to a small isolated mountain range located about 50 km east of the Canadian Rockies in Alberta, Canada . ImmigraIn both populations, parentage was originally determined with ~30 microsatellite loci using the 95% confidence threshold in Cervus . For theIn addition to markers used for the initial pedigree reconstruction, microsatellites putatively distributed throughout the genome of our focal species were identified using the domestic sheep IMF map version 4.7 ,51. MarkWe constructed population-specific linkage maps as well as an integrated map where populations were treated as independent families using CRI-MAP . The sam10 likelihoods. The relative sex-averaged length of different maps was compared by summing the length of intervals that were present in both maps  of Lovich and Gibbons . This inSince the length of an interval partly depends on the subset of markers included in a linkage analysis, we assessed the validity of comparing intervals between maps constructed using different number of markers (the domestic sheep IMF map 4.7 contains about 1400 markers). To accomplish this, we repeated cross-species analyses using information derived from additional linkage maps based solely on markers mapped in both species. Results and conclusions were essentially the same as for previous analyses and are therefore not presented. These maps are available in Additional file All research protocols were approved by the University of Alberta Animal Use and Care Committee, affiliated with the Canadian Council for Animal Care (Certificate 610901).JP designed the study, conducted laboratory work, performed data analysis and wrote the manuscript. JTH designed and supervised fieldwork at NBR and performed paternity analyses. CSD implemented laboratory methods and performed laboratory work. JMM participated in laboratory work and data analysis. JFM provided marker information and constructed a domestic sheep linkage map composed solely of markers mapped in bighorn sheep. DWC planned and supervised the study. All co-authors read and commented on draft versions of the manuscript. All authors read and approved the final manuscript.List of markers, map position and variability. Excel document displaying List of markers, map position and variability.Click here for fileComparison of bighorn sheep population-specific maps. PDF displaying comparison of bighorn sheep population-specific maps.Click here for fileComparison of intervals present in both population-specific bighorn sheep maps. XLS file displaying comparison of intervals present in both population-specific bighorn sheep maps.Click here for fileComparison of intervals present in bighorn sheep and domestic sheep maps. XLS file displaying comparison of intervals present in bighorn sheep and domestic sheep maps.Click here for fileBighorn sheep mapping pedigrees. PDF file displaying bighorn sheep mapping pedigreesClick here for fileBighorn sheep and domestic sheep linkage maps based on shared markers only. XLS bighorn sheep and domestic sheep linkage maps based on shared markers onlyClick here for file"}
+{"text": "Implantation of pacemakers can be challenging in the context of dilated cardiac chambers and valvular regurgitation. We report a difficult case of single chamber pacemaker implantation in a patient with restrictrive cardiomyopathy resulting in grossly enlarged atria and severe tricuspid regurgitation. In this situation, use of a slittable guiding sheath, more typically used for coronary sinus lead implantation, greatly facilitated rapid and stable deployment of the right ventricular lead. An initial attempt at single chamber pacing using a screw-in right ventricular lead was difficult due to lead instability and took 3 hours   , Panel AGuiding sheaths are commonly used to facilitate coronary sinus lead implants  and paciOther strategies that could be considered in difficult pacing cases are alternative lead placement strategies by using either pre-shaped stylets  or self-shaped stylets. If apical positioning is difficult, then placement of the lead into the right ventricular outflow tract septum can be facilitated by shaping a stylet with a generous distal curve with a swan neck deformity (angulated posteriorly). The whole lead, with the stylet either fully inserted, or pulled back from the tip, is then inserted into the pulmonary artery initially, before being pulled down into a stable right ventricular outflow tract septal position .  The usOther strategies that might be considered include left ventricular lead placement through the coronary sinus , or use During acute implantation, the presence of a stable R wave suggests a good pacing site. Recent studies have shown that the current of injury is better than R wave, slew rate and impedance measurements at predicting acute stability during active fixation lead implants ,8. In chAlternative lead placement strategies, including the use of appropriately-selected tools may greatly facilitate difficult cases, even when these tools are not part of conventional equipment typically used for single chamber pacemaker implantation."}
+{"text": "While increased pulmonary arterial expression of sGC has been reported in this mouse model of pulmonary hypertension, chronic hypoxia had minimal effects on relaxation to an NO donor. Catalase markedly restored contraction to phenylephrine and the aortic relaxation to hypoxia. Chronic treatment of mice with cobalt protoporphyrin IX, which induces heme oxygenase and ecSOD, attenuated the development of pulmonary hypertension without restoring relaxation to ACh. In addition, chronic treatment of mice with delta-aminolevulinic acid, a precursor to the sGC activator protoporphyrin IX and heme needed for sGC activation and heme oxygenase activity, also attenuated pulmonary hypertension development without restoring responses to ACh. Thus, redox mechanisms regulating PKG seem to be important contributors to vascular oxygen sensing mechanisms. In addition, increased ecSOD expression and PKG-mediated vasodilation to endogenously generated peroxide and other sGC activators may function as a protective mechanism against the development of hypoxia-induced pulmonary hypertension.There is much controversy in mechanisms controlling the pulmonary arterial response to acute and chronic hypoxia. Our previous work suggests bovine pulmonary arteries (BPA) contract to hypoxia via removal of a relaxation mediated by hydrogen peroxide derived from superoxide generated by Nox4 . In cont"}
+{"text": "Abiotic stress conditions adversely affect plant growth, resulting in significant decline in crop productivity. To mitigate and recover from the damaging effects of such adverse environmental conditions, plants have evolved various adaptive strategies at cellular and metabolic levels. Most of these strategies involve dynamic changes in protein abundance that can be best explored through proteomics. This review summarizes comparative proteomic studies conducted with roots of various plant species subjected to different abiotic stresses especially drought, salinity, flood, and cold. The main purpose of this article is to highlight and classify the protein level changes in abiotic stress response pathways specifically in plant roots. Shared as well as stressor-specific proteome signatures and adaptive mechanism(s) are simultaneously described. Such a comprehensive account will facilitate the design of genetic engineering strategies that enable the development of broad-spectrum abiotic stress-tolerant crops. Abiotic stresses such as drought, salinity, flood, and cold vastly affect plant growth and metabolism that ultimately disturbs plant life \u2014acetone precipitation and phenol extraction method helped to overcome the above challenges to certain extent  . Firstly, breakthroughs in soft ionization methods such as matrix assisted laser desorption ionization (MALDI)  are also involved in the response of roots to drought stress.Evidence from several proteomic studies showed that roots respond to drought stress using mechanisms similar to those occurring in damaging cells. For instance, enhanced levels of proteosomal factors were detected in drought-tolerant varieties of rapeseed seedlings  in soil. Root is the primary organ of exposure and hence responds rapidly. Several proteomic-based investigations have provided new insight into root responses and adaptation against high salinity.++ signaling protein or Ca++ binding protein, (4) phosphoproteins involving activation of kinase cascade, and (5) ethylene receptors. Receptor protein kinases (RPKs) in rice roots  and calreticulin (CRT)  alteration in carbohydrate and energy metabolism, (2) changes in ion homeostasis and membrane trafficking, (3) ROS scavenging, and (4) dynamic reorganization of cytoskeleton and redistribution of cell wall components.Alteration in carbohydrates and energy metabolism under salinity can be addressed by the high abundance of enzymes involved in glycolysis, TCA cycle, electron transport chain (ETC), and ATP synthesis  was produced , amino acids (aspartate aminotransferase), and lipids (lipoxygenase) were induced as early flood responsive proteins  or freezing (<0\u00b0C) temperatures can induce ice formation in plant tissues, leading to cellular dehydration  were found to be higher in abundance as a chilling stress response in roots of rice (Cui et al., Several other proteome signatures provided insights on plants' preparation for recovery once the stress is being released. For example proteins involved in cellulose synthesis, such as UDP-glucose pyrophosphorylase were highly abundant in rice roots upon 48 h chilling stress (Amor et al., Proteomic analyses on plant roots under various abiotic stress conditions revealed important information on proteins involved in the abiotic stress response. This leads to the identification of molecular and cellular mechanisms that are specific to certain abiotic stress or shared between two or more abiotic stress conditions Figure . For insde novo protein synthesis, growth-related signaling, and secondary metabolism were enhanced during recovery from flood stress as a replenishment of the stress-induced effects. Together, these changes suggested a compensatory mechanism by which the stress-induced effects could significantly be recovered.At the recovery phase, increased lignin biosynthesis was found following cold and drought stress. This molecular mechanism results in enhanced mechanical strength of roots by hardening cell wall at the root tip. Changes in abundance for cytoskeleton associated proteins were also observed, that can be looked upon as compensation against reduced cell size as well as repairing injuries caused by drought, salinity, and flood stress. Moreover, the levels of proteins related to As mentioned in this review, majority of literature reported proteomic analyses of the root response at least after 24 h of exposure to cold, drought, high salinity, or flooding stress. Therefore, early proteomic changes associated with individual abiotic stress remain to be elucidated, which will allow the identification of distinct sets of effectors for stress signaling. The function of these early effectors may be masked by secondary processes at a later stage. Technically, most of these proteomic studies have utilized the gel based separation approaches Table  that resThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Strix occidentalis, the northern goshawk, Accipiter gentilis, and the Pacific fisher, Martes pennanti. Whether protection of these upper-trophic level species confers adequate conservation of avian forest diversity is unknown.As a result of past practices, many of the dry coniferous forests of the western United States contain dense, even-aged stands with uncharacteristically high levels of litter and downed woody debris. These changes to the forest have received considerable attention as they elevate concerns regarding the outcome of wildland fire. However, attempts to reduce biomass through fuel reduction  are often opposed by public interest groups whose objectives include maintaining habitat for species of concern such as the spotted owl, 2 area in the Sierra Nevada. Our approach, which accounts for variations in detectability of species, estimates occurrence probabilities of all species in a community by linking species occurrence models into one hierarchical community model, thus improving inferences on all species, especially those that are rare or observed infrequently. We address how the avian community is influenced by covariates related to canopy cover, tree size and shrub cover while accounting for the impacts of abiotic variables known to affect species distributions.We use a multi-species occurrence model to estimate the habitat associations of 47 avian species detected at 742 sampling locations within an 880-kmEnvironmental parameters estimated through our approach emphasize the importance of within and between stand-level heterogeneity in meeting biodiversity objectives and suggests that many avian species would increase under more open canopy habitat conditions than those favored by umbrella species of high conservation concern. Our results suggest that a more integrated approach that emphasizes maintaining a diversity of habitats across environmental gradients and minimizing urbanization may have a greater benefit to ecosystem functioning then a single-species management focus. Biodiversity is integral to ecosystem functioning Forested ecosystems support over 80% of terrestrial biodiversity worldwide and have high species diversity for many taxonomic groups, including birds Strix occidentalisMartes pennantiAccipiter gentilisStrix occidentalis occidentalis, and Pacific fisher are typically associated with denser, closed-canopy, multi-storied stands. Modification of these habitats to reduce the threat of fire is perceived to decrease habitat suitability for these old-growth forest associated species and fuel treatments in the Sierra Nevada are required to make special considerations for them. For instance, stands within spotted owl protected activity centers around known nests are required to be managed to maintain a minimum of 70 percent tree canopy cover and to retain dominant and co-dominant trees that are at least an average of 61 cm in diameter at breast height (DBH) Fuel reduction treatments are increasingly being applied in an attempt to reduce the risk of high-severity fire and increase forest resiliency Conservation of upper-trophic level species, such as the spotted owl, is thought to provide an umbrella of protection to other species that have similar habitat associations but have smaller area requirements 2 conservation area, the Lake Tahoe Basin, located in the central Sierra Nevada Mountains , white fir (Abies concolor), red fir (A. magnifica), incense-cedar , lodgepole pine (P. contorta), and sugar pine (P. lambertiana).The Lake Tahoe Basin is located on the eastern crest of the Sierra Nevada straddling the states of California and Nevada . ElevatiAvian point counts were conducted at 742 locations in the upland forested areas of the Lake Tahoe Basin Management Unit during the course of the breeding season (mid-May to early July) of 2002 to 2005 Sample locations were selected using a combination of systematic/grid sampling and stratified random sampling. Four points were randomly selected from within a hexagonal grid laid across the Lake Tahoe Basin using spacing parameters of the Forest Inventory and Analysis program (N\u200a=\u200a98). An additional 74 locations were randomly selected across a range of urban development classes. At each of these primary sampling locations, a cluster of additional sampling points was conducted 200 m from each primary point count station. Sampling locations for each year of the study were selected randomly. Combined, these sampling designs ensured that data points were distributed across the basin and adequately addressed the influence of urbanization. There was a minimum distance of 200 m between all sampling points.We characterized habitat using several explanatory variables with Geographic Information Systems (GIS) for the area within a 150-m radius of the survey locations. Although birds were recorded only when detected within 100 m of a sample point, we selected a 150-m radius to define our habitat variables as birds on the edge of the sampling radius are likely responding to surrounding forest conditions. Habitat parameters were derived from a GIS vegetation layer (30-m\u00d730-m raster cell) based on IKONOS satellite imagery collected in 2002 i, iz, is a Bernoulli process where the probability that species i is present at location j : We analyzed the data using a hierarchical multi-species modeling approach developed in Dorazio and Royle i at location j during sampling occasion k, denoted i at location j during sampling occasion k given that the species was present. We similarly modeled species detection probabilities using the logit link function:i species  implemented in the programs R and WinBUGS with flat priors for each of the community-level parameters. We ran three chains of the model for 15000 iterations after a burn-in of 10000 iterations and saved every fifth estimate . We assessed that the model had convergence using the R-hat statistic Calypte anna, blue-gray gnatcatcher Polioptila caerulea, bushtit Psaltriparus minimus, lazuli bunting Passerina amoena, and orange-crowned warbler Oreothlypis celata) and were considered vagrants or non-breeding periodics . The house finch Carpodacus mexicanus and mourning dove Zenaida macroura were also excluded from our analyses as their presence in forests is dependent upon urban development (i.e. they are not expected in forests lacking urbanization). These species were excluded from the model because they would not be representative of the community. Seven additional species considered very rare, Calliope hummingbird Stellula calliope, Hammond\u2019s flycatcher Empidonax hammondii, lesser goldfinch Spinus psaltria, Pacific-slope flycatcher Empidonax difficilis, purple finch Carpodacus purpureus, ruby-crowned kinglet Regulus calendula, and yellow warbler Dendroica petechia), were observed fewer than 20 times, and they were included in our hierarchical model but not in our presentation of covariate estimates for individual species because their covariate estimates could be misleading. The mean and standard deviation of the occurrence and detection probabilities for all species included in the model are presented in We recorded 61 species of birds during 2021 visits to 742 point count stations. Of these 61 species detected, we excluded five species from our models as they typically breed at lower elevations  is likely to decrease the occurrence probabilities for old-forest associates. Further, our results also underscore the consistently negative impact of urban development on many avian species in the Lake Tahoe Basin and suggest that actively managing the extent and placement of urban development to minimize biodiversity impacts is as important as considerations of forest structure.Forest thinning projects have frequently been opposed by those concerned with maintaining suitable habitat for old-forest associated species of concern, such as the spotted owl, which require old forest conditions, namely high canopy cover and large trees Spizella passerina, that specialize on forest edge habitats and require both highly forested areas and shrub fields to meet their life history requirements. The results of our model indicate that past practices and management approaches that lead to increased homogenization of the forest will have negative impacts on avian diversity. Management approaches, such as fuel reduction treatments, or the use of prescribed or managed wildland fire, may be designed to restore at least some of the variability within and among stands that existed during an active fire regime, thereby enhancing habitat conditions for conserving avian biodiversity.Parameters estimated through our multi-species model emphasize the importance of within and between stand-level heterogeneity in meeting biodiversity objectives. At the stand level, some species responded positively to higher variance in tree size and canopy cover; thus, increasing forest heterogeneity in forest stands would improve habitat suitability for these species see . SpeciesThe link between habitat heterogeneity and biodiversity has been well-established (reviewed in Appendix S1Upland forest bird frequency status (ranging from very common to very rare) and mean detection and occupancy probabilities with one standard deviation.(DOCX)Click here for additional data file.Appendix S2Mean parameter estimates for upland bird species included in our analysis. Values indicate the change in occurrence predicted for each change in one standard deviation in the response variable. Bold indicates that the posterior interval did not overlap zero. The following seven species were excluded from this table  because they were observed fewer than 20 times: Calliope hummingbird Stellula calliope, Hammond\u2019s flycatcher Empidonax hammondii, lesser goldfinch Spinus psaltria, Pacific-slope flycatcher Empidonax difficilis, purple finch Carpodacus purpureus, ruby-crowned kinglet Regulus calendula, and yellow warbler Dendroica petechia).(DOCX)Click here for additional data file."}
+{"text": "Personalized medicine in the days of genetic research is seen as molecular biologic specification in individuals, not as individualized care oriented to patients needs in the sense of person-centered medicine. Yet the question can be raised whether this focus can ameliorate health care needs in view of the invested resources. Studies suggest that patients often miss authentically patient-centred care and individual physician-patient interaction and therefore decide to choose complementary and alternative medicine (CAM). By means of a meta-ethnography this project explored patients\u2019 views about individualized medicine and described the patients\u2019 perspectives of integrative and person-centred services.The procedure included first an electronic databases search for \u2018qualitative research\u2019 AND \u2018CAM\u2019 AND \u2018patient expectations\u2019 subject headings, supplemented with citation searches and hand searching. Second, studies were assessed using an inclusion/exclusion checklist and a quality score according to an adjusted checklist of Behrens and Langer. The third step was meta-ethnography according to Noblit and Hare's method to synthesize and interpret key concepts of individualized medicine using a line of argument synthesis.A set of 67 electronic databases including CAM, nursing, nutrition, psychological, social, medical databases, the Cochrane Library and DIMDI were searched. Nine thousand five hundred seventy-eight citations were screened, 63 full text publications reviewed, 38 appraised and 30 articles were included. The third-order constructs emerging through the synthesis and interpretation conducted by the multidisciplinary research team were: \"Personal development\", \"holism\", \"alliance\", \"room for connecting different models\", \"self activation\", \"dimensions of well-being\".The perspective of patients choosing alternative and complementary medicine regarding individualized care clearly differs from the current idea of personalized genetic medicine. Individualized medicine has therefore concurrently to bear in mind the humanistic approach of holistic, transformative, integrative and self-activation needs of patients. The allocation of resources should consider patients needs to enhance a high-quality biomedical or scientific health care system."}
+{"text": "Reaxys is an authoritative web-based workflow solution designed for chemistry researchers in drug discovery, chemicals and academic research . Reaxys With historical coverage dating right back to 1771 and continuing through todays cutting-edge research, Reaxys covers the most important chemistry-related literature and patent sources and provides unparalleled depth of information on reactions, substances and related property data.To make the most effective use of this information Reaxys offers two new entry points into the data:\u2022 Chemical space analysis, analogue sourcing, fuelling hit-to-lead programs and IP prior-art searching are possible through the Reaxys Structure Flat File.\u2022 Programmatic interaction with the database by custom clients, downloading bulk data from Reaxys using scripts, executing batch queries and integrating Reaxys into server-based data-intensive pipelining or workflow applications are possible through the Reaxys APIs.The Reaxys Structure Flat File and the Reaxys APIs will facilitate chemoinformaticians and information managers to integrate Reaxys into chemical information processing environments. In our poster, we present common use cases and possible applications. In addition, we describe successful implementations, illustrating how additional insights and efficiency can be gained."}
+{"text": "Astatotilapia latifasciata (Figure Haplochromis obliquidens. This species was described as Haplochromis latifasciatus [Astatotilapia [Haplochromis \"zebra obliquidens\" in the aquarium trade. Astatotilapia latifasciata has been reported to occur in Lake Nawampasa a small satellite lake of the much larger Lake Kyoga, and in Lake Kyoga located north of Lake Victoria in Uganda [After the publication of our work , we detea Figure , was errasciatus  and lateotilapia . Our misn Uganda ."}
+{"text": "The 2011 EMBO Conference Series on the Assembly and Function of Neuronal Circuits was held from 25 to 30 September 2011 at Monte Verit\u00e0 in Ascona, Switzerland. Approximately 100 participants explored current challenges and approaches to studying neural circuit function and organization. The 2011 EMBO Conference Series on the Assembly and Function of Neuronal Circuits was held from 25 to 30 September 2011 at Monte Verit\u00e0 in Ascona, Switzerland. Approximately 100 participants explored current challenges and approaches to studying neural circuit function and organization. The conference was organized into two sessions of oral presentations per day followed by an evening lecture and a nightly poster session at the Centro Stefano Franscini. The generously timed meals and coffee breaks offered additional opportunities for more informal and intimate discussions throughout the meeting.Caenorhabditis elegans, Drosophila, zebrafish, songbirds, rodents and macaques to electric fish, turtles and Egyptian fruit bats. In addition to experimental approaches, a few computational studies were presented that provide models to describe circuit dynamics, such as the influence of cortical inhibition.The topics spanned themes such as the importance of inhibition and its interplay with excitation in shaping circuit activity, the effects of neuromodulators on neurons and behavior, the genetic underpinnings of behavior and how specific neuron types wire and communicate. There was a notable trend toward the use of combinations of genetic, optical, electrophysiological and behavioral methods. We noticed a surge in the use of optogenetics for fine manipulation of genetically defined neurons, as well as many studies in awake, behaving animals, with the use of imaging or electrophysiology. A wide range of model organisms was used, from the traditionally popular Herein we sample a few highlights from the meeting that showcase the breadth of current research in neuronal circuits. Owing to space limitation, we apologize that we cannot comment on all of the presentations.Massimo Scanziani presented work on the mouse primary visual cortex (V1) and lateral geniculate nucleus (LGN). He expressed light-activated opsins, Channelrhodopsin-2 (ChR2) and archaerhodopsin (Arch) in layer VI (L6) pyramidal neurons and found that L6 excitation decreases firing rates in more superficial layers (presumably via interneurons) and in LGN . Sonja Hofer, who received a prize for the best short oral presentation, used a combination of two-photon microscopy and patch-clamp recordings to study the connectivity and tuning preferences of different cell types in mouse V1. She found that whereas excitatory pyramidal neurons receive sparse input from neurons with similar tuning preferences, parvalbumin (PV)-positive GABAergic interneurons receive input with high probability from neurons with diverse stimulus preferences. Yang Dan expressed ChR2 in subsets of interneurons and Arch in pyramidal neurons in mouse V1. Exciting PV neurons sharpened orientation tuning and enhanced direction selectivity . Exciting somatostatin neurons enhanced direction selectivity but did not change orientation tuning. Kevin Franks examined how recurrent connectivity in the piriform cortex (PCx) gates sensory information from the olfactory bulb. He found that a distributed and excitatory recurrent network in PCx activates strong feedback inhibition such that, if recurrent activity precedes sensory input, feedback inhibition will arise to suppress bulb-evoked spiking.Drosophila brain learn to select for sexually receptive females. He found that courtship learning depends on the activation of a specific class of dopaminergic neurons in the protocerebrum which project to neurons with a subtype of dopamine receptors in the mushroom body. David Anderson presented new techniques for the study of the role of dopaminergic neurons involved in hunger in Drosophila.Barry Dickson presented his work on how neural circuits in the male C. elegans to decide whether to exploit a food patch or to abandon it and explore other options. She found that this decision depends on the expression of the catecholamine receptor tyra-3, a homolog of the vertebrate adrenergic receptor. Alex Shier described the importance of hypocretin in sleep regulation in larval zebrafish and showed a promising technique for identifying drug targets using high-throughput behavioral screening.Cori Bargmann probed the genetic mechanisms that allow N-methyl-D-aspartate receptors at cortical dendrites. Bartlett Mel described theoretical approaches to understanding excitatory and inhibitory synaptic input to dendrites and stressed that dendrites must be considered processing units in their own right. Michael Ha\u00fcsser showed in vivo patch recordings from orientation-tuned mouse V1 dendrites. Erin Schuman showed the existence of many mRNAs at dendrites, suggesting a place to look for a molecular basis for dendritic computation.Dendritic computation was featured in several studies. Jackie Schiller demonstrated supralinear summation between thalamocortical and corticocortical synapses via Drosophila olfactory system wires, and Oscar Mar\u00edn showed how Cajal-Retzius cells in layer I in cortex are distributed across the future cortical surface. Tania Rinaldi Barkat showed that the auditory critical period for thalamocortical modification depends on telencephalin, a membrane adhesion protein, and that its loss induces precocious spine maturation on pyramidal cells in layer IV of the primary auditory cortex.A few talks addressed how neurons find their targets during development. Andrew Huberman described work addressing the problem of how retinal ganglion cells find their targets in the brain. Liqun Luo showed how the Nirao Shah showed that a sexually dimorphic gene with higher expression in the male mouse bed nucleus of the stria terminalis and medial amygdala may play a role in sexual behavior. Allison Doupe and Bence \u00d6lveczky presented recordings from nuclei in songbirds to demonstrate the role of variability in producing learned motor patterns. Peer Wulff presented a study on how the selective ablation of PV neurons in the medial prefrontal cortex of mice impairs spatial working memory and cognitive flexibility. Daniel Salzman showed that neurons in the monkey basolateral amygdala (BLA) may contribute to selective attention via their projections to extrastriate cortex. Single BLA neurons showed sustained excitation or inhibition from stimuli that indicate high- or low value rewards. Adi Mizrahi showed that, by patching neurons in primary auditory cortex, pup odors modulate responses to ultrasonic pup vocalizations in lactating mothers, but not in na\u00efve virgins. Alla Karpova observed abrupt and synchronous firing of neuronal ensembles in medial prefrontal cortex during transitions in behavioral strategies of rats performing two-alternative choice tasks. Nachum Ulanovsky demonstrated a large-scale cognitive map in bats and presented recordings from place cells in the hippocampus. He showed three-dimensional representations of space in the hippocampus as bats flew in the laboratory.Jeff Lichtman showed how axons at the neuromuscular junction connect to the muscle and showed preliminary efforts to image the mouse cortical connectome via large-scale serial electron microscopic reconstruction. Hongkui Zheng, from the Allen Institute for Brain Science, presented new initiatives to provide a whole-brain, three-dimensional map of axonal projections using cell-type specific creatinine (Cre) lines and Cre-dependent viral tracers.Amid talks about the remarkable wiring specificity of particular circuits, Haim Sompolinsky gave a thought-provoking lecture on how random connectivity may be an efficient strategy for encoding of sensory stimuli. He reviewed new developments in the field of compressed sensing and offered a glimpse of its potential use in neuroscience.The diversity of topics covered at this year's conference reflects the wide range of approaches neuroscientists currently use to study neuronal circuits. From examining the molecules and genes of specific cell-types to developing models of how networks of randomly connected neurons behave, the study of neuronal circuits is rapidly expanding, and we predict that it will continue to grow in the future.Arch: archaerhodopsin; BLA: basolateral amygdala; ChR2: channelrhodopsin-2; LGN: lateral geniculate nucleus; PCx: piriform cortex; PV: parvalbumin; V1: primary visual cortex.The authors declare that they have no competing interests.AYW and JYC wrote the meeting report, and both authors approved the final manuscript."}
+{"text": "In eukaryotic organisms, DNA is packaged into chromatin structure, where most of DNA is wrapped into nucleosomes. DNA compaction and nucleosome positioning have clear functional implications, since they modulate the accessibility of genomic regions to regulatory proteins. Despite the intensive research effort focused in this area, the rules defining nucleosome positioning and the location of DNA regulatory regions still remain elusive.Ab initio physical descriptors derived from molecular dynamics were used to develop a computational method that accurately predicts nucleosome enriched and depleted regions.Naked (histone-free) and nucleosomal DNA from yeast were digested by microccocal nuclease (MNase) and sequenced genome-wide. MNase cutting preferences were determined for both naked and nucleosomal DNAs. Integration of their sequencing profiles with DNA conformational descriptors derived from atomistic molecular dynamic simulations enabled us to extract the physical properties of DNA on a genomic scale and to correlate them with chromatin structure and gene regulation. The local structure of DNA around regulatory regions was found to be unusually flexible and to display a unique pattern of nucleosome positioning. Our experimental and computational analyses jointly demonstrate a clear correlation between sequence-dependent physical properties of naked DNA and regulatory signals in the chromatin structure. These results demonstrate that nucleosome positioning around TSS (Transcription Start Site) and TTS (Transcription Termination Site) (at least in yeast) is strongly dependent on DNA physical properties, which can define a basal regulatory mechanism of gene expression. Further4 -9.in vivo is really dictated by the DNA sequence is still an issue of strong discussion [DNA underlying sequence has long been considered to be an important contributor to nucleosome assembly -13. Crysscussion -27.ab initio physical descriptors derived from molecular dynamics (MD) simulations of short DNA oligonucleotides [Our group and others have provided indirect evidence highlighting the connection between DNA physical properties and chromatin organization -30. In pleotides -35. Thisleotides ,37. VeryYeast DNA fragments were prepared and sequenced following the experimental approach described in Figure -8), while the same tetramer was rarely present at primary cutting sites  unveiled that LRs  are located in regions with large variations in flexibility, where an extremely flexible site is surrounded by stiff motifs ,The MNase tetramer preferences Tables  and 2 arAs previously suggested by other groups ,11,43-50-503. WheThe analysis of MD-derived descriptors of naked DNA showed that key genomic regions, such as at TSSs and TTSs, were marked by unusual flexibility properties  intrinsic physical properties of naked DNA determine major nucleosome location signals in yeast, especially those at TSS and TTS. This hypothesis is indirectly supported by very recent studies , where nEssential regions for gene regulation like TSSs and TTSs are characterized by unusual physical properties that disfavor positioning of nucleosomes and therefore expose DNA to interaction with regulatory proteins. This property of regulatory regions is quite general across the genome. The genes with well-defined CLRs at regulatory regions did not differ from those with more diffuse signals in terms of Gene Ontology analysis , promoteDrosophila melongaster genome with the high-resolution genomic nucleosome map available [All conclusions drawn here have been derived from the analysis of yeast genome and thus concerns exist whether they can be validated for higher eukaryotes with a different sequence composition at regulatory regions. Therefore, we compared the sequence-dependent physical properties of the vailable . The comvailable . Extensivailable . All theSaccharomyces cerevisiae BY4741 strain,  DNA were isolated from Cleaved DNA samples were sequenced on the Illumina/Solexa Genome Analyzer (GA) IIx to generate reads of 54 bp length. Data were processed with standard GA base calling pipeline to convert initial raw images into sequences. All sequencing experiments were done in duplicates. Pooled data highly converged, as the reproducibility of individual experiments was very large in all cases . Correction of nucleosomal digestion profiles was done by using the degradation profiles obtained for naked DNA as background  account for regions were MNase degradation has been especially extensive. Low coverage regions (LRs) were detected in both nucleosomal and naked DNA as genomic segments with non-zero coverage below certain thresholds , considering the equilibrium conformation as the origin of energies following the approach suggested by Lankas and others [tilt, kroll, kshift, ktilt, krise and kslide) are taken from the diagonal of the matrix. Ktotal is obtained as the product of the six pure stiffness constants and gives a rough global estimate of the flexibility of each base pair step  in solvent water by using a newly developed force-field . Base pad others ,32,42,41T \u0398 X; where \u0398 is the stiffness matrix derived from MD simulations; X (or XT) is the deformation vector (or its transposed), given by translating a relaxed DNA fiber into the coiled nucleosome core DNA conformation as described for averaging and smoothing of X-ray structures  declare that they have no competing interestsThe authors have made the following declarations about their contributions: MO had the idea and make the general planning of the study. Conceived and designed the experiments: OD MS MO. Performed the experiments: OD. Analyzed the data: OF FB AP MO. All authors contributed to the writing of the manuscript. All authors read and approved the final manuscript.Additional Methods, Additional Figures and Additional Tables. PDF document with detailed methods and additional results.Click here for file"}
+{"text": "Understanding population-level responses to human-induced changes to habitats can elucidate the evolutionary consequences of rapid habitat alteration. Reservoirs constructed on streams expose stream fishes to novel selective pressures in these habitats. Assessing the drivers of trait divergence facilitated by these habitats will help identify evolutionary and ecological consequences of reservoir habitats. We tested for morphological divergence in a stream fish that occupies both stream and reservoir habitats. To assess contributions of genetic-level differences and phenotypic plasticity induced by flow variation, we spawned and reared individuals from both habitats types in flow and no flow conditions. Body shape significantly and consistently diverged in reservoir habitats compared with streams; individuals from reservoirs were shallower bodied with smaller heads compared with individuals from streams. Significant population-level differences in morphology persisted in offspring but morphological variation compared with field-collected individuals was limited to the head region. Populations demonstrated dissimilar flow-induced phenotypic plasticity when reared under flow, but phenotypic plasticity in response to flow variation was an unlikely explanation for observed phenotypic divergence in the field. Our results, together with previous investigations, suggest the environmental conditions currently thought to drive morphological change in reservoirs  may not be the sole drivers of phenotypic change. Understanding how populations respond to widespread and rapid environmental change will be a first step in elucidating the evolutionary consequences of disturbed habitats. Habitats altered by humans may destine populations to extirpation . We also predicted C. venusta offspring reared in flowing water would have more fusiform body shapes compared with fish reared in lentic conditions and would parallel shape variation observed in reservoir and stream habitats.Here, we tested for phenotypic divergence of ats Fig. . Althougats Fig.  had prevC. venusta from three reservoirs in the Hilly Gulf Coastal Plains in northwest Mississippi, USA  were combined  from each population were split evenly  and stocked into one of four experimental stream units  located at the Lake Thoreau Environmental Center near Hattiesburg, MS  that transferred water from the outflow end of units to the upstream riffle  of groundwater. Thus, we had a 2 \u00d7 2 factorial design with population crossed with flow and nonflow treatments. Adult C. venusta were allowed to spawn and then removed once juvenile fish were observed. All adults were removed by 3 July 2012. Experimental stream units were then monitored, and juveniles were culled to keep densities approximately equal among the four units. Spawned C. venusta were removed on 10 September 2012 and then 1 December 2012, euthanized by overdose of MS-222 and preserved in 10% formalin. We only used individuals that had reached adult size in analyses.We assessed potential genotypic differences and flow-induced phenotypic plasticity in morphology between reservoir and stream populations by spawning http://life.bio.sunysb.edu/morph/) and R (R Development Core Team n = 18) but because some shape variables often do not explain an appreciable amount of variation . All mancova models assume multivariate normality, homogeneity of covariance matrices, independence of observations, linear relationships between covariates and dependent variables, and homogeneity of slopes among groups (Rencher mancova model included 8 shape variables (explaining 89.9% of the variation in shape) as dependent variables, standard length (SL) as a covariate , habitat type (to test for effects of stream or reservoir habitats), basin (to test for basin-level effects) as fixed factors. Heterogeneity of slopes was tested among basins, and between habitat types by including SL in the respective interaction terms. All nonsignificant interaction terms were removed from the final model, and F-values were approximated using Wilk's lambda. Because of the statistical power associated with mancova of shape data, we focused our interpretation of model results on effect strengths by use of partial eta squared  by the shape variables matrix to yield habitat divergence vector scores for each individual. This divergence vector summarizes the shape variation that was elicited in fish from reservoir and stream habitats. The nature of this shape change was visualized using thin-plate spline transformation grids.To assess the nature of morphological divergence in reservoir habitats, we calculated a morphological divergence vector as defined by Langerhans  between mancova to test for population-level differences and flow-induced phenotypic plasticity on body shape variation within mesocosm-reared C. venusta. The mancova model included 8 shape variables as dependent variables (explaining 89.0% of the variation in shape), Population (stream or reservoir) and treatment (flow or no flow) were included as fixed factors, and SL as a covariate. Heterogeneity of slopes was tested between populations and treatment by inclusion of SL in each respective interaction term. Nonsignificant interaction terms were omitted from the final model. To quantify the nature of population-level and flow-induced plasticity of body shape variation of mesocosm-reared individuals, divergence vectors for population and treatment were calculated from the final model (similar to above). We visualized shape deformations along each population and treatment divergence vector using thin-plate spline transformation grids. All analyses were conducted in R unless otherwise stated . We predict these species-specific responses are more likely due to underlying genetic variation and ecologies between the species that are interacting with similar environmental conditions in reservoirs.Repeated morphological divergence in replicate reservoirs suggests these habitats are facilitating phenotypic changes in populations of Franssen  demonstrC. venusta and C. lutrensis may explain their disparate responses to reservoir habitats, although data on their ecologies are limited. A better understanding the ecologies of these species or differences in their underlying genetic architecture may help elucidate mechanisms behind their disparate morphological changes in reservoir habitats.Morphological diversification in fishes has been linked to dissolved oxygen concentrations and light availability . This reversal of caudal regions of the two populations in mesocosms compared with field-collected fish likely indicates fish in the field are exposed to plasticity-inducing factors that were absent in mesocosms. In fishes, there is a general propensity for species inhabiting moving water to be more streamlined than fishes in lentic habitats . While continued exposure to environmental cues that elicit plasticity of traits can result in canalization . Nonetheless, the mancova of body shape variation of field-collected individuals indicated Basin and the Basin \u00d7 Habitat interaction had significant effects on body shape variation, indicating fish body shape varied among basins and had dissimilar responses to reservoir habitats among basins. However, both of these effects explained less variation than the habitat term, suggesting variation between habitat types had a stronger influence on body shape variation than variation due to genetic variation among basins. While the lack of basin-level replication in the mesocosm experiment was not ideal, we think it is unlikely and have no evidence that would suggest nonadaptive evolutionary processes shaped the genetic structure of C. venusta in the Grenada basin.Lack of basin-level replication in the mesocosm experiment may limit our ability to extrapolate our results and interpretations to other reservoir systems. This would be especially true if drift, mutation, or recombination had stronger effects than selection on the genetic structure of C. venusta in reservoir habitats (compared with C. lutrensis) indicates selective pressures may vary among reservoirs or that different species respond to similar selective pressures in different fashions. Together, investigations of morphological changes of fishes in reservoir habitats may suggest that the reduction in factors that can contribute to morphological variation to one or two variables  may be an over-simplification when comparing phenotypic variation in different habitats. Indeed, a multitude of environmental conditions likely covary between these different habitats. A better understanding of the spatial and temporal variation in other potential environmental selective pressures and how these conditions interact with genetic variation to produce phenotypic variation will be needed to understand how reservoirs can alter the evolutionary trajectories of resident populations.The inability to elicit similar phenotypic variation in individuals reared in flow variation (this paper) and in the presence of predators Franssen  to morphMost organisms live in environments that have been altered at least to some extent by humans Palumbi . It will"}
+{"text": "Patients with Turner's syndrome have increased cardiovascular (CV) morbidity and mortality, potentially over and above that explained by the higher rate of both congenital heart disease and associated endocrine disorders and hypertension. GH administration to maximise adult height is a well-established treatment form but may affect cardiovascular status, ventricular mechanics and myocardial function. Furthermore, given the adverse CV effects of supra-physiological GH levels associated with acromegaly and in the field of sports doping, concern has been voiced about potential risks associated with this form of treatment.CMR based strain derivatives offer advanced analysis of myocardial deformation and function. Such technologies are thought to increase sensitivity and may allow detection of \"pre-clinical\" disease not apparent by assessment of conventional parameters such as ventricular volumes and ejection fraction (EF).52 patients with Turner syndrome underwent a comprehensive CV CMR study. Patients with structural heart disease such as aortic coarctation, haemodynamically important valve disease, previous myocardial infarction or cardiac surgery were excluded. Of the remaining 35 adult patients 14 had a history of previous exposure to GH (GH +ve), 21 had no history of GH treatment (GH -ve).Assessment of ventricular mass, volumes and derived EF was performed by means of signal intensity thresholding based detailed endocardial contouring using commercial software . LV/RV longitudinal and LV circumferential strain was analysed using an endocardial feature tracking software package .The demographic and haemodynamic data of both groups is summarised in Table Childhood GH exposure appears to have no detectable detrimental late effects on LV/RV ventricular performance. This study therefore provides further reassurance regarding the long term safety of childhood GH administration in patients with Turner's syndrome.None."}
+{"text": "To assess our preoperative pickup of malignant axillary lymph nodes by ultrasound and FNA compared with one-stop nucleic acid amplification (OSNA) and final histology.At our unit all patients with invasive breast cancer undergo axillary ultrasound, and those with suspicious or equivocal findings undergo axillary FNA. If FNA is positive we proceed to axillary node clearance (ANC). If axillary assessment is normal we perform sentinel node biopsy (SNB) with intraoperative OSNA, unless planned for neoadjuvant chemotherapy or primary medical therapy. In patients with positive OSNA, further surgery is performed as per hospital protocol. Retrospective correlation of preoperative axillary ultrasound and FNA findings with intraoperative OSNA in the SNB group and final histology in the ANC group was performed, with patients diagnosed with invasive breast carcinoma between September 2010 and September 2011.n = 27: 22 imaging normal, three equivocal, two abnormal).See Figure This is the first study correlating preoperative imaging with OSNA. Our high rate of preoperative diagnosis is encouraging, but suggestions for improvement are discussed."}
+{"text": "In clinical practice, the risk of cerebrovascular events originating from carotid atherosclerotic plaques is correlated to the degree of luminal narrowing, commonly designated the degree of stenosis. Though the degree of stenosis is a proven marker of plaque vulnerability, it is widely recognized that better risk markers for cerebrovascular events are needed. Known morphological features of plaque vulnerability are large lipid-rich necrotic cores (LR-NC) with thin fibrous caps that generate localized elevated mechanical stresses within the fibrous cap separating arterial lumen from LR-NC. Thus, determination of local biomechanics using computational simulations may have clinical implications.Biomechanical stress levels could be indicative of plaque rupture risk. Thus, we wished to determine whether different plaque morphologies in a longitudinal section affects the level of local mechanical forces.Two patients scheduled for carotid endarterectomy were scanned using MRI and idealized anatomical 2D models of individual carotid bifurcations were created figure . KeepingSignificant differences were apparent comparing the two different patient morphologies using surface plots of degree of stenosis, peak principal mechanical stresses, and fibrous cap thickness figure . In partIdentical plaque morphologies may yield significantly different mechanical stress levels depending on vessel geometry. Further studies are needed to determine if the varying stress levels are indicative of differing risks of plaque rupture."}
+{"text": "The ability to accurately identify bird species is crucial for wildlife law enforcement and bird-strike investigations. However, such identifications may be challenging when only partial or damaged feathers are available for analysis.Meleagris gallopavo), Canada goose (Branta canadensis), blue heron (Ardea herodias) and pygmy owl . The mtDNA was successfully obtained from 'fresh' feathers, historic museum specimens and archaeological samples, demonstrating the sensitivity and versatility of this technique.By applying vigorous contamination controls and sensitive PCR amplification protocols, we found that it was feasible to obtain accurate mitochondrial (mt)DNA-based species identification with as few as two feather barbs. This minimally destructive DNA approach was successfully used and tested on a variety of bird species, including North American wild turkey (By applying appropriate contamination controls, sufficient quantities of mtDNA can be reliably recovered and analyzed from feather barbs. This previously overlooked substrate provides new opportunities for accurate DNA species identification when minimal feather samples are available for forensic analysis. Accurate identification of bird species is crucial for wildlife law enforcement and other aspects of wildlife forensics. Currently, many birds and bird products (such as feathers) are protected under the US Migratory Bird Treaty (MBTA), the US Endangered Species Act (ESA) and the Convention on International Trade in Endangered Species (CITES). Identification of these protected species by law enforcement personnel may be challenging when only partial or damaged feathers are available for examination. Additionally, other criminal investigations, such as bird larceny, may also be contingent upon accurate species identification of bird feathers . Althouget al. [GenBank: BLAST: Basic Local Alignment Search Tool; EDTA: ethylene diamine tetraacetic acid; PCR: polymerase chain reaction; MSSC: modified silica-spin column; QDIK: Qiagen's DNA Investigator Kit; SFU: Simon Fraser University.The authors declare that they have no competing interests.CFS participated in the design of the study, performed DNA extractions and PCR amplifications, conducted sequence alignments and species identifications, and drafted the manuscript. GPN conceived of the study, participated in its design and helped to draft the manuscript. DYY participated in the design and coordination of the study, performed DNA extractions and amplifications, and helped to draft the manuscript. All authors read and approved the final manuscript."}
+{"text": "International policy is placing increasing emphasis on adaptation to climate change, including the allocation of new funds to assist adaptation efforts. Climate change adaptation funding may be most effective where it meets integrated goals, but global geographic priorities based on multiple development and ecological criteria are not well characterized. Here we show that human and natural adaptation needs related to maintaining agricultural productivity and ecosystem integrity intersect in ten major areas globally, providing a coherent set of international priorities for adaptation funding. An additional seven regional areas are identified as worthy of additional study. The priority areas are locations where changes in crop suitability affecting impoverished farmers intersect with changes in ranges of restricted-range species. Agreement among multiple climate models and emissions scenarios suggests that these priorities are robust. Adaptation funding directed to these areas could simultaneously address multiple international policy goals, including poverty reduction, protecting agricultural production and safeguarding ecosystem services. The need for adaptation to climate change is an emerging focus of international policy . The impEcosystem-based Adaptation is the use of ecosystem services to help people adapt to climate change. Intact ecosystems provide clean water, shoreline protection, and other services in the face of climate change, providing adaptation options that are often cheaper and more enduring than technical or engineering solutions . MaintaiPriorities linking ecosystems and food production are particularly important because human and natural responses to climate change are interwoven \u20138. ImpovAdaptation action in these areas could simultaneously enhance food security and maintain ecosystem function. This has policy relevance on multiple levels, as food security and ecosystem integrity are two of the three major benchmarks for climate change response established in the United Nations Framework Convention on Climate Change (UNFCCC), and make substantial contribution towards sustainable development, thus helping meet all three UNFCCC criteria . However2) which are indicative of highly complex and biodiverse ecosystems  pre pre43] pUncertainty associated with species and agricultural modeling is more difficult to constrain. In the tropics, species ranges may not sample all climatic conditions that are physiologically tolerable, resulting in over-estimation of range loss. Adaptation priorities for non-avian restricted-range species may not match those for birds, due to different taxonomic climatic tolerances. SDM are fitted to empirical data using current climatic conditions and may not simulate future range changes well when future climatic conditions are outside the range of current climate. Adaptation in agriculture may moderate crop losses, resulting in over-estimation of crop impacts. For instance, consumption may switch to crops which may be grown in a region but are not culturally favored, once suitability for preferred crops declines. For these reasons, regional analyses incorporating social factors, taxa other than birds, and analyses of adaptation capacity are essential complements to this global analysis.The priorities identified here reinforce and expand on the findings of other research into agricultural and biodiversity responses to climate change. Areas of agricultural vulnerability identified in this study overlap with those defined in other global assessments of agricultural impacts of climate change \u201346. For Possible adaptation responses in these priority areas might include actions that integrate adaptation for agriculture and ecosystems. For instance, agroforestry can help reduce soil temperatures and maintain soil moisture as air temperatures increase, and, with the appropriate choice of tree species, can help provide habitat for restricted-range birds and other wildlife. Protecting upland forests that provide fog interception or provide watershed protection for dams may be critical for agriculture in areas of declining precipitation, at the same time providing habitats that will permit range migrations in forest birds responding to climate change. Many of these solutions require planning on scales broader than individual farms or protected areas, which is why we have aggregated our results at spatial scales roughly coincident with scales of ecosystem and regional planning (one degree).It is likely that finer-grained analyses will confirm some or all of the regional priority areas identified  will be required. Both approaches can be effective , so wiseAdaptation practice is currently being pioneered in first-generation projects around the world. These efforts are addressing the adaptation needs of communities and ecosystems, increasingly recognizing deep interdependencies between the two. Meeting short-term development needs while establishing long-term sustainability of ecosystem services is a fundamental challenge. Among the best places to build experience in melding human and ecosystem responses will be regions experiencing substantial change in both. Innovative solutions and lessons from these areas can inform second-generation adaptation responses worldwide. Investment in the priority regions identified here is therefore a first step in developing a lasting, multi-sector approach to adaptation.Table S1Species and parameters used for EcoCrop modeling.Some crop species contained different species and varieties, so the model adapted the widest range of environmental requirement among species/varieties. The list of species used in the model appears below the table. Minimum and maximum temperature/precipitation requirements represent the environmental range where crop growth is possible and optimal minimum and maximum temperature/precipitation requirements are the environmental range of optimal growth.(DOCX)Click here for additional data file.Figure S1Performance of each SDM tested by overall accuracy, Kappa, TSS, MCC, specificity and sensitivity.Maxent scored highest performance except sensitivity that RF scored the highest performance.(TIF)Click here for additional data file.Figure S2Global map of crop suitability and suitability for range restricted birds change in 2050 under A2 emission scenario.Areas in which overall decreases are anticipated in crop suitability are shown in green, with increasing color intensity indicating multiple GCM agreement. Areas of declining climatic suitability for restricted range birds are shown in blue, with increasing color intensity indicating multiple GCM agreement. Overlap of declining crop suitability and declining restricted range bird climatic suitability is shown in shades of yellow (lowest GCM agreement) to red (highest GCM agreement).(TIF)Click here for additional data file.Figure S3Global map of crop suitability and suitability for range restricted birds change in 2050/2090 under B1 emission scenario.Areas in which overall decreases are anticipated in crop suitability are shown in green, with increasing color intensity indicating multiple GCM agreement. Areas of declining climatic suitability for restricted range birds are shown in blue, with increasing color intensity indicating multiple GCM agreement. Overlap of declining crop suitability and declining restricted range bird climatic suitability is shown in shades of yellow (lowest GCM agreement) to red (highest GCM agreement).(TIF)Click here for additional data file.Figure S4Global map of crop suitability and suitability for range restricted birds change in 2050/2090 under A2 emission scenario using the ensemble mean of 5 GCMs.Areas in which overall decreases are anticipated in crop suitability are shown in green. Areas of declining climatic suitability for restricted range birds are shown in blue. Overlap of declining crop suitability and declining restricted range bird climatic suitability is shown in red.(TIF)Click here for additional data file.Figure S5Global map of crop suitability and suitability for range restricted birds change in 2050/2090 under B1 emission scenario using mean of 5 GCMs.Areas in which overall decreases are anticipated in crop suitability are shown in green. Areas of declining climatic suitability for restricted range birds are shown in blue. Overlap of declining crop suitability and declining restricted range bird climatic suitability is shown in red.(TIF)Click here for additional data file.Figure S6Global map of crop suitability and suitability for range restricted birds change in 2090 under A2 emission scenario using 6 Species Distribution Model results.Areas in which overall decreases are anticipated in crop suitability are shown in green, with increasing color intensity indicating multiple GCM agreement. Areas of declining climatic suitability for restricted range birds are shown in blue, with increasing color intensity indicating multiple GCM agreement. Overlap of declining crop suitability and declining restricted range bird climatic suitability is shown in shades of yellow (lowest GCM agreement) to red (highest GCM agreement).(TIF)Click here for additional data file."}
+{"text": "Stress myocardial perfusion MRI allows for accurate detection of flow-limiting stenosis in the coronary artery. However, reduced diagnostic accuracy of stress myocardial perfusion MRI was reported in patients with coronary artery bypass grafts (CABG). Flow measurement in CABG is another MR approach that permits functional assessment of graft stenosis. The purpose of this study was to evaluate the value of MR study that combines MR flow measurement of CABG and stress myocardial perfusion MRI in detecting graft stenosis.Thirty-two consecutive patients  with previous CABG surgery who had recurrent chest pain were studied. All patients gave informed consent and underwent both coronary angiography and cardiac MRI. After obtaining cine MRI, stress-rest myocardial perfusion MRI and late gadolinium enhanced (LGE) MRI, blood flow volume in the resting state was quantified in 61 graft conduits by using phase contrast cine MRI. The presence or absence of myocardial ischemia was visually determined by identifying stress-induced hypoenhancement in the absence of LGE or hypoenhancement larger than LGE. Stenoses \u226570% in grafts or grafted native vessels were considered significant on coronary angiography.Coronary angiography revealed significant stenoses in the grafts or grafted native vessels in 19 (31%) of the 61 CABG conduits. Stress-rest perfusion CMR alone yielded the sensitivity and specificity of 73% and 81%, respectively. Receiver operating characteristic analysis demonstrated that the optimal cutoff values of MR blood flow volume was 28mL/min for predicting significant stenosis on angiography . By combining MR blood flow measurement and stress-rest perfusion MRI, the sensitivity and specificity of MR study were improved to 95% and 81%.MR flow measurement of CABG combined with stress-rest perfusion MRI can provide excellent diagnostic accuracy for predicting significant stenoses in the grafts or grafted native vessels in patients with previous CABG.Departmental reseach funding."}
+{"text": "Previously proposed panels of liver fibrosis usually include 2 to 7 blood markers. The majority of publications were concerned with liver fibrosis among patients with chronic hepatitis C (CHC). However, few studies have assessed drug-mediated liver fibrogenesis, non-alcoholic fatty liver disease (NAFLD), Schistosoma mansoni-induced liver fibrosis, and hepatitis B virus-related liver fibrosis. In the work entitled \"Noninvasive assessment of liver fibrosis with the aspartate transaminase to platelet ratio index (APRI): Usefulness in patients with chronic liver disease,\" authors The authors came to the conclusion that APRI was significantly associated with fibrosis score in patients with CHC and NAFLD, but not in patients with CHB. However, some reports showed a significant correlation between fibrosis scores and APRI in Chinese  and KoreConsequently, studies that investigate populations with etiologically different liver fibrosis may require the use of indices that involve direct fibrogenesis and/or oxidative stress markers, in addition to liver specific markers. The limited number of variables in APRI may minimize its potential in monitoring the basic events in scar formation, which is the common scenario in etiologically different fibrosis. However, the contradictory outcomes of different studies in the last few years may raise the question: Do we need a common liver fibrosis index or etiology-related indices?"}
+{"text": "This study is to evaluate the early results treatment of patients with total occlusion of the left main coronary artery. Total occlusion of the left main coronary artery is a very rare finding in patients with acute coronary syndrome. In these cases, patients present various clinical symptoms, however the symptoms and the survival of these patients depend on the development of collaterals and adequate medical intervention.Between January 2002 till May 2013, four patients with acute coronary syndrome caused by total occlusion of the left main coronary artery underwent emergent coronary artery bypass grafting(CABG). All patients presented chest pain, signs of cardiogenic shock with CK-MB level above100 ng/ml on admission. IABP was inserted and emergent PCI and consecutive surgery within 24 hrs were performed. One patient out of the four underwent on-pump beating heart CABG, the rest of the patients underwent classical CABG with induced cardiac arrest using blood cardioplegia with maintained normothermia. Early postoperativeevaluation was performed in terms of: ejection fraction, bleedings, CK-MB level and deaths.Three patients, who underwent classical CABG with induced cardiac arrest using blood cardioplegia with maintained normothermia, survived, whereas patient who underwent on-pump beating heart CABG died in the post-operative period due to hemodynamic failure with an ineffective response to reanimation.It is very difficult to treat such patients with acute coronary syndrome complicated with cardiogenic shock caused by total occlusion of left main coronary artery. Such patients could develop massive myocardial infarction and should be treated immediately with emergent PCI, IABP and emergent CABG within 24 hours.On-pump beating heart CABG is possible in these patients, however we recommend treating such highly risky patients by CABG with induced cardiac arrest using blood cardioplegia with maintained normothermia."}
+{"text": "Lupus nephritis belongs to the most serious organ involvements in juvenile systemic lupus erythematosus (SLE) and its adequate treatment is crucial for the prognosis of the disease. The intensity of the treatment should be determined by the kidney biopsy findings scored by the WHO or ISN/RPS classifications. Considering the benefits and risks of the kidney biopsy, some authors have suggested indications for its performance in lupus nephritis based on clinical manifestations comprising significant proteinuria, haematuria with proteinuria, presence of cellular casts and elevated serum creatinine. However, many studies have revealed notable discrepancies between the clinical signs and biopsy findings. Thus, performing kidney biopsy especially in a juvenile SLE patient with no clinical signs of renal disease remains controversial.To emphasize the role of renal biopsy in patients with juvenile SLE with normal clinical kidney manifestations.A case report of a patient diagnosed and treated in a pediatric rheumatology centre in multidisciplinary collaboration.A thirteen-year-old boy presented with arthritis and pleural effusion. His laboratory tests showed elevated ESR, anemia, leukopenia, decreased C3 and C4, positive ANA and anti-dsDNA. Despite normal urine sediment, creatinine clearence and no proteinuria, kidney biopsy was performed and revealed diffuse proliferative lupus glomerulonephritis class IV-S(A) according to the ISN/RPS 2003 classification. In the next course Libman-Sacks endocarditis occurred. With diagnose of juvenile SLE with severe kidney involvement the patient was treated with corticosteroids and intravenous cyclophosphamide followed by azathioprine, which was later switched to cyclosporine A, subsequently in combination with mycophenolate mofetil. Despite the serious course of the disease urine analysis and creatinine clearence remained normal for the whole period.Based on our experience with a patient with juvenile SLE with severe lupus nephritis despite their normal urine analysis and creatinine level, in accordance with some other authors, we recommend performing kidney biopsy in newly diagnosed juvenile SLE patients unless the risk to benefit ratio of the procedure is very high."}
+{"text": "This case report highlights an unusual case of sudden sensorineural hearing loss related to superficial siderosis (SS). Our patient had a craniotomy for medulloblastoma 23 years earlier, and this may represent a delayed complication related to this procedure. Magnetic resonance imaging (MRI) remains the key diagnostic investigation to illustrate the imaging features of superficial siderosis and exclude other pathologies. Increased awareness of progressive and sudden hearing complications caused by SS is important in the otolaryngologic community to expedite management and better counsel patients during the consent process. Superficial siderosis (SS) classically affects the leptomeninges, brain, brainstem, cerebellum, cranial nerves and spinal cord secondary to hemorrhage and hemosiderin deposition . Hemosid It is an uncommon condition with only approximately 100 cases reported . Early c This case report provides an account of a young male who presented with sudden sensorineural hearing loss. A 30-year-old Caucasian male patient presented to our clinic with sudden-onset left-sided sensorineural hearing loss and nonpulsatile tinnitus. His medical background was remarkable for a medulloblastoma treated with a suboccipital craniotomy and tumour resection with adjuvant radiotherapy at the age of seven. The patient had no postoperative complications or evidence of tumour recurrence on long-term followup. Examination revealed bilateral sensorineural hearing loss on tuning fork testing with normal otoscopic findings. Dysdiadochokinesia, past pointing, and intention tremor were also noted affecting the patient's left upper limb. Audiometry showed bilateral down-sloping moderate-severe sensorineural hearing loss, which was slightly worse on the left side. No prior audiometry was available for comparison.  The pathogenesis of SS results from chronic hemorrhage into the subpial layers with a predilection for the superior vermis, crests of the cerebellar folia, basal frontal lobe, temporal cortex, brainstem, spinal cord, nerve roots, and cranial nerves one and eight. The sources of hemorrhage are cerebrospinal fluid (CSF) cavity lesions, tumors, and vascular abnormalities .  The exhaustion of ferritin biosynthesis by the microglial cells as a result of iron overload subsequently causes neuronal injury . Cerebel The patient's history of previous intradural cranial surgery for medulloblastoma is a risk factor for later development of SS  and may  T2-weighted fast imaging employing steady-state acquisition (FIESTA) magnetic resonance imaging (MRI) revealed hypointense thickened bands along the vestibulocochlear nerves bilaterally which represent classic diagnostic features of SS . FIESTA  SS is a well-described delayed complication following craniotomy. Patients and their carers must be counseled regarding its association with sensorineural hearing loss, both sudden and progressive, during the consent process. Increased awareness of SS amongst the otolaryngologic community is important so that appropriate audiometric testing, imaging, and management may be expedited."}
+{"text": "Weight suppression has been found to negatively predict treatment completion of cognitive behavioural therapy (CBT). However, subsequent attempts to replicate these findings have failed. In light of this, the current study revisits the relationship between weight suppression and treatment outcomes in bulimia nervosa. We propose that moderator effects may assist in interpreting previous inconsistency. Moderators tested were parent history of overweight, chubby/overweight childhood body shape, higher pre-treatment body mass index, and highest ever adult weight discrepancy. Participants were 117 female outpatients aged 16-54 years with bulimic disorders treated with enhanced cognitive behavioural therapy at a specialist community clinic. Logistic regression indicated that pre-treatment weight suppression did not predict drop-out or poor treatment outcome. No moderator effects were observed when hypothesised moderator features were included in treatment completion or treatment outcome models. The current study calls into question the association between weight suppression and treatment outcome. Future research into moderator models, using a larger sample, could assist us to refine conceptualizations of why some patients who have a weight suppression history are vulnerable to poor treatment adherence and outcome and to establish clinical interventions that enhance prognosis.Adult Treatment and Services stream of the 2013 ANZAED Conference.This abstract was presented in the"}
+{"text": "Lobular capillary hemangioma (LCH) is a benign lesion of vascular origin. It rarely involves nasal cavity which most commonly manifests as progressive nasal obstruction and epistaxis. In this report we present a case of LCH of the nasal cavity which occurred approximately one month after delivery. There was no recurrence after complete endoscopic resection during one year follow up.  Lobular capillary hemangioma (LCH) is a benign lesion of vascular origin. The most common sites of lesion are the skin and oral mucosa. LCH rarely involves nasal cavity which most commonly manifests as progressive nasal obstruction and epistaxis. Trauma and hormonal changes are presumed as two major predisposing factors -4. In thA 32-year-old woman came to hospital clinic with complaint of progressive right-sided nasal obstruction associated with intermittent mild epistaxis, muco-purulant rhinorrhea and post nasal drip since 10 months ago began one month after her uncomplicated delivery of a normal baby. She was completely asymptomatic during her pregnancy.. She didn\u2019t mention any history of nasal trauma or nasal intubation but she has had history of multiple nasal packing during recent months. Endoscopic examination of nasal cavity revealed a red large polypoid mass which bled easily and originated from posterior part of middle turbinate.A CT scan of the paranasal sinuses also revealed a right nasal cavity soft tissue mass without any evidence of bony destruction or extension of the mass into the adjacent paranasal sinuses .The patient was taken to the operating room where the soft tissue mass was completely excised using endoscopic techniques. The surgery involved partial resection of the middle turbinate .Histologic finding showed proliferation of small capillaries lined by plump endothelial cells in a loboular pattern .There was no recurrence during the one-year follow-up period.Hemangiomas are vascular neoplasms that morphologically classified in to capillary, cavernous, arteriovenouse and epitheliod type . LCH, whThe etiology of LCH remains unknown but trauma and hormonal changes, such as those that occur in pregnancy, are thought to be major etiologic factors. Viral oncogenes, microscopic arteriovenous malformations, cytogenetic abnormalities and production of angiogenic factors are also associated with LCH . In fourA giant pyogenic granuloma of the posterior part of the nasal septum that occurred after prolonged use (30 days) of a nasogastric feeding tube has also been recorded . In a st Clinical symptoms include nasal obstruction, Epistaxis, Epiphora, purulant or mucous rhinorrhea and nasal deformity . In a stThe treatment of choice for these lesions is complete excision using endoscopic approach even for large lesions. In our case, there was no recurrence after complete endoscopic resection during one year follow up."}
+{"text": "Grass pollen allergens are a major cause of allergic respiratory disease but traditionally prescribing practice for grass pollen allergen-specific immunotherapy has favoured pollen extracts of temperate grasses. Here we aim to compare allergy to subtropical and temperate grass pollens in patients with allergic rhinitis from a subtropical region of Australia.Paspalum notatum), Johnson grass  and Bermuda grass (Cynodon dactylon) as well as the temperate Ryegrass (Lolium perenne) were measured by skin prick in 233 subjects from Brisbane. Grass pollen-specific IgE reactivity was tested by ELISA and cross-inhibition ELISA.Sensitization to pollen extracts of the subtropical Bahia grass (Patients with grass pollen allergy from a subtropical region showed higher skin prick diameters with subtropical Bahia grass and Bermuda grass pollens than with Johnson grass and Ryegrass pollens. IgE reactivity was higher with pollen of Bahia grass than Bermuda grass, Johnson grass and Ryegrass. Patients showed asymmetric cross-inhibition of IgE reactivity with subtropical grass pollens that was not blocked by temperate grass pollen allergens indicating the presence of species-specific IgE binding sites of subtropical grass pollen allergens that are not represented in temperate grass pollens.Subtropical grass pollens are more important allergen sources than temperate grass pollens for patients from a subtropical region. Targeting allergen-specific immunotherapy to subtropical grass pollen allergens in patients with allergic rhinitis in subtropical regions could improve treatment efficacy thereby reducing the burden of allergic rhinitis and asthma. Grass pollens are amongst the most frequently recognised aeroallergens worldwide ,2. AllerLolium perenne) which is the major clinically relevant allergenic grass pollen in temperate regions of Australia [Paspalum notatum), Johnson grass  and Bermuda grass (Cynodon dactylon) were among the most abundantly observed grasses [Despite the clinical importance of grass pollen allergy in allergic respiratory diseases, it has not been established which of the grass pollens are most relevant to Australian environments, with the exception of Ryegrass  grass pollen extracts, house dust mites , cat hair , moulds , and Ragweed pollen .Skin prick testing were performed according to the guidelines of the Australian Society for Clinical Immunology and Allergy . BrieflyArachis hypogaea extract) was prepared as a control allergen [Proteins from non-defatted pollen grains of Ryegrass, Bahia, Timothy, Johnson and Bermuda grasses  were extracted in phosphate buffered saline with complete protease inhibitor cocktail  for three hours on a rotating wheel at 4\u00b0C and clarified as previously described . Raw peaallergen .Plasma samples diluted 1/10 were tested by ELISA with microtiter plate wells coated with 5 \u03bcg/ml of whole grass pollen extract as described previously . InhibitData was assessed for normality by Kolmogorov-Smirnov test and assessed for differences by Friedman's ANOVA with Dunn's multiple comparison tests. P values less than 0.05 (*), < 0.01 (**), or < 0.001 (***) were considered significant. Correlations of SPT and IgE reactivity between different grass pollens were determined by Spearman's rank test for paired data.Participants were recruited from amongst patients presenting to an Immunology or Respiratory clinic at a major public hospital in Brisbane, as well as amongst healthcare and laboratory workers. Seventy seven participants were skin prick test (SPT) negative to all aeroallergens tested. Eighty subjects were SPT positive to allergens other than grass pollens with house dust mite being the most frequently recognized allergen. Seventy six of the 233 participants assessed by skin prick tests showed positive reactions to at least one grass pollen extract . There were 48 grass pollen-allergic subjects for whom SPT data was available for each of Ryegrass, Bahia, Johnson and Bermuda grass pollens. Of these 48 subjects there were eight (16%) who only showed positive SPT to subtropical grasses, whereas three (6%) showed a positive SPT to Ryegrass pollen only.SPT wheals were significantly larger with Bahia and Bermuda grass pollens than with Ryegrass pollen Figure . InteresThere were significant correlations in allergic sensitivity between each of the grass pollens Table . The strIgE reactivity with each of the grass pollens was tested by ELISA in 175 subjects for whom plasma was available. The IgE reactivity of the 70 SPT-negative, non-atopic donors was used to define the normal range. Concentrations greater than three standard deviations above the mean IgE reactivity of normal subjects were considered positive; these cut off values were as follows - Bahia grass , Bermuda grass (0.129 OD) and Ryegrass (0.187 OD). Using this definition, of 50 subjects with allergies other than grass pollen, there were one, two, two and four subjects who tested positive for IgE reactivity with Bermuda, Johnson, Bahia and Ryegrass pollen, respectively. Forty five of 55 (81%) of grass pollen-allergic subjects with positive SPT to any grass pollen showed IgE reactivity with at least one of the four grass pollens by ELISA. There were ten subjects (18%) who only showed IgE reactivity with subtropical grass pollens whereas only four (7%) subjects showed IgE reactivity with Ryegrass pollen only. Mostly, subjects showed IgE reactivity with more than one grass pollen but there were differences in the levels of IgE reactivity.The IgE reactivity of the grass pollen-allergic donors was higher with Bahia grass pollens than with Johnson and Ryegrass pollens Figure . IgE reaPlasma IgE reactivity with each of the grass pollens were well correlated amongst the grass pollens Table . HoweverReciprocal cross-inhibition assays were performed in a subset of subjects known to have grown up in the Brisbane area and who would represent patients primarily exposed to subtropical grass pollens, in order to compare the strength of IgE reactivity with subtropical versus temperate grass pollen allergens Figure . The relHitherto grass pollen allergy has been primarily studied in subjects living in regions with temperate climates such as parts of Europe and North America where Timothy grass pollen is the predominant clinically important grass pollen. Ryegrass pollen has been considered to be the most clinically important grass pollen allergen in Australia ,13. HoweHere we show marked differences in the relative avidity of IgE binding between different grass pollens in dose responsive four-way reciprocal cross-inhibition experiments. Other studies of patients from temperate regions focused on inhibition of IgE reactivity with Timothy grass pollen extract or its allergenic components with an excess of pollen inhibitor and reported maximal inhibition capacity but not relative avidity as revealed by decreasing doses of pollen inhibitor ,27. PoolThere were differences in the degree of correlation of SPT sensitivity Table  and plasThere are known to be differences in allergen composition amongst grass pollens. Pollens of different species of temperate grasses all contain several major allergen families including group 1, 2, 4 and 5 whereas the subtropical grass pollens lack the group 2 and 5 allergen families . There aThe difference in allergic sensitivity and allergen recognition depends not only on biological differences between the pollens but also upon the origin of the patients investigated. Our observations with patients from a subtropical region is in contrast to IgE reactivity of patients from the temperate region city of Melbourne, who showed substantially higher IgE reactivity with pollens of Ryegrass compared with Bahia and Bermuda grasses . SimilarWe also sought to compare the allergic sensitivity and IgE reactivity amongst subtropical grass pollens. The same heterogeneity evident within temperate grass pollen allergens discussed earlier might be expected for pollen allergens of the subfamilies of subtropical grasses. Indeed we observed Johnson grass pollen elicited lower SPT and plasma IgE reactivity than Bahia grass pollen as well as lower capacity to inhibit serum IgE reactivity with other grass pollens, including Bahia grass pollen suggesting that there may be allergenic differences between these Panicoideae grass pollens. It is worth considering that although both these grasses belong to the one subfamily they align to different subtribes, Paniceae for Bahia grass and Andropogoneae for Johnson grass, which may explain why these grass pollens were not interchangeable. A difference between Bahia and Bermuda grass pollens was not evident by SPT but Bahia grass pollen showed higher levels of IgE reactivity than Bermuda grass pollen. We noted that Bermuda grass pollen appeared to be more allergenically distinct from Ryegrass than Bahia grass pollen since in three of five donors IgE reactivity with Bermuda was only substantially inhibited by itself and it had only limited capacity to block IgE reactivity with Ryegrass, Johnson or Bahia in some subjects. Also, SPT and plasma IgE reactivity with Bermuda showed the least correlation with Ryegrass suggesting greater allergenic differences between Bermuda and Ryegrass pollens than between Bahia and Ryegrass. However, further studies are warranted to confirm this observation with a wider representation of patients from subtropical regions.The outcomes of this study are likely to impact upon the clinical efficacy of grass pollen allergen-specific immunotherapy in patients from a subtropical region. Whilst for many treatment for allergic rhinitis can be managed by allergen avoidance and pharmacotherapy, for others with more severe disease, specific immunotherapy is indicated . Grass pHere we demonstrate higher SPT and IgE reactivity with subtropical grass pollens than Ryegrass in patients from a subtropical region. We also observed incomplete and asymmetric cross-inhibition of serum IgE between subtropical grass pollens and the Ryegrass pollen allergen in patients with grass pollen allergy in Brisbane. Further studies are warranted to assess difference in allergic sensitization in other parts of Australia, including arid and wet tropical regions where there are hotter climates and subtropical grass pollens are likely to contribute to grass pollen sensitization. It will be necessary in the longer term to investigate whether differences observed here in IgE recognition of subtropical and temperate grass pollen affect the efficacy of immunotherapy for patients primarily sensitized to subtropical grass pollen allergens in Australia and other regions with similar climatesELISA: Enzyme-linked immunosorbant assay; IC50: Inhibitor concentration giving 50% inhibition; IgE: Immunoglobulin E; OD: Optical density units; SPT: Skin prick test.JMD has received grants from the Asthma Foundation of Australia, Australian Society for Clinical Immunology and Allergy, The University of Queensland and the National Health and Medical Research Council of Australia, has collaborations with Sullivan Nicolaides Pathology (Queensland) and Phadia Pty Ltd , and is an inventor on an Australian and US patent on \"Novel immunogenic molecules and uses thereof (Bahia grass)\". JMD has also received consulting fees from Stallergenes Pty Ltd  and has a collaborative research agreement with this company. MT has received Honoraria from Novartis for asthma nurse education presentations. JWU has been paid Honoraria from Astra Zeneca to present updates on asthma at approved medical education events.JD was the senior author of this manuscript. JD designed the study, analysed data, prepared and edited the manuscript. HZL performed the ELISA experiments. MG and MT assisted with patient recruitment and skin prick testing. JWU was involved with subject recruitment and provided intellectual input to the study. All authors read and approved the final manuscript."}
+{"text": "Monilethrix is an autosomal dominant hair shaft disorder characterized by intermittent constrictions result in short and fragility hair. We present here two afghan siblings girl, 5 and 3 years, born of consanguineous marriage, come to our department of dermatology with complains of hair loss and inability to growth long hair of the scalp since birth. When the hairs reached a certain length, they were broking. There was no relevant familial history. On examination, we found diffuse thinning of scalp hair with broken, short and spars hairs. The length of hairs was less than 2 centimeter. Multiple keratotic papules were present on entire the scalp. Hairs in eyebrows also were involved. Diffuse hair loss seen in trunk and extremity. Nails and dental were normal appearance. Other systemic examination of hair showed beaded appearance with certain interval. Histopathologic examination of scalp showed misdirection with abnormal and tortuous appearance and bulb shaped shaft in some foci considering for monilethrix. Its differential diagnosis include monilethrix-like congenital hypothericosis, alopecia areata with variable activity in the course of disease, primary cicatricial alopecia (border of fibrotic area), chemotherapy induced alopecia, monilethrix-like effect from hair styling gel and pseudo-monilethrix. There is no specific treatment of monilethrix. Improvement by hormonal treatment reported in one study that hair growths increased after first menstrual period, so it suggested hormonal influence may improve hair growths. In literatures many different options for treatment of monilethrix proposed such as oral retinoid Griseofulvin and recently topical minoxidil 2%. One study showed improvement molinethrix after treatment by iron supplementation in iron deficiency anemia."}
+{"text": "Eliciting effective antibody responses are key to the design of HIV vaccines. While the HIV envelope protein is highly immunogenic and provokes a high-titer antibody response during viral infection and experimental immunization, affinity-matured antibodies capable of neutralizing diverse HIV isolates are rarely elicited. While recent vaccine regimens have focused on DNA, viral vector, VLP, or attenuated virus vaccines, of increasing interest are improved recombinant envelope protein immunogens. Immunizations with trimeric gp140 proteins induce higher-titer neutralizing antibody responses and have structural benefits over monomeric gp120 immunizations. Novel approaches being taken for recombinant trimeric gp140 immunogens include the use of consensus and multi-clade gp140 trimers. A consideration for these synthetic proteins that is key to vaccine efficacy: do these proteins structurally represent a native trimeric envelope?To address potential differences in the functional conformation of gp140 trimers, we evaluated the conformational characteristics of trimeric gp140 proteins from varying HIV-1 strains as well as engineered consensus gp140s via binding studies using surface plasmon resonance with a panel of well-characterized monoclonal antibodies (MAbs).Consensus trimers were recognized by more monoclonal antibodies than the primary strain gp140s, suggestive of the benefits of engineered trimers. However, analysis revealed a low trimer concentration that is competent to bind the quaternary-recognizing MAb PG9. Considering the binding to other conformational MAbs, this suggests that while the consensus gp140s contain appropriately conformational monomers and are trimeric, the vast majority of the protein is not in a proper quaternary structure.These data suggest that it is important to fully assess structural differences of immunogens even though obvious phenotypic differences may not be present. Taken together, these observations demonstrate the need to evaluate immunogens in a manner that allows the measurement of functional epitope exposure and solution conformation to assess the potential to elicit a potent, broadly-neutralizing antibody response."}
+{"text": "FUS is a DNA/RNA binding protein found to be mutated in some cases of both sporadic and familial forms of ALS. It is still not clear how ALS-causing mutations in FUS leads to motor neuron degeneration. Here, we exploited a Drosophila model and mammalian neuronal cell lines to elucidate the role of the RNA-binding ability of FUS in regulating FUS-mediated toxicity. To determine the role of the RNA binding ability of FUS in ALS, we mutated FUS RNA binding sites  to leucines and generated RNA binding-incompetent mutants (4F-L) with and without ALS causing mutations R518K or R521C. We found that mutating 4F to L residues makes FUS RNA binding-incompetent. We observed that ectopic expression of RNA binding-incompetent FUS in fly brain, eyes and motor neurons strongly blocks neurodegenerative phenotypes as compared to RNA-binding-competent FUS carrying ALS causing mutations. Interestingly, RNA-binding deficient FUS strongly localized to the nucleus of Drosophila motor neurons and mammalian neuronal cells whereas FUS carrying ALS linked mutations was distributed to the nucleus and cytoplasm.in vivo unbiased genetic screen that led to the discovery of several dominant modifiers of mutant FUS toxicity including proteins involved in regulating SG dynamics, mitochondrial functions and RNA splicing. These genetic modifiers would help in identifying potential therapeutic targets for ALS.Importantly, we found that incorporation of mutant FUS into stress granules is dependent on the RNA-binding ability of FUS. SGs are dynamic aggregates composed of proteins and RNA that are formed when cells are under a variety of stresses. We observed that normally cytoplasmic SGs rapidly disassemble when stress conditions end, whereas cytoplasmic SGs formed in ALS patient cells having a FUS mutation fail to disassemble. This suggests that mutant FUS sequesters proteins and RNAs important for cellular homeostasis and the defect in disassembly of cytoplasmic SGs contributes to ALS. Finally, following up these observations we performed an"}
+{"text": "Pompe disease (glycogen storage disease type II) is an autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme acid alpha-glucosidase. Enzyme replacement therapy (ERT) with alglucosidase alfa has resulted in a clinical benefit in a subset of patients. Cross-reactive Immunological Material (CRIM)-negative status is associated with poor prognosis. Patients with CRIM-negative infantile Pompe disease mount a strong immune response against alglucosidase alfa ERT, resulting in a clinical decline and death despite therapy. Most develop high sustained antibody titers. Based on our clinical and laboratory experience, about 40 percent of patients with infantile Pompe disease develop HSAT. Early identification of patients at risk is needed to allow for treatment intervention with immune tolerance induction (ITI) protocols. These protocols have included the use of agents such as rituximab, methotrexate, IVIG, and agents that target the plasma cells. Different treatment approaches are needed for patients with Pompe disease treated with ITI in the na\u00efve setting as compared to patients with high sustained antibody titers. Without ITI, the CRIM-negative patients do poorly on ERT alone. We will present a successful global experience in 15 cases and discuss the safety, efficacy and feasibility of a clinical algorithm developed at our institution to identify CRIM-negative status and allow timely initiation of ERT and ITI in this vulnerable population. Our data show that the clinical algorithm of rapidly diagnosing and initiating ITI coincident with the start of ERT in CRIM-negative patients is feasible and can be achieved in a timely manner."}
+{"text": "Xenograft mouse models represent helpful tools for preclinical studies on human tumors. For modeling the complexity of the human disease, primary tumor cells are by far superior to established cell lines. As qualified exemplary model, patients\u2019 acute lymphoblastic leukemia cells reliably engraft in mice inducing orthotopic disseminated leukemia closely resembling the disease in men. Unfortunately, disease monitoring of acute lymphoblastic leukemia in mice is hampered by lack of a suitable readout parameter.Patients\u2019 acute lymphoblastic leukemia cells were lentivirally transduced to express the membrane-bound form of Gaussia luciferase. In vivo imaging was established in individual patients\u2019 leukemias and extensively validated.Bioluminescence in vivo imaging enabled reliable and continuous follow-up of individual mice. Light emission strictly correlated to post mortem quantification of leukemic burden and revealed a logarithmic, time and cell number dependent growth pattern. Imaging conveniently quantified frequencies of leukemia initiating cells in limiting dilution transplantation assays. Upon detecting a single leukemia cell within more than 10,000 bone marrow cells, imaging enabled monitoring minimal residual disease, time to tumor re-growth and relapse. Imaging quantified therapy effects precisely and with low variances, discriminating treatment failure from partial and complete responses.For the first time, we characterized in detail how in vivo imaging reforms preclinical studies on patient-derived tumors upon increasing monitoring resolution. In the future, in vivo imaging will enable performing precise preclinical studies on a broad range of highly demanding clinical challenges, such as treatment failure, resistance in leukemia initiating cells, minimal residual disease and relapse. Preclinical mouse models are helpful tools for studying biology and therapy of diseases. Novel therapeutic approaches undergo detailed preclinical evaluation before translation into clinical trials In cancer research, a variety of different mouse models exist including xenotransplantation models and syngeneic models At best, xenotransplanted tumor cells generate a disease in mice which highly resembles the disease in men Nevertheless, sensitive follow up of leukemia progression in mice remains a limitation of the model. Invasive bone marrow aspirations in mice require prolonged periods of recuperation; blood sampling is hampered by late and heterogeneous presence of tumor cells into the peripheral blood In vivo imaging based on molecular cell marking represents a sensitive readout parameter to monitor xenotransplanted tumors in mice, e.g., using bioluminescence Here, we established the molecular labeling of patient-derived ALL cells and characterized in detail, how bioluminescence in vivo imaging enables a novel level of precision for future preclinical studies. In vivo imaging enabled quantification of treatment effects and monitoring of minimal residual disease in mice. The improved mouse model will allow performing decisive and complex preclinical studies on individual leukemias in the future.Ethikkommission@med.uni-muenchen.de, April 15/2008, number 068-08) and with the Helsinki Declaration of 1975, as revised in 2000.Written informed consent was obtained from all patients and from parents/carers in the cases where patients were minors. The study was performed in accordance with the ethical standards of the responsible committee on human experimentation .All animal trials were performed in accordance with the current ethical standards of the official committee on animal experimentation , 1 mM sodium pyruvate and 50 \u00b5M 1-thioglycerole  in the absence of further cytokines as described The IVIS Lumina II Imaging System was used . Mice were anesthetized using isoflurane, placed into the imaging chamber in a supine position and fixed at the lower limbs and by the inhalation tube. Coelenterazine  was dissolved in acidified methanol (HPLC grade) at concentration 10 mg/ml and diluted shortly before injection in sterile HBG buffer . Immediately after intravenous tail vein injection of 100 \u00b5g of native Coelenterazine, mice were imaged for 15 seconds using a field of view of 12,5 cm with binning 8, f/stop 1 and open filter setting. To monitor tumor growth, mice were imaged once weekly; after therapy, mice were imaged every other day.4 photons per second per cm2 per solid angle of one steradian (sr). Different regions of interest (ROI) were defined and signals were considered positive, when light emission exceeded background in each ROI; background was measured in 15 mice harboring GLuc negative leukemias; a ROI covering the entire animal was used (background 4\u00d7106 photons per second); as an exception and to determine early engraftment\u200a=\u200aminimal disease, a small ROI  was set at femurs at the location, where and when first light emission became visible; depending on the expression level of the transgenes, overt leukemia was considered above 109\u20131010 photons per second using the ROI covering the entire animal; overt leukemia served as criterion for ending experiments, as it shortly preceded onset of clinical signs of disease in mice.The Living Image software 4.x  was used for data acquisition and quantification of light emission using a scale with a minimum of 1,8\u00d710Control animals received physiological salt solution intraperitoneally; treatment group mice were injected i.p. with a single dose of either Etoposid  or Cyclophosphamide  diluted in 0.9% NaCl.http://bioinf.wehi.edu.au/software/elda).Mean and standard error of the mean (SEM) were calculated using the Microsoft Excel 2010 software . To determine significance of treatment effects in vivo, Mann-Whitney Rank Sum Test and the Sigma Plot 12 software  was used. CSC frequencies were calculated according to Poisson statistics using the ELDA software application  was chosen in its membrane-bound form Leukemia cells are notoriously difficult to transfect and patient-derived leukemia cells do not allow antibiotics-based selection in vitro. Therefore, lentiviral transduction was chosen, although transgene integration into unsuitable genomic sites might alter cell function. GLuc was cloned into a lentiviral vector harboring additionally copepod green fluorescence protein (GFP) . PrimaryAll 9 samples from children with ALL  were successfully transduced, although transduction efficiencies and levels of transgene expression varied widely between samples . While hFor imaging, the convenient IVIS Lumina II Imaging System  was used together with an optimized protocol (for details see suppl. Results). Kinetics of GLuc-emitted light from leukemia cells was similar to published kinetics on GLuc-expressing T-cells Bioluminescence in vivo imaging using GLuc visualized engraftment of patient-derived ALL cells in mice first in the lower extremities where bones and bone marrow are located directly under the fur . Over tiLikewise, light emission strongly depended on the number of cells injected, indicating that both kinetic and dose response were clearly represented by in vivo imaging in this model . The groTo reassure that imaging reliably visualized the leukemic disease, in vivo imaging data were correlated to conventional post mortem readouts. Single mice engrafted with sample ALL-50 were sacrificed weekly and bone marrow and spleen were analyzed by flow cytometry and immunohistochemistry to quantify leukemic cells. Imaging was more sensitive in detecting leukemic infiltration in bone marrow than in spleen arguing towards the highest sensitivity of imaging in visualizing ALL in bone marrow located directly under the fur , but wasTo quantify light emission, regions of interest were defined and analyzed using the Living Image software 4.0 . In close correlation to the visual impression, quantification revealed first engraftment in a region covering the lower extremities, while inner organs became visible at late time points followed by extremely rapid signal increase . For furQuantification of light emission revealed a strictly logarithmic growth of patient-derived leukemia cells in mice covering up to 4 orders of magnitude . SimilarIndividual leukemias were obtained from patients with very different clinical parameters, including primary disease and relapse, and contained completely different cytogenetic and molecular alterations . Light emission quantification of ALL samples showed that all samples grew in a logarithmic pattern in mice . Thus, logarithmic growth appears as general principle how human leukemia cells behave in mice. Nevertheless and according to published data To control quality parameters of the model, assay variances were estimated. Imaging showed a highly reproducible growth of leukemia in mice with surprisingly low intra- and inter-assay variances considering that an in vivo model was studied  represents a major clinical threat as MRD is difficult to treat and often followed by relapse. Appropriate preclinical models to study MRD are required 4 photons per second using defined criteria, see Methods for details), most mice were sacrificed and bone marrow and peripheral blood analyzed by flow cytometry, quantitative real time PCR and immunohistochemistry. All remaining mice showed constant light increase similar to the kinetic shown in To test, whether GLuc-based in vivo imaging could visualize MRD, its sensitivity was measured. Groups of mice were engrafted with equal cell numbers of the same sample and were imaged three times weekly. Upon crossing a clearly defined detection threshold  are able to maintain tumor growth and therefore represent the most important targets for anti-cancer therapy Bioluminescence in vivo imaging allowed observing each group of mice within the LDTA repetitively over time . TherebyTNF-related, apoptosis-inducing ligand) prior to transplantation significantly reduced engraftment of cells in mice . Imaging allowed starting treatment in mice with equal tumor burdens, although rarely mice had to be excluded, as leukemia grew highly homogenously in mice . Mice were treated with conventional cytotoxic drugs by systemic bolus injections in concentrations modeling drug doses typically applied in patients Individual leukemias were grown until advanced disease . Treatment nearly eliminated tumor cells from peripheral blood, while imaging visualized the remaining tumor burden post treatment . Due to limited sensitivity, conventional measurement in peripheral blood appears overestimating therapeutic effects, although this readout was most frequently used for disease monitoring until today.In our model, each mouse harbors the leukemia of an individual patient. Imaging-guided preclinical treatment trials in mice revealed that individual ALL samples retained individual sensitivities towards conventional cytotoxic drugs. While the T-ALL sample ALL-4S was sensitive towards treatment with Cyclophosphamide, it was resistant towards Etoposid; in contrast, the B-ALL sample ALL-199 was resistant towards Cyclophosphamide, but sensitive towards Etoposid . AccordiMost importantly, imaging was able to quantify therapeutic responses and to visualize tumor regrowth. Due to low assay variances, imaging allowed distinguishing treatment failure/drug resistance/progressive disease from partial or complete response . As addiTaken together, in vivo imaging allowed the rapid, precise and individual quantification of treatment responses.The sensitivity of tumor cells towards treatment depends on the disease stage at which the drug is given After treatment, imaging reliably quantified residual disease. Short-interval imaging revealed short \u201clag phase\u201d of no-growth after a single application for certain, but not all drugs and samples . In the Taken together, we have introduced and validated in detail GLuc-based bioluminescence in vivo imaging in the xenograft mouse model of individual patient\u2019s ALL. Imaging was easy to perform and gave rise to highly sensitive and reliable results which enable the non-invasive accurate and detailed monitoring of disease progression and treatment responses.GLuc-based bioluminescence in vivo imaging was introduced and intensively validated as novel readout parameter for the preclinical model of patient-derived ALL growing in mice. In vivo imaging allowed performing preclinical trials on a novel level of accuracy and precision including stage-specific therapy and quantification of treatment responses. In the future, improvement of the individualized ALL mouse model by in vivo imaging will allow performing preclinical trials more exactly and in more detail.Imaging allowed modeling disease stages in mice which represent current challenges in the clinics such as minimal residual disease and tumor regrowth. Imaging was highly sensitive and continuous and correlated well with post mortem results regarding tumor distribution. Assay variances were minimal which will reduce the number of animals required per experiment. In addition, tumor growth was orthotopic and homogenous and tumor cells were derived from individual patients with genetically defined tumors; limiting dilution assays were easily visualized to study drug sensitivity of leukemia initiating cells. Taken together, GLuc-based imaging will allow performing high quality and convenient preclinical treatment trials in the individual mouse model of ALL in the future.The most important challenges in cancer treatment represent treatment failure and relapse. Using in vivo imaging, treatment failure is easily detectable in the first days after treatment as light emission continues increasing despite of therapy; short-period treatment quantification will allow speeding up preclinical treatment trials. Tumor regrowth is visualized by quantification of post-therapeutic residual disease followed by monitoring increase in light emission. Thus, our model is able to exactly map both important clinical challenges for preclinical trials.In addition to bioluminescence imaging, fluorescence imaging represents an interesting alternative with a better anatomical resolution, especially using near- infrared fluorochromes Recently, two groups published the use of firefly luciferase for in vivo imaging of transplanted individual ALLs The major advantage of using GLuc instead of firefly luciferase for in vivo imaging is the markedly increased light emission from superficial organs such as bone marrow in the lower extremities of mice Leukemic disease serves as a suitable model disease for cancer in general since leukemia cells are easier in handling compared to solid tumor cells. Many important research discoveries in cancer biology were first described in leukemia; for example, oncogenic mutations are best characterized in acute myeloid leukemia Taken together, GLuc-based in vivo imaging in the individualized preclinical model of ALL enables performing treatment trials on a novel level of accuracy and precision. It enables quantifying therapy effects and remaining disease burdens as well as exact modeling of distinct disease stages. The model facilitates the detailed preclinical analysis of novel therapies for preparing their translation into the clinics. The model allows preclinical trials addressing the most demanding current clinical challenges, such as treatment failure, resistance in leukemia initiating cells, minimal residual disease and relapse.Supporting Information S1(PDF)Click here for additional data file."}
+{"text": "The link between high maternal blood pressure and poor pregnancy outcome is well established. Similarly the causal relationship between acute maternal hypotension and acute fetal distress is well recognised. The link between poor pregnancy outcome and persistent maternal hypotension is less well known.McClure Brown  was the It is problematic that previously reported studies have defined maternal hypotension differently. However, Warland  attempteIn summary, there is a small body of research which has consistently demonstrated the negative effect of persistent maternal hypotension on poor pregnancy outcome including stillbirth. These studies have been conducted using a range of approaches including prospective cohort, retrospective case-control and population based data bank analysis. Many questions remain unanswered, including the definition of hypotension, the level at which hypotension becomes problematic, and how best to manage maternal hypotension in pregnancy."}
+{"text": "BCR-ABL translates into an abnormal tyrosine kinase that accelerates development of chronic myelogenous leukemia [Gene fusions are hybrid genes formed when two discrete genes are incorrectly joined together. Gene fusions are found to play roles in tumorigenesis. For example, the fusion gene leukemia . A netwoleukemia  performeWe mined three public databases for cancer-related gene fusion sequences, and one database for fusions records from cancer studies, transcriptome analysis, and genetic disorders. Specifically, we processed each dataset by removing incomplete entries and then extracted gene-fusion pairs. Genes serve as the nodes in the network and each fusion pair is joined by an edge. Repeating pairs were represented once. We used Cytoscape to build five networks: one for each dataset and the fifth that encompasses all datasets. We graphed the occurrence of degree in each single dataset network to determine an empirical definition for hub genes.MLL and MALAT1, both of which have roles in tumorigenesis. The network also highlights genes such as WDR74 and COL1A1, which are not much studied.The comprehensive network includes 9852 genes, displays 12,791 relationships, and highlights 1248 hub genes. The network highlights genes such as This preliminary network analysis provides interesting features of tumorigenesis-related fusions. Further systematic analysis of gene fusion networks may aid researchers to better understand cancer gene fusions and test novel fusions in specific types of cancer."}
+{"text": "Thirty-four countries worldwide have abnormally high sex ratios (>102 men per 100 women), resulting in over 100 million missing women. Widespread sex selective abortion, neglect of young girls leading to premature mortality, and gendered migration have contributed to these persistent and increasing distortions. Abnormally high adult sex ratios in communities may drive sexually transmitted disease (STD) spread where women are missing and men cannot find stable partners. We systematically reviewed evidence on the association between high community sex ratios and individual sexual behaviors.Seven databases  were searched without restrictions on time or location. We followed PRISMA guidelines and evaluated quality according to STROBE criteria. 1093 citations were identified and six studies describing 57,054 individuals were included for review. All six studies showed an association between high community sex ratios and individual sexual risk behaviors. In high sex ratio communities, women were more likely to have multiple sex partners and men were more likely to delay first sexual intercourse and purchase sex. Only two studies included STD outcomes.High community sex ratios were associated with increased individual sexual risk behavior among both men and women. However, none of the studies examined unprotected sex or appropriately adjusted for gendered migration. Further studies are needed to understand the effect of community sex ratios on sexual health and to inform comprehensive STD control interventions. Sex selective abortions have become so widespread that the global sex ratio at birth has increased from 105 to 107 High sex ratios establish communities where surplus men cannot form stable partnerships with women, potentially driving risky sexual behaviors that accelerate transmission of sexually transmitted diseases (STDs). Increased STD burden in high sex ratio communities may be due to increased unsafe commercial sex The potential for high adult sex ratios to drive STD transmission has been previously hypothesized surplus men, forced bachelor, sex ratio, male-female ratio, or gender ratio, and HIV/AIDS, std, sexual behavior, sexually transmitted disease, risk behavior, sex workers, or commercial sex. Our PubMed search terms are available in We conducted a literature search through 30 August 2012 of articles that addressed the association between adult community sex ratios and individual sexual risk behaviors and STD biomarkers. We searched abstracts using combinations of the key words Abstracts were checked for potential relevance, and had to meet the following criteria: only quantitative, English-language population-based research studies; sex ratios measured across multiple partner markets (a community unit defined by each study); and reported individual sexual risk outcomes (behaviors or biomarkers). In order to conduct a comprehensive global systematic review, no limits were placed on study date, location, race or ethnicity of study participants, or the definition of sex ratio. Partner markets were defined as discrete geographic units in which individuals were more likely to find a stable partner. Behavioral outcomes included in the study were multiple sex partners, sex with commercial sex workers, forced sex, premarital sex, recent sex, and self-reported sexually transmitted disease. Biomarker outcomes included a positive test for any sexually transmitted disease. We excluded studies conducted in settings with primarily low sex ratios  and studies that were not population-based. Outcomes related to health seeking behaviors, mental health, or unrelated to sexual behavior were excluded. Case studies, qualitative studies, and ecological studies were excluded.We used PRISMA guidelines to identify and exclude studies (Text S2). Two independent reviewers (CB and JT) analyzed full-text articles for inclusion in the review. The reference sections of the remaining articles were then searched to identify other studies that met our inclusion criteria. Source data were reviewed (by JT and CY) and data were abstracted into tables. We contacted study authors to retrieve missing study data. Effect size was measured according to parent data, as either the coefficient or odds ratio. In some cases, statistical significance was converted to a p-value. We used adjusted odds ratios in studies with both crude and adjusted data.We graded the quality of each study using the STROBE reporting criteria for cross-sectional studies  [30]. WeOur search yielded a total of 1093 studies . Most inSix studies were included in this review describing 57,054 individuals. Three studies were conducted in high-income countries Definitions of adult sex ratios, migration, and partner markets substantially differed between studies. Although the adult sex ratio is typically reported as the number of men per 100 women of a certain age, two studies reported the number of women per 100 men. These measures were not converted into standard measures of sex ratios in order to preserve apparent effect sizes from the studies. None of the studies included individual-level data for migration, although two of the studies included migrants in community-level census data but excluded migrants in the study sample All six studies found an association between high sex ratios and increased sexual risk outcomes . Among tTwo studies found a concurrent decrease in some sexual risk outcomes and increase in other sexual risk outcomes Few of these studies examined mechanisms linking the connection between high community sex ratio and individual behavior. Two studies examined purchasing of sex among men High adult sex ratios are increasingly common in many parts of the world, but the impact of these global demographic changes on individual sexual behaviors is poorly understood. The proportion of men older than 25 years old who fail to marry in China will nearly triple in the next twenty years, even if sex ratio trends reverse now Our review found limited evidence that high sex ratios were associated with increased sexual risk behavior among women. One study in China Our review suggests increased sexual risk behaviors among men in high sex ratio communities as well. Two studies found that men in high sex ratio communities delay first sexual intercourse, but have an increased risk of purchasing sex, compared to men in normal sex ratio communities Understanding the mechanisms that link community sex ratios and individual risk can guide risk-reduction strategies, from community-level to individual-level interventions. However, we found little evidence that linked the impact of community sex ratios and individual sexual risk behaviors . The onlMigration of surplus men away from high sex ratios is a critical issue because it may inadvertently increase sex ratios in destination communities. However, none of the studies examined gendered migration as either a potential driver of increased sex ratios or a potential cause of individual risk behavior. One study of migrant communities in North Carolina with high sex ratios found an increase in commercial sex use among in communities with fewer women Despite our comprehensive search strategy, our review highlights the relatively limited literature on community sex ratios and sexual health. The reporting quality of some of the studies was poor. One study presented only data that did not differentiate male and female sexual behaviors Our review has several limitations. First, meta-analysis was not possible due to substantial variation in study methodology. Although sex ratios are commonly reported as number of males per 100 females, two studies reported sex ratios as the number of females per 100 males. Variations in study definition of sex ratio and outcomes measures did not permit comparisons of effect size. In order to broaden the scope of the review, we did not place any restrictions on time or location of included studies. Nevertheless, our study included data from only four countries, introducing the possibility of publication and location bias. Three of the included studies were conducted in countries with high sex ratios, but other nations, particularly those in Asia, also have abnormally high sex ratios. Future studies in these settings are warranted. Increased understanding of the mechanisms that drive sexual risk behavior in high sex ratio communities will strengthen comparability between study settings. We did not include studies where sex ratios are predominately low, a demographic phenomenon noted in African-American communities, communities that experience net out-migration, and nations in Eastern Europe Profound demographic changes will fundamentally shift population structures across the globe. Sex ratios will continue to rise in many regions of the world, but their effect on human health, particularly sexual health, remains poorly described. Our review found evidence that high community sex ratios may be associated with increased sexual risk behaviors among both men and women. More epidemiology research, especially among men, is needed to understand the mechanisms driving this association. In addition, prospective studies that include individual STD and migration data are warranted to further assess the findings in this review. Understanding the impact of community sex ratios on sexual health will inform structural STD control interventions, which can better target populations at increased STD risk.Table S1STROBE reporting criteria for cross-sectional studies (full-text).(DOCX)Click here for additional data file.Text S1PubMed Search Strategy.(DOCX)Click here for additional data file.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file."}
+{"text": "Arabidopsis veins provide an experimental system to identify such switches. The extent of ingrowth deposition responds to various abiotic and applied stresses, enabling bioinformatics to identify candidate regulatory genes. Furthermore, simple fluorescence staining of PP TCs in leaves enables phenotypic analysis of relevant mutants. Combining these approaches resulted in the identification of GIGANTEA as a regulatory component in the pathway controlling wall ingrowth development in PP TCs. Further utilization of this approach has identified two NAC -domain and two MYB-related genes as putative transcriptional switches regulating wall ingrowth deposition in these cells.In species performing apoplasmic loading, phloem cells adjacent to sieve elements often develop into transfer cells (TCs) with wall ingrowths. The highly invaginated wall ingrowths serve to amplify plasma membrane surface area to achieve increased rates of apoplasmic transport, and may also serve as physical barriers to deter pathogen invasion. Wall ingrowth formation in TCs therefore plays an important role in phloem biology, however, the transcriptional switches regulating the deposition of this unique example of highly localized wall building remain unknown. Phloem parenchyma (PP) TCs in  These cells inuities . The incArabidopsis  often develop extensive wall ingrowths. Well-known examples include companion cells (CCs) in pea , phloem bidopsis , and botvulgaris . In pea,vulgaris , and in e PP TCs . TCs aree PP TCs , particue PP TCs . Wall inVicia faba cotyledons have established that auxin (V. faba cotyledons (Arabidopsis that enabled a combined bioinformatics and reverse genetics approach to be undertaken to discover that GIGANTEA (GI)is a component of a pathway regulating wall ingrowth deposition in PP TCs. Further, we describe preliminary results using this approach to identify previously uncharacterized members of the NAC -domain and MYB-related gene families as putative transcriptional regulators of wall ingrowth deposition in PP TCs.Transfer cell development occurs across normal developmental windows but also in response to biotic and abiotic stress . Recent at auxin , ethylenat auxin , and reaat auxin  functiontyledons  and endotyledons , 2012 inArabidopsis are known to occur in PP of the minor vein network in both leaves . Higher magnification views revealed that the Calcofluor White staining showed a distinctive mottled appearance, a characteristic consistent with staining the patchy and tangled wall ingrowths seen in leaf PP TCs by scanning electron microscopy . Double labeling experiments have shown that Aniline Blue gives the same mottled patterns of staining for PP TCs as does Calcofluor White . The levels of reduced abundance in each line, while significant, were not comparable to that seen for the gi-2 mutant (Table 1), indicating the possibility that these transcription factors may be acting redundantly with unidentified orthologs in controlling wall ingrowth deposition. In silico expression data (eFP and Genevestigator) shows that all four genes are expressed at very low levels in leaves, and qPCR confirmed this observation directly for both expanding and fully expanded leaves . Low expression might be expected for genes operating as putative regulators of wall ingrowth deposition specifically in PP TCs, since the number of PP TCs relative to most other cell types in the leaf is exceedingly low (AtSWEET11 promoter) over-expression to test the role of these transcription factors as regulators of wall ingrowth deposition in Arabidopsis.Based on the successful approach used by ngly low , and manngly low . Given ttrans-differentiation of non-vascular cells into metaxylem- and protoxylem-like vessel elements, respectively  or VND7, both NAC-domain transcription factors, causes ectively , a proceectively  and AtMYectively  also cauectively . Buildinectively , thus ouectively , 2009.Arabidopsis has proven useful to identify candidate genes operating as putative transcriptional regulators of wall ingrowth deposition in TCs. The discovery of GI as a component in the pathway regulating wall ingrowth deposition, and identification of NAC-domain and MYB-related genes as putative \u201cmaster switches\u201d involved in controlling this process, provides new lines of investigation to understand the genetic control of TC development and the cell biology of localized wall ingrowth deposition. Ultimately, identifying master switches which respond to various inductive signals to coordinate wall ingrowth deposition in TCs may provide new opportunities for improving crop yield by manipulating this process.The formation of wall ingrowths in TCs impacts on phloem loading and post-phloem unloading processes in many species, with corresponding impacts on plant development and reproduction. Development of an experimental system to investigate PP TCs in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Ciliopathies is an emerging class of genetic disorders due to altered cilia assembly, maintenance or function. Syndromic ciliopathies affecting bone development have been classified as skeletal ciliopathies. Mutations in genes encoding components of the intraflagellar transport (IFT) complex A, that drives retrograde ciliary transport, are a major cause of skeletal ciliopathies. Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure and early-onset severe retinal dystrophy.IFT140 mutations in seven MSS families. The effect of the mutations on IFT140 localization was assessed using flagged-IFT140 mutant proteins which showed a partial to nearly complete loss of basal body localization associated with an increase of cytoplasm staining while the wild-type Flagged-IFT140 protein predominantly localized to the basal bodies in RPE1 cells. To assess the impact of IFT140 mutations on ciliogenesis, abundance and morphology of primary cilia were studied in cultured fibroblasts of patients and detected absent cilia in a high proportion of patient cells compared to controls. Ciliary localization of anterograde IFTs were altered in MSS patient fibroblasts supporting the pivotal role of IFT140 in proper development and function of ciliated cells.We collected 16 families presenting three diagnostic criteria of MSS. Through ciliome re-sequencing combined to Sanger sequencing, we identified IFT140 mutations in seven MSS families. After Sensenbrenner and Jeune syndromes, MSS is the ultimate skeletal ciliopathy ascribed to IFT disorganization.Here we report on compound heterozygosity or homozygosity for"}
+{"text": "Obsessive-compulsive disorder (OCD) is characterized by an excessive focus on upsetting or disturbing thoughts, feelings, and images that are internally-generated. Internally-focused thought processes are subserved by the \u201cdefault mode network\" (DMN), which has been found to be hyperactive in OCD during cognitive tasks. In healthy individuals, disengagement from internally-focused thought processes may rely on interactions between DMN and a fronto-parietal network (FPN) associated with external attention and task execution. Altered connectivity between FPN and DMN may contribute to the dysfunctional behavior and brain activity found in OCD.The current study examined interactions between FPN and DMN during rest in 30 patients with OCD (17 unmedicated) and 32 control subjects (17 unmedicated). Timecourses from seven fronto-parietal seeds were correlated across the whole brain and compared between groups.OCD patients exhibited altered connectivity between FPN seeds (primarily anterior insula) and several regions of DMN including posterior cingulate cortex, medial frontal cortex, posterior inferior parietal lobule, and parahippocampus. These differences were driven largely by a reduction of negative correlations among patients compared to controls. Patients also showed greater positive connectivity between FPN and regions outside DMN, including thalamus, lateral frontal cortex, and somatosensory/motor regions.OCD is associated with abnormal intrinsic functional connectivity between large-scale brain networks. Alteration of interactions between FPN and DMN at rest may contribute to aspects of the OCD phenotype, such as patients' inability to disengage from internally-generated scenarios and thoughts when performing everyday tasks requiring external attention. Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts, feelings, or images (obsessions) and repetitive behaviors (compulsions) aimed at reducing anxiety associated with obsessions. Neuroimaging studies examining brain activation in OCD at rest, during symptom provocation, and in response to cognitive tasks have made critical advances in elucidating the neurobiological substrates of the disorder, pointing to dysfunction in several cortical and subcortical regions. While dysfunction in orbital, medial frontal, and striatal areas composing fronto-striatal circuits A growing body of literature in neuroscience has begun to emphasize the importance of interactions between brain regions, due to the realization that a typical brain area is likely to support multiple cognitive functions and that unique functionality is most likely to emerge through inter-regional connectivity Recent investigations of rs-fcMRI in OCD focusing on the striatum The investigation of competitive interactions between FPN and DMN at rest is particularly relevant for the study of OCD. Not only are nodes of these networks found to be abnormal during task-based studies of OCD, but the phenomenology of the disorder is consistent with the idea of a disrupted relationship between ongoing internal thought and external information, in that patients often excessively focus on internally-generated fears that are inconsistent with evidence present in the external environment This research was approved by the Institutional Review Board of the University of Michigan Medical School, following the principles set forth by the Declaration of Helsinki. All subjects provided written informed consent. Resting-state functional connectivity data were acquired for a total of 69 subjects. Seven subjects were excluded due to technical problems , leaving a total of 62 participants including 30 OCD patients and 32 control subjects for further analysis. Seventeen OCD patients were unmedicated for a minimum of 6 months prior to study participation (uOCD) and 13 were medicated (mOCD), primarily with serotonin-reuptake inhibitors  without psychiatric diagnoses and 15 medicated patient controls (mPC). Subjects with any history of OCD were excluded from both control groups. Subjects in the mPC group were patients with remitted major depression who were on SRI medication  and had Subjects were evaluated by a trained clinician using the Structured Clinical Interview for DSM-IV . A T1-weighted image was acquired in the same prescription as functional images to facilitate co-registration. Functional images were acquired with a T2*-weighted, reverse spiral acquisition sequence  sensitive to signal in ventral frontal regions 3, normalized to the template MNI152 brain , and smoothed with a 5 mm isotropic Gaussian smoothing kernel using the Statistical Parametric Mapping (SPM) 2 package .Physiologic signals (heart rate and respiration) were removed from the data using RETROICOR www.nitrc.org/projects/conn, see ref. Analysis of functional connectivity of LFBFs was carried out with the \u201cconn\" toolbox  controlled for correlations due to movement. Data were filtered between .01 and .10 Hz. We examined connectivity patterns separately for seven different seed regions-of-interest (ROIs) located in FPN. Given abundant evidence of positive correlations among FPN nodes, the timecourses for these separate seeds are not likely to be completely orthogonal; thus we cannot make strong claims about distinct patterns of connectivity between the different seeds. Nevertheless, given recent evidence identifying dissociable cingulo-opercular and dorsolateral prefrontal and parietal systems within FPN Coordinates (in MNI format) for these seeds were taken from prior studies, which have identified a \u201ccore\" task-set network that includes bilateral dorsal anterior insula  and posterior medial frontal cortex  Although not our main focus of analysis, we also sought to investigate within-DMN patterns of connectivity, due to two prior reports of reduced connectivity in OCD Relationships with symptom severity were examined by extracting connectivity values from regions showing group differences and correlating these with Y-BOCS scores  in the OCD group.Several post-hoc analyses were performed to examine the impact of other variables on results  and adjacent regions of posterior temporal cortex, and dorsomedial prefrontal cortex (DMPFC) . PatientHyper-connectivity in OCD was also found with dorsolateral and anterior inferior parietal seeds of FPN, although differences with DMN were less robust than with anterior insula seeds. For the left dorsolateral prefrontal (DLPFC) seed, patients had greater connectivity with right anterior insula/frontal operculum \u2013 also a part of FPN \u2013 as well as ventral occipital lobe/cerebellum. For the right DLPFC seed, patients not only had greater connectivity with the posterior cingulate cortex in the DMN, but also showed increased coupling with right lateral frontal regions of FPN.Fewer group differences emerged for connectivity with anterior inferior parietal seeds, with the left hemisphere exhibiting more connectivity with left pre-postcentral gyrus and the right hemisphere exhibiting more connectivity with PCC/precuneus for OCD patients as compared to controls.There were no regions within DMN that exhibited group differences in connectivity with anterior medial frontal (aMFC) or PCC seeds at the current threshold, which was corrected for multiple comparisons. However, as two prior studies have reported altered resting-state connectivity within DMN in OCD Connectivity between the right anterior insula seed and right thalamus was significantly related to Y-BOCS scores, with greater severity of symptoms associated with reduced connectivity . No other connectivity values were related to OC symptom severity.As is shown in the Supporting information , group dwithin DMN itself, although these effects only emerged at lower levels of significance. Negative connectivity among controls was evident despite the fact that global normalization was not used in the analysis Primary results from the current study revealed reduced negative connectivity between the fronto-parietal network and default mode network in OCD. Patients also showed more positive connectivity between fronto-parietal seeds and several areas outside DMN, including somato-motor areas  and other FPN regions . However, not all group differences reflected increased connectivity in OCD, as patients showed less positive connectivity than control subjects Research on DMN has garnered much interest since the initial observation of reduced blood flow within several anatomically-widespread brain regions during cognitive tasks versus passive viewing Recent evidence has identified dissociable sub-networks within FPN, with dorsal regions of anterior insula and medial frontal cortex forming a \u201ccore\" network involved in implementing and maintaining attention to external task demands and detecting salient events Connectivity differences with FPN occurred across a number of DMN regions, including PCC, pIPL, DMPFC/aMFC, and parahippocampus. Despite the consistent activation of these brain regions across several different tasks involving internally-directed cognition OCD patients also showed greater positive interactions between FPN seeds and several areas outside of DMN, including pre-postcentral gyrus and posterior insula, which are part of a somatosensory/interoceptive and motor network Although the general absence of correlations with Y-BOCS scores might seem surprising, this may indicate that group differences reflect stable biomarkers of OCD not sensitive to symptom severity differences, similar to the mechanism suggested for the error-related negativity Unlike group differences found with FPN seeds, OCD patients showed less positive connectivity than controls subjects within DMN, a finding that was not due to differential motion. Although this effect was found only at a lowered threshold, it is consistent with two prior reports To our knowledge, this is the first report of altered intrinsic connectivity between distributed regions of fronto-parietal and default mode networks in OCD. However, there are several limitations of the current study, many of which could be addressed by future research. Given that results were not corrected for multiple seed comparisons, replications using a larger sample size are necessary. In addition, OCD and controls groups were not matched on generalized depression/anxiety and education levels. Although post-hoc inclusion of these factors in multiple regressions indicated that these effects were not driving the reported group differences in connectivity, future studies would benefit from investigating the effects of these variables on brain connectivity. Of particular interest for the study of psychopathology, hyperactivity in DMN has been identified in other psychiatric disorders Click here for additional data file.Table S1Medications taken by OCD patients (mOCD) and medicated control subjects (mPC). SSRIs\u200a=\u200aselective-serotonin reuptake inhibitors; SNRIs\u200a=\u200aserotonin-norepinephrine reuptake inhibitors; TCAs\u200a=\u200atricycle antidepressants. All subjects except 1 mOCD patient were taking a serotonin reuptake inhibitor (SSRI or SNRI). Two mOCD and 3 mPC subjects were taking more than one medication .(DOCX)Click here for additional data file.Table S2Significance of diagnosis in predicting connectivity separately for unmedicated and medicated participants. Results obtained from multiple regressions also including generalized anxiety/depression and education as predictors. PCC\u200a=\u200aposterior cingulate cortex; pIPL\u200a=\u200aposterior inferior parietal lobule; DMPFC\u200a=\u200adorsomedial prefrontal cortex; aMFC\u200a=\u200aanterior medial frontal cortex; aI/fO\u200a=\u200aanterior insula/frontal operculum.(DOCX)Click here for additional data file."}
+{"text": "In children compliance with breath-hold instructions and motion control can be significantly reduced and there is limited data on CMR reproducibility.In adults CMR is the gold standard technique for evaluation of LV function, with reportedly excellent interstudy reproducibilityTo determine the interstudy reproducibility of cardiovascular magnetic resonance (CMR) measurements of left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), cardiac output (CO), end-systolic mass (ESM) and end-diastolic mass (EDM) in children and examine the influence of analysis technique.CMR was performed in 10 healthy children aged 9 years as part of a study of developmental influences on cardiovascular structure and function. Contiguous short axis steady state free precession LV cine images were acquired. Scans were repeated following a short interval. Interstudy variability was assessed on datasets analysed using a manual post processing technique (Osirix). Each dataset was analysed with the papillary muscles and trabeculae included or excluded from the blood pool. Intra- and interobserver reproducibility was assessed on 10 datasets using both techniques.Inter-study coefficients of variation (CVs) were similar for measurements including or excluding the papillary muscles and trabeculae, though marginally smaller for the latter. CVs for measurements excluding the papillary muscles and trabeculae were generally higher than those reported from studies of adults . Nonetheless, for all parameters the variability between subjects was greater than the interstudy and interobserver variability combined (e.g. for CO standard deviations were 1.83 for between subject variability and 0.42 for interstudy variability respectively).CMR measurements of cardiac structure tend to be less reproducible in children than in adults, probably due to difficulty in following breath hold instructions. Nonetheless, between subjects variability is greater than interstudy and interobserver variability, indicating that useful measurements can be obtained for research studies."}
+{"text": "Although social workers encounter many clients with substance use problems, curricula rarely require education on addictions. The screening, brief intervention, and referral to treatment (SBIRT) model was initially directed to practicing physicians. Recently, training has evolved to include medical students. This study describes the first known application of SBIRT training to social work students. The goal was to assess students\u2019 knowledge of and attitudes toward alcohol misuse before and after SBIRT training. Students were given a questionnaire assessing attitudes, knowledge and perceived skills with regard to substance misuse. A computerized training session focused on symptoms of at-risk drinking and implementing SBIRT. Descriptive statistics explained overall knowledge, attitudes, and perceived screening and intervention skills. T-tests compared changes pre- and post-test. Seventy-four social work students (33 undergraduate and 41 graduate) completed the training modules and pre- and post-tests. Significant differences were found in seven of the 13 questions. Students reported more confidence in their ability to assess for alcohol misuse and successfully intervene with clients who have substance use behaviors. They reported feeling more strongly that routine screening and brief intervention were crucial to clinical practice. Incorporating alcohol screening and brief intervention techniques into social work practice is an important aspect of effective treatment. Training students to screen and intervene is critical to improving treatment skills. Teaching SBIRT is a simple and effective way to implement addictions education into social work curricula. Such training appears to increase students\u2019 perceptions of their ability to change client behaviors and reduce client alcohol misuse."}
+{"text": "This survey determined the extent to which the herb Moringa oleifera commonly used for medicinal and nutritional purposes is being consumed among HIV positive patients.The study was a cross-sectional survey carried out at Parirenyatwa Hospital Opportunistic Infections Clinic. A convenience sample of 263 HIV-infected adults was taken from the Zimbabwe National Antiretroviral Roll-out Program. Using a previously piloted researcher administered questionnaire; patients who reported to the clinic over six months were interviewed about their use of herbal medicines. The focus was on Moringa oleifera use, and included plant part, dosage, prescribers and the associated medical conditions.Sixty-eight percent (68%) of the study participants consumed Moringa oleifera. Of these, 81% had already commenced antiretroviral drugs. Friends or relatives were the most common source of a recommendation for use of the herb (69%). Most (80%) consumed Moringa oleifera to boost the immune system. The leaf powder was mainly used, either alone (41%) or in combination with the root and/or bark (37%).Moringa oleifera supplementation is common among HIV positive people. Because it is frequently prescribed by non-professionals and taken concomitantly with conventional medicine, it poses a potential risk for herb-drug interactions. Patient medication history taking should probe for herbal supplementation and appropriate counselling done. Further experimental investigations into its effect on drug metabolism and transport would be useful in improving the clinical outcome of HIV positive patients on HAART."}
+{"text": "Stroke trial outcomes are usually classified in ordered functional categories, e.g. the modified Rankin Scale (mRS). Using a single cut-off to distinguish \"good\" and \"poor\" outcome is statistically inefficient and could miss effects in subgroups where few patients can be expected to achieve good outcome. \"Ordinal shift analysis\", using ordinal logistic regression to estimate a common odds ratio for all possible outcome category thresholds, is more efficient but could still obscure clinically important differences in response among prognostic subgroups. An alternative \"prognosis based outcome\" (PBO) approach defines separate, clinically meaningful good and poor outcome thresholds (GOTs and POTs) within each prognostic stratum. The strata are then combined in an overall trichotomous comparison of \"good\"/\"intermediate\"/\"poor\" outcomes.We defined prognostic categories, based on initial neurological scores, and derived suitable GOTs and POTs for the mRS, using data from a hospital stroke register. We then validated these thresholds using baseline and outcome data from the Scandinavian Candesartan Acute Stroke Trial (SCAST). Finally we performed trichotomous PBO analysis on the SCAST data.PBO analysis confirmed the overall neutral results of SCAST but did identify a notable negative treatment effect within the good prognosis group.This subgroup effect was not predicted, so requires independent confirmation. The PBO approach is clinically intuitive, can be used to analyse treatment response within different prognostic groups (as in cancer staging systems), and is statistically efficient. Also, it does not require multivariable modelling, making it easier to combine data from different studies in individual patient data meta-analysis."}
+{"text": "Spinal lesions substantially impair ambulation, occur generally in young and otherwise healthy individuals, and result in devastating effects on quality of life. Restoration of locomotion after damage to the spinal cord is challenging because axons of the damaged neurons do not regenerate spontaneously. Body-weight-supported treadmill training (BWSTT) is a therapeutic approach in which a person with a spinal cord injury (SCI) steps on a motorized treadmill while some body weight is removed through an upper body harness. BWSTT improves temporal gait parameters, muscle activation patterns, and clinical outcome measures in persons with SCI. These changes are likely the result of reorganization that occurs simultaneously in supraspinal and spinal cord neural circuits. This paper will focus on the cortical control of human locomotion and motor output, spinal reflex circuits, and spinal interneuronal circuits and how corticospinal control is reorganized after locomotor training in people with SCI. Based on neurophysiological studies, it is apparent that corticospinal plasticity is involved in restoration of locomotion after training. However, the neural mechanisms underlying restoration of lost voluntary motor function are not well understood and translational neuroscience research is needed so patient-orientated rehabilitation protocols to be developed. Spinal cord injuries (SCIs) cause substantial social, economic, and health burdens. In the majority of cases, the spinal cord is not completely severed and thus some fiber tracts and segmental spinal cord circuits remain intact , which dIn addition to spontaneous reorganization of the brain after SCI, spinal cord circuitries have the capacity to alter their structure and function with motor training , as suppIn humans, BWSTT improves lower extremity motor scores, increases the amplitude of muscle activity in the ankle extensors during the stance phase of walking, and improves walking ability and clinical outcome measures \u201331. A reBased on the aforementioned findings, it is apparent that BWSTT contributes to restoration of locomotion. Because remodeling of neuronal circuits as a result of plasticity occurs at multiple sites of the central nervous system , 32 restThe corticospinal tract is the most direct pathway between the cerebral cortex and spinal cord with corticospinal axons monosynaptically synapsing onto spinal motor neurons. Even though neurons of the motor cortex are not required for simple locomotion, they exhibit a profound step-related frequency modulation in the cat \u201335. ThisThe involvement of supraspinal neural control in human walking can be assessed by a variety of techniques utilized in isolation or in combination, including electroencephalography (EEG), electromyography (EMG), transcranial magnetic and electric stimulation (TMS and TES), and neuroimaging , 46. SinA single stimulus of TMS produces a synchronized discharge of cortical interneurons and pyramidal neurons that travel down the corticospinal tract. Epidural electrodes in the spinal cord detect several waves following TMS, termed direct (D) and indirect (I) waves. I waves originate in the motor cortex most likely through activation of corticocortical projections onto corticospinal neurons , while D\u03b1-motor neurons and interneurons [However, the MEP amplitude is not a reliable measure of corticospinal excitability. This is because TMS-induced action potentials in cortical axons spread transynaptically to many other neurons  that actrneurons .The aforementioned limitations can be counteracted by reducing the TMS intensity below the MEP threshold. Direct recordings in awake human subjects have shown that TMS at subthreshold MEP intensities, which does not evoke any descending corticospinal volleys, depresses the MEP evoked by a subsequent suprathreshold TMS  and the Various training protocols in uninjured subjects induce reorganization of corticospinal actions on lumbosacral motor neurons. For example, balance training decreased the TA and soleus MEP amplitudes , while 3In motor incomplete SCI subjects at rest, MEPs are either absent or very small in amplitude with prolonged latencies, which are considered signs of impaired transmission of the fastest conducting corticospinal neurons \u201377. FurtfMRI showed a greater activation in sensorimotor cortical and cerebellar regions following 36 BWSTT sessions [Reorganization of corticospinal actions with training in neurological disorders has been shown in few studies. In 4 male SCI subjects with tetraparesis, sessions  consistesessions . Three-tsessions . Furthersessions . The lowsessions .One person  with an American Spinal Injury Association (ASIA) Impairment Scale (AIS) D at Thoracic 5\u20137 received 60 BWSTT sessions  with a robotic exoskeleton device (Lokomat). Before training, the patient stepped at 0.5\u2009m/s with 50% body\u2009weight\u2009support (BWS), and after training the patient stepped at 0.89\u2009m/s with 20% BWS. Electrophysiological tests, illustrated as a schema in The TA MEPs evoked at 1.3 TA MEP threshold during assisted stepping before and after training are shown in The spinal cord constitutes the final common pathway for segmental and supraspinal pathways underlying motor behavior. Electrical stimulation of a mixed peripheral nerve at low intensities activates primary (Ia) afferent axons which synapse in the spinal cord. Alpha motor neurons activated monosynaptically by Ia afferent volleys induce a synchronized reflex response known as the Hoffmann-(H-) reflex , which iCortical control of spinal reflex circuits has been extensively investigated in awake humans by means of TMS. Subthreshold TMS produces a short-latency inhibition on the soleus H-reflex followed by a period of facilitation , 87\u201389 wIn addition to the H-reflex, the TA long-latency (or M3) ankle stretch reflex was facilitated when the MEP arrived in the spinal cord at the same time . HoweverPersistent changes in H- or stretch reflex amplitudes may be regarded as signs of learning and plasticity as a result of training, which have been shown after various training protocols. For example, 30\u2009min ankle cocontraction training decreased the ratio of maximal H-reflex versus maximal M wave (Hmax/Mmax) and improved motor performance defined as the difference between the maximum and minimum torque displacements within 1\u2009min . The solNonetheless, the aforementioned changes in H-reflex amplitude can result from modifications of interneuronal circuits interposed in the spinal pathway or by changes on the strength of descending pathways, since the latter is potent regulator of spinal reflex circuits behavior \u2013107. ThiLimited evidence exists on plastic changes of the cortical control of spinal reflexes after locomotor training in neurological disorders. Forty BWSTT sessions in 29 patients with incomplete SCI reestablished the TMS-induced long-latency soleus H-reflex facilitation with subjects at rest . It shouIn One of the spinal interneuronal circuits with paramount contribution to the neural control of movement is that of disynaptic reciprocal Ia inhibition. Reciprocal inhibition refers to an automatic antagonist motor neuron inhibition when an agonist muscle contracts. Following an SCI, the reciprocal inhibition is either reduced or replaced by reciprocal facilitation \u2013124 leadRegulation of locomotion by reflexly mediated spinal circuits that integrate sensory inputs is well established. The contribution of muscle afferents mediating information about the amplitude and rate of muscle stretch is easily recognized by the phase-dependent modulation of short-latency spinal reflexes during walking. The short-latency soleus and quadriceps extensor reflexes  in humans are modulated in a way that promotes bipedal gait. The ankle stretch and soleus H-reflexes increase progressively from mid- to late stance in parallel with the soleus EMG activity and are significantly depressed or abolished during the swing phase of gait \u2013115, 125\u03b1 motor neurons coincided with activity of Ia inhibitory interneurons [The soleus H-reflex depression during the swing phase in humans has been partly ascribed to reciprocal Ia inhibition exerted from common peroneal nerve group I afferents on soleus motor neurons, which is regulated in a similar manner to that reported in animals and corresponds largely to absent reciprocal inhibition in the stance phase and maximal in the swing phase , 128. Durneurons , 130. Iarneurons .Animal studies through intracellular recordings provided a detailed knowledge of the pathway and integration of segmental and supraspinal convergence at the interneuronal level \u2013135 withDescending control of reciprocal inhibition has clearly been postulated in humans. In particular, the reciprocal inhibition exerted from common peroneal nerve group I afferents on soleus motor neurons was observed 50\u2009ms before the onset of TA EMG activity . FurtherFindings on the reorganization of reciprocal inhibition as a result of motor training in health and disease are limited. Stimulation of the common peroneal nerve with a train of 10 pulses at 100\u2009Hz with and without motor cortex stimulation potentiated reciprocal inhibition in control subjects . ReciproIn D-C)-(B-A) whereas A is the test soleus H-reflex (baseline soleus H-reflex modulation pattern during stepping), B is the soleus H-reflex conditioned by subthreshold TMS, C is the soleus H-reflex conditioned by common peroneal nerve stimulation , and D is the reciprocal inhibition conditioned by subthreshold TMS. Positive values indicate potentiation of reciprocal inhibition and negative values indicate attenuation of reciprocal inhibition. Locomotor training contributed significantly to attenuation of reciprocal inhibition exerted from ankle flexor afferents to extensor motor neurons during the stance phase. Most importantly, potentiation of reciprocal inhibition at swing phase initiation (i.e., bin 9 in The net effects of subthreshold TMS on the reciprocal inhibition during BWS-assisted stepping before and after 60 BWSTT sessions are indicated in SCI changes the human body homeostasis leading to myriad changes of multiple systems. In most cases, the spinal cord is not completely severed and thus some fiber tracts and segmental spinal cord circuits remain intact. Based on the plastic capabilities of the central nervous system, it is apparent that the adult lesioned motor system reorganization occurs spontaneously after an injury and after training. Electrophysiological studies have shown that BWSTT increases the MEP amplitude, changes the common drive of antagonist muscles from corticospinal inputs with subjects seated, and alters the TA MEP modulation pattern during BWS assisted stepping. Further, BWSTT reestablished the TMS-induced long-latency soleus H-reflex facilitation and potentiated the short-latency soleus H-reflex depression following subthreshold TMS with subjects at rest, while cortical modulation of the soleus H-reflex during stepping changed significantly. Lastly, BWSTT changed the cortical control of reciprocal inhibition during BWS assisted stepping in a manner that promotes bipedal gait. These findings support the notion that improvements in locomotor function from treadmill training are mediated, in part, by changes in the corticospinal drive of spinal reflex circuits, spinal interneuronal circuits, and output of leg muscles during walking.Plasticity in the brain and spinal cord underlying restoration of lost function can be driven by appropriately designed interventions , 151. De"}
+{"text": "These DNA modifications occur only during nuclear development and programmed genome rearrangement. We describe these modifications in three classes of eliminated DNA: germline-limited transposons and satellite repeats, aberrant DNA rearrangements, and DNA from the parental genome undergoing degradation. Methylation and hydroxymethylation generally occur on the same sequence elements, modifying cytosines in all sequence contexts. We show that the DNA methyltransferase-inhibiting drugs azacitidine and decitabine induce demethylation of both somatic and germline sequence elements during genome rearrangements, with consequent elevated levels of germline-limited repetitive elements in exconjugant cells. These data strongly support a functional link between cytosine DNA methylation/hydroxymethylation and genome stability, highlighting the ability of the cells to distinguish and specifically methylate aberrant chromosomes but not their properly structured isoforms. In addition, we identify a motif strongly enriched in some methylated/hydroxymethylated regions of parental MAC chromosomes, and we propose that this motif recruits DNA methylation machinery to specific chromosomal regions in the parental macronucleus. No recognizable methyltransferase enzyme has yet been described in O. trifallax, raising the possibility that it might employ a novel cytosine methylation machinery to mark DNA sequences for elimination during genome rearrangements.Cytosine methylation of DNA is conserved across eukaryotes and plays important functional roles regulating gene expression during differentiation and development in animals, plants and fungi. Hydroxymethylation was recently identified as another epi-genetic modification marking genes important for pluripotency in embryonic stem cells. Here we describe"}
+{"text": "Cerebral small vessel disease  leads to dementia and stroke-like symptoms. Lacunes, white matter lesions (WML) and microbleeds are the main pathological correlates depicted in in-vivo imaging diagnostics. Early studies described segmental arterial wall disorganizations of small penetrating cerebral arteries as the most pronounced underlying histopathology of lacunes. Luminal narrowing caused by arteriolosclerosis was supposed to result in hypoperfusion with WML and infarcts.We have used the model of spontaneously hypertensive stroke-prone rats (SHRSP) for a longitudinal study to elucidate early histological changes in small cerebral vessels. We suggest that endothelial injuries lead to multiple sites with blood brain barrier (BBB) leakage which cause an ongoing damage of the vessel wall and finally resulting in vessel ruptures and microbleeds. These microbleeds together with reactive small vessel occlusions induce overt cystic infarcts of the surrounding parenchyma. Thus, multiple endothelial leakage sites seem to be the starting point of cerebral microangiopathy. The vascular system reacts with an activated coagulatory state to these early endothelial injuries and by this induces the formation of stases, accumulations of erythrocytes, which represent the earliest detectable histological peculiarity of small vessel disease in SHRSP.In this review we focus on the meaning of the BBB breakdown in CSVD and finally discuss possible consequences for clinicians. The clinical picture of cerebral small vessel disease (CSVD) is complex since the disease develops insidiously and its etiology is only partly understood. Limited correlations between neurological symptoms, imaging diagnostic and pathological findings impede an early enough diagnostic and therefore therapy. It\u2019s obvious, however, that an illness of rather small blood vessels leads to subtle development of dementia and / or episodes of stroke-like symptoms if neurological sensitive areas are affected by so called strategic infarcts. Lacunes, diffuse white matter lesions  and microbleeds are the pathognomonic pathological correlates detectable with modern imaging diagnostic.Lacunes, found in 6% to 11% of autopsied brains, are defined as scars or remnants of small infarcts with a diameter ranging from 3 to 20\u00a0mm predominantly found in the basal ganglia, thalamus, pons, subcortical and cerebellar white matter areas[More than 40\u00a0years ago Fisher described the \u201csegmental arterial wall disorganization\u201d of small penetrating cerebral arteries defined by vessel enlargement due to wall remodeling with \u201closs of meshwork\u201d, \u201chemorraghic extravasation\u201d and deposits of fibrinoid material as one uFrom the current point of view the chronic small vessel wall alterations found in CSVD comprise three subtypes including lipohyalinosis, arteriolosclerosis and cerebral amyloid angiopathy (CAA). EspeciaMoreover, common acute lesions found in CSVD are cerebral microbleeds and primary intracerebral hemorrhages, discussed as consequence of small vessel wall fragility converging with acute hemodynamic changes possibly caused by fluctuations of the blood pressure,8. MicroOcclusions of degenerative altered small vessels, typically found in cerebral macroangiopathy associated with thrombotic or embolic stroke, might be a reasonable explanation for lacunar infarcts, but those occlusions are a rather rare event in brain autopsy of patients with CSVD. Thus, WWe have recently collected data in the model of spontaneously hypertensive stroke-prone rats (SHRSP) that strikingly support the importance of an early BBB dysfunction for the development of CSVD, which will be discussed in this review.Only few animal models have been recognized to be suitable for describing CSVD,10. AlthSHRSP were obtained by selective breeding from spontaneously hypertensive rats (SHR) for the development of spontaneous infarcts-13 and e3, larger non-territorial infarcts anyhow commonly distributed in specific territories of the large cerebral arteries, rarely covering multiple vascular territories or seen in the border zones of the large cerebral arteries as well as territorial infarcts in some cases affecting the whole hemisphere[SHRSP develop small lacunar-like lesions with a volume ranging from 2 to 57\u00a0mmmisphere,19,20. Tmisphere. Howevermisphere.Ischemic lesions are predominately found in cortical areas  and In contrast, the exact localization and extent of WML have been rarely investigated in SHRSP and therefore the respective existing data is quite incomplete. Myelin stainings show a rarefication of white matter substance accompanied by a general volume expansion in SHRSP with BBB leakage. For theBy genetic factors SHRSP develop a vascular risk profile, which comprises arterial hypertension, insulin resistance and hyperinsulinemia, mixed hyperlipidemia and elevated levels of free fatty acids. This geStarting a longitudinal study with around 130 SHRSP  we were able to define some kind of pathological cascade which is described in the following: The small vasculature of rather juvenile SHRSP is not distinguishable from age matched Wistar controls. However starting from an age of 12\u00a0weeks, in SHRSP we occasionally found in capillaries of the basal ganglia, the hippocampus and cortical areas intraluminal accumulations of erythrocytes  within their walls and within the adjacent perivascular parenchyma indicating associated BBB damage at already young ages  FigureI would tDisturbances of autoregulation of small vessel tonus represent another possible reason that at least promotes the formation of stases. This is reflected in constrictions and dilatations of the vessel wall we occasionally found in arteriolar segments with stases  SHR (SHRSR), an animal model with polygenetic and multifactorial inheritance of chronic arterial hypertension, including renal factors, prostaglandin-adrenergic interactions and abnormalities of the pituitary gland, developConcluding, SHRSP exhibit a complex cascade of CSVD and until now it is unclear, whether SHR develop a comparable natural course of microvascular dysfunction accompanied by histopathological phenomena exceeding their described BBB leakage.Thus, coming back to the headline of this review we can state that the SHRSP develops overt infarcts that mainly originate from breakdown of the BBB and not from occluded vessels. Thrombotic occlusions of small penetrating vessels occur only at the end of a pathological cascade originated by endothelial damage. This may have important clinical consequences. Patients with stroke-like symptoms caused by thrombotic or embolic occlusions of large vessels generally benefit from an anti-thrombotic treatment. But the effect of such a treatment could be even detrimental if stroke patients suffer from multiple small vessel lesions originally caused by BBB leakage.Moreover, one has to ask what is the main difference between SHRSP and controls? Do control rats develop the pathology of CSVD cascade only later on or in other words: Are the vascular risk factors in SHRSP some kind of accelerator for a pathology caused in controls simply by aging? We also found an increasing number of stases in older control rats correlating with vascular changes in the kidney comparable to the findings in SHRSP. Control rats exhibit limited mini- and microbleeds and so far no one exemplar developed overt ischemic lesions. Thus, it is obvious that the vascular system also in control rats undergoes an age-dependent impairment. But probably only a very little fraction of them will develop the typical pathological cascade of CSVD we have found in SHRSP.The genetically most related population to SHRSP is the SHRSR. The risk profile also includes chronic arterial hypertension with disturbances of renal factors. HoweverThus, besides aging and vascular risk factors we suppose that CSVD pathology needs a certain combination of genetic risk factors and is in its development positively or negatively influenced by lifestyle. In this regard it is very important to mention that the incidence and development of overt infarcts in SHRSP can be heavily promoted by a high salt diet. Moreover, an application of a salt-loaded diet induces an abrupt malign increase of the arterial blood pressure, associated with forced vessel wall ruptures leading to an extended breakdown of the BBB with associated cerebral edema and large primary intracerebral hemorrhages,19,20,38Concluding, the conglomerate of vascular and genetic risk factors in SHRSP obviously favors an initially small and insidious age-dependent developing of endothelial injuries leading to an increasing BBB leakage. The vascular system seems to react with a restricted coagulation which causes stases of erythrocytes as a rather byproduct.It is a challenge for modern imaging diagnostics to detect these early vascular changes to selectively recognize patients with an elevated vascular risk profile. One approach could be the development of new, especially renal biomarkers in blood and urine. Therefore, in SHRSP we have just started to investigate urine concentrations of the kidney-injury-molecule-1 (KIM-1), marking a renal tubular damage. We are Meanwhile our probably best weapon against small cerebral vascular diseases is the promotion of healthy campaigns persuading people to prevent the age driven progress of CSVD under the slogan:More physical activity, less salt, no smoking!A\u03b2: Amyloid-\u03b2; BBB, Blood brain barrier; CAA: Cerebral amyloid angiopathy; CE-\u03bcMRA: Contrast-enhanced magnetic resonance microangiography; CSVD: Cerebral small vessel disease; HE: Hematoxylin Eosin; IgG: Immunoglobulin G; KIM-1: Kidney-injury-molecule-1; MCA: Middle cerebral artery; MRI: Magnetic resonance imaging; MRA: Magnetic resonance angiography; SHR: Spontaneously hypertensive rats; SHRSP: Spontaneously hypertensive stroke-prone rats; SHRSR: Spontaneously hypertensive stroke-resistant rats; SPECT: Single photon emission compute tomography; STL: Solanum tuberosum lectin; vWF: Von-Willebrand factor; WML: White matter lesions.The authors declare that they have no competing interests.SS, CB, CC and HB wrote the manuscript. All authors read and approved the final manuscript."}
+{"text": "Hyperglycemia and hypoglycemia have been linked to worse outcomes in critically ill patients. While there is controversy as to the optimal tightness of glucose control in critically ill patients, there is agreement that an upper limit to safe glucose levels exists and that avoiding hypoglycemic episodes should be prioritized. Our algorithm can assist clinicians in maintaining blood glucose ([Gbl]) within a desired target range while avoiding hypoglycemia.Our model predictive control (MPC) algorithm uses insulin and glucose as control inputs and a linearized model of glucose-insulin-fatty acid interactions. To allow the controller model to learn from data, a moving horizon estimation (MHE) technique tailored the tissue sensitivity to insulin to individual responses. Patient data  were from the HIDENIC database at the University of Pittsburgh Medical Center. [Gbl] measurements, typically hourly, were interpolated to impute a measurement every 5 minutes. The model captured patient [Gbl] via nonlinear least squares by adjusting insulin sensitivity (SI) and endogenous glucose production (EGP0). The resulting virtual patient (VP) is used to evaluate the performance of the MPC-MHE algorithm.MPC controller performance on one VP is shown in Figure The MPC-MHE algorithm achieves targeted glucose control in response to changing patient dynamics and multiple measured disturbances for a pilot population of 10 VPs. Furthermore, the MHE scheme updates patient parameters in real time in response to changing patient dynamics."}
+{"text": "Female genital tuberculosis (TB) remains as a major cause of tubal obstruction leading to infertility, especially in developing countries. The global prevalence of genital tuberculosis has increased during the past two decades due to increasing acquiredimmunodeficiency syndrome (AIDS). Genital TB is commonly asymptomatic, andit is diagnosed during infertility investigations. Despite of recent advances in imaging tools, such as computerized tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasongraphy, hysterosalpingography is still the standard screeningtest for evaluation of tubal infertility and a valuable tool for diagnosis of femalegenital tuberculosis. Tuberculosis gives rise to various appearances on hysterosalpingography (HSG) from non-specific changes to specific findings. The present pictorialreview illustrates and describes specific and non-specific radiographic features of femalegenital tuberculosis in two parts. Part I presents specific findings of tuberculosis relatedto tubes such as \"beaded tube\", \"golf club tube\", \"pipestem tube\", \"cobble stone tube\"and \"leopard skin tube\". Part II describes adverse effects of tuberculosis on structure ofendometrium and radiological specific findings such as \"dwarfed\" uterus with lymphaticintravasation and occluded tubes, \"T-shaped\" tuberculosis uterus, \"pseudounicornuate\"uterus and \"Collar-stud abscess\", which have not been encountered in the majority ofnon-tuberculosis cases. Female genital tuberculosis (FGTB) is one formof extrapulmonary manifestations of tuberculosis,while it includes 5% of all female pelvic infectionsand 10% of pulmonary tuberculosis cases . Itis mThe reported prevalence of genital tuberculosishas shown a descending trend in developed countries,but recently, its rate has started to increaseagain due to co-infection with human immunodeficiencyvirus (HIV) and the development of drug-resistantstrains of Mycobacterium tuberculosis -6.Primary infection of the female genital organs isvery rare , and is Diagnosis of genital TB may be difficult becausemajority of cases are asymptomatic; in addition,facilities for mycobacterium culture and histopathologyare limited in high-prevalence countries-11. In tThis pictorial review describes specific and nonspecificradiographic features of tubes caused bytuberculosis as seen on HSG.Mycobacterium tuberculosis is responsible fordisease in approximately 90-95% of cases and producesgranulomatous salpingitis and endometritisleading irregular menstrual bleeding and infertility.In 5-10% of patients, the infection results from Mycobacteriumbovis, especially when the source ofinfection is acquired from the gastrointestinal cases, 18.Genital tuberculosis usually spread to genitalsite from three routes, including hematogenous,lymphatic or adjacent viscera , while iPrimary infection of genital TB is rare, and mayresult from direct introduction of TB bacilli atsexual intercourse with a male partner with genitourinaryTB. Ascending spread of infection fromthe vagina, cervix and the vulva has been reported.Tha fallopian tubes are the initial focus of femalegenital tuberculosis, and usually involved bilaterallynot symmetrically . The patThe transitional region between the isthmusand ampulla is the most frequent site of tubalobstruction. Sometimes, hydrosalpinx or pyosalpinxwith thick fibrotic wall is formed at thedistally blocked fallopian tube.The ovaries areoften seen in normal appearance and the diagnosisis established only on histopathologicalstudies .In some cases, ovarian tubercle, adhesion, capsularthickening and ovarian or pelvic abscess areformed .Most of the cases involved in genital TB have been detected in reproductive age; a range of 20-45 year-old . GenitalTuberculous lesions of the cervix present withpostcoital bleeding, abnormal discharge and,on examination, have appearances similar tocancer of the cervix . InvolveHysterosalpingographic presentation of tubalTB vary from non-specific changes such as hydrosalpinxto specific pattern such as \"beadedtube\", \"golf club tube\", \"pipestem tube\", \"cobblestone tube\" and the \"leopard skin tube\". Of courThe presence calcified lymph nodes in thepelvis or in the course of fallopian tubes mayenable the diagnosis of the TB. Plain films ofthe pelvis may show such calcifications whichmust be differentiated from other causes of calcificationssuch as calcified pelvic nodes, calcifieduterine myomas, urinary calculi, pelvicphleboliths and calcification in an ovarian dermoid. The calCaseous ulceration of tubal mucosa createsan irregular, ragged or divertucular appearanceon the contour of the tubal lumen on HSG. Divierticularcavities surrounding of the ampullarportion may give it a \"tufted\" like appearance. Isthmic diverticula may resemblesalphingitis isthmica nodosa, \"TB-SIN\" likeappearances can be differentiated from classicSIN . In \"TB-SIN diverticular outpouchingare larger, asymmetric, with a morebizarre pattern (in size and number) and arenot usually restricted to the isthmic portionof the tube as compared with those of SIN ,16. TheTubal occlusion in tuberculosis is consideredthe most common finding seen on HSG and occursmost commonly at the junction between theisthmus and ampulla. in the region of isthmus andampulla. Although cornual occlusion followingampullar obstruction is the most common site oftubal occlusion caused with any factor, it is not socommon in tuberculosis.Multiple constrictions along the course of fallopiantube may form due to scarring and present as\"beaded\" appearance . While tOcclusion of the isthmus or fimbrial end of thetube filled with serous or clear fluid produce aretort-shaped dilation of the tube (large-sausageshaped)which initially is a pyosalpinx that changeto hydrosalpinx. Hydrosalpinx is usually moderateor slight with a \"golf club like appearance\" to theampulla  16)..16).Twisting of the hydrosalpinx may result in afloral pattern- \"the floral hydrosalpinx\" .ThickenIntraluminal scarring can give rise to a cobblestonepattern which is an effective radiographic sign of intraluminaladhesions in hydrosalpinges and associatedwith concern of infertility  34). A . A 34). In chronic tuberculosis, following repeatedepisodes of acute exacerbation, a dense peritubalconnective tissue scarring occurs in andaround the tubes, leading to peritubal adhesions.The tubes become vertically or horizontallyfixed, interfering with access of fallopiantubes to the ovary at ovulation and transport ofthe ovum.In this non-specific finding, the contrastspill from a vertically fixed tube appears to bebounded laterally by adhesions, which givesrise to straight spill appearance . ThefalDense adhesions may resemble lead to visualizationof septations and bizarre \"criss-crossspill\" pattern. Sometimes, peritoneal granulomasformation produces small rounded fillingdefects seen additionally to these septations.Everted fimbria with a patent orifice impartingcharacteristic \"tobacco pouch\" appearance.HSG is considered as an important diagnostic tool inthe investigation of internal architecture of female genitaltract and helpful procedure in diagnosis of femalegenital tuberculosis. Tubal and uterine lesion scarringremained of genital TB, are presented as specific andnon-specific radiographic features which should bediffered from other pathological conditions. Since theincidence of genital tuberculosis has been increasedduring the past two decades, the clinicians increasinglyfaced with cases of genital TB and its consequencessuch as infertility, so reviewing of these features areconsidered in differential diagnosis of the causes of infertilityand timing intervention and treatment."}
+{"text": "Recent findings from electrophysiology and multimodal neuroimaging have elucidated the relationship between patterns of cortical oscillations evident in EEG/MEG and the functional brain networks evident in the BOLD signal. Much of the existing literature emphasized how high-frequency cortical oscillations are thought to coordinate neural activity locally, while low-frequency oscillations play a role in coordinating activity between more distant brain regions. However, the assignment of different frequencies to different spatial scales is an oversimplification. A more informative approach is to explore the arrangements by which these low- and high-frequency oscillations work in concert, coordinating neural activity into whole-brain functional networks. When relating such networks to the BOLD signal, we must consider how the patterns of cortical oscillations change at the same speed as cognitive states, which often last less than a second. Consequently, the slower BOLD signal may often reflect the summed neural activity of several transient network configurations. This temporal mismatch can be circumvented if we use spatial maps to assess correspondence between oscillatory networks and BOLD networks. It is understood that whereas functional MRI (fMRI) can effectively describe the spatial activation patterns of whole-brain networks, it is limited to measuring the delayed hemodynamic response observed in the blood oxygen level dependent (BOLD) signal. This delay limits its ability to describe rapid changes in neural activity underlying the sequential processing stages inherent to any cognitive task. We can obtain much higher temporal resolution from electroencephalography (EEG), magnetoencephalography (MEG), or electrocorticography (ECoG) data. However, due to limitations on the number and location of feasible electrode placements and to difficulties in measuring signals from sub-cortical regions, these methods do not provide complete whole-brain neural activity measures with a spatial precision equivalent to that of fMRI. The above temporal and spatial limitations can be addressed through studies combining fMRI data with simultaneously recorded EEG data, or with co-registered MEG or ECoG data recorded in separate sessions. To best interpret the results of such multimodal studies, one must understand the relationship between the BOLD signal, neuronal activity at a local level, oscillations in neuronal assemblies, and the large-scale rapid oscillatory networks measurable with EEG, MEG, and ECoG. Here, we describe how cortical oscillations organize post-synaptic potentials and neuronal firing, functionally connecting activity in disparate regions to form the widespread cortical networks observed in the BOLD signal.At the local level, several studies have used invasive techniques to simultaneously record action potentials (APs), BOLD signal strength, and cortical oscillations. It should be noted that the BOLD signal might be expected to correspond less closely to APs measured via single-cell and multi-unit recordings than to local field potentials (LFPs), which reflect post-synaptic potentials summed across large numbers of neurons, because a single fMRI voxel typically contains more than a million neurons  and slow (30\u201350\u2009Hz) gamma ranges  may organize activity at a local level by integrating some signals while segregating others, and simultaneously coordinate multiple organized local patterns across much greater distances. These multi-frequency patterns provide an optimal explanation for the mechanisms of cognitive processing because they dynamically change at the same pace as cognition.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Rapamycin binds with FK- binding protein 12 to inhibit the mechanistic  Target of Rapamycin (mTOR) protein [Rapamycin  is a macrocyclic antibiotic produced by the bacteria in vitro is less pronounced than the Warburg effect in cancer, identifying the cellular metabolism behind fibrosis suggests at potential therapies directed at fibroplasia. Our investigations into fibroblast metabolism and rapamycin's inhibitory effect suggests at a critical link between cellular metabolism and unregulated fibroblast proliferation that could elucidate rational druggable targets to mitigate LTS and fibrosis in general.Fibrosis is the terminal pathological outcome of myriad chronic inflammatory diseases. The process is defined by the excessive accumulation of fibrous connective tissue components of the extracellular matrix  in inflamed tissue . The excmTOR's regulatory role makes the protein a critical node between metabolism and cell proliferation. Environmental factors such as stress and energy influence mTOR, which in turn regulates protein, lipid, and nucleotide biosynthesis, mitochondrial proliferation and function, cell growth and development amongst other cell functions. In fibroblasts mTOR regulates cell kinetics and collagen and other extracellular matrix molecule production. Inhibition of mTOR has been explored in cancer, cardiovascular disease, autoimmunity, and metabolic disorders. In immune cells including T-lymphocytes and macrophages, mTOR subunit inhibition results in reduced metabolism which in turn impacts immune cell activation and function . Based oAlternatively myofibroblasts have been the focus of extensive research in fibrosis, given their role in secreting ECM and collagen along with their fundamental contribution to wound contracture. Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to myofibroblasts. EMT is increasingly recognized as a contributing factor to tissue fibrosis following epithelial injury and a fundamental process involved in carcinogenesis and metastasis. Inhibition of mTOR signaling through rapamycin has been shown to attenuate the process of EMT. This offers additional mechanistic rationale for mTOR inhibition as a therapeutic strategy in human fibrosis.Strong preclinical and human evidence also offers support for the use of rapalogs beyond its effects modulating the end-effectors of fibrinogenesis (fibroblasts & myofibroblasts). In preclinical models, immunocompromised mice exhibit decreased fibrosis during wound repair . T-cell Rapamycin is a Food and Drug Administration (FDA)-approved drug that promotes long term tolerance in organ transplant patients, and is incorporated within coronary stents to reduce restenosis and accelerated arteriopathy. Rapamycin and rapalogs mechanism of action is to bind to FKBP12 to inhibit a subunit protein of mTOR, mTORC1 , 7. FiguOutstanding questions to be addressed include the specific signaling pathway by which rapamycin inhibits fibroplasia, and if more specific targeting of these cellular mechanisms would be effective in treating the disease in the trachea as well as other organs. Future studies will also address therapeutic delivery with sustained topical application ideal to address organ specific fibrosis and avoid side effects associated with systemic administration. Specific to LTS, a rapamycin-eluting stent could assist in suppressing the inflammatory response, fibroblast proliferation, and collagen synthesis seen in LTS while providing structural support of the tracheal wall."}
+{"text": "Healthy animals perform better than those that are diseased; therefore there are significant benefits from preventing disease on farm by investigating new vaccine delivery systems. Recently, viral vectors have risen to prominence as candidates for generating immune responses. Of these viral candidates, lentiviruses are attractive as they have the ability to transduce non-dividing antigen presenting cells. For example, lentiviral vectors have been shown to produce an antigen-mediated immune response in mice, providing long term, sterile protection against Malaria.Transformed human embryonic kidney 293T) cells were transfected with four plasmids which encode the various vector components for the production of lentiviral vectors. Vectors produced so far contain an eGFP reporter cassette to facilitate measurement of infectivity by flow cytometry. Self-inactivating (SIN) vectors have been produced to decrease the probability of the generation of replication-competent virus[93T cellsin vitro. Integration deficient vectors appear to have to correct phenotype as eGFP-positive cells decreased over time in dividing cells.Stable expression of antigens is important to a successful vaccine, therefore the stability of ovine lentiviral transduction was evaluated over a 4 week period with eGFP-positive cells measured periodically. 50% of cells remained eGFP-positive after 4 weeks in rapidly dividing cells suggesting a sustained, stable transduction. Ovine lentivirus vectors have the ability to infect a wide range of cell types from different species with similar efficiency to the well characterised murine leukaemia virus (MLV) vector. Self-inactivating vectors with non-active LTRs retain the ability to express transgenes in vitro. Future studies will investigate ovine lentiviral vectors mechanisms of immune response in vitro and study their efficiency to deliver appropriate immunity in vivo.We have created a novel, self-inactivating, integration deficient ovine lentiviral vector which retains the ability to express transgenes"}
+{"text": "Pulmonary vein stenosis (PVS) is a known complication after catheter ablation of arrhythmias. Surprisingly, little information is available on its manifestations in the lung. We describe the case of a 39-year-old woman who presented from an outside hospital with worsening shortness of breath after catheter ablation of pulmonary veins for atrial fibrillation. After an initial diagnosis of pneumonia and its nonimprovement with antibiotics, a surgical lung biopsy was done and interpreted as nonspecific interstitial pneumonia (NSIP) with vascular changes consistent with pulmonary arterial hypertension. Later, she was admitted to our institution where a transthoracic echocardiogram (TTE) and subsequent computed tomography (CT) angiogram of the heart showed severe stenosis of all four pulmonary veins. The previous lung biopsy was rereviewed and reinterpreted as severe parenchymal congestion mimicking NSIP. Our case demonstrates that PVS is an underrecognized complication of catheter ablation, and increased awareness among both clinicians and pathologists is necessary to avoid misdiagnosis.  A 39-year-old woman with no history of smoking presented with a nine-month history of progressive dyspnea on exertion and dry cough. One month before the onset of symptoms, she underwent a successful cardiac ablation of pulmonary veins for refractory atrial fibrillation. Computed tomography (CT) of the chest was done eight weeks prior to presentation and revealed bilateral scattered ground-glass opacities, diffuse septal thickening, and patchy consolidations in left lung Figures . After fAt admission, she was comfortable at rest, saturating at 92% with clear lungs on auscultation. Repeat imaging showed continued presence of diffuse septal thickening and ground-glass opacities Figures . BecauseSubsequently, her steroids were tapered, and, after we discussed the case with cardiologists at our institution, the patient underwent balloon angioplasty with pulmonary vein stenting . Six weeThe incidence of PVS after catheter ablation for atrial fibrillation ranges from 1% to 3% . Lung paIn conclusion, postablative patients with any pulmonary symptoms should have a high suspicion for PVS. It not only mimics other disease entities clinically and radiographically, but also can mimic other etiologies histologically, as seen with our case. Such delay and misdiagnoses subject patients to erroneous treatment and can cause irreversible secondary pulmonary parenchymal and vasculature changes with poorer outcomes ."}
+{"text": "Although motivational disturbances are common in schizophrenia, their neurophysiological and psychological basis is poorly understood. This electroencephalography (EEG) study examined the well-established motivational direction model of asymmetric frontal brain activity in schizophrenia. According to this model, relative left frontal activity in the resting EEG reflects enhanced approach motivation tendencies, whereas relative right frontal activity reflects enhanced withdrawal motivation tendencies. Twenty-five schizophrenia outpatients and 25 healthy controls completed resting EEG assessments of frontal asymmetry in the alpha frequency band (8\u201312 Hz), as well as a self-report measure of behavioral activation and inhibition system (BIS/BAS) sensitivity. Patients showed an atypical pattern of differences from controls. On the EEG measure patients failed to show the left lateralized activity that was present in controls, suggesting diminished approach motivation. On the self-report measure, patients reported higher BIS sensitivity than controls, which is typically interpreted as heightened withdrawal motivation. EEG asymmetry scores did not significantly correlate with BIS/BAS scores or with clinical symptom ratings among patients. The overall pattern suggests a motivational disturbance in schizophrenia characterized by elements of both diminished approach and elevated withdrawal tendencies. Motivational impairment has been linked to schizophrenia since Kraepelin\u2019s inversely related to regional activity. Left frontal activity  is believed to reflect approach motivation, whereas right frontal activity  is associated with withdrawal motivation. These asymmetrical frontal EEG findings are supported by lesion studies, though hemodynamic studies have been less consistent Considerable evidence supports the motivational direction model of asymmetric frontal brain activity Frontal asymmetries assessed in the resting EEG are believed to relate to stable dispositional motivational tendencies. Consistent with this notion, several studies demonstrate associations between degree of lateralization of activation and scores on conceptually related self-report motivational trait measures. For example, in studies using the BIS/BAS scales Frontal asymmetry and motivational tendencies have been examined explicitly in schizophrenia in only two prior studies. One found that recent-onset patients showed more right frontal lateralization  than healthy controls during a two-minute recording with eyes closed The current study assessed both resting frontal EEG asymmetries and self-reported approach/withdrawal tendencies in schizophrenia. The prior literature, though very limited, led to the prediction that patients would show relatively more right frontal lateralization and higher BIS scores than matched healthy controls. We also explored whether frontal asymmetries relate to individual differences on the BIS/BAS and to symptom levels among patients.Twenty-five outpatients with schizophrenia and 25 healthy control subjects participated in this research. Schizophrenia patients were recruited from outpatient treatment clinics at the Veterans Affairs (VA) Greater Los Angeles Healthcare System and through presentations in the community. Patients met criteria for schizophrenia based on the Structured Clinical Interview for DSM-IV Axis I Disorders SCID . None ofHealthy controls were recruited through flyers posted in local newspapers, websites, and posted advertisements. An initial screening interview excluded potential control participants with identifiable neurological disorder or head injury, had schizophrenia or other psychotic disorder in a first-degree relative, or were not sufficiently fluent in English. Potential controls were screened with the SCID and excluded for history of schizophrenia or other psychotic disorder, bipolar disorder, recurrent depression, lifetime history of substance dependence, or any substance abuse in the last 6 months. Potential controls were also administered portions of the Structured Clinical Interview for DSM-IV Axis II Disorders SCID-II  and exclAll SCID interviewers were trained through the Treatment Unit of the Department of Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center (MIRECC) to a minimum kappa of 0.75 for key psychotic and mood items For all patients, psychiatric symptoms during the previous month were rated using the expanded 24-item UCLA version of the Brief Psychiatric Rating Scale BPRS  by a traAll participants completed the BIS/BAS The research design and methods reflect standard procedures for studies of frontal EEG asymmetry Off-line analysis was performed using Brain Vision Analyzer software . All EEG data were re-referenced to the average of the mastoids t-tests and for categorical variables with chi-square tests; descriptive data for clinical symptom ratings in the patient group are also presented. For the main data analyses, group differences in alpha asymmetry scores and self-reported BIS/BAS scores were evaluated with independent samples t-tests. Finally, we evaluated whether asymmetry scores were associated with BIS/BAS scores and symptoms (patients only) using Pearson correlation coefficients within each group.For demographic data, group differences for continuous variables were evaluated with Demographic information for both groups and clinical data for the schizophrenia group are presented in The schizophrenia group had a typical age of onset and was chronically ill. They showed mild to moderate levels of clinical symptoms at the time of testing that are comparable to prior studies of stabilized outpatients Descriptive statistics and results of between-group comparisons are summarized in Although patients had numerically lower mean scores on the secondary index (F8\u2013F7) than controls, the groups did not significantly differ. Finally, for the analysis of the P4\u2013P3 electrodes, there was no significant group difference in parietal asymmetry scores.As shown in Among patients the F4\u2013F3 asymmetry index was not significantly correlated with BIS, BAS, or any of the three BAS subscales . Similarly, for controls, the F3\u2013F4 asymmetry index was not significantly correlated with BIS, BAS, or BAS subscale scores . There were no significant correlations between asymmetry and total symptoms or symptom subscale scores on the BPRS . Results for the correlation analyses were essentially identical using Spearman correlation coefficients.In this first study to evaluate approach and withdrawal motivation in schizophrenia using both self-report and EEG measures, patients showed an atypical pattern of differences from controls. On the resting EEG measure patients failed to show the left lateralized activity that was present in controls, suggesting diminished approach motivation in the schizophrenia group. On the self-report measure, patients reported higher BIS sensitivity than controls, which is typically interpreted as heightened withdrawal motivation. EEG asymmetry scores however, were not significantly correlated with self-reported motivational traits in either group. The overall pattern of group differences converges to suggest a motivational disturbance in schizophrenia characterized by elements of both diminished approach tendencies and elevated withdrawal tendencies.The current between-group motivational differences confirm and extend the few prior studies using either EEG or self-report measure alone. Regarding EEG, the two groups showed opposite asymmetry patterns at mid-frontal sites, the most commonly examined sites in the frontal asymmetry literature The patients\u2019 elevated self-reported scores on the BIS scale, but normal scores on the BAS scales, also converge with the few prior relevant studies in schizophrenia Overall, the current findings suggest that when it comes to understanding motivational factors that hold people with schizophrenia back from pursuing personally relevant goals, it is important to consider multiple processes. Diminished initiation and persistence in goal-directed activities may stem from a lack of desire to pursue potentially rewarding outcomes and/or a strong drive to avoid potentially unpleasant emotions and cognitions associated with efforts to pursue desired outcomes.Results from the current study are not fully consistent with prior studies, in that frontal asymmetry scores did not significantly correlate with symptom levels or with BIS/BAS scores. Regarding symptoms, Jetha et al. We also did not find significant correlations between frontal asymmetry and scores on the BIS/BAS scales in either patients or controls. Such correlations have been reported in some studies in clinical and healthy samples, though a number of studies have failed to find significant correlations, particularly for the BIS scale The current finding of increased withdrawal motivational tendencies in schizophrenia should be interpreted in the context of some limitations. First, this cross-sectional study of chronically ill patients cannot address the question of whether this pattern precedes the onset of schizophrenia or is the consequences of living with a severe mental illness. Although prior research demonstrating the same asymmetry pattern is present in recent-onset patients and that asymmetry scores show good longitudinal stability in schizophrenia is consistent with the notion that elevated right frontal lateralization reflects an enduring trait that is present from at least the early post-onset period Although the approach and withdrawal motivational framework has been extensively studied in internalizing and externalizing disorders, the current findings suggest it may be informative for understanding motivational disturbances in the psychosis dimension of psychopathology as well. The framework has treatment implications for schizophrenia patients with elevated withdrawal motivation. For example, CBT, emotion regulation, and mindfulness interventions that target symptoms such as anxiety and hyper-arousal may be useful for these individuals, and frontal asymmetries have been found to provide an informative biomarker in the context of these types of treatment studies Data S1(SAV)Click here for additional data file."}
+{"text": "Hypertrophic cardiomyopathy (HCM) with midventricular hypertrophy is an uncommon phenotypic variant of the disease. Midventricular hypertrophy predisposes to intracavitary obstruction and downstream hemodynamic sequelae.We present a case of HCM with midventricular hypertrophy and obstruction diagnosed after a CT scan of the abdomen incidentally revealed a filling defect in the left ventricular apex. Transthoracic echocardiography demonstrated mid left ventricular hypertrophy and obstruction, as well as an aneurysmal apex containing a large thrombus. Cardiovascular MRI showed a spade-shaped left ventricle with midcavitary obliteration, an infarcted apex and regions of myocardial fibrosis. Due to the risk of embolization and a relative contraindication to anticoagulation, the patient underwent surgery including thrombectomy, septal myectomy and aneurysmal ligation.Hypertrophic cardiomyopathy with midventricular hypertrophy leads to cavity obstruction, increased apical wall tension, ischemia and ultimately fibrosis. Over time, patchy apical fibrosis can develop into a confluent scar resembling a transmural myocardial infarction in the left anterior descending coronary artery distribution. Aneurysmal remodeling of the left ventricular apex potentiates thrombus formation and risk of cardioembolism. For these reasons, hypertrophic cardiomyopathy with midventricular obstruction portends a particularly poor prognosis and should be recognized early in the disease process. Hypertrophic cardiomyopathy is defined as a myocardial disease characterized by unexplained left ventricular hypertrophy in association with non-dilated ventricular chambers . The dis2) status-post gastric bypass surgery over ten years prior to presentation was admitted for evaluation of an upper gastrointestinal bleed. Postoperatively following gastric bypass surgery, the patient became hemodynamically unstable and developed acute kidney injury. Although her renal function improved, the underlying etiology of her postoperative complications remained unknown. An abnormal electrocardiogram noted several years later suggested a prior myocardial infarction, retrospectively hypothesized incurred perioperatively. The abnormal electrocardiogram prompted invasive coronary angiography which showed no evidence of obstructive coronary artery disease. During the current admission for upper gastrointestinal bleeding, an abdominal CT scan with intravenous contrast serendipitously revealed a filling defect in the left ventricular apex. Transthoracic echocardiography confirmed the presence of a large, heterogeneous apical mass and additionally showed midventricular hypertrophy measuring 20 mm in the interventricular septum, resulting in systolic apposition of the midventricular segments  with midcavity hypertrophy , a measured ejection fraction of 65% and an aneurysmal apex , oxygen supply-demand mismatch, ischemia and ultimately infarction and fibrosis. Patients with HCM also have abnormally thickened intramural arteries with decreased luminal size . CoupledThe increasingly utilized CMR technique of native T1 mapping characterizes myocardium based on quantitative T1 relaxation times, altered by the presence of fibrosis, without the need for intravenous gadolinium contrast agent. Increased T1 relaxation times in hypertrophic cardiomyopathy correlate with abnormalities in left ventricular systolic function even in the absence of late gadolinium enhancement . In the Patients with HCM and midventricular obstruction may exhibit a characteristic echocardiographic Doppler pattern of blood flow in the left ventricle . Due to This morphological variant of HCM deserves clinical recognition. In a Japanese study  of 490 cMaron et al.  have queHypertrophic cardiomyopathy with midventricular hypertrophy and obstruction is a relatively uncommon variant of HCM that may lead to an infarcted apex and aneurysm formation. Mid ventricular obstruction with apical aneurysm formation predisposes to thrombus formation and portends a poor prognosis. Repercussions of aneurysm formation included ventricular arrhythmias, thromboembolism, predisposition to end stage disease and death. Physicians should be aware of this variant and consider these patients to be at higher risk when making management decisions."}
+{"text": "Iron oxide nanoparticles (IONPs) are frequently used for biomedical applications including magnetic resonance imaging, drug delivery or tumor treatment by hyperthermia. Since IONPs can reach the brain from periphery or are directly applied into the brain, the investigation of potential adverse effects of IONPs on properties and functions of the different types of brain cells is an important task. In order to directly compare different types of brain cells concerning the uptake and toxicity of IONPs, we synthesized fluorescent IONPs and characterized these BODIPY-labeled particles regarding their physicochemical properties. In the medium used for the cell studies, these particles had a hydrodynamic diameter of around 158 \u00b1 28 nm and a negative surface charge with a zeta-potential of -10 \u00b1 2 mV. Exposure of primary cultures of rat astrocytes, neurons and microglial cells revealed that among these cell types, microglial cells accumulated IONPs most rapidly. However, microglial cells were also most vulnerable towards acute IONP-induced stress while astrocytes and neurons were not acutely damaged by IONPs. In microglial cells, but not in astrocytes or neurons, IONPs were found to be localized in lysosomes and large amounts of reactive oxygen species (ROS) were observed after IONP-exposure. The IONP-induced toxicity in microglial cells was prevented by neutralizing lysosomes or by chelation of intracellular ferrous iron ions, suggesting that the toxic potential of IONPs in microglia involves rapid particle uptake, liberation of ferrous iron from the internalized IONPs in the acidic lysosomal compartment and iron-catalyzed ROS formation. These data suggest that also in brain IONPs may harm microglial cells and compromise microglial functions."}
+{"text": "Abnormal accumulation of cytosolic aggregates or inclusion bodies is a hallmark of several neurodegenerative diseases. Many common or specific molecular components such as ubiquitin, \u03b1-synuclein, TDP-43, or tau in neuronal cytosolic inclusion bodies have been identified as being associated with cellular pathogenic mechanisms of disease. Recently, stress granule (SG) marker proteins such as PABP and G3BP were found in cytosolic inclusion bodies of patients with frontotemporal lobar dementia (FTLD), alzheimer's disease (AD), or amyotrophic lateral sclerosis (ALS), suggesting that inappropriate SG dynamics contribute to pathogenic mechanisms . MoreoveFUS mutations [atg7 siRNA increased the number of SGs, whereas activation of autophagy reduced SG accumulation. Further analysis showed that mutant FUS-positive SGs were regulated by autophagy regulation in post-mitotic neurons. Most importantly, autophagy activation reduced mutant FUS-positive SG accumulation as well as mutant FUS-mediated neurite fragmentation and cell death in response to oxidative stress in disease-associated cultured neurons, suggesting a role for persistent SGs in neurodegeneration as well as involvement of autophagy in ALS-linked SG regulation. However, this finding needs to be confirmed in transgenic animal models and patients with specific iPSC-derived neurons associated with persistent SGs and SG aggregates [To address these questions, our study investigated the role of autophagy, which controls the quality of proteins or organelles, in the regulation of ALS-linked SGs and neurodegeneration in disease-associated cultured neurons . Fused iutations . Interesgregates .Our study provides important insights into the roles of autophagy and disease-associated SGs in neurodegeneration. SGs are generally considered as a defense mechanism in neurons under stress conditions. However, persistent SGs in neurons might actually inhibit protein translation by sequestering mRNA and RNA-binding proteins, which are normally involved in transcriptional regulation in the nucleus or transport of mRNAs into dendrites/axons. Therefore, persistent SGs can lead to accumulation of toxic components/loss of essential components even after stress. According to our unpublished data, mutant FUS sequesters mRNAs that are involved in neuronal integrity into persistent SGs, which induces neurite fragmentation/shrinkage caused by oxidative stress in cortical neurons.atg5\u2212/\u2212 MEFs causes SG formation/accumulation without any stress, suggesting that cellular homeostasis of SGs is tightly associated with autophagy. During normal aging or disease progression in the brain, dysregulated or insufficient autophagy combined with environmental factors such as acute or chronic stresses may accelerate SG formation and development of persistent SGs into larger cytosolic inclusions, leading to increased stress vulnerability in neurons as well as neurodegeneration.Moreover, our studies have shown that autophagy deficiency in However, the following questions remain to be answered in the context of autophagic regulation of SGs in physiology and pathology: How do cells regulate and harmonize formation/disassembly/autophagic degradation of SGs in response to different stresses in physiology and pathology? Which signals induce autophagic clearance of physiological or pathological SGs as opposed to disassembly of SGs or fusion with P-bodies? How are transient or persistent SGs recognized by autophagy machineries? What is the specific role of autophagy in regulation of SGs in relation to neuronal RNA granules such as P-bodies or transporting RNA granules in polarized neurons? More detailed studies are needed to elucidate autophagic regulation of SGs. Therefore, future efforts will provide novel opportunities for therapeutic intervention by targeting regulation of SGs via manipulation of the autophagic pathway in several neurodegenerative diseases associated with SGs such as ALS ."}
+{"text": "Odorant Receptor genes). To identify whether shifts in pheromone composition among related lineages of orchid bees are associated with divergence in chemosensory genes of the olfactory periphery, we searched for patterns of divergent selection across the antennal transcriptomes of two recently diverged sibling species Euglossa dilemma and E. viridissima.Insects rely more on chemical signals  than on any other sensory modality to find, identify, and choose mates. In most insects, pheromone production is typically regulated through biosynthetic pathways, whereas pheromone sensory detection is controlled by the olfactory system. Orchid bees are exceptional in that their semiochemicals are not produced metabolically, but instead male bees collect odoriferous compounds (perfumes) from the environment and store them in specialized hind-leg pockets to subsequently expose during courtship display. Thus, the olfactory sensory system of orchid bees simultaneously controls male perfume traits (sender components) and female preferences (receiver components). This functional linkage increases the opportunities for parallel evolution of male traits and female preferences, particularly in response to genetic changes of chemosensory detection .We identified 3185 orthologous genes including 94 chemosensory loci from five different gene families . Our results revealed that orthologs with signatures of divergent selection between Our results suggest that rapid changes in the chemosensory gene family occurred among closely related species of orchid bees. These findings are consistent with the hypothesis that strong divergent selection acting on chemosensory receptor genes plays an important role in the evolution and diversification of insect pheromone systems.The online version of this article (doi:10.1186/s12862-015-0451-9) contains supplementary material, which is available to authorized users. Olfaction allows animals to perceive volatile chemicals from the environment and is therefore essential for the detection and discrimination of food resources, predators, and conspecifics in a diverse array of taxa , 2. In iOstrinia nubilalis, has shown that divergence in pheromone recognition might be best explained by nucleotide substitutions in pheromone receptor genes ."}
+{"text": "Historically, the catheter peak-to-peak pressure gradient (PPG) has been used as the diagnostic gold standard to evaluate the degree of pulmonary outflow tract obstruction in congenital heart disease (CHD) and was employed to decide when to intervene. Today, estimated maximal Doppler gradients are generally decisive. Cardiovascular phase contrast magnetic resonance (PCMR) measurements are frequently performed during routine follow-up. However, it remains unclear how to deal with PCMR flow velocities that can also serve for the estimation of pressure gradients.In 75 patients with pulmonary outflow tract obstruction maximal and mean PCMR gradients were compared to maximal and mean Doppler gradients. Additionally, in a subgroup of 31 patients maximal and mean PCMR and Doppler pressure gradients were compared to catheter PPG.Maximal and mean PCMR gradients underestimated pulmonary outflow tract obstruction as compared to Doppler . However, in comparison to catheter PPG, maximal PCMR gradients and mean Doppler gradients revealed best agreement . Mean PCMR gradients underestimated, while maximal Doppler gradients systematically overestimated catheter PPG .Estimated maximal PCMR pressure gradients and mean Doppler gradients from routine CHD follow-up agree well with invasively assessed PPG. There is evidence to either apply maximal PCMR gradients or mean Doppler gradients  to evaluate the severity of pulmonary outflow tract obstruction during follow-up of CHD.N/A."}
+{"text": "Gradually increasing prosthetic ankle stiffness influenced the shape of the prosthetic ankle plantarflexion moment, more closely mirroring the intact ankle moment. Increasing ankle stiffness also corresponded to increased prosthetic ankle power generation  and increased braking ground reaction forces of the amputated leg. These findings further our understanding of how to deliver assistance with powered knee-ankle prostheses and the compensations that occur when specific aspects of assistance are added/removed.Powered knee-ankle prostheses are capable of providing net-positive mechanical energy to amputees. Yet, there are limitless ways to deliver this energy throughout the gait cycle. It remains largely unknown how different combinations of active knee and ankle assistance affect the walking mechanics of transfemoral amputees. This study assessed the relative contributions of stance phase knee swing initiation, increasing ankle stiffness and powered plantarflexion as three unilateral transfemoral amputees walked overground at their self-selected walking speed. Five combinations of knee and ankle conditions were evaluated regarding the kinematics and kinetics of the amputated and intact legs using repeated measures analyses of variance. We found eliminating active knee swing initiation or powered plantarflexion was linked to increased compensations of the ipsilateral hip joint during the subsequent swing phase. The elimination of knee swing initiation or powered plantarflexion also led to reduced braking ground reaction forces of the amputated  The number of individuals with lower-limb amputations living in the U.S. is projected to grow dramatically , and comand ankle joints affect the walking mechanics of amputees. This is especially true when examining outcomes in transfemoral amputees and during overground walking. Interesting prior studies have sought to emulate autonomous prosthetic systems with externally-powered devices and treadmill-based test beds to answer some of these questions regarding the plantarflexive assistance occurring during the mid- to late stance phase of walking  are comg . While and ankle assistance influence the walking mechanics of transfemoral amputees. With the rapid advances in powered prosthetic hardware and the encouraging prior studies that demonstrate the potential benefits of these devices [Little is known about how combinations of knee  devices , 27, theThree male subjects with unilateral amputations at or above the knee . Repeated trials were conducted until five clean force plate contacts were captured for both amputated and intact legs. Ground reaction force (GRF) and kinematic data  were collected using an eight-camera motion capture system . For each subject, reflective markers were placed on the posterior sacrum and bilaterally on the posterior superior iliac spine (PSIS), anterior superior iliac spine (ASIS), greater trochanter, lateral and medial femoral epicondyle, lateral and medial malleolus, posterior heel, dorsal foot, and fifth metatarsal head. Clusters of three markers affixed to thermoplastic shells were wrapped bilaterally to the thigh and shank.\u03c4, at the knee and ankle joints as a function of three impedance parameters: joint stiffness, k, equilibrium angle, \u03b8e, and damping coefficient, b, according to i corresponded to the knee or ankle joint, \u03b8 was the joint angle and Subjects wore a powered knee and ankle prosthesis featuring on-board mechanical sensors, including sensors to measure knee and ankle position and velocity, as well as axial load applied through the shank . Sensor xtension . TransitTo provide knee swing initiation, the prosthesis knee equilibrium angle was increased from 0\u00b0 to 60\u201375\u00b0 flexion (ranged across subjects) during terminal stance as a linear function of decreasing prosthesis vertical load ; the stiSpatiotemporal, kinematic and kinetic data were analyzed using Visual3D  and Matlab . Kinematics were segmented from heel contact to heel contact; kinetic data were segmented from heel contact to toe-off (stance phase) and toe-off to heel contact (swing phase), and normalized to body mass (kg). All data were low-pass filtered and averaged across strides. Average peak values were calculated for joint kinematics. Average positive and negative values were calculated for GRF and joint kinetics during stance, and also calculated for joint kinetics during swing. To provide objective comparisons of these metrics across all conditions, across-subject statistics were performed . For each quantity, two analyses of variance with repeated measures (ANOVAs) were evaluated (\u03b1 = 0.05). One two-way ANOVA tested the effects of powered plantarflexion and increasing ankle stiffness. The second tested the effect of swing initiation. Post-hoc tests using a Bonferroni correction factor were used to identify differences between conditions.Increasing ankle stiffness had a significant effect on stance time of the intact leg (p = 0.02), with a trend toward reduced stance time. There were no differences in step length, step time, swing time, overall cycle time, walking speed, stride length, or stride width for either amputated or intact legs .amputated leg was affected by increasing ankle stiffness (p = 0.023) and powered plantarflexion  of the Powered plantarflexion had a significant effect on the peak stance phase knee flexion angle of the intact leg (p = 0.002), with a trend toward less knee flexion with powered plantarflexion. Knee swing initiation increased peak knee flexion of the amputated leg in swing , and powered plantarflexion and increasing ankle stiffness had a significant interaction effect on average positive hip power , knee flexion moment (p = 0.043), and ankle plantarflexion moment , were decreased and others increased. We found in the absence of knee swing initiation, these transfemoral amputees compensated by reducing the braking  ground reaction force of the intact leg . This fien shown . In thisintact leg also occurred with a lack of powered plantarflexion in the presence of knee swing initiation  the knee extension moment in early stance, irrespective of ankle stiffness . While many studies have been focused on reducing the metabolic cost of amputee walking by providing assistance at the ankle joint exclusively, this investigation reveals that the synchronization of ankle and knee power in late stance and monitoring how these changes influence kinetics of proximal joints and joints of the intact leg may be especially important to resolve the increased metabolic cost of amputee walking. Finally, based on the biomechanical outcomes evaluated in this study, when fitting elderly patients or other patients at risk of exhibiting gait instability or sustaining fall-related injuries with active knee-ankle prostheses, control strategies that deliver both active knee and ankle assistance may prove to be detrimental. Powered plantarflexion and knee swing initiation were shown to increase braking ground reaction forces relative to conditions that did not provide these functions, which would likely influence stability in the sagittal plane. Thus, hybrid solutions which selectively deliver active knee or ankle assistance could be beneficial. These implications are subjective, and we also understand that individual patient needs could be coupled and be presented simultaneously. Thus, as mechanically-active devices become more commonplace, studies which comprehensively identify how specific aspects of active knee and ankle control influence the biomechanics of locomotion are likely to become increasingly important."}
+{"text": "Mucormycosis is an invasive mycotic disease caused by fungi in the zygomycetes class. Although ubiquitous in the environment, zygomycetes are rarely known to cause invasive disease in immunocompromised hosts with a high mortality even under aggressive antifungal and surgical therapy. Clinically, mucormycosis frequently affects the sinus occasionally showing pulmonary or cerebral involvement. However skeletal manifestation with Rhizopus microsporus (RM) osteomyelitis leading to emergency surgical proximal femoral resection with fatal outcome has not been described yet.We report the case of a 73-year-old male suffering from myelodysplastic syndrome with precedent bone marrow transplantation. Six months after transplantation he consulted our internal medicine department in a septic condition with a four week history of painful swelling of the right hip. Radiography, computed tomography and magnetic resonance imaging revealed multiple bone infarcts in both femurs. In the right femoral head, neck and trochanteric region a recent infarct showed massive secondary osteomyelitis, breaking through the medial cortex. Emergency surgical proximal femoral resection was performed due to extensive bone and soft tissue destruction. Microbiological and basic local alignment search tool (BLAST) analysis revealed RM. Amphotericin B and posaconazole treatment with septic revision surgery was performed. However the disease ran a rapid course and was fatal two months after hospital admission.This alarming result with extensive RM osteomyelitis in the proximal femur of an immunocompromised patient may hopefully warn medical staff to perform early imaging and aggressive surgical supported multimodal treatment in similar cases.The online version of this article (doi:10.1186/1471-2334-14-488) contains supplementary material, which is available to authorized users. Zygomycetes are environmental nonseptate molds widely distributed in soil, plants, and decaying material , 2. The Previously reported risk factors for mucormycosis are prolonged neutropenia, immunosuppression, iron overload and prolonged hyperglycemia or manifest diabetes. Patients treated with allogeneic hematopoietic stem cell transplantation  often suffer from a combination of these risk factors . The proHere we describe the unique case of fatal invasive osteomyelitis in an allo-HSCT recipient caused by RM. Extensive diagnostic evaluation revealed multiple old bone infarcts complicated with invasive fungal disease. Although systemic antifungal treatment and repetitive radical surgery was started immediately cure could not be provided.We report on a 73-year-old male with recently diagnosed myelodysplastic syndrome RAEB I showing complex karyotype. A routine-checkup revealed a tricytopenia in the blood count as well as a mild splenomegaly, further examinations including bone marrow biopsy confirmed the diagnosis. Facing the high-risk constellation of this disease  and theEleven months later allogeneic matched unrelated donor stem cell transplantation after conditioning chemotherapy with fludarabine, treosulfane as well as antithymocyte globuline and prophylactic immunosuppressive medication containing of cyclosporine and mycophenolatmofetile was performed successfully. No relevant complications occurred during the first weeks of follow-up besides moderate acute graft versus host disease of the skin which was immediately responsive to steroid treatment. Bone marrow examinations one month after transplantation showed complete cytogenetic remission of the disease as well as complete donor chimerism. With no further signs of graft versus host disease and a good clinical condition of the patient the immunosuppressive treatment could be constantly tapered during the following months. Continuous prophylactic antiinfectious medication with acyclovir, co-trimoxazole and posaconazole was administered.Six months after transplantation without remaining medication the patient was presented to our internal emergency department with a critical septic condition showing fever (body temperature above 40\u00b0C) and dyspnea, and was immediately transferred to the intensive care unit (ICU). Intubation and mechanical ventilation had to be initiated due to respiratory failure. Computed tomography (CT) scan revealed bilateral infiltrations referring to atypical pneumonia and regional osteopaenia with mild focal bone lysis at the level of the lumbar spine. Lumbar spondylodiscitis was ruled out by magnetic resonance tomography imaging (MRI).No relevant bacterial, viral or fungal cause could be identified by bronchoalveolar lavage and multiple blood culture collections during the stay on the ICU. Cardiac echocardiography was performed and culture-negative endocarditis could be ruled out. The patient constantly improved under combinatory empiric antibiotic, antiviral and antifungal (azole) medication, extubation could be performed 7\u00a0days after intubation. While the respiratory situation completely stabilized, the clinical condition of the patient constantly deteriorated in the following days. For the first time the patient reported right hip pain.In consequence ultrasound, CT and MRI of the right hip and thigh were performed in order to identify and localize a potential inflammatory focus. The imaging revealed multiple old bone infarcts in both femurs as well as a new infarct with massive secondary osteomyelitis in the right femoral head, neck and trochanteric region, breaking through the medial cortex into the surrounding soft tissue Figure\u00a0. With emInvasive disseminated Rhizopus-infections develop in fewer than \u00bc of localized forms and have an estimated mortality rate of 78\u2013100% in allo-HSCT recipients [Immunocompromised patients, particularly suffering from hematological diseases treated by allo-HSCT face a high risk of invasive fungal infections . InvasivCompared to focal RM fungal infections disseminated infections are even more seldom , 13, 14.Mucormycosis spreads from isolated infection hematogenously to other organs. The most common sites of origin are sinuses (39%), lungs 24%), and skin (19%) 4%, and s. DissemiFurthermore establishing the diagnosis of invasive fungal infections, primarily based on standard culture-based mycological methods is often difficult, especially in early stages . AccordiTherapy for mucormycosis infections includes systemic antifungal drugs and local surgical debridement . RegardiThis dramatic case of rapidly progressive and ultimately fatal RM infection of the bone illustrates the diagnostic and therapeutic challenges of mucormycosis in immunocompromised hosts. Amongst others, abscess formations should always be suspicious of invasive fungal infection under these circumstances. Rapid and exact diagnosis by both morphology and molecular techniques is crucial for starting early treatment of fungal infection. Amphotericine B should be used as soon as mucormycosis is suspected. If the patient\u2019s condition is not improving, addition of posaconazole should be considered. At the same time, early and aggressive surgical debridement has to be performed first to detect the pathogen and second to establish local control. Comprehensive multimodal therapy for mucormycosis may create more opportunities to improve patient\u2019s outcome despite the very low overall survival rate in disseminated cases.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal."}
+{"text": "A rat model of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides reveals crescentic glomerulonephritis as seen in human renal biopsies and diffuse lung hemorrhage that is not well documented in human lung biopsies. A 64-year-old male, with shortness of breath and mild elevation of serum creatinine, was found to have a positive serum test for ANCA, but negative antiglomerular basement membrane antibody. A renal biopsy showed pauci-immune type of crescentic glomerulonephritis and focal arteritis. The prior lung wedge biopsy was retrospectively reviewed to show diffuse hemorrhage and hemosiderosis with focal giant cells. In addition, small arteries revealed subtle neutrophil aggregation, and margination along vascular endothelium, but no definitive vasculitis. The pathology of ANCA associated vasculitides results from activated neutrophils by ANCA and subsequent activation of the alternative complement cascade with endothelial injury, neutrophil aggregation and margination. Our findings, after the correlation between lung biopsy and renal biopsy, imply that the top differential diagnosis in the lung biopsy should be microscopic polyangiitis when diffuse pulmonary hemorrhage and hemosiderosis are present in this ANCA-positive patient. In humans, ANCA associated systemic vasculitides clinically range from microscopic polyangiitis to granulomatosis with polyangiitis  to eosinophilic granulomatosis with polyangiitis . The systemic vasculitides mainly involve small vessels of the lungs and kidneys, causing compromised lung function and rapid progressive renal failure \u20134. ConveA 64-year-old male had progressive dyspnea over six-month duration. The patient had a history of asthma but never smoked. A recent cardiac evaluation included normal echocardiogram and stress test. Computerized tomography (CT) chest imaging without contrast revealed bilateral mild ground-glass opacities in the lungs, slightly greater within the middle and lower lobes on the right side, suggestive of mild interstitial lung disease. He was found to have positive serum p-ANCA at titer of 1\u2009:\u2009640 while the antiglomerular basement membrane antibody was negative. His serum test for myeloperoxidase was positive at greater than 8 units  while his serum level of proteinase-3 was negative. Wedge lung biopsies from the right upper, middle, and lower lobes were performed to reveal red to purple color from pleural surface and red color on the cross sections grossly. Microscopically, the biopsies mainly revealed diffuse hemorrhage and hemosiderosis  Figures , but no The patient's renal biopsy showed cellular crescents in 3 of 12 glomeruli and focal fibrinoid vasculitides in a small artery Figures  with milPulmonary hemosiderosis indicates chronic hemorrhage, as iron positivity is identified in hemosiderin-laden macrophages. Traditionally, the differential diagnosis for diffuse pulmonary hemosiderosis includes idiopathic pulmonary hemosiderosis versus Goodpasture's syndrome, which is supported by a positive test for antibasement membrane antibody , 16. GooUnlike Goodpasture's syndrome with one positive antibody and one main finding of pulmonary hemorrhage and hemosiderosis, ANCA associated vasculitis can range from microscopic polyangiitis to granulomatosis with angiitis and eosinophilic granulomatosis with polyangiitis in lung biopsies. Pathologic morphology of ANCA associated microscopic polyangiitis in lung biopsies is not well established , 9, but In summary, a positive ANCA test is an additional serology biomarker suggestive of systemic vasculitis. The criteria for ANCA associated variants of pulmonary vasculitis should be further investigated beyond traditional morphologic findings, which were established many years before ANCA test was discovered. The animal model of ANCA associated systemic vasculitides appears coupled with our findings after the current correlation between the lung biopsy and renal biopsy, implying that microscopic polyangiitis should be on the top differential diagnosis when diffuse pulmonary hemorrhage and hemosiderosis are the main findings in ANCA-positive patients."}
+{"text": "About 90% of mortality associated with cancer is attributable to metastatic disease. Thus, our ability to treat cancer is largely dependent on the capacity to prevent metastasis. Metabolic reprogramming is recognized to support cellular transformation and tumor initiation; however, whether or how metabolism supports metastasis remains an open question. This study seeks to identify metabolic predictors of metastasis, with the rationale that understanding metabolic changes will lead to novel insights into metastasis and perhaps new therapies to treat metastatic disease.A patient-derived xenograft model was used in which metastasis in mice strongly correlates with metastatic history of patient donors. Tumor cells were originally obtained from melanoma patients and passaged exclusively in highly immunocompromised mice . In thisUnsupervised hierarchical clustering revealed that in every case, a given tumor biopsy was most closely related to all other biopsies descended from the same parental tumor. In addition, as a frequent mutation in melanoma, BRAF-mutant tumors were easily distinguished from BRAF-wild type tumors by their metabolomic signatures. More importantly, several metabolic pathways were found altered significantly when metabolomics profiles between melanoma lines with high or low metastatic potentials were compared.The MS-based metabolomic analysis of patient-derived melanoma xenografts demonstrates that tumors contain individual metabolomic identities that can be tracked. It may be possible to identify metabolomic features from primary tumors that predict various aspects of tumor biology, including the propensity to metastasize. The altered metabolic pathways in highly metastatic melanomas are potential therapeutic targets."}
+{"text": "Depression and anxiety disorders are characterized by complex and idiopathic etiologies. One prominent hypothesis, termed \u201cthe neurogenesis hypothesis,\u201d posits that stress-induced decreases in hippocampal neurogenesis underlie depressive episodes , the other brain structure that integrates new neurons in the adult mammalian brain, remains unspecified. Subventricular zone (SVZ) neuroblasts migrate to the OB along the rostral migratory stream (RMS). Chronic stress affects this migration  within the olfactory epithelium or OB sensory afferentation (OMP+ cells), suggesting deficits in odor processing rather than detection. Corticosterone administration decreased cell proliferation in the dentate gyrus (DG), but did not affect cell proliferation in the SVZ. These data suggest a different mechanism by which corticosterone affects neuroblasts destined for the OB. To investigate this, survival of newly born neurons maturing in the DG and OB was examined. Glucocorticoids decreased cell survival in both regions; this effect was prevented by co-administration of FLX. Additionally, dendritic complexity of newly integrated neurons increased following FLX administration, potentially contributing to the partially rescued phenotype. Taken together, these results link major depressive disorder and neurogenesis-dependent olfactory deficits within the DG and OB. Understanding the implications of impaired olfactory function and neurogenesis in depressed humans warrants further investigation; additional mechanisms by which glucocorticoids modulate neurogenesis and functional synapse formation should be examined.A new study Siopi et al.  provides+) in the SVZ and OB relative to psychiatrically healthy people (Maheu et al., + cells in the SVZ was reduced without simultaneous reductions in the OB. These data suggest that impaired migration and ectopic differentiation leads to neuroblast accumulation in the OB of unmedicated depressed individuals. Antidepressant treatment facilitates neuroblast migration out of the SVZ, but cells that differentiated ectopically prior to treatment persist (Maheu et al., The translational significance of these new data is worth considering in the context of vast species differences in rates of olfactory neurogenesis and reliance on olfaction. Rodents rely more heavily on olfaction than humans, and neurogenic rates in the OB are minimal in adult humans (Kam et al., Although stress-induced increases in glucocorticoids directly regulate neurogenesis, immune cells are also responsible for maintenance of the neurogenic niche (Ziv et al., In sum, Siopi and colleagues suggest that chronic elevated glucocorticoids reduce hippocampal and olfactory neurogenesis, leading to depressive-like states and impaired olfactory function Figure . FluoxetAll authors contributed equally to the writing and review of this manuscript.JB is supported by an OSU Presidential and Pelotonia pre-doctoral fellowship. YC was supported by National Institute of Dental and Craniofacial Research Grant T32DE014320.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Dear Editor,Recently, we conducted a preclinical investigation to find the ameliorative properties of metformin on renal biochemical and histologic alterations of gentamicin-induced kidney damage in male Wistar rats . In this"}
+{"text": "Voriconazole is an established first-line agent for treatment of invasive fungal infections in patients undergoing allogeneic stem cell transplantation (ASCT). It is associated with the uncommon complication of periostitis. We report this complication in a 58-year-old female undergoing HSCT. She was treated with corticosteroids with minimal improvement. The symptoms related to periostitis can mimic chronic graft-versus-host disease in patients undergoing HSCT and clinicians should differentiate this from other diagnoses and promptly discontinue therapy. Invasive fungal infections lead to significant morbidity and mortality in patients who are undergoing allogeneic stem cell transplantation (ASCT) \u20133. TreatA 58-year-old woman with intermediate risk acute myeloid leukemia in first complete remission underwent ASCT from an HLA-matched sibling. Her initial induction was complicated by hypoxia, pulmonary infiltrates, and fevers despite broad-spectrum antibiotics. She was treated with voriconazole with clinical improvement and was presumed to have invasive fungal infection. Voriconazole was continued throughout her transplant course given persistent chest CT abnormalities.At day 79 after ASCT, the patient complained of swelling in her left middle finger. Physical examination revealed discrete tender swelling of the middle phalanx on the third finger. This continued to worsen and one month later she was complaining of further swelling involving the fourth finger . In addiVoriconazole is a triazole antifungal that is indicated for the treatment of invasive aspergillosis. Common adverse effects include visual disturbances, hallucinations, QT prolongation, and hepatotoxicity. With prolonged use however, newly described adverse effects, including periostitis, alopecia, and development of skin cancers, have been noted . PainfulMost cases of voriconazole-induced periostitis have been reported in patients who have undergone solid organ transplantation \u20137. Few cThe clinical presentation and radiologic findings of patients who develop voriconazole-induced periostitis are nonspecific and insidious and may be confused with rheumatologic or endocrinologic disorders. In the setting of ASCT, symptoms may mimic cGVHD. Prior cases reported in the ASCT setting were also treated with corticosteroids for cGVHD, resulting in temporary symptom relief and a delay in discontinuing voriconazole \u201311. In oGiven that long-term voriconazole therapy is increasingly common, clinicians managing ASCT patients should be aware of this complication. We recommend periodic measurement of ALP and fluoride levels in patients on prolonged voriconazole therapy. In patients on voriconazole who report nonspecific musculoskeletal complaints following ASCT, drug-induced periostitis should be included in the differential diagnosis along with cGVHD."}
+{"text": "Arthroscopic treatment of these disordersproduces more favourable results than open procedures.We report two patients who were not responding toconservative management and were treated with directarthroscopic distal clavicle excision and subacromialdecompression in single setting. Both patients gained goodpostoperative outcome in terms of pain score, function andstrength improvement assessed objectively with visualanalogue score (VAS) and University of California LosAngeles Score (UCLA).Shoulder impingement syndrome and acromioclavicularjoint osteoarthritis often occur simultaneously andeasily missed. Kay et al. reported excellent results withcombined arthroscopic subacromial decompression andresection of the distal end of the clavicle in patients withboth disordersAcromioclavicular joint arthritis, distal clavicle excision,Arthroscopy, Mumford operation. Resection of the distal clavicle, as described byMumford 2, is a reliable surgical option in acromioclavicularjoint (ACJ) osteoarthritis and shoulder impingementsyndrome. Symptom improvement has been satisfactory inmost reported series. Historically, distal clavicle resectionhas been performed using an open incision over the ACJ withdetachment of the deltoid and trapezius muscles. Significant morbidity may follow with these open procedures. Woundinfection, residual acromioclavicular joint instability,cosmetically unacceptable scar, postoperative shoulderweakness and stiffness are among the common complicationsreported from these open procedures 3.Symptomatic acromioclavicular osteoarthritis and distalclavicle osteolysis can be treated effectively with both nonoperativeand operative means. Non-operative treatmentsincluding physiotherapy, non-steroidal anti-inflammatorydrugs (NSAIDS) and corticosteroid injection may help torelieve the symptoms. However, surgical Patient OneAn active 64 year old lady with no previous history of traumawas referred for evaluation of persistent anterosuperiorleft shoulder pain for one year. The pain worsened whenshe tried to reach across the body or behind the back. Shealso experienced discomfort with rotational and overheadmovements of the left shoulder. Physical examinationrevealed tenderness over the left acromioclavicularjoint. Cross body adduction and active compression testsreproduced the symptoms at the acromioclavicular joint.Neer and Jobe impingement tests were positive. Plainradiographs revealed osteoarthritis of acromioclavicularjoint with narrowing of joint space The patient was put on beach chair position. Through astandard posterior portal, the arthroscope was insertedto screen for underlying pathology. Meanwhile, anotheranterior portal was made via outside in technique withspinal needle, in line with the AC joint (to facilitate the AC joint resection later). Osteophytes were shaved throughthe anterior portal first, and then switched to posteriorportal for bursectomy as this facilitated subacromialspace viewing and subacromial decompression. Lateralportal was created with spinal needle, 3cm to the lateral of acromion edge. By viewing the scope from the lateralportal, resection of inferior part of AC joint was performeddirectly from the anterior portal. Further resection of ACjoint, especially at the superior edge was achieved withthe 70-degree scope to shave from anterior portal. Using the 70-degree scope from the standard lateral portal andalso posterior portal, the entire AC joint could be viewedin detail which helped preserving the superior capsule andligament. Finally, we switched the scope to the anteriorportal for final checking for remnants of osteophytes anddistal clavicle.Postoperative, patient went through standard rehabilitationprotocol, with early range of movement exercises from dayone postoperatively. The shoulder was protected with armsling for 7 to10 days. The patient returned to her normalactivities at six weeks following surgery. Both VAS andUCLA scores showed improvements compared withpreoperative findings. During follow up at six months, sheremained pain free and achieved full range of movementsof the shoulder without impingement signs Patient TwoA 54 year old male presented with a 4 year historyof gradually worsening right anterosuperior shoulderpain. He had a history of a motor vehicle accident in2009, sustaining direct trauma to his right shoulder.Arthroscopic debridement had been carried out in 2010but the pain was only partially relieved. The patient hadsought to relieve his pain with anti-inflammatory drugs,corticosteroid injection and physiotherapy but to littleavail. Patient had limited range of movement of the rightshoulder especially adduction. He experienced difficultyreaching for his wallet and tucking his shirt behind his back. Physical examination revealed healed previousarthroscopic portals. Positive tests included cross-bodyadduction and active compression, with pain locatedspecifically at the acromioclavicular joint. There was noevidence of impingement signs or glenohumeral instability.Standard radiographs demonstrated maintenance of theacromioclavicular joint space, but marked hypertrophicdegenerative changes Postoperative radiographs demonstrated adequate boneresection and no obvious translation of the clavicle relativeto the acromion 4.Arthroscopic resection of the distal clavicle andsubacromial decompression can avoid complicationsarising from the open method. Preserving the posteriorand superior aspects of the acromioclavicular capsuleavoids creating iatrogenic distal clavicular anteroposteriorinstability. Moreover, arthroscopic excision provides theadvantage of evaluating glenohumeral joint at the time ofsurgery. Other shoulder joint pathology such as rotator cuffdisease, loose bodies, labral tears and chondral injurieswill not be missed. Hence, there will be only a singleprocedure needed to solve the patient\u2019s shoulder problems.Arthroscopic subacromial decompression and arthroscopicresection of the acromioclavicular joint as separateprocedures have been well documented. However, there islittle documentation on the success rate of resection withconcomitant subacromial decompression. In our case, wefound excellent results with arthroscopic resection of theacromioclavicular joint and subacromial decompressionin a single setting. Maintaining the integrity of the capsular attachments minimizes the amount of bleedingand trauma into the subacromial space, thereby decreasingpostoperative pain while avoiding creating iatrogenic distalclavicular horizontal instability. When this procedure is performed on properly selected patients, there are fewerpostoperative complications. Patients return to activitiesearlier while achieving similar long-term outcomes asthe open procedure"}
+{"text": "Most healthcare professional training programs lack sufficient curricula on substance use-3, and eIn year two of the project, students training began integrating SBIRT into their clinical experiences. Implementation packets were distributed to students with resources and instructions tailored to fit the varied needs of the programs and clinical sites. Clinical practice was supervised by SBIRT-trained clinical preceptors when possible or self-evaluated by students using the Brief Intervention Observation Sheet fidelity scale. Qualitative feedback was collected from faculty, clinical preceptors, and students to identify facilitators and barriers to integration of SBIRT into clinical experience.Preliminary data showed that 56 students  practiced SBIRT at their clinical site during the first semester of implementation, with 9% completing screening only (no BI indicated) and 91% completing screening and BI. Fidelity ratings revealed strong completion of BI steps with no significant difference between the groups , although BSN students demonstrated stronger motivational style . Qualitative data revealed institutional barriers to integrating SBIRT into some nursing clinical sites, while MSW clinical sites generally facilitated student practice and some adopted SBIRT agency-wide.Students need opportunities to integrate SBIRT practice into clinical experience and receive supervised feedback to achieve competency. Plans must be tailored to meet the institutional needs of clinical sites, which can vary for BSN and MSW students."}
+{"text": "Nephronophthisis is an autosomal recessive renal ciliopathy that constitutes the leading monogenic cause of end-stage renal disease in children. The KOUNCIL consortium is a collaboration between the UMC Utrecht, the Radboud UMC Nijmegen and UC London aimed at elucidating the genetic etiology and pathophysiological mechanisms underlying nephronophthisis and identifying drugs that prevent or delay renal insufficiency. Our goal is to improve genome diagnostics, genetic counselling and therapeutic options for nephronophthisis patients.in vitro and in vivo models. Genotypic and phenotypic patient characteristics are registered in a nephronophthisis database, facilitating correlation analyses and identification of early phenotypic markers. Newly identified nephronophthisis-genes are incorporated into diagnostic next-generation sequencing panels of ciliary genes. We use a systems-biology approach to identify and functionally characterize nephronophthisis-associated protein modules. Finally, we use high-throughput repurposing screens in zebrafish embryos to identify FDA-approved drugs that halt renal failure.We employ next-generation sequencing to identify novel disease genes in 100 nephronophthisis patients included within the AGORA biobank project. The functional effect of novel mutations is assessed using IFT172, WDR34 and WDR60) for nephronophthisis-related disorders. Clinical guidelines and new diagnostic tools for nephronophthisis are developed and implemented in diagnostics. We expect to identify drugs that can lead to novel therapies for nephronophthisis.With this approach, we expect to uncover the causal mutation in 60-90% of nephronophthisis patients. KOUNCIL members were involved in the recent identification of three novel genes (The KOUNCIL study is designed to advance understanding of renal ciliopathies and improve clinical care for nephronophthisis patients."}
+{"text": "This survey sought to evaluate differences in the understanding and management of shunt-dependent hydrocephalus among the senior North American Pediatric Neurosurgery membership.Surveys were sent to all active American Society of Pediatric Neurosurgeons (ASPN) members from September to November 2014. A total of 204 surveys were sent from which 130 responses were recorded, representing 64% of active ASPN membership. Respondents were asked 13 multiple choice and free response questions focusing on four problems encountered in shunted hydrocephalus management: Shunt malfunction, cerebrospinal fluid (CSF) overdrainage, chronic headaches and slit ventricle syndrome (SVS). Qualtrics\u00ae online survey software was used to distribute and collect response data.ASPN surgeons prefer three varieties of shunt valves: 41% differential pressure, 29% differential with anti-siphon device (ASD), and 27% programmable. Respondents agree shunt obstruction occurs most often at the ventricular catheter due to either in-growth of the choroid plexus (67%), CSF debris (18%), ventricular collapse (8%), or other reasons (9%). Underlying causes of obstruction were attributed to small ventricular size, catheter position, choroid plexus migration, build-up of cellular debris, inflammatory processes, or CSF overdrainage. The majority of respondents (>85%) consider chronic overdrainage a rare complication. These cases are most often managed with ASDs or programmable valves. Chronic headaches are most often attributed to medical reasons  and managed with patient reassurance. The most popular treatments for SVS include shunt revision (88%), cranial expansion (57%) and placement of an ASD (53%). SVS etiology was most often linked to early onset of shunting, chronic overdrainage and/or loss of brain compliance.This survey shows discrepancies in shunt-dependent hydrocephalus understanding and management style among a representative group of experienced North American pediatric neurosurgeons. In particular, there are differing opinions regarding the primary cause of ventricular shunt obstructions and the origins of SVS. However, there appears to be general consensus in approach and management of overdrainage and chronic headaches. These results provide impetus for better studies evaluating the pathophysiology and prevention of shunt obstruction and SVS."}
+{"text": "The insular cortex (IC) is considered a rich hub for context-sensitive emotions/social cognition. Patients with focal IC stroke provide unique opportunities to study socio-emotional processes. Nevertheless, Couto et al.  have rec The insular cortex (IC), a brain region localized deep in the lateral sulcus, has been recently considered an interoceptive region , the right IC (whose lesion did not impair disgust recognition in Straube\u2019s) is supposed to index negative emotions and disgust, as reported in several other studies  of the IC renders focal damage extremely infrequent in clinical practice , we assessed interoceptive sensitivity in the same two patients and found that interoceptive-related behavior was differentially impaired in each case: the insular lesion affected cardiac interoceptive measures whereas the subcortical lesion yielded preserved performance. Thus, the subcortical patient\u2019s impairments in social cognition and negative emotion cannot be explained by canonical interoceptive signals running through autonomous  pathways. These factors notwithstanding, further studies would elucidate the relationship between interoceptive sensitivity and social cognition in subcortical lesions.The neuroanatomical and behavioral evidence offered by Couto et al.  also sugThe predictive coding approach is gaining acceptance within the neuroscience community Friston, . PredictPredictive coding principles apply not only to basic brain function but also to social cognition  by subcortical areas (lower in the hierarchy). PE-signals affecting the insular region would modulate connections, whereas PE-signals targeting more frontal areas would reach minimization.The above hypothesis suggests a two-sided explanation of the behavioral effects reported by Couto et al. On the one hand, PEs and response times are strongly correlated  suggest high variability in the patients\u2019 performance. This variability can be interpreted in terms of preserved/affected hubs connecting the lesion sites with other ipsilateral regions and with their contralateral regions. Here, we have proposed that effective connectivity analysis constitutes a novel approach to examine functional connectivity and explain why only some stroke patients are impaired in these domains. Specifically, effective connectivity studies allow us to assess compensatory, contralateral, and subsidiary networks. Moreover, given the existence of transitory post-stroke deficits in empathy and other social cognition domains, this approach may be used to test the functional-remapping hypothesis in cases of IC damage and similar hypotheses in patients with lesions to other brain regions. Dynamic causal models of effective connectivity may provide an opportunity to achieve \u201ceffective\u201d cross-talk between clinicians and basic neuroscientists (Kahan and Foltynie, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The purpose of this case is to describe the complex perioperative management of a 30-year-old woman with congenital heart disease and multiple resternotomies presenting with pulmonary homograft dysfunction and evaluation for percutaneous pulmonary valve replacement. Transvenous, transcatheter Melody valve placement caused left main coronary artery occlusion and cardiogenic shock. An Impella ventricular assist device (VAD) provided rescue therapy during operating room transport for valve removal and pulmonary homograft replacement. ECMO support was required following surgery. Several days later during an attempted ECMO wean, her hemodynamics deteriorated abruptly. Transesophageal and epicardial echocardiography identified pulmonary graft obstruction, requiring homograft revision due to large thrombosis. This case illustrates a role for Impella VAD as bridge to definitive procedure after left coronary occlusion and describes management of complex perioperative ECMO support challenges. Venoarterial ECMO was then instituted via femoral vessels and she was transported to the ICU in critical condition. On the fourth day of ECMO support, she developed a large hemothorax requiring chest tube decompression, six units of RBCs, and two units of platelets. The heparin infusion was subsequently held and bleeding resolved over several hours. The following day, the patient was requiring minimal inotropic support and the decision was made to go to the operating room and attempt to wean ECMO. Unexpectedly, when ECMO was stopped her blood pressure suddenly dropped to 43/35 and the end tidal CO2 was lost (<10\u2009mm\u2009Hg) despite adequate ventilation. Transesophageal echocardiography was urgently performed demonstrating probable RVOT graft obstruction ) in the catheterization laboratory. After initial balloon inflation, there was visible homograft enlargement, and simultaneous aortic root angiogram was performed demonstrating patent right and left coronary arteries (LCA). The right ventricular outflow tract was then prepared with successful placement of two Palmaz stents. Repeat coronary angiography demonstrated patent LCA prior to Melody valve deployment. The Melody valve was then deployed and the patient developed progressive, severe hypotension, bradycardia, and cardiogenic shock. Transthoracic echocardiogram (TTE) demonstrated akinesis of the lateral and anterior walls of the left ventricle (LV) and severe acute mitral valve regurgitation. She instantly developed severe pulmonary edema with fluid filling the endotracheal tube and anesthesia circuit . A repeatruction  with esttruction . Epicardtruction . The obsThis case illustrates the known potential complication from Melody valve implantation with left coronary artery compression \u20134 despit"}
+{"text": "Candida spp. sepsis. This is the first observational study describing the altered immune response of patients with candidemia. The authors included non-neutropenic critically ill patients with candidemia and non-septic controls, and excluded patients with human immunodeficiency virus infection, who had undergone solid or bone marrow transplantation or with other known causes of impaired immune response. The authors hypothesized that their findings may help explain why patients with fungal sepsis show a high mortality despite appropriate antifungal therapy.We read with great interest the article by Spec et al.  investigIn our opinion, the observed T-cell exhaustion associated with candidemia may also contribute to explain the paradox of the evidence published recently about invasive fungal infection (IFI) prevention . From ouImplications for future research may include potential additional mechanisms of impaired immunological function to fill the gap between bedside data and pre-clinical findings.IFI, invasive fungal infection"}
+{"text": "Improving Handover of Patients in Critical Care following Cardiac Surgery: an audit and successful implementation of an electronic quality improvement toolFollowing cardiac surgery, professional responsibility and accountability for patients is transferred from the operating theatre to critical care. Optimising 'handover' is imperative and we sought to improve safety, quality and effectiveness of this within our unit.A closed loop audit for all post-operative patients (Aug 2014 - Nov 2014) was performed to assess the handover process including personnel, environment and documentation on the electronic patient record (Metavision).Prior to the first cycle, relevant stakeholders were consulted - anaesthetists, cardiac surgeons and nurses. A subsequent survey determined 'gold standard criteria' for handover before undertaking the second cycle.A new electronic tool was created on Metavision to implement a change where specific anaesthetic and surgical representatives could document their plans including parameters and post-operative instructions.Our audit showed objective improvement in presence of team members, especially surgeons; more frequent 'sterile cockpit' environment; significantly better documentation to guide the critical care MDT.We demonstrated improvements in handover by following a system that utilizes the F1 racing model in the critical care setting. Moreover, a novel electronic tab dedicated for patient handover has significantly improved documentation. With ongoing challenges of maintaining continuity of care, we suggest other units adopt our strategy."}
+{"text": "The ability to estimate societal cost-savings given a change in population lifestyles is of interest to health promotion specialists and decision makers. A population-based model named Risk factors, Health and Societal Costs (RHS) was developed to simulate changes in incidence and related societal costs of several chronic diseases after five to ten years, following assumed changes in four common risk factors for disease: obesity (BMI>30), daily tobacco smoking, lack of physical activity and risky consumption of alcohol.The RHS model is based on relative risks (RR) and potential impact fractions (IF) that simulate the changes in disease incidence of reducing the exposure to risk factors . RelativThe scenarios, which assume a certain reduction in population risk factor prevalence, show that considerable health gains and savings in societal costs can arise from modest changes in population lifestyle habits. As an example, a 1% reduction in prevalence in daily smoking under five years among Stockholm county population is estimated to lead to health gain of 64 QALYs and societal savings  of 13 million Swedish krona (1.2 million GBP).The RHS model estimates future cases of illness and related societal costs due to lifestyle risk factors in the population. By creating scenarios with assumed changes in risk factors, the model can estimate potential health gains and societal costs savings, which can be used as relevant arguments in discussions with decision-makers for a more health-promoting health care system."}
+{"text": "Gluten related disorders a range of inflammatory disorders of the small intestine characterized by malabsorption after ingestion of gluten in individuals with a certain genetic background. Clinical presentation can vary from full-blown malabsorption to subtle and atypical symptoms. Diagnosis currently relies on clinicopathologic studies including mucosal biopsy, serologic tests, and the effects of a diet free of gluten on the symptoms. Mucosal pathologic features are also variable, ranging from mild abnormalities, including intraepithelial lymphocytosis, to completely flat mucosa . Since tCeliac diseaseNon Celiac Gluten Sensitivity"}
+{"text": "Movement disorders in idiopathic normal pressure hydrocephalus (iNPH) are represented by gait disturbance . However, upper extremity bradykinesia was frequently found among iNPH patients. We assessed their upper extremity function by quantitative finger tapping test and checked the correlation with other demographic factors.We evaluated the 10-second finger tapping movements of 8 patients  using magnetic-sensor coil system. Clinical symptoms were evaluated by the iNPH grading scale, mini-mental state examination and frontal assessment battery (FAB). The correlation of tapping parameters with clinical indicators was estimated.The patient's age correlated significantly with 6 of 21 finger-tapping parameters, including total tapping distance , coefficient of variation of maximum amplitude , energy balance , average maximum opening acceleration , tapping frequency , and average finger tapping interval . The severity of illness represented by iNPH grading scale correlated with other 2 parameters, including average maximum closing velocity  and coefficient of variation of maximum closing velocity .Our data support the diagnostic value of quantitative finger tapping test for estimating the severity of bradykinesia underlying the iNPH symptomatology. Though preliminary, different patterns of correlations found in this study could potentially indicate the fundamental processes discriminating aging and disease progression."}
+{"text": "Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly that usually manifests as severe left-sided heart failure and mitral valve insufficiency during the first one to two months of life. The majority of these cases die in infancy if not corrected early upon presentation. Adulthood presentation is rare and most of the untreated patients who reach adulthood present with left ventricular dysfunction, severe mitral regurgitation, and sometimes myocardial infarction. Here we report a case of a 20-year-old woman with a history of exercise intolerance since childhood that was misinterpreted as asthma until a 2D-Echo revealed ALCAPA with RCA collaterals to the left anterior descending artery, preserved LV ejection fraction, and absence of apparent mitral valve abnormality. One month after the ALCAPA diagnosis, she successfully underwent surgical reconstruction of left main and pulmonary artery without any major complications. She had normal left ventricular function without apparent ischemic cardiac symptoms eighteen months after procedure. Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly occurring in 1 of 300,000 live births  and accoThe ALCAPA anomaly may result from abnormal septation of the conotruncus into the aorta and pulmonary artery, or from persistence of the pulmonary buds together with involution of the aortic buds that eventually form the coronary arteries. ALCAPA is usually an isolated cardiac anomaly that does not present prenatally because of the favorable fetal physiology that includes equivalent pressures in the main pulmonary artery and aorta secondary to a nonrestrictive patent ductus arteriosus, and the relatively equivalent oxygen concentrations due to parallel circulations. This results in normal myocardial perfusion and, therefore, no stimulus for collateral vessel formation between the right and left coronary artery systems is present. Shortly after birth, as the circulation becomes one in series, pulmonary artery pressure and resistance decrease, as does oxygen content of pulmonary blood flow. This causes a drop in antegrade flow and oxygen content of the anomalous left coronary artery, leading to myocardial ischemia. Furthermore, collateral circulation between the right and left coronary systems ensues and the left coronary artery flow reverses and enters the pulmonary trunk due to the low pulmonary arterial pressure, causing coronary steal phenomena. Consequently, fixed ischemia or myocardial infarction occurs. Eighty-five percent of all cases of ALCAPA present within the first two months of life. The typical clinical course involves severe left-sided heart failure and significant mitral valve insufficiency secondary to papillary muscle ischemia, permanent fibrosis, or left ventricular dilatation. The late presentation is extremely rare and usually with significant cardiac function compromise.A 20-year-old woman presents with chronic dyspnea on exertion and exercise intolerance that was attributed to and treated as presumed exercise-induced asthma since childhood. She experienced worsening left-sided chest heaviness and was subsequently referred to our institute. She has no coronary risk factors and no family history of premature coronary artery disease or congenital heart condition. Physical examination was normal except a subtle continuous murmur at apex and lower right sternal border. ECG showed sinus rhythm without ST or T wave changes . Chest X-ray showed no cardiomegaly . Serial cardiac enzymes were negative. In the light of cardiac murmur, an echocardiogram was obtained and revealed anomalous coronary arteries with a large left coronary artery to main pulmonary artery fistula. There was mild left ventricular enlargement with preserved left ventricular contractile function and an ejection fraction of 65%. The appearance of the left ventricle and left atrium was consistent with a systemic to pulmonary vascular shunt with increased stroke volumes in the left heart. There were no structural abnormalities of the aortic, mitral, tricuspid, or pulmonic valves, and there was very mild mitral regurgitation by Doppler. A subsequent cardiac catheterization confirmed the diagnosis of ALCAPA with retrograde filling through collaterals arising from an enlarged right coronary artery (12\u2009mm) (As a rare congenital heart condition, ALCAPA even more rarely has a late presentation in adulthood as few of these patients survive past childhood without surgical repair . Among tIn infants, most of the patients with surgically corrected ALCAPA show normalization of both ventricular function and mitral valve insufficiency , 12. EstIn conclusion, even as a rare scenario of a rare disorder, diagnosis of adulthood ALCAPA should be considered not only in adult patients presenting with clear evidence of ischemic heart disease, left ventricular dysfunction, or arrhythmias, but also more importantly in patients with minor symptoms of exercise intolerance or dyspnea that could be easily misinterpreted or missed without high clinical suspicion and detailed physical and diagnostic evaluation, as early diagnosis and timely surgical treatment usually results in an excellent prognosis.Supplemental Figure 1: 12-lead ECG showed normal sinus rhythm with no specific ST and T changes.Supplemental Figure 2: Chest x-ray showed no cardiopulmonary pathology.Click here for additional data file."}
+{"text": "Although intravascular injection of contrast media is very important in diagnostic radiology but may lead to acute renal failure and hospitalization. It seems that, pathogenesis of contrast media nephrotoxicity acts through renal vasoconstriction, medullary ischemia, tubular cell death and production of reactive oxygen species. Pretreatment with antioxidants attenuated renal side effects of contrast media in patients and laboratory animals.et al. used green tea (Camellia sinensis) extract in combat with contrast media nephrotoxicity in rats for the first time  have been completely observed by the author.None declared."}
+{"text": "Spontaneous intracerebral hemorrhage (ICH) is a particularly severe type of stroke for which no specific treatment has been established yet. Although preclinical models of ICH have substantial methodological limitations, important insight into the pathophysiology has been gained. Mounting evidence suggests an important contribution of inflammatory mechanisms to brain damage and potential repair. Neuroinflammation evoked by intracerebral blood involves the activation of resident microglia, the infiltration of systemic immune cells and the production of cytokines, chemokines, extracellular proteases and reactive oxygen species (ROS). Previous studies focused on innate immunity including microglia, monocytes and granulocytes. More recently, the role of adaptive immune cells has received increasing attention. Little is currently known about the interactions among different immune cell populations in the setting of ICH. Nevertheless, immunomodulatory strategies are already being explored in ICH. To improve the chances of translation from preclinical models to patients, a better characterization of the neuroinflammation in patients is desirable. Intracerebral hemorrhages (ICH) account for 10\u201315% of all strokes  into neurotoxic components such as heme and iron which are major contributors to secondary brain injury  to various stimuli. Neuroinflammation after ICH involves the early activation of resident microglia, release of proinflammatory mediators and the influx of peripheral leukocytes and has major role in the pathophysiology of secondary brain damage  and mitogen-activated protein kinase signaling pathways  serum reduced BBB breakdown, axonal injury and neurological deficit  days. As cellular parts of the adaptive immune system, B cells participate in humoral immune responses, while T cells are involved in cellular immunity. T cells express either the CD4 or the CD8 cell surface marker determining their function: modulating immune responses or eliciting cytotoxicity.Increasing evidence suggests an important role of adaptive immunity and particularly T lymphocytes in secondary brain damage after ischemia  where it decreased peri-hematomal edema and reduced neurological impairment compared with control individuals  is one of the main effector molecule of T lymphocytes  is upregulated  and 64Cu-labeled nanoparticles conjugated with anti-ICAM-1 antibody  for PET imaging have been developed (Wunder et al., In vivo labelling is performed using MRI agents including iron-oxide nanoparticles (Stuber et al., To investigate the mechanisms underlying the trafficking of systemic immune cells into the brain, contrast media targeting endothelial selectin, ICAM and VCAM have been developed. These include in vivo neuroimaging has been barely used to investigate the ICH-induced inflammatory processes. In collagenase-induced ICH, enhanced MRI with microparticles of iron oxide targeted to VCAM-1 revealed the maximal VCAM-1 expression 24 h after ICH which returned to baseline 5 days following hemorrhage induction (Gauberti et al., The above detailed labeling methods are increasingly used in clinical and experimental studies to characterize inflammatory processes in neurologic disorders including cerebral ischemia, multiple sclerosis, Alzheimer\u2019s and Parkinson\u2019s disease (Jacobs and Tavitian, Inflammatory processes are increasingly recognized as important players in the pathophysiology of secondary brain damage after ICH. There is now solid information on the infiltration pattern of leukocytes in experimental ICH. The pathophysiological role of specific leukocyte populations is beginning to be better understood but little is known about the interactions among these immune cells. Because of the delayed nature of brain damage after ICH, adaptive immune cells may play an important role in the subacute and the regenerative phases after ICH. Translation of preclinical findings into the clinical setting is challenging because of limitations of current animal models of ICH. Moreover, the local and systemic neuroinflammatory response in ICH patients remains to be better characterized.All authors were involved in writing the review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Suppression of lipid signal is a basic requirement in coronary magnetic resonance angiography (CMRA) because coronary arteries are embedded in epicardial fat and signal from fat can decrease coronary vessel conspicuity. Most CMRA scans are currently performed with fat suppression techniques such as Spectral Presaturation with Inversion Recovery (SPIR). However, methods based on spectrally-selective fat saturation are sensitive to B0 and B1 field inhomogeneities. Recent improvements in chemical shift based water fat separation methods such as Dixonprovides This work was performed on a 3T scanner  equipped with a 32-element cardiac receiver coil. Data were acquired in eight healthy volunteers  and eight patients with suspected coronary artery disease . Two different scans were performed in each of them: 1) Conventional whole heart CMRA with SPIR fat suppression and 2) two-point Dixon CMRA. Two experts readers, blinded to the methods used, scored the image quality for each dataset. In addition, signal-to-noise ratio of blood, fat and myocardium, contrast-to-noise ratio (CNR) between blood, fat and myocardium, and right coronary artery sharpness and length were measured to compare these two techniques quantitatively. A Wilcoxon Signed-Rank was used for statistical analysis for comparison between images acquired with Dixon and SPIR.All scans were successfully performed and produced good quality images in all volunteers. Figure These findings demonstrate that Dixon water-fat separation leads to higher SNR of coronary blood and myocardium and improved image quality scores for coronary artery visualization at high field strengths. Furthermore, the additional fat data that is available with Dixon protocols may be an important biomarker and improve the diagnostic value of CMRA.Wellcome Trust and ESPRC Medical Engineering Centre."}
+{"text": "Eutrophication increases the phytoplankton biomass that can be supported during a bloom, and the resultant uptake of dissolved inorganic carbon during photosynthesis increases water-column pH (bloom-induced basification). This increased pH can adversely affect plankton growth. With OA, basification commences at a lower pH. Using experimental analyses of the growth of three contrasting phytoplankton under different pH scenarios, coupled with mathematical models describing growth and death as functions of pH and nutrient status, we show how different conditions of pH modify the scope for competitive interactions between phytoplankton species. We then use the models previously configured against experimental data to explore how the commencement of bloom-induced basification at lower pH with OA, and operating against a background of changing patterns in nutrient loads, may modify phytoplankton growth and competition. We conclude that OA and changed nutrient supply into shelf seas with eutrophication or de-eutrophication (the latter owing to pollution control) has clear scope to alter phytoplankton succession, thus affecting future trophic dynamics and impacting both biogeochemical cycling and fisheries.Human activity causes ocean acidification (OA) though the dissolution of anthropogenically generated CO Taken together with other climate change events, notably changes in temperature and water-column stability, OA has the potential for various impacts upon marine plankton communities and production  ,34. Studher [H+] , it is u sources ,37, to b"}
+{"text": "Intracranial infection of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of susceptible strains of mice results in an acute encephalomyelitis, accompanied by viral replication in glial cells and robust infiltration of virus-specific T cells that contribute to host defense through cytokine secretion and cytolytic activity. Mice surviving the acute stage of disease develop an immune-mediated demyelinating disease, characterized by viral persistence in white matter tracts and a chronic neuroinflammatory response dominated by T cells and macrophages. Chemokines and their corresponding chemokine receptors are dynamically expressed throughout viral infection of the CNS, influencing neuroinflammation by regulating immune cell infltration and glial biology. This review is focused upon the pleiotropic chemokine receptor CXCR2 and its effects upon neutrophils and oligodendrocytes during JHMV infection and a number of other models of CNS inflammation. Intracranial infection of susceptible mice with the JHM strain of mouse hepatitis virus (JHMV) causes an acute encephalomyelitis followed by a chronic demyelinating disease. JHMV, after initially infecting ependymal cells lining the ventricles, rapidly disseminates to astrocytes, oligodendroglia, and microglia throughout the brain and spinal cord  chemokine family CXCL1 and CXCL2. CXCL1 and CXCL2 are potent chemoattractants for peripheral mononuclear cells (PMNs), binding and signaling through their receptor CXCR2 . Neutralization of CXCR2 almost completely abrogated neutrophil infiltration into the CNS Figures . Without+ T cells are all capable of direct permeabilization  induction, and their presence precedes axonal damage, demyelination, and clinical disease  chemokine signaling on oligodendroglia during JHMV-induced neuroinflammation. It will be important to analyze the effects of selectively ablating CXCR2 on oligodendroglia during JHMV-induced demyelination, while simultaneously manipulating the cellular sources of ELR-positive chemokines in the CNS that may promote neuroprotection during chronic JHMV-induced disease.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To meet these challenging demands, we and others developed physiologically relevant mouse models and characterized their hearts with planar AP mapping. Here, we summarize the progress toward panoramic fluorescence imaging and its prospects for the mouse heart. In general, several high-resolution cameras are synchronized and geometrically arranged for panoramic voltage mapping and the surface and blood vessel anatomy documented through image segmentation and heart surface reconstruction. We expect that panoramic voltage imaging will lead to novel insights about molecular arrhythmia mechanisms through quantitative strategies and organ-representative analysis of intact mouse hearts.To investigate the dynamics and propensity for arrhythmias in intact transgenic hearts comprehensively, optical strategies for panoramic fluorescence imaging of action potential (AP) propagation are essential. In particular, mechanism-oriented molecular studies usually depend on transgenic mouse hearts of only a few millimeters in size. Furthermore, the temporal scales of the mouse heart remain a challenge for panoramic fluorescence imaging with heart rates ranging from 200 min In addition, AP duration (APD) and the stability of cardiac repolarization are regulated by distinct K+ channel types, e.g., during ischemia activation of ATP-sensitive K+ channels (KATP) leads to APD shortening thereby preventing potentially detrimental intracellular Ca2+ overload. While each principle contributes to impulse generation, propagation and/or modulation in heart tissue, the molecular mechanisms of AP modulation and disease changes are exceedingly complex and depend on thorough analysis in intact heart tissue based on non-invasive imaging methods.Molecular physiology and genetic engineering studies have established complex genetic and cellular determinants of impulse propagation in mouse models. Four distinct molecular principles were identified: connexin channels at gap junctions control solute flux between myocytes and electrical current flow throughout the myocardial syncytium Figure ; cardiac2+ dye) have become a central strategy to study impulse propagation in transgenic mouse hearts in which EC coupling cycles occur an order of magnitude faster than human heart. High VSDI based resolution has allowed the functional characterization of anisotropic impulse propagation in mouse hearts. This has revealed the physiological relevance of select Nav1.5 channel membrane targeting mechanisms and led to the concept of distinct, locally confined pools of Nav1.5 channels at the intercalated disc (ICD) vs. the lateral cell membrane  or multiparametric imaging  and a planar resolution of 50\u2013100 \u03bcm are achieved. Each sensor pixel records the fluorescent signal average of multiple cells. The tissue-specific propagation of epicardial AP wave fronts can be analyzed during sinus rhythm Figure  or durinFurthermore, both physiological and pathological changes of cardiac repolarization can be analyzed. Abnormal AP formation  as mechanism of triggered arrhythmias, abnormal AP propagation , and reentry contribute to arrhythmia initiation and/or propagation. Optical signals recorded by individual pixels can be analyzed to determine local APD, e.g., repolarization at 80% of the signal amplitude Figure . Similar2+ transients) cannot be analyzed continuously throughout the whole surface of the mouse heart, especially the spatially complex 3D impulse spread during fast arrhythmias. In addition, the high curvature-to-volume ratio of mouse hearts distorts fluorescent signals originating from shallow angles of peripheral boundaries, limiting the effective ROI of single camera approaches , while ex vivo imaging additionally facilitates detailed analysis about the time and location of residual chaotic activity in the heart. Finally, detailed experimental knowledge about the electrical activity on the cardiac surface together with internal tissue structures can be combined through 3D computational methods to reconstruct the hidden spatiotemporal dynamics of arrhythmias and therapeutic interventions inside the heart tissue in a non-invasive manner.External and internal cardioverter defibrillators (ICDs) are routinely used in clinical medicine, but electrical shocks can cause significant side effects including tissue damage and traumatic pain. Recently, a new strategy for arrhythmia control using low-energy antifibrillation pacing (LEAP) was developed. LEAP uses a series of five low-energy pulses to terminate atrial fibrillation 2+ transients. Recent data from transgenic mouse hearts identified novel molecular determinants of ion channel expression and targeting in cardiac myocytes with marked effects on the conduction properties of the ventricles. This led to the realization that complex molecular mechanisms underlie the anisotropic activation pattern of the intact hearts, namely ion channel complexes at gap junctions, lateral membranes, and T-tubules, and all with specific effects on conduction properties. In general, acquired or genetic changes result in decreased spatiotemporal AP propagation and conduction delay, which may contribute to arrhythmogenesis. Panoramic imaging of mouse and larger hearts will contribute to better understanding of arrhythmia propensity and onset, as well as support clinical translation of important new therapeutic concepts, in particular 3D-MIMS and LEAP.In summary, panoramic imaging of rabbit and larger mammalian hearts has been successfully developed whereas panoramic imaging of smaller, particularly transgenic mouse hearts will most likely be realized in the near future based on the success of VSDI and multiparametric readouts such as combined CaThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Middle East respiratory syndrome (MERS) cases continue to be reported from the Middle East. Evaluation and testing of patients under investigation (PUIs) for MERS are recommended. In 2013\u20132014, two imported cases were detected among 490 US PUIs. Continued awareness is needed for early case detection and implementation of infection control measures. Middle East respiratory syndrome coronavirus (MERS-CoV) infection was first reported in September 2012 in a patient with fatal pneumonia in Saudi Arabia (http://www.cdc.gov/coronavirus/mers/index.html). The PUI guidance was created to assist health care providers determine which patients should be considered for MERS-CoV evaluation and testing. To inform state and local health departments of the basic demographic and clinical characteristics of PUIs and on assay use, we summarized the descriptive analysis of PUIs in the United States.Using World Health Organization guidelines and definitions  assays for detection of MERS-CoV , other pathogen testing was not performed or detected pathogens were not reported . Timely >2 weeks before specimen collection, testing using the CDC MERS-CoV serologic assay on a single serum specimen is recommended. CDC also recommends testing for common respiratory pathogens , but identification of a respiratory pathogen should not preclude MERS-CoV testing (Currently in the United States, the preferred method for detecting MERS in PUIs with recent symptom onset is to test lower respiratory, naso-oropharyngeal, and serum specimens by using the CDC rRT-PCR assay. For PUIs in whom symptom onset occurred The 2 US cases of imported MERS were detected in health care providers from Saudi Arabia. These cases prompted a CDC guidance update recommending evaluation and testing of persons with less severe respiratory illness who had strong epidemiologic risk factors, particularly heath care exposure, for MERS-CoV infection. Occupation, recent travel history, recent visit to a health care facility, and contact will ill persons should be determined when evaluating persons with respiratory illness. As testing increases, especially serologic testing, additional MERS cases, including mildly symptomatic cases and cases among younger persons are being identified. These cases highlight the range of severity of MERS-CoV infection and the need to consider testing persons with a compatible travel history who may not match the clinical profile of the initially described case-patients. CDC plans to revise MERS-CoV guidance as needed."}
+{"text": "Headache is one of the most common causes of access to Emergency Departments (ED). Primary headaches and headaches secondary to benign conditions (e.g headache attributed to acute sinusitis) represent the majority of cases, while secondary life-threatening headaches are less frequent. The primary objective in the ED setting is to decide whether the headache is primary or secondary and recognize serious life-threatening conditions presenting with headache and requiring prompt medical diagnosis and care, such as subarachnoid hemorrhage (SAH), intracerebral hemorrhage, cerebral venous sinus thrombosis (CVST), cervical artery dissection (CAD), brain tumors, pituitary apoplexy, spontaneous intracranial hypotension, or intracranial infections. Careful history taking and physical examination remain the most important part of the assessment of the headache patient. A thoro"}
+{"text": "Dictyostelium discoideum is triggered by starvation. When placed on a solid substrate, the starving solitary amoebae cease growth, communicate via extracellular cAMP, aggregate by tens of thousands and develop into multicellular organisms. Early phases of the developmental program are often studied in cells starved in suspension while cAMP is provided exogenously. Previous studies revealed massive shifts in the transcriptome under both developmental conditions and a close relationship between gene expression and morphogenesis, but were limited by the sampling frequency and the resolution of the methods.Development of the soil amoeba Here, we combine the superior depth and specificity of RNA-seq-based analysis of mRNA abundance with high frequency sampling during filter development and cAMP pulsing in suspension. We found that the developmental transcriptome exhibits mostly gradual changes interspersed by a few instances of large shifts. For each time point we treated the entire transcriptome as single phenotype, and were able to characterize development as groups of similar time points separated by gaps. The grouped time points represented gradual changes in mRNA abundance, or molecular phenotype, and the gaps represented times during which many genes are differentially expressed rapidly, and thus the phenotype changes dramatically. Comparing developmental experiments revealed that gene expression in filter developed cells lagged behind those treated with exogenous cAMP in suspension. The high sampling frequency revealed many genes whose regulation is reproducibly more complex than indicated by previous studies. Gene Ontology enrichment analysis suggested that the transition to multicellularity coincided with rapid accumulation of transcripts associated with DNA processes and mitosis. Later development included the up-regulation of organic signaling molecules and co-factor biosynthesis. Our analysis also demonstrated a high level of synchrony among the developing structures throughout development.D. discoideum development as a series of coordinated cellular and multicellular activities. Coordination occurred within fields of aggregating cells and among multicellular bodies, such as mounds or migratory slugs that experience both cell-cell contact and various soluble signaling regimes. These time courses, sampled at the highest temporal resolution to date in this system, provide a comprehensive resource for studies of developmental gene expression.Our data describe The online version of this article (doi:10.1186/s12864-015-1491-7) contains supplementary material, which is available to authorized users. D. discoideum exhibits a developmental program unique among model organisms , and the complete time series data sets are accessioned at the NCBI Gene Expression Omnibus .Further analyses of these data may focus on identifying additional co-regulated transcriptional regulators and target genes. The enhanced temporal resolution of these data provides more informative transcription profiles than previous studies. Perhaps clustering of genes by expression pattern will yield improved hypotheses regarding shared regulation and function. As future studies examine the phenotypic consequences of transcription factor knockout mutations, as well as the binding specificity of important transcriptional regulators, these data will serve as a critical reference point for inferring regulatory interactions. To facilitate exploration by the larger community, user-friendly analysis tools for these data are available at dictyExpress . These data may also be viewed and analyzed using the dictyExpress toolkit [www.dictyExpress.org].The additional material includes the Additional file"}
+{"text": "Visual category perception is thought to depend on brain areas that respond specifically when certain categories are viewed. These category-sensitive areas are often assumed to be \u201cmodules\u201d (with some degree of processing autonomy) and to act predominantly on feedforward visual input. This modular view can be complemented by a view that treats brain areas as elements within more complex networks and as influenced by network properties. This network-oriented viewpoint is emerging from studies using either diffusion tensor imaging to map structural connections or effective connectivity analyses to measure how their functional responses influence each other. This literature motivates several hypotheses that predict category-sensitive activity based on network properties. Large, long-range fiber bundles such as inferior fronto-occipital, arcuate and inferior longitudinal fasciculi are associated with behavioral recognition and could play crucial roles in conveying backward influences on visual cortex from anterior temporal and frontal areas. Such backward influences could support top-down functions such as visual search and emotion-based visual modulation. Within visual cortex itself, areas sensitive to different categories appear well-connected  and their responses can be predicted by backward modulation. Evidence supporting these propositions remains incomplete and underscores the need for better integration of DTI and functional imaging. A current challenge for visual neuroscience is to explain how perception of complex and meaningful objects is achieved. High-level vision is associated with anatomically-focal, functionally-defined brain areas in human occipitotemporal cortex, usually localized using functional magnetic resonance imaging (fMRI). These \u201ccategory-sensitive\u201d areas are typically inferred to be specialized for processing their preferred visual categories   or estimate their effective connectivity using functional brain imaging methods including fMRI, electroencephalography (EEG) or magnetoencephalography (MEG). However, few studies to date have combined DTI and effective connectivity techniques. DTI maps structural connections composed of axonal fiber tracts. In contrast, effective connectivity measures how functional responses influence (or \u201ccause\u201d) each other. However, they share the similar goal of inferring functional integration, with DTI showing which areas are connected and effective connectivity showing the experimental conditions under which these structural connections might enact their influence. Studies using these methods have not provided a comprehensive picture of human structural connections or the effective interactions supported by these structures. Nevertheless, the findings reviewed here suggest specific structural and effective network properties that are relevant to visual analysis of complex stimuli. These network properties include influences of major, long-range fiber bundles, backward connections from higher to lower-level areas and interactions between areas with dissimilar category preferences. These network properties can potentially explain diverse phenomena, including top-down, attentional and emotional modulation of visual cortex, oscillatory power changes and repetition-related response modulations. This review covers these findings, discusses the deficiencies of existing theories and describes how a functional integration approach is well-suited to advance understanding of visual processing in human occipitotemporal cortex. in vivo in humans.Responses in category-sensitive brain areas are likely to be influenced by the different types of connections associated with hierarchical networks. Hierarchical structures , which would then guide visual object processing via backward connections Bar, . SimilarVisual cortex appears to contain a hierarchical apparatus and therefore response specificity in visual cortex likely depends on distinguishable forward and backward influences. Moreover, mainstream computational models make important assumptions about the influences of forward and backward influences. While many models rely solely on forward influences, models such as predictive coding posit specific roles for backward connections. While the DTI and effective connectivity studies performed to date and reviewed herein do not yet support any particular computational theory in detail, they provide evidence for a role of backward influences during perception of high-level visual stimuli.Multiple areas that are sensitive to the same category have been described as hierarchies. At the most general level in visual cortex, all areas may be associated with the dorsal or ventral hierarchical streams . Effective and structural connectivity measures are complementary, even though their relationship is not fully understood , mostly oriented along a posterior-anterior axis. These bundles have been observed using human post-mortem dissection and can be imaged using DTI , arcuate/superior longitudinal (AF/SLF) and inferior occipitofrontal (IFOF) fasciculi. ILF projects down the length of the temporal lobe, with fibers terminating posteriorly in inferior occipital cortex (near OFA) and fusiform gyrus (near FFA) and anteriorly in the temporal pole, amygdala and hippocampus  and superior longitudinal (SLF) fasciculi share overlapping anatomical courses and are often considered together . The OFC/VMFC could influence visual areas directly, via IFOF, or indirectly, via the uncinate fasciculus, which connects OFC/VMFC to the anterior temporal lobe and the amygdala  in different fiber bundles. To date, the details of these dissociations are still not clear, as they are different in each study, with mixed evidence for a selective role of the ILF for face recognition. Although no major fiber bundle is likely to contribute to recognition of any single category (such as face or scene perception), the function of a given fiber bundle might contribute more to recognition of some categories than others. Thus, linking behavioral recognition performance to fiber bundle properties is a promising research method. Research linking fiber bundles with behavior has also been well-served by combining DTI with fMRI functional localization . These studies therefore only considered reciprocal models  OFC/VMFC via IFOF; (2) OFC/VMFC via the uncinate fasciculus and ILF; and (3) inferior frontal cortex via AF/SLF. Frontal influences on visual cortex have been tested in a number of effective connectivity studies, and these studies suggest that frontal areas can sensitize occipitotemporal visual areas to detect expected stimuli, particularly during visual search.The more prevalent evidence for this top-down modulation involves OFC or VMPFC  faces, chairs or houses during fMRI scanning, significant category-specific bilinear parameters were observed on connections from prefrontal cortex to face-, chair- and house-sensitive ventral temporal areas  Effective connectivity analyses should be combined with DTI to investigate the functional specialization of the major fiber bundles . (2) These fiber bundles may support fast feedforward shortcut pathways that trigger early influences of backward connections  may be useful for understanding computations outside the visual system. Oscillations are another widespread phenomenon which can be investigated using connectivity-based methods and have been proposed to be a fundamental mechanism for brain communication . Effective connectivity analysis cannot determine whether a connection between two areas is direct or indirect. Methods such as DTI, effective connectivity and conventional functional imaging methods based on the general linear model can overcome their weaknesses when used in conjunction.Effective connectivity analysis applied to fMRI data can also be problematic, due to the uninformative temporal resolution of the blood-deoxygenation response signal. This problem is acute for methods such as Granger Causality and structural equation modeling, which depend on exact timing of fMRI response signals to draw inferences about connectivity between underlying neuronal sources  computationally tractable; (2) includes all plausible models; and (3) can be adequately compared to model spaces used in similar studies. The present review presents the outcomes of model comparisons, even though the model spaces used by each study vary widely, often omit plausible models that are of theoretical interest or estimate the parameters of only one model. Newer methods such as post hoc model comparison (Rosa et al., A particularly vexing challenge in applyingThis article reviews recent work examining structural and effective connectivity associated with category-sensitive areas in high-level visual cortex in the human. These studies add to our knowledge of the functions of forward and backward interactions between visual areas and top-down influences from frontal areas and the amygdala. More work is needed to develop theory that moves beyond a focus on the modular nature of individual areas with only feedforward interactions. Structural and effective connectivity studies have not yet given us a complete picture of network interactions and, like any method, possess both strengths and limitations. Nevertheless, they allow direct testing of connectivity in ways that complement more conventional uses of brain imaging and therefore hold promise for answering numerous future research questions.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Advances in target-based drug discovery strategies have enabled drug discovery groups in academia and industry to become very effective at generating molecules that are potent and selective against single targets. However, it has become apparent from disappointing results in recent clinical trials that a major challenge to the development of successful targeted therapies for treating complex multifactorial diseases is overcoming heterogeneity in target mechanism among patients and inherent or acquired drug resistance. Consequently, reductionist target directed drug-discovery approaches are not appropriately tailored toward identifying and optimizing multi-targeted therapeutics or rational drug combinations for complex disease. In this article, we describe the application of emerging high-content phenotypic profiling and analysis tools to support robust evaluation of drug combination performance following dose-ratio matrix screening. We further describe how the incorporation of high-throughput reverse phase protein microarrays with phenotypic screening can provide rational drug combination hypotheses but also confirm the mechanism-of-action of novel drug combinations, to facilitate future preclinical and clinical development strategies. The evolution of many complex human diseases has generated multiple biological redundancies in the genetics, pathway signaling networks and pathophysiology of disease thus counteracting the efficacy of new therapeutics. In such complex diseases exemplified by cancer, neurodegeneration, cardiovascular, bacterial, and viral infections, combination therapies represent the standard of care  strategies provides a new opportunity to discover and prioritize drug combination and polypharmacology strategies objectively while appropriately tailoring their use to complex disease during early stage drug discovery  platform  and Compound Synergy Extension (Genedata Screener\u00ae). Such tools enable rapid drug combination screening across phenotypic assays at scale to enable a more transparent review of drug combination data placed into context of multiple drug combination sets to aid benchmarking and prioritization. Incorporation of genomically annotated patient derived cell panels into high capacity drug combination screening activity further supports pharmacogenomics and personalized healthcare approaches to drug combination strategies. High-content single cell analysis of specific phenotypic events over both dose and time enable a significantly more robust evaluation of the quality of drug combination data. Such considerations support the interpretation of whether synergistic and additive drug combination data occur at physiologically relevant doses.A limitation of screening large compound libraries in complex cell based assays compared with more traditional biochemical drug screening is throughput and cost. Both throughput and cost are particularly limiting when considering the evaluation of multiple drug combinations across a factorial dose-ratio matrix where the number of individual combination dose ratios increases quadratically with the number of agents under study. For practical reasons, medium to high-throughput phenotypic screening across cancer cell lines have traditionally employed simple single endpoint analysis of tumor cell viability or cell proliferation in 2D mono-culture  circumvents many of the challenges associated with co-dosing distinct components in vivo. Thus, application of more systematic approaches to evaluate the kinetics and sensitivity of drug combinations across broad dose ranges and multiple phenotypic parameters promise to enhance the quality and robustness of preclinical drug combination data and support more informed prioritization of the most appropriate combination strategies to move forward into in vivo and clinical settings.A significant challenge to translating effective drug combinations identified from in vitro or in vivo models ; the Human Antibody Initiative ; and the Human Protein Atlas Project (www.proteinatlas.org/) to derive high quality mono-specific antibodies are poised to further advance antibody-based proteomics into broader areas of human pathway biology. Correlation of basal RPPA post-translational dataset with compound EC50 values from phenotypic assays performed across cell panels has identified protein level markers of drug sensitivity and resistance  models is correlation of phenotypic response with genomic biomarkers. Such pharmacogenomic studies support biomarker discovery and patient stratification hypothesis. However, as described in this review article, adaptive resistance mechanisms that guide combination response are often operating only at the post-translational level. Thus, RPPA analysis applied to related monotherapy and drug combination arms can be correlated with additive, synergistic, or antagonist phenotypic response across a dose matrix study to identify pharmacodynamic biomarkers that confirm the mechanism-of-action of the drug combination effect and provide biomarkers to guide future clinical development.In 2010, the US FDA issued an updated draft guidance to support the further development of novel drug-combination therapies. Previous guidance recommended demonstrative evidence of a positive efficacy and safety response across all monotherapy and combination arms. The updated guidance now supports the proposal of clinical trial designs where single or multiple monotherapy arms can be left out on the grounds that no efficacy benefit would be expected. This new update now provides an opportunity to exploit synthetic lethality and multi-drug cocktails. Phenotypic screening campaigns are particularly suited to discovery of synthetic lethality by performing screens on matched pairs of cell models, representing suspected natural or engineered genetic vulnerabilities or distinct sensitivities to known agents. The latest advances in phenotypic screening technologies combined with high-throughput pathway profiling are now well placed to provide high quality preclinical data that provide for a more robust, transparent and objective prioritization of drug combinations.Both authors contributed to the conception of this review article, drafted the paper, and approved the version for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "PRKCSH and SEC63) or ADPKD (PKD1 and PKD2) confirm the clinical diagnosis. Genetic studies showed that accumulation of somatic hits in cyst epithelium determine the rate-limiting step for cyst formation. Management of adult PLD is based on liver phenotype, severity of clinical features and quality of life. Conservative treatment is recommended for the majority of PLD patients. The primary aim is to halt cyst growth to allow abdominal decompression and ameliorate symptoms. Invasive procedures are required in a selective patient group with advanced PCLD, ADPKD or liver failure. Pharmacological therapy by somatostatin analogues lead to beneficial outcome of PLD in terms of symptom relief and liver volume reduction.Polycystic liver disease (PLD) is the result of embryonic ductal plate malformation of the intrahepatic biliary tree. The phenotype consists of numerous cysts spread throughout the liver parenchyma. Cystic bile duct malformations originating from the peripheral biliary tree are called Von Meyenburg complexes (VMC). In these patients embryonic remnants develop into small hepatic cysts and usually remain silent during life. Symptomatic PLD occurs mainly in the context of isolated polycystic liver disease (PCLD) and autosomal dominant polycystic kidney disease (ADPKD). In advanced stages, PCLD and ADPKD patients have massively enlarged livers which cause a spectrum of clinical features and complications. Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ. Renal failure due to polycystic kidneys and non-renal extra-hepatic features are common in ADPKD in contrast to VMC and PCLD. In general, liver function remains prolonged preserved in PLD. Ultrasonography is the first instrument to assess liver phenotype. Indeed, PCLD and ADPKD diagnostic criteria rely on detection of hepatorenal cystogenesis, and secondly a positive family history compatible with an autosomal dominant inheritance pattern. Ambiguous imaging or screening may be assisted by genetic counseling and molecular diagnostics. Screening mutations of the genes causing PCLD ( Polycystic liver disease (PLD) is a collection of rare human disorders that result from structural changes in the biliary tree development ,2. GenetThree PLD entities are recognized in adults. Von Meyenburg complexes  with characteristic small, non-hereditary nodular cystic lesions [ORPHA386] ,5. IsolaThis paper reviews the pathological and clinical features of these 3 adult cystic disorders that share presence of numerous hepatic cysts with an intact biliary tree architecture.PLD is a rare inherited Mendelian disorder that is characterized by development of multiple hepatic cysts. The classification of PLD follows the histological changes that are due to ductal plate malformation (DPM) during fetal development ,7. Definth week of gestation by formation of single layered hepatoblasts surrounding the portal vein . Duplication of ductal plate cells forms a double layer that finally dilate to a tubular structure, the primitive bile duct. Hepatoblast differentiation to a biliary phenotype and tubulogenesis is stimulated by the Notch, TGF-\u03b2 and canonical Wnt signaling pathways  and SEC63 [OMIM*608648] may confirm the clinical diagnosis and differentiate it from other PLD  and Caroli syndrome (CS). PLD is characterized by intrahepatic disease, a more late onset of disease in adulthood and absence of congenital hepatic fibrosis (CHF).Young and adult ADPKD patients are difficult to distinguish with other hepatorenal fibrocystic diseases such as ARPKD and other ciliopathies . ARPKD hCD is characterized by saccular, cystic dilations of the more larger intrahepatic biliary system. In CS large and small intrahepatic bile duct ecstasies are accompanied with CHF. CS has been typically associated with renal disease as in ARPKD . The incBoth PCLD and ADPKD have an autosomal dominant inheritance pattern and the recurrence risk is 50%. Genetic studies indicate an evident inter-familial clinical heterogeneity in PLD disease course among similar-aged patients. Secondly, intra-familial studies suggested a considerable phenotypic variability of hepatic cysts Figure\u00a0. ClinicaThese considerations raise the question whether it is appropriate to screen members or children at-risk. Counseling should include discussion about insurance, employment and psychological factors. Genetic counseling is recommended in severely affected PLD and may afford differentiation between ADPKD and PCLD ,12.Molecular diagnostics may assist the counseling process to establish a firm diagnosis in symptomatic patients and families. In particular ADPKD, determination of the responsible gene is useful for those who are at-risk in order to develop a strategy to prevent severe progressive disease events or complications . If the VMC is an asymptomatic condition without long-term consequences and treatment is not warranted. The primary aim of PLD therapy is to reduce symptoms by curtailing hepatic cyst development. The treatment of choice is driven by individual complaints . AlthougThe first advice in PCLD and ADPKD is to stop oral anticonceptives ,78. AlthThe different invasive approaches with possible beneficial outcomes in independent studies include aspiration sclerotherapy, laparoscopic cyst deroofing or liver transplantation ,40,84. CTreatment of portal hypertension and ascites are not different from that in patients with other causes. In a selected patient group were invasive procedures such as a vascular or bile duct stent placement optional for decompression of the portal vein, inferior vena cava or bile duct, or in HVOO treatment ,85. In gRecent development of pharmacological options opened up new treatment strategies for severe PLD patients. Long-term follow-up studies with somatostatin analogues demonstrated that these agents consistently lower total liver volume in PLD patients ,87. A rePLD compromises a clinically heterogeneous liver phenotype identified in VMC, ADPKD and PCLD patients. Massively enlarged livers are present in a subset of ADPKD and PCLD. Genetics and environmental factors such as exogenous estrogen intake and number of pregnancies contribute to disease progression. A considerable intra-familial variability in liver phenotype and extra-hepatic features makes screening modalities uncertain in PCLD. Evaluation of PLD-related symptoms and quality of life are necessary to decide beneficial management.th September 2013; http://www.biobase-international.com/product/hgmd.Human Gene Mutation Database for Human Genetics Research; HGMD\u00ae Professional 2013.3 - 27AAA: Abdominal aorta aneurysm; ADPKD: Autosomal dominant polycystic kidney disease; ARPKD: Autosomal recessive polycystic kidney disease; CD: Caroli disease; CS: Caroli syndrome; CT: Computer tomography; CHF: congenital hepatic fibrosis; DPM: Ductal plate malformation; ER: Endoplasmic reticulum; HVOO: Hepatic venous outflow obstruction; ICA: Intracranial aneurysm; IVC: Inferior vena cava; LVH: Left ventricle hypertrophy; MELD: Model for end-stage liver disease; MRI: Magnetic resonance imaging; PC1: PC2 polycystin-1, -2; PCLD: Isolated polycystic liver disease ; PKD1: PKD2 polycystic kidney disease-1, -2; PLD: Polycystic liver disease; PRKCSH: Protein kinase C substrate 80\u00a0K-H ; SEC63: Saccharomyces cerevisiae homolog 63; VMC: Von Meyenburg complexes.Authors declare that they have no competing interests.WC researched the data and drafted the manuscript. WC and JD contributed to the content and wrote the article. JD is responsible for critical revision of the content. Both authors read and approved the final manuscript."}
+{"text": "Cortical dysplasia is associated with intractable epilepsy and developmental delay in young children. Recent work with the rat freeze-induced focal cortical dysplasia (FCD) model has demonstrated that hyperexcitability in the dysplastic cortex is due in part to higher levels of extracellular glutamate. Astrocyte glutamate transporters play a pivotal role in cortical maintaining extracellular glutamate concentrations. Here we examined the function of astrocytic glutamate transporters in a FCD model in rats. Neocortical freeze lesions were made in postnatal day (PN) 1 rat pups and whole cell electrophysiological recordings and biochemical studies were performed at PN 21\u201328. Synaptically evoked glutamate transporter currents in astrocytes showed a near 10-fold reduction in amplitude compared to sham operated controls. Astrocyte glutamate transporter currents from lesioned animals were also significantly reduced when challenged exogenously applied glutamate. Reduced astrocytic glutamate transport clearance contributed to increased NMDA receptor-mediated current decay kinetics in lesioned animals. The electrophysiological profile of astrocytes in the lesion group was also markedly changed compared to sham operated animals. Control astrocytes demonstrate large-amplitude linear leak currents in response to voltage-steps whereas astrocytes in lesioned animals demonstrated significantly smaller voltage-activated inward and outward currents. Significant decreases in astrocyte resting membrane potential and increases in input resistance were observed in lesioned animals. However, Western blotting, immunohistochemistry and quantitative PCR demonstrated no differences in the expression of the astrocytic glutamate transporter GLT-1 in lesioned animals relative to controls. These data suggest that, in the absence of changes in protein or mRNA expression levels, functional changes in astrocytic glutamate transporters contribute to neuronal hyperexcitability in the FCD model. Development of seizures in children is often associated with focal cortical dysplasia  arise in part from deficits in astrocytic glutamate uptake.Many of the anatomical and electrophysiological characteristics of human FCD are reproduced following transcortical freeze-lesions in the newborn rat  to avoid receptor desensitization or excitotoxicity . Under physiological conditions, experimental evidence indicates it is difficult to overwhelm astrocytic glutamate transporters. High frequency stimulation for prolonged periods does not affect glutamate clearance from the ECS; Diamond and Jahr, in vivo, can effectively reduce glutamate to ambient levels when challenged repeatedly with 100-fold glutamate increases over physiological [Glu\u2212]out levels  following neuronal activity and maintaining out and [Glu\u2212]in. This is achieved by coupling glutamate transport to Na+ and K+ transport down their respective concentration gradients and the hyperpolarized astrocyte membrane potential (Anderson and Swanson, Glutamate uptake is achieved against a ~1000-fold concentration gradient between [GluOur data clearly indicate significant alterations in glutamate transporter function. We observed a near 10-fold reduction in TBOA sensitive transporter function. Furthermore, application of DHK, a GLT-1 specific non transportable inhibitor, suggests ~90% of the currents in both sham-operated and lesioned astrocytes are mediated by GLT-1. Application of the same concentration of glutamate in puffing experiments ruled out the possibility that the reduced glutamate transporter responses in the lesioned astrocytes were the result of less glutamate release following stimulation in lesioned animals. Inefficient clearance of glutamate by astrocytic glutamate transports following electrical stimulation contributed to an enhanced hyperexcitability in the dysplastic cortex, which can be explained in part by altered kinetics of the NDMA receptor-mediated currents.+ has been used to study reverse glutamate transport (Szatkowski et al., +, coupled with our reported depolarized membrane potential in glia cells would create the perfect environment for transporters to function in reverse (Brew and Attwell, + which plays a significant role in neuronal excitability.We postulated that the loss in GLT-1 transporter function would be paralleled by decreased protein and mRNA expression. To our surprise, this is not what we observed. Given our data, it seems likely that a change in transporter effectiveness may underlie the observed decreases in evoked transporter currents. The activity of glutamate transporters is affected by a variety of neuromodulators and second messenger systems. Decreases in transporter activity are induced by caffeine (Shin et al., in utero MAM cortical dysplasia model (Harrington et al., Elevated levels of extracellular glutamate have been reported in patients with epilepsy (During and Spencer, Susan L. Campbell performed whole cell voltage clamp electrophysiology in neurons and astrocytes, immunohistochemistry and contributed to the writing of the manuscript. John J. Hablitz oversaw aspects of experimental design, implementation and writing of the manuscript. Michelle L. Olsen performed whole cell voltage clamp electrophysiology in astrocytes, neurons, Western blots, qPCR, immunohistochemistry and writing the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Coronary perfusion pressure is a combination of proximal perfusion pressure and distal coronary artery pressure resulting from contraction and relaxation of the myocardium and the consequences on the microcirculation. Wave intensity analysis (WIA) defines dominant waves causing coronary filling during the cardiac cycle and allows separation of proximally and distally originating waves.Reduced myocardial perfusion has been shown to predict mortality in hypertrophic cardiomyopathy (HCM), however no study has assessed the relationship between coronary filling patterns and downstream absolute myocardial perfusion.To obtain data for WIA, simultaneous pressure and coronary flow velocity in the proximal coronary arteries was obtained in 20 patients with HCM at rest and with adenosine. Patients then underwent cardiovascular magnetic resonance (CMR) perfusion imaging at rest and with adenosine. Myocardial blood flow (MBF) was quantified from CMR perfusion images using a pixel-wise model-constrained deconvolution algorithm.All patients completed the study successfully. No patients had significant epicardial coronary artery disease. On WIA, distally originating waves predominated compared to proximally occurring waves. The backward expansion wave, which occurs due to myocardial relaxation, correlated with MBFat rest . On CMR, myocardial perfusion reserve was reduced (mean 1.52\u00b10.42) withan endocardial to epicardial ratio that worsened with adenosine .Patients with HCM had predominantly distal waves governing coronary filling, emphasisingthe importance of the microcirculation in this disease. There was an increased backward compression wave during systole in keeping with compression of the microcirculation with a relative reduction in the size of the backward expansion wave. CMR demonstrated the downstream effects of these abnormalities, with reduced myocardial perfusion and an abnormal endocardial to epicardial ratio. Patients with a smaller backward expansion wave had a lower MBF, suggesting that impaired myocardial relaxation results in poorer myocardial perfusion.This work was funded by the British Heart Foundation and the NIHR Cardiovascular BRU."}
+{"text": "Since INR was developed only to monitor long-term treatment of vitamin K antagonists (VKA), effects of other coagulation conditions, i.e., antiplatelet treatment, thrombocytopenia, hyperfibrinolysis or inherited platelet disorders can not be detected by INR measurements. A possible application for POC coagulometers in the prehospital setting is to assess INR in emergency patients treated with VKA. However, this issue was extensively studied in large (non-emergency) cohorts involving appropriate sample sizes and valid study designs [With great interest we read the recent article of Beynon et al. . The aut designs , 4.In the past decades, VKA accounted for the most prescribed anticoagulants worldwide in patients with atrial fibrillation and deep vein thrombosis. This practice is now under considerable change since non-vitamin K antagonist oral anticoagulants (NOAC) are available . The dimWe agree with the authors that the implementation of POC coagulometers might be feasible in pre-hospital emergency settings but the search for an easily available parameter enlightening the complexities of the entire coagulation system continues."}
+{"text": "Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike. Cancer has been traditionally typified by a stepwise accumulation of mutations in key oncogenes and tumor suppressors . For decMeanwhile, tumors are often described as heterogeneous, owing to the intricate genetic diversity and assorted morphological phenotypes they embody . IntratuAdvances in next-generation sequencing techniques and the inception of The Cancer Genome Atlas (TCGA) have revealed extensive heterogeneity at the molecular level . HoweverIn this review, we will revisit the key milestones in tumor evolution, highlight the evolving concepts of tumor heterogeneity, and provide insight on the clinical challenges facing researchers and clinicians alike.Three hundred years after the invention of the microscope, concurrent with the dawn of Darwinian evolution, German physiologist Johannes Muller and his assistants applied microscopy to human tumor samples in 1833. Until this point, all recorded knowledge of tumors was collected with the naked eye, leaving layers of critical information untapped. Applying methods used by botanists and plant physiologists, Muller transformed pathology and modern medicine with his monograph on cancer. This led to his conjecture that tumors are composed of new cells within a diseased organ. Muller and colleagues morphologically distinguished carcinoma subtypes within a single tumor and noted variation among tumor-adjacent connective tissues, detailing the vast heterogeneity observed. It was Muller\u2019s student, famed pathologist Rudolf Virchow, who later determined that all tumors derive from normal cells. Muller and Virchow transformed modern medicine not just by inventing the field of pathology, but also by recording some of the earliest evidence that tumors are heterogeneous , 10.All tumors possess some form of somatic mutation, and our current understanding of tumor heterogeneity is built upon the principle that acquired mutations are heritable . EssentiGenetic heterogeneity of tumors is rooted in one of the key hallmarks of cancer: genetic instability . Severalet al. challenged this with stochastic simulation of tumor evolution and reasoned that, though individually weak, the cooperative burden of small-scale accumulated passenger mutations has a present role in tumor progression, and may be the cause for complex oncological events that remain unanswered by the driver-centric model [Tumor cells undergo a series of genetic events that contribute to genomic instability throughout tumor progression Figure\u00a0A. Howeveic model .Figure 2C. albicans suggest aneuploidy promotes fitness throughout drug resistance evolution, similar to cancer, contrasting S. cerevisiae, which displays growth deficits as a result of aneuploidy [S. cerevisiae diploids exhibit an increased number aneuploidy events under strong selection pressure [Genomic analyses have provided evidence that drastic rearrangement events such as aneuploidy, a defining feature of genetic instability and cancer, and chromothripsis drive cancer progression . Despiteeuploidy . Others pressure . ComparaIn the past 10\u00a0years, genetic sequencing data from independent laboratories and collective efforts from The Cancer Genome Atlas (TCGA) and ICGC  produced global genetic profiles of different types of cancer \u201336. As dThe epigenome is defined as the whole suite of epigenetic factors that regulate expression of the genome and includes both heritable and non-heritable cellular changes that have been shown to contribute to tumor development and progression . Temporaet al. found that epigenetic alterations can be influenced by adjacent genes [et al. applied ChIP-seq to show epigenetic enabling of the von Hippel-Lindau (VHL) tumor suppressor activation of hypoxia inducible factors (HIFs) for metastasis [et al. recently reported an increased variance of putative CpG sites in tumor cells compared to normal cells across several types of cancer [Next generation sequencing techniques have advanced the current understanding of the epigenome and further complicated the current concept of tumor heterogeneity. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) offers single nucleotide resolution, an unlimited dynamic range, and the capacity to multiplex samples . Recentlnt genes . Anothertastasis . More ovf cancer . Signifif cancer .Cancer evolution and heterogeneity is a long debated subject that questions the tumor origin. Borrowing principles of evolution and biodiversity, scientists have reasoned that tumors originate in stem cell populations, as the innate longevity of stem cells increases the chance of acquiring harmful mutations . Increasin vitro assays are not a true assessment of self-renewal capacity [et al. isolated the reputed CSC population using classical stem cell markers from patient peripheral blood and demonstrated that a subpopulation of progenitor cells could recapitulate AML in SCID mice and displayed potential for self-renewal. These findings formed the basis for the modern CSC hypothesis and led to the further identification of cancer stem-like cells tumor initiating cells in breast cancer and brain tumors [Early clonogenic and tumor sphere forming assays showed evidence of stem like cells in heterogeneous tumors; however, these capacity . Furthercapacity . Moreovecapacity . Lapidotn tumors .The traditional CSC hypothesis implies that cellular hierarchies exist in tissues with stem cells  or CSC (in tumors) at their respective apices . Chafferet al. compiled an extensive molecular taxonomy report across several different cancer types where tissue of origin provided the strongest identification signal [et al. provides direct evidence that the tumor stroma harbors a deregulated ECM that promotes malignancy and intratumoral heterogeneity in mammary gland models [It is abundantly clear that the evolutionary selection of fit clones is a system-wide process that occurs in a dynamic tissue milieu termed the tumor microenvironment (TME) . Bisselln signal . This ked models . Michor d models . These ret al. used 3D cell culture to demonstrate that hypoxia inhibits differentiation of colon cancer cells and maintains a stem-like phenotype [et al. demonstrated that myofibroblasts secrete factors that maintain the CSC population in colon cancer cell culture models [et al. reported basal breast cancers cells retain the ZEB1 promoter in a configuration allowing ample response to environmental signals [Stem cell self-renewal and differentiation is dictated by the microenvironment, or stem cell niche. Normal stem cell niches are generally located in hypoxic tissue niches  that promote the stem cell phenotype. Poorly vascularized tumors contain hypoxic regions with undifferentiated \u2018stem-like\u2019 tumor cells that survive under control of HIFs . Yeung ehenotype . In addie models . They sh signals . These ret al. recently demonstrated that, in the context of chronic liver inflammation, depletion of a p53-dependent senescence program in tumor cells results in increased cirrhosis and fibrosis that promotes adjacent epithelial malignant transformation and transient intratumoral heterogeneity [Studies on deregulation of the tumor secretome provide compelling evidence for the TME as a major contributor to compositional tumor heterogeneity. Substantial evidence supporting a role for inflammation in cancer progression has been reported in the last decade and is commonly accepted as a hallmark characteristic of the TME . One of ogeneity .The collective interplay between the CSCs and the TME results in compositional intratumor heterogeneity Figure\u00a0B. HoweveThe dawning of the age of \u2018omics\u2019 brought with it great hope for discovery and validation of novel biomarkers, relevant drug targets, and disease-specific signatures . Powerfuet al. recently generated a computer model to further study multifocal prostate cancer based on data obtained from 152 human prostatectomy specimens evaluated by DNA microarray analysis, where they demonstrated heterogeneous individual foci with a common clonal precursor [et al. reported another mathematical model of personalized treatment that integrates dynamics of evolutionary genetics into analysis and treatment design. Their analyses of hypothetical cases as well as a simulated clinical trial of over 3 million qualified \u2018patients\u2019 showed that augmented and, occasionally counterintuitive, nonstandard treatment strategies may lead to improved patient survival compared with the current model of personalized medicine [Careful consideration of the complete tumor context is essential to understanding and developing more effective personalized treatments that address tumor heterogeneity. The first challenge is whether genetic and compositional profiling of multifocal tumors of monoclonal origin displaying intrafocal heterogeneity can be effectively manage . Multiforecursor . Beckmanmedicine .et al. showed evidence of two genetically distinct tumor cell subclones in communication to maintain the tumor population [et al. employed advanced genomics techniques to further understand the underlying mechanisms driving pancreatic cancer progression and metastasis. Despite showing vast genetic diversity, the authors were able to elucidate a distinct pattern of genomic instability [et al. recently used integrated genomics to characterize the functional role of key genetic driver mutations in luminal breast cancer and correlated specific genetic signatures with poor prognosis [A number of new concepts have emerged in recent years. The concept of intratumoral cell competition among heterogeneous clones reshaped our classic hierarchical view of heterogeneity and potentially can be exploited as therapeutic entry points in eradicating multifocal cancers . Cleary pulation . This letability . Moreoverognosis . Althouget al. used Pathway Recognition Algorithm using Data Integration on Genomic Models (PARADIGM) analyses based on copy number alterations (CNAs) and mRNA expression of data from the MicroMetastases Project (MicMa) cohort to show that integrated analysis of DNA copy number alteration and mRNA expression leads to improved prognostic discrimination of patients compared to separate analysis of any other molecular levels [With massive omics data generated from The Cancer Genome Atlas (TCGA), various algorithms and tools for recognition of activated and altered pathways exist for integrative analysis of two or more types of omics data and are rapidly proving worthwhile . Notablyr levels . Five dir levels . Similarr levels . Among tr levels .Taken together, future integrated omics analyses with consideration of compositional heterogeneity inferred by interplay between intratumoral subclones and TME will allow us to identify more robust biomarkers and devise therapeutic strategies for cancer treatment, such as staggering targeted therapies to keep selection pressures minimal . Mapping"}
+{"text": "IbGGPS, was isolated from sweetpotato storage roots. Green fluorescent protein (GFP) was fused to the C-terminus of IbGGPS to obtain an IbGGPS-GFP fusion protein that was transiently expressed in both epidermal cells of onion and leaves of tobacco. Confocal microscopic analysis determined that the IbGGPS-GFP protein was localized to specific areas of the plasma membrane of onion and chloroplasts in tobacco leaves. The coding region of IbGGPS was cloned into a binary vector under the control of 35S promoter and then transformed into Arabidopsis thaliana to obtain transgenic plants. High performance liquid chromatography (HPLC) analysis showed a significant increase of total carotenoids in transgenic plants. The seeds of transgenic and wild-type plants were germinated on an agar medium supplemented with polyethylene glycol (PEG). Transgenic seedlings grew significantly longer roots than wild-type ones did. Further enzymatic analysis showed an increased activity of superoxide dismutase (SOD) in transgenic seedlings. In addition, the level of malondialdehyde (MDA) was reduced in transgenics. qRT-PCR analysis showed altered expressions of several genes involved in the carotenoid biosynthesis in transgenic plants. These data results indicate that IbGGPS is involved in the biosynthesis of carotenoids in sweetpotato storage roots and likely associated with tolerance to osmotic stress.Sweetpotato highly produces carotenoids in storage roots. In this study, a cDNA encoding geranylgeranyl phyrophosphate synthase (GGPS), named  Carotenoids are widely produced in many plants and provide potent nutritional benefits to human and animal health. The biosynthetic pathway of carotenoids has gained relatively intensive investigations in different plants , 2. CaroGGPS cDNAs have been cloned from multiple plant species. A gene expression study using sunflower seedlings showed that the HaGGPS was expressed after 2 days of seed imbibition , 39ArabiIbGGPS gene was cloned from storage roots of sweetpotato. Subcellular localization, transgenic approach and metabolite analysis demonstrated its involvement in the biosynthesis of carotenoids. Transgenic plants showed its expression associated with an osmotic stress tolerance. These data will be instructional to future sweetpotato breeding for high production of carotenoids and stress-tolerant varieties.In conclusion, an"}
+{"text": "Antiphosphospholipid syndrome (APS) secundary to systemic lupus erythematosus (SLE) can be recognised in children with arterial or venous thrombosis. Amaurosis due to thrombosis of central retinal vene is rarely presenting manifestation of SLE with secondary APS.To present APS secundary to SLE with aggresive ophtalmological onset in 17 years old female.We report a patient with unilateral amaurosis due to thrombosis of central retinal vene. Amaurosis was a reason for her urgent admission at Ophtalmology. She was transferred to Pediatric rheumatology department as suspected SLE. The patient had rapidly developing disease. Eleven days after the attack of retinal vene thrombosis, she became febrile with malar rash, facial ulcer, neurological symptoms (right Mingazzini positive), arterial hypertension, haemathological abnormalities, proteinuria and immonological disorders. Head MRI-MRA was performed and suboclusion of left medial cerebral artery was found. The diagnosis of APS secundary to SLE was established.The patient significantly improved with aggresive immunosupresive and prompt anticoagulant therapy but ohtalmological complication have been improved slowly with uncertain prognosis.The patients with SLE related symptoms have to be reffered to rheumatologist immediately because APS secundary to SLE may have aggressive thrombotic onset and cause serious organs damages.None declared."}
+{"text": "New extensive use of thoracic ultrasound (TUS) takes information also from physical acoustic phenomena that are not directly convertible into images of the human body.This tenNo evaluation on technical issues feasibly , no comparison of the results of TUS and those of a reference standard (i.e. CXR);Diagnostic access bias , bias from reader/training experience on CXR (no paediatric radiologists);Imaging analysis bias i.e. absence of preliminary definition of the methods for imaging (CXR) interpretation, selection bias (patients from birth to adult undergoing chest radiography for suspected community acquired pneumonia)."}
+{"text": "Optical mapping provides long-range information of the genome and can more easily identify large structural variations. The ability of optical mapping to assay long single DNA molecules nicely complements short-read sequencing which is more suitable for the identification of small and short-range variants. Direct use of optical mapping to study population-level genetic diversity is currently limited to microbial strain typing and human diversity studies. Nonetheless, optical mapping shows great promise in the study of plant trait development, domestication and polyploid evolution. Here we review the current applications and future prospects of optical mapping in the field of plant comparative genomics.Optical mapping has been widely used to improve  Optical mapping is a molecular technique that produces fingerprints of DNA sequences in order to construct genome-wide maps . The seqde novo genome assembly and identification of relatively large structural variants in genetic diversity studies. While optical mapping is readily available across a wide range of organisms including bacterial, fungi, plant and mammalian genomes [Optical mapping offers several unique advantages over traditional mapping approaches, including single molecule analysis and the ability to assay long DNA molecules  data support each other, but are both inconsistent with linkage maps, especially in heterochromatic regions where recombination is scarce [Similar to optical maps, genetic maps could be a useful guide in anchoring scaffolds and identifying assembly issues ,19. Howes scarce . Similars scarce . Genome s scarce ,20.Genome \u2018upgrades\u2019\u2009, or improvement of genome assemblies are possible through the incorporation of the optical mapping information into existing sequences. For example, optical mapping was essential in upgrading the rice Nipponbare reference genome in several important ways ,18. FirsSimilar to rice, optical maps have been extensively used to improve the Medicago genome assembly starting with release version Mt3.5, and were helpful both during the chromosomal anchoring and to correct errors in the linkage maps ,22. To bOptical mapping can be very useful in assisting the assembly of polyploid and highly heterozygous plant genomes, which are notoriously difficult to assemble . Many plDespite recent progress in genome assembly methodologies, a significant portion of many genomes remains inaccessible to assembly by short sequencing reads . A comprde novo assembly is still challenging and large amounts of true SVs may be lost during the assembly process. For most organisms, the \u2018reference\u2019 genome only represents a single individual and requires substantial amount of investment for the initial genome assembly and subsequent finishing. Most assemblies can only reach \u2018draft\u2019 status, often containing a large number of sequence gaps and assembly errors that could easily show up as false SVs during sequence comparisons.Pairwise sequence alignments between assembled genomes remains one of the most powerful tools for plant comparative genomics, and could identify SVs with the best accuracy if the assemblies themselves were correctly reconstructed. However, Split reads at the same position could indicate genomic breakpoints derived from inversions, deletions and insertions. Discordant pairs reveal spacing difference due to deletions or insertions, or presence-absence variations (PAVs). Read depth variations can be used to identify copy number variations (CNVs) that are likely derived from tandem or segmental duplications  retrotransposon-mediated gene duplication [Some important agronomic traits are directly caused by structural variations which could be studied with a whole genome association framework across varieties or diversity panels. For example, the lication . Currentet al. uncovered large structural variants that are associated with selective sweeps in Arabidopsis lines from Sweden, based on a suite of methods from \u2018manual\u2019 detection of breakpoints to de novo assembly. They acknowledged that many polymorphisms may be complex and difficult to resolve using short-read sequencing data [In addition to agronomic traits, a wide range of studies in plants, including domestication, polyploidy, population history and natural selection could benefit from optical mapping. Long ing data . Re-sequing data , althougBrassica napus genome, an allotetraploid merged from two diploid Brassica genomes [The application of optical mapping could reveal structural changes following polyploidy events in plants that might be difficult to study using other techniques. Studies show that homeologous exchanges (HEs) occur frequently between subgenomes inside polyploid genomes and often involve large chromosomal segments. This was studied in the  genomes . Each HE genomes . While r genomes . The dirOptical mapping is an important technique that can provide long genomic linkage information in a high-throughput manner, which has substantially improved the assemblies of several important model plant genomes sequenced to date. Direct comparisons of genome structures have so far been lacking in plants, but optical mapping shows great promises at revealing genomic regions that are not easily accessible through conventional sequencing methods. Optical mapping could become an integral part of the mapping tools in the study of plant domestication, polyploid evolution, and trait development."}
+{"text": "Here we used a well-characterized panel of lung cancer cell lines to develop the most comprehensive view of cancer cell metabolism to date.Cancer cells display oncogene-driven rewiring of metabolism to produce energy and macromolecules for growth. Inhibition of growth-promoting metabolic pathways may prove to be a useful therapeutic strategy in cancer. We previously identified distinct metabolic platforms that enabled cancer cells to produce macromolecular precursors from glucose and glutamine, the two most abundant nutrients. However, neither the full breadth of cancer cell metabolic diversity, nor the complement of mechanisms by which tumor mutations elicit metabolic reprogramming, are known. Because metabolic flux can be analyzed in vivo.81 non-small cell lung cancer cell lines were analyzed for a set of well-defined metabolic parameters. These cell lines were also subjected to extensive genomic, epigenetic, and gene expression analysis, and tested for sensitivity to chemotherapeutic agents and genome-wide siRNA screens. These rich data sets will streamline the establishment of novel correlations between metabolism and molecular/cell biological features. All cell lines were characterized for nutrient utilization, nutrient addiction, and focused flux assays to trace the metabolism of isotope-labeled glucose and glutamine in identical culture condition. Ongoing experiments are assessing metabolism of the same cells grown The 81 cell lines displayed surprising metabolic heterogeneity. Although all cells used glucose and glutamine to produce biosynthetic precursors, contributions of these two nutrients varied considerably, as did the pathways used. For individual isotopic labeling patterns, differences of >30-fold were observed across the panel. Unsupervised clustering produced two metabolic superfamilies differentiated by relatively glucose carbon contribution into precursor pools, as well as numerous subfamilies which may correlate to different metabolic pathways. Although KRAS-mutant cells were distributed across panel, the LKB1/KRAS co-mutation cells aggregated into the low-glucose m0 superfamily. Ongoing work will examine the ability of metabolic phenotyping to predict combinatorial mutations and vulnerabilities to drugs and siRNAs.Focused metabolic assays can produce a highly informative view of the metabolic phenotyping among large panels of cell lines. It describes an unparalleled view of the connections between genetics, drug sensitivity and cell-autonomous metabolism in NSCLC."}
+{"text": "Using our experience of over 500 patients who have undergone pre-biopsy mpMRI  and subsequent transperineal saturation prostate biopsy, we aim to:\u2022 Illustrate the commonly overlooked areas in diagnosing prostate cancer with mpMRI.\u2022 Emphasise technical factors that can contribute to suboptimal image interpretation.\u2022 Highlight normal anatomical structures and non-cancerous abnormalities that mimic tumour.\u2022 Demonstrate the use of mpMRI to direct further management.mpMRI may be used in the pre-biopsy setting to determine type of biopsy , and predict biopsy outcome to the extent that biopsies may be avoided altogether. Tumour localisation within the prostate gland aids targeted biopsy and influences treatment . Tumours with unusual appearances and those in uncommon sites hinder MRI interpretation, potentially leading to false-negative or \u2013positive findings. These areas of pitfall can be divided into normal anatomical structures in the peripheral or transitional zones or non-cancerous abnormalities that mimic tumours (e.g. granulomatous prostatitis).It is also important to acknowledge that mpMRI itself has limitations. Technical challenges in relation to DWI may lower tumour sensitivity due to anatomical distortion, inadequate suppression of benign prostate tissue and suboptimal ADC map windowing.It is paramount that radiologists are aware of the commonly missed locations of prostate cancer, tumour mimics and the limitations of mpMRI, particularly in the context of a multidisciplinary team setting. This would serve to improve diagnostic accuracy, target areas for biopsy more precisely and correctly influence management."}
+{"text": "Most researchers leverage bottom-up suppression to unlock the underlying mechanisms of unconscious processing. However, a top-down approach \u2013 for example via hypnotic suggestion \u2013 paves the road to experimental innovation and complementary data that afford new scientific insights concerning attention and the unconscious. Drawing from a reliable taxonomy that differentiates subliminal and preconscious processing, we outline how an experimental trajectory that champions top-down suppression techniques, such as those practiced in hypnosis, is uniquely poised to further contextualize and refine our scientific understanding of unconscious processing. Examining subliminal and preconscious methods, we demonstrate how instrumental hypnosis provides a reliable adjunct that supplements contemporary approaches. Specifically, we provide an integrative synthesis of the advantages and shortcomings that accompany a top-down approach to probe the unconscious mind. Our account provides a larger framework for complementing the results from core studies involving prevailing subliminal and preconscious techniques. The unconscious mind fascinates and challenges human thinking . PervasiRecovering from a volatile history plagued by quackery and charlatanism, hypnosis has become a viable venue of cognitive science . At leasUsing hypnosis in the study of the unconscious mind dates back to early psychodynamic conceptions when analysts leveraged hypnotism to probe unconscious thoughts and feelings of analysands . RevisitWe review contemporary suppression and inattention techniques to assess their relative merits and drawbacks. Thereafter, we contrast the strengths and weaknesses of contemporary approaches \u2013 i.e., subliminal and preconscious methods \u2013 with those of instrumental hypnosis. Showcasing findings using hypnosis, we sketch out how this top-down approach provides the experimental means to foster new perspectives to study the unconscious mind.Subliminal and preconscious approaches represent active areas of research within the domain of unconscious cognition . Guided Figure 1; The global workspace model entails that unconscious processing of sensory events occurs in two ways: conscious suppression of sensory signals, corresponding to perceptual failures, and preconscious processing of sensory events reflecting attentional failures . In this procedure, both stimuli compete to access consciousness, resulting in the temporary conscious suppression of the ineffective stimulus , which elicits longer and deeper suppression compared to BR (Frontiers in Psychology research topic on conscious suppression). Importantly, interocular suppression techniques yield competition at the sensory level and at the representational level . Bistable representations reflect the inherent ambiguity conveyed by these images as our brain processes resolve these competing interpretations , these failures to detect prominent task-irrelevant stimuli occur when individuals engage in a demanding cognitive task  and CB mainly reflect lapses of attention, wherein unattended signals lack the necessary energy and sustainability to reach conscious perception . Both exUnattended events during IB and CB induce preconscious processing, yielding priming effects e.g., , impliciIn a stream of rapidly presented visual stimuli, attending to a task-related stimulus impairs attentional processing of subsequent stimuli at short latencies . This atFigure 1; Subliminal approaches exploit the limits of perception to suppress awareness of sensory events . These tThe broad range of mechanisms selectively engaged by each of the abovementioned methods challenges our capacity to generalize findings across different tasks. As we explained, these techniques yield important findings about the scope and depth of subliminal and preconscious processing. Notably, bottom-up approaches afford researchers with plentiful experimental control, yet offer limited ecological validity. Conversely, top-down approaches, such as IB and CB, propose an ecological tactic to investigate unconscious processing , but remFigure 3), we follow the criteria put forth in the literature (To assess the aforementioned techniques (see terature . This se(i)Generality: whether the technique applies to a broad range of stimuli or only to a select few.(ii)Stimulus location: whether the stimulus has to be presented at the center or the periphery of the visual field.(iii)Temporal constraint: whether the technique imposes a temporal constraint relative to the duration of the stimulus presentation.(iv)Robustness: whether this technique completely abolishes awareness.(v)Invariant stimulation: whether conscious suppression requires significant modifications of sensory events to make a stimulus invisible \u2013 e.g., adding a mask to induce conscious suppression during backward masking.Hypnosis represents an increasingly popular area of research in cognitive science, including notable ventures in the domains of perception, attention, memory, and motor control . For exaTheoretical frameworks for hypnosis largely cluster around the appellations of state and non-state models. State theories posit that hypnosis implies a particular psychological state \u2013 e.g., an altered state of consciousness \u2013 whereas non-state theories typically argue that hypnosis essentially reduces to sociocognitive factors such as motivation and compliance . In spitTop-down regulatory processes \u2013 e.g., attention, cognitive control and monitoring \u2013 play a central role in mediating responses to hypnotic suggestions . SpecifiEmphasizing the importance of individual variability, compliant participants frequently report using different cognitive strategies to successfully respond to the very same suggestion . This inFigure 4; Figure 5), a significant experimental benefit to better isolate the NCC. The content of hypnotic suggestions selectively targets specific mental functions and behaviors. Thus, we will demonstrate how hypnosis encompasses a wide variety of experimental possibilities to investigate unconscious processes . Here we discuss several avenues based on such research developments.Hypnotic suggestions divide as a function of type and content .Hypnosis also modulates phenomenological aspects of conscious experience, such as pain perception . Called Posthypnotic amnesia (PHA) represents memory lapses of events that took place under hypnosis, after termination of hypnotic induction . AffordiPast research shows that temporarily irretrievable material influences behavior nonetheless . For exaContrary to PHA, few studies looked at the effects of hypnotic agnosia \u2013 i.e., the functional inability to access semantic knowledge . This reHypnosis can decouple volitions and actions . HypnotiIntrusive cognitions and emotions often accompany psychopathology . In ordeIn experimental psychopathology, hypnotic suggestions target specific functions and dramatically influence cognitions and behaviors . For exaThe fields of neuropsychology and behavioral neurology often feature deficits that are amenable to top-down influences  at diffeWhether hypnosis acts through suppressive means or influences attention to impede conscious access, this top-down methodological approach possesses formidable potential to study the unconscious mind. Two general features make hypnosis a unique approach. First, hypnotic suggestions afford researchers with a wide spectrum of experimental possibilities. Second, whereas the prevailing approaches either take advantage of perceptual limitations or interfere with top-down amplification processes, hypnosis harness top-down processes to investigate both subliminal and preconscious phenomena. Indeed, due to the variety of hypnotic suggestions, hypnosis can prompt perceptual and attentional failures. Also, the accuracy of hypnosis  allows rFigure 1). During hypnotically induced subliminal and preconscious processing, hypnotic responses recruit frontal networks implicated in top-down attentional regulation, control and monitoring processes : this approach applies to a broad range of visual and non-visual stimuli; works equally well for stimuli presented centrally or peripherally; hardly necessitates temporal constraint relative to the presentation of the stimulus or variation in sensory events. Finally, various experiments imply the robustness of unconscious hypnotic phenomena, even if the phenomenological dimensions of hypnosis remain roughly defined (Overall, the use of hypnosis to investigate the cognitive unconscious compares favorably to contemporary methodologies (see  defined . This ap defined . In compDespite these benefits, certain obstacles to the use of hypnosis in the context of the suppression of consciousness might arise. Here we address some of these concerns. First, HHSs are often carefully selected in hypnosis experiments to demonstrate the full potential of hypnotic suggestions , despiteA final concern pertains to the objective control of subjects\u2019 awareness, a central issue that transcends research on conscious and unconscious processes . AlongsiHere we herald instrumental hypnosis as a new experimental vehicle to probe the structure and functioning of the cognitive unconscious. Whereas most current techniques investigate the unconscious mind via subliminal approaches that challenge our perceptual limitations and preconscious approaches that rest on inattention, the hypnosis lens facilitates both suppression and inattention via top-down mechanisms. Beyond the empirical potential to explore novel ideas and hypotheses, top-down control provides scientists with increased experimental flexibility by allowing target processing of specific sensory events. Moreover, hypnotic hallucinations provide an efficient means to capture the NCC using a full two-by-two balanced design allowing for a direct comparison of conscious and unconscious conditions. Thus, scholars stand to benefit from the use of hypnosis in their quest to better understand the underpinnings of the unconscious mind . IncorpoThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The cerebellum plays an important role in motor control. The cerebellar key players include Purkinje cells (PCs), mossy fibers, climbing fibers, and parallel fibers. Each PC receives inputs from many parallel fibers and from a single climbing fiber. Cerebellar outputs originate from the deep cerebellar and vestibular nuclei. Cerebellar nuclei (CN) neurons receive inhibitory inputs from PCs and excitatory inputs from mossy fiber and climbing fiber collaterals. In this work, we studied how regular and irregular, as well as synchronous and asynchronous, PC firing frequencies affect the eye movements in mice and CN neuron model behavior. Floccular PCs on one side of the head were optogenetically stimulated . We use"}
+{"text": "Mental health care services play an important role following disasters  program over a 2-year period following two major Australian bushfire and flood/cyclone disasters. Predictor variables examined in negative binomial regression analysis included consumer  and event characteristics (disaster type).The bushfire disaster resulted in significantly greater service volume, with more than twice the number of referrals and nearly three times the number of sessions. Service delivery for both disasters peaked in the third quarter. Consumers affected by bushfires, diagnosed with depression, anxiety, or both of these disorders utilized sessions at significantly higher rates.The substantial demand for primary mental health services following disaster can vary with disaster type. Disaster type and need-based variables as key drivers of service use intensity indicate an equitable level of service use. Established usage patterns assist with estimating future service capacity requirements. Flexible referral pathways can enhance access to disaster mental health care. Future research should examine the impact of program- and agency-level factors on mental health service use and factors underpinning treatment non-adherence following disaster."}
+{"text": "The ideal cancer therapy not only induces the death of all localized tumor cells, but also activates a systemic antitumor immunity. High intensity focused ultrasound (HIFU) has the potential to be such a treatment, as it can non-invasively ablate a targeted tumor below the skin surface, and may subsequently augment host antitumor immunity.This talk is to introduce increasing animal and clinical evidences linking antitumor immune response to HIFU ablation, review the potential mechanisms, and discuss challenges and opportunities involved in HIFU-enhanced host antitumor immunity.It is concluded that HIFU immunotherapy may play an important role in preventing local recurrence and metastasis of cancer after HIFU treatment."}
+{"text": "The last decade has witnessed an exponential increase in the researches being carried out to combat aging using drug therapy. Few specific drugs like Metformin, Rapamycin and Resveratrol have displayed promising results in anti-aging research of mice, fruit fly and worm. Basically these drugs interfere genetically with the important aging pathways such as IIS, TOR, and NAD+ dependent pathway, and results in lifespan extension in a number of species ranging from worm to mammals .Drosophila resulting in lifespan extension along with increased stress resistance, reduced fecundity and increased lipid levels. Also rapamycin treatment has shown to further extend the lifespan of some long lived IIS mutants, and dietary restricted flies, indicating additional mechanisms of lifespan extension [Rapamycin which was originally an immuno-suppressive drug used for kidney transplant patients for years, is an inhibitor of protein kinase target of rapamycin (TOR). Rapamycin inhibits the TOR by forming a complex with FKBP12, which goes on to bind with TOR complex1. The mechanism of rapamycin mediated lifespan extension has largely remained conserved in different model species, for example the genetic mutations/deletions of S6K and 4E-BP in mice and its homologues in worms have resulted in extended lifespan. Rapamycin treatment has led to reduced phosphorylation of S6K in Drosophila. In flies the midgut stability is maintained by multipotent intestinal stem cells (ISCs) in hindgut proliferation zone (HPZ) and controlled by locally emanating Wingless  and Hh signals. Under the stress conditions such as aging, pathogen exposure, genotoxins or ROS inducing compounds, the ISC proliferation increases strongly in order to restore the large parts of intestinal epithelium. The epithelial integrity is disrupted by this regenerative event leading to accumulation of mis-differentiated cells and resulting in a dysplastic pheno-type [Gut has been considered as an unique important target organ in mediating the lifespan extension at the organismal level because of its immunity and nutrition intake . Also theno-type . Intereseno-type .Drosophila as a model system to carry out such study [Drosophila intestinal epithelium. We have proposed that, along with inhibiting mTOR, rapamycin can also significantly delay the microbial expansion by upregulating the negative regulators of IMD/Rel pathway in the aging guts , is significantly up regulated in rapamycin treated flies suggesting that rapamycin can improve the intestinal capacity for antioxidants. The autophagy genes atg1, atg5 and atg8b displayed increased mRNA expression level in intestinal tissues, indicating that rapamycin can induce autophagy and increase the lifespan. The anti-microbial peptide (AMP) gene dpt and the dual oxidase gene (duox), which is associated with reactive oxygen species (ROS) levels, were significantly decreased in rapamycin treated aged guts, indicating that rapamycin may reduce the intestinal ROS accumulation in aging flies . Thus raThese findings clearly show that rapamycin treatment maintains the gut stability during aging in Drosophila, leading to healthspan and lifespan extension. It should be noted that due to the high evolutionary conservation of mTOR pathway in different species, the same mechanism underlying rapamycin treatment could apply in other species as well. Thus rapamycin holds great future potential in various gastrointestinal disorders and cancers along with lifespan extension."}
+{"text": "Paraneoplastic neurological syndromes (PNS) are neurologic deficits triggered by an underlying remote tumor. PNS can antedate clinical manifestation of ovarian malignancy and enable its diagnosis at an early stage. Interestingly, neoplasms associated with PNS are less advanced and metastasize less commonly than those without PNS. This suggests that PNS may be associated with a naturally occurring antitumor response.N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. An approach to the diagnostic workup of underlying tumors is discussed.We review the literature on the diagnosis, pathogenesis and management of PNS associated with ovarian tumors: paraneoplastic cerebellar degeneration (PCD) and anti-PCD can precede the manifestation of ovarian carcinoma. Anti-NMDAR encephalitis in young women appears often as a result of ovarian teratoma. Since ovarian tumors and nervous tissue share common antigens , autoimmune etiology is a probable mechanism of these neurologic disorders. The concept of cross-presentation, however, seems insufficient to explain entirely the emergence of PNS. Early resection of ovarian tumors is a significant part of PNS management and improves the outcome.The diagnosis of PNS potentially associated with ovarian tumor indicates a need for a thorough diagnostic procedure in search of the neoplasm. In some patients, explorative laparoscopy/laparotomy can be considered. PNS precede clinical manifestation of ovarian tumors and enable their diagnosis at an early stage.Paraneoplastic cerebellar degeneration (PCD) can coexist with ovarian carcinoma.Anti-NMDAR antibodies detected in patient affected with encephalitis are highly suggestive of ovarian teratoma.Ovarian tumors and nervous tissue share common antigens in PNS \u2014the concept of cross-presentation, however, may not be sufficient to explain an emergence of PNS.Cell-mediated immune response plays a role in the pathogenesis of PNS.Antibody-mediated immune response is a major mechanism of anti-NMDAR encephalitis and other NSAS.In patients with PNS associated potentially with ovarian tumors, transvaginal ultrasound examination and pelvic CT scan are indicated\u2014if negative, PET imaging is required.If imaging studies remain normal, explorative laparoscopy/laparotomy should be considered.An early resection of ovarian tumors is a significant part of PNS management and improves the outcome.Paraneoplastic neurological syndromes (PNS) are defined as the pathologic involvement of the nervous system in the course of malignancy. This entity does not include tumor infiltration, compression or metastasis of the nervous system , balance and gait disturbances, speech disorder (dysarthria) and altered ocular movements   may display pleocytosis (with a high fraction of lymphocytes), elevated protein or oligoclonal bands  in PCD can reveal cerebellar atrophy  strongly indicates the presence of ovarian tumor in patients with neurological deficit. If the tumor is not identified, an obligation for systematic screening exists. Surgery and immunomodulatory treatment are considered as the most important management among such a group of patients."}
+{"text": "In this guest editorial, Andrew Beck discusses the importance of open access to big data for translating knowledge of cancer heterogeneity into better outcomes for cancer patients. Cancer is a heterogeneous disease, which is comprised of a collection of diseases traditionally categorized by tissue type of origin. A distinct set of etiologic causes, treatments, and prognoses are associated with different cancers, and even within a given tissue type, cancer shows significant variability in molecular and clinical features across patients. This interpatient heterogeneity is a major rationale for large-scale research efforts  to comprehensively profile the molecular landscape of patient cancer samples across all major cancers ,2. ThesePLOS Medicine show the potential clinical utility of measuring intratumoral genetic heterogeneity in clinical cancer samples.A major challenge in cancer therapy is the development of resistance to molecularly targeted therapies. Although targeted therapies may show initial benefit in the subset of patients carrying a targeted molecular alteration, most patients will nevertheless go on to develop resistance for most advanced solid cancers. Identifying and overcoming drug resistance represents one of the most significant challenges facing cancer researchers today . It is iIn one, James Brenton, Florian Markowetz, and colleagues applied the Minimum Event Distance for Intra-tumour Copy-number Comparisons (MEDICC) algorithm they recently developed for phylogenetic quantification of intratumoral genetic heterogeneity from multiregion DNA copy number profiling data  to prediThe second study comes from James Rocco and colleagues . PreviouThe continuing generation of high-quality, open-access Omics data sets from large populations of cancer patients will be critically important to enable the development of computational methods to translate knowledge of cancer heterogeneity into new diagnostics and improved clinical outcomes for cancer patients. As one step towards this goal, the DREAM  consortium will use open innovation crowd sourcing to identify top-performing computational methods for inferring genetic heterogeneity from next-generation sequencing data provided by a large multi-institutional community of cancer genomics projects, including the ICGC and TCGA . If succIn parallel with these advances in computational methods for inferring intratumoral heterogeneity from genomics data, genomics technologies for measuring intratumoral heterogeneity at increasingly fine levels of granularity continue to improve. For example, recent advances in single-cell sequencing of DNA have provided detailed portraits of intratumoral genetic heterogeneity and clonal evolution in cancer ,21, and Establishing the clinical utility of these new approaches for measuring intratumoral molecular heterogeneity will require applying these methods to large sets of archival tumor samples from randomized trials of cancer therapeutics  and high"}
+{"text": "High density microelectrode arrays (MEAs) provide extracellular recordings from thousands of closely spaced electrodes and with sub-millisecond resolution. These devices offer thus novel capabilities to investigate the interplay between ongoing and evoked electrophysiological signaling within networks in-vitro. However, to effectively take advantage from the spatiotemporal resolution of these MEAs, adapted analysis tools are needed. Here we report on our recent advancements toward this goal. A novel high density MEA with on-chip stimulating electrodes was used to record from 4096 electrodes and electrical stimulation was delivered alternatively through one of the 16 equally spaced electrodes on hippocampal primary cultures derived from mouse. The evoked activities propagated reliably across the network and were specific to the stimulating electrode ). Here,"}
+{"text": "In routine cardiac MRI (CMRI) practice, radiological technologists are expected to optimize and utilize EKGs in gating and physiological monitoring. Many cardiac sequences are critically dependent on heart rate and rhythm and EKG gating problems lead to poor or non-diagnostic images. The technologist's syllabus does not routinely include formal EKG recognition or CMRI trouble-shooting techniques.In this educational exhibit, we describe common EKG rhythms and discuss imaging parameter options for overcoming magneto-hemodynamic effects, dealing with high or low heart rates and abnormal rhythms.An image sequence/EKG rhythm quick algorithm is included for reference and will be the basis of the exhibit.Basic EKG rhythm recognition and imaging optimization tips are the building blocks of good cardiac MRI - something every good CMRI technologist should know but are rarely formally taught.None."}
+{"text": "The adult liver has unique regenerative capabilities. Adult livers generally regenerate fully functional liver cells when injured, unlike other vital adult organs which typically respond to cell loss by forming scar tissue. The mechanisms underlying these differences are not well understood, particularly since adult livers are perfectly capable of scarring. In fact, transient scar formation normally occurs in situations that lead to efficient and complete recovery of functional liver mass, such as 70% partial hepatectomy (PH). Scarring also occurs to some extent during many types of chronic liver injury, although progressive scarring (dubbed cirrhosis) occurs in only a minority of individuals with chronic liver injury. Even in cirrhotic livers, however, scarring has been shown to regress gradually once factors driving chronic injury are alleviated. The aggregate data suggested to us that the unique regenerative capabilities of adult livers are linked to its ability to control the formation and regression of scar. Our research has focused on delineating the mechanisms that control scarring. The results will help to clarify why injured livers typically regenerate healthy parenchyma, as well as why other organs replace wounded tissue with scar.The wound healing process necessitates some degree of scarring. Scarring is characterized by excessive extracellular matrix deposition, but also involves inflammation, vascular remodeling, and accumulation of cell types that are relatively inconspicuous in healthy tissues, such as progenitors and myofibroblasts (MF). In adult livers, each of these scarring-related responses is regulated by Hedgehog (Hh), a fetal morphogenic signaling pathway that reactivates during adult liver injury . Hh pathRecently, we proved that canonical Hh signaling controls the fate of liver MF . MF accuRecently, we have begun to evaluate a related novel hypothesis, namely, that Hedgehog controls liver regeneration after PH by modulating the differentiation of these multi-potent myofibroblastic progenitor cells. Transgenic mice were generated to permit conditional deletion of either floxed-Smoothened or floxed-YFP alleles in aSMA-expressing cells. By studying the Smoothened-deleted mice, we were able to determine how selectively abrogating Hh signaling in aSMA(+) cells (and their progeny) influenced regenerative responses to PH. By studying the YFP-marked mice, we were able to track the fate of cells that expressed aSMA after PH. The results demonstrate that Hh signaling in aSMA(+) cells orchestrates both scarring and regeneration after PH; prove that these processes are required for the liver to regenerate normally after PH; and show that post-PH regeneration involves differentiation of myofibroblastic progenitors into hepatocytic and ductular cells .Regeneration of adult livers requires Hh-dependent modulation of epithelial-mesenchymal transitions in multipotent progenitors. Data generated by studying models of acute and chronic liver injury reveal that robust epithelial to mesenchymal transitions (EMT) normally occur in injured livers, and show that conditionally abrogating canonical Hedgehog signaling in multi-potent aSMA-expressing cells blocks these EMT, instead triggering a cascade of mesenchymal-to-epithelial transitions (MET). This has global consequences for liver wound healing. Regeneration of different types of liver cells becomes unbalanced, leading to excessive accumulation of quiescent HSC but reduced outgrowth of hepatocytic and ductular progenitors and their progeny, as well as depletion of MF populations. Thus, de-regulating Hh-sensitive EMT/MET responses disrupts both scarring and regeneration of injured livers. These findings, in turn, suggest that the liver is uniquely suited for regeneration because it harbors large populations of multi-potent progenitors and is generally able to constrain signals, such as Hedgehog, that modulate the differentiation of these cells towards less epithelial  phenotypes."}
+{"text": "The human genome contains nearly 400,000 sequences related to retroviruses that have accumulated due to ancient infections of the germ line and subsequent fixation during evolution. Most of these endogenous retroviral sequences (ERVs) currently exist as solitary long terminal repeats (LTRs), the product of recombination between LTRs of the integrated proviral form. Since retroviral LTRs naturally contain transcriptional promoters and enhancers, these sequences have great potential to impact regulation of individual genes and gene regulatory networks. Numerous cases of LTRs serving as promoters for human genes have been described by our group and others, and some examples will be presented. While such co-option of LTRs as regulatory gene modules indeed occurs in normal cells, particularly in placenta or in early development, transcriptional activity of most endogenous LTRs is epigenetically suppressed in somatic tissues, likely as a host defense against unregulated transcription. Cancer cells represent an abnormal epigenetic environment where LTRs and other classes of transposable elements (TEs) are often hypomethylated, leading to their transcriptional activation. This activation could result in abnormal, cancer-specific expression of nearby genes. To study this phenomenon, we are analyzing whole transcriptome data of cancers specifically to identify gene deregulation due to transcriptional activity of LTRs or other TEs. Our results suggest that the regulatory potential of these sequences is often used by cancer cells, providing one avenue to up-regulate genes. Thus, while some LTRs/TEs have been co-opted to serve in normal gene expression, the same regulatory qualities can be exploited in carcinogenesis."}
+{"text": "Introduction. Chronic pancreatitis (CP) is considered an inflammatory disease that may cause varying degrees of pancreatic dysfunction. Conservative and surgical treatment options are available depending on dysfunction severity. Presentation of Case. A 36-year-old male with history of heavy alcohol consumption and diagnosed CP underwent a duodenal-preserving pancreatic head resection (DPPHR or Beger procedure) after conservative treatment failure. Refractory pain was reported on follow-up three months after surgery and postoperative imaging uncoveredstones within the main pancreatic duct and intestinal dilation. The patient was subsequently subjected to another surgical procedure and intraoperative findings included protein plugs within the main pancreatic duct and pancreaticojejunal anastomosis stricture. A V-shaped enlargement and main pancreatic duct dilation in addition to the reconstruction of the previous pancreaticojejunal anastomosis were performed. The patient recovered with no further postoperative complications in the follow-up at an outpatient clinic. Discussion. Main duct and pancreaticojejunal strictures are an unusual complication of the Beger procedure but were identified intraoperatively as the cause of patient's refractory pain and explained intraductal protein plugs accumulation. Conclusion. Patients that undergo Beger procedures should receive close outpatient clinical follow-up in order to guarantee postoperative conservative treatment success and therefore guarantee an early detection of postoperative complications. Chronic pancreatitis (CP) is a progressive inflammatory disease that may lead to exocrine and endocrine organ dysfunction . An overA 36-year-old male was referred to an outpatient clinic due to constant chronic abdominal pain. The subject had a history of heavy alcohol intake and was diagnosed with CP. Initial conservative treatment included Omeprazole, Pancreatin, nonsteroidal analgesics, and lifestyle modifications that consisted in a fractionated diet and alcohol intake cessation. Despite conservative treatment, symptoms persisted with progressive weight loss and mild steatorrhea was reported. Initial CT scan showed small calcification areas on pancreatic head and sparse calcifications in pancreatic body and tail. Mild enlargement of the pancreatic head and fibrosis without defined focal lesions  was also present. Main pancreatic duct (maximum diameter of 1.0\u2009cm) and common bile duct dilation were evidenced (maximum diameter of 1.4\u2009cm). Following a 3-year conservative treatment failure, the patient underwent Beger procedure in January 2014 with no intraoperative complications and consisted in pancreatic head resection with main pancreatic duct stenotic portion responsible for main pancreatic duct dilation. Also, no further signs of intrinsic obstruction were found. The subject developed a biliodigestive anastomosis fistula as a postoperative complication that was conservatively treated and was discharged from the hospital. Three months after the Beger procedure, subject reported new onset epigastric and bilateral hypochondrial abdominal pain but no fever, vomiting, weight loss, or any signs of obstruction . Subsequent laboratory findings excluded the possibility of biliary tract obstruction. A CT scan revealed diffuse thickening of small intestine and suggested inflammation near the residual pancreatic parenchyma. A subsequent MRI  evidenceThree surgical approaches have been described so far for chronic pancreatitis: decompression, pancreatic resection, and denervation. Some surgical procedures employ a combination of these approaches. Decompression therapies consist of duodenal-preserving pancreatic head resection (DPPHR) and local resection of the pancreatic head with extended longitudinal pancreaticojejunostomy (LR-LPJ), known as Beger and Frey procedures, respectively. Trials comparing Beger and Frey procedures have shown no statistical difference concerning morbidity, mortality, and pancreatic function, as both ensure gastrointestinal continuity. Frey procedure preserves the posterior capsule of the pancreas and requires pancreaticojejunal anastomosis, while DPPHR requires a pancreaticojejunal and a biliodigestive anastomosis. Therefore, surgical experience should be taken into consideration when electing which technique to perform . ExocrinDuring clinical investigations of refractory pain after Beger procedure, imaging may reveal worsened pancreas parenchymal abnormalities and protein plugs due to defective drainage of a narrowed main pancreatic duct or pancreaticojejunal anastomosis stricture. This case demonstrates an uncommon complication of Beger procedure. Therefore, patients that undergo surgical treatment have to be closely monitored in an outpatient clinic in order to guarantee postoperative conservative treatment and early detection of possible complications related to the initial surgical procedure."}
+{"text": "Vestibular migraine (VM) has been increasingly recognized as a possible cause of episodic vertigo, but its pathophysiology is still unclear.We used advanced non-invasive neuroimaging to examine the functional response of neural pathways associated with vestibular stimulation in patients with VM.Twelve patients with VM underwent whole-brain blood oxygen level-dependent (BOLD) fMRI during ear irrigation with cold water. The functional response of neural pathways to this stimulation in patients with VM was compared to age- and gender-matched patients with migraine without aura (MwoA) and healthy controls (HC). Secondary analyses explored associations between BOLD signal change and clinical features of migraine in patients.We observed a robust cortical and subcortical pattern of BOLD signal change in response to ear irrigation across all participants. Patients with VM showed significantly increased thalamic activation in comparison with both patients with MwoA and HC. The magnitude of thalamic activation was positively correlated with the frequency of migraine attacks in patients with VM.We provide novel evidence for abnormal thalamic functional response to vestibular stimulation in patients with VM. These functional abnormalities in central vestibular processing may contribute to VM pathophysiology.No conflict of interest."}
+{"text": "Periodontitis is an established common chronic disease, yet its burden on health care costs remains largely neglected. The aim of this study was to estimate the cost of periodontal procedures in dental specialist clinics in the Malaysian public sector.Five periodontal specialist clinics in the Ministry of Health were randomly selected. A list of periodontal procedures was identified by an expert group. Procedures were classified as diagnostics, non-surgical periodontics and periodontal surgeries. Costing for each procedure was primarily activity-based to measure cost of dental equipment, consumables and labour cost (average treatment time). Expenditures for administration, utilities and maintenance at clinics used unit cost calculations employed from step-down approach. A total of 165 patients newly diagnosed with periodontitis were followed up for one year to determine the cost of managing these patients during the said period.A total examination package costed USD38, but separate diagnostics procedures such as full-mouth periodontal assessment, electric pulp test, intraoral and panoramic radiographs costed an average of USD23. For nonsurgical procedures, full-mouth supragingival scaling costed USD68 and full-mouth subgingival debridement costed USD135, higher if with systemic/ local delivery antibiotics. Costs for desensitisation, occlusal adjustments (with selective grinding) and splinting were USD41, USD42 and USD50, respectively. Surgical procedures cost an average of USD294 for resective surgeries and USD613 for regenerative surgeries. The total provider costs for managing periodontitis patients for one year was estimated to be USD805. The costs borne for patients requiring surgeries  was about three-fold  compared to those who required only nonsurgical periodontal treatment (USD540).Specialist dental treatment for periodontitis patients in the public sector is costly. Cost estimates obtained from this study are useful for estimating economic burden of specialist periodontitis management at the national level, as well as providing the basis for economic evaluation of the specialist periodontal care programme."}
+{"text": "WGS) and Next Generation Sequencing (here: NGS-CA) approaches were witnessed in the past few years, since cataloging or landscaping all possible cancer aberrations appears to be both scientifically relevant and useful for therapeutic strategies. This search has been performed through Medline using NGS with appropriate cancer types/subtypes definitions and paying particular attention to the major overviews from groups on both sides of the Atlantic . The scope here is to overview general pitfalls and perspectives in the whole area of NGS-CA studies and to suggest probable trends and prudent recommendations.Great increase in Whole Genome Sequencing (elstein:  and 2]))WGS) andWGS-NGS studies have been published so far on neuroblastoma or other pediatric tumors  is stCAN-GEN approach ) demo) demoint pursued  ."}
+{"text": "A 73-year-old lady sustained mutliple injuries including pelvic fractures and extensive soft tissue injuries to her left groin and thigh after being run over by a car and trailer. Closed internal degloving injury of the left thigh was diagnosed and required surgical management.How should this patient be managed initially?What is a Morel-Lavallee lesion?Describe the pathophysiology of this injury?How is this injury managed surgically?The patient was transferred to a major trauma hospital with injuries to her left arm, trunk, groin, and leg for assessment and management. Initial management followed the Advanced Trauma Life Support principles. On arrival to the emergency department, her airway was patent, breathing spontaneously, with a heart rate of 70, blood pressure of 100/60, and Glasgow Coma Scale of 15. Examination revealed multiple soft tissue and skeletal injuries. Initial investigations showed Hb 90, unremarkable chest X-ray with plain trauma films demonstrating comminuted left superior and inferior pubic rami fractures and left wrist fractures. Computed tomographic scan showed the pelvic fractures and subcutaneous emphysema involving the left anterior thigh and anterior abdominal wall due to extensive thigh degloving injury.The lady sustained significant soft tissue injury and pelvic trauma from a low-velocity motor vehicle accident. On examination, she had extensive contusions and abrasions to the left proximal thigh extending to groin and posteriorly to the buttock, as well as a perineal hematoma. Closed internal degloving injury is caused by blunt injury producing significant soft tissue injury that is associated with pelvic trauma. A Morel-Lavallee lesion is a closed internal degloving injury overlying the greater trochanter.1The injury occurs when the subcutaneous tissue is sheared from the underlying fascia with avulsion of the perforating vessels. The cavity is filled with hematoma and liquefied adipose tissue. The force exerted on the superficial soft tissue also disrupts the vascular supply to the skin. This can also cause abrasions or friction burns.The patient underwent exploration and washout in theater with 1.7 L of haemoserous fluid drained initially from the cavity. Thorough debridement of devascularized tissue is the mainstay of surgical management of internal degloving injuries. Often multiple debridement procedures are required to excise nonviable tissue, with vacuum-assisted closure useful for temporary coverage. (3) In some instances, the patient's condition may dictate a delay to complete debridement. Similarly, extensive open avulsion type soft tissue injuries require staged debridement. (2) Expanding hematoma in the zone of injury may further jeopardize the overlying tissue and requires immediate drainage, either percutaneously or open. (4) Delayed closure of skin flaps and/or split-thickness skin graft are used to repair the defect after adequate debridement. Undamaged but avascular skin can be reapplied to the debrided surface as a full-thickness skin graft after excising the subcutaneous fat. (2) The patient was stabilized in intensive care unit, and the left thigh skin was allowed to demarcate and then debridement and application of negative pressure dressing (vacuum-assisted closure) was performed. She required multiple procedures for further washouts and change of dressings. The defect was reconstructed with split-thickness skin graft  and skin flap repair with sutures and autologous platelet enriched/bovine thrombin glue.Closed internal degloving injuries require prompt surgical assessment. Patient factors including severity of skeletal injuries direct the surgical management of the associated soft tissue injury but debridement and delayed repair remains the mainstay of treatment."}
+{"text": "Ranitomeya variabilis. This species deposits its tadpoles and egg clutches in phytotelmata and chemically recognizes and avoids sites with both predatory conspecific and non-predatory heterospecific tadpoles . Combining chemical analyses with in-situ bioassays, we identified the molecular formulas of the chemical compounds triggering this behavior. We found that both species produce distinct chemical compound combinations, suggesting two separate communication systems. Bringing these results into an ecological context, we classify the conspecific R. variabilis compounds as chemical cues, advantageous only to the receivers (the adult frogs), not the emitters (the tadpoles). The heterospecific compounds, however, are suggested to be chemical signals , being advantageous to the emitters (the heterospecific tadpoles) and likely also to the receivers (the adult frogs). Due to these assumed receiver benefits, the heterospecific compounds are possibly synomones which are advantageous to both emitter and receiver \u2012 a very rare communication system between animal species, especially vertebrates.The evolution of chemical communication and the discrimination between evolved functions  and unintentional releases (cues) are among the most challenging issues in chemical ecology. The accurate classification of inter- or intraspecific chemical communication is often puzzling. Here we report on two different communication systems triggering the same parental care behavior in the poison frog  Communication in the biological sense is defined by Wilson  as the aRanitomeya variabilis )S1 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."}
+{"text": "One of the most critical shifts must be away from top-down mercury policy toward active engagement with ASGM communities to effectively address the underlying social and economic reasons why mercury is used. Notably, Annex C of the Convention  requiresStrategies should reflect lessons learned in past programs about the mining policies required for mercury reduction solutions to take hold in ASGM communities. The United Nations Industrial Development Organization (UNIDO) conducted mercury abatement programs in ASGM that yielded some positive results , includiTo convey messages about mercury risks and mercury-free alternatives, community-based approaches can be more effective than conventional technical strategies that have dominated mercury-reduction initiatives. In Zimbabwe, UNIDO mercury abatement campaigns had some promising results in promoting cleaner technologies using such alternative approaches . In KadoFinally, public health officials and others should ensure that ambitious mercury reduction targets are not used as a rationale for harshly policing impoverished mining communities. The government of Zimbabwe implemented heavy-handed police crackdowns on ASGM between 2006 and 2009, which had negative environmental and social repercussions, weakening trust between regulators and low-income mining communities . More thThe challenges of reducing mercury use in ASGM have long been documented, as noted previously . We stro"}
+{"text": "Controversy exists regarding the structural and functional causes of hallux limitus including metatarsus primus elevatus, long first metatarsal, first ray hypermobility, shape of the first metatarsal head and the presence of hallux interphalangeus. Papers have reported on the radiographic evaluation of these measurements in feet affected by hallux limitus, however no study to date has made direct comparisons between the affected and unaffected foot in a group of patients with unilateral hallux limitus. This case-control pilot study aimed to establish if any such differences existed.Dorsoplantar and lateral weightbearing x-rays of both feet in 30 patients with unilateral hallux limitus were assessed for grade of disease, lateral intermetatarsal angle, metatarsal protrusion distance, plantar gapping at the first metatarso-cuneiform joint, metatarsal head shape and hallux abductus interphalangeus angle. Data analysis was performed using SPSS version 22.0.0.0 .Mean radiographic measurements for both affected and unaffected feet demonstrated that metatarsus primus elevatus, a short first metatarsal, first ray hypermobility, a flat metatarsal head shape and hallux interphalangeus were prevalent in both feet. There was no statistically significant difference found between feet for any of the radiographic parameters measured .No significant differences exist in the presence of structural risk factors examined between the affected and unaffected foot in patients with unilateral hallux limitus. The influence of other intrinsic factors including footedness and family history should be investigated further."}
+{"text": "Hypertrophic cardiomyopathy is a common cardiovascular genetic disease characterized by sarcomeric gene mutations which lead to findings of cardiac hypertrophy, myocyte disarray, and fibrosis. While late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) detects focal, macroscopic regions of replacement fibrosis non-invasively, novel T1 CMR measurement techniques including extracellular volume fraction (ECV) diffuse interstitial fibrosis throughout the myocardium. Plasma B-type natriuretic peptide levels are often elevated in situations of increased wall tension and volume overload. Given that such states may be associated with myocardial fibrosis, and because BNP levels provide independent prognostic insight in HCM, we sought to determine the association between BNP and ECV measurement by CMR.We recruited 50 consecutive patients referred to the UPMC Hypertrophic Cardiomyopathy Center and UPMC Cardiovascular Magnetic Resonance Center for clinical evaluation to participate in a prospective cohort formed to describe the association between CMR data and outcomes. Contemporaneous echocardiography, treadmill stress echocardiography, and clinical evaluation data were recorded. BNP levels were obtained as part of routine clinical care or drawn the same day as CMR study using research funding. We computed ECV from measures of pre and post contrast T1 of mid-myocardium and blood (short axis prescriptions at the base and mid ventricle) using modified Look-Locker inversion recovery (MOLLI) pulse sequences. BNP levels were natural log transformed given their skewed distribution. Univariable and multivariable regression models tested for associations between markers of cardiac remodeling as well as other predictors of BNP , left ventricular outflow obstruction, body mass index(BMI), findings of late gadolinium enhancement, ECV). Models were constrained to 4 independent variables to avoid overfitting.There was a moderate correlation  between lnBNP and ECV (Figure We found a novel association between lnBNP and ECV by CMR, after adjustment for confounding variables. The relationship persisted even after including LGE in regression models and stratifying by its presence. BNP and ECV are both strong predictors of adverse events. Detection of diffuse interstitial fibrosis by ECV may be a meaningful imaging biomarker to characterize HCM status, progression, and outcomes and warrants further study.American Heart Association, Pittsburgh Foundation."}
+{"text": "Saccadic eye movements are made about twice a second to shift our gaze either consciously or unconsciously. Brainstem burst neurons trigger each saccade with a bursting activity closely related to saccadic velocity that must be transformed into persistent firing activity to maintain post-saccadic eye position. A conceptual neural mechanism achieving this velocity to position integration is the oculomotor neural integrator (NI). Neurons in the nucleus of prepositus hypoglossi (NPH) in mammals and equivalently Area I (AI) in goldfish have been demonstrated to exhibit persistent activity relating to eye position. Ipsilateral positive feedback found in NPH and AI , and comThe model consists of an excitatory burst neuron (EBN), an inhibitory burst neuron (IBN), a tonic neuron (TN), and a bilateral NI network in which 15 integrator neurons (INs) are included unilaterally. Each IN receives input from TN, EBN, and IBN, and also has positive recurrent feedback connections from all ipsilateral INs including commissural inhibitory connections from all contralateral INs. The output of EBN, IBN, and each NI are weighted-summed at a motor neuron whose output is sent to an eye plant model to simulate eye movements. These neuron models are described as conductance-based spiking neurons. Synaptic weights in the model were carefully tuned to reproduce saccades and post-saccadic stable eye positions. Following individual modification of either the synaptic weights of ipsilateral feedback connection or those of commissural inhibition we measured post-saccadic eye position drift.Simulation results showed that persistent firing activity of INs is maintained principally by the ipsilateral positive feedback. By contrast, commissural inhibition contributed mainly to null eye position which is the asymptote from which the NI becomes leaky. These findings are the first demonstration by a NI neuronal network model assigning specific and different roles to the ipsilateral positive feedback and the commissural inhibition. In future work, we will use this model to evaluate the elective eye holding properties within the two hemi-field NIs."}
+{"text": "Parkinson\u2019s disease (PD) is one of the most common movement disorders in adults, often cannot be adequately controlled with medical treatment, and thereby treated with the neurosurgical procedures. Unilateral pallidotomy, making a lesion in the globus pallidus pars interna (GPi), was the predominant surgical technique until early 1900s. Thereafter, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a mainstream surgical technique for managing not only the cardinal dopaminergic features of PD, but also levodopa-induced motor fluctuations and dyskinesia.Recent review studies, however, reported that unilateral pallidotomy also has long-term effect on both cardinal symptoms  and motor complications . Currently, transcranial magnetic resonance guided focused ultrasound (MRgFUS), without necessity of opening the cranium, has been developed as a minimal invasive surgical technique, generating precise and focal thermal lesion in the brain compared to previous radiofrequency thermal lesion.The authors underwent world first MRgFUS pallidotomy to confirm its efficacy as well as potential side effects. We hereby demonstrated the beneficial effects of MRgFUS pallidotomy in PD patient for improving levodopa induced dyskinesia as well as motor symptoms."}
+{"text": "Volition is generally considered as a defining human faculty; but the outcome of a voluntary decision can be predicted by brain activity even before subject\u2019s conscious awareness , and simGymnotus sp. revealed a bimodal distribution of electric organ discharge rate (EODR) demonstrating Down- and Up-states of sensory sampling and neural activity; movements only occurred during Up-states and Up-states were initiated before movement-onset. EODR during voluntary swimming initiation exhibited greater trial-to-trial variability than the sound-evoked increases in EODR. The sensory sampling variability increased before, and declined after voluntary movement onset as previously observed for the neural variability associated with decision-making in primates [Cortical activity precedes self-initiated movements by several seconds in mammals; this observation has led into inquiries on the nature of volition . Preparaprimates . In contprimates . SpontanUsing statistical analyses of spontaneous exploratory behaviors and associated preparatory sensory sampling increase, we conclude that electric fish exhibit all the established hallmarks of volition, and that voluntary behaviors in vertebrates may generally be preceded by increased sensory sampling. The dorsal telencephalon is required for spatial learning in teleosts and might initiate movement via its projections to the tectum . Our res"}
+{"text": "Subarachnoid hemorrhage may be complicated by neurogenic stunned myocardium, a catecholamine-induced transient cardiomyopathy that displays a wide clinical spectrum of cardiac abnormalities, including electrocardiographic changes, arrhythmias, myocardial necrosis, and left ventricular systolic and diastolic dysfunction. However, less is known about the cardiac metabolic consequences of acute subarachnoid hemorrhage. Prunet and coworkers\u2019 recent study provides scintigraphic evidence suggesting that glucose metabolism and sympathetic cardiac innervation are severely and globally depressed during the acute phase of the disease. Metabolic and innervation abnormalities are largely overlapped and are probably not causally related to myocardial ischemia, suggesting that impaired glucose metabolism is probably neurogenic in nature. The scintigraphic defects seem to reverse slowly, within months of the onset of cerebral bleeding. Interestingly, scintigraphic evidence of metabolic myocardial alterations may exist even in the absence of clinical features of cardiac disease, possibly representing a subclinical type of neurogenic stunned myocardium. Critical Care deals with this poorly studied area [Subarachnoid hemorrhage (SAH) may cause transient cardiac dysfunction, possibly attributed to massive release of catecholamines. The influence of catecholamine oversecretion on cardiac metabolism has been extensively studied in Takotsubo cardiomyopathy (TTC), which is also considered catecholamine induced in nature. However, data regarding acute myocardial metabolic alterations in SAH are sparse. The recent article by Prunet and colleagues in ied area .18\u2009F-fluorodesoxyglucose positron emission tomography) and sympathetic innervation (studied by 123I-meta-iodobenzylguanidine scintigraphy) in 83.3% (25/30) and 90% (27/30), respectively, of 30 patients with acute SAH. Despite extensive changes in glucose metabolism and innervation, coronary perfusion was not affected. The topography and extent of metabolic and innervation scintigraphic defects were largely overlapped, supporting the hypothesis that metabolic shifts occurred secondarily to neurocardiogenic injury rather than cardiac ischemia [123I-meta-iodobenzylguanidine scintigraphy 6\u00a0months later [In their recent article, Prunet and coworkers assessed myocardial glucose metabolism and sympathetic innervation in SAH by means of scintigraphy, and investigated the possible associations with left ventricular (LV) systolic and diastolic dysfunction, troponin elevation and SAH outcomes . The autSAH-induced neurocardiogenic injury demonstrates comparable scintigraphic features ,5 with TAlthough increased adrenergic tone has been accounted for in both SAH and TTC , there mWhat is remarkable in the study by Prunet and colleagues is not the detection of neurometabolic myocardial alterations in SAH \u2013 such changes might probably be expected, since similar findings have been described in TTC. No, what is remarkable is that regional scintigraphic defects may widely exist within myocardium of SAH patients without clinical, echocardiographic or laboratory evidence of neurogenic stunned myocardium (NSM). The term NSM has been introduced to describe myocardial injury and dysfunction occurring after diverse types of acute brain injury (including SAH) as a result of imbalance of the autonomic nervous system . The diaOne should point out that the presence of neurometabolic cardiac abnormalities showed no association with clinical outcomes in Prunet and colleagues\u2019 study . HoweverIn conclusion, the study by Prunet and colleagues underlines two different aspects in SAH. First, alterations in glucose metabolism, possibly neurogenic in origin, may affect widely the myocardium during the acute phase of SAH. Second, and more important, the study emphasizes that prolonged and slowly reversible neurometabolic abnormalities may globally occur in SAH even when conventional cardiac evaluation is negative for NSM. The clinical impact of such neurometabolic shifts may be greatly underestimated, as they are difficult to diagnose in the clinical practice. Additional research, including also hemodynamically unstable patients with depressed LV function, is necessary to clarify further the role of neurometabolic cardiac alterations in acute SAH."}
+{"text": "Diagnostic assays that leverage bloodborne neuron-derived  nanoscale extracellular vesicles (nsEVs) as \u201cwindows into the brain\u201d can predict incidence of Alzheimer's Disease (AD) many years prior to onset. Beyond diagnostics, bloodborne neuronal nsEVs analysis may have substantial translational impact by revealing mechanisms of AD pathology; such knowledge could enlighten new drug targets and lead to new therapeutic approaches. The potential to establish three-dimensional nsEV analysis methods that characterize highly purified bloodborne nsEV populations in method of enrichment, cell type origin, and protein or RNA abundance dimensions could bring this promise to bear by yielding nsEV \u201comics\u201d datasets that uncover new AD biomarkers and enable AD therapeutic development. In this review we provide a survey of both the current status of and new developments on the horizon in the field of neuronal nsEV analysis. This survey is supplemented by a discussion of the potential to translate such neuronal nsEV analyses to AD clinical diagnostic applications and drug development. Bloodborne neuron-derived  nanoscale extracellular vesicles (nsEVs) have shown substantial potential as \u201cwindows into the brain\u201d that enlighten central nervous system (CNS) disorder-associated changes in brain biochemistry and intercellular communication \u20137. This There are no universally accepted criteria for classifying nsEVs. This lack of standard taxonomy creates ambiguity in interpreting and communicating the results of nsEV-related experiments. Our simple classification system defines nsEVs as cell-derived vesicles with submicron diameters and groups them into two categories: exosomes and ectosomes.Exosomes are manufactured within multivesicular bodies (MVBs), cytoplasmic vesicles that have diameters in the 250\u20131,000\u2009nm range , 9, and Others have categorized ectosomes into a number of somewhat ambiguous subclasses: shedding vesicles, microvesicles, exosome-like vesicles, nanoparticles, microparticles, and oncosomes . AlthougnsEVs with diameters between 100\u2009nm and 200\u2009nm can be either exosomes or ectosomes; the vesicle category into which a given nsEV would be classified would be determined by whether the nsEV is formed within a MVB or budded off from the cell plasma membrane. The preceding sentence is framed in a hypothetical sense because, as suggested by the above remarks regarding tetraspanins being common to both exosomes and ectosomes, there are no existing analytical methods that allow one to determine whether a given nsEV isolated from blood was formed inside of a MVB or is instead the product of budding from the plasma membrane.nsEVs encapsulate nucleic acids, primarily microRNAs (miRNAs) and messenger RNAs (mRNAs). nsEVs also feature integral membrane proteins, proteins covalently bound to nsEV membranes, proteins noncovalently associated with nsEV membranes, and proteins that occupy nsEV interior volumes. nsEVs' principal function is transferring signals from sender to recipient cells. nsEVs originating from sender cells can fuse with membranes of and release their contents into the cytoplasm of recipient cells  or have Given the desire to leverage bloodborne nsEV analysis in enlightening AD-associated changes and brain biochemistry and intercellular signaling processes, we note here that neuronal nsEVs have been observed to migrate from the CNS into the bloodstream in animal experiments . The exiThe predictive ability of bloodborne neuronal nsEV analysis illustrated by the biomarker validation studies of Goetzl and coworkers, which accurately forecasted AD onset up to ten years prior to clinical diagnosis \u20134, has gThe first step in Goetzl's nsEV AD biomarker quantification process was chemical precipitation (CP) to isolate nsEVs from plasma. After nsEV precipitation, neuronal nsEVs were enriched from the bulk nsEV population using streptavidin-coated agarose beads loaded with biotinylated anti-neuronal marker protein (CD171) Abs. Finally, nsEVs were exposed to lysing conditions and biomarker proteins in nsEV lysates were quantified by ELISA. The Cartesian coordinate system of As illustrated in The third nsEV analysis dimension, biomarker abundance, differs from the other two dimensions in that biomarker abundance, and thus position on the biomarker abundance axis, is dictated by nsEV composition. The researcher chooses which biomarker(s) to quantify and thus defines biomarker abundance axis label(s). As discussed in The underexplored opportunity in the area of leveraging bloodborne neuronal nsEV omics profiling in AD biomarker discovery for drug molecule and therapeutic modality development is well framed by discussing existing neuronal nsEV AD biomarker validation and discovery-related literature; the latter is particularly relevant to utilizing neuronal nsEV analysis in identification of novel drug targets and establishment of new treatment paradigms. In this discussion we define nsEV biomarkers as protein or nucleic acid nsEV constituents with abundances that differ in diseased relative to normal subjects. This definition encompasses nsEV-associated molecules with relative abundances that change prior to clinical manifestation of disease symptoms and thus can be predictive of disease onset as well as molecules with abundances that change as functions of disease progression or reversion due to positive treatment responses.\u03b242)  experiments featuring nanogold-conjugated Ab labeling  of respeThere are several technical considerations that are important for generating nsEV omics datasets that would enable 3D nsEV analysis such as depicted in Obtaining neuronal nsEV omics datasets using methods described above will provide omics analyses with even greater translational potential. Next generation analyses could be enabled by advances in two emerging areas: microfluidic devices that sort bloodborne neuronal nsEV subpopulations directly from plasma based on abundances of multiple nsEV surface markers and engineered Abs or aptamers that bind epitopes exclusive to AD neuronal nsEV exteriors.6-fold lower than cell volumes, to flow cytometric sorting of individual nsEVs. First, nsEV flow rate must be rigorously controlled to prevent \u201cswarming,\u201d a phenomenon causing groups of nsEVs to be detected as single fluorescence events and leading to encapsulation of multiple nsEVs within sorted fluid droplets [There are two primary obstacles, which arise from nsEV volumes being 10droplets . Second,droplets . The utiFurther development of existing nonstandard flow cytometers could allow swarming and autofluorescence issues to be overcome. Regarding swarming, Pulse Laser Activated Cell Sorter (PLACS) microfluidics devices  achieve Proteins with posttranslational modifications such as glycation, glycosylation, and nitration \u201337 can gAntigen-loaded Dynabeads are routinely used for probe library screening . As suchMulticolor nsEV cytometry with various combinations of AD nsEV-specific probes and/or commercial Abs against AD nsEV biomarker surface proteins identified by proteomic profiling can address the important question of whether the overall bloodborne neuronal nsEV population is comprised of distinct subpopulations featuring different combinations of AD-specific surface proteins and/or epitopes. Sorting nsEV subpopulations would facilitate downstream omics and/or individual AD biomarker analyses that may enlighten both cell-to-cell heterogeneity of AD-associated changes in neuronal molecular composition and the existence of neuronal nsEVs that carry distinct groups of signaling molecules. Knowledge of such heterogeneity and distinct modes of intercellular communication could enlighten the interplay among different mechanisms of AD pathology and thus be a valuable facilitator of AD drug target identification and therapeutic development.With respect to forthcoming developments in the area of neuronal nsEV diagnostics hardware for clinical applications, recent progress in miniaturizing complex laboratory operations suggests that the future may prove to hold substantial advances in terms of constructing portable devices for point-of-care quantification of neuronal nsEV biomarkers. Regarding the specifics of this recent progress, protein microarray-based multiplex fluorescent ELISA assays  and accuAdvances in neuronal nsEV isolation and analysis methods that leverage neuronal nsEVs could provide \u201cwindows into the brain\u201d using noninvasive diagnostic assays, requiring only microliters of blood obtained during routine doctor's office visits, which quantify Alzheimer's Disease (AD) biomarker proteins in nsEVs. Such assays could enable rapid diagnosis for CNS disorders and facilitate the development of personalized treatment programs. Continued increases in public and private funding for nsEV-focused research should enable realization of this goal in a timely manner and hasten the development of next generation nsEV analyses that provide a more accurate analysis of AD biomarkers in plasma. Although it will take time, as has been the case for the human genome sequence, to translate omics-derived AD biomarker discoveries from bench-to-bedside, it is clear that the ever-increasing convergence of biomedical research will augment the relative rate of translation. As such, it is anticipated that we are only years, rather than decades, away from seeing drugs and/or therapeutic modalities inspired by 3D bloodborne neuronal nsEV analyses have a clinical impact in treating this devastating disease."}
+{"text": "ReGeneraTing Agents (RGTAs) are a family of polymers bioengineered to stabilise heparin-binding growth factors by mimicking HeparanSulphate (HS) thereby protecting them and promoting tissue repair and regeneration. In inflammation, destruction of HS exposes the ExtraCellularMatrix \u2013 ECM  to the actions of proteases and glycanases which break them down and also act on cytokines and growth factors to prevent adequate repair. In injured tissue, RGTAs would replace destroyed HS by binding to the structural proteins and reconstruct the ECM scaffold. Growth factors will also bind to RGTA and resume position and organization resembling that of non-injured tissue. Hence RGTAs showed they induce a regeneration process by restoring -the proper cellular micro-environment. More recently a RGTA named CACIPLIQ20 was adapted to skin lesions and has shown efficacy in various trials of non-healing leg ulcers.In this pilot prospective study, we applied the same RGTA with meticulous wound care techniques practiced on 10 patients with wounds of varying sizes (average of 13cm\u00b2) and depth but with the same underlying theme of poor vascularity and using the recommended sterile application technique twice a week until the wounds healed or over-granulation occurred.All wounds eventually healed, even chronic ones. We found that granulation tissue grew again where there was dead skin  and no visible underlying blood supply which in usual circumstances would have resulted in loss of limb length,dry gangrene or at best healing by severe scarring. Exposed tendons were also covered with granulation tissue, but instead of a scarred non-mobile digit, simultaneous therapy resulted in a fair range of motion. Full thickness palmar and dorsal wounds also granulated and the dorsal wound healed beautifully reproducing a flexible movable dorsal surface not seen in granulating, scarred healing.The revascularisation, development of non-adherent coverage reproducing normal skin features and mobility preserved overlying tendons all suggest that RGTA is a promising alternative treatment."}
+{"text": "Only scarce data is available on early infection by human T-lymphotropic virus (HTLV). In particular, the modes of clonal selection during primary infection cannot be analyzed due to the paucity of available samples. Therefore, we addressed this question in a closely related animal model, bovine leukemia virus (BLV). As HTLV, BLV persist indefinitely into its host and is generally asymptomatic but can also lead to lymphoma or leukemia. Both viruses replicate by colonizing new lymphocytes or via clonal proliferation of infected cells. However, the modes of replication occurring soon after infection of new hosts are currently unknown. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the BLV-infected B-cell population (i.e. the number of distinct clones and abundance of each clone). We found that BLV propagation shifts from cell neoinfection to clonal proliferation in less than 3 months post-inoculation. Initially, BLV proviral integration significantly favors transcribed regions of the genome. Negative selection then eliminates more than 96% of the clones detected at seroconversion and disfavoring BLV-infected B-cells carrying a provirus located close to a promoter or a gene. This selection is more stringent in animals where proviral load set point is low. Among the surviving proviruses, clone abundance nevertheless positively correlates with proximity to a transcribed unit or a CpG island. We conclude that massive clone selection occurs during primary infection disfavoring proviruses located nearby genes and this selection is stronger in low proviral load animals."}
+{"text": "A 49-year-old man with intermittent headaches and right sided parietal lump was found to have an intraosseous right parietal lesion on computed tomography (CT) and magnetic resonance imaging (MRI). A stereotactic craniectomy and excision of the lesion were performed with histopathology confirming features consistent with primary lipomatous meningioma with intraosseous extension. Lipomatous meningiomas are very uncommon subtype of meningiomas, with ongoing discussions as to their true pathogenesis. To our knowledge this case represents the first reported case of a lipomatous meningioma with predominant intraosseous extension. A 49-year-old Caucasian male who works as a joiner presented with intermittent headaches and a progressively increasing right sided parietal lump. He denied any history of trauma or infective process and past medical history was unremarkable. The physical examination was normal apart from a palpable nonfluctuating, nontender mass overlying the right parietal region.Skull X-ray, CT brain, and MRI brain revealed a single solitary lytic lesion within the right parietal bone with immense thinning of the outer table and erosion through the inner table without intracranial extension , althougThe patient underwent a stereotactic craniectomy of the right parietal lesion. A wide craniotomy was performed and upon elevation of the bone flap a small defect in the dura was present with what appeared to be an arachnoid granulation, consistent with the observations on the MRI. A pale white, well-delineated tumour could be seen eroding through the bone. A dural resection was performed around a small attached tan coloured tumour and the brain was inspected with no evidence of tumour involvement. Ensuring clear margins, duraplasty and cranioplasty were performed.Histology of the skull flap revealed cyst-like spaces surrounded by meningioma with foci showing typical meningothelial morphology interspersed with areas composed of cells showing variable vacuolation Figures . Area ofLipomatous meningiomas are rare subtypes of meningiomas. First described by Bailey and Bucy in 1931 . The WHOMetaplastic lipomatous meningiomas can be defined as meningiomas with striking focal or widespread mesenchymal areas, including osseous, cartilaginous, lipomatous, myxoid, or xanthomatous tissue components . LipomatThroughout the English literature 41 cases of lipomatous meningiomas have been described , one ass"}
+{"text": "This clinical trial is testing whether drugs that inhibit pain processing pathways in the brain can help with pain in the hand caused by osteoarthritis. Other clinical studies include the \u2018Pain Perception in Osteoarthritis\u2019, or PAPO study, investigating tissue damage and pain in people undergoing knee replacement surgery for osteoarthritis. Both studies are on the UK NIHR portfolio of network-adopted studies.The Sofat laboratory currently investigates the mechanisms responsible for pain and tissue damage in arthritis. Clinical studies include \u2018Pain management in osteoarthritis using centrally acting analgesics\u2019  to decipher regions of damage in affected joints and evaluating which brain regions are activated by arthritis pain. We also use non-invasive quantitative sensory testing (QST) methods to identify pain pathways. QST identifies sensation and pain thresholds by stimulating the skin.Our laboratory research uses a basic science mechanistic approach to investigate the influence of endogenous damage-associated molecular patterns (DAMPs) in driving chronic inflammation in joints. Molecules of interest include interaction of the DAMPs tenascin-C and fibronectin with oral pathogens."}
+{"text": "Chest compression during cardiopulmonary resuscitation (CPR) could bring out unintended complications which are mainly composed of chest injuries. The aim of this study was to assess whether there was a significant difference in the complications of CPR between out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) survivors using multidetector computed tomography (MDCT).We performed a retrospective cohort study in the emergency departments of two academic tertiary care centres from January 2009 to May 2014. We enrolled both OHCA and IHCA patients who underwent successful CPR. The enrolled patients had undergone a chest CT within 48 hours after ROSC. We evaluated the MDCT findings of the CPR-related chest injuries and compared complications between OHCA and IHCA patients.[AQ1]A total of 148 patients were finally enrolled in this study, OHCA were 89 (60.1%) and IHCA were 59 (39.8%). The mean CPR time, both in-hospital and total, was longer in OHCA survivors. Rib fractures were detected more in OHCA survivors. Frequency of multiple rib fractures was higher in OHCA survivors. Frequency of sternum fractures was higher in OHCA survivors, showing no significant difference. In lung injuries, lung contusion and pneumothorax account for the large part, and OHCA survivors had higher incidence in both complications but statistically insignificant. Major complications occurred in eight cases in OHCA survivors and three cases in IHCA survivors during the study period. After adjusting for the time factor in multiple logistic regression analysis, rib fractures and multiple rib fractures became statistically significant in OHCA survivors. See Figures Frequency of rib fractures and multiple rib fractures were higher in OHCA survivors. Further investigation is needed into the relation between the location of CPR and the CPR-related injuries, efforts to reduce the complications after CPR."}
+{"text": "Boechera stricta (rockcress), a close perennial relative of model plant Arabidopsis. First, using Bayesian kriging, we mapped the topography and environmental gradients and explored the spatial distribution of naturally occurring rockcress plants and two neighbors, Taraxacum officinale (dandelion) and Solidago missouriensis (goldenrod) found in close proximity within a typical diverse meadow community across topographic and environmental gradients. We then evaluated direct and indirect relationships among variables using Mantel path analysis and developed a network displaying abiotic and biotic interactions in this community. We found significant spatial autocorrelation among rockcress individuals, either because of common microhabitats as displayed by high density of individuals at lower elevation and high soil moisture area, or limited dispersal as shown by significant spatial autocorrelation of naturally occurring inbred lines, or a combination of both. Goldenrod and dandelion density around rockcress does not show any direct relationship with rockcress fecundity, possibly due to spatial segregation of resources. However, dandelion density around rockcress shows an indirect negative influence on rockcress fecundity via herbivory, indicating interspecific competition. Overall, we suggest that common microhabitat preference and limited dispersal are the main drivers for spatial distribution. However, intra-specific interactions and insect herbivory are the main drivers of rockcress performance in the meadow community.This study investigates the relative influence of biotic and abiotic factors on community dynamics using an integrated approach and highlights the influence of space on genotypic and phenotypic traits in plant community structure. We examined the relative influence of topography, environment, spatial distance, and intra- and interspecific interactions on spatial distribution and performance of  Boechera stricta (rockcress), an emerging ecological model plant species . Second, we determined the spatial structure of environmental and intra- and interspecific variables (see Methods for detailed description of these variables) using piecewise Mantel correlograms , aspen (Populus tremuloides), birch (Betula spp.), and burr oak (Quercus macrocarpa). Other common plant species that inhabited the meadow were goldenrod (Solidago missouriensis), dandelion , mouse-ear chickweed (Cerastium vulgatum), snowberry , and sedge (Carex spp.). The relief between the highest and the lowest measured point across the study area was 9.55 m.We studied spatial distribution and performance of rockcress  grid. Please refer to Appendix for exact intervals for individual parameters. Flat priors  and reproduction , and line] of rockcress, density of neighboring plants (goldenrod density and dandelion density), and herbivory on rockcress leaves . Data were standardized before calculating Euclidean distances  of the individual bins of lag distance at every 2.5 m in the correlograms. A pairwise correlation between all the variables was determined using simple Mantel test that guided the path analysis.A correlogram in this context is a plot of the spatial autocorrelation with lag distance, and the Mantel test can be used to test the significance of the correlations. A simple Mantel test Mantel,  was perfa priori hypothesis that A effects B and B effects C, the partial Mantel test can be used to test if C effects A in the absence of B, C~ A|B. If A and/or C displayed significant spatial autocorrelation then space was added as an additional partial, C~A|Space + B, in the partial Mantel test  on underlying ecological processes by looking at the relationship between two variables and keeping all other variables constant. For example, given the P = 0.05, Figure P \u2264 0.05) spatial autocorrelation among rockcress individuals  as well as a positive relationship between soil moisture and rockcress   Figure . The rel) Figure . Vapor p) Figure  and no i) Figure  but thisrosette diameter), reproduction , and line were significantly spatially autocorrelated  to 20.8 m (rosette diameter). Genetically similar individuals were found in close proximity of one another  spatial autocorrelation   around rockcress was positively correlated with rosette herbivory  was negatively correlated with fruit production (fruit number)  spatial autocorrelation in neighboring densities of goldenrod (range = 12.6 m) and dandelion (range = 12.6 m)  was the lowest among intra-specific traits that indicates greater intra-specific diversity of rockcress plants within short distances. Inter-specific interactions showed some indirect influence on rockcress distribution mediated through increased herbivory  than did performance or fitness measures (8\u201320 m) and landscape attributes , indicating that clustering of similar sized plants had both genetic and micro-environmental influences. To date, local adaptation in rockcress for defensive traits has been documented on a broad geographic scale  of rockcress is usually found in other mountain ranges (about 2500 m) . Probably as a consequence of lower and drier habitats in the Black Hills, we find rockcress on N-facing slopes and in shaded areas. Recent genotyping studies indicate that rockcress in the Black Hills probably originated from lower latitudes in the southern Rockies  are much lower than elevations where this species  that flea beetles tend to attract one another. It should be noted that we did not detect a significant correlation between line and herbivory, despite the detection of significant genetic variation from common garden experiments among these lines in resistance and glucosinolate toxin production in previous studies  and dense   enhanced our understanding of the underlying ecological processes of complex spatial interactions and allowed us to dissect direct and indirect effects of biotic and abiotic factors on distribution and performance of a rockcress population. Our attention to spatial distributions and associations expands the possible causations underlying community assembly associations over non-spatial analyses and our results help generate hypotheses for future experimental studies in ecological and evolutionary genomics.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Determining the exact genetic causes for a patient and providing definite molecular diagnoses are core elements of precision medicine. Individualized patient care is often limited by our current knowledge of disease etiologies and commonly used phenotypic-based diagnostic approach. The broad and incompletely understood phenotypic spectrum of a disease and various underlying genetic heterogeneity also present extra challenges to our clinical practice. With the rapid adaptation of new sequence technology in clinical setting for diagnostic purpose, phenotypic expansions of disease spectrum are becoming increasingly common. Understanding the underlying molecular mechanisms will help us to integrate genomic information into the workup of individualized patient care and make better clinical decisions. Medical textbooks usually provide characteristic descriptions of a disease and its progression. In reality, it can be challenging to recognize clinical presentations in an individual patient due to disease variations. Besides a few cases with classical presentations, many patients have atypical or overlapping manifestations. Understanding the similarities and differences between phenotypic abnormalities of human disease remains a major task for clinicians throughout their long medical training and practice. Meanwhile, precise and individualized diagnosis is often limited by current knowledge of disease etiologies. The large number of diseases, broad and incompletely understood phenotypic spectrums, and various genetic heterogeneity are all the contributing factors that hamper the diagnostic yield. A report from a clinical laboratory specializing in diagnostic exome sequencing discovered that about 5% of individuals in their patient cohort had two definitive genetic disorders . Such oc CFTR gene. Unlike this well-studied disorder, patients with defects in other single genes are often found to have broad clinical presentations without well-defined genotype-phenotype correlations. For example, DNA polymerase gamma (POLG) deficiency can lead to multiple categories of diseases, such as progressive external ophthalmoplegia, Alpers' syndrome, Parkinsonism, and juvenile spinocerebellar ataxia-epilepsy syndrome [ POLG related diseases is generally recessive, while autosomal dominant POLG mutations also exist. The clinical heterogeneity often makes diagnosis considerably difficult and contributes to diagnosis dilemmas. The clinical presentations of mitochondrial DNA (mtDNA) related disorders also show a wide spectrum of clinical variations. Despite relatively high prevalence of mitochondrial disorders, it is widely acknowledged that they are complex diseases to make a definite clinical diagnosis if based on clinical presentations exclusively [ SURF1 gene was found segregating with the disease; therefore, the diagnosis was revised to be Leigh syndrome [ VLDLR-associated congenital cerebellar ataxia with intellectual disability syndrome. However, the original clinical diagnosis is pontocerebellar hypoplasia since the clinical features were different from symptoms described for VLDLR-associated disease.Cystic fibrosis is a well-recognized single-gene disorder, and its disease severity can be roughly correlated to mutations observed in thesyndrome . The inhlusively . Presencsyndrome . In anot EBP gene encoding emopamil-binding protein [ EBP gene.Recently, a novel clinical syndrome was described for male patients with digital abnormalities, intellectual disability, and short stature in a multigeneration family . Extensi protein . As defe MAB21L2 gene were recently identified as a new cause of eye malformations. Interestingly, both dominant and recessive inheritance patterns were observed. The patients with the monoallelic mutations showed much more severe eye abnormalities as well as defects in other systems such as skeletal dysplasia, macrocephaly, and learning disability, while others with a biallelic mutation had only a mild eye phenotype and subtle dysmorphic facial features. This evidence indicated that the zygosity of a genetic defect can contribute to different pathogenic mechanisms [The type of genetic abnormalities can contribute to phenotype variations of a disease. A relatively large size of genomic aberration in terms of copy number variations (CNVs) is commonly seen in autosomal dominant or X-linked diseases. Point mutations are often observed in single-gene related autosomal recessive disorders. When types of point mutations range from nonsense, missense to splice site mutation, the corresponding clinical presentation can also differ considerably. Patients with nonsense mutation in alpha-1 type I collagen can have milder skeletal manifestation than these with missense mutation . Missenschanisms .Currently, clinicians need to know a variety of methodologies in order to request testing for a complete molecular profile of a gene. Patients can only afford a limited number of tests due to financial burden and thus do not have the necessary genetic workup. It is now possible to obtain a relatively comprehensive genetic workup within one assay to detect both point mutation and copy number variation for a set of different genes , 10. As  TBX6 gene [ TBX6 haplotype in this disease. After extensive linkage and genotyping analysis, it was revealed that copresence of a TBX6 null allele and a common haplotype containing three common single-nucleotide polymorphisms (SNPs) can lead to congenital scoliosis in patient. Thus, this common TBX6 haplotype acts as a hypomorphic genetic modifier to modulate the penetrance of the disease presentation in carriers of TBX6 null mutations.The penetrance of a disease phenotype can be influenced by combinatory effect of two alleles. Most recently, sequencing a cohort of patients with sporadic congenital scoliosis identified multiple heterozygous null mutations inBX6 gene . The disGenetic heterogeneity is one of the important factors to consider during genetic workup for disorders with overlapping clinical presentations. For disorders with relatively defined clinical phenotypes, such as glycogen storage disorder, both clinical evaluation and routine laboratory testing may provide initial clues leading to a correct clinical diagnosis. Regarding disorders with nearly indistinguishable clinical phenotypes, such as congenital defects of glycosylation, the result from biochemical testing may not be sufficient to narrow down a possible underlying genetic cause. As to disorders with a broad spectrum of clinical presentations, the large number of genes associated with these phenotypes makes it difficult or impossible to pinpoint an exact gene if molecular testing is not requested. Disease-targeted multigene panels and whole-exome sequencing allow precise molecular diagnosis made for patients with previously unrealized genetic defects , 14. MorEpistatic interactions have been recognized to play important roles in pathogenesis and phenotype variability . When moThe rapid progress of high-throughput genomic sequencing and corresponding analysis tools in molecular diagnosis have revolutionized the practice of clinical diagnosis . ComprehEnding the diagnostic odyssey, the FORGE (Finding of Rare Disease Genes) Canada Consortium identified genetic causes for 146 disorders over a 2-year period through a nation-wide collaboration effort among clinicians and scientists . Precisi"}
+{"text": "July is National Cleft and Craniofacial Awareness and Prevention Month, an observance intended to raise awareness and improve understanding of birth defects of the head and face. Common craniofacial birth defects include orofacial clefts , craniosynostosis (when the skull sutures join together prematurely), and anotia/microtia .This year, CDC highlights research on the association between smoking during early pregnancy and orofacial clefts. Although the causes of most orofacial clefts are unknown, the 2014 Surgeon General\u2019s report confirmed that maternal smoking during early pregnancy can cause orofacial clefts in babies (http://www.nccapm.org/about.html.Orofacial clefts occur very early in pregnancy. Health-care providers should encourage women who are thinking about becoming pregnant to quit smoking before pregnancy or as soon as they find out that they are pregnant. Additional information regarding National Cleft and Craniofacial Awareness and Prevention Month is available at"}
+{"text": "We present the case of a 63-year-old woman with limited metastatic colorectal cancer to the lungs and liver treated with FOLFIRI-bevacizumab, followed by consolidative hypofractionated radiotherapy to right paratracheal metastatic lymphadenopathy. We treated the right paratracheal site with 60 Gy in 15 fractions . The patient tolerated the treatment well, and six months later started a five-month course of FOLFIRI-bevacizumab for new metastatic disease. She presented to our clinic six months after completing this, complaining of productive cough with scant hemoptysis, and was found to have localized tracheal wall breakdown and diverticulum in the region of prior high-dose radiation therapy, threatening to progress to catastrophic tracheovascular fistula. This was successfully repaired surgically after a lack of response to conservative measures. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy. Bevacizumab is a monoclonal antibody that antagonizes the pro-angiogenic vascular endothelial growth factor (VEGF), and can be a highly effective agent for treating metastatic cancer; it inhibits tumor growth by limiting its blood supply. Bevacizumab has also been shown to be effective when given concurrently and adjuvantly with radiotherapy in the treatment of glioblastoma multiforme . HoweverWe report a case of a patient with oligometastatic colorectal cancer who was treated with FOLFIRI-bevacizumab followed two months later by hypofractionated radiotherapy, and six months later treated with\u00a0FOLFIRI-bevacizumab again. This patient unfortunately experienced a tracheal diverticulum 17 months after radiotherapy and six months after her second course of FOLFIRI-bevacizumab   imaging. Her most recent bronchoscopy, 15 months postsurgery, shows continued resolution of the tracheal diverticulum Figure . In thisCombination bevacizumab and radiotherapy has been shown to be effective for glioblastoma multiforme, but may be associated with significant adverse effects for treatment of other sites. This risk may be highest when treating mucosal sites. Stephens et al. showed increased rates of tracheoesophageal fistula within the radiation field in patients treated with VEGF inhibitors after hypofractionated radiotherapy adjacent to the esophagus . GoodgamIn this case, we administered highly conformal hypofractionated radiation therapy with definitive intent to an ultra-central right paratracheal nodal metastasis with the high dose region including a portion of the tracheal wall contralateral to the esophagus. Rather than tracheoesophageal fistula, we observed localized tracheal wall breakdown and diverticulum into the mediastinal fat after bevacizumab-containing systemic therapy was administered with a substantial time gap after the completion of radiation therapy. Because of concern of progression to potentially catastrophic fistula between the trachea and superior vena cava, a serratus muscle flap repair was performed with good success.The hypofractionated radiation therapy regimen we used, 60 Gy in 15 fractions, was intensive because of definitive intent. By conventional linear-quadratic modeling, the equivalent dose in 2 Gy fractions would be 70 Gy for early/tumor effects  and 84 Gy for late effects . Even so, this falls within the range of what has been used safely in dose escalation studies of conventionally fractionated radiation therapy alone and chemoradiation for locally advanced lung cancer involving mediastinal nodes, and substantially less than stereotactic ablative radiotherapy regimens used safely for central and ultra-central  tumors such as 50 Gy in 4 fractions or 60 Gy in 8 fractions  . We haveIt is unclear, however, when or if there is a safe way to combine bevacizumab with dose-intensive hypofractionated radiotherapy overlapping mucosal sites. Mucosal irradiation may preclude future administration of bevacizumab due to risk of toxicity, as bevacizumab may inhibit wound-healing after radiotherapy by diminishing angiogenesis to radiation-damaged tissue, which increases risk of treatment-related toxicity. We urge caution when considering dose-intensive radiotherapy to mucosal locations in association with VEGF inhibitors, and recommend close communication with medical oncologists to continue holding VEGF inhibitors after radiotherapy has been completed.We present a case of tracheal diverticulum following bevacizumab and paratracheal radiotherapy. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy."}
+{"text": "Diagnostic ultrasound (DUS) pressures have the ability to induce inertial cavitation (IC) of systemically administered microbubbles; this bioeffect has many diagnostic and therapeutic implications in cardiovascular care. Diagnostically, commercially available lipid-encapsulated perfluorocarbons (LEP) can be utilized to improve endocardial and vascular border delineation as well as assess myocardial perfusion. Therapeutically, the liquid jets induced by IC can alter endothelial function and dissolve thrombi within the immediate vicinity of the cavitating microbubbles. The cavitating LEP can also result in the localized release of any bound therapeutic substance at the site of insonation. DUS-induced IC has been tested in pre-clinical studies to determine what effect it has on acute vascular and microvascular thrombosis as well as nitric oxide (NO) release. These pre-clinical studies have consistently shown that DUS-induced IC of LEP is effective in restoring coronary vascular and microvascular flow in acute ST segment elevation myocardial infarction (STEMI), with microvascular flow improving even if upstream large vessel flow has not been achieved. The initial clinical trials examining the efficacy of short pulse duration DUS high mechanical index impulses in patients with STEMI are underway, and preliminary studies have suggested that earlier epicardial vessel recanalization can be achieved prior to arriving in the cardiac catheterization laboratory. DUS high mechanical index impulses have also been effective in pre-clinical studies for targeting DNA delivery that has restored islet cell function in type I diabetes and restored vascular flow in the extremities downstream from a peripheral vascular occlusion. Improvements in this technique will come from three dimensional arrays for therapeutic applications, more automated delivery techniques that can be applied in the field, and use of submicron-sized acoustically activated LEP droplets that may better permeate the clot prior to DUS activation and cavitation. This article will focus on these newer developments for DUS therapeutic applications.The online version of this article (doi:10.1186/s40349-016-0062-y) contains supplementary material, which is available to authorized users. Although diagnostic ultrasound (DUS) systems and lipid-encapsulated perfluorocarbons (LEP) like Definity  or Sonazoid  have been approved only for imaging applications; these two products have significant therapeutic potential for non-invasive targeted thrombolysis and drug delivery. Ultrasound and microbubbles alone as a method of dissolving thrombi was first introduced in 1997 . SubsequThe potential for intermittent high MI impulses from a DUS transducer was first examined in a canine model of arteriovenous graft thrombosis, where intermittent high MI impulses all <1.9 MI) were applied when low MI imaging detected microbubbles within the risk area . These h.9 MI werThis study prompted subsequent investigations which examined the efficacy of DUS high MI impulses in restoring microvascular and epicardial blood flow in porcine models of acute ST segment elevation myocardial infarction, or STEMI \u201312. ThesSlight prolongations in pulse duration on a DUS transducer may improve the amount of thrombus dissolution. By increasing pulse duration from <5 to 20\u00a0\u03bcs on a DUS transducer, a higher epicardial recanalization rate was achieved with DUS-guided therapy added to \u00bd dose tissue plasminogen activator. Despite the higher epicardial recanalization rate, both short and longer pulse duration high MI impulses were equally effective in ST segment resolution and improvement in wall thickening within the risk area . The guiIn an ischemic stroke, transcranial DUS and intravenous LEP microbubbles, even in the absence of tissue plasminogen activator, have recanalized intravascular and microvascular thrombi in a large porcine animal model . In thisA considerable number of small animal studies have demonstrated the ability of DUS-guided cavitation of LEP to target the delivery of DNA or RNA \u201322; Tabl2; Tabl2.The use of a commercially available LEP and DUS for targeted thrombolysis is now being tested in the first clinical trials , with prOne problem with microbubbles is that they are confined to intravascular spaces, and inertial cavitation can only increase subendothelial delivery. The LEP can also be formulated into droplets, even for the lower molecular weight fluorocarbons like octafluoropropane . Since tDUS, diagnostic ultrasound; IC, inertial cavitation; LEP, lipid-encapsulated perfluorocarbons; MI, mechanical index; NO, nitric oxide; PWD, pulsed wave Doppler; STEMI, ST segment elevation myocardial infarction"}
+{"text": "The mere sight of foods may activate the brain\u2019s reward circuitry, and humans often experience difficulties in inhibiting urges to eat upon encountering visual food signals. Imbalance between the reward circuit and those supporting inhibitory control may underlie obesity, yet brain circuits supporting volitional control of appetite and their possible dysfunction that can lead to obesity remain poorly specified. Here we delineated the brain basis of volitional appetite control in healthy and obese individuals with functional magnetic resonance imaging (fMRI). Twenty-seven morbidly obese women (mean BMI = 41.4) and fourteen age-matched normal-weight women (mean BMI = 22.6) were scanned with 1.5 Tesla fMRI while viewing food pictures. They were instructed to inhibit their urge to eat the foods, view the stimuli passively or imagine eating the foods. Across all subjects, a frontal cortical control circuit was activated during appetite inhibition versus passive viewing of the foods. Inhibition minus imagined eating (appetite control) activated bilateral precunei and parietal cortices and frontal regions spanning anterior cingulate and superior medial frontal cortices. During appetite control, obese subjects had lower responses in the medial frontal, middle cingulate and dorsal caudate nuclei. Functional connectivity of the control circuit was increased in morbidly obese versus control subjects during appetite control, which might reflect impaired integrative and executive function in obesity. In our modern society humans are surrounded by food advertisement and palatable visual food cues are readily available and on display in supermarkets and restaurants. Despite complex homeostatic mechanisms that govern eating and appetite , the merThe sight of food cues engages the brain\u2019s reward circuit and it shows greater activation encountering palatable versus bland foods , especiafunctional connectivity of the cognitive control networks and the reward circuit has remained elusive. It is indeed possible that the previously reported elevated reward circuit responses to palatable foods in obese individuals [The evidence of the influence of obesity on the functioning of the fronto cortical appetite control systems remains mixed, nevertheless. Some studies have reported no effects of Body Mass Index (BMI) on cortical inhibitory circuits , while sividuals \u20136 could Here, we used functional magnetic resonance imaging (fMRI) to study brain circuits supporting cognitive appetite control in normal-weight and morbidly obese individuals. Participants viewed pictures of foods, while their task was to either inhibit their urges to eat, imagine eating the foods or watch the foods passively. We hypothesized that volitional control of appetite would engage the fronto-cortical circuits, and that obese individuals would have lower frontal activations reflecting failure to volitionally inhibit their urges to eat. In line with this, we also predicted that functional connectivity of the control circuit would be lowered in obese individuals.http://www.clinicaltrials.gov). All participants signed an ethical committee-approved, informed consent form prior to scans.The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethical Committee of the Hospital District of South-Western Finland  were recruited for the study  were recruited as a control group  to assess the nutritional state .inhibition condition, they had to inhibit urges to eat the food, during passive viewing condition they had to view the foods passively, and during imaginary eating condition they had to imagine eating the foods. The blocks were presented in a fixed, pseudo-randomized order, which was counterbalanced across participants. Altogether there were twenty blocks of each condition, and total scanning time was approximately 19 minutes. Participants were given written and spoken instructions before entering the scanner, and they practiced the task in the scanner before the experiment began. The participants were also interviewed after the experiment to assure that they had finished the task as instructed.Stimuli and design are summarized in The stimulus presentation and behavioral data collection were controlled with Presentation software . Stimuli were projected from an LCD projector onto a non-magnetic screen mounted at the foot of the bore, and an angled mirror reflected images onto the screen into the participants\u2019 field of vision.3 resolution) were acquired using a T1-weighted sequence .Altogether 380 functional volumes were acquired. Furthermore, four \u2018dummy\u2019 volumes were acquired and discarded at the beginning to allow for equilibration effects. The dummy volumes were not included in the analysis. Data were pre-processed and analyzed using SPM8 software (http://www.fil.ion.ucl.ac.uk/spm/) running on Matlab 2011b. The EPI images were realigned to the first scan image by rigid body transformations to correct for head movements. Echoplanar and structural images were co-registered and normalized to the T1 standard template in MNI space  using linear and non-linear transformations, and smoothed with a Gaussian kernel of 8 mm full width at half maximum\u2014FWHM 8 mm.MR imaging was performed with Philips Gyroscan Intera 1.5 T CV Nova Dual scanner at Turku PET centre. Whole-brain functional data were acquired with T2* weighted echo-planar imaging (EPI) sequence, sensitive to the blood-oxygen-level-dependent (BOLD) signal contrast . High-resolution anatomical images  corrected at the cluster level.A whole-brain random effects model was used. This two-stage process (first and second level) assesses effects on the basis of inter-subject variance and thus allows inferences about the population that the participants are drawn from. For each participant, we used a general linear model (GLM) to assess regional effects of task parameters on brain activation. The first level model included all three experimental conditions  as well as the six realignment parameters as effects of no interest. Low-frequency signal drift was removed using a high-pass filter (cut-off 128 s) and we applied autoregressive AR(1) modeling of temporal autocorrelations. The individual contrast images were generated using the t-contrasts i) inhibition minus viewing, ii) imaginary eating minus viewing, and iii) inhibition minus imaginary eating, as well as the opposite contrasts. The contrast images of the voxel-wise difference in beta estimates for the contrasts of interest. The second-level analysis used these contrast images in a new GLM from which generated statistical images, that is, SPM t-maps across all subjects and between subject groups. When the second-level analysis has balanced designs at first level with similar numbers of similar events for each subject it closely approximates a true mixed-effects design, exhibiting within- and between-subject variance. In addition, second-level analysis in SPM is considered to be robust against unequal group sizes, when unequal variances are assumed. The inhibition minus passive viewing and imaginary eating versus passive viewing contrasts were used to delineate the brain regions involved in cognitive control of appetite and mental processing of the hedonic value of the foods. The appetite control contrast (inhibition minus imaginary eating) was considered the main contrast of interest for revealing the neural basis of appetite control, as this enabled contrasting the two active food-related tasks directly against each other, thus accounting for effects of increasing task complexity in the active versus passive viewing conditions . Data weThe connectivity between brain regions can vary as a function of the psychological context . This isSource regions for the brain\u2019s inhibition network were selected from a previous meta-analysis on inhibitory processing in Go/No-Go tasks , 11 and Contrasting the inhibition condition with passive viewing revealed widespread activation in fronto-cortical regions , Table 3In inhibition minus imaginary eating comparison, normal-weight subjects showed stronger activations than obese subjects in bilateral dorsal caudate nuclei and anterior cingulate cortex , Table 5Across all subjects, the right caudate nucleus showed increased task-driven (inhibition versus passive viewing) connectivity with bilateral precunei and cunei and parietal cortices . InferioBetween-group comparisons revealed that obese subjects had stronger functional connectivity between middle frontal cortex and bilateral supplemental motor area (SMA), right putamen and right middle temporal gyrus , Table 6Hunger ratings  did not Here we show that volitional appetite control while viewing visual food cues activates a network of prefrontal, frontal and parietal and inferior cerebellar cortical regions. This confirms that the fronto cortical control system \u2013 well known for inhibition and error monitoring ,9 is alsEating and appetite are controlled by complex homeostatic mechanisms . In realThese findings from the task-evoked BOLD responses to cognitive appetite control accord with those made by Yokum et al. They compared the neural responses of three cognitive reappraisal strategies when adolescent subjects viewed visual food cues and thought of the long-term costs or benefits of not eating the food and suppressing cravings for the food. They found increased activation in inhibitory prefrontal and superior frontal regions during these mental tasks, yet in that study participants\u2019 BMI did not modulate the intensity of brain activation . FurtherDuring the inhibition versus imaginary eating condition, normal-weight individuals showed stronger responses than obese individuals in medial frontal and orbitofrontal cortices, as well as in dorsal caudate nucleus . With moenhanced rather than diminished connectivity of the appetite control network in obese versus normal-weight individuals (Against our predictions, functional connectivity analysis revealed ividuals . Obese iAltogether these findings imply that modulating the brain activity of the whole inhibitory circuitry may prove effective to combat our urges to eat excessively. Indeed, most of the currently available anti-obesity pharmaceuticals modulate widespread neurotransmitter systems . InteresWe did not measure blood glucose or insulin levels, which are shown to influence fMRI responses to food pictures . HoweverWe conclude that premotor areas, superior frontal cortices and the precuneus support cognitive control of appetite upon encountering visual food cues. Although these areas seem to function similarly in obese and normal-weight individuals, dorsal striatal responses during volitional appetite control are reduced in obese individuals. This suggests that even though frontal inhibitory function seems to be largely preserved in obesity, altered reward and homeostatic signaling together with heightened functional connectivity within the cognitive control circuit likely play an important role in the pathophysiology of obesity, and drive excessive eating and contribute to development and maintenance of obesity."}
+{"text": "Inflammation is the first biological response of the immune system against infection or irritation. However, accumulating epidemiological and clinical study indicates that zealous acute inflammation or chronic inflammatory reaction is a significant risk factor to develop various human diseases. Controlling or modulating inflammation is therefore important to prevent or ameliorate certain diseases, such as organ transplantations, allergic diseases, and autoimmune diseases. T. wilfordii extract in patients with rheumatoid arthritis , cyclosporin A (CsA), rapamycin, tacrolimus (FK506), and fingolimod FTY720) (summarized in review ). In add0 (summarThis special issue will introduce you to the valuable research reports on anti-inflammatory natural products, ranging from basic researches to exploring roles of natural products against inflammatory diseases. We hope this timely special issue will encourage the research and development of valuable natural products and finally lead to the development of novel therapeutic agents to provide better care to patients.Yifu YangYifu YangLifei HouLifei HouAbdelfattah El OuaamariAbdelfattah El OuaamariLijun XinLijun Xin"}
+{"text": "The primary complication of any available anticoagulant therapy is the risk of bleeding. Rapid reversal of anticoagulation may be necessary in patients requiring emergency treatment due to uncontrolled bleeding. Prothrombin complex concentrates (PCC) are frequently used to reverse the effect of vitamin K antagonists such as warfarin and have also been suggested to be potentially effective in reversing the effects of the new oral anticoagulants. The present study was therefore designed to determine whether the four-factor PCC Beriplex\u00ae (25 to 75 IU/kg). Bleeding was assessed based on the time to hemostasis and the total blood loss after induction of a standardized kidney injury. In parallel, the following biomarkers of hemostasis were determined: factor Xa inhibition, prothrombin time (PT), activated partial thromboplastin time (aPTT), whole blood clotting time (WBCT), and thrombin generation (TGA).Rabbits were treated with a high intravenous bolus dose of edoxaban  followed by the administration of Beriplex\u00ae resulted in a dose-dependent reversal of edoxaban-induced bleeding as indicated by reduced time to hemostasis and total blood loss. Both parameters achieved statistical significance compared with placebo at the Beriplex\u00ae dose of 50 IU/kg under fully blinded study conditions. The biomarkers correlating best with Beriplex\u00ae-mediated edoxaban anticoagulation reversal included PT, WBCT and endogenous thrombin potential.The results confirmed increased and prolonged bleeding of edoxaban-treated animals following standardized kidney injury compared with vehicle administration. Parallel monitoring of biomarkers of hemostasis showed a prolongation of PT, aPTT, WBCT, and changes in thrombin generation parameters. Subsequent administration of Beriplex\u00ae treatment effectively reversed edoxaban-induced anticoagulation in an animal model of acute bleeding at clinically relevant dose levels.In summary, Beriplex"}
+{"text": "Post-stroke care after hospital discharge suffers from lack of intersectoral collaboration within the public health sectors. Hence, primary care remains the only option in managing stroke patients in underserved areas in Malaysia. This study aimed to identify the areas, which can be better coordinated to deliver optimal post-stroke care in community setting. A seamless transfer of care model known as integrated Care Pathway for Post Stroke patients (iCaPPS) was designed to address this issue.Expert panel discussions comprising of family physicians, neurologists, rehabilitation physicians and therapists, and nurse managers from both Ministry of Health and the academia were conducted. Modified Delphi technique was employed to resolve practice variations through additional literature support. Care algorithms were designed around existing work schedules and available resources at public health centres.Identified areas for coordinated transfer of care include: identification of patient criteria suitable for long-term stroke management at primary care facilities, information required at transfer of care, stroke risk factors treatment targets, screening for stroke complications and rehabilitation guide for primary care team. Care algorithm including appropriate tools were summarised to identify patients requiring further multidisciplinary rehabilitation interventions i.e. assessment for those uninitiated or missed out on rehabilitation and leisure intervention for those indicated, screening for swallowing disorders as well as mental health disorders (i.e. depression and dementia).The iCaPPS would facilitate coordinated primary care-led post-stroke management for patients residing at home in the community, hence promoting better collaboration within public health sectors. Clinical outcomes and cost effectiveness of iCaPPS can be evaluated for benefit of stakeholders and stroke survivors."}
+{"text": "Chronic migraine is a debilitating disease particularly in women and underlying pathophysiology remains unclear. Clinically relevant migraine models are missing.The aim of this study is to mimic chronic migraine model in rats and to test migraine drugs.Study was approved the Institutional Animal Care and Use Committee and care and handling of animals were in accord with National Institute of Health guidelines. Nasociliary nerve (NCN), which is the rat correlate of opthalmic branch of trigeminal nerve is ligated to mimic chronic headache. Glyceroltrinitrate (GTN) was administered to induce acute migraine attack. Sumatriptane and CGRP receptor antagonist were administered. Pain, anxiety related behavior were recorded. Mechanical allodynia, thermal hyperalgesia was tested by VF/ EVF and acetone; anxiety by elevated plus maze (EPM). Activated areas were investigated by c-fos immunoreactivity and plasma extravasation was studied by horse radish peroxidase.NCN ligation, GTN administration model demonstrated mechanical allodynia, thermal hyperalgesia. Anxiety accompanying pain was confirmed by EPM. Extravasation in dura mater was shown by Horse radish peroxidase. Significantly c-fos immunoreactivity was increased in ipsilateral brainstem TNC compared to contralateral and also in cortical structures constituting pain matrix. CGRP antagonists decreased pain related behavior and c-fos positive cells.Mechanical allodynia, thermal hyperalgesia, c-fos staining confirming central and peripheral sensitization is exhibited in NCN ligated rats and pain related anxiety is confirmed. CGRP receptor antagonists are effective for chronic headache treatment. This chronic migraine model is relevant to human migraine and eligible for further drug investigations.No conflict of interest."}
+{"text": "Infectious diseases are a major health problem worldwide, causing many serious complications, including autoimmune disorders in unvaccinated populations. The vaccinations represent the most effective method of preventing infectious diseases and cost benefit analysis of vaccination programmes demonstrated their utility. On the basis of Orphanet database, in Italy rare diseases affect almost 2 million people, and 70% of them are children. Among neurodegenerative disorders, children with spinal muscolar atrophy should receive routine immunizations, including influenza and pneumococcal vaccines; for pediatric patients affected by Becker's Muscular Dystrophy influenza and pneumococcal vaccines are indicated in case of severe weakness of respiratory muscles . Immunoc"}
+{"text": "Plasmodium sporozoites may function as protective immune responses. They cover immune induction quite extensively but discuss virtually nothing on effector mechanisms of antibody responses against sporozoites. Because their review should be balanced by reference to studies describing effector mechanisms, this commentary will confine itself to recounting some of these.Dups et al.  assess hIn vitro exposure to serum from immunized mice results in an antibody-mediated precipitant projecting from sporozoites (In vitro inhibition of sporozoite motility by serum from immune animals subsequently suggested that anti-sporozoite antibodies can function by blocking sporozoite motility (in vitro studies showed that monoclonal antibodies against the CS antigen blocked in vitro invasion by sporozoites into target cells (in vivo inhibition of sporozoite motility and inhibition of sporozoite invasion of dermal blood vessels by antibodies (rozoites . Becausemotility . Furtheret cells , 5. Substibodies . And an tibodies .Plasmodium berghei sporozoites injected by mosquitoes into sporozoite-immunized vs. non-immunized mice showed significantly fewer sporozoites were deposited in immune mice (in vitro (in vitro and in vivo (Anti-sporozoite antibodies act even earlier during challenge by mosquito bite, by inhibiting release of sporozoites from the mosquito proboscis into skin . This apune mice . CS protin vitro  and intoin vitro , 11. Thu in vivo .Some sporozoites injected by mosquitoes into immunized hosts may successfully escape into the blood. Indeed, sporozoites that bypass skin by being injected intravenously by syringe into mice passively immunized with immune serum are cleared effectively from the circulation , indicatIn vitro studies have documented that opsonized sporozoites are prone to phagocytosis (in vivo. Furthermore, antibodies also inhibit invasion and traversal through hepatocytes, events that rely on sporozoite motility (Conceivably, antibody-coated sporozoites may be blocked during attempted passage through Kupffer cells prior to hepatocyte invasion , 14. In ocytosis \u201317, suggmotility .Thus, anti-sporozoite antibodies can act sequentially against sporozoites at different stages of sporozoite invasion from the skin to invasion of dermal blood vessels, to passage from Kupffer cells into hepatocytes, and subsequent traversal of sporozoites through a series of hepatocytes.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Recruiting patients to research and collecting study data in a primary care setting, combined with maximising retention rates from a primary care population can be challenging and requires recruitment and retention methods which are innovative, efficient and transferrable.To apply low resource intensive and rapidly implemented recruitment and retention innovations for use in primary care settings that ensure patient recruitment and follow-up targets are achieved.A range of innovative recruitment and retention strategies are utilised by Keele CTU including; electronic aide-memoires linked to Read codes; physical aide-memoire prompts in consulting rooms; automated referral methods; postcard, repeat, email, SMS and minimum data collection reminder mailings; death and departure auditing.Methods used; sustain routine care whilst simultaneously screening for research data and participants; provide flexible instruments compatible with all general practice infrastructures; increase clinical precision in identifying suitable participants; automates recording of study data collection; ensures minimal impact on consultation time; contribute towards the delivery of excellent retention rates.Recruitment aide-memoires, automated innovations and retention strategies can all be embedded easily into a primary care setting. These tools, without over burdening the busy primary care practitioner, result in simple and effective methods of prompting patient recruitment and retention. Excellent recruitment and retention rates are possible, despite encountering differences in primary care infrastructure. Such methods should be utilised more widely to facilitate primary care research, if this is where many conditions are diagnosed and managed."}
+{"text": "Coregonus sardinella) is a bellwether for Arctic lakes as an important consumer and prey resource. To explore the consequences of climate warming, we used a bioenergetics model to simulate changes in Least Cisco production under future climate scenarios for lakes on the Arctic Coastal Plain. First, we used current temperatures to fit Least Cisco consumption to observed annual growth. We then estimated growth, holding food availability, and then feeding rate constant, for future projections of temperature. Projected warmer water temperatures resulted in reduced Least Cisco production, especially for larger size classes, when food availability was held constant. While holding feeding rate constant, production of Least Cisco increased under all future scenarios with progressively more growth in warmer temperatures. Higher variability occurred with longer projections of time mirroring the expanding uncertainty in climate predictions further into the future. In addition to direct temperature effects on Least Cisco growth, we also considered changes in lake ice phenology and prey resources for Least Cisco. A shorter period of ice cover resulted in increased production, similar to warming temperatures. Altering prey quality had a larger effect on fish production in summer than winter and increased relative growth of younger rather than older age classes of Least Cisco. Overall, we predicted increased production of Least Cisco due to climate warming in lakes of Arctic Alaska. Understanding the implications of increased production of Least Cisco to the entire food web will be necessary to predict ecosystem responses in lakes of the Arctic.Lake ecosystems in the Arctic are changing rapidly due to climate warming. Lakes are sensitive integrators of climate-induced changes and prominent features across the Arctic landscape, especially in lowland permafrost regions such as the Arctic Coastal Plain of Alaska. Despite many studies on the implications of climate warming, how fish populations will respond to lake changes is uncertain for Arctic ecosystems. Least Cisco ( Lakes are prominent features across the Arctic landscape, especially in lowland permafrost regions where the landscape comprises thousands of lakes and the lake area fraction (lake area/land area) can exceed 40%, such as on the Arctic Coastal Plain of Alaska  and loons (Gavia spp.). Therefore, changes in growth rates and size structure of Least Cisco could have implications throughout the food web. Least Cisco will likely have strong responses to climate warming as temperatures exceed the optimum temperature of 16.8\u00b0C for coregonids  and Alaska blackfish , whereas widely distributed, but found more often in highly connected systems, are Least Cisco, Broad whitefish (Coregonus nasus), and Arctic grayling . Similar to nearby systems in the Brooks Range , Dolly varden , rainbow smelt (Osmerus mordax), Humpback whitefish (Coregonus oidschian), and the top predators Northern pike (Esox lucius) and burbot ]; Seigle To parameterize the Least Cisco model to lakes on the Arctic Coastal Plain, we assumed Least Cisco feed primarily in the water column and their diet remains constant throughout the year. In the model, diets were evenly divided among expected prey groups of bosmina (1674 J/g wet mass), copepods (2792 J/g wet mass), other cladocerans (2514 J/g wet mass), diptera (1763 J/g wet mass), and leptodora (867 J/g wet mass) using previously published values for prey energy density  for different climate scenarios by holding annual ration and pCmax constant at the level determined for current conditions. By holding annual ration and pCmax constant, we can predict growth for future temperature scenarios. Holding feeding rate and food availability constant has been useful in projecting growth differences with climate change predictions in other systems  of Least Cisco indicates growth only occurs during the summer under current temperatures for all age classes  estimated for growth under current temperatures ranged from 0.33 to 0.59 across age classes of Least Cisco  and accumulated biomass (g) of Least Cisco increased under all future scenarios of warmer temperatures with a constant pCmax Figs. , 6A. MorAge classes of Least Cisco responded differently to increasing temperatures. Relative growth shows an exponential decrease from younger to older age classes for all the climate scenarios produced by the SNAP projections Fig. . YoungerThe annual ration estimated for growth under the current temperatures ranged from 5.61% to 3.18%  in Lake Michigan  and Cisco (Coregonus artedii), by reducing suitable habitat with warmer temperatures  in headwater streams of southern British Columbia, Canada in which their growth rates were more sensitive to prey quality than temperature  in Lake Michigan (Madenjian et al. Using the generalized coregonid model for comparing differences in Least Cisco growth on the Arctic Coastal Plain provides relative comparisons of future climate projections and identifies knowledge gaps. We used a value for the respiration parameter (Wohlschag The empirical data available on the physical and biological components of Arctic freshwater systems are increasing; however, our only option was to compile data from a variety of sources and regions. With a spatially focused assessment of Least Cisco, a more robust model could be built as large differences occur across the landscape. For example, climate warming in the winter is expected to affect coastal areas more than inland areas due to the influence of a longer marine ice-free period. In contrast, during the summer, the projected temperature increases are of a lesser magnitude on the coast and more pronounced in inland areas. Within a region, systematic differences in lake size and morphometry can generate differences in both ice phenology and summer water temperatures despite common climate conditions (Shuter et al."}
+{"text": "Gender-based differences in the cardiac morphology and function in patients with volume-overload cardiac pathologies has been widely examined. However the relationship between gender and contractility is not well defined.Therefore we evaluate the gender influence on contractile capacity in patients with volume overload, present with severe mitral valve regurgitation and preserved left ventricular function.Right auricle samples from 40 patients  with severe mitral regurgitation, scheduled for elective mitral valve surgery, were obtained before extracorporal circulation (ECC). The fibers were prepared and skinned to remove membrane-dependent properties and exposed to gradual increase of calcium concentration.Female fibers achieve higher force values than male patients at the highest step of calcium concentration . Male and female fibers show an anticyclical course when exposed to increasing steps of calcium concentrations: starting with lower force values at lower calcium concentrations in males, the steepness of pCa-force-curve is flatter compared to female counterparts . At higher force values females achieve higher maximal forces and lower force values for males .Calcium sensitivity, given as half maximal concentration, is achieved at pCa 5.0 in females and between 6 and 5.5 for males (p 0.04).Male and female fibers from patients with severe mitral regurgitation show adverse calcium induced force properties. Male fibers achieve lower maximal force values, starting at higher base values in low calcium concentration condition and might therefore have higher sensitivity to calcium."}
+{"text": "Auditing is an integral part of quality assurance in trials. The introduction of risk-based monitoring in industry coupled with reduced funding for academic trials indicates a need to enhance the comprehensive oversight of trials. Generating an internal audit system streamlines quality management across the clinical trials unit. We aimed to pilot a robust in-house process that prioritises patient safety and monitors trial delivery.Ten healthcare professionals within our team voluntarily formed an internal audit group and received appropriate training. Sub-teams were assigned individual trials to audit over a three month period. Quality and SOP compliance data was collated in a comprehensive audit spreadsheet and processes covered included examination of Site Files, Case Report Forms, Serious Adverse Events (SAE), and source data verification (SDV). Findings were amalgamated into a Corrective Action Preventative Action (CAPA) Plan and fed back to the wider team. Team actions were subsequently reviewed after six weeks as a follow-up measure.Preliminary findings of five internal audits highlighted areas for improvement within data and procedural systems including; informed consent, SAE reporting, and SDV. Additionally, the Audit Group proved a useful measure in developing overall quality standards of the team, highlighted by staff learning, improved knowledge and adherence to regulatory standards.In line with upcoming EU legislation and ICH GCP, maintaining rigorous auditing processes and adherence to quality standards is of utmost importance. The ongoing quarterly internal audit cycle will be continuously reviewed, feeding into an evolving quality management system ensuring best practice across the unit."}
+{"text": "Plant immunity relies on a complex network of hormone signaling pathways in which jasmonic acid (JA) plays a central role. Successful microbial pathogens or symbionts have developed strategies to manipulate plant hormone signaling pathways to cause hormonal imbalances for their own benefit. These strategies include the production of plant hormones, phytohormone mimics, or effector proteins that target host components to disrupt hormonal signaling pathways and enhance virulence. Here, we describe the molecular details of the most recent and best-characterized examples of specific JA hormonal manipulation by microbes, which exemplify the ingenious ways by which pathogens can take control over the plant\u2019s hormone signaling network to suppress host immunity. Agricultural productivity depends on the capacity of plants to adapt to changing environmental conditions. In nature, plants live in complex environments in which they intimately interact with a broad range of microbial pathogens with different infection strategies. To defend themselves, plants have evolved sophisticated strategies to perceive their attacker during the infection process and to translate this perception into an effective immune response. Recognition of highly conserved microbe-associated molecular patterns (MAMPs) by host cell transmembrane pattern recognition receptors (PRRs) leads to MAMP-triggered immunity (MTI) that restricts pathogen growth . To overBotrytis cinerea, whereas the SA pathway is primarily induced by and effective in mediating resistance against biotrophic and hemi-biotrophic pathogens such as Pseudomonas syringae . . P. syrit manner . Of noteelopment . In combd by COR .P. syringae mutants unable to produce COR show reduced virulence . In. InB. cidefenses . SSITL rdefenses . FurtherLaccaria bicolor, support host growth by providing growth-limiting nutrients to their plant host through a mutualistic symbiotic relationship within the plant roots [L. bicolor. MiSSP7 is an effector protein indispensable for the establishment of mutualism with their host plants [in planta or through transgenic overexpression of the PtJAZ6 gene [Beneficial microbes establish long-term relationships with their host plants to fulfill their life cycles . Ectomycnt roots . In ordet plants . Upon pet plants ,80. In tAZ6 gene . This inThe importance of signaling molecules in plant immunity is a well-established notion in plant biology and the molecular mechanisms regulating the phytohormone-mediated defenses have been extensively studied in the last decades. In this context, the role of hormones in plant immunity is further highlighted by the increasing number of pathogens producing phytohormones or phytohormone mimics and by the identification of a plethora of microbial effectors targeting hormonal pathways to promote disease or establish beneficial interactions. Of note, virulence activities of effectors on specific hormonal components can lead to the identification of novel mechanisms of host hormonal regulation unknown to date. In addition, an improved mechanistic understanding of how pathogenic toxins and effectors manipulate host hormonal components will be instrumental in identifying new defensive hubs and to develop new plant varieties with improved resistance to pathogens."}
+{"text": "Pulseless electrical activity cardiac arrest is associated with poor outcomes and the identification of potentially reversible reasons for cardiac arrest is fundamental.We describe the case of a 46-year-old male with the rare coincidental finding of supravalvular aortic stenosis and coronary vasospasm leading to recurrent pulseless electrical activity cardiac arrest. Extracorporeal life support was successfully applied for hemodynamic stabilization. Supravalvular aorticstenosis underwent surgical repair. The patient survived five time resuscitation and was discharged after full neurological recovery.Coronary vasospasm and supravalvular aortic stenosis are rare but potentially reversible causes of pulseless electrical activity cardiac arrest. Extracorporeal life support allows accurate diagnostic and possibly therapy even of uncommon reasons for cardiac arrest.The online version of this article (doi:10.1186/s12872-016-0284-5) contains supplementary material, which is available to authorized users. Cardiac arrest due to pulseless electrical activity (PEA) is associated with poor survival and neurological outcome when compared to a shockable rhythm , 2. To pWe describe here for the first time the case of a patient with the rare coincident finding of coronary vasospasm and supravalvular aortic stenosis leading to recurrent pulseless electrical activity cardiac arrests.A 46-year-old male was successfully resuscitated for out-of-hospital cardiac arrest due to ventricular fibrillation Fig.\u00a0. CoronarBecause of the development of a severe acute respiratory distress syndrome five days after admission our ECMO team established a veno-venous extra-corporeal membrane oxygenation (vvECMO) system using a 31 Fr bi-caval cannula and transferred the patient to our center  that was confirmed by CT (Fig.The patient has no family history of cardiac death. He underwent patch-repair for supravalvular aortic stenosis during childhood. On day 6 transthoracic and transesophageal echocardiography revealed a remaining supravalvular aortic stenosis (Vy CT Fig..The patient had full neurological recovery and was discharged to follow-up treatment. A cardiac defibrillator was implanted for secondary prevention of the initial VF.We report a case of recurrent cardiac arrests due to coronary vasospasm and supravalvular aortic stenosis.The patient survived five episodes of cardiac arrest, four of them with PEA which is an uncommon complication of vasospastic angina. Patients with vasospastic angina pectoris are at higher risk of sudden cardiac death and most often cardiac arrest occurs due to tachycardic ventricular arrhythmia . NeverthVeno-arterial ECMO is considered as the preferred method for extracorporeal life support to allow further diagnosis and therapeutic measures when standard life support fails to achieve ROSC . PercutaIn conclusion, the coincidence of coronary vasospasm and supravalvular aortic stenosis lead to recurrent pulseless electrical activity cardiac arrest in this case. Unusual causes for refractory cardiac arrest should be considered during and after resuscitation. Extracorporeal life support provides the opportunity for accurate diagnostic and therapy when routine diagnostic measures are not sufficient.CT, computer-assisted tomography; ECLS, extracorporeal life support; ECMO, extracorporeal membrane oxygenation; PEA, pulseless electrical activity; ROSC, return of spontaneous circulation."}
+{"text": "It seems that renal tubular damages in acute renal failure involved in gentamicin nephrotoxicity or ischemia/reperfusion mainly induced by increasing of reactive oxygen species (oxidative stress). According to this attitude, many researchers have been used different antioxidant agents in combat with gentamicin nephrotoxicity. Treatment of animal with metformin against gentamicin revealed that gentamicin might be induced renal tubular damages via energy depletion in renal tubular cells besides inducing of oxidative stress. More studies are needed to clarify renal protective effect of adenosine monophosphate-activated protein kinase (AMPK) activator such as metformin in combat with gentamicin nephrotoxicity.In spite of undesirable gentamicin nephrotoxicity,\u200f this antibiotic is commonly used versus Gram-negative bacteria and still constitutes the only effective therapeutic alternative against microorganisms-pseudomonas, proteus and serratia \u2013 that are insensitive to other antibiotics . MoreoveThe pathological mechanisms involved in gentamicin induced nephrotoxicity include induction of oxidative stress, apoptosis, necrosis, up regulation of transforming growth factor B, elevation of endothelin I , increase of monocyte/macrophages infiltration , phospholipidosis an increase of intracellular sodium ions ,3. GentaGentamicin nephrotoxicity is characterized functionally by an increase of serum creatinine, blood urea nitrogen, and decrease in glomerular filtration rate , which mMore investigations showed that antioxidant agents inhibited or attenuated gentamicinnephrotoxicity in rats. Usage of antioxidants improved histological injuries such as tubular necrosis, tubular cell edema and apoptosis in gentamicin-injected rats -8.Metformin that used by diabetic patients showed oxidative stress inhibitor activity and adenosine monophosphate-activated protein kinase (AMPK) activator. Some researchers evaluated effects of metformin against gentamicin nephrotoxicity. They reported beneficial effect of metformin in combat with renal histopathological changes induced by gentamicin -10.Alterations in epithelial cell polarity and in the subcellular distributions of epithelial ion transport proteins are key molecular consequences of acute kidney injury and intracellular energy depletion. AMPK, a cellular energy sensor, is rapidly activated in response to renal ischemia, and renal epithelial cells subjected to energy depletion .In the study of Baradaran and colleague for the first time combination effect of metformin and garlic extract evaluated against gentamicin nephrotoxicity. They showed that this treatment attenuated renal histopathological injuries including epithelial cell vacuolization, degeneration, tubular cell flattening, hyaline cast, tubular dilatation, and debris materials in tubular lumen- induced by gentamicin . TreatmeThe author wants to thank from the personals of Department of Anatomy, Lorestan University of Medical Sciences.MT is the single author of the manuscript.The author declared no competing interests.Ethical issues  have been completely observed by the author.None declared."}
+{"text": "Objective: The purpose of this study was to assess central (aortic) vascular dysfunction in post renal transplant patients by high-resolution cardiovascular magnetic resonance imaging (CMR). Background: Renal transplant recipients are at increased risk of cardiovascular (CV) disease. The cardiac phenotype in post-transplant recipients is not well defined. A recent study suggested myocardial perfusion is impaired in renal transplant patients irrespective of the degree of left ventricular hypertrophy.We hypotMethods: Twenty-five asymptomatic renal transplant patients (RT) and 17 hypertensive controls (HT) underwent CMR scanning at 1.5 T. Myocardial function, late enhancement, aortic pulse wave velocity and first-pass perfusion at rest and stress was performed. Myocardial Perfusion Reserve Index (MPRI) was calculated as the ratio of hyperemic to resting myocardial blood flow by dividing the myocardial perfusion at stress by rest perfusion (corrected to rate pressure product). Pulse wave velocity (PWV) was calculated as the ratio between the distance and time from ascending aorta to descending aorta at the level of main pulmonary artery. Statistical analyses were performed using mixed effects modelling for MPRI and linear regression for relationship between MPRI and PWV.Results: Baseline clinical characteristics were similar for RT and HT control groups. Mean inter-ventricular septal thickness and LV mass indexed to body surface area were similar in both RT cases and HT controls. MPRI was significantly lower in the RT group compared to the HT group , globally and in all three coronary artery territories[Conclusions: In our cohort population, there is no evidence of increased aortic stiffness in post renal transplant patients compared to hypertensive patients. Although these patients demonstrate impaired myocardial perfusion reserve, this is not correlated with increased aortic stiffness.None."}
+{"text": "Rapidly destructive coxarthrosis (RDC) is a rare syndrome that involves aggressive hip joint destruction within 6\u201312 months of symptom onset with no single diagnostic laboratory, pathological, or radiographic finding. We report an original case of RDC as an initial presentation of seronegative rheumatoid arthritis (RA) in a 57-year-old Caucasian woman presenting with 6 months of progressive right groin pain and no preceding trauma or chronic steroid use. Over 5 months, she was unable to ambulate and plain films showed complete resorption of the right femoral head and erosion of the acetabulum. There were inflammatory features seen on computed tomography (CT) and magnetic resonance imaging (MRI). She required a right total hip arthroplasty, but arthritis in other joints showed improvement with triple disease modifying antirheumatic drugs (DMARD) therapy and almost complete remission with the addition of adalimumab. We contrast our case of RDC as an initial presentation of RA to 8 RDC case reports of patients with established RA. Furthermore, this case highlights the importance of obtaining serial imaging to evaluate a patient with persistent hip symptoms and rapid functional deterioration. Rapidly destructive coxarthrosis (RDC) of the hip joint was initially coined in 1970 . The joiA 57-year-old Caucasian woman was referred to our rheumatology outpatient center from the orthopedics service for assessment of a possible inflammatory etiology for her rapidly destructive arthritis. Initial diagnostic work-up was significant for elevated inflammatory markers, weakly positive antinuclear antibody (ANA) and otherwise negative autoimmune markers including both rheumatoid factor (RF) and anticitrullinated peptide (anti-CCP) . All culInitial plain films of her right hip and pelvis showed femoral head lucencies compatible with subchondral cysts (but no definite fracture) and moderate diffuse articular joint space loss with flattening of the femoral head . Over a Three right hip aspirations were attempted with sufficient sample in only one attempt, which showed bloody fluid, 0.6 nucleated cells (17% neutrophils), and presence of only extracellular but not intracellular calcium pyrophosphate dehydrate (CPPD) crystals. Synovial biopsy did not reveal any crystals. Historically, CPPD crystal deposition disease can cause such acutely destructive disease on imaging and pathology , but theThe major differential diagnosis of this atypical case of destructive arthritis is outlined in In order to definitively differentiate between chronic sepsis, malignancy, and a chronic inflammatory process, an open biopsy of the hip was performed by the orthopaedic service, which showed overall morphology with features of chronic inflammation, fibrosis, multinucleated giant cell reaction with dystrophic calcification, and reactive synovial proliferation . CultureAn inflammatory etiology was most likely given multiple swollen joints, elevated inflammatory markers, constitutional symptoms, evidence of inflammatory features on imaging, and other causes excluded. Hence, a diagnosis of seronegative rheumatoid arthritis (RA) was ultimately made, fulfilling 4/7 of the 1987 RA American College of Rheumatology (ACR) classification criteria  and scorInflammatory arthritis is a rare cause of RDC with only 8 case reports of patients with preexisting RA , 9\u201311. LAnother atypical feature of this patient's presentation was an associated benign soft tissue mass with enhancement involving the articular region, acetabulum, sacroiliac region, and anterior pelvis . A previTotal hip arthroplasties have been used as a treatment modality for severe RDC with good response in a retrospective review of total hip arthroplasties performed on patients with RDC . HoweverTo conclude, rheumatoid arthritis is a rare cause of rapidly destructive coxarthrosis (RDC). We present the first case report of RDC as the initial presentation of seronegative rheumatoid arthritis in a 57-year-old woman who required right total hip arthroplasty, but whose other active joints had a good response to DMARD and biologic therapy. This case also highlights the importance of obtaining serial imaging to evaluate a patient with persistent hip symptoms and rapid functional deterioration."}
+{"text": "Laparoscopic appendectomy is increasingly accepted as the preferred surgical treatment for acute appendicitis and represents one of the most common emergency operations performed in both adult and paediatric populations. However, in patients with perforated appendicitis laparoscopy is associated with an increased incidence of postoperative intraabdominal infections compared to open appendectomy. Nowadays urgent imaging is commonly requested by surgeons when postoperative complications are suspected. Due to the widespread use of laparoscopy, in hospitals with active surgical practices clinicians and radiologists are increasingly faced with suspected postappendectomy complications. This pictorial essay illustrates the normal cross-sectional imaging findings observed shortly after laparoscopic appendectomy and the spectrum of appearances of iatrogenic intraabdominal infections observed in adults and adolescents, aiming to provide radiologists with an increased familiarity with early postoperative imaging. Emphasis is placed on the role of multidetector CT, which according to the most recent World Society of Emergency Surgery (WSES) guidelines is the preferred and most accurate modality to promptly investigate suspected intraabdominal infections and highly helpful for correct therapeutic choice, particularly to identify those occurrences that require in-hospital treatment, drainage or surgical reintervention. In teenagers and young adults MRI represents an attractive alternative modality to detect or exclude iatrogenic abscesses without ionising radiation.Teaching pointsLaparoscopic appendectomy is the preferred surgical treatment for uncomplicated acute appendicitis\u2022 In perforated appendicitis laparoscopy results in increased incidence of intraabdominal infections\u2022 Multidetector CT promptly assesses suspected iatrogenic intraabdominal infections\u2022 Interpretation of early postoperative CT requires knowledge of normal postsurgical imaging findings\u2022 Postsurgical infections include right-sided peritonitis, intraabdominal, pelvic or liver abscesses\u2022  Acute appendicitis (AA) represents one of the most common surgical emergencies worldwide and often occurs in young people, adolescents and children. Nowadays laparoscopic appendectomy (LA) has become increasingly accepted as the preferred surgical procedure in adult patients with suspected or documented AA \u20134.However, despite several published studies it is still unclear whether the classical open appendectomy (OA) remains superior to LA in terms of efficacy and safety. Although with similar overall short-term morbidity and mortality compared to OA, in adults LA is associated with lower incidence of wound infection, postoperative ileus and analgesics use, an earlier resumption of normal diet, shorter hospitalisation and more rapid recovery to normal activities , 5, 6. PSimilarly, in paediatric populations LA currently represents the preferred surgical procedure for most cases of AA and is associated with shorter hospitalisation, earlier resumption of normal diet and activities, and a reduced morbidity including lower incidence of wound infections and postoperative ileus , 10. How2 pneumoperitoneum and a local thermal effect from surgical instrumentation , 2221, 2Exceptionally, intraabdominal infections may seed via a patent processus vaginalis leading to the formation of a scrotal abscess .Furthermore, as with other abdominal surgeries, the portal venous system should be carefully scrutinised for signs of dilatation and filling defects. Following appendectomy pylephlebitis has been occasionally reported to involve the superior mesenteric vein, particularly in patients with underlying coagulopathy or when the operation is performed in advanced stages of the disease with peritonitis .Appendectomy remains one of the most common emergency surgical procedures and is increasingly performed using laparoscopy. Partly due to fear of litigation, urgent diagnostic imaging is increasingly requested by surgeons when postoperative complications are suspected after laparoscopic procedures. Prompt cross-sectional imaging investigation with MDCT and familiarity with the normal postoperative findings and the imaging appearances of IAA are helpful for accurate diagnosis and correct therapeutic choice, particularly to identify those occurrences that require prolonged in-hospital treatment, drainage or surgical reintervention. When available, MRI represents a valuable alternative modality that allows avoiding ionising radiation in young patients and adolescents in good clinical condition , 15."}
+{"text": "The incorporation of tidal inundation information and detailed data on landscape features, such as the structure of saltmarsh vegetation at mangrove boundaries, should improve the accuracy of models that are being developed to forecast mangrove distributional shifts in response to sea-level rise.Few studies have empirically examined the suite of mechanisms that underlie the distributional shifts displayed by organisms in response to changing climatic condition. Mangrove forests are expected to move inland as sea-level rises, encroaching on saltmarsh plants inhabiting higher elevations. Mangrove propagules are transported by tidal waters and propagule dispersal is likely modified upon encountering the mangrove-saltmarsh ecotone, the implications of which are poorly known. Here, using an experimental approach, we record landward and seaward dispersal and subsequent establishment of mangrove propagules that encounter biotic boundaries composed of two types of saltmarsh taxa: succulents and grasses. Our findings revealed that propagules emplaced within saltmarsh vegetation immediately landward of the extant mangrove fringe boundary frequently dispersed in the seaward direction. However, propagules moved seaward less frequently and over shorter distances upon encountering boundaries composed of saltmarsh grasses versus succulents. We uniquely confirmed that the small subset of propagules dispersing landward displayed proportionately higher establishment success than those transported seaward. Although impacts of ecotones on plant dispersal have rarely been investigated  Impacts of climate change may be displayed by a variety of responses at the individual population, species, community, or ecosystem level. Populations are predicted to track their niche and shift predictably towards suitable areas , 2, but Although directional dispersal of individuals towards those areas suitable for sustaining populations has often been discussed , 8 and msensu boundary permeability  within the buffer. Conversely, propagules from succulent-grass plots rooted a mean (\u00b1 se) distance of 6.7 (\u00b1 5.1) cm seaward of the starting position. On the last sampling date, we also observed a trend towards greater leaf production by A. germinans seedlings (71% produced leaves) from the grass monoculture treatment compared to leaf production by seedlings (52%) that were emplaced into the succulent-grass ecotone treatment. Finally, A. germinans propagules that had been emplaced into grass monoculture plots produced a slightly higher number of leaves than that recorded for individuals emplaced into succulent-grass plots .The composition of the experimental saltmarsh boundaries into which propagules were emplaced also influenced spatial patterns of mangrove establishment. By 6 weeks, 50.8% of all propagules had successfully rooted . Of the ositions . AdditioFactors influencing an inland niche shift of the black mangrove emerge from our quantification of landward movement of mangrove propagules upon encountering saltmarsh boundaries. Our study demonstrates that biotic boundaries erected by saltmarsh plants play a key role in directing the initial sequence of landward migration of mangroves expected under conditions of increasing sea-level. More specifically, hydrochorous transport vectors  and structural features of saltmarsh plants combine to determine permeability of inland boundaries to dispersing mangrove propagules. By recording both propagule retention and seedling establishment at landward mangrove margins we newly identified processes that contribute to successful mangrove persistence during inland migration. Our work provides empirical assessment of responses by early life-history stages of the black mangrove to the spatial arrangement of co-occurring coastal taxa thereby adding insight into the adaptive capacity for mangroves to respond to challenges from climate change.in situ work on mangrove dispersal [In agreement with ispersal , mangrovispersal , 20. Theispersal . This fiSporobolus virginicus, because both frequency and distance of seaward dispersal of propagules was reduced compared to the boundary containing succulent plants. Where succulents were present, comparatively higher proportions of propagules transported seaward led to a reduced abundance of potential colonizers remaining at the leading edge of mangrove migration. Propagule dispersal through saltmarsh plants  was likely influenced by the physical characteristics of the saltmarsh taxa, such as structural complexity [Although propagules emplaced into either boundary condition, i.e., grass monoculture or succulent-grass, generally moved seaward, the influence of saltmarsh taxa on the inland movement of the remaining propagules varied in a consistent way. Notably, propagule retention was improved at the saltmarsh boundary composed of monocultures of the saltmarsh grass, mplexity , height Rhizophora mangle propagules, which are considerably larger and distinctly different in shape than A. germinans [A. germinans propagules through succulent saltmarsh vegetation at our study site.Various types of saltmarsh-mangrove boundaries occur throughout the Caribbean and Gulf of Mexico , 28, 30.erminans , may becerminans ; whereaspersonal observations), suggest that some propagules transported landward are able to survive and ultimately achieve reproductive success. As appears to be true for mangroves, studies of migration by terrestrial plants challenged by climate drivers have also reported examples of directional dispersal running counter to the predicted direction of a niche shift [Aglaia aff. flavida were preferentially deposited uphill by Casuarius bennetti while, in contrast, most undispersed seeds moved downhill. Thus spatial shifts of both this montane plant and black mangrove appear to depend upon a comparatively small subset of propagules that are transported to, and successfully establish in, suitable sites.Landward transport of mangrove propagules at the saltmarsh boundary occurred within days; yet a pattern demonstrating inland recruitment persisted for at least 6 weeks, after which time most propagules became established seedlings. Moreover, a proportional increase in seedling establishment and leaf production was recorded for propagules that dispersed landward relative to seaward. These observations are aligned with Rabinowitz  who docuhe shift , 15, 16.he shift , 14, 43 he shift . Directihe shift . Mack [4Previously unavailable information on the direction of mangrove propagule dispersal across saltmarsh boundaries and spatial patterns of seedling establishment in the context of landscape features emerged from our experiments. Building on these findings, conditions under which boundary permeability to tidally-dispersed mangrove propagules and subsequent recruitment patterns might be altered can be identified. For instance, the potential for mangroves to be transported landward and establish at comparatively higher tidal elevations should vary if dispersal vectors or saltmarsh community composition are modified because of associated impacts to boundary function , 36, 39.Climate change is expected to increase the frequency/intensity of storms , which mAdditionally, propagule dispersal may be altered if the ecotone between saltmarsh succulents and grasses itself responds dynamically to climate drivers by shifting landward . As struFurthermore, complex biotic interactions between mangroves and saltmarsh taxa may operate not only during mangrove dispersal and recruitment, as shown here, but also during later life stages . In thisIn summary, our results suggest that interplay between tidal transport and physical attributes of saltmarsh vegetation assumes a critical role in directing the initial phase of shifting mangrove distributions and thus the capacity of black mangroves to respond to rising sea-level. These combined findings imply that any modification of tidal conditions or changes in plant composition of intertidal/supratidal landscapes through which propagules must disperse should impact the rate of successful mangrove migration as a consequence of altered mangrove dispersal and boundary permeability. The next challenge is to evaluate the capacity of mangroves to migrate inland as the coastal landscape is rearranged not only by rising sea-level but also other climate drivers.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file."}
+{"text": "The accurate definition of organs at risk (OARs) is required to fully exploit the benefits of intensity-modulated radiotherapy (IMRT) for head and neck cancer. However, manual delineation is time-consuming and there is considerable inter-observer variability. This is pertinent as function-sparing and adaptive IMRT have increased the number and frequency of delineation of OARs. We evaluated accuracy and potential time-saving of Smart Probabilistic Image Contouring Engine (SPICE) automatic segmentation to define OARs for salivary-, swallowing- and cochlea-sparing IMRT.Five clinicians recorded the time to delineate five organs at risk  for each of 10 CT scans. SPICE was then used to define these structures. The acceptability of SPICE contours was initially determined by visual inspection and the total time to modify them recorded per scan. The Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm created a reference standard from all clinician contours. Clinician, SPICE and modified contours were compared against STAPLE by the Dice similarity coefficient (DSC) and mean/maximum distance to agreement (DTA).For all investigated structures, SPICE contours were less accurate than manual contours. However, for parotid/submandibular glands they were acceptable . Modified SPICE contours were also less accurate than manual contours. The utilisation of SPICE did not result in time-saving/improve efficiency.Improvements in accuracy of automatic segmentation for head and neck OARs would be worthwhile and are required before its routine clinical implementation. The accurate definition of organs at risk (OARs) is required to fully exploit the benefits of intensity-modulated radiotherapy (IMRT) for head and neck cancer. HoweverFollowing head and neck radiotherapy, adverse late effects are highly prevalent and these impact on both organ function and more general domains of well-being, such as physical, mental and social health. RadiatiSwallowing dysfunction is seen in up to half of patients treated with definitive synchronous chemo-radiotherapy and is the most common late grade \u22653 toxicity; the incidence has increased with intensification of treatment including addition of chemotherapy or altered fractionation-16. ThisPermanent and predominantly high frequency sensori-neural hearing loss may occur in 40-60% of patients who receive radiotherapy to areas such as the nasopharynx, para-nasal sinuses and parotid bed-31. ThisSignificant anatomic changes and alteration in dose to target volumes and OARs may occur during a course of head and neck radiotherapy-37. A stSmart Probabilistic Image Contouring Engine (SPICE) is an automated commercially available algorithm, which combines an atlas-based and model-based approach to segmentation of head and neck lymph node levels and OARs. The atlThis study aims to evaluate accuracy and time-saving of SPICE to define OARs for salivary-, swallowing- and cochlea-sparing IMRT.utilisation of SPICE in clinical practice (clinician review and modification). These also demonstrate introduction of bias by automatic segmentation .Ten radiotherapy planning CT scans were selected where the OARs of interest were not distorted by tumour or artefact . Five clinicians (four Consultants/Attending Physicians and one Fellow) recorded for each scan the time to manually delineate the parotid and submandibular glands, larynx (supraglottic and glottic larynx defined as one structure), pharyngeal constrictor muscles  and cochleae according to a locally agreed protocol based on published guidelines ,48,49. SThe Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm employs a probability map to create a \u2018best fit\u2019 from a collection of contours Figure\u00a050]. Th. Th50]. t-test (to determine efficiency in the utilisation of SPICE). Significance was assessed at the p\u2009<\u20090.05 level.Statistical comparisons using multiple linear regression analysis  were made between mean values of all matrices for: SPICE against STAPLE versus manual against STAPLE (to determine the accuracy of SPICE); and modified SPICE against STAPLE versus manual against STAPLE . As a further measure of accuracy, SPICE was compared with the most discordant clinician contours (determined against STAPLE and by ranking of clinicians) for each structure measured by DSC and DTA, using the Wilcoxon signed rank test. The total times to manual versus modify SPICE contours for all structures and clinicians were compared using Student\u2019s paired SPICE submandibular gland \u20181\u2019 and parotid gland \u20182\u2019 contours demonstrated best concordance with STAPLE Table\u00a0 and4. SThe total proportions of SPICE contours determined by visual inspection not to require alteration were: parotid glands 17%), submandibular glands (41%), larynx (8%), pharyngeal constrictor muscles (4%), and cochleae (28%). The mean DSCs were significantly reduced for modified SPICE contours compared with manual for all structures Figure\u00a0. However%, submanThe respective per scan overall mean times for manual and modified SPICE contours were 14.0 and 16.2\u00a0minutes  Figure\u00a0. Only onThis study showed that for head and neck OARs: (i) SPICE contours were less accurate than manual contours, but acceptable for the definition of parotid and submandibular glands; (ii) modified SPICE contours remained inferior to manual contours; and (iii) the utilisation of SPICE compared with manual delineation did not result in time-saving/improve efficiency.et al compared for two CT scans and eight clinicians, manual and automatic modified contours for delineation of the clinical target volume as well as parotid glands, spinal cord, brainstem and (for one scan) the optic apparatus[ISOgray atlas-based auto-segmentation algorithm was evaluated for definition of the brainstem, parotid glands and mandible[Automatic segmentation to define selected head and neck OARs may reduce inter-observer variability,55. Chaopparatus. For theBrainlab automated segmentation algorithm, which employs atlas-based and deformable registration, was assessed for accuracy of definition of neck nodal regions and selected head and neck OARs[The updated eck OARs. In 10 \u2018Clinical validation of a multiple-subject atlas-based autosegmentation tool was performed by measuring the DSC and mean DTA for manual contours (outlined by one of 10 clinicians and agreed by an expert panel) and modified contours (outlined by one of two clinicians) for neck levels, parotid and submandibular glands in 12 patients. For manWe found that SPICE automatic contours were less accurate/inferior to manual contours for all investigated structures, but acceptable for the parotid and submandibular glands. For the parotid and submandibular glands, the DSCs were satisfactory;,52 for pWhether differences between manual, automatic or modified contours result in clinically relevant alterations in measured doses to OARs is uncertain. This will partly depend on proximity of normal structures to the treatment volume and the dose gradient. In this study, the target volumes were not defined. This may have influenced the low percentage of OARs determined by visual inspection not to require alteration i.e., clinicians only considered the conformity of automatic contours to normal structures rather than clinical relevance or requirement for this.This study represents an independent clinical evaluation of automatic segmentation using SPICE and its utilisation for head and neck OARs. It determined the accuracy of SPICE by comparison against a reference standard created using STAPLE, for five head and neck OARs important in function-sparing IMRT. Future work should evaluate automatic segmentation in the presence of distortion by tumour or artefact e.g., dental amalgam; and determine the variation in measured dose to OARs between manual, automatic and modified contours.For the investigated head and neck OARs, SPICE automatic segmentations were less accurate than manual contours. However, these were acceptable for the definition of parotid and submandibular glands. The modification of SPICE contours improved accuracy, but these remained inferior to manual contours and the process did not result in time-saving. Improvements in automatic segmentation of head and neck OARs would be worthwhile and are required before routine clinical implementation.OARs: Organs at risk; IMRT: Intensity-modulated radiotherapy; SPICE: Smart Probabilistic Image Contouring Engine; STAPLE: Simultaneous Truth and Performance Level Estimation; DSC: Dice Similarity Coefficient; DTA: Distance to agreement; PARSPORT: Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer; Gy: Gray; kV: kilovoltage; CT: Computed tomography.The authors declare that they have no competing interests.DT designed and coordinated the study, participated in contouring, analysed part of the data, interpreted data, drafted the manuscript. CB performed STAPLE and volume overlap measurements. TL analysed the data. AA provided the DTA algorithm and helped with volume overlap measurements. LL, BY, AJS, NJS participated in contouring. CR/NJS conceived the study, participated in its design and coordination and helped draft the manuscript. All authors read and approved the final manuscript."}
+{"text": "To assess medical and nursing students\u2019 intentions to migrate abroad or practice in rural areas.We surveyed 3199 first- and final-year medical and nursing students at 16 premier government institutions in Bangladesh, Ethiopia, India, Kenya, Malawi, Nepal, the United Republic of Tanzania and Zambia. The survey contained questions to identify factors that could predict students\u2019 intentions to migrate. Primary outcomes were the likelihoods of migrating to work abroad or working in rural areas in the country of training within five\u00a0years post-training. We assessed predictors of migration intentions using multivariable proportional odds models.Among respondents, 28% (870/3156) expected to migrate abroad, while only 18% (575/3158) anticipated a rural career. More nursing than medical students desired professions abroad . Career desires before matriculation correlated with current intentions for international  and rural  careers. Time spent in rural areas before matriculation predicted the preference for a rural career  and against work abroad .A significant proportion of students surveyed still intend to work abroad or in cities after training. These intentions could be identified even before matriculation. Admissions standards that account for years spent in rural areas could promote greater graduate retention in the country of training and in rural areas. We know very little regarding the characteristics of students inclined to work in rural areas or remain in the country in which they train.\u2013http://biostat.mc.vanderbilt.edu/StudentMigration).Previous studies on health worker retention are mainly from high-income countries,\u2013We considered countries in sub-Saharan Africa and south-east Asia that were classified by WHO as having a critical shortage of health service providers .,To enhance similarity between study institution governance structure and founding principles, we excluded countries without both a government medical and nursing school, or in which either school was established after 1993. This date corresponds to a period of increased attention to health sector reform in developing countries that may have affected guiding missions of health training institutions established thereafter.The 16 study sites selected are listed in We conducted the study from September 2011 to April 2012. Students eligible for our study were first- or final-year students enrolled in medical  or nursing (Bachelor of Science) degree programmes. At each institution, a self-administered questionnaire was given to all eligible students attending a mandatory class lecture. Written informed consent was obtained before survey administration. Survey items assessed student background characteristics such as socioeconomic status and place of origin, attitudes towards rural and international careers and student career intentions (Appendix). Questions, derived from literature review (Appendix), consisted largely of multiple-choice items and five-point Likert scales. Surveys were in English. To minimize potential bias from variable English proficiency, official language translations were provided as an aide alongside the English questions in five countries  where English is not an official language. Translations were validated using independent back-translation. Field testing was performed in each country and country-specific modifications were made to ensure relevant terminology. The two primary outcomes were self-reported likelihood of choosing to work outside the country or in a rural setting inside the country within five years post-training.Questionnaire results were entered electronically and data entry audited by randomly selecting 22 electronic questionnaires from each country for comparison with hard copies. Audit sample size was calculated to ensure an estimated data entry error rate less than\u20095% with 95% confidence interval (CI). Questionnaires with more than\u200925% of responses missing were excluded from analysis.http://www.r-project.org) for data analyses.For each country, we used summary statistics to describe respondent characteristics and multivariable proportional odds models to estimate the independent relationship between 14 selected characteristics  and the likelihood to work internationally or in rural areas. The number of characteristics selected was computed using the smallest country sample size.At the 16 institutions studied, 3822 students were enrolled in first- or final-year medical or nursing degree classes . Of thesTen schools in sub-Saharan Africa comprised 66% (2118/3199) of the study population, while six South Asian schools encompassed 34% (1081/3199) . MedicalOf all students, 28% (870/3156) reported being very likely to choose work abroad within five years of completing training . InternaMultivariable analysis showed that nursing students were more likely than medical students to intend careers abroad . Final-year students were less likely to plan international careers than first-year counterparts  of all students reported high likelihood of choosing a rural career within five years of training, including 16% (360/2257) of medical and 24% (215/901) of nursing students . In sub-As with international migration intentions, individuals who upon school entry had desired a rural career were now nearly five times more likely to plan one . Our aggregate class response rate is high (84%). Our study is systematic, employing rigid yet relevant selection criteria to identify study sites. All participating nations face significant health worker shortages and ongoing emigration, but possess stable environments where retention policies are not superseded by larger systemic sociopolitical motivators of migration. We independently analysed 14 student characteristics to identify predictors for a career in the country or in rural areas. Our results have implications for education and health-care policy-makers in LMIC and donor nations.Our sample cannot be generalized to areas where internal conflict or political turmoil may drive migration regardless of student characteristics, nor can it be extrapolated to non-Anglophone countries. Sub-Saharan African countries have comparable physician emigration rates regardless of national language,,,,,Our data suggest that students\u2019 career desires before matriculating may persist into the last year of training. Although our study design cannot exclude recall bias, the direction of recall error is unclear and should be further investigated through longitudinal assessment. Similarly, under-reporting of true migration intentions due to perceived values of the school professionals might create a social bias. However, if such bias is present it would strengthen our results, since the true number of students intending to migrate may be higher and those planning to work in rural areas even lower than we report. Social bias was mitigated by survey anonymity and is unlikely to have affected class years differently. Our cross-sectional questionnaire of students\u2019 intentions is not validated for predicting actual migration behaviour. Nonetheless, the similarity of our results to existing migration statistics suggests that students\u2019 intentions may resemble such behaviour.,Further research is needed to understand the migration intentions of students. Our study focused on students at premier public schools, where institutional missions focus on producing practitioners for domestic service and health-care leadership, and where public funds offset educational expenses. Migration ambitions may differ at private or newly-established public institutions with varying school resources, values and admissions standards. Also, longitudinal analysis is needed to discern whether differences in career plans between first- and final-year classes represent an evolution of students\u2019 preferences during the schooling period or a change in class composition resulting from recent enrolment expansions at many institutions studied. Finally, additional migration routes of health professionals in LMIC remain to be studied: from public to private sector and from clinical to administrative sector. This is important research since health professionals\u2019 movements from clinical public-sector work threaten already fragile public-health systems.\u2013,,,Increased demand for health professionals in developed countries is projected to attract even more LMIC graduates,With nearly 64% of people in sub-Saharan Africa and 69% in South Asia residing in rural areas,"}
+{"text": "Addiction services organizations have been slow to adopt and implement evidence-based practices (EBPs) for substance abuse and dependence. This is due in part to poor worker morale and organizational climates that are not conducive to successful learning and integration of these practices . Person-Direct service providers (N = 120) from four addiction services organizations in a large Midwestern city responded to a survey assessing provider morale, organizational learning climate, agency expectations for EBP use, agency resources for EBP use, and provider attitudes towards EBP use. Difference scores between provider- and agency-level factors were computed to model provider-agency fit. Linear regression models were accounted for in all analyses, but were determined to be insufficiently sensitive in modeling the curvilinear (inverted U-shaped) relationships expected in this study. Therefore, quadratic regression analyses were conducted to more adequately model the level of the dependent variables across the entire \u201cfit continuum.\u201dMisfit between agency expectations and provider attitudes and between agency resources and provider attitudes were associated with poorer provider morale and weaker organizational learning climate. For all hypotheses, the curvilinear model of provider-agency misfit significantly predicted provider morale and organizational learning climate Figures  and 2. MThis research benefits from a strong theoretical framework, consistent findings, and significant practical implications for substance abuse treatment agencies. Provider morale and organizational learning climate are important indicators of successful EBP implementation. Comprehensive attempts to strengthen these outcomes must consider both provider- and agency-level characteristics regarding EBP use. Managers and supervisors should consider conducting periodical self-assessments of their agency\u2019s cultural predispositions toward EBP implementation  and addiction service providers\u2019 openness, abilities, and general attitudes towards using EBPs. Organizational efforts to more closely align provider attitudes and agency priorities will likely constitute a key strategy in fostering the implementation of EBPs in addiction services organizations."}
+{"text": "In MOF the competition for the amino acid arginine between the microcirculation and the inflammatory response is important. The endothelial nitric-oxide synthase (eNOS) uses arginine to produce nitric oxide (NO), which results in microcirculatory vasodilatation, whereas arginase and the inflammatory nitric-oxide synthase (iNOS) use arginine in the inflammatory response to produce acute phase proteins and to stimulate the host response. Enhanced arginine consumption combined with decreased arginine To investigate the role of the NOS enzymes during endotoxemia and the effect of citrulline supplementation on the arginine-NO synthesis and microcirculation.-/-; n= 39), deficient eNOS mice  and double knock-out (KO) mice  received a continuous LPS  infusion for 18 hrs alone or combined with citrulline (37.5mg) for the last 6 hrs. SDF-imaging was used to evaluate the microcirculation in jejunal villi and the NO production in jejunal tissue was determined by in vivo NO spin trapping and quantified by electron spin-resonance spectrometry. After the microcirculatory measurements or in vivo NO spin trapping, mice were sacrificed, blood and tissues were sampled. Amino-acid concentrations in blood and tissue were measured by High Performance Liquid Chromotography.Wildtype (n= 39), deficient iNOS mice, (iNOS-/- or eNOS-/- mice this was not accompanied by a decreased intracellular arginine availability. Jejunal NO production was significantly decreased in all mouse strains during endotoxemia, except for eNOS-/- mice. LPS infusion resulted in a significantly decrease in jejunal microcirculation in wildtype and iNOS-/- mice. However, mice lacking a functional eNOS enzyme, as present in eNOS-/- and double KO mice, perfusion in jejunal tissue did not decrease during LPS infusion. Also the beneficial effects of citrulline supplementation during LPS infusion on the microcirculation were not present in eNOS-/- or double KO mice, although citrulline significantly enhanced the plasma arginine availability in all mouse strains. In addition, tissue arginine availability did not increase in citrulline supplemented NOS deficient mice.LPS infusion significantly decreased plasma arginine availability in all mouse strains. However, in the jejunal tissue of iNOSde novo synthesis during sepsis, however to enhance the microcirculation during sepsis, citrulline requires a functional eNOS enzyme. Therefore, future research needs to focus both on improvement of the arginine de novo synthesis and maintenance of a functional eNOS enzyme during sepsis.Citrulline improves the arginine"}
+{"text": "There is increasing integration of qualitative research within randomised controlled trials (RCTs). However, how these methods are applied at the pre-trial stage to inform trial design and conduct is less well explored. Here we describe how qualitative methods were used in a feasibility study to inform the design of a pilot RCT.Semi-structured interviews with purposely sampled clinicians (n=61) and patients (n=32) explored current clinical practice and views about the proposed trial interventions and protocol. Analysis used constant comparative approaches. Emerging findings were disseminated through focused reports/presentations to the study management group and steering committee as research progressed.Qualitative findings informed changes to fundamental aspects of trial design and proposed outcome measures. Clinicians' interpretations of the original interventions were variable, and descriptions of current practice/terminology consistently differed with assumptions made in the grant proposal and commissioned call for research. New outcomes were recognised, prompted by clinicians'/patients' priorities. Measuring and reporting these outcomes was deemed crucial for a full trial's potential to impact future practice. Interviews with clinicians also prompted new \u2018in trial\u2019 data collection requirements, as clinicians anticipated potential changes to their clinical practice to accommodate the trial interventions. These changes had potential to impact the primary outcomes, prompting recommendations to measure/record these practices during trial conduct.Qualitative research at the pre-trial stage can transform fundamental aspects of trial design/delivery. Presenting emergent findings as the research progresses is one approach to enhancing impact, facilitated by participation of qualitative researchers as core members of investigator teams."}
+{"text": "In contrast, remarkable advances in its basic genomics have not been sufficiently translated into the molecular epidemiology of diphtheria. A recent report by Zasada . More recently, a multilocus sequence typing (MLST) scheme for C. diphtheriae was developed . The second approach is locus oriented and makes use of the repetitive DNA sequences, namely, variable number tandem repeats (VNTR) and clustered, regularly interspaced short palindromic repeats (CRISPR) loci.Two in silico\u2013inspired approaches have recently been pursued toward more precise molecular genetics and epidemiology of diphtheria. The first approach is based on whole-genome sequencing (WGS). After years of stagnation, the number of complete C. diphtheriae   analysis might offer a broader range of possible general solutions from global tracing of large clonal clusters (current threshold) toward fine-tuned strain discrimination. At the same time, a multicenter evaluation of recently developed inexpensive and discriminatory VNTR and CRISPR methods is warranted to see if and how they could complement regional surveillance."}
+{"text": "The brainstem is the major site of trigeminal pain processing and modulation and plays a key role in the pathophysiology of various headache disorders. However, comprehensive human imaging studies on function and activity of brainstem areas following trigeminal nociceptive stimulation are scarce.To develope a viable protocol for brainstem fMRI of standardized trigeminal nociceptive stimulation.21 healthy participants  were scanned on a 3T scanner with a standardized trigeminal nociceptive stimulation protocol for event-related fMRI using a specifically designed sequence for high resolution brainstem echo planar imaging as well as a brainstem specific noise correction technique and brainstem template.We observed significant BOLD responses in areas typically involved in trigeminal nociceptive processing such as the spinal trigeminal nuclei (sTN), thalamus, SII, insular cortex and cerebellum as well as in a pain modulating network including the dorsal raphe nuclei (DRN), periaqueductal grey area (PAG), hypothalamus (HT) and nucleus cuneiformis (CN) . Using PPI analyses, we found enhanced connectivity of the sTN with the HT and the CN.Our results are in line with previous animal and human imaging studies on brainstem processing of nociceptive stimuli. However, using the proposed high resolution imaging technique, we achieved a more detailed insight into brainstem pain processing as compared to whole brain fMRI. High resolution brainstem fMRI of trigeminal nociceptive stimulation offers a unique opportunity to better understand headache pathophysiology.No conflict of interest."}
+{"text": "The mechanism by which this activity regime is generated is well-known [While the physics of local field potential (LFP) generation are well-established, the complexity of neural network dynamics means that interpreting LFP measurements in terms of the underlying neural activity is very difficult . Recent ll-known , and manWe describe three key results from our simulations. Firstly, we found that perisomatic synaptic currents on pyramidal neurons resulting from basket interneuron firing dominate the LFP during gamma oscillations, in agreement with recent experimental results ,4. We pr"}
+{"text": "Peripheral neuropathy is a common complication of arsenic toxicity. Symptoms are usually mild and reversible following discontinuation of treatment. A more severe chronic sensorimotor polyneuropathy characterized by distal axonal-loss neuropathy can be seen in chronic arsenic exposure. The clinical course of arsenic neurotoxicity in patients with coexistence of thiamine deficiency is only anecdotally known but this association may potentially lead to severe consequences.We describe a case of acute irreversible axonal neuropathy in a patient with hidden thiamine deficiency who was treated with a short course of arsenic trioxide for acute promyelocytic leukemia. Thiamine replacement therapy and arsenic trioxide discontinuation were not followed by neurological recovery and severe polyneuropathy persisted at 12-month follow-up.Thiamine plasma levels should be measured in patients who are candidate to arsenic trioxide therapy. Prophylactic administration of vitamin B1 may be advisable. The appearance of polyneuropathy signs early during the administration of arsenic trioxide should prompt electrodiagnostic testing to rule out a pattern of axonal neuropathy which would need immediate discontinuation of arsenic trioxide. She had a medical history of lobular carcinoma of the left breast treated with mastectomy and chemotherapy in 2012, Hashimoto thyroiditis, arterial hypertension. There was no prior neurological disorder and physical examination was unremarkable. Coagulation tests showed reduced prothrombin time ratio (59%) and normal activated partial thromboplastin time, a slightly reduced fibrinogen  and increased D-dimer (8634 \u03bcg/L). Bone marrow evaluation was consistent with acute promyelocytic leukemia (APL) according to French-American-British (FAB) classification system. The patient was started on all-trans retinoic acid (45 mg/m2) according to protocol APL0406Although polyneuropathy is common following arsenic trioxide therapy of subjects with acute promyelocytic leukemia (APL), symptoms are generally mild and they disappear after completion of arsenic treatment. In November 2014, a 72-year old Caucasian woman was admitted to this Unit with fever and pancytopenia , neurological symptoms were attributed to sodium-related hyperosmolarity.Over the following days an impaired level of consciousness and lethargy was noticed. Progressive and appropriate normalization of natriemia did not improve neurological dysfunction.Additional diagnostic procedures were performed. A CT scan of the brain did not reveal abnormalities related to the acute clinical picture, showing only age-related mild cerebral and cerebellar atrophy. Cerebrospinal fluid showed only mild protein elevation.Plasma levels of vitamin B1 were low  and supplementation was started. Over the following 5 days the patient showed a slow but progressive full recovery of cognitive functions.Unexpectedly, at normalization of cognitive function, a pattern of symmetric peripheral neuropathy involving upper and lower limbs became clinically evident. Physical examination showed that left and right hands were severely weak, particularly the abductor pollicis brevis, with mild strength reduction in the proximal arms. Deep-tendon reflexes were absent. There was bilateral foot drop, and the patient was unable to walk. Strength in the ankle dorsiflexors, extensor hallucis longus, extensor digitorum brevis, and toe flexors was severely compromised. There was no muscle atrophy or fasciculation, and the remainder of the neurologic examination was normal. Electromyography (EMG) showed a severe sensory-motor axonal neuropathy of the upper and lower extremities with a greater reduction of sensory action potential.Meanwhile on day 28 arsenic trioxide had been stopped according to the therapy protocol. Bone marrow evaluation showed molecular remission. At that time the patient was bedridden because of a severe neurological impairment, so we chose not to administer consolidation therapy as it would have been required according to standard protocol.Over the following on 6 months from arsenic trioxide discontinuation, the patient regained full proximal muscle strength but with almost complete persistence of marked distal weakness of the hands,ly finger and wrist extensors, weakness of foot dorsiflexors bilaterally and the inability to maintain an upright position. Neurological examination and EMG were substantially unchanged at the 12-month follow-up evaluation.We believe that occult thiamine deficiency exacerbated arsenic trioxide neurotoxicity causing an unexpected and irreversible distal axonal symmetric neuropathy. This is the first report of acute and irreversible axonal neuropathy in a patient treated with arsenic trioxide with a background of thiamine deficiency. Peripheral neuropathy has long since been associated with the use of arsenic. Several clinical studies have been published on ATO treatment of patients with APL .2\u201312 AltSevere and irreversible arsenic neurotoxicity in the setting of thiamine deficiency can be explained by their common metabolic target. In fact, thiamine deficiency and arsenic exposure severely impair pyruvate dehydrogenase (PDH) activity, an enzyme responsible for converting glucose to energy in high yield. As neural tissues are highly dependent on carbohydrates for energy production and cellular metabolism, it is tempting to speculate a synergic detrimental neuropathic effect leading to the severe toxicity observed in our patient. Of interest, we found electrophysiological findings consistent with acute axonal dysfunction without pattern of demyelination. This type of damage is the classic electrophysiological and histopathological finding in beriberi neuropathy whereas arsenic axonal toxicity characteristically coexists with segmental demyelination.17In conclusion, occult thiamine deficiency may contribute to arsenic toxicity and the combination may cause irreversible axonal neuropathy which must be considered when monitoring APL patients on arsenic trioxide therapy. Prophylactic administration of thiamine may be considered in this setting."}
+{"text": "Mental disorders affect up to 40 % of all individuals living in Europe at least once a life time. Serious mental disorders with chronic or relapsing course like major depression bipolar disorder and schizophrenia are disabling and often disintegrating disorders. The early identification of subjects being at risk for serious mental disorders holds the promise of early intervention and better long-term outcomes. However, still reliable early indicators are largely missing to date. Like in dementia research major research initiatives need to be developed to address those urgent issues.New MRI imaging technique, genotyping, gene methylation analyses, metabolom analyses, validated questionnaires for the assessment of psychosocial risk factors.Advanced statistical modeling of brain imaging data, support vector machine approaches, systems integration of OMICS data; data mining approaches for risk marker identification.The identification of peripheral risk indicators of severe mental diseases is probably limited to rare but highly penetrative genetic variants. Possibly gene-methylation patterns that emerge in the light of abuse and traumatization be constitute another source of valuable information. The non-invasive MRI imaging technologies might be very promising but still time consuming and expensive. Especially functional MRI studies are only feasible in specialist centers. The most promising approach seems to create a set of specific markers throughout the different levels of information to integrate biological, psychosocial and structural information on each subject."}
+{"text": "Spontaneous cortical activity can show very complex collective emerging features, with, in some cases, the alternation of \"down states\" of network quiescence and \"up states\" of generalized spiking and neuronal depolarization . Results"}
+{"text": "THHOBO data loggers and rainfall was recorded daily using GENERALR wireless rain gauges. Thin plate spline (TPS) was used to interpolate, with the degree of data smoothing determined by minimizing the generalized cross validation. The dataset provide information on the status of the current climatic conditions along the two mountainous altitudinal gradients in Kenya and Tanzania. The dataset will, thus, enhance future research.Climate change is a global concern, requiring local scale spatially continuous dataset and modeling of meteorological variables. This dataset article provided the interpolated temperature, rainfall and relative humidity dataset at local scale along Taita Hills and Mount Kilimanjaro altitudinal gradients in Kenya and Tanzania, respectively. The temperature and relative humidity were recorded hourly using automatic onset  Specifications TableValue of the data\u2022The data provide information on the status of the climatic conditions along the two mountain altitudinal gradients in Kenya and Tanzania, and includes data accessible for reuse.\u2022The data are important to farming communities, agricultural extension agents, government institutions, international and local non-governmental organizations engaged in agricultural interventions, including useful data to researchers, students and academics.\u2022The data can be used for mapping and spatial modeling in a geographical information system (GIS).\u2022The data is valuable for improvements computational facilities, insufficient climate data and reliable downscaling at a local scale.\u2022The data are important in making confidentially informed decisions, giving scientists accurate spatially continuous data cross a region for making justified interpolation.12R wireless rain gauges were installed at station across study sites to keep track of daily temperatures, relative humidity and rainfall, respectively x\u2013y coordinates position and altitudes were recorded using a Global Positioning System (GPS) (German eTrex Vista(R)). The thin plate spline (TPS) algorithm 2); (ii) the Root Mean Square Error (RMSE); and (iii) the Relative Root Mean Square Error (RMSEr).The details of the sites have been described in our previous study"}
+{"text": "Diverse monogenic autoinflammatory diseases share responsiveness to interleukin (IL)-1 blockade. This study explored the utility of anakinra (an IL-1 receptor antagonist) as a treatment option for clinically heterogeneous systemic inflammatory disease with autoinflammatory presentations where a genetic cause was not defined.A total of ten adult cases with ongoing inflammatory episodes, where alternative diagnoses, including malignancy and infection, were evaluated. Genetic screening was also performed to exclude known genetic causes of autoinflammatory disorders (e.g. cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), etc.)All patients had presentations that were atypical of recognised autoinflammatory disorders and all were negative on genetic screening. Eight of ten cases showed rapid responsiveness to anakinra with the ability to subsequently taper alternative immunosuppression. Good responses to anakinra were maintained with inadvertent drug discontinuation being linked to disease flares.The spectrum of poorly defined clinical and genetic autoinflammatory disorders that show responsiveness to anakinra is considerable. In fact, responsiveness to anakinra appears to be useful in diagnosis given the characteristically rapid onset of efficacy and symptomatic improvement."}
+{"text": "Aging may lead to pathologies due to the physiologic decline or aberrancy in the functions of adult stem cells, whose intrinsic capacity for self-renewal helps maintain tissue homeostasis. The majority of cancers arise from replication-induced somatic mutations in adult stem cells , which pAPC or CTNNB1 mutations, which are found in >90% of early colon adenomas [mut) in late colon adenomas drive their malignant transformation to cancer by further promoting WNT activation through \u03b2-catenin nuclear localization [per se, even when targeted to murine colon stem cells to constitutively activate their intestinal stem cell program, was capable of initiating colon adenomas but not invasive colon cancers [Hitherto, the initiation of colon cancer has been attributed mainly to the aberrant activation of WNT signaling as a result of adenomas . Indeed,lization . However cancers . Nearly  cancers . Thus thmut further increases this tumorigenic and dedifferentiation program [mut to dedifferentiate APC mutated colon adenoma cells depends on their moderate plasticity, since KRASmut by itself in the cellular context of differentiated epithelial cells cannot induce the embryonic stem cell-like program [in vivo plasticity model in which the achievement of high plasticity, as exemplify by KRASmut mediated induction of the embryonic stem cell-like program in colon adenomas, optimizes colon cancer initiation. Currently, there are two conflicting theories for the colon cancer cells of origin. The top-down theory requires that differentiated crypt top colon cells undergo dedifferentiation to become the colon cancer cells of origin. The bottom-up theory suggests that crypt base WNT activated colon stem cells, which give rise to colon adenomas, are the colon cancer cells of origin [in vivo plasticity model helps explain the paradoxical findings that lend support to both the top-down and bottom-up theories on the colon cancer cells of origin.We have found that embryonic stem cell-like program activation is a major mechanistic driver of colon cancer initiation, and the presence of KRAS program . The abi program , 7. We hf origin . Howevermut tumors.Intriguingly, embryonic stem cells arise at the beginning of human ontogeny and cancer cells arise dramatically toward the end. Thus cancer cells have come nearly full circle in reactivating the embryonic stem cell-like program, which imparts greater phenotypic plasticity to thrive with environmental variations. Cancers may be the unfortunate failed manifestations of nature's quest for the fountain of youth. Nevertheless, the inhibition of the embryonic stem cell-like program offers novel therapeutic strategies to prevent cancer and inhibit KRAS"}
+{"text": "A striking property of the mutualism between figs and their pollinating wasps is that wasps consistently oviposit in the inner flowers of the fig syconium, which develop into galls that house developing larvae. Wasps typically do not use the outer ring of flowers, which develop into seeds. To better understand differences between gall and seed flowers, we used a metatranscriptomic approach to analyze eukaryotic gene expression within fig flowers at the time of oviposition choice and early gall development. Consistent with the unbeatable seed hypothesis, we found significant differences in gene expression between gall- and seed flowers in receptive syconia prior to oviposition. In particular, transcripts assigned to flavonoids and carbohydrate metabolism were significantly up-regulated in gall flowers relative to seed flowers. In response to oviposition, gall flowers significantly up-regulated the expression of chalcone synthase, which previously has been connected to gall formation in other plants. We propose several genes encoding proteins with signal peptides or associations with venom of other Hymenoptera as candidate genes for gall initiation or growth. This study simultaneously evaluates the gene expression profile of both mutualistic partners in a plant-insect mutualism and provides insight into a possible stability mechanism in the ancient fig-fig wasp association. Mutualisms are ubiquitous in nature and often enhance the nutrition, protection, and/or reproduction of participating partners see , 2). Yet. Yet2]).Ficus spp.) and fig wasps  arose >80 million years ago ).Use of only a subset of available flowers by foundresses cannot be explained by physical limitations in ovipositor length or egg number , 23, 24.Based on observations that foundresses are selective in choosing flowers for oviposition, West and Herre  proposedFicus obtusifolia, a monoecious fig that grows natively in lowland forests in Panama. Specifically we compared metatranscriptomes of gall and seed flowers before and after fig wasps entered syconia to determine (1) biochemical and metabolic differences between these two flower types that may influence oviposition by foundress wasps, and (2) gene expression in floral tissue at gall initiation ). The high level of expression of these genes suggests that fig wasps were undergoing embryogenesis when gall flowers were collected.The hymenopteran transcript with the highest level of expression was assigned to the gene properly . AdditioA maternal secretion, which is deposited in every flower that receives an egg, has been associated with the initiation of gall growth in fig flowers , 67, 68.th highest expressing in all Hymenoptera transcripts) was assigned to icarapin, which has an active role in honeybee venom [Nasonia vitripennis, the only well-studied venom among wasps in the superfamily of Chalcidoidea, eight genes coding for proteins harboring signal peptides also shared homology with genes coding for venom proteins. Three are hypothetical proteins and the remaining five match genes predicted as serine protease, lysosomal acid phosphatase, chymotrypsin, lipase, and metalloproteinase (Table G in Eulophus pennicornis [Only 196 (2.8%) of the Hymenopteran transcripts observed here contain a signal peptide Click here for additional data file.S1 FileNumber of transcripts assigned to taxonomic groups for each sample (Table A). Overrepresented GO terms of up-regulated genes in receptive gall flowers compared to receptive seed flowers (Table B). Transcripts assigned to overrepresented GO terms associated with chalcone synthase in receptive and pollinated gall flowers (Table C). Transcripts uniquely expressed in receptive gall flowers (Table D). Transcripts assigned to overrepresented GO terms associated with carbohydrate metabolism in receptive gall flowers (Table E). Overrepresented GO terms of up-regulated genes in pollinated gall flowers compared to receptive gall flowers and pollinated seed flowers (Table F). Transcripts with assignment to Hymenoptera (Table G).(XLSX)Click here for additional data file."}
+{"text": "Women seeking to become pregnant and pregnant women are currently advised to consume high amounts of folic acid and other methyl donors to prevent neural tube defects in their offspring. These diets can alter methylation patterns of several biomolecules, including nucleic acids, and histone proteins. Limited animal model data suggests that developmental exposure to these maternal methyl supplemented (MS) diets leads to beneficial epimutations. However, other rodent and humans studies have yielded opposing findings with such diets leading to promiscuous epimutations that are likely associated with negative health outcomes. Conflict exists to whether these maternal diets are preventative or exacerbate the risk for Autism Spectrum Disorders (ASD) in children. This review will discuss the findings to date on the potential beneficial and aversive effects of maternal MS diets. We will also consider how other factors might influence the effects of MS diets. Current data suggest that there is cause for concern as maternal MS diets may lead to epimutations that underpin various diseases, including neurobehavioral disorders. Further studies are needed to explore the comprehensive effects maternal MS diets have on the offspring epigenome and subsequent overall health. Mounting evidence suggests that developmental exposure to extrinsic factors  leads to pronounced epigenetic and phenotypic effects, commonly referred to as the \u201cdevelopmental origin of health and disease (DOHaD)\u201d Barker, . Epigene12, and zinc , folate (vitamin B9), betaine (trimethylglycine), choline, Vitamin BAnimal model studies have examined how maternal methyl supplemented (MS) diets impact the epigenome and/or phenotypic outcomes in developing offspring Table . Some ofOther factors likely interact with maternal diet to influence the net effect of these diets. Examples include genetic background, sex, developmental windows of exposure, and tissue/cell-specific vulnerabilities, which are discussed below.vy/aA offspring), pregnant a/a female mice exposed to the endocrine disrupting compound (EDC) bisphenol A (BPA) gave birth to a greater percentage of yellow coat color compared to brown coat color (vy/aA) offspring   coat color animals that are concomitantly less prone to these adult diseases. Combined prenatal treatment with a BPA and methyl-supplemented diet in these females was reported to offset the BPA-induced shift in coat color distribution from metabolic deleterious yellow morphs to an increase in brown coat color, healthier offspring  within this allele is hypomethylated, vyA/a status) over several generations (through F5) to increase percentage of pseudoagouti animals possessing a methylated IAP promoter site , an extracellular modulator of bone morphogenetic protein signaling, exhibit midline facial and jaw defects. However, maternal MS diet prevented their jaw defects  promoter  with metabolic disorders, discussed above, and FuAxin mice exhibiting tail dysmorphogenesis, or \u201ckinky\u201d tail  to high concentrations of folic acid resulted in newborn mouse pups exhibiting disrupted cerebral gene expression for transcripts and their protein products implicated in normal neural development  in children  for maternal consumption of prescription prenatal vitamins (containing > 1 mg of folic acid) and ASD incidence in offspring , as well as tissue/cell specificity and concentration and duration of exposure to these nutritional supplements. All of these factors should be considered when employing maternal MS diets to combat fetal disease.Comprehensive long term animal and human epidemiological studies should be undertaken to assess the global effects of these nutraceuticals and to resolve the current conflicting data in regards to maternal MS diet. Until then, women requesting prenatal/perinatal vitamin support should be advised against consuming methyl supplements,  in doses that exceed the current recommendations for preventing fetal neural tube defects.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Salmonella enterica serovar Typhimurium monophasic variant  strains involved in a long-term salmonellosis outbreak that occurred in central Italy in 2013 to 2014.Here, we present the draft genome sequences of 19  Salmonella is a Gram-negative foodborne pathogen distributed worldwide. Even if few lineages have been detected, its antibiotic resistance pattern is very heterogeneous, spanning from multidrug-resistant to largely susceptible strains .Nineteen strains, chosen among clinical and environmental isolates on the basis of their spatial-temporal distribution and familiar kinship, were subjected to whole-genome sequencing together with three unrelated strains as outgroups. Genomic DNA was extracted by Qiagen EasyPrep, libraries were prepared using the Hi-Q sequencing kit, and sequencing was performed on a PGM Ion Torrent platform. Raw reads were submitted to the SRA repository , while bramework  plus somN50 values and GenBank accession numbers.The results from the genome annotation  are summarized in The availability of the assembled sequences allowed us to better understand antibiotic resistance mechanisms and to clarify genomic relationships among the isolates.The sequences described here have been deposited at GenBank under the accession numbers indicated in"}
+{"text": "The genomic sequences of phages isolated on mycobacterial hosts are diverse, mosaic and often share little nucleotide similarity. However, about 30 unique types have been isolated, allowing most phage to be grouped into clusters and further into subclusters . Many toWe computed tetranucleotide usage deviation, the ratio of observed counts of 4-mers in a genome to the expected count under a null model . Tetranuhttps://github.com/bsiranosian/tango_final.Genome analysis based on tetranucleotide usage shows promise for evaluating host-parasite coevolution and gene exchange within the mycobacteriophage population. These methods are computationally inexpensive and independent of gene annotation, making them optimal candidates for further research aimed at clustering phage and determining evolutionary relationships. Code for genome analysis and data used in this project are freely available at"}
+{"text": "Upogebia deltaura upon temporal variation in the abundance of genes representing key N-cycling functional guilds. The abundance of bacterial genes representing different N-cycling guilds displayed different temporal patterns in burrow sediments in comparison with surface sediments, suggesting that the burrow provides a unique environment where bacterial gene abundances are influenced directly by macrofaunal activity. In contrast, the abundances of archaeal ammonia oxidizers varied temporally but were not affected by bioturbation, indicating differential responses between bacterial and archaeal ammonia oxidizers to environmental physicochemical controls. This study highlights the importance of bioturbation as a control over the temporal variation in nitrogen-cycling microbial community dynamics within coastal sediments.In marine environments, macrofauna living in or on the sediment surface may alter the structure, diversity and function of benthic microbial communities. In particular, microbial nitrogen (N)-cycling processes may be enhanced by the activity of large bioturbating organisms. Here, we study the effect of the burrowing mud shrimp  Upogebia deltaura and Callianassa subterranea, which are active and abundant decapods that create large, complex burrow systems in marine sediments , bacterial communities exhibited less seasonal change in structure than those communities inhabiting surface sediment  compared with those within tidal flat surface and subsurface sediments  to investigate temporal variation in the abundance of specific bacterial and archaeal genes representing key N-cycling functional guilds within sediment samples taken from the walls of amoA); bacterial denitrifiers (nirS) and bacteria capable of the anammox process (Planctomycetes-specific 16S rRNA). Clone library analysis confirmed the specificity of each of the primer pairs used for subsequent q-PCR. In particular, sequence analysis showed that the Planctomycetes-specific 16S rRNA primers used here specifically targeted anammox bacteria, as shown previously  and \u2018sampling month\u2019. Bacterial 16S rRNA and nirS gene abundances showed no significant variation with either sediment category or sampling month. However, the abundances of each of the other genes studied  varied significantly with sampling month  Fig. . The metnirS varied significantly with sampling month, and as for bacterial amoA and anammox 16S rRNA, there was a significant interaction between sampling month and sediment category ; this effect was not evident for surface sediments. We may interpret these differing seasonal patterns in gene abundance within the context of environmental factors known to impact upon microbial community dynamics in coastal sediments.In general, the abundances of all genes in surface sediments were highest in both July 2009 and 2010, and lowest in May, with an additional peak in March Fig.  showed sFor example, variation in microbial community abundance and activity in surface sediments is generally assumed to be driven by changing environmental conditions, such as pH and salinity, or stochastic processes, such as sediment turnover during a storm. On seasonal timescales, the most important regulators of N-cycling functional guild abundance may be temperature, which exerts a major control over all life processes  with the blooming populations of autotrophs has been shown to adversely affect benthic ammonia oxidizing bacteria (AOB) abundance , during irrigation events . Ammonia oxidizing archaea (AOA) have been found in greater abundance than AOB in a variety of benthic marine and estuarine environments  amoA copies per cell  from marine sediments by denitrification (nirS) and anammox. Nr-removal processes play a critical role in coastal sediments, where terrestrial run-off can stimulate eutrophication events in coastal waters, particularly during autumn, when both precipitation rates and the input of agricultural nutrients into estuarine waters are high . The impacts of bioturbation on the activity of the denitrifying bacteria could therefore be an important consideration in future models of the benthic response to coastal environmental change.The activity of amoA target specifically the \u2018high-ammonium\u2019 ecotype identified by Sintes and colleagues  is directly influenced by bioturbation activity, and such effects vary between different bacterial and archaeal N-cycling guilds. These data are interpreted with the caveat that the PCR primers used here target specific bacterial and archaeal phylotypes and/or ecotypes; for example, our primers for archaeal lleagues . We alsoS Rusch, . Howevera priori factors used here: sediment category (surface vs. burrow) and sampling month. This study therefore highlights the importance of temporal variation coupled to macrofaunal bioturbation activity in driving microbial community dynamics in coastal sediments. In particular, this study emphasizes the importance of the often overlooked interactions between macrofaunal and microbial communities upon key biogeochemical cycling processes within coastal benthic ecosystems. Our suggestions for the ways in which shrimp behaviour influence gene abundance patterns may act as a useful starting point for future investigations into the environmental controls on microbial functional diversity and activity.It is also worth noting that the presence of a functional gene does not mean that function is operating within the specific environment, and an important continuation to this study would be to identify whether these genes correlate with the relevant biogeochemical rate processes. Nevertheless, we have observed gene abundances that fit within the ranges of previously reported values for these genes in similar marine environments Table  and vary"}
+{"text": "Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder of unknown etiology with a wide range of clinical manifestations. Since CRMO is a systemic disorder that can affect multiple skeletal sites, whole-body imaging techniques (whole body bone scintigraphy -WBBS- or whole body magnetic risonance -WBMRI-) provide major contribution to the initial diagnostic approach, as well as during follow-up.To compare WBMRI with WBBS in the assessment of bone lesions in patients with CRMO.We retrospectively evaluated all WBMRI examinations performed between January 2010 and December 2014 in 18 patients with clinical, laboratory and histology findings suggestive for CRMO.WBMRI were evaluated independently by two experienced paediatric radiologists, who eventually reached consensus. All patients also underwent WBBS within four weeks; WBMRI and WBBS findings were compared. Signal hyperintensity compared with normal bone on STIR images and increased tracer activity in bone delayed scans on WBBS were considered indicative of disease involvement.WBMRI and WBBS showed 225 and 132 lesions, respectively. In the appendicular skeleton, WBMRI demonstrated 143 lesions and WBBS 66 lesions; in the axial skeleton, WBMRI demonstrated 63 lesions and WBBS 18 lesions. WBMRI demonstrated joint involvement in 19 sites and WBBS in 48. The higher concordance between the two methods was observed in the sacroiliac joint (13 lesions for both methods); the higher discordance was observed in spine (WBMRI showed 55 lesions and WBBS 5) and in sterno-clavicular joint (WBMRI showed 2 lesions while WBBS 12).Both WBBS and WBMRI confirmed to be useful tools for the detection of CRMO lesions, as it is reported in literature. Discordance between WBBS and WBMRI is probably due to several factors. In the evaluation of axial skeleton (in particular of the spine), WBMRI shows higher spatial resolution than planar WBBS, but tomographic acquisition (SPECT) enhances the sensitivity of WBBS. Moreover, age-related conversion of hematopoietic marrow to fatty marrow in children may create a confusing appearance on MRI and may be misleading. Finally, in particular in WBMRI performed during treatment and follow-up, clinical relevance of the WBMRI-positive but WBBS-negative lesions is unclear, as still debated in current literature."}
+{"text": "Clarkia (Onagraceae) sister taxa. Consistent with our predictions, one outcrosser (C. unguiculata) exhibited faster pollen germination and less variation in pollen tube growth rate (PTGR) among pollen donors than its selfing sister species, C. exilis. Contrary to our predictions, the selfing C. xantiana ssp. parviflora exhibited faster PTGR than the outcrossing ssp. xantiana, and these taxa showed similar levels of variation in this trait. Pollen performance following self- vs. cross-pollinations did not differ within either selfing or outcrossing taxa. While these findings suggest that mating system and pollen performance may jointly evolve in Clarkia, other factors clearly contribute to pollen performance in natural populations.We tested three predictions regarding the joint evolution of pollen performance and mating system. First, due to the potential for intense intrasexual competition in outcrossing populations, we predicted that outcrossers would produce faster-growing pollen than their selfing relatives. Second, if elevated competition promotes stronger selection on traits that improve pollen performance, then, among-plant variation in pollen performance would be lower in outcrossers than in selfers. Third, given successive generations of adaptation to the same maternal genotype in selfers, we predicted that, in selfing populations (but not in outcrossing ones), pollen would perform better following self- than cross-pollinations. We tested these predictions in field populations of two pairs of  The evolutionary and ecological factors that have promoted the diversity of plant sexual reproductive strategies have been a long-standing area of inquiry among evolutionary biologists. The evolutionary transition between outcrossing and selfing, in particular, has received considerable attention, in part because mating system shifts are widespread and have occurred independently within and across numerous taxa ,2,3. IntPollen performance traits are often genetically based ,21,22,23Evidence from studies conducted in natural populations suggests that pollen competition may regularly result in conditions favoring rapid pollen tube growth. First, although pollen limitation has been detected experimentally in many wild plant populations , theRecently, we proposed three predictions regarding the evolution of pollen performance in predominantly self-fertilizing and outcrossing taxa . Our preSecond, because selfing reduces the number of distinct pollen genotypes deposited on individual stigmas, the comparatively stronger opportunity for selection on pollen performance traits in outcrossing taxa should have purged variation in these traits more effectively in outcrossers relative to selfers. Accordingly, we predicted that outcrossing taxa would harbor less genetically based variation among individual pollen donors in pollen performance traits than closely related selfing taxa. This prediction is based on the expectation that intense pollen competition among pollen genotypes will result in selection favoring rapid pollen germination and/or growth in outcrossing taxa. It should also be noted that maternal plant identity and environmental factors such as temperature and resource availability may also contribute to among-donor variation in pollen tube growth and germination in outcrossing taxa ,63,64,65i.e., combinations of alleles at different loci that result in particularly high performance) that influence pollen performance are likely to be reliably and consistently inherited over multiple generations and thus accumulate in populations. In other words, because the pollen of selfers experiences successive generations of pollen germination and pollen tube growth in genetically consistent maternal plant tissue, their pollen should evolve to be particularly well adapted to grow within its parental genotype. By contrast, because outcrossers typically mate with multiple, genetically distinct partners over their lifetimes, such beneficial epistatic interactions are more likely to break down due to recombination, and are therefore less likely to remain stable in outcrossing taxa than selfing taxa. Moreover, outcrossers should experience strong selection favoring the ability of pollen to perform well in a wide variety of stigmatic and stylar genotypes, while selection favoring such tolerance may be comparatively weak in autogamous selfers, whose pollen grains rarely germinate on foreign maternal genotypes. Consequently, we hypothesized that in regularly selfing taxa, pollen should have evolved to perform better following self-pollinations than following cross-pollinations. By contrast, in habitually outcrossing taxa, we predicted that pollen would either perform better following cross-pollinations than self-pollinations  or thats e.g., ,67,68).,68.i.e.,Clarkia tembloriensis (Onagraceae) populations and cultivated in growth chambers provides preliminary support for our predictions. Smith-Huerta . The objective of these analyses was to assess the effect of pollination type on PTGR and the proportion of the style length travelled by viable pollen grains. Therefore, zero values, which were associated with pollen grains that did not germinate or whose tubes failed to enter the style 2.5 hours post-pollination, were excluded from these analyses. Temperature-adjusted performance traits for unguiculata were calculated using the residuals from linear regressions in which a given pollen performance trait (PTGR or the proportion of the style traveled) was regressed on temperature at the time of pollination (\u00b0C). For xantiana and parviflora we used the residuals from polynomial regressions in which a given measure of pollen performance (PTGR or the proportion of the style travelled) was regressed on (temperature at style harvest) and (temperature at style harvest)2 because these regressions gave a better fit than the linear regressions. See 2r values associated with these models. For the Stark Creek exilis population, we controlled statistically for the effect of temperature by using the residuals from polynomial regressions in which PTGR or the proportion of the style traveled was regressed on temperature at the time of pollination (\u00b0C) and (temperature at the time of pollination)2. See 2r values associated with these models. For each taxon, variance components associated with the random effects of Pollen Donor and Pollination Type nested within Pollen Donor were estimated using the REML method for each temperature-adjusted pollen performance trait. For unguiculata, xantiana,and parviflora, we conducted these two-factor analyses after initial models including three random effects  indicated that pollen performance did not differ significantly between populations of the same species or subspecies. The 95% confidence intervals spanning the variance components associated with the Population effect included zero. All analyses were performed using JMP 9.0 (SAS Institute).We calculated Clarkiaexilis and its outcrossing sister species, C. unguiculata, in a manner that is consistent with the hypothesis that pollen competition promotes the evolution of rapid pollen performance in outcrossing taxa relative to their selfing counterparts. Plants from unguiculata populations exhibited faster or more frequent pollen germination than plants from exilis populations; unguiculata pollen tubes were more likely to have entered the style within 2.5 hours of pollination. Surprisingly, we found that C. xantiana ssp. parviflora exhibited faster PTGR and greater proportional distance travelled within the style than its outcrossing counterpart, C. xantiana ssp. xantiana. These contrasting patterns suggest that gamethophytic evolution following mating system transitions is likely to involve a variety of genetic and ecological factors. The extent to which the evolution of pollen performance traits is influenced either by local environmental conditions or by strong correlations with plant traits other than mating system in the Clarkia taxa studied here, however, merits further investigation. Case studies evaluating additional pairs of sister taxa are needed before generalizations regarding the joint evolution of mating system and pollen performance can be made. Nevertheless, the contrasting patterns that we observed in the two pairs of Clarkia sister taxa are likely driven in part by differences in the magnitude of gametophytic competition in unguiculata and xantiana populations. In populations characterized by consistent pollen limitation, such as xantiana, selection on pollen performance traits may be weak or neutral. Consequently, this study highlights the importance of evaluating the joint evolution of pollen performance and mating system in field populations, where abiotic and biotic ecological factors may influence the phenotypic expression of and ultimately the evolution of sexually selected traits. Differences between selfers and outcrossers in the diversity of potential pollen donors that arrive on stigmas have been predicted to drive the evolutionary divergence of sexually selected traits, such as the speed by which pollen grains germinate and travel through the style. Here we demonstrate that pollen performance differs under field conditions between"}
+{"text": "Patients with chronic renal failure may develop sensorineural hearing loss. Cochlear implantation has rarely done after organ transplantation. Herein, we report on a 33-year-old kidney transplantation recipient who underwent cochlear implantation for her progressive sensorineural hearing loss in Khalili Hospital Cochlear Implant Center, affiliated to Shiraz University of Medical Sciences. The implantation was done successfully with no complications. Cochlear implantation may be an appropriate therapeutic option for sensorineural hearing loss caused by chronic renal failure. Cochlear implantation has revolutionized the treatment of profound hearing loss. This procedure is relatively safe and it becomes the treatment of choice for both children and adults. Most of the patients reported improved quality of life, speech recognition and communication. Recently, patients with chronic diseases like chronic renal failure with hearing impairment, have also considered for cochlear implantation. Chronic kidney disease may result in high frequency sensorineural hearing loss (SNHL). The probable causes include uremia , congeniA 15-year-old Iranian girl developed chronic renal failure due to post-streptococal glomerulonephritis. Although she was on maintenance hemodialysis for seven months, she developed end-stage renal disease and underwent living non-related kidney transplant in 1992. One month later, she was treated for pleural effusion and pneumonia and received the ototoxic drug, amikacin for several weeks and developed bilateral progressive SNHL confirmed by pure tone audiometry and auditory brainstem response audiometry. She was then referred to our center and received a powerful hearing aid which was not successful to increase her speech awareness threshold. Therefore, she was considered for cochlear implantation. Before performing the procedure, multidetector high resolution computed tomography of temporal bone revealed normal anatomy of the temporal bone including mastoid, middle ear, inner ear and internal auditory canal with no evidence of mastoiditis or pathologic findings. The cochlear turns in both sides appeared normal with normal semicircular canals. After evaluation, the right ear was selected for the implantation. An advance bionics prosthesis (HiRes 90 K) was used and the active electrode was inserted fully in an appropriate position in the year 2011. After the operation, the patient was hospitalized in the ENT ward for 24 hours and discharged in good condition with antibiotics. She continued her routine immunosuppressant drugs till now without any signs of wound infection or other complications.Hearing aids are the principle means of auditory rehabilitation for patients with SNHL. Hearing aids also have important roles in the management of conductive hearing loss. Implantable hearing aid has several advantages for patients with hearing loss such as increasing gain and dynamic range, reducing feedback, reducing maintenance, improving appearance and being free to occlude one of the ear canals . CochleaHearing loss is one of the most common debilitating conditions in patients who begin renal replacement therapy. The incidence of hearing loss in children is 8.6% . The effFor cochlear implantation, immunosuppressive drugs can be continued preoperatively without dose adjustments , 5, 9. FWe concluded that cochlear implant may help properly selected renal transplant recipients with SNHL."}
+{"text": "Mungos mungo), a cooperative mammal in which multiple females conceive and carry to term in each communal breeding attempt. As predicted, lower ranked females had lower reproductive success, even among females that carried to term. While there were no rank-related differences in faecal glucocorticoid (fGC) concentrations prior to gestation or in the first trimester, lower ranked females had significantly higher fGC concentrations than higher ranked females in the second and third trimesters. Finally, females with higher fGC concentrations during the third trimester lost a greater proportion of their gestated young prior to their emergence from the burrow. Together, our results are consistent with a role for rank-related maternal stress in generating reproductive skew among females in this cooperative breeder. While studies of reproductive skew frequently consider the possibility that rank-related stress reduces the conception rates of subordinates, our findings highlight the possibility of detrimental effects on reproductive outcomes even after pregnancies have become established.Dominant females in social species have been hypothesized to reduce the reproductive success of their subordinates by inducing elevated circulating glucocorticoid (GC) concentrations. However, this \u2018stress-related suppression' hypothesis has received little support in cooperatively breeding species, despite evident reproductive skews among females. We tested this hypothesis in the banded mongoose ( The stress-related suppression hypothesis proposes that dominant females suppress subordinate reproduction through behaviours that lead to chronic elevations in circulating glucocorticoids (GCs) and consequent reproductive downregulation \u20134. Notabin utero or early post-natal development and affect offspring health, condition and survival [While socially induced GC elevations have frequently been considered a potential cause of reduced conception rates among subordinates, they also have the potential to compromise the outcomes of established pregnancies. For example, elevated GCs during pregnancy may impact survival ,7. Whilesurvival ,8, whethMungos mungo). Banded mongooses live in stable cooperatively breeding groups comprising a \u2018core\u2019 of breeding adults  that reproduce three to four times per year, alongside a subset of younger individuals that breed occasionally [Here, we test these three predictions with a detailed investigation of faecal glucocorticoid (fGC) concentrations and reproductive success in female banded mongooses  between December 2010 and April 2014. All animals were marked and habituated to close observation (less than 5 m). Groups were observed every 1\u20134 days to record all breeding events. We ran generalized linear mixed models (GLMMs) using the lme4 package  with PoiPregnancy can be detected at around 40 days by swelling of the abdomen  and birtWe collected 218 faecal samples from 35 females prior to and during gestation . Full details of sample collection and hormone analysis including validations are given in . In brie(a)We calculated three measures of reproductive success for each female recorded as having given birth: (i) the number of fetuses, (ii) the number of emergent offspring, and (iii) the proportion of fetuses surviving to emergence. We fitted each of these three measures as a response variable in GLMMs. Rank (determined by ranked age following ) was fit(b)We fitted fGC concentrations as a response variable in a GLMM with rank as the main predictor of interest. As GC concentrations may vary within a breeding attempt, we also fitted an interaction between rank and stage of pregnancy  as well as fixed effects of female age, group size, rainfall and pre-conception body mass to control for other factors which may contribute to fGC variation.(c)We fitted the number of emergent offspring and the proportion of fetuses surviving to emergence as response variables in two separate GLMMs with fGCs during the third trimester as the predictor of interest. We focused this analysis on fGCs in the third trimester because that is when we saw the clearest difference in fGCs between low- and high-ranking females.3.p = 0.041; figure\u00a01a) and the proportion of fetuses surviving to emergence . There was no effect of rank on the number of fetuses carried by a female (p = 0.87). We found a significant interaction between female rank and pregnancy stage on fGC concentrations: lower ranking females did not differ from higher ranking females prior to conception or during the first trimester but had elevated fGCs during the second and third trimesters  and a lower proportion of their fetuses survived to emergence . Full model outputs are included in the electronic supplementary material S1.Lower ranking females that carried to term experienced lower reproductive success than higher ranking females, both when measured as the number of assigned offspring , both when measured as the proportion of fetuses surviving to emergence and the number of emergent offspring. Although higher and lower ranked females had similar fGC concentrations prior to gestation and during the first trimester, lower ranked females showed significantly elevated fGC concentrations during the second and third trimesters. These results highlight the possibility that stress-related suppression of subordinate reproduction arises through gestational effects that compromise offspring survival either during the latter stages of pregnancy or soon after birth (prior to emergence from the burrow). Accordingly, females that experienced higher fGC concentrations during the third trimester had fewer emergent pups and a lower proportion of fetuses surviving to emergence.in utero, this rank-related difference in reproductive success could well have arisen from pre-natal developmental impacts on offspring survival either during late pregnancy or during the early post-natal period. A role for rank-related maternal stress during late gestation in generating these effects on offspring survival would be consistent with experimental evidence that late-gestational GC elevations can inhibit offspring development [Rank-related differences in reproductive success among female mammals commonly occur due to differences in conception rates, either because subordinate females exercise reproductive restraint or because their ability to conceive is compromised by active interference by dominant females ,19. By celopment ,20. In telopment , play a per se. However, the gestational GC elevations of lower ranked females could arise at least in part from energetic differences during gestation. For example, subordinates may be competitively excluded from resources by dominant females. Alternatively, as intra-sexual conflict among females may frequently be resolved without overt physical conflict, these GC elevations could also reflect responses to more subtle rank-related outcomes, such as social isolation [The stress-related suppression hypothesis posits that elevated GC concentrations observed in lower ranking females are a result of aggression from dominant females. However, conspicuous aggression among female banded mongooses is rare outside of eviction events . As suchsolation . Either"}
+{"text": "How receptions of sensory inputs information turn into perceptions in our brain? To address these questions, we proposed method reconstructs the neuronal tracts by applying the shortest path graph algorithm between functional regions in the Drosophila brain. With these neuronal tracts, we analyze and draw a network diagram of projection neurons (PNs) relaying sensory input to higher brain centers in the Drosophila brain. Drosophila is a widely used genetic model system for understanding human biology ,2. WhileThe network diagram shows hierarchical structure, small-world characteristics, and is composed of functional modules corresponding to the sensory modalities. This ultimate goal of such an atlas is to identify connectivity between neurons for understanding the function/circuit relationships."}
+{"text": "Improving NK cell persistence in\u2009vivo via autocrine IL-2 and IL-15 stimulation, enhancing tumor targeting by silencing inhibitory NK cell receptors such as NKG2A, and redirecting tumor killing via chimeric antigen receptors, all represent approaches that hold promise in preclinical studies. This review focuses on available methods for genetic reprograming of NK cells and the advantages and challenges associated with each method. It also gives an overview of strategies for genetic reprograming of NK cells that have been evaluated to date and an outlook on how these strategies may be best utilized in clinical protocols. With the recent advances in our understanding of the complex biological networks that regulate the ability of NK cells to target and kill tumors in\u2009vivo, we foresee genetic engineering as an obligatory pathway required to exploit the full potential of NK-cell based immunotherapy in the clinic.Given their rapid and efficient capacity to recognize and kill tumor cells, natural killer (NK) cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. However, technical and biological challenges associated with gene delivery into NK cells have significantly tempered this approach. Recent advances in viral transduction and electroporation have now allowed detailed characterization of genetically modified NK cells and provided a better understanding for how these cells can be utilized in the clinic to optimize their capacity to induce tumor regression  Natural killer (NK) cells are immune cells primarily found in the blood, liver, spleen, bone marrow, and to a lesser extent, in lymph nodes . They weNK cells can mediate cytotoxicity via multiple distinct mechanisms. Degranulation is the most studied cytotoxicity pathway, where NK cells release cytotoxic granules upon contact with the target. Cytotoxicity via this pathway is dictated by a balance of signals from an array of germline encoded activation and inhibitory cell surface receptors. Most activation receptors need simultaneous co-stimulation by other activation receptors to trigger NK cell cytotoxicity . One excin\u2009vivo persistence, and doubts regarding their ability to migrate to tumor tissues following adoptive infusions. Although recent data have shown CMV reactivation reduces the risk for AML relapse following HSCT  following hematopoietic stem cell transplantation (HSCT) and that adoptively infused mature donor NK cells could induce remission in AML patients , 10. Desing HSCT  potentiain\u2009vivo holds potential to advance the efficacy of NK cell-based cancer immunotherapy. However, until relatively recently, the genetic manipulation of NK cells has proven to be challenging. Viral transduction, successfully used for T cells, has been associated with low levels of transgene expression and unfavorable effects on cell viability when used with NK cells. Recent optimization of viral transduction and the establishment of electroporation technologies for efficient gene transfection have revived the enthusiasm for studies evaluating genetic modification of NK cells. Investigators around the world are now exploring the potential of multiple different NK cell modalities to genetically reprogram with the overall aim of further improving upon their capacity to kill tumors in cancer patients. One example of how this technique can be utilized is to introduce genes into NK cells coding for gamma-cytokines (IL-2 and IL-15) to induce independence from the obligate need of exogenous cytokines for proper in\u2009vivo persistence and expansion post infusion. This and similar strategies may further improve the efficacy of NK cell-based immunotherapy, as tumor regression following adoptive NK cell infusions in AML patients has been reported to be dependent on their ability to expand in\u2009vivo  resulted in an average 69 and 71% transduction efficiency, respectively .More recently, studies evaluating transduction of NK cells using lentiviral vectors have been pursued. In contrast to transduction with retro- and adenoviral vectors, lentiviral vectors can incorporate transgenes into the genome of non-dividing cells. Further, lentiviral vectors allow for gene modification of NK cells without altering their phenotypic and functional properties as occurs following stimulation with i.e., cytokines. The first report on the successful use of lentiviral vectors for genetic modification of NK cells was performed in primary murine NK cells , with suIn summary, viral transduction of NK cells results in variable transduction efficacies and may require multiple rounds of transduction and/or post transduction cell enrichment to achieve acceptable transgene expression. Further, viral associated cell death and the need for post-transduction enrichment may compromise the clinical utility of this approach. Finally, although the risk may be low, the possibility of viral-induced insertional mutagenesis and immunogenicity , 44 occuelectroporation (including nucleofection) or lipofection. Since the latter has been used only in a few studies  human NK cells  and the transcription activator-like effector nucleases (TALEN) technologies, the recently developed clustered regularly interspaced short palindromic repeats (CRISPR) technique has rapidly become a popular tool for targeted gene integration . The CRIin\u2009vivo persistence and expansion, tumor tissue migration, and the tumor targeting capacity of adoptively infused NK cells  donors were found to have substantially augmented ADCC following electroporation with mRNA coding for the HA-CD16  compared to those who carry the low-affinity CD16-158F (LA-CD16) polymorphism , 66, sev LA-CD16 . Recentl HA-CD16 . These dIntroduction of genes that render NK cells insensitive to suppressive cytokines such as TGF-\u03b2, thereby preserving their cytotoxicity, has also been studied. Yang et al. generated an NK-92 cell line resistant to the suppressive effects of TGF-\u03b2 by genetically modifying them to express the dominant negative mutant form of TGF-\u03b2 type II receptor (DNT\u03b2RII) on their surface . Adoptivin\u2009vitro and in a preclinical mouse model  exploiting the role for CAR19-expressing Genetic engineering of NK cells to make them cytokine independent and thereby improve persistence, while boosting their cytotoxic capacity, may be one avenue to further explore. The advantage with this approach would be that exogenous cytokines would be unnecessary following NK cell infusion, which may reduce the risk of mobilizing regulatory T cells that directly suppress NK cell cytotoxicity . Challenin\u2009vivo homing of infused gene engineered NK cells have yet been published.Migration to the tumor tissue is another aspect governing proper tumor targeting. This aspect has been largely overlooked and could potentially improve clinical outcome if infused NK cells are redirected to the tumor site instead of circulating non-specifically into mostly non-tumor-bearing tissues. No studies aimed at improving the in\u2009vitro have been explored. Introduction of CARs represent the most studied and developed approach that has recently reached clinical evaluation , thereby giving genetically reprogramed NK cells an additional layer of target specificity. However, many additional preclinical studies will be needed before these approaches can reach clinic.As discussed above, numerous strategies for redirecting or boosting NK cell tumor killing on Table . Expressex vivo manipulation.The choice of method for genetic reprograming of NK cells is another important factor that needs to be considered when taking genetically engineered NK cells to clinical evaluation. Viral transduction has the advantage of stable expression; however, as mentioned above, viral transduction of NK cells, especially primary cells, does not always lead to a satisfactory level of transgene expression and may require multiple rounds of transduction followed by selection of transgene positive cells. Moreover, proper expression of transgenes induced by viral transduction can take days, which may be of disadvantage since the lifespan of an NK cell may be relatively short following adoptive transfer . Future studies are warranted to better understand if multiple infusions of transfected NK cells can compensate transient transgene expression or if stable transgene expression is a prerequisite for inducing clinical responses following adoptive transfer of genetically engineered NK cells. Studies are also needed to fully understand the lifespan of NK cells, particularly those that have undergone in\u2009vivo (ex vivo for clinical infusion (The optimal method for genetic manipulation of NK cells to be used in a clinical trial may also depend on what NK cell preparation is used Box . The advin\u2009vivo . Moreoveinfusion . IdeallyBox 3Anti-tumor antibodies and CAR T cells have established immunotherapy as a viable treatment option for patients with cancer. Given their rapid and efficient method of recognizing tumor cells, NK cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. However, technical and biological challenges associated with gene delivery into NK cells have significantly tempered this approach. Viral transduction of NK cells initially resulted in low transgene delivery efficiencies that often required multiple rounds of transduction and/or cellular enrichment to achieve acceptable numbers of transgene expressing cells. Nevertheless, recent improvements in retro- and lentiviral transduction of NK cells have led to a flurry of preclinical studies on gene engineered NK cells. A number of studies have also shown that NK cells can be genetically reprogramed using mRNA electroporation. In contrast to viral transduction, this approach offers high transfection efficiencies without compromising their viability and does not require high-level biosafety laboratories. Although promising preclinical data on mRNA electroporated NK cells have emerged recently, concerns have been raised regarding the clinical utility of this approach as it only results in transient transgene expression.in\u2009vivo, and with rapid developments in clinically compliant techniques to genetically manipulate NK cells, we foresee genetic engineering as an obligatory pathway to exploit the full potential of adoptive NK cell immunotherapy in patients with cancer.Recently initiated clinical trials will soon give insight into the potential effectiveness of cell-based cancer immunotherapy strategies that utilize genetically modified NK cells. Nevertheless, further optimization of both viral transduction and electroporation of NK cells is still needed before this approach can be fully exploited in the clinic. With the recent advances in our understanding of the complex biological networks that regulate the capacity of NK cells to target and kill tumors The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Mitochondrial fusion-fission dynamics play a crucial role in many important cell processes. These dynamics control mitochondrial morphology, which in turn influences several important mitochondrial properties including mitochondrial bioenergetics and quality control, and they appear to be affected in several neurodegenerative diseases. The molecular machineries behind mitochondrial fusion and fission events are relatively well known. The regulation of fusion and fission events beyond the molecular machinery involved is less clear, fusion and fission are not random occurrences but form a cycle whereby fission typically follows fusion. Mitochondrial fission machinery may somehow sense mitochondrial length and become active when the mitochondrion is oversized and cease when mitochondria are smaller. In contrast, mitochondrial fusion events depend heavily on mitochondrial trafficking. Fusion only takes place when two mitochondria meet and motile mitochondria will be more likely to encounter one another. In cultured cortical neurons, for example, only one in every 14th contact between mitochondria results in fusion. The purpose of this presentation is to provide insight into the complex crosstalk between different processes involved in mitochondrial fusion-fission dynamics and to discuss the potential physiological purpose of mitochondrial fusion and fission."}
+{"text": "Numerous complex regulatory mechanisms influence the development and function of the peripheral and central nervous system. Among them, hormones belong to the most potent regulatory factors. Various particles known for their hormonal activity serve as neurotransmitters. Additionally, hormones secreted systemically modulate the function of the nervous system both on the brain level and in peripheral organs. Thyroid function has been shown to play a crucial role in the proper cognitive development but also in many other aspects of nervous system activity, in mechanisms involving direct interaction with intrinsic regulatory circuits or indirectly by systemic effects exerted e.g. on the circulatory system or metabolic pathways. Due to these close relations with the nervous system function, disturbances of thyrometabolic state are associated with a vast spectrum of neurological signs and symptoms including: mood and cognitive disorders, headache, ophthalmoplegia, tremor and other movement disorders, muscle weakness etc. Both hyper- and hypothyroidism may cause psychiatric symptoms like depressive or anxiety disorder, memory deficits, executive inability and even psychosis. The severe decompensated hypothyroidism may result in myxoedema coma - a life-threatening condition with sequentially progressing encephalopathic symptoms. Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAAT) represents another form of encephalopathic disorder associated with thyroid disease and causing potentially serious clinical complications. In the periphery, the thyrometabolic disturbances may affect muscle function resulting in subjective tiredness and low exercise tolerance and in some cases  in objective myopathic signs. Also peripheral nervous system may be affected, mainly in hypothyroid patients, with greater tendency to develop peripheral polyneuropathy and entrapment neuropathies such as carpal tunnel or Guyone canal syndromes.Importantly, the autoimmune thyroid disease has been shown to coexist with other autoimmune processes which may potentially cause neurological symptoms such as myasthenia, Guillain-Barre syndrome or pernicious anaemia. Such conditions have to always be taken in consideration as differential diagnoses in patients presenting with neurological signs and symptoms associated with thyroid disease."}
+{"text": "Coronary stent fracture is a known complication of coronary arterial stent placements. Multiple long-term risks are also associated with drug eluting stents. 64-slice multidetector CT (MDCT) coronary angiography has been shown to detect poststent complications such as instent stenosis, thrombosis, stent migration and stent fractures. We report a case of stent fracture in a patient who underwent RCA stenting with associated RCA perforation and almost complete thrombosis of the RCA and peristent fibrinoid collection. This is a rare case of stent fracture with perforation of the RCA. The paper highlights the role of 64-row multidetector computed tomography (MDCT) in evaluation of such poststent placement complications. Stent fracture (SF) has been suggested as one of the leading risk factors of thrombosis and instent restenosis (ISR) in patients who have intracoronary drug-eluting stent (DES) implants ; howeverA 65-year-old male patient presented with a tuberculous knee joint effusion and occasional chest pain. He also had a drug eluting stent inserted in the mid RCA, two years back. However, the patient had recurrent angina within a month of stent placement. A catheter angiography done at that time revealed total occlusion of the RCA stent, with grade III collaterals. He was now referred to our department with a request for CT chest to exclude pulmonary tuberculosis. The CT chest revealed no signs of pulmonary tuberculosis but revealed an irregular localised pericardial fluid collection along the RCA stent . A dedicStent fracture is an important and potentially serious complication of drug-eluting stents (DES) . IncreasNakazawa et al. have graded stent fractures into five categories  and conc64-slice CT coronary angiography is an extremely fast and accurate imaging modality available for the evaluation of stents and their complications. It is found to be more sensitive in detecting stent fractures than conventional catheter angiography. Besides demonstrating in-stent thrombosis, it can effectively evaluate stent fractures, migrations, buckling, or collapse; rare complications such as perforations and aneurysms. This is a rare case of long standing stent fracture with RCA rupture and associated in-stent total occlusion and highlights a unique complication of stent placement: stent fracture causing coronary arterial rupture and subsequent stent migration. It also highlights the utility of 64-row MDCT imaging in effectively demonstrating such serious complications; which may or may not be convincingly shown on conventional catheter angiography."}
+{"text": "In contemporary oncology practices there is an increasing emphasis on concurrent evaluation of multiple genomic alterations within the biological pathways driving tumorigenesis. At the foundation of this paradigm shift are several commercially available tumor panels using next-generation sequencing to develop a more complete molecular blueprint of the tumor. Ideally, these would be used to identify clinically actionable variants that can be matched with available molecularly targeted therapy, regardless of the tumor site or histology. Currently, there is little information available on the post-analytic processes unique to next-generation sequencing platforms used by the companies offering these tests. Additionally, evidence of clinical validity showing an association between the genetic markers curated in these tests with treatment response to approved molecularly targeted therapies is lacking across all solid-tumor types. To date, there is no published data of improved outcomes when using the commercially available tests to guide treatment decisions. The uniqueness of these tests from other genomic applications used to guide clinical treatment decisions lie in the sequencing platforms used to generate large amounts of genomic data, which have their own related issues regarding analytic and clinical validity, necessary precursors to the evaluation of clinical utility. The generation and interpretation of these data will require new evidentiary standards for establishing not only clinical utility, but also analytical and clinical validity for this emerging paradigm in oncology practice.  Traditional pharmacogenomic applications used to direct molecularly targeted therapy rely on testing tumor tissue for a single genomic marker followed by using tumor-marker specific therapy. There are several established pharmacogenomic applications that are used clinically to aid in treatment decisions for breast, colon, lung and other solid-tumor cancers Table 1). With advances in high-throughput \u2013omic technologies and plummeting costs of next-generation sequencing (NGS), researchers have begun to move beyond testing single genes, to multi-gene panels, to sequencing the entire human cancer genome in order to better understand the underlying molecular pathways driving tumorigenesis. With adClinically available NGS tests are used to characterize an individual\u2019s cancer genome through targeted sequencing of pre-specified candidate genes believed to provide clinically actionable molecular targets. Using a single test to detect a broad spectrum of genomic alterations in the biological pathways from a single biopsy is thought to be a more efficient treatment decision process than the single-marker single-treatment approach,,An established clinical test integrating NGS technology for tumor DNA sequencing requires a standardized protocol with details describing pre-analytic, analytic and post-analytic processes. The pre-analytic variables include the patient\u2019s clinical characteristics as well as details describing the collection and preparation of tumor samples. The analytic variables that may affect the precision and accuracy of the targeted sequencing of pre-specified molecular targets  refer to the actual sequencing process itself and are related to the specific NGS platform used to conduct the massively parallel sequencing as well as individual laboratory procedures. The post-analytic variables  relevant to NGS include variant calling, functional and clinical interpretation, reporting results to clinicians, and data storageThe expanded reach of NGS platforms provides researchers with a much more comprehensive picture of a tumors genomic architecture. In an effort to leverage the technical advances in sequencing technology and expanded vision of a tumors molecular signature several NGS platforms have been integrated into commercially available solid-tumor sequencing panels to identify clinically actionable variants (Table 2). Despite the lack of consensus as to what constitutes a clinically actionable variant, three general categories may be used to classify variants: 1) variants linked to an FDA-approved drug within a specific tumor type; 2) variants linked to an FDA-approved drug outside of the patients specific tumor type; 3) variants linked to non-FDA approved drugs in preclinical testing or early phase clinical trialsTo date, the application of multi-marker tumor panels using NGS has primarily focused on individuals with advanced metastatic disease who have exhausted standard therapies for their particular condition. In such cases, these tests may provide unconventional therapeutic options against an otherwise refractory disease. It is unclear at what point this testing and treatment strategy will become a part of the standard molecular profiling of newly diagnosed malignancies, expanding the potential population impact. As evidence emerges on driver-mutations common across a number of cancer types, newly developed molecularly targeted therapies will provide a means to improve cancer treatment outcomes across a number of cancers with common biological/molecular mechanistic pathways. A more complete picture of an individual\u2019s tumor genome may also be integrated within existing frameworks including age, disease burden, and histologic/molecular features for developing more effective cancer treatment and management strategies-This approach to cancer therapy has received widespread interest from patients, healthcare providers and payersIn a working paper, UnitedHealth spoke to the larger contextual issues of using molecular testing in clinical oncology. A broad emphasis was placed on the expanding opportunities for molecularly targeted therapy using tumor genome sequencing and for improving the process of determining the effectiveness of molecular testing-The analytic workflow of FoundationOne\u2122, hybrid-capture libraries sequenced with Illumina HiSeq2000, was shown to have an analytic sensitivity between 95% and 99%  and a positive predictive value greater than 99% using pooled cell lines as the reference standard ,There appears to be consistency in the pre-analytic factors across the commercially available tests related to tissue sample requirements, collection and preservation (Table 2). All the organizations listed in Table 2 report the sequencing is done in Clinical Laboratory Improvement Amendments (CLIA) certified facilities. While this does provide a limited amount of standardization, the fundamental requirements to establish analytic validity requires a reliable reference standard to align and annotate massively parallel sequence dataTable 3 shows the vast array of molecular targets included in the commercially available tumor panels, with only 34 genes included in all three tests . FoundationOne was reported to detect at least one clinically actionable variant in 76% of samples (N=2200) with an average of 1.57 clinically actionable variants detected per sample (range: 0 to 16)There is a growing body of evidence identifying genomic alterations common across multiple cancer typesBenefits At this time there is no evidence of improved treatment outcomes from using the tests described in Table 2 to direct molecularly targeted therapy in solid-tumors. In addition to the absence of evidence of clinical utility for the commercially available tests, there is also a need to further explore the validity and utility of the underlying hypothesis driving the development and implementation of these tests. One challenge in developing studies investigating the general hypothesis as well as establishing clinical utility is the limited generalizability due to diversity in the evolving panel composition and variation in the clinical interpretation and treatment recommendations . There is a need to standardize the composition of panels and develop standard criteria for classifying variants as clinically actionable. It may also be necessary to prioritize specific variant/therapy combinations when multiple variants with associated therapies are identified, as there may be overlapping toxicities and drug-drug interactions. Characteristics of studies investigating clinical utility, including molecular heterogeneity of study participants as well as specific study designs will also impact generalizability.HarmsNone of the test descriptions included details of patient consent or how incidental findings would be communicated to clinicians or patients. As these tests are intended to be implemented at the point of care, such protocols may be left to the ordering physician and their home institution to determine processes for informed consent, delivery of appropriate pre-test genetic counseling, and disclosure of incidental findings. Given the analytic workflow of the available tests (Table 2) and diverse panel composition (Table 3) it is uncertain how the ACMG recommendations,Another potential harm from implementing this testing and treatment strategy arises from uncertainty in the cost-benefit ratio of the off-label use of expensive chemotherapeutic drugs. As mentioned previously, these tests are currently being offered to patients with advanced disease in whom time spent delivering ineffective therapy may pose a significant risk as a wasted opportunity. Many of the available drugs are associated with well characterized adverse effects (e.g. cardiotoxicity from the kinase inhibitors)Several ongoing clinical trials have incorporated the commercially available tests (Table 4). Designed as feasibility assessments, two non-randomized trials are using FoundationOne (Foundation Medicine) to identify participants with metastatic breast cancer (IMAGE)Recent advances in sequencing technology provide new opportunities for genomic medicine. With these opportunities come the promises of personalized medicine that are changing oncology practice. However, aspects of analytic and clinical validity and clinical utility of the current paradigm shift has yet to be clearly established. Developing the necessary evidence to establish clinical validity and utility may require novel thinking to adapt to the dynamic challenges associated with implementing NGS tumor sequencing into clinical practice. Researchers must also address several limitations in the underlying concepts of this approach including patient selection, analytic workflows, characteristics of the tumor panels (performance characteristics and panel composition), study design, and outcome selection. Several ongoing clinical trials are investing both the feasibility and utility of incorporating NGS technology into clinical practice and will help define the evidentiary standards for evaluating such tests.The GAPP Knowledge Base (GAPP KB) was searched using the term \u201cnext-generation sequencing\u201d to identify commercially available multi-marker solid tumor tests using NGS technology. A Google search supplemented the GAPP KB search for eligible tests as well. The following search string was used to search PubMed to identify relevant systematic reviews and guidelines:(((neoplasms/therapy[mesh]) OR (neoplasms/genetics[mesh]) OR (neoplasms/diagnosis[mesh])) AND  OR (molecular targeted therapy/methods[mesh]) OR (genetic testing[mesh]) OR )) AND (humans[mesh])In addition to searching PubMed, the commercially available tests websites were searched to identify relevant literature pertaining to the analytic validity, clinical validity, and clinical utility of the respected test. Ongoing studies were identified in clinicaltrials.gov by searching on the trade name of each commercially available test and company offering the tests described in Table 2. This was supplemented by using the term \u201cnext-generation sequencing\u201d to identify additional studies not using any of the tests listed in Table 2."}
+{"text": "Background. Cisplatin is a well known platinum-based chemotherapeutic agent used for the treatment of various malignant tumours. A frequent side effect of cisplatin therapy is ototoxicity. Unfortunately, currently there are no available treatments. Material and Methods. Experimental, clinical studies and reviews published between 2004 and 2014 in the English medical literature concerning ototoxicity were selected using Medline, PubMed, and Google Scholar databases. Inclusion criteria were cisplatin-induced ototoxicity and therapy aimed at preventing or curing this disorder. Molecular mechanisms and clinical, audiological, and histological markers of cisplatin-induced ototoxicity are described. Moreover, experimental and clinical strategies for prevention or treatment of hearing loss were also reviewed. Results and Discussion. Experimental studies demonstrate a wide range of otoprotective molecules and strategies efficient against cisplatin-induced hearing loss. However, only dexamethasone proved a slight otoprotective effect in a clinical study. Conclusion. Further research must be completed to bring future therapeutic options into clinical setting. Cisplatin (cis-diamminedichloroplatinum II) is a well-known chemotherapeutic alkylating agent very effective in the treatment of various malignant tumors, especially squamous cell cancers of the head and neck regions, in both the pediatric and adult age groups . Though A review of the literature from 2004 to 2014 was performed, using the Medline, PubMed, and Google Scholar databases. The search terms included cisplatin-induced hearing loss, protective therapy for inner ear diseases, intratympanic therapy, systemic therapy, and gene therapy. Only original experimental and clinical research papers were included. A total of 43 relevant papers were selected for the present review.Cisplatin inflicts injuries mainly to outer hair cells, progressing from the third to the first row and to some extent to inner hair cells of the organ of Corti in the basal turn of the cochlea followed by alterations in sensorial cells situated in the apex. Cisplatin also targets supporting cells, marginal cells of the stria vascularis, and the spiral ligament . The vesMolecular mechanisms of cisplatin-induced hearing loss involve the creation of reactive oxygen species and depletion of antioxidant glutathione and its regenerating enzymes as well as increased rate of lipid peroxidation, oxidative modifications of proteins, nucleic acids damage by caspase system activation , and S-nOxygen free radicals in the cochlea are produced principally in the wake of nicotinamide adenine dinucleotide phosphate oxidase 3 isoform (NOX3) activation. NOX3 is known to be upregulated by cisplatin. Cochlear tissues fight the oxidative stress by means of antioxidant defence systems including glutathione, glutathione reductase, superoxide dismutase, and catalase . CisplatThe extent of ototoxicity due to cisplatin administration can be assessed clinically through measurements of hearing loss by means of pretreatment and follow-up serial audiologic tests and experimentally through histological examinations . The forIn experimental animals, hearing loss after cisplatin treatment can be assessed by audiological study of the auditory brainstem responses where threshold measurement defines the lowest intensity of sound stimulus that evokes a clear, visually detectable, reproducible waveform .\u03b1) and other inflammatory cytokines  were also detected by immunostaining in the outer hair cells, stria vascularis, spiral ligament, and spiral ganglion neurons in cisplatin exposed cochleae [Histologic examinations of inner ear after cisplatin administration reveal destruction primarily of outer hair cells and to some extent inner hair cells and associated nerves, degeneration of the vestibular organs, stria vascularis edema, and detachment of the myelin sheath of the spiral ganglion cells . Light mcochleae .2 are used the hearing impairment may progress from high frequencies to involve the middle frequencies. Reducing the total amount of cisplatin by limitation of the total dose per cycle, dose intensity and the cumulative dose would diminish the antitumor effect which is not desirable. Various otoprotective compounds have been tested both in experimental animals and humans. If given systemically, they should be nontoxic, must attain efficient concentrations in the inner ear to protect labyrinthine tissues from cisplatin ototoxicity, and should not hamper the antitumor effect of cisplatin. Higher concentrations of otoprotective molecules can be achieved by intratympanic administration. This latter route provides direct access of the protective agents to inner ear structures while avoiding systemic side effects and interference with the antineoplastic activity of cisplatin [Cisplatin pharmacokinetics in the inner ear after intravenous injection is influenced by its strong binding to the plasma proteins rendering a large part of it nonactive and by the barrier systems in the cochlea, the blood-perilymph barrier, separating blood from perilymph, and the intrastrial fluid-blood barrier, separating blood from endolymph . The amoisplatin .Several otoprotective molecules and strategies against cisplatin-induced ototoxicity have been tested in experimental animals. Some, like diethyldithiocarbamate, exerted important side effects in humans . A summaHyperbaric oxygen therapy consists of intermittent inhalations of 100% oxygen at a pressure higher than 1\u2009atm and is used as adjuvant therapy in pathological processes like soft tissue infections, radiation injury, gas gangrene, and decompressive disease. Its main effect is tissue hyperoxygenation through plasma dissolved oxygen and was successfully tested in guinea pigs as a protective agent against cisplatin ototoxicity. Efficacy of otoprotection by hyperbaric oxygen therapy after cisplatin administration was evaluated by otoacoustic emissions following hyperbaric treatment and by scanning electron microscopy examination. The study confirmed that cisplatin induces dose-dependent cochlear alterations consisting of cellular lesions and significant hair damage in outer hair cells. Analysis of anatomical changes in cochlear outer hair cells indicated signs of otoprotection against cisplatin in animals treated with hyperbaric oxygen therapy although in functional studies distortion product acoustic emission were absent reflecting a certain degree of hearing loss, most probably reversible and related to experimental artefacts. The study concluded that hyperbaric oxygen therapy has otoprotective effects against cisplatin-induced ototoxicity. However, further studies are necessary to test other effects of high pressure oxygen on the cochlea .Another study investigated the effect of epigallocatechin gallate (EGCG) on the transcription factor STAT1, an important mediator of cell death. STAT1 phosphorylation is involved in both hair cells and support cells transformation after experimental exposure of mouse utricule to cisplatin. EGCG proved its efficiency as an otoprotective agent against cisplatin ototoxicity due to its inhibition of STAT1. The hypothesis was further supported by the failure of EGCG to provide protection against cisplatin in STAT1-deficient mice .Former studies showed that lactate injected intratympanically in guinea pigs treated with ototoxic levels of cisplatin allowed near total preservation of otoacoustic emissions . Since lMost of the existing studies focus on exogenous administration of antioxidants. Pharmacological activation of intrinsic defence mechanisms against oxidative stress in the inner ear caused by cisplatin therapy also proved helpful as showed by an experimental animal study using systemic administration of thiamine pyrophosphate (TPP). Thiamine pyrophosphate functions as coenzyme for peroxisomes being a crucial factor for energy metabolism, antioxidation, and myelinisation of nerve cells. Its intraperitoneal injection increased the level of natural antioxidants like glutathione and antioxidant enzymes  and reduced the content of malonildialdehyde, an indicator of lipid peroxidation following increased levels of oxygen reactive species resulting from cisplatin toxicity. The histologic evaluation of cochleae harvested from TPP treated animals showed preservation of the morphology of the organ of Corti and outer hair cells and no destruction of spiral ganglion cells and stria vascularis following cisplatin therapy .The wide range of therapeutic molecules studied for their otoprotective effect against cisplatin-induced ototoxicity also includes sertraline, an antidepressant with neuroprotective effects in rats . The selAn experimental single dose model of cisplatin ototoxicity in guinea pigs showed the otoprotective effect of systemic histone deacetylase inhibitor sodium butyrate. Distortion product otoacoustic emissions testing were chosen to provide a sensitive assay of the functional state of outer hair cells after systemic cisplatin insult on the cochlea. The systemic administration of the otoprotective agent avoided the side effects of the more invasive tympanic local route of administration. Moreover, sodium butyrate did not interfere with the tumoricidal effect of cisplatin providing both protections from reactive oxygen species and a certain degree of antitumor activity according to former reports. Acetylation of different cell proteins, including histones, is responsible both for the protective effect against oxidative stress and for the cell division inhibition and subsequent anticancer activity. The experiment's weak point is that it only showed the effect of sodium butyrate in a single dose of cisplatin model whereas in clinical practice cisplatin is typically given repeatedly at a couple of weeks intervals for several months .\u03b2 [The unique isoform of NADPH oxidase, NOX3, found in the cochlea and its involvement in the generation of reactive oxygen species was at the base of an animal study showing the efficacy of short interfering RNA in preventing cisplatin ototoxicity by reducing the expression of NOX3 in outer hair cells, spiral ganglion cells, and stria vascularis in the rat. Auditory brainstem responses were used to certify reduced threshold shifts in cisplatin treated animals who received transtympanic NOX3 siRNA. Since cisplatin administration has been previously associated with upregulation of NOX3 in the inner ear, Nox3 is thought to be a major source of free radicals in the cochlea following cisplatin exposure. The resulting free radicals initiate the inflammatory process in the cochlea by activating signal transducer and activator of transcription-1 (STAT1), followed by activation of p53 and increase in inflammatory mediators like TNF-alpha and interleukin-1\u03b2 . A singl\u03b2 .Among various strategies that have been devised in experimental settings to prevent cisplatin ototoxicity, minocycline, a tetracycline derivative, proved its partial efficacy in vivo and in vitro. The anti-inflammatory and neuroprotective properties of minocycline have been previously reported. The biochemical mechanisms involve caspase-1 and caspase-3 inhibition, which decreases the amount of interleukin-1 and prevents apoptosis. The protective effect of minocycline has been tested both on cisplatin treated cell cultures and in experimental animals which underwent cisplatin intraperitoneal therapy after systemic administration of the otoprotective agent. Cell viability assays showed that minocycline had a protective effect against cisplatin toxic action. Yet, minocycline failed to protect cells at higher concentrations of cisplatin. Recordings of auditory brainstem responses and evaluation of the scanning electron microscopy sections of inner ears harvested from minocycline plus cisplatin treated animals indicated a partial preservation of the function and morphology of the outer hair cells as compared to those from animals treated with cisplatin alone .The effect of intraperitoneal administration of erdosteine on cisplatin-induced ototoxicity in a guinea pig model was also studied. Erdosteine is a thiol derivative with established antioxidant properties due to its active sulfhydryl groups following liver first-pass metabolism. Pre- and posttreatment auditory brainstem responses measurements were performed in living animals while outer hair cell counts were analyzed by scanning electron microscopy of the cochleae removed from euthanized animals. Although the study had limitations , the results outlined the systemic administration of erdosteine as a promising therapeutic strategy for cisplatin-induced ototoxicity .In a first murine model for cisplatin-induced ototoxicity, it was shown that intratympanic dexamethasone prevents hearing loss in a frequency related manner. Evoked brainstem responses audiometry indicated that 8\u2009kHz and 16\u2009kHz stimulus elicited responses in cisplatin plus dexamethasone treated mice while high frequency stimulus (32\u2009kHz) perception was affected. Apparently, cisplatin had deleterious effects on outer and inner ear cells situated in the basal turn of the cochlea despite intratympanic administration of protective dexamethasone . FurtherThe intratympanic administration of dexamethasone avoids diminishing the tumoricidal activity of cisplatin. Downregulating apoptosis genes in tumour cells are responsible for this common side effect of systemic steroid therapy . An expeOtoprotection with dexamethasone against cisplatin-induced age-related hearing loss was investigated in a guinea pig model following observations that persons older than 65 years account for more than half of the newly diagnosed malignancies. Hearing loss due to the aging process shares the same cause  with hearing loss due to ototoxic chemotherapeutic agents. A single dose of cisplatin was administered intraperitoneally in old mice preceded and followed by dexamethasone injected intratympanically to counteract the cisplatin toxic effect on inner ear hair cells. Pre- and posttreatment auditory brainstem responses were recorded to evaluate hair cell function. The results of the study pointed out that no synergistic action between age related hearing loss and cisplatin-induced hearing loss exists since threshold shifts were smaller in older animals than those in young mice. Another finding of the study was that the protective effect of dexamethasone against cisplatin-induced ototoxicity was a function of stimulus frequency in old mice. Susceptibility to otoprotective effect of dexamethasone was higher in mid to basal cochlear regions (at and above 24\u2009kHz) in old mice, whereas in young mice, dexamethasone bestowed more protection in apical regions of the cochlea (at 16\u2009kHz and below). Age-related changes of the mechanism of distribution of dexamethasone in scala tympani perilymph after round window membrane application in guinea pigs seem to account for the frequency dependent otoprotective effect .Intratympanic dexamethasone failed to protect against cisplatin-induced ototoxicity in a multidose cisplatin ototoxicity mouse model. The study was prompted by typical clinical protocols of cancer treatments which require administration of multiple, smaller cisplatin doses, exerting their curative effect through cumulative dosing. Contrary to previous experimental studies, the mice received five doses of cisplatin throughout five days, mimicking the cumulative exposure seen in malignant tumours treatment. Intratympanic dexamethasone was administered on the same days as the intraperitoneal cisplatin. The results mirrored by auditory brainstem responses threshold measurements demonstrated continued change in hearing thresholds several weeks after cisplatin exposure and no protective effect of intratympanic dexamethasone against cisplatin ototoxicity .An experimental study focused on systemic administration of steroid for protection against cisplatin-induced ototoxicity showed no otoprotection following several days' prophylaxis with a high dose dexamethasone treatment. Only a slight decrease of TNF-alpha expression in the cochlea was demonstrated by immunohistochemical staining of anatomical samples harvested from systemic cisplatin plus dexamethasone treated animals. Dexamethasone also seemed to protect stria vascularis from morphological alterations, probably owing this effect to higher concentrations of steroid in the lateral cochlear wall following increased cochlear flow and a naturally highly vascularised stria vascularis. Still, a functional otoprotective effect of systemic dexamethasone against cisplatin-induced hearing loss was not observed .Among naturally occurring molecules, Rosmarinic acid, a water-soluble polyphenolic compound extracted from Dansam-Eum, was tested for its protective effect against cisplatin-induced ototoxicity in laboratory settings. The results of the study showed that Rosmarinic acid inhibited cisplatin-induced caspase-1 activation providing protection against stereocilia loss in the primary organ of Corti explants .Another natural remedy, the Maytenus ilicifolia aqueous extract, was evaluated for its possible otoprotection in guinea pigs. Despite the well-known South America plant's antioxidant effects , functional tests did not demonstrate any protective action on the cisplatin exposed cochleae. Yet, the extract improved the clinical status and weight of guinea pigs and diminished mortality after cisplatin exposure .Resveratrol, a polyphenol found in grape skin and seed, has antioxidant, neuroprotective, and dose dependent antiapoptotic properties . Recent Intratympanic dexamethasone was clinically tested for its otoprotective effect in patients suffering from neoplastic diseases for which the treatment protocol included cisplatin. Intratympanic dexamethasone has already been tested clinically for the treatment of idiopathic sudden sensorineural hearing loss and Meniere disease . IntratyTranstympanic L-N-acetylcysteine was also clinically tested in head and neck cancer patients undergoing cisplatin therapy. Thiol compounds are known to either directly bind cisplatin or act as free radical scavengers. Based on that, their intratympanic administration was suggested to avoid the decrease of oncologic effectiveness of cisplatin and to reduce the oxidative stress caused by it. Intratympanic L-N-acetylcysteine was well tolerated by patients receiving multiple doses of cisplatin as part of their oncologic treatment. The relation between dose and otoprotection was not taken into account. Higher concentrations may have yielded better otoprotection. The study protocol required the L-NAC injection to be approximately 1 hour before systemic administration of cisplatin, for the sake of better timing. The outcome of the pure tone audiometry testing at 1 and 2 months after the last cycle of cisplatin showed that L-N-acetylcysteine was overall not significantly otoprotective. Still, hearing loss was reduced in two patients out of eleven who completed the study. The study protocol had several challenges like the difficulty in maintaining high enough concentrations of aqueous solution of L-N-acetylcysteine in the middle ear due to the technique of administration. Another study flaw was the different initial hearing thresholds due to preexisting hearing loss .http://clinicaltrials.gov/ct2/results?term=cisplatin+ototoxicity/) are listed in Few clinical studies tested systemic otoprotective molecules for preventing cisplatin-induced hearing loss. Amifostine, a phosphorylated aminothiol designed to protect against radiation damage, was known to counteract the toxic effect of different anticancer treatments without interfering with the tumoricidal effect. Although significant protection of amifostine against haematological toxicity after high dose carboplatin therapy in a child with medulloblastoma was reported , a cliniThe well-isolated inner ear organ makes it prone to targeted genetic therapies. Viral or nonviral gene vectors can be delivered through a transtympanic route without the risk of dispersing them and reaching other tissues with subsequent undesirable genetic alteration. Long term effects after single administration, cellular selectivity, and replacement of genetically flawed nucleic acid sequences are the main benefits of gene therapy. Common viral vectors include herpes simplex virus, recombinant adenoassociated virus, recombinant adenovirus, and adenovirus, used to amplify the expression of targeted genes. Cells are infected with the vectors (transfection) which transfer genes whose expressed proteins influence important processes like growth, oxidative stress, and apoptosis. Chemical transfection can also be achieved with plasmid vectors. Short interfering RNA can be used to shut down target genes.Among inner ear target genes dealt with by the gene therapy studies are ATOH1 (Math1), CAT , SOD1 (Cu/Zn superoxide dismutase), SOD2 (Mn superoxide dismutase), BDNF (brain-derived neurotrophic factor), HGF (hepatocyte growth factor), GJB2 (gap junction protein), Bcl-xL (B-cell lymphoma-extra large), FGF2 (basic fibroblast growth factor). The gene therapy modifies the synthesis of a wide range of proteins including neurotrophic factors , apoptosis mediators , oxidases , an antioxidant response regulator (Nfe2l2), a cytoprotective enzyme (HO-1), copper transporters (Ctr1), a nonselective cation channel (Trpv1), and protein Otospiralin (Otos).Cisplatin-exposed tissues can benefit from genetically induced upregulation of neurotrophic factors, inhibition of apoptosis, and generation of endogenous antioxidant enzymes.Experimental animal studies and in vitro experiments show the efficacy of gene therapy for cisplatin-induced ototoxicity. Clinical applications require further studies regarding safety, immunogenicity, and consequences of genetic manipulation .Another strategy to avoid cisplatin-induced hearing loss would be the pretreatment genotyping to find out patients at risk for the ototoxic effect of cisplatin . GeneticForty-three publications were reviewed concerning prevention or treatment of cisplatin induced ototoxicity. Publications were devised in either experimental or clinical studies. Experimental studies sustained the efficiency of hyperbaric oxygen therapy, epigallocatechin therapy, and intratympanic lactate. The latter two therapies provide exogenous antioxidants while pharmacologic activation of endogenous antioxidants by means of intratympanic thiamine pyrophosphate was consistent with higher levels of natural antioxidants. Oral sertraline, besides its otoprotective effect against cisplatin induced ototoxicity, also has therapeutic value concerning the depression occurring frequently in oncologic patients. Sodium butirate proved its efficiency against cisplatin induced hearing loss in a monodose cisplatin model. Yet, in clinical practice the patient receives multiple doses of cisplatin. The production of endogenous radicals of oxygen species was reduced after intratympanic administration of short interfering RNA which reduces the expression of NOX3 in the cochlea. Minocycline appeared to be efficient only at low doses of cisplatin while systemic erdosteine showed promising results. Dexamethasone in experimental studies combined efficiency against cisplatin induced ototoxicity with preservation of the tumoricidal activity of cisplatin. When older mice were treated, the dexamethasone was more otoprotective at higher frequencies compared to experiments including younger subjects. Rosmarinic acid also proved to be otoprotective while the Maytenus ilicifolia aqueous extract was not. Resveratrol had contradictory effects, systemic low doses, and in vitro administration preventing ototoxicity, whereas high oral doses seem to enhance cisplatin ototoxicity. There also were experimental studies which showed inefficiency of intratympanic N-acetylcysteine and intratympanic and systemic dexamethasone. N-Acetylcysteine also had a damaging effect on middle and inner ear structures.Clinical studies proved a minor otoprotective effect of intratympanic dexamethasone and no effect of systemic amifostine and intratympanic L-N-acetylcysteine. New perspectives are brought about by genetic therapy using viral vectors and genotyping to anticipate interindividual variability in cisplatin ototoxicity.Hearing loss prevention and treatment during cisplatin therapy for cancer needs further research to find new strategies and optimize old ones. The intratympanic route of administration along with the gene therapy appears to be the most attractive objective for further experimental and clinical studies."}
+{"text": "The real benefit of alternative cannulation technique for repair of acute type A aortic dissection remains controversial.We evaluated our results of ascending aortic cannulation compared with femoral cannulation in acute type A aortic dissection.From January 2000 to December 2014, 121 patients were operated on for acute type A aortic dissection. Cannulation was accomplished in 79 patients through the ascending aorta and 42 patients through the femoral artery.Patient characteristics such as preoperative complications and shock status were almost similar between the groups. Although intraoperative parameters such as total cardiopulmonary bypass time, hypothermic circulatory arrest time, minimum bladder temperature and percentage of total arch replacement were also similar between the groups, ascending aortic cannulation significantly reduced arterial pressure on cardiopulmonary bypass circuit , core-cooling time  and operation time . There were no significant differences in postoperative 30-day mortality and in-hospital mortality between the groups. However, incidence of temporary neurological dysfunction  and respiratory failure  as postoperative complications were significantly lower in the aortic cannulation group, although the incidence of stroke and renal failure did disclose any differences between the groups. Moreover, ascending aortic cannulation significantly reduced the hospital stay .The ascending aortic cannulation for repair of acute type A aortic dissection can be advantageous to rapid cooling after the establishment of cardiopulmonary bypass. It might offer benefit on the incidence of postoperative complications and the length of hospitalization in patients with of acute type A aortic dissection."}
+{"text": "Maintaining DNA integrity is essential for cell survival and proper functioning. Therefore, many cancer therapies, including radiotherapy and several chemotherapeutic drugs, induce damage to the DNA leading to genomic instability . There aWe have used NMR based targeted profiling  to compaWe observed several similarities in the metabolic responses caused by different DDRs and also identified specific metabolite markers on treatment with these DNA damaging agents. PARP inhibition restored most of the metabolic changes observed in MMS-treated cells suggesting that the metabolic response observed after MMS treatment may be predominantly due to PARP activation.In this study, we identified several similarities and differences in metabolic responses induced by different types of DDRs, which suggests the redirection of metabolic fluxes in a DNA damage-dependent manner. We also observed that recruitment of PARP during the DNA repair process can lead to widespread metabolic changes by observing the effect of PARP inhibition in MMS-treated cells. These results have identified novel metabolic responses in cancer cells following DNA damage and on inhibiting activity of proteins involved in DNA repair processes."}
+{"text": "Helicobacter pylori infection remains one of the most challenging infectious diseases causing high mortality and morbidity. The prevalence of infection varies greatly between industrial and developing countries as well as between different geographic areas.Helicobacter pylori (H. Pylori) infection remains one of the most challenging infectious diseases causing high mortality and morbidity. The prevalence of infection varies greatly between industrial and developing countries as well as between different geographic areas  and indirect (non-invasive). Direct methods involve biopsies of ulcer margins by endoscopy and microscopic examination, endoscopy with phenols staining, rapid urease test, and histological specimen culture and polymerase chain reaction. Indirect methods include antibody serology test, stool antigen test, urea breath test, examining of teeth plaque, urine and gastric juice examination  have been completely observed by the author.None declared."}
+{"text": "Naegleria fowleriBalamuthia mandrillarisAcanthamoeba species.Infections caused by free-living amebae (FLA) are severe and life-threatening. These infections include primary amebic meningoencephalitis (PAM) caused by B. mandrillaris and Acanthamoeba species infections treated with a miltefosine-containing regimen is small, it appears that a miltefosine-containing treatment regimen does offer a survival advantage for patients with these often fatal infections  protocol in effect with the Food and Drug Administration to make miltefosine available directly from CDC for treatment of FLA in the United States. The expanded access IND use of miltefosine for treatment of FLA is partly supported by 26 case reports of FLA infection in which miltefosine was part of the treatment regimen . Miltefosine generally is well-tolerated, with gastrointestinal symptoms the most commonly reported adverse effects. Clinicians who suspect they have a patient with FLA infection who could benefit from treatment with miltefosine should contact CDC to consult with an FLA expert. For diagnostic assistance, specimen collection guidance, specimen shipping instructions, and treatment recommendations, clinicians should contact the CDC Emergency Operations Center at 770-488-7100."}
+{"text": "We report a unique first case of benign heterotopic pancreas arising within the proximal hepatic bile duct, containing a focus of intraductal papillary mucinous neoplasm (IPMN). The condition was diagnosed on pathological explant after left hepatic lobectomy with total extrahepatic bile duct excision. The condition of heterotopic pancreas is a relatively common finding, where small foci of pancreatic rest tissue arise in intra-abdominal sites other than the pancreas. First described in 1727, aberrant pancreatic tissue is defined as ectopic location of pancreatic tissue without vascular, neural, or anatomic connections to the anatomically normal pancreas . The majAn obese otherwise healthy 47-year-old female (body mass index 36) presented with intermittent nausea and right upper quadrant discomfort after intentional weight loss of 27\u2009kg. The serum lipase was found to be mildly elevated at 132 units. Abdominal ultrasound demonstrated focal dilatation of the intrahepatic left hepatic ducts, and a subsequent contrast-enhanced magnetic resonance cholangiopancreatogram (MRCP) and endoscopic retrograde cholangiopancreatogram (ERCP) demonstrated an occlusive filling defect within the proximal main biliary tree . An intrThe imaging findings were concerning proximal hepatic duct cholangiocarcinoma (Klatskin tumor), although the CA19-9 was not elevated. The patient then underwent surgical exploration where a palpable filling defect was identified within the proximal hepatic duct. Intraoperative ultrasound demonstrated no additional lesions. For oncological clearance, a left hepatectomy with caudate lobectomy was completed, which required a triple right-sided bile duct Roux-en-Y reconstruction (two posterior and one anterior right bile ducts) over temporary externalized 5 French stents. No blood products were required, and no inflow occlusion was used. She had a smooth and relatively uncomplicated recovery other than a superficial wound infection.Surgical pathology demonstrated histological features consistent with heterotopic pancreatic tissue with IPMN contained within the proximal biliary tree .Sections showed superficial atypia with areas suggestive of papillary formation. There was also prominent bland duct proliferation with lobular architecture and microscopic foci of pancreatic acini surrounding the bile duct. The histological diagnosis was consistent with heterotopic pancreatic tissue. The superficial atypia with papillae suggests a low grade IPMN of the bile duct.At follow-up at 2 months, the patient had recovered fully, and the biliary stents were removed uneventfully.Continued advancement in cross-sectional and other imaging modalities facilitates early diagnosis and more precise treatment for hepatobiliary malignancies. We describe an extremely rare condition of IPMN arising within heterotopic pancreatic tissue obstructing the proximal hepatic duct. We believe this to be the first report of this condition arising within and obstructing the biliary tree. Interestingly SpyGlass cholangiography was able to demonstrate the lesion but was not able to precisely define the pathology. Furthermore, obstruction of the proximal biliary tree necessitated definitive resectional treatment. Had we been confident preoperatively of the benign nature of the filling defect, a less aggressive localized bile duct resection with hepatic parenchymal preservation could potentially have been entertained. However, the presence of IPMN change with potential for malignant transformation would still have provided concern. Preoperative diagnosis of heterotopic pancreas may be challenging and typically this is an incidental finding.Heterotopic pancreas is most commonly found in the proximal jejunal wall of the gastrointestinal tract. Pathological changes that occur within the native pancreas may also occur rarely within the heterotopic gland, including pancreatitis, abscess, and occasionally malignant transformation . IPMNs aIn conclusion, although the condition of heterotopic pancreas is usually asymptomatic and is often discovered incidentally, IPMN with potential for malignant transformation may rarely occur remotely within the biliary tree."}
+{"text": "Hyperammonemic encephalopathy may occur when urease-positive bacteria in the urinary tract produce ammonium which directly enters systemic circulation. Predisposing conditions such as a neurogenic bladder can increase both urinary tract infection and urine stagnation.We describe the case of a 66\u00a0years old woman with a neurogenic bladder who twice developed hyperammonemic encephalopathy following urinary tract infection. During the second episode Escherichia coli and Enterococcus faecalis have been isolated in the urine. The neurologic examination showed psychomotor slowing, weak photomotor reflex, nystagmus in the lateral gaze and asterixis. The EEG showed triphasic waves which disappeared along with clinical recovery.Escherichia coli and Enterococcus faecalis are commonly considered urease-negative bacteria. Although frequently involved in urinary tract infections, their role in causing hyperammonemic encephalopathy have not been previously reported. Moreover, despite only one case with a neurogenic bladder have been described so far, our is the first patient with reoccurring hyperammonemic encephalopathy secondary to urinary tract infections. The occurrence of hyperammonemic encephalopathy is frequently related to liver disease and portal hypertension, where hepatic detoxification process is impaired. In patients with urinary divertion, vesico-colonic fistula or congenital anomalies affecting urinary tract function, ammonium may bypass portal circulation draining directly into the hypogastric veins and inferior vena cava. During urinary tract infections (UTI), urea splitting organisms may determine ammonium production primarily within the urinary system. There are rare conditions when the urine remains into a dilated bladder long enough to allow ammonium reach systemic circulation: this can be due to large diverticula , a neuroWe report the case of a patient with a neurogenic bladder who presented two episodes of hyperammonemic encephalopathy three years apart as a result of UTI. During the last episode, urine culture revealed Escherichia coli and Enterococcus faecalis which are considered urease-negative bacteria.A 66-years-old female, with a history of urinary retention and recurrent UTI, became progressively somnolent during one week, complaining at the same time dysuria and bladder pain, for which she had been assuming trimethoprim-sulfamethoxazole. She was conducted to our department after the execution of a brain CT  and the detection of hyperammonemia (89\u00a0\u03bcmol/L) in the emergency room. The neurologic examination showed psychomotor slowing, weak photomotor reflex, nystagmus in the lateral gaze and asterixis. Her past medical history highlighted that, three years before, she had experienced a similar event . She underwent laboratory blood and urine tests, which showed increased pH (8.0) and a urinary tract infection caused by Escherichia coli and Enterococcus faecalis along with mild increase of serum creatinine, but without impairment of hepatic function; EEG showed alterations consistent with toxic metabolic encephalopathy Figure\u00a0. UnderlyHyperammonemic encephalopathy occurs when hyperammonemia causes glutamine-mediated effects on the brain, such as astrocytic swelling, cerebral edema, and raised intracranial pressure . An incrOur patient has been suffering from urinary retention for many years because of an idiopathic neurogenic bladder. Urinary retention not only predisposed her to the infection, but also increased the absorption of ammonia from the leftover urine through the bladder walls .Although hyperammonemic encephalopathy determines a similar clinical and EEG picture independently of the cause (UTI or hepatic failure), the urinary origin is likely to result in a faster (days or weeks) onset of the symptoms, compared with the chronic and peculiar clinical picture of patients with hepatic dysfunction.To our knowledge this is the first described case where urinary retention was associated with urinary tract infection and recurring hyperammonemic encephalopathy. Moreover no previous cases have been reported where urinary tract infection by Escherichia coli and Enterococcus faecalis caused hyperammonemia.The present case focuses on urinary tract infection related to neurogenic bladder as a potential cause of hyperammonemia, which nevertheless can lead to metabolic encephalopathy. It is important to underline that bacteria usually considered urease-negative may be related to ammonium production within the urinary tract.Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.UTI: Urinary tract infection; CT: Computed tomography; EEG: Electroencephalogram.The authors declare that they have no competing interests.All the authors have read and approved the manuscript. In addition all authors have contributed in the composition, write-up, and review of the manuscript."}
+{"text": "However, recent experiments in which sensory-evoked local dendritic spikes were observed in vivo have provided valuable constraints on possible spatiotemporal patterns of synaptic input [Theoretical modelling and experiments e neuron ,2. Whileic input -5. For eic input . Here, win vivo [in vivo experiments [First, we adapted a detailed active compartmental model of a neocortical layer 2/3 pyramidal neuron [in vivo , such asin vivo occur preferentially when excitatory synaptic inputs are interspersed with inhibitory synaptic inputs. Furthermore, local spikes preceding backpropagating action potentials lead to the highest instantaneous dendritic spike frequencies. The highest sustained frequencies are generated by local spikes initiated sequentially in several neighbouring dendritic branches. Notably, only some of the high frequency dendritic events are effective in evoking action potential output, while others remain local. We use cluster analysis to establish the local and global conditions under which specific spatiotemporal patterns of synaptic input can influence neuronal output.Next we analyzed which spatiotemporal synaptic input patterns precede the generation of local dendritic events. We find that local spikes are preferentially triggered by excitatory synapses which are spatially and temporally clustered in the local dendritic branch and neighbouring branches. While there is great variability in the spatial distribution of synapses triggering local dendritic spikes, temporal patterns of excitatory synaptic input are stereotyped and tend to be sparse. High-frequency dendritic spikes similar to those observed In summary, we have derived spatial and temporal rules for synaptic input and identify input patterns that locally exploit the non-linear integration capacities of dendrites. Which computations can be implemented by spiking dendrites receiving such synaptic input patterns? These constraints on synaptic input patterns, together with the realistic intrinsic properties displayed by the model, put us in a position to investigate the role of dendritic excitability in shaping the input-output relation of the neuron."}
+{"text": "RAS proteins are key signalling hubs that are oncogenically mutated in 30% of all cancer cases. Three genes encode almost identical isoforms that are ubiquitously expressed, but are not functionally redundant. The network responses associated with each isoform and individual oncogenic mutations remain to be fully characterized. In the present article, we review recent data defining the differences between the RAS isoforms and their most commonly mutated codons and discuss the underlying mechanisms. RAS proteins are membrane-bound small GTPases that act as molecular switches downstream of cell-surface receptors. Upon GTP binding, RAS changes conformation, revealing an effector-binding site that can interact with proteins harbouring a RAS-binding domain . RelocalIn the human genome, three genes encode HRAS, KRAS and NRAS. Alternative splicing of HRAS and KRAS generates protein variants with altered C-termini . The N-tDespite their similarity, RAS proteins are not functionally redundant. Furthermore, the oncogenic mutations that make RAS constitutively active may not all be equivalent in their functional consequences. We discuss the evidence for this together with the potential mechanisms underlying these phenomena.RAS proteins cycle between the inactive GDP-bound and the active GTP-bound conformations . This cyThe reason for the bias in RAS mutations associated with individual cancers is unclear, although several models have been proposed. One simple possibility is that isoform-specificity could mean that a more oncogenic network response is generated when KRAS is rendered constitutively active by mutation compared with the other RAS isoforms. This is supported by mouse models harbouring G12D mutated KRAS that exhibited widespread colonic hyperplasia and neoplasia. In contrast, NRAS G12D stimulated cell survival pathways . FurtherKRAS revealed a strong bias for rare codon usage resulting in significantly reduced protein translation compared with a codon-optimized KRAS sequence [RAS is known to induce senescence rather than proliferation [KRAS leads to low endogenous protein levels, meaning that oncogenically activated KRAS would not be expressed highly enough to induce the senescent phenotype. Absolute quantification of RAS isoform protein abundance in normal tissues has not been performed to date; however, comparative analysis of RAS isoform protein levels in a panel of cancer cell lines revealed that KRAS is typically the most abundant isoform  of RAS isoforms change their orientation with respect to the membrane . The extKRAS knockout resulted in embryonic lethality [HRAS into the endogenous KRAS locus, resulting in normal embryonic development, but induced dilated cardiomyopathy during adulthood [Finally, relative expression differences of the isoforms will influence competition for regulator and effector binding and therefore signalling network responses. An example of this can be seen in studies of mouse development. Whereas ethality , a subsedulthood . This suRAS alleles, panels of cancer cell lines and mouse models.This illustrates the importance of studying isoform-specific function in an endogenous context, since a subset of isoform-specific differences may result from the disparity in their expression. Future work is likely to rely less on ectopic overexpression and more on isogenic cells harbouring endogenous wild-type and mutant RAS proteins exhibit a spectrum of isoform-, codon-, point-mutation- and context-specific network responses. These remain poorly understood, which precludes simple prediction of the likely consequences of any given mutation. Wherever possible, it is important to study RAS function in an endogenous context to avoid the perturbing influence of overexpression on the signalling networks. With the recent emergence of new cellular tools, xenopatient and genetically engineered mouse models and more sophisticated systems biology approaches to studying RAS function, there are likely to be significant improvements in our understanding of RAS biology in the near future."}
+{"text": "Familial Mediterranean fever (FMF) is an autosomal recessive auto-inflammatory disease, presenting with recurrent episodes of fever and polyserositis. Diagnosis of FMF is may be challenging especially in pediatric population. Mitochondrial fatty acid oxidation disorders and porphyrias can present with periodic abdominal and muscle pain. Incidence of both FMF and inherited metabolic disorders (IMD) are increased in Turkish patients partially due to high consanguinity rates.The aim of the present study is determine the inherited metabolic disorders in differential diagnosis of Turkish pediatric FMF patients.174 patients who were diagnosed as FMF enrolled the study. In all patients, a fasting dry spot blood sample was taken for acyl-carnitine analyses by tandem mass spectrometry. Fresh, light-protected spot urine test was performed for porphobilinogen screening. Second-tier test with urine organic acid analysis and urine porphyrin metabolites were performed if pathologic findings were detected in acyl-carnitine profile or in porphobilinogen screening, for confirmation. An age matched healthy 50 children served as control group.Of the 174 patients diagnosed with FMF, none of our patients was diagnosed with porphyria; two patients with fatty acid oxidation defect, one with multiple acyl-CoA dehydrogenase deficiency and one with possible medium-chain acyl-CoA dehydrogenase deficiency were detected during the study.Our data revealed that screening for porphobilinogen for pediatric FMF patients is unnecessary, but an investigation of tandem mass based acyl-carnitine analyses can be helpful for the differential or additional diagnosis of FMF in developing countries that does not have nationwide expanded newborn screening programme."}
+{"text": "Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors  have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases. Microglia are macrophage-like immune cells that reside in the central nervous system (CNS), where they play multiple roles: presenting antigen to initiate immunological reactions, directing attack against non-self antigens, debris clearance, support of neuronal circuit development . CaMK activates neuronal nitric oxide synthase (nNOS) and increases the intracellular concentration of nitric oxide (NO). NO in turn inhibits mitochondrial respiratory chain complex IV, resulting in a rapid reduction in intracellular ATP levels. Ultimately, the loss of intracellular energy pools suppresses dendritic and axonal transport, leading to bead-like accumulation of cytoskeletal and motor proteins along neurites and the formation of neuritic beading. Thus, a low-energy state results in neuronal dysfunction. Persistence of this neuronal dysfunction eventually causes neuronal death [i.e., excitotoxic neuronal death or non-cell-autonomous neuronal death , metabolites , and nucleotides  between adjacent cells . These toxic molecules are propagated from injured cells to healthier cells through gap junctions. Ischemic conditions also induce uncoupled hemichannels to open, leading to paracrine transfer of toxic molecules  and an animal model of this disease, experimental autoimmune encephalomyelitis (EAE). In particular, downregulation of oligodendrocytic Cx32 and Cx47 and astrocytic Cx43 have been observed in the active lesions of MS patients and EAE mice , Cx43 (43gap 27), or Panx1 (10panx1) non-specifically block both connexins and pannexins  (Block et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Multivariate analyses identified significant spatial and temporal variation in benthic fluxes, demonstrating key differences between the Northeast Pacific and Salish Sea. Moreover, Northeast Pacific slope fluxes were generally lower than shelf fluxes. Spatial and temporal variation in benthic fluxes in the Salish Sea were driven primarily by differences in temperature and quality of organic matter on the seafloor following phytoplankton blooms. These results demonstrate the utility of multivariate approaches in differentiating among potential drivers of seafloor ecosystem functioning, and indicate that current and future predictive models of organic matter remineralization and ecosystem functioning of soft-muddy shelf and slope seafloor habitats should consider bottom water temperature variation. Bottom temperature has important implications for estimates of seasonal and spatial benthic flux variation, benthic\u2013pelagic coupling, and impacts of predicted ocean warming at high latitudes.The upwelling of deep waters from the oxygen minimum zone in the Northeast Pacific from the continental slope to the shelf and into the Salish Sea during spring and summer offers a unique opportunity to study ecosystem functioning in the form of benthic fluxes along natural gradients. Using the ROV ROPOS we collected sediment cores from 10 sites in May and July 2011, and September 2013 to perform shipboard incubations and flux measurements. Specifically, we measured benthic fluxes of oxygen and nutrients to evaluate potential environmental drivers of benthic flux variation and ecosystem functioning along natural gradients of temperature and bottom water dissolved oxygen concentrations. The range of temperature and dissolved oxygen encountered across our study sites allowed us to apply a suite of multivariate analyses rarely used in flux studies to identify bottom water temperature as the primary environmental driver of benthic flux variation and organic matter remineralization. Redundancy analysis revealed that bottom water characteristics (temperature and dissolved oxygen), quality of organic matter (chl  Marine carbon, nitrogen, and phosphate cycles are linked through their fixation by phytoplankton in surface waters and their remineralization in the water column and on the seafloor . The decOn the continental shelf, close benthic\u2013pelagic coupling typically occurs over time scales of days. The benthic community generally responds rapidly to increased particulate organic carbon (POC) flux to the seafloor, resulting in measurable increases in benthic respiration . This rein situ studies that utilize natural variation such as those that occur along environmental gradients could potentially highlight the main environmental drivers of benthic fluxes, organic matter remineralization and ecosystem functioning in natural systems 76], OPD Bio-irrigation may also have influenced oxygen uptake; Archer and Devol  found thGiven that the marine nitrogen cycle arguably represents the most complex of all biogeochemical cycles in the ocean , a compla:phaeo and C:N), bottom water DO, and sediment MGS as the best predictors of silicate benthic efflux variation. Because we did not measure bio-irrigation, we cannot directly link silicate effluxes with this variable. However, increased oxygen penetration with bottom water oxygen concentration suggests higher bio-irrigation at the shallower and more oxygenated shelf sites than in deeper and oxygen-depleted slope sites on the NE Pacific. Lower oxygen concentration can also change macrobenthic community structure to one that primarily inhabits and reworks the surface of the seafloor and poorly bio-irrigates sediment at depth [Our study shows generally higher silicate effluxes from shallower shelf sites than deeper slope sites, with some seasonal variation. Silicate variation often reflects small-scale differences in sediment properties, bioturbation, and irrigation . Hammondat depth . Much hiat depth . Moreoveat depth  suggesteat depth . We ther-2 d-1 in BC300) to release (697.0 \u03bcmol m-2 d-1 in SoGC-05). Although Nixon et al. [a:phaeo, porosity, MGS and prokaryote abundance can explain 88% of the variation in phosphate flux. Our study apparently encompassed most of the key drivers for phosphate flux, allowing us to predict benthic phosphate flux at these locations. These results are supported by a recent study that modelled benthic phosphate fluxes using three of the variables that we identified  along with mineral bound inorganic phosphorous [Many factors influence seafloor phosphate fluxes , which vn et al.  reportedn et al.  reportedsphorous .a:phaeo and C:N ratios, 11.8 and 7.9% respectively) and sediment characteristics . In their Beaufort Sea study, Link et al. [a and phaeopigments, and bottom water dissolved oxygen as key environmental drivers of multivariate benthic flux variation. However, in contrast to our study, where temperatures varied by >5.5\u00b0C across sampling locations and dates, temperatures recorded at the time of sampling varied by <2\u00b0C and therefore contributed little to benthic flux variation, just as Rowe and Phoel [Multivariate dbRDA allowed us to examine all benthic fluxes simultaneously within the same analysis. Environmental drivers related to bottom water characteristics, quality of organic matter, and sediment characteristics, explained 51.5% of the variability in overall oxygen and nutrient fluxes. Bottom water characteristics explained most of the variability , followed by quality of organic matter  in the same analysis to determine the best combination of environmental drivers for all benthic fluxes, hence of seafloor organic matter remineralization. On the other hand, the multiple linear regression approach analysed each benthic flux separately  to determine the best combination of environmental drivers for each specific benthic flux. Given some commonalities in benthic fluxes but different degrees of influence by some environmental drivers on each benthic flux , the linear regression method identifies the environmental drivers of each benthic flux whereas the dbRDA method identifies the common environmental drivers that influence all benthic fluxes and examines seafloor organic matter remineralization as a whole.The dbRDA and multiple linear regression approaches identified some differences in environmental drivers of benthic fluxes. On the one hand, the dbRDA approach combines all benthic fluxes  on flux rates of oxygen, nitrate, phosphate, silicate and, for the most part, ammonium, where flux rates changed only after oxygen decreased by 50\u201380% from ambient values , 74. Thia:phaeo and C:N ratios) following significant deposition of particulate organic matter to the seafloor and, to a lesser extent, sediment characteristics (MGS and porosity). Although multiple biological and environmental factors influence different seafloor flux rates (O2 and nutrients), our study used a suite of multivariate approaches in tandem to demonstrate that a subset  of the large number of environmental variables measured  could explain benthic flux variation. We also found that simultaneous and single flux analyses in tandem provided a more comprehensive understanding of the interplay between OM remineralization and flux of O2 and individual nutrients.Our study indicates strong variation in spatial and temporal flux, driven primarily by differences in bottom water characteristics (bottom water DO and temperature), quality of organic matter  at our study sites allowed us to identify bottom water temperature as the key driver of benthic flux variation. These results indicate that current and future predictive models of organic matter remineralization and ecosystem functioning of shelf and slope soft-muddy seafloor habitats should consider bottom water temperature variation. Temperature could have important implications for estimates of seasonal and spatial benthic flux variation, benthic-pelagic coupling, and potential impacts of predicted ocean warming, particularly at high latitudes.S1 Appendix(DOCX)Click here for additional data file."}
+{"text": "Human dental pulp inflammation can progress to periapical lesion formation and conventional root canal treatment (RCT) has been the traditional method for disease management. This observational study presents two cases of vital pulp therapy in mature molars diagnosed with irreversible pulpitis and associated with apical periodontitis. In these two clinical cases, the involved teeth had deep carious lesions with a history of spontaneous/lingering pain and radiographic examinations revealed the presence of apical radiolucencies. A conservative miniature pulpotomy (MP) using calcium-enriched mixture (CEM) was performed and the teeth were permanently restored with amalgam. Clinical evaluations indicated resolution of pain 24 hours after treatment; the teeth showed normal vitality, remained asymptomatic and maintained normal function after recall examinations. Furthermore, the 18-month radiographic evaluation showed healing of the apical lesions. Vital pulp therapy using the MP technique with CEM appeared successful in avoiding RCT intervention. These two reports of case outcome suggest that simple MP using a CEM bioregenerative technique may provide a favorable outcome for permanent teeth diagnosed with irreversible pulpitis and associated with apical periodontitis.  Irreversible pulpitis is an inflammatory condition of the dental pulp characterized by long lasting or lingering pain after removal of a specific stimulus. If this inflammatory process progresses, immune responses in the periapical region, can advance and eventually lead to the development of apical periodontitis. It has been demonstrated that periradicular lesions may be detected before the actual necrosis of dental pulp . Scientipy (RCT) . Vital pulp therapy (VPT) is a simple, biologic, regenerative, conservative and economic method that shows a favorable success rate; treatment includes direct/indirect pulp capping and miniature/partial/complete pulpotomy using various pulp capping agents , 8. MiniMineral trioxide aggregate (MTA), which has the ability to induce hard tissue formation, is universally used in VPT  but it hThis clinical report describes successful MP treatment of two mandibular molars diagnosed with irreversible pulpitis and associated with periapical involvement using CEM cement. Case 1A 38-year-old female presented to our clinic with the chief complaint of spontaneous and severe lingering pain provoked by chewing and exposure to cold fluids. The patient\u2019s medical history was noncontributory and clinically, the left mandibular second molar exhibited a deep carious lesion. The involved tooth responded with prolonged exaggerated pain (>10 seconds) to a cold test and demonstrated sensitivity to percussion. Radiographic examination revealed a deep carious lesion and complete root-end apical closure, widening of periodontal ligament and presence of a periapical lesion . AccordiA mouth rinse with 0.2% chlorhexidine gluconate was first initiated and the patient then received inferior alveolar nerve block anesthesia with 2% lidocaine and 1:80000 adrenalin . The tooth was isolated with a dental dam and then caries were completely excavated under magnification. The exposed surface of the dental pulp was lightly brushed with a sterile round diamond bur  using a high-speed handpiece and copious water irrigation; the removal of the pulp did not exceed 1 mm. Hemostasis was achieved by irrigation with sterile saline solution and gentle application of moistened sterile cotton pellets for three min. CEM cement powder and liquid  were mixed according to the manufacturer\u2019s instructions. A small bulk of the cement was gently condensed into the pulpal cavity using dry sterile cotton pellets. After 5 min [Case 2A healthy 40-year-old man was referred to our clinic with a chief complaint of spontaneous and temperature related pain including pain on chewing in the left mandible. Clinically, the mandibular left first molar exhibited an advanced distal carious lesion  and was The patient was recalled after one week and the tooth was clinically asymptomatic. The tooth showed normal vitality to cold testing, with no evidence of clinical or radiographic pathology at the 18-month recall. An important radiographic finding was formation of a hard tissue bridge beneath CEM cement and complete resolution of the apical lesions .As our knowledge in pulpal biology and endodontic biomaterials advances, the initial management of vital teeth with associated apical lesions employing simple VPT procedures may now be considered a potential treatment strategy. VPT is a valuable treatment, particularly for teeth with open apices and vital pulps which are mechanically or cariously exposed -15. UsuaIn this report, two cases with irreversible pulpitis and symptomatic apical periodontitis were treated by MP using CEM bioceramic. Follow-up examinations demonstrated favorable outcomes that maintained pulpal vitality and promoted periapical healing using CEM as a VPT bioceramic. The biological response to VPT is highly influenced by the healing potential of the inflamed pulp as well as the biocompatibility and sealing ability of pulp capping agent . The sucMP is a conservative VPT strategy, which results in removal of injured odontoblast cells, operative debris, potentially infected tissue and exposes deeper layers of the pulp to the proximity of the capping agent where mesenchymal or dental pulp stem cells are present. The advantages of MP include better irrigation and cleaning of the surgical pulp wound from contaminated dentinal chips and accessibility to areas with less pulpal inflammation where hemostasis can be more easily attained. The procedure also creates adequate space for the suitable pulp capping agent or biomaterial, thus producing a superior three dimensional antibacterial seal . Current research data indicates that the hard tissue barriers generated under CEM cement are thicker than those produced by MTA and that the layer of odontoblast-like cells formed underneath the capping material appears to be more consistent in CEM specimens . It has The mechanism by which CEM encourages pulp healing still remains unclear. However, this feature may be attributed to several properties including sealing ability, antimicrobial effect, low cytotoxicity, similarity to dentine, hydroxyapatite formation and the ability to induce hard barrier formation , 27-30. Miniature pulpotomy provides an easy, conservative, and biologically-based treatment that maintains pulpal vitality and shows the ability to resolve emerging apical pathosis under certain conditions. Although more clinical trials with larger sample sizes and longer-term follow-ups may be required, using CEM cement or other bioceramic materials for MP may be considered an alternative option to conventional RCT in symptomatic vital permanent teeth diagnosed with irreversible pulpitis."}
+{"text": "Measures of small-area deprivation may be valuable in geographically targeting limited resources to prevent, diagnose, and effectively manage chronic conditions in vulnerable populations. We developed a census-based small-area socioeconomic deprivation index specifically to predict chronic disease burden among publically insured Medicaid recipients in South Carolina, a relatively poor state in the southern United States. We compared the predictive ability of the new index with that of four other small-area deprivation indicators.To derive the ZIP Code Tabulation Area-Level Palmetto Small-Area Deprivation Index , we evaluated ten census variables across five socioeconomic deprivation domains, identifying the combination of census indicators most highly correlated with a set of five chronic disease conditions among South Carolina Medicaid enrollees. In separate validation studies, we used both logistic and spatial regression methods to assess the ability of Palmetto SADI to predict chronic disease burden among state Medicaid recipients relative to four alternative small-area socioeconomic deprivation measures: the Townsend index of material deprivation; a single-variable poverty indicator; and two small-area designations of health care resource deprivation, Primary Care Health Professional Shortage Area and Medically Underserved Area/Medically Underserved Population.Palmetto SADI was the best predictor of chronic disease burden (presence of at least one condition and presence of two or more conditions) among state Medicaid recipients compared to all alternative deprivation measures tested.A low-cost, regionally optimized socioeconomic deprivation index, Palmetto SADI can be used to identify areas in South Carolina at high risk for chronic disease burden among Medicaid recipients and other low-income Medicaid-eligible populations for targeted prevention, screening, diagnosis, disease self-management, and care coordination activities. In the United States persons with chronic conditions are overrepresented in Medicaid , a publiIncreasingly, small-area measures of social and material deprivation  are usedAlthough the Townsend deprivation index, single-variable poverty index, and health care resource deprivation designations are used widely in health planning and evaluation, these measures may not be optimally suited for purposes of community health need assessment in all geographic regions or across diverse population groups. Indeed, a marked trend exists in the development of region/population-specific small-area deprivation indexes for health research. Since 2000, for example, deprivation measures have been constructed and applied in health studies in Quebec, Canada ; Verona,To our knowledge, no socioeconomic deprivation measure has been developed specifically for assessment of a Medicaid population in the United States. To facilitate health policy and programming, we developed a census-based small-area socioeconomic deprivation index optimized to predict chronic disease burden among Medicaid recipients in South Carolina, a largely impoverished Southern state where more than one in five residents are enrolled in the Medicaid system . Based oThe US Census Bureau provides detailed population and housing data at multiple geographic levels. US census and survey data products are updated regularly and are available online at no cost, making them especially valuable to state and local health planners with limited financial resources. We sought to create a census-based index of socioeconomic deprivation to predict chronic disease burden among South Carolina Medicaid enrollees at the ZIP Code Tabulation Area (ZCTA) level. Census-defined ZCTAs are comprised of whole census blocks and spatially approximate USPS five-digit ZIP Code mail delivery areas . These sBased on a literature review, we evaluated a range of Census 2000 population and housing indicators  for inclWe evaluated chronic disease burden among South Carolina Medicaid recipients across five adverse chronic health conditions: cardiovascular disease (CVD); diabetes; end-stage renal disease (ESRD); hypertension; and obesity. These diagnostic categories are among the most common and costliest chronic conditions affecting South Carolina Medicaid enrollees. Chronic disease status for the state\u2019s approximately 1 million Medicaid recipients was determined using primary and secondary diagnosis codes contained in South Carolina Medicaid administrative data sets from fiscal year 2010 (July 2009 to June 2010) . ZCTA-leXi) using Fisher\u2019s Z-transformation to create a set of Z-score variables (Zi) defined for ni observations j = 1,\u2026,ni based on the associated original variableith predictor. This transformation ensures that each of the Z-score variables is standardized to have mean 0 and variance 1. We then calculated the mean correlation of each transformed variable across the set of five chronic condition prevalence rates. The single predictor with the highest mean correlation was the first component Condi)N = 392).In developing the new socioeconomic deprivation index, we sought to minimize the total number of census-based predictor variables while maximizing correlation with ZCTA-level Medicaid chronic disease rates. We scaled each predictor . Two chronic disease burden indicators\u2014one reflecting the presence of at least one chronic condition and the other representing the presence of two or more conditions\u2014were created for a random sample of 5,000 Medicaid recipients geocoded at the ZCTA level using recipient residential address data. Utilizing this sample, we performed logistic regression analyses to evaluate the ability of Palmetto SADI and four alternative measures of small-area deprivation to predict chronic disease burden among Medicaid enrollees based on their ZCTA of residence.AUCOo isAUCi is the area under the curve of the model estimated from the ith bootstrap sample.In these analyses Palmetto SADI, Townsend, and poverty were evaluated as continuous measures; PC-HPSA and MUA/MUP were modeled as binomial variables. We evaluated the performance of all models using the area under the Receiver Operating Characteristic curve (AUC). This statistic summarizes a model\u2019s discrimination, i.e., ability to correctly classify individuals\u2019 chronic disease status. AUC values close to 1 show near perfect discrimination. The model fit was evaluated using the corrected Akaike information criterion measure (AIC). This is a measure of the model\u2019s deviance or difference from a saturated (perfectly predicting) model. Lower values of AIC indicate a preferable model. Bootstrapping was used to estimate standard errors of the AUC and AIC values which allowed assessment of significant differences across models; by this approach, we generated 199 random samples (with replacement) from the original data and re-estimated each of the five models. Approximate standard errors were given by the standard deviation of results from the bootstrap samples. For example, the standard error of the observed area under the curve N = 1,024,034). We further derived two ZCTA-level chronic disease burden counts (presence of at least one chronic condition and presence of two or more conditions). We calculated odds ratios to assess associations between high socioeconomic deprivation as measured by Palmetto SADI, the Townsend index, and the poverty measure (top versus bottom quartile of each continuous deprivation measure distribution) and each of the seven chronic condition indicators . Similarly, we calculated odds ratios to evaluate associations between two binomial measures of health care provider resource deprivation  and each of the seven chronic condition measures.Next, we derived ZCTA-level total Medicaid population and chronic disease counts for each of the five chronic conditions represented in logistic regression analyses, based on georeferenced data for the entire Medicaid population (N = 372). The operationalization of small-area deprivation measures for this set of ZCTAs is summarized in Table\u00a0We performed Ordinary Least Squares (OLS) and spatial regression analyses to further evaluate small-area deprivation measure associations with chronic disease burden at the ZCTA level, again based on georeferenced data for the entire Medicaid population. Chronic disease prevalence rates were calculated for five conditions . Two chronic disease burden prevalence rates (presence of at least one chronic condition and presence of two or more conditions) also were calculated. As in previous logistic regression analyses, Palmetto SADI and four alternative measures of small-area deprivation were modeled. Preliminary OLS regression analyses with spatial diagnostics (Moran\u2019s I) indicated statistically significant spatial autocorrelation in all models tested. Spatial regression models  were employed to account for the spatial autocorrelation of modeled variables. Spatial regression results are reported. AIC and Schwarz Bayesian information criterion (BIC) values from spatial regressions were used to evaluate goodness of fit for each small-area deprivation model, with lower values indicating preferable models. To ensure greater prevalence rate stability and protect recipient confidentiality in mapped results, all ZCTA-level index validation analyses were restricted to ZCTAs with at least 30 Medicaid enrollees N = 37. The opeP < 0.001) and a significantly lower AIC (P < 0.001) compared to all four alternative models  were highest when Palmetto SADI was used to identify high socioeconomic deprivation Table\u00a0.Table 4ZConsistent with logistic regression results, spatial regression analyses identified Palmetto SADI as the best small-area deprivation predictor of chronic disease burden  among all Medicaid recipients at the ZCTA level. Compared to the four alternative deprivation models tested, the Palmetto SADI model yielded lower AIC and BIC values, thus indicating the preferability of the derived index Table\u00a0. SeparatFigure\u00a0We found significantly higher levels of chronic disease in high- versus low-deprivation ZCTAs, regardless of the deprivation measure used, a result that is consistent with a growing international body of literature indicating higher rates of wide-ranging adverse health outcomes in resource-poor communities , 30, 52.Although small-area deprivation measures have proven useful in geospatial assessments of population health and health inequality, such measures are subject to criticism, particularly in terms of variable selection and index construction . We baseBeyond the recognition of conceptual and methodological challenges associated with the construction of any socioeconomic deprivation measure, several limitations specific to the development, validation, and application of Palmetto SADI should be identified. First, chronic disease status was determined using diagnostic codes in Medicaid administrative data sets. Administrative data are widely used in health studies and the validity of such data sets has been established . More acAs indicated by specific policy or programming requirements, the methodology described might be used to construct census-based socioeconomic deprivation measures for both smaller  and larger  areas. \u201cTailored\u201d deprivation indexes  also migThe development of Palmetto SADI is consistent with calls for better measures of social and health deprivation that permit the identification and reduction of health disparities across time and space  and thatDecision making to prevent and more effectively manage chronic disease in vulnerable populations requires consideration of factors other than small-area socioeconomic deprivation. Palmetto SADI may be most valuable as a policy and program planning tool when combined with other small-area assessment strategies measuring such factors as healthy food availability , health As a predictor of chronic disease burden among South Carolina Medicaid recipients, Palmetto SADI outperformed all alternative small-area deprivation measures tested. Palmetto SADI can be used to identify areas in South Carolina at high risk for chronic disease burden among Medicaid recipients and other low-income Medicaid-eligible populations for targeted prevention, disease management, and care coordination activities."}
+{"text": "In field conditions, plants are often simultaneously exposed to multiple biotic and abiotic stresses resulting in substantial yield loss. Plants have evolved various physiological and molecular adaptations to protect themselves under stress combinations. Emerging evidences suggest that plant responses to a combination of stresses are unique from individual stress responses. In addition, plants exhibit shared responses which are common to individual stresses and stress combination. In this review, we provide an update on the current understanding of both unique and shared responses. Specific focus of this review is on heat\u2013drought stress as a major abiotic stress combination and, drought\u2013pathogen and heat\u2013pathogen as examples of abiotic\u2013biotic stress combinations. We also comprehend the current understanding of molecular mechanisms of cross talk in relation to shared and unique molecular responses for plant survival under stress combinations. Thus, the knowledge of shared responses of plants from individual stress studies and stress combinations can be utilized to develop varieties with broad spectrum stress tolerance. Arabidopsis thaliana plants accumulate sucrose instead of proline  more severely than the individual stresses  increased indicating the synthesis of proline from glutamate. However, under combined stress, a decrease in the activity of P5CS and increase in the activity of ornithine aminotransferase (OAT) was observed suggesting that under the combined stress, proline synthesis occurred from ornithine through ornithine aminotransferase (OAT). The occurrence of proline synthesis through OAT has been observed in plants under some conditions . Cappelli is characterized by higher WUE and lower stomatal conductance compared to Ofanto. The combined stress led to a higher leaf temperature in Cappelli as compared to Ofanto  plants heat stress response was found to be the most dominating (Supplementary Table T. aestivum plants by cDNA amplified fragment length polymorphism (cDNA-AFLP). The study revealed that 380 genes were modulated in all the three stress conditions. Out of 242 up-regulated genes, 44, 15, and 90 genes were specifically induced by heat, drought and combined stress, respectively. While 18 genes were commonly up-regulated in heat and drought stress, 51 and 24 up-regulated genes were common among individual heat, drought and the combined heat and drought stress, respectively. Therefore, in case of T. aestivum, the response under combined stress constituted more of unique than shared response. Similarly, transcriptomic analysis of individual and combined stressed Sorghum bicolor plants  genes, dehydrin, photosynthesis related genes, and genes encoding enzymes involved in pentose pathway and anthocyanin biosynthesis , ROS detoxification enzymes, and enzymes involved in photosynthesis and glycolysis  and thioredoxin peroxidase (TPX). Drought stress led to the induction of catalase (CAT) and glutathione peroxidase (GPX). However, under combined stress, genes encoding alternative oxidase (AOX), GPX, glutathione reductase (GR), copper\u2013zinc superoxide dismutase (CuZnSOD), and glutathione S transferase (GST) were found to be specifically induced.Although combined and individual stress response of plants constituted a number of commonly regulated genes, differences were observed in their expression levels in individual and combined stress conditions i.e., the expression was tailored to combined stress condition. For example, when compared to individual drought and heat stressed plants, combined stressed plants exhibited higher induction of HSP coding genes  protein] was found to be up-regulated exclusively under heat stress. Sb01g021320 (homologous to LEA D34 protein) and Sb05g017950  were found to be up-regulated exclusively under drought and combined stress , small GTP-binding proteins, MYB transcription factors, transporters, aquaporin membrane intrinsic protein  radiation, and nutrient stress dramatically alters the response of plants to biotic stresses. Similarly, interaction of plants with pathogens affects their responses to abiotic stresses. The outcomes of these interactions can either provide resistance or susceptibility toward any of the two stresses depending on the plant species, pathogen and stress intensity.L. esculentum, drought stress reduced infection of necrotrophic fungus Botrytis cinerea  by 50% and suppressed the biotrophic fungus Oidium neolycopersici  infection with concomitant two-fold increase in ABA compared to well-watered infected plants  resulted in increased plant tolerance to drought stress due to de novo xylem formation resulting in enhanced water flow  in a concentration dependent manner , increasing leaf senescence and resulting in premature defoliation , exhibit severe cell death, whereas in the drought acclimated plants the extent of cell death was much reduced  causes pathogen-induced drought in Vitis vinifera by reducing water potential \u2014and resistance (R)\u2014gene mediated defense responses to P. syringae pathovars  and viral elicitors were compromised at high temperatures, allowing increased growth of these pathogens  and Tomato spotted wilt virus . TMV is able to overcome the N-gene mediated resistance at temperatures above 28\u00b0C in N. tabacum  and combined drought and TuMV indicated the presence of both shared and unique molecular response in combined stressed plants  which is responsible for synthesis of osmoprotectants galactinol and raffinose. The response characteristically seen under combined stresses in V. vinifera plants consisted of early induction of ABA biosynthesis gene, 9-cis epoxycarotenoid dioxygenase (NCED), and calceneurin B like interacting protein kinase (CIPK). Overall, drought stress and bacterial infection in this case led to activation of ABA mediated drought response that led to enhanced development of disease  infection were more susceptible to viral infection. The authors observed that combination of heat and viral infection led to enhanced transcript accumulation of P3 gene, which is a marker for viral replication  infection, eight also responded to abiotic stresses substantiating them as an important point of cross talk , Capsicum annum WRKY40 (CaWRKY40), MAPK like Gossypium hirsutum MPK16 (GhMPK16), and OsNAC6 have been successfully used to impart biotic and abiotic stress resistance to plants (Supplementary Table A number of transcription factors belonging to myeloblastosis (MYB) transcription factors family e.g., OsMYB4, ethylene responsive factors (ERF) like GmERF and botrytis-susceptible1 (BOS1) are important regulators of different hormone signaling pathways and have a role in imparting biotic and abiotic stress resistance to plants , glutathione-S-transferase F12 (GSTF12), mitogen activated protein kinase 9 (AtMAPKK9), MAPKK16 are common to drought and combined virus and drought stress response of A. thaliana plants subjected to combined drought and TuMV infection (Prasch and Sonnewald, The transcriptome analysis of The stress response mechanism of plants against the abiotic and biotic stress combinations is governed by interaction between responses evoked by individual stresses at both physiological and molecular level. As already stated, the interaction is governed by factors like severity of stresses, age of plant, and whether the plant is tolerant or susceptible to any one of the individual stress. Even plants belonging to same genus may show different molecular response to a stress combination (Aprile et al., The increasing demand for food, deteriorating environmental conditions as well as emergence of newly evolved pathogens have necessitated the development of crops which are better equipped to deal with biotic and abiotic stresses and produce better yields. The fact that occurrence of combination of stresses instead of individual stress are important challenges for crop production demands thorough and intensive studies to understand plants response to stress combinations. A couple of studies in this direction throwing light on shared and unique responses of plants under combined stresses have already been published. It is now required to extend these studies to major crop plants. For proper understanding of plants responses to combined stress which occur under field conditions, the experiments should be carefully designed so that they nearly mimic the field conditions. It is also pertinent to identify the stages vulnerable to the combined stresses by studying the stage specific effect of combined stresses on the transcriptome of different plants. The transcriptomic analysis of plants under combined stresses can generate useful and substantial information regarding common and unique genes modulated under combined stresses. The advances in NGS and high throughput sequence analysis platforms for precise detection and accurate quantification of even small changes in the transcriptome as well as the recently developed genetic engineering tools can be useful in exploring the molecular responses of plants under combined stresses.The reviewer Yasuhiro Ishiga declares that, despite having previously collaborated with the authors Muthappa Senthil-Kumar and Venkategowda Ramegowda, the review process was conducted objectively. The reviewer Ramu S. Vemanna also declares that, despite having previously collaborated with the author Muthappa Senthil-Kumar, the review process was conducted objectively. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A major obstacle to anticipating the cross-species transmission of zoonotic diseases and developing novel strategies for their control is the scarcity of data informing how these pathogens circulate within natural reservoir populations. Vampire bats are the primary reservoir of rabies in Latin America, where the disease remains among the most important viral zoonoses affecting humans and livestock. Unpredictable spatiotemporal dynamics of rabies within bat populations have precluded anticipation of outbreaks and undermined widespread bat culling programs. By analysing 1146 vampire bat-transmitted rabies (VBR) outbreaks in livestock across 12 years in Peru, we demonstrate that viral expansions into historically uninfected zones have doubled the recent burden of VBR. Viral expansions are geographically widespread, but severely constrained by high elevation peaks in the Andes mountains. Within Andean valleys, invasions form wavefronts that are advancing towards large, unvaccinated livestock populations that are heavily bitten by bats, which together will fuel high transmission and mortality. Using spatial models, we forecast the pathways of ongoing VBR epizootics across heterogeneous landscapes. These results directly inform vaccination strategies to mitigate impending viral emergence, reveal VBR as an emerging rather than an enzootic disease and create opportunities to test novel interventions to manage viruses in bat reservoirs. A centrDesmodus rotundus) are the most important source of human and animal rabies, a lethal encephalitis transmitted by the bites of infected animals )Travelling waves have been identified in several other wildlife zoonoses (e.g. Ebola virus , rabies This study demonstrates the power of animal health surveillance systems to generate high-resolution insights into the spatiotemporal dynamics of zoonotic viruses that would probably be impossible to detect relying on studies within a wildlife reservoir alone. The travelling waves that we detected in Peru directly inform management of viral spillover from bats by providing recommendations for where and when livestock should be vaccinated and educational campaigns should be carried out, while creating a unique opportunity to trail experimental interventions in bat populations to block spatially replicated advancing epizootics."}
+{"text": "It should be highlighted that \u2018cancer\u2019 is a namegenerically given to a widely heterogeneous group of diseases; in comparison to solidtumors, hematological neoplasms show a number peculiar features. Among the most relevant,it should be emphasized the urgency of starting anti-cancer therapy, as often required inhigh-grade hematological neoplasms as acute leukemia and aggressive lymphomas. Specificresearch on this subgroup is warranted, considering the potential prognostic impact of theunderlying neoplasm behavior and center-specific features .Advances in treatment of cancer patients and improved understanding of pathophysiologicalmechanisms behind malignant diseases contribute to increased survival and, consequently,increasing needs of intensive care support for this population. Currently,refusing ICU admissions based only on the type of hematological cancer is no longerjustifiable. Therefore, the intensive care specialty faces new challenges represented byseverely ill patients with malignant underlying diseases requiring, in addition totraditional intensive care, progressively more specific knowledge on oncology.In the past two decades, intensive care units (ICU) increasingly played a relevant role,both treating infective intercurrences and severe complications related to the canceritself and its therapy; and preventive admissions of high-risk patients undergoingchemotherapy. A suitable example of such cooperation is giving urgent intravenouschemotherapy to hematological patients during their ICU stay. This cooperation has beenshown feasible, adding a positive impact on selected patients\u2019 prognosis, including forthose with highly severe diseases.,5These new and progressive challenges require the intensivist to be capable of offering boththe best clinical care and appropriate advice for patient and family members regardingprognosis, therapeutic options and preferences. Therefore, some behavioral changes arerequired, particularly regarding improved cooperation between intensivists andoncologists/hematologists. In addition to influencing the clinical practice and decisionmaking on anti-cancer therapy, this interaction may contribute to appropriately selectpatients who may better benefit from intensive care.,7Now, the challenge is to evaluate if these findings translate into bedside benefits indifferent scenarios. So far, most ofthe studies assessing this population outcomes in Brazilian ICUs have included solidtumors, rendering difficult interpreting the results.Some independent aspects associated to poor prognosis in severely ill hematological cancerpatients have been identified, such as the need of invasive respiratory support, more organdysfunctions, poor performance status and neoplasm organ infiltrations. Although conducted inone single center, this study adds relevant information on the scenario of hematologicalpatients in Brazilian ICUs. The authors observed a high prevalence of cancer, 81.6% of thishematological patients\u2019 sample. This translated into one out every six ICU admissions inthis timeframe. The reported ICU and hospital mortality rates were 47.8% and 73.2%,respectively. Multiple factors may have contributed to such high rates. Among them, thedisease severity upon ICU admission, assessed by SAPS 3 score, was shown to be anindependent mortality predictor. These findings highlight the results of recent studiesstressing the relevance of early intensive care in severely ill patients. Expertrecommendations for widening criteria for admitting hematological cancer patients to theICU and full intensive care within the first days should be aligned with identifying earlystage of critical diseases. Ideally, before organ dysfunctions are installed. Thus, a possible intervention target isapparent, particularly in Brazil, where the access to intensive care is jeopardized bysystem ineffectiveness and/or shortness of intensive care beds. Recently a European study including hematological cancerpatients in 17 ICUs located in France and Belgium identified that ICU admission within thefirst 24 hours after hospital admission is associated to better survival rates incomparison to the a priori anticipated. The reported hospital mortalitywas 39%, and both cancer disease control and health-related quality of life followingdischarge were considered satisfactory, suggesting that appropriate cost-benefit ratio wasachieved.In this issue of RBTI, Barreto et al. report on the two-year assessment of 157hematological disease adult patients admitted to a general ICU in a Brazilian universityhospital. regards the encouraging hospital survivalrates found in patients undergoing noninvasive mechanic ventilation (NIMV). These rateswere similar to those found in patients requiring no respiratory support at all. Yet inpatients failing to NIMV, the mortality rate was high, even above the rate observed inpatients whose first respiratory support option was invasive mechanic ventilation. Theseresults confirm previous results,14 supporting both decisions for electinginvasive respiratory support in selected patients and the importance of earlyidentification of NIMV failure associated features. In the study by Barreto et al. thesubgroup failing to NIMV had more severe respiratory dysfunction and increased use ofhemodynamic support within the first 24 hours following ICU admission; this agrees with theliterature. According to thecurrent knowledge, upon identification of these features, invasive respiratory supportwould be the preferable starting strategy.Respiratory failure is known to be the main cause leading hematological patients tointensive care admission; another relevant contribution by Barreto et al. reportson relevant information about features of hematological diseases in severely ill patients.However, additional research is warranted to better understand the profile of thispopulation of patients, increasingly admitted to Brazilian ICUs. New data on long-termmortality, health-related quality of life following ICU discharge and characterization ofpossibly outcome-related ICU issues are necessary for better assessing the care provided tothese patients.The study by Barreto et al."}
+{"text": "Maternal obesity during pregnancy is an important public health problem in Western countries. Currently, obesity prevalence rates in pregnant women are estimated to be as high as 30\u00a0%. In addition, approximately 40\u00a0% of women gain an excessive amount of weight during pregnancy in Western countries. An accumulating body of evidence suggests a long-term impact of maternal obesity and excessive weight gain during pregnancy on adiposity, cardiovascular and metabolic related health outcomes in the offspring in fetal life, childhood and adulthood. In this review, we discuss results from recent studies, potential underlying mechanisms and challenges for future epidemiological studies. Obesity, cardiovascular disease and type 2 diabetes are major public health problems. These common diseases have a large impact on morbidity and mortality in the general adult population \u20134. VarioIn Western countries, maternal obesity during pregnancy is an important adverse risk factor for an excessive nutritional in utero environment , 34. CurAs described previously, both maternal prepregnancy obesity and excessive gestational weight gain seem to have persistent effects on various childhood outcomes . This reMaternal prepregnancy obesity and excessive weight gain during pregnancy are important risk factors for a variety of adverse fetal outcomes Table\u00a0. A meta-It is well-known that maternal prepregnancy obesity and excessive gestational weight gain are associated with an increased risk of large-size-for gestational age at birth , 43. A rFewer studies assessed the direct influence of maternal obesity during pregnancy on placental and fetal cardiovascular and metabolic development. It has been shown that maternal prepregnancy obesity is associated with higher placental weight, placental vascular dysfunction, placental inflammation and alterations in placental transporters activity and mitochondrial activity \u201355. A stThus, both maternal prepregnancy obesity and excessive gestational weight gain lead to increased risks of adverse fetal outcomes. Overall, maternal prepregnancy obesity appears to be more strongly associated with adverse fetal outcomes than excessive maternal gestational weight gain , 47.Maternal prepregnancy obesity and excessive gestational weight gain are associated with an increased risk of obesity in childhood and adolescence Table\u00a0. A meta-Several studies aimed to identify critical periods of maternal weight during pregnancy for childhood outcomes. A study performed among 5154 UK mother-offspring pairs showed that especially gestational weight gain in the first 14\u00a0weeks of pregnancy was positively associated with offspring adiposity at 9\u00a0years of age . In lineThus, next to the risks of adverse fetal outcomes, maternal prepregnancy obesity and excessive gestational weight gain may lead to increased risks of adiposity and adverse cardiovascular risk factors in childhood and adolescence.Multiple studies have shown that a higher maternal prepregnancy body mass index is associated with a higher adult body mass index in the offspring, independent from socio-demographic and lifestyle-related confounding factors \u201376 Tabl. SimilarThus, in line with the associations of maternal prepregnancy obesity and excessive gestational weight gain with childhood outcomes, these adverse maternal exposures are associated with an increased risk of adiposity and cardiovascular and metabolic disease and mortality in the adult offspring.The major limitation of these observational studies is confounding. Various family-based socio-demographic, nutritional, lifestyle related and genetic characteristics may explain the observed associations of maternal prepregnancy body mass index and gestational weight gain with adverse health outcomes in the offspring. Few studies used more sophisticated study designs to obtain further insight into the role of confounding in the observed associations, including sibling comparison studies, maternal and paternal offspring comparisons analyses, Mendelian randomization studies, and randomized controlled trial analyses, as described previously .First, sibling comparison studies enable better control for potential confounding factors shared within families . A sibliSecond, several studies compared the strength of associations of maternal and paternal body mass index with offspring outcomes as an aid to further disentangle underlying mechanisms. Stronger associations for maternal body mass index suggest direct intrauterine mechanisms, whereas similar or stronger associations for paternal body mass index suggest a role for shared family-based, lifestyle-related characteristics or genetic factors . StudiesThird, Mendelian randomization approaches use genetic variants, known to be robustly associated with the exposure of interest and not affected by confounding, as an instrumental variable for a specific exposure . AssociaFourth, randomized controlled trials are considered as the golden standard for causality studies. Because randomized studies are difficult to perform when maternal prepregnancy obesity and excessive gestational weight gain are the major exposures of interest, previous studies focused on influencing determinants of obesity and excessive gestational weight gain, such as dietary factors and physical activity levels . Based oAltogether, results from studies specifically designed to explore the causality for the associations of maternal obesity\u00a0during pregnancy with offspring outcomes are not conclusive yet.The mechanisms underlying the associations of maternal obesity or excessive gestational weight gain with cardiovascular and metabolic disease in the offspring are not known yet. The fetal overnutrition hypothesis suggests that increased placental transfer of nutrients to the developing fetus in obese mothers and mothers with high levels of gestational weight gain, may subsequently affect fetal development, fetal fat deposition and the development of the hypothalamic-endocrine system that controls appetite and energy metabolism \u201393. ThesMaternal prepregnancy obesity and excessive gestational weight gain are complex traits, which reflect multiple components. Maternal prepregnancy obesity reflects maternal nutritional status, fat accumulation and low-grade inflammation, whereas maternal weight gain during pregnancy additionally reflects maternal and amniotic fluid expansion and growth of the fetus, placenta and uterus .Maternal prepregnancy obesity is an indicator of a poor quality maternal diet. Both macronutrients and micronutrients intake related to a Western diet may influence fetal cardiovascular and metabolic development, through influences on placental transfer and subsequently offspring fat deposition, adipocyte function, pancreatic function and food preference , 94. A sMaternal prepregnancy obesity and excessive gestational weight gain partly reflect maternal fat accumulation, which is important for fetal development . HoweverLow grade systemic inflammation may be involved in pathways leading from maternal obesity or excessive gestational weight gain to adverse offspring outcomes. Obesity is associated with low-grade systemic inflammation and oxidative stress, also during pregnancy \u2013118. AddBoth maternal obesity and excessive gestational weight gain as well as the correlated nutritional, body fat distribution, metabolic and inflammatory exposures may lead to programming effects in the offspring through several pathways.Epigenetic changes in the offspring are likely to play an important role in developmental programming . EpigeneOffspring from mothers with prepregnancy obesity or excessive gestational weight gain during pregnancy have higher fetal growth rates and are at increased risk of being born large for their gestational age. Higher birth weight is associated with an increased risk of obesity in later life . The assThe associations of maternal prepregnancy body mass index and gestational weight gain with adverse cardiovascular and metabolic outcomes in the offspring appear to be largely mediated through offspring obesity. However, direct cardiovascular and metabolic programming effects of maternal obesity during pregnancy may also be present . Animal Thus, multiple mechanisms may be involved in the intra-uterine pathways leading from maternal obesity and excessive weight gain during pregnancy to long-term adverse offspring health outcomes.Current evidence from epidemiological studies suggests that maternal obesity and excessive weight gain during pregnancy have important adverse consequences on cardiovascular and metabolic development from fetal life onwards, leading to disease in later life. Yet, there remain important issues to be addressed. These include identification of the extent of causality of the observed associations, the underlying exposures and their critical periods, the developmental adaptations, and the potential for development of preventive strategies Table\u00a0.Table\u00a03KFirst, despite extensive adjustment for potential confounding factors in these observational studies, residual confounding may still be an issue. The causality of the observed associations needs to be further addressed. Large observational studies that are able to apply more sophisticated methods, such as parent-offspring comparison studies, sibling comparison studies and Mendelian randomization-studies are needed to obtain further insight into the causality of the associations of interest. Long-term follow-up of participants in trials focused on reducing maternal weight throughout pregnancy will also provide further insight into the causality. Large meta-analyses are needed to obtain further insight into the strength, consistency and independency of the associations.Second, the underlying mechanisms of the observed associations of maternal obesity during pregnancy with offspring health outcomes remain unclear. Animals studies have identified multiple pathways that may be involved in these associations, but these pathways remain largely unexplored in humans. Maternal prepregnancy obesity and excessive gestational weight gain are complex traits, which reflect multiple lifestyle-related and biological components, which complicates identification of potential underlying pathways. Future studies may benefit from detailed assessments of the studied exposures and outcomes throughout the life-course, which could provide further insight into potential underlying mechanisms. Studies with repeated maternal weight measurements during pregnancy available can identify critical periods of maternal weight gain. To obtain further insight into the different components associated with offspring outcomes, studies are needed with more detailed measurements of maternal nutritional status, body composition, metabolic and inflammatory measures, pregnancy-related hemodynamic adaptations and fetal growth. For the offspring outcomes, more detailed measurements of growth, body composition and cardio-metabolic factors, including cardiac structures, endothelial function, pulse wave velocity, lipid spectrums and glucose responses, might also lead to further insight into the underlying growth, vascular and metabolic mechanisms present in the observed associations. Since early pregnancy appears to be a critical period for offspring outcomes, studies are needed with detailed maternal measurements from early pregnancy onwards to already assess their influence on placental and embryonic growth and development. Long-term follow up of participants in observational studies is needed to assess the influence on the risk of obesity and related cardio-metabolic disorders throughout the life-course. In addition, it is of interest to conduct follow-up studies of the third generation offspring from these large observational studies, as this may provide further insight into the intergenerational effects of maternal obesity during pregnancy on especially female offspring.Third, further research is needed focused on prevention of adverse health outcomes in offspring through optimizing maternal prepregnancy body mass index, weight gain and diet during pregnancy. Studies are needed to assess the optimal amounts of maternal weight gain for short-term and long-term maternal and offspring health outcomes to further improve the IOM recommendations for gestational weight gain. Identification of specific maternal dietary components associated with offspring health outcomes is needed to improve maternal dietary recommendations during pregnancy. Long term follow up of mothers and their children participating in randomized trials focused on improving maternal diet and reducing maternal weight throughout pregnancy will provide insight into the effectiveness of these maternal lifestyle interventions during pregnancy for improving long-term health of offspring.Maternal prepregnancy obesity and excessive weight gain during pregnancy seem to be important risk factors for an adverse in utero environment and long-term adverse cardiovascular and metabolic outcomes in the offspring. Well-designed epidemiological studies are needed to identify the extent of causality of the observed associations, the underlying exposures and their critical periods, the developmental adaptations, and the potential for development of preventive strategies to improve long-term health outcomes of offspring."}
+{"text": "High cross-taxon congruence in species diversity patterns is essential for the use of surrogate taxa in biodiversity conservation, but presence and strength of congruence in species turnover patterns, and the relative contributions of abiotic environmental factors and biotic interaction towards this congruence, remain poorly understood. In our study, we used variation partitioning in multiple regressions to quantify cross-taxon congruence in community dissimilarities of vascular plants, geometrid and arciinid moths and carabid beetles, subsequently investigating their respective underpinning by abiotic factors and biotic interactions. Significant cross-taxon congruence observed across all taxon pairs was linked to their similar responses towards elevation change. Changes in the vegetation composition were closely linked to carabid turnover, with vegetation structure and associated microclimatic conditions proposed causes of this link. In contrast, moth assemblages appeared to be dominated by generalist species whose turnover was weakly associated with vegetation changes. Overall, abiotic factors exerted a stronger influence on cross-taxon congruence across our study sites than biotic interactions. The weak congruence in turnover observed particularly between plants and moths highlights the importance of multi-taxon approaches based on groupings of taxa with similar turnovers, rather than the use of single surrogate taxa or environmental proxies, in biodiversity assessments. Obtaining a good understanding of the mechanisms that underlie species richness and species composition presents one of the most significant challenges facing ecologists, biogeographers and conservation planners alike13485610Previous studies of diversity congruence have primarily focused on \u03b1-diversity within natural or semi-natural ecosystem, while few studies have focused on the effects of anthropogenic disturbance gradient on cross-taxa congruence in species turnover patterns121313861110186131721High cross-taxon congruence has been related both to similarities in the response patterns of these taxa to changes in environmental variables and to biotic interactions5192324212235242891322302662233Our study builds on earlier investigations showing that the \u03b1-diversity patterns of four taxonomic groups, vascular plants and three insect taxa , are highly non-congruent in our study area composed of plots situated along both altitudinal and anthropogenic gradients in an anthropogenically transformed mountainous landscape matrix5In establishing the degree of cross-taxon congruence in species turnover patterns across these four taxonomic groups, we particularly focused on the partial contributions of environmental factors and biotic interactions. We first of all hypothesize that a strong congruency exists between vascular plants and carabid beetles. Both taxa are chiefly composed of weak dispersers, with plants strongly relying on passive dispersal and with most carabid species known to chiefly disperse over limited distances of only up to 50\u2009mWe recorded a total of 415 vascular plant species, while 14692 specimens representing 110 species of geometrids and 1543 individuals representing 20 arctiinid species were caught in light traps, and 3663 carabids representing 73 species were sampled in the pitfall traps. Each study site and habitat had its own, unique species of vascular plants. For carabids, all study sites, but not all habitat types at all sites contained unique species. For geometrids, only woodland and grassland habitats harbored unique species. Two sites, Dayushu and Gaojiaying, and none of the habitats harbored unique arctiinid species .The non-metric multidimensional scaling (NMDS) showed that both moth assemblages formed very distinct study site-specific clusters . A clearThe turnover in all taxonomic groups was significantly correlated with elevation and also the habitat type \u2018cultivated land\u2019, with the latter being particularly significant for vascular plants and carabids (P\u2009<\u20090.001). Additionally, vascular plants were significantly correlated with all environmental variables except soil texture and landscape diversity (SHDI). Apart from elevation and cultivated land, carabid turnover was also significantly linked to the % of semi-natural land area (SNP), while arctiinid turnover was additionally correlated with changes in total N and soil texture .All comparisons of turnover patterns between pairs of taxa showed significant positive correlations in There are two contrasting views on the role of environmental conditions on cross-taxon congruence. A range of studies links significant cross-taxon congruence to common response patterns of the different taxa to changes in key environmental factors1618191017The most important environmental determinant of turnover across taxa was elevation, which commonly represents a whole array of environmental factors. These include temperature, radiation and barometric pressure, which all show monotonic responses to changes in elevation, as well as precipitationBeyond the influence of elevation, the strong overall congruence observed between the turnover in vascular plants and carabids can be explained by both of them additionally reacting strongly towards a similar set of additional environmental variables, particularly to land cultivation and the proportion of semi-natural land present in the plot vicinity. These parameters chiefly reflect the anthropogenic disturbance gradient, with the results confirming our expectations. Cultivation impacted on the species composition of both vascular plants and carabids due to its direct associations with habitat management43Biotic interactions, including trophic interactions, host\u2013parasitoid interactions, but also intraspecific interactions at the same trophic level, may promote cross-taxon congruence112416In contrast to our second hypothesis and these studies, the assemblage structure of the two herbivorous moth taxa which rely heavily on the vegetation as key food resource for their caterpillars and as nectar source of adult moths5292836et al.et al.et al.With most ground beetles being predatory or omnivorous244244Our results are indicative of a highly complex and variable interplay of environmental factors and potential biotic interaction in explaining cross-taxon congruence in turnover patterns of the investigated taxon pairs. These differentiations are also expected in relation to spatial scales and biogeographic processes acting within them21025Spatial differentiations in species assemblages also strongly relate to dispersal limitations, with the species composition between two sites generally increasing in dissimilarity with increased geographic distance26134A key finding of our study is the low congruence between vascular plants and herbivorous, pollinating moth taxa in this anthropogenically transformed landscape matrix, especially once the influence of abiotic factors is controlled for. Previous studies across a variety of taxonomic groups, natural ecosystems and spatial scales, have also reported low cross-taxon congruence of species turnover patterns between insect and other taxa or between different groups of insects49172021459132417However, our results also indicate that the subset of taxa could be representative of biodiversity4et al.Our study was conducted at four distinct sites in our large study region  located within the mountain ranges between Beijing and the Inner Mongolian Plateau in northern China. The four study sites were located within the vicinity of four villages  situated at elevations of about 500\u2009m, 900\u2009m, 1400\u2009m and 1650\u2009m, and therefore covering substantial proportions of the regional elevation gradient. Three representative habitat types were subsequently selected at each site according to the prevailing management intensity, natural vegetation and farming regime  placed above a plastic funnel leading into a plastic bucket. The weak light source allows targeted attraction of moths from the direct vicinity of the trapet al.The exact latitude, longitude and elevation of each plot were established using maps and a Garmin GPS III. Differences in latitude and longitude between plots were subsequently transformed into geographic distances and treated separately, while changes in elevation were jointly considered with the other environmental parameters in the analysis. Five soil samples were randomly taken from the upper 20\u2009cm of the mineral soil at each plot and then mixed. These samples were analyzed for their contents in SOM, total nitrogen, and soil pH  which we used here, the index provides an overview of changes in the structure of the entire assemblage. To investigate changes in vascular plant assemblages where complete sampling can be assumed, a S\u00f8rensen dissimilarity matrix based on presence\u2013absence data of all plant species per plot was calculated. All dissimilarity matrices were computed using COMPAH96Dissimilarities of species composition between sampling plots for each of the three insect taxa were calculated based on the Chord-Normalized Expected Species Shared  index. This index is particularly tailored for cases where samples are incomplete, contain many rare species and are of different size and diversityWe tested the correlation between the dissimilarity matrices for each taxon and each environmental distance matrices using partial Mantel tests. When significant spatial correlationsin species turnover patterns were found across all four taxa , the geoWe finally used variation partitioning in a series of Multiple Regressions on distance matrices (MRMs) to quantify the proportion of variation in taxonomical dissimilarity between plots that can be explained by the dissimilarity matrix of another taxon, as well as by geographic and environmental distanceet al.We therefore adopted the procedure introduced by Jones All mantel tests and MRMs were calculated using the Ecodist-PackageHow to cite this article: Duan, M. et al. Disentangling effects of abiotic factors and biotic interactions on cross-taxon congruence in species turnover patterns of plants, moths and beetles. Sci. Rep.6, 23511; doi: 10.1038/srep23511 (2016)."}
+{"text": "Advances in optical coherence tomography have enabled a better appreciation of the role of pathologic choroidal changes in a variety of retinal disease. A \u201cpachychoroid\u201d (pachy-[prefix]: thick) is defined as an abnormal and permanent increase in choroidal thickness often showing dilated choroidal vessels and other structural alterations of the normal choroidal architecture. Central serous chorioretinopathy is just one of several pachychoroid-related macular disorders. This review summarizes the current state of knowledge of the pachycoroid spectrum and the hallmark features seen with multimodal imaging analysis of these entities Rapid progress in retinal imaging has provided new insights into a variety of chorioretinal disorders. Advances in optical coherence tomography (OCT) are perfect examples of this trend. Following the first descriptions of retinal OCT imaging \u20133, the sThree different layers of choroidal tissue may be differentiated between Bruch\u2019s membrane and the sclera-choroidal junction: choriocapillaris is the innermost portion; Sattler\u2019s layer, composed of small oval vascular patterns, and Haller\u2019s layer consisting of large outer oval vascular patterns . This quThe term pachychoroid (pachy-[prefix]: thick) was proposed as a term indicating an abnormal and permanent increase in choroidal thickness, This entity often occurs in eyes with central serous chorioretinopathy (CSC) or CSC-like features \u201319. EyesCentral Serous ChorioretinopathyCentral serous chorioretinopathy is characterized by the presence of subretinal fluid often associated with serous pigment epithelial detachment (PED). Abnormalities of the choroidal circulation are believed to play an important role in the pathophysiology of this entity. Choroidal congestion and hyperpermeability have been frequently described in this disease \u201322. The Pachychoroid Pigment Epitheliopathyformae frustae of CSC, similar in nature to the findings often seen in the fellow eye of patients presenting with unilateral acute CSC.Pachychoroid pigment epitheliopathy (PPE) is a newly described entity with characteristic features on multimodal imaging of the macula . This enFundus examination often shows an orange-reddish appearance and absence of normal tessellation what indicates an underlying pachychoroid. Present changes in pigment include: RPE alterations that might be mistaken for age-related maculopathy (ARM), a pattern dystrophy of the RPE or non-neovascular age-related macular degeneration (AMD). These changes may include sub-RPE deposits similar in appearance to typical drusen.OCT imaging shows numerous, scattered small elevations of the RPE representing RPE hyperplasia and sub-RPE drusen-like deposits . OccasioIndocyanine green angiography (ICGA) reveals choroidal hyperpermability as mid-phase hyperfluorescence that co-existent with the areas of RPE disturbances.Fundus autofluorescence shows areas of granular hypoatuofluorescence and mixed stippled hyper- and hypoautofluorescence. Signs of antecedent subretinal fluid, such as gravitational tracts, zonal areas of hyperautofluorescence or focal areas of speckled hyperautofluorescence are never seen in PPE.Pachychoroid NeovasculopathyPachychoroid neovasculopathy (PNV) is considered a late complication of PPE and chronic CSC in patients who presumably carry a genetic risk for choroidal neovascularization . The uniOptical coherence tomography imaging in PNV shows a broad shallow elevation of the RPE representing neovascular proliferation within Bruch\u2019s membrane (26). This form of type 1 neovascularization is typically found overlying an area of localized choroidal thickening with dilated choroidal vessels .Indocyanine green angiography often shows both mid-phase patchy areas of choroidal hyperpermability and a discrete plaque of late hyperfluorescence corresponding to type 1 neovascular tissue.Eventually, polypoidal choroidal vasculopathy (PCV) may develop, within or at the margins of the slow-growing type 1 neovascular tissue. The polyps may produce an exudative maculopathy that includes both lipid deposition and hemorrhagic complications. The polyps are easily identified with ICGA as early focal areas of intense hyperfluorescence that may show either late leakage or \u201cwash-out\u201d appearance depending on their degree of activity.Enhanced depth imaging and SS OCT have enabled a better appreciation of the role of pathologic choroidal changes in CSC. Furthermore, they have helped defining an expanded spectrum of pachychoroid-related macular disorders. Recognition of these entities is important as they may mimic other diagnoses that have different natural courses and treatments. For example, the clinical appearance of PPE may simulate ARM, AMD, or pattern dystrophies. Similarly, without choroidal imaging, PNV may easily be mistaken for neovascular AMD.sui generis.The occurrence of PCV in eyes with PNV adds further evidence that PCV is a natural evolution of type 1 neovascular proliferation rather than a disease In our experience, eyes with exudation due to PNV, irrespective of the presence of PCV, are more resistant to anti-vascular endothelial growth factor (anti-VEGF) agents than eyes with choroidal neovascularization (CNV). This is presumably due to the typical AMD and myopic macular degeneration. Thus, the recognition of an underlying pachychoroid in neovascularized maculo- pathies may have important implications regarding their management. Since the photodynamic therapy is intended to reduce choroidal thickness and hyperpermeability, it surely warrants further exploration ,30."}
+{"text": "Upper tract urothelial carcinomas (UTUC) have high prevalence rates in patients with chronic kidney disease (CKD), including dialysis patients and kidney transplant recipients. Analgesic nephropathy, Balkan endemic nephropathy, and aristolochic acid (AA) nephropathy share the common association with the development of CKD and UTUC. Genome studies allow identification of patients with genetic predisposition to Balkan endemic nephropathy and AA nephropathy. Furthermore, the identification of aristolactam deoxyribonucleic acid (DNA) adducts now provides robust evidence for AA exposure in UTUC patients, even in the absence of recallable exposure history. Diagnosis and treatment of UTUC in CKD patients are challenging. Clinical diagnosis of UTUCs in CKD patients with the available urological and imaging methods is much more difficult than in patients with normal renal function due to atrophic kidneys and poor excretory functions in these patients. High prevalence rates of contralateral upper tract and urinary bladder involvements of UC in CKD, either at presentation or recurrence, raise concerns of the necessity and techniques as well as perioperative risk of complete urinary tract exenteration. The standard treatment of radical nephroureterectomy with bladder cuff excision for UTUC patients may result in deterioration of renal function, rendering adjuvant chemotherapy unsuitable. This special issue collectively addresses these important topics regarding UTUC in CKD patients.The authors in one paper nominate three mutant genes  in Balkan endemic nephropathy patients, which are associated with angiogenesis. This finding suggests that angiogenesis might play an important role in the development of Balkan endemic nephropathy. Another paper shows an elevated risk of urothelial carcinomas (UC) in ESRD patients with the analysis of a national wide cohort in Taiwan. Female patients have 9\u201318 folds of increased risk of UC as compared to 4\u201314 folds in male ESRD patients, which may reflect female predominance in AA consumption. One paper discusses the challenges of UTUC diagnosis in CKD patients. It reviews the detection rate of UTUCs in dialysis patients and kidney transplant recipients with the use of a variety of imaging and urological methods in the literature. Combination use of urological and imaging methods has been suggested for diagnosing UTUCs in symptomatic dialysis patients and kidney transplant recipients.Another paper develops a predictive model for postoperative renal insufficiency in UTUC patients undergoing radical nephroureterectomy, which help in selecting eligible patients for cisplatin based adjuvant chemotherapy. Older age, lower estimated glomerular filtration rate before surgery, smaller tumor size, renal pelvis tumor, and absence of hydronephrosis or multifocal tumors are predictors for ineligibility for adjuvant chemotherapy. One paper describes modified incision complete urinary tract exenteration for UC in dialysis patients, providing short operative time, early oral feeding, and no major perioperative complications of this modified surgical procedure. Another paper reviews epidemiological evidence of AA exposure associated with occurrence of nephropathy and UC, including AA exposure scenarios in Belgium, Taiwan, and the Danube River as well as occupational exposure in Chinese herbalists. The identification of aristolactam DNA adducts in these patients further corroborates biological plausibility of AA exposure contributing to the occurrence of UTUC.Li-Jen\u2009\u2009WangJo\u00eblle L.\u2009NortierBin\u2009\u2009Tean\u2009\u2009TehCheng-Keng\u2009\u2009ChuangShen-Yang\u2009\u2009Lee"}
+{"text": "Tuberculosis (TB) remains a major global health problem, because (i) diagnosis is usually made too late to avoid spread of infection to contacts; (ii) vaccination with bacillus Calmette\u2013Gu\u00e9rin (BCG) does not prevent the most prevalent pulmonary disease; and (iii) defaulting from lengthy chemotherapy leads to an increase in drug resistant strains. The continued impact of human immunodeficiency virus (HIV) co-infections remains a major aggravating factor in TB resurgence. Intensive research on the specificity and function of immunological responses is of major importance since protective host defense is critically dependent on T cells, which selectively recognize only certain antigens and epitopes of the tubercle bacillus. Such knowledge is therefore necessary for designing a novel effective vaccine and better diagnostic tools. The specificity of the host immune response may also help to explain how the intracellular tubercle bacilli evade host resistance, probably by decoy pro-inflammatory actions of some of their antigens and/or immunomodulatory constituents, which lead to chronic infection and lung pathology.Mycobacterium tuberculosis (Mtb). The abundant occurrence of major histocompatibility complex (MHC) class II-permissive epitopes in tubercle bacilli has important implications for the development of both subunit vaccines and diagnostic tests  proteins, and new HLA-class Ia or Ib (HLA-E) restricted Mtb epitopes, recognized by classical and non-classical CD8 T cells . Several test kits can detect latent Mtb infection with better specificity than the tuberculin based skin test. However, these kits still need improving on their sensitivity and fail to distinguish active TB from latent infection. Moreover, biomarkers for predicting the risk of latent TB progressing into active TB are yet to be found (be found , 3, 4. Fbe found .Identifying those antigenic determinants, which lead to host protection, is mandatory for designing more effective vaccination strategies. A recently failed vaccine trial in children employed Ag85A, which is highly immunogenic, but changes in its expression in infected cells could influence the susceptibility of infected cells to host immunity . Hence, Although classical CD4 and CD8 T cells recognize peptide epitopes bound to MHC, molecules with different chemical structures could be of potential importance. Thus, T cells recognizing lipid antigens may contribute to natural host protection and might potentially be exploited for subunit based vaccination . AnotherIn conclusion, further research on Mtb antigen and epitope specificities seems mandatory for realizing the crucially important aims of both prophylactic and post exposure vaccination against TB. Advancing the knowledge of antigenic determinants is essential also for differentiating patients with active TB from latently infected healthy subjects. There is potential in the ambitious search for specific immunological biomarkers for predicting the reactivation of TB in populations, both without and with HIV infection. These endeavors will undoubtedly need to be combined with better knowledge of the functional phenotypes of the respective T cell subsets. Other potential avenues are the construction of fusion proteins with improved vaccine adjuvanticity  and the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Most health-care professional training programs lack educational curricula on substance use disorders and strategies for early intervention or referral to treatment. The University of Missouri-Kansas City Screening, Brief Intervention and Referral to Treatment (UMKC-SBIRT) training project educates baccalaureate nursing, advanced practice nursing, and master\u2019s of social work students through didactics threaded throughout coursework; role-plays with classmates and faculty; standardizes patient practice; and offers clinical experience to help students achieve competency.In year one of the training grant, students completed surveys prior to, immediately after, and 30 days after SBIRT training. Surveys covered attitudes and knowledge. Skills were assessed by expert coding of an audiotaped interaction with a standardized patient actor using an SBIRT fidelity scale. Qualitative feedback regarding training experience, knowledge, and attitudes was collected at post-training focus groups.Students showed increased knowledge of SBIRT, improved perceptions toward working with patients who use substances, increased comfort in dealing with substance use issues, and progress in developing skills to provide SBIRT interventions.Training on SBIRT can be readily implemented into nursing and social work education, improving future health professionals\u2019 perceptions and providing a valuable skill through which they can help patients lead healthier lives."}
+{"text": "During aging, many neurodegenerative disorders are associated with reduced neurogenesis and a decline in the proliferation of stem/progenitor cells. The development of the stem cell (SC), the regenerative therapy field, gained tremendous expectations in the diseases that suffer from the lack of treatment options. Stem cell based therapy is a promising approach to promote neuroregeneration after brain injury and can be potentiated when combined with supportive pharmacological drug treatment, especially in the aged. However, the mechanism of action for a particular grafted cell type, the optimal delivery route, doses, or time window of administration after lesion is still under debate. Today, it is proved that these protections are most likely due to modulatory mechanisms rather than the expected cell replacement. Our group proved that important differences appear in the aged brain compared with young one, that is, the accelerated progression of ischemic area, or the delayed initiation of neurological recovery. In this light, these age-related aspects should be carefully evaluated in the clinical translation of neurorestorative therapies. This review is focused on the current perspectives and suitable sources of stem cells (SCs), mechanisms of action, and the most efficient delivery routes in neurorestoration therapies in the poststroke aged environment. With an increased aging population, the prevalence of age-related diseases will increase. The aging process is associated with a higher risk factor for stroke in both men and women and remains an important health issue without an accepted therapeutic strategy, except thrombolysis with recombinant tissue plasminogen activator for ischemic stroke , 2. StudStem cell therapy is focused on the functional improvement in the early stages after stroke rather than tissue replacement. Also, due to plastic capacity and tropism for damaged tissue, stem cells can be a useful tool for gene therapy in regenerative medicine , 9. CellAccording to their source, stem cells can be obtained from blastocyst cells (embryonic stem cells (ESCs)), adult stem cells (bone marrow derived stem cells (BMSCs) derived from peripheral blood or other tissues like adipose tissue), umbilical cord blood cells, and induced pluripotent stem cells (iPSCs). Bone marrow mononuclear cells (BM-MNCs), bone marrow derived mesenchymal stem stromal cells (BM-MSCs), umbilical cord stem cells (UCSCs), and neural stem cells (NSCs) are the most promising cells for recovery after cerebral ischemia. However, stem cells must be fully investigated for safety and therapeutic potential on animal models of neurological diseases in order to use it for clinical applications.Bone marrow derived mononuclear cells (BM-MNCs) are a promising tool for acute stroke therapy, but most preclinical trials were performed using young animals without comorbidities. Preclinical pilot studies using autologous BM-MNCs have already been performed. In one study, Savitz and colleagues showed that the IV administration of BM-MNC extracted from the iliac crest is safe and feasible in stroke patients between 18 and 80 years old . HoweverAlso, the administration route has a greater impact on the biodistribution, migration, and survival of transplanted stem cells. Using single photon emission computed tomography/computed tomography (SPECT/CT) and helical CT scan after intra-arterial (IA) and intravenous (IV) administration of BM-MNCs and BM-MSCs, M\u00e4kel\u00e4 end colleagues showed that the BM-MNCs accumulated in the spleen and bones and the BM-MSCs had relatively higher uptake in the kidneys. The IA transplantation decreased the deposition of BM-MSCs in the lungs and increased uptake especially in the liver. However, both administration routes using porcine model were found to be safe . IntrastIntrastriatal administration of the stem cell (SC) in the aged rats with striatal infarct leads to an elevated cell density in the ischemic area and can be monitored by magnetic resonance imaging (MRI). Injection of NPCs into lesioned striatum promotes a hypothetical neuronal network weeks later that can improve functional outcome .Preclinical data suggests that autologous bone marrow derived mononuclear cell therapy attenuates the effects of inflammation in the early posttraumatic brain injury period .One clinical trial indicated that the IV administration of 280.75 million BM-MNCs at 18,5 days after stroke onset is safe, but there is no beneficial effect of treatment on stroke outcome . Also, WIn the last decade, cells derived from the human umbilical cord (HUC) have emerged as a potential therapeutic alternative for stroke because of their capacity to differentiate into neural progenitor cells and their unlimited availability. Umbilical cells consist of a mixture of both hematopoietic stem cells (HSCs) and mononuclear fraction of mesenchymal stem cells (MSCs). An advantage of umbilical cord blood (UCB) derived cells is that the regulatory T-cells administration (1\u20135% from HUC cells) can prevent graft versus host diseases and can improve neurogenesis in the aging brain , 19.Studies on HUC-derived cell population in rat model showed that the IA administration of cord blood mononuclear cells (cbMNCs) and cord blood mesenchymal stromal cells (cbMSCs) at 24\u2009h after stroke onset is associated with a reduction in neurological deficit and infarct area . Also, icbMNCs tend to restore the reduction of brain-derived neurotrophic factor (BDNF) level after stroke, increase the glutathione peroxidase-4 (GPx-4) mRNA expression, and decrease the number of activated microglia resulting in decreased neuroinflammation and neuronal cell death and increased neurologic recovery , 22.Wharton's jelly, part of the umbilical cord, contains myofibroblast-like stromal cells originated from mesenchyme that possess many unexplored advantages compared with adult stem cells. Wharton's jelly derived cells may secrete macromolecules like glycoproteins, mucopolysaccharides, glycosaminoglycans, or extracellular matrix proteins and showed capacity to differentiate into neural progenitor cells which improved neovascularization, myelination, and neurogenesis in an animal model of stroke \u201325.However, other studies using cryopreserved cbMNC failed to demonstrate neurorestorative properties in spontaneously hypertensive rats (SHR) stroke model .Adipose derived stem cells (ASCs) can be obtained from adipose tissue with minimal side effects and are able to differentiate into multiple cells that play an important role in the recovery of damaged tissue. Studies before have showed that the ASCs, in specific condition, can differentiate into the cells that express neuronal markers (NeuN and nestin) and glial markers  . In anim\u03b2) that can be increased in hypoxic conditions  [ASCs were found to produce different growth factors like vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor (TGF- stroke) , 29. In  stroke) .The recently discovered possibility to reprogram human adult somatic cells (iPS) has added a very exciting tool to the profile of the available SC and provided new perspective for neurorestorative therapy. iPS possess the potential and characters of embryonic stem cells, self-renewal and pluripotency, which allow the production of unlimited amount of precursor cells or all cell types of the body. On the other side, iPS allow the possibility to create biobanks and to avoid graft rejection. An advantage is that iPS can be obtained from blood cells and fibroblasts that are easily accessible. Chau and colleagues proved that the iPS can improve recovery after stroke in neonatal rats (P7) and adult brain by multiple mechanisms that promote angiogenesis and neurogenesis and provide essential trophic factors \u201334. HoweDespite these exciting findings, these studies still lack proof of mechanisms of iPS that promote the improvement of functional outcome after stroke in aged brain.Although rehabilitation is important for improving functional recovery in the early stages after stroke, it does not provide a replacement for the lost neuronal cells and ultimately brain function. Neural tissue transplantation has been first explored as an experimental technique for tissue repair and functional recovery after stroke \u201339. The Many studies report that stem cell therapy in combination with other compounds appears to be more effective than monotherapies alone. Our group showed that the combination of BM-MSCs with granulocyte colony-stimulating factor (G-CSF) promotes angiogenesis in the ischemic area of the aged brain, without significant improvement of cognitive function , 44.Association of UCB cells with G-CSF was showed to reduce neuroinflammation, enhance neurogenesis, and improve functional outcome after traumatic brain injury (TBI) , 46.The study by Cui et al. revealed that a combination of subtherapeutic doses of UCB cells and simvastatin amplified endogenous angiogenesis and increased and enhanced vascular remodeling by increasing Ang1/Tie2 signalling pathway in the ischemic brain .Gene therapy has been described as a powerful tool in treating nerve injury. Pereira and colleagues showed that the vascular endothelial growth factor (VEGF) gene and granulocyte colony-stimulating factor (G-CSF), delivered using endothelial progenitor cells (EPCs), promote regeneration and improve functional outcome , 49.VEGF delivery using endothelial progenitor cells (EPCs) was found to increase migration and proliferation of human endothelial cells after ultrasonic microbubble transfection . EPCs caThe efficacy of stem cell therapies so far is discouragingly low mainly because the time course of interactions between host neuroinflammatory response, the main obstacle to exogenous-mediated neuronal precursor cells, and exogenously administered stem cells is still unknown. Although MSC transplantation into the brain has ascribed beneficial effects in preclinical studies of neurodegenerative or neuroinflammatory disorders , 54, onlTo conclude, these findings strongly suggest that UCB derived cells have significant neurogenic potential but this potential has to be used in a more efficient manner to treat neurological diseases like stroke in aged people. Antineuroinflammatory therapies are a potential target to promote regeneration and repair in diverse injury and neurodegenerative conditions by stem cell therapy. Therefore, the challenge now is to determine in detail the cross talk between different populations of immune cells and grafted neural stem progenitor cells (NSPCs) at different phases after stroke in aged brain. In"}
+{"text": "Phragmites australis over four years to determine their effects on potential denitrification rates relative to three untreated Phragmites sites and adjacent sites dominated by native Typha angustifolia. Sediment ammonium increased following the removal of vegetation from treated sites, likely as a result of decreases in both plant uptake and nitrification. Denitrification potentials were lower in removal sites relative to untreated Phragmites sites, a pattern that persisted at least two years following removal as native plant species began to re-colonize treated sites. These results suggest the potential for a trade-off between invasive-plant management and nitrogen-removal services. A balanced assessment of costs associated with keeping versus removing invasive plants is needed to adequately manage simultaneously for biodiversity and pollution targets.Establishing relationships between biodiversity and ecosystem function is an ongoing endeavor in contemporary ecosystem and community ecology, with important practical implications for conservation and the maintenance of ecosystem services. Removal of invasive plant species to conserve native diversity is a common management objective in many ecosystems, including wetlands. However, substantial changes in plant community composition have the potential to alter sediment characteristics and ecosystem services, including permanent removal of nitrogen from these systems via microbial denitrification. A balanced assessment of costs associated with keeping and removing invasive plants is needed to manage simultaneously for biodiversity and pollution targets. We monitored small-scale removals of  Invasive species are often presumed to degrade ecosystem functioning. By causing local extinctions, invasives are thought to reduce biodiversity , which iPhragmites australis  were analyzed with a one-way ANOVA. A separate two-way ANOVA was used to compare Phragmites and Typha communities sampled at the reference sites at two additional sampling times . Measurements of sediment nitrogen and carbon collected August 2010-September 2012 were also analyzed with a two-way ANOVA to compare the three dominant vegetation groups. For each two-way ANOVA, potential interactions between vegetation type and sampling time were tested for significance.Differences in plant traits  measured in September 2012 among the three dominant vegetation types  that were sampled across all \u201csampling times\u201d , both before and after herbicide treatment. For these ANOVAs, significant impacts of herbicide treatment on dependent variables  were tested as planned comparisons within the interaction term (treatment x sampling time). In the second statistical design, we compared four treatments  for sampling times that occurred after herbicide treatment . For these ANOVAs, significance of herbicide treatment was assessed for the dependent variables listed above and additional measurements added in 2011 [total organic carbon and nitrogen content of sediments] using planned comparisons of treatments.Measurements of denitrification potential, sediment porewater nutrients, and total sediment organic content were analyzed at the stand scale using two-way ANOVA. Because the \u201cReference-The sediment properties and processes we measured are notoriously variable as a result of measurement difficulties and spatial variability , and samPhragmites sampling times were used to test for significant differences between sites where Phragmites was removed relative to sites where Phragmites was left intact. Planned comparisons of Reference-Typha and Reference-Phragmites were used to test whether sites dominated by plant species differed when left undisturbed. Though we attempted to control for phenology by sampling at peak biomass in each of our sampling years (late August/early September), we acknowledge that other factors such as temperature may influence sediment chemistry and microbial activity. The sampling conducted in June 2012 was added to provide further insight into the short-term trajectory of sediment recovery in treated sites. Planned comparisons of treatment and reference sites statistically control for interannual and seasonal variability when detecting treatment effects. All statistical analyses were performed in JMP [Planned comparisons of Ramshorn-Removal and Reference-d in JMP . Graphs d in JMP . CompletPeltandra virginica . For Phragmites-dominated communities, this correlation was weak and of small effect  across all treatments throughout our study. Therefore, only results of porewater ammonium are reported. Following initial herbicide treatment, porewater ammonium concentrations in removal sites increased by over an order of magnitude relative to all vegetated sites .Phragmites-dominated reference locations Click here for additional data file."}
+{"text": "Perineuronal nets (PN) form a specialized extracellular matrix around certain highly active neurons within the central nervous system and may help to stabilize synaptic contacts, promote local ion homeostasis, or play a protective role. Within the ocular motor system, excitatory burst neurons and omnipause neurons are highly active cells that generate rapid eye movements \u2013 saccades; both groups of neurons contain the calcium-binding protein parvalbumin and are ensheathed by PN. Experimental lesions of excitatory burst neurons and omnipause neurons cause slowing or complete loss of saccades. Selective palsy of saccades in humans is reported following cardiac surgery, but such cases have shown normal brainstem neuroimaging, with only one clinicopathological study that demonstrated paramedian pontine infarction. Our objective was to test the hypothesis that lesions of PN surrounding these brainstem saccade-related neurons may cause saccadic palsy.Together with four controls we studied the brain of a patient who had developed a permanent selective saccadic palsy following cardiac surgery and died several years later. Sections of formalin-fixed paraffin-embedded brainstem blocks were applied to double-immunoperoxidase staining of parvalbumin and three different components of PN. Triple immunofluorescence labeling for all PN components served as internal controls. Combined immunostaining of parvalbumin and synaptophysin revealed the presence of synapses.Excitatory burst neurons and omnipause neurons were preserved and still received synaptic input, but their surrounding PN showed severe loss or fragmentation.Our findings support current models and experimental studies of the brainstem saccade-generating neurons and indicate that damage to PN may permanently impair the function of these neurons that the PN ensheathe. How a postulated hypoxic mechanism could selectively damage the PN remains unclear. We propose that the well-studied saccadic eye movement system provides an accessible model to evaluate the role of PN in health and disease. Saccades are rapid conjugate eye movements that bring target images onto the fovea for exploring visual scenes, reading, and resetting the eyes during optokinetic or vestibular nystagmus. Two critical components of the brainstem saccade network are premotor burst neurons (PBN) and omnipause neurons (OPN). PBN include excitatory burst neurons (EBN) and inhibitory burst neurons (IBN) firing up to 1,000 spikes/s during saccades  and in tPerineuronal nets (PN) are condensed, extracellular matrices of macromolecules ensheathing fast-firing neurons such as PBN and OPN. PN consist of a hyaluronic acid backbone attached to glycoproteins and chondroitin sulfate proteoglycans (CSPG) such as aggrecan (ACAN) and hyaluronan and proteoglycan link protein (HPLN1) . PN may Infarction, metabolic or degenerative disorders targeting PBN or OPN may slow or abolish saccades \u201313. DrawSimilar cases have been reported without neuropathologic evaluation \u201326, typiA previously reported  healthy Ten months postoperatively, general neurological examination was notable only for diffuse hyporeflexia. Visual acuity, pupils, visual fields, and fundoscopic examination were normal. Straight-ahead fixation was steady, and no saccadic intrusions or nystagmus were seen with ophthalmoscopy. She made no reflexive saccades, and volitional saccades consisted of extremely slow eye movements that eventually reached the target, except for slightly faster downward saccades . PursuitEye movements were recorded with video-oculography. Horizontal saccades were absent during a random saccade paradigm, but sinusoidal smooth pursuit was normal across all frequencies tested. Vertical eye movements demonstrated similar findings. Additionally, rotary chair sinusoidal vestibular and optokinetic testing generated normal vestibular slow phases and optokinetic ocular following reflex, but absent vestibular and optokinetic quick phases of nystagmus.The patient was last examined two years later and was clinically unchanged except for some emerging memory complaints. She remained on warfarin for her mechanical valve. Subsequently, she developed cirrhosis attributed to increasing alcohol abuse. Memory loss remained mild. Eight years after her cardiac surgery, with an increased bleeding diathesis from over-anticoagulation and liver dysfunction, she developed massive hematemesis and melena from a bleeding peptic ulcer, profound anemia, shock, renal failure, and somnolence. She expired in hospice one week later.ex vivo 7 tesla MRI, as previously described [The whole brain was collected the day of death and fixed in 10% formalin for 2 weeks. Next, the brain was suspended in Fomblin  for escribed . After r2O2 resulting in a bluish-black reaction product [After deparaffinizing and antigen retrieval by boiling the sections 3x10 minutes in a microwave in 0.01M citrate buffer (pH 6) the slides were transferred to 0.1M phosphate-buffered saline . Saccade-related neurons were identified by immunostaining with mouse monoclonal antibodies directed against non-phosphorylated neurofilaments  and the calcium-binding protein parvalbumin . Antigen binding sites were detected with incubation with biotinylated horse antibodies recognizing mouse IgG  for 2 h at room temperature. Following 3 buffer washes and an 1 h incubation with ExtrAvidin-peroxidase conjugates  immunoreactivities were visualized with nickel-enhanced diaminobenzidine (DAB-Ni) and H product .PN were detected by immunostaining for different components with either mouse monoclonal anti-cat chondroitin sulfate proteoglycan , or anti- human aggrecan core protein , or polyclonal goat anti-human link protein . Synapses were identified with affinity-purified rabbit antibodies directed against the presynaptic vesicle protein synaptophysin , which was visualized by the avidin-biotin-technique and DAB-Ni as described above. In selected sections, double immunoperoxidase staining was applied to concomitantly detect PN or synapses and PAV-positive saccade-related neurons. Thereby, PN-related antibodies or synaptophysin were revealed by immunoperoxidase double staining with bluish-black DAB-Ni followed by immunodetection of PAV with plain DAB producing a brown reaction product.In selected sections, main components of PN were visualized by triple immunofluorescence labeling. The tissue was primarily blocked with 5% normal donkey serum in TBS (containing 0.3% Triton X-100) for 1 hour and then incubated with a cocktail consisting of polyclonal rabbit anti-CSPG  [For normal controls, the brains of 4 subjects from the Neurobiobank Munich who died without any history of ocular motor or relevant neurological disorders were evaluated. All cases underwent identical neuropathological examination, immunostaining with monoclonal mouse antibodies against human-PHF-Tau , beta-Amyloid 17\u201324 , alpha-synuclein  and polyconal rabbit anti-TDP-43 , as well as triple immunofluorescence labeling.Control 1 (shown in figures) was a 62-year-old male who died of pancreatic cancer without brain metastases or hepatic encephalopathy whose neuropathological examination demonstrated small old hemorrhages in the adenohypophysis, arteriosclerosis, and Braak stage I of Alzheimer changes . ControlWritten consent was obtained from all patient and control subjects or the next of kin for use of these tissue samples in research. The patient provided written consent for video recording (that authorizes publication among other uses). The next of kin of the patient has provided written informed consent for brain autopsy and (as outlined in the PLOS consent form) to publish these case details and the video. Control samples were collected as part of the Neurobiobank Munich. The Neurobiobank Munich and this research project have been approved by the ethics committee of the Ludwig Maximilians University.in vivo and ex vivo 7 tesla MRI studies [As previously reported, gross inspection of the brain was unremarkable  and was  studies . Atheros studies . The tisThe gross and histologic examination of the pons in the region of the abducens and omnipause neurons found no lesion. Staining the OPN area with LFB-PAS, GFAP, and CR3/43 showed no evidence of demyelination, reactive gliosis, or abnormal microglia activation . ImmunolImmunostaining patterns of HPLN1- and ACAN-based PN in the abducens nuclei  and arouIn the nucleus raphe interpositus (RIP) of control subjects, all PAV-positive OPN were ensheathed by PN immunostained for ACAN, CSPG, or HPLN1 . In the The PAV-positive putative excitatory saccadic burst neurons in the PPRF and in the RIMLF were ensheathed only by fragments of PN, unlike in the control case . As alsoWe describe a patient with profound enduring saccadic palsy following cardiac surgery whose brain showed preserved saccade-generating neurons but disruption of the PN that are thought to be essential for normal functioning of these neurons. These findings raise a number of important issues for discussion regarding the localization of saccade dysfunction, the role of PN, broader damage to the central nervous system, mechanisms of injury, and implications for understanding PN function.Brainstem neurons that generate saccades (PBN and OPN) receive descending inputs from cortical eye fields, via the basal ganglia, superior colliculus, and cerebellum ,33. The Additional evidence that this selective saccadic palsy was due to a brainstem process comes from studies of chemical lesions or pharmacological inactivation of the PPRF, RIMLF, or OPN in macaque reporting selective slowing or absence of saccades with spared pursuit and vestibular eye movements \u201342. Suchselective saccadic palsy spares ocular motor nuclei and supranuclear pathways from the cerebral hemispheres, basal ganglia, and cerebellum involved in pursuit and vestibular eye movements. While there was some focal loss of cerebellar Purkinje cells, which are susceptible to ischemia or alcohol [We conclude that our patient\u2019s saccadic palsy was due to dysfunction of the brainstem saccade-generating network of neurons because of her isolated loss of horizontal, vertical, and torsional saccades and reflexive quick phases but preserved pursuit, vergence, and vestibular eye movements. This  alcohol ,45, thes alcohol  but have alcohol . The patThe main novel finding of this clinicopathologic study is that neurons in the brainstem reticular formation\u2019s saccadic network appeared histologically normal with preserved synapses despite their loss of function. However, our immunostaining demonstrated that PN surrounding OPN and EBN were absent or severely fragmented. Great methodological care ensured that poor PN staining was not due to effects of preservation, fixation, or postmortem delay by using three antibodies to detect different PN components (even in the same section with immunofluorescence). Furthermore, intact PN were present in adjacent related  and unrelated (superior olive) areas. This finding supports the critical role current models place for OPN and EBN in generating normal velocity saccades . It alsoSeveral functions have been suggested for PN that may underlie the mechanism for malfunction of OPN and EBN . PN coulin vivo and in vitro spontaneous epileptiform discharges from the CA3 area months after global ischemia, combined with loss of GABAergic interneurons, a finding associated with aberrant sprouting of glutamatergic fibers leading to enhanced synaptic excitation and reduced synaptic inhibition in temporal lobe epilepsy models [Damage to PN might also explain other phenomena following cardiac surgery. PN surround GABAergic projection neurons in portions of the globus pallidus and substantia nigra as well as in subpopulations of striatal and thalamic inhibitory neurons . Hypoxiay models . WhetherHow could saccade-related PN be damaged during cardiopulmonary bypass while sparing the highly active neurons they enwrap? PN may be particularly vulnerable to hypoxia, as a focal cerebral ischemia rat model found that ischemia damages PN more than the ensheathed neurons in the peri-infarct zone . Unlike Selective saccadic palsy could be developed into an animal model to clarify the role of PN. Saccades are an ideal system for studying neural control of movement since they are well understood and can be measured precisely ,57. The Understanding the role of PN in different disorders may create therapeutic opportunities. Status epilepticus is associated with reduced PN-stabilizing components and aggrecan expression . The rolIn summary, this study provides the first evidence that saccadic palsy following cardiac surgery can be caused by damage to supporting tissues surrounding saccadic network neurons rather than to the neurons themselves. It also suggests an accessible model in which eye movements could be used to study the unique role and requirements of PN experimentally. However, some caution is required in interpreting our results, which rest on careful studies of one patient. More studies are required to confirm our findings, including examination of PN in patients without saccadic palsy who have died of exsanguination.S1 MovieTo make rapid head-free gaze shifts, the patient used exaggerated head turns associated with blinks; contraversive vestibular slow phases moved the eyes into the corner of the orbits until the head was maximally rotated, and then the eyes slowly drifted toward the target. She made no reflexive saccades. With the head fixed, volitional saccades consisted of extremely slow eye movements that eventually reached the target, except for slightly faster downward saccades. Pursuit was smooth and full in range both horizontally and vertically, even at higher frequencies. Visually enhanced vestibulo-ocular reflex was normal. When she viewed a horizontally rotating optokinetic drum, her eyes became fixed laterally in the orbits without any corrective quick phases. Torsional head rolling produced normal ocular counter-rolling but without any torsional quick phases. See text for additional details not shown in the movie.(M4V)Click here for additional data file."}
+{"text": "We would like to comment on the excellent review by Chen and colleagues highlighting the safety and efficacy of combining extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) for fluid and electrolyte control .As a high-flow system equipped with heparin-coated membranes and circuits, ECMO requires no or only minimal additional anticoagulation to assure circuit patency ,3. In coFor these reasons, we strongly argue against the combined use of ECMO and CRRT within a single circuit. In addition, a separate CRRT device can perfectly run under a proper dedicated anticoagulation therapy . This permits avoidance of ECMO-induced anticoagulant dilution, resulting in less thrombotic events ."}
+{"text": "The Drug Addiction Treatment Act of 2000 created an opportunity for primary care physicians and addiction treatment agencies to integrate, as primary care physicians became able to prescribe opiate treatment medications from their practices. Fourteen years later, a National Institute on Drug Abuse evidence-based practice implementation trial in Ohio is finding that physician capacity is becoming a primary barrier to use of buprenorphine. This presentation will document: a) the degree of the physician capacity barrier for specialty addiction treatment providers wanting to expand their buprenorphine programs; b) strategies being considered to overcome this barrier, including telemedicine; and c) what workflow challenges implementation of telemedicine can expect .The mixed-methods approach documents physician capacity limitations and to what degree telemedicine is being considered to remedy physician capacity shortfalls. Data collection includes written surveys from 47 treatment centers; qualitative interviews with 39 treatment centers; and patient simulations of VA telemedicine programs. For the data analysis, summary statistics are provided, including characteristics of organizational participants and buprenorphine prescribing patterns. The qualitative inductive analysis is designed to identify contextual and process factors that affect telemedicine implementation.Fifty percent (sample = 42) of Ohio treatment providers report lack of access to buprenorphine-prescribing physicians as a barrier to implementation and expanded use of buprenorphine. Thirty-eight percent of those identifying this barrier consider telemedicine as an option to access physician prescribers. Barriers to telemedicine implementation are technology incompatibility; inability for telemedicine sites and specialty treatment providers to agree on dosing protocols (including diversion prevention expectations); and workflow interruptions that occur due to patient and clinical information not being effectively transferred between telemedicine sites and community treatment providers. Organizational strategies to overcome lack of physician capacity and telemedicine implementation challenges are discussed.The lack of physician-prescribing capacity for buprenorphine is preventing this evidence-based practice from achieving higher penetration rates among specialty treatment providers. Telemedicine provides one solution to re-allocate the distribution of this scarce resource. However, there will also be challenges in implementing telemedicine that need to be understood, and evidence-based strategies need to be developed to overcome these challenges. Successful use of telemedicine may ultimately lead to greater integration between primary care and specialty addiction treatment.Clinicaltrials.gov NCT01702142NIDA 5R01DA030431-03"}
+{"text": "Enthesitis Related Arthritis Category of Juvenile Idiopathic Arthritis (JIA-ERA) is the most common category of JIA seen in Asian Indians. Transcriptome analysis is a useful tool to analyse pathways involved in disease pathogenesis. Peripheral blood mononuclear cells (PBMC) and SFMC analysis showed involvement of innate immune cells in JIA-ERA. However PBMC/SFMC have variable number of different cells and that can affect interpretation. No data is available on cell type specific transcriptome analysis of blood and synovial fluid in children with JIA-ERA.To study the cell type specific transcriptome analysis of blood and synovial fluid in children with JIA-ERA.Six samples each of peripheral blood and synovial fluid were collected from patients with ERA-JIA. Blood from 6 healthy controls was also collected. Mononuclear cells were separated by density gradient centrifugation. B cells, T cells and monocytes were separated using MACS columns and purity assessed by flow cytometry. After RNA extraction and checking the quality of RNA (RIN > 8) microarray was done using Illumina chips WG 12 for whole PBMC/SFMC population, T cells, B cells and monocytes. Some of the significant genes were validated by qRT-PCR.Unsupervised hierarchical clustering revealed that cell subsets could be distinguished based on their gene expression profile. No significant differences were observed between PBMC of patients and healthy controls. Comparison of SFMC and PBMC reconfirmed the results seen earlier. Among T cells and B cells the differential athways identified were related to inflammation like Cell adhesion, antigen processing, cytokine and chemokine signaling,BCR signaling and leukocyte migration.Results obtained with monocytes are summarized below in table Monocyte probably play a major role in pathogenesis of JIA-ERA and TLR signalling may be the pathway involved.None declared."}
+{"text": "Dear Editor-in-Chief,A recent article published in the Journal of Human Kinetics  describeResistance exercise with blood flow restriction (REBFR) is considered alternative training for enhancing strength and muscle size (hypertrophy) to high intensity conventional resistance training . It is often recommended to include REBFR in clinical population, including hypertension (HTA), as this type of training carries a lower risk of injury. Additionally, it has been reported that REBFR is safe . For insTherefore, further investigation is required to assess the physiological effects on hypertensive subjects comparing: a) resistance training with different levels of blood flow restriction; b) different intensities in resistance training; c) REBFR versus traditional resistance training; d) REBFR versus traditional aerobic training in hypertensive subjects."}
+{"text": "Cardiovascular disease (CVD) is the major cause of mortality in industrialized countries. Atherosclerosis is characterized by a long lag time between onset and clinical manifestations. There is evidence that CVD initiate before birth by developmental changes in utero. Genetic and environmental factors may interact in specific periods of life , giving rise to altered developmental plasticity and epigenetic modifications with abnormal phenotypic expression of genetic information without altering DNA sequence. Nutritional imbalances and other environmental clues may cause intrauterine growth delay, decreased gestational age, low birth weight and postnatal catch-up growth. Fetal exposure to maternal hypercholesterolemia has been associated with increased risk and progression of atherosclerosis. Oxidative stress seems to play a major role in the atherosclerotic process by activating both platelets and monocytes forming proinflammatory and proaterogenic substances, resulting in endothelial dysfunction, decreased flow-mediated dilation, and increased carotid intima-media thickness ,2. CVD p"}
+{"text": "Orangutans are an endangered species whose natural habitats are restricted to the Southeast Asian islands of Borneo and Sumatra. Along with the African great apes, orangutans are among the closest living relatives to humans. For potential species conservation and functional genomics studies, we derived induced pluripotent stem cells (iPSCs) from cryopreserved somatic cells obtained from captive orangutans.OCT4, SOX2, KLF4, and c-MYC factors. Candidate orangutan iPSCs were characterized by global gene expression and DNA copy number analysis. All were consistent with pluripotency and provided no evidence of large genomic insertions or deletions. In addition, orangutan iPSCs were capable of producing cells derived from all three germ layers in vitro through embryoid body differentiation assays and in vivo through teratoma formation in immune-compromised mice.Primary skin fibroblasts from two Sumatran orangutans were transduced with retroviral vectors expressing the human We demonstrate that orangutan skin fibroblasts are capable of being reprogrammed into iPSCs with hallmark molecular signatures and differentiation potential. We suggest that reprogramming orangutan somatic cells in genome resource banks could provide new opportunities for advancing assisted reproductive technologies relevant for species conservation efforts. Furthermore, orangutan iPSCs could have applications for investigating the phenotypic relevance of genomic changes that occurred in the human, African great ape, and/or orangutan lineages. This provides opportunities for orangutan cell culture models that would otherwise be impossible to develop from living donors due to the invasive nature of the procedures required for obtaining primary cells.The online version of this article (doi:10.1186/s13104-015-1567-0) contains supplementary material, which is available to authorized users. Pongo pygmaeus) and Sumatra (Pongo abelii) .Gene expression scores and .cel files supporting the results of this article are available in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) repository [Series Accession Number GSE69603 and"}
+{"text": "To examine acute alterations in lower-extremity sagittal plane joint moments due to isolated and/or combined experimental knee joint pain and effusion during walking.Nineteen able-bodied subjects walked four different conditions , with a week between each condition. We used previously-used injury models of pain  and joinThe FANOVAs detected between-session differences for the involved (right) and uninvolved legs (left; Figure Stimulation of the receptors specific to joint pressure appears to cause higher impact on alterations in sagittal plane joint moment compared to the nociceptor stimulation. Simultaneous knee joint pain and effusion produced a summative effect on sagittal plane joint moments. Since knee joint effusion and pain are common symptoms in knee joint injuries, both variables should be controlled in acute and chronic phase of rehabilitation in order to avoid altered joint moments."}
+{"text": "Increased aortic stiffness may lead to insufficient flow wave dampening and subsequent transmission of excessive pulsatile energy towards end-organs such as the brain. It has been shown that CMR-assessed aortic stiffness may augment cerebral small vessel disease in patients with hypertension, as assessed by conventional structural magnetic resonance imaging (MRI). However, in addition to these overt brain abnormalities, currently it is unknown whether aortic stiffening relates to subtle changes in brain tissue integrity, which may be a precursor to overt brain abnormalities. Diffusion tensor imaging (DTI) in the brain has been used to evaluate such subtle changes in tissue integrity. The aim of this study was to assess the association between aortic arch pulse wave velocity (PWV) as a marker of arterial stiffness and brain changes assessed by conventional structural MRI as well as DTI in patients with hypertension.78 patients with hypertension  were prospectively included. Aortic imaging was performed using 1.5T MRI. To assess PWV over the aortic arch, one-directional through-plane velocity-encoded MRI was performed, planned perpendicular to the ascending aorta and additionally transecting the proximal descending aorta  and grey matter integrity  (Table Our data suggest that aortic arch stiffness is independently associated with changes in brain tissue integrity in patients with hypertension. Subtle changes in brain microstructure are related to increased stiffness of the aortic arch, even in absence of overt brain abnormalities.N/A."}
+{"text": "Stroke is the leading cause of disability in the United States. Despite the high incidence and mortality of stroke, sensitive and specific brain-based biomarkers predicting persisting disabilities are lacking. Both neuroimaging techniques like electroencephalography (EEG) and non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) have proven useful in predicting prognosis, recovery trajectories and response to rehabilitation in individuals with stroke. We propose, however, that additional synergetic effects can be achieved by simultaneously combining both approaches. Combined TMS-EEG is able to activate discrete cortical regions and directly assess local cortical reactivity and effective connectivity within the network independent of the integrity of descending fiber pathways and also outside the motor system. Studying cortical reactivity and connectivity in patients with stroke TMS-EEG may identify salient neural mechanisms underlying motor disabilities and lead to novel biomarkers of stroke pathophysiology which can then be used to assess, monitor, and refine rehabilitation approaches for individuals with significant disability to improve outcomes and quality of life after stroke. Stroke is the fourth leading cause of death  have shown promise in identifying neurophysiological mechanisms associated with network reorganization in the human brain after stroke. Neuroimaging approaches have identified functional neural correlates of impaired arm movements after stroke demonstrating relationships between brain function and motor impairment  at rest and during isotonic contraction TMS can noninvasively and transiently modulate cortical excitability in the human brain  or offline imaging approaches   in response to a single TMS pulse has been repeatedly confirmed , several other TEP-based indices have been employed to index certain aspects of cortical reactivity or effective connectivity Table . For exaTMS-EEG has provided candidate biomarkers for a variety of different neurologic conditions. Altered TEPs, in particular a reduced N100 component of the TEP evoked at M1, have been identified in children with attention deficit hyperactivity disorder (ADHD)  Electrical confounds: magneto-electric induction creates fast and high amplitude currents in the EEG electrodes and leads (during stimulation itself and when recharging capacitors) and also electrode-electrolyte interface polarization (Ilmoniemi and Kici\u0107, Concurrent TMS-EEG has the potential to improve our understanding of the neurobiology of stroke and stroke recovery by offering a sophisticated paradigm to non-invasively characterize human brain excitability and connectivity after stroke. Revealing the causal mechanisms of altered cortical excitability and cortical network reorganization has important clinical implications. If successful, TMS-EEG could provide new tools to improve prognosis, refine treatment approaches, monitor recovery trajectories and individualize care to improve recovery outcomes for patients after stroke.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "One of the most widely employed quantitative measurements for assessing tumour response to treatment is the tumour diameter (RECIST criteria), usually determined on cross-sectional CT or MRI. This simple measurement is relatively reproducible and reduction in the maximum tumour diameter by 30% or more following therapy is taken as a sign of effective treatment. However, new targeted therapies may be effective without significantly reducing tumour size and other quantitative response criteria are being evaluated.Some of the response criteria being evaluated combine tumour diameter measurement with other quantitative assessment (e.g. CT density). These have been applied towards the evaluation of gastrointestinal stromal tumours (CHOI criteria) and renal cell carcinoma (modified or revised CHOI criteria) undergoing multi-kinase inhibitor treatment; and hepatocellular carcinoma (modified RECIST criteria) treated with novel therapeutics or chemoembolization. In these clinical settings, the applications of such criteria for tumour response assessment have shown better correlation with clinical outcome compared with conventional RECIST criteria. When immunotherapy is administered, conventional RECIST criteria may erroneously ascribe the appearance of new lesions to disease progression; whereas this phenomenon is given due consideration within the immune-related response criteria (irRC).As quantitative imaging becomes increasingly important in oncology, quantitative indices are being applied and developed in CT, MRI and PET imaging for tumour response assessment. Using perfusion CT technique, the change in CT attenuation value with time resulting from the passage of contrast through tissue can be used to calculate quantitative vascular parameters such as permeability surface area product (PS), blood flow (F) and mean transit time (MTT). Using dual energy CT, it is possible to obtain quantitative iodine contrast distribution in soft tissue.MRI is a powerful multiplex imaging technique because depending on how the scans are performed, it can yield different quantitative information. Two of the most widely employed quantitative techniques for tumour assessment are dynamic contrast enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI). The former has been used in early phase trials for the assessment of antivascular/ antiangiogenic therapies. The latter has shown potential as an early response biomarker to a range of effective treatments including chemotherapy, radiotherapy, chemoemobolization treatment and novel therapeutics. Other clinical MR techniques include intrinsic susceptible contrast imaging and magnetic resonance spectroscopy (MRS). However, these have currently limited value for assessing tumour response to treatment.PET imaging using 18FDG tracer enables the semi-quantitative standardised uptake value (SUV) to be derived. PET imaging is increasing utilized for tumour response assessment, and forms the basis of standard criteria for assessment of tumour response in lymphoma. By performing dynamic imaging, it is also possible to calculate the quantitative tracer uptake in tissues. The strength of PET imaging is the range of radiolabelled tracers that are now available clinically to probe a range of tissue properties.In early phase trials, quantitative imaging other than tumour size measurements using CT, MRI or PET can provide mechanistic information about drug action, and also therapeutic effects on specific aspects of tumour biology . By using multimodality imaging, there is also an opportunity to corroborate imaging measurements made using one technique with another. However, quantitative techniques require a process of quality control and quality assurance; as well as knowledge of their measurement reproducibility so that they can be applied with confidence in clinical practice."}
+{"text": "There are errors in the Data Availability section. The correct data availability information is as follows: The authors confirm that all data underlying the findings are fully available without restriction. All sequence data are in the Short Read Archive (SRA) at the NCBI database under accession numbers: bean LTD SAMN03223377, bean NOI SAMN03223381, bean NTD SAMN03223380, and bean LOI SAMN03223378."}
+{"text": "Amyris is a renewable products company providing sustainable alternatives to a broad range of petroleum-sourced products. Amyris applies its industrial synthetic biology platform to convert plant sugars into a variety of molecules - flexible building blocks that can be used in a wide range of products.\u00ae, Amyris's brand of farnesene, a long-chain branched hydrocarbon, manufactured using our engineered microbes in fermentation.Amyris's initial portfolio of commercial products is based on BiofeneFirst generation renewable fuels have been an important part of the effort to reduce the world's petroleum dependence and greenhouse gas emissions associated with transportation fuels. However, these first generation renewable fuels have some limitations, ranging from lower energy density than petroleum fuels and lack of fungibility with existing petroleum distribution systems.Amyris renewable fuels are designed to be optimal transportation fuels. Specifically, our fuels are designed to be drop-in, cost competitive replacements for petroleum-derived fuels, compatible with existing engines yet with superior performance.Building on our Biofene hydrocarbon building block, we are currently selling renewable diesel in metropolitan areas in Brazil and are pursuing industry certification for our renewable jet fuel."}
+{"text": "Clinically, pancreatic tumors have proven to develop resistance to available treatment options; however, efficacy might be achieved if the required levels of drugs reach the tumor site. Tumor microenvironment (TME) leads to extensive desmoplasia and chemo-resistance, contributing immensely to the invasive and metastatic process of pancreatic carcinoma . DesmoplOur study, published in Cancer Research , provideConsidering the huge fibrotic nature of pancreatic tumors and to overcome the vast heterogeneity observed within the tumors, we have prepared a PLGA [poly(lactic-co-glycolic acid)] based nanoparticle formulation of ormeloxifene and discussed its enhanced efficacy in an article published in Biomaterials . The forIn conclusion, management of TME using this novel therapeutic modality and potential delivery system might add clinical benefit to existing standard treatments utilizing combination treatment regimens. Our studies support the understanding that manipulation of TME may overcome the stromal barrier for effective treatments in pancreatic cancer."}
+{"text": "Myeloid-derived suppressor cells (MDSCs) are a naturally occurring immune regulatory population capable of suppressing inflammation, and are often associated with cancer, chronic infection and traumatic injury . GrowingActivation of the inflammasome can be via endogenous damage-associated molecules termed DAMPs Figure . We havein vitro and in the context of GvHD [ex vivo suppressive capacity of MDSC was also reduced. The temporal nature of MDSC loss of function was addressed by applying multiple consecutive doses of MDSC-IL13 , resulting in enhanced overall survival, suggesting MDSC functionality is compromised early due to GvHD conditions and that maintaining a suppressive environment using repetitive MDSC infusions could overcome the loss of suppression of an individual MDSC infusion. In support of an inflammasome mediated loss of function, genetic ablation of the inflammasome-associated adaptor protein ASC (Apoptosis-associated speck-like protein containing a CARD) prevented MDSC inflammasome activation and resulted in improved survival relative to wild-type MDSC in GvHD mice. Moreover, ASC\u2212/\u2212 MDSC-IL13 recovered from day 5 post transplant recipients did not produce IL-1\u03b2 and better retained their capacity to suppress T cell proliferation ex vivo than wild-type MDSC-IL13 recovered from GvHD mice. The translational potential of these findings are supported by the fact that we observed human peripheral blood-derived MDSC to be susceptible to in vitro inflammasome activation and had reduced suppressive function under these conditions.Myeloid cells are uniquely responsive to their environment and in our efforts to improve MDSC function, we investigated their inflammasome activation status both  of GvHD . In as l\u2212/\u2212 MDSC, and clinically viable options including mRNA or gene knockdown or knockout technologies such as sh/siRNA or nucleases that target one or more inflammasome components. Pharmacologic agents such as small molecule inhibitors designed to repress inflammasomes currently being developed to circumvent GvHD pathology are expected to act on transferred MDSC as well, and we would predict aid in maintenance of function. Other implications from this work include the potential to conversely promote inflammasome activation locally at the site of tumor burden for the purposeful enhancement of immune activation and anti-tumor immune therapy, as MDSC are nearly ubiquitously observed in the setting of solid tumors. Our findings suggest that the degree of inflammation is critical for MDSC functional support, and anti-tumor therapies may benefit from local or systemic priming of inflammasome activation, converting tumor-associated MDSC and releasing their suppressive potential.Myeloid cells play a critical role in developing, shaping and sustaining immune responses and are remarkably adaptable to their environment. Therefore, adoptive cell therapies using MDSC need to be tailored and monitored carefully, as culture conditions are vastly different then the conditions MDSC are exposed to upon transfer. An important question that remains is elucidating which inciting factors are involved in transplant/GvHD associated inflammasome activation. While ATP/P2x7R and Nlrp3/miR-155 are recognized as important targets with relevance in GvHD, a wide variety of factors are known to activate inflammasomes including DAMPs, bacterial & viral (dsDNA) products and environmental stimuli  and may contribute to MDSC inflammasome activation. Whether it is possible or necessary to globally inhibit these upstream pathways for inflammasome activation is yet unclear. Our future aims are to produce higher functioning MDSC that are capable of sustained function in the harsh early post transplant setting of GvHD. Methods for tailoring MDSC to resist conversion include genetic alterations to prevent inflammasome activation, as seen using ASC"}
+{"text": "It is becoming clear that immune cells play many important but sometimes conflicting roles in cancer. Immune profile changes at sites of immune-cancer interactions, such as the tumor microenvironment and tumor-draining lymph nodes (TDLNs), may represent a sensitive predictor of local and distant tumor metastasis. However, standard pathologic analysis of tumor sections has remained at the visual assessment of one marker per serial section level; it would be extremely useful to be able to visualize the distributions of multiple phenotyped immune and other cells in-situ in solid tumors to dissect the complex interplay between immune/stromal cells and cancer cells within tumors, tumor-draining lymph nodes (TDLNs), and blood. We generate immune profiles that include complete immunophenotyping and identification of cellular spatial relationships within and between the tumor microenvironment and TDLNs from formalin-fixed paraffin-embedded lymph node and tumor specimens from cancer patients using a combination of multiplexed IHC/IF, multispectral imaging, and automated image analysis which delivers quantitative per-cell measures of each marker. These per-cell intensities are then translated into a phenotype for each cell. We have found that immune cell populations as well as their spatial distributions and clustering patterns have strong correlation with clinical outcome."}
+{"text": "A key systemic regulatory hormone is growth hormone (GH), which has a developmental role in virtually all tissues and organs. This review catalogs the impact of GH on tissue programming and how perturbations early in development influence GH function.Developmental programming of the fetus has consequences for physiologic responses in the offspring as an adult and, more recently, is implicated in the expression of altered phenotypes of future generations. Some phenotypes, such as fertility, bone strength, and adiposity are highly relevant to food animal production and  The fundamental role of normal fetal development is best exemplified by pattern formation in the embryo. \u201cProgramming\u201d was a term coined in 1986 to reflect that events occurring c traits  and the c traits ,4. The iRecent data highlight that the metabolic environment experienced by the fetus influences phenotypic expression and disease susceptibility in later life ,6. SmallIgf-2 gene with the paternal copy as the sole source of IGF-2 during development and the maternally inherited copy silenced. It is hypothesized that the maternal and paternal expression are balanced to maximally promote fetal growth while preventing excessive depletion of the dam\u2019s resources [Although not developmental programming, the most familiar illustration of developmental epigenetic imprinting is the insulin-like growth factor-2 (IGF-2) pathway. The methylation status differs between the paternally and maternally inherited esources . Anotheresources . The genesources  to regulesources .Importantly, developmental programming may have multigenerational consequences transmitted through epigenetic modifications of the genome. Transgenerational epigenetic programming was initially recognized as a result of malnourishment. The Dutch famine, sometimes referred to as the \u201cHunger winter\u201d, is most often cited as the initial epidemiological human case study illustrating the impacts of nutritional stress upon both physical and behavioral traits in subsequent generations (reviewed in ). More rin utero [The accepted role of GH and the GH-IGF axis in tissue development is predominantly postnatal with other hormones assuming importance in utero . Yet GH in utero  and calvin utero ,24. Thesin utero .in utero growth restriction. Furthermore, adult height is correlated with placental GH expression. Genetic variation within the sequence of the placental-form of GH is significantly associated with mature height confirming that altered expression of GH in utero governs longitudinal bone growth potential [Evidence that fetal perturbations program GH signaling is also emerging. A common model used to define the role of GH in developmental programming is the neonate that experienced impaired fetal growth, specifically SGA infants, who are characterized by compromised bone growth and reduced body mass. Infants having low birth weights trend to lower circulating GH as young adults  indicatiotential . Immune otential  indicatiBirth weight and neonatal growth is predictive of adult circulating GH levels suggesting that the intrauterine environment programs GH secretion  or tissuin utero reduces birth weights of calves [in utero exerts long term consequences on the offspring possibly through alteration of maternal metabolic pathways and placental function.The role of GH in normal development was established decades ago through ablation studies and assessing the physiological consequences of the absence of GH. Additional models to characterize GH action elevate the hormone either through exogenous administration of GH, GH-transgene expression, or chemical compounds that induce GH. Elevated GH f calves , lambs [f calves , and rodf calves . In sheef calves . For rodf calves . Furtherf calves . Similarf calves . Ewes trf calves ,43. Takein utero growth inhibition and restore overall bone length [Elevated GH postnatally has significant effects on bone, muscle, and adipose. Human SGA infants given GH respond with increased bone growth velocity for the duration of GH treatment . In rodee length . GH exere length . Provisiin utero for lambs.Lambs given HMB during the first 3 postnatal weeks show elevated circulating levels of GH, IGF-1, and biochemical markers of bone turnover. However once the HMB treatment concludes, these indices all fall to control values indicating resistance to long term bone programming by HMB when provided postnatally . The faiThe enhanced gain accompanying elevated GH has a greater proportion of protein than normal tissue accrual in rodents. Rodent development is characterized by each unit of gain being composed of the same proportions of water, lipid, protein and ash across the entire growth phase, despite the speed of accrual . In contTherapeutic GH treatment of SGA children offers growth advantages as noted above, yet the elevated GH also reduces insulin sensitivity potentially increasing the risk of diabetes. Recent studies of children born SGA and treated with GH would suggest this is not a valid concern as they have normal insulin post-GH treatment . HoweverIn utero or postnatal exposure to elevated GH in a GH-transgenic mouse model increases adipose storage by increasing adipocyte hyperplasia, differentiation, and cellular lipid content [The role of GH in adipogenesis is complex.  content ,54,55. A content . Postnat content . This ne content .in utero [The interplay with leptin adds more complexity to the influence of GH on adipose. Leptin, synthesized by adipose cells, regulates energy metabolism (reviewed in ) and infin utero  with potEarly dysregulation of GH promotes adipogenesis which in turn elevates leptin that influences adipose function at later ages. Elevated GH in a GH-transgenic mouse model increases plasma leptin  while miStudies in multiple mammalian species demonstrate that aberrant programming of adult tissue response is associated with stress-induced glucocorticoid secretion during fetal and perinatal development. Maternal stress in humans is known to impact neurological circuitry of the offspring: infants have an increased risk of neuropsychiatric disease when the mother experienced psychological stress during the first trimester (reviewed in ). SimilaEarly research demonstrated that adult GH secretory patterns are influenced by perturbations during the perinatal period. For example, male rats normally express a high amplitude secretory pattern of GH whereas females have low amplitude pulses within a higher basal background. Transient manipulation of sex steroids in the neonatal period can modify the GH secretory pattern to that of the opposite sex . GlucocoMothers who are undernourished during pregnancy give birth to SGA infants and when adult those children exhibit adult-onset obesity, insulin resistance, hypertension, and metabolic dysfunction. Maternal nutritional deprivation stress also is implicated in intergenerational epigenetic programming to alter future generations\u2019 growth and metabolic phenotypes. This phenomenon is suggested to account for the rising cases of human obesity, diabetes, and coronary disease (reviewed in ).Levels of placental GH found in maternal circulation are positively correlated with fetal birth weight and in times of maternal nutrient deprivation and SGA pregnancies, placental GH secretion is reduced . A recenAs noted above, there are generalized consequences of SGA on bone characteristics but SGA due to nutritional deprivation also programs bone through the GH- IGF axis. The necessity of adequate fetal and neonatal nutrition for normal bone growth and adult bone integrity was underscored by Eastell and Lambert in their review . In ratsAnother mechanism of nutritional programming on bone is by its effects on the formation of the embryonic skeletal anlage. Fetal and postnatal bone growth depends upon chondrocyte hypertrophy and hyperplasia. Fibroblast growth factors (FGF) and their cognate fibroblast growth factor receptors (FGFR) are key signaling molecules of chondrocyte function in developing bone. Activation of different FGFR family members both promote and inhibit chondrocyte proliferation . The FGFIn rats, restricting maternal dietary protein to induce intrauterine growth restriction enlarges abdominal adipose depots when animals are adult . The enlIntrauterine growth restricted babies, piglets, and rodent pups have reduced leptin at birth and then propensity for obesity at adulthood ; provisiPhysical stressors, often modeled with induced hypoxia, have been used to assess the epigenetic consequences of stress. Hypoxia-inducible factor 1 (HIF-1), induced under conditions of hypoxia to adapt to reduced oxygen supply, is also required for normal fetal tissue and skeletal development . The traGrowth hormone has a pivotal role in pre and postnatal development although its effects on intergenerational programming are as yet under studied. Given the plasticity of postnatal development, defining fetal and neonatal programming and the effect upon later phenotypes is important to maximize the expression of desirable traits in food animals. This is particularly important on the impact of more permanent epigenetic alterations of gene expression that may have future consequences. Historically, classical genetic selection has permitted extremely favorable phenotypic advances. The implementation of quantitative trait loci selection schemes for livestock based upon genomic signatures will accelerate genetic improvement. Overlaid upon genetic selection one must be mindful of the epigenetic programming that environmental perturbations can exert on future trait expression and how that may factor into selection schemes for agricultural livestock production in a changing environment. Better defined knowledge of the mechanisms of programming will facilitate incorporation of epigenetic factors into selection."}
+{"text": "Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is trigeminal autonomic cephalalgias which is characterized by repetitive short lasting, severe attacks. Headache attacks are distribution of the ophtalmic and maxillary trigeminal divisions and associated with ipsilateral autonomic phenomena .A growing body of literature has focused on brain magnetic resonance imaging (MRI) evidence of neurovascular compression in these syndromes. There is some evidence supporting microvascular decompression of the trigeminal nerve in selected patients who have medically refractory SUNCT and a demonstrable ipsilateral aberrant vessel on magnetic resonance imaging (MRI). Here, we describe two cases concerning a 52-year-adult and a 69-year-elderly with short-lasting, recurrent headache combined with cranial autonomic features. Pain was described as excruciating, and was non-responsive to most traditional analgesic drugs. We report two patients of SUNCT syndrome with MRI cisternography and tractography findings of neurovascular compression. We performed MRI cisternography and tractography for delineates structural changes in the trigeminal nerve. Pain was completely relieved after surgery that microvascular decompression.We suggest that SUNCT patients with brain MRI should always be performed with a dedicated view to exclude neurovascular compression. In this case reports we performed MRI tractography delineates structural changes in the trigeminal nerve for SUNCT. MRI tractography is the first reports for SUNCT patients in the literature."}
+{"text": "In the framework of better risks management in hospital environment and in perspective to improve quality and safety care, university hospital center Farhat Hached Sousse (Tunisia) has developed a medical device-vigilance system in order to monitor incidents or risks of incidents that may arise through using medical devices allowed-on in market.Our objective is to determine medical staff knowledge\u2019s, attitudes and practices in university hospital center Farhat Hached Sousse (Tunisia) regarding medical device-vigilance system establishment.We conducted a descriptive study, type KAP , in December 2014, among all medical staff exercising at university hospital center Farhat Hached Sousse (Tunisia) who are in direct contact with medical devices. Measuring instrument used is a self-administered questionnaire, preestablished, and pretested. Seizure and data analysis was made by the SPSS software 20.0.More than half of participating physicians do not know, nor institution correspondent local )), neither existence of standardized form for reporting )). Concerning attitudes, majority of investigations )) shall notify interest of creating medical device-vigilance system. Participants in study report their desire to receive more information about medical device-vigilance system but they relate their desires to follow a training )).Our study highlights lack of information and training in field yet sensitive and heavily regulated. This needs to affirm medical nature relatively to medical device-vigilance by integrating it into health care professional\u2019s curriculum study but also by strengthening awareness and communication around medical device-vigilance system. Success system\u2019s functionality must be supported by promulgation laws and regulations and better organization of regulatory agencies.None declared."}
+{"text": "Noma is a devastating ancient illness that causes severe facial disfigurement in >140,000 children every year mainly in Africa, South America and India. The cause of noma remains unknown but infection, oral hygiene and immune status likely all contributeEfforts have been deployed over the 2 past decades to identify microbial agents  responsible for nomaResearch in the field of microbial identification has benefited from dramatic technical improvements. Until the late 90\u2019s culture based methods were predominantly used. More recently, culture-independent methods were used to identify bacteria in noma patients. We present three approaches used to study hundreds of gingival samples from noma patients and local control samples collected from villages near Zinder, Niger (Africa): large-scale cloning sequencing methods used at the beginning of 2000, high-density microarrays and high-throughput sequencing (HTS) devicesFusobacterium necrophorum as the causative agent of noma, while culture-independent methods identify higher levels of Fusobacteriales in healthy controls. Cloning-sequencing strategies identify disequilibrium in microbial communities from noma patients particularly in Fusobacteria, Prevotella intermedia and Peptostreptococcus genus abundance. This was also detected in studies using semi-quantitative microarrays. More recently, the utilization of HTS provided a detailed analysis of microbial flora in noma patients and identified Clostridiales, Bacteroidales, and Spirochaetales as indicators of noma. Our epidemiological investigations excluded the possible role of viruses such as cytomegalovirus or morbillivirus as possible significant contributor of noma diseaseCulture-based methods identified Although we identify a unique distribution and composition of microbial communities in noma wound sites compared to unaffected samples from the same mouths and healthy controls, the etiology of noma disease remains elusive. Future studies should include longitudinal sampling in high risk areas and detailed exploration of microbiota before and during development of lesionsNone declared."}
+{"text": "Reviewing progress in the fabrication of diverse odorant and flavored sol-gels, shows us how different synthetic strategies are appropriate for practical application with important health and environmental benefits.Microencapsulation has become a hot topic in chemical research. Technology mainly used for control release and protection purposes. The sol-gel micro encapsulation approach for fragrance and aroma in porous silica-based materials leads to sustainable odorant and flavored materials with novel and unique beneficial properties. Sol-gel encapsulation of silica based micro particles considered economically cheap as capital investment in manufacturing is very low and environmentally friendly. Amorphous sol-gel SiO Encapsulation technology arouse as a sparkle in recent world accounting significant health and environmental benefits. Industry grow with wide range of applications in all fields specifically, Deodorants, food, oils, synthetic nitro and polycyclic musk's, detergents, cosmetics (perfumes), personal care , food (flavors), and home care (laundry and detergents) etc.  given by Avnir and co-workers in 1984. Simple addition or entrapment of organic molecules in inner porosity of silica used as matrix at the onset of sol-gel process can be shown as below in Equation (1) Where Extraction and GC analysis performed for aroma load show total mass of sol-gel powders best described by following Equation (4)mi = mass of the aroma component in the extraction sample, mW the mass of water, mSE the mass of dry silica subjected to extraction Aroma retention of different components i in matrix found by Equation (5)Where the subscript 0 stands for the initial conditions  and bergamot oil in different silica based microcapsules widely applied in perfumes  and octylmethoxycinnamate (OMC) used initially as sunscreen but show endocrine disruption and estrogenic activity .The SPF calculations obtained for each subject and represented in Table Oils also commonly used in perfumes, cosmetics, agriculture, and food due to aromatic properties. On the basis of origin and composition, properties of EOs can be changed by encapsulation using widely used technique called coacervation. Lemon, thyme, citronella, vanilla, menthol, eucalyptol, clove, peppermint are some of EOs used (Martins et al., Microscopy, a powerful tool used to analyze microcapsule morphology. For example: Thyme oil droplets encapsulated as spherical particles demonstrated by optical microscopy and cryogenic scanning electron microscopy confirms rough surface with some pinholes, pores, and cracks of microcapsules. Release of Thyme oil affected by film thickness and polymer concentration whereas diffusion not only affected by polymer membrane but also by type of oil used. Such difference occurs due to hydrophilic characteristic of the oil (Ashraf et al., Sol-gel encapsulation of silica based micro particles considered economically cheap as capital investment in manufacturing is very low and environmentally friendly. Stobber process (Stober et al., TEOS used as a cheap solvent therefore main cost of sol-gel encapsulation supposed only for labor. An overall value of sol-gel products in global market in 2006 estimated $1 billion with annual growth rate of 6.3% until 2011 as shown in Figure Positive impacts of silica based materials involving sol-gel encapsulation leading to sustainable fragrances on human health and environment apart from technical and economical feasibility are highly appreciated. Comparing synthetic perfumes which are highly poisonous causing neuromodulations in human neuroblastoma cells at extremely low concentration with EOs, being natural renewable shows multiple human health benefits. Double encapsulation of EOs first caged in \u03b2-cyclodextrin following silica encapsulation using water based route turning oil to more stabilized and resistant toward temperature, humidity, and light. Today commercialized water based products also present in tone scale in broad variety are available. In US 50 largest companies generate about 70% of revenue from this industry. This technology also enables to produce and stabilize costly active ingredients by enhancing precision and effectiveness of actions and delivered where needed in required amount. First leading Europe's chemical engineering company, sol-gel technology Ltd. constructed in 2001 installed a plant in Israel. Green technology since, 1990s grow with advancement in nanomaterial synthesis (Dahl et al., In this article, we have discussed and demonstrated encapsulation technique based on silica micro particles and its applications in different fields which offer improved products for the benefit of human beings and are environmentally friendly. Sol-gel encapsulation proves highly flexible technology that can be applied to multiple systems. Further innovation to this unique process may include isolation of incompatible compounds through their independent encapsulation within a common formulation. In order to check biological properties of encapsulated materials in food, agriculture and cosmetic industry, supplementary studies are still required.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Ischemia/reperfusion injury (IRI) and organ failure especially IRI-induced remote and multiple organ failure contribute significantly to postoperative mortality and morbidity, and reperfusion induced oxidative stress plays a critical role in this pathology , 2.Reactive oxygen species (ROS) induced vascular endothelial dysfunction plays an important role in the development of IRI in various organs. In this special issue, Q. Yang et al. reported that the otherwise cardiac protective polymerized hemoglobin, when used at high dose, failed to alleviate cardiac IRI due to induction of oxidative damage in coronary artery. On the other hand, natural herbal extracts such as Licochalcone B as reported by J. Han et al. in this special issue conferred protection against myocardial IRI through attenuating ischemia-reperfusion induced oxidative damage.The intravenous anesthetic propofol possesses antioxidant capacity and has been shown to attenuate IRI in patients undergoing cardiac surgery and in animal models of myocardial  and inte mitochondrial homeostasis play critical roles in Acute Organ Failure [ mitochondrial homeostasis alterations during these pathologies is largely unclear. In this special issue, S. Cao et al. provided genome-wide expression profiling of cardiomyocytes subjected to hypoxia-reoxygenation injury in an effort to uncover the roles of mitoKATP in energy homeostasis and its regulation.Disturbances of Failure  and in p Failure , while tWe hope that the original and review articles presented in this special issue, representing the current advances in the oxidative stress-mediated ischemia-reperfusion injury, with respect to their potential impact in cellular survival pathways and therapeutic strategies, will stimulate further exploration of this important area. Despite diversity, it is our belief that the articles comprised in this special issue could represent an important advancement and contribution to improve our knowledge of the mechanisms governing reperfusion injury."}
+{"text": "Tissue microarrays (TMAs) have become a valuable resource for biomarker expression in translational research. Immunohistochemical (IHC) assessment of TMAs is the principal method for analysing large numbers of patient samples, but manual IHC assessment of TMAs remains a challenging and laborious task. With advances in image analysis, computer-generated analyses of TMAs have the potential to lessen the burden of expert pathologist review.In current commercial software computerised oestrogen receptor (ER) scoring relies on tumour localisation in the form of hand-drawn annotations. In this study, tumour localisation for ER scoring was evaluated comparing computer-generated segmentation masks with those of two specialist breast pathologists. Automatically and manually obtained segmentation masks were used to obtain IHC scores for thirty-two ER-stained invasive breast cancer TMA samples using FDA-approved IHC scoring software.\u03ba=0.81) than between pathologists' masks (\u03ba=0.91), this had little impact on computed IHC scores (Allred; Although pixel-level comparisons showed lower agreement between automated and manual segmentation masks (The proposed automated system provides consistent measurements thus ensuring standardisation, and shows promise for increasing IHC analysis of nuclear staining in TMAs from large clinical trials. With the improvements in clinical outcome in women treated for breast cancer such that 5 year survival now approaches 90% and 10 year survival 80%, adjuvant clinical trials require very large numbers of patients and tissue samples for biomarker studies to drive changes in clinical practice. Many such large clinical trials have moved towards generating tissue microarrays  staining or molecular analyses of a single TMA slide with representation from 20\u201340 patients and multiple samples per patient is an efficient use of human tissue, antibodies and laboratory processes, there remains the problem of skilled detection and assessment of biomarkers. Such reading of the biomarker status is laborious and time consuming, requiring expert assessment. Thus, there has been increasing attention paid to the potential for automated reading of breast TMA biomarker slides rather than relying on pathology review . HoweverIn previous studies comparing automated and manual IHC scores . Stained slides were scanned with lossy compression using an Aperio Scanscope XT  on a \u00d7 20 objective with the optical doubler in place . Each slide was then segmented into the individual constituent stained spots, each spot representing a section from a tissue core.Breast TMAs were generated, for research purposes, from primary, previously untreated breast cancers using excess tissues from routine clinical practice after written, informed consent from the donor patients. Ethical permission was granted by Tayside Tissue Bank, Dundee, UK, under delegated authority of the Tayside Local Research Ethics Committee. In brief, surgically resected primary breast cancer from otherwise unselected patients was fixed in buffered formalin, stored at controlled temperature (18\u201322\u2009\u00b0C) overnight and processed to formalin-fixed paraffin-embedded blocks. Whole mount sections stained with Haematoxylin and Eosin were marked to highlight relevant invasive cancer or normal tissue to allow TMA generation of up to six 0.6\u2009mm cores per cancer. TMAs were then constructed using a manual tissue arrayer . Four micron TMA sections were cut, mounted onto poly-Thirty-two uncompressed TIFF format images of TMA spots from thirty-two breast cancers were used. The perimeter of each spot was delineated and pixels exterior to this perimeter were excluded from subsequent analyses. Each spot image was \u223c3000 pixels in diameter and contained invasive cancer.T) or non-tumour (N). Each spot took on average 23\u2009min to annotate by each pathologist; however the task of annotating TMAs was spread over several days.Tumour regions in the TMA spots were manually segmented using Aperio Technologies Spectrum Software with TMA Lab and the Webscope interface (Aperio Technologies). Segmentation involved manually tracing the boundaries of invasive tumour regions on a Wacom Bamboo Fun tablet (model CTH-461) using the stylus for precision; the software tool displayed filled regions overlaid on the TMA spot images as they were annotated. Each spot was annotated independently by two specialist breast pathologists (pathologist A and pathologist B), resulting in two sets of tumour masks. Pixels in each mask were labelled as either tumour  assigned to each pixel. There are four possibilities when comparing a pixel's labels in two masks: , ,  and . However, there are qualitative differences between segmented regions that are not well captured by simply counting the numbers of pixels that fall into each of these four categories. Therefore, when comparing two segmentation masks, we categorised pixel label disagreements into three types as follows  were passed to the scoring algorithm. The Aperio IHC algorithm identifies nuclei automatically and outputs a staining intensity score (ranging from 0 to 3) and an estimate of the percentage of positively stained cells. From these measurements, IHC scores (Allred score and Quickscore) were computed for manually and automatically obtained segmentation masks. Comparisons are reported to assess the extent to which differences in these segmentations affected scoring.The FDA-approved Aperio IHC Nuclear Version 10 algorithm (Aperio Technologies) was used to estimate ER scores based on the segmentation masks obtained. Only regions labelled as tumour  and false negatives .In pixel-level comparison of manually hand-drawn segmentation masks, pathologists differed in their labelling of 9% of pixels . AutomatWhen distributions of agreements and disagreements were visualised , some vaIntensity scores and percentage of positive cells were measured by the Aperio IHC Nuclear algorithm (Aperio Technologies) when provided with segmented tumour regions. Percentage of positive ER cells computed by Aperio were also evaluated . Agreeme   and 0.92 (Quickscore) .This study addressed the need for automated interrogation of TMAs using ER nuclear staining of primary breast cancer as an exemplar. Although previous studies have shown that image analysis can increase workflow and reduce inter- and intra-observer variability . However determining the impact of pixel-level disagreements in clinical practice is challenging. Therefore in this study, a method of categorising disagreements was presented, given the intended usage of the application is IHC scoring. Proportion of disagreement types , equivalent to USCAP 1% cut-off, resulted in almost complete agreement between all reported segmentations. Using Quickscores (cut-off >3), two TMA spots were labelled as ER+ve from automated segmentations and the same spots labelled ER\u2212ve from manually obtained segmentations. The remaining 30 spots, 20 ER+ve and 10 ER\u2212ve, were in complete agreement across all segmentations. Generally there was an overall agreement in treatment decisions, however results varied between scoring systems and non-standardized cut-offs. These discrepancies suggest more work may be required before automation is applied for treatment decisions as suggested for studies comparing visual and automated assessment of Ki67 markers in breast cancers (Despite pixel-level disagreements averaging 16% , computeThe automated segmentation method sometimes had difficulty distinguishing ER\u2212ve cancer cells from ER\u2212ve healthy epithelial cells. Availability of a greater number of TMA spots containing both ER\u2212ve cancer cells and ER\u2212ve healthy epithelial cells, along with accurate annotations of those spots for training, is therefore likely to be of substantial benefit. Indeed, increased volumes of annotated spots for training to more fully represent a range of staining conditions, tissue structures and artefacts can potentially improve segmentation accuracy and further align automated analyses with those of specialist pathologists. The impact of using larger volumes of annotations during training can be usefully explored in future work.In summary, the use of automated annotations for scoring breast TMAs using the methods developed for and exemplified in this study concord closely with expert pathology reviews. 27% of pixel disagreements relate to minor misalignment of drawn tumour boundaries. Classification differences rarely resulted in a change of overall score that would be likely to change clinical management. Using the exemplar of nuclear ER staining, the methods of automated annotation employed here hold promise for reducing the expert pathology time required and speeding up analysis of IHC-stained TMAs from large data sets drawn from clinical trials."}
+{"text": "The degree of genetic differentiation among populations experiencing high levels of gene flow is expected to be low for neutral genomic sites, but substantial divergence can occur in sites subject to directional selection. Studies of highly mobile marine fish populations provide an opportunity to investigate this kind of heterogeneous genomic differentiation, but most studies to this effect have focused on a relatively low number of genetic markers and/or few populations. Hence, the patterns and extent of genomic divergence in high-gene-flow marine fish populations remain poorly understood.Gasterosteus aculeatus) distributed across a steep salinity and temperature gradient in the Baltic Sea, by utilizing >30,000 single nucleotide polymorphisms obtained with a pooled RAD-seq approach. We found that genetic diversity and differentiation varied widely across the genome, and identified numerous fairly narrow genomic regions exhibiting signatures of both divergent and balancing selection. Evidence was uncovered for substantial genetic differentiation associated with both salinity and temperature gradients, and many candidate genes associated with local adaptation in the Baltic Sea were identified.We here investigated genome-wide patterns of genetic variability and differentiation in ten marine populations of three-spined stickleback  contains supplementary material, which is available to authorized users. While local adaptation is likely to be of commonplace occurrence, demonstrating its occurrence can be difficult and take substantial research efforts -3. TradiOutlier detection methods have become particularly popular in identifying population structuring and adaptive differentiation in marine fishes, which generally show very low levels of genetic differentiation in neutral marker genes -22 and iGasterosteus aculeatus; e.g.,  and log-transformed geographic distances separating sampling locations.To compare the patterns of genetic variability and differentiation in SNP markers with those in microsatellite markers, we retrieved data from 40 microsatellite loci genotyped for these same populations . A simplTo validate estimates of allelic frequency from the pool-seq data, we genotyped a subset of 30 SNPs from each of the individual fish used for the pooled DNA analyses using the iPlex Gold\u00ae assay on the MassARRAY\u00ae platform (Sequenom) system. This genotyping was performed by the Technology Centre of the Institute for Molecular Medicine Finland at the University of Helsinki. Allele frequencies from this data were estimated with a custom Perl script and compared to estimates from pooled data as obtained using the procedures above.Sequences underlying this study have been deposited in NCBI\u2019s Sequence Read Archive and accession numbers are SRR1596320, SRR1596321, SRR1596322, SRR1596323, SRR1596324, SRR1596325, SRR1596326, SRR1596327, SRR1596328, and SRR1596329."}
+{"text": "The International Federation of Gynecologists and Obstetricians (FIGO) has recently revised the staging of ovarian cancer . It inclThe standard of care for patients with newly diagnosed advanced ovarian cancer has been comprehensive staging laparotomy and primary optimal surgical cytoreduction followed by adjuvant chemotherapy. However, the use of neoadjuvant chemotherapy followed by interval debulking surgery (IDS) as a suitable alternative is supported by multicenter randomized controlled trials . ImagingCT is the primary imaging modality used to stage ovarian cancer. It is complimentary to surgical staging identifying possible sites of unsuspected disease such as pelvic peritoneum, paraaortic nodes, diaphragm and chest ,4. The t"}
+{"text": "A 27-year-old immigrant sought care for inflammatory nodular swelling lesions over the right arm extending upto the neck with axillary and cervical fistulas lasting for six months (A). His medical history was marked by a long forest stay due to conflicts in his homeland . A deep biopsy was made for infectious and histopathological examinations. Cultures were negative. Microscopy on hematoxylin and eosin stained sections showed nodular abscesses organized around multilobated grains showing Splendore-Hoeppli Phenomenon (B). Special stains  were positive. Thus, the histological diagnosis of actinomycetoma probably due to Nocardia was given. In addition, laboratory tests revealed an active hepatitis B infection. After consulting hepatologists, treatment with trimethoprim-sulfametoxazol was introduced, substituted by amoxicillin clavulanate for months with partial clinical response. The evolution was characterized by the reduction of right arm lesions but extension of the infection to the chest wall."}
+{"text": "We urgently need new therapies to improve outcomes after cardiac arrest. Initial studies typically target surrogate endpoints, and these studies help to inform subsequent larger trials that are powered to measure more patient-orientated clinical outcomes such as survival. The competing risk of death and premature assessment of neurological prognosis pose significant challenges to measuring these surrogate endpoints after cardiac arrest. We urgently need new therapies to improve survival with good neurological outcomes after cardiac arrest . CardiacCritical Care, Donnino and colleagues present the results of a randomized controlled trial targeting one such surrogate endpoint, the reversal of shock after cardiac arrest [In this issue of c arrest . Specific arrest . The triHowever, some experts may offer other potential interpretations for the apparent lack of a biological effect, including timing of medication initiation or inclusion of patients without adrenal insufficiency. Another possible explanation is that many patients died before they could achieve shock reversal, rendering this surrogate endpoint unable to discriminate between responders and non-responders. Indeed, more than two-thirds (34/50) of patients died before hospital discharge, and it is unclear how many died before shock reversal . The resUsing a surrogate endpoint becomes even more problematic when it does not actually sit on the causal pathway. Ideally, a surrogate endpoint should have a clear relationship as an intermediate event occurring between the exposure of interest and the more meaningful clinical outcome , in thisCurrent evidence-based guidelines now recommend delaying neurological prognostication for at least 72\u00a0h after return of spontaneous circulation owing to the inaccuracy of clinical examinations performed before this time point . As a co"}
+{"text": "It is now well established that gut flora and chronic liver diseases are closely interrelated. This association is most evident at late stages of the disease: cirrhosis and impaired liver function are associated with intestinal bacterial overgrowth, small bowel dysmotility, increased gut permeability, and decreased immunological defenses, all of which promote bacterial translocation from the gut to the systemic circulation, leading to infections that in turn aggravate liver dysfunction in a vicious circle . For a lNAFLD encompasses a spectrum of hepatic pathology . Accumulation of triglycerides in hepatocytes (hepatic steatosis) is the most common liver phenotype in NAFLD. Some individuals with hepatic steatosis develop nonalcoholic steatohepatitis (NASH), a more severe type of liver damage characterized by hepatic inflammation and liver cell death. In some individuals with the NASH phenotype, liver regeneration cannot keep pace with the increased rate of hepatocyte death, and liver scarring (fibrosis) ensues. Over time, some of these individuals accumulate sufficient fibrosis to develop cirrhosis. Because cirrhosis dramatically increases the risk for both primary liver cancer and overall liver-related mortality, liver cirrhosis is the NAFLD phenotype that has the worst prognosis. Epidemiologic studies indicate that NAFLD is now the most common cause of liver disease in many countries, including the United States . It is eClostridium coccoides [The first evidence that gut dysbiosis might be involved in NAFLD pathogenesis was provided by a few cross-sectional studies that evaluated the association between gut microbiota and the liver phenotype in NAFLD patients. Using quantitative polymerase chain reaction (qPCR) for selected bacteria in a small cohort of 50 patients , Mouzaki et al. showed that NASH patients had decreased fecal Bacteroidetes and increased occoides . The negBlautia and Faecalibacterium genera. The increase in Proteobacteria was mainly explained by an increased abundance of Enterobacteriaceae, especially Escherichia, which was the only abundant genus within the whole bacteria domain exhibiting a significant difference between the obese and the NASH groups. Interestingly, Escherichia are known alcohol-producing bacteria, and serum alcohol concentration was significantly higher in NASH patients compared to obese or control groups.Zhu et al. screened the whole gut microbiota using 16S ribosomal RNA pyrosequencing in a pediatric cohort of 63 children that included 16 healthy controls, 25 obese subjects without known liver disease, and 22 patients with biopsy-proven NASH . They foThe Mouzaki and Zhu studies may seem quite conflicting, the first showing a decrease in Bacteroidetes and the second an increase. However, different populations were studied  using different approaches (qPCR versus pyrosequencing). Both works were also limited by small sample size. Thus, further studies including larger and well-characterized cohorts are required to better identify the associations between gut microbiota and the various liver phenotypes observed in NAFLD.Cross-sectional studies allow for the discovery of potential associations between liver phenotype and certain gut bacteria, but they cannot establish a causal link. By using gut microbiota manipulations, recent animal studies have demonstrated direct roles for gut microbiota in each liver lesion observed in NAFLD: steatosis, NASH, fibrosis, and liver cancer.Conventional C57BL/6J mice fed with a high-fat diet (HFD) for 16 weeks generally display liver steatosis, hyperglycemia, and systemic inflammation (responders), but some mice are nonresponders, developing no metabolic disorder with this dietary manipulation . To explInterindividual differences in the intestinal microbiome and severity of NASH, a more serious NAFLD phenotype, have also been linked. Targeted disruption of the NLRP3 or NLRP6 inflammasome altered the gut microbiota and was associated with enhanced colonic inflammation and NASH in mice fed methionine-choline-deficient-diets . By studGut microbiota can also promote liver fibrosis, a known risk factor for NAFLD-related cirrhosis. In a recent study, mice fed a HFD before bile duct ligation (BDL) developed more severe liver fibrosis than control mice that were fed a standard chow diet before BDL . HFD-relA recent study established a link between the gut microbiota and NAFLD-related hepatocellular carcinoma . NeonataThere are thousands of bacterial species in the gut, and they all display an incredibly wide range of metabolic functions. Now that we realize that gut microbiota modulate NAFLD-related pathophysiology, the challenge is to decipher the mechanisms by which they exacerbate NAFLD severity . As mentNAFLD is associated with a higher prevalence of gastro-oesophageal reflux  that reqIn summary, NAFLD is an extremely common, complex disease that results from interactions between susceptible polygenic backgrounds and environmental factors. Recent evidence has introduced gut microbiota as a new crucial player in this complex story. Deciphering the mechanisms linking gut microbiota to NAFLD and its severity will advance understanding of the disease\u2019s pathogenesis, thereby identifying new therapeutic targets that will ultimately improve the outcome in patients with this disease."}
+{"text": "Injury to the central nervous system (CNS) results in oligodendrocyte cell death and progressive demyelination. Demyelinated axons undergo considerable physiological changes and molecular reorganizations that collectively result in axonal dysfunction, degeneration and loss of sensory and motor functions. Endogenous adult oligodendrocyte precursor cells and neural stem/progenitor cells contribute to the replacement of oligodendrocytes, however, the extent and quality of endogenous remyelination is suboptimal. Emerging evidence indicates that optimal remyelination is restricted by multiple factors including (i) low levels of factors that promote oligodendrogenesis; (ii) cell death among newly generated oligodendrocytes, (iii) inhibitory factors in the post-injury milieu that impede remyelination, and (iv) deficient expression of key growth factors essential for proper re-construction of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement; (4) the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and (5) the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of remyelination for CNS repair. Cnp1, which encodes 2\u2032,3\u2032-cyclic nucleotide phosphodiesterase in oligodendrocytes, show no structural abnormality in myelin but develop axonal swelling and degeneration (Myelin is a cholesterol rich extension of oligodendrocytes and Schwann cells (SCs) plasma membrane, which serves as a specialized insulation sheath for axons in the nervous system. Myelin facilitates axon signal conduction through enabling \u201csaltatory conduction\u201d (see review by neration . These sneration . Survivaneration . ConsideOligodendrocyte precursor cells (OPCs) and neural stem/progenitor cells (NPCs) are two endogenous cell populations, capable of replacing lost oligodendrocytes and remyelinating spared axons following injury . DespiteShiverer mice that lack MBP demonstrate dysmyelinated axons associated with axonal dysfunction and motor impairments . Node of Ranvier is the gap between two adjacent myelin sheaths and contains high concentrations of voltage-dependent Na+ channels on the axonal membrane  and KCNQ K+ channels . Among these molecules, \u03b2IV-spectrin and ankyrin G play a major role in stabilizing the Nav channels at nodal region .In myelinated axons, node of Ranvier was characterized by the localization of voltage-gated sodium .Paranode is the adjacent segment to the node of Ranvier where myelin loops provide an anchor by tethering the myelin to the axonal membrane . Evidencmembrane . The parmembrane . Caspr imembrane . Caspr dmembrane  . Upon receiving of an action potential, Nav channels open, allowing an influx of Na+ into the axon causing depolarization. After each depolarization, Na+/K+ ATPase pumps, located at the juxtaparanodal and internodal regions, exchange axonal Na+ for extracellular K+ . Sodium channel redistribution causes an overall increase in Na+ influx during impulse conduction and increased demand for ATP during repolarization  . Inhibition of sodium channels and NCX has been shown to prevent axonal degeneration , a marker for axonal injury, whereas it is only expressed in 20% of axons, which are \u03b2-APP negative . Our investigations on dysmyelinated Shiverer mice and Long Evans Shaker (LES) rats elucidated the role of K+ channels in axonal function  and non-specific (4-AP) blockers improved axonal conductance; however, this effect was shown to be more dependent on a combination of subunits as a specific blocker of Kv1.1 failed to improve axonal conduction significantly  axons showed 2.2-fold increase in the size of stationary mitochondria sites and 47% increase in the velocity of motile mitochondria following demyelination  showed normal OPC proliferation, differentiation and initiation of myelination. However, these FGF receptor null animals demonstrated defective myelin thickening during postnatal period and remained defective throughout their adulthood  is another growth factor known to promote OPCs survival, migration, and differentiation into mature myelinating oligodendrocytes . Nrg-1 iCurrent evidence shows that remyelination is additionally limited by inhibitory modifications in the post-SCI niche caused by secondary injury mechanisms particularly in chronic SCI . Newly fin vitro and in vivo , Wnt signaling, and Semaphorin 3A (Sema3A) . LINGO-1Collectively, these findings demonstrate that endogenous remyelination was impeded by the inhibitory microenvironment following injury and activated astrocytes and microglia/macrophages seem to play pivotal roles in this inhibition. We will discuss recent studies on the role of resident glial cells and peripherally recruited immune cells in modulating oligodendrocyte replacement and remyelination following CNS injury.Astrocytes play critical role in several aspects of myelination in pathologic CNS including clearance of myelin debris, modulating the activity of oligodendrocytes, myelin maintenance, and renewal . Using aIntercellular connections between astrocytes and oligodendrocytes are critical for the proper physiology of oligodendrocytes. While there are no gap junctions between oligodendrocytes themselves, they are connected to astrocytes through gap junctions, which make oligodendrocytes indirectly interconnected . EvidencAstrocytes provide trophic support to oligodendrocytes by producing growth factors. In an ethidium bromide (EB) induced rat model of spinal cord demyelination, In vivo and in vitro observations have shown that CSPGs limit the ability of OPCs to migrate, mature and myelinate axons , a Toll-like receptor-4 (TLR-4) agonist, caused a significant increase in NG2feration . Interesferation . Of noteferation .Several mechanisms have been proposed for the positive role of macrophages in remyelination. Among the main proposed mechanisms are removal of myelin debris  and prodAltogether, evidence indicates that the type of immune response is a determining factor that can promote or inhibit remyelination in demyelinating CNS lesions , these studies have suggested that remyelination is a key mechanism in promoting functional recovery following SCI and demyelinating conditions . When we transplanted brain-derived NPCs into the spinal cord of subacutely injured rats, we found that survival and oligodendrocyte differentiation of NPCs was limited in the injury microenvironment . Similarly, in our rat SCI studies, evidence of NPC-derived remyelination was confirmed with immunoelectron microscopy against YFP expression in transplanted YFP-NPCs  in enhancing oligodendrocyte differentiation and maturation has been established in the CNS and PNS . GeneticAltogether, current evidence suggests that NPCs can be engineered to act as environmental modulators in addition to their role in cell replacement. This strategy presents a therapeutic avenue for improving microenvironment and optimizing the outcome of cell transplantation in CNS trauma and demyelinating diseases.Due to challenges with oligodendrocyte differentiation of NPCs, transplantation of differentiated glial-restricted precursors (GRP) and OPCs has been pursued in SCI and demyelinating conditions . Early sApplication of OPCs has also shown promising results in supporting remyelination. The potential of human ESC derived OPCs for remyelination has been evaluated in animal models of SCI and demyelination . These sOne important outcome of the Keirstead study was the inability of transplanted OPCs to remyelinate chronically demyelinated axons despite their survival and the capacity to differentiate into oligodendrocytes . This evEfficacy of transplanted OPCs has also been investigated in chronic demyelinating conditions. Transplantation of mouse ESC derived OPCs into a radiation induced rat model of cervical spinal cord demyelination 4 months after radiation therapy, showed successful survival, and migration of these cells toward the lesion and their capacity for oligodendrocyte remyelination . MoreoveIn addition to their role in replacing remyelinating oligodendrocytes, OPCs are known to enhance axo-neuronal growth and survival by producing growth factors such as brain derived neurotrophic factor (BDNF), IGF-1, glial derived growth factor (GDNF), neuregulins (NRGs), and neurotrophins  that potOlfactory ensheathing cells (OECs) have been extensively examined for their potential for remyelination after SCI and demyelinating lesions . OECs arStudies by Another study in nonhuman primate demonstrated the ability of OECs to remyelinate spinal cord axons following demyelination lesions . In thisSince SCs and OECs demonstrate similar characteristics, their behavior and response have been compared in demyelinated spinal cord in co-transplantation studies , 2014. IWhile extensive evidence suggests a direct role for OECs in axonal ensheathing and remyelinating, there are also some reports that have questioned their myelinating capability in SCI . Boyd etRegardless of their direct role in axonal remyelination, OECS are shown to recondition injury environment by producing a host of trophic factors including NGF, BDNF, and CNTF that can support endogenous repair . Studiesin vitro and in vivo studies using specific markers of OECs and SCs is required to specifically distinguish these two cell populations and confirm the myelinating capacity of OECs.Collectively, while application of OECs has shown promising results in experimental models of SCI and demyelination, the ability of OECs for CNS remyelination is still a matter of debate due to their similarities with SCs and potential contamination of OEC cultures with SCs. Further While cell translation is a promising approach for enhancing remyelination following injury, graft rejection due to the host immune reaction poses a major challenge to the success of cell-based therapies . SuccessGeneration of induced pluripotent stem cells (iPSCs) using autologous somatic cells has opened new avenues for developing clinically feasible cell transplantation approaches . Since tin vitro (Shiverer mice, human iPSC-derived OPCs integrated with the host neonatal brain tissue after transplantation, differentiated to MBP expressing oligodendrocytes, remyelinated the dysmyelinated Shiverer axons, and constructed the nodes of Ranvier (Shiverer mice exhibited increased lifespan (Remyelination has been considered as a mechanism underlying the functional improvement observed in iPSCs transplantation strategies . A recenin vitro . In immu Ranvier . No tumolifespan .Table 1, we have listed cell therapies that have been developed to promote oligodendrocytes replacement and remyelination after SCI and MS conditions.Taken together, emerging evidence shows the potential and feasibility of transplanting iPSCs derived NPCs and OPCs for promoting oligodendrocyte replacement and remyelination in demyelinating conditions such as MS and traumatic CNS injury. While promising, the risk of tumorigenicity and proper cell differentiation of this therapy have yet remained to be carefully investigated. In The myelin sheath is an essential component in the CNS and PNS that ensures rapid signal transduction in axons through the nervous system. Myelinated fibers show a highly specialized and organized structure at the node of Ranvier that is vital to their proper functioning. Damage to oligodendrocytes due to trauma or disease results in demyelination that causes aberrant localization and expression of ion channels associated with axonal dysfunction. Although considerable remyelination occurs spontaneously by endogenous CNS progenitor cells, the quality and extend of myelination is not optimal to restore structural and physiological properties of injured axons. Emerging research evidence has uncovered several mechanisms by which oligodendrocyte differentiation and remyelination are regulated within the microenvironment of injury. Inhibitory role of activated glial cells and insufficient expression of promoting factors are major limiting factors that impede remyelination. Over the past years, extensive research efforts have been made to therapeutically promote remyelination following CNS trauma or demyelinating disease. Outcomes of the recent pharmacological and cell-based therapies indicate the impact of remyelination as a mechanism for improving function after injury. Further investigations are needed to develop effective and feasible repair strategies with potential for clinical translation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Hippocrates famously advised, \u201cLet food be thy medicine and thy medicine be thy food.\u201d Numerous plant-derived compounds are used as cancer therapeutics including antimitotics, topoisomerase inhibitors, and kinase inhibitors. Here we will review emerging evidence suggesting that diet derived small RNAs may be an inexpenisive, non-invasive and affordable way to deliver cancer treatments.RNA interference (RNAi), the use of short double-stranded RNA sequences to silence endogenous genes is emerging as the next generation of therapeutics. A well-designed RNAi molecule is able to differentially silence a mutated oncogene with just a single mutated base, leaving the wild-type unaffected. Further, due to the use of intrinsic cellular mechanisms for gene silencing, RNAi exerts an amplified stoichiometric effect, suppressing expression of thousands of mRNA transcripts per RNAi molecule. The challenge with the use of RNAi therapeutics remains their efficient uptake and transportation to target cells. Various delivery techniques are being investigated including viral delivery, engineered nanoparticles and modified nucleic acid chemistry. Each method faces a unique set of challenges including efficiency, safety, and immunogenicity. Utilization of therapeutics by the oral route promises low costs, minimal invasiveness, and high compliance, making this the holy grail of delivery methods.In 2012, a study demonstrated a dietary microRNA (miRNA) from rice was packaged and systemically circulated in consuming mice to silence a liver gene . Our worCells are known to release small vesicles (exosomes and microvesicles) from their membranes, packaging and protecting their contents . Though the biological role of these vesicles is still being explored, the packaging of specific subsets of cellular molecules suggests that exosomes function as mediators of systemic intercellular communication. Recent examples have also suggested that exosomes are able to cross barriers between species. Reports have described the detection of cow's milk-derived miRNAs in serum of the consumers at physiologically relevant concentrations . In mousC. elegans has been well described and transporters for these small RNAs characterized. Animal genomes contain sequences that are homologous to those responsible for the systemic RNAi effect seen in C. elegans. Could we impact dietary miRNA uptake by altering the localization and kinetics of these putative endogenous transporters? We favor a model where therapeutic plant-based miRNAs within the plant matrix display enhanced bioavailability compared to synthetic plant-based miRNAs. Scientists are in the process of expressing therapeutic miRNAs in crops plants to assess efficacy of these engineered foods fed to patients.The future of dietary miRNAs as therapeutics requires new tool development and mechanistic insights regarding uptake and delivery. Dietary miRNA studies are confounded by high variation and low copy number detection. These issues need to be addressed with judicious and standardized detection methods. Use of sensitive tissue sensors will help identify both the presence and functionality of low-level absorbed miRNAs. Dietary RNAi function in In addition, the milk-based approach to therapeutic miRNA delivery may prove especially useful in infants. The developing fetus and newborns may lack acquired \u2018protective' mechanisms in the gut that deter small RNA uptake in adults. Perhaps nature has already provided an ideal mechanism for the safe and efficient delivery of next generation therapeutics, allowing us to rekindle the notion of using foods as medicine."}
+{"text": "Stenting of conduit stenoses are more commonly reported[2].Although percutaneous placement of intravascular stents in congenital heart disease is a common practice, there are few reports regarding native right ventricular outflow tract (RVOT) stenting in children In the preoperative setting, palliation of significant cyanosis by balloon valvuloplasty or RVOT stenting has been advocated by some as a means for reducing symptomatic cyanosis in patients with severe annular hypoplasia. Improvement in antegrade flow is thought to simultaneously enhance pulmonary arterial growth by augmenting pulmonary blood flow. [3]. Most of transcatheter interventions for relieving RVOT were done for conduit stenosis. There are few reports about native RVOT stenting, and to the best of our knowledge there are very few reports on native RVOT stenting in tetralogy of fallot (TOF) with absent left pulmonary artery A 9-year-old child was admitted with cyanosis noted from birth with failure to thrive, cyanotic spells and worsening cyanosis. The patient had undergone central modified Blalock- Tausig (MBT) shunt and right MBT shunt at the ages of three and six respectively. At this admission the child weighed 17 kg, had severe systemic desaturation (<55%) and severe cyanosis, digital clubbing and a New York Heart Association (NYHA) classification of class IV. Clinical examination revealed unremarkable pulmonary examination and 3/6 systolic heart murmur at pulmonary focus.  EKG revealed normal sinus rhythm, right axis deviation and severe right ventricular hypertrophy (RVH). Echocardiography showed TOF anatomy, severe RVOT stenosis with 75 mmHg pressure gradient, RVH, abscent left pulmonary artery branch (LPA), non-functioning previous MBT shunts and major collateral arteries originating from descending aorta. On catheterization, both previous MBT shunts were occluded, the right pulmonary artery (RPA) was small with fairly acceptable arborization. Left lung was supplied by major collateral arteries originating from descending aorta and severe RVOT stenosis was present . RVOT st The arterial oxygen saturation rose to 83%. At six-month follow-up, his arterial oxygen saturation was maintained at above 80% and NYHA functional class was improved to class II. Palliative procedures for relieving RVOT stenosis include either surgical or transcatheter interventions. The indications for RVOT stenting are RV-to-PA conduit stenosis, residual infundibular stenosis after intracardiac repair, TOF with hypoplastic branch pulmonary arteries after palliative shunt surgery, pulmonary atresia after perforation of atretic segment, and RV hypertrophic cardiomyopathy and also as a bridge to surgery. RVOT stenting is also usually indicated in cases in those patients who are not amenable to total surgical repair. Our patient had absent LPA, small RPA and poor clinical condition. Thus, we carried out percutaneous RVOT stenting.RVOT stenting in such patients theoretically can lead to two major problems: overflow and edema of the right lung with resultant vasculopathy in the long term, and free pulmonary valve regurgitation with its consequences that include right ventricular dilatation and dysfunction. In our case, none of these complications occurred, because we chose the stent size with scrutiny and we did not sacrifice the pulmonary valve. Also we did not have complications such as stent migration, ventricular arrhythmias, collapse or fracture of the stent and recurrent stenosis during follow up. To our knowledge the patient has not undergone any curative operation by now. RVOT stenting provides an effective palliative modality for children with TOF and unfavorable pulmonary artery anatomy. Although re-stenosis can occur but it responds to re-dilatation.[4]. In conclusion native RVOT stenting is an effective and safe procedure in appropriately selected patients, especially in whom total correction is not possible. This procedure causes better growth of pulmonary artery branches, decreases right ventricular hypertrophy and increases left ventricular volume. Although many of these stents cannot be dilated to adult size, their efficacy in small infants and children in whom further surgery will ultimately be required is remarkable.  In high risk patients such as our patient with severe cyanosis and high hemoglobin level and blood viscosity, the RVOT stenting decreases perioperative morbidity and mortality"}
+{"text": "Impaired mucociliary clearance (MCC) is a hallmark of acquired chronic airway diseases like chronic bronchitis associated with chronic obstructive pulmonary disease (COPD) and asthma. This manifests as microbial colonization of the lung consequently leading to recurrent respiratory infections. People living with HIV demonstrate increased incidence of these chronic airway diseases. Bacterial pneumonia continues to be an important comorbidity in people living with HIV even though anti-retroviral therapy has succeeded in restoring CD4+ cell counts. People living with HIV demonstrate increased microbial colonization of the lower airways. The microbial flora is similar to that observed in diseases like cystic fibrosis and COPD suggesting that mucociliary dysfunction could be a contributing factor to the increased incidence of chronic airway diseases in people living with HIV. The three principal components of the MCC apparatus are, a mucus layer, ciliary beating, and a periciliary airway surface liquid (ASL) layer that facilitates ciliary beating. Cystic fibrosis transmembrane conductance regulator (CFTR) plays a pivotal role in regulating the periciliary ASL. HIV proteins can suppress all the components of the MCC apparatus by increasing mucus secretion and suppressing CFTR function. This can decrease ASL height leading to suppressed ciliary beating. The effects of HIV on MCC are exacerbated when combined with other aggravating factors like smoking or inhaled substance abuse, which by themselves can suppress one or more components of the MCC system. This review discusses the pathophysiological mechanisms that lead to MCC suppression in people living with HIV who also smoke tobacco or abuse illicit drugs. With the introduction of combination antiretroviral therapy (cART) dramatic declines in morbidity and mortality from HIV/AIDS have been seen  can directly regulate MCC and this is evident in diseases like primary ciliary dyskinesia where attenuated ciliary beating leads to cough, infection, and airway obstruction  and CBF activation rely on the common adenylate cyclase/cAMP/PKA pathway for activation making this pathway critical in maintenance of optimal MCC. HIV infection, environmental stimuli/pollutants like cigarette smoke and smoked substance abuse like crack cocaine, marijuana, methamphetamine can affect one or more components of the MCC system facilitating microbial colonization leading to recurrent lung infections and chronic airway diseases.CO (Diffusing capacity of the lung for carbon monoxide), and anatomic and radiographic emphysema , a significant proportion of HIV-infected individuals are cigarette smokers or smoked substance abusers . Almost 60% of People living with HIV are also smokers . Cocaine was also shown to suppress Cl\u2212 efflux in response to CFTR potentiators like \u03b22-agonsits  and CBF depend on the adenylate cyclase/cAMP/PKA pathway. Hence therapeutics that potentiate this pathway can be used to restore MCC in HIV infected individuals and/or smoked substance abusers Figure . \u03b22-adre van As, , activat van As, , and con van As, . AlternaNormal mucociliary function fails with dysfunction of any one of the major components of the MCC apparatus namely mucus production, ciliary beating, and ASL depth maintenance fail. Suppression of MCC leads to an inefficient clearance of pollutants, pathogens, and allergens. This leads to chronic inflammation and microbial colonization which manifests as chronic airway diseases like asthma, chronic bronchitis associated with COPD, and recurrent lung infections pervasive in HIV infected individuals and/or smoked substance abusers. Smoked substance abuse can suppress MCC independently and an underlying HIV infection can have an additive effect as each of these can suppress one or more components of MCC system. Under these conditions, therapeutics that can restore CFTR function or CBF can restore MCC and prevent microbial colonization consequently decreasing the incidence of pneumonia in People living with HIV.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "V600BRAF mutant melanoma, but acquired resistance is almost universal. Early understanding of how melanomas acquire resistance to BRAFi via MAPK pathway reactivation has guided the development of specific BRAFi-anchored inhibitor combinations designed to overcome resistance. The first of these successful combinations has been between BRAF and MEK inhibitors. Combined BRAF/MEK targeted therapy improves upon BRAFi therapy but is still beset by acquired resistance. Thus, studying how melanomas escape from BRAFi and how these processes are similar or distinct from acquired resistance mechanisms to BRAFi+MEKi remains of the utmost importance to melanoma therapeutics. Recent whole-exome analysis of patient-paired melanoma samples obtained pre-BRAFi treatment and post-disease progression after initial responses have provided landscape genetic perspectives into the nature of tumor heterogeneity, clonal evolution, and core resistance pathways. This benchmark understanding is helping to guide and prioritize clinical studies of BRAFi-based combinations such as that between BRAFi and AKTi. Recent work on the genetic mechanisms of acquired BRAFi+MEKi resistance has shed key insights into the molecular limitations of this therapeutic approach but also novel therapeutic opportunities. Overall, genetic alterations affecting individual genes are not highly recurrent and collectively cannot account for a significant subset of clinical acquired resistance to BRAF or combined BRAF/MEK targeted therapies (MAPKi). Thus, understanding the entire spectrum of genetic and non-genetic mechanisms of acquired MAPKi resistance and the temporal continuum of these evolutionary processes promises to usher in a new era of personalized medicine for melanoma patients.BRAF inhibitors (BRAFi) elicit rapid antitumor responses in the majority of patients with"}
+{"text": "The existing clinical biomarkers for prostate cancer (PCa) are not ideal, since they cannot specifically differentiate between those patients who should be treated immediately and those who should avoid overtreatment. Current screening techniques lack specificity, and a decisive diagnosis of PCa is based on prostate biopsy. Although PCa screening is widely utilized nowadays, two-thirds of the biopsies performed are still unnecessary. Thus, the discovery of noninvasive PCa biomarkers remains an urgent unmet medical need. Once metastasized, there is still no curative therapy. A better understanding of sustained androgen receptor signalling in castration resistant prostate cancer (CRPC) has now led to the development of more effective therapies. We need a better understanding of the molecular and cellular aspects of prostate carcinogenesis and progression. Identification of cancer initiating cells and therapies against these populations is a promising way forward to fight this disease."}
+{"text": "During the last decades research all over the world has highlighted the deleterious effects of pollution on respiratory health of adults and children. Nevertheless, air pollution still represents a significant threat to health. Children are more sensitive than adults to pollutants for several factors: increased respiration relative to body size; physiologic immaturity of respiratory and immunologic systems; low metabolic capacity; longer life expectancy.2), ozone (O3), sulfur dioxide (SO2), may provoke cytotoxic and functional damages in the airways through oxidative stress and inflammation. During the last decades the amount of pollutants from vehicular traffic has significantly increased, especially in urban areas. Recent epidemiological studies have shown that vehicular traffic represents the main source of outdoor pollutants and that it may increase the risk of respiratory outcomes  in children through short-term and long-term effects on airways, lung function and allergic sensitization [Several studies demonstrated an association between exposure to outdoor pollutants and respiratory diseases in childhood. Outdoor pollutants, such as nitrogen oxides (NOx), particulate (PM), carbon monoxide (CO), carbon dioxide . Indoor pollutants concentration depends on external environmental pollutants filtered inside buildings, pollutants generated inside buildings (domestic work) and pollutants generated by personal activities. Combustion products (tobacco smoke and wood burning), CO, CO2, volatile organic compounds (VOC), microbial agents , organic products  are the most important indoor pollutants. There is growing epidemiological evidence that indoor allergen exposure may contribute to the development of allergic respiratory symptoms, such wheezing, coughing and asthma in children [third-hand smoke\u2019 (THS), represents a new concept in the field of tobacco control [Tobacco smoke is one of the environmental pollutants influencing morbidity and death rate in childhood as it is responsible for adverse health effects in both prenatal and postnatal life. Homes remain a site where children are dangerously exposed to environmental tobacco smoke (ETS). The combination of tobacco smoke pollutants which remain in an indoor environment, the so-called \u2018 control .Children still need to be protected with strict air quality standards, in order to improve their respiratory health. Therefore, policies that ensure better air quality are strongly desirable all over the world."}
+{"text": "Recent studies report promising results regarding extracorporeal magnetic separation-based blood purification for the rapid and selective removal of disease-causing compounds from whole blood. High molecular weight compounds, bacteria and cells can be eliminated from blood within minutes, hence offering novel treatment strategies for the management of intoxications and blood stream infections. However, risks associated with incomplete particle separation and the biological consequences of particles entering circulation remain largely unclear. This article discusses the promising future of magnetic separation-based purification while keeping important safety considerations in mind. The direct removal of disease-causing compounds is an inherently attractive treatment modality for a range of pathological conditions, including intoxications and blood stream infections . While lMagnetic separation-based blood purification is especially attractive for the removal of high molecular weight compounds, which are poorly removed by conventional (diffusion-based) blood purifications systems  Fig.\u00a0 2]. The. The2]. 18 single particles). Magnetic measurements for ultrasensitive magnetic nanoparticle detection are now increasingly being explored, which would allow detection of off-target accumulation of nanomaterial and biodegradation of nanomaterials, which in turn could initiate acute and long-term effects such as tumorigenesis, fibrosis and toxic effects.When bringing magnetic blood purification processes closer to clinical evaluation, safety of operation becomes pivotal. Extracorporeal blood purification has been suggested previously to provide a possible alternative to direct in vivo application (injection) of magnetic nanoparticles and to prevent off-target accumulation of magnetic capturing agents (e.g. in the liver or lung). Recent studies have shown that the capturing efficiency of magnetic iron oxide nanoparticles is significantly decreased under clinically desirable blood flow rates, thereby potentially compromising the procedure\u2019s efficiency and safety . Blood fOther important safety aspects include non-specific adsorption of blood constituents  as well as activation of inflammatory reactions in the blood compartment . Such poUnfortunately, there is an ever growing disequilibrium between manuscripts reporting on the synthesis of new nanomaterials and their promising applications and studies actually performing comprehensive risk evaluation of the synthesized materials . At presIn summary, extracorporeal magnetic separation-based blood purification is a promising strategy to rapidly and selectively remove high molecular weight compounds from blood. The technique has been successfully evaluated in vivo in experimental settings investigating the clinically relevant scenarios of intoxication and sepsis in rat models . However"}
+{"text": "Tissue-engineering technologies have progressed rapidly through last decades resulting in the manufacture of quite complex bioartificial tissues with potential use for human organ and tissue regeneration. The manufacture of avascular monolayered tissues such as simple squamous epithelia was initiated a few decades ago and is attracting increasing interest. Their relative morphostructural simplicity makes of their biomimetization a goal, which is currently accessible. The mesothelium is a simple squamous epithelium in nature and is the monolayered tissue lining the walls of large celomic cavities  and internal organs housed inside. Interestingly, mesothelial cells can be harvested in clinically relevant numbers from several anatomical sources and not less important, they also display high transdifferentiation capacities and are low immunogenic characteristics, which endow these cells with therapeutic interest. Their combination with a suitable scaffold  may allow the manufacture of tailored serosal membranes biomimetics with potential spanning a wide range of therapeutic applications, principally for the regeneration of simple squamous-like epithelia such as the visceral and parietal mesothelium vascular endothelium and corneal endothelium among others. Herein, we review recent research progresses in mesothelial cells biology and their clinical sources. We make a particular emphasis on reviewing the different types of biological scaffolds suitable for the manufacture of serosal mesothelial membranes biomimetics. Finally, we also review progresses made in mesothelial cells-based therapeutic applications and propose some possible future directions. Tissue engineering has emerged as a promising alternative to conventional medicine to achieve the healing and regeneration of human damaged tissues and organs. The manufacture of functionally optimal bioartificial tissues is an extremely complex process relying on a comprehensive stepwise combination of cells with scaffolds, extracellular matrices (ECM), and molecular signals. The achievement of such objective usually relies on the combination of advanced knowledge and skills from interdisciplinary specialists, making tissue engineering one of the most challenging fields of biomedical research.Elaborated bioartificial soft tissues and inclusively some bioartificial organs are under current experimental development and evaluation in laboratories  and the surface of celomic visceral organs  and water channels (aquaporins)  used in experimental animal models for human inflammatory diseases. Their protective effects was found to be largely attributed to their hypoimmunogenicity and capacity to regulate innate immune cells functions through secretion of soluble and membrane-bound factors with potent immunosuppressive and/or immunomodulatory activities .+ and CD8+ T lymphocytes (T cells), through their secretion of the immunosuppressor TGF-\u03b2  to harvest mesothelial cells. Due to its largest size, the abdominal cavity is the predominant anatomical source from where mesothelial cells are harvested. Specific peritoneal sources and isolation procedures are reviewed below.2. Like other visceral mesotheliums, the omental mesothelium displays a high cellularity and can provide around one million mesothelial cells from each square centimeter of omental tissue  could significantly improve their healing and reduce the score of peritoneal adhesions , which is the parietal mesothelium of the testicular cavity, has been identified as another reliable source of mesothelial cells  derived from plants or animals are highly sophisticated molecules that emerged from millions of years of natural evolution. They are usually endowed with desirable properties such as high degradability, excellent biocompatibility, and biomechanical properties such as elasticity, tensile strength, and transparency, which make them excellent candidate materials in biomedical engineering applications . We below review different types of biologic materials that have been previously proposed or used in tissue engineering of diverse types of simple squamous epithelia or related tissues  to generate scaffold with a desired form, porosity, and stiffness. Furthermore, and not less important, the polymer chitosan is particularly rich in chemical side groups, that allow covalent binding with other biomaterials to produce biodegradable biocomposites with increased strength and cell adhesion potential  is considered as a new bioengineering treasure by a majority of the biomedical community. Its outstanding biophysical and biochemical properties such as robustness, flexibility, biocompatibility, biodegradability, and processing properties have prompted a general interest for its use in tissue-engineering applications . The prBioartificial functionalized SF fibrous scaffolds have been yet applied for tissue engineering of vascular endothelium and corneal endothelium biomimetics , or scaffolds subjected to posterior treatments (cross-linking) to improve their mechanical properties, can however lose biological properties such as poor cells adhesion index and may require surface treatments with basement membrane proteins. In that sense, different tissue-engineering applications aimed at reproducing and fixing a synthetic basement membrane on top of biologic or synthetic scaffolds to improve adhesive and functional properties of their surface. As example, a study demonstrated that electrospun SF/polycaprolactone meshes posteriorly coated with major basement membrane proteins such as collagen IV, laminins, entactins, and proteoglycans could improve The cellular homogeneity and density achieved in a bioengineered mesothelium or in other types of simple squamous epithelial-like tissues are two critical parameters. The static cell-seeding technique, which basically consists in the manual pipetting of a concentrated cells suspension onto the scaffold, has been shown to be a convenient approach for the establishment of mesothelial cells layers , this \u201csmart polymer\u201d is capable of hydrophobic to hydrophilic reversible transition in response to temperature changes. By only decreasing the culture temperature below its lower critical solution temperature (LCST) that is around 32\u00b0C in pure water, PNIPAAm become hydrophobic, and consequently force the release of cells monolayer from the dishes  represents the main clinical strategy to prevent or reduce post-operative peritoneal adhesions .The development of new adhesion barriers remains however under current research due to the partial effectiveness of the commercially available adhesion barriers. A host of experimental approaches involving pharmacologic treatments and anti-adhesive polymers or molecules promoting endogenous mesothelialization are also under intense research  arterial grafts seeded with mesothelial cells however generated markedly divergent outcomes, suggesting that the adhesion capacity of mesothelial cells on this type of synthetic material is reduced and thus strongly influences their long-term patency . Thin membranes created from electrospun bombyx mori silk fibroin (BMSF) are transparent and were shown to support the growth of human corneal epithelial (HCE) cells  is made up of two types of synoviocytes: \u201cphagocytic or absorptive\u201d macrophage-like cells (Type A) and \u201csecretory\u201d fibroblast-like synoviocytes (Type B), these later accounting for around 80% of the total intimal cells Smith, . SynoviaInterestingly, a careful revision of the literature provides evidence of phenotypic similarities between fibroblast-like synoviocytes and mesothelial cells. Hence, both cellular phenotypes are mesodermal epithelial-like cells which display abundant microvilli on their apical membrane, a structural feature that is commonly found in cells secreting fluid Smith, . In addiThe evidence of phenotypic similarities between fibroblast-like synoviocytes and mesothelial cells stated above could lead to the suggestion that mesothelial cells may represent a putative cellular surrogate of fibroblast-like synoviocytes and suggest thus that mesothelial cells could be potentially useful for the regeneration of the synovial membrane lining.The vestibular duct  is a small cavity filled with perilymph inside the cochlea of the inner ear. The scala vestibuli is separated from the scala media by a very thin membrane termed vestibular membrane or Reissner\u2019s membrane. The Reissner\u2019s membrane facing the scala vestibuli is covered by a monolayer of mesothelial cells. The opposite side facing the cochlear duct a cavity filled by endolymph is covered by an epithelium. A thin basal lamina separates the mesothelium and epithelium layers : Structural molecules produced by cells and excreted to the extracellular space within the tissues and that provide cohesive structure to hold tissues together.Great omentum: A large fold of the peritoneum hanging down from the stomach and containing abundant vasculature and perivascular adipose tissue.Heterologous transplant: Cells, grafts, or tissues derived from an individual of a different species in which they are transplanted, being therefore antigenically dissimilar.Immunomodulation: The adjustment of the immune response to a desired level through immunopotentiation, immunosuppression, or induction of immunologic tolerance.Immunosuppression: Reduction of the immune response, generally through the use of drugs, active molecules, or cells to prevent grafts rejection or control autoimmune diseases.Lineage tracing study: Identification and follow-up of all progeny of a single cell using different experimental strategies available for lineage tracing such as live-cell imaging, fluorescent reporter constructs, inducible gene expression, and inducible recombinases.Matrix: The intercellular substance of a tissue or the tissue from which a structure develops.Mesoderm: One of the three primary germ layers developing in the early embryo.Mesothelial cells: A type of simple squamous epithelial cells lining the walls of celomic body cavities and visceral organs located inside.Mesothelioma: Tumor arising from malignant transformation of mesothelial cells.Myofibroblast: A fibroblastic cell with some contractile properties and that is usually considered an intermediate cell between fibroblasts and smooth muscle cells.Parietal mesothelial cells: The mesothelial cells lining the parietal surface of serous body cavities.Polymeric molecules: Molecules of high molecular weight generated through polymerization of smaller molecules (monomers). They are produced either by living organisms or chemically.Regulatory T cells: A subtype of T lymphocytes with immunosuppressive properties and capacities to abrogate autoimmune diseases.Serosal membranes: Membranes lining serous cavities and composed of a single layer of simple squamous epithelial resting on a basement membrane underneath.Simple squamous epithelium: A simple epithelium composed by a single layer of thin and flat polygonal epithelial cells with secretive properties.Transdifferentiation: The transformation of a differentiated somatic cell into another type without the need of reverting into an intermediate pluripotent state.Vascular endothelium: The monolayer of cells lining the lumen of blood vessels.Visceral mesothelial cells: Mesothelial cells covering visceral organs inside body cavities.Visceral organs: Organs located within internal body cavities, especially those located within the abdomen.Christian Claude Lachaud, Abdelkrim Hmadcha, and Bernat Soria are inventors of the Patent  filed by the Fundaci\u00f3n Progreso y Salud, Vissum Corporation and NewBiotechnic SA. Berta Rodriguez-Campins is an employee of NBT SA."}
+{"text": "ETCO2 is currently the only parameter proven to correlate with the likelihood of return of spontaneous circulation (ROSC), although the prediction of long-term outcome based on ETCO2 values has not been established [2 adequately, invasive airway management is necessary and measured values are influenced by different lung pathologies.The goal of cardiopulmonary resuscitation (CPR) is to preserve the pre-arrest neurological state by maintaining sufficient cerebral blood flow and oxygenation, but the predictors thereof remain largely unknown. Despite recent attempts to improve the quality of basic and advanced life support, no monitored link to the neurological and physiological response of these CPR efforts has been established. The difficult decision to end pre-hospital resuscitation efforts is currently based on the circumstances of cardiac arrest, length of resuscitation efforts (if available), knowledge of pre-morbid physiological reserves, and (if present) end-tidal carbon dioxide  measures the regional difference between oxygenated and deoxygenated hemoglobin, which expresses the difference in oxygen supply and demand. It determines cerebral tissue saturation non-invasively and independent of pulsatile flow. M\u00fcllner and colleagues  were theAlmost 20\u00a0years after the first published study on cerebral saturation monitoring during CPR, a revival of cerebral saturation measurement during CPR is taking place. Recent published research measures cerebral saturation in patients with ongoing CPR at arrival to the emergency department, but different cerebral saturation devices and different methods for analysis of NIRS data are used. The latest research on NIRS in the CPR setting focuses on two main questions.Firstly, can cerebral saturation values predict ROSC or neurological outcome? Ito and colleagues  observedThe second question recently addressed is whether cerebral saturation values can guide CPR efforts. Cerebral saturation measurements are probably more useful as a dynamic measurement instead of a static, single value. Hence, low cerebral saturation values could be interpreted as a need for interventions aimed at improving cerebral oxygenation during CPR. Sustained low cerebral saturation values, despite these interventions, could indicate futile CPR efforts. It has been noted that no patients with a mean cerebral saturation of less than 30% achieved ROSC . In contIn conclusion, preliminary data suggest that monitoring of cerebral saturation during CPR seems a likely predictor of both ROSC and neurological outcome and that it might have a role guiding CPR interventions. Although the current knowledge, obtained from small observational studies, is limited, both the further development of NIRS devices and the likely execution of well-designed large blinded observational trials, particularly in the difficult environment of out-of-hospital CPR, bode well for the future. A real-time monitoring tool providing vital information on the neurological and physiological response to CPR efforts and with predictive value for neurological outcome seems close at hand."}
+{"text": "Stone tools provide some of the most abundant, continuous, and high resolution evidence of behavioral change over human evolution, but their implications for cognitive evolution have remained unclear. We investigated the neurophysiological demands of stone toolmaking by training modern subjects in known Paleolithic methods  and collecting structural and functional brain imaging data as they made technical judgments  about planned actions on partially completed tools. Results show that this task affected neural activity and functional connectivity in dorsal prefrontal cortex, that effect magnitude correlated with the frequency of correct strategic judgments, and that the frequency of correct strategic judgments was predictive of success in Acheulean, but not Oldowan, toolmaking. This corroborates hypothesized cognitive control demands of Acheulean toolmaking, specifically including information monitoring and manipulation functions attributed to the \"central executive\" of working memory. More broadly, it develops empirical methods for assessing the differential cognitive demands of Paleolithic technologies, and expands the scope of evolutionary hypotheses that can be tested using the available archaeological record. Enhancement of prefrontal executive control is seen as critical to the emergence of modern human cognition \u20134, but eExperimental replication of prehistoric behavior is a core research method in archaeology , 15 thatOur previous research examined brain responses to naturalistic stone toolmaking behavior execution , 21 and physical accuracy of predicted outcomes vs. their strategic appropriateness in achieving toolmaking goals. This manipulation approximates a conventional archaeological distinction between savoir-faire (know-how) and connaissance (knowledge about) in stone toolmaking . Although progress in archaeological and comparative research has fostered healthy skepticism regarding such naive appraisals , results5. Althou"}
+{"text": "Transfer cells are ubiquitous plant cells that play an important role in plant development as well as in responses to biotic and abiotic stresses. They are highly specialized and differentiated cells playing a central role in the acquisition, distribution and exchange of nutrients. Their unique structural traits are characterized by augmented ingrowths of invaginated secondary wall material, unsheathed by an amplified area of plasma membrane enriched in a suite of solute transporters. Similar morphological features can be perceived in vascular root feeding cells induced by sedentary plant-parasitic nematodes, such as root-knot and cyst nematodes, in a wide range of plant hosts. Despite their close phylogenetic relationship, these obligatory biotrophic plant pathogens engage different approaches when reprogramming root cells into giant cells or syncytia, respectively. Both nematode feeding-cells types will serve as the main source of nutrients until the end of the nematode life cycle. In both cases, these nematodes are able to remarkably maneuver and reprogram plant host cells. In this review we will discuss the structure, function and formation of these specialized multinucleate cells that act as nutrient transfer cells accumulating and synthesizing components needed for survival and successful offspring of plant-parasitic nematodes. Plant cells with transfer-like functions are also a renowned subject of interest involving still poorly understood molecular and cellular transport processes. Products secreted by nematodes through their stylet induce the differentiation of root cells into feeding structures and the content of this secretion remains largely unidentified  and RKN nematodes (family Meloidogynidae) are considered the major economically important plant parasitic species . FeedingFigures 2A,B; Root-knot nematodes induce galls composed of giant cells surrounded by neighboring cells (NCs), giving the root a shape of a knot  genes  genes ,b; polygenes PG;  and pect PG; PE; ,b. This  trans-differentiation of parenchyma vascular cells into giant or syncytial TCs.Apart from cell wall changes pathogens may also locally interfere with signaling pathways changing the concentration of sugars such as sucrose  or plantFigure 3; Figures 1A and 3; As mentioned above, RKN species induce root galls containing giant-feeding cells in a large variety of plant hosts. In giant cells induced by RKN, wall thickening is observed as patches expanding, merging, branching and often of uneven cell wall material deposition at early stages of giant cell development suggesting an existing mechanism responsible for depositing irregular cell wall material  of the Potato leaf roll polerovirus fused to GFP , although showing a strong reduction in wound callose and papillary callose formation after mechanical wounding and infection with Sphaerotheca fusca  family were verified to be upregulated in young nematode feeding sites  and three down-regulated  genes in syncytia were validated by quantitative RT-PCR. While STP4, STP7, and STP12 belong to the STP sugar transport protein family, MEX1 and GTP2 are plastidial transporter genes, and SFP1 is a senescence-related monosaccharide transporter. A T-DNA insertion line of the most up-regulated gene (STP12) showed that insufficient sugar in feeding sites resulted in increased male ratios since females need higher sugar concentration in order to grow and reproduce , and PSK (phytosulfokines) are also associated with the RKN or CN feeding cell formation  and the transport occurring within these solute transfer sites involving the feeding cell and numerous phloem and xylem elements along this sink. It remains ambiguous as to what switches ordinary plant cells into transfer-feeding cells that supply nematodes with solutes for their development and reproduction. These plant cellular morphological changes might be caused directly or indirectly by secreted products or feeding activity employed by the nematode during parasitism. What triggers and regulates the switch from apoplasmic to symplastic solute supply and the gating of PD is yet to be discovered. Further functional genetic approaches as well as microscopic studies will help to elucidate genes involved in this process in order to comprehend how nematode induced TCs operate.Nematode-induced syncytia or giant cells constitute a multinucleate model of TCs, and it is generally believed that wall protuberances arise as a result of nematode demand for nutrients. Although some information on solute supply has been mostly reported for syncytia induced by The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Endocannabinoids (eCBs) are bioactive lipids which primarily influence synaptic communication in the nervous system. They are synthesized by neurons but also by microglia, especially under inflammation. To exert their function, eCBs travel across the intercellular space. However, how eCBs move extracellularly remains obscure. Our recent evidence indicates that reactive microglia release extracellular vesicles (EVs), which may represent an ideal vehicle for the transport of hydrophobic eCBs. Hence, in this study we investigated whether microglial EVs carry eCBs and may influence neurotransmission. First we analyzed the eCB content of EVs and found a clear enrichment of anandamide (AEA) in EVs relative to parental microglia. This analysis revealed higher AEA levels in EVs shed from the plasma membrane (microvesicles), compared to those which originate from the endocytic compartment (exosomes). To bioassay the activity of vesicular AEA, we used patch clamp analysis of miniature inhibitory post-synaptic currents (mIPSC) on hippocampal neurons in vitro. Exposure of neurons to microvesicles (MVs) induced a significant decrease in mIPSC frequency, mimicking the action of CB1R agonists. The involvement of vesicular AEA in this phenomenon was inferred from the ability of the CB1R antagonist SR141716A to block the reduction of mIPSC frequency evoked by MVs. Western blot analysis showed that MVs induces an increase in ERK phosphorylation, which was completely inhibited by SR141716A. This indicate that CB1R activation by AEA-storing MVs translates into downstream signaling. Finally, consistent with a surface localization of AEA, MVs membranes maintained their capability to decrease mIPSC frequency. Overall, this study shows that microglial MVs carry AEA on their surface to stimulate CB1R on target GABAergic neurons thus playing a crucial role in the modulation of inhibitory transmission."}
+{"text": "Trichomes are differentiated epidermal cells on above ground organs of nearly all land plants. They play important protective roles as structural defenses upon biotic attacks such as herbivory, oviposition and fungal infections, and against abiotic stressors such as drought, heat, freezing, excess of light, and UV radiation. The pattern and density of trichomes is highly variable within natural population suggesting tradeoffs between traits positively affecting fitness such as resistance and the costs of trichome production. The spatial distribution of trichomes is regulated through a combination of endogenous developmental programs and external signals. This review summarizes the current understanding on the molecular basis of the natural variation and the role of phytohormones and environmental stimuli on trichome patterning. Plants have evolved sophisticated morphological and chemical systems to cope with biotic and abiotic challenges. Differentiated epidermal cells such as leave hairs or trichomes represent one of these systems. Trichomes develop on above ground organs including seeds and fruits and occur in a large variety of morphologies. They can be single-celled or multicellular, branched or unbranched, and glandular or non-glandular, characteristics often used for species identification , 2008. TIn adverse environments, trichomes are beneficial because they influence the water balance, protect photosynthesis and reduce photoinhibition. Their density is negatively correlated with the rate of transpiration  and thatSolanum lycopersicum) with its parasite Cuscuta pentagona  on grapevine buds (Botrytis cinerea on harvested tomato (Phoma clematidina on clematis (Beauveria bassiana on poppy (Solanum berthaultii) and its resistance to Phytophthora infestans (Cicer arietinum) with Ascochyta rabiei the concentration of a highly acidic trichome exudate is crucial. At low concentrations the exudate promotes germination of Ascochyta rabiei conidia while at high concentrations germination is inhibited (Nicotiana tabacum) produce a potent inhibitor, T-phylloplanin, which inhibits germination of the oomycete Peronospora tabacina  and negative regulators . GL2 encodes a homeodomain protein required for subsequent phases of trichome morphogenesis such as endoreduplication, branching, and maturation of the cell wall. The negative regulators are seven partially redundant single-repeat MYBs such as CAPRICE (CPC), TRIPTYCHON (TRY), ENHANCER OF TRY AND CPC 1, 2, 3 , and TRICHOMELESS1 and 2  promote trichome initiation and morphogenesis  by inducn leaves  and appln leaves . For then leaves .Arabidopsis (As mentioned above trichomes can be induced by wounding and insect attack  and the bidopsis  and thatbidopsis .CONSTITUTIVE EXPRESSION OF PR GENE (cpr) mutants  lines  mapping. The first QTL analysis discovered a major locus, named REDUCED TRICHOME NUMBER (RTN) in Arabidopsis thaliana and used recombinant inbred lines (RIL) derived from a cross between the low trichome density Ler and the medium density Col-accessions . With the availability of the 1001 Arabidopsis genomes association studies of the remaining candidate genes are now straight forward  lines . Larkin cessions . This locessions  and evencessions  as majorT2 SAD2; , TTG2, C density . While t forward .Arabidopsis they are still not sufficient to explain all the naturally occurring variations in this plants species. Great potential for the identification of still missing regulators will come from next generation sequencing possibilities in combination with classical genetic, population genetic and comparative approaches using different plant species. There are already several examples where trichome patterning regulators from wild relatives or even crops and distantly related species such as cotton, tomato and hop have been successfully and functionally studied in the model plant Arabidopsis (Although the major players of trichome density regulation have been identified in the model plant bidopsis . HoweverThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Abdominal stab injury is potential life-threatening injuries. Operation should be considered if wound violate the peritoneal layer and/or complicated with hemodynamic compromise, peritonitis, impalement, or evisceration. It is well known there are several diagnostic tools to evaluate the necessity of operation for a patient with abdominal stab injury. Despite numerous diagnostic tools, including local wound exploration, CT, diagnostic peritoneal lavage, or FAST, were currently performed in emergent department neither of them has satisfying sensitivity and specificity. Abdominal wall ultrasonography has been used many abdominal wall disease, like hernia, abdominal wall hematoma. We used abdominal wall ultrasonography for diagnosis of abdominal wall stabbing injuryFeasibility of abdominal wall ultrasonography for diagnosis of abdominal wall stabbing injuryA 76-year-old man visited our emergent department due to multiple anterior abdominal stab wounds for suicide. His initially vital signs were relatively stable. Physical examination revealed multiple stabbing wound with bleeding, local tender over wound without rebounding tenderness. Laboratory finding is nothing particular. Patient received local wound exploration by senior surgical resident but inconclusive. Focused Assessment of Sonography for Trauma also showed negative result. Therefore, we perform the abdominal wall ulrasonography and revealed an apparent penetrating tract through the abdominal wall and disruption of peritoneal layer.(figure 2 and video 1) We use Toshiba Nemio in sterile method from start to finish. Computed tomography also revealed penetrating injury of abdominal wall and no obvious free air.(figure 3) Finally, the patient underwent the laparoscopic surgery and revealed four abdominal wall stab wounds at the mild abdomen near the umbilicus and the epigastric area(fiugre 4), perforation of transverse colon. Then he received laparoscopic repair of abdominal wall injury and colostomy. Patient was discharged smoothly after surgery.We performed the abdominal wall ultrasonography to evaluate the stab wound and successfully diagnosed the wound penetrating peritoneal layering. Moreover, in comparison with other diagnostic tools, abdominal wall ultrasonography can provide additional advantages, such as rapid, painless, non-invasion, non-radiation and more detail of wound tract structure. By using the ultrasonography, which could follow the tract of abdominal stab injury (the direct sign) and hematoma beneath the stab wound(the indirect sign) in another case(figure 5), or positive of FAST. Abdominal wall ultrasonagraphy can help clinicians to make the decision easier in further management of abdominal stab injury.The abdominal wall ultrasonography could demonstrate the tract of stab wound, and provide more detail of wound, and help the decision making, especially in hemodynamic stable patient. Further prospective study is need for evaluating the abdominal wall ultrasonograpy in stabbing wound."}
+{"text": "We built a network of curated interactions between human proteins involved with centrioles, centrosomes, basal bodies and cilia to provide a global functional characterization of the Cilia/Centrosome Complex interactome (CCCI).http://string-db.org). Network analyses were performed using Cytoscape and communities were extracted using the MCODE algorithm. The gene-wise network was explored by Gene Ontology (GO) analysis. The transcription factor (TF) analysis was performed using information obtained from \"ConsSites\" and \"tfbsConsFactors\" track of the UCSC Genome Browser.Human ciliary genes were collected from available databases and interactions among genes were obtained from the STRING database  and in ciliopathy genes. We found 11 communities enriched in 30 TFs. The identified TFs are involved in developmental processes, cell cycle control, in the immune response and in muscle differentiation.CCCI is a publically available tool, which will allow to clarify the roles of previously unknown ciliary functions and to elucidate the molecular mechanisms underlying ciliary-associated phenotypes."}
+{"text": "Recent advances in biomaterial science and tissue engineering technology have greatly spurred the development of regenerative endodontics. This has led to a paradigm shift in endodontic treatment from simply filling the root canal systems with biologically inert materials to restoring the infected dental pulp with functional replacement tissues. Currently, cell transplantation has gained increasing attention as a scientifically valid method for dentin-pulp complex regeneration. This multidisciplinary approach which involves the interplay of three key elements of tissue engineering\u2014stem cells, scaffolds, and signaling molecules\u2014has produced an impressive number of favorable outcomes in preclinical animal studies. Nevertheless, many practical hurdles need to be overcome prior to its application in clinical settings. Apart from the potential health risks of immunological rejection and pathogenic transmission, the lack of a well-established banking system for the isolation and storage of dental-derived stem cells is the most pressing issue that awaits resolution and the properties of supportive scaffold materials vary across different studies and remain inconsistent. This review critically examines the classic triad of tissue engineering utilized in current regenerative endodontics and summarizes the possible techniques developed for dentin/pulp regeneration. A routine clinical treatment for infected or necrotic pulp tissue is root canal therapy (RCT) which involves the extirpation of injured pulp and the filling of root canal systems with bioinert synthetic materials. In spite of its satisfactory clinical efficacy in infection control and pain elimination, classical treatment modalities like RCT only seek to seal the space of root canal system without restoring its original function. Therefore, various complications such as tooth fractures and reinfection occur more often in teeth that have undergone RCT due to their loss of sensory function and consequent lack of natural defense mechanisms . The hisstitutes . in vitro cultured cells and scaffolds into target anatomic location [Tissue engineering, an emerging popular domain of bioscience, is a multidisciplinary research area with the ultimate aim of restoring, maintaining, and regenerating damaged/lost tissue with biologically engineered replacements through combining the principles of biology, medicine, and engineering . The advlocation . This re in vitro colony formation, and trilineage mesenchymal differentiation potential [Stem cells are commonly defined as clonogenic cells that exhibit remarkable long-term self-renewal and multilineage differentiation capacity. Based on their distinction in plasticity , stem cells can be further subdivided into embryonic stem cells (ESCs) and postnatal stem cells . Althougotential . Numerou in vitro [Gronthos et al. were the pioneers that identified and characterized a stem cell population within adult human dental pulp tissue , 10. Isoin vitro \u201313. Whenin vitro , 14. In in vitro , 14, 15. in vitro osteogenic/odontogenic, adipogenic, and neurogenic differentiation capacity when induced by respective stimuli. In vivo studies employing animal models also demonstrated the odontogenic capacity of SCAP [SCAP were initially isolated and characterized by Sonoyama et al. from the apical papilla, an embryonic-like soft tissue located at the apex of incompletely developed human permanent teeth . Similar of SCAP , 17. Typ of SCAP . Conside of SCAP . in vitro differentiation potential towards the osteogenic and adipogenic lineages compared to DPSCs [ In vivo transplantation of SHED loaded on scaffolds/tooth slices into immunocompromised mice has resulted in the formation of tissue that closely resembles physiological dental pulp in cellular morphology and histological architecture [SHED were first isolated by Miura et al. from vital pulp remnants of exfoliated deciduous teeth . Althougto DPSCs . In vivoitecture , 22. An itecture .\u2212/CD146\u2212 side population (SP) cells with type I and III collagen led to the formation of pulp-like tissues with capillaries and neuronal processes by day 14 [\u2212/CD146\u2212 SP cells and CD 105+ cells with stromal cell-derived factor-1 (SDF-1) successfully induced complete regeneration of pulp-like tissue with vasculogenesis and neurogenesis within 14 days. This was followed by further formation of a continuous dentin-like structure along the dentinal wall of root canals [Positive or negative isolation strategy is normally adopted for the selection of a specific, more homogeneous subpopulation of MSCs with optimal phenotypes. Recently, these techniques have also been reported in the fractionation of dental pulp stem cells, designed to isolate subpopulations that possess higher angiogenic and neurogenic potentials, both of which contribute to pulp homeostasis . In a cay day 14 . In a cat canals , 27. In \u2212 SP cells with SDF-1 yielded tissues that were morphologically identical to that derived by transplanted pulp CD31\u2212 SP cells and all three regenerated tissues possess functional properties similar to normal pulp [Given that the availability and quality of dental pulp tissue sharply decline with age, nonodontogenic stem cells have been investigated as alternative sources among which stem cells harvested from bone marrow and adipose tissue showed greatest promise owing to their advantageous biological properties and partially shared gene expression profile of various growth factors, extracellular matrix (ECM) proteins, and transcriptional regulators , 29. Ishmal pulp . Consistmal pulp . Further in vitro [ in vivo study demonstrated the formation of dentin-like and dental pulp-like structures upon transplantation of the reconstructed tooth germs derived from miPSCs together with epithelium and mesenchyme into mouse subrenal capsule [The generating of induced pluripotent stem cells (iPSCs) is a groundbreaking work that revolutionizes the present scenario of regenerative medicine. This can be realized through reprograming adult somatic cells or terminally differentiated cells back to a pluripotent state via overexpression of four defined transcription factors \u201334. Analin vitro . These N capsule . DespiteWhen cell-based therapy is adopted for dentin/pulp tissue regeneration, the procuring of a readily available stem cell source is of the highest priority. While the favorable properties of low immunogenicity and immunosuppression exhibited by oral-derived adult stem cells offer much possibility for allogeneic cell transplantation, these adult stem cells will likely express histocompatibility antigens upon differentiation and will thus not be able to sustain the immunosuppressed state \u201341. HencConventionally, infected or inflamed pulp tissue will be completely removed by pulpectomy in order to create a sterile environment for the subsequent restorative treatment. However, a considerable portion of healthy and vital pulp tissue might also be discarded as medical waste together with the necrotic dental pulp. Recently various studies have reported successful isolation of viable stem cells from inflamed dental pulp, but with conflicting regenerative effects on dentin/pulp tissue. Yazid et al. showed that MSCs obtained from primary inflamed pulp exhibited highly dysfunctional MSCs stemness and minimal immunoregulatory capacity . By contThe right time for banking cells is a thought-provoking question. There seems to be a noticeable progressive age-associated reduction in regenerative capacity of MSCs present in multiple adult organs including teeth . MoleculIn addition to the physical state of dental tissue, other general health-associated parameters like smoking and nutrition are possible factors that can influence the physiological activity of dental pulp cells (DPCs) and overall biological properties of dental pulp tissue, although the evidence is weak , 54.A scaffold is one of the three essential components of classic tissue engineering strategy. Functionally, scaffolds provide a three-dimensional (3D) temporary structural framework for cell seeding, adhesion, proliferation, and spatial distribution until their complete replacement by the newly synthesized matrix of endogenous host cells , 56. Cur in vitro and also facilitating pulpal tissue regeneration in a full-length root canal in vivo [Collagen, a major macromolecular constituent of dentin ECM with excellent biocompatibility, is the most extensively studied naturally occurring material for dental tissue engineering. Comparison of different natural polymers including collagen type I, collagen type III, chitosan, and gelatin suggests that hDPCs plated on collagens, particularly type I collagen, perform best in terms of proliferation and mineralization capacity . Combine in vivo . When cu in vivo . de novo regeneration of vascularized pulp-like tissue in an empty root canal space accompanied by deposition of dentin-like tissues along dentinal walls formed by newly derived odontoblast-like cells [Synthetic materials such as polylactic acid (PLA), polyglycolic acid (PGA), and their copolymer poly lactic-glycolic acid (PLGA) have attained approval from the United States Food and Drug Administration (FDA) for wide application due to their nontoxic properties. An earlier study demonstrated that PGA accelerated collagen deposition and appeared to be more conducive to DPCs proliferation compared to alginate or collagen scaffolds . A highlke cells .\u03b21 (TGF-b \u03b21), and TGF-b \u03b22, when platelets are activated [Platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) are other potential materials easily obtained from autologous blood and thus can minimize the risk of adverse immunological response. These can release many vasculogenesis-associated factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-b ctivated , 64. Recctivated , 65.In a nutshell, although both natural polymers and synthetic materials have demonstrated promising therapeutic effects on dentin/pulp regeneration, neither of them embraces all the favorable properties that can recapitulate the cellular physiological microenvironment. Natural polymers are usually afflicted with issues of purity and antigenicity. Synthetic polymers, albeit circumventing the potential risks of immunoreactivity and being more readily amenable to clinical applications with tailor-made physiochemical properties, still lack bioactive molecules present in native ECM that are necessary for cellular recognition and interaction, in addition to various technical challenges in regulating pore sizes and achieving high porosity structures .Recently, nanofibrous polymer scaffolds have been synthesized to biomimic ECM in structure and function. They appear superior to other scaffold materials at microstructural level or other morphological arrangements owing to their interconnected porous networks and advantages in high surface area to volume ratio . Most st in vivo. Comparisons of data extracted from different studies suggest that the fate of implanted stem/progenitor cells may be site-associated rather than being influenced by their origin, with a tendency to differentiate into the odontoblast phenotype when transplanted into the pulp chamber but into other cell lineages when transplanted into other target locations [ in situ dentin/pulp regeneration, may be lost during the transplantation process. It cannot be ruled out that the quiescent host stem cells residing in the niche of the transplantation site may be stimulated and recruited into the regenerated construct together with pulp-derived stem cells and thus pulp cell may lose its predominant effect on tissue mineralization [ in situ pulp regeneration is often disadvantaged by ischemic conditions due to the constricted opening at the root apex allowing for blood microcirculation while root fragments or tooth slices rarely face this problem. Despite the deficiency of ectopic models in mimicking the in situ tooth microenvironment in clinical practice, the implementation of orthotropic model encounters formidable challenges. After transplantation into the pulpectomized teeth, the fabricated tissue replacement has a tendency to adhere to the coronal portion of root canals, leaving the middle and apical parts incompletely filled [Several preclinical animal models based either on ectopic or on orthotropic transplantation approach have been developed to translate cell-based therapy into clinical reality. Although a substantial body of evidence has confirmed the regeneration of mineralized tissue, some studies still failed to detect the presence of dentin-like tissue but instead found tissues with bone-like morphology . This isocations . SCAP, alization . Additioy filled . This isy filled . In addiy filled , 82.The critical requirements for successful dentin/pulp regeneration are not confined to the morphogenesis of dentin/pulp-like tissue but should also be accompanied with angiogenesis and neurogenesis. It must be noted that the deposited dentin-like tissues on existing dentin structure are produced by the newly differentiated odontoblasts from the dentinal wall within the root canal space. Currently, potential strategies dedicated to optimizing stem cell-mediated dentin/pulp regeneration are directed towards two main objectives: firstly angiogenesis induction and, secondly, the promotion of tissue mineralization.The long-term survival of tissue-engineered implants largely depends on rapid establishment of adequate blood supply at the graft sites which functions as a conduit for nutrient transportation, oxygen delivery, and metabolic waste excretion. This principle is particularly relevant to dentin/pulp regeneration given that the opening at root apex is too constricted to allow for intracanal blood infusion . Due to  ex vivo pulp cell culture and expansion are normally conducted. For these reasons, some investigators have tried to simulate the conditions of pulp hypoxia and explore how DPCs respond to low oxygen levels. Amemiya et al. demonstrated that canine DPCs under hypooxygenation conditions exhibited higher formazan production and growth rate compared to pulp cells incubated under normoxic conditions [ in vitro than those incubated under normoxic conditions [ in vitro and in vivo [\u03b1, ephrinB2, and VEGF [Hypoxia is a common phenomenon encountered by dental pulp tissue under both pathological and nonpathological conditions. Due to their unique anatomical structure that is surrounded by hard dentin with only a narrow opening at root apices, DPCs are typically susceptible to ischemia during traumatic injuries when surrounding vascular bundles are severely ruptured or during restorative treatment whereby local anesthetics containing vasoconstrictors slow down the velocity of blood microcirculation. Exposure to ischemia blocks the oxygen influx transported by the blood stream and thus disrupts the oxygen homeostasis of dental pulp . In addinditions . Subsequnditions , 86. Lid in vivo . Consistand VEGF . Collect\u03b1-smooth muscle actin and several mesenchymal and endothelial cell markers by perivascular cells [ in vitro and found that HUVECs dramatically facilitated the osteogenic/odontogenic differentiation of cocultured DPSCs compared with either DPSC-alone or HUVEC-alone cultures. In turn, DPSCs stabilized and increased the longevity of the preexisting HUVEC-formed vasculature [ ex vivo tubular-like networks than coculture of ECs with bone marrow mesenchymal stem cells (BMMSCs). Interestingly, this study not only proved the pericyte-like topography and potential function of DPSCs but also identified that the mechanism of DPSCs in angiogenic induction was VEGFR-2 dependent [ in vitro study demonstrated that coculture of SCAP and HUVEC under hypoxia enhanced the formation of vessel-like structure with increased tubular length and branching points and that the secretion of VEGF by SCAP might be utilized by HUVECs [ in vivo study implied that contribution of DPSCs to vascular morphogenesis when coimplanted with HUVECs not only was confined to the paracrine effects of secreted proangiogenic factors like VEGF, but also involved cell migratory mechanisms and corresponding scaffold disruption [In recent years, many research groups have succeeded in vascularizing artificial tissue constructs via codelivery of ECs with MSCs of various types. The significance of coculture system is based on the speculation that intricate signaling cross talk may be established among heterogenous cell populations, possibly regulated by direct cellular interaction or paracrine signaling . This hyar cells . Dissanaculature . DPSCs hculature , 94. Conependent . Anothery HUVECs . Furthersruption . While p in vitro culture system specifically for DPCs [Conventionally, stem cells are combined with exogenous scaffold materials to form a 3D engineered structure before transplanting into target sites. However, in addition to those biomaterial-associated problems, this well-recognized technique has long been questioned due to the inadequate cell migration and cell retention within the supporting scaffolds. Above all, the aforementioned biomaterials are far from being able to replicate the natural ECM or the surface of implantable device. A decade ago, Iohara et al. pioneered a 3Dfor DPCs . Unlike for DPCs . Considefor DPCs . in situ evaluation of scaffoldless delivery system is required in large animal models.Recently, a similar but different innovative \u201cscaffold-free\u201d approach developed for regenerative medicine, designated as \u201ccell sheet technology\u201d (CST), has become a popular topic of active research in the field of periodontal tissue engineering \u2013100. SupThe introduction of preengineered 3D tissue constructs into transplantation sites requires a viable and effective delivery system. In general, scaffold adopted for bone or another body tissue regeneration is often fabricated with a rigid structure in order to provide sufficient physical support. Proof-of-principle transplantation experiments have provided valuable mechanistic information for dentin/pulp regeneration when using relatively rigid scaffolds like PLLA casts with tooth slices or fragments to deliver pulp stem cells . However in vitro and locally delivered into engineered tissue.The lineage commitment and differentiation of dental stem cells during dentin/pulp tissue repair and regeneration markedly differ depending on multiple factors. Apart from their intrinsic gene expression and epigenetic profiles, the cellular fate of dental pulp-derived stem cells seems more likely to be determined by the bioactive signaling molecules within the local microenvironment , 108. Cu in vitro and in vivo [ in vitro study in which SCAP were cocultured with HUVECs, VEGF secreted by SCAP were metabolized by HUVECs to facilitate the formation of new vasculatures and the maturation of sprouted capillary networks [ in vivo study demonstrated that bFGF increased the survivability of DPSCs seeded on silk fibroin scaffold and resulted in the formation of pulp-like tissue replete with vasculature formation and calcium mineral deposition along the radicular dentinal wall after transplantation into SCIDM [Nakashima demonstrated recombinant human BMP2 and BMP4  induced tubular dentin and osteodentin formation on canine amputated tooth pulp when capped with inactivated dentin matrix , 111. St in vivo . In an inetworks . bFGF hanetworks , 117. Itnetworks . Notablynetworks . Recentlto SCIDM . However in vivo study further confirmed the efficacy of BMP-2 transfection therapy in potentiating tissue mineralization within the regenerated construct in favor of bone-like structure rather than dentin-like morphology [Loading scaffolds with bioactive drugs or protein molecules intended for promoting dental tissue regeneration has achieved favorable results . Neverthrphology . Howeverrphology . Additio de novo pulp regeneration in the full-length root. In addition, cells trapped within fibrin clots during revitalization/revascularization have neither a definite origin nor a predictable quantity and thus the phenotype of regenerated replacements filling in root canals cannot be well characterized, leading to variations in overall therapeutic efficacy. In comparison, cell transplantation based on the utilization of the meticulous triad of classic tissue engineering including stem cells, scaffolds, and signaling molecules has achieved promising outcomes. This cell-based method is capable of repairing tissue defects with an extensive size [ ex vivo cell manipulation, and ultimate shipping back to practitioners is a rather time-consuming process and the cost involved may be too excessive over relatively mature alternative therapies like dental implants or RCT. During the expansion period, cell senescence, loss of stemness, and microbial contamination are likely to occur, leading to biological deterioration and even cellular apoptosis. Worse still, MSCs are prone to experience malignant genetic transformation and thus arouse safety concern of tumorigenesis [Owing to the recent advances in the field of biomedicine, tissue engineering, and material science, great progress has been achieved in the development of regenerative endodontics. We are now at a stage of paradigm shift in endodontic treatment from traditional restoration to complete replacement of the compromised dental pulp tissues which can be realized by two scientifically meritorious approaches, cell transplantation and cell mobilization, including revitalization/revascularization procedure. While simple to operate, the cell mobilization approach may not be suitable to tissues with large size defects, especially in the circumstance ofive size , 122. Deigenesis . If thesTo date, no randomized clinical controlled trials have been conducted to compare the efficacy of cell mobilization or cell transplantation therapy and traditional endodontic treatment. Superior to tooth restoration, regenerative therapy is considered as a potential solution to address the deficiencies in tooth homeostasis, immune defense system, blood supply, and functional dentin-pulp complex formation. Moreover, it prolongs the life of natural dentition, defers the extraction fate of teeth with partially necrotic pulp, and thus ultimately improves the overall oral health-related quality of life. Collectively, additional studies in these fields should continue in order to work out a clinically translatable platform on dentin/pulp regeneration. Future research prospects in regenerative endodontics rely on the multidisciplinary collaboration of clinicians, biomaterial scientists, and engineers with expertise in their own fields and their joint contributions to the development of dentin/pulp regeneration therapy."}
+{"text": "Existing literature suggests that organizational readiness for change (ORC) can influence implementing and sustaining an intervention program. Individual attitude toward innovation is one of the important components of ORC. There is a growing research effort to identify facilitators and barriers regarding positive attitudes toward innovation in clinical settings. The current study aims to explore how occupational stress and social support for work may affect attitudes toward innovation among health care providers in HIV clinics in China.323 health care providers were recruited from 42 HIV clinics across 12 cities/counties in Guangxi, China to participate in a self-administered survey including measures on demographics, work-related characteristics , occupational stress, social support for work (from the family and colleagues), and attitudes toward innovation. We conducted mediation analysis and Sobel testing to examine the relationship among variables of interest.After controlling for demographics  and work-related characteristics , occupational stress was negatively associated with positive attitudes toward innovation  while higher levels of social support from the family was associated with more positive attitudes toward innovation . Social support from the family significantly mediated the impact of occupational stress on attitudes toward innovation . However, no significant association was detected between social support from colleagues and attitudes toward innovation (p = 0.600).Social support for work from the family not only promotes attitudes favoring innovation, but also buffers the negative impact of occupational stress on attitudes toward innovation among health care providers in HIV clinics. Our findings suggest integrating both individual and family level factors into the strategies of improving ORC in HIV clinical settings."}
+{"text": "The transdiagnostic theory of eating disorders proposes that clinical perfectionism, core low self-esteem, interpersonal problems and mood intolerance can maintain eating disorder psychopathology in some individuals. The current study aimed to explore eating disorder symptom severity as a function of these maintaining mechanisms in a community sample. Participants completed questionnaires online and were classified according to whether they met criteria for zero, one, or two or more mechanisms. A greater number of maintaining mechanisms was found to be significantly associated with higher global eating disorder examination questionnaire (EDE-Q) scores, and a higher prevalence of binge eating, purging and driven exercise. Moreover, participants with 2 or more maintaining mechanisms had more severe eating disorder symptoms than participants with 1, who in turn had more severe symptoms than participants with no maintaining mechanisms. Regression models evaluated the role of each maintaining mechanism in predicting different aspects of eating disorder pathology. Self-esteem, perfectionism and mood intolerance all predicted unique variance in global EDE-Q scores. There were differences in the maintaining mechanisms that predicted binge eating, purging and driven exercise. These results provide support for the transdiagnostic model of eating disorders and have implications for detecting and treating eating disorders in community samples.Peter Beumont Young Investigator award finalist stream of the 2014 ANZAED Conference.This abstract was presented in the"}
+{"text": "Surgical resection of colorectal liver metastases is not achievable in more than 70% of the cases. Although the liver directed therapies have become a part of the stand of care, lack of a preclinical model impedes the assessment of toxicity and therapeutic benefits attributed several candidate drugs or treatment regimens that can be designed. In the present study we aim develop and characterize a rat colorectal liver metastasis model.Growth characteristics of CC-531 cells were determined in vitro followed by subcapsular liver implantation in syngeneic WAG/Rij rats. Tumor growth progression was followed over 3 weeks by ultrasound (US) and magnetic resonance imaging (MRI). Growth characteristics were also assessed by histopathology and immunohistochemistry in harvested tumor tissues.The doubling time of CC-531 cells was found be under 24hrs and all the implanted rats grew tumors. US imaging showed hypoechoic masses and MRI showed contrast enhancement representing complex tumor microenvironments. Hematoxylin and Eosin staining confirmed tumor growth and uniform CD31 staining in tumor confirmed even vessel density.CC-531 can be used as a metastatic rat tumor colorectal liver metastases model with well-defined characteristics that can be readily followed by imaging whilst having a therapeutic window for interventions. In interventional oncology, many animal models of disease have been utilized to understand ablative and trans-catheter intra-arterial therapies. To date, there are many models of orthotopic hepatocellular carcinoma in a rat model, including the Morris (McA-RH7777),  NovikoffDeveloping this type of preclinical animal model of colorectal liver metastases can be challenging. One approach to achieving liver metastases is to implant colon cancer cells directly into the liver.  This modThe current study focused on validating this model of colorectal liver metastases, which can be used rapidly and reliably in a preclinical setting. By using a subcapsular injection of metastatic cells, distinct tumors develop and progress in situ. Changes in their microenvironment can be monitored non invasively and continuously early after implantation . Though In conclusion, CC-531 is an immunocompetent and orthotopic translational rodent model of colorectal liver metastases mimicking tumor microenvironment with liver metastases easily established, tracked and characterized by US and MR imaging."}
+{"text": "Apical HCM tends to have a favorable outcome compared to other types. The presence and extent of late gadolinium enhancement (LGE), reflecting myocardial fibrosis, is closely correlated with increased cardiac mortality and strongly associated with surrogates of arrhythmia and subsequent sudden cardiac death. This study sough to investigate the difference in cardiac magnetic resonance (CMR) and echocardiographic and clinical manifestations between apical hypertrophic cardiomyopathy (HCM) and non-apical HCM.A total of 350 consecutive patients diagnosed with HCM  underwent CMR and echocardiography. Clinical characteristics including risk factors for sudden cardiac death were collected. Eighty-five patients were classified as apical type. On CMR, left ventricle (LV) volumetric parameters were measured, and the amount of LGE was calculated with gray-scale thresholds of 6 SD above the mean signal intensity for normal remote myocardium and also expressed as a ratio against total LV volume. Echocardiographic evaluations included left atrial volume index (LAVI), mitral inflow pattern, tissue Doppler of mitral annulus and LV dimension.Patients with apical HCM were less likely to present with history of syncope  and have family history of sudden cardiac death than those with non-apical HCM . Functional class was also more favorable in apical HCM . CMR volumetric parameters were not different between the two groups except LV mass index . LGE was less frequently detected , and the amount of LGE was significantly smaller in apical HCM . The E/e level and LAVI were also lower in apical HCM patients .Apical hypertrophy shows relatively small burden of myocardial fibrosis and less severe diastolic dysfunction, and subsequently more favorable clinical manifestations in comparison with other HCMs. This may be one explanation of why most patients with apical HCM show a benign course of disease compared to non-apical HCM.None."}
+{"text": "Differential accessibility of DNA to nuclear proteins underlies the regulation of numerous cellular processes. Although DNA accessibility is primarily determined by the presence or absence of nucleosomes, differences in nucleosome composition or dynamics may also regulate accessibility. Methods for mapping nucleosome positions and occupancies genome-wide (MNase-seq) have uncovered the nucleosome landscapes of many different cell types and organisms. Conversely, methods specialized for the detection of large nucleosome-free regions of chromatin  have uncovered numerous gene regulatory elements. However, these methods are less successful in measuring the accessibility of DNA sequences within nucelosome arrays.Here we probe the genome-wide accessibility of multiple cell types in an unbiased manner using restriction endonuclease digestion of chromatin coupled to deep sequencing (RED-seq). Using this method, we identified differences in chromatin accessibility between populations of cells, not only in nucleosome-depleted regions of the genome , but also within the majority of the genome that is packaged into nucleosome arrays. Furthermore, we identified both large differences in chromatin accessibility in distinct cell lineages and subtle but significant changes during differentiation of mouse embryonic stem cells (ESCs). Most significantly, using RED-seq, we identified differences in accessibility among nucleosomes harboring well-studied histone variants, and show that these differences depend on factors required for their deposition.Using an unbiased method to probe chromatin accessibility genome-wide, we uncover unique features of chromatin structure that are not observed using more widely-utilized methods. We demonstrate that different types of nucleosomes within mammalian cells exhibit different degrees of accessibility. These findings provide significant insight into the regulation of DNA accessibility.The online version of this article (doi:10.1186/1471-2164-15-1104) contains supplementary material, which is available to authorized users. Eukaryotic genomes are wrapped around histone octamers to form nucleosome arrays, which are further packaged into the nucleus. Although chromatin compaction facilitates storage of large quantities of DNA within small nuclear compartments, it drastically reduces the accessibility of genomic DNA to proteins that require access. Nucleosomal DNA is relatively inaccessible to DNA binding proteins due to both the occlusion of approximately half of its surface by contacts with histones, as well as the distortion of the normal B-form structure that occurs when DNA is wrapped around a histone octamer . Consequin vivo.Although protection of DNA from nuclear factors by the formation of tight interactions with histones appears to be the major method by which DNA accessibility is regulated, many different isoforms of the histone octamer exist within most eukaryotes, each with distinct biochemical and biophysical properties \u20138. TheseAlong with differences in chromatin structure within distinct genomic regions in individual cell types, cell type-specific chromatin structural differences facilitate gene expression patterns specific to cells of different lineages . In embrMethods have been developed to study DNA accessibility based on either the protection of nucleosomal DNA from general endonuclease digestion or the differential solubility properties of open and closed chromatin. Deoxyribonuclease I (DNase I) , 19 prefet al. developed a genome-wide method to probe chromatin structure using restriction enzymes, finding that chromatin accessibility correlated broadly with gene expression in hematopoietic cell lineages and became progressively restricted during differentiation , plotted as in Figure\u00a0Additional file 2:a GEO:GSE0254, ploSequences of barcoded and biotinylated adaptors.(PDF 42 KB)Additional file 3:Sequences of qPCR primers for DHSs.(PDF 40 KB)Additional file 4:Sequences of qPCR primers for CTCF binding sites.(PDF 48 KB)Additional file 5:"}
+{"text": "Lung cancer is difficult to treat with a poor prognosis and a five year survival of 15%. Current molecularly targeted therapies are initially effective in non-small cell lung cancer (NSCLC) patients; however, they are plagued with difficulties including induced resistance and small therapeutically responsive populations. This mini review describes the mechanism of resistance to several molecularly targeted therapies which are currently being used to treat NSCLC. The major targets discussed are c-Met, EGFR, HER2, ALK, VEGFR, and BRAF. The first generation tyrosine kinase inhibitors (TKIs) resulted in resistance; however, second and third generation TKIs are being developed, which are generally more efficacious and have potential to treat NSCLC patients with resistance to first generation TKIs. Combination therapies could also be effective in preventing TKI resistance in NSCLC patients. The focus of current lung cancer treatment has been shifted from more traditional options to newly developed molecularly targeted therapies. Many of the molecularly targeted therapies are utilized to target specific biomarkers that are commonly overexpressed and have important roles in tumorigenesis; these biomarkers contribute to cancer-related processes such as cell proliferation, survival and migration. While initially effective, many targeted therapies have been associated with increased drug resistance after their initial use. Acquired resistance to current molecularly targeted therapies in lung cancer presents a major clinical challenge. Current research focuses on identifying potential novel biomarkers and mechanisms involved in resistance to these therapies. There are several clinical challenges associated with current molecularly targeted therapies including the induction of various types of resistance mechanisms, which are not clearly defined, and the lack of effective combinatorial therapies designed to prevent and overcome the problem of drug resistance in lung cancer.Common molecularly targeted therapies target receptor tyrosine kinases (RTKs) including hepatocyte growth factor receptor (HGFR/c-Met), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), anaplastic lymphoma kinase (ALK), and endothelial growth factor receptor (VEGFR), which are commonly mutated in NSCLC cases . Recentlc-Met is a RTK for the ligand hepatocyte growth factor (HGF), which is secreted by mesenchymal cells and cancer cells . There hEpidermal growth factor receptor (EGFR) is a transmembrane receptor that plays an essential role in regulating cell proliferation, survival, and growth . EGFR TKThe anaplastic lymphoma kinase (ALK) is a RTK typically expressed in the central and peripheral nervous system regions ,20. ALK Overexpression of vascular endothelial growth factor (VEGF), an angiogenic factor, and its receptors are related to poor prognosis in NSCLC patients . BevacizBRAF  is a member of the RAF serine/threonine protein kinases family. Mutations in BRAF have been shown to be associated with tumor development in NSCLC with a frequency of 2\u20133%. Recently, a BRAF inhibitor dabrafenib, the first drug of its class, is shown to be effective for the treatment of advanced NSCLC patients with BRAF V600E mutation in a phase II clinical study . HoweverAlthough current molecularly targeted therapies are very effective for NSCLC patients, almost all patients eventually acquire resistance to these therapies. To combat this resistance against first generation TKIs, second and third generation TKIs have been developed. These new generations of TKIs are either completing clinical trials or have been FDA approved to treat NSCLC patients. However, their therapeutic potential needs to be further validated and established. Various secondary mutations and alternative signaling pathways have been identified as distinct resistance patterns for several TKIs targeting EGFR, c-Met, and ALK. However, further studies are required to determine the specific mechanisms of acquired resistance to HER2, VEGFR and BRAF. Combinatorial strategies could be effective in overcoming TKI resistance in lung cancer patients. These strategies may require targeting both mutations involved in resistance and alternative signaling pathways."}
+{"text": "Xanthomonas citri subsp. citri, three Candidatus Liberibacter spp and Citrus leprosis virus C (CiLV-C). In plant-pathogen interactions, the role of salicylic acid (SA) in activating defense related genes is well recognized  seedlings grown in test tubes containing MS culture medium. The presence of the transgene will be evaluated by PCR using specifics primers that amplify part of the ubiquitin promoter and part of the gene. SABP2 expression levels in transgenic plants will be assessed through qPCR. After bud multiplication, transgenic plants will be evaluated for their response to citrus canker, HLB and leprosis.A total of 620 explants in three independent experiments were introduced and approximately 336 shoots were regenerated. The GUS histochemical test was performed and confirmed the transformation of 30 positive shoots. These shoots are being grafted onto Carrizo citrange ["}
+{"text": "I first overview motor neuron developmental biology to provide some context for reviewing recent studies interrogating pathways that influence the generation of MN diversity. I conclude that motor neurogenesis from PSCs provides a powerful reductionist model system to gain insight into the developmental logic of MN subtype diversification and serves more broadly as a leading exemplar of potential strategies to resolve the molecular basis of neuronal subclass differentiation within the nervous system. These studies will in turn permit greater mechanistic understanding of differential MN subtype vulnerability using in vitro human disease models.Resolving the mechanisms underlying human neuronal diversification remains a major challenge in developmental and applied neurobiology. Motor neurons (MNs) represent a diverse pool of neuronal subtypes exhibiting differential vulnerability in different human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The ability to predictably manipulate MN subtype lineage restriction from human pluripotent stem cells (PSCs) will form the essential basis to establishing accurate, clinically relevant  Human neurodegenerative disorders represent a spectrum of progressive and untreatable clinical diseases, characterized by selective loss of neurons, usually in a region-specific  and/or subtype-specific  fashion. There is a great experimental need for renewable sources of clinically relevant, region-specific, and subtype-specific neurons. Lineage restriction and the generation of neuronal diversity within the developing neuraxis are consequences of the interplay of multiple developmental signals, which are regulated in a spatiotemporal manner. Precise cellular and molecular mechanisms through which these complex sequential and progressive developmental processes are orchestrated remain unresolved. The ability to generate defined neuronal cell types from PSCs offers a unique experimental opportunity to study the developmental mechanism(s) underlying generation of neural diversity during human embryogenesis , 2 Figu. In turn in vitro with fidelity and precision , 1312, 1 postmitotically is a key determinant of neuronal subtype diversification [Experiments involving intercolumnar fate switching have demonstrated a consequent and congruent change in axonal trajection. For example, ectopic expression of Hoxc10 (lumbar) at thoracic levels causes a fate change to LMC MNs, which then project into the lower limb . These efication , 53, 54.fication , 54. Sucfication . ExperimAgainst the background of these studies, it is clear that the descriptive term \u201cMN\u201d is an oversimplification and the numerous motor neuronal subtype differences described above  begin to demonstrate some of the necessary complexity inherent in MN diversification. The developmental biology that underpins MN differentiation is relatively well understood and thus provides a rational basis for using human stem cell-based systems to allow further elucidation of mechanisms responsible for generating MN subtype diversity. in vitro. PSCs respond predictably to developmental cues such that their fate can be systematically manipulated to differentiate into myriad cell lineages from any of the 3 germ layers. There are 3 principal properties that characterize PSCs: (i) the ability to self-renew, (ii) pluripotency  [ in vitro culture conditions for the propagation of undifferentiated vertebrate tumor cell lines in the 1970s [ in vitro fertilization clinics [There are different sources of species-specific stem cells including embryonic, fetal, and adult varieties. Embryonic stem cells (ESCs) are a type of PSC thus possessing the greatest developmental potentialderived) , and  also represents a potential problem because this cannot, at present, be predictably altered using extrinsic signals. This tissue specific \u201cmultipotency\u201d  is a relative disadvantage when studying cell fate specification, where the pluripotent state represents an ideal investigative tool. Attempts to derive PSCs by different methods have partially tempered the ethical controversy in which the human ESC field is immersed . These e neurons . These d\u03b2 signaling superfamily permits highly efficient neural conversion of PSCs and represents the most widely adopted method employed to date [Predictable and scalable directed differentiation of PSCs to the neural lineage is necessary for studying human neural development, modeling disease, and drug discovery. Several well established methods can robustly achieve neural conversion of PSCs in chemically defined conditions \u201398. Effi to date .The elucidation of developmental inductive cues and transcriptional programmes for MN specification  have bee in vitro work using human PSCs suggest that, soon after neural induction, precursors initially assume a rostral and dorsal positional identity through the combined actions of the BMP, WNT, and FGF signaling pathways, which have unique spatiotemporal influences on positional identity and cell fate decisions [ in vitro [Insights from developmental studies across different species and fromecisions , 6. Mousin vitro , 103. On versus simultaneous administration of morphogenetic signals is another interesting subject, which merits discussion here. In the case of motor neurons, for example, the first directed differentiation of MNs from mouse ESCs employed simultaneous administration of RA and Shh [ in vivo motor neuron lineage restriction.Important future studies would include systematic analyses of the requisite time for neural patterning prior to terminal differentiation, which has yet to be definitively addressed. Some studies have suggested that accelerated neural conversion and patterning protocols are possible. The question of sequential and Shh , whereas and Shh  the cuesThere is an increasing wealth of literature around the mechanisms underlying neurodevelopment, revealing a remarkable and previously unrecognized extent of neuronal diversity. Functionally relevant differences in molecular phenotype, axonal projection, dendritic arborization, and electrophysiological attributes have been demonstrated between different neuronal subtypes throughout the neuraxis \u2013110. TheTo date, the vast majority of studies using ESCs have focused on deriving MNs generically, while comparatively few studies address the issue of motor neuronal subtype diversification. Most protocols for motor neuron specification from PSCs (either ESCs or iPSCs) utilize the application of a simplistic programme of morphogenetic signals to achieve neural patterning, followed by standard terminal differentiation conditions. Signaling mechanisms and transcriptional events involved in the postmitotic diversification of motor neuronal subtypes from human ESCs remain poorly characterized. Currently, no study has systematically investigated the influence of a morphogenetic signal during both MN precursor \u201cpatterning\u201d and terminal differentiation in order to establish their relative contributions to subtype choice during these distinct developmental stages. in vivo studies [MNs are a diverse collection of neuronal subtypes displaying differential vulnerability in different human neurodegenerative diseases. During embryogenesis, retinoid signaling contributes to caudal precursor specification generically and subsequent MN subtype diversification. RA typically results in a cervical or brachial positional identity , 106. Ag studies . Therefo studies . Collect studies , 111\u2013113 studies  (a small studies .Separately, the use of suspension culture , 116 ver in vitro. Access to human PSCs allows questions around early cell fate acquisition to be addressed. Developmental competence to extrinsic morphogenetic signals during embryonic patterning is both spatially and temporally restricted. Human PSCs faithfully recapitulate the key milestones of neurodevelopment and thus permit studies that will improve our understanding of the relative contributions of extrinsic signals, cell-intrinsic transcriptional programmes, and intercellular/paracrine communication to direct cell fate decisions. This reductionist model system, together with the use of a fully defined cell culture medium, provides a unique experimental opportunity to understand the relevance of how signaling pathways function individually or combinatorially to direct lineage restriction at different developmental stages. In turn, such knowledge will permit more predictable manipulation of PSCs to generate desired progeny for experimental study. PSCs therefore represent an unparalleled opportunity to study human neurodevelopmental processes. It is likely that, for future strategies aimed at generating distinct subtypes of MN, controlled extrinsic morphogenetic instruction during both precursor specification and terminal differentiation will be key determinants of success. As a final remark, although there is a considerable degree of conservation in neuraxial systems between rodents and humans, important differences in architecture, computational power, and functional capacity exist. Such evolutionary divergence strongly reinforces the indispensability of human experimental systems to complement, but not replace, existing rodent-based approaches.Elucidating efficient protocols to generate enriched populations of MN subtypes has important biotechnological implications for disease modeling, drug discovery, and potentially cell-based therapy. Such approaches would permit comprehensive mechanistic studies of differential MN subtype vulnerability"}
+{"text": "Peromyscus leucopus) utilized space and depredated two incidental prey items: almonds  and maple seeds . We estimated mouse population densities with trapping webs, quantified mouse consumption rates of these incidental prey items, and measured local mouse activity with track plates. We predicted that 1) mouse activity would be elevated near full feeders, but depressed at intermediate distances from the feeder, 2) consumption of both incidental prey would be high near feeders providing less-preferred food and, 3) consumption of incidental prey would be contingent on predator preference for prey relative to feeders providing more-preferred food. Mouse densities increased significantly from pre- to post-experiment. Mean mouse activity was unexpectedly greatest in control treatments, particularly <15 m from the control (empty) feeder. Feeders with highly preferred food (sunflower seeds) created localized refuges for incidental prey at intermediate distances (15 to 25m) from the feeder. Feeders with less-preferred food (corn) generated localized high risk for highly preferred almonds <10 m of the feeder. Our findings highlight the contingent but predictable effects of locally abundant food on risk experienced by incidental prey, which can be positive or negative depending on both spatial proximity and relative preference.Abundant, localized foods can concentrate predators and their foraging efforts, thus altering both the spatial distribution of predation risk and predator preferences for prey that are encountered incidentally. However, few investigations have quantified the spatial scale over which localized foods affect predator foraging behavior and consumption of incidental prey. In spring 2010, we experimentally tested how point-source foods altered how generalist predators (white-footed mice,  Predator foraging behaviors, and the resulting distribution of predation risk within a landscape, are influenced by what prey are available and where they are located. Optimal foraging theory provides a framework for predicting predator choice of prey on the basis of energetic profitability , as wellZea mays) spatially concentrate foraging by raccoons (Procyon lotor), increasing predation risk for nearby nests of wild turkeys  and turtles /11 = 0.44. This subtle but potentially important reduction in risk is an important consideration when interpreting results showing elevated risk of generalist predation near artificial food sources [Regarding our second prediction, we did not observe a general pattern of depressed track activity at intermediate distances from either filled or empty feeders. This lack of result is likely related to the difference in spatial areas: for example, the annulus between radii of 10 and 25 m has an area 21 times larger than the circular area within 5 m of the feeder. Thus, the shift of a fixed amount of mouse activity from the annulus to the circle would cause an increase in activity density near the center 21 times greater than the corresponding decrease in the annulus. Such a subtle decrease in activity is likely to require very high sample size to reliably detect. However, even subtle modifications in predator activity, and thus predation risk, over large areas can disproportionately increase prey survival rates. Concentrating predation risk in space generally increases overall survival of relatively sessile prey because depletion of prey in high-risk areas quickly generates a negative spatial correlation between prey abundance and risk , 61. Jen sources , 63, 64.Regardless of the cause of spatial variations in mouse activity, we expected that consumption rates of incidental prey would reflect the local risk of discovery, as indicated by mouse activity, mediated by predator preference for these prey relative to the provided food treatment. Based on these expectations, our third prediction was that consumption rates for both incidental prey items would be elevated near feeders providing a less-preferred food (corn). This prediction was partially supported for almonds but not for maple seeds. On the other hand, sunflower seeds have higher energy density and protein content than corn, so we predicted that feeders providing sunflower seeds would elevate local consumption of almonds but depress consumption of less-preferred maple seeds. However, consumption of both almonds and maple seeds was depressed near feeders providing sunflower seeds. Taken together, these deviations from our predictions regarding consumption rates imply that the incidental prey items we deployed were consistently devalued relative to the food provided in feeders. Incidental prey may be devalued by handling time cost imposed by seeds being embedded in wax. However, predation by small mammals (mainly white-footed mice) was much greater for freeze-dried gypsy moth pupae affixed to burlap with beeswax than for naturally occurring gypsy moth pupae at the same microsites and times , so wax Sciurus niger) over-utilized poor-quality habitat patches [The findings of this study may be applied to other generalist consumers and their prey . Abundant food sources can decrease rodent predator activity levels , 58, inf patches  and decr patches . DifferePanthera leo), deviated from optimal foraging expectations by choosing suboptimal prey based on prey group size, prey distance from the hunting group, and prey group composition [The results of this investigation may be broadly applied to predator and prey interactions. Optimal foraging theory provides a general predictive framework for predator foraging behavior and choice of prey. However, generalist predators can deviate from optimal expectations by altering their space use and consuming suboptimal prey. Large predatory mammals, like African lions (position . Avian cposition . Differe"}
+{"text": "HIV transmission occurs predominantly across mucosal surfaces. An ideal preventive strategy would be to target HIV at mucosal entry sites to prevent infection. We developed a novel epithelial stem cells-based AIDS preventive approach in female macaques. This approach is based on the ability of therapeutic lentiviral vectors integrated in mucosal epithelial stem cells to induce virus-specific cellular immune responses at mucosal sites of viral entry. We first intended to expose the cervicovaginal tract to conditions used for intravaginal vaccine delivery and non-invasively image local tissues to determine the vaccination effects on epithelial integrity and generation of antigen-specific mucosal immune responses.Experimental cervicovaginal vaccinations were carried out on 12 uninfected female macaques, in conjunction with deliberate abrasion of epithelium using Depo-Provera, 4% nonoxynol-9 treatments, or gentle abrasions to reduce vaginal epithelial height and cell layers number. Longitudinal study was performed for baseline levels of hormones, antibodies, cytokine profiles during normal cycling with/without vaccination. Endoscopic colposcopy followed by optical coherence tomography (OCT) helped monitor macaque cervical-vaginal epithelium pre-, post-, without treatment to measure epithelial thickness changes. Colposcopy help visualizing the vagina and cervix. Blood samples and biopsies were collected at various time-points to evaluate immune responses to vaccination.OCT imaging provided quantitative measurements of epithelial changes and detected minute changes in epithelial thickness and morphology. Colposcopy and OCT imaging correlated with hormone levels and biopsies imaging. Depo-Provera gave better results in epithelium thinning but naturally cycling macaques showed clearer thickness differences. All collected secretions, biopsies and blood samples gave a better understanding of the correlation between menstrual cycle, hormonal level, epithelial thickness changes. Optimal conditions for vaccine delivery were determined and revealed virus-specific T cell response in all vaccinated animals.OCT is well suited for the examination of superficial mucosal layers and close underlying stromal structures of tissues. In this study, we demonstrated the feasibility of using epithelial stem cells as mucosal antigen-presenting cells to induce viral specific immune responses at mucosal sites, and improved our knowledge of the role of mucosal surfaces."}
+{"text": "Granulomatosis with polyangiitis is a systemic disease resulting in necrotizing vasculitis of small- and medium-sized vessels. Cardiac involvement is rare and when present usually manifests with pericarditis and coronary artery vasculitis. We report here a case of granulomatosis with polyangiitis involving the native coronary arteries, bypass graft, and pericardium with interesting imaging findings on contrast-enhanced CT and MRI. A 57-year-old man with a history of chronic headaches presented to the emergency room with syncope. Contrast-enhanced CT demonstrated extensive soft tissue attenuation around the native coronary arteries and bypass graft. Contrast-enhanced MRI demonstrated enhancing nodular soft tissue surrounding the coronary arteries, bypass graft, and pericardium. Pericardial biopsy revealed a necrotizing granulomatous pericarditis with vasculitis concerning for granulomatosis with polyangiitis. The patient demonstrated MPO-positive and PR-3 negative serologies. After being discharged on rituximab and prednisone, follow-up CT 3 years later showed significant improvement of the soft tissue thickening surrounding the coronary arteries, bypass graft, and pericardium. Granulomatosis with polyangiitis (GPA) is a form of systemic vasculitis with necrotizing granulomatous inflammation of the upper and lower respiratory tracts and kidneys . GPA invThe literature concerning cardiac involvement is limited. The few case reports and general reviews show that the two most common histologic cardiac manifestations are pericarditis and coronary arteritis. The most frequent clinical manifestation is cardiac arrhythmias, typically supraventricular tachyarrhythmias. We report an unusual case of GPA initially presenting with cardiac involvement affecting the coronary arteries, bypass graft, and pericardium.A 57-year-old white male with history of Graves' disease with ophthalmopathy and coronary artery disease status after 3-vessel CABG presented to the ER after a syncopal episode during a doctor's office appointment. He had been having severe frontal headaches for several months with workup prior to this admission revealing an elevated ESR and bilateral temporal artery biopsies which were negative for giant cell arteritis. A lumbar puncture revealed elevated protein, increased opening pressure, elevated WBC, IgG index, and oligoclonal bands. A bone marrow biopsy performed for microcytic anemia was unremarkable.Given his history of syncope, a CT angiogram of the chest was performed to exclude a pulmonary embolism. No evidence of pulmonary embolism was seen; however, soft tissue attenuation around the coronary arteries, bypass graft, and pericardium raised concern for vasculitis Figures  and 2. FA pericardial biopsy demonstrated dense scar tissue associated with a mononuclear infiltrate comprised mostly of nodular aggregates of monocytes and macrophages . Within Myeloperoxidase associated ANCA vasculitis with orbital pseudotumor and pericardial involvement was considered to be the most likely diagnosis. He was discharged after being placed on prednisone and rituximab. Subsequent contrast-enhanced chest CT 3 years later showed significant improvement of the soft tissue thickening around the coronary arteries, bypass graft, and pericardium .GPA affects multiple organ systems and may involve any part of the body. The upper respiratory tract is involved in nearly all patients. In addition, a vast majority of patients with GPA will also have pulmonary (90%) and renal (80%) involvement . ElevatiCardiac involvement is relatively rare in GPA even though autopsy results show that GPA related cardiac abnormalities are present in one-third of patients . CardiacThe coronary arteries are frequently involved in systemic arteritis. The inflammatory infiltrate damages the intima and may trigger the occurrence of coronary thrombosis. Morbini et al. report an extreme example of an elderly female with intimal inflammation in multiple sites of a coronary tree with and without atherosclerosis which triggered coronary thrombosis. She died after cardiac arrest from a clinically unrecognized systemic autoimmune-inflammatory disorder with necrotizing arteritis. Autopsy showed findings typical of GPA and systemic arteritis with fibrinoid necrosis and systemic arteritis. Although there were no clinical signs of cardiac involvement, the coronary arteries showed inflammation associated with multiple mural and occlusive thrombi .Ohkawa et al. reported a case of generalized GPA with extensive cardiac involvement at autopsy. Necrotizing angiitis and severe granulomatous inflammatory foci affected the common bundle of His and right bundle branch in addition to the myocardium .Cardiac valvular involvement is an uncommon manifestation of GPA. Espitia et al. reported the case of a 60-year-old woman with severe inflammatory aortic and mitral valvular involvement characterized by GPA with typical histopathological valvular lesions. Cardiac valvular involvement is a rare and potentially fatal complication of GPA and may misleadingly suggest infectious endocarditis .Currently, multiple imaging modalities are increasingly used as first-line noninvasive diagnostic tools to assess target-organ involvement in GPA, although biopsy with pathological testing represents the gold standard . In our To the best of our knowledge this is the first case report showing involvement of a bypass graft, native coronary arteries, and pericardium as the initial manifestation of GPA.In conclusion, cardiac involvement of GPA is rare. It must be included in the differential diagnosis when soft tissue thickening involves the coronary arteries and pericardium, even when no pulmonary or airway findings are identified."}
+{"text": "On the evening of 13 November 2015, three terrorists equipped with military-grade firearms and explosive jackets penetrated Bataclan, a Paris music hall containing 1500 people [Immediately, RAID , the French national police counter-terrorism team, and the BRI (Research and Intervention Brigade) were engaged. As previously reported , 3, thesFirst, RAID police officers and tactical physicians proceeded to zoning. Priority was given to police operation and safety . They deWhile police operators were getting into position within the theater and thus repelling terrorists, two RAID tactical physicians performed triage in the combat zone , 4. TheyIn the combat zone, RAID tactical physicians applied tourniquets to 15 invalid patients [Once salvage therapies were performed , more thTwo tactical physicians joined the operation theater. They perform damage control resuscitation to casualties within the dressing station . SeveralThe initial tactical physicians then joined the assault team to act as forward medical officers. The remaining two terrorists committed suicide, detonating their bombs during a final assault, without causing additional fatalities.Because the environment remained under the threat of explosives, despite terrorists\u2019 neutralization, conventional rescue teams were maintained out of the exclusion zone until the end of mine-clearing operations. All five physicians continued to perform damage control resuscitation on invalid patients until they were transferred to the casualty receiving station. When conventional rescue teams received clearance to penetrate the theater, all living casualties had already been extracted. The teams discovered 89 fatalities.Owing to the mismatch between the number of casualties and tactical physicians, the latter first decided to secure non-invalid casualties before treating invalid patients with severe but accessible lesions. The tangle of numerous dead bodies might have hidden living casualties from tactical physicians\u2019 view, preventing the former from receiving care in time.Not all the concepts of damage control resuscitation were performed. Some of the casualties did not even receive damage control resuscitation, owing first to the aforementioned mismatch between the number of casualties and tactical physicians and second to an insufficient amount of available medical equipment.Maintaining conventional rescue teams out of danger was consistent with prehospital disaster plans. This appeared a safe option because mine-clearing operators discovered a bag filled with explosives. Of note, despite dynamic adaptation of the exclusion zone boundaries to the threat, post hoc analysis revealed that the distance between the dressing station within the theater and the casualty receiving station was excessive."}
+{"text": "RECIST criteria use changes in tumour diameters to quantitatively obtain response assessments for traditional chemotherapeutic cancer treatments: Positive responses are identified by reductions in tumour size while tumour growth signifies non-response.transarterial chemo embolization (TACE) can be used alone or in combination. Local treatment, radiation therapy, immunotherapy and targeted therapy can each result in an increased tumour diameter in spite of treatment response at the cellular level and increased survival times. As a result, tumour diameter can no longer stand alone when assessing oncological treatment strategiesTraditional chemotherapies work primarily by damaging cells that are undergoing rapid growth and division. Immunotherapies work by stimulating the immune system to reject and destroy tumour cells. Targeted cancer therapies block the growth of cancer cells by interfering with specific molecules needed for tumour growth and carcinogenesis. These oncological treatments as well as stereotactic radiation therapy and local treatments, such as image-guided ablations and Tumour heterogeneity and contrast enhancement often change during treatment, and tumour enhancement combined with tumour size has been shown to be successful in assessing treatment response in gastrointestinal stromal tumours (CHOI criteria). Modified CHOI criteria could potentially be used for monitoring the effect of oncological treatment strategies in metastatic renal cell cancer and hepatocellular carcinoma.Dynamic contrast-enhanced imaging  uses changes in tumour enhancement following the intravenous injection of a contrast media to create a time-versus-signal curve. From such curves, reliable quantitative estimates of blood flow, blood volume and permeability can be obtained. Diffusion-weighted MRI and PET can also be used to obtain quantitative measures of physiological processes. A major advantage of DWI-MRI and PET is the possibility of whole body coverage, while DCE imaging is limited to a single tumour or a comparatively small region.Although quantitative assessments of oncological treatment response using physiological parameters have been shown to be superior to size-based response in several studies, the methods mentioned are not yet standardized, and randomized multicentre studies have not yet been performed. When planning such studies, it is important to note that clinical endpoints such as progression free survival and overall survival are superior to morphological imaging results.In the routine assessment of oncological treatment responses, it is becoming increasingly important for the radiologists to know exactly what kind(s) of treatment that the patient has received. Simply reporting changes in tumour size using RECIST is no longer sufficient considering the large percentage of patients who receive advanced and often combined treatment regimens."}
+{"text": "Our patient presented dramatically with a previously unrecognized FAP complicated by heart failure requiring heart transplantation at the age of 49 years and liver transplantation at the age of 51 years. Direct DNA sequencing of the TTR gene showed a heterozygous Glu89Lys mutation in the proband and her daughter (published in Transplantation 2011).Longitudinal follow-up with clinical scores with ancillary testings.After her double transplantation, the patient reported over the 8 subsequent years slowly progressive increasing pain and loss of sensation in the feet, slow bowel habit, and delayed urine flow. On examination, we found orthostatic hypotension, sensory loss, muscle weakness, and mild atrophy in the distal lower extremities with reduced Achilles tendon reflexes. Nerve conduction studies revealed a mild decrease of amplitude of motor and absent sensory action potentials and normal velocities except for bilateral slowing within the carpal tunnels. The sympathetic skin response and Sudoscan responses to electrical stimuli was normal in the palms but not in the soles. No complications were seen, such as acute rejection, portal vein thrombosis, or infectious diseases resulting from administration of immunosuppressive drugs.As already described, some late-stage patients continue to show FAP progression even after liver transplantation, and longstanding disease is correlated with increased morbidity related to continuing amyloid fibril formation."}
+{"text": "TARVA is an NIHR HTA funded portfolio randomised controlled trial (RCT) comparing total ankle replacement (TAR) and arthrodesis (fusion) surgery in NHS patients aged 50-85 with end-stage ankle arthritis. 328 patients will be randomly allocated to TAR or arthrodesis on an equal basis.Clinician and patient treatment equipoise is critical to recruit surgeons and patients successfully.The TARVA Trial team has developed novel surgeon and patient engagement techniques involving technology and multi-media tools to achieve our aims. Examples include an award-winning video, a white-labelled patient information brochure, professional newsletters and blogs, and a particular focus on the use of social networking tools to engage both investigators and patients.http://anklearthritis.co.uk).The impartial trial information video featuring consultant foot and ankle surgeons and patients who have undergone TAR or fusion surgery can be accessed through the trial website (The pilot phase began with the randomisation of the first patient in March 2015. An overview of our techniques alongside recruitment data accumulated until November will be presented at the ICTM conference."}
+{"text": "Planning malaria interventions requires the prediction of likely impacts of different intervention strategies. Simulation models can provide such predictions but weak information about pre-control levels of transmission, intervention coverage and access to care often makes it challenging to correctly parameterize them. We consider a number of low malaria transmission sites in Madagascar, with available historical prevalence and entomological inoculation rate (EIR) estimates (by mosquito sampling), giving disparate estimates of historical exposure. Information about implementation of Long Lasting Insecticide Nets (LLINs) and Indoor Residual Spraying (IRS), and access to healthcare, collated from malaria surveys and on-going cross-sectional studies were used to parameterise simulations of malaria transmission, prevalence and burden within the OpenMalaria platform. Multiple parameterisations were considered using various sources of data for pre-intervention transmission level, intervention coverage and access to healthcare. In some sites the simulated impact of existing vector control programs matches reasonably well the malaria prevalence measured in a recent national survey. In others it predicts lower than observed prevalence, very likely because the models do not capture residual local transmission foci. The simulations suggest that the most cost-effective vector control strategy would be to scale-up LLINs or IRS only, depending on the transmission level. Indeed, preliminary results show no additional benefit of IRS where LLINs were used. These preliminary results suggest that historical prevalence data, combined with current coverage information are potentially adequate for planning intervention strategies. The outcome of intervention scale-up is essentially unpredictable if baseline information is poor. Reproducing the observed epidemiology of malaria through simulations both provides confidence in the use of the model but serves as a basis for prospective studies that support decision-making, including cost-effectiveness analyses."}
+{"text": "Reversing anthropogenic impacts on habitat structure is frequently successful through restoration, but the mechanisms linking habitat change, community reassembly and recovery of ecosystem functioning remain unknown. We test for the influence of edge effects and matrix habitat restoration on the reassembly of dung beetle communities and consequent recovery of dung removal rates across tropical forest edges. Using path modelling, we disentangle the relative importance of community-weighted trait means and functional trait dispersion from total biomass effects on rates of dung removal. Community trait composition and biomass of dung beetle communities responded divergently to edge effects and matrix habitat restoration, yielding opposing effects on dung removal. However, functional dispersion\u2014used in this study as a measure of niche complementarity\u2014did not explain a significant amount of variation in dung removal rates across habitat edges. Instead, we demonstrate that the path to functional recovery of these altered ecosystems depends on the trait-mean composition of reassembling communities, over and above purely biomass-dependent processes that would be expected under neutral theory. These results suggest that any ability to manage functional recovery of ecosystems during habitat restoration will demand knowledge of species' roles in ecosystem processes. Significant advances have been made in understanding the cascading effects of global environmental change on biodiversity loss and associated ecosystem functioning Restoration ecology has long sought to identify the mechanisms that determine trajectories of community assembly One effective platform for linking species responses to environmental change with the functional consequences of shifting trait composition has been to employ a response-effect trait framework In this study, we test the trait determinants of dung beetle community responses to experimental habitat restoration in the land-use matrix surrounding heavily degraded montane rainforest edges in Nigeria. Habitat loss, and subsequent degradation of rainforest edges due to cattle encroachment, fire, and altered biotic and abiotic conditions, are amongst the most severe drivers of biodiversity loss and alteration of ecosystem functioning in tropical forests Although terrestrial invertebrates are the second most represented taxa in studies investigating trait-mediated ecosystem processes This study was conducted in Afromontane forest at the Ngel Nyaki Forest Reserve, located on the Mambilla Plateau near the south-eastern border of Nigeria . No specific permissions were required regarding collection of invertebrate specimens in this location and our study did not involve any known endangered or protected species. The forest reserve is an outlying section of the West African montane forest network within the Cameroon Highlands ecoregion As part of the Nigerian Montane Forest Project (NMFP) aimed at protecting Ngel Nyaki Forest Reserve from land clearing, burning and cattle grazing, three fenced exclusion zones were established up to 200 m outside the dense sub-montane forest zone, 3 years prior to the sampling procedure. These regenerating sites could then be compared with degraded edge zones where no restoration in the adjacent matrix had been established . The lenth October to 29th November 2009. To quantify the interactive effects of habitat edges and adjacent matrix restoration on dung beetle community structure and associated ecosystem processes, we sampled dung beetle communities and dung removal rates along three replicate forest-to-matrix edge gradients in both degraded and regenerating sites (n\u200a=\u200a6). Although treatment-level replication was low, it is important to note that this is an experimental manipulation of matrix structure which was specifically targeted at a single experimental site where all edges had previously had a common history of edge degradation (just 3 years prior to sampling), and sampling completeness was high Sampling was conducted at Ngel Nyaki Forest Reserve during the late rainy season from 4Degraded edges spanned forest-to-matrix habitats that were fully exposed to anthropogenic threats typical of the area (such as intensive cattle grazing and fires), compared to the regenerating edges where these threats had been entirely excluded for three years . One addca 20 cm above the cup using wooden stakes. From this trap cover, dung bait was suspended with string so that the bottom of the bait was level with the rim of the cup. The bait was contained within muslin mesh which allowed the scent of the bait to easily permeate into the surrounding atmosphere but was fine enough to exclude insects from directly accessing the bait and thus altering its attractiveness. The cup was filled with approximately 200 ml of water and five drops of highly concentrated, odourless, and clear detergent which served to break the surface tension of the water. Pig dung was used as bait because omnivore dung is recognised as the most widely attractive to dung beetles We used pitfall traps baited with 40 g of pig dung placed at each distance across the edge gradient for two consecutive 24 hour periods (pooled 48 hour samples for each edge gradient transect) to ensure adequate sampling of the local community To quantify the impact of edge effects and matrix restoration on dung removal rates we placed experimental dung piles at each of the 101 sampling points and measured the proportion of dung removed in 24 hrs. Dung removal experiments were undertaken 1\u20132 days prior to baited pitfall trapping of dung beetles at each site, in order to avoid potential trap depletion effects on beetle communities that might otherwise have confounded dung removal rates. It should be noted that there could still have been potential interference of the removal experiment on pitfall trapping, as beetles that had already been attracted to dung placed out in the removal experiment may still have been buried in the soil, either laying eggs, provisioning brood balls, or already satiated. However, there is little reason to expect that this effect would have operated inconsistently across our treatments and is unlikely to have been systematically biased toward particular morphological traits of dung beetles, so we expect any such effect to have had a minor influence on our overall results. At each sampling point  debris such as dead wood or leaves within a 15 cm radius of dung placement was removed down to the topsoil and 40 g of fresh pig dung was placed directly on top of the bare soil. This amount of dung was sufficient to avoid complete removal and allow reliable comparisons among sampling points, but still equal to the amount of bait used in pitfall traps so that dung removal rates could be realistically compared to sampled dung beetle communities. After 24 hours, the remaining dung was collected and, after removing any attached debris, dry mass loss was calculated after taking into account moisture content loss, yielding a rate of dung removed per 24 hrs see .2), multiplied by two for total wing area, which was then used to calculate wing loading as the ratio of body mass to total wing area. To take into account within-species trait variation, we measured multiple individuals within each species for all samples collected. However, for highly-abundant species, we used a randomized subsampling procedure so that at least 20 individuals were measured per sample for each abundant species  or by variation in the abundances of species with differing traits, we used a hierarchical path modelling approach Second, dung removal rates might be dependent on average trait values expressed in a given community. To test this hypothesis, we included all measured traits  within the path model. Because we suspected there could be collinearity among the trait predictors, we checked for correlations among variables while constructing the path model. In most cases, predictors within the GLMMs were sufficiently weakly correlated so that interpretation of the models was considered reliable (|r|<0.7) Third, we hypothesised that there might be a niche complementarity effect whereby community functional trait dispersion determines dung removal efficiency of dung beetle communities. As a measure of functional trait complementarity, we calculated a distance-based metric of trait functional dispersion (FDis) using the \u201cFD\u201d package A total of 4705 dung beetles were captured across all sites, comprising 33 species in 12 genera . Of thesDung removal rates also varied dramatically across habitat edge gradients, ranging from an average of >75% dung removal over a 24-hr period in the forest interior to \u223c0% removal in the matrix habitat . MoreoveResults from the multilevel path analysis revealed that dung removal rates were influenced by trait-dependent effects, over and above the positive influence of total beetle biomass on removal rates . First, Second, community-weighted trait composition also responded significantly to both edge effects and matrix restoration, but with variable responses across different traits. For instance, at degraded edge gradients there was a significant increase in mean pronotum width, wing loading and BSI of individual species from the forest into the matrix habitats . HoweverAs expected, variation in the trait-mean composition of species strongly influenced functional trait dispersion, particularly with respect to wing area, body mass, and pronotum width effects, together explaining 76% of variation in functional dispersion across samples. For our study system, however, there were no apparent direct influences of edge effects or matrix restoration on functional trait dispersion after controlling for variation in community-weighted trait composition. There was also no flow-on effect of functional trait dispersion on rates of dung removal, despite the strong association of trait composition with dispersion.Finally, the relative partitioning of trait mean effects, functional trait dispersion, and mass-dependent neutral effects did not capture all the potential proximate factors mediating the effect of anthropogenic disturbance on dung removal rates. There was a significant interaction effect between matrix restoration and edge effects that had a residual direct influence on dung removal rates at matrix restoration sites, although at degraded sites there was no residual direct effect of edge impacts on dung removal rates  . This suWe demonstrate that matrix habitat restoration can have a profound influence on nutrient cycling-related ecosystem functioning at degraded tropical forest edges. For the removal of dung by dung beetles, the path to functional recovery depended not only on the random reassembly processes contributing to total dung beetle biomass , but also on the body sizes (i.e. pronotum widths) of recolonizing individuals. Given the importance of restoring ecosystem functioning in restoration efforts The key to determining the pathways through which matrix restoration drives functional recovery was the application of a response-effect trait framework within a path-modelling context. While this approach has been widely adopted in modelling human impacts on ecosystem processes within degraded systems, it holds untapped promise in a restoration context. From this analysis, we showed that matrix restoration substantially ameliorated the negative impacts of habitat edge effects on dung beetle biomass and community trait composition observed between forest and matrix habitats at the degraded sites. In particular, edge effects on community-weighted trait means of dung beetle pronotum width and wing loading at degraded edges were significantly reduced by the restoration of the adjacent matrix habitat. Given that small-bodied invertebrate species typically have lower physiological tolerance to anthropogenic disturbance In many ways, this rapid rate of recovery is surprising after just three years of experimental matrix regeneration. Many previous studies have suggested there can be long lag-times to faunal community re-assembly following revegetation, particularly for small-bodied species with low dispersal capacity 2 (despite maximum wing area of 1098.53 mm2), the key driver of variation in trait dispersion was the distribution of the few rare beetles with large body mass and relatively large wing area . Interestingly, there was a significant negative effect of community-weighted pronotum width on functional dispersion . We interpret this as species that are smaller than expected based on their body mass making a greater contribution to high trait dispersion.Surprisingly, matrix habitat restoration had no direct influence on community-wide trait dispersion at forest edges, but there were significant indirect effects observed via the mediating effects of community-weighted trait means on functional trait dispersion. In particular, there were highly significant effects of community-weighted mean body mass, pronotum width, and wing area on functional trait dispersion, with all three traits having equivalent standardized effect sizes. Because the vast majority of dung beetles captured (>86%) had a body mass of <10 mg (despite maximum body mass of 1543.07 mg) and wing area of <20 mmBy partitioning community-wide responses into separate trait-mean variables versus overall variability in community-level trait dispersion, our results demonstrate the varying sensitivity of different trait measures to environmental change. Functional trait dispersion was strongly affected by matrix habitat restoration at forest edges, but these effects were only manifested indirectly via the shared influence on multiple components of trait variation. No single trait response variable could explain the observed response in functional trait dispersion in its own right, suggesting the need to quantify multiple traits in order to capture their role in community assembly during restoration. At the same time, though, only very few trait responses were required (three in this case) to explain a relatively high proportion of the variation (76%) in community-wide trait dispersion.Trait determinants of community responses to environmental change also had a significant influence on rates of beetle-mediated dung removal. Although we found no niche complementarity effect on dung removal driven by variation in functional trait dispersion, there was a clear effect of community-weighted mean trait composition on dung removal rates, over and above neutral mass-dependent effects. This was demonstrated by the relatively large standardised effect size of community-weighted mean pronotum width on dung removal (\u22120.319), which had almost as strong a standardised effect on dung removal as total beetle biomass (0.342), supporting the claim that neutral processes alone may not be able to fully explain functional processes et al. Surprisingly, the mediating effect of community-weighted mean pronotum width on dung removal was negative, suggesting that in samples with a smaller weighted-average body size of dung beetles, the removal rate of dung was proportionately greater per unit mass of beetles. Many previous studies have pointed to the importance of large dung beetles in dung decomposition rates, whereby body size is assumed to be positively correlated with amount of dung sequestered In addition to mass- and trait-dependent effects, we also detected a significant residual interaction effect of our treatment drivers on overall rates of dung removal, with matrix restoration mitigating the low rates of dung removal observed at degraded edges significantly more than could be explained by recovery in dung beetle biomass or trait-dependence in reassembly processes alone. This is almost certainly due to unmeasured variation in environmental parameters along edge gradients, such as substantial reduction in dung desiccation rates at regenerating edges  and facilitation or competition from other dung-associated organisms that are likely to alter removal rates differentially among regenerating and degraded edge gradients. Furthermore, it is possible that other unmeasured traits such as dung removal strategy or diel activity patterns could help to explain some of this residual variation. A better mechanistic understanding of these processes is still needed in order to understand how other contributing factors such as these might help to explain variation in ecosystem functioning following restoration.Overall, this experiment has shown that restoration of the matrix surrounding degraded tropical forest remnants can drive large increases in the biomass of organisms and their associated ecosystem processes, even over very short time periods. Interestingly, the enhancement of dung removal rates through restoration could not be explained solely as a function of increasing biomass of decomposer organisms without recourse to trait-dependence in ecosystem process rates. A notable proportion of variation in dung removal was explained by community-mean body size that in turn resulted in significant effects on dung removal, suggesting that \u2018neutral\u2019 measures of community assembly alone cannot explain functional outcomes of habitat restoration. Rather, we found that recovery of a suite of disturbance-sensitive species with low dispersal power and small body size, but high per capita dung removal efficiency (for their size), resulted in higher dung removal rates at habitat edges undergoing adjacent matrix restoration. The observed mediating effects of response and effect traits on dung removal are likely to have far-reaching consequences for heavily-degraded tropical forest remnants, through cascading changes in insect-mediated ecosystem functions such as nutrient cycling rates and secondary seed dispersal that can have strong deterministic impacts on plant communities S1 FigureLayout of edge gradient sampling transects.(DOCX)Click here for additional data file.S2 FigureEdge-gradient sampling design.(DOCX)Click here for additional data file.S3 FigureExample of the left hind wing of an individual male Onthophagus sp. 1.(DOCX)Click here for additional data file.S4 FigureContour plot demonstrating the combined effects of total beetle biomass and community-weighted mean body mass on proportion of dung removed.(DOCX)Click here for additional data file.S1 TableTrait mean values for dung beetle species.(DOCX)Click here for additional data file.S2 TableList of dung beetle species and their occurrences.(DOCX)Click here for additional data file.S3 TableAkaike Information Criterion (AIC) scores obtained from the edge function fitting procedure.(DOCX)Click here for additional data file.S4 TableComplete basis set of independence claims for the selected best-fit path model.(DOCX)Click here for additional data file.S1 AppendixMeasuring rates of dung removal.(DOCX)Click here for additional data file.S2 AppendixMeasurement of dung beetle traits.(DOCX)Click here for additional data file.S3 AppendixContinuous edge response models.(DOCX)Click here for additional data file.S4 AppendixConstructing generalised multilevel path models.(DOCX)Click here for additional data file."}
+{"text": "Adult skeletal muscle possesses extraordinary regeneration capacities. After muscle injury or exercise, large numbers of newly formed muscle fibers are generated within a week as a result of expansion and differentiation of a self-renewing pool of muscle stem cells termed muscle satellite cells. Normally, satellite cells are mitotically quiescent and reside beneath the basal lamina of muscle fibers. Upon regeneration, satellite cells are activated, and give rise to daughter myogenic precursor cells. After several rounds of proliferation, these myogenic precursor cells contribute to the formation of new muscle fibers. During cell division, a minor population of myogenic precursor cells returns to quiescent satellite cells as a self-renewal process. Currently, accumulating evidence has revealed the essential roles of satellite cells in muscle regeneration and the regulatory mechanisms, while it still remains to be elucidated how satellite cell self-renewal is molecularly regulated and how satellite cells are important in aging and diseased muscle. The number of satellite cells is decreased due to the changing niche during ageing, resulting in attenuation of muscle regeneration capacity. Additionally, in Duchenne muscular dystrophy (DMD) patients, the loss of satellite cell regenerative capacity and decreased satellite cell number due to continuous needs for satellite cells lead to progressive muscle weakness with chronic degeneration. Thus, it is necessary to replenish muscle satellite cells continuously. This review outlines recent findings regarding satellite cell heterogeneity, asymmetric division and molecular mechanisms in satellite cell self-renewal which is crucial for maintenance of satellite cells as a muscle stem cell pool throughout life. In addition, we discuss roles in the stem cell niche for satellite cell maintenance, as well as related cell therapies for approaching treatment of DMD. Skeletal muscle is the most abundant tissue in the mammalian body accounting for approximately 40% of body weight, and is composed of multinucleated fibers that contract to generate force and movement. In addition, skeletal muscle possesses a remarkable ability to regenerate, and can go through rapid repair following severe damage caused by exercise, toxins or diseases. Muscle satellite cells were discovered by Alexander Mauro in 1961  , indicating the heterogeneity of quiescent satellite cells  mice display reduced significant reduction in satellite cell number, resulting in the failure of muscle growth and neonatal lethality of most Pax7 KO mice  mice display neural tube and cardiac chamber malformations, missing limb muscles which originate from migratory myogenic cells from somites, and die embryonically by day E14  satellite cells demonstrated the equivalent regenerative potency compared to wild-type satellite cells  was significantly increased compared to wild-type myoblasts following intramuscular injection into regenerating mouse muscle  and -206 (miR-206) are up-regulated, while Pax3 is down-regulated by miR-1 and miR-206 via direct binding of these miRNAs to the 3' untranslated region (UTR) of Pax3. This Pax3 down-regulation in activated satellite cells is also mediated by miR-27b  pathway  quiescent satellite cells were YFP(\u2212) cells, indicating that these YFP(\u2212) quiescent satellite cells have never expressed Myf5. Since Myf5 is one of the myogenic regulatory factors and known to regulate embryonic myogenesis, YFP(\u2212) satellite cells may be less committed cells compared to the YFP(+) population. In addition, the transplantation experiments clearly revealed that Pax7(+)YFP(+) cells preferentially underwent myogenic differentiation while Pax7(+)YFP(\u2212) cells were able to extensively contribute to generate satellite \u201cstem cell\u201d in regenerating muscle  lineage using CreMyf5/+/loxP/loxPPax7 mice revealed that the majority of adult satellite cells originate from Myf5-expressing myogenic cells, and that the majority of satellite stem cells are replenished from Myf5-expressing cells /Myf5(\u2212) myogenic progenitor cells also give rise to Pax7-positive satellite cells during development  self-renewing cells   showed delayed muscle regeneration and reduced satellite cell self-renewal  surrounding muscle cells is also known to undergo extensive remodeling during muscle regeneration. Consequently, excessive composition of interstitial ECM promotes the appearance of connective tissue or fibrosis in muscle under certain conditions such as those seen in DMD or aging muscles. Urciuolo and colleagues have recently demonstrated that an ECM protein, collagen VI, is critical as an extracellular niche protein to maintain the satellite cell pool (Urciuolo et al., in vitro. Satellite cells cultured on this substrate have shown higher potency of self-renewal than those cultured on traditional plastic dishes. Additionally, myoblasts cultured on hydrogel could promote the efficacy of cell engraftment and the reconstitution of satellite stem cells in vivo, indicating that substrate elasticity is also an important factor of satellite cell self-renewal (Gilbert et al., As described above, accumulating evidence has elucidated the signaling network for self-renewal in satellite cells while Gilbert and colleagues provide us new insight that the skeletal muscle microenvironment potentially regulates stem cell fate (Gilbert et al., In addition to cell commitment, recent reports indicate that physiological conditions in satellite cells may influence the regulation of self-renewal. Liu and colleagues have proposed that hypoxia does not affect myoblast proliferation but instead promotes satellite cell self-renewal through up-regulating Pax7 (Liu et al., It is widely accepted that satellite cells are essential for postnatal muscle growth and muscle regeneration. Despite high potency of myogenic differentiation in satellite cells, these cells are currently not applicable for cell transplantation therapy against DMD due to severe limitations, such as low cellular survival, incomplete myogenic differentiation, and especially poor satellite cell formation (Tedesco and Cossu, Recently, accumulating evidence has revealed the satellite cell heterogeneity and the molecular mechanisms of cell fate determination, specifically whether satellite cells differentiate into myocytes or self-renew as stem cells. These studies demonstrated that maintenance of the satellite cell pool is intrinsically and extrinsically regulated by many regulators. Novel knowledge about muscle regeneration through satellite cells may provide us new therapeutic approaches for DMD patients. Additionally, there are multiple unexplained muscular diseases, such as sarcopenia or muscle atrophy. In order to discover ideal therapies for muscular diseases, it is essential to explore fundamental molecular mechanisms of muscle satellite cells using new methodological technologies such as sequencing-mediated global gene regulation.Norio Motohashi and Atsushi Asakura wrote the manuscript. Both authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Preeclampsia is a unique pregnancy-related disease that affects 5-7% pregnancies worldwide. Placental architecture is modified in PE and eclampsia. Placental morphology and cellular arrangement are important for oxygen delivery from the mother to the fetus. Fetal growth and well-being after 20 weeks of gestation are dependent upon successful placental development. This, in turn, is achieved by an enhanced maternal blood supply to the placenta  and growth/ differentiation of the gas-exchanging placental villi. Conversely, pregnancy with severe placental insufficiency exhibits abnormalities both in uterine artery and in umbilical artery Doppler, and results in adverse perinatal outcome. The evaluation of placental functioning is possible nowadays through ultrasound examinations. Sonographic images associated with placental lesions include cystic areas, heterogeneous appearance of the placental mass, and thick or thin placentas. Sonographic evidence of destructive placental lesions is defined as the evolution of irregular cystic spaces with echogenic borders \u2013 the echogenic cystic lesions. Histological examinations of placenta may confirm these antepartum observations. Decidual vasculopathy and accelerated villous maturity are considered indicative of uteroplacental vascular insufficiency. Perivillous fibrin deposition and intervillous fibrin are considered indicative of intervillous coagulation. Detailed sonographic evaluation of the placenta and histopathological confirmation after birth are used to identify lesions associated with preeclampsia, intrauterine growth restriction and adverse short and long-term perinatal outcome, but the presence of cystic images in the placenta is not uniformly associated with adverse perinatal outcome. Combining Doppler studies with placental texture studies may lead to satisfactory results. Abbreviations: PE = preeclampsia; IUGR = intrauterine growth restriction; PI = pulsatility index; RIH = rounded intraplacental haematomas; TV = trophoblastic villi; MRI = magnetic resonance imaging Because of lack of predictive early markers and effective pharmaceutical interventions, PE is a serious obstetric complication leading to increased maternal and fetal morbidity and mortality.Preeclampsia (PE) is a unique pregnancy-related disease that affects 5-7% pregnancies worldwide. It is associated with hypertension and proteinuria. Despite long years of research, the mechanisms underlying the cause and progression of PE remain poorly understood. Risk factors include maternal and paternal family history of PE, nulliparity, ethnicity and existing disorders with several vascular dysfunctions, hypertension or inflammation such as diabetes, chronic hypertension, obesity, kidney disease, systemic lupus erythematosus and antiphospholipid syndrome .Diagnostic procedures during pregnancy complicated with pregnancy-induced hypertension/ preeclampsia include clinical examinations , ultrasound examinations, laboratory testing, fetal well-being assessments. Detailed ultrasound examination of the fetus at 18\u201320 weeks also includes placenta-related information beyond the fetal measurements and morphology: determination of placental length and thickness, number of cord vessels, cord insertion, and the assessment of placental texture. Uterine artery Doppler evaluation is performed by color and pulsed Doppler mapping. Mean pulsatility index (PI) values > 1.45 or bilateral early diastolic notches are considered abnormal . The ultrasound appearance shows an echodense region inside an echolucent area (or a hypoechogenic image with a hyperechogenic rim), without demonstrable blood flow inside (a recently formed hematoma). Old hematomas within an infarcted area might not be identified by ultrasound, as they tend to appear echolucent; with time, a definitive diagnosis can only be made through histopathologic examinations .A detailed sonographic evaluation of cysts includes an evaluation of shape, size and content as well as the absence/ presence of blood flow around or inside the cyst. Cystic areas are frequently observed in association with preeclampsia, growth restriction or fetal demise. Well-defined rounded cystic areas in the placenta are related to a higher risk of preeclampsia and intrauterine growth restriction. Several authors describe them as \u201crounded intraplacental haematomas\u201d (RIH) and report that more than 50% of these cystic lesions were associated with placental infarcts reflecting maternal vascular underperfusion. Magnetic resonance imaging is also useful in diagnosing early placental insufficiency. Heparin is proposed as a treatment choice in preeclampsia with placental infarctions  . Insertions of the umbilical cord into the placenta margin or into the fetal membranes (velamentous insertion) rather than into the main placental mass are associated with smaller placentas and smaller infants. Non-marginal, but markedly eccentric cord insertion associates with a weaker chorionic vascular distribution, inefficient transport gradient and a reduced birthweight for a given placental weight   specifically vary in PE. The total numbers of TV are significantly lesser, indicating distal villous hypoplasia . Numerous avascular TV surround the arteriosclerotic stem villi, possibly reflecting failure of vascular organization (villitis). TV syncytiotrophoblasts invariably develop clusters and sprouts to form syncytial knots. Histomorphometric findings indicate that the PE placentas have less villous surface area and smaller diameters, whereas the density of the TV was significantly higher .Several studies propose the use of low molecular-weight heparin and aspirin when placental lesions suggestive of infarcts are observed in the ultrasound scan. The studies suggest that the identification of placental lesions with ultrasound in the absence of fetal growth restriction may be managed by antithrombotic treatment. The association of fetal testing may more correctly identify the appropriate time for fetal birth, avoiding in utero fetal demise [10]. Combining Doppler studies with placental texture studies may lead to satisfactory results. This is important for adequate referral to a tertiary perinatal center, for improved clinical outcome, both for mother and fetus .A detailed sonographic evaluation of the placenta and histopathological confirmation after birth are used to identify lesions associated with preeclampsia, intrauterine growth restriction and adverse short and long-term perinatal outcome, but the presence of cystic images in the placenta is not uniformly associated with adverse perinatal outcome [Pregnancies complicated by PE are reflected in the placenta both macroscopically and microscopically and may be diagnosed early by thorough placental serially ultrasound examinations. Although the placenta adapts well to the hypoxic condition in PE, the compensatory changes that occur are insufficient. These compensatory changes cause placental suboptimal development and placental dysfunction that leads to chronic fetal hypoxemia."}
+{"text": "In vivo Cardiac Diffusion Tensor Imaging (cDTI) offers the potential to detect myocardial disarray and describe mean intravoxel myocyte orientation; however to date there is little quantitative cDTI data in the normal heart. In this study, we aim to establish the impact of physical and cardiac characteristics on cDTI parameters in a cohort of healthy volunteers.Myocardial disarray is considered an important histological feature of hypertrophic cardiomyopathy (HCM). In vivoWe recruited 46 healthy volunteers for cDTI at 3T. Three short axis mid-ventricular slices were acquired with multiple breath holds at the systolic pause. Data was post-processed with a platform, developed in-house, to create Fractional anisotropy (FA), Mean diffusivity (MD) and Helical Angle (HA) maps.Two of the original 46 volunteers were excluded due to ECG irregularities. Data was successfully acquired in the remaining 44 volunteers table . FA, MD Our data suggests that the cDTI parameters FA and MD, which describe intravoxel myocyte organisation and average myocardial diffusivity respectively, are independent of physical characteristics in healthy subjects. However, there is an association between age and epicardial HA which may be the result of age related loss in longitudinal function. Future NIHR cardiovascular BRU Royal Brompton Hospital & Imperial College."}
+{"text": "Multipotent stem cells have been isolated from multiple sources including, bone marrow, adipose tissue, placenta, umbilical cord and cardiac tissue. It is predicted that large numbers of therapeutically-active cells isolated from these tissue sources will be required to treat patients inflicted with various disorders. Experimental evidence suggests that these various cell types can exhibit distinct characteristics depending upon tissue source and method of expansion: differential expression of cellular markers is sometimes detected, doubling times and expansion limits can differ, and physical differences that influence the ability of cells to adhere to various synthetic surfaces are observed. A novel prototype microcarrier recently developed by Pall promotes rapid attachment and growth of multiple cell types in stirred-tank reactors. Additionally, peptide-coating provides an alternative animal component-free substrate for cell expansion. These desirable attributes manifest in both serum-containing and animal component-free medium formulations.A spherical microcarrier with a chemistry that promotes rapid attachment and superior growth of multiple cell types under a variety of environmental condition has recently been developed. The microcarrier chemistry was optimized through an iterative process using these parameters to guide development. Figure Human bone marrow-derived mesenchymal stem cells expanded on this new microcarrier type reached acceptable cell densities in spinner cultures under a variety of environmental conditions. Harvest efficiencies achieved in small scale cultures were excellent, and cell identity was maintained. Conditions optimized in small-scale spinners were successfully employed in environmentally-controlled bioreactor. Cell harvesting optimization studies at larger scale are currently underway. Results to-date indicate that this novel microcarrier type will provide a superior substrate for large-scale propagation of MSCs under various environmental conditions.In conclusion, two novel animal protein-free microcarrier types that support excellent attachment and growth of human mesenchymal stem cells were generated; optimal surface charge density which promotes rapid cell attachment and subsequent growth was identified; peptide concentrations and coating conditions that support efficient growth of hMSCs were identified; excellent growth of cells was achieved; cell harvest at small scale demonstrated efficient removal of cells with standard enzymatic treatment; cell growth on novel microcarrier types was similar to that achieved with commercially-available collagen-coated microcarriers; environmental conditions were optimized to support excellent growth and harvest efficiencies from two liter bioreactors yielded reached 1 to 2.5 billion cells. Excellent harvest efficiencies from microcarriers were obtained using enzymatic treatment and application of moderate shear force. Harvest efficiencies of 97% with >95% viability were obtained with hMSC. Human mesenchymal stem cells retained the ability to differentiate into adipocytes and osteocytes after growth on novel microcarrier types."}
+{"text": "A 30-year-old male, who underwent previous pars plana vitrectomy and silicone oil tamponade due to endogenous endophthalmitis originated from Klebsiella liver abscess, was referred for evisceration. At 2 months after vitrectomy with silicon oil tamponade, conjunctival chemosis and ocular pain were aggravated. Diffuse eyelid swelling and large subconjunctival mass with lipid droplets were noted. On MRI examination, subconjunctival mass and intra- and extraconal orbital mass around superior rectus muscle were observed. Excision of subconjunctival and orbital mass was performed. Histopathologic examination showed multiple silicone oil vacuoles surrounded by foreign body giant cells and fibrosis, which confirmed silicone oil granuloma. In a patient with suspicious melting sclera in diseases such as endophthalmitis, large silicone oil granuloma may be complicated in a rapid fashion after intravitreal silicone oil tamponade due to silicone oil leakage. Silicone oil has been widely used for decades in complex vitreoretinal surgeries. Although it has been known to be inert material, a number of complications such as cataract, glaucoma, and retinal toxicity have been reported . HoweverTo our knowledge, there have been no previous reports of early onset of large granuloma caused by extraocular migration of intravitreal silicone oil. We report subconjunctival and orbital silicone oil granuloma that resulted from the leakage of intravitreal silicone oil in a patient with endogenous endophthalmitis.A 30-year-old male suddenly developed left eyeball pain and visual loss with fever and chilling sensation. He was diagnosed as endogenous Klebsiella endophthalmitis that originated from liver abscess. He underwent pars plana vitrectomy and silicone oil tamponade  in the left eye for severe endogenous endophthalmitis. The infection had been calmed down after the surgery until the eyelid swelling and chemosis were aggravated at 2 months postoperatively. He was referred to oculoplastic clinic for evisceration under the impression of uncontrolled endophthalmitis.On ophthalmologic examination, he had no light perception in the left eye. The intraocular pressure was 14\u2009mmHg in the right eye and 9\u2009mmHg in the left eye. And left upper eyelid showed diffuse swelling and redness with complete ptosis . Large uOrbital magnetic resonance image (MRI) examination showed shrinkage of the eyeball and large subconjunctival and orbital mass. The mass was located in superior part of the orbit between levator muscle and eyeball, surrounding superior rectus muscle. It demonstrated septate cystic form with low signal intensity in T1- and T2-weighted image and heterogenous enhancement in Gd-enhanced image .The authors performed excision of subconjunctival and orbital mass. Large subconjunctival mass was observed under the entire upper bulbar conjunctiva. The conjunctiva was separated from the underlying mass by blunt dissection. Granulomatous mass was removed  and the Histopathology revealed silicone oil globules with inflammatory cellular infiltration. Multiple small and large lipid droplets (silicone oil) surrounded by foreign body giant cells were noted Figures . The fibAt 6 months after the surgery, the patient showed no evidence of recurrence. The patient was comfortable with no pain and showed good cosmesis wearing the prosthesis.Silicone oil is an established tamponade in treating complex vitreoretinal diseases such as retinal detachments, proliferative diabetic retinopathy associated with tractional retinal detachment . It is aIn the present study, silicone oil granuloma developed rapidly within 2 months through the melted sclera in a patient who underwent silicone oil tamponade for endogenous Klebsiella endophthalmitis originated from liver abscess. Endogenous Klebsiella endophthalmitis has generally poor prognosis in which most patients result in either no light perception or evisceration or enucleation . AlthougTo our knowledge, there have been no previous reports of early onset of silicone oil granuloma which was caused by large amount of silicone oil leakage through the melted sclera. Granulomatous inflammation associated with silicone oil leakage can develop rapidly progressing subconjunctival and orbital mass in patients with weakened sclera. In view of this case, surgeon should be prudent to perform silicone oil tamponade in a patient with suspicious melting sclera such as severe or uncontrolled endophthalmitis."}
+{"text": "Hyrtios sp. extract induces apoptosis in human colorectal carcinoma RKO cells with different p53 status; Andrographolide induces apoptosis of C6 glioma cells via the ERK-p53-caspase 7-PARP pathway; and osthole induces human colon cancer cell death and inhibits migratory activity.Natural bioactives are generally referred to the compounds exclusive of essential nutrients that have specific biological activity to human. From several decades ago to now, cancer continues to be the leading lethal cause worldwide. Studies have shown that natural phytochemicals derived from certain plants have the capability to prevent carcinogenesis. In this special issue, we collected numerous studies which provide novel evidence to support the opinion. For instance, epigallocatechin gallate inhibits migration of human uveal melanoma cells; marine spongeWe also collected some review articles in this special issue. A paper evaluated the cancer therapeutic potential of cardiac glycosides. A paper proposed vitamin A as the potent anticancer agent on targeting cellular retinol binding proteins. Three other papers addressed the anticancer molecular mechanisms of betulin, Goniothalamin, and Zerumbone. In summary, it is therefore believed that the appropriate application of natural bioactives should be a supplementary and safe way that enhances the efficacy of cancer therapy.Yih-Shou HsiehShun-Fa YangGautam SethiDan-Ning Hu"}
+{"text": "Endovascular aneurysm repair has revolutionized the therapeutic strategy for abdominal aortic aneurysm. However, hostile proximal aneurysmal neck and tortuosity of access vessels remain challenges in selecting optimal stent-grafts in abdominal aortic aneurysms with difficult anatomy.A 65-year-old woman complained of intermittent abdominal pain for one week. Computed tomography angiogram demonstrated a tortuous infrarenal abdominal aortic aneurysm with a tapered neck and a 136\u00b0 of infrarenal angulation. Aneurysmal dilatation and severe calcification of bilateral iliac arteries and tortuous aortoiliac access were also showed. Endovascular approach using Endurant stent-graft was attempted at an outside hospital, but failed because of the significant tortuosity of the abdominal aorta and iliac arteries. Since the patient refused to have open aneurysm repair, he was transferred to our hospital for further evaluation and possible EVAR with a different approach. EVAR was performed successfully using Gore Excluder stent-grafts . During the procedure, cannulation of the contralateral limb was unable to be achieved because of the tortuous aortoiliac course. Therefore, a snare was inserted from right radial artery, through the contralateral gate, to grasp the wire from left femoral artery. Two iliac stent-grafts were sequentially deployed with the lower end distal to the opening of the left internal iliac artery. Angiography confirmed complete sealing of the aneurysm with patency of bilateral renal arteries and external iliac arteries. The postoperative courses were uneventful and follow-up computed tomography angiogram at 6\u00a0months demonstrated patent bilateral femoral and renal arteries without endoleaks or stent migration.Although endovascular repair of aortic aneurysm with hostile neck and tortuous access is rather challenging, choosing flexible stent-grafts and suitable techniques is able to achieve an encouraging outcome. Endovascular aneurysm repair (EVAR) has revolutionized the therapeutic strategy for abdominal aortic aneurysm (AAA) with low operative mortality and morbidity, short hospital stay, and minimal blood loss compared with open repair ,2. The aA 65-year-old woman presented to an outside hospital with complaining of intermittent left-lower quadrant abdominal pain for one week. Computed tomography angiogram (CTA) demonstrated a severely tortuous descending thoracic aorta and an infrarenal AAA with maximum diameter of 80\u00a0mm and hostile neck   during AAA repair has been associated with buttock claudication, impotence, colon ischemia and pelvic necrosis . But witAs far as we know, no data exist on direct comparison of the performance of different stent-graft type in EVAR for AAA, and optimal selection of stent-graft type in hostile neck remains unclear . A retroBeside hostile proximal neck anatomy, challenging artery access conditions such as small-caliber vessels, iliac tortuosity, excessive calcification and occlusive diseases, represent the second most common excluding factor for EVAR . TechnicEVAR in AAA with severely angulated neck and tortuous access is technically challenging. Choosing flexible stent-graft system and various alternative techniques may make the difficult cases feasible, and achieve an encouraging early outcome. Further long-term randomized studies are needed to confirm the safety and durability of EVAR in patients with hostile anatomy.Written informed consent was obtain from the patient for publication of this case report and any accompanying images. A copy of writen consent is available for review by the editor of this journal."}
+{"text": "Patched 1 receptor, which senses the Sonic Hedgehog morphogen and limits its mobility in the limb bud. Second, evolutionary changes to the degree of programmed cell death between digits influence their development after their initiation. Similarly, evolutionary modification of leaf margin outgrowths occurs via two broad pathways. First, species-specific transcription factor expression modulates outgrowth patterning dependent on regulated transport of the hormone auxin. Second, species-specific expression of the newly discovered REDUCED COMPLEXITY homeodomain transcription factor influences growth between individual outgrowths after their initiation. These findings demonstrate that in both plants and animals tinkering with either patterning or post-patterning processes can cause morphological change. They also highlight the considerable flexibility of morphological evolution and indicate that it may be possible to derive broad principles that capture how morphogenesis evolved across complex eukaryotes.An open problem in biology is to derive general principles that capture how morphogenesis evolved to generate diverse forms in different organisms. Here we discuss recent work investigating the morphogenetic basis for digit loss in vertebrate limbs and variation in form of marginal outgrowths of angiosperm (flowering plant) leaves. Two pathways underlie digit loss in vertebrate limbs. First, alterations to digit patterning arise through modification of expression of the  A key question in biology is how morphological diversity is generated. Although plants and animals evolved multicellularity independently, within each kingdom conserved gene regulatory networks (hereafter termed networks) control the development of one or more body parts. In this context evolution operates as a \u201ctinkerer,\u201d being strongly influenced by the materials currently at hand as well as prior history . Consequcis elements, leading to their mutation having a lower propensity to generate pleiotropic effects that would compromise development  might be more readily available for evolutionary tinkering . HoweverTwo recent papers have explored the significance of patterning versus post-patterning events on development by studying digit loss in mammals and leaf shape formation in angiosperms and revealed a strong link between altered, species-specific gene expression domains and morphological variation. Both studies suggest considerable versatility in how evolutionary tinkering with developmental processes can ultimately arrive at similar phenotypes.Msx2 , a Shh receptor, is reduced toward the posterior limb bud. Ptch1 acts to restrict the spread of Shh by sequestration, thus reduction in Ptch1 expression leads to an expanded region of Shh activity and more uniform expression of its target genes, presumably causing a shift in limb axis symmetry to the space between digits III and IV  transcription factors are expressed in the meristem to maintain its organ-generating potential (PIN-FORMED 1 (PIN1) efflux transporter, coupled to a self-reinforcing feedback of auxin on PIN1 expression and polarization, likely creates sequential local auxin activity maxima at the flanks of the SAM. This process appears to be self-organizing and the resulting auxin maxima are required for sequential primordium development (CUP-SHAPED COTYLEDON (CUC) genes mark the leaf primordium boundary and allow its separation by repressing growth at the flanks  homeobox gene, of which a loss of function allele simplifies the leaf without causing pleiotropic phenotypes, suggesting a specific requirement for RCO in leaflet formation. RCO evolved in the Brassicaceae family from a gene duplication of LATE MERISTEM IDENTITY 1 (LMI1); originally identified in A. thaliana as a floral regulator (RCO is specifically expressed at the base of leaflets (Figure LMI1 is expressed more distally, in a complementary pattern, along the leaf margins. RCO does not appear to influence PIN1-mediated auxin patterning, but instead functions by repressing cellular growth between individual leaflets in C. hirsuta, a post-patterning process that allows leaflet separation. RCO was lost in A. thaliana during evolution, contributing to its leaf simplification, but re-introducing RCO into A. thaliana drives expression in basal regions of the leaf and increases leaf complexity, partially reversing the consequences of evolution. These results, together with a follow-up study in the sister species Capsella rubella and Capsella grandiflora by RCO is a key regulator of leaf shape and diversity in the Brassicaceae and provide a striking example of organ shape diversification by tinkering with local growth regulation at the flanks of a growing organ primordium (RCO study is that this gene was discovered through performing a forward genetics study in C. hirsuta and could not have been found in A. thaliana, where the gene has been lost, thus highlighting the importance of unbiased studies in diverse taxa for understanding the genetic basis for the evolution of form.Until recently, no genes had been identified that specifically influence leaflet formation without also affecting meristem function or leaf initiation. Such findings suggested that leaflets form through the redeployment of processes that acted earlier in development during leaf initiation . To idenegulator . They fos Figure , while Limordium . AnotherTaken together, these two studies illustrate how evolution can exploit both patterning and post-patterning processes to create morphological diversity in both plants and animals. It will be interesting to explore whether bias might exist for variations of either kind or for particular developmental pathways across different kingdoms. For example, plants and animals have evolved distinct biophysical properties and morphogenetic strategies that pose different constraints for evolution. Whereas animal morphogenesis involves the use of large-scale apoptosis and cell migration, these mechanisms are used to more limited extent  or not aThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "LMNA-related congenital muscular dystrophy and other rare clinical entities). We performed imaging studies on a large cohort of subjects bearing either LMNA or EMD gene mutations; each patient enrolled displayed variable compromise on posterior legs\u2019 muscles, ranging from mild compromise on soleus and medial head of gastrocnemius to overt alterations on soleus, medial head of gastrocnemius[LMNA or EMD gene mutations and lead to hypothesize a common mechanism in the process of damage of skeletal muscles fibers.Laminopathies are a heterogeneous group of disorders related to alterations on genes coding for proteins of the nuclear envelope. Among these clinical entities, there are several diseases affecting mainly the cardiac and skeletal muscles. These disorders include forms with a selective cardiac compromise and muscular dystrophies (autosomal and X-linked forms of Emery-Dreifuss muscular dystrophy, Limb girdle muscular dystrophy 1B, rocnemius. Of note"}
+{"text": "Though several implementation and quality improvement strategies have been shown to be effective in implementing programs and practices in routine clinical settings ,2, littlThe study tested the effectiveness of the implementation (IF) strategy hypothesizing that, compared to national technical assistance support alone, national support plus IF would improve implementation of PC-MHI. The RE-AIM  Framework guided testing of the IF strategy's effectiveness ,9.Two regions were recruited to receive the IF strategy and two matched regions were recruited for comparison. Regional MH leadership identified primary care (PC) clinics unlikely to implement PC-MHI without assistance. PC clinics in comparison regions were matched to clinics in IF regions. The sample included 14 PC clinics, 174 PC providers and 98,758 PC patients. To evaluate implementation outcomes, administrative data was extracted for two six month periods, 9-15 months and 21-27 months following completion of an implementation plan at IF clinics. Generalized estimating equations were used to control for observations clustered within sites.Reach)  than patients at comparison clinics. PC providers were more likely to refer at least one patient to PC-MHI (Adoption)  than providers at comparison clinics and a greater proportion of PC providers' patients were referred to PC-MHI (Adoption)  at IF clinics. There was no difference between IF and comparison clinics in the likelihood of patients being referred for a first time visit to specialty mental health care (Effectiveness) or the percentage of patients receiving same day access to PC-MHI (Implementation). Similar results occurred during the second six month period (Maintenance).For the first six month period, PC patients at clinics receiving IF were more likely to be seen by PC-MHI providers  can help healthcare system change agents learn how to facilitate implementation of evidence-based programs. For two and a half years, we conducted monthly debriefing interviews with a national expert external facilitator (EF) who was mentoring and coaching two internal regional facilitators (IRFs) in facilitating implementation of a VA policy initiative for Primary Care-Mental Health Integration (PC-MHI) at eight primary care clinics. Interviews focused primarily on the EF's efforts to help the IRFs become experts in IF processes. We also conducted two semi-structured qualitative interviews with each facilitator, midway through and at the end of the intervention.Our qualitative content analysis revealed that although the EF helped IRFs learn general implementation facilitation knowledge and skills, the EF also identified IRFs' individual strengths and weaknesses and tailored mentoring and coaching activities to their characteristics. The EF used a variety of methods to help IRFs learn IF skills, including both active methods  and participatory ones. She also used cognitive supports  and psychosocial supports, as well strategies to promote self-learning. Additionally, the EF tailored the process to sites' implementation needs. Over time, the EF pulled back from IRFs, increasingly turning responsibility for IF activities over to them. IRFs responded differently to this process with one IRF independently \"breaking away\" and the other being \"pushed out of the nest.\" In addition to helping IRFs learn the skills they needed for facilitating PC-MHI implementation, the EF helped IRFs to identify and modify interpersonal styles that could hinder success of facilitation efforts.This study addresses the critical but understudied area of how implementation scientists can transfer facilitation skills that incorporate evidence-based implementation interventions and strategies to internal change agents to help healthcare organizations implement effective programs."}
+{"text": "Vaccinations against infectious diseases are one of the major achievements in medicine in the last century and the most effective method for preventing infections. Concern about safety of vaccinations has been heightened by several reports of possible vaccine-induced autoimmune phenomena following various vaccinations. So far no study was able to show a casual connection between any vaccine and autoimmune syndrome.Few studies were published showing that induction of autoantibodies following various vaccination is possible, but without clinical significance. In few cases antibodies after vaccination were elevated even 6 months after vaccination. Induction of autantibodies, mainly antiphospholipid antibodies, in selected apparently healthy individuals was reported after influenza, hepatitis B and hepatitis A vaccination.Autoimmune manifestations reported have been only temporally related to the respective vaccine. Guillian Barre syndrome was described following vaccination against influenza and few other vacines, multiple sclerosis and arthritis were mainly reported after hepatitis B vaccination. There are some evidence to suggest a connection of reactive arthritis and rubella vaccine. Dermatomyositis was described following hepatitis B, tuberculosis, influenza and tetanus vaccinations. Recently a new syndrome Autoimmune-Autoinflammatory syndrome induced by adjuvants-ASIA has been described.Highlights of lecture:- autoimmune adverse events following vaccinations is possible in selected individuals but the risk of autoimmune disease after vaccination is, comparing to advantages of vaccination, negligible.- induction of autoantibodies in selected individuals after vaccination has no clinical significance.- new generation vaccine, mainly oriented on finding safer and effective adjuvants, are needed. At present few effective adjuvants are considered safe for use in humans.None declared."}
+{"text": "Neural systems show a wide variety of complex dynamics on different time scales. Specifically, on the short time scale of neuronal activations (milliseconds to seconds), several theoretical models  demonstIn this study we analyze how this coexistence of transient dynamics and cell assemblies can emerge in one neural circuit. The neural network, we investigate, consists of rate- based neurons with connections adapted by a generic combination of Hebbian plasticity and synaptic scaling . A subse"}
+{"text": "Philadelphia chromosome positive acute lymphoblastic leukemia is classified as a very high-risk group and it requires an intensive chemotherapy regimen associated with tyrosine-kinase inhibitors and allogeneic hematopoietic stem cell transplant from related or unrelated HLA matched donor. Most times, intensive chemotherapy regimens are associated with prolonged and profound pancytopenia when the risk of invasive fungal infection increases. After Candida and Aspergillus species, Mucormycosis is the third frequent fungal infection in hematology patients and it is associated with a reduced overall survival. When suspected, immediate treatment is needed. We present the case of 24-year-old patient diagnosed with Philadelphia chromosome positive acute lymphoblastic leukemia who developed right rhino-sino-orbital fungal infection with a favorable response to systemic antifungal treatment and noninvasive surgery. Later, patient refused consolidation and allogeneic hematopoietic stem cell transplant from an unrelated HLA matched donor but accepted the first generation tyrosine kinase inhibitor (Imatinib) and maintained a complete hematological and molecular response.Abbreviations: ENT = ear nose throat; BMB = bone marrow biopsy; ALL = acute lymphoblastic leukemia; TKI = tyrosine kinase inhibitor; IFI = invasive fungal infection; BMB = bone marrow biopsy; HE = hematoxylin and eosin; IHC = immunohistochemistry; CD = cluster of differentiation; ob = objective; Tdt = terminal deoxynucleotidyl transferase It represents the most frequent form of acute leukemia in pediatric population. Opposite to paediatric population where complete remission is achieved in 75% of cases, in adult population the results are modest .Mucormycosis is a fungal infection from Mucorales species . The most frequent site of infection is the sinus and associates with brain extension. When Mucormycosis is suspected, urgent treatment should be started and it consists of surgical, antifungal treatment and correction of risk factors  .BCR-ABL1 positivity for p190 transcript.Qualitative and quantitative molecular tests showed In February 2014, induction according to GMALL protocol was started and followed by febrile pancytopenia that required large spectrum antibiotics and antimycotic (Fluconazole).The bone marrow exam performed on day 14 of induction showed hypercellular marrow due to 75-80% blast infiltration. It was considered a treatment failure and the patient received salvage treatment according to GRAAL 2003 protocol and first generation tyrosine-kinase inhibitor (Imatinib), followed by prolonged febrile pancytopenia and grade 4 mucositis for which multiple broad-spectrum antibiotics and antimycotics (Voriconazole) were used.On day 14 of salvage regimen, the patient presented abrupt onset of right side headache followed by chemosis, photophobia and right ptosis.Bacterial screening including pharyngeal swab and palatine swab showed Zygomycetes filamentous fungi.Cerebral MRI showed pan sinusitis, inflammation of eye\u2019s structures and excluded cavernous sinus thrombosis.Right rhino-sinus-orbital Mucormycosis was suspected and liposomal B Amphotericin was started. ENT consult suggested radical surgery but due to the patient\u2019s refusal, right medial maxillectomy with complete resection of right inferior and medium nasal cornet and right anterior-posterior ethmoidectomy with mucocel derange from right retrobulbar recess were performed. Mycological exam of secretion taken during the procedure confirmed Mucormycosis invasive fungal infection.The patient\u2019s status improved after 33 days of liposomal B Amphotericin treatment and palliative surgical intervention.Although complete remission with salvage treatment was achieved, the patient refused consolidation treatment and allogeneic hematopoietic stem cell transplant from unrelated HLA matched donor and accepted Imatinib and Posaconasole treatment.12 months after the Mucormycosis episode, the patient maintained complete hematologic and major molecular remission without any signs of Mucormycosis infection.Table 1).The 5-year survival rate of adult population with ALL is 39%. 25% of this population presents positivity for Philadelphia chromosome and for those patients, the prognosis is reserved. Most patients receive intensive chemotherapy and tyrosine kinase inhibitors (TKI). Imatinib, first generation TKI, improved complete remission rate and increased the number of patients receiving hematopoietic stem cell transplants . In case of suspicion, urgent antifungal and surgical debridement treatment are required. The mortality rate of untreated Mucormycosis infection is of 70- 100%.Table 2) [5].Pagano and al. published a study in which the most affected organs were: lungs (47%), eye and face sinuses (25%), cerebral (19%) and extremely rare, small bowel (necrosis enterocolitis). The most common haematological diseases complicated with IFI are acute myeloid leukemia and acute lymphoblastic leukemia  and surgical removal of necrotic tissues. It has been proved that immediate surgical debridement of necrotic tissues increases the rate of cure but sometimes, this maneuver is difficult in thrombocytopenic patients. For those patients, multidisciplinary strategy is most beneficial  [The case report represents a double challenge: first, to induce the complete remission of progressive ALL and second, to treat Mucormycosis in a pancytopenia patient. The patient maintained complete remission after salvage treatment only with Imatinib and without allogeneic hematopoietic stem cell transplant. For Mucormycosis, the palliative surgical debridement and antifungal treatment (Amphotericin B followed by Posaconazole) were successful in curing IFI without physical mutilation and intact affected organ functions with good quality of life.In this case report, we presented a young patient who was treated unconventionally for Philadelphia positive ALL and Mucormycosis. Due to rapid Amphotericin B treatment and minimum surgical debridement of affected areas, the patient achieved an overall and disease free survival of 12 months with good quality of life. At the time of publication, the patient maintained complete hematological and molecular remission with first generation TKI (Imatinib).Acknowledgment: This work was supported by the grant PN 41-087/ 2007 from the Romanian Ministry of Research and Technology. The authors express the gratitude to European LeukemiaNet for their permanent support.Disclosures: None"}
+{"text": "Chronic myelogenous leukemia is often treated using tyrosine kinase inhibitors such as dasatinib. Here we describe a rare case of inflammatory myopathy in a patient with chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib.A 69-year-old Caucasian man with imatinib-resistant chronic myelogenous leukemia achieved complete molecular remission in response to dasatinib therapy. However, from a normal initial serum creatine kinase level, he developed elevated serum creatine kinase levels and gradual-onset progressive muscle weakness after dasatinib therapy was initiated. Our patient was eventually diagnosed with inclusion body myositis. However, we were unable to determine the mechanism underlying the dasatinib-associated muscle weakness. Given the efficacy of dasatinib in the treatment of chronic myelogenous leukemia and our patient\u2019s mild symptoms of inclusion body myositis, he continued to receive dasatinib under close clinical and laboratory observation.Despite the wide use of dasatinib and its documented safety, we report a case of severe muscle injury of unknown etiology. Therefore, patients with chronic myelogenous leukemia receiving dasatinib and perhaps all tyrosine kinase inhibitors should be carefully monitored for signs of muscle injury, especially if this is associated with significant elevations in serum creatine kinase levels. Chronic myelogenous leukemia (CML) accounts for approximately 15\u201320% of all leukemia cases in adults in the USA . DasatinThe common side effects of dasatinib therapy include recurrent pleural effusions, myelosuppression, and rash. Other treatment-related adverse events include mild to moderate diarrhea, peripheral edema, and headache , 7. ElevA 69-year-old Caucasian man who was diagnosed with chronic phase CML in 1990 demonstrated a reasonable response to initial treatment with interferon and omacetaxine mepesuccinate (homoharringtonine), which was discontinued 14 years later when he began receiving imatinib mesylate (Gleevec) therapy. Our patient became resistant to imatinib one year after its first administration and developed accelerated phase disease; dasatinib was prescribed as second-line treatment. His initial serum CK level was normal. A marked elevation in his serum CK level was noted  and in 7% of those resistant or intolerant to imatinib therapy (minimum follow-up of 36 months) . Other pWe have reported the case of a patient with CML who developed significantly elevated serum CK levels while receiving dasatinib therapy, and who was subsequently diagnosed with IBM. This is what we believe to be the first report of a patient developing muscle weakness while receiving dasatinib, although causality could not be established. Furthermore, the plausible mechanisms underlying dasatinib-induced muscle injury could not be determined. Although dasatinib has been widely used in clinical practice and is safe, based on our experience, severe muscle injury should be investigated. Patients with CML receiving dasatinib or other TKIs should be carefully monitored for symptoms or signs of muscle injury, especially if this is associated with significant elevations in serum CK levels. Further studies are needed to determine the underlying pathophysiology of muscle injury in such patients.Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "A 47-year-old male presented with a subacute inferior myocardial infarction (MI)complicated by inferobasal ventricular septal rupture (VSR) and underwent emergencysurgical repair of VSR with a pericardial patch. In the postoperative period he remainedhypotensive, with low exercise tolerance and a holosystolic murmur was present.Echocardiography showed persistence of VSR with left-right shunt  and reveIn conclusion, this patient presented with an inferior MI complicated by rightventricular infarction, inferobasal VSR and inferior pseudoaneurysm with organizedthrombus inside. Mechanical complications are rare nowadays due to earlyrevascularization. The multimodality imaging approach is essential for their correctdiagnosis."}
+{"text": "Lupus nephritis affects 30 to 70% of systemic lupus erythematosus (SLE) patients and its treatment remains insufficiently effective and excessively toxic. Although biomarkers for nephritis are being identified there is still no reliable way of predicting an impending renal flare or determining which patients will respond to therapy. Because human renal tissue cannot be obtained sequentially during remission and relapse, animal models are often used to study progression of lupus nephritis. To elucidate the molecular mechanisms involved in renal inflammation during the progression, remission and relapse of nephritis we performed a transcriptome analysis of renal tissue from two murine lupus models, NZB/WF1 mice that develop proliferative glomerulonephritis and NZM2410 mice that develop glomerulosclerosis with minimal inflammation.Kidneys from NZB/W F1 and NZM2410 mice were harvested at intervals during their disease course or after remission induction with either combination cyclophosphamide/costimulatory blockade or with BAFF inhibition. Genome-wide expression profiles were obtained from microarray analysis of perfused kidneys. Real-time PCR analysis for selected genes was used to validate the microarray data. Comparisons between groups using SAM, and unbiased analysis of the entire dataset using singular value decomposition and self-organizing map were performed.Few changes in the renal molecular profile were detected in pre-nephritic kidneys but a significant shift in gene expression, reflecting inflammatory cell infiltration and complement activation, occurred at proteinuria onset. Subsequent changes in gene expression predominantly affected mitochondrial dysfunction and metabolic stress pathways. Remission induction reversed most, but not all, of the inflammatory changes and progression towards relapse was associated with recurrence of inflammation, mitochondrial dysfunction and metabolic stress signatures. Endothelial cell activation, tissue remodeling and tubular damage were the major pathways associated with loss of renal function.Immune cell infiltration and activation is associated with proteinuria onset and reverses with immunosuppressive therapy but disease progression is associated with renal hypoxia and metabolic stress. Optimal therapy of SLE nephritis may therefore need to target both immune and nonimmune disease mechanisms. In addition, the overlap of a substantial subset of molecular markers with those expressed in human lupus kidneys suggests potential new biomarkers and therapeutic targets."}
+{"text": "To review the spectrum of imaging findings of chemotherapy- induced cardiomyopathy in correlation with most common cytotoxic drugs and regimens.Cardio toxic effect of chemotherapy is a well-recognised problem in cancer patients. Cardio toxicity depends on multiple predisposing factors, specific components of the chemotherapy regimen, length of treatment, and dosage.We will present the spectrum of most common cardiotoxic chemotherapy agents and their combinations, specific effects on the myocardium, and imaging features of cardiomyopathies induced by chemotherapy.We will review pathophysiology of chemotherapy induced cardiomyopathy including:\u2022 Dose dependent cardiomyopathy\u2022 Predisposing conditions \u2013diabetes, presence of coronary artery disease, age.\u2022 Potential reversibilityWe will discuss imaging characteristics of chemotherapy induced cardiomyopathy\u2022 Imaging modalities \u2022 Importance of monitoring cardiac function during and after treatment\u2022 Distribution of late Gadolinium enhancement (LGE)\u2022 Emerging technologies for early diagnosis of cardiomyopathy in cancer patientsChemotherapy induced cardiomyopathy is a common problem among cancer patients, increasing long term morbidity and mortality and often leading to disability. Patients receiving chemotherapy treatment, particularly cardio toxic agents, should be routinely assessed for cardiac function to diagnose cardiomyopathy during the early phase of treatment and to prevent development of irreversible heart failure."}
+{"text": "In medication-overuse headache (MOH) pain modulation is probably dysfunctional at cortical and subcortical level, resulting in disequilibrium between pain inhibition and facilitation. Volumetric grey matter changes have been found in cortical regions, but also in the brainstem , the latSurface-based morphometric analyses should complement volumetric findings, providing more specificity in the metric affected (thickness vs. gyrification). Whereas cortical thickness alterations probably rely on altered trajectories of cortical maturation or neurodegenerative processes, cortical folding (gyrification) abnormalities are thought to reflect early alterations to brain development.In the present study we investigated cortical thickness and gyrification in 29 patients with MOH according to International Headache Society criteria and 29 age- and gender matched controls, using FreeSurfer. Correction for multiple comparisons was performed.In patients with MOH cortical thickness was decreased in the left middle frontal gyrus  compared to controls, whereas local gyrification was increased in the right fusiform gyrus and adjacent temporal regions, as well as in the right occipital pole.Decreased cortical thickness in frontal regions corresponds to decreased grey matter volume in similar regions. Increased local gyrification in the right fusiform gyrus corresponds to increased grey matter volume in the previous volumetric study. Increased gyrification in occipital regions might be related to increased susceptibility for cortical spreading depression."}
+{"text": "To investigate the patterns and mechanisms of audiovestibular dysfunction in intracranial hypotension.We had consecutively recruited 16 adult patients with intracranial hypotension at the Dizziness Center of Pusan National University Hospital between November 2011 to November 2013. Spontaneous, gaze-evoked, and positional nystagmus were recorded using 3D video-oculography. Most patients had pure tone audiometry, and bithermal caloric tests.Out of the 16 patients with intracranial hypotension, five (31%) had neuro-otological symptoms along with the orthostatic headache. One of them presented with recurrent spontaneous vertigo and tinnitus mimicking meniere's disease (MD). Oculographic analysis documented abnormal eye movements in 38%, which include spontaneous downbeat nystagmus with variable positional modulation  and positional upbeat nystagmus . During the attack of vertigo in the patient with MD-like symptoms, we observed unidirectional horizontal and torsional nystagmus with normal head impulse test. Bithermal caloric tests were normal in all patients who tested. Audiometry showed unilateral or bilateral sensorineural hearing loss in about half of the patients.Our study demonstrates that intracranial hypotension can induce higher frequency of audiovestibular dysfunction, which may be attributed to both irritation or dysfunction of the peripheral labyrinth or vestibulocochlear nerve, and brainstem or cerebellar dysfunction due to brain sagging.No conflict of interest."}
+{"text": "Clinician related factors have been implicated as important reasons for low rates of recruitment to randomised controlled trials (RCTs). Clinicians can experience discomfort with some underlying principles of RCTs and experience difficulties in conveying them positively to potential trial participants. Recruiter training has been suggested to address identified problems but a synthesis of this research is lacking. We therefore systematically reviewed the available evidence on training interventions for RCT recruiters.Studies that evaluated training programmes for trial recruiters were included. Those that provided only general communication training not linked to RCT recruitment were excluded. Data extraction and quality assessment were completed by two reviewers independently.15 studies from 7,337 potentially eligible titles and abstracts were included in the review: three RCTs, three non-randomised controlled studies, six pre-test-post-test studies, two qualitative studies and a post-training questionnaire survey. Most studies were of moderate or weak quality. Training programmes were mostly set within cancer trials, and usually consisted of workshops with a mix of health professionals over one or two consecutive days covering generic and trial specific issues. Recruiter training programmes were well received and there was evidence that some increased recruiters\u2019 self-confidence in communicating key RCT concepts. There was, however, very little evidence that this training increased recruitment rates or patient understanding, satisfaction, or levels of informed consentThere is a need to develop training programmes that can enable recruiters to explain key concepts effectively and evaluate whether they lead to improved recruitment and informed consent in RCTs."}
+{"text": "Carcinogenesis is an exceedingly complicated process, which involves multi-level dysregulations, including genomics (majorly caused by somatic mutation and copy number variation), DNA methylomics, and transcriptomics. Therefore, only looking into one molecular level of cancer is not sufficient to uncover the intricate underlying mechanisms. With the abundant resources of public available data in the Cancer Genome Atlas (TCGA) database, an integrative strategy was conducted to systematically analyze the aberrant patterns of colorectal cancer on the basis of DNA copy number, promoter methylation, somatic mutation and gene expression. In this study, paired samples in each genomic level were retrieved to identify differentially expressed genes with corresponding genetic or epigenetic dysregulations. Notably, the result of gene ontology enrichment analysis indicated that the differentially expressed genes with corresponding aberrant promoter methylation or somatic mutation were both functionally concentrated upon developmental process, suggesting the intimate association between development and carcinogenesis. Thus, by means of random walk with restart, 37 significant development-related genes were retrieved from a priori-knowledge based biological network. In five independent microarray datasets, Kaplan\u2013Meier survival and Cox regression analyses both confirmed that the expression of these genes was significantly associated with overall survival of Stage III/IV colorectal cancer patients. Colorectal cancer (CRC) is the third most common cancer in men  and the second in women  worldwide, accounting for roughly 694,000 deaths per yearIt is putatively accredited that carcinogenesis is caused by multi-level dysregulations, including genomics [majorly caused by somatic mutation and copy number variation (CNV)]468101112131617212223262728BRAF could activate MAPK pathway, thus influencing the massive dysregulation of gene activityCNV, aberrant promoter methylation and somatic mutation could all influence gene activation or suppression, thereby influencing the process of carcinogenesis. CNVs may alter gene dosage by changing the number of copies of a gene that is present in the genome303132The multi-level genomic dysregulations during carcinogenesis indicated that while looking into the dysregulation of gene expression in cancer, the aberrant patterns of multi-level events should also be paid considerable attention to shed light on the underlying intricate mechanisms of cancer initiation and deterioration. Therefore, the integrative analysis of cancer genomics, methylomics and transcriptomics is urgently needed to comprehensively dissect cancer etiology and provide clinical guidance.The Cancer Genome Atlas (TCGA) database is an immeasurable source of knowledge launched in 2005, which provides publicly available cancer genomic datasetsIn this study, we first collected genes with significant dysregulations with regard to DNA copy number, DNA promoter methylation, gene expression, and somatic mutation from TCGA paired samples. Differentially expressed genes (DEGs) with consistent aberrant promoter methylation or somatic mutation were found both exhibiting remarkable functional unity in developmental process. Gene to gene regulatory network was constructed by means of merging Human Protein Reference Database (HPRD), and Kyoto Encyclopedia of Genes and Genomes (KEGG) networks. By combining multi-dimensional genomic data of CRC and priori knowledge network, we applied a computational strategy, i.e. random walk with restart, to obtain the genes which were affected considerably by aberrant promoter methylation or somatic mutation. The most of these significant genes were connected in the network, and proven to hold profound prognostic information in late stage (Stage III/IV) patients, which might be helpful for constructing prognosis prediction models and providing novel tools to guide clinical implementations for this deadly disease.A schematic for the study is depicted in https://tcga-data.nci.nih.gov/tcga/). Four levels of paired data  were downloaded, including 32 paired RNA sequencing level 3 data [raw counts and RNASeq by Expectation Maximization (RSEM) normalized read counts], 500 paired DNA copy number level 3 data  and the risk score  generated by these 37 significant genes were significantly associated with patient\u2019s OS. Multivariate Cox analysis indicated the risk score was an independent prognostic factor .Meta-analysis of 37 significant genes and risk score in five Clinicinfo data sets also confirmed the result of survival analysis with both fixed-effect model  and rand53ALK could disrupt the development of central nervous system585960TIAM1, expressed in the base of intestinal crypts, established a fundamental role for Wnt-signaling pathway in the development and maintenance of normal intestinal physiologyTIAM1 and canonical Wnt-signaling pathways could significantly influence intestinal tumor formation and progressionThe booming amount of high-throughput and multi-dimensional genomic data usher us into a new era, when the tremendously complicated molecular mechanism of carcinogenesis were perceived and dissected in a more integrative perspective. In this study, we systematically analyzed CRC genomic data, including CNV, somatic mutation, DNA promoter methylation and gene expression, to discover novel and important molecules and genomic dysregulations in a more comprehensive manner. Paired samples in TCGA database were used to identify differential gene expression and genetic or epigenetic abnormalities, respectively, and collected three groups of candidate genes with differential gene expression pattern and upstream corresponding dysregulations. The result of GO analysis indicated the functions of DEGs with abnormal promoter methylation (Group B) and somatic mutation (Group C) both majorly concentrated on developmental process, of which the outcome is an anatomical structure , or organism over time from an initial condition to a later conditionPTCH1 is a key regulator of development, whose overexpression could drive skin carcinogenesis7172Notch1 signaling pathway, activated during development, are proven to be reactivated in the process of carcinogenesis7472767778It has been more than 150 years since Rudolf Virchow first advocated that neoplasms arise \u201cin accordance with the same law, which regulates development\u201d in 1858. Emerging evidences supported the cellular behavioral similarity between ontogenesis and oncogenesis, for instance, in the process of epithelial-to-mesenchymal transition (EMT)In our study, we adopted a simple and effective computational strategy to randomly walk DPRGs with aberrant promoter methylation or somatic mutation in HPRD and KEGG merged biological network. Random walk with restart was adopted to decipher gene to disease association in priori-knowledge based network, whose performance was proven to be much more superior to other methods, such as neighborhood approaches8081TGFBR1 is a central molecule in TGF-\u03b2 pathway, whose alteration could strikingly enhance the susceptibility to CRCEP300 may be a feature of gastric and colorectal cancersPRKCA and PRKCB are both member of Protein kinase C (PKC) family, which have a role in cell proliferation, differentiation, angiogenesis, and apoptosisPRKCB inhibition by enzastaurin could lead to mitotic missegregation and preferential cytotoxicity toward colorectal cancer cells with chromosomal instability; loss of PRKCA signaling is a general characteristic of colorectal tumors regardless of other underlying genetic defects, pointing to the importance of this pathwayThe majority of these significant genes were connected to form a relatively compact biological module , implyinSince candidate genes were collected based on aberrant patterns in multi-omic level of TCGA genomic data, we used microarray data sets with OS information from GEO database instead of TCGA to test the prognostic value of these significant genes. Recent expression profiling datasets lack of consistent results between the studies due to different technological platforms and lab protocols8791In summary, with the increasing availability of multidimensional genomic data, we collected genes with high rate of somatic mutation, differential expression, promoter methylation dysregulation and significant CNV, using paired samples in TCGA database. Three groups of DEGs with corresponding genetic or epigenetic abnormalities were obtained; the GO enrichment and overlapping analysis suggested DEGs with aberrant promoter methylation or somatic mutation were both functionally centering on developmental process. Random walk with restart was used to extract significant developmental genes most affected by aberrant promoter methylation and somatic mutation in merged regulatory network. In addition, the significant genes were closely related to OS of late stage patient. It is also very tempting that the identification of the functional regulators of these genes might be profusely beneficial to the discovery of new drug targets for CRC treatment. It is our hope that our preliminary exploration would be helpful for the further study upon cancer etiology and treatment guidance.How to cite this article: An, N. et al. Developmental genes significantly afflicted by aberrant promoter methylation and somatic mutation predict overall survival of late-stage colorectal cancer. Sci. Rep.5, 18616; doi: 10.1038/srep18616 (2015)."}
+{"text": "In the above article (in vivo. While TEC-based constructs do not have the same ability as scaffold-based constructs to control the internal structures of regenerated tissues, they still have potential utility in certain clinical scenarios.Oxygen delivery is the greatest limiting factor to large-volume tissue engineering. Regenerating post-mastectomy breast tissue requires avascular adipose tissue to be transferred as thin \u201cmicro-ribbons\u201d to avoid central necrosis . Similar article , Morrisoin vivo soft tissue regeneration because its function does not depend on tissue microanatomy or organ gross anatomy. However, adipose tissue regeneration with TEC lacks major clinical utility because, with proper technique and recipient site preparation, large-volume autogenous adipose tissue transfers can already safely be performed for reconstruction of breasts and other soft tissue defects (Adipose tissue is an ideal model for  defects . Alterna defects . ReproduMorrison has also contributed to other rodent TEC studies that have successfully regenerated large volumes of functioning pituitary , thymic Whole organ regeneration would require the vascularity associated with TEC and the internal anatomy associated with cell scaffold-based constructs. An intricate combination of TEC and a cell-scaffold based construct might create a solution; however, this concept seems well ahead of our current capabilities given the widely varied results Morrison and colleagues obtained using TEC in humans.Morrison and colleagues should be commended for their novel work. While these findings cannot yet impact clinical practice, they should encourage researchers to continue making strides towards translating tissue engineering breakthroughs to the clinical arena. TEC clearly has great potential for regeneration of human tissues, but before advancing any further, TEC must demonstrate the ability to consistently produce predictable outcomes.The authors have no conflicts of interest to disclose."}
+{"text": "Salvinorin A is a potent and selective agonist of kappa opioid receptors in the brain. Recent studies in several animal models have revealed that Salvinorin A has anti-addiction, anti-depression properties and exhibits pronounced neuroprotective effects against hypoxia/ischemia induced brain damage, and have raised interest in potential clinical applications in several acute pathologies involving oxygen deficiency in the brain. This review focuses on the chemical and physical properties of Salvinorin A and their impact on development of a rational formulation to enable its translation from a research compound to a novel therapeutic agent. Salvinorin A (SA) is a psychoactive neoclerodane diterpenoid  isolatedSince the discovery of SA as the only known naturally-occurring, non-nitrogenous kappa opioid receptor (KOR) agonist ,5] rese rese5] rIn this review we discuss the chemical and physical properties of Salvinorin A and their roles in the process of defining a rational translation pathway for formulating the drug substance into a clinically deliverable dosage form for acute medical situations.Physical and chemical properties of SA see  reveal aLacking ionizable functional groups, Salvinorin A cannot form soluble salts. SA has eight hydrogen-bond acceptor sites, all oxygen atoms, and no hydrogen-bond donor groups. It would thus appear likely that its crystal lattice should comprise only weak non-bonded interactions between adjacent molecules and a resultant diminished lattice energy reflected in a low melting point. In factThe chemical stability of Salvinorin A has not been examined in published literature to date. Nonetheless, any clinically relevant formulation will need to circumvent hydrolytic conditions that may affect the ester and lactone moieties essential to the activity of SA at the KOR receptors. For example, hydrolysis of the acetate in SA produces the well-known derivative Salvinorin B which lacks KOR affinity. FurtherIn view of Salvinorin A\u2019s susceptibility to enzymatic degradation as well as being a substrate for P-glycoprotein efflux, the PO route of administration is clearly not viable. Not surprisingly due to the poor aqueous solubility of Salvinorin A, intravenous (IV) formulations described in numerous in vivo studies over the past 15 years have largely employed pharmaceutically unacceptable solvents . IV formulations using moderately high percentages of ethanol and propylene glycol as co-soDespite the poor apparent bioavailability of Salvinorin A when dosed via the oral cavity by recreational drug users, for acutIntranasal administration for direct to brain drug delivery offers several important advantages over other administration routes: rapid onset of therapeutic activity; bypassing the blood brain barrier; avoiding hepatic first pass metabolism. In the Inhalation of Salvinorin A via smoking or vaporization is well known to provide very rapid brain uptake and intense psychotropic effects, 19. InhIn this review we have examined the chemical and physical properties of Salvinorin A, a potential novel drug for neurological diseases, to define viable approaches to developing formulations that can be translated to clinically relevant dosage forms for treatment of acute onset illnesses outside a hospital setting. Salvinorin A exists as a stable stoichiometric hydrate and exhibits very poor solubility in aqueous vehicles. Intravenous administration may be achievable with elevated co-solvent vehicles or nanocrystalline suspensions, although its utility in the absence of medical staff is doubtful. Dosage forms targeting the oral mucosa appear worthy of further investigation: while the bioavailability is low, the ability to readily deliver high doses to the oral cavity (a highly accessible site) may allow maintenance of therapeutic drug levels in the brain. Intranasal drug delivery affords rapid, direct access of the drug to the brain bypassing the hepatic circulation. A multitude of choices for formulation and delivery devices exist, but patient to patient variability to this route of drug delivery remains uncertain particularly for administration by non-medical persons. Preferred among recreational drug users, delivery of Salvinorin A via inhalation offers clear advantages in terms of rapidly reaching therapeutic drug levels in the brain. For the purposes of acute treatment of an unresponsive patient, inhalation delivery may not be suitable."}
+{"text": "Antiretroviral therapy (ART) currently enables long-term survival of persons living with HIV (PLWH), but the respite from escalating pandemic AIDS-related deaths is undermined by both emergence of drug-resistant HIV and failure to develop HIV vaccines . Such reAlthough binding of host self antigens by antibodies risks host damage, such binding may occur without resulting in appreciable harm. In support of this view, an apparent lack of pathological manifestations has been noted among healthy individuals who developed circulating antiplatelet autoantibodies  subsequent to immunization with recombinant HIV gp160 ; and cerin vivo, to block infection without producing excessive damage. Such targeting of host self epitopes might be sufficient to block infection ; otherwise, infection still might be blocked by simultaneous binding of both host self- and pathogen-associated epitopes by synergistically acting antibodies . Furthermore, host self epitopes tend to be highly conserved, which could facilitate vaccine design for entire host populations. The risk\u2013benefit trade-off posed by host-reactive antibody-mediated immunity could be explored initially through passive immunization with monoclonal antibodies (mAbs), before committing to active-immunization strategies . The mAbs could be developed in tandem with specific antidotes  for treating any adverse reactions that might occur, for instance, due to effector mechanisms such as complement activation and antibody-dependent cell-mediated cytotoxicity (ADCC). Antibody-mediated complement activation might be minimized by avoiding the juxtaposition of target epitopes , whereas damage due to any activated complement could be mitigated by complement-inactivating agents ; and damage due to ADCC might be addressed by suppression of natural killer (NK) cell activity. Such complications could pose barriers to regulatory approval, albeit perhaps less so for therapeutic versus prophylactic vaccines particularly where net benefit  would be strongly compelling. Nevertheless, either or both complement activation and ADCC still might contribute to net benefit if they actually decreased pathogen replication [e.g., possibly with antibodies to the scavenger receptor CD36, which have been shown to inhibit HIV-1 release from infected macrophages by clustering newly formed virions at their site of budding , particularly against human rhinovirus (for which ICAM-1 serves as the major host receptor) . Anti-inThe scheme described herein thus shifts the focus of immunity-oriented approaches in health care, from immune destruction of specific targets back to the original object of vaccination, namely host protection against disease. This widens the scope of vaccines and immunotherapeutics, by placing due emphasis on immune targeting of host self epitopes as a potential means for host protection associated with negligible or justifiably limited host damage. More generally, immune targeting of epitopes may be broadly conceptualized in terms of high-level functional outcomes including both familiar consequences of conventional immunization regimens  as well as less obvious and possibly even counterintuitive but nonetheless beneficial results . Such a perspective provides the basis for an expanded paradigm of biomedically enhanced immune function, the essence of which is concisely expressed as the idea of epitopes for protective immunity targeting antigens of pathogen and/or host (EPITAPH).The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Liposarcoma (LPS) is rare malignant tumor of fat cells in deep soft tissue that affects adults between the ages of 40 and 60 . This tuWDLPS and DDLPS subtypes have a characteristic feature of amplified region of chromosome 12q13-15 containing several well-known oncogenes such as MDM2, CDK4 and HMGA2 . We founNext, whole exome sequencing and targeted exome sequencing identified various known cancer related and novel genes recurrently mutated in different subtypes of LPS. MAPK, ErbB, JAK-STAT, Wnt, apoptosis, cell cycle, DNA replication and repair and axon guidance pathways were found to be potentially involved in liposarcomagenesis. We identified recurrent mutations in previously unidentified genes in LPS associated with DNA damage repair pathways. LPS tumors with DNA repair mutations could be completely dependent on other backup repair pathways for the survival which may be exploited to induce synthetic lethality as therapeutic approach in these tumors.Interestingly, we reported for the first time multi-region genomic analysis of single LPS patient's tumor signifying intra-tumor mutational and copy number heterogeneity. The current basis for most of the personalized medicine approaches depends on the genomic landscape of a single tumor biopsy sample. Due to the frequent large size of LPS tumors compared to other solid tumors, intra-tumor heterogeneity will lead to difficulties in identifying biomarkers and therapeutic targets. Our preliminary analysis of intra-tumor heterogeneity mandates the need for future detailed studies exploring the evolution of LPS tumors leading to progression.In summary, our recent work gave insights into global genomic spectrum of LPS cohort for development of novel therapeutic strategies and for understanding the pathogenesis this deadly disease."}
+{"text": "Thymallus arcticus) and rainbow trout (Oncorhynchus mykiss) exhibited kilometer-scale movements among streams during the summer growing season. Although we monitored movements at a small fraction of all tributaries used by grayling and rainbow trout, approximately 50% of individuals moved among two or more streams separated by at least 7 km within a single summer. Movements were concentrated in June and July, and subsided by early August. The decline in movements coincided with spawning by anadromous sockeye salmon, which offer a high-quality resource pulse of food to resident species. Inter-stream movements may represent prospecting behavior as individuals seek out the most profitable foraging opportunities that are patchily distributed across space and time. Our results highlight that large-scale movements may not only be necessary for individuals to fulfill their life-cycle, but also to exploit heterogeneously spaced trophic resources. Therefore, habitat fragmentation and homogenization may have strong, but currently undescribed, ecological effects on the access to critical food resources in stream-dwelling fish populations.Stream-dwelling fishes inhabit river networks where resources are distributed heterogeneously across space and time. Current theory emphasizes that fishes often perform large-scale movements among habitat patches for reproduction and seeking refugia, but assumes that fish are relatively sedentary during growth phases of their life cycle. Using stationary passive integrated transponder (PIT)-tag antennas and snorkel surveys, we assessed the individual and population level movement patterns of two species of fish across a network of tributaries within the Wood River basin in southwestern Alaska where summer foraging opportunities vary substantially among streams, seasons, and years. Across two years, Arctic grayling ( River networks are hierarchically structured systems characterized by a continuum of downstream changes in biota and ecosystem processes, which generate coarse-scaled patterns of biotic and abiotic heterogeneity ,2. HowevMovement among habitats is one strategy animals have evolved to track spatially and temporally variable resources. For freshwater fishes, it has been widely acknowledged that relatively long-distance movements are necessary for the long-term persistence of populations . HoweverThymallus arcticus) and rainbow trout (Oncorhynchus mykiss) are two species of non-anadromous (resident) salmonids that co-occur in streams and rivers throughout western Alaska. Grayling and rainbow trout play a large ecological and economic role in the region, as they can often comprise the majority of resident stream biomass and are the mainstay of recreational fisheries )It is interesting to consider why movements at larger spatial scales are rarely documented in freshwater fishes. One explanation is that the range of observed movement distances will directly depend on the interplay between the finest spatial and temporal resolution studied (grain) and the size of the entire study area or duration  by year and stream. Only \"returning\" fish were used in movement analyses.(DOCX)Click here for additional data file.S1 Figin (A) Hidden Creek, (B) Lynx Creek, (C) Teal Creek, and (D) Stovall Creek.(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file."}
+{"text": "Technology in cataract surgery is constantly evolving to meet the goals of both surgeons and patients. Recent major advances in refractive cataract surgery include innovations in preoperative and intraoperative diagnostics, femtosecond laser-assisted cataract surgery (FLACS), and a new generation of intraocular lenses (IOLs). This paper presents the latest technologies in each of these major categories and discusses how these contributions serve to improve cataract surgery outcomes in a safe, effective, and predictable manner. With cataract surgery regarded as the most widely performed surgical procedure, a demand exists for continued innovation and technology. The latest advances evolved through application of well-defined principles to current surgical goals and patient expectations. For example, femtosecond laser technology emerged after fifty years of employing laser technology in ophthalmology . TheodorMore than ever, patients have the desire to reduce their dependence on spectacles after cataract surgery. Physicians now have access to advanced diagnostics that can better quantify conditions such as dry eye, light scatter, and posterior corneal astigmatism. These technologies can enhance refractive measurements and appropriate IOL selection.McDonald recently reported that the postoperative prevalence of dry eye related symptoms is approximately 88% . AnalysiEvaluation of optical quality also aids in decision making between corneal or lens-based procedures. The C-Quant  assesses straylight subjectively by utilizing a compensation comparison method . The AcuBoth anterior and posterior corneal astigmatism should be taken into account in IOL planning, particularly in patients desiring astigmatic correction. Inaccuracies arise when posterior corneal astigmatism is measured based on the assumption of a fixed-ratio relationship with the anterior curvature . The CasPatients with a history of corneal refractive surgery expect reduced dependence on spectacles after cataract surgery. The use of intraoperative aberrometry can adjunctively guide the future of IOL power selection . The OptThe use of the electroretinogram (ERG) has been well described and may have a novel application for refractive cataract surgery. Dr. Richard Mackool described the use of flash ERG testing with office-based electroretinography  in preoperative cataract evaluation. It can provide an objective evaluation of macular function and could be useful in influencing lens selection for patients with conditions such as epiretinal membrane, diabetic retinopathy, and age-related macular degeneration. More studies evaluating ERGs in preoperative cataract assessment need to be done to further assess its value and implications .Femtosecond laser-assisted cataract surgery (FLACS) has realized increasing popularity. Noninferiority has been established relative to manual cataract surgery, and some reports have suggested superiority relative to manual methods . Potenti\u2122 by Alcon), Mayer et al. showed that redocking was unnecessary when a modified soft interface was used, even though some cases resulted in incomplete incisions requiring manual opening [The docking process using the femtosecond laser-eye interface uses a suction ring to stabilize the eye, thereby allowing imaging and laser delivery through a clear optical pathway. Considerations for docking include complete coupling, patient comfort, intraocular pressure elevation, and minimal distortion of anatomy to avoid disruption of the beam path. In a study using Alcon's LenSx platform to compare curved direct contact and modified soft interfaces ; Infinite Vision IOL ; and mechanically adjustable IOLs . These are currently being studied in vivo with promising preliminary results. The second category includes magnetically adjustable IOLs , light adjustable IOLs , and the Perfect Lens . The latter is a novel platform, which can be adjusted with the femtosecond laser based on the concept of refractive index shaping. The light adjustable IOL is currently in FDA clinical trials. Its mechanism involves the use of infrared light to polymerize photosensitive silicone macromers, which results in changes in lens morphology and optical properties .A new generation of optics with extended depth of focus, multifocal rotational symmetry and asymmetry, and accommodating capabilities offers promising strategies to advance functional vision in refractive cataract surgery. The Tecnis Symfony (AMO) is an extended depth of focus IOL that works by correcting chromatic aberration using diffractive optics and reduces glare and halo symptoms classically associated with conventional multifocal IOLs . MultifoAccommodating IOLs aim to simulate the natural mechanism of accommodation. The FluidVision IOL  has silicone oil inside the lens that moves in response to ciliary contraction forces. An electroactive IOL with a liquid crystal that is sensitive to electric current is also in development . Dual accommodating IOLs designed for sulcus placement include the DynaCurve IOL  and the Lumina IOL  . The injThe future of refractive cataract surgery is exciting; in time, these new technologies may be the standard of care. With refinements of the latest technology, FLACS and other parallel advances will provide surgeons with the potential to perform an even safer, predictable, and effective surgery."}
+{"text": "Escherichia coli (E. coli) strains that cause ABU have evolved from uropathogenic E. coli (UPEC) by reductive evolution and loss of the ability to express functional virulence factors. For instance, the prototype ABU strain 83972 has a smaller genome than UPEC strains with deletions or point mutations in several virulence genes. To understand the mechanisms of bacterial adaptation and to find out whether the bacteria adapt in a host-specific manner, we compared the complete genome sequences of consecutive reisolates of ABU strain 83972 from different inoculated individuals and compared them with the genome of the parent strain. Reisolates from different hosts exhibited individual patterns of genomic alterations. Non-synonymous SNPs predominantly occurred in coding regions and often affected the amino acid sequence of proteins with global or pleiotropic regulatory function. These gene products are involved in different bacterial stress protection strategies, and metabolic and signaling pathways. Our data indicate that adaptation of E. coli 83972 to prolonged growth in the urinary tract involves responses to specific growth conditions and stresses present in the individual hosts. Accordingly, modulation of gene expression required for survival and growth under stress conditions seems to be most critical for long-term growth of E. coli 83972 in the urinary tract.During asymptomatic bacteriuria (ABU), bacteria colonize the urinary tract for extended periods of time without causing symptoms of urinary tract infection. Previous studies indicate that many  Normal flora furnishes the host with ecological barriers that prevent pathogen attack while maintaining tissue homeostasis. Despite their vast numbers and staggering molecular complexity, microbiomes of the gut, respiratory and urogenital tracts persist without triggering a destructive host response. This lack of destructive inflammation is fascinating and important, as it reflects exquisite molecular regulation of the host environment by commensal bacteria. Simultaneously, the host regulates permitted and unwanted paths of immune activation by discriminating attacking pathogens from beneficial commensals.The failure of asymptomatic carrier strains to trigger disease-associated signaling pathways and pathology has generally been attributed to their lack of virulence and, until recently, it was not clear if, in addition, asymptomatic carrier strains enhance their persistence by actively modifying the host environment. We have discovered that commensal bacteria modulate host gene expression to ensure that destructive immune activation will not occur . These iUTI constitutes a highly relevant model of microbial adaptation, in which the contrasting roles of pathogens and commensals are clearly displayed . PathogeEscherichia coli (UPEC) activate an innate immune response through virulence factor\u2013specific TLR4 signaling, the TRIF/TRAM adaptors, MAPK-, p38- and CREB phosphorylation and IRF3/IRF7, AP1-dependent transcription. We have shown that \u2212/\u2212Irf3 mice develop severe, acute symptoms accompanied by urosepsis and renal abscess formation, demonstrating that the innate immune response orchestrated by IRF-3 is crucial for bacterial clearance and for renal tissue integrity. Human disease relevance is suggested by an increased frequency of functionally relevant IRF3 promoter polymorphisms in about 70% of patients with recurrent acute pyelonephritis . The. The7]. oolgirls  and was E. coli strain VR50, have been also shown to evolve from commensal strains by gaining colonization factors [Bacteria increase their fitness in new host niches by rapid adaptation to changing environmental conditions. They lose or gain genetic material and, through selection, new variants become fixed in the population. Evolution has mainly been assumed to favor virulence, which promotes host-to-host spread and tissue attack. Until recently, evolution of commensalism had not been considered. We have proposed that ABU strains evolve towards commensalism in human hosts, as defined by a reduction in overall genome size, inactivation of virulence genes and modifications of transcriptional regulators ,11. Some factors .E. coli 83972 genome revealed a common ancestry with uropathogenic E. coli strains but a smaller genome size due to multiple deletions and mutations, suggesting that this strain adapted to the human urinary tract by undergoing reductive evolution [fim deletion and several papG point mutations abolish fimbrial expression and adherence [Epidemiologic studies have established that the severity of UTI reflects the virulence profile of the infecting strain, with a higher frequency of tissue-attacking virulence factors expressed by UPEC strains than by most strains causing ABU ,14, despvolution ,16 . Reisolates with slower growth rates in urine were also less competitive relative to ancestor strain 83972. Many reisolates formed less biofilm than parent strain 83972. This phenotype could be correlated with motility and flagella expression [E. coli is modulated in response to the individual host. Further genome-wide, transcriptome and proteome analysis proved that these genomic changes altered bacterial gene expression, resulting in unique adaptation patterns in each patient affecting iron uptake strategies as well as protection against oxidative or nitrosative stress, general stress response, and utilization of different carbon sources [Diverse pheno- and genotypic comparisons uncovered striking differences among patients  . So farE. coli 83972 monoculture populating the bladder [in vivo growth in the urinary tract could include phenotype switching. Alternatively, the occurrence of heterogeneous populations at symptomatic episodes may represent spontaneous stochastic events including minor transient populations [Interestingly, we observed phenotypic variation in the  bladder . This ph bladder  suggests bladder . Small c bladder . Therefoulations .E. coli 83972 colonizes the human urinary tract without inducing a strong immune response and can even actively suppress host gene expression. Genome comparison demonstrated that this strain is a deconstructed, attenuated uropathogen. Although we were able to shed some light on bacterial strategies and conditions which may promote attenuation and E. coli adaptation during prolonged colonization of the urinary tract, specific genomic features of strain 83972, which may account for all aspects of the asymptomatic bladder colonization, have not yet been identified. The detailed analysis of the molecular mechanisms required for the specific bacterium-host interaction resulting in a weak host response will be an important task for future studies to understand how this strain actively modifies the host environment in order to promote persistence."}
+{"text": "Identification of disease causing mutations in genetically heterogeneous conditions such as intellectual disability by Sanger sequencing is time-consuming, costly and often unsuccessful. The advent of NGS techniques is paving the way for novel large scale approaches with an unforeseen diagnostic power. However, the plethora of variants of unknown significance detected by genome-wide approaches requires distinctive strategies to identify actually disease-related mutations. We recently showed that exome sequencing of patient-parent trios in sporadic cases of unspecific severe intellectual disability may unravel disease causing mutation in more than 50% of previously unsolved cases. Thereby it became also evident, that the current descriptions of phenotypes associated with mutations in a certain gene, are heavily biased towards certain recognizable patterns. However, while whole exome sequencing may currently provide theoretically the highest cost-efficient diagnostic power, it may miss mutations due to incomplete coverage of certain genes. Therefore in some phenotypes a \u201cclinical exome\u201d limited to a set of genes with currently known monogenic mutations may also be useful."}
+{"text": "Prostate cancer remains significant public health concern amid growing controversies regarding prostate specific antigen (PSA) based screening. The utility of PSA has been brought into question, and alternative measures are investigated to remedy the overdetection of indolent disease and safeguard patients from the potential harms resulting from an elevated PSA. Multiparametric MRI of the prostate has shown promise in identifying patients at risk for clinically significant disease but its role within the current diagnostic and treatment paradigm remains in question. The current review focuses on recent applications of MRI in this pathway. An estimated 233,000 newly diagnosed cases of prostate cancer (CaP) are estimated for 2014, with a projected 29,480 CaP deaths in the same year [The shortcomings of PSA and prostate biopsy have propelled the search for alternative measures to improve its diagnostic yield and efficiency. Transrectal ultrasound (TRUS) guided biopsy of the prostate currently remains the gold standard for tissue diagnosis but itself has limitations. The systematic yet random and blinded sampling of TRUS biopsy served a useful purpose from its introduction in the 1980s, when biopsy of palpable, large-volume disease was representative of whole gland pathology. The introduction of PSA and subsequent identification of organ-confined, low volume disease have made TRUS biopsy gradually more antiquated and now CaP remains the only solid organ tumor diagnosed without tumor imaging and a directed sampling method.Multiparametric MRI (mp-MRI) of the Prostate. The role of prostate biopsy has evolved from a purely diagnostic tool to include one that informs clinical decision-making. As such, it is essential to ensure that the appropriate individuals receive a biopsy thus averting unnecessary harm and that biopsy information represents what it truly intends to measure. In an effort to improve on the current standard, PSA-derived markers, PSA kinetics, and patient characteristics including genomic profiling and imaging have all been investigated to refine patient selection with variable results. The application of mp-MRI of the prostate has emerged as a powerful tool that provides detailed anatomical and functional information where it is currently lacking. In addition to high resolution T2 weighted (T2W)  imaging, the integration of diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE) imaging, and spectroscopic  imaging in combination has allowed radiologists to better identify areas of benign and potentially malignant disease  , extracapsular extension (ECE), and even pelvic lymph node involvement. Recent series have reported sensitivity of >80% and specificity of >90 \u201325. SoylHigh-quality imaging is a fundamental component for patient selection for focal therapy of prostate cancer . Until rThe most valuable utilization of PSA remains after whole-gland treatment, where increases in PSA correlate well with disease recurrence. MP-MRI can be used to identify local recurrence after both radical prostatectomy and external beam radiation with functional imaging sequences driving detection in these patients . The addThe detailed anatomic information afforded from mp-MRI enables its versatile use intraoperatively where PSA falls short. Higher PSA values may provide generalized information, from which inferred risk is calculated based on large datasets but fails to provide patient-specific information that can guide surgery. Improved risk stratification, imaging, and novel therapeutic approaches have enhanced efforts for focal therapy in prostate cancer. Focal therapy techniques including high intensity focused ultrasound and laser induced thermal therapy are largely guided by real-time MRI. MRI can assist in tumor localization and probe placement in addition to treatment monitoring intraoperatively. Novel MR-TRUS fusion platforms for guidance of focal therapy are also beginning to emerge . MR TherOverdetection of clinically insignificant, low-grade, low-volume CaP has spurred the adoption of active surveillance (AS) as an accepted management strategy. AS allows patients with low risk disease to defer definitive therapy, potentially indefinitely, until objective evidence of disease progression is noted. PSA is utilized as both an entry criterion and a mainstay of surveillance in conjunction with random prostate biopsy for AS. MP-MRI and targeted biopsy are able to better differentiate those patients with indolent disease, selecting patients who better represent low-risk disease . Of patiInvestigation of novel technologies harnessing the properties of mp-MRI is showing promise in the staging of prostate cancer. Current models including the UCSF-CAPRA scoring system and the Partin tables integrate PSA to provide valuable insight into presence of metastasis and predictions of organ confined disease. Ultrasmall superparamagnetic particles of iron oxide (USPIO) have shown promise in the preoperative staging of bladder and prostate cancer patients, allowing for detection of metastasis. DWI combined with USPIO has demonstrated potential in discrimination of malignant versus benign pathology in even normal size lymph nodes, though wide adoption has been hindered due to variability in interpretation . In addiFinally, Positron emission tomography (PET) by itself demonstrates high sensitivity for prostate cancer detection but nonspecific uptake in benign lesions limits its diagnostic utility. However, PET/MRI has recently shown promise with a sensitivity and specificity for CaP detection in lesions >5\u2009mm being 84% and 80%, respectively, when correlated with whole mount pathology at radical prostatectomy . FurtherThe novel applications of MP-MRI are encouraging and but are not a panacea to our PSA woes. MRI interpretation is challenging, requiring considerable experience before proficiency. As mp-MRI has gained acceptance, the need for standardized protocols and reporting and high quality studies has been realized . DetermiPSA remains the cornerstone to screening, staging, and surveillance after treatment despite its numerous shortcomings. Currently, mp-MRI is proving an essential adjunct to supplement PSA in proper patient selection for biopsy, treatment, and surveillance. High-quality studies are required to validate the initial encouraging body of literature supporting the use of MRI in this arena."}
+{"text": "Information derived from functional magnetic resonance imaging (fMRI) during wakeful rest has been introduced as a candidate diagnostic biomarker in unipolar major depressive disorder (MDD). Multiple reports of resting state fMRI in MDD describe group effects. Such prior knowledge can be adopted to pre-select potentially discriminating features for diagnostic classification models with the aim to improve diagnostic accuracy. Purpose of this analysis was to consolidate spatial information about alterations of spontaneous brain activity in MDD, primarily to serve as feature selection for multivariate pattern analysis techniques (MVPA). Thirty two studies were included in final analyses. Coordinates extracted from the original reports were assigned to two categories based on directionality of findings. Meta-analyses were calculated using the non-additive activation likelihood estimation approach with coordinates organized by subject group to account for non-independent samples. Converging evidence revealed a distributed pattern of brain regions with increased or decreased spontaneous activity in MDD. The most distinct finding was hyperactivity/hyperconnectivity presumably reflecting the interaction of cortical midline structures  with lateral prefrontal areas related to externally-directed cognition. Other areas of hyperactivity/hyperconnectivity include the left lateral parietal cortex, right hippocampus and right cerebellum whereas hypoactivity/hypoconnectivity was observed mainly in the left temporal cortex, the insula, precuneus, superior frontal gyrus, lentiform nucleus and thalamus. Results are made available in two different data formats to be used as spatial hypotheses in future studies, particularly for diagnostic classification by MVPA. Mental disorders featuring depression as a predominant symptom and more specifically major depressive disorder (MDD) are important worldwide public health concerns. In recent years significant progress has been achieved regarding the identification of biological correlates and potential neural mechanisms involved in the pathogenesis of MDD. These scientific efforts comprise studies of genetic foundations, molecular mechanisms including neurotransmitter systems and structural as well as functional neuroimaging  studies in MDD has applied stimulus-based acquisition protocols. Participants were confronted with predefined stimuli in the scanner, e.g., pictures of emotional faces. Brain activity in response to these stimuli was analyzed  or the  amplitude of characteristic low-frequency fluctuations (ALFF or fALFF). Functional connectivity (FC) can be operationalized as the temporal correlation of signal fluctuations in remote brain areas. Conventional FC-analyses are seed-based but FC-analyses in a wider sense include independent component analyses or complex graph theoretical network measures. A minority of studies has applied analyses of effective connectivity   methods have been proposed to identify a subset of most informative features to be used with the aim to increase classification accuracy  and pooled studies with SPECT and PET data  search using the following query on August 20, 2013: (\u201cdepression\u201d OR \u201cdepressive\u201d) AND  AND .We conducted a PubMed  using the non-additive activation likelihood estimation (ALE) approach with coordinates organized by subject group (ALE-S method) to account for non-independent samples  and 1000 permutations  and a high resolution anatomical template with isotropic voxels in MNI space as distributed with GingerALE.Anatomical labels were automatically assigned in GingerALE. Visualizations were created using Mango  for hypothesis-driven group comparisons and particularly for FS  of spontaneous brain activtiy   or single-photon emission computed tomography (SPECT)  and less consistently the cingulate cortex and thalamus  and derivative techniques: reduced anisotropy measures, a potential marker of fiber integrity, were observed in parts of the superior frontal white matter presumed to connect the dorsolateral prefrontal cortex and anterior cingulate cortex with subcortical nuclei  with lateral frontal areas related to externally-directed cognition. Alterations that can be captured by rs-fMRI seem to differ from those identifiable with other neuroimaging modalities but show considerable overlap. Results of this meta-analysis are provided as coordinates and detailed maps in MNI space to be readily applicable for ROI selection in further rs-fMRI studies in MDD including feature selection for classification approaches with diagnostic intention. By emphasizing spatial precision and sensitivity this approach only provides limited information about the exact functional meaning of altered spontaneous brain activity in MDD.Benedikt Sundermann and Bettina Pfleiderer conceived and designed the study. Mona Olde l\u00fctke Beverborg and Benedikt Sundermann identified and screened the articles. Benedikt Sundermann, Bettina Pfleiderer and Mona Olde l\u00fctke Beverborg participated in final study selection and group assignment. Benedikt Sundermann and Mona Olde l\u00fctke Beverborg conducted the ALE-analyses. Benedikt Sundermann, Bettina Pfleiderer and Mona Olde l\u00fctke Beverborg participated in interpretation of the results. Benedikt Sundermann drafted the manuscript. All authors critically revised the manuscript for important intellectual content and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Combined PET/MR is a promising tool for simultaneous investigation of soft tissue morphology and function. However, contrary to CT, MR images do not provide information on photon attenuation in tissue. In the currently available systems issue is solved by synthesizing attenuation maps from MR images using segmentation algorithms. This approach has been shown to provide reason-able results in most cases. However, sporadically occurring segmentation errors can cause serious problems. Recently, algorithms for simultaneous estimation of attenuation and tracer distribution (MLAA) have been introduced. So far, validity of MLAA has mainly been demonstrated in simulated data. We have integrated the MLAA algorithm  into thePhantom data were acquired using a whole body phantom with three cylindrical inserts filled with different substances . MLAA-estimated mu-maps of the phantom were compared to the mu-maps resulting from transmission measurements with an ECAT HR+ scanner. We also performed a first qualitative evaluation of the attenuation maps obtained in patient studies.Evaluation of the phantom study showed good concordance between measured and estimated attenuation coefficients for all types of substances used in the phantom. Evaluation of patient data showed some substantial improvements of the MLAA attenuation maps compared to the segmented MR-based attenuation maps.Preliminary results show that for the Philips Ingenuity PET/MR scanner the MLAA algorithm allows to obtain attenuation maps which outperform the MR based maps in several aspects. However, a more detailed analysis is still required to address the question of possible cross-talks in regions with high activity. Additionally, MLAA algorithm substantially increases computational burden leading to long processing times, which makes it currently impractical for clinical application."}
+{"text": "Tracheal penetration of esophageal self-expanding metallic stents (SEMS) with/without tracheoesophageal fistula (TEF) formation is a rare occurrence. We report the case of a 66-year-old female patient with advanced esophageal squamous cell carcinoma who had undergone palliative esophageal stenting on three occasions for recurrent esophageal stent obstruction. On evaluation of symptoms of breathing difficulty and aspiration following third esophageal stent placement, tracheal erosion and TEF formation due to the tracheal penetration by esophageal stent were diagnosed. The patient was successfully managed by covered tracheal SEMS placement under flexible bronchoscopy. Esophageal SEMS placement has evolved into a first line approach for the palliative relief of dysphagia for patients with advanced esophageal cancer . The sucDespite the widespread use of esophageal SEMS placement for the numerous previously described indications, delayed prolapse and erosion of esophageal SEMS into the tracheobronchial tree are rarely reported , 3\u20136. HoA 66-year-old female presented with history of persistent cough and shortness of breath of 2-week duration. Cough used to worsen immediately on intake of liquids/solids and, for the same reason, patient complained of marked reduction in oral intake. There was no history of hemoptysis, wheezing, hoarseness of voice, or chest pain.Patient had been diagnosed with advanced stage carcinoma of the esophagus, 15 months ago. At that time, patient had been evaluated for symptoms of dysphagia, loss of appetite, and significant weight loss. Upper gastrointestinal endoscopy examination (UGIE) performed at that time revealed circumferential growth at 25\u2009cms from incisors and biopsy demonstrated moderately differentiated squamous cell carcinoma. Fine needle aspiration from a palpable right supraclavicular lymph node at that time also confirmed metastatic squamous cell carcinoma. Flexible bronchoscopy (FB) examination at that time was normal. In view of grade III dysphagia and metastatic disease, patient underwent covered esophageal SEMS  placement in November 2012 and palliative chemoradiotherapy , radiotherapy) was concurrently administered. For recurrence of dysphagia six months following esophageal stenting, UGIE was performed which demonstrated tumor in-growth for which a covered SEMS  was placed inside the previous stent. Tumor in-growth recurred nine months later for which another covered esophageal SEMS was placed inside the two previous stents. Symptoms of cough and dyspnea occurred one month following the third esophageal SEMS placement and the patient was referred to the pulmonary outpatient clinic.On examination, patient appeared emaciated. Pulse rate was 100/min, respiratory rate was 25/min, and rest of the vital signs and general physical examination were normal. On examination of the respiratory system, inspiratory crepitations were audible in bilateral lung bases. A clinical possibility of airway-esophageal fistula was considered and FB examination was performed.http://dx.doi.org/10.1155/2014/567582) On distal inspection, the wire mesh of the esophageal stent was seen over the posterior tracheal wall extending up to 1-2\u2009cms above the carina. A diagnosis of tracheal erosion of the esophageal SEMS with TEF was confirmed. The patient was unfit for any surgical intervention and therefore bronchoscopic management was planned.FB demonstrated prolapse and erosion of the proximal end of esophageal stent through the posterior tracheal wall and formation of tracheoesophageal fistula (TEF) through which bubbling secretions was visualized.  was successfully deployed under flexible bronchoscopy and conscious sedation, to successfully cover the entire extent of the eroded esophageal SEMS and the TEF  and four months had passed since tracheal SEMS placement.Reported major complications associated with the placement of esophageal SEMS include significant bleeding, tumor obstruction, stent migration, airway-esophageal fistulization, gastroesophageal reflux, aspiration pneumonia, and persistent chest discomfort . EsophagDespite these factors, delayed tracheal erosion and TEF formation due to esophageal SEMS is a rarely described occurrence. However, erosion of esophageal SEMS into adjacent structures apart from the trachea such as aorta, bronchi, carotid arteries, and vertebral arteries has been described and vascular perforation is usually associated with a fatal outcome , 8. AggrThe most important principle of management in the situation of tracheal erosion by esophageal SEMS is to stabilize the airway and to seal off the esophageal-respiratory communication. The same may involve a combination of or either of the following steps: esophageal stent removal and/or repeat esophageal stent placement/coaxial esophageal SEMS/tracheal covered SEMS placement/surgery in cases of benign disease . BronchoA prophylactic approach for the prevention of this complications has also been suggested wherein parallel tracheal and esophageal stenting may be considered especially in situations where the large esophageal tumor burden increases the propensity of airway obstruction following esophageal SEMS deployment. In fact, in case a covered esophageal SEMS completely prolapses into trachea, fatal asphyxiation may occur which may not occur in case an uncovered stent had been utilized wherein the wire mesh can allow ventilation to continue .The present case highlights the fact that, in rare circumstances, esophageal SEMS can penetrate into the tracheobronchial tree and present with emergent and often life threatening airway obstruction or aspiration. Occasionally, short of a frank rupture into the trachea, the stent can cause compression effect and tracheal lumen compromise also and sometimes a limited penetration by a stent wire has also been reported . EndoscoVideo of the flexible bronchoscopy examination demonstrating the presence of eroded esophageal SEMS into the trachea. Covered metallic tracheal stent is being deployed using the flexible bronchoscope to cover the prolapsed esophageal SEMS."}
+{"text": "Rice growth is severely affected by toxic concentrations of the nonessential heavy metal cadmium (Cd). To elucidate the molecular basis of the response to Cd stress, we performed mRNA sequencing of rice following our previous study on exposure to high concentrations of Cd . In this study, rice plants were hydroponically treated with low concentrations of Cd and approximately 211 million sequence reads were mapped onto the IRGSP-1.0 reference rice genome sequence. Many genes, including some identified under high Cd concentration exposure in our previous study, were found to be responsive to low Cd exposure, with an average of about 11,000 transcripts from each condition. However, genes expressed constitutively across the developmental course responded only slightly to low Cd concentrations, in contrast to their clear response to high Cd concentration, which causes fatal damage to rice seedlings according to phenotypic changes. The expression of metal ion transporter genes tended to correlate with Cd concentration, suggesting the potential of the RNA-Seq strategy to reveal novel Cd-responsive transporters by analyzing gene expression under different Cd concentrations. This study could help to develop novel strategies for improving tolerance to Cd exposure in rice and other cereal crops. Cadmium (Cd) is a widespread heavy metal pollutant that is highly toxic to living cells. Accumulation of the nonessential metal Cd in plants is a major agricultural problem. Specifically, Cd is absorbed by the roots from the soil and transported to the shoot, negatively affecting nutrient uptake and homeostasis in plants, even in very small amounts. Many agricultural soils have become contaminated with Cd through the use of phosphate fertilizers, sludge, and irrigation water containing Cd. Cd exposure inhibits root and shoot growth and ultimately reduces yield. Furthermore, Cd accumulation in the edible parts of plants such as seed grains places humans at a risk because of its highly toxic effects on human health. Reducing the Cd concentration in plants below the maximum level indicated by the Codex Alimentarius Commission of FAO/WHO  is necesCd causes oxidative stress and generates reactive oxygen species, which can cause damage in various ways such as reacting with DNA causing mutation, modifying protein side chains, and destroying phospholipids . VariousOryza sativa L. cv. Nipponbare) under a high Cd concentration using the RNA-Seq platform. A clear and detailed view of the transcriptomic changes triggered by Cd exposure is important to understand the gene expression network of the basal response to Cd stress. This could not be obtained from past studies using the microarray platform, but RNA-Seq can accurately quantify gene expression levels over a broad dynamic range with high resolution and sensitivity  ) . Enriched GO terms significantly in each cluster may represent the functional categories in rice under Cd exposure. Enriched GO terms of gradually upregulated transcripts under Cd exposure include metal ion transport (GO:0030001) , which may function in Cd transport. Response to oxidative stress (GO:0006979) and responsive to oxidative stress (GO:0006979) were also included in cluster 3 and cluster 4, respectively. This suggested that they might function in defense against Cd. Enriched GO terms of gradually downregulated transcripts under Cd exposure include translation (GO:0006412), translation elongation (GO:0006414), DNA replication (GO:0006260), and DNA repair (GO:0006281) . Photosynthesis, light harvesting (GO:0009765), and photosynthesis (GO:0015979) were also included in both clusters. These may function in plant growth. Thus, these correspond to the observed changes in phenotype  encoding iron-regulated transporter 1 (IRT1) was upregulated more than 5-fold under low Cd concentrations but responded only slightly under the high Cd concentration. IRT1s often transport Cd because of their low substrate specificity  that may function in Cd transport under Cd exposure. The expression of 183 transport transcripts was compared between low and high Cd concentration treatments in roots and shoots at 1\u2009d, because Cd uptake from the hydroponic culture and efflux pumping are initial responses to Cd exposure (cificity \u201326, 30. We generated gene expression profiles for rice seedlings grown under low Cd concentrations. Phenotypic observations and constitutive gene expression indicated that low Cd concentrations cause growth retardation but are far from being fatal in rice. Several genes associated with defense systems were strongly upregulated; the expression of metal ion transporter genes tended to correlate with Cd concentration and GO enrichment analysis of the clustered genes based on their expression patterns, suggesting that our transcriptome profiles reflect responses to Cd in rice. Our data also suggest that it could be dangerous to eat plants that do not show specific Cd pollution symptoms growing in soil contaminated by small amounts of Cd. Establishing the exact composition and organization of the transcriptional network underlying the response to Cd exposure will provide a robust tool for improving crops in the future, for example, by creating low Cd uptake plants.Mapping of RNA-seq reads obtained from root and shoot samples to the reference IRGSP-1.0 genome sequence."}
+{"text": "Immune-mediated pathogenesis has been suggested for idiopathic sensorineural hearing loss (iSNHL). Recent studies have investigated the relationship between iSNHL and autoantibodies against inner ear antigens, but specific tests are not available.To assess the positivity of autoantibodies against inner ear in a series of pediatric patients with idiopathic sensorineural hearing loss.We conducted a prospective, non-interventional observational study in a series of pediatric patients affected with iSNHL. Autoantibodies against inner ear , previously described in the serum of patients with Cogan's syndrome, were detected in our populations. The characteristics of children who resulted positive were also evaluated to verify if clinical data, disease progression and response to treatment could confirm an immune-mediated pathogenesis.Eleven patients were enrolled and 9 of them resulted positive for the inner ear antibodies detected. Non-organ specific autoantibodies were present in 5 children out of 9. An immune-mediated condition was diagnosed in 2 cases and minor immune manifestations were found in other 2 patients. In 5 cases hearing loss remained stable with no therapy, otherwise 4 children developed hearing loss progression. Two subjects were treated with steroids and methotrexate achieving hearing improvement. Another subject started methotrexate treatment showing hearing loss stabilization.Most of clinical characteristics and comorbidities described, added to immunologic tests results and to treatment efficacy, suggest an immune-mediated pathogenesis of hearing loss. Inner ear autoantibodies are not able to identify children affected with autoimmune sensorineural hearing loss but, integrated with clinical data, they can represent a diagnostic aid for the physician. Large prospective studies are needed to investigate usefulness, diagnostic and prognostic role of these autoantibodies.None declared."}
+{"text": "Endovascular aneurysm repair (EVAR) is perhaps the most widely utilized surgical procedure for patients with large abdominal aortic aneurysms. This procedure is minimally invasive and reduces inpatient hospitalization requirements. The case involves a 72-year-old male who presented to the emergency department with right testicular ischemia two days following EVAR. Given the minimal inpatient hospitalization associated with this procedure, emergency physicians are likely to encounter associated complications. Ischemic and thromboembolic events following EVAR are extremely rare but require prompt vascular surgery intervention to minimize morbidity and mortality. Endovascular aneurysm repair (EVAR) is becoming the first-line treatment option for many patients with large abdominal aortic aneurysms (AAA) . IschemiA 72-year-old Caucasian male with a history of abdominal aortic aneurysm presented to the emergency department two days after abdominal aortic endovascular stent grafting. He presented with right flank, right lower abdominal, and right testicular pain. He reported persistent pain following surgery and was discharged from the hospital less than 24 hours prior to presentation on a bowel regimen and pain medication. Despite regular bowel movements and pain medication consumption, the pain persisted leading to his emergency department visit. He denied any recent fever, chills, headaches or vision changes, chest pain, shortness of breath, nausea, vomiting, dysuria, hematuria, or diarrhea. The pain is not improved with lying flat nor is the patient sexually active.On physical examination, his heart rate, blood pressure, respiratory rate, and temperature were within normal limits. Pertinent examination findings included a soft, exquisitely tender right testicle in vertical alignment with normal positioning and intact cremasteric reflex bilaterally. The pain persists despite testicular elevation. The abdomen was mildly distended with diffuse tenderness that was worse on the right. No peritoneal signs or costovertebral angle tenderness were noted. Femoral and dorsalis pedis pulses were present and equal bilaterally.Urology was consulted with coinciding history and physical exam findings. Following their clinical examination, urology recommended against performing emergent manual detorsion because the presentation was not consistent with testicular torsion. The patient subsequently underwent ultrasonographic evaluation  of the sIntermittent torsion was considered less likely. This was followed by a computed topographic angiogram (CTA) study , which rAn abdominal aortic aneurysm (AAA) is an abnormal dilation of the major abdominal artery found in 5% to 10% of men aged 65 to 79 years , 5. SeveSurgical repair of AAA can be attained via open surgical repair (OSR) or endovascular stent grafting known as endovascular aneurysm repair (EVAR) . EVAR isOf the known complications of EVAR, leakage of blood into the aneurysm sac (endoleak) is most common. Additional complications include stent migration, aneurysm sac expansion, stent occlusion, and delayed rupture , 6. IschIn a case report by McKenna et al., a man of similar age presented with acute onset left scrotal pain following EVAR . One notIn the case presented, acute ischemia was suspected clinically and confirmed ultrasonographically. Blood flow to the right testicle was reduced with right testicular decreased echogenicity following EVAR, without clinical signs of torsion or infarction. As opposed to the previously mentioned cases, this patient was managed conservatively with symptom control and close observation and required no surgical intervention. Repeat ultrasound demonstrated stable blood flow to the right testicle and symptoms had resolved prior to discharge.The exact pathophysiology of testicular ischemia and infarction following EVAR is not clear as this is a rare complication with scarce literature. McKenna et al.  report tEndovascular aneurysm repair is becoming the primary treatment option for many patients with operative AAA. Given the decreased intraoperative complications and reduced inpatient requirements, postoperative complications are more likely to occur at home and present to the emergency department for evaluation. These patients should be evaluated closely and in conjunction with vascular surgeons for potential end-organ damage secondary to acute ischemia and thromboembolic events."}
+{"text": "Sustainable forest management is based on functional relationships between management actions, landscape conditions, and forest values. Changes in management practices make it fundamentally more difficult to study these relationships because the impacts of current practices are difficult to disentangle from the persistent influences of past practices. Within the Atlantic Northern Forest of Maine, U.S.A., forest policy and management practices changed abruptly in the early 1990s. During the 1970s-1980s, a severe insect outbreak stimulated salvage clearcutting of large contiguous tracts of spruce-fir forest. Following clearcut regulation in 1991, management practices shifted abruptly to near complete dependence on partial harvesting. Using a time series of Landsat satellite imagery (1973-2010) we assessed cumulative landscape change caused by these very different management regimes. We modeled predominant temporal patterns of harvesting and segmented a large study area into groups of landscape units with similar harvest histories. Time series of landscape composition and configuration metrics averaged within groups revealed differences in landscape dynamics caused by differences in management history. In some groups (24% of landscape units), salvage caused rapid loss and subdivision of intact mature forest. Persistent landscape change was created by large salvage clearcuts (often averaging > 100 ha) and conversion of spruce-fir to deciduous and mixed forest. In groups that were little affected by salvage (56% of landscape units), contemporary partial harvesting caused loss and subdivision of intact mature forest at even greater rates. Patch shape complexity and edge density reached high levels even where cumulative harvest area was relatively low. Contemporary practices introduced more numerous and much smaller patches of stand-replacing disturbance  and a correspondingly large amount of edge. Management regimes impacted different areas to different degrees, producing different trajectories of landscape change that should be recognized when studying the impact of policy and management practices on forest ecology. Forest policy and management practices within the U.S. have changed substantially following widespread dissatisfaction with management overly focused on the production of wood fiber and game species habitat. Over the past several decades, managers of public and private lands have to varying degrees incorporated a much wider set of objectives including the protection or provision of amenities, biodiversity, and ecosystem services ,2. Much The sustainable management of forest landscapes and development of effective forest policy requires an understanding of the functional relationships between management practices, changes in landscape conditions, and ecological response. Abrupt changes in forest policy or other drivers of landscape dynamics make it fundamentally more difficult to evaluate these relationships. Because ecological processes operate over a wide range of temporal scales, responses to landscape change are time-dependent. Changes in species presence or abundance are frequently delayed following periods of rapid landscape change, and ecological communities take time to equilibrate to new landscape dynamics imposed by new management practices \u20138. DelayEmpirical studies of forest loss or fragmentation effects commonly rely on a space-for-time substitution , where rSatellite images provide the synoptic views needed to characterize forest conditions and landscape change. The ~40-year depth of the Landsat image archive in particular facilitates studies of forest landscape dynamics. However, there are relatively few retrospective analyses of landscape dynamics following abrupt changes in forest management practices. In the Pacific Northwest region of the U.S., Landsat image time series have been used to address the consequences of federal forest policy change e.g., ,17). Lan. Lan17])Choristoneura fumiferana (Clem.)), a native pest that causes widespread defoliation and mortality of balsam fir  and spruce (Picea spp.) trees [The Atlantic Northern Forest of the northeastern U.S. encompasses roughly 11 million hectares within a transition zone between the northern boreal forest and the southern temperate deciduous-dominant forest. A substantial portion of this area lies within northern Maine, the largest contiguous block of undeveloped forestland in the nation (~4 Mha). Despite a long history of logging and commercial management for fiber production, major changes in management practices within recent decades have led to contemporary landscape conditions with little historical precedent. The spruce-fir forests of the region are subject to periodic infestations of the eastern spruce budworm (.) trees ,21. Main.) trees . Public .) trees  in 1989 .) trees  and less.) trees .Management practices in Maine have elicited concerns regarding the sustainable provision of forest values. During the budworm outbreak, salvage logging rates were well above recognized long-term allowable levels . RegenerThe objective of our research was to characterize predominant patterns of cumulative landscape change in the Atlantic Forest of northern Maine, and to evaluate how pre- and post-FPA management regimes have influenced landscape conditions across space and time. We used Landsat imagery and forest inventory data to develop and validate forest composition maps and a time series of forest harvest maps (1973\u20132010). We modeled predominant temporal patterns of harvesting and segmented a large study area into groups of landscape units with similar harvest histories. We then linked harvest history with changes in landscape composition and configuration in order to characterize the evolution of landscape conditions in response to forest management practices before and after abrupt change induced by the FPA. Our approach provided an objective synthesis of predominant patterns of change associated with specific landscape units, with the spatial and temporal resolution needed to attribute change to different management regimes.Acer rubrum, Acer saccharum, Betula alleghaniensis, Betula papyrifera, Fagus grandifolia) predominate across lower hilltops and at mid-slope. Spruce-fir species  predominate where soil or microclimatic conditions exclude the more demanding hardwoods. Mixedwood stands commonly occur along ecotones or as a result of successional dynamics following disturbance. Shade-intolerant hardwood species  are commonly found following intense disturbance. Periodic defoliation by spruce budworm is the most prominent form of natural disturbance. Windthrow is common but generally results in small canopy gaps [Our northern Maine, U.S.A. study region  was defiopy gaps . Virtualopy gaps  and rougForest harvest and composition maps were assembled from a time series of Landsat Multispectral Scanner (MSS), Thematic Mapper (TM), and Enhanced Thematic Mapper Plus (ETM+) images acquired during summer leaf-on conditions . ConsecuForest harvest maps were produced using a change detection procedure based on vegetation index values calculated from sequential Landsat images. As initially described by Sader and Winne , forest The improved sensitivity of the NDMI to partial canopy disturbance is generally attributable to the heightened sensitivity of mid-infrared wavelengths to differences in forest canopy structure, leaf area, and biomass ,35.We classified three-date NDMI and NDVI composites to produce forest change maps from TM/ETM+ and MSS image sequences, respectively. MSS imagery lacks a mid-infrared band required for calculation of the NDMI. This difference, coupled with reduced spatial and radiometric resolution, limits the efficacy of MSS imagery for detection of partial canopy disturbance. Disturbances mapped using MSS imagery (1973\u20131988) represent stand-replacing events, predominantly spruce budworm salvage clearcuts. Disturbances mapped using TM/ETM+ imagery (1988\u20132010) represent a wide range of intensities, and we differentiated two intensity classes interpreted as stand-replacing and partial canopy disturbance. The stand-replacing class was intended to represent harvests in which a new cohort was established following removal of a large proportion of the canopy, whether by clearcut as defined by the FPA ,37 or byHarvest maps were produced by unsupervised classification of overlapping three-date NDVI or NDMI image sequences . Classification of a three-date sequence mitigates the impact of cloud cover in the second image provided the first and third give clear views. An ISODATA algorithm applied to each three-date composite produced 50 statistical classes that were interpreted into forest disturbance, regrowth, and no-change information classes. Stand-replacing and partial harvest classes derived from TM/ETM+ imagery were differentiated based on the relative magnitude of NDMI change, guided by visual interpretation of Landsat imagery and available aerial photography. Confusion between light partial harvests and changes induced by factors such as atmospheric effects or interannual variability in forest phenology were resolved through on-screen editing . IndividWe produced a time series of maps depicting cumulative harvest impact (1975\u20132010) by overlaying successive harvest maps. For each time series date, a pixel was labeled as regenerating forest if preceding intervals included a harvest 1973\u20131988 or a stand-replacing harvest 1988\u20132010. A pixel was labeled as partially harvested if preceding intervals included only a single partial harvest. When preceding intervals included multiple partial harvests, pixels were labeled as regenerating forest, reflecting the anticipated ecological and silvicultural effects of multiple entries within the ~20-year period over which partial harvests were mapped (1988\u20132010). For each date of our time series, the result depicts the cumulative footprint of harvest operations since 1973.We mapped forest composition using equivalent unsupervised classification methods applied to each of the 1975 MSS and 2004 TM images. Dates were selected on the basis of cloud cover and image quality. For the purpose of forest type mapping, small areas of cloud cover in the 2004 image were replaced with data from the 2001 ETM+ image. Statistical classes produced from an ISODATA algorithm were aggregated to coniferous-dominant (>75% coniferous), deciduous-dominant (>75% deciduous), and mixed type classes through visual interpretation of Landsat imagery, with reference to available aerial photography and existing land cover maps. In some previously disturbed areas, exposed soils, woody debris, or herbaceous vegetation precluded the assignment of forest type and pixels were instead assigned to an indeterminate class. Patches less than 0.81 ha in size were removed and a 3x3 majority filter was applied to each map to consolidate patch boundaries and simplify the 2004 patch structure to more closely match the 1975 data.Assignment of ISODATA classes to forest types was subjective and sometimes difficult. A mistaken assignment could lead to bias in the representation of forest type extent. If for example pixels representing forest with a deciduous component of 70\u201375% were mistakenly committed to the deciduous-dominant class rather than the mixed class, the extent of the deciduous class would be overestimated according to the class definition of >75% deciduous. We used validation data obtained from field plots  Program provides quality-assured measurements of forest attributes from a national network of field plots adhering to a systematic sampling design . We madeFIA estimates of forest age have been used to validate Landsat-derived disturbance time series under the assumption that trees sampled for age estimation germinated at the time of disturbance . HoweverIn Maine, the contemporary FIA inventory design was established in 1999, with 20% of plots surveyed annually during sequential 5-year cycles. Although data are available from plots measured during earlier inventories, coordinate locations are known for only a fraction of those plots. We therefore used data collected during contemporary inventory cycles to discriminate past harvest intensity. A harvest event identified by image interpretation was labeled stand-replacing provided FIA age dated stand origin to 1970 or later  and field crews labeled the stand as either sapling or poletimber. However, for plots harvested after 1999, recorded stand age was an unreliable indicator of stand-replacing disturbance because age estimates frequently corresponded to a few residual stems rather than a newly established cohort. In these cases, intensity classes were discriminated using plot measurements made during consecutive 5-year inventory cycles; a harvest was labeled stand-replacing if plot basal area  was reduced by >70%.Our validation sample of 509 plots was insufficient to produce reasonably precise accuracy estimates for individual time series intervals. We therefore aggregated intervals into six validation classes: 1973\u20131988 stand-replacing harvest, 1988\u20131999 stand-replacing harvest, 1988\u20131999 partial harvest, 1999\u20132010 stand-replacing harvest, 1999\u20132010 partial harvest, and intact mature forest . Map and reference validation class labels were assigned in a manner consistent with the construction of cumulative harvest maps. Where multiple entries occurred, labels were assigned based on the date of first stand-replacing disturbance. Where multiple partial harvests occurred, labels of either 1988\u20131999 or 1999\u20132010 stand-replacing were assigned based on the date of second entry. Map and reference labels were compiled into an error matrix. Overall accuracy, user accuracy (the complement of class commission error), producer accuracy (the complement of class omission error), and corresponding standard error estimates were calculated by poststratification ,43. AddiThe 1975 and 2004 forest type maps were validated using FIA plot measurements of coniferous and deciduous live tree basal area collected during 1980\u20131982 and 1999\u20132003 inventories, respectively. Differences in dates between maps and field inventories were resolved by excluding samples where intervening harvests occurred. For 2004 map validation, we excluded plots mapped as harvested from 1999\u20132004; for 1975, we excluded plots mapped as harvested from 1975\u20131982. A sample of 445 plots remained for validation of the 2004 map; only 70 plots were available for validation of the 1975 map. As previously described, we identified coniferous-dominant and deciduous-dominant class thresholds for which errors were best balanced and mapped class extents least biased. Following refinements made to improve consistency between maps, an error matrix was compiled for each map based on selected threshold values. Estimates of overall, user, and producer accuracy were calculated by poststratification ,43.To quantify harvest rates through time, identify trends, and associate trends with changes in landscape conditions, we tessellated our study area into landscape units using a 5 km square grid . A 5 km TX and are equivalent to the loading vectors or principal components of a PCA. The spatial amplitudes correspond to the PCA scores obtained by projecting the time series of X onto the subspace spanned by the EOFs.An EOF analysis identifies a sequence of uncorrelated patterns or modes of variability that characterize variation within a two-dimensional data set . EOF anaA traditional EOF analysis or PCA is sensitive to extreme observations and outliers, which can distort the outcome such that dominant modes of variability represent contrasts between anomalous and regular observations rather than patterns of variability within regular observations . We perfPaired EOFs and amplitude functions comprise orthogonal modes of variability, ordered by the amount of total variance explained. We modeled cumulative harvest time series as linear combinations of dominant EOFs, selected based on the proportion of overall variance explained by successive modes. By including only dominant modes, modeled time series represent statistically coherent variability in harvesting patterns that occurred over large portions of the study area. The ROBPCA algorithm provides a measure of orthogonal distance between samples and the subspace defined by dominant EOF modes. Unusually large orthogonal distances indicate outlying samples that do not conform to characteristic patterns defined by dominant modes. We identified 12 orthogonal outliers using the ROBPCA nominal cutoff value  and exclTo classify predominant temporal patterns of harvesting from the EOF analysis and to associate those patterns with groups of grid cells, we performed an agglomerative hierarchical clustering  of modelLandscape composition metrics were calculated for grid cells and averaged within groups to evaluate changes associated with predominant harvesting trends. Within our time series of cumulative harvest maps, available forestland was classified as either regenerating, partially harvested, or intact mature forest . The EOF and cluster analyses produced time series of cumulative harvest area, the reciprocal of intact mature forest area. We also produced time series of cumulative partial harvest and regenerating forest area to evaluate changes in harvest intensity associated with predominant harvesting trends. Available forestland was summarized by 1975 forest type to associate harvest history and landscape change with initial landscape composition. To evaluate composition change as a legacy of harvest practices, we quantified forest type change between 1975 and 2004 for areas harvested before 2004. Composition change in unharvested forestland was not evaluated as part of this research.Early successional and intact late successional forest patches are landscape elements of particular interest, given the expansion of partial harvest practices in the 1990s. Cumulative changes in the patch configuration of regenerating and intact mature forest were evaluated by calculating time series of landscape metrics. We selected a small number of metrics of general relevance to forest ecology that quantify primary aspects of class configuration thought to have been affected by changes in management practices. Metrics were calculated using Fragstats version 4.2 . Area-weHarvest validation classes were mapped with an overall accuracy of 88% . User anForest type classes for 1975 and 2004 were mapped with overall accuracies of 76% and 68%, respectively Tables . User anBy 2010, 61% of available forestland was mapped as harvested, and 40% regenerated by stand-replacing or multiple partial harvests. Averaged across all grid cells, harvest rates increased ca. 1985 and then remained quite constant at about 2% per year  [Lepus americanus), are found at highest density within coniferous and mixed regenerating forest ~15\u201335 years post-harvest [Martes americana) [The changes in landscape composition and configuration we have quantified imply potentially important impacts on forest ecology and wildlife. Salvage clearcuts created large blocks of early successional forest habitat, benefitting the federally threatened Canada lynx (adensis) . In Main-harvest \u201359. The -harvest . Additioericana) . For speS1 AppendixDescription of image processing steps performed prior to forest harvest and composition mapping.(DOCX)Click here for additional data file.S2 AppendixDescription of the procedures used to validate cumulative forest harvest (1973\u20132010) and forest type maps (1975 and 2004), and a brief interpretation of validation outcomes.(DOCX)Click here for additional data file."}
+{"text": "Fine needle aspiration (FNA) cytology is a well-established diagnostic method based on the microscopic interpretation of often scant cytological material; therefore, experience, good technique and smear quality are equally important in obtaining satisfactory results.We studied the use of fresh surgical pathology specimens for making so-called mock-FNA smears with the potential of cytohistological correlation. Additionally, we studied how this process aids the improvement of preparation technique and smear quality.Cytological aspirates from 32 fresh biopsy specimens from various sites: lung (20), lymph nodes (6), and breast (6) were obtained, all with a clinical diagnosis of tumor. Aspiration was performed from grossly palpable tumors. 25G needle and Cameco-type syringe holder was used with minimal or no suction.Unfixed surgical specimens provided sufficient cytological material that resulted in good quality smears. After standard processing of specimens into microscopic sections from paraffin embedded tissues, cytohistological case-series were created. No significant alteration was reported in tissue architecture on hematoxylin-eosin stained sections after the aspiration procedure. A gradual, but steady improvement was observed in smear quality just after a few preparations.Our study proved that surgical specimens may be used as a source of cytological material to create cytohistological correlation studies and also to improve FNA cytology skills. The use of very fine gauge needle  during the sampling process does not alter tissue architecture therefore the final histopathological diagnosis is not compromised. We conclude that by using fresh surgical specimens useful cytohistological collections can be created both as a teaching resource and as improving experience. Fine needle aspiration cytology or biopsy (FNAC/FNAB) is a well-established diagnostic method used in many countries as a first-line diagnostic procedure aiding preoperative management of various palpable and non-palpable lesions. The history of needle biopsy spans several centuries; however, its use as a routine diagnostic technique was established mostly during the twentieth century To accelerate the learning process and experience of recognizing specific cellular morphology we propose here the use of fresh (i.e. unfixed) surgical pathology specimens as a source of creating FNA smears and cytohistological correlation series. This procedure also might serve as a model for learning the basics of FNAC including sampling and smear preparation. Our main objective was to demonstrate how fresh surgical specimens may used as a source for cytological material with respect to creating cytohistological correlation case series. Additional objective was to study the usefulness of surgical pathology specimens in the practice of fine needle aspiration technique including sampling and smear preparation.The study was conducted in Mures County Emergency Clinic/Spitalul Clinic Judetean de Urgenta Mures, university hospital within the University of Medicine and Pharmacy of Tirgu Mures. Upon submission a signed written informed consent was obtained from all patients acknowledging that bioptic specimens removed by surgery due to therapeutic considerations might undergo additional studies. For conducting our study we did use only some parts of the bioptic specimens, without altering in any way the final histological diagnosis. Since no additional tissues/cells were removed from any patient, other than it would anyway be removed, approval of the ethics committee was not necessary. Samples presented in this study were not described nor published in other study, including parts or the whole material.The authors of this article did not interact with any of the patients whose surgical pathology specimens constituted the main subject of this article. The identity of patients was protected at several levels. All cases were designated with an ID number, starting with one. After the cyto-histological correlation series were created only these ID numbers identified each case. From clinical data only tumor localization, size, age, sex and histopathological type was linked to the identification numbers. This way patient confidentiality was respected by anonymizing bioptic specimens. The obtained cyto-histological correlation cases were archived according to case numbers  plus the above mentioned minimal clinical data, without any other data that could be linked to any individual .Fresh, unfixed, surgical biopsies, mostly whole-organs were used as the source for cytological material aspiration, prior formalin fixation. We obtained cytological aspirates from 32 fresh biopsy specimens from various sites: lung (20), lymph nodes (6), and breast (6). All organs were submitted to the pathology laboratory with a clinical diagnosis of tumor. Aspiration was performed exclusively from grossly palpable tumors. Cytological material was obtained using standard fine needle aspiration technique as described by Stanley A Cameco-type syringe holder mounted with a 10 ml three-piece syringe was used. For staining, we used two commercially available staining kits Cytocolor and Hemacolor  and standard Papanicolaou stain. In each case, we used the following two gauge type needles: 23G  and 25G .Aspired material was spread on standard pre-cleaned glass slides  using the standard one-step method described by Stanley and colleagues and its modification Most of the surgical specimens provided sufficient cellular quantity using the standard FNA technique. However, material obtained from lesions showing extensive desmoplasia or were rich in conjunctive stroma resulted in less cellularity. Nevertheless all cytological metrials obtained resulted in sufficient and mostly good quality smears. All the specimens were processed according to specific protocols and paraffin-embedded tissue blocks were created. Thus from all lesions microscopic slides were made and stained with hematoxylin-eosin. This permitted the creation of cytohistological correlation pairs. As depicted in There was no perceivable morphological differences between smears prepared with material aspired with 23G or 25G needles, both proved to be sufficent. In more fibrous or desmoplastic lesion 25G needles, handled too firmly, had a tendency to bend.The one-step method described by Stanley prooved to be optimal in preparing cytological material obtained from fresh speciemens Fine-needle aspiration cytology or biopsy (FNAC/FNAB) is increasingly performed as an economical, safe and rapid minimally invasive technique for diagnosis of various lesions including tumors and non-neoplastic lesions Using fresh surgical pathology specimens offers the possibility to experiment with various smearing and preparation techniques, the ultimate goal being to produce good quality smears. Before performing FNA at the patient\u2019s side both dexterity and smear preparation skill may be improved by practicing on fresh surgical material without altering the histopathological interpretation of these specimens. Nevertheless there are few models described for practicing FNA technique, sampling and slide preparation. Some of these models include the use of fresh animal (beef and pork) liver introduced into a double layered latex glove, while others describe models made of silicone Finally, using surgical specimens also ensures that in addition to cytology, also paraffin-embedded tissue sections are also available at end of the day, enabling the development of the third foundation of cytodiagnosis, by the use of cytohistological correlation series see  and 2.We described our experience of using surgical pathology specimens (tissue biopsies) for practicing FNAB proficiency. Fresh surgical pathology specimens, especially whole-organs may be used for training residents prior to the beginning of FNAB performance on patients in the clinical setting. Surgical specimens may be used as a source of cytological material to improve FNAB skills. These specimens also provide cytological material to study preparation conditions that may alter smear quality. We found that fresh surgical pathology specimens used prior formalin-fixation were a good source of cytological material and may be used for practicing sampling and smear preparation.Additionally, using biopsy specimens offers the great opportunity to study cytohistological correlations. The creation of cytological smears has little impact on a laboratory\u2019s financial expenses. No special equipment is needed and standard dyes (such as Papanicolaou and Romanowsky-types stains) may be used. For each specimen up to 3\u20134 cytological smears are optimal without significantly hindering grossing or delaying routine practice. Compared to standard histology additionally to glass-slides, stains and coverslips, only needles (with no larger gauge than 23\u201325G) and syringes  and fixative are needed that may be acquired at low cost. We consider that the costs of such materials are far beyond the benefits the introduction of mock-FNA into daily routine may represent.Aspired material can also be used to study and experiment with the various conditions that may critically alter smear quality and potentially hinder the formulation of the correct diagnosis. To become proficient in sampling and smearing, it is necessary to perform many biopsies on patients. However, the process can be significantly accelerated by performing practice sessions with fresh surgical pathology specimens before attempting the procedure in the clinical setting."}
+{"text": "Healthy hearing depends on sensitive ears and adequate brain processing. Essential aspects of both hearing and cognition decline with advancing age, but it is largely unknown how one influences the other. The current standard measure of hearing, the pure-tone audiogram is not very cognitively demanding and does not predict well the most important yet challenging use of hearing, listening to speech in noisy environments. We analysed data from UK Biobank that asked 40\u201369 year olds about their hearing, and assessed their ability on tests of speech-in-noise hearing and cognition.About half a million volunteers were recruited through NHS registers. Respondents completed \u2018whole-body\u2019 testing in purpose-designed, community-based test centres across the UK. Objective hearing (spoken digit recognition in noise) and cognitive  data were analysed using logistic and multiple regression methods. Speech hearing in noise declined exponentially with age for both sexes from about 50 years, differing from previous audiogram data that showed a more linear decline from <40 years for men, and consistently less hearing loss for women. The decline in speech-in-noise hearing was especially dramatic among those with lower cognitive scores. Decreasing cognitive ability and increasing age were both independently associated with decreasing ability to hear speech-in-noise  among the population studied. Men subjectively reported up to 60% higher rates of difficulty hearing than women. Workplace noise history associated with difficulty in both subjective hearing and objective speech hearing in noise. Leisure noise history was associated with subjective, but not with objective difficulty hearing.Older people have declining cognitive processing ability associated with reduced ability to hear speech in noise, measured by recognition of recorded spoken digits. Subjective reports of hearing difficulty generally show a higher prevalence than objective measures, suggesting that current objective methods could be extended further. The DTT choice of single digit words promotes easy understanding and the opportunity to \u2018fill-in\u2019 missed acoustic information, while steady-state, speech-shaped noise enables masking across the speech range, but does not allow the \u2018glimpsing\u2019 that can reduce masking in more complex noise. Overall, DTT performance correlates more closely with PTA than do some other SiN tests Self-report of hearing difficulties, using questionnaire instruments or often only one or two questions, has commonly been used to assess the prevalence of hearing loss in large epidemiological studies In this study we investigated the relation between DTT SRT and cognitive ability as a function of age, sex, socioeconomic status, and noise exposure. The results were compared with self-report of hearing difficulties and findings from other studies, including some previously unpublished data from the NIH Toolbox www.ukbiobank.ac.uk.Complete details of all UK Biobank procedures are available at This research was covered by the UK Biobank ethics agreement. Within England, UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC). All participants provided written informed consent.Participants , about one third of the participants  of cards showing 3 and 6 pairs of shapes, respectively. The shapes were concealed and the participant was required to recall locations of matching shape pairs. Correct responses were confirmed. The Reaction Time test of processing speed sequentially presented twelve pairs of shapes. The participant pressed a button as quickly as possible if a pair of shapes matched. Finally, in the Digit Span (\u2018Numeric memory\u2019) test of verbal working memory participants were initially presented on the screen with two digits and were required to key in the digits in reverse order. After each correct response the digit sequence was increased by one. The task ended after two incorrect responses. Raw score was the maximum number of correctly recalled and ordered digits. Performance on the Prospective Memory, Reaction Time and Digit Span tests additionally depended on executive function and all tests depended on alerting and orienting attention.Variable numbers of participants completed each test , primariAnalysis of self-report measures used binary logistic regression. Standardised scores, which each maximised the variability within the sampled population, were derived for each cognitive test using principal components analysis. A composite score was defined as a simple sum of the five standardised scores. Both individual and composite cognitive scores were standardised to have zero mean and unit standard deviation, such that higher values corresponded to higher ability. Scores were grouped into deciles for analysis. Regression modelling techniques accounting for sex, socio-economic deprivation  tone detection thresholds declined from 18\u201385 years (NIH Toolbox data (DOCX)Click here for additional data file."}
+{"text": "The physiological role of CNS regeneration inhibitors in the na\u00efve, or uninjured, CNS remains less well understood, but has received growing attention in recent years and is the focus of this review. CNS regeneration inhibitors regulate myelin development and axon stability, consolidate neuronal structure shaped by experience, and limit activity-dependent modification of synaptic strength. Altered function of CNS regeneration inhibitors is associated with neuropsychiatric disorders, suggesting crucial roles in brain development and health.The growth inhibitory nature of injured adult mammalian central nervous system (CNS) tissue constitutes a major barrier to robust axonal outgrowth and functional recovery following trauma or disease. Prototypic CNS regeneration inhibitors are broadly expressed in the healthy and injured brain and spinal cord and include myelin-associated glycoprotein (MAG), the reticulon family member NogoA, oligodendrocyte myelin glycoprotein (OMgp), and chondroitin sulfate proteoglycans (CSPGs). These structurally diverse molecules strongly inhibit neurite outgrowth  Proper function of the adult mammalian CNS requires precise assembly, refinement, and maintenance of an elaborate network of neuronal connections. During development, axon guidance molecules facilitate the formation of intricate neuronal networks. After this initial assembly, many circuits are refined in an activity-dependent manner during a short time period of heightened plasticity, called the critical period (CP). At the end of the CP, the fine tuning of networks is complete and they acquire their mature shape. Synaptic contacts in the mature brain are stable over long time periods , display striking similarities to Mag null mice, suggesting that gangliosides may be the primary receptors responsible for MAG-mediated axon protection -anchor. OMgp is expressed by OLs and neurons in the CNS , are extracellular matrix (ECM) proteoglycans that consist of a protein core with covalently attached glycosaminoglycan (GAG) side chains , and its homolog RPTP\u03c3  and long-term depression (LTD) of synaptic transmission are opposing forms of activity-dependent synaptic strength modifications, and are thought to underlie aspects of learning and memory formation   signaling. At the cell surface, BDNF binds TrkB to activate several growth promoting pathways, including mTOR complex 1 (mTORC1) and MAP kinase/ERK. However, CSPG binding to RPTP\u03c3 attenuates activity of TrkB (Kurihara and Yamashita, NgR1 null mice show impaired memory function, including impaired fear extinction and consolidation (Park et al., NgR1 and NogoA have been associated with schizophrenia (Sinibaldi et al., Many human neuropsychiatric disorders are associated with defects in synaptic structure or function and may be caused by a shift in excitatory/inhibitory balance (Pittenger, CNS regeneration inhibitors play important physiological roles in the uninjured brain and spinal cord. The myelin-associated inhibitors MAG, NogoA, and OMgp regulate myelin formation and axon-myelin interactions. NogoA, OMgp, and CSPGs regulate synapse formation and maturation, and they influence activity-dependent synaptic strength. Growing evidence suggests that some CNS regeneration inhibitors participate in an intricate cross-talk with growth promoting molecules at the level of several key signaling molecules. This finely tuned balance of excitation and inhibition in the developing and mature CNS may be necessary for proper formation and function of neural networks.The physiological role of these molecules raises important considerations for therapeutic strategies designed to promote neural regeneration following injury. The acquisition of a large number of ligand-receptor systems that restrict neural network plasticity may have been a prerequisite that enabled the evolution of larger and more powerful neural networks. Larger and more complex brains may be more vulnerable to aberrant changes in synaptic connectivity and therefore, once fully developed, need to be consolidated and protected by molecules that constrain excessive network rearrangement. Following injury to the adult CNS, molecules that restrict aberrant growth and plasticity may be detrimental since they limit attempts to modify or rebuild nearby networks to compensate for lost neural circuits. Therefore, a deeper understanding of the physiological roles played by CNS regeneration inhibitors is of great interest both clinically and biologically.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Local field potentials (LFPs), measured using extracellular electrodes, provide information about local neuronal population activity. The development of multi-electrode arrays (MEAs) that measure LFPs simultaneously at different network locations has led to a renewed interest in the LFP as a measure of neuronal network activity . While tin vitro.Here, we describe two contributions to the effort to understand LFP generation in neuronal networks. First, we investigated reduced compartmental models to assess their suitability for producing realistic spatial LFP characteristics. We show that the chosen reduction method  creates"}
+{"text": "ICR-CTSU introduced EDC in 2012 necessitating the development of EDC specific training materials for participating sites.Training of site staff on EDC systems is essential to ensure data quality and returns are maximised. Guidance notes are issued to support standardised completion of case report forms. However, due to the technical nature of EDC, guidance notes alone provide insufficient support for most site staff. Provision of effective, consistent and timely EDC training across a trial's lifespan is a continuing challenge, particularly for large trials or those with long follow-up where site staff turnover is an added consideration.ICR-CTSU created a custom EDC system user guide, developed training slides and included instructional text within the EDC system. Since the implementation of EDC, ICR-CTSU have developed short training videos covering key topics including logging in, record navigation, data entry and query response. The videos illustrate the EDC screen view and are accompanied by scripted voice over guidance. Training materials are accessible online via the ICR-CTSU website.Whilst customised EDC system user guides and in-built instructions form the basis of site staff training, supplementary technical training is required. This can be provided to site staff individually through webinars, teleconferences and centre initiation visits, however the online training videos provide a more consistent and accessible resource. This solution should reduce demand on ICR-CTSU resources for ongoing site training."}
+{"text": "Ischaemic heart disease is most prevalent in the ageing population and often exists with other comorbidities; however the majority of laboratory research uses young, healthy animal models. Several recent workshops and focus meetings have highlighted the importance of using clinically relevant models to help aid translation to realistic patient populations. We have previously shown that mice over-expressing the creatine transporter (CrT-OE) have elevated intracellular creatine levels and are protected against ischaemia-reperfusion injury. Here we test whether elevating intracellular creatine levels retains a cardioprotective effect in the presence of common comorbidities and whether it is additive to protection afforded by hypothermic cardioplegia.+ cardioplegic arrest, as used during cardiac surgery and donor heart transplant, was further enhanced in prolonged ischaemia (90 minutes) in CrT-OE Langendorff perfused mouse hearts .CrT-OE mice and wild-type controls were subjected to transverse aortic constriction for two weeks to induce compensated left ventricular hypertrophy (LVH). Hearts were retrogradely perfused in Langendorff mode for 15 minutes, followed by 20 minutes ischaemia and 30 minutes reperfusion. CrT-OE hearts exhibited significantly improved functional recovery (Rate pressure product) during reperfusion compared to WT littermates . Aged CrT-OE mouse hearts (78\u00b15 weeks) also had enhanced recovery following 15 minutes ischaemia . The cardioprotective effect of hypothermic high KThese observations in clinically relevant models further support the development of modulators of intracellular creatine content as a translatable strategy for cardiac protection against ischaemia-reperfusion injury. This was attributed to increased phosphocreatine (PCr) buffer capacity, elevated myocardial glycogen, improved \u2018energy reserve\u2019 and the ability of creatine to reduce the open probability of the mitochondrial permeability transition pore . CardiopRapid revascularization of ischaemic regions within the heart by thrombolysis or primary percutaneous coronary intervention remains at the clinical forefront to effectively treat AMI ,19. Pre-It should be noted that previous work from our laboratory has shown that very high myocardial [Cr] may itself cause LV hypertrophy and dysfunction , and defWe also performed experiments in mice aged 18 months since the ageing heart is known to have altered cardiac substrate metabolism , is more+ and Mg2+ ions to reduce metabolic demand and prolong ischaemic tolerance [ex vivo rat hearts [Cold, cardioplegic arrest of the heart remains the gold standard for effective myocardial protection during cardiac surgery  and hearolerance . In thisolerance  and in polerance  undergoit hearts . Howevert hearts . These bt hearts  and not ex vivo not in vivo experimental approaches and ideally we would have both. This reflects the limitations of having sufficient numbers of aged animals and the welfare implications of combining TAC surgery with ischaemia-reperfusion surgery. Furthermore, we did not perform tetrazolium staining in our ex vivo hearts since the period of reperfusion was insufficient for complete washout of NADH from necrotic tissue, which would lead to under-estimation of infarct sizes [During ischaemia, the heart undergoes many metabolic changes including a reduction in intracellular PCr . We did ct sizes . It is tct sizes .We have shown that elevating creatine levels in the mouse heart improves functional recovery following ischaemia-reperfusion even in the presence of old age or LVH. Both conditions previously associated with loss of cardioprotective efficacy. Furthermore, elevating intracellular creatine is additive to standard hypothermic cardioplegia for recovery from prolonged ischaemia. Together these findings support the development of small molecule activators that increase intracellular Cr , which wS1 File(DOC)Click here for additional data file."}
+{"text": "Hemoptysis is a common complication in all kinds of surgery. However, it is rarely critical because it resolves with or without intervention.Here the authors present what is believed to be an unprecedented report of a case involving a fatal idiopathic bronchial hemorrhage complication during cardiac surgery. Eighty-five-year-old female with severe aorticvalve stenosis had elective aortic valve replacement. Subsequently, she developed diffuse bilateral severe idiopathic bronchial hemorrhage which required maximum intervention such as external bronchial ligation, V-A ECMO, coil embolization of bronchial artery and internal airway blockage by spigot.Airway bleeding is not a rare complication in cardiac surgery, but this case should increase awareness of this potentially life threatening perioperative complication.The online version of this article (doi:10.1186/s13019-016-0477-0) contains supplementary material, which is available to authorized users. Airway bleeding during or after heart surgery is common, but is rarely reported because it is generally minor and resolves spontaneously in most cases. Here the authors report an unusual case of exsanguinating diffuse airway bleeding during cardiac surgery. The complication required aggressive intervention measures such as extra-corporeal membrane oxygenation (ECMO), bronchial ligation, bronchial artery coil embolization and internal airway blockage using an intrabronchial spigot.The case involved an 85-year-old female with congestive heart failure caused by severe aortic valve stenosis. Aortic valve replacement with a bioprosthetic valve was conducted electively. After the ascending aorta was unclamped, anesthetist noticed blood coming up from the endotracheal tube. Intraoperative flexible bronchoscopy confirmed massive hemoptysis coming up from all peripheral bronchi and mainly from the bilateral inferior lobes. The left chest was inspected through additional anterolateral thoracotomy connected perpendicularly to median sternotomy wound at 4th intercostal space. And the left hilum was exposed and lower bronchus was ligated externally to reduce the amount of intrabronchial bleeding. Repeated bronchoscopy showed persisting large-volume airway bleeding  have beThere is no doubt that systemic heparinization in cardiac surgery triggered the diffuse bronchial hemorrhage. Complete heparin reversal and expeditious weaning from cardiopulmonary bypass is reported to be the best and the only way to manage major hemoptysis \u20135. HowevUnderlying pulmonary disease such as bronchiectasia or tuberculosis can also cause perioperative hemoptysis. Pulmonary capillaritis such as Wegener\u2019s granulomatosis or Goodpasture syndrome are also known to be related to pulmonary hemorrhage . AlthougIn summary, this was a rare case of diffuse exsanguinating hemoptysis during cardiac surgery. Even after all the aggressive intervention and intensive care administered, the patient\u2019s respiratory status failed to show improvement in terms of lung compliance and oxygenation. Practicing cardiothoracic surgeons should note this unusual but catastrophic perioperative complication.All authors have approved the manuscript. Patient\u2019s family has agreed with submission of the case report. Upon acceptance, authors will transfer copyright to the Publisher. All authors have no ethical problem or conflicts of interest to declare."}
+{"text": "This survey sought to evaluate differences in the understanding and management of shunt-dependent hydrocephalus among the senior North American Pediatric Neurosurgery membership.Surveys were sent to all active American Society of Pediatric Neurosurgeons (ASPN) members from September to November 2014. A total of 204 surveys were sent from which 130 responses were recorded, representing 64% of active ASPN membership. Respondents were asked 13 multiple choice and free response questions focusing on four problems encountered in shunted hydrocephalus management: Shunt malfunction, cerebrospinal fluid (CSF) overdrainage, chronic headaches and slit ventricle syndrome (SVS). Qualtrics\u00ae online survey software was used to distribute and collect response data.ASPN surgeons prefer three varieties of shunt valves: 41% differential pressure, 29% differential with anti-siphon device (ASD), and 27% programmable. Respondents agree shunt obstruction occurs most often at the ventricular catheter due to either in-growth of the choroid plexus (67%), CSF debris (18%), ventricular collapse (8%), or other reasons (9%). Underlying causes of obstruction were attributed to small ventricular size, catheter position, choroid plexus migration, build-up of cellular debris, inflammatory processes, or CSF overdrainage. The majority of respondents (>85%) consider chronic overdrainage a rare complication. These cases are most often managed with ASDs or programmable valves. Chronic headaches are most often attributed to medical reasons  and managed with patient reassurance. The most popular treatments for SVS include shunt revision (88%), cranial expansion (57%) and placement of an ASD (53%). SVS etiology was most often linked to early onset of shunting, chronic overdrainage and/or loss of brain compliance.This survey shows discrepancies in shunt-dependent hydrocephalus understanding and management style among a representative group of experienced North American pediatric neurosurgeons. In particular, there are differing opinions regarding the primary cause of ventricular shunt obstructions and the origins of SVS. However, there appears to be general consensus in approach and management of overdrainage and chronic headaches. These results provide impetus for better studies evaluating the pathophysiology and prevention of shunt obstruction and SVS."}
+{"text": "Isolated coarctation of aorta is usually diagnosed and treated surgically in most of patients during childhood, but optimal management strategies for adult patients with coarctation of aorta associated with stenosed bicuspid aortic valve are controversial.We aim to treat such rare patients successfully by less invasive two staged hybrid management.We report a case of 18 years old female with history of dyspnoea on exertion since 4 years, with complaints of headache and bilateral lower limb claudication, clinical findings revealed no characteristic clinical feature of Turner syndrome, on examination femoral pulses were delayed and diminished bilaterally, laboratory examination were unremarkable with negative karyotyping for Turner syndrome, chest x-ray showed enlarged cardiac silhouette with rib notching, echocardiography revealed severely stenosed bicuspid aortic valve with left ventricular hypertrophy, descending aortogram showed post ductal coarctation and collaterals, pressure analysis revealed gradient of 70 mmHg across coarctation. She underwent successful hybrid approach with percutaneous catheter balloon coarctoplasty (PCBC) with stenting in the first stage, followed by surgery for aortic valve replacement in the second stage.Post operatively she was asymptomatic and had uneventful recovery after each stage of management, post-operative echocardiography findings were within acceptable limits, and at 6 months follow up the mean echocardiographic aortic arch gradient was within acceptable limits.Two staged hybrid approach of (PCBC) with stenting for coarctation of aorta and aortic valve replacement for coexistent stenosed bicuspid aortic valve is a safe, less invasive and can be effective alternative to complete surgical approach, if done meticulously.Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."}
+{"text": "Giant cell reparative granuloma (GCRG) is a rare, benign intra osseous lytic lesion occurring especially in gnathis bone but also seen in feet and hands. It has similar clinical and radiological presentations than giant cell tumor, chondroblastoma, aneurysmal bone cyst, and hyperparathyroidism brown tumors but with specific histological findings We report a case of a GCRG of hallux phalanx in 18 years old patient appearing many years after enchondroma curettage and grafting. Radiographs showed a multiloculated osteolytic lesions involving whole phalanx with cortical thinning and without fluid-fluid levels in CT view. Expected to be an enchondroma recurrence, second biopsy confirmed diagnosis of GCRG with specific histological findings. Although if aetiopathogeny remains unknown, GCRG is reported to be a local non neoplasic reaction to an intraosseous hemorrhage. Our exceptional case claims that this tumor can appear in reaction to cellular disturbance primary or secondary. Giant cell reparative granuloma (GCRG) is a rare, benign intraosseous lytic lesion occurring especially in gnathic bones and also in hands and feet phalanx \u20133. It isA 13- year-old boy presented in emergency room with left hallux painful evolving for several months without any underlying trauma. The physical examination noted a localized swallowing of the dorsum of the right hallux base with no inflammatory local signs and a pain sensitivity induced by examination. Mobility of the adjacent joint was normal and no biological abnormalities were found. Radiographic examination showed a well-defined lytic lesion of the hallux proximal phalanx. Neither cortex erosion nor soft tissues abnormalities were noticed . An initInitially described by Jaffe  in 1953,This case suggests a potential connection between GCRG and enchondroma and hypothesis that GCRG could appear in reaction of cellular disturbance primary or secondary to enchondroma surgical treatment."}
+{"text": "Praelongorthezia praelonga (Hemiptera: Ortheziidae), an important pest of citrus orchards. The data presented in this article are related to the article entitled \u201cSeasonal prevalence of the insect pathogenic fungus Colletotrichum nymphaeae in Brazilian citrus groves under different chemical pesticide regimes\u201d C. nymphaeae, emerges through the thin cuticular intersegmental regions of the citrus orthezia scale body revealing orange salmon-pigmented conidiophores bearing conidial masses, as well as producing rhizoid-like hyphae that extend over the citrus leaf. By contrast, nymphs or adult females of this scale insect infected with Lecanicillium longisporum exhibit profuse outgrowth of bright white-pigmented conidiophores with clusters of conidia emerging from the insect intersegmental membranes, and mycosed cadavers are commonly observed attached to the leaf surface by hyphal extensions. These morphological differences are important features to discriminate these fungal entomopathogens in citrus orthezia scales.We describe symptoms of mycosis induced by two native fungal entomopathogens of the citrus orthezia scale,  Specifications Table\u2022C. nymphaeae and L. longisporum.Data show symptoms of two important fungal diseases in the citrus orthezia scale caused by \u2022Simple and practical recognition of these entomopathogenic fungi can be achieved on the basis of their conspicuous morphological characters, including conidiophores and conidia, from mycosed scale insects.\u2022The importance of using morphological features based on symptoms of fungal diseases can serve as a guideline to facilitate recognition and quantification of these pathogens in citrus orthezia scale populations.1C. nymphaeae and L. longisporum  of infected citrus orthezia scales with two native fungal pathogens, namely gisporum . Images 2L. longisporum or C. nymphaeae from citrus groves located in a commercial farm  were taken to the laboratory to record the morphological features of mycosis in individuals of the citrus orthezia scale. Images of mycosed insects were acquired by using a stereo-microscope at 10\u201330\u00d7 magnification, while images of conidiospores were taken by phase-contrast and scanning electron microscopy. These morphological characters related to signs of fungal diseases were used as a guideline for identification and quantification of these fungal entomopathogens in this insect population during field surveys Field collected insects infected with"}
+{"text": "Cancers depend on one or more ubiquitously activated oncogenes to survive and maintain their tumorigenic phenotype. The MYC oncogene is critically important in a variety of hematological malignancies, including Burkitt's lymphoma, acute lymphoblastic leukemia, and multiple myeloma. Cancers' reliance on few oncogenes, aptly termed oncogene addiction, presents an exploitable vulnerability. Indeed, targeted therapies inhibiting key oncogenes in a multitude of cancer types are routinely used in clinic . HoweverExperimental model systems of MYC oncogene inactivation in various cancers have revealed molecular mechanisms of oncogene addiction, escape from oncogene dependence resulting in tumor recurrence . InactivRecently, we gained insight into the mechanism of tumor recurrence. We found that when either of two tumor suppressor genes, ARF or p53, is lost or mutated, tumor recurrence rapidly always occurs . We prevWe found that ARF loss prevented MYC inactivation from inducing cellular senescence through a p53 independent mechanism . Our obsThe mechanism through which ARF regulates innate immunity is not clear. Analysis of gene expression revealed a signature of genes involved in innate immunity . ARF, itEmerging immunotherapies have intensified interest in the therapeutic role of the innate and adaptive immune system. Biologics targeted at tumor cells for enabling antibody-dependent cell-mediated cytoxicity (ADCC) rely on innate immune system for elimination of cancer cells . Since ACells undergoing senescence secrete factors that bolster the senescent phenotype in both autocrine and paracrine fashion by engaging innate immune system . ARF losOur research has uncovered ARF as a common regulator of senescence and tumor clearance that appears to require the innate immune system. However, there are several questions awaiting answers. First, we have identified innate immune-related gene expression changes due to ARF loss; yet direct causality of these changes in macrophage infiltration into regressing tumors has not been established. Second, the mechanism by which cellular senescence is dependent upon macrophage recruitment is unclear. Third, whether ARF loss in tumors affects other immune infiltrates, such as NK cells, monocytic and granulocytic myeloid cells, or even adaptive immune cells, needs to be investigated. Fourth whether ARF's effect on innate immune-related genes and recruitment of macrophages extends to other types of cancers remains to be determined. Finally, it is of paramount interest whether ARF status may influence efficacy of immunotherapies."}
+{"text": "Cancer imaging is frequently at the cutting edge of new imaging techniques which are often rapidly incorporated into routine use.Skeletal metastatic disease is a frequent complication of neoplastic conditions, and results in specific challenges to the general radiologist and specialist oncological radiologist alike.Non-neoplastic conditions and normal variants may simulate skeletal metastases, and the radiologist must recognise such cases and avoid over-investigation and unnecessary treatment.This lecture will briefly review standard imaging techniques and demonstrate normal appearances, normal variants and non-neoplastic lesions that mimic primary and secondary skeletal malignancy, and will then review a spectrum of malignancy-associated bone lesions with the use of standard and more specialised imaging techniques, including PET MRI, PET CT and diffusion weighted imaging,.Expected post treatment imaging findings, and treatment-associated complications will also be discussed."}
+{"text": "To investigate through Structural Equation Modelling (SEM), the relationship between parenting styles, teasing about body weight/shape or eating, internalization of the thin ideal and body dissatisfaction amongst eating disorders (EDs) and controls and to see whether the risk factor model differed across various European countries and ED subtypes.The total sample comprised 1373 participants(ED patients=618).The Cross-Cultural Questionnaire (CCQ) was used to assess the above-mentioned risk factors.SEM analyses showed that the best fitting model was one allowing risk paths to vary across countries . In all countries teasing about weight/shape or eating was associated with body dissatisfaction.There was a strong significant path from body dissatisfaction to ED.Teasing about weight/shape or eating also directly predicted EDs .There was however a weak effect of parenting on both teasing about weight/shape or eating and EDs directly.Risk models slightly varied across ED diagnoses.Our hypothesised model was partially confirmed; in particular the central role of teasing on EDs both directly and mediated by internalization of the thin ideal and body dissatisfaction was shown across five European countries.Conversely, the effect of parenting varied by country and therefore might have cross-cultural effects.Prevention & Public Health stream of the 2014 ANZAED Conference.This abstract was presented in the"}
+{"text": "A hallmark feature of the neural system controlling breathing is its ability to exhibit plasticity. Less appreciated is the ability to exhibit metaplasticity, a change in the capacity to express plasticity . Recent advances in our understanding of cellular mechanisms giving rise to respiratory motor plasticity lay the groundwork for (ongoing) investigations of metaplasticity. This detailed understanding of respiratory metaplasticity will be essential as we harness metaplasticity to restore breathing capacity in clinical disorders that compromise breathing, such as cervical spinal injury, motor neuron disease and other neuromuscular diseases. In this brief review, we discuss key examples of metaplasticity in respiratory motor control, and our current understanding of mechanisms giving rise to spinal plasticity and metaplasticity in phrenic motor output; particularly after pre-conditioning with intermittent hypoxia. Progress in this area has led to the realization that similar mechanisms are operative in other spinal motor networks, including those governing limb movement. Further, these mechanisms can be harnessed to restore respiratory and non-respiratory motor function after spinal injury. As with most neural systems, a hallmark of the neural system controlling breathing is its ability to express plasticity; defined as a persistent (>60 min) change in neural network function after an experience/stimulus has ended  after the stimulus is removed. Neuromodulators often work through metabotropic G protein coupled receptors, which alter cell excitability through covalent modifications of membrane channels. Modulation does confer system flexibility and can initiate cellular mechanisms resulting in plasticity  is augmented by concurrent application of another (substance P).Plasticity (long-term) is a persistent (>60 min) change in function that outlasts the initiating stimulus , a long-lasting increase in phrenic motor output observed following acute intermittent hypoxia  but otherwise the same AIH protocol  in humans (Lee et al., per se (Ling et al., Enhanced pLTF could occur and/or be modified at any site in the neural network transmitting chemosensory activity to PMN; including chemoreceptors themselves, their afferent terminations in the nucleus of the solitary tract, neurons of the ventral respiratory column, raphe neurons, spinal phrenic interneurons and/or PMN Figure . There iAlthough relatively little is known concerning sites and signaling mechanisms of CIH metaplasticity, CIH-enhanced moderate AIH-induced pLTF is still serotonin-dependent (Ling et al., Because CIH elicits respiratory metaplasticity, we initially had contemplated CIH as a treatment option to restore respiratory control in clinical disorders that impair breathing capacity; such as cervical spinal injury (Fuller et al., Less intensive rAIH preconditioning protocols retain the ability to elicit plasticity and metaplasticity without the known pathogenic effects of CIH (Lovett-Barr et al., AIH-induced pLTF is modified by a number of other pre-treatments that enhance and diminish its expression (Mitchell et al., Of these, the best characterized is enhanced pLTF following CDR. Twenty-eight days following bilateral CDR, moderate AIH induced pLTF is doubled, with an equivalent increase in serotonin terminal density in the immediate vicinity of identified PMN (Kinkead et al., One week post-CDR, ventral spinal BDNF and neurotrophin-3 concentrations are increased (Johnson et al., Although considerable effort has been devoted to investigations of detailed cellular mechanisms giving rise to AIH-induced pLTF (Devinney et al., With our significant progress in understanding cellular mechanisms of AIH-induced pLTF, it is an advantageous model to study metaplasticity in respiratory motor control. Such studies are warranted from a basic science perspective, but also because rAIH is rapidly moving towards clinical application as a treatment for respiratory insufficiency in disorders that compromise breathing capacity (Lovett-Barr et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In plant leaves, resource use follows a trade-off between rapid resource capture and conservative storage. This \u201cworldwide leaf economics spectrum\u201d consists of a suite of intercorrelated leaf traits, among which leaf mass per area, LMA, is one of the most fundamental as it indicates the cost of leaf construction and light-interception borne by plants. We conducted a broad-scale analysis of the evolutionary history of LMA across a large dataset of 5401 vascular plant species. The phylogenetic signal in LMA displayed low but significant conservatism, that is, leaf economics tended to be more similar among close relatives than expected by chance alone. Models of trait evolution indicated that LMA evolved under weak stabilizing selection. Moreover, results suggest that different optimal phenotypes evolved among large clades within which extremes tended to be selected against. Conservatism in LMA was strongly related to growth form, as were selection intensity and phenotypic evolutionary rates: woody plants showed higher conservatism in relation to stronger stabilizing selection and lower evolutionary rates compared to herbaceous taxa. The evolutionary history of LMA thus paints different evolutionary trajectories of vascular plant species across clades, revealing the coordination of leaf trait evolution with growth forms in response to varying selection regimes. Although leaf morphology has evolved manifold variations across vascular plant species, there is strong evidence of a universal spectrum constraining leaf functioning from rapid resource capture to efficient resource use  shaping trait evolution within lineages  from 180 published and unpublished studies and electronic databases . Second, node ages were estimated using the bladj module of the Phylocom software  + \u03c32dt, where the parameter \u03b1 controls the rate of adaptive evolution to the optimum  to test for the existence of phylogenetic structure in the trait data. The PI model ignores phylogenetic relatedness across species as if they were placed at equal distance on a star phylogeny. It serves as a null hypothesis which supposes the absence of phylogenetic covariance in the trait distribution.\u03bb , while a value of \u03bb = 1 indicates that the phylogenetic pattern conforms to Brownian motion on the given phylogeny  to \u22121, indicating strong negative association. It has an expected value of n is the number of tips, under the null hypothesis of no correlation between trait values and phylogenetic distance. We also calculated I within different classes of divergence time  which were chosen to ensure a sufficient number of observations within each class. This was used to build a resulting phylogenetic correlogram, which represents how trait similarity among species varies with the time since their divergence. In theory, this temporal pattern allows one to discriminate the BM from the OU models : Pagel's \u03bb Pagel , BlomberDW, which measures the degree of divergence (or trait radiation) between the child clades of each node. An ancestral node was considered as diversifying when the corresponding DW value was higher than expected at random, and as conservative when DW was lower than expected at random. Significant divergence widths were detected by testing the statistic against the null hypothesis PI using permutations (n = 105) and correcting for multiple comparisons , indicate past diversifying events (trait radiation) followed by subsequent conservatism within daughter clades. On the other hand, significantly conservative nodes correspond to divergences of low amplitude between daughter clades thus displaying similar trait values and phylogenetic conservatism thereafter.We analyzed the phylogenetic signal at clade level using the analysis of traits procedure . This analysis can detect functionally diversifying and conservative ancestral splits in trait values across daughter clades  to 1479.1 g.m\u22122 in Hakea leucoptera (Proteaceae). LMA ranges largely overlapped across the major clades in Tracheophyta, but on average, Lycopodiophyta and Monilophyta (ferns) exhibited the lowest LMA, while Gymnospermae showed the highest LMA compared to the other major clades . Of these 62 nodes, 12 corresponded to diversifying nodes with trait radiation , was investigated across a large set of vascular plant species. Using comparative phylogenetic methods and a global trait database of over 5000 species, we detected that leaf strategies were overall weakly, albeit significantly, conserved during the diversification of vascular plants. This low conservatism appeared to be associated with multiple regimes of stabilizing selection, that is differing adaptive optima across the major clades. Importantly, we highlight the strong interaction between the evolution of growth forms and of leaf strategies, with woody species displaying slower leaf diversification and higher conservatism in LMA than herbaceous plant species.Spermatophytae) on the other, and between Angiospermae and Gymnospermae (Fig. Angiospermae clade, diversity in LMA reflects the wide adaptive radiation of flowering plants into a range of ecological strategies, involving diverse growth forms and ecological niches both within and across habitats (Ricklefs and Renner, Angiospermae. In fossil floras, basal plant clades display a higher diversity of growth forms than is currently observed among extant species: treelike plants existed within Lycopodiophyta, as well as ruderal herbaceous taxa within gymnosperms (Rothwell et al. Leaf mass per area appeared significantly but weakly conserved. This low phylogenetic signal captures the fact that distantly related species may occupy similar positions along the leaf economics spectrum. The large variability found within clades here evidenced a pattern of functional convergence across clades over a broad phylogenetic scale. However, significant levels of trait conservatism imply that, to a certain extent, closely related species do tend to invest dry matter similarly within leaf tissues and hence occupy nearby positions along the leaf economics spectrum. In particular, evolutionary splits identified as conservative nodes were mostly found at the level of genera. As might be expected, the degree of similarity in resource-use strategies varied with the length of the period of common evolution along lineages (Hansen and Martins, mae Fig. . Within in natura set constraints on plant strategies that may directly or indirectly affect achievable LMA values. A recent study of the evolution of the leaf economics spectrum highlighted the nature of evolutionary forces on LMA (Donovan et al. Models of continuous trait evolution supported the hypothesis that stabilizing selection shaped the phylogenetic pattern in LMA, against the hypothesis of evolution by drift alone. Given the breadth of sampling in our dataset, over a large taxonomic scale and a range of ecological situations, the stabilizing selection we detected likely reflects selection against extreme phenotypes that infringe structural and physiological limitations to LMA. The phylogenetic patterns evidenced here showed simultaneously conservatism, mostly within genera, and convergence across large clades. Congruence between radiation and restrictive environmental conditions, such as within the Proteales, also suggests strong filtering effects that may lead to conservatism at larger phylogenetic scales and functional distinctiveness (Cornwell et al. Recent analyses of molecular sequences have shown that woody species have evolved more slowly than herbaceous species (Smith and Donoghue, The observed patterns in the evolution of LMA raise the issue of selective pressures resulting in different selection regimes at large evolutionary scales. Fossil evidence suggests that large spatiotemporal scale changes in climate and disturbance regime were partially responsible for the diversification of vascular plants Stebbins  and thisBy exploring the evolutionary history of LMA we have revealed different evolutionary trajectories involving coordination and trade-offs between leaf traits and plant traits related to growth form. As a consequence, different optimal phenotypes of resource-use strategies have evolved in vascular plants setting fundamental limits on the structure and physiology of organisms and therefore on ecological processes within communities. Continuing advances in genomics (Leebens-Mack et al."}
+{"text": "The intestinal epithelia rely on resident stem cells to undergo homeostatic growth as well as tissue repair upon injury. In response to insults elicited by pathological bacterial infection or tissue damaging chemicals such as dextran sodium sulfate (DSS), intestinal stem cells (ISCs) speed up their proliferation and differentiation to effectively replenish lost cells. Despite numerous studies, the regulatory mechanisms underlying the control of stem cell activity during homeostasis and regeneration still remain poorly understood.Drosophila adult midgut provides a powerful system to address these problems because sophisticated genetic tools are available to allow the manipulation of gene function in any cell types within the intestinal epithelia as well as in surrounding tissues. Our recent study, which was published in The Journal of Cell Biology, established a critical role of Hh signaling in the regulation of regenerative stem cell proliferation in Drosophila adult midguts [The Hedgehog (Hh) pathway governs animal development in species ranging from fruit fly to human. In additional to their role as morphogen to control cell differentiation and pattern formation in embryonic development, the secreted Hh glycoproteins also function as mitogen to regulate cell proliferation in adult tissue homeostasis and tumorigenesis . Hh sign midguts .Drosophila midguts constantly turn over and are replaced by new cells derived from ISCs localized at the base of the epithelia. ISCs divide to produce themselves and enteroblasts (EBs) that subsequently differentiate into more specialized cell types. Previous studies revealed that ISC proliferation was elevated upon intestinal injury caused by DSS feeding [Similar to mammalian intestines,  feeding . Here we feeding .In searching for the effectors that mediate the Hh function in midguts, we found that Hh signaling in EBs upregulated several cytokines and mitogens, most notably, the JAK-STAT pathway ligand Upd2. Indeed, inaction of Upd2 in EBs blocked ISC proliferation induced by either DSS feeding or ectopic Hh signaling. Taken together, our study suggests that DSS stimulates Hh signaling in EBs where it increases the production of Upd2, which in turn activates the JAK-STAT pathway in stem cells to fuel their proliferation. Interestingly, a recent study revealed a similar Hh-JAK-STAT signaling axis that drives tumorigenesis in mouse skin , suggestupd2 or indirectly through an intermediate pathway. In this regard, it is interesting to note that the Hippo (Hpo) pathway is also involved in DSS-stimulated ISC proliferation [Drosophila midguts and perhaps also in other settings.How Hh production is upregulated upon injury remains poorly understood but our study revealed that DSS increased Hh expression in part through the JNK pathway although the precise mechanism remains to be further explored. Another unresolved issue is how Hh signaling regulates the production of Upd2. Hh could directly regulate the transcription of feration , raising"}
+{"text": "Journal of Experimental Botany (pages 2573\u20132586), Rebetzke et al. take the debate forward, showing that wheat awns are associated with specific grain traits in different environments.Awns, which are derived from floral structures in grasses, are known to be critically important for photosynthesis and transpiration. However, arguments about the costs and benefits of their growth and development for crop grain yield are still ongoing. In this issue of Triticum dicoccoides (K\u00f6rn. ex Asch. & Graebner) Schweinf.], the awns flex as humidity levels change, which can help bury the seeds (T. durum and T. aestivum) have shorter or non-existent awns to facilitate grain harvesting, handling and storage . Therefore, raising grain yield is still the main goal for wheat breeding, particularly as recent decades have seen a reduced rate of increase in wheat yields globally. Increasing assimilate partitioning into wheat\u2019s grain-bearing structures, the spikes, is an important strategy for improving yield. The introduction of dwarfing Reduced height (Rht) genes greatly enhanced the partitioning of assimilates towards spikes . HoweverAwns can be considered an alternative target for the improvement of wheat grain yield through their known functions, including photosynthesis, carbohydrate storage and increased water-use efficiency  four spring wheat populations with a range of diverse genetic backgrounds were developed containing multiple Near-Isogenic Line (NIL) pairs with variation for the presence and absence of full awns; (2) four separate sets of experiments representing a total of 25 environments  were conducted depending on the germplasm and environments sampled; and (3) for comparisons a number of important agronomic traits were measured in multiple years and environments while some traits were related to spike morphology. Separate glasshouse studies were also undertaken.Manipulating source\u2013sink relations is an important strategy for wheat breeding. Spike morphology is a crucial phenotype for displaying the distribution of assimilates. Spike morphology-related traits  demonstrate great variation under variable growth conditions. Therefore, environmentally induced plasticity of spike morphology-related traits can in principle show the redistribution of assimilates.The influence of wheat awns on grain yield can be summarized as a balance between the costs of awn setting and the benefits of awn functions. As hypothesized by Flowering time is commonly considered to be an important determinant for grain yield."}
+{"text": "High-density lipoprotein (HDL) and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms. The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM). HDL may mediate effects on glucose metabolism through actions in multiple organs  by three distinct mechanisms: (i) Insulin secretion from pancreatic beta cells, (ii) Insulin-independent glucose uptake, (iii) Insulin sensitivity. The molecular mechanisms appear to involve both direct HDL signaling actions as well as effects secondary to lipid removal from cells. The implications of glucoregulatory mechanisms linked to HDL extend from glycemic control to potential anti-ischemic actions via increased tissue glucose uptake and utilization. Such effects not only have implications for the prevention and management of diabetes, but also for ischemic vascular diseases including angina pectoris, intermittent claudication, cerebral ischemia and even some forms of dementia. This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies. There is accumulating experimental and clinical evidence that HDL particles can control glucose metabolism via a variety of mechanisms . At a meThe action of HDL to move glucose from the circulation and into tissues has potential clinical relevance in terms of both reducing vascular complications by removing excess glucose from the circulation in the setting of T2DM, and also in providing adequate glucose to tissues for energy production, particularly in the context of ischemia. HDL therapeutics may therefore have application not only for the prevention and management of T2DM , but alsThis review will discuss the growing evidence for a role of HDL in glucose metabolism in the context of the evolving HDL hypothesis. It is now recognized that the main clinical variable used to assess HDL, HDL cholesterol, fails to provide an accurate representation of the multiple functions of heterogeneous HDL particles, which are composed of many hundreds of lipids and multiple proteins . The rolT2DM, insulin resistance and glucose intolerance are associated with low HDL cholesterol levels . While tOn the other hand, a recent Mendelian randomization study showed that genetically reduced HDL cholesterol does not associate with increased risk of T2DM . While tHigh-density lipoprotein has been implicated in the modulation of insulin secretion in cellular and animal studies with corroborating evidence from human intervention trials. The diverse functionality of HDL to combat cellular lipid accumulation, endoplasmic reticulum (ER) stress and apoptosis are three potential mechanisms that may preserve pancreatic beta cell function.Pancreatic lipid accumulation and lipotoxicity have been well-documented to inhibit insulin production and secretion . We haveAt the signaling level the HDL transporters ATP-binding cassette, sub-family A, member 1 (ABCA1) and ATP-binding cassette, sub-family G, member 1 (ABCG1) have both been implicated in HDL-mediated effects on insulin secretion. Beta cell-specific deletion of the ABCA1  and ABCGHDL may also influence insulin secretion via mechanisms other than cholesterol depletion, including via actions on insulin transcription . At doseThe ability of HDL to inhibit ER stress-induced beta cell apoptosis could be another important mechanism by which HDL may ameliorate beta cell dysfunction . Bioacti2+ influx and activation of calcium/calmodulin activated protein kinase kinase (CaMKK)  . Subsequ (CaMKK)  and faciin vivo effects of HDL on glucose disposal in the absence of a change in circulating insulin. Such effects may be mistakenly attributed to increased insulin sensitivity.Beyond glucose uptake, HDL has been shown to activate Akt in ApoA-I transgenic mice and directly enhance both glycolysis and glucose oxidation in mouse C2C12 muscle cells . These iTissue lipid deposition and chronic inflammation associated with obesity, metabolic syndrome and T2DM establishes a functional deficit in skeletal muscle and the heart, impairing how these metabolically active tissues respond to insulin. The insulin resistance associated with lipid accumulation and a pro-inflammatory milieu promotes lipolysis, increasing circulating free fatty acids, thus perpetuating dyslipidemia and insulin resistance . It is sin vivo is more complex due to the fact that increased glucose disposal relative to insulin may not necessarily reflect increased insulin sensitivity. As discussed in the previous section, such observations may actually be explained by direct actions of HDL on glucose disposal by mechanisms which do not involve insulin. Nevertheless, there are two recent in vivo studies consistent with the cellular studies, which suggest that HDL/ApoA-I can increase peripheral insulin sensitivity. The first of these employed intraperitoneal glucose and insulin tolerance tests in high fat diet fed mice treated for 2\u20134 weeks with lipid-free ApoA-I (8 mg/kg body weight) and showed improved glucose and insulin tolerance compared to untreated mice on the same high fat diet  testing or hyperinsulinemic-euglycemic clamp studies to examine direct effects on insulin sensitivity. Definitive evidence for an effect of HDL on insulin sensitivity in humans is also lacking. However, HDL cholesterol elevation by CETP inhibition has been shown to improve glycemic control in the face of reduced plasma insulin in people with T2DM in the ILLUMINATE trial . As evidThe actions of HDL on glucose metabolism have potential benefit beyond vascular protection. The ability of HDL to stimulate tissue glucose uptake has implications for cellular metabolism in the brain, as well as for cell viability in other organs under ischemic/anoxic conditions where glucose becomes the predominant metabolic substrate. This latter mechanism may have particular relevance to ischemic vascular conditions, including coronary, cerebral and peripheral artery diseases.We have recently established that HDL increases insulin-independent glucose uptake in rat cardiomyocytes via an Akt signaling pathway . In thisInsulin resistance may directly contribute to the increased risk of ischemic heart disease and poorer outcomes after infarction in patients with T2DM . It is pThe emerging actions of HDL and its bioactive components on glucose metabolism in the myocardium may contribute to the demonstrated protective effects of HDL in the context of ischemia-reperfusion injury . Such acFor the same reasons that HDL-mediated effects on glucose metabolism may protect the ischemic myocardium, these actions may equally act in the brain to protect against transient ischemic attacks and stroke. In fact, the reliance of the brain on glucose for ATP production means that mechanisms controlling glucose uptake may be of even greater significance than in other organs. Even minor changes in cerebral blood flow have the potential to impact on neuronal viability via reduction in glucose supply. Indeed cerebral hypoperfusion and hypometabolism coincide in patients with dementia .The implications of reduced blood flow, and thus glucose supply to the brain, extend beyond acute stroke risk to Alzheimer\u2019s disease, which has a significant vascular component . In thisGiven the well-established positive actions of HDL on vascular function, it is not surprising that several co-morbidities associated with increased Alzheimer\u2019s disease risk are themselves associated with decreased HDL function . A role in vitro efficacy of ApoA-I at similar concentrations. More recently, in vitro primary cell culture experiments, suggest that plasma ApoA-I gains access to the CNS primarily by crossing the blood-CSF barrier via specific cellular mediated transport  barrier . ApoA-I ransport . The bloransport , which mThere is now convincing evidence that HDL modulates glucose metabolism in multiple tissues. These actions have deepened our understanding of the pathophysiology of a variety of disease states associated with low or dysfunctional HDL. While there are still many unanswered questions relating to the underlying mechanisms and key HDL component(s) responsible for the metabolic effects, this opens up the possibility of targeting glucose metabolism with HDL therapeutics currently in development. Future preclinical investigations and clinical trials will determine the relevance of HDL-mediated modulation of glucose metabolism to both glycemic control as well as tissue glucose supply to vital organs including the heart and the brain, especially under ischemic conditions.AS, SH, BK drafted, critically revised and approved the final version of this review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. BK has received product from CSL Behring and patient plasma from Hoffman La Roche both for investigator initiated clinical trials, with no associated research funding. She has also partnered with Resverlogix to fund an investigator-initiated clinical trial."}
+{"text": "Plasmodium falciparum-infected children with cerebral malaria (CM) die from respiratory arrest, but the underlying pathology is unclear. Here we present a model in which the ultimate cause of death from CM is severe intracranial hypertension. Dynamic imaging of mice infected with P. berghei ANKA, an accepted model for experimental CM, revealed that leukocyte adhesion impairs the venous blood flow by reducing the functional lumen of postcapillary venules (PCV). The resulting increase in intracranial pressure (ICP) exacerbates cerebral edema formation, a hallmark of both murine and pediatric CM. We propose that two entirely different pathogenetic mechanisms\u2014cytoadherence of P. falciparum-infected erythrocytes in pediatric CM and leukocyte arrest in murine CM\u2014result in the same pathological outcome: a severe increase in ICP leading to brainstem herniation and death from respiratory arrest. The intracranial hypertension (IH) model unifies previous hypotheses, applies to human and experimental CM alike, eliminates the need to explain any selective recognition mechanism Plasmodium might use to target multiple sensitive sites in the brain, and explains how an intravascular parasite can cause so much neuronal dysfunction.Most  P. falciparum causes injury to a sensitive location such as the brainstem, where a small lesion could have fatal consequences  infected mice, an accepted model for experimental cerebral malaria (ECM), in the context of recent advances in the understanding of the pathogenesis of human cerebral malaria (HCM). For the purpose of this Perspective, we focus on pediatric HCM, because African children with HCM tend to exhibit more BBB dysfunction, monocyte and platelet accumulation in the brain, and intracranial hypertension (IH) compared to adult HCM patients in Southeast Asia  patients die from respiratory arrest  cause death is not completely understood. Several models have been proposed over the decades to explain the pathogenesis of HCM  expressing iRBC that bind to the endothelial protein C receptor (EPCR)  ExtP. yoelii XL (PyXL)-infected mice, which develop hyperparasitemia without neurological signs , we found more platelets, CD8+ T cells, neutrophils, and macrophages accumulated in postcapillary venules (PCV) from PbA-infected mice with ECM compared to Arteriolar vasospasms during ECM  with poor outcomes in pediatric HCM patients in Kenya  Ute Frevert, the review process was handled objectively. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Foot ulceration is one of the most significant complications of diabetes, and will affect 15-20% of people with diabetes at some point in their lives. Such ulcers frequently become infected with very serious sequelae which can often lead to amputation making diabetes is the most common cause of lower extremity amputations. Infections cause increased morbidity  which means that they represent significant clinical events, requiring immediate attention in relation to local and systemic complications thus requiring well-coordinated management. Unfortunately diabetic foot infections (DFI) frequently fail to display overt signs and symptoms of infection including purulence, erythema, pain, tenderness, warmth and induration. This makes it difficult for clinicians to detect infection, and to make timely interventions to limit the highly undesirable consequences of DFIs. Alternative means of rapidly diagnosing infection are urgently required.To determine if the presence/absence of microorganisms, and ultimately the presence of infection, are affected by diabetic foot ulcer (DFU) wound fluid pH.DFUs of patients (n=55) were assessed in terms of presence/absence of clinical signs of infection as part of their routine clinical appointment at a High-Risk Foot Clinic. Wound fluid samples were also collected from the DFUs by filter paper absorption and/or pipette aspiration. The pH of samples was determined using a micro-electrode pH meter. Bacteria in the wound fluid were recovered by 24hr incubation in Tryptone Soya Broth, and plating on selective agars which included; MacConkey Agar , Pseudomonas Agar Base (Pseudomonas spp). Chromocult Agar , Baird Parker Agar (Staphylococcus spp) and Columbia Blood Agar (Streptococcus spp). Organisms identified as Staphylococcus Aureus cultured on Muller Hinton Agar and and MRSA present detected using Oxacillin and Cefoxitin antibiotic disks.Sample pH values ranged from 6.2 to 8.5. Recovered bacteria included Pseudomonas, Enterobacter, Staphylococcus and Streptococcus spp. Correlations were observed between DFU fluid pH values, the presence/absence of these species and the presence/absence of clinical signs of infection. This presentation will discuss the potential clinical implications of these findings.pH conditions within DFUs influence bacterial presence/absence in these wounds. pH conditions also influence the presence/absence of clinical signs of infection. Timely monitoring of DFU fluid pH could enhance clinicians\u2019 abilities to rapidly detect and more effectively manage DFU infections. An improved understanding of the interactions between DFU pH and bacterial metabolism may identify ways to limit the duration and wider impact of DFU infections.Governance compliance statement - Ethical approval and research governance has been granted for the clinical study to take place and all research governance procedures are being adhered to during the completion of the study."}
+{"text": "Cerebral collateral circulation is a subsidiary vascular network, which is dynamically recruited after arterial occlusion, and represents a powerful determinant of ischemic stroke outcome. Although several methods may be used for assessing cerebral collaterals in the acute phase of ischemic stroke in humans and rodents, they are generally underutilized. Experimental stroke models may play a unique role in understanding the adaptive response of cerebral collaterals during ischemia and their potential for therapeutic modulation. The systematic assessment of collateral perfusion in experimental stroke models may be used as a \u201cstratification factor\u201d in multiple regression analysis of neuroprotection studies, in order to control the within-group variability. Exploring the modulatory mechanisms of cerebral collaterals in stroke models may promote the translational development of therapeutic strategies for increasing collateral flow and directly compare them in term of efficacy, safety and feasibility. Collateral therapeutics may have a role in the hyperacute  phase of ischemic stroke, prior to recanalization therapies. Cerebral collateral circulation is a subsidiary vascular network which is dynamically recruited after arterial occlusion and may provide residual blood flow to ischemic areas. Cerebral collateral flow during acute ischemic stroke is highly variable among different individuals and is emerging as a strong prognostic factor either in unselected stroke patients and in patients treated with intravenous rtPA or endovascular recanalization therapy . ExperimHere, we review the current methods for assessing cerebral collaterals during acute ischemic stroke and the most promising collateral therapeutic strategies, focusing on experimental stroke models.Many similarities, with some notable differences, exist between humans and rodents in term of cerebral collateral circulation. The circle of Willis includes the anterior communicating artery in humans, while this vessel is totally absent in rodents, whose proximal segments of anterior cerebral arteries (ACA) converge to form one single median artery called Azigos ACA. In case of occlusion of cervical arteries, the circle of Willis represents a compensatory system to rapidly redistributing blood flow in both species. In rodents, the pterygopalatine artery originates from the proximal internal carotid artery (ICA) and provide extracranial collateral connections between external carotid artery and ICA via many arterial branches to facial, orbital and meningeal districts. In both humans and rodents, each cerebral artery provides blood flow to its vascular territory ramifying along the cortical surface to form a pial arteriolar network, creating anastomotic connections among different vascular territories, known as leptomeningeal anastomoses (LMAs). LMAs are mostly developed between cortical branches of middle cerebral artery (MCA) and ACA or posterior cerebral artery. In case of proximal occlusion of a cerebral artery, dynamic blood flow diversion through these anastomoses may provide residual (retrograde) blood flow to the cortical surface of the occluded artery territory, distally from the occlusion.The anatomy of cerebral collaterals in acute stroke patients can be assessed using conventional digital subtraction angiography (DSA), CT angiography (CTA) or MR angiography (MRA), while their functional performance can be studied through tissue perfusion evaluation, via CT and MR perfusion techniques (PCT and PWI). At present, there is no agreement in clinical practice on which imaging should be performed, when after stroke and which patients would benefit most from cerebral collateral imaging. DSA is the gold standard for evaluating the recruitment of cerebral collaterals, but it is invasive and usually reserved for patients selected for endovascular procedures. CTA is able to provide direct visualization of collateral flow after arterial occlusion Fig.\u00a0 3]. How. How3]. In experimental stroke models, both the site and the duration of arterial occlusion are controlled. Continuous or repeated assessment of cerebral collateral flow could be performed, including pre-stroke assessment. For these reasons, preclinical research could play a crucial role for a deeper understanding of collateral response during cerebral ischemia and promote the translational development of collateral-based therapies. However, both cerebrovascular differences between different species and strains and inter-individual variability need to be meticulously considered to achieve effective results in this field .Although some techniques used in stroke patients, such as DSA or MRI, could be used in stroke models for assessing cerebral collateral flow \u201314, signLaser speckle contrast imaging (LSCI)  providesIn contrast to LSCI, two photon laser scanning microscopy (TPLSM) is an optical technique providing quantitative measure of blood flow velocity and direction in single vessels, with depth resolution up to 1\u00a0mm. Single arterioles, venules and capillaries of both surface and subsurface vasculature are resolved after intravenous injection of dextran conjugated with a fluorescent dye. A cranial window is required and scanning procedure is time-consuming. Collateral response after occlusion of both pial and penetrating arterioles in rats  were stu3 volume. Real-time relative cortical CBF values are obtained, while absolute CBF quantification cannot be achieved [Laser-Doppler flowmetry (LDF) is a well-established technique for tissue perfusion monitoring and is recommended to confirm successful occlusion and exclude subarachnoid hemorrhage in experimental ischemic stroke . Opticalachieved . Our groachieved . A custoThe use of any of these methods (or a combination of them) to monitor arterial occlusion and collateral perfusion cannot be over emphasized to improve accuracy of pre-clinical stroke research. Advantages and drawbacks, in terms of temporal and spatial resolution, invasiveness and affordability of each technique are shown in Table\u00a0Despite over 1000 putative neuroprotective agents obtained promising results in experimental stroke models , no succA well-recognized limitation of preclinical stroke models is outcome variability , particuThe variability of cerebral hemodynamics during ischemia has been largely neglected in preclinical research, as well as the influence of drugs on CBF . MonitorAnimal stratification by collateral flow during MCAO represents a promising tool to adjust for outcome variability in experimental stroke studies. Using cerebral collateral flow during MCAO as a covariate in multiple regression analysis may represent a simple method to stratify animals in term of pre-treatment perfusion deficit, reducing the within group variability and improving efficacy analysis in preclinical neuroprotection studies. Further studies are needed to determine the more suitable method, timing and statistical tool for collateral flow assessment in pre-clinical neuroprotection trials.Intravenous thrombolysis with rtPA (Alteplase) within 4.5\u00a0h from symptom onset (for any vessel occlusion) and endovascular thrombectomy within 6\u00a0h from symptom onset (for large vessel occlusion) are currently the best therapeutic options for acute ischemic stroke , 39. UnfIncreasing systemic blood pressure represents a first strategy. Phenylephrine, a selective \u03b11-adrenergic receptor agonist, causes systemic vasoconstriction with very limited effects on cerebral vessels. A 30\u00a0% augmentation of blood pressure obtained through phenylephrine infusion after distal MCAO induction in mice enhanced cortical CBF both in core and penumbra . In smalIncreasing intravascular volume may represents a second strategy. Cerebral blood volume augmentation by plasma expansion and haemodiluition could improve cerebral perfusion in experimental stroke models . HoweverInduction of selective cerebral vasodilation is a third strategy. Nitric oxide (NO) is a strong endogenous vasodilator with therapeutic potential for ischemic stroke . NO inha2 levels, causing pial arteriolar vasodilation and increased cortical perfusion in piglets [Selective cerebral arteriolar vasodilation could be obtained using acetazolamide, which inhibits carbonic anhydrase and consequently augments CO piglets . In clin piglets . Quite s piglets , was perCerebral flow diversion is a fourth strategy. Gravitational influences of head positioning after acute vascular occlusion may affect pressure gradients in cerebral circulation, which enhancement may promote leptomeningeal recruitment. Augmentation of cerebral perfusion and increased MCA blood flow velocity has been reported in stroke patients after flat head positioning , 61 and A limited number of clinical and preclinical stroke studies focused on cerebral collateral circulation. Generally, neuroprotective effects are being sought, whereas the contribution of collateral blood flow is rarely considered or just inferred. Preclinical stroke research has the potential to directly study the adaptive capacity and modulatory mechanisms of cerebral collateral flow during focal cerebral ischemia, using different methods and in different experimental conditions. These preclinical efforts are likely to be worthwhile and may produce useful translational concepts and direct comparisons of the different strategies to enhance cerebral collateral flow, including some therapeutic approaches which did not prove successful in past clinical trials conducted in the pre-thrombolysis era."}
+{"text": "HEart and BRain interfaces in Acute ischemic Stroke (HEBRAS) study aims to assess whether an enhanced MRI set-up and a prolonged Holter-ECG monitoring yields a higher rate of pathologic findings as compared to diagnostic procedures recommended by guidelines .An effective diagnostic work-up in hospitalized patients with acute ischemic stroke is vital to optimize secondary stroke prevention. The Prospective observational single-center study in 475 patients with acute ischemic stroke and without known atrial fibrillation. Patients will receive routine diagnostic care in hospital as wells as brain MRI, cardiac MRI, MR angiography of the brain-supplying arteries and Holter-monitoring for up to 10\u00a0days. Study patients will be followed up for cardiovascular outcomes at 3 and 12\u00a0months after enrolment.By comparing the results of routine diagnostic care to the study-specific MRI/ECG approach, the primary outcome of HEBRAS is the proportion of stroke patients with pathologic diagnostic findings. Predefined secondary outcomes are the association of stroke localization, autonomic dysbalance and cardiac dysfunction as well as the effect of impaired heart-rate-variability on long-term clinical outcome.The investigator-initiated HEBRAS study will assess whether an enhanced MRI approach and a prolonged ECG monitoring yield a higher rate of pathological findings than current standard diagnostic care to determine stroke etiology. These findings might influence current diagnostic recommendations after acute ischemic stroke. Moreover, HEBRAS will determine the extent and clinical impact of stroke-induced cardiac damage.NCT02142413.Clinicaltrials.gov  Variations and delays in the diagnostic procedures during hospitalization after acute ischemic stroke are common \u20133. At thRecent studies have shown that magnetic resonance imaging (MRI) and MR angiography are able to detect cardiac , 6, aortHEart and BRain interfaces in Acute ischemic Stroke (HEBRAS) study therefore aims to assess the detection rate of pathologic findings relevant to stroke etiology as obtained by an enhanced MRI set-up  and a prolonged, non-invasive, commonly available Holter monitoring (of up to 10\u00a0days duration) in comparison to findings obtained by routine diagnostic procedures after acute stroke. In addition, the underlying pathophysiological mechanisms and the prognostic impact of stroke-induced cardiac damage are still poorly understood  or the Find-AFRANDOMISED trial [Besides feasibility and diagnostic value of enhanced MRI, HEBRAS will assess the ability of extended systematic analysis of ECG-recording to improve AF detection compared to the current clinical standard, as similarly done in currently ongoing trials such as the ED trial , as wellED trial , 29. DetED trial . A fasteAnother unique feature of the investigator-initiated HEBRAS study is the systematic assessment of stroke-induced autonomic dysfunction and cardiac damage by using a laboratory data. It has long been recognized that acute cerebrovascular events may coincide with or trigger cardiac dysfunction and elevation of cardiac biomarkers such as troponin. Several studies reported on elevation of cTn in patients with acute ischemic stroke \u201332. HoweIn addition, natriuretic peptides  have been shown to be independently associated with atrial fibrillation in stroke cohorts \u201336, but In summary, the HEBRAS study aims to clarify whether recent technical advantages can improve etiologic work up after acute ischemic stroke. This study has the potential to set essential modifications of current diagnostic standards after acute ischemic stroke, aiming at improving secondary stroke prevention. Moreover, the HEBRAS study will hopefully elucidate mechanisms of stroke-induced autonomic dysfunction and cardiac damage."}
+{"text": "Autism spectrum disorders (ASD) are characterized by two seemingly unrelated symptom domains\u2014deficits in social interactions and restrictive, repetitive patterns of behavioral output. Whether the diverse nature of ASD symptomatology represents distributed dysfunction of brain networks or abnormalities within specific neural circuits is unclear. Striatal dysfunction is postulated to underlie the repetitive motor behaviors seen in ASD, and neurological and brain-imaging studies have supported this assumption. However, as our appreciation of striatal function expands to include regulation of behavioral flexibility, motivational state, goal-directed learning, and attention, we consider whether alterations in striatal physiology are a central node mediating a range of autism-associated behaviors, including social and cognitive deficits that are hallmarks of the disease. This review investigates multiple genetic mouse models of ASD to explore whether abnormalities in striatal circuits constitute a common pathophysiological mechanism in the development of autism-related behaviors. Despite the heterogeneity of genetic insult investigated, numerous genetic ASD models display alterations in the structure and function of striatal circuits, as well as abnormal behaviors including repetitive grooming, stereotypic motor routines, deficits in social interaction and decision-making. Comparative analysis in rodents provides a unique opportunity to leverage growing genetic association data to reveal canonical neural circuits whose dysfunction directly contributes to discrete aspects of ASD symptomatology. The description of such circuits could provide both organizing principles for understanding the complex genetic etiology of ASD as well as novel treatment routes. Furthermore, this focus on striatal mechanisms of behavioral regulation may also prove useful for exploring the pathogenesis of other neuropsychiatric diseases, which display overlapping behavioral deficits with ASD. The earliest clinical descriptions of autism highlighted two symptom domains, focusing on social behaviors and the regulation of motor output. Kanner's seminal article \u201cAutistic Disturbances of Affective Contact\u201d carefully described the profound social deficits of his patients, concluding \u201cthese children have come into the world with innate inability to form the usual biologically provided affective contact with people\u2026\u201d Kanner, . ShortlyFrom the outset, it is worthwhile considering the utility of exploring nervous system disease pathophysiology from the vantage of neural circuit dysfunction. This approach seeks to uncover alterations in defined, reproducibly interconnected sets of neurons that are responsible for discrete behavioral phenomenon seen in neuropsychiatric diseases such as schizophrenia , which can prevent excessive computational demands on cortical structures  supporting goal-directed behavioral responding, the dorsal lateral striatum  supporting automated behaviors and the nucleus accumbens mediating motivational states and reward processing , together with whole-exome and genome sequencing, has demonstrated a substantial amount of genetic heterogeneity underlying ASD etiology, with some estimates predicting that 300\u2013800 loci will eventually be associated with increased risk for ASD , a key repressor of translation at central synapses, has been a central model for exploring the pathogenesis of mental retardation and accompanying developmental disorders including autism  in the development of ASD-associated behaviors.Through a series of experiments, a unifying mechanism emerged in which oxytocin signaling regulated the release of serotonin in the nucleus accumbens, which subsequently modulated excitatory synaptic strength by acting at presynaptic serotonergic receptors on excitatory afferent fibers Figure . DespiteApplying a similar \u201ccircuit dissection\u201d approach, we attempted to explore how ASD-associated mutations could promote development of the restricted and repetitive behaviors so frequently observed in ASD patients  neurons either uniquely or more highly express ASD-associated genes such that loss-of-function is more acutely sensed, or (2) neurons do not express alternative family members of ASD-associated genes that would typically allow for genetic compensation. Using a computational approach that analyzed autism genetic datasets to correlate mutations to known biological networks, it was found that autism-associated mutations are preferentially found in genes whose expression levels are enriched in both populations of striatal medium spiny neuron, as well as cortical inhibitory and projection populations, deep cerebellar nuclei and layer 6 corticothalamic neurons  examining heterozygous mutations, disease-associated point mutations or genetic modifiers, (2) exploration of environmental interactions with mutations (3) physiological analysis of behaviorally relevant circuits through selective optogenetic recruitment and (4) highly quantitative analysis to detect subtle changes in discrete components of complex behaviors. Even with these improvements, it is important to acknowledge the intra-species differences in brain complexity, genomic regulation and behavioral repertoire, which may place limits on the generalizability of rodent-based research findings  and a McCabe Fund Award (University of Pennsylvania).The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Colorectal Carcinoma (CRC) is a heterogeneous disease with different molecular characteristics associated with the sites from which, the tumours originate. Such heterogeneity is compounded by the multitude of genetic and epigenetic variations acting as passengers or drivers of the tumour. Majority of CRC develops via chromosomal instability (CIN) pathway. CIN is often exacerbated by inactivation of the Wnt signalling pathway \"master regulator\" APC gene, activating mutations of KRAS or BRAF oncogenes, or deletions of the 18q, and 17p chromosomal regions with deleterious effects on the tumour suppressor genes TP53 and DCC. Defective Mismatch Repair (MMR) pathway results in a subtler form of genomic instability, namely Microsatellite Instability (MSI). High levels of MSI (or MSI-H) in sporadic CRC are usually caused by hypermethylation of the MLH1 promoter. In terms of methylation, the CpG island methylator phenotype (CIMP) pathway is the second most common pathway in sporadic CRC. CIMP-positive (CIMPp) CRC tumours are usually associated with the proximal colon of older females. CIMPp CRC tumours have better prognosis if the tumours are also MSI-H. However, CIMPp CRC tumours that are Microsatellite Stable (MSS) have poor clinical outcome. To gain insight into the molecular mechanisms underpinning CRC in Saudi Arabian patients, we profiled the DNA methylation frequency of key genes  in 120 sporadic CRC cases. CRC tumours originating from the rectum, left, and right colons are represented in this cohort. Expression patterns of different proteins playing important role in CRC carcinogenesis also studied by using Immunohistochemistry (IHC) technique and their impact as CRC prognosticators was evaluated."}
+{"text": "Arc-indexed odor networks of awake rats. Arc-indexed networks are sparse and distributed, consistent with current views. However Arc provides representations of repeated odors. Arc-indexed repeated odor representations are quite variable. Sparse representations are assumed to be compact and reliable memory codes. Arc suggests this is not necessarily the case. The variability seen is consistent with electrophysiology in awake animals and may reflect top-down cortical modulation of context. Arc-indexing shows that distinct odors share larger than predicted neuron pools. These may be low-threshold neuronal subsets. Learning\u2019s effect on Arc-indexed representations is to increase the stable or overlapping component of rewarded odor representations. This component can decrease for similar odors when their discrimination is rewarded. The learning effects seen are supported by electrophysiology, but mechanisms remain to be elucidated.We first review our understanding of odor representations in rodent olfactory bulb (OB) and anterior piriform cortex (APC). We then consider learning-induced representation changes. Finally we describe the perspective on network representations gained from examining  Arc-indexed odor representations. These data modify our view of odor representations and their modulation by reward. How Arc expression is recruited by odor is also considered.Here we first characterize our understanding of odor representations in the olfactory bulb (OB) and anterior piriform cortex (APC). We next review learning-related modulation of those odor representations. Finally, we discuss data using It has long been recognized that odor representations require across-fiber coding  technique to visualize Arc mRNA and characterize odor representations. Arc, as one of the immediate early genes, offers an important feature for examining representations repeatedly in the same animal  early odor preference learning in rat pup Figure ; and (2)In the rat pup model  vs. untrained rats (5%), with a reduction in the variable neuronal component. The overlap component did not show an absolute increase with training, but became a larger proportion of the representation. Thus, as in the rat pups (Shakhawat et al., Electrophysiology had not revealed learning differences in APC firing patterns for simple discriminations (Chapuis and Wilson, In the mixture discrimination, the two individual odor components were responded to as rewarded odors during behavioral probes, suggesting rats learned the components during mixture training or pattern-completed from partial cues. The degree of overlap between peppermint and vanillin in control rats was ~20% while overlap was ~45% in trained rats, consistent with the two odors becoming representationally highly similar (Shakhawat et al., In the difficult discrimination, the odor representation size was ~3% and did not change with learning (Shakhawat et al., The mechanisms for associating odor and reward, presumably resulting in the increases in stability components seen here, have been examined earlier. In the rat pup, norepinephrine paired with odor can alter behavior and AMPA receptor-mediated connectivity in OB (Cui et al., Arc imaging made possible was the finding of high variability in repeated odor representations and the finding of a high degree of overlap between representations of distinct odors. If cells encoding distinct odors were drawn at random from populations with replacement such that the same cell could participate in multiple representations, then the predicted overlap would be the representational size squared. In Arc studies, representational size varies from 1% to 10%, consistent with other estimates (e.g., Lin da et al., Arc.The two novel results that Arc itself indicates. While it is related to neuronal activation, neural firing cannot be its sole initiator. Mitral cells fire at high spontaneous levels (Rinberg et al., Arc activation. Arc recruitment is likely linked to glutamatergic excitatory synaptic driving (Cole et al., Finally we come to the issue of what Arc recruitment. Odor activation firing patterns in OB and APC are dynamic spatially and temporally (Friedrich and Laurent, Arc represent the initial pattern and its variability or the combined early and later patterns and their cumulative variability? This would be another contribution to the high variability observed.But even if that is the case, one must ask which driving patterns are encoded by Arc patterns, we would predict a larger stable component with increasing concentrations supporting more rapid discriminations.How many neurons are excited in a single synchronized odor representation? The size of odor representations appears to be normalized and varies less for concentration increases Cleland,  than oneArc-indexed cell networks portray odor representations in both OB and APC as sparse and distributed consistent with current understanding. Arc-indexed networks also reveal a considerable variability in the awake mammalian odor representation consistent with the electrophysiological evidence. This methodology further reveals a larger component of common neuronal activation for distinct odors than predicted by theory. Appetitive learning modifies odor representations to increase the proportion of stable neurons. Network representations can also decrease the proportion of stable neurons when increased behavioral discrimination is required.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In August 2016, more than 10,000 athletes representing over 200 countries will converge inRio de Janeiro for the 'biggest sporting event on the planet'This special issue on SPORTS in the Brazilian Journal of Physical Therapy comes at anopportune time for practitioners who work with athletes of all levels of ability andthroughout various phases of their rehabilitation recovery. With contributions by aninternational group of 'elite' practitioners in their field, readers will be sure to findtheir topic of interest in this special SPORTS issue. These topics range from expertclinical commentaries and critical reviews to presentations of original research related tocommon sports injuries.While the World Cup generates an international enthusiasm for soccer, it also informs theviewer about the injuries to soccer players. The article \"SPORTS INJURIES PROFILE OF AFIRST DIVISION BRAZILIAN SOCCER TEAM: A DESCRIPTIVE COHORT STUDY\" by Reis and colleaguesprovides information from a descriptive cohort study regarding injury profiles in firstdivision Brazilian soccer players, including the influence of player's age and position oninjuries. An appropriate and relevant follow up to this manuscript is presented byHespanhol Junior and colleagues: \"MEASURING SPORTS INJURIES ON THE PITCH: A GUIDE TO USE INPRACTICE.\" This paper reviews the basic concepts of injury monitoring systems in sportsparticipation and encourages the implementation of these concepts in practice.Runners are featured in the manuscript \"MALE AND FEMALE RUNNERS DEMONSTRATE DIFFERENTSAGITTAL PLANE MECHANICS AS A FUNCTION OF STATIC HAMSTRING FLEXIBILITY\". In this article,Blase Williams and colleagues assess the effect of hamstring length on running mechanics inboth male and female runners and discuss the implications for injury. For athletes who havesustained a knee injury, the timing for when it is safe to return to sports can bechallenging. In the manuscript \"A CONCEPTUAL FRAMEWORK FOR A SPORTS KNEE INJURY PERFORMANCEPROFILE (SKIPP) AND RETURN TO ACTIVITY CRITERIA (RTAC),\" Logerstedt and colleagues discussa comprehensive system that focuses on specific indicators of rehabilitation progression,and present criteria for safe return to sports following knee injury.Patellar tendinopathy is a common problem in athletes whose sports require jumping. In thearticle \"PHYSICAL THERAPISTS' ROLE IN PREVENTION AND MANAGEMENT OF PATELLAR TENDINOPATHYINJURIES IN YOUTH, COLLEGIATE, AND MIDDLE-AGED INDOOR VOLLEYBALL ATHLETES\" Kulig andcolleagues discuss intervention strategies that include education, rehabilitation, trainingand return to sport that are athlete-specific. Patellar tendinopathy is not the onlycondition linked to sports involving jumping. Achilles tendinopathy is also common andhighly problematic in jumping activities. In the manuscript \"CLINICAL COMMENTARY OF THEEVOLUTION OF THE TREATMENT FOR CHRONIC PAINFUL MID-PORTION ACHILLES TENDINOPATHY\" Alfredsondiscusses the results of research that evolved and changed practice, including the newesttreatment for Achilles tendinopathy.Given that Golf will be returning to the 2016 Summer Games for the first time in 112 years,Evans and Tuttle's \"IMPROVING PERFORMANCE IN GOLF: CURRENT RESEARCH AND IMPLICATIONS FROM ACLINICAL PERSPECTIVE\" is a well-timed contribution. Using best evidence from biomechanicaland motor control research, the manuscript offers a pragmatic approach to enhancing golfperformance.Core stability is frequently a focus of an athlete's rehabilitation program, yet there islittle evidence to support the link between core stability and injury. The article bySilfies and colleagues, \"CRITICAL REVIEW OF THE IMPACT OF CORE STABILITY ON UPPER EXTREMITYATHLETIC INJURY AND PERFORMANCE\" provides an in-depth review of the existing scienceregarding core stability and its association between upper limb injuries and athleticperformance. The upper limb is also featured in the article by Cools and colleagues,\"PREVENTION OF SHOULDER INJURIES IN OVERHEAD ATHLETES: A SCIENCE BASED APPROACH.\" Theauthors discuss the key risk factors that may be used to guide injury prevention and returnto sports after shoulder injury.Finally, an in-depth commentary regarding the importance of study design for injury riskprediction is presented in the manuscript by Hewett and colleagues \"MULTI-CENTER TRIAL OFMOTION ANALYSIS FOR INJURY RISK PREDICTION: LESSONS LEARNED FROM PROSPECTIVE LONGITUDINALLARGE COHORT COMBINED BIOMECHANICAL -EPIDEMIOLOGICAL STUDIES.\" In their paper, the authorsillustrate the research process and emphasize the need for continued, collaborative work inprospective study designs.Passion and Transformation: this is the essence of theemblemParab\u00e9ns Brasil! Guest Co-editor, SPORTS Special IssueBrazilian Journal of Physical TherapyDeborah A. Nawoczenski PT, PhD"}
+{"text": "The mixing problem of electroencephalography (EEG) in the presence of common source could affect directed functional connectivity measures, resulting in an incorrect directionality of information flow between two signals. Here we introduce directed Weighted Phase Lag Index (dWPLI), a signed version of Weighted Phase Lag Index (WPLI) and compare this measure to Granger Causality (GC), Symbolic Transfer Entropy (STE), Phase Slope Index (PSI), and directed Phase Lag Index (dPLI) under common source effects. Robustness of the measures was tested in both analytic and simulating ways.For the simulated time series, signals were generated from unidirectionally coupled autoregressive model and linearly mixed to achieve volume conduction and common noise effects.As expected from the analytic calculation, dPLI and dWPLI were unaffected by the volume conduction while PSI, GC and STE were largely affected. Figure . The meaFor the common noise case, only dPLI and dWPLI had their signs preserved. Figure . The meaFurthermore, the dWPLI outperformed dPLI for the common noise case  which was also predicted from analytic calculation.Present study shows the common source effects might lead to biased results with incorrect directionality of information flow. Among the five directed functional connectivity measures, dWPLI is much less affected by common source effects."}
+{"text": "Regular physical activity (PA) in the early school years is recommended by several scientific associations for primary prevention of cardiovascular disease. Long-term observational studies have shown that subjects who exercise regularly have significantly less coronary heart disease (CHD) and a reduced risk of cardiovascular disease (CVD). Exercise reduces serum triglycerides, increases serum high density lipoprotein-cholesterol, lowers the blood pressure in patients with primary hypertension . RegularRegular exercise, on the other end, is associated with potential adverse effects ; however, the absolute risk of kidney disease during exercise is low . ConsensExercise induces profound changes in the renal haemodynamics and in electrolyte and protein excretion. Proteinuria, hematuria and changes in serum electrolyte balance have been reported during intense PA; the increase in glomerular filtration may explain these transient alterations but the \u201cnutcracker\u201d compression on the renal vein may have a role. Haemoglobinuria and myoglobinuria may be observed under special exercise conditions .PA does not worse nor reverse kidney disease but may reduce cardiovascular risk in chronic renal disease . Childre"}
+{"text": "Regenerative medicine has the promise to alleviate morbidity and mortality caused by organ dysfunction, longstanding injury and trauma. Although regenerative approaches for a few diseases have been highly successful, some organs either do not regenerate well or have no current treatment approach to harness their intrinsic regenerative potential. In this Review, we describe the modeling of human disease and tissue repair in zebrafish, through the discovery of disease-causing genes using classical forward-genetic screens and by modulating clinically relevant phenotypes through chemical genetic screening approaches. Furthermore, we present an overview of those organ systems that regenerate well in zebrafish in contrast to mammalian tissue, as well as those organs in which the regenerative potential is conserved from fish to mammals, enabling drug discovery in preclinical disease-relevant models. We provide two examples from our own work in which the clinical translation of zebrafish findings is either imminent or has already proven successful. The promising results in multiple organs suggest that further insight into regenerative mechanisms and novel clinically relevant therapeutic approaches will emerge from zebrafish research in the future. Regenerative medicine offers the promise of regaining organ function after acute or chronic injury. Regenerative approaches aim to promote, enhance and re-establish organ-specific repair processes to reconstitute organ structure and function after injury or in the setting of disease progression or treatment. Currently, the impact of the field of regenerative medicine in clinical practice is limited to a few specialized although highly successful practices, such as autologous bone marrow transplantation , partialRegeneration  identified essential genes, and gave insight into the physiology and pathophysiology of a variety of disease states. These mutants also frequently highlighted the genetic diversity contributing to morphologically similar disorders, potentially providing insight into the varied responses to current therapeutics or providing a platform for rational development of treatment options. For example, many diseases affecting blood formation and red blood cell physiology have been either explained by or modeled in zebrafish mutants, including the identification of previously uncharacterized genetic defects causing human disease  with disease phenotypes, including many tumor suppressors and oncogenes. The first iteration of these \u2018reverse genetic\u2019 approaches, known as TILLING  , took adic level . Furtheric level , as wellic level . These iic level . Althougex utero enables efficient introduction of foreign nucleic acids by microinjection. Long used as an effective means to \u2018rescue\u2019 mutant phenotypes to prove causation and produce transgenic fluorescent-tagged reporters of select genes of interest, microinjection has also enabled both transient and targeted gene knockdown. Although not without the caveats of potential nucleotide toxicity or off-target effects, morpholino oligonucleotide (MO) injection has been effectively used to antagonize translation in an antisense manner, thus blocking or diminishing protein production and revealing gene function. Furthermore, the procedure is titratable, providing the ability to bypass phenotypes associated with early embryonic lethality. For example, in zebrafish, just as in mice, complete loss of Wnt signaling   . APAP ovcetamol) . In thisIn addition to those discussed above, an increasing number of groups have utilized zebrafish to study regenerative repair after injury induced by a variety of methods in a broad array of organs, ranging from muscle repair after crush- or laser-induced injuries  and retiAlthough many zebrafish studies have the goal of therapeutic relevance, actual translational application of findings from zebrafish investigations is still in its infancy relative to mammalian models. That said, recent investigations stemming from chemical screening approaches focused on highly conserved aspects of regenerative biology of a select organ system, as discussed above, have directly shown the full potential of the zebrafish model for discoveries in the field of regenerative medicine. Here, we summarize the major attributes of two such studies from our own work. These investigations exploited conserved regenerative models (blood and liver) and a chemical screening approach, combined with the vast array of established tools for modulating the pathways of interest. This facilitated translational testing in mammalian systems, enabling fast translational application of the results from zebrafish to humans.S-nitrosoglutathione reductase (GSNOR), which negatively regulates protein nitrosylation, was shown to mediate the effects of NO on liver growth. To determine conservation of effect in organ regeneration, models of both physical  and chemical (acetaminophen) liver injury were used. Treatment with a novel GSNOR inhibitor (GSNORi) after liver resection in adult fish enhanced cellular proliferation and regeneration. In acetaminophen-exposed larvae and adults, GSNORi significantly prevented hepatocyte necrosis, enhanced proliferation, and improved survival alone and in combination with the current clinical therapeutic intervention, N-acetylcysteine. Significantly, the impact of GSNOR modulation is evolutionarily conserved, as GSNOR knockout mice and GSNORi-treated wild-type mice were similarly protected from acetaminophen-induced liver injury. GSNORi combines hepatoprotective and pro-proliferative properties, and represents a novel therapeutic approach for patients with toxic liver failure.As mentioned above, liver injury induced by acetaminophen exposure is the leading cause of acute liver failure. Identifying factors involved in regulation of embryonic liver growth could reveal conserved pathways with the potential to enhance liver regeneration after injury. We performed a chemical genetic screen in fluorescent reporter embryos , which rin vivo HSC reporters. In contrast, cyclooxygenase inhibition using both non-selective and specific inhibitors reduced HSC number. Adult irradiation recovery assays showed maintenance of the effect in regenerative repair, and murine embryonic stem cell differentiation studies showed conservation of function across vertebrate species. Long-term hematopoietic repopulation of the murine bone marrow following irradiation injury and limiting-dilution competitive transplantation of PGE2-exposed donor cells revealed increased in vivo regenerative potential in mammalian models. Subsequent investigations in zebrafish and mice indicated that PGE2 enhanced HSC function through cAMP-mediated enhancement of Wnt signaling, providing a useful biomarker for translational applications . In this study, both neutrophil engraftment and bone marrow chimerism will be assessed as primary clinical end points. Together, these examples from our own collaborative investigations indicate that zebrafish can be effectively used as a relevant preclinical therapeutic screening and regenerative model system that enables direct application and efficient translation to the clinical setting.Following collaborative discussions with transplant physicians and acquisition of toxicity profiles from earlier clinical endeavors, translational application of PGE2 in hematopoietic transplantation therapy clinical trials was approved by the FDA, the first such study to arise from a chemical genetic screening approach in zebrafish. In phase 1 trials primarily designed to establish safety, PGE2-treated HSC samples showed substantial changes in clinical end points, with both predominant engraftment of PGE2-treated cord blood samples and accelerated recovery of the blood counts in patients receiving the transplants compared to historical controls ; there wRegenerative medicine holds great promise for the alleviation of morbidity and mortality associated with organ failure or injury. Tissue repair and regeneration can be driven by modulation of the pathways that govern stem cell behavior and organ development. The zebrafish has traditionally been an excellent model to study early development and organogenesis, demonstrating high genetic and functional conservation with mammals. Given the inherent connection between developmental pathways and organ repair, this strength combined with a growing list of innovative regenerative models makes the zebrafish an ideal system to study regenerative processes, with the potential to translate relevant findings across species and toward clinical application. In light of the many promising projects mentioned here, developed over such a brief time frame, we anticipate an increasing number of valuable studies and novel therapeutics inspired by and discovered through zebrafish research will be developed in the field of regenerative medicine."}
+{"text": "TissueMark for automated tumor annotation and percentage tumor nuclei measurement in NSCLC using computerized image analysis. Evaluation of 245 NSCLC slides showed precise automated tumor annotation of cases using Tissuemark, strong concordance with manually drawn boundaries and identical EGFR mutational status, following manual macrodissection from the image analysis generated tumor boundaries. Automated analysis of cell counts for % tumor measurements by Tissuemark showed reduced variability and significant correlation (p < 0.001) with benchmark tumor cell counts. This study demonstrates a robust image analysis technology that can facilitate the automated quantitative analysis of tissue samples for molecular profiling in discovery and diagnostics.The discovery and clinical application of molecular biomarkers in solid tumors, increasingly relies on nucleic acid extraction from FFPE tissue sections and subsequent molecular profiling. This in turn requires the pathological review of haematoxylin & eosin (H&E) stained slides, to ensure sample quality, tumor DNA sufficiency by visually estimating the percentage tumor nuclei and tumor annotation for manual macrodissection. In this study on NSCLC, we demonstrate considerable variation in tumor nuclei percentage between pathologists, potentially undermining the precision of NSCLC molecular evaluation and emphasising the need for quantitative tumor evaluation. We subsequently describe the development and validation of a system called  Personalised medicine aims to stratify patients\u2019 cancers into new molecular subtypes who can benefit from individualised therapy \u20133. The tExtracting DNA and RNA from tumor cells in the context of FFPE samples is not straightforward. Most tissues containing tumor also contain a mixture of cell types such as non-neoplastic epithelial cells, mesenchymal tissue, inflammatory cells and acellular material such as mucin which has an influence on subsequent processes including nucleic acid isolation, PCR amplification and next generation sequencing . TherefoRAS, EGFR, BRAF mutational analysis, commercial tests such as Oncotype DX, Mammaprint, Prolaris and more recent clinical sequencing panels (e.g. Foundation One). Given that this role falls primarily to the pathologist, the rapid rise in the investigation of solid tumor molecular tests and their delivery in diagnostic molecular laboratories is putting a strain on pathology services. Molecular labs without in-house pathology competency, must transport slides to a qualified pathologist for review and manual annotation. The centralization of some molecular tests, despite having clear sample guidelines on their test request forms, must review the slides centrally and ensure sufficient tumor is present before macrodissection and analysis.Macrodissection is a manual process in which the region of tumor is physically scraped from the slide using a scalpel into a receptacle for subsequent nucleic acid extraction and molecular analysis. Marking the regions of viable tumor within tissue samples relies on the visual assessment of haematoxylin and eosin (H&E) tissue sections, usually by an experienced pathologist and typically performed at low power magnification. Manual macrodissection aims to enrich the proportion of neoplastic cell nucleic acid by removing non-tumor containing regions, not only increasing the likelihood of detecting a relevant mutation if it exists but also increasing the certainty that a mutant signature originates from the malignant cell isolate. Percentage tumor evaluation and macrodissection underpin most of the new and emerging molecular tests for solid tumors including et al . Us. UsTissuTissueMark image analysis method can overcome the shortfalls of visual estimation and provide a more objective measure of tumor cell sufficiency. In order to benchmark this, subjective visual estimations of tumor cell percentage accuracy were not sufficient. Instead we hand-counted a series of tissue images to get precise numbers of tumor and non-tumor cells and an absolute, gold standard measurement of percentage tumor nuclei. Similar types of manual cell counts were carried out by Smit et al  was also computed for each tile to indicate the likelihood for tumor or non-tumor class membership. This could be presented as a ROC) curve, (iii) concordance index and (iv) false discovery rate (FDR). These are fully described in It was important to compare manually drawn tumor boundaries with boundaries generated using automated image analysis. Visual assessment by an experienced pathologist allowed us to determine the quality and accuracy of automated tumor annotation as well as a visual comparison between manual and automated annotation and an evaluation on whether deviations would have impact on molecular testing. These were largely subjective evaluations. In addition, however, we devised four methods to measure boundary differences: (i) inclusion rate vs. exclusion rate, (ii) receiver operating characteristic , previously genotyped for"}
+{"text": "The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25\u201330% of ischaemic stroke survivors develop immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood\u2013brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. \u2022Ischaemic injury is common among long-term stroke survivors\u2022About 25% stroke survivors develop dementia with a much greater proportion developing cognitive impairment\u2022Risk factors of dementia after stroke include older age, vascular comorbidities, prior stroke and pre-stroke impairment\u2022Current imaging and pathological studies suggest 70% of dementia after stroke is vascular dementia\u2022Severe white matter changes and medial temporal lobe atrophy as sequelae after ischaemic injury are substrates of dementia\u2022Controlling vascular risk factors and prevention strategies related to lifestyle factors would reduce dementia after stroke This demands enormous resources from healthcare systems Deaths from stroke have declined in high-income countries and many middle- and low-income countries. The key element in this decline is reduced incidence of stroke 2The clinical diagnosis of stroke is usually accurate but the precise type of stroke and exact localization may be less straightforward. Determination of the pathological type of stroke is best achieved by early brain imaging usually computed tomography (CT) or by autopsy confirmation. In western countries, cerebral infarction accounts for approximately 80% of first-time strokes, and parenchymal brain haemorrhage for 20%. In Africa, however, the burden of haemorrhagic strokes are reported to be significantly greater by more than 10% at a ratio of 66:34 ischaemic to haemorrhagic 3Dementia developing after stroke is thought to be a clinical entity to define any type of dementia occurring subsequent to stroke injury irrespective whether it involves vascular, neurodegenerative or mixed processes. It can therefore entail a complex aetiology with varying combinations of large and small vessel disease as well as non-vascular neurodegenerative pathology. The development of dementia after stroke depends on several factors including the location and volume of the stroke, degree of related neuronal damage, presence of pre-existing cognitive impairment or other cerebral pathology. The direct influence of any specific genetic factor(s) is not clear. However, the heritability estimate for all ischaemic strokes was determined to be 38% but varied considerably by subtype with the greatest associated with large vessel (40%) and cardioembolic disease (33%) and lowest with small vessel disease (16%) Cognitive impairment or dementia after stroke is predominantly defined by dementia that occurred within three months after stroke onset. Irrespective, many stroke survivors develop delayed dementia beyond three months or only after recurrent stroke(s). The recognition of cognitive impairment in the acute phase after stroke may offer vital information to the clinician for early cognitive rehabilitation Recent prospective studies suggest stroke survivors may unmask or trigger varied pathologies including those attributed to subcortical VaD, multi-infarct dementia and even strategic infarct dementia The cognitive domains involved in the development of dementia after stroke may also vary depending on stroke characteristics such as stroke type, volume, numbers, location and severity. Regarding the stroke type, patients with ischemic strokes usually have higher survival rates than do those with hemorrhagic strokes, which explains why ischemic strokes lead to psychiatric morbidity more frequently than do hemorrhagic strokes In post-stroke cohorts, the presence of executive syndrome and depression is the predictor of poor long-term survival rather than depression itself Dementia associated with cerebrovascular diseases is clinically diagnosed using the widely accepted DSM IIIR or IV criteria. The apparent \u201cgold standard\u201d for diagnosis has been based on the results of the extensive neuropsychological examination, clinical presentation, and information from a close relative as well as the usefulness of R-CAMCOG Dementia after stroke may incorporate different types of dementias but these there is hardly any pathological confirmation for most of the clinical or prospective studies 4As the risk of death from strokes has declined, the number of stroke survivors with cerebral compromise and cognitive dysfunction has increased. Stroke survivors are at increased risk of cognitive impairment Cognitive impairment after stroke is a frequent but neglected consequence compared to other neurological deficits such as sensory or motor impairment 5In tandem with the age-related increased incidence of stroke itself, older age is the strongest risk factor for VCI and dementia after stroke . This isHypertension is the most common modifiable risk factor for stroke. Elevations in both systolic and diastolic blood pressures are associated with increased risk of stroke and by extension stroke related dementia . In addiStudies from general community populations indicate that VaD is more frequent in males than in females, but most studies suggested no substantial gender difference for the risk of dementia after stroke. Recent findings suggest this is attributable to neuroprotective role of adiponectin because of the relatively steeper decline of serum adiponectin levels associated with ageing in females than in males APOE) gene APOE \u05114 allele was reported to be associated with greater progression of cognitive decline The risk of dementia is likely more when vascular comorbid conditions occur. Thus, hypertension, atrial fibrillation, diabetes mellitus, myocardial infarction, and congestive heart failure can often co-exist in various proportions NOTCH3 and HTRA1 genes linked to cerebral autosomal dominant (CADASIL) and recessive (CARASIL) disorders. Both common and rare SNPs in the NOTCH3 gene show increased risk of age-related WM changes in hypertensive subjects HTRA1 gene were identified to be associated with hereditary SVD of unknown aetiology COL4A2 gene were identified to be associated with symptomatic small vessel disease, particularly WM disease and deep intracerebral haemorrhage Variants in genes associated with familial small vessel diseases of the brain 6Neuroimaging has been very useful to recognise that a combination or interaction of different types of brain lesion, including neurodegenerative markers, and preexisting underlying processing are players in the development of cognitive decline after clinical stroke. Brain lesion correlates of dementia after stroke include a combination of infarct features , the presence of WM changes , as well as brain atrophy 7Much of the current knowledge of the ischaemic injury cascade comes from experimental studies. The cascade consists of a complex series of events which are highly heterogeneous c and subsequent stimulation of caspase-3 whereas the extrinsic pathway is initiated by the activation of cell surface death receptors, which belong to the tumour necrosis factor superfamily, by Fas ligand, resulting in the stimulation of caspase-8. There is some evidence that ischaemic cell death may also be mediated by autophagy, which is activated during cerebral ischaemia for the bulk removal of damaged neuronal organelles and proteins Experimental studies suggest neuronal death following ischaemic injury is largely attributed to necrosis. However, recent developments indicate that significant cell death occurs by apoptotic as well as hybrid mechanisms (e.g. necroptosis) along an apoptosis\u2013necrosis continuum. While the infarcted core is necrotic be it macro- or microinfarction, within the penumbra caspase-mediated apoptosis is activated although secondary necrosis results from failure to implement the apoptotic signalling pathways fully, as they require energy. Ischaemic injury triggers two general pathways of apoptosis. The intrinsic pathway originates with mitochondrial release of cytochrome Neuroinflammation and immunodepression are also associated with stroke, ageing, and infection. These likely have a detrimental role in cognitive function after stroke Compared to neuroimaging correlates the pathological substrates associated with dementia after stroke or VaD have generally lagged behind. This is particularly true in defining those substrates associated with executive dysfunction. There is selective atrophy (30\u201340%) of pyramidal cells in layers III and V of the dorsolateral prefrontal cortex compared to the anterior cingulate and orbitofrontal cortices of the frontal lobe in subjects with dementia after stroke, VaD and, of mixed and AD versus normal ageing controls and those who did not have dementia after stroke 8Constant perfusion of the WM by deep penetrating arterioles is essential for functioning of axons and oligodendrocytes. Depending on the duration and severity of ischaemic or oligaemic injury, several features may be readily evident in the WM. These include activated microglia, clasmatodendritic astrocytosis, myelin breakdown, presence of axonal bulbs and degeneration, reactivation and loss of oligodendroglia. During subsequent (chronic) periods of arteriolar changes, perivascular spacing and apoptotic oligodendroglia are seen accompanied by degeneration of myelin and expression of hypoxia markers. WM hyperintensities as seen on brain T2-weighted or FLAIR magnetic resonance imaging (MRI) are associated with varying degrees of cognitive dysfunction in stroke, cerebral small vessel disease and dementia. The pathophysiological mechanisms within the WM accounting for cognitive dysfunction remain unclear. Stroke patients with more severe WM changes have an increased risk of recurrent strokes. Thus, the presence and severity of WM changes seen on MRI may be predictive of post-stroke dementia Recent clinicopathological studies 9Medial temporal lobe and global atrophy are both shown to be associated with dementia after stroke 10Several studies have consistently reported that cerebral silent infarcts detectable with computed tomography or MRI were independently predictive of dementia after stroke 11The risk of dementia after stroke is increased in patients with pre-stroke cognitive decline, with about one-third of patients meeting the criteria for AD and two-thirds meeting the criteria for VaD 12Any measure that reduces or controls vascular disease would be preventative for dementia after stroke Stroke is related to two- to nine fold increase in risks of dementia 13Cognitive impairment after ischaemic stroke injury is common in different populations. Although dementia after stroke is a clinical entity, current neuroimaging and pathological studies suggest that majority of older age-related dementia after stroke can be classed as VaD. Emerging small vessel disease associated genetic traits, severe WM changes and medial temporal lobe atrophy are important features in the development of dementia after stroke injury. The well-established relationship between vascular risk factors and dementia provides a rationale for the implementation of interventions. Control of vascular disease risk and prevention of recurrent strokes are obviously key to reducing the burden of cognitive decline and dementia after stroke.The authors declare no competing interests.Transparency document"}
+{"text": "Acute myocardial infarction (AMI) is a major cause of death worldwide and affects both global and regional left ventricular function. Regional function can be determined by CMR i.e. wall thickening, and velocity encoded (VE) strain analysis. Aim: The aims of this study were to investigate how regional myocardial wall function, assessed by CMR velocity encoded strain and regional wall thickening, change after acute myocardial infarction and to determine if these variables can be used to differentiate between ischemic, adjacent and remote myocardium after experimentally induced myocardial infarction.Ten pigs underwent baseline CMR study for assessment of wall thickening and VE-strain. Ischemia was then induced for 40-minutes by intracoronary balloon inflation in the left anterior descending coronary artery. During occlusion, 99mTc tetrofosmin was administered intravenously and myocardial perfusion SPECT (MPS) was performed for determination of the ischemic area, followed by a second CMR study. Based on ischemia seen on SPECT, the 17 AHA segments of the left ventricle was divided into 3 different categories . Regional wall function measured by wall thickening and VE strain analysis was determined before and after ischemia.Changes in wall thickening and strain before and after ischemia are shown in Figure Both wall thickening and VE strain decrease significantly in both the ischemic and adjacent myocardium acutely after reperfused coronary occlusion. Differentiation thresholds for ischemic, adjacent and remote myocardium, could be determined. Thresholds will however, have limited applicability due to low sensitivity and specificity.Swedish Research Council, Region of Scania, Swedish Heart-Lung Foundation and the Medical Faculty at Lund University."}
+{"text": "Cell Regeneration, Cai and colleagues reported that epithelial sheets derived from human induced pluripotent stem cells (iPSCs) can functionally substitute for tooth germ epithelium to regenerate tooth-like structures, providing an appealing stem cell source for future human tooth regeneration.A major challenge in stem cell-based bioengineering of an implantable human tooth is to identify appropriate sources of postnatal stem cells that are odontogenic competent as the epithelial component due to the lack of enamel epithelial cells in adult teeth. In a recent issue  of  Stem cell-based tissue engineering is a promising approach to replace or repair lost or damaged tissues or even organs in humans. Two major types of stem cells currently used in tissue engineering research and clinical application are embryonic stem cells (ESCs) and adult stem cells. However, ethical concerns in using ESCs and difficulties in isolation, expansion, and differentiation of adult stem cells limit their clinical application. The advent of iPSCs has provided a promising alternative source of stem cells for tissue bioengineering .Whole tooth bioengineering has given hope to dental replacement and regenerative therapy , 3. In tTooth development relies on reciprocal tissue interactions between ectoderm-derived dental epithelium and cranial neural crest-derived mesenchyme . In miceCell Regeneration , Cai and colleagues reported their studies on ameloblastic differentiation capability of integration-free human urine-derived iPSCs (ifhU-iPSCs) [Attempts have been made to identify alternative sources of human postnatal stem cells as the epithelial component for human whole tooth regeneration. It has been demonstrated that keratinocytes isolated from human foreskin and gingival epithelial cells isolated from patients\u2019 gingival tissue are able to differentiate into enamel-secreting ameloblasts when recombined with mouse embryonic molar mesenchyme that possesses odontogenic potential , 20. HowU-iPSCs) . They fiCertainly, identification of novel adult human stem cell sources is not yet the final solution for tooth regeneration. Based on the characteristic features of tooth development, to generate an implantable tooth germ in vitro, one of the cell sources, either epithelial or mesenchymal population, must acquire odontogenic potential to initiate regenerative process. In fact, despite the fact that human iPSC-derived epithelial cells  as well"}
+{"text": "Aeropyrum pernix and Sulfolobus tokodaii, were determined approximately 15 years ago. In these genome datasets, 47 and 46 tRNA genes were detected, respectively. Among them, 14 and 24 genes, respectively, were predicted to be interrupted tRNA genes. To confirm the actual transcription of these predicted tRNA genes and identify the actual splicing patterns of the predicted interrupted tRNA molecules, RNA samples were prepared from each archaeal species and used to synthesize cDNA molecules with tRNA sequence-specific primers. Comparison of the nucleotide sequences of cDNA clones representing unspliced and spliced forms of interrupted tRNA molecules indicated that some introns were located at positions other than one base 3' from anticodon region and that bulge-helix-bulge structures were detected around the actual splicing sites in each interrupted tRNA molecule. Whole-set analyses of tRNA molecules revealed that the archaeal tRNA splicing mechanism may be essential for efficient splicing of all tRNAs produced from interrupted tRNA genes in these archaea.Based on the genomic sequences for most archaeal species, only one tRNA gene (isodecoder) is predicted for each triplet codon. This observation promotes analysis of a whole set of tRNA molecules and actual splicing patterns of interrupted tRNA in one organism. The entire genomic sequences of two Creanarchaeota,  Many tRNA molecules have been purified from original host organisms, and the respective tRNA nucleotide sequences were determined via direct RNA sequencing. Additionally, tRNA molecules are known to contain many different kinds of modified nucleotides.Mycoplasma carpicolum ..A. perniable arm . The predon stem . We alsotructure A\u2013C 15]..A. pernierformed . These aBy isolating cDNAs representing actual tRNA molecules and identifying the actual splicing events in the archaeal tRNA system, we have contributed important and useful information on expression and processing of tRNA genes."}
+{"text": "Candida species are the most frequently found fungal pathogens causing nosocomial disease in a hospital setting. Such species must be correctly identified to ensure that appropriate control measures are taken and that suitable treatment is given for each species. Candida albicans is causing most fungal disease burden worldwide; the challenge lies in differentiating it from emerging atypical, minor and related species such as Candida dubliniensis and Candida africana. The purpose of this study was to compare identification based on MALDI-TOF MS to standard identification systems using a set of nosocomial isolates.HWP1).Eleven nosocomial samples were collected from 6 third-level hospitals in Bogot\u00e1, Colombia. All the samples were identified by combining MALDI-TOF MS with morphological characters, carbohydrate assimilation and molecular markers  and cluster analysis, differences being revealed between Candida albicans, Candida africana, Candida dubliniensis reference spectra and two clinical isolate groups which clustered according to the clinical setting, one of them being clearly related to C. albicans.The present work describes the first collection of atypical Colombian Candida albicans-related and atypical C. albicans species, thereby overcoming conventional identification methods. This is the first report of hospital-obtained isolates of this type in Colombia; the approach followed might be useful for gathering knowledge regarding local epidemiology which could, in turn, have an impact on clinical management. The findings highlight the complexity of distinguishing between typical and atypical Candida albicans isolates in hospitals.This study highlights the importance of using MALDI-TOF MS in combination with morphology, substrate assimilation and molecular markers for characterising  Candida albicans is the pathogenic fungus most commonly found in the general population; its ease of transmission in hospitals causes high comorbidity rates  rCO_B isolates had a common hospital origin and more diverse clinical settings, lacking antifungal prophylactic guidelines. This factor could lead to less stressful conditions for nosocomial isolates and less selective pressure; the latter has been considered by Maubon et al., (2014)  as beingC. albicans isolates require further molecular and susceptibility studies for understanding their ability to adapt (this includes phenotypic plasticity) and their potential for harming a vulnerable host.The clinical and epidemiological aspects of infection are relevant, since the pathological implications of these atypical"}
+{"text": "The prodigious capacity of our brain to process information relies on efficient neural coding strategies. In engineered systems, bandwidth is often increased through multiplexing - multiple signals are simultaneously, yet independently, transmitted through a single communication channel. We have proposed previously that neural systems might implement the same sort of solution . Here, wa priori knowledge of which signal evokes which spikes) whereas treating all spikes as equivalent compromised STA measurement, especially for the fast signal (meaning that one needs to subdivide spikes according to their level of synchrony). Beyond simply measuring STAs, Figure To test our hypothesis, we built a feed-forward neural network comprising Morris-Lecar (ML) model neurons. All neurons received a common input constructed from two distinct signals, slow and fast, plus uncorrelated fast noise. According to our hypothesis, slow and fast signals are independently encoded by different types of spikes; in other words, differentially correlated output spikes, namely, asynchronous (Async) and synchronous (Sync), enable encoding of slow and fast signals, respectively. To assess the feasibility of the multiplexed coding scheme, recorded spikes were classified into two independent classes based on the peristimulus time histogram (PSTH) calculated from the entire set of neurons. Spikes whose instantaneous rates exceeded a threshold were designated \"Sync\" and all others were designated \"Async\". The spike triggered average (STA) was calculated for slow and fast signals using Sync and Async spikes, resulting in four different STAs. The Async-slow and Sync-fast STAs were clearly structured whereas the other two were not Figure . Using tOur results demonstrate the feasibility of multiplexed coding using synchronous and asynchronous spiking. Decoding the two signals requires that spikes are distinguished by their cross-correlation; this is difficult to do with experimental data in which only a subset of neurons are recorded, but it is straightforward for the brain using downstream neurons that operate as coincidence detectors or integrators that respond preferentially depending on input correlation."}
+{"text": "Habitat loss and fragmentation are leading causes of species extinctions in terrestrial, aquatic and marine systems. Along coastlines, natural habitats support high biodiversity and valuable ecosystem services but are often replaced with engineered structures for coastal protection or erosion control. We coupled high-resolution shoreline condition data with an eleven-year time series of fish community structure to examine how coastal protection structures impact community stability. Our analyses revealed that the most stable fish communities were nearest natural shorelines. Structurally complex engineered shorelines appeared to promote greater stability than simpler alternatives as communities nearest vertical walls, which are among the most prevalent structures, were most dissimilar from natural shorelines and had the lowest stability. We conclude that conserving and restoring natural habitats is essential for promoting ecological stability. However, in scenarios when natural habitats are not viable, engineered landscapes designed to mimic the complexity of natural habitats may provide similar ecological functions. Coastal habitats host diverse ecological communities and provide numerous ecosystem services that affect the health, security and quality of life of human societies ,2. The dThe concepts of stability and resilience have been central foci of both fundamental ecology and applied conservation for at least the past half-century \u201314. StabThe utilization of engineered coastal structures such as vertical walls and revetments directly replaces natural shoreline habitats, disrupts land-water exchange, and alters the biophysical environment , potentially indirectly harming other natural habitats ,21,22. OAlthough the societal and ecological costs of coastal habitat degradation are becoming increasingly recognized \u201325, coasThis study involves the analysis of data resulting from routine fisheries research and monitoring efforts by the State of Alabama Department of Conservation and Natural Resources\u2014Marine Resources Division (ADCNR-MRD). ADCNR-MRD research and monitoring is regulated and permitted by the State of Alabama. ADCNR-MRD\u2019s standard protocol for sampling vertebrate fishes involves the live release of specimens when possible. This study did not involve endangered or protected species. The data analyzed and interpreted in this study were collected in Mobile Bay, Alabama USA .2 of bay water surrounded by 235 km of shoreline  . The GSAEleven years of monthly data on coastal fish communities (2001\u20132011) were acquired from a fishery-independent state survey designed to monitor juvenile and adult finfish populations. The survey was initiated in 2001 with a randomly stratified sampling scheme throughout five zones in the northern and southern regions the bay  across shoreline types using permutational multivariate analysis of variance (PERMANOVA) and non-metric multidimensional scaling (nMDS) analysis on Bray-Curtis distances . To quanAnalysis of the Euclidean distance in ordination space between mean annual fish community structure observed in all pairs of years revealed that temporal variability of fish communities was related to shoreline condition . CommuniTo determine whether these stability differences between shoreline conditions were present at sub- and super-annual periods, we computed the global wavelet power spectrum, which measures the average temporal variability at each period from 2001 to 2011. For average abundance, communities associated with natural shorelines had much lower temporal variance  than that of the engineered shorelines at periods ranging from 2\u201340 months . For speWe found that natural landscapes support more stable fish communities than engineered landscapes. However, not all engineered landscapes performed identically. For instance, the stability of coastal fish communities was significantly higher near engineered shorelines characterized by rubble and riprap revetments than vertical walls or vertical walls with riprap. This finding suggests that structural complexity can in some instances reduce the negative effect of engineered structures on community stability. Natural habitats such as saltmarsh, oyster reef and submerged aquatic vegetation are structurally complex and widely recognized for providing essential habitat and nursery grounds for a variety of coastal species \u201334. On tBy analyzing community similarity and variability at annual and monthly intervals, we assessed typical fluctuations or trends of stability and evaluated the potential impacts of discrete events of disturbance. For both the sequential and overall annual time series analyses, communities associated with natural shorelines exhibited higher community similarity and fluctuated less than all engineered shoreline conditions. The global wavelet power analyses indicated that the high resilience of natural landscapes, which was observed at annual timescales, also applies at shorter time periods. During the 11 years that were examined in our study, the Alabama Gulf coast was impacted by several hurricanes and tropical storms including Allison in 2001, Ivan in 2004, Dennis, Katrina and Rita in 2005 and Ike in 2008. The Gulf of Mexico also experienced a massive oil spill following the explosion of the Deepwater Horizon drilling rig in 2010. However, studies of tidal marsh creeks following Ivan and seagrass meadows following Katrina found very little impact of the hurricanes on coastal habitats ,37. The Although engineered shorelines that mimic the complex structure of natural coastal habitats can partially restore community stability at local scales, preserving natural habitats may be important for community stability at both local and regional scales by \u201cspilling over\u201d via dispersal. Indeed, in fluctuating and interconnected metacommunities experiencing different environmental conditions , connectivity can have a large impact on community stability across scales ,40. In tThe legacy and extraordinary degree of shoreline alteration in Mobile Bay, like many other coastal systems, dates back far longer than comprehensive ecological monitoring, making it quite challenging to understand how current fish communities adjacent to different shoreline types actually compare to a natural coastal community. However, the emergence of landscape ecology and the availability of longer term data series on ecosystem change have greatly improved our ability to understand how human activities have transformed the structure and function of natural landscapes \u201346. For S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file."}
+{"text": "Smoking during pregnancy increases the risks of many pregnancy-related complications. MiQuit is a tailored, self-help, text-message intervention developed to help pregnant smokers to stop. A pilot RCT investigated feasibility of recruitment of women attending hospital antenatal clinics by using NIHR Clinical Research Network (CRN) research midwives (RMs); findings will be used to plan a future definitive trial to investigate MiQuit efficacy. We aimed to describe the facilitators and barriers to trial recruitment that RMs perceived, and relate these to key recruitment processes.We conducted 14 semi-structured telephone interviews with RMs from 13 of 15 pilot trial recruiting centres. All interviewees had been involved in local study set-up, participant recruitment and follow-up. Data were transcribed verbatim, transcripts were coded simultaneously and inductive thematic analysis was used to analyse data.Emergent findings suggest a number of pertinent themes, most notably with participant identification and screening. For example, experienced RMs generally felt that a screening questionnaire intended to be given to all women attending antenatal clinics, and therefore prevent smokers from feeling unfairly targeted, was ineffective when used in the proposed manner and could cause greater discomfort on both sides. Instead, RMs indicated that they preferred to pre-identify smokers and discreetly approach them.Qualitative exploration of research staff views can help maximise the value of pilot work, identifying key aspects of trial design and conduct that may affect recruitment. We will discuss how these findings can assist planning a definitive trial, highlighting issues which may be generalisable to other studies."}
+{"text": "Copy number variations (CNVs) consist of duplications or deletions of chromosomal regions ranging from a few hundred to more than a million bases in size, and are likely to play a role in phenotypic diversity and evolution. Recent advances in the identification and mapping of CNVs among normal individuals and in model systems, using bioinformatics and hybridization-based methods, are beginning to shed light on the functional importance of CNVs.Most CNVs are harmless; however, some are associated with human diseases including neurodevelopmental disorders. Hundreds of CNVs have been linked to neurological phenotypes, including autism, schizophrenia, and bipolar disorder. Some CNVs, such as duplications involving VIPR2 on 7q36.3 and deletions of NRXN1 on 2p16.3 have been identified in autism, schizophrenia, and bipolar disorder [Recently, model systems for human genetic disorders have emerged based on the use of human pluripotent stem cells (hPSCs). These approaches include human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). These models offer unique advantages for the study of developmental biology. hPSCs can be differentiated into various types of somatic cells including neurons to examine molecular and cellular mechanisms involved in disease causation. Differentiated hiPSCs have enabled the development of human in vitro model systems that capture the inherent pathologies based on the genetic background of the source material. These stem cell lines derived from patients with various diseases offer unique advantages for the study of inherited neurological disorders. Such patient-specific hiPSCs allow examination of underlying genetic factors in human organ systems that affect neural development.MRI scans and post-mortem studies of autism spectrum disorders suggest abnormal brain development due to initial brain overgrowth followed by premature growth arrest . DuplicaSchizophrenia is a complex genetic neurodevelopmental disorder that carries increased CNV burden. Using iPSC technology, Brennand and coworkers showed that hiPSC neurons from schizophrenia patients exhibit diminished neuronal connectivity and reduced neurite outgrowth and glutamate receptor expression . In addiNovel genome engineering approaches using ZFNs, TALENs, and CRISPRs have been applied to study specific functions in hPSCs. These tools provide the opportunity for correction of disease-causing mutations in patient-derived hiPSC models. Importantly, genetic and epigenetic instabilities, including enhanced de novo CNV induction have been observed during long-term propagation of hPSCs . These cStem cell technology using patient-derived hiPSCs with well-defined CNVs recapitulates the developmental programs that guide formation or malformation of brain region-specific neurons. The application of genomeediting tools to studies of hiPSCs will give important insights into the genome structural changes that underlie fundamental disease processes at the cellular level. These combined approaches are a boost to developmental neuroscience that could be transformative in the years ahead."}
+{"text": "Nicotiana species in the graft union zone, within a tissue culture system. This has led to the formation of alloploid cells that, under laboratory conditions, gave rise to a novel, alloploid Nicotiana species, indicating that natural grafts may play a role in plant speciation, under certain circumstances.Grafting, an old plant propagation practice, is still widely used with fruit trees and in recent decades also with vegetables. Taxonomic proximity is a general prerequisite for successful graft-take and long-term survival of the grafted, composite plant. However, the mechanisms underlying interspecific graft incompatibility are as yet insufficiently understood. Hormonal signals, auxin in particular, are believed to play an important role in the wound healing and vascular regeneration within the graft union zone. Incomplete and convoluted vascular connections impede the vital upward and downward whole plant transfer routes. Long-distance protein, mRNA and small RNA graft-transmissible signals currently emerge as novel mechanisms which regulate nutritional and developmental root/top relations and may play a pivotal role in grafting physiology. Grafting also has significant pathogenic projections. On one hand, stock to scion mechanical contact enables the spread of diseases, even without a complete graft union. But, on the other hand, grafting onto resistant rootstocks serves as a principal tool in the management of fruit tree plagues and vegetable soil-borne diseases. The \u2018graft hybrid\u2019 historic controversy has not yet been resolved. Recent evidence suggests that epigenetic modification of DNA-methylation patterns may account for certain graft-transformation phenomena. Root grafting is a wide spread natural phenomenon; both intraspecific and interspecific root grafts have been recorded. Root grafts have an evolutionary role in the survival of storm-hit forest stands as well as in the spread of devastating diseases. A more fundamental evolutionary role is hinted by recent findings that demonstrate plastid and nuclear genome transfer between distinct  Cucurbitae and Solanaceae species. Thus, the majority of recent grafting research concerns physiological and pathological aspects of vegetable grafting. Grafting also plays an important role in various types of physiological investigations . A broad range of classical grafting techniques can be found in igations , in partigations . An overigations . The hisigations . Undoubtresearch  has openCapsicum annuum L.), old-stage homografts (58 days old plants) had slower graft-take than young-stage (34 days) homografts. Old-stage grafts had a lower percentage of xylem connections and seemed to suffer from drought stress  are presumably always compatible. In heterografts, broadly speaking, intraspecific grafts  are nearly always compatible, interspecific grafts (= rootstock and scion belonging to different species of the same genus) are usually compatible, intrafamilial grafts are rarely compatible, and interfamilial grafts are essentially always incompatible . Examinat stress . The timrequired  but Yin ts e.g., .Graft incompatibility may be defined as failure to form a successful graft union. Yet, despite innumerous follow-ups of graftage in various types of plants, the reasons for graft incompatibility are still vague. Initial healing of the graft union does not in itself ensure long-term compatibility. In cucurbits, apparently successful grafts proved incompatible 25 days after grafting . In certSolanaceae, reciprocal grafts of tomato (Solanum lycopersicum L.) and pepper were considered severely incompatible, whereas tomato and eggplant (Solanum melongena L.) only moderately so, in comparison with compatible tomato homografts (Cucumis melo L.) onto 22 Cucurbitae rootstocks (Cucurbitae species (Castanea) species  onto dwarfing rootstocks  scions and quince (Cydonia oblonga Mill.) rootstocks. Prunasin, a cyanogenic glucoside, rises from the quince rootstock into the pear scion, where it is catabolized enzymatically by pear glycosidase to liberate cyanide at the graft interface. Cyanide \u2018poisons\u2019 the graft union tissues, causing cellular necrosis at the graft interface, leading to severe incompatibility (Prunus persica L. Batsch) grafted on myrobalan plum (Prunus cerasifera L. Ehrh) suggested a more general poisoning mechanism, due to progressive impairment of the phloem carbohydrate transport and accumulation of starch above the graft union , which presumably involves some kind of mobile RNA, was one of the pioneering findings in this area , in a distant organ , does not in itself prove its vascular transport, since this compound could also be synthesized in the presumably recipient organ. Therefore, grafting of genetically distinct mutants/transgenes is still being used as a principal means to distinguish between the site of biogenesis and the recipient organs . Roots oagnitude . FurtherSolanum tuberosum L.) tuberization by the graft transmissible miR156 is another recently studied case (Gibberellic Acid Insensitive (GAI) mRNA, including the anticipated changes in plant phenotype  through a variety of tracks, including natural, underground root grafts. This avenue of disease transmission has been underestimated , just asSantalales) and dodder (Cuscuta sp.) transmit pathogens very efficiently, even among intergeneric and interfamilial plant species (Parasitic plants such as mistletoes (= parasitic plants in the order  species . Dodder  species .Persea americana Mill.) transferred a citrus viroid to avocado; the grafted citrus budwood remained viable for almost a year without forming a true graft union (Catharanthus sp.) seems to be unique in its ability to form distant interspecific grafts. The apple proliferation phytoplasma disease was transmitted from infected apple scions to periwinkle rootstocks  rootstocks to overcome the Phylloxera grapevine plague (Citrus tristeza virus (Closterovirus) and other virus-like diseases exploited every possible graft combination  had PGIP activity. PGIP was detected in xylem exudates of untransformed grapevine scions grafted onto transgenic rootstocks expressing pPGIP, indicating that the PGIP protein is graft\u2013transmissible. Such scions revealed improved tolerance toward grapevine diseases caused by Xylella fastidiosa and Botrytis cinerea  also seem to play a role in rootstock-induced disease resistance. Polygalacturonase-inhibiting proteins (PGIPs) are plant cell proteins that specifically inhibit the cell wall degrading endo-polygalacturonases of plant pathogens . Leaf ex cinerea . Followi cinerea . This idFigure 2).Of all grafting issues, the least understood and most controversial is the \u2018graft hybrid\u2019 concept. According to this concept grafting may involve stock to scion transfer of genetic material (= graft transformation), leading to heritable changes in the scion. The scion which has acquired certain heritable traits from the rootstock is regarded as a \u2018graft hybrid.\u2019 However, graft transformations occur only under \u2018Mentor grafting\u2019 conditions, which presumably enforce the transfer of genetic material from stock to scion  are removed throughout the experiment. Stock fruits are also removed in attempt to maximize flow of substances from the stock to the scion . InteresThe graft hybrid concept, which was developed and demonstrated by the Soviet horticulturist Solanaceae, in particular pepper (Within the \u2018graft hybrid\u2019 supportive evidence some specific characteristics can be defined. (a) The frequency of the appearance of variant plants is highly variable, sometimes below 1% . Thus, tr pepper , which ir pepper  has beenr pepper  but no fIn their review, Epigenetics refers to reversible heritable changes in genome function that occur without a change in the DNA sequence and may have morphological, physiological, and ecological consequences . ChangesSolanaceae . Root grafting could be induced artificially between potted l months . Naturall months . Althougl months , it may Assessment of the evolutionary significance of grafting involves discussion at two levels: its benefits for plant survival and its potential role in the formation of new species. The plausible ecological benefits of root grafting have been discussed by Addressing the significance of grafting as a potential evolutionary mechanism must take into account the ancient belief that grafting may give rise to new plant species . The \u2018grNicotiana species (Recent research has brought us much closer to a potentially real evolutionary grafting mechanism. In their early report  species . Interes\u201c\u2026 do not lend support to the tenet of Lysenkoism that \u2018graft hybridization\u2019 would be analogous to sexual hybridization. Instead, our finding that gene transfer is restricted to the contact zone between scion and stock indicates that the changes can become heritable only via lateral shoot formation from the graft site.\u201dNicotiana species was thus obtained, tentatively named Nicotiana tabauca. Still, natural evolutionary formation of new species via this pathway would depend upon natural graft formation and emergence of adventitious lateral shoots, as previously discussed.However, in a more recent report  Bock andNicotiana under tissue culture conditions require further confirmation with other plants in natural settings (The hypothetical possibility of cell fusion graft hybrids has already been mentioned by settings . It is dArabidopsis model has opened the way for meticulous, in-depth grafting research. The currently available molecular tools are expected to advance our understanding and eventually resolve the long standing grafting mysteries.While the technology of grafting has advanced tremendously, the long-term survival of grafted, composite plants is still somewhat unpredictable. The complexity of stock/scion interactions attains a new dimension when pathogenic agents enter the scenery. More enigmatic are the graft hybrid conundrum and the broader evolutionary significance of grafting. The extensive horticultural grafting research has not usually addressed these basic questions. The recently adopted The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This is a case report of 22-year-old girl admitted with abdominal distension, vomiting, and chronic constipation since birth. Abdomen was distended, and perineal examination revealed imperforate anus with vestibular fistula (ARM). So far worldwide very few cases have been reported about anorectal malformation presenting in adulthood, and thus extremely little data is available in the literature about an ideal management of anorectal malformation in adults. In our case in the treatment instead of conventional procedure of posterior sagittal anorectoplasty (PSARP) anal transposition was done and till two years after the definitive treatment during follow-up patient has been doing well with Kelly's score of six. Our experience suggests that anal transposition provides satisfactory outcome in adults presenting late with anorectal malformation. Though anorectal malformation (ARM) is pediatric problem, in India because of poverty and ignorance one may encounter it in adults also. Posterior sagittal anorectoplasty (PSARP) is now accepted as a standard treatment in children, but there is very little literature guiding an ideal treatment of anorectal malformation in adults. Here we present a case of an adult female who was neglected since childhood and presented with congenital low type of anorectal malformation, we performed anal transposition which gave her a good outcome.22-year-old female presented with features suggestive of large bowel obstruction, chronic constipation since birth and regular passage of small quantity of stool through an opening in the perineum. Perineal examination revealed no separate anal opening , dry stoTransverse diameter inside the fistulous opening appeared very large on P/R exam and stool gave a firm feel to finger. X-ray abdomen showed loaded colon. She had no other congenital anomalies. In the first setting after primary resuscitation an emergency laparotomy was carried out and proximal diverting transverse loop colostomy was done to relieve the obstruction. After this under anesthesia stepwise instrumental evacuation of stool was performed through fistulous opening as hard and enormous quantity did not yield to conservative treatment, through either stoma or distal fistula. Few days later distal cologram showed decompressed distal colon and finally patient was planned for definitive procedure.Under spinal anaesthesia patient was put in lithotomy position, thorough examination was done, and previous clinical findings were confirmed. Tractions sutures applied to expose the operative area , Inj. AdDiagrammatic representation of the procedure has been shown sequentially in Figures Skin sutures were removed after 12 days and 2 weeks after the procedure sequential anal dilatation started, patient was continent. For 2 months along with anal dilator she was maintained on stool softener and high fibre diet. After 2 months stool softener use was tapered. Three months later distal loop cologram showed patent passage, so temporary colostomy was closed. Her anal manometry study was satisfactory. She had voluntary defecation without soling or constipation. She was advised to strictly follow dietary modification onwards. We used Kelly's score to assess her physiologic function during follow-up. At the end of 1 year she was continent without soiling or constipation. She could differentiate between feces and flatus and had strong effective squeeze, with Kelly's overall score of six. Though no objective evaluation was done, she was satisfied with perineal cosmetic outcome.The most common anorectal malformation defect in females is imperforate anus with vestibular fistula. In females this anovestibular fistula is a low type of disease and it opens near the vagina at the posterior fourchette and is directed posteriorly and upward with adhesion to posterior vaginal wall , 2. In aWe feel anal transposition provides satisfactory results in adult patients and also those presenting with anorectal malformation, it provides clear recognition of sphincteric complex with good cosmetic and functional outcome, and result is comparable with PSARP done for children."}
+{"text": "The inflammatory response of sepsis results in organ dysfunction, including myocardial dysfunction. Myocardial dysfunction is particularly important in patients with severe septic shock who progress to a hypodynamic pre-terminal phase. Multiple aspects of this septic inflammatory response contribute to the pathogenesis of decreased ventricular contractility. Inflammatory cytokines released by inflammatory cells contribute as does nitric oxide released by vascular endothelium and by cardiomyocytes. Endotoxins and other pathogen molecules induce an intramyocardial inflammatory response by binding Toll-like receptors on cardiomyocytes that then signal via NF-\u03baB. These processes alter cardiomyocyte depolarization and, therefore, contractility. The particular role of the cardiomyocyte sodium current has not been characterized. Now new information suggests that the septic inflammatory response impairs normal depolarization by altering the cardiomyocyte sodium current. This results in decreased ventricular contractility. This is important because new targets for therapeutic intervention can be considered and new approaches to evaluation of this problem can be contemplated. Critical Care, Koesters and colleagues [In the previous issue of lleagues  contribulleagues . Vasodillleagues . It coulThe septic inflammatory response involves a surprising number of intersecting pathways, many of which contribute to ventricular dysfunction. Pathogen-associated molecular patterns (PAMPs) released by infecting organisms bind innate immune receptors on inflammatory cells  but also bind innate immune receptors in the heart  and withCritical Care Koesters, Engisch and Rich investigate the role of cardiomyocyte sodium current [Alteration of intracellular calcium flux is a fundamental later step in the mechanistic pathway to decreased cardiomyocyte and ventricular contractility. In the previous issue of  current . AlteratTo determine whether other channel currents could have contributed, additional characteristics of the septic action potential were measured. There was no significant change in resting potential, a property influenced by non-voltage gated K channels. Membrane resistance and action potential duration decreased only slightly in septic action potentials, suggesting a limited role, at best, for voltage gated K and Ca channels. Inhibition of the L-type Ca current reduced contractility, as expected.Thus, these novel results raise the possibility that sepsis-induced decreases in sodium channel flux may contribute to ventricular dysfunction during sepsis. This conjecture is based on similarity between sepsis-induced and tetrodotoxin-induced changes and therefore is not mechanistic proof of a role of the sodium channel. Nevertheless, moving the focus of investigation towards intracellular signaling expands our knowledge of potential mechanistic pathways contributing to myocardial dysfunction of sepsis. This is important because new targets for therapeutic intervention can be considered and new approaches to evaluation of this problem can be contemplated, possibly even based on surface measurements of electrical properties of the heart.ICAM: Intracellular adhesion molecule; NF-\u03baB: Nuclear factor kappa B; NO: Nitric oxide; PAMP: Pathogen-associated molecular pattern.The author declares that he has no competing interests."}
+{"text": "Microvascular disease results in reduced skin blood flow (SkBF) and an increased risk of poor healing, ulceration and amputation, particularly in the lower extremity. Regular exercise is known to produce significant cardiovascular benefits and improved functional outcomes in people with chronic disease. However, it is unknown if these benefits also translate into improvements in SkBF. The purpose of this study was to evaluate the efficacy of exercise training on altering SkBF in adults by systematic review and meta-analysis.Relevant databases were searched to July 2014 for controlled trials evaluating the effect of exercise training interventions versus a non-exercise control on SkBF in adults.Eight studies met the inclusion criteria for this review. Individual studies employing an exercise intervention tended to have small sample sizes, with six of the eight studies showing a benefit of exercise but only three reaching statistical significance. Subsequent meta-analysis demonstrated aerobic exercise had a statistically significant effect on improving SkBF .To date, individual studies employing an exercise intervention have lacked sufficient power to detect clinically relevant benefits to SkBF, partially due to limited sample size. In primarily healthy previously sedentary adult cohorts, pooled analysis revealed a clear benefit of regular aerobic exercise on improving SkBF. Regular aerobic exercise provides a cost-effective option for improving SkBF in adults and may be of benefit to those with cardiovascular disease and metabolic disorders such as diabetes."}
+{"text": "Graft ischemia results in inhibition of Na+\u2013K+ ATPase, inhibition of K+ ATP channels, drop of intracellular K+, and the absence of flow favors cell membrane depolarization (+ ATP channels would be associated with increased NADPH oxidase (NOX2) activity and increased production of reactive oxygen species (ROS)  . Decreaspro IL18 . Both IL++-sensitive K+ channels during lung graft ischemia would be expected to provide protection through antagonizing membrane depolarization , which would attenuate ROS production, leading to abortion of inflammasomes priming and activation, and accordingly the release of pro-inflammatory cytokines.Accordingly, the enhancement of Caex vivo lung perfusion , which correlated with decreased incidence of primary graft dysfunction and chronic lung allograft dysfunction after transplantation (++-activated K+ channels (The Toronto team of lung transplantation has achieved significant inhibition of cytokines production within the lung graft through gene therapy during antation . Howeverantation . HO-1 cachannels .++-activated K+ channels during lung graft ischemia. Accordingly, further studies should be conducted to investigate the actual status of these channels during lung graft ischemia prior to transplantation. In addition, pharmacological activation of these channels could be a good target to protect the lung graft during transplantation, with corresponding improvement of the clinical outcome.These findings highlight the possible protective role of the enhancement of CaThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "This project is set out to: i) Establish a collection of astrocytoma cell lines generated from Saudi patients, ii) Select drug resistant brain tumour CSCs, iii) Characterize drug resistant brain tumour CSCs individually, and iv) Deduce common features for drug resistant brain tumour CSCs.The Cancer Stem Cells (CSCs) hypothesis proposes that malignant brain tumours are organized into aberrant cell hierarchies where a subset of parent CSCs replicate asymmetrically and unlimitedly to produce differentiated daughter cell ,2. Thesein vivo tumourgenic assays.A range of methodologies will be applied including, tumour cell line derivation methods, the clonogenic selection assay, cytogenetics profiles, neuronal cancer stem cells characterisation assays and Optimisation of methods used to establish astrocytoma cell lines generated from Saudi patients was completed. To date two novel primary astrocytoma cell lines have been derived. Full clinical data related to the cell lines was retrieved. Currently, optimisation of the clonogenic selection assay and immunostaining for cancer stem cells markers are under progress.Successful retrieval of primary astrocytoma cell lines was possible to accomplish. Important clinical information data relevant to the cell lines were obtained providing clear identification reference. Further work is required for the characterization of the drug resistant cancer stem cell component within these cell lines. Once completed, this research will assist in understanding some of the molecular mechanisms relevant to drug resistance, especially for patients in the Kingdom of Saudi Arabia."}
+{"text": "Cumulative studies during the past 30 years have established the correlation between opioid abuse and human immunodeficiency virus (HIV) infection. Further studies also demonstrate that opioid addiction is associated with faster progression to AIDS in patients. Recently, it was revealed that disruption of gut homeostasis and subsequent microbial translocation play important roles in pathological activation of the immune system during HIV infection and contributes to accelerated disease progression. Similarly, opioids have been shown to modulate gut immunity and induce gut bacterial translocation. This review will explore the mechanisms by which opioids accelerate HIV disease progression by disrupting gut homeostasis. Better understanding of these mechanisms will facilitate the search for new therapeutic interventions to treat HIV infection especially in opioid abusing population. Substantial epidemiologic studies report a greater risk of human immunodeficiency virus (HIV) infection in opioid addicts . AlthougRecent studies focusing on the gastrointestinal (GI) immune system illustrate that the gut associated lymphoid tissue (GALT) is the primary target of HIV during all stages of infection  and the The GI tract is considered the largest immunologic organ in the body and plays an important role in maintaining host immune homeostasis. Maintaining gut homeostasis requires balanced interactions among specialized epithelial cells, specialized lymphoid tissues, and commensal bacteria .Figure 1; The intestinal epithelium is the first line of defense in the gut luminal environment. The well-organized intestinal epithelial cells not only provide physical barrier preventing potential pathogen or antigen invasion, but also is integral for nutrient support and water transport thereby maintaining homeostasis of the whole organism . The smaThe major function of the colon is reabsorption of water and any remaining soluble nutrients from the food. The lack of villi in the colon results in a much smaller surface area compared to the small intestine. Organizationally, the epithelial stem cells are located in the lower parts of gut crypts and the differentiated cells migrate to the apical position and populate the colonic epithelial surface .To avoid para-cellular leak of bacteria from gut lumen, the intercellular junctions known as tight junctions join adjacent cells together by extending from the cytoskeleton proteins of one cell into the extracellular matrix, finally joining with the tight junction proteins of another cell . Tight jFigure 2). These cells can modulate the intestinal microenvironment by secreting antibodies, cytokines, or chemokines as well as mediate interaction with the enteric nervous system (ENS).Different types of immune cells are distributed in GALT like PPs and isolated lymphoid follicles, mesenteric lymph node (MLN), and the lamina propria. The major immune cell population within gut tissues includes macrophages, dendritic cells, mucosal mast cells, neutrophilic granulocyte, eosinophilic granulocyte, T lymphocytes, and plasma cells -17A, IL-17F, and IL-22  includes dendritic cells, macrophages, and neutrophils. These cells recognize antigens from the gut lumen and present them to adaptive lymphocytes (T cells and B cells) to initiate the immune responses. Various cytokines and chemokines produced by these APCs are also involved in the regulation of intestinal inflammation . Most land IL-22 . The rolnization .Taken together, both adaptive and innate immune cells are collectively important for maintaining homeostasis within the GI tract. Disruption of any cellular component may potentially predispose hosts to infections or initiate an abnormal immune response that accelerates disease progression.Salmonella due to impaired IgA production and diminished T cell response  \u03bc-receptors, (ii) \u03b4-receptors, (iii) \u03ba-receptors, and (iv) non-classical opioid receptors . OriginaFigure 3), opioids exert both pharmacological and adverse effects in the gut, including alleviating abdominal pain, modulating GI motility, and suppressing intestinal immune functions.By activating these opioid receptors in intestinal tissues  in the infected individuals. All these studies consistently showed that opioid abusers experience more severe neurocognitive defects including HIV-associated dementia , 2006. FFigure 5). As previously described, both HIV/SIV infection and morphine treatment can induce the intestinal epithelial barrier damage. Indeed, humans infected with HIV who use heroin have been shown to have greater amounts of LPS in their serum compared with non-users  and HIV-1 susceptibility (CCR5 and \u03b14\u03b27 integrin) were also increased in morphine-treated animals . Recent Cumulative studies focusing on gut homeostasis help us recognize the central role of gut mucosal tissues in the pathogenesis of AIDS following HIV infection. Virus infection can induce compromised gut epithelial barrier function, abnormal immune activation within the gut tissues, and the dysbiosis in the gut microbiome, which in turn facilitates HIV replication and the disease progression.Additionally, more recent studies demonstrate that opioid abuse can disrupt gut homeostasis in the HIV-infected individuals. The severe disruption of gut homeostasis observed with opioids and models of HIV infection supports what is observed in the clinical studies as HIV patients who inject opioids have higher levels of bacterial translocation than patients who do not use opioids, which is likely why HIV patients who abuse opioids have more severe pathogenesis of HIV and develop AIDS much more quickly than non-users. However, the molecular mechanisms underlying the interactions of opioid abuse and HIV-induced enterotoxicity are still not well understood. Better understanding of these mechanisms may allow for therapeutic interventions to prevent or slow the pathogenesis in the gut following HIV infection, which will finally lead to more powerful strategy to control HIV disease progression especially in the opioid using and abusing population.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Bilateral vocal fold immobility may result from bilateral recurrent laryngeal nerve paralysis or physiologic insults to the airway such as glottic scars. The progression of mucosal injury to granulation tissue, and then posterior glottis stenosis, is an accepted theory but has not been photodocumented. This paper presents serial images from common postintubation injury to less common posterior glottic stenosis with interarytenoid synechia. Various pathologic conditions may be observed by the otolaryngologist following endotracheal intubation, including edema, ulcers, cartilage exposure, granulation tissue formation, or glottic stenosis. Management of the most common injuries is often conservative as granulation tissue and ulceration typically resolve spontaneously. The patients with progression to granulation formation are at risk of interarytenoid adhesion formation or early posterior glottic stenosis (PSG) and, therefore, should be closely monitored. While the majority of patients show some laryngeal injury after two days , less thIntubation trauma to the posterior commissure mucosa is theorized to cause ulceration, granulation, and then scar formation, which can fix the vocal cords , 2, 4\u20137.While numerous articles have described treatment methods for various stages of PGS based upon this theory, none has documented the progression from intubation injury to early posterior glottic stenosis , 9. We pInstitutional review board (IRB) exemption was obtained. This retrospective review of two cases demonstrates early posterior glottic stenosis formation after intubation. Patients complained of progressive voice complaints and exhibited reduced vocal fold mobility. The photomicrographs shown here document the progressive changes over two months (patient 1) and 6 months (patient 2) after acute endotracheal tube injury. Patient 1. A 23-year-old male with a history of traumatic multilimb amputation injury was emergently intubated. He presented with symptoms of acute dysphonia, breathy voice, and vocal fatigue following extubation.Early endoscopic examination of the patient after his hospitalization revealed granulation tissue overlying the mucosa of the medial surface of the bilateral vocal process of the arytenoid . ConservPatient 2. A 30-year-old male with traumatic brain injury after an assault required prolonged intubation. Following extubation, the patient was found to have a granuloma expanding the posterior commissure (mmissure . Transcummissure . SurgicaEndolaryngeal injuries continue to exist despite advances in endotracheal tube design and improvements in critical care management of patients on a mechanical ventilator. Mucosal injury typically occurs at one or more of the three most sensitive mucosal areas: the medial surfaces of the vocal process, the interarytenoid area, and the posterior subglottis along the inferior aspect of the cricoid cartilage .While temporary dysphonia and mucosal injury to the glottis following tracheal intubation are quite common, glottic stenosis is less common and reportedly varies from 4 to 14%, with higher rates following prolonged intubation , 6. DuraFactors such as local infection, inflammatory disorders, chronic disease states, hypotension, gastric reflux, tube mobility, and impaired pulmonary toilet are likely to be significant in the development of postintubation complications . AdditioBogdassarian and Olson divided PGS into four categories of increasing severity . Type 1 Early edema and granulation tissue usually resolve within three weeks but the authors recommend that the airway should be monitored closely for resolution of symptoms. Nonoperative treatment recommendations vary considerably and are beyond the scope of this discussion. Development of changes in voice or dyspnea on exertion or other aerodigestive complaints a few weeks to months after intubation should prompt suspicion of restrictive posterior glottic stenosis. Immobile vocal cords may be best assessed during operative direct laryngoscopy with palpation of the arytenoid complex. Laryngeal electromyography may also be used to differentiate immobile vocal folds from paralysis or other neurologic disorders.While postintubation injury is common, long-term complications are uncommon. This report demonstrates the development of PGS from postintubation granuloma, which has long been suspected but not documented. We emphasize the importance of serial examination of any patient who develops persistent voice alteration with findings of posterior glottic granulation tissue or with immobility or reduced mobility of the arytenoids after intubation. The photodocumentation shows the progression of common postintubation mucosal injury to much less common posterior glottic stenosis."}
+{"text": "Mechanical ventilation in newborns, children and adults leads to lung injury and has been shown to induce the formation of proteinaceous lung oedema causing epithelial disruption and resulting in changes in lung perfusion. Lung injury leads to reduced compliance, worsening of shunt fraction and an inflammatory response that results from high end-inspiratory transpulmonary pressures (Ptp) and inadequate End Expiratory Lung Volume (EELV). Lung injury results if a lung is ventilated from collapsed state with each ventilator cycle. Thus the first concept of treatment in acute hypoxic respiratory failure is: \u201cOpen collapsed lung units and keep them open without overdistending them\u201d. The open lung is one in which there is little or no atelectasis and an optimal gas exchange. Lung recruitment strategies transiently increase Ptp to reopen the alveolar units not aerated or poorly aerated but recruitable.Lung recruitment maneuvers may restore EELV resulting in more stable alveoli, and reduce shear stress associated with the alveolar cyclic opening and closing. Lung recruitment can be performed in several ways: in delivery room with a T-piece device, in the NICU setting by using a conventional or high frequency oscillation (HFO) ventilator, and is commonly achieved by increase of end-expiratory lung volume with positive end expiratory pressure (PEEP) or end inspiratory lung volume by inspiratory holds or sustained inflation. Recruitment during both, HFO and CMV , follows similar concepts when using small tidal volume ventilation but is easier to achieve at bedside during HFO.- and/or death) were not improved.The Sustained Inflation maneuver (SI) applies a high pressure to the lung for a short period (30 sec) before returning to previous mean airway pressures. This volume recruitment strategy has been shown to be as protective as high frequency oscillatory ventilation (HFO) at similar lung volumes. Infants treated with a SI in delivery room had improved short-term respiratory outcomes , but major outcomes (BPD Bronchopulmonary dysplasiaRecent reports describe improvements in arterial oxygenation with the use of recruitment maneuvers during CMV and/or HFO. However, the impact of these strategies on patient important outcomes such as survival is still unclear.Further clinical studies are needed to evaluate the efficacy of SI, including selection of patients, setting of SI maneuver in terms of duration and peak pressure, timing of surfactant administration. Further studies are also needed to elucidate the impact of recruitment maneuvers during mechanical ventilation, including survival and BPD."}
+{"text": "We generated a novel fully human anti-EGFR antibody showed lower toxicity and higher efficacy in the preclinical, toxicological and pharmacological studies when compared to a commercial drug Cetuximab. In this research, we aimed to understand the probably mechanism.Firstly, the mAb prefers binding to higher expression of EGFR. Its binding avidity on IgG form of the mAb to EGFR was equivalent to Cetuximab, while the Fab affinity was significantly lower. As a result, Higher EGFR expression tissues like tumor obtained the equivalent efficacy as Erbitux, while normal tissues with lower EGFR expression consequently showed lower toxicity.Secondly, the new mAb had higher concentration in tumor tissue than Erbitux. The accumulation of antibody in tumor local might induce stronger ADCC effect, and resulted in higher anti-tumor efficacy than Erbitux in a Hu-WBC NOD SCID xenograft mice model."}
+{"text": "Localised prostate cancer, in particular, intermediate risk disease, has varied survival outcomes that cannot be predicted accurately using current clinical risk factors. External beam radiotherapy (EBRT) is one of the standard curative treatment options for localised disease and its efficacy is related to wide ranging aspects of tumour biology. Histopathological techniques including immunohistochemistry and a variety of genomic assays have been used to identify biomarkers of tumour proliferation, cell cycle checkpoints, hypoxia, DNA repair, apoptosis, and androgen synthesis, which predict response to radiotherapy. Global measures of genomic instability also show exciting capacity to predict survival outcomes following EBRT. There is also an urgent clinical need for biomarkers to predict the radiotherapy fraction sensitivity of different prostate tumours and preclinical studies point to possible candidates. Finally, the increased resolution of next generation sequencing (NGS) is likely to enable yet more precise molecular predictions of radiotherapy response and fraction sensitivity. Heterogeneity in tumour biology between prostate tumours results in a varied response to radiotherapy. At present no molecular tissue biomarkers are in routine clinical use to risk-stratify patients with localised prostate cancer. Instead, current management of localised prostate cancer is based upon established clinical risk factors including presenting PSA, clinical or radiological T (tumour) stage, and the total Gleason score. However, estimates of recurrence and survival vary considerably; for example, in the National Comprehensive Cancer Network (NCCN) intermediate risk group biochemical failure at five years following definitive local therapy varies from 2% to 70% . AlthougThe lethality of radiotherapy is centred on the creation of chromosomal lesions including DNA double strand breaks (DSB), which are particularly lethal when they cluster in close physical proximity to each other . Cells tAnother important radiobiological question at present is the radiotherapy fraction size sensitivity of prostate cancer, as measured by the alpha/beta ratio. An expanding body of evidence points to the alpha/beta ratio of prostate adenocarcinoma being as low as 1.5 , suggestRecent rapid progress in next generation sequencing techniques offers huge potential for personalisation of radiotherapy treatment, despite some of the required technological expertise being currently beyond the scope of most routine pathology laboratories. Other routinely available histopathological techniques such as immunohistochemistry (IHC) or genomic techniques such as fluorescent in situ hybridisation (FISH), comparative genomic hybridisation (CGH), and polymerase chain reaction (PCR) have identified many candidate biomarkers which with further validation could rapidly enter the clinic.Molecular biomarker development following prostatectomy has progressed at an accelerated pace compared to following radiotherapy due to limited tissue availability with the latter treatment . CriticsThis paper aims to review biomarkers predicting radiotherapy response in prostate cancer incorporating genomic signatures and individual candidates as well as biomarkers identified by longer established techniques. It does not address microRNA or biomarkers involved in the diagnosis of prostate cancer or prognostication outside of radiotherapy treatment; these were comprehensively reviewed in a recent paper in this journal .IHC enables direct evaluation of protein expression, which is advantageous as proteins are determinants of cellular function. Recent comprehensive genomic and proteomic work suggests that changes in nucleic acid do not necessarily translate to corresponding changes in protein expression . IHC is The Radiation Therapy Oncology Group (RTOG) 8610 and 9202 clinical trials of radiotherapy and varying lengths of androgen deprivation for localised prostate cancer have reported several biomarkers predicting outcome using IHC . A consiPollack et al. recently modelled the risk of distant metastases using expression of the above 5 candidates plus the apoptotic proteins Bcl-2 and Bax with competing risks hazard regression, adjusting for age, PSA, the Gleason score, T-stage, and treatment . The resThe role of hypoxia markers in prognostication following radiotherapy is more controversial. VEGF and HIF1-alpha were not included in the RTOG modelling of risk of distant metastases because an earlier RTOG study failed to demonstrate a significant association of VEGF with any survival outcomes following radiotherapy . HoweverThere are several possible reasons for conflicting data regarding hypoxic biomarkers and prediction of radiotherapy response. These include differences in the size of patient cohorts, NCCN risk group, and IHC cut points used to determine high expression of VEGF and HIF1-alpha. Furthermore, our understanding of how hypoxia impacts DNA repair is evolving rapidly. Recent studies suggest that hypoxia induces downregulation of proteins within the DNA double strand break repair pathways of homologous recombination (HR) and nonhomologous end joining (NHEJ) \u201349. ThisWith regard to DNA repair, error prone NHEJ operates in all phases of the cell cycle to repair DNA DSB; DNA PKcs has a key role in NHEJ by forming a synaptic complex bringing the free broken ends of DNA together with other ligating enzymes. Nuclear expression of DNA PKcs using IHC showed an independent association with biochemical recurrence after radiotherapy. However, other NHEJ proteins, also evaluated with IHC, such as Ku70, Ku80, and XRCC4 were not predictive of relapse .The TMPRSS2/ERG fusion is an important cellular rearrangement occurring in 50% of localised prostate tumours and ERG protein expression using IHC has been shown to be a robust surrogate for detecting the gene fusion . HoweverThere is thought to be direct cross talk between the EGFR cellular proliferation pathway and DNA repair. This provides a possible biological rationale for the observed correlation between high EGFR expression and poor prognosis following prostate radiotherapy . HoweverThe antiapoptotic protein Bcl-2 and proapoptotic Bax both have key roles in determining cell fate following radiotherapy. Independent prediction of survival outcomes has been demonstrated in some , 23, 43, in vitro clonogenic assays rodent cell lines with defects in NHEJ showed loss of fraction size sensitivity [ in vivo irradiated human skin showed that a 10-fold increase in the use of HR to repair radiation-induced DNA DSB towards the end of radiotherapy correlated with loss of fractionation sensitivity seen clinically [Identifying biomarkers of radiotherapy fraction size sensitivity is another area of unmet need. There is a tight association between proliferative indices and fraction size sensitivity of normal tissues . Normal sitivity , 66. In inically . On averinically . HoweverUse of a fluorogen with FISH, rather than a chromogen as in IHC, means that interpreting expression can be more straightforward than with IHC . In addiFISH has been used to demonstrate a role for biomarkers of cell proliferation such as PTEN and c-myc in predicting radiotherapy response. Loss of the tumour suppressor gene PTEN and amplification of the oncogene c-myc have both been associated with inferior outcomes following radiotherapy  Table 2Table 2. PCR array involves synthesis and amplification of complimentary DNA (cDNA) prior to expression profiling. Although amplification can introduce bias, this multiplex technique is particularly useful when tissue and hence nucleic acid quantity is limited. A reduction in mRNA (messenger RNA) of the cell-cell adhesion molecule E-cadherin has recently been associated with poor outcome after radiotherapy, but not after primary androgen deprivation therapy alone using PCR array . The autCGH differs from Reverse Transcription Polymerase Chain Reaction (RT-PCR) in that it measures DNA copy number variations rather than messenger RNA expression. It thus enables a measure of genomic instability and can calculate the percentage of genomic alteration (PGA) per tumour sample. Today CGH arrays are able to evaluate global copy number variations with as little as 100\u2009ng of DNA . This isUsing CGH, copy number loss of several novel biomarkers with diverse functions has been proposed, as well as further validation of previously identified candidates including PTEN  Table 3Table 3. A number of RNA expression signatures have been proposed to risk-stratify in localised prostate cancer , 75. TheThe first known DNA based signature to predict recurrence after EBRT has recently been reported  and was Next generation sequencing (NGS) offers enormous potential for personalisation of treatment. It enables assessment of genomic events usually affecting more than 1\u2009kbp such as structural copy number alterations and chromosomal rearrangements including translocations, inversions, and recombination events. In addition, the powerful resolution of NGS also enables detection of events affecting less than 1\u2009kbp such as substitutions, insertions, and deletions . To our Fundamental aspects of cancer biology including DNA repair and hypoxia are intimately related to the efficacy of radiotherapy. It is therefore not surprising that over recent decades a number of promising tissue biomarkers have been developed using a range of molecular techniques. Whilst the majority of biomarker candidates are protein markers developed using IHC, markers of genomic instability using more quantitative techniques have shown excellent prognostic capability. Validation of these biomarkers is a priority so that the added benefit to standard clinical parameters can be clearly quantified and existing inconsistencies resolved. Development of predictive biomarkers that differentiate benefit from different local treatments and active surveillance would further enhance personalised management of early prostate cancer. Challenges include the need for standardised reproducible protocols and antibodies for IHC, together with the technical limitations of using very small biopsies for genomic techniques. However, technology continues to advance rapidly and the potential for molecular biomarkers to improve prediction of both sides of the therapeutic ratio of radiotherapy for localised prostate cancer is hugely promising."}
+{"text": "Tool, protocol feasibility, recruitment process, electronic data capture, multi-centric clinical trials.The EHR4CR central query workbench supports pharma and CRO users in various stages of the multi-centric clinical trial lifecycle ranging from protocol feasibility, over subject identification and recruitment to clinical trial execution and adverse event reporting. It offers an intuitive graphical user interface for building, managing and executing formalized eligibility criteria queries Figure  to suppoThe EHR4CR central workbench facilitates the patient recruitment process by offering workflow-driven administration and monitoring of the recruitment process for multi-centric trials. The study manager can select clinical sites of interest and invite them to participate in the study. Study metadata including protocol definition and formalized eligibility criteria queries are exchanged and synchronized with the participating clinical sites. The overall study status and individual clinical site participation status are continuously monitored and updated. The study manager is automatically informed about relevant changes occurring at each of the engaged clinical sites such as changes in the number of potential candidate patients, the number of consenting patients, patients in screening, included or excluded patients at each site.In order to support clinical trial execution workflows, the EHR4CR central workbench will provide \u201cRetrieve Form for Data Capture\u201d (IHE-RFD)  capabiliProtocol feasibility functionality has been evaluated in three separate UAT rounds involving specialists from pharma and 11 pilot clinical sites. Subject identification and recruitment functionality is being evaluated. Support for clinical trial execution is still in development (November 2014).Pharma, CRO .http://www.ehr4cr.eu"}
+{"text": "Gambusia) inhabiting tidal creeks across six Bahamian islands. We found that genital shape and allometry consistently and repeatedly diverged in fragmented systems across all species and islands. Using a model selection framework, we identified three ecological consequences of fragmentation that apparently underlie observed morphological patterns: decreased predatory fish density, increased conspecific density, and reduced salinity. Our results demonstrate that human modifications to the environment can drive rapid and predictable divergence in male genitalia. Given the ubiquity of anthropogenic impacts on the environment, future research should evaluate the generality of our findings and potential consequences for reproductive isolation.The aim of this study rests on three premises: (i) humans are altering ecosystems worldwide, (ii) environmental variation often influences the strength and nature of sexual selection, and (iii) sexual selection is largely responsible for rapid and divergent evolution of male genitalia. While each of these assertions has strong empirical support, no study has yet investigated their logical conclusion that human impacts on the environment might commonly drive rapid diversification of male genital morphology. We tested whether anthropogenic habitat fragmentation has resulted in rapid changes in the size, allometry, shape, and meristics of male genitalia in three native species of livebearing fishes (genus:  Humans are altering ecosystems worldwide, but the evolutionary consequences of such impacts are poorly understood Palumbi . A wide Changes in environmental conditions  commonly alter the strength or mode of sexual selection in diverse taxa  human impacts alter the environment, (ii) ecological variation frequently influences the nature or strength of sexual selection, and (iii) sexual selection drives rapid and divergent evolution of male genital morphology. Understanding whether human impacts may ultimately drive genital diversification is critical because it carries important consequences for fitness, gene flow among populations, and the formation of new species. For instance, variation in male genital shape and size affects insemination and fertilization success in various taxa  transfer sperm internally to females both cooperatively and coercively using a nonretractable, modified anal fin called the gonopodium. Gonopodium size varies greatly across poeciliid species, ranging from 20% to 70% of the body length  and directly contacts the female during copulation  Gambusia hubbsi Breder 1934 is known to inhabit the northwestern islands of the Great Bahama Bank , (ii) Gambusia manni Hubbs 1927 appears to inhabit all other islands within the Great Bahama Bank, as well as overlap with G. hubbsi on New Providence , and (iii) a yet unnamed species, Gambusia sp., inhabits the islands of the Little Bahama Bank . Bahamian tidal creeks are shallow, tidally influenced systems typically characterized by a relatively narrow creek mouth that broadens landward to wetlands dominated by Rhyzophora mangle (red mangrove). Most of the water flux in these systems arises from tidal exchange , so salinities in unfragmented systems are typically around 35 ppt and the biotic communities comprise marine taxa , Strongylura spp. (needlefish), and Lutjanus spp.  inhabiting Bahamian blue holes where similar ecological differences over thousands of years have resulted in divergent evolution of male genital morphology. Specifically, we predict smaller gonopodia with more elongate and bony distal tips in unfragmented tidal creeks and larger gonopodia with more rounded distal tips possessing greater areas of soft tissue in fragmented tidal creeks  across six Bahamian islands  in March\u2013April 2010 using dip nets and minnow traps. For each species, we collected multiple populations from both fragmented and unfragmented tidal creeks on two separate islands  due to concern that reduced visibility might bias the survey. We measured density of piscivorous fish using underwater visual census (UVC) methods , Nassau grouper (Epinephelus striatus Bloch 1792), jacks (Caranx spp.), and lionfish (Pterois spp.). Nearly all of the predators encountered in our surveys comprised known predators of Gambusia\u2014barracuda, needlefish, and snappers (>99%)\u2014with other potential predators rarely observed. We used our survey counts to calculate piscivore density (#/km2) for each site. We measured mosquitofish density using quadrat surveys, in which we counted all Gambusia individuals within 20 0.25 m2 quadrats within each tidal creek. We randomly chose quadrat locations across the microhabitats where Gambusia were observed, with all quadrats >2 m apart. For these surveys, the observer approached each predesignated area, stood still 1 m from the quadrat location, and waited 1 min prior to counting fish. We used the average of these 20 quadrat counts to calculate our estimate of Gambusia density (#/m2) for each site. This method proved highly effective due to water clarity and these fishes' general tendency to be undisturbed by our presence. We measured salinity and dissolved oxygen using a YSI 85 handheld multiparameter meter , water turbidity using an Oakton T-100 turbidimeter , and pH using a Hanna HI 98128 handheld meter . All six ecological parameters were measured multiple times over multiple years within a subset of tidal creeks to estimate repeatability\u2014all parameters exhibited significant repeatability, confirming that our snapshot estimates provided meaningful estimates for comparison among sites  and the interaction between log10-transformed standard length and fragmentation status . Because we observed significant heterogeneity of slopes across fragmentation regimes , we could not simply interpret differences in relative gonopodium size\u2014rather, the key source of variation involved allometry. Thus, we conducted analyses specifically designed to test for among-population variation in allometric slopes.To test for shared and unique responses of gonopodium size to tidal-creek fragmentation across the species and islands, we conducted a GLMM as described above, but with logTo directly investigate potential differences in scaling relationships among populations, we calculated allometric slopes for each population with a sample size >5 . This excluded three populations. Because it remains unclear whether slopes calculated using ordinary least squares (OLS) or reduced major axis (RMA) regression is most appropriate for allometric studies . Gonopodial distal-tip shape was quantified for 235 fish . We captured three to five images of each gonopodial distal tip at 128\u00d7 magnification and stacked the photographs to comprise one composite image using Helicon Focus software  to test for shared and unique effects of habitat fragmentation on gonopodial distal-tip shape across species and islands. The 15 relative warps served as response variables. Log-transformed gonopodial distal-tip centroid size, residual gonopodium size (from log-log regression of surface area on standard length), and log-transformed standard length were included as covariates to control for multivariate allometry, as all three factors could exhibit allometric effects on gonopodial distal-tip shape. These three potential sources of allometry exhibited low multicollinearity ; VIFs <10 are not considered problematic . We used this multivariate axis to visualize gonopodial distal-tip shape differences between fragmentation regimes in tpsRelw. Individual scores along d were employed in remaining analyses involving gonopodial distal-tip shape.To obtain a single value that described gonopodial distal-tip shape for each individual, we calculated scores along n = 235). We employed GLMs for analysis of meristics because the counts  met assumptions of normality. We investigated shared and unique effects of habitat fragmentation on gonopodial distal-tip meristics across species and islands using separate GLMMs. Model terms included in each model mirrored that described above for gonopodial distal-tip shape .In addition to investigating potential divergence in multivariate gonopodial distal-tip shape, we wished to discover whether any traditional meristic characters on the distal tip have shifted as a result of habitat fragmentation. We counted the number of serrae on gonopodial fin ray 4a and the number of spines on gonopodial fin ray 3  from disGambusia density, salinity, turbidity, pH, and dissolved oxygen. For each environmental factor, our model included our five terms of interest. Consistent differences between fragmentation regimes were evident for piscivore density, Gambusia density, and salinity and were suggestive for turbidity , confirming that fragmentation status was not confounded with body size . Male Gambusia from fragmented tidal creeks exhibited a marginally nonsignificant trend toward possessing smaller gonopodia than counterparts in unfragmented sites , while the second best model included only salinity . These environmental factors tended to explain 50%  to 60% (Gambusia density) as much variance as a term for \u2018fragmentation status,\u2019 suggesting that much of the observed allometric differences between fragmentation regimes ultimately derived from some aspects of Gambusia density and salinity.Explicit examination of mean population allometric slopes revealed significant differences in allometry between fragmented and unfragmented tidal creeks using both ordinary least squares and reduced major axis regression approaches Table . Populates Table . The topd, mosquitofish exhibited more rounded gonopodial distal tips with larger areas of soft tissue in fragmented tidal creeks, while males in unfragmented sites exhibited more elongate gonopodial distal tips with more densely positioned bony segments  were largely attributed to differences in piscivore density and salinity  and salinity . The second-best model found significant effects of piscivore density alone . These environmental factors explained 65% (top model) to 67% (second model) as much variance as a term for \u2018fragmentation status.\u2019 Thus, some aspects of piscivore density and salinity appear responsible for the majority of observed differences between fragmentation regimes in gonopodial distal-tip shape.Model selection revealed that differences in gonopodial distal-tip shape between fragmentation regimes , multiple aspects of male genital morphology exhibited consistent differences across six Bahamian islands, with some changes matching our Gambusia species that found males from environments experiencing reduced predation risk evolved larger gonopodia, resulting from trade-offs between natural and sexual selection under different ecological conditions . Differences in salinity might also indirectly contribute to this pattern if correlated with other unmeasured factors associated with resource availability, such as copepod or zooplankton density. Variation in population density or salinity could affect the relative strengths of selection on gonopodium and body size, potentially mediated by female preference or locomotor requirements for foraging and social/sexual behaviors, which could also contribute to allometric differences between populations  confirms that genital shape can indeed affect sperm transfer, at least during forced copulations  than those for altering overall distal-tip shape. However, multiple sources of allometry were associated with both number of serrae and spines on the gonopodial distal tip, and serrae number differed among species. Although we have little functional understanding of serrae and spine number, these meristics have often proved useful in taxonomic work in Gambusia fishes , our study revealed that habitat fragmentation ultimately resulted in consistent differences in multiple aspects of genital morphology. While we uncovered differences among species in some traits  and among islands for some traits , the magnitude of differences between fragmentation regimes was typically as large or larger than these differences, and the nature of differences between fragmentation regimes did not significantly differ among species or islands. This suggests that human-induced ecological changes caused similar and strong selection on male genital morphology in fragmented tidal creeks and that population responses to similar selection were rapid, general, and repeatable.Gambusia affinis occurred over a roughly similar timescale as examined here (Langerhans et al. Although we did not test for a genetic basis for differentiation in gonopodial morphology in tidal-creek mosquitofish, previous work has demonstrated a genetic basis to population differences in gonopodial distal-tip shape and gonopodium size in congeners (Langerhans et al. Gambusia inhabiting fragmented and unfragmented tidal creeks have led to increased levels of reproductive isolation has not yet been investigated, but would provide valuable insight into the capacity of human impacts on the environment to promote the formation of new species on ecological timescales.Rapid differentiation of male genital morphology might result in reproductive isolation between ecologically dissimilar populations by inhibiting gene flow. Genitalia are vital for successful reproduction in internally fertilizing organisms, and mechanical and sensory incompatibilities might affect sperm transfer and fertilization success. Genital differences represent the first proposed mechanism of speciation Dufour , and to Drosophila buzzatti (Soto et al. Drosophila mediopunctata (Andrade et al. How general is the phenomenon of rapid genital differentiation associated with human-induced environmental changes? Although not yet a major focus of research, the idea that variation in ecological factors can affect the mechanisms of sexual selection influencing genital evolution is gaining traction (e.g., Rowe et al."}
+{"text": "Corneal confocal microscopy (CCM) examination revealed a reduction of corneal small fiber sensory nerve number and branching in ALS patients. Quantitative analysis demonstrated an increase in tortuosity and reduction in length and fractal dimension of ALS patients\u2019 corneal nerve fibers compared to age-matched controls. Moreover, bulbar function disability scores were significantly related to measures of corneal nerve fibers anatomical damage. Our study demonstrates for the first time a corneal small fiber sensory neuropathy in ALS patients. This finding further suggests a link between sporadic ALS and facial-onset sensory and motor neuronopathy (FOSMN) syndrome, a rare condition characterized by early sensory symptoms , followed by wasting and weakness of bulbar and upper limb muscles. In addition, the finding supports a model of neurodegeneration in ALS as a focally advancing process.Although subclinical involvement of sensory neurons in amyotrophic lateral sclerosis (ALS) has been previously demonstrated, corneal small fiber sensory neuropathy has not been reported to-date. We examined a group of sporadic ALS patients with corneal confocal microscopy, a recently developed imaging technique allowing  Corneal confocal microscopy has a number of comparative advantages over previous techniques such as skin biopsy, allowing non invasive, potentially repeatable and quantitative analysis of small sensory fibers at the microscopic level  is a fatal disorder primarily characterized by progressive degeneration of upper (UMN) and lower motor neurons (LMN), in the brain and spinal cord  = 5 years) were recruited consecutively, upon obtaining written informed consent. Seven age-matched healthy individuals served as controls  and the sub-basal nerve plexus was imaged, as previously described .Between group differences were assessed with the Mann-Whitney test. In ALS patients, correlation between clinical and CCM data was investigated with Spearman\u2019s rank correlation (r). Statistical significance was considered at \u22121) compared with controls . These data suggest that a corneal sensory neuropathy exists in ALS patients. Amyotrophic lateral sclerosis-Functional Rating Scale-bulbar score was significantly related to CNL  and CNFD ; coherently, ALS-SS-bulbar score was significantly related to both CNL  and CNFD   Figure , Table 2Our study demonstrates for the first time a corneal small fiber sensory neuropathy in sporadic ALS patients, consistent with previous clinical, pathological and neurophysiological studies showing subclinical sensory neuron involvement in this disease and confirming that neurodegeneration exceeds the neuronal system upon which clinical diagnosis relies  involvement in sporadic ALS, contributing to the understanding of the pathomechanisms of this disease.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Skeletal muscle physiology is influenced by the presence of chemically reactive molecules such as reactive oxygen species (ROS). These molecules regulate multiple redox-sensitive signaling pathways that play a critical role in cellular processes including gene expression and protein modification. While ROS have gained much attention for their harmful effects in muscle fatigue and dysfunction, research has also shown ROS to facilitate muscle adaptation after stressors such as physical exercise. This manuscript aims to provide a comprehensive review of the current understanding of redox signaling in skeletal muscle. ROS-induced oxidative stress and its role in the aging process are discussed. Mitochondria have been shown to generate large amounts of ROS during muscular contractions, and thus are susceptible to oxidative stress. ROS can modify proteins located in the mitochondrial membrane leading to cell death and osmotic swelling. ROS also contribute to the necrosis and inflammation of muscle fibers that is associated with muscular diseases including Duchenne muscular dystrophy. It is imperative that future research continues to investigate the exact role of ROS in normal skeletal muscle function as well as muscular dysfunction and disease. Current research is revealing new perspectives regarding the biological significance of free radicals and other chemically reactive molecules in numerous physiological processes and pathological conditions. Reactive oxygen species (ROS), when generated in excess amounts, contribute to oxidative stress. ROS produced from contracting skeletal muscle are known to affect both muscle adaption and function  can be produced within skeletal muscle fibers from L-arginine by NO\u2022 synthase (NOS). Three major isoforms of NOS exist: neuronal NOS (nNOS or NOS I); inducible NOS (iNOS or NOS II); and endothelial NOS (eNOS or NOS III)  , which is a potent oxidizing agent  via superoxide dismutases (SOD). However, H2O2 can, in turn, form highly reactive hydroxyl radicals (\u2022OH) through a Fenton reaction  pathway. ONOOIncreases in ROS production are generated through a variety of signaling mechanisms. For example, interleukin (IL)-13 plays a critical role in the immune system maintaining normal homeostasis as well as responding to pathogens   , and calcineurin all play a marked role in adaptation to events including exercise training  affect mtDNA more extensively than nuclear DNA   Table  (Barbierc) Table . ROS indc) Table  (Barbierc) Table . Accordic) Table .Since neurons continuously generate free radicals, a sufficient supply of endogenous antioxidants is necessary to maintain homeostasis (Galea et al., 2+ associated with muscular dystrophy (Table ROS are involved in the modulation of skeletal muscle contractions (Zuo et al., hy Table  (Bellinghy Table . ROS oxihy Table  (Goldstehy Table .The research reviewed in this article has identified many of the reactive species that affect skeletal muscle function. The pathways mediated by ROS/RNS signaling have been discussed as well as their role in skeletal muscle physiology. ROS have both beneficial and harmful effects on skeletal muscle function as they are ubiquitously involved in gene expression, immune responses, mitochondrial oxidative stress, skeletal muscle atrophy, as well as neuromuscular dystrophies. Redox-sensitive pathways continue to be an area of much needed research. Such studies in the future will shed significant insight into the exact role of ROS in health and disease.LZ designed the outline of the paper and wrote the paper; BP wrote the paper.This work was supported by OSUCOM-HRS Fund 013000.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The Affordable Care Act and the Medicaid redesign in New York City offer opportunities to explore alternative methods for measuring the effectiveness of behavioral health interventions. Quality of life (QOL) measures have been underutilized in substance use disorders treatment (SUDT). The objective of this study was to determine how a validated QOL instrument could be used in SUDT as a measure of health-related patient outcomes.t-tests. We examined change in QOL scores among OTP participants stratified by major health conditions.NYC outpatient drug treatment (DT) and opioid treatment programs (OTP) were invited to participate in a pilot evaluation. Newly admitted patients completed counselor-administered surveys at admission, and 90 and 180 days. Surveys included demographic  and clinical items  in addition to the World Health Organization QOL instrument, the WHOQOL-BREF ; scoringBetween July and September 2013, 1269 newly admitted patients were surveyed. Follow-up surveys were completed for 616 patients at 90 days (49%) and 336 at 180 days (26%). See Table Preliminary findings indicate that individuals in SUDT have lower QOL scores than healthy populations and experience improvements in QOL during treatment. Small positive changes among individuals with health conditions suggest the importance of integrating physical health care with SUDT. High dropout rates, multiple survey administrators, and an English-only survey instrument may limit our conclusions. Future investigations need to examine the feasibility of incorporating QOL measures into SUDT more broadly, including its impact on clinical interventions and longer-term patient outcomes, including maintenance of QOL gains achieved during SUDT."}
+{"text": "Telomeres are dynamic nucleoprotein structures that protect the ends of chromosomes from degradation and activation of DNA damage response. For this reason, telomeres are essential to genome integrity. Chromosome ends are enriched in heterochromatic marks and proper organization of telomeric chromatin is important to telomere stability. Despite their heterochromatic state, telomeres are transcribed giving rise to long noncoding RNAs (lncRNA) called TERRA (telomeric repeat-containing RNA). TERRA molecules play critical roles in telomere biology, including regulation of telomerase activity and heterochromatin formation at chromosome ends. Emerging evidence indicate that TERRA transcripts form DNA-RNA hybrids at chromosome ends which can promote homologous recombination among telomeres, delaying cellular senescence and sustaining genome instability. Intriguingly, TERRA RNA-telomeric DNA hybrids are involved in telomere length homeostasis of telomerase-negative cancer cells. Furthermore, TERRA transcripts play a role in the DNA damage response (DDR) triggered by dysfunctional telomeres. We discuss here recent developments on TERRA's role in telomere biology and genome integrity, and its implication in cancer. Telomeres are nucleoprotein structures assembled at the extremities of eukaryotic chromosomes that protect chromosome ends. By doing so, telomeres prevent chromosome ends from being recognized as sites of DNA damage, protecting them from degradation and inappropriate recombination events due to erroneous activation of DNA repair pathways  followed by a single-stranded G-rich 3\u2032 overhang. Electron microscopy and super-resolution fluorescence imaging have shown that telomeric DNA forms higher order structures where the 3\u2032 single-stranded overhang invades the homologous double-stranded region forming a telomeric loop (T-loop)  pathway or members of the heterogeneous nuclear ribonucleoprotein family (hnRNPs) which bind TERRA, increases localization of TERRA at chromosome ends without affecting its overall levels or stability    is bound by the ssDNA binding protein RPA which is required for activation of the ATR checkpoint .Telomerase is an established key target for cancer therapies Harley, . Yet recThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Compounds containing guanidine-related molecules have been used since medieval times to relieve symptoms of diabetes mellitus. Guanidine itself was too toxic but two linked guanidine rings (biguanides) were useful and generally safer. For 20 years, phenformin was used before adverse effects led to removal from the US and European markets. Metformin continues to be widely prescribed for diabetes treatment and is associated with improved survival compared to other diabetes drugs. With the current interest in using the more potent phenformin for cancer therapy, it is timely to review the risks, benefits, and potential contraindications.Nnmt). NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor for NAD+, an important cofactor linking cellular redox states with energy metabolism. NNMT expression is increased in adipose tissue and liver of obese and diabetic mice. Furthermore, NNMT knockdown in adipose tissue and liver using anti-sense oligonucleotides in mice on a high fat diet, protects against diet-induced obesity by augmenting cellular energy expenditure. This involves a novel mechanism which could provide new strategies for prevention and treatment of obesity and type 2 diabetes. Since NNMT is also elevated in many cancers, NNMT knockdown could be beneficial for cancer prevention and/or treatment.The adipose cell is as an endocrine organ in addition to its role in energy storage. Adipocytes secrete hormones, cytokines and other factors that influence energy balance, glucose homeostasis, insulin sensitivity and vascular biology. In humans with obesity and type 2 diabetes, expression of the Glut4 glucose transporter is down-regulated selectively in adipocytes resulting in systemic insulin resistance. Knocking out Glut4 selectively in adipocytes in mice increases the risk of diabetes while adipose-specific Glut4 overexpression confers enhanced glucose tolerance in spite of increased adiposity. To understand how adipocytes regulate glucose homeostasis and insulin sensitivity, we performed DNA microarray analysis of adipose tissue from mice with adipose-specific knockdown or overexpression of Glut4. The most highly reciprocally regulated gene is nicotinamide N-methyltransferase ("}
+{"text": "Genome duplication is temporarily coordinated with sister chromatid cohesion and DNA damage tolerance. Recently, we found that replication fork-coupled repriming is important for both optimal cohesion and error-free replication by recombination. The mechanism involved has implications for the etiology of replication-based genetic diseases and cancer. To maintain genome stability, chromosome replication must faithfully preserve genome content in an optimal chromatin structural context. This requirement is met by temporal coordination of DNA replication with DNA damage tolerance (DDT), which promotes completion of replication, and with pathways associated with chromosome structural integrity, such as sister chromatid cohesion (SCC).et\u00a0al., we report that replicative helicase-coupled repriming is important for efficient error-free replication by template switching, thus preventing the high levels of mutagenesis and faulty strand-annealing events associated with genome rearrangements.Chromosome replication is carried out by the replisome machinery, which is initially assembled at replication origins.Cohesin is essential for SCC establishment during DNA replication.First, our study indicates that error-free replication following genotoxic stress is greatly influenced by replication fork-coupled repriming. When this repriming function is compromised, DNA metabolism events that are kinetically disfavored in wild-type cells and involve fork reversal and genome rearrangements become more frequent . The relThe repriming conditions that we recently described are not only associated with defective error-free DDT and altered replication fork architecture, but also negatively influence SCCNo potential conflicts of interest were disclosed."}
+{"text": "Human tumours typically harbour multiple mutations in tumour suppressor genes and oncogenes. Histologically identical tumours in different patients often exhibit different combinations of genetic alterations and it is now also evident that considerable genetic heterogeneity can exist between cells within individual tumours. A major ongoing research challenge remains to determine the functional significance of this enormous genetic diversity and heterogeneity in terms of impact on tumour phenotypes and responses to therapies. Autochthonous mouse models of human tumours have provided many insights into the combinations of genetic alterations that are causal to tumour initiation and progression in different tissues. However, conventional germline-based genetic approaches, such as the generation of compound mutant mice based on transgenics and knockouts, are limited by the time and cost associated with extensive intercrossing of mouse lines. Faster and more powerful genetic tools are required to accelerate the functional annotation of cancer mutational cataloguing studies. Excitingly, several new viral vector-mediated genetic approaches offer the ability to directly modify the genome of somatic cells in mouse tissues and these have recently been applied to the rapid generation of complex mouse tumour models that harbour multiple genetic changes.Trp53 and Nf1 or that co-express oncogenic Hras and shRNA against Trp53 were employed to generate autochthonous mouse models of glioma [http://www.addgene.org/kits/mule-system/) that provides a highly flexible genetic toolbox allowing combinatorial gene knockdown, knockout, mutation or overexpression, together with tagging of infected cells with useful markers such as luciferase or fluorescent proteins [Hras and shRNAs against Cdkn2a or Trp53 or against both Trp53 and Pten, induced the formation of pleomorphic sarcomas that could be quantitatively monitored using luciferase-based imaging [Trp53 and activation of oncogenic Kras in germline-modified mice [The use of lentiviral gene delivery vectors for cancer modelling studies offers the advantage that the proviral DNA integrates into the genome of infected cells, providing heritability of the introduced genetic alterations. Injections of lentiviruses that co-express shRNAs against proteins . We demoied mice , validatTrp53, Lkb1 and Kras, together with a template for homology directed repair to insert an oncogenic Kras mutant into the endogenous locus, allowed the generation of lung tumours driven by three different genetic mutations [Trp53 and oncogenic Kras alleles provided a series of lung cancer models with complex genetic backgrounds [Eml4-Alk chromosomal rearrangement [Several genetically complex lung cancer models in mice have recently been generated using different types of viral vectors. Adenovirus and Adeno-associated virus (AAV) DNA remains episomal in infected mouse cells and is lost by dilution upon repeated cell division, which has historically limited the use of these vectors in tumour modelling. However, in the context of the CRISPR/Cas9 system, the episomal nature of viral infection is in fact advantageous as the introduced viral DNA represents a template that can be used for homology directed repair following Cas9-induced DNA double strand breakage. Taking advantage of transgenic mice expressing Cre-activatable Cas9, the intratracheal delivery of AAV9 viruses expressing Cre, luciferase, sgRNAs against kgrounds . Finallyangement .in vivo screens based on combinatorial genetics and will potentially allow experiments that better mimic intratumoural genetic heterogeneity. These new genetic tools will assist researchers in tackling the challenges of understanding the functional implications of the genetic complexities of human malignancies.These studies collectively highlight the new genetic power that is offered by the use of viral vector-mediated somatic genetics in wild type or germline modified mice. By employing different types of lentiviral, retroviral, adenoviral and AAV vectors, together with the use of cell-type specific promoters or infection of germline-modified mice that allow cell type-specific Cre, tTA or rtTA expression, it should be possible to specifically direct genetic modulations to diverse somatic cell types. The ability to clone libraries (eg. shRNA or sgRNA) into these viral expression vectors will pave the way for"}
+{"text": "Neck dissection has traditionally played an important role in the management of patients with regionally advanced head and neck squamous cell carcinoma (HNSCC) treated with radical radiotherapy alone. However, with the incorporation of chemotherapy in the therapeutic strategy for advanced HNSCC and resultant improvement in outcome the routine use of post chemo-radiotherapy neck dissection is being questioned.Published data for this review was identified by systematically searching MEDLINE, CANCERLIT & EMBASE databases from 1995 until date with restriction to the English language.There is lack of high quality evidence on the role of planned neck dissection in advanced HNSCC treated with chemo-radiotherapy. A systematic literature search could identify only one small randomized controlled trial (Level I evidence) addressing this issue, albeit with major limitations. Upfront neck dissection followed by chemo-radiotherapy resulted in better disease-specific survival as compared to chemoradiation only. Several single arm prospective and retrospective reports were also identified with significant heterogeneity and often-contradictory conclusions.Planned neck dissection after radical chemo-radiotherapy achieves a high level of regional control, but its ultimate benefit is limited to a small subset of patients only. Unless there are better non-invasive ways to identify residual viable disease, the role of such neck dissection shall remain debatable. A large randomized controlled trial addressing this issue is needed to clarify its role and provide evidence-based answers. The optimal management of the neck in loco-regionally advanced head & neck squamous cell carcinomas (HNSCC) following primary chemo-radiotherapy remains controversial ,2. TradiPublished data for this review was identified by systematically searching the MEDLINE, CANCERLIT & EMBASE databases from 1995 until date with restriction to the English language. \"Head & Neck cancer\" OR \"HNSCC\" was combined with \"chemo-radiotherapy\" OR \"chemo-radiation\" as Medical Subject Heading (MeSH) terms and each of the following phrase used as text words: \"adjuvant neck dissection\"; \"planned neck dissection\"; and \"neck management\". Relevant cross-references were also considered.There is only one small randomized control trial (American Society of Clinical Oncology  Level I In absence of high quality evidence, the best available evidence tempered with clinical judgment often guides decision-making. Two of the recently published reports ,12 somewArgiris  et al evBrizel  et al idApart from the afore-mentioned two reports, there are a few reasonably large studies (involving >50 patients: Table The potential benefit of planned neck dissection after a course of intensive chemo-radiotherapy in terms of improved regional control with or without an impact on survival needs to be weighed against the expected morbidity associated with the surgical procedure ,14,25. OPlanned neck dissection after radical chemo-radiotherapy achieves a high level of regional control, but its ultimate benefit is limited to a small subset of patients only. The morbidity of such dissection is small, but significant. Its impact on survival is yet to be completely realized. In the majority of patients it is either unnecessary because there is no residual disease in the neck or futile because of unsalvageable primary recurrence or distant metastases. Nevertheless, it is recommended that planned neck dissection be performed for patients with less than a complete response in the neck after combined modality therapy to optimize regional control, provided the primary is controlled and there is no evidence of distant metastases. It should also be performed as part of salvage surgery for locally persistent or residual disease at primary site. The criterion for planned neck dissection for patients with advanced nodal disease with a CCR in the neck following chemo-radiotherapy should incorporate not only the nodal staging but also the actual size of the involved lymph nodes. Unless there are better non-invasive ways to identify residual viable disease, which could include functional imaging like Positron Emission Tomography and biological assays like hypoxia markers, the role of such neck dissection shall remain debatable. A large randomized controlled trial across several institutions addressing these issues is needed to clarify the role of planned neck dissection in advanced HNSCC treated with primary chemo-radiotherapy and provide evidence-based answers.No source of funding involved in this reviewNone declared.Dr JP proposed the idea of systematic review on the issueDr TG did the literature search & prepared the manuscriptDr JP critically reviewed and revised the manuscript"}
+{"text": "These newer options and various anti-tumor necrosis factor (anti-TNF) therapies are used as either first-line therapy or as an option when therapy is switched.The rising direct health care costs over the past 10 years attributable to Inflammatory Bowel Disease (IBD) is largely driven by expenditures on biological medications.non-medical switching or discontinuation of anti-TNF therapies is associated with worse clinical outcomes and increased health care resource utilization.2 In addition, uncontrolled moderate to severe IBD leads to a negative impact on the quality of life, work productivity, and increased risk for IBD-related surgeries and hospitalizations.3With an appropriate emphasis on value-based health care, cost implications of managing complex IBD patients are becoming increasingly important. However, Measuring validated clinical outcomes or surrogate markers of clinical outcomes whiles on different biologic therapies with different costs provides some guidance for cost-effective management in IBD.CC360, Chiorean et al report their findings on healthcare resource utilization and associated costs in a cohort of IBD patients switching to a second biologic agent. Their retrospective study titled \u201cEconomic Outcomes of Inflammatory Bowel Disease Patients Switching to a Second Anti-Tumor Necrosis Factor or Vedolizumab\u201d lends some insight to costs implications versus outcomes of switching out of class in patients failing initial anti-TNF agents.In this issue of fewer all-cause and IBD-related outpatient visits.The total and treatment costs were generally higher for patients switching to vedolizumab. The exception was in patients with ulcerative colitis who switched to golimumab. Regarding outcomes, adalimumab and other switchers had Our treatment choices when switching biologics in IBD patients should primarily be guided by each unique clinical scenario. This is particularly pertinent when there is not always a benefit in outcomes from using newer therapiesThe cohort studied was derived from claims data and disease severity was determined by proxy variables. In addition, there are other factors contributing to the costs including point of care costs, and unique contracts between health care systems and payers which cannot be evaluated in this study design.However, this study is one more reminder to be cognizant of economic implications versus desirable outcomes when switching biologic therapy."}
+{"text": "Cyto-histopathological correlation is a key player in measuring quality in a quality programme . It was The Special Issue collected together articles dealing with various aspects of cyto-histological correlation and its role in cytological diagnosis routine. Gynecological samples form the highest proportion of all cytological specimens. Its cyto-histological correlation as a part of quality assurance programmes was covered in the literature ,2. AsatuThyroid fine needle aspiration cytology is important and expanding field of cytology. Preoperative diagnosis of rare medullary carcinoma is essential for lesion management, so Asia-Pacific international multi-institutional cytomorphological analysis of smears prepared with different staining methods has impact on practice improvement and quality worldwide . A Prof.Pulmonary cytopathology is an emerging field with personalized medicine and immunotherapy related techniques application to cytology specimens in growing proportion. Swedish colleagues studied concordance of PD-L1 expression between cytology and histology specimens in pulmonary non-small cell carcinomas; the concordance was better in bronchoalveolar lavage and bronchial brushing than in pleural effusions . This kiThe contributory role of cell blocks (CBs) in salivary gland cytology classified according to The Milan System for reporting Salivary Gland Cytology (MSRSGC) was demonstrated by Tommola et al. . The appNew cytopathology terminologies were also studied in three other papers ,13,14. TThe International System for Reporting Serous Fluid Cytology (TIS) was applied by Portuguese and Greek cytopathologists ,14. A seLast, but not least I thank all authors, reviewers, editors and editorial office staff who contributed to the success of this Special Issue."}
+{"text": "Studies have shown that health education can improve dietary intake, exercise, and energy balance, which improves health outcomes and quality of life. However, diverse low-income older adults may have low self-efficacy coupled with potentially negative opinions regarding the aging process. Emerging research suggests that asset-based approaches utilizing persuasive and hopeful messages may be particularly effective with diverse populations of older adults who may be struggling with negative perceptions of self-efficacy. Research also shows that health behavior change interventions are most likely to be successful among diverse populations when they incorporate messages of resilience and facilitate information sharing and diffusion among participants. This presentation outlines the program curriculum development process of a student-led health promotion program by an interdisciplinary team of university researchers. Public health, dietetics, and communication faculty utilized Persuasive Hope Theory (PHT) and Self-Efficacy Theory to create a 15-week program to improve fruit and vegetable intake and physical activity among low-income adults aged 55+ living in Anchorage, Alaska. We will also detail the curricular components for this NIA-funded program which will be delivered in Fall 2022."}
+{"text": "Understanding who will experience cognitive dysfunction and dementia is as important as identifying methods to combat such deterioration. This symposium seeks to highlight new advances in understanding cognitive deterioration and promote resilience in adulthood. Odd and colleagues utilized a national sample  to show that 9-year decreases in executive function and episodic memory predicted increased risk of dying. Use of a brief cognitive assessment administered via telephone was unique \u2013 a method that may assist clinicians administering cognitive screenings to older adults in isolated areas. Graham and colleagues utilized a daily diary approach in 116 older adults (aged 60-90) to show that greater daily fluctuations in mindfulness were associated with higher episodic memory and executive functioning. Further, mediational evidence suggested that on days when mindfulness was greater, individuals perceived a younger subjective age. Willroth and colleagues provide evidence that higher scores on eudaimonic well-being in older adults (n=349) predicted greater cognitive resilience. Specifically, even though some participants had neuropathological burden , they did not exhibit pronounced cognitive declines. Using data from 14 longitudinal studies, Yoneda and colleagues examined the impact of physical activity on cognitive impairment and death. Multi-state survival analyses demonstrated engagement in more physical activity reduced risk of cognitive impairment and death. This symposium suggests that examining changes in cognition, incorporating subjective and objective indices of cognitive impairment, utilizing long-term longitudinal and daily diary designs, and testing key modifiable behaviors is crucial to understanding and promoting optimal cognitive functioning in adulthood."}
+{"text": "Gordeeva et al. described a 3D embryoid body differentiation model and compared the spatiotemporal growth and patterning dynamics of embryoid bodies formed from different stem cell origins and culture conditions. Min et al. profiled the proteome and the protein phosphorylation of blastoids\u2013blastocyst-like 3D structures derived from extended pluripotent stem cells (EPSC). By comparing the protein expression profiles of EPSC blastoids with mouse blastocysts, they indicated that glucose metabolism is key to blastoid formation and brought new insights into the similarities and differences between blastoid and blastocyst at the proteome level. In addition, Luijkx et al. provided a comprehensive comparison of current protocols for mouse (Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have enabled the modeling of human development and helped to illuminate mechanisms of monogenic disease, complex disease, and cancer. Lately, the striking ability of PSCs to self-organize has engendered three-dimension (3D) models of human development. The 3D embryonic cell models partially reconstruct the complex architecture of mammalian early embryonic structures and therefore hold great potential for stem cell and developmental studies. In this Research Topic, or mouse  and humaor mouse  blastoidex vivo organoid cultures has gained substantial attention as a model to study regenerative medicine and diseases in several tissues since the seminal work in 2009 . A clear example is the development of stem cell derived kidney progenitors and organoids that may be utilized to provide a reliable source of proximal tubule cells that are needed in commercializing the bioartificial kidney device. Liu et al. reviewed kidney disease model studies using in vitro tools including kidney organoids derived from normal human fetal/adult tissues, human PSCs and primary tissues of kidney cancer. They covered many topics including polycystic kidney disease and other genetic kidney diseases, and non-genetic kidney diseases. Both papers also discussed the remaining challenges of translating advances in kidney organoid research into new therapies.Chronic kidney disease (CKD) is a general term for heterogeneous disorders affecting kidney structure and function. When kidney function continues to decline, CKD patients may develop end-stage renal disease . Organ transplantation and dialysis continue to represent the only therapeutic options available. However, in the last two decades major advances in stem cell biology, gene editing, and bioengineering are now delivering options in regenerative medicine to treat CKD. Ramirez-Calderon et al. summarized the most advanced 3D methods for deriving human cardiac organoids from human PSCs and discussed the potential applications of cardiac organoids in the pharmaceutical and bioengineering fields, including the emerging question of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection in the heart.Human cardiac lineages can be differentiated in traditional two-dimensional monolayer culture or by adopting 3D culture methods. Klein et al. argue that paying due attention to culture environments is critical to improve the reproducibility and translation of preclinical research. They outline the main sources of cell culture environmental instability and deliver best practice recommendations, thus making an important step towards enhancing the physiological relevance of in vitro cellular models. Additionally, a higher resolution understanding of the molecular events unfolding during development or tissue homeostasis could guide better 3D differentiation protocols. Single-cell OMICs analysis promise to deliver unprecedented insights into human development and disease pathogenesis. In this Research Topic, Xu et al. applied single-nucleus RNA sequencing (snRNA-seq), which could resolve multiple cell types better than single-cell RNA sequencing (scRNA-seq), to profile cell types, dynamics of cellular composition, and hepatocyte differentiation trajectories during postnatal murine liver development. A complete understanding of the development of complex organs such as the brain requires not only cell type taxonomy (which scRNA-seq excels at) but also spatial information of cells or genes at the organ level. Cheng et al. applied Stereo-seq, a DNA nanoball patterned array-based high-resolution spatial transcriptomic technology, to medial structures in postnatal mouse brain. Their data provided subcellular distribution of 27,330 genes, region-specific gene regulatory networks, 41 cell types localized in different regions. This rich resource for developmental study is accessible as an open and interactive database (https://db.cngb.org/stomics/datasets/STDS0000139?tab=explore). Li et al. performed integrative scRNA-seq and single cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis in mesenchymal stem/stromal cells derived from placenta (PMSCs). Their data revealed subsets of PMSCs and nominated potential cis and trans regulatory factors in the subtypes.These primary research and reviews highlight the fact that organoids are heterogeneous in shape and size; moreover, the absence of blood supply and interactions with non-parenchymal cell types limit their potential. For these reasons, future works are needed to standardize organoid cultures, including co-cultures with other cells , and to improve cell maturation to generate more faithful models. To this end, improvements in culture methodology could make 3D stem cell models more robust and reproducible. Shams et al. showed that signaling through the chemokine receptor CXCR4 is essential to normal early activation, proliferation and self-renewal of muscle stem cells (or satellite cells), which are responsible for regenerating muscle fibers following acute skeletal muscle injury. Among mammals, deer has the unique ability to fully regenerate a lost organ, the antler. Guo et al. explored the gene expression changes during the activation of the pedicle periosteum (harboring stem-like cells) that triggers the initiation of antler regeneration. Their findings suggest that calreticulin (CALR), an androgen response gene, is likely a downstream mediator of androgen hormones for initiating antler regeneration.Besides high-through profiling of mRNA and chromatin accessibility, mechanistic dissection of regulatory pathways during tissue regeneration pays dividends for improving stem cell differentiation and developing novel therapies. In this regard, The topic editors hope the readers enjoy reading these new papers centered around stem cell models as much as we do. The exciting research advances summarized in this volume will undoubtedly have a positive impact on the translational values of stem cell models."}
+{"text": "Community gerontology integrates scholarship on aging and communities through the lens of mesolevel environments, the diverse continua of settings linking micro and macro contexts of aging. This interdisciplinary symposium brings together research exploring the interconnections of older adults\u2019 engagement across and within the socio-ecological levels of their lived experiences, place-based communities, and policy contexts. Yeh et al.\u2019s paper elucidates the promises of visual methods in critical qualitative research with older adults to subvert power dynamics and advance social justice in gerontology. Latham-Mintus\u2019 paper explores how \u201cweak ties\u201d created by the interaction of social infrastructure within geospatial places and spaces can facilitate longer, healthier lives. Reyes\u2019 paper uses an intersectional life course perspective to explore placemaking as civic participation among Latinx immigrants and African American older adults across time and social environments. Plasencia\u2019s paper focuses on aging in community among diverse older adults using a photovoice to assess their perceptions and needs within the lived urban environment. Pope and colleagues explore how a multi-state sample of older adults perceive their roles in age-friendly initiatives at individual, organizational, and community levels. Taken together, the papers discuss and contextualize the multidirectional ways older adults engage their place-based communities within larger macro sociopolitical structures \u2013 an analysis that highlights the embeddedness of mesolevel community environments both within and between micro and macro spheres. This session further speaks to the importance of centering older adults\u2019 experiences in community gerontology by illuminating the ways older adults not only age in community but through layers of community."}
+{"text": "Recent years have seen important progress in the characterisation and refinement of organoid culture systems. Here, we address several open questions in the field, including how closely organoids recapitulate the tissue of origin, how well organoids recapitulate patient cohorts, and how well organoids capture diversity within a patient. We advocate deeper characterisation of models using single cell technologies, generation of more diverse organoid biobanks and further standardisation of culture media.Organoids have become a prominent model system in pulmonary research. The ability to establish organoid cultures directly from patient tissue has expanded the repertoire of physiologically relevant preclinical model systems. In addition to their derivation from adult lung stem/progenitor cells, lung organoids can be derived from fetal tissue or induced pluripotent stem cells to fill a critical gap in modelling pulmonary development  Customised media have been developed to expand specific cellular subpopulations from iPSCs; in the airways, basal cells and secretory progenitor cells have all been induced from iPSCs  and, whein vivo tissue of origin remarkably well, despite the absence of stroma in vitro  of single nucleotide variants (SNVs) and copy number alterations (CNAs). Although whole exome sequencing has been performed in some studies , others The extent to which lung cancer organoids diverge from tumour tissues at the phenotypic level is much less clear. Since organoid culture systems were originally developed to expand epithelial stem cells , it is uThe majority of lung organoid cultures are currently performed as mono  cultures, although investigations of epithelial-fibroblast  or epithin vivo complexity of epithelial-stromal or epithelial-immune interactions, nor systemic variables such as nutrient availability, mechanical forces and circadian rhythms.While we advocate a better phenotypic characterisation of lung organoids to investigate their resemblance to lung tissue, it must be emphasised that organoids will always remain a reductionist model. The generalisation or translational relevance of results obtained in this culture system is best validated using orthogonal model systems  or datasets (including publicly available omics datasets). Moreover, it is not possible to reproduce the complete A second important aspect of organoid modelling is the extent to which it is possible to capture the biology of the target population. Primary human bronchial epithelial cell cultures can show wide inter-patient variability in differentiation potential and response to stimulation, and so studying sufficient numbers of patient cultures is crucial, particularly when studying phenomena that are likely to vary with biological characteristics of the donor, such as age and/or sex . At presOrganoids have been derived from patients across a wide range of respiratory diseases, including pulmonary fibrosis , primaryTo date, lung cancer research has benefited most from organoid-based disease modelling. As many hundreds of organoid lines have been developed by multiple laboratories worldwide, it is possible to assess the extent to which they reflect non-small cell lung cancer (NSCLC) patient cohorts. Surprisingly, organoid establishment rates are similar for lung squamous cell carcinomas or adenocarcinomas , despiteTo date, most studies have generated lung cancer organoids from surgical resections of primary tumours. To our knowledge, no organoid models have been generated from pre-invasive disease, but pre-cancer organoids would be particularly valuable to study events in early tumourigenesis. Since most lung cancer patients die from metastatic disease, representing these in organoid collections would be valuable. One study established organoids from malignant effusions from patients with advanced lung cancer with a high success rate , suggestAn alternative approach to deriving organoids from lung disease patient cohorts, is to use the available model systems to investigate specific hypotheses related to the disease process. In this regard, pluripotent cell-derived organoids have proved useful pulmonary fibrosis models. Introducing Hermansky-Pudlak syndrome (HPS) mutations associated with interstitial pneumonia using CRISPR-Cas9 promotes fibrotic changes in ES-derived lung organoids  or iPSCsIntra-patient heterogeneity likely represents an understudied source of variation in lung organoid research. At present, authors typically report the diagnosis of the patient from whom organoids were derived and the tissue of origin. However, airway epithelial cell phenotype is known to vary in the proximal-distal axis within normal lungs with cells from the upper airways having distinct transcriptomic profiles , innate in vitro. Indeed, one study reported a low correlation of variant allele frequencies (VAFs) between organoids and original tumours in approximately half of the samples analysed (Lung cancers are genetically and phenotypically heterogeneous, but the extent to which this is maintained in lung cancer organoid cultures is so far poorly characterised. Given the variable establishment rates of lung cancer organoids, bottlenecks are expected that restrict heterogeneity analysed . Evidencanalysed  and coloanalysed . This coanalysed , there ianalysed . The estanalysed . Evaluatin vivo processes, the ability of organoid collections to accurately reflect population level inter-individual variability and intra-patient heterogeneity (Lung organoids provide a cell culture platform to study lung development, stem/progenitor cell biology and disease pathogenesis. Several open questions remain, however, concerning their ability to recapitulate the tissue of origin and ogeneity . We advo"}
+{"text": "Oncogenic viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein Barr virus (EBV), and Kaposi Sarcoma Herpes virus (KSHV) contribute to a significant proportion of the world\u2019s cancers. Given the sizeable burden of virus mediated cancers, development of strategies to prevent and/or treat these cancers is critical. While large population studies suggest that treatment with hydroxymethylglutaryl-CoA reductase inhibitors, commonly known as statins, may reduce the risk of many cancer types including HBV/HCV related hepatocellular carcinoma, few studies have specifically evaluated the impact of statin use in populations at risk for other types of virus mediated cancers.Studies of populations with HBV and HCV suggest a protective, dose-dependent effect of statins on hepatocellular carcinoma risk and support the theory that statins may offer clinical benefit if used as chemoprophylactic agents to reduce liver cancer incidence. However, no population level data exists describing the impact of statins on populations with other oncogenic viral infections, such as HPV, EBV, and KSHV.Further study of statin use in diverse, global populations with or at high risk for oncogenic viral infections is essential to determine the impact of statin therapy on virus mediated cancer risk. Cancers caused by infections represented more than 13% of the global cancer burden in 2018, including more than 1.2 million cancers caused by viruses  for lipophilic statin users and 0.51 [0.31\u20130.85] for hydrophilic statin users) . In contIn contrast to HBV/HCV, few epidemiologic studies describe the impact of statin use on HPV-, EBV-, or KSHV-mediated cancers. For HPV, one retrospective cancer database study of 1638 individuals with head and neck cancers found a statistically significant inverse association between ever using a statin and death from HPV\u2009+\u2009head and neck cancers  .Available data suggest a protective, dose-dependent effect of statins on HCC risk in populations with chronic HBV and/or HCV infections. Thus, statins may show clinical benefit if used as chemoprophylactic agents to reduce the public health burden of HCC, and randomized clinical trials evaluating the effectiveness of statins in HCC outcomes both with other therapies (NCT03275376) and to prevent recurrent HCC (NCT03024684) are ongoing. Trials being planned should include comparisons of lipophilic or hydrophilic statins in their designs.The promise of statins in preventing HCC warrants extrapolation of epidemiologic and clinical study of statin therapy to populations at risk for other oncogenic viral infections, particularly HPV, EBV, and KSHV. Importantly, despite the much larger global burden of cervical cancer, the only published study describing the impact of statins on HPV is in HPV-related head and neck cancers, which are predominantly diagnosed in men in high income countries. Future studies must rectify this disparity by evaluating the impact of statins on cervical cancer, particularly in low- and middle-income countries where cervical cancer rates are higher due to poor access to HPV vaccines and surveillance programs, but also in high income countries where cervical cancer remains an important cause of cancer morbidity and mortality despite robust HPV prevention programs. Statin therapy might prevent or slow the development of cervical cancer if initiated immediately after detection of high-risk HPV subtypes or cervical dysplasia in women undergoing cervical cancer screening. Though pre-clinical data suggest that statin therapy may ameliorate EBV-related cancers, no epidemiologic studies have evaluated statins in prevention or as an adjunctive therapy in at risk populations. Such studies are needed to determine whether statin intervention trials are warranted to prevent EBV-related cancers. Though KSHV afflicts a large proportion of the population, particularly in sub-Saharan Africa, no investigations into the ability of statin therapy to limit the development of KSHV-associated cancers exist; study of the relationship between KSHV and statins should be initiated via in vitro and animal model studies. Finally, HIV hugely impacts risk of morbidity and mortality in those co-infected with the oncogenic viruses covered in this Review, and several anti-retroviral therapies in widespread use are known to contribute to dyslipidemia. Future research should include investigation of statins as agents to prevent virus mediated cancers in people with HIV, as these individuals may have different outcomes or require different statin doses.The studies outlined in this article provide preliminary evidence that statins may induce mechanisms that slow virus-mediated cancer development, which should be further investigated in epidemiologic studies of populations at risk for HPV, EBV, and KSHV infection. Randomized trials and large community-based prevention trials prospectively evaluating use of specific statins in populations with or at high risk for oncogenic viral infections will be needed to further explore the potential benefit of statins in decreasing virus mediated cancer risk."}
+{"text": "Co-occurrence of obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) features is well stablished. Diagnosis of OCD increases the risk of a later diagnosis of ASD, and vice versa. Moreover, a recent combined genome-wide association study identified a shared polygenic risk between the two disorders. Our preliminary results also indicate that OCD patients have higher levels of autistic traits than individuals from the community.To determine which autistic dimensions  are predictors of OC symptoms.39 OCD patients  answered the Portuguese versions of the Autism-Spectrum Quotient for Adults and Obsessive Compulsive Inventory \u2013 Revised (OCI-R). Spearman correlation and linear multiple regression tests were performed using SPSS.The OCI-R global score showed positive correlations with some AQ dimensions . The regression model showed that attention to detail  and attention switching  explained 36% of obsessive-compulsive symptoms variance.Our results are in line with a dimensional perspective of psychopathological continua and indicate that the overlap between OCD and ASD occurs through shared neurocognitive processes. We suggest that, besides being a predisposing factor for social difficulties  in ASD, attention to detail and deficits in attention switching may also lead to difficulties to dismiss repetitive thoughts or extinguish behaviours in OCD. Future studies should investigate the distinctive features and underlying processes between OCD/ASD."}
+{"text": "Although minimally invasive percutaneous disc nucleoplasty (PDN) has been widely used for discogenic back pain or soft-disc herniation of the lumbar spine, complications can occur. Although rare, iatrogenic vascular injuries during PDN are serious complications that can be fatal without rapid diagnosis and effective management. Here, we present the case of a 38-year-old male patient with an injury to the right fifth lumbar artery that occurred during PDN, which was successfully treated using emergent transarterial embolization. To the best of our knowledge, this is the first report of successful transarterial embolization without open hematoma evacuation for a lumbar artery injury that occurred during PDN."}
+{"text": "Regulatory T cells (Treg) are a major immunosuppressive cell subset in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies, whereupon Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these compensatory mechanisms may be patients with locally advanced PCa undergoing neoadjuvant therapy (neoTx). In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform.+ myofibroblastic cancer-associated fibroblasts (myCAF) and increased proportions of CD8+ cytotoxic T lymphocytes in the tumor. In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform.Regulatory T cells (Treg) are one of the major immunosuppressive cell subsets in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells mechanisms form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these complex compensatory mechanisms may be the tumors of patients who underwent neoTx. Here, we observed a parallel decrease in the numbers of both intratumoral Tregs and MDSC after neoTx even in locally advanced PCa. NeoTx also led to decreased amounts of \u03b1SMA PCa is one of the deadliest human neoplasms and is projected to become the second leading cause of cancer-related death worldwide by 2030 . Its poo+CD25+Foxp3+ T cells, are a subpopulation of lymphocytes that are crucial in maintaining tolerance to self-antigens and innocuous foreign antigens under physiological conditions, but can also be co-opted by tumor cells to avoid the host immune response . TAM. TAM+ mypatients .Even in locally advanced tumors, perioperative chemotherapy led to a parallel decrease in both Treg and MDSC which was associated with tumor shrinkage and prolonged survival. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas the inverse association was seen in advanced PCa, urge a comprehensive analysis of the phenotype and frequency of these major immunosuppressive cell subsets through pancreatic tumorigenesis. Such a \u201chuman\u201d example demonstrates that the reaction of Treg cells and MDSC in locally advanced PCa may not actually be antagonistic but concurrent, and that these two immune cell populations should not be perceived as being mutually suppressive or substituting. The question whether the compensatory network between Treg cells and MDSCs intensifies in patients with late-stage metastatic PCa, remains yet unexplored.Therefore, the underlying mechanisms behind the complex interplay between myeloid cells and Treg cells still needs further elucidation . A bette"}
+{"text": "Our results imply that microorganisms classically considered as sulfate reducers control the potential for DNRA within coastal sediments when redox conditions oscillate and therefore retain ammonium that would otherwise be removed by denitrification, exacerbating eutrophication.The oscillating redox conditions that characterize coastal sandy sediments foster microbial communities capable of respiring oxygen and nitrate simultaneously, thereby increasing the potential for organic matter remineralization, nitrogen (N)-loss and emissions of the greenhouse gas nitrous oxide. It is unknown to what extent these conditions also lead to overlaps between dissimilatory nitrate and sulfate respiration. Here, we show that sulfate and nitrate respiration co-occur in the surface sediments of an intertidal sand flat. Furthermore, we found strong correlations between dissimilatory nitrite reduction to ammonium (DNRA) and sulfate reduction rates. Until now, the nitrogen and sulfur cycles were assumed to be mainly linked in marine sediments by the activity of nitrate-reducing sulfide oxidisers. However, transcriptomic analyses revealed that the functional marker gene for DNRA (nrfA) was more associated with microorganisms known to reduce sulfate rather than oxidise sulfide. Our results suggest that when nitrate is supplied to the sediment community upon tidal inundation, part of the sulfate reducing community may switch respiratory strategy to DNRA. Therefore increases in sulfate reduction rate in-situ may result in enhanced DNRA and reduced denitrification rates. Intriguingly, the shift from denitrification to DNRA did not influence the amount of N The permeable sandy sediments that fringe coastlines act as highly effective biocatalytic filters that remineralize organic carbon, and remove fixed nitrogen through denitrification \u20135. The mMany of the microorganisms within permeable sediments appear to be adapted to the oscillating oxic and anoxic conditions . Such adTypically, microorganisms in marine sediments employ different electron acceptors over depth, largely in accordance with their decreasing energy yield, which often leads to an apparent spatial separation of sulfate reduction from nitrate reduction \u201324. ThisSeveral lines of evidence suggest that sulfate reduction in intertidal permeable sediments should be tolerant of nitrate. Sulfate reducers are present and highly active in the upper layers of sediment, even though this area is frequently exposed to both nitrate and oxygen , 37\u201340. Desulfovibrio vulgaris can prevent this competitive inhibition of sulphite reductase via constitutive expression of periplasmic cytochrome c nitrite reductase (Nrf) to remove the nitrite, although there are contrasting reports as to whether this is also linked to energy generation http://enSupplementary InformationSupplementary Tables 4, 5"}
+{"text": "Cancer therapies for older adults have accelerated at breakneck speed in the last few decades, necessitating evaluation of their delivery and uptake to ensure patients receive their maximum benefit. Among the vast array of evaluation tools available, those utilizing naturally occurring data\u2014data produced without intervention from a researcher\u2014are a powerful but underused tool. In this presentation, we will review two methods for examining naturally occurring data, participant observation and conversation analysis (CA), in an educational intervention study of multiple myeloma patients receiving autologous stem cell transplant. First, we will review how participant observation of nurse-led education visits (n=70) was incorporated to iteratively improve video-based education. Next, we will review use of CA in reviewing audio recordings containing reference to the education videos of 12 nurse-led education visits (1011 minutes of audio). Ultimately, understanding the purposes of and ways of using naturally occurring data have potential for improving the evaluation of patient education."}
+{"text": "For this qualitative, pilot study, seven Massachusetts nursing home Directors of Nursing (DONs) were interviewed remotely about palliative care provision before and during the COVID-19 pandemic. Interview data were analyzed using thematic analysis. Palliative care addresses physical, emotional, psychological, and spiritual suffering that accompanies serious illness. Symptom management and goals of care is especially valuable for seriously ill nursing home residents. We investigated the solutions nursing home staff developed to provide palliative care during the COVID-19 pandemic despite restrictions on external resources. Before the pandemic, palliative care was delivered primarily by nursing home staff depending on formal and informal consultations from palliative care specialists affiliated with hospice providers. When COVID-19 lockdowns precluded these consultations, nursing staff did their best to provide palliative care, but were often overwhelmed by shortfalls in resources, resident decline brought on by isolation and COVID-19 itself, and a sense that their expertise was lacking. Advance care planning conversations focused on hospitalization status and options for care given COVID-19 resource constraints. Nevertheless, nursing staff discovered previously untapped capacity to provide palliative care on-site as part of standard care, building trust of residents and families. Nursing staff rose to the palliative care challenge during the COVID-19 pandemic, albeit with great effort nursing home payment and quality standards should support development of in-house staff capacity to deliver palliative care while expanding access to the formal consultations and family involvement that were restricted by the pandemic."}
+{"text": "The population of family caregivers (FCGs) of persons with Alzheimer's Disease and related Dementias (ADRD) is growing, as is the proportion of males taking on this traditionally female role. Most caregiving research has mainly focused on females. Although female caregivers have reported more negative outcomes, men still report significant levels of burden. With the aging population and increased need for caregivers, there is a gap in knowledge exploring the male caregiving experience. Understanding male caregiving experiences can inform clinicians on developing future strategies to tailor support for this underrepresented group. The purpose of this qualitative descriptive study was to explore the experiences of male FCGs of people with ADRD. The Caregiver Identity Theory (CIT) was used to guide the study exploring participants\u2019 perception of self-identity within their caregiving relationship and self-identity as a male. Eleven male caregivers, recruited through social media and community resources, were interviewed by telephone or Zoom. Interviews were recorded, transcribed, and analyzed using thematic analysis. Four major themes emerged highlighting males\u2019 struggles with the unfamiliar caregiving role and changing identity; their acknowledgement of personal growth and discovery through caregiving, challenges in finding the \u201cright\u201d kind of support, and perceived reshaping of masculinity through the caregiving role. Male caregivers express unique experiences as FCGs suggesting future research is needed to explain gender differences in caregiving and identify additional factors that influence male caregivers\u2019 experiences. Furthermore, findings indicate clinicians should tailor support strategies for male FCGs\u2019 as they fulfill this potentially unfamiliar role."}
+{"text": "Molecular psychiatry research needs a deeper characterization of emotional and cognitive neural underpinnings, along with a broader recognition of trauma-related circuitries and their involvement in shared pathological endophenotypes. One such endophenotype is unbalanced approach avoidance conflict (AAC), a highly recurrent trait of psychopathology. A translationally validated rodent model of AAC is the elevated plus maze (EPM) test, recently shown to be pharmacologically controlled in human and rodents via homologous neural substrates. Thanks to this test, we identified the involvement of the epigenetic enzyme LSD1 as a molecular restrainer of anxiety. We identified LSD1 aberrant regulation within the hippocampus of suicidal victims, suggesting its broad functional involvement in maladaptive behaviors. Interestingly, thanks to the parallel employment of rodent models, we evaluated a stress-related LSD1 homeostatic regulation that transiently limits memory formation-instrumental gene expression in the hippocampus upon trauma. Our work shed new light on epigenetic processes devoted to trauma resiliency through a negative regulation of anxiety plasticity.No significant relationships."}
+{"text": "This quantitative cross-sectional sub project investigated the effects of organizational context and individual characteristics on psychological empowerment of care aides working in nursing homes. We analyzed data collected from 3765 care aides from 91 nursing homes across Western Canada between 09/2019 and 03/2020. From the random-intercept mixed effects regression models we identified significant predictors at different levels for each component of psychological empowerment. At the organizational outer context level: region and home ownership model. At the inner context (care unit) level: formal interactions , evaluation , culture , communication , and social capital . At the individual level: care aides\u2019 sex, language and job satisfaction.These findings suggest important ways in which contextual elements may influence staff quality of work life characteristics and underscore the need to consider context operating at different levels, as well as consider individual and contextual interaction."}
+{"text": "Area-level residential instability (ARI), an index of social fragmentation, has been shown to explain the association between urbanicity and psychosis. Urban upbringing has been shown to be associated with decreased gray matter volumes (GMV)s of brain regions corresponding to the right caudal middle frontal gyrus (CMFG) and rostral anterior cingulate cortex (rACC).We hypothesize that greater ARI will be associated with reduced right posterior CMFG and rACC GMVs.Data were collected at baseline as part of the North American Prodrome Longitudinal Study. Counties where participants resided during childhood were geographically coded using the US Censuses to area-level factors. ARI was defined as the percentage of residents living in a different house five years ago. Generalized linear mixed models tested associations between ARI and GMVs.This study included 29 HC and 64 CHR-P individuals who were aged 12 to 24 years, had remained in their baseline residential area, and had magnetic resonance imaging scans. ARI was associated with reduced right CMFG  and right rACC volumes . The interaction terms (ARI X diagnostic group) in the prediction of both brain regions were not significant, indicating that the relationships between ARI and regional brain volumes held for both CHR-P and HCs.Like urban upbringing, ARI may be an important social environmental characteristic that adversely impacts brain regions related to schizophrenia.No significant relationships."}
+{"text": "Ancestral sequence reconstruction (ASR) infers predicted ancestral states for sites within sequences and can constrain the functions and properties of ancestors of extant protein families. Here, we compare the likely sequences of inferred nitrogenase ancestors to extant nitrogenase sequence diversity. We show that the most-likely combinations of ancestral states for key substrate channel residues are not represented in extant sequence space, and rarely found within a more broadly defined physiochemical space\u2014supporting that the earliest ancestors of extant nitrogenases likely had alternative substrate channel composition. These differences may indicate differing environmental selection pressures acting on nitrogenase substrate specificity in ancient environments. These results highlight ASR's potential as an in silico tool for developing hypotheses about ancestral enzyme functions, as well as improving hypothesis testing through more targeted in vitro and in vivo experiments. Ancestral sequence reconstruction (ASR) is widely used for modeling sequence properties and functions of ancient enzyme variants. Maximum-likelihood reconstructions combine substitution models with aligned sequence data and phylogenetic information to calculate the residue likelihood of aligned sites for all internal nodes in a tree . This apNitrogen-fixing nitrogenases are the lynchpin of Earth's biological nitrogen cycle, and have been extensively studied for their role in global biogeochemistry . Modern 2) fixation, modern nitrogenases can promiscuously reduce other linear, triple-bond-containing molecules at the FeMoCo active site (2), carbon monoxide (CO), acetylene (C2H2), and hydrogen cyanide . A library of plausible sequence ancestors for this collection of sites was generated, and their relative probabilities calculated. We applied a simple hypothesis-testing strategy: Are likely ancestral active site sequence states found within sampled extant nitrogenase diversity? We find that this is not always the case, permitting the possibility that early nitrogenase ancestors had substrate binding channels with properties distinct from modern enzymes.A higher affinity for alternative substrates in ancestral nitrogenases would likely require different amino acid residues in the substrate-binding part of the enzyme (the substrate channel), while preserving catalytic activity. As ASRs are inherently probabilistic, individual sites may be inferred to have several possible ancestral states with non-negligible probabilities. Variation across sampled extant diversity allows the combinations within likely ancestor sequences to explode, producing a far greater number of plausible sequence ancestors than can be experimentally tested. Here, we use ASR to reconstruct the amino acid identities of alignment sites directly interacting with the substrate binding channel in the common ancestor of the active site-containing nitrogenase subunit (Azotobacter vinelandii Nif (P > 0.10) in the predicted nitrogenase ancestor  and Group II Nif  of reconstructed ancestors contained substitutions yielding a combination not represented by extant sequences or physicochemical types . Of the The effects of substitution models and topology on predicted ancestor sequence and type were also evaluated by repeating tree construction and ASR under WAG + R10 (the highest likelihood non-LG model) and BLOSUM62 + R10 . Substitution models slightly impacted recovered tree topologies within recently diverged lineages but did not alter phylogenetic relationships between major nitrogenase types and their outgroups. Relative likelihoods for specific amino acids are generally conserved at sites 495, 496, and 603, and sample the same plurality at site 576  and site 348  . MoreoveChloroflexales bacterium ZM16-3. The top ten most-likely ASR residue combination physicochemical types were represented by very few extant sequences, and only within the divergent group of Nif that also contains the alternative nitrogenases. Divergent homologs within this clade may sample ancestral sequence patterns to a greater extent than type I or II nitrogenases. If so, characterizing these extant genes could provide useful analogs for ancestral phenotypes.These results suggest that the inferred ancestor of Nif, Vnf, and Anf nitrogenases most likely contained a substrate channel sequence distinct from that found in extant sequence space. Twenty-two of the 23 highest likelihood sequence combinations of the five variant substrate channel ancestral sites are not observed within known modern nitrogenases; the only represented sequence pattern occurs in only one observed extant enzyme, that of The conservative substitutions observed in the highest likelihood predicted ancestors are unlikely to radically influence substrate affinity or binding, at least when compared with the extant enzymes in the Nif/Anf/Vnf group. In the case of HCN, for example, because both modern Vnf  and Nif Extant nitrogenases that remain unsampled and excluded from the tree could contain currently missing high-likelihood sequence combinations in the ASR. Additionally, likelihood ratios calculated from only a handful of sites do not represent overall sequence likelihoods, as site likelihoods are calculated independently. Thus, the most-likely ancestral site combinations in the substrate channel are unlikely to identify the sequence in the most-likely overall ancestor. However, the likelihood calculations for these substrate binding sites may be more informative for inferring ancestral phenotype changes than the overall ancestral sequence of the enzyme. Indeed, physicochemical type combinations predicted by the ASR are more robust to changes in substitution model and tree topology than sequence-level variation ; this unThe results highlight the value of ASR as a first step in evaluating enzyme evolution hypotheses. In some cases, ASR itself may prove sufficient to refute certain evolutionary hypotheses; for example predicted ancestral states may be sterically incompatible with hypothesized substrate interactions or protein folding. Such results would preclude additional experimental work. It is also possible that when ASR fails to identify combinations of key ancestral residues absent from extant diversity, the null hypothesis of uniform phenotype across the reconstructed history should be preferred. However, even in this case, ASR will efficiently identify key sites to target for mutagenesis for in vitro or in vivo analyses\u2014such as the novel sequence and type combinations sampled in this work.A. vinelandii (WP_012698832.1). Hits were included for molybdenum (NifD), vanadium (VnfD), and iron-only (AnfD) nitrogenases and manually curated to remove partial sequences, prune oversampled clades, and ensure the presence of conserved sequence features known to be critical for N2 reduction . The curated initial data set included 385 nitrogenase sequences and 385 outgroup sequences from light-independent protochlorophyllide oxidoreductases (nfaD; nif/anf/vnf ancestor as an internal node in the tree. The tree was rooted along the split between nitrogenases and the other oxidoreductases. Maximum-likelihood tree construction and subsequent ASR were performed in IQ-Tree (An initial data set of extant nitrogenase D-subunit homologs was constructed from hits gathered using BLASTp to search NCBI's non-redundant protein database with a query sequence from ductases . These iductases . Outgroues nfaD;  was prof IQ-Tree , under t"}
+{"text": "Transitions of care also exist within the operating room and contribute to an increased risk of adverse events.Hospitalized patients with severe infections may warrant intravenous (IV) antibiotics and surgical intervention for effective treatment of their infection. Surgical interventions require multiple transitions of care, which are well-studied sources of medication-related errors and inappropriate antimicrobial use. Furthermore, intraoperative bacteremia is common during elective surgeries. For patients requiring surgery for infection source control, maintaining adequate serum antibiotic levels may be particularly important in preventing bacteremia while infected tissue is surgically manipulated.Errors in antibiotic use in the perioperative period may negatively affect patient outcomes. Patients who experience diminished serum and tissue concentrations of antibiotics during surgical closure have higher risks of postoperative wound infections. no studies have investigated perioperative antibiotic use for inpatients already on IV antibiotic regimens. The lack of guidelines introduces further complexity because it allows for additional and potentially inappropriate antibiotic administration for patients already receiving broad-spectrum antibiotics. In this study, we examined the incidence and nature of inappropriate antibiotic use in the perioperative period among inpatients on IV antibiotic regimens.Although data exist on optimal timing of antibiotic administration for surgical antimicrobial prophylaxis,We conducted a retrospective cross-sectional study at a Veterans\u2019 Affairs medical center. We included all inpatients who underwent noncardiac surgery in 2019 who were aged >18 years or older and were on an IV antibacterial regimen prior to surgery. Patients receiving only surgical antimicrobial prophylaxis were excluded. Study and waiver of consent were approved by the Institutional Review Board of the VA Ann Arbor Healthcare System.Through manual chart review by 2 physicians, we collected information on prescribed IV antibiotic regimens and timing of antibiotic doses in the perioperative period. Errors were classified as follows: missed doses, delayed doses, additional doses of prescribed IV antibiotics, or additional surgical antimicrobial prophylaxis. Delayed antibiotics were administered between 2 and 4 hours after the scheduled administration time, and missed antibiotics were either omitted or administered at least 4 hours after the scheduled administration time. Administration of surgical antimicrobial prophylaxis was defined as an error in patients already receiving IV antibiotics with the same or broader antimicrobial coverage.Of the 290 inpatients who underwent surgery in 2019, 163 patients (56%) received an IV antibiotic regimen prior to surgery. Complete data were available for 153 patients (94%). Errors in antibiotic administration in the perioperative period were identified in 60 patients (39%). The most common error was a missed dose of an IV antibiotic, which occurred in 22 patients (39% of errors)  was a missed dose of an antibiotic. Also, antibiotic overuse  accounted for 36% of errors. For example, patients already on broad-spectrum antibiotics for their infection were given additional antibiotics  for surgical site infection prophylaxis. We suspect that these errors are related to the multiple transitions of care in the perioperative period. Some errors are also likely related to documentation of medications administered during an anesthetic in a separate part of the electronic medical record than medications administered on the hospital ward.This study had several limitations. This was a single-center, retrospective study, and including multiple VA institutions would be a powerful next step. Second, the generalizability of these results may be limited because institutions using other electronic medical records may have different processes for documentation. However, we believe that the presurgical period in a patient\u2019s hospitalization represents an underrecognized opportunity for antimicrobial stewardship given the transitions of care involved. and misuse of antibiotics is common in these patients. Education-based stewardship interventions and clinical decision support tools implemented in surgical units have been shown to lead to reductions in antimicrobial consumption and improved trends in percentages of resistant bacterial strains. However, research evaluating interventions that specifically target perioperative antibiotic misuse for inpatients already on antibiotics for active infections is limited. This period may present a valuable opportunity for multidisciplinary stewardship intervention. Collaboration between antimicrobial stewardship programs, anesthesiology, and surgery departments should be encouraged to improve local practices in perioperative antibiotic prescribing and to address systems-based challenges that lead to inappropriate antibiotic use. Further research will be essential to the evaluation of outcomes of patients who experience errors in perioperative antibiotic administration.In conclusion, surgical patients account for significant proportions of inpatient antibiotic use,"}
+{"text": "Socioemotional theories suggest that surviving challenging experiences enhances emotional resilience with age, yet the role of memories is overlooked in most models of emotion regulation. In parallel, cognitive accounts focus on age-related memory deficits associated with overlapping hippocampal neural representations across unique memories . We propose a novel framework supporting enhanced late-life reappraisal via hippocampal dedifferentiation of memory representations across current and past experiences. We review classic studies supporting mood benefits from integrated positive narratives following adverse autobiographical events. We also discuss multivariate neuroimaging evidence supporting overlapping hippocampal representations and ventromedial prefrontal cortex (vmPFC) involvement in meaning-making processes. We posit that greater hippocampal dedifferentiation across life memories may facilitate associative binding of current and past stressors as well as reappraisals in vmPFC. This process may provide avenues for generalizing past reappraisals to novel contexts and reducing cognitive demands of reappraisal. In addition, we discuss the possible age-related facilitation of this process, as a greater number of life experiences may become increasingly integrated with one another over the lifespan. These integrated neural associations may serve to make reappraisals from the past more readily accessible and applicable in new contexts over time, increasing routes to positive narratives following stress. We discuss future directions for testing components of the proposed model using multivariate neuroimaging methods. We conclude by briefly reviewing the possible clinical impact of mnemonic emotion regulation in promoting emotional well-being among older adults, using a strengths-based approach that leverages wisdom from experience and neural processes facilitated with age."}
+{"text": "Despite growing research linking stressors with poorer cognition, less research explicitly considers stress from several sources, which often co-occurs and accumulate to influence health. We used the Global Gateway Harmonized data  to examine whether higher cumulative stress is associated with lower levels of and faster decline in cognitive function. We fit linear mixed effect models to assess the stress-cognition associations. After adjusting for all covariates, baseline cumulative stress was associated with lower baseline cognitive function in both HRS  and ELSA . Unexpectedly, higher baseline cumulative stress was associated with slower cognitive decline in HRS  but not in ELSA. The stress-cognition associations may differ among adults in the US and the UK. Future research should investigate how cumulative stress may operate differently to influence cognitive function across different populations."}
+{"text": "Developmental theories suggest that midlife and older adulthood are stages in which individuals may begin to focus their time on contributing to society . During these stages, individuals may engage in socially responsible behaviors that protect against negative affect resulting from a lower sense of purpose in later life . Social responsibility includes both subjective measures of an individual\u2019s felt contribution to society  and objective measures reporting actual time volunteering in different settings . We utilized data from the Midlife in the United States Refresher survey study and Biomarker Project  to explore how self-perceptions of generativity and time spent volunteering predicted negative affect for individuals in midlife and older adulthood. Preliminary analyses indicate that higher generativity (p<.001) and older age (p<.001), but not average time spent volunteering, were associated with higher negative affect. Further, we considered age as a potential moderator for the associations between generativity, volunteering, and negative affect. Age significantly interacted with generativity (p<.01), such that the effects of generativity on reducing negative affect decrease with age. Age did not significantly interact with time spent volunteering. Discussion will focus on how actual engagement in socially responsible behaviors and perceived societal contributions might yield different outcomes regarding protection against negative affect in mid- and later-life. Future directions may include exploring daily indicators of time spent volunteering, generative beliefs, and affect."}
+{"text": "The purpose of this study is to determine whether a 12-week exercise course influences obese African American older women\u2019s health capabilities and life satisfaction levels. Participants, who passed an initial screening and pre-assessment, were asked to measure current health capabilities and life satisfaction levels both prior to, and following, the 12-week exercise training. Researchers found that improvement in health capabilities, although there were no significant differences following exercise training participation, while obese African American older women had significantly higher life satisfaction levels. The findings suggest that a 12-week exercise training can be beneficial to enhance obese African American older women\u2019s health capabilities and life satisfaction levels. Professionals in the field of gerontology and exercise should provide the appropriate exercise trainings so that obese African American older women would be able to optimize their life satisfaction levels."}
+{"text": "Sarbecovirus), given that several closely related viruses have been discovered and sarbecovirus\u2013host interactions have gained attention since SARS-CoV-2 emergence. We assessed sampling biases and modelled current distributions of bats based on climate and landscape relationships and project future scenarios for host hotspots. The most important predictors of species distributions were temperature seasonality and cave availability. We identified concentrated host hotspots in Myanmar and projected range contractions for most species by 2100. Our projections indicate hotspots will shift east in Southeast Asia in locations greater than 2\u00b0C hotter in a fossil-fuelled development future. Hotspot shifts have implications for conservation and public health, as loss of population connectivity can lead to local extinctions, and remaining hotspots may concentrate near human populations.Global changes in response to human encroachment into natural habitats and carbon emissions are driving the biodiversity extinction crisis and increasing disease emergence risk. Host distributions are one critical component to identify areas at risk of viral spillover, and bats act as reservoirs of diverse viruses. We developed a reproducible ecological niche modelling pipeline for bat hosts of SARS-like viruses (subgenus  Global Rhinolophus affinis , Rhinolophus marshalli (virus BANAL-236) and Rhinolophus pusillus (virus BANAL-103) ..SarbecovRhinolophus pearsonii . Most species' populations are currently declining (n = 8) or have unknown population trends . Local species loss values were almost twice the number of maximum gain . Along with climate change mitigation, strategies for maintaining landscape-level habitat connectivity will allow populations to reach refugia and lower extinction risk. This could be done by developing landscape connectivity surfaces that maximize diversity hotspot extensions, with monitoring effective dispersal through genetics [There are conservation implications from our findings. Range contractions are projected for several species, even for species using variable habitats, such as genetics ,86 and pgenetics .Our results identify broad regions where bats reported positive for sarbecoviruses most probably occur and co-occur. These hotspots coincide, but are not restricted only to Rhinolophidae diversity hotspots  and to hOur future projections assume models using present data perform adequately. However, our models do not account for biotic components that also interfere with suitability, so we are limited to inferences of distribution derived from landscape and climate drivers. Projections will therefore need validation with new data and new predictions. Related, small changes may be relevant for local health and conservation initiatives, and coronavirus hosts are a focus of increasing research . Data ch"}
+{"text": "Candida albicans, non-albicans strains including C. auris, Aspergillus and Fusarium isolates from worldwide sources.ARIA is a new annual global surveillance initiative collecting yeast and fungal isolates from worldwide designed to determine resistance to antifungal agents and trends over time. The ARIA program was developed in 2020 to provide a repository of recent clinical fungal isolates with known susceptibility profiles and to monitor resistance trends over time. ARIA reports the susceptibility patterns of its earliest data concerning echinocandins, second-generation triazoles, and fluconazole against clinical Isolates were collected from hospital worldwide during 2020, shipped to a central laboratory and re-identified by MALDI-TOF or molecular methods. MIC tests were performed by broth microdilution method in line with CLSI susceptibility testing standards. Percentage of susceptibility was calculated according to CLSI breakpoints. Antifungals tested were amphotericin B (AMB), anidulafungin (ANID), fluconazole (FLU), isavuconazole (ISA), micafungin (MIC), posaconazole (POS), and voriconazole (VOR). All testing was performed according to CLSI M27-A4 and M38-A2 methodologies.See table.Ongoing antifungal resistance surveillance like the ARIA program is of utmost importance in order to monitor the efficacy of traditional empirical therapy and for the development of novel antifungal agents. This repository and ongoing ARIA program will provide a resource to better support the biopharmaceutical industry\u2019s goals to develop new and more potent antifungal agents.All Authors: No reported disclosures."}
+{"text": "Are nursing homes exposed to potential hurricane-related inundation more likely to meet Centers for Medicare & Medicaid Services criteria for adequate emergency preparedness?In this cross-sectional study of 5914 nursing homes, a higher prevalence of emergency preparedness deficiencies among nursing homes exposed to hurricane-related inundation in the Mid-Atlantic region was observed. Exposure status remained positively associated with the presence and number of emergency preparedness deficiencies after adjustment for facility characteristics, with the converse for facilities within the Western Gulf Coast.These findings suggest opportunities to reduce regional heterogeneity and improve the alignment of nursing home emergency preparedness with surrounding environmental risks. This cross-sectional study estimates the prevalence of nursing homes that are subject to severe hurricane-related inundation within the Coastal Atlantic and Gulf Coast states and evaluates whether exposure status is associated with adherence to emergency preparedness standards across regulatory regions. Whether US nursing homes are well prepared for exposure to hurricane-related inundation is uncertain.To estimate the prevalence of nursing homes exposed to hurricane-related inundation and evaluate whether exposed facilities are more likely to meet Centers for Medicare & Medicaid Services (CMS) emergency preparedness standards.This cross-sectional study included CMS-certified nursing homes in Coastal Atlantic and Gulf Coast states from January 1, 2017, to December 31, 2019. The prevalence of facilities exposed to at least 2 feet of hurricane-related inundation used models from the National Hurricane Center across coastal areas overseen by 5 CMS regional offices: New England, New York metropolitan area, Mid-Atlantic region, Southeast and Eastern Gulf Coast, and Western Gulf Coast. Critical emergency preparedness deficiencies cited during CMS life safety code inspections were identified.The analysis used generalized estimating equations with binomial and negative binomial distributions to evaluate associations between exposure status and the presence and number of critical emergency preparedness deficiencies. Regionally stratified associations (odds ratios [ORs]) and rate ratios [RRs]) with 95% CIs, adjusted for state-level fixed effects and nursing home characteristics, were reported.Of 5914 nursing homes, 617 (10.4%) were at risk of inundation exposure, and 1763 (29.8%) had a critical emergency preparedness deficiency. Exposed facilities were less likely to be rural, were larger, and had similar CMS health inspection, quality, and staffing ratings compared with unexposed facilities. Exposure was positively associated with the presence and number of emergency preparedness deficiencies for the nursing homes within the Mid-Atlantic region . Conversely, exposure was negatively associated with the number of emergency preparedness deficiencies among facilities within the Western Gulf Coast . The associations for the number of emergency preparedness deficiencies remained after correction for multiple comparisons.The findings of this cross-sectional study suggest that the association between exposure to hurricane-related inundation and nursing home emergency preparedness differs considerably across the Coastal Atlantic and Gulf regulatory regions. These findings further suggest that there may be opportunities to reduce regional heterogeneity and improve the alignment of nursing home emergency preparedness with surrounding environmental risks. It is also uncertain whether nursing homes at increased risk of exposure are adequately prepared to safeguard residents upon encountering environmental hazards.Nursing homes\u2019 emergency preparedness is vital due to projected increases in the frequency with which coastal communities are exposed to severe weather events.11 This requires that facility administrators and staff assess, document, and plan for potential hazards, including severe weather events, that are expected to impact their geographical region.11 Emergency preparedness is then audited by state survey agencies, which are overseen by CMS regional offices.11The paucity of information regarding nursing homes\u2019 preparedness for local environmental hazards may be attributed, in part, to the inherent complexity of characterizing small-area variation in environmental exposures. Because environmental exposures vary across communities, the Centers for Medicare & Medicaid Services (CMS) has advised an all-hazards approach to emergency preparedness.12 nursing home management and staff and the superstructure of state survey agencies and CMS regional offices may not be well positioned to appraise and prepare for potential environmental hazards. Therefore, the CMS encourages partnerships with municipal agencies to ensure that nursing homes are embedded within community disaster planning and response.13 Despite this recommendation, nursing home integration into community disaster preparedness efforts remains variable.15 Prior assessments of nursing home emergency preparedness, moreover, have identified widespread deficiencies in critical competencies that include appropriate specification of evacuation routes and preparedness to shelter residents in place.16 These preventable deficiencies heighten the risk of resident morbidity and mortality following exposure to severe weather events.17Considering their competing responsibilities,In this study, we estimate the prevalence of nursing homes that are subject to severe hurricane-related inundation within Coastal Atlantic and Gulf Coast states. We then evaluate whether exposure status is associated with adherence to emergency preparedness standards by nursing homes across regulatory regions overseen by 5 CMS regional offices. The results of this study should inform practices and policies designed to align nursing home emergency preparedness with the hurricane-related inundation risk to which facilities are exposed.STROBE) reporting guideline. This research was deemed exempt from review and informed consent by the Yale University Institutional Review Board under 45 CFR 46.104.This cross-sectional study followed the Strengthening the Reporting of Observational Studies in Epidemiology , leading to a final analytic sample of 5914 facilities.We utilized the CMS Provider Information Catalog to identify certified nursing homes within states that are at risk of exposure to hurricane-related inundation along the Coastal Atlantic and Gulf Coast regions as per the National Hurricane Center (NHC) (n\u2009=\u20096167).20 Our primary exposure threshold was informed by the US National Weather Service determination that roads are impassable at inundation heights above 18 to 24 inches,21 which would preclude the safe ground evacuation of residents and transport of essential medications or subsistence provisions. The NHC data do not project inundation within levee systems because its predictions are constrained to land that is normally dry.19 We classified the 46 nursing homes within leveed areas as exposed because levee systems are both subject to failure and concentrated in areas with disproportionate risk of severe flooding.22We defined exposed nursing homes as those at risk of at least 2 feet of inundation during Saffir-Simpson Hurricane Wind Scale category 1 to 5 hurricanes as per the NHC storm surge hazard maps.19 Briefly, the NHC storm surge hazard maps aggregate maximum inundation heights, assuming a high-tide initial water level.19 Storm surge events occur when the height of water generated by a storm rises above that of normal astronomical tides.19Inundation, the height of water above the ground surface, is estimated by subtracting the height of land elevation from that of the storm surge.19 The NHC uses the Sea, Lake, and Overland Surges from Hurricanes (SLOSH) model to simulate a representative sample of hypothetical storms, resulting in 2 data products.19 The first, maximum envelopes of water, represents the maximum inundation resulting from tens of thousands of hypothetical storms, with varying meteorological assumptions.19 The second represents the maximum composite value across the maximum envelopes of water.19The methods used by the NHC to model inundation have been described previously.23 From the 252 potential emergency preparedness deficiencies, we selected a subset deemed to be most critical in accordance with prior literature and emergency preparedness guidance . We used LTCFocus (Long-Term Care Focus) data to link lagged (2018) indicators of the payer mix and quantified the percentage of residents within each facility primarily insured by Medicaid.We first estimated the percentage of nursing homes at risk of exposure to at least 2 feet of hurricane-related inundation using their geocoded addresses. We described facility characteristics for the full sample and compared these characteristics among facilities according to their inundation exposure status. We also assessed the prevalence of critical emergency preparedness deficiencies across the nursing homes within each CMS regional office designation (described hereinafter).We evaluated associations between location within an inundation-exposed area and emergency preparedness deficiencies (presence and count) using generalized estimating equations with binomial and negative binomial distributions, respectively, clustered by facility identification numbers, with robust standard errors. To address potential confounding, the models were adjusted for facility characteristics.30 we included fixed effects for state within each stratified model. We used the Benjamini-Krieger-Yekutelli correction to account for multiple comparisons.31 In sensitivity analyses, we reran the models for the 5 regional office strata after increasing the severity of the inundation exposure threshold to at least 4 feet and at least 6 feet. We conducted analyses using ArcGIS Pro (Esri), Python, version 3 (Python.org), and Stata, version 17 (StataCorp LLC). Two-sided P\u2009<\u2009.05 indicated statistical significance.We stratified our analysis across the 5 CMS regional offices overseeing state survey agencies along the Coastal Atlantic and Gulf Coast. Regional office 1 of the CMS oversees New England ; regional office 2, the New York metropolitan area (New York and New Jersey); regional office 3, the Mid-Atlantic region ; regional office 4, the Southeast and Eastern Gulf Coast ; and regional office 6, the Western Gulf Coast (Louisiana and Texas). Regional office 5 was not evaluated because it oversees Midwestern states. To adjust for state-level variation in inspection practices and patterns,The most common emergency preparedness deficiencies among the 5914 nursing homes related to appropriate emergency preparedness training and procedures, as well as the establishment and maintenance of an emergency preparedness program , exposure status appeared to be protective against emergency preparedness deficiencies. New England facilities  demonstrated a similar pattern for the presence and number of critical emergency preparedness deficiencies, although these associations were not statistically significant. The most prevalent deficiencies are related to the ability of nursing homes to safely shelter in place or evacuate residents. Especially concerning is the high prevalence of inadequate subsistence provisions or standby power systems, as these factors may prompt unnecessary evacuations and thereby compound risks to vulnerable residents.34 The stark regional variation in emergency preparedness by exposed nursing facilities suggests that it may be useful to isolate and disseminate the strategies used by nursing home administrators, staff, and regulators within high-performing regions.35 Because Western Gulf Coast nursing homes exhibited emergency preparedness adherence that was well aligned with the local environmental risks , they could potentially serve as a model for other regions. Possible explanations for the risk-responsive emergency preparedness of nursing homes in the Western Gulf Coast may include reforms following their prior experience in hurricane response.36 For example, Gulf Coast nursing home residents incurred substantial morbidity and loss of life in the wake of Hurricanes Katrina and Rita.36 Ensuing investigations determined that inadequate emergency preparedness and inappropriate evacuation decisions contributed to these costs, prompting increased federal, regional, and state oversight.37Considering the differential susceptibility of nursing home residents to external stressors, emergency preparedness should be better aligned with the likelihood and severity of exposure to environmental hazards, including hurricane-related inundation. Projected increases in the intensity and geographic distribution of hurricanes within coastal regions further heighten the importance of this issue.15 we suggest that state survey agencies and CMS regional offices consider stronger oversight and enforcement of these partnerships. Because it would be impractical for CMS regional offices to appraise and monitor environmental risks, partnerships with local and regional emergency planning agencies should be relied upon to identify facilities exposed to salient regional and local environmental hazards. In turn, regulators could identify which facilities should be prioritized for oversight based upon their historical audit performance. A regulatory framework that is responsive to environmental hazards might involve a relatively greater inspection frequency for facilities that have outstanding critical emergency preparedness deficiencies and are at disproportionate risk of exposure to regionally concentrated environmental hazards .15 Although facilities meeting these criteria should receive more intensive oversight, these changes may produce a cost-effective and more efficient allocation of oversight responsibilities.39 These partnerships may also offer valuable insight as to the alignment between facilities\u2019 exposure risk and their structural ability to withstand inundation, as determined by available building code guidance.40In addition to learning from high-performing regions, improved integration of nursing homes into local disaster planning agencies may better align emergency preparedness with the magnitude of environmental risks to which facilities are exposed. Based on our results, which support concerns that nursing homes may be poorly integrated into community disaster response models under the CMS all-hazards framework,41 Second, physical processes affecting water levels outside of the areas for which the SLOSH models are validated cannot be modeled.19 Because the storm surge hazard maps represent maximum inundation scenarios, without probabilities corresponding to hurricane category, it would be desirable to repeat this analysis with a broader range of risk scenarios as such data products become available. We refrained from incorporating assumptions regarding the respective probabilities of Saffir-Simpson Hurricane Wind Scale categories to avoid compounding uncertainties across distinct climate models as risk projections continue to evolve.42 Third, the NHC data are constrained to hurricane-related inundation and may, therefore, underestimate inundation exposure due to factors including heavy rainfall.43 It would be instructive to replicate this analysis using geospatial data that reflect the risk of severe flooding due to multiple potential causes.This study has some limitations. Our ability to classify exposure is restricted to information aggregated within the NHC storm surge hazard maps. The developers of this resource note several potential limitations regarding the assumptions required to build this product. First, the data products do not account for increases in water levels due to waves, which may result in the underestimation of inundation by 10% to 50%.We cannot exclude the possibility that state surveyors were more vigilant in issuing emergency preparedness deficiencies based on perceived inundation risk. To address this limitation, we conducted sensitivity analyses that evaluated associations between emergency preparedness and increasingly severe exposure thresholds. Because regulators\u2019 sensitivity to exposure increments has not been previously evaluated, we used a multiplicative scale to test the effect of large differences in inundation thresholds. Although the results of our additional analyses did not suggest a dose-response association between exposure severity and the likelihood of critical emergency preparedness deficiencies, they cannot rule out differences in the behavior of state surveyors or regional oversight practices.14 Nonetheless, the CMS standards subsume foundational competencies that are well aligned with national emergency preparedness guidance and prior literature.25 Moreover, inadequate emergency preparedness has contributed to adverse resident outcomes during prior emergencies due to severe weather events.2Our evaluation assumes that administrative deficiencies are reasonable indicators of nursing homes\u2019 emergency preparedness, but adherence to CMS emergency preparedness guidance does not necessarily ensure effective execution of organizational emergency planning or response.Additionally, the observational nature of this study precludes our ability to isolate organizational or regulatory behaviors and practices that may underlie regional differences in the emergency preparedness of nursing homes at increased risk of exposure to hurricane-related inundation. Complementary qualitative analyses may help to elucidate the mechanisms underlying regional variation and identify practices that better align emergency preparedness and local environmental risk.Ensuring adequate nursing home emergency preparedness is vital to the safety and well-being of vulnerable older persons, especially as community exposure to hurricane episodes is projected to increase. We demonstrated considerable regional variability in the emergency preparedness of nursing homes exposed to hurricane-related inundation. We observed an association between emergency preparedness and potential inundation exposure for Mid-Atlantic nursing homes, suggesting that these exposed facilities with critical emergency preparedness deficiencies should be prioritized for remediation. Given their competing responsibilities and lack of formal training in this domain, nursing home administrators and staff may require additional support with their assessment and response to environmental risks under an all-hazards approach. Based on our findings, CMS regional offices may need to enhance enforcement of nursing home partnerships with local emergency planning agencies, which are better equipped to appraise and address environmental risks. Finally, the favorable preparedness of nursing homes within the Western Gulf Coast region suggests that this region could serve as an exemplar of risk-responsive emergency planning and oversight."}
+{"text": "Crisis management Managing crises often requires diverging from predetermined plans. In this paper, we investigate how public health authorities in Finland acted, what kind of roles they adopted and how the expected roles and actions appeared in relation to the legislative framework and preparedness plans during the COVID-19 pandemic. Based on inter-country comparisons, Finland has managed COVID-19 pandemic relatively well. The study provides qualitative insights on pandemic governance in a decentralized multi-stakeholder public health system.Semi-structured interviews (n = 53) with key public health actors at central, regional and local levels were conducted during March 2021-February 2022. The data was analysed with thematic analysis.The predetermined roles and duties for pandemic management were not unequivocal in practice and appeared unrealistic considering the resources of the public health system. Responsibility was divided between several actors, but lack of interaction enhanced emerging tensions between them. Local and regional actors experienced national steering intervening in operational decisions. At central level distrust towards the capabilities of local and regional actors was expressed. The pandemic was framed and managed as a health crisis despite of its wider societal effects. This challenged local and regional decision-making, where wider societal impacts had to be considered.Public health authorities in Finland interpreted their roles and responsibilities in pandemic governance in various ways: some actors adopted more active agency than others and the roles were not always in line with the existing regulative framework.\u2022\u2002Interpretation of the roles outlined in preparedness plans are context dependent and may lead to conflicts between different actors.\u2022\u2002In a system with multiple actors at multiple levels, building trust and improving interaction are important for coordinated action."}
+{"text": "Prostate cancer (PCa) is the leading cause of male cancer deaths in Africa. In USA, African American men (AA) experience higher mortality rate compared to European American men (EA). While socioeconomics factors contribute toward these disparities, distinct molecular mechanisms in AA remain important drivers. For example, in previous work, we discovered that PCa form AA men harbored a significantly higher expression of Aminopeptidase N (ANPEP) as compared with EA. Aminopeptidase N regulates immune cell function and mediates tumor cell migration but its role in PCa remains uninvestigated.We explored ANPEP expression related to a range of genomic classifiers in multiple datasets. We then prospectively examined the differentially expressed genes in PCa tissues collected from 120 AA and 120 EA patients enrolled on the VANDAAM clinical trial. We further correlated ANPEP expression with various signatures related to immune and metabolic activity. We also experimentally examined the expression of ANPEP in different components of tumor microenvironment.In the VANDAAM study, ANPEP represents the top differentially expressed gene between AA and EA men. Our data driven approach revealed that ANPEP correlates with signature of cholesterol transport and androgen signaling. Interestingly, these signatures dominate in PCa with high macrophage infiltration. Deconvolution of immune cell content using computational approaches indeed demonstrated that only AA patients with high ANPEP expression significantly accumulated high content of inflammatory macrophages. Further experimental findings showed that ANPEP indeed represents a marker of tumor-associated macrophages, a type of immune cells known to contribute to PCa progression.We have identified ANPEP as a macrophage-related gene with a potential role in cholesterol metabolism and AR signaling in AA. Future work will focus on the functional role of ANPEP activity in the tumor immune microenvironment using Liquid chromatography-high resolution mass spectrometry and explants derived from AA and EA PCa patients."}
+{"text": "Freezing of gait (FoG) is a paroxysmal and sporadic gait impairment that severely affects PD patients\u2019 quality of life. This review summarizes current neuroimaging investigations that characterize the neural underpinnings of FoG in PD. The review presents and discusses the latest advances across multiple methodological domains that shed light on structural correlates, connectivity changes, and activation patterns associated with the different pathophysiological models of FoG in PD. Resting-state fMRI studies mainly report cortico-striatal decoupling and disruptions in connectivity along the dorsal stream of visuomotor processing, thus supporting the \u2018interference\u2019 and the \u2018perceptual dysfunction\u2019 models of FoG. Task-based MRI studies employing virtual reality and motor imagery paradigms reveal a disruption in functional connectivity between cortical and subcortical regions and an increased recruitment of parieto-occipital regions, thus corroborating the \u2018interference\u2019 and \u2018perceptual dysfunction\u2019 models of FoG. The main findings of fNIRS studies of actual gait primarily reveal increased recruitment of frontal areas during gait, supporting the \u2018executive dysfunction\u2019 model of FoG. Finally, we discuss how identifying the neural substrates of FoG may open new avenues to develop efficient treatment strategies. There hAlthough FoG in PD patients is more prevalent when the patients are OFF dopaminergic treatment (60%) than when ON (36\u201338%) , FoG shoNotably, the prevalence of PD in our aging population is predicted to substantially increase by approximately 30% by 2030 , with a 1.1The knowledge about the neural mechanisms controlling human gait is still incomplete, mainly due to the complexity of the human locomotor system and the technical limitations of studying locomotion. Accordingly, the current knowledge about the neural control of human gait is primarily derived from animal models. Studies on gait regulation in animals revealed widespread neural circuitries spanning different nervous system levels, including cortical, subcortical, brainstem, and spinal cord structures . HoweverThe neural networks that govern human gait are organized in an evolutionary hierarchy see  that proThe top of the gait control hierarchy comprises higher-level control centers in the cerebral cortex and the basal ganglia (BG) that modulate indirectly and directly the locomotor regions\u2019 activity in generating efficient volitional gait regulation. At rest, the globus pallidus internus (GPi) and the substantia nigra reticularis (SNr) provide constant GABAergic inhibitory signals to the MLR/PPN that restrict the information flow in the spinal cord and prevent unwanted movements. During motor activity, input from frontoparietal areas can amplify or reduce these inhibitory signals . In partIn conclusion, the neural systems underlying gait control in humans comprise complex mechanisms with intertwined structures, in which higher-order cortical areas indirectly regulate the output of the locomotor regions via established reciprocal connections with subcortical structures. This hierarchical bi-directional organization allows the human gait control system to adapt its motor output to changing intentions and environments flexibly. However, this flexible planning and execution of walking movements is deficient in PD patients since the underlying neurodegenerative disease process affects the gait control system at different levels.1.2Five non-exclusive pathophysiological models have been proposed to explain the origin of FoG in PD . These mabnormal gait pattern generation\u2019 hypothesis proposes that the asymmetric and uncoordinated gait preceding episodes of freezing . Due to the deficient cortico-subcortical crosstalk, the signals from the cognitive, motor, and limbic cortical areas overwhelm the limited processing capacity of the striatum in PD patients and lead to an overinhibition of brainstem structures, eventually manifesting in FoG (decoupling\u2019 between posture preparation (SMA) and step initiation (the motor cortex) causes multiple dysfunctional anticipatory postural adjustments that are manifested as knee trembling during FoG  \u2018freezing  results g in FoG . Anotherring FoG . The bre changes . This mo changes . Finallye of FoG . AccordiThe apparent heterogeneity of the mechanisms underlying FoG in PD proposed by the five non-exclusive pathophysiological models of FoG indicates that consensus on the neurological underpinnings of FoG is far from reach and, consequently, extensive research is warranted to unravel the complexities of this phenomenon. Studies employing imaging techniques contribute valuable new data for a better understanding of the physiology and pathophysiology of human gait control. Identifying major neural substrates of FoG may open new avenues for developing novel and efficient treatment strategies for FoG in PD patients. This review summarizes and critically evaluates the recent imaging studies on FoG in PD across multiple methodological domains to shed light on structural correlates, connectivity changes, and activation patterns associated with the pathophysiology of FoG in PD patients. Furthermore, the disparate imaging results are related to current pathophysiological models of FoG in PD. For a complementary review that discusses electrophysiological findings in light of the pathophysiological models of FoG, the reader is referred to the recent review by 2The review encompasses articles not previously covered or thoroughly discussed by recent reviews on FoG in PD patients . The incThe PubMed database and Google Scholar were used to collect the articles with the search queries \u2018Parkinson\u2019 AND \u2018Freezing of gait\u2019 AND . After a systematic assessment of the articles\u2019 eligibility, the total number of reported articles in this review is 40 articles. These articles were divided into 18 resting-state MRI studies , 13 task-based MRI studies , and 9 functional near-infrared spectroscopy (fNIRS) studies.In order to further assess the quality of evidence provided by the different imaging studies, we systematically graded each reported study based on six pre-defined criteria, i.e., studied sample, clinical groups, FoG/gait assessment, correction for multiple comparisons, control for differences in covariates, and experimental design  structural connectivity investigate abnormalities in WM tracts by diffusion tensor imaging (DTI) and examine mainly mean diffusivity (Md) and fractional anisotropy (FA). Several findings have emerged from different WM connectivity studies, despite differences in experimental methods and analysis approaches, namely whole-brain voxel-wise analysis and region of interest (ROI) correlation analysis.Several structural connectivity studies report patterns of WM abnormalities that constitute potential biomarkers supporting the \u2018interference model\u2019, i.e., deficient crosstalk between cortical areas and the BG. Notably, structural imaging studies revealed a distributed pattern of reduced WM tracts connecting subcortical structures, encompassing the cerebellum , subthalper se but may be related to other confounding factors such as cognitive impairment and general (motor) deficits associated with Parkinson\u2019s disease.Other structural imaging studies align with the \u2018executive dysfunction\u2019 model of FoG, which proposes a decoupling between the frontal lobe and the BG. These studies report WM tract disruptions between frontal areas and subcortical structures  and dist3.2A promising approach to investigate the neural mechanisms underlying FoG in PD patients is resting-state fMRI (rs-fMRI). This neuroimaging approach has been extensively used in studying the neural correlates of FoG in patients with PD as it permits the assessment of the whole brain without an experimental task. Rs-fMRI quantifies the functional connectivity between spatially disparate neural networks  by detecting fluctuations in spontaneous BOLD signals across the whole brain . The parSeveral rs-fMRI studies reveal a reorganization of the intrinsic functional connectivity (FC) within higher cortical regions  and subcIt is well established that PD patients, and those suffering from FoG in particular , rely moDysfunctional network connectivity between subcortical and cortical areas extended beyond cognitive and sensorimotor areas, also affecting visuospatial networks. In PD patients with FoG, abnormal FC was observed between the visual cortex, mainly of the right hemisphere, and left caudate , right PSeveral studies converge in reporting a decrease in resting-state FC between several cortical areas along the dorsal stream of visuomotor processing . In partThe significant findings derived from resting-state fMRI (rs-fMRI) studies primarily support the \u2018interference\u2019 or the \u2018perceptual dysfunction\u2019 models of the pathophysiology of FoG in PD. These findings should nevertheless be treated with caution, given several inherent limitations of the rs-fMRI method in FoG in PD. On the one hand, rs-fMRI studies of FoG mainly adopt a cross-sectional approach that compares the neurophysiological changes of PD patients with FoG with those of healthy controls or PD patients without FoG at a given time. A fundamental shortcoming of such a cross-sectional approach is the failure to consider the contribution of interindividual variability in FoG severity within groups of PD patients with FoG. In particular, the sole comparison of resting-state FC changes in PD patients with FoG versus healthy controls can be even more problematic than the comparison of PD patients with FoG with PD patients without FoG, as the former comparison cannot differentiate between specific neuroanatomical/-physiological changes related to FoG and those related to other more general deficits  in Parkinson\u2019s disease. To circumvent these limitations of cross-sectional approaches, the alternative study design adopted by On the other hand, rs-fMRI studies can only indirectly correlate resting state FC to FoG measures, as these studies relate neurophysiological changes measured when lying supine in the MRI scanner to objective or subjective gait assessments obtained outside the scanner. Except a few studies that related resting-state FC changes with objective measures of FoG recorded during a turning or walking task before the scanning session, most of the rs-fMRI studies on FoG in PD related resting-state FC changes with subjective self-reports of FoG, i.e., using the FoG-Questionnaire. However, the reliability of subjective recall of FoG symptoms may be hampered by cognitive deficits. An alternative objective assessment tool of FoG that can be considered in future rs-fMRI studies is the rating instrument developed by 4Task-based fMRI studies can detect real-time correlations of neurophysiological alterations with gait-related performance measured during the scanning session. These studies mainly adopt virtual reality (VR) and motor imagery (MI) paradigms that correlate neurophysiological changes with foot-pedaling performance and with the mental simulation of pre-instructed (gait-related) actions, respectively. In addition to VR and MI paradigms, a recent study adopted a novel paradigm of dorsal or plantar foot-flexion movement in response to auditory stimuli, which meant to approximate the sensorimotor activity during normal gait without inducing episodes of FoG . Importa4.1In combination with functional neuroimaging, virtual reality (VR) paradigms were used in several studies to explore the underlying pathophysiology of FoG in PD patients. Virtual reality is supposed to permit an objective and safe evaluation of FoG in PD patients in an ecologically valid environment. The reported VR paradigms consist of first-person perspective navigation. Participants navigate using MRI-compatible foot pedals through a virtual environment that displays several triggers known to produce FoG in PD patients . In these studies, FoG is measured as an episode of motor arrest, consistently defined across studies as an abnormally long period of between-footstep latency compared to the mean between-footstep latency computed during normal walking. Measures of these motor arrests were positively correlated with self-reported severity of FoG , suggestShine and colleagues conducted a series of VR studies revealing consistent alterations in BOLD activation levels and functional connectivity (FC) changes between cortical and subcortical regions of PD patients with FoG. Increased activation in frontoparietal regions was negatively related to freezing severity, whereas reduced activity in the BG, thalamus  and pre-In agreement with the findings reported by Shine and colleagues, further VR studies revealed abnormal functional connectivity (FC) patterns between cortical and subcortical structures . NotablyMost of the above-reported abnormalities concentrate on the \u2018hyper-direct\u2019 pathway see , comprisDespite differences in the implemented VR experimental paradigms, most of the neuroimaging findings revealed by task-based VR paradigms support the predictions made by the 'interference model' . Taken t4.2Motor imagery (MI) paradigms are adopted to assess and modulate gait impairments in PD patients. MI is defined as the mental simulation of action without overt execution . MI simuFollowing the reported hypoactivation in subcortical regions in VR studies , imagingSeveral MI studies revealed abnormal patterns of activation encompassing cortical areas along the dorsal visuomotor pathway that were more pronounced in the right hemisphere of PD patients with gait impairments . During Studies adopting MI paradigms report various neurophysiological changes that primarily show agreement with either the \u2018interference\u2019 or the \u2018perceptual dysfunction\u2019 models of FoG in PD. The variability in observed findings across MI studies is partly due to the differences in complexity across the implemented MI paradigms and differences in the studied samples of PD patients. The latter is particularly problematic for a cross-studies comparison since the included patients show a wide range of disease severity. Moreover, the lack of FoG assessments in some MI studies renders it difficult to precisely distinguish between neurophysiological changes associated with general symptoms of PD and those mainly linked to FoG in PD.4.3Functional near-infrared spectroscopy (fNIRS) is a neuroimaging method that recently gained popularity in studying the neurophysiology of gait impairments and FoG in PD. Like fMRI, this technique detects hemodynamic changes (of oxygenated and deoxygenated hemoglobin) in cerebral blood flow produced by neurovascular coupling. Being both portable and wireless, fNIRS permits measurements of brain activity during actual walking, i.e., while being in an upright position, thus having the advantage of also assessing the postural and balance control mechanisms involved in bipedal gait (in contrast to the supine position when lying in an MRI scanner). Moreover, fNIRS studies allow the direct correlation of neurophysiological changes with real-time behavioral gait metrics measured by wearable gait sensors. Studies investigating prefrontal activity with fNIRS during a walking task converge on reporting higher activity within the PFC  and the Furthermore, studies assessing the effect of dopamine treatment on the recruitment of executive functions during gait indicate that PD patients with FoG exclusively employ executive functions to alleviate the loss of movement automaticity, as evidenced by increased recruitment of the PFC during gait . In contSince all fNIRS studies to date were restricted to the investigation of frontal brain regions associated with executive functions, i.e., the PFC and the DLPFC, their findings are largely discussed in light of the \u2018executive dysfunction\u2019 model of FoG in PD. Nevertheless, some fNIRS results indicate a potential reliance on other strategies, e.g., visuospatial strategies, to compensate for the loss of gait automaticity in PD patients with FoG. Given that dual-task turning requires higher cognitive control than single-task turning and, consequently, higher activation of the PFC, the counterintuitive observation of lower recruitment of PFC in PD patients suffering from FoG during dual-task turning  suggests5meta-analysis of neuroimaging studies revealed that gait impairments in PD are associated with lower SMA and higher CLR activation  in PD patients and discusses the neural correlates in light of the different pathophysiological models of FoG. Although the imaging findings do not converge on a single pathophysiological model of FoG, evidence suggests that FoG in PD is associated with more than a single neural mechanism. The studies converge on highlighting functional decoupling between cortical and subcortical regions as well as abnormal activation patterns, particularly within frontoparietal and parieto-occipital regions and the striatum. The current review demonstrates that despite multiple pathophysiological insights across the different studies, systematic comparisons are limited due to differences in neuroimaging modalities and targeted brain mechanisms. Notably, the potential differential neural substrates underlying FoG during walking and FoG during gait initiation remain unaddressed. Thus, developing novel experimental paradigms that tackle this distinction is warranted. Besides, future studies should adopt multimodal neuroimaging and address the above-mentioned limitations that currently hamper comprehensive imaging studies of FoG in PD patients. These future imaging studies will hopefully permit the improvement of current treatment strategies and set the ground to devise novel treatments for FoG in PD that are tailored to the individual patient and thus more efficient.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Ecologists usually find that plant demography  changes along with plant size and environmental gradients, which suggests the effects of ontogeny-related processes and abiotic filtering. However, the role of functional traits underlying the size\u2013 and environment\u2013demography relationships is usually overlooked. By measuring individual-level leaf traits of more than 2700 seedlings in a temperate forest, we evaluated how seedling traits mediated the size\u2013 and environment\u2013demography relationships. We found leaves were larger for taller seedlings; leaf economics traits were more conservative in taller seedlings and under high-light and low-elevation conditions. Structural equation modelling showed that a higher survival probability for taller seedlings was indirectly driven by their larger leaf area. Although taller seedlings had lower growth rates, larger and more resource-conservative leaves could promote the growth of these tall seedlings. Environmental variables did not influence seedling survival and growth directly but did influence growth indirectly by mediating trait variation. Finally, species-specific variation in traits along with size and environments was associated with the species-specific variation in seedling survival and growth. Our study suggests that not only plant ontogeny- and environment-related ecological processes, but functional traits are also important intermediary agents underlying plant size\u2013 and environment\u2013demography relationships. The seedling stage is a bottleneck stage for plant survival and growth because of the production of more individuals than could occupy open spaces and their general susceptibility to surrounding abiotic and biotic environments . Given tWith the increasing number of studies exploring seedling survival and growth, especially in permanent forest dynamics plots, most studies find that seedling height is the most important factor influencing survival and growth, and superior to other biotic and abiotic factors . Ac; )"}
+{"text": "Transcatheter heart valve (THV) embolization is a rare complication of transcatheter aortic valve implantation (TAVI) generally caused by malpositioning, sizing inaccuracies and pacing failures. The consequences are related to the site of embolization, ranging from a silent clinical picture when the device is stably anchored in the descending aorta to potentially fatal outcomes . Here, we present the case of a 65-year-old severely obese woman affected by severe aortic valve stenosis who underwent TAVI complicated by embolization of the device. The patient underwent spectral CT angiography that allowed for improved image quality by means of virtual monoenergetic reconstructions, permitting optimal pre-procedural planning. She was successfully re-treated with implantation of a second prosthetic valve a few weeks later."}
+{"text": "Editorial on the Research TopicAdvances in rehabilitation intervention after limb amputationThe tenth anniversary of the Boston Marathon Bombings is soon approaching on April 15, 2023. This mass casualty event highlighted the extraordinary role of bystanders and first responders who applied tourniquets, highly skilled trained trauma teams at the five Boston level I Trauma academic medical centers, followed by high quality, coordinated acute rehabilitation care in ensuring the best possible outcomes for the survivors  pressures and residuum muscle activation after transfemoral osteomyoplastic amputations (OTFA) during brisk and self-paced gait compared to the performance with that of intact controls. They showed that RSI pressures were distributed throughout the residuum-socket and that muscles were engaged and often co-contracted at key times during the gait cycle. Their recommendations include enhancing specific therapeutic exercises as part of OTFA rehabilitation to improve control activation of hip adductors, hamstrings, and quadriceps in the intact and distal-residual limbs, thereby optimizing overall gait performance stability and reducing excessive energy expenditure. This study highlights that new reconstruction techniques require that new, patient-centered rehabilitation protocols be developed and studied.Efforts to incorporate newer technical developments in amputation surgery and reconstruction demonstrate a shift toward an outcomes-oriented approach in amputee care \u201313. SurgKhetarpaul et al. focuses on the interdisciplinary team approach (Frontiers | Socioecological model-based design and implementation principles of lower limb preservation programs as partners for limb-loss rehabilitation programs\u2014A mini-review. Their review article can be helpful to healthcare institutions and organizations seeking to develop, expand, or refine their ability to provide comprehensive limb care. The model system of care includes presurgical planning, postsurgical and early pre-prosthetic rehabilitation care, and prosthetic and lifelong care. Rehabilitation care includes coordination with community resources, such as peer support, and vocational, recreational, and driving assessment. The emphasis on prior mental health concerns and new concerns that arise with limb loss should also be addressed by mental health professionals in the multidisciplinary care provider team model.When treating individuals with severe limb trauma, important decisions around limb salvage vs. amputation and optimal amputation level are ideally made through an interdisciplinary approach to optimize both surgical and functional outcomes . The lasapproach  as the mWe are confident that this series of articles will advance the multidisciplinary surgical and rehabilitation care that takes place before and after limb amputation and will provide a successful framework for ongoing research."}
+{"text": "Drosophila. We use embryos that greatly differ in length and, importantly, possess distinct length-scaling characteristics of the Bicoid (Bcd) gradient. We systematically analyze the dynamic movements of gap gene expression boundaries in relation to both embryo length and Bcd input as a function of time. We document the process through which such dynamic movements drive both an emergence of a global scaling landscape and evolution of boundary-specific scaling characteristics. We show that, despite initial differences in pattern scaling characteristics that mimic those of Bcd in the anterior, such characteristics of final patterns converge. Our study thus partitions the contributions of Bcd input and regulatory dynamics inherent to the AP patterning network in shaping embryonic pattern's scaling characteristics.How patterns are formed to scale with tissue size remains an unresolved problem. Here we investigate embryonic patterns of gap gene expression along the anterior-posterior (AP) axis in  PatternDrosophila, the maternally-derived morphogenetic protein Bicoid (Bcd) forms a concentration gradient along the AP axis to instruct embryonic patterning .Prof Jun Ma was supported by National Key R&D Program of China [2021YFC2700403 & 2018YFC1003203], National Key R&D Program of China [2021YFC2700403 & 2018YFA0800102], 10.13039/501100001809National Natural Science Foundation of China [31871249].Prof Feng He was supported by Data will be made available on request.The authors declare no competing interests."}
+{"text": "Liver diseases are responsible for over 2 million deaths each year and the number is rapidly increasing. There is a strong link between edibles, gut microbiota, liver fat and the liver damage. There are very limited therapeutic options for treatment specifically for Alcoholic liver disease (ALD) and Non-Alcoholic liver disease (NAFLD). Recently, identified Edible Exosomes-like nanoparticles (ELNs) are plant derived membrane bound particles, released by microvesicular bodies for cellular communication and regulate immune responses against many pathogens. Many studies have identified their role as hepatoprotective agent as they carry bioactive material as cargoes which are transferred to recipient cells and affect various biological functions in liver. They are also known to carry specific miRNA, which increases the copy number of beneficial bacteria and the production of lactic acid metabolites in gut and hence restrains from liver injury through portal vein. Few in-vitro studies also have been reported about the anti-inflammatory, anti-oxidant and detoxification properties of ELNs which again protects the liver. The properties such as small size, biocompatibility, stability, low toxicity and non-immunogenicity make ELNs as a better therapeutic option. But, till now, studies on the effect of ELNs as therapeutics are still at its infancy yet promising. Here we discuss about the isolation, characterization, their role in maintaining the gut microbiome and liver homeostasis. Also, we give an outline about the latest advances in ELNs modifications, its biological effects, limitations and we propose the future prospective of ELNs as therapeutics. Liver diseases have pathological spectra ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is one the most common diet and fat associated non-communicable disease. Presently, 25%-35% and 5%-15% of the general population of Western and Asian countries, respectively, are affected by this disease. This proportion is even higher in people with type 2 diabetes (60%-70%), and in those who are obese or morbidly obese (75%-92%) compared to the general population. Like alcoholic liver disease there is no effective treatment to date for NAFLD. In the absence of a proven effective therapy, we must follow a multi-disciplinary approach in NAFLD treatment. Treatment is mainly directed towards weight loss and risk factor reduction, as most patients are obese or have metabolic syndrome. Dietary modification plays a key role since a carbohydrate-rich diet, especially with high fructose, is the major cause of obesity, insulin resistance and NAFLD development.in vitro and in vivo are related to gastrointestinal cell lines or diseases such as inflammatory bowel diseases, gastric cancer, colitis, etc. so far reported.Liver disease patients also exhibit gut bacterial overgrowth, enhanced gut permeability and increased paracellular leakage of gut luminal antigens, factors that promote liver damage. A dietary intervention in obese or overweight subjects, consisting of administering an energy-restricted high protein diet during six weeks, increased the diversity of species in the gut, along with decreased adiposity, which reverted to basal levels after the diet was stopped. Dietary components are not only consumed by the host (humans) but also by the gastro-enteric microbiota. The kind of diet we consume effects the microbiota composition as well as the nutritional, toxicological, and biochemical components availability after processing of food in the gut. Though hepatoprotective dietary products have been identified, there is still a need for further investigation to completely understand the mechanism of action of various components in the diet. The major problem is that to attain a certain amount of nutrient, gut microbiota modulation, a large quantity has to be consumed. Hence, a prospective solution to it can be Edible exosomes-Like Nanoparticles (ELNs). ELNs are small membrane vesicles which carry various biomolecules as cargoes The liver is one of the vital organs which readily acts as scavenger, contributes in immune surveillance, and is the only organ to have regenerative property. Gut derived products transported into liver by portal vein to liver and in feedback gut receive bile hence forming the interface of gut-liver axis. This interface maintains the gut homeostasis by maintaining the gut microbiota and host immune cells. Mostly in liver diseases this barrier has found disrupted leads to invasion of microbes and microbial particles inside host tissue. There are many therapeutic options which are available for various liver diseases are based on synthetic drugs, prebiotics, probiotics and synbiotics. In this review, we have summarised about ELNs in accordance to their structure, biochemical composition and bio-availabity to target cells, and their promising future therapeutic applications in liver diseases as this could be one of the potent prebiotics which will be safe, efficient and affordable for the treatments.For isolation of ELNs, there exist various methods, among which differential ultracentrifugation is considered the gold standard. Firstly, edible part of plants are grounded in to juice using mixture then further procedure followed to remove large plant debris or fibres and other unwanted aggregates. Differential ultracentrifugation involves a multistep process that includes low speed centrifugation i.e. 1000 \u00d7 g to get rid of larger particles or fibres, followed by medium- speed centrifugation of 10,000 \u00d7 g for removal of larger debris and intact organelles. At last, high-speed ultracentrifugation of 100,000- 150,000 \u00d7 g was used for pelleting down exosomes or exosome-like particles Like other mammalian EVs, ELNs can be characterized by various ultrasensitive microscopic methods that are Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM) or Atomic force Microscopy (AFM) and for structural analysis at subcellular level ELNs ultrastructural analysis has been reported by cryo-Electron Microscopy. Where the cup shaped spherical subcellular structures can be seen with their double membranous lipid bilayer and hence identified as ELNs. Characterization of mammalian EVs is also possible by Flow-cytometry as they have specific markers according to their cell of origin. But for ELNs till now there are no specific markers reported, hence this restricts us from using various methods for their characterization. For determination of size and charge of these particles, Dynamic Light Scattering (DLS) has been extensively used. Now days to analyse their size along with concentration Nanoparticle Tracking Assay (NTA) has been followed as it can analyse the Brownian motion of these particles with respective size and concentration. To determine the dispersity or their repulsive nature to avoid aggregation along with stability Zeta analyser can be used to calculate their membrane potential Fig. .The variable surface glycoprotein and lipid compositions among all EVs acts as ligands which are responsible for bio-distribution and specific binding to target cells. Mostly, ELNs uptake had been identified by various ways such as membrane fusion, phagocytosis, macro-pinocytosis and receptor mediated endocytosis. Membrane fusion generally depends on same membrane fluidity of both ELNs and membrane of target cell which requires a low pH 5 Lactobacilus, PC- enriched grapefruit derived ELNs and these were preferentially taken up by Ruminococcaceae whereas the PA and PC depleted vesicles are not taken up by these bacteria. Considering the in vivo bioavailability of this ELNs PA enriched vesicles generally accumulate in gut whereas PC enriched vesicles reach out to liver when given orally. Still the need of understanding the effect of membrane lipid composition in uptake of ELNs by their target cells is open for research.Bio-distribution mainly depends on several factors like parent cell source, uptake mechanism of ELNs by target cells and their retention in circulation along with the membrane composition. Studies of mammalian EVs, RBC-derived EVs showed a gradual uptake by liver (44.9%), bone (22.5%), skin (9.7%), muscle (5.8%), spleen (3.4%), kidney (2.7%) and lung (1.8%). EVs of mammalian cells have specific markers or receptors according to their parent cells which helps them in easy availability to their target cells with the respective ligands for interaction In vivo oral administration of ELNs are well explained by pharmacodynamic study of Acerola ELNs (AELNs) using PKH26 fluorescent dye. They mainly reach out to mice intestine, liver, bladder and ovary after 1hr of consumption All plant derived EVs have been reported to carry different types of proteins, and nucleic acids as cargos which play a substantial role in intercellular communication. Nucleic acids i.e. miRNAs have been detected. EVs also carries DNA, that can be used for identification of translational biomarkers or mutational modifications in parent cells but their physiological significance is currently unknown.In 2006, for the first time presence of functional extracellular RNA was reported in murine stem-cell derived EVs Lactobacillus rhamnassus GG (LGG) that results in production of lactic acid and its derivatives which acts as ligands to activate anti- inflammatory pathways in host  mitigates Clostridioides difficile infections (CDI) which is a leading cause of antibiotic resistant colitis Clostridiaceae, Ruminococcaceae and Lachnospiraceae hence regulate the production of short chain fatty acids (SCFAs) that helps in enhancing intestinal immunity in mice Plant derived ELNs are present in our diet and reach the gut with daily intakes. They can also able to withstand the digestive juices and the harsh condition during digestion of food, hence maintains their integrity at gut. Many studies reveals the therapeutic implications of various plant- derived ELNs in mitigating diseases concerned to intestinal barrier and gut microbiota homeostasis such as colitis, inflammatory bowel diseases, colorectal cancer. Ginger derived ELNs carrying miR396e were successfully taken up by ost Fig.  30. At tMany therapeutic studies using ELNs have been reported till date. Most studies explaining the biological significance of ELNs reported against dextran sulphate sodium (DSS) induced colitis, inflammatory bowled diseases and on gut- microbiota. ELNs had shown their potentials like anti-inflammatory, anti- cancerous and anti-oxidant effects by changing the fate of recipient cells. There are few clinical trials which are already registered for liver diseases Table .Zhuang et al. 2015 reported the hepatoprotective effect of ginger-derived ELNs (GELNs) against alcohol-induced liver damage in mice. They identified Shogaol, the dehydrated analogue of gingerol activates the nuclear factor erythroid 2-related factor 2 (Nrf2) in a TLR4/ TRIF-dependent manner lead to the expression of liver detoxifying/ antioxidant genes like HO-1, NQO1, GCLM, and GCLC. Apart from antioxidant defences, Nrf2 also have critical roles in modulating various cellular processes like hepatocyte proliferation during liver regeneration, inflammation [Nrf2 is involved in maintaining hepatocyte identity during liver regeneration] Fig.  and drug in vitro.CD98 have a potential role in Non- alcoholic fatty liver diseases (NAFLD), hence co-localization of garlic ELNs indicates to be a promising target for both therapeutic and drug therapy in vivo, but due to the reduced absorption of triglycerides at jejunum, helps in systemic reduction of lipid which might lead to amelioration of steatosis. With increase in gene expression of junctional proteins such as CLD1, OCLN, ZO1 it also enhance the recovery of barrier permeability in colitis. Its contribution in concentration of amino acids and bioactive lipids in the jejunum, which are deficient in obese patients, could accelerate the restoration of intestinal functions during weight loss in obese patients.In context to metabolic syndrome diseases like hyperlipidaemia, obese- associated intestinal complications, OELNs increases the villi size in jejunum by lowering the fat absorption and chylomicrons production by targeting microsomal triglyceride transfer protein (MTP) hence reduced the plasma lipid concentration. It also acts upon angiopoietin-like protein-4 (ANGPTL4) Apart from oral administration of ELNs, the effect of Shiitake mushroom ELNs intraperitoneally alleviates haemorrhage and cell death in fulminant hepatic failure within 6 hrs administration Clostridial clusters IV and XIVa of Firmicutes helps in lowering the pH of colon thereby inhibit growth of pathogens In vivo studies using OELNs also suggests inhibition in lipid absorption at intestinal epithelia and at liver as well which also makes them perfect candidates to mitigate metabolic syndromes associated to liver diseases Lactobacillus, Bifidobacteria, Enterobacter, Bacteroides, Clostridium produces bileFaecalibacterium prausnitzii along with Bifidobacterium releases cholines Lactobacilluslactobacillus and streptococcus as well along with push them to produce metabolites which help in inter-bacterial communication in the gut E.coli they also strengthen the gut immunity and proof their selves as potential therapeutic elements. Hence targeting gut microbiota using ELNs for therapeutic interventions like probiotics could help in developing chronic liver diseases and the metabolic syndromes that are associated to liver. Apart from gut microbes in gut-liver axis, from physiological point of view there exist a strong correlation between High fat Diet and insulin resistance in development of Type 2- Diebetes Various studies suggested that alteration in gut microbiota i.e. gut dysbiosis leads to several diseases. Small intestinal bacterial overgrowth (SIBO) results into production of endotoxins leads to damage intestinal epithelia known as leaky gut and this translocation resulting into hyper inflammation, bacterial peritonitis, hyperdynamic or portal hypertension states. The strategic distal position of liver downstream to gut makes it the most effective organ by the endotoxins or microbiota produced components among other distal organs lactobacillus rhamnassus GG (LGG) used as probiotics and found to give promising results in recovery of disordered gut hence improving liver disease conditions. Before reaching to their site of action i.e. intestinal region live probiotic bacteria had to tolerate the bactericidal effects of various gastric juices, one of the challenges in applications of probiotics. Their preservation in different climatic zones accordance with transportation also found as obstacles. The gut microbiota varies from one person to another the species of bacteria could be same but the strains varies accordingly. Hence considering probiotics as a common solution cannot be fruitful.Interface of gut-liver axis constitute the multilayer defence of physical, humoral and immunological barrier to protect the body from primary exposure of endotoxins and other infectious particles that entered through gut. Liver diseases resulted due to alcoholic and non- alcoholic associated parameters. Alcohol breaches the barrier and this injury compels specific changes in gut microbiota that can enhance alcohol induced liver diseases. Continuous alcohol consumption increases endotoxin producing bacteria and reduction in autochthonous taxa that produces short- chain fatty acids (SCFAs) leads chronic liver disease to cirrhosis and alcoholic hepatitis Considering the therapeutic approaches, scientists surmount many challenges mainly safety delivery of therapeutic molecules to reach specific target site, low toxicity and economic production costs. Formation of such cost effective pharmaceutical molecules or nanoparticles with low immunogenicity, cytotoxicity needs complex fabrication processes In development of pristine plant derived nanovesicles (PNVs), the major concern was the preparation of uniform-sized with efficient loading of desired drug molecules to reach specific target site. For which researchers employed the Bligh and Dyer technique based on hydration of a lipid that earlier used for the fabrication of liposomes  in vivo have seen to be effective against brain GL- 26 brain tumour Aiming to the specificity and biocompatibility with lesser side effects PNVs encapsulated with desired molecules has been implemented against various diseases. It improves the delivery of therapeutic drug molecules that mainly involves hydrophobic drugs, siRNAs, miRNAs or proteins as they easily penetrate into tissues and with an enhanced circulation period. Grape fruit EVs (GfEVs) has been found as efficient carriers for the delivery of exogenously loaded Alexa fluor tagged Bovine Serum Albumin (BSA) and Heat Shock Protein 70 (HSP 70) into Peripheral Blood Mononuclear cells and colon cancer cells. They found as safe, potential and effective carrier for the delivery of exogenous proteins as compared to the proteins without EVs ELNs can be considered as the future of therapeutics specially for the gut and liver diseases. With the advancement of technology, the techniques to isolate, enumerate and characterize makes it much easier to use it as therapy. Not only this, the cargoes information in ELNs, and its association with restoration of gut microbiome homeostasis, hepatoprotective role makes it more potent as treatment option Fig. . With re"}
+{"text": "Methods and Applications in Exercise Physiology aimed to highlight the latest experimental techniques and methods relating to research and practice. In this series, we capture recent advances in measurement techniques for 1) cardiorespiratory exercise testing, 2) athletic performance, and 3) health monitoring.Exercise physiology is pivotal in optimizing health and performance as it influences various aspects of life, from sports performance to clinical rehabilitation and occupational health. 2peak measured by a single graded exercise test (GXT) is representative of an individual\u2019s true maximum capacity, Hebisz et al. found no appreciable differences with verification tests performed 15\u00a0min after the GXT (cycling) or on a separate day. The ventilatory threshold and respiratory compensation point are other common markers of cardiorespiratory fitness measured during GXTs. Kim et al. developed and validated an automated method to identify these inflection points objectively. Together, these studies help to improve the way we measure key indicators of cardiorespiratory fitness.Valid assessment of maximum oxygen uptake and ventilatory threshold have been hallmarks of cardiorespiratory exercise testing for assessing athletic performance. Investigating whether VOHu et al. analyzed the results of twelve studies, concluding that although tDCS does not significantly improve upper limb muscle strength, significant improvements in upper limb endurance performance  can be achieved. Alternatively, the study by Lu et al. shows that tDCS can significantly improve muscle strength and explosive force of the non-dominant knee. Taken together, tDCS shows promise in offering an avenue to improve indicators of muscular performance.Improvements in athletic performance are synonymous with enhanced muscular strength and endurance. Recent research has sought to elucidate if non-invasive brain stimulation technology can promote these outcomes. Transcranial direct current stimulation (tDCS) induces focal and transient changes in cortical excitability by applying a low-intensity direct current to the scalp. In a systematic review, Date et al. have shown that surface EMG of Brachialis muscle activity accurately reflects intramuscular EMG. As such, surface EMG offers a non-invasive, easy to perform, less uncomfortable technique for research and clinical practice. On the sports field, COD performance plays a pivotal role in match-winning situations. Among youth basketball players, Chen et al. demonstrated that 505 COD performance measured with the COD timer app could be used to accurately capture timing data, compared to more expensive timing gate methods. Confirmation that these less expensive methods are valid and reliable will enable a broader range of applications for these performance assessments.Simpler and more accessible approaches have also been proposed for measuring muscle activity and change of direction (COD) performance. While monitoring muscle activity has conventionally involved intramuscular electromyography (EMG), which is invasive and requires specialized expertise, Zhang et al. examined the accuracy of a flash glucose monitoring device among overweight/obese persons during sitting and walking before, during, and after an individual\u2019s postprandial peak. Although absolute glucose readings from the flash glucose monitoring device underestimated plasma glucose, its overall accuracy was clinically acceptable during postprandial sitting and walking conditions in overweight or obese young adults, highlighting the potential for this technique to have widespread health-monitoring implications.To help individuals with diabetes or poor glucose control improve glycemic control, continuous glucose monitoring has increasingly been adopted as a novel and feasible tool. Potter et al. investigated whether an abdominal circumference-focused method of percent body fat estimation accurately represented dual-energy x-ray absorptiometry. Their large-scale study of participants from the US Marine Corps concluded that the abdominal circumference estimate of percent body fat provides a field expedient method to classify individuals for obesity prevention but was not suitable for research-grade assessments.Body composition assessment has been an important aspect of research in exercise physiology for decades. Assessment techniques range widely in expense, required expertise, and validity. In favour of developing low-cost and readily applicable measurement techniques, Overall, this special issue on the methods and applications used in exercise physiology showcases the many diverse advances being made to the techniques used in research and practice. Less expensive methods that require minimal expertise and can be easily applied in field settings will continue to enhance our ability to measure, understand, and enhance human health and performance."}
+{"text": "Aedes aegypti [Dengue is a mosquito-borne viral infection transmitted to humans, caused by four types of dengue virus (DENV)  and primarily carried by the species Pakistan first reported an epidemic of Dengue fever in 1994 and since November 2005 annual recurrence has become apparent . AccordiThis higher than usual monsoon rainfall raises an alarming concern for a potential outbreak of dengue fever in the country. Pakistan is already dealing with 6th wave of COVID-19 and an outbreak of Cholera , hence aNone required.None.Muttia Abdul Sattar, Hadia Nadeem. All authors contributed the same.None.Name of the registry:Unique Identifying number or registration ID:Hyperlink to your specific registration (must be publicly accessible and will be checked):Muttia Abdul Sattar.None required."}
+{"text": "Digital solutions to HPV vaccination by Hopfer S, Dyda A and Brandt HM. (2022). Front. Digit. Health. 4:972234. doi: 10.3389/fdgth.2022.972234Editorial on the Research Topic The rapid growth and diffusion of digital solutions, technologies and online media consumption is changing the landscape of implementing health behavior change campaigns and interventions as well as how individuals and families access and consume health information , 2. NoveMassey et al.; Zhang et al.; Sundstrom et al.; Buller et al.; Hopfer et al.). The special issue also presents feasibility studies on web-based or mobile applications  that tailor vaccine information to parents, adolescents, and young adults through a variety of approaches. Most digital solutions presented are stand-alone, yet one intervention presents digital efforts integrated as a component of a multi-level clinic intervention to reach rural populations and reduce missed HPV vaccine recommendation opportunities . Other studies  suggest that mobile apps could be used to complement clinical pediatric well-child visits or could be disseminated by state health departments, school health officials, and pharmacy chains. The advantages of digital health not only become apparent by the structural channel affordances that lend themselves to greater engagement and tailoring with audiences but also accommodate busy schedules of parents and young adults.This special issue showcases predominantly social media studies as digital solutions that show promise for reaching parents and youth about HPV vaccination , such as those reported by Sundstrom et al. and Buller et al., to deliver vaccine messaging through trusted peers presents a promising approach for increasing HPV vaccination. Another benefit of digital interventions is the ability to deliver vaccine messaging in other languages e.g., Spanish to Latinx communities  or target vaccine messaging via parent personas . Social media studies delivered vaccine messaging across multiple channels testing the impact of disseminating through different platforms  in private and public groups, synchronous/asynchronous discussion groups, webinars, bi-weekly emails, weekly messaging, and lifestyle messaging .Digital approaches inherently hold promise to make vaccine information more accessible for many populations who might otherwise not be reached and where messaging can be targeted to reach subgroups. Digital strategies may be delivered Zhang et al.), another study focused regionally on South Carolina  and yet another on rural Colorado (eno & Dempsey). These U.S. regions are characterized by low HPV vaccination rates and high HPV-cancer incidence.Geographic targeting can also be achieved with digital messaging: one study focused on Northern rural California with low vaccination and high cancer rates , showcases the potential to take advantage of answering parent and youth questions real-time and debunking misinformation, but also answering questions asynchronously through newsletters, blogs, discussion forums, chat rooms, and portals . A devoted moderator who can respond real-time to questions and correct misinformation was a recurring theme in combination with more automated digital interventions. The flow of unsolicited, real-time comments from parents give insight into vaccine concerns as well as exposure to circulating rumors and misinformation. Predominant vaccine concerns remain around HPV vaccine confidence and HPV complacency.Engagement, as observed through analysis of comments and posts  while another study applied dialog theory to segment HPV vaccine videos and adapt them to the social media environment . An ideal area of opportunity lies in strengthening the integration of theoretical foundations into digital health solutions in HPV vaccination.Communication and behavior change theories were adapted to understand the digital health environment: these ranged from social cognitive theory (SCT), diffusion of innovation (DOI), extended parallel process model (EPPM), 3C model of vaccine hesitancy, and a champion network approach. One study integrated persona theory with health communication and human-centered design , highlighting the emerging nature of digital solutions to increase vaccination. However, data on outcomes was also presented with results from randomized trials . This accrued evidence from the studies in this special issue on digital solutions highlights the various ways in which digital approaches are likely to increase HPV vaccination rates particularly in relation to increasing access and improving health promotion reach, through peer- and trusted channels and messengers. Use of narratives and informal peer dialogue  show promise to increase user engagement in the digital environment while also being able to answer and debunk circulating rumors real-time . Social media platforms offer one strategy to make information accessible . Additional strategies of using peer-champions , point-of-care delivered vaccine messages , and real-time tailoring  also show promise as digital solutions to increase HPV vaccination.A number of these studies were in the development or piloting stage ("}
+{"text": "Migraine is a highly prevalent disorder with significant economical and personal burden. Despite the development of effective therapeutics, the causes which precipitate migraine attacks remain elusive. Clinical studies have highlighted altered metabolic flux and mitochondrial function in patients. In vivo animal experiments can allude to the metabolic mechanisms which may underlie migraine susceptibility. Understanding the translational relevance of these studies are important to identifying triggers, biomarkers and therapeutic targets in migraine.Functional imaging studies have suggested that migraineurs feature metabolic syndrome, exhibiting hallmark features including upregulated oxidative phosphorylation yet depleted available free energy. Glucose hypometabolism is also evident in migraine patients and can lead to altered neuronal hyperexcitability such as the incidence of cortical spreading depression (CSD). The association between obesity and increased risk, frequency and worse prognosis of migraine also highlights lipid dysregulation in migraine pathology. Calcitonin gene related peptide (CGRP) has demonstrated an important role in sensitisation and nociception in headache, however its role in metabolic regulation in connection with migraine has not been thoroughly explored. Whether impaired metabolic function leads to increased release of peptides such as CGRP or excessive nociception leads to altered flux is yet unknown.Migraine susceptibility may be underpinned by impaired metabolism resulting in depleted energy stores and altered neuronal function. This review discusses both clinical and in vivo studies which provide evidence of altered metabolic flux which contribute toward pathophysiology. It also reviews the translational relevance of animal studies in identifying targets of biomarker or therapeutic development. Migraine is a highly prevalent and disabling disorder, affecting over 1 billion people worldwide . In addiMigraine is a prevalent feature of both mitochondrial and metabolic disorders , which Sensitization of the trigeminovascular system and cortical hyperexcitability are two mechanisms thought to be crucial to pathophysiology of migraine.The trigeminovascular system is composed of trigeminal sensory neurons innervating the dura mater as well as cerebral and pial blood vessels. They synapse in the pars caudalis of the ipsilateral spinal trigeminal nucleus. The main projection of these nociceptive fibres is the ventral posteromedial thalamic nucleus, which then relays to the primary sensory cortex. This system is fundamental to nociception and migraine pathophysiology . TrigemiHyperexcitability of the cerebral cortex is also thought to contribute towards migraine pathophysiology . It has Glucose is the major energy substrate of the brain. It diffuses across the blood\u2013brain-barrier via the glucose transporter GLUT1 and can be taken up by neurons via GLUT3 . Its majGlucose metabolism is fine-tuned within and among cells to ensure maintenance of adequate concentrations of substrates. At rest, the metabolism of the brain is compartmentalised between neurons and astrocytes; neurons can rely on both glycolytic and oxidative metabolism, whereas astrocytes tend to be primarily glycolytic and can metabolically support neurons . At timeIn vivo murine models have been useful in providing in-depth understanding of mechanisms linking abnormal glycolysis and migraine\u00a0Table . In rodeIn clinical practice, migraineurs often report that attacks are precipitated by fasting or skipping meals,  and indeThe gold standard to assess cerebral glucose uptake in vivo in patients is 18F-Fluorodeoxyglucose PET (18F-FDG PET) which has provided further evidence for the role of downregulated glycolysis in migraine. The cerebral areas affected by glucose hypometabolism appear to be different in episodic migraineurs compared to chronic patients. In episodic migraineurs both with and without aura, hypometabolism has been detected in temporal , and froIn the absence of sufficient oxygen, lactate is produced via anaerobic glycolysis of pyruvate\u00a0Fig. , hence, 1H-MRS) studies during CSD, [Results of animal and clinical studies suggest that lactate excess may be related to CSD. This hypothesis was corroborated in rat proton magnetic resonance spectroscopy , \u201361 with Importantly, such direct associations with cholesterol and LDL may provide an explanation for the increased cardiovascular and stroke risk in migraine , 64. TheAn association between obesity and headache is also evident in secondary headache disorders including idiopathic intracranial hypertension (IIH). IIH is characterised by raised intracranial pressure and features headache with migraine-like characteristics . Over 90Prolonged activity neurons leads to upregulated \u03b2-oxidation and consequently increased reactive oxygen species (ROS) and peroxidated fatty acids , 75. UsiFatty acids also play a role in modulating neuroinflammation, which is a function potentially of benefit in neurodegenerative diseases . Hence, Healthy neurons rely primarily on oxidative phosphorylation for energy, a process hosted by mitochondria which are vital organelles.+ allows quantification of changes in mitochondrial redox potential [For the investigation of mitochondrial function in vivo, most models utilise CSD as a mechanism of migraine. Use of two-photon fluorescent imaging to measure the ratio of autofluorescent reduced NADH to non-fluorescent NADotential . Using totential , 83, 84.otential . Moreoveotential . Dural eotential . In thes31P-MRS). Studies in migraine have consistently highlighted primary mitochondrial dysfunction in patients as evidenced by increased ADP in those with aura and FHM [31P-MRS studies of mitochondrial cytopathies and some neurodegenerative conditions such as amyotrophic lateral sclerosis [31P-MRS data in patients may reciprocate findings in CSD animal models, since migraine with aura patients most frequently demonstrate alterations in mitochondrial function. Results regarding changes in ATP concentrations remain divided, with most studies either not reporting ATP levels, or concentrations remaining unchanged or similar to that of controls [The modality of choice to investigate mitochondrial function in vivo in humans is 31-Phosphorus magnetic resonance spectroscopy  supplementation. CoQ10 is an electron acceptor in the electron transport chain which has been shown to improve mitochondrial respiration in mitochondrial cytopathies . SeveralInsulin has become a hormone of interest in migraine since numerous studies have identified insulin resistance in patients \u2013109. ResAnimal studies have revealed that insulin may potentially modulate the release of CGRP. In particular, insulin can induce the release of CGRP via sensitization of neuronal Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRVP1\u2014Fig.\u00a0CGRP is also able to regulate insulin secretion  via TRPVAlthough antagonism of CGRP signalling has demonstrated significant efficacy in migraine prophylaxis, the effects on insulin function have not yet been assessed in patients. CGRP receptor antagonism in mice has shown moderate improvements in oral glucose tolerance . CGRP-\u03b1 Amylin is a pancreatic hormone co-released with insulin in response to food intake . It loweWhilst CGRP has become a popular target for migraine therapeutics, the therapeutic potentials of amylin antagonism have not yet been fully explored. Pramlintide, an amylin receptor agonist, is currently licensed for diabetes in the United States . It may The pathophysiology of migraine is evolving and may also feature mitochondrial and metabolic deficits. Moreover, migraine is prevalent in those with mitochondrial disorders and structural and biochemical impairments in electron transfer chain have been identified in migraineurs . Interes"}
+{"text": "Endovascular therapy for acute ischemic stroke secondary to large vessel occlusion (LVO) is time-dependent. Prehospital patients with suspected LVO stroke should be triaged directly to specialized stroke centers for endovascular therapy. This review describes advances in LVO detection among prehospital suspected stroke patients.Clinical prehospital stroke severity tools have been validated in the prehospital setting. Devices including EEG, SSEPs, TCD, cranial accelerometry, and volumetric impedance phase-shift-spectroscopy have recently published data regarding LVO detection in hospital settings. Mobile stroke units bring thrombolysis and vessel imaging to patients.The use of a prehospital stroke severity tool for LVO triage is now widely supported. Ease of use should be prioritized as there are no meaningful differences in diagnostic performance amongst tools. LVO diagnostic devices are promising, but none have been validated in the prehospital setting. Mobile stroke units improve patient outcomes and cost-effectiveness analyses are underway. Endovascular therapy (EVT) using mechanical thrombectomy with or without intravenous thrombolysis (IVT) has been proven superior to standard medical care, including IVT alone for patients with acute ischemic stroke secondary to large vessel occlusion (LVO) , 2. MoreIn 2021, a multi-society consensus statement from leading stroke and emergency medical services (EMS) experts recommended that regional stroke destination plans prioritize the transportation of suspected LVO patients to Comprehensive Stroke Centers (CSC) for emergent EVT when within acceptable transportation times . CSCs prEMS transportation of IVT and EVT eligible LVO stroke patients to a closer non-EVT center may facilitate faster IVT; however, IVT recanalization rates are low for LVO stroke, and interfacility transfers for EVT are associated with treatment delays and worse outcomes \u201315. In sThis review details the use of varying methods of LVO identification in patients with suspected stroke, including updates in clinical prehospital stroke scales performed by EMS personnel, various portable medical devices, and mobile stroke units.The American Heart Association (AHA)/American Stroke Association (ASA) provides the Mission Lifeline: Stroke EMS Acute Stroke Routing Algorithm as a model for prehospital LVO triage using currently available prehospital stroke scales . The firWith consensus statements and triage algorithms now available, the remaining question is which validated stroke severity tool to use. Overall, the data quality has dramatically improved since the 2018 systematic review that determined there is insufficient evidence to conclude that any single severity tool is better than the others . This isThe ACT-FAST Stroke Algorithm created by Zhao et al. has also been validated in the prehospital setting and includes a unique treatment eligibility screen step. The algorithm provides a binary positive or negative result with relatively high and balanced sensitivity (75.8%) and specificity (81.8%) when using an extended definition of LVO that includes proximal LVOs plus M2s, P1s, and symptomatic stenoses. However, direct comparisons with the severity tools prospectively and simultaneously evaluated in the studies above are difficult because ACT-FAST was omitted. Most striking is the difference in positive predictive values (PPVs), which exceeded 50% for the ACT-FAST extended LVO definition. In comparison, most severity scores studied by Nguyen et al. in the Netherlands had PPVs in the 20% range . DiffereGiven the similarities in stroke severity tool performance and goal of widespread adoption by EMS providers, ease of use is a reasonable consideration when choosing among them. The easiest approach in the USA would be to change the CPSS, which is currently used as a positive or negative prehospital stroke identification screen, into a stroke severity tool with scores ranging from 0 to 3 , 31. TheWith so many reasonable choices, our focus should shift from which severity tool to use to clarifying our diagnostic and patient care priorities. Most prehospital stroke severity tools have multiple possible scores and choosing a lower score cutpoint would allow for higher sensitivity (not missing an LVO treatment opportunity) to be prioritized over specificity. More false positives would accompany this shift in priorities because these tools are not simultaneously sensitive and specific. However, it is important to prioritize sensitivity in highly morbid diseases with time-sensitive and profoundly effective interventions like EVT for LVO stroke.This is not as daunting as it may seem. Multiple modeling studies have found that LVO triage may not result in overwhelmed stroke centers or missed thrombolysis opportunities , 36, 41.Ultimately, prehospital stroke severity tools are limited by their sensitivity and specificity tradeoffs. Hopefully, the addition of the technologies discussed below will someday allow for highly sensitive and highly specific LVO triage that will expedite access to EVT while minimizing false positives.There has been increasing interest and research in portable and non-invasive external diagnostic devices for prehospital LVO stroke identification and triage. We will briefly discuss various forms of biometric devices reported in the peer-reviewed literature, including electroencephalography with or without somatosensory evoked potentials, transcranial Doppler, cranial accelerometry, and volumetric impedance phase-shift spectroscopy .Electroencephalography (EEG) analyzes normal and abnormal brain electrical activity by transducing electrical potential differences on the patient\u2019s scalp. EEG is primarily used to diagnose seizures and manage epilepsy. It has been used to monitor cerebral ischemia, particularly in the intraoperative setting during carotid artery surgery and, more recently, in acute ischemic stroke . EEG canA recent publication by Sergot and the EDGAR Study Group investigated a portable LVO-detection device (PLD) that used EEG combined with somatosensory evoked potentials (SSEPs) to identify LVO stroke in emergency departments \u2022. The stTranscranial Doppler (TCD) is a safe ultrasound-based method of evaluating cerebral hemodynamics and documenting blood flow in the middle cerebral artery. A pulsed Doppler ultrasound transducer is used to assess intracerebral blood flow through cranial \u201cwindows\u201d . A systeCranial accelerometry is used to measure the headpulse and has been investigated as a tool to diagnose LVO stroke by the authors of this review. Headpulse refers to nearly imperceptible head movements with each cardiac contraction cycle in response to blood flow forces transmitted via the carotid and vertebral arteries. This is measured using accelerometers in contact with the skull combined with electrocardiogram leads. Patients with LVO stroke may have chaotic head pulse patterns that do not correlate with cardiac contraction cycles; this is hypothesized to be due to the obstruction of blood flow on one side by the LVO. Cranial accelerometry alone  was 73% sensitive and 87% specific for LVO in an initial study . In a suVolumetric impedance phase-shift spectroscopy (VIPS) technology involves passing low-power electromagnetic waves through the brain to detect asymmetries and electrolyte concentration changes . A devicAt present, none of the LVO devices in development have reported the results of external validation, prehospital feasibility, or diagnostic accuracy studies in ambulances with suspected stroke patients. As investigators design these studies, it will be critical to follow the Standards for Reporting of Diagnostic Accuracy Studies (STARD) guidelines. Many peer-review journals require completion of the STARD checklist during submission, and more importantly, adherence to their guidance will reduce the impact of avoidable biases, increase transparency, and enable researchers to draw meaningful conclusions from new studies as the field advances .The concept of mobile stroke units (MSUs) was published in 2003 by Fassbender to \u201cbring treatment to the patient, rather than the patient to the treatment\u201d and was first established in Germany in 2008 . MSUs tyA recent publication by Ebinger and colleagues in Berlin demonstrated an association between MSUs and improved functional outcomes in acute ischemic stroke patients . They coThe BEST-MSU study is the first multicenter randomized controlled trial comparing standard ambulance care versus MSU care, including prehospital thrombolysis. It began in 2014 in Texas and has demonstrated the safety and feasibility of MSUs, the reliability of telemedicine technology, as well as faster door-to-groin puncture times for patients requiring thrombectomy . ResultsPrehospital triage of patients with suspected LVO to EVT centers is now recommended. The Mission Lifeline: Stroke EMS Triage Algorithm provides a framework that includes neurological examination-based prehospital stroke severity tools. Decisions regarding which severity to tool to use can likely be based on ease of use as prospective comparative studies did not demonstrate meaningful performance differences. Standard score cutpoints of many of these tools favor specificity over sensitivity, which will lead to many missed LVO strokes. Sensitivity should be prioritized, and CPSS \u2265 2 provides similar performance compared to other sensitive stroke severity tool cutpoints but would not require significant training to implement. Several LVO stroke diagnostic devices have published peer-review initial studies, but each device will require prehospital validation before becoming available for use. Mobile stroke units improve patient outcomes and, when available, can perform vessel imaging on scene to diagnose or rule out LVO stroke. Cost-effectiveness analyses are planned. Ongoing improvements in prehospital LVO triage will likely require tailoring the diagnostic approach to the needs of each region."}
+{"text": "Termites are a prototypical example of the \u2018extended phenotype\u2019 given their ability to shape their environments by constructing complex nesting structures and cultivating fungus gardens. Such engineered structures provide termites with stable, protected habitats, and nutritious food sources, respectively. Recent studies have suggested that these termite-engineered structures harbour Actinobacteria-dominated microbial communities. In this review, we describe the composition, activities, and consequences of microbial communities associated with termite mounds, other nests, and\u00a0fungus gardens. Culture-dependent and culture-independent studies indicate that these structures each harbour specialized microbial communities distinct from those in termite guts and surrounding soils. Termites select microbial communities in these structures through various means: opportunistic recruitment from surrounding soils; controlling physicochemical\u00a0properties of nesting structures; excreting hydrogen, methane, and other gases as bacterial energy sources; and pretreating lignocellulose to facilitate fungal cultivation in gardens. These engineered communities potentially benefit termites by producing antimicrobial compounds, facilitating lignocellulose digestion, and enhancing energetic efficiency of the termite \u2018metaorganism\u2019. Moreover, mound-associated communities have been shown to be globally significant in controlling emissions of methane and enhancing agricultural fertility. Altogether, these considerations suggest that the microbiomes selected by some animals extend much beyond their bodies, providing a new dimension to the \u2018extended phenotype\u2019. This review discusses how and why termites select for beneficial microbial communities by constructing mounds, nests, and fungal gardens, and explores the ecological and biogeochemical impacts of these termite-engineered communities. Mounds contain complex networks of internal chambers that facilitate gas exchange, harbour the colony, and allow food storage or fungiculture , instead cultivates bacterial combs as a food source  to chemically analyze the degree of pretreatment of lignin and polysaccharides during the fungus garden maturation in O. formosanus laboratory colonies; this revealed that the fungus-comb microbiome contributes to significant polysaccharide and lignin cleavage, leaving the mature comb enriched in more digestible cellulosic oligomers that are eventually ingested by termite host  or, primarily in the case of fungus-farming termite combs and subterranean C. formosanus opportunistically recruits potentially defensive Streptomyces from surrounding soils and provides favourable nutrients for their proliferation , all of which is rapidly consumed to subatmospheric levels by mound communities  and Methylocystis methanotrophs, which appear to be kinetically adapted to elevated methane concentrations (Chiri et al. In addition to providing multifaceted benefits to termites, the microbial communities associated with termite nesting structures offer a range of ecosystem services Fig.\u00a0. Of thesTermite-associated bacteria also enhance soil fertility, especially in savanna and dryland regions, by mediating various supporting services. Termite nest and mound soils promote growth of a wide range of plants both in natural environments and agricultural settings Watson . It was With respect to provisioning services, termite nesting communities are also relevant for understanding and tackling the antimicrobials arm race. Hundreds of novel natural products have been identified from termite nests, especially combs of fungus-farming termites, often with potent antibacterial or antifungal properties (Sujada et al. Increasing evidence suggests that the microbial communities residing within termite nesting structures engage in symbiotic relationships with termites. The microorganisms benefit from a relatively stable and selective habitat, high nutrient availability, and pathogen exclusion mechanisms. The microorganisms recruited to termite nesting structures likely span the spectrum of commensals to mutualists, though the majority appear to benefit termites by mediating antimicrobial production, lignocellulose digestion, and nutrient recycling. Yet in other respects, mound-associated bacteria are atypical of classical symbionts: they are generalist bacteria that can adopt both free-living and mound-associated lifestyles; are opportunistically recruited and sustained through normal nest-building and digestive activities of termites; and exhibit strong geographic variations in community composition even within species. However, strong arguments have been presented that animals can dependably acquire microbial symbionts if potential symbionts are widely distributed and promiscuous associations can form (Moran and Sloan"}
+{"text": "The corporate political activities of harmful industries, including the use of agnogenic (ignorance or doubt producing) practices and the construction of dystopian narratives, directed at influencing policymaking are well documented. However, the use of agnogenic practices by industry-funded organisations who deliver industry-favoured education-based measures remains unexplored. This study aims to build understanding of this by analysing three UK gambling industry-funded youth education programmes that represent key policy responses to gambling harms.Using a published typology of corporate agnogenic practices the ways that evidence is used within the programmes\u2019 resources to legitimise their content and implementation were analysed. Programme evaluations and claims about the programmes\u2019 evidence base and effectiveness were also analysed.Agnogenic practices, including confounding referencing, misleading summaries and evidential landscaping, that resemble those adopted by harmful industries are used within gambling industry-funded youth education programmes and by the charities that oversee their delivery. These practices serve corporate interests, distort the limited evidence in support of youth gambling education measures, and legitimise industry favoured policies.This novel study demonstrates that agnogenic practices are used to construct utopian narratives that claim that gambling industry-favoured youth education programmes are evidence-based and evaluation-led. These practices misrepresent the literature and evaluation findings and may undermine effective policymaking to protect children and young people from gambling harms.\u2022\u2002Gambling industry-funded education programmes warrant greater scrutiny and conflicts of interest need to be addressed.\u2022\u2002The methods and findings of this study are of relevance to other contexts and areas in the field of the commercial determinants of health given other harmful industries adopt similar approaches."}
+{"text": "Editorial on the Research TopicAdvancing the understanding of surgical management for degenerative spine conditionsDegenerative spine conditions are common in adults, especially among the elderly. In parallel with the aged tendency of population worldwide, the prevalence of degenerative spine diseases has been increasing. There has also been an increasing trend in spine surgery worldwide \u20133. HowevQian et al. that may because the laminoplasty releases dorsal spinal cord from compression in pinching cervical spondylotic myelopathy (PCSM). Yang et al. took advantage of finite element analysis of CT images and found the maximum stress in involved segments of cervical spondylotic myelopathy (CSM) was higher compared with the control group. Two papers summarized theoretical knowledge of certain spine diseases. Xu et al. gave a detailed and authoritative review for ponticulus posticus, including the epidemiology, pathology, anatomy, clinical presentation, radiographic examination and surgical significance of ponticulus posticus. Mei et al. gave us a rare case of camptocormia related to Parkinson's disease and reviewed the literature on camptocormia.Learning the basic knowledge of spinal disorders helps to give us an overall understanding of surgical treatment. Several papers in this Research Topic gave us their understandings of pathogenesis of some spine diseases. The reason why cervical sagittal curvature of certain patients will be lordotic after laminoplasty is unclear. As pointed out by Wasinpongwanich et al. in their systematic review and meta-analysis, summarized fusion rate, operative time, clinical outcomes, complications  for transforaminal lumbar interbody fusion (TLIF) vs. other techniques used in lumbar spine diseases. Focusing on elderly patients with single-level thoracolumbar severe osteoporotic vertebral compression fracture (sOVCF), Zhou et al. provided evidence for the effects of percutaneous kyphoplasty (PKP) with vs. without posterior pedicle screw fixation (PPSF) on long-term spinal sagittal balance. Due to limited guideline information on whether indirect decompression is sufficient after oblique lumbar interbody fusion (OLIF), Tseng et al. compared the effectiveness of the indirect decompression by OLIF with direct posterior decompression among lumbar foraminal stenosis patients. Radiofrequency denervation, as a common interventional treatment for chronic low back pain, has different emerging types such as pulsed radiofrequency denervation. In their systematic review, Li et al. comprehensively reviewed literature on radiofrequency denervation therapy in treating facet joint-derived chronic low back pain and compared efficacy of different radiofrequency denervation interventions using network meta-analysis.A number of papers in the current Research Topic focused on comparing different surgical procedures used in spine surgery. Chen et al. evaluated the learning curve of UBE using the cumulative summation (CUSUM) method analysis.Understanding the learning process of surgical techniques is beneficial to surgeons who hope to master one surgical technique. For the past few years, unilateral biportal endoscopic (UBE) has become a popular technique for spinal surgery. However, even for skilled spinal surgeons, there may be obstacles in the learning process of UBE technology. To this end, Briguglio et al. tried to develop a hemoglobin-based prediction model to predict long-term recovery after spine surgery but regrettably, this model may not be reliable due to the low specificity. Nevertheless, as indicated by Briguglio et al. preoperative hemoglobin, interestingly, is one of the key laboratory biomarkers to predict long-term recovery after spine surgery. Identifying prognostic factors for patients who received spine surgery is also of great importance. By finding out factors which could provide prognostic information for patients, we may forecast the future outcomes in patients with a particular health condition and thus choose more suitable treatment under a specific situation. The risk factors for postoperative shoulder imbalance are rarely reported in adult scoliosis (AS). Hence, Ke et al. performed a detailed assessment of risk factors related to radiography in AS patients who underwent correction surgery. Deng et al. gave a comparison of sagittal balance and functional outcomes in lumbar fracture surgery patients using different intermediate pedicle screws with different insertion depth. Wei et al. examined risk factors of bone graft nonfusion for spinal tuberculosis patients who underwent lesion removal, bone graft fusion and internal fixation.Prognosis research is of great importance in the context of current spine surgery. Several papers published in this Research Topic developed prediction model and investigated prognostic factors in different kinds of spine surgery. Clinical prediction models have plenty of applications in clinical practice. For instance, clinical prediction models help us to decide whether we need further testing, whether we need to start a treatment and which treatment need to be performed . BriguglJin et al. compared the subsidence rate in zero profile anchored spacer (ROI-C) and conventional cage and plate construct (CPC) in patients undergoing anterior cervical decompression and fusion (ACDF). Cases series by Florence et al. provided eight cases who had hardware complications after placement of interspinous process devices (IPDs) and gave us experience in management of high risk IPD patients.Complications after surgery also deserve more attention. Focusing on postoperative cage subsidence, a common complication after spine surgery, Xu et al. developed a new surgical plan for adults with tibial-eminence fracture (TEF) and assessed the clinical effectiveness of day case arthroscopic-surgery treatment. Interestingly, thromboelastography (TEG) markers could forecast the occurrence of ecchymosis after total knee arthroplasty (TKA), as found by Chen et al.This Research Topic also included papers related to other orthopedic surgery, which give an additional view for spine surgery. For instance, We sincerely thank all authors who contributed to the current Research Topic \u201cAdvancing the Understanding of Surgical Management for Degenerative Spine Conditions\u201d. We appreciate the reviewers' valuable comments and constructive suggestions. Also, we express our gratitude to the editorial team for their support.We unfeignedly hope that articles in this Research Topic will help surgeons make the right decisions and inspire researchers to give a further exploration of surgical management for degenerative spine conditions."}
+{"text": "Botrytis, Colletotrichum, and Fusarium.Crop plants are constantly exposed to diverse biotic stressors during their lifetime. Fungal pathogens represent a predominant biotic stress of crops and account for 80-85% of known diseases leading to significant yield losses. Host plant resistance against fungal pathogens is due to diverse factors such as plant genetic background, physiological status, agroecological, and environmental conditions. In addition, the microbiome associated with host plants has also been shown to contribute to resistance by producing metabolites that modulate host plant defense pathways or exhibit antimicrobial properties. The advancement in next-generation sequencing (NGS) technology for genome/RNA sequencing and modern omic approaches such as proteomics, metabolomics, and interactomics have profusely helped to define host plant resistance mechanisms. These technological advances have made possible introgression of resistance traits into agronomically important varieties by traditional or molecular breeding. Recently, the application of highly sophisticated biotechnological tools using RNAi or CRISPR-Cas9-based gene editing has enabled us to precisely manipulate the integration and expression of key genes for enhanced host resistance. This special issue compiles articles that highlight mechanisms underlying host plant-fungal interactions that govern susceptibility or resistance to fungal pathogens including Botrytis cinerea (B. cinerea) negatively impacts strawberry production worldwide. The fungus preferentially infects flowers and fruits of strawberry. Using B. cinerea resistant and susceptible cultivars and global mRNA sequencing, Xiao et\u00a0al. demonstrated higher expression of defense-related genes and lower expression of genes associated with cell wall degrading enzymes and peroxidases in the resistant cultivar during early stages of infection. The authors also showed increased expression of calcium signaling pathway related genes namely CPKs, RBOHDs, CNGCs, and CMLs and genes associated with jasmonic acid, auxin, and phenylpropanoid metabolism in the resistant cultivar. The work presented here could be useful for future breeding efforts or transgenic manipulation of candidate genes to improve gray mold resistance in strawberry.Gray mold disease in strawberry caused by the necrotrophic fungus B. cinerea, Zhao et\u00a0al. delineated the molecular basis of resistance. Using resistant and susceptible genotypes and a combination of tools including gene expression, quantification of metabolites, and microscopy, the authors dissected leaf-associated factors in woodland strawberry potentially contributing to resistance against the fungus. Higher basal (in absence of the fungus) expression of resistance related genes rather than induction of genes in response to the fungus was observed in the resistant genotype. Metabolites such as total phenolics, total flavonoids, glucose, galactose, citric acid, and ascorbic acid were positively correlated with B. cinerea resistance, whereas H2O2 and sucrose were negatively correlated with resistance. The authors suggested higher innate antioxidant profile of leaves as one of the key factors contributing to resistance against the fungus.In another study addressing strawberry leaf resistance against Hordeum vulgare L. var. nudum), Tibetan hulless barley grown in higher elevation regions, is not fully understood. Using genome and transcriptome mining through bioinformatics, Wang et\u00a0al. demonstrated the role of specific members of the TLP gene family in biotic (powdery mildew) and abiotic  stress tolerance. Analysis of promoter regions of this gene family showed presence of putative transcription factor binding motifs associated with growth and development, hormone signaling, light and stress responses. Gene expression analysis using qRT-PCR validated the induction of specific members of TLPs in response to sodium salicylate and methyl jasmonate treatments. The work presented here provides future opportunities for crop improvement in Qingke which is a staple crop in Tibet.In plants thaumatin-like proteins (TLPs) have been implicated in a wide range of physiological processes including stress response and growth and development. The role of this gene family in Qingke  is an economically important tree species and highly susceptible to the fungal pathogen Colletotrichum fructicola. Zheng et\u00a0al. dissected the role of specific plant secondary metabolites in resistance against this fungus using C. paliurus resistant and susceptible cultivars. Through multiomic approaches namely mRNA sequencing and metabolomic analyses, the authors demonstrated that early induction and reprogramming of the flavonoid biosynthetic pathway potentially contribute to resistance to C. fructicola. The information presented here provides valuable information on biomarker/s for future resistance breeding in C. paliurus and/or using natural flavonoid extracts from a resistant cultivar as an antifungal treatment against this fungus.Wheel wingnut . The authors found that faba bean\u2013wheat intercropping under field conditions significantly improved Fusarium wilt disease severity in comparison to monoculture of faba bean plants. Reduction in cellular contents of H2O2 and O2 accompanied by increased expression and activities of superoxide dismutase and catalase enzymes in the roots of faba bean plants were observed when intercropped with wheat. In addition, reduced benzoic acid and cinnamic acid in the rhizosphere soil of faba bean plants improved the stability of root cells. The authors used a reverse approach and showed that exogenous application of benzoic acid and cinnamic acid to the roots of faba bean plants increases Fusarium wilt symptoms under greenhouse conditions. This demonstrates the role of allelopathic compounds in the rhizosphere of faba bean crop in resistance to Fusarium wilt.Overall, the work presented in this volume advances our understanding towards plant-fungal interactions and sets a good foundation for future breeding approaches to improve crop resistance to fungal pathogens.All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Phaeodactylum tricornutum (UTEX 466) using different loadings of fungal pellets (Aspergillus sp.) and model the process through kinetics and equilibrium models. Active P. tricornutum cells were not required for the fungal-assisted immobilization process and the fungal isolate was able to immobilize more than its original mass of microalgae. The Freundlich isotherm model adequately described the equilibrium immobilization characteristics and indicated increased normalized algae immobilization  under low fungal pellet loadings. The kinetics of algae immobilization by the fungal pellets were found to be adequately modeled using both a pseudo-second order model and a model previously developed for fungal-assisted algae immobilization. These results provide new insights into the behavior and potential applications of fungal-assisted algae immobilization.Immobilizing microalgae cells in a hyphal matrix can simplify harvest while producing novel mycoalgae products with potential food, feed, biomaterial, and renewable energy applications; however, limited quantitative information to describe the process and its applicability under various conditions leads to difficulties in comparing across studies and scaling-up. Here, we demonstrate the immobilization of both active and heat-deactivated marine diatom  The insights and modeling techniques demonstrated here will help to provide industrially relevant benchmarks for the immobilization of other species of commercial or environmental interest and provide necessary data for future techno-economic and life cycle assessments."}
+{"text": "Social isolation is prevalent among community dwelling older adults. Low income older adults living in subsidized housing may have increased risk for social isolation. To examine resident experiences and perspectives relating to their social connections during the COVID-19 pandemic, we conducted semi-structured interviews with 13 older adults (62+) who are English, Spanish, and Mandarin speaking recruited from a large non-profit affordable housing organization with communities in 22 states. Twelve housing communities were identified based on distributions of socio-demographic factors and prevalence of self-reported social isolation l in the housing community\u2019s annual survey of residents in order to maximize site diversity. We used qualitative thematic analysis methods to examined participants\u2019 views about their social connections before and during the COVID-19 pandemic, as well as their personal and the housing community\u2019s strategies to mitigate experiences of social isolation. Emerging themes include loss of common facilities and opportunities to socialize with other residents due to COVID-19 restrictions, and increased use of technology to stay connected."}
+{"text": "Neighborhoods are diverse and may or may not present opportunities for stress reduction or social engagement depending on their qualities. Based on the stress connectome , psychosocial stress may accelerate cognitive aging, which explains place-based disparities in cognitive function. This study examines two attributes of the neighbourhood environment, and their potential to influence cognitive function through semantic fluency.Using aggregated baseline  data from N=1,010 neighborhoods with 5 or more respondents in the Canadian Longitudinal Study on Aging, we examined the effects of neighborhood greenness and cohesion on aggregates of age-, sex-, and education-adjusted cognitive test scores. Participants were community-dwelling adults aged 44 and above. Semantic fluency was assessed using the Animal Fluency Test (AFT). Delayed recall was assessed using Rey\u2019s Auditory Verbal Learning Test (RAVLT), whereas executive function was assessed using Mental Alternation Test (MAT). Neighborhood qualities were found to affect delayed recall  and executive function  through semantic fluency . Semantic fluency fully mediated the effects of neighborhood attributes on cognitive function. Further stratifying these neighborhoods by socioeconomic status showed that cohesion has stronger effects in poorer neighborhoods (B indirect=.104) than richer neighborhoods (B indirect=.066). The effect of greenness was no longer significant upon stratification. Neighborhoods offer an important social arena for adults in mid- and late-life to practice conversing, especially in poorer neighborhoods, which improves cognitive function. Creating opportunities for socialization by improving cohesion and neighborhood parks may reduce place-based disparities in cognitive health. Causality remains to be ascertained."}
+{"text": "Examining the neural circuits of fear/threat extinction advanced our mechanistic understanding of several psychiatric disorders, including anxiety disorders (AX) and posttraumatic stress disorder (PTSD). More is needed to understand the interplay of large-scale neural networks during fear extinction in these disorders. We used dynamic functional connectivity (FC) to study how FC might be perturbed during conditioned fear extinction in individuals with AX or PTSD. We analyzed neuroimaging data from 338 individuals that underwent a two-day fear conditioning and extinction paradigm. The sample included healthy controls (HC), trauma-exposed non-PTSD controls, and patients diagnosed with AX or PTSD. Dynamic FC during extinction learning gradually increased in the HC group but not in patient groups. The lack of FC change in patients was predominantly observed within and between the default mode, frontoparietal control, and somatomotor networks. The AX and PTSD groups showed impairments in different, yet partially overlapping connections especially involving the dorsolateral prefrontal cortex. Extinction-induced FC predicted ventromedial prefrontal cortex activation and FC during extinction memory recall only in the HC group. FC impairments during extinction learning correlated with fear- and anxiety-related clinical measures. These findings suggest that relative to controls, individuals with AX or PTSD exhibited widespread abnormal FC in higher-order cognitive and attention networks during extinction learning and failed to establish a link between neural signatures during extinction learning and memory retrieval. This failure might underlie abnormal processes related to the conscious awareness, attention allocation, and sensory processes during extinction learning and retrieval in fear- and anxiety-related disorders. Conditioned fear inhibition is achieved by the repeated presentations of the conditioned stimulus in the absence of the unconditioned stimulus. This fear extinction process is critical for fear reduction in the aftermath of trauma exposure or when exposed to fear- and anxiety-inducing stimuli. Failure to appropriately extinguish fear could contribute to the maintenance of anxiety-related symptoms, which is thought to characterize posttraumatic stress disorder (PTSD) and anxiety disorders , 2. PavlMost human neuroimaging studies have yet to establish a connection between cognitive/attention networks and the subjective measures of fear and anxiety. Recent studies started to emerge in support of the LeDoux-Pine concept. For example, meta-analyses revealed the engagement of multiple cortical regions during the fear conditioning and extinction tasks , but theIn this study, we examined the dynamic changes of large-scale FC across extinction learning in healthy individuals and in patients diagnosed with anxiety disorders or PTSD. We estimated whole-brain connectivity of participants during different timepoints of extinction learning, compared the FC change between groups, and evaluated the relevance of extinction-induced FC changes to various fear- and anxiety-related clinical metrics. Based on our previous study , and givWe analyzed data from a total of 338 individuals (see Supplementary Methods). Of those, 77 were healthy controls (HC), 91 were diagnosed with anxiety disorders (AX), 81 were diagnosed with PTSD, 89 were trauma-exposed non-PTSD controls (TENC)  procedure , r\u2009=\u20090.48, p\u2009<\u20090.001), but not in the AX group  or the PTSD group . Steiger\u2019s Z test confirmed that the HC group showed significantly higher correlation than the other two groups . A significantly positive correlation between \u0394FC and vmPFC activation was also observed in the HC group using the network identified with HC vs. PTSD  group as a control group, we conducted additional FC analyses comparing the PTSD to TENC. These additional analyses mostly replicated the results of HC vs. PTSD analyses (see Supplementary Results for details); revealing a significant network component that mainly involved connections between the DMN with other networks , supporting the robustness of the identified canonical variate. We then calculated the canonical loadings to examine how the individual clinical measure and connectivity contributed to the canonical variate  in the HC and AX groups . The canonical loadings indicated that the symptom measure positively contributed to the clinical variate, while \u0394FC negatively correlated with the connectivity variate  in the TENC and PTSD groups  and patients diagnosed with anxiety disorders (AX) or PTSD. From early to late extinction learning, HC exhibited an increase in FC that was specific to the conditioned cue. The AX and PTSD groups exhibited widespread FC impairments during extinction learning. The relative FC reductions in patient groups were predominantly in the interactions between the default mode network (DMN), frontoparietal control network (CON), somatomotor network (SMN), and attention networks (DAN/VAN). The extinction-induced FC changes were predictive of vmPFC activation during extinction recall only in the HC group. FC changes during extinction learning positively and negatively correlated with FC during recall in the HC and the AX groups, respectively. Finally, extinction-induced FC was associated with subjective measures of fear- and anxiety-related clinical metrics.Animal literature shows that learning-induced plasticity can change both neural activity and neuronal synchronization . Neural Prior fear extinction studies have focused predominantly on neural circuits associated with expression and inhibition of conditioned threat responses. The conscious awareness of fear, and the feeling of no longer being afraid, would require multiple cognitive processes, including perception, attention, conscious awareness, and memory construction. These multi-level processes are likely to require coordinated interactions between distributed brain regions . A recenThe distinct dysfunction in some networks and the partial overlap in some others across the AX and PTSD groups suggest both divergent and shared mechanistic impairments pertinent to fear inhibition across these psychopathologies. While there was an overlap in the FC dysfunction across multiple brain regions between the patient groups, the dlPFC\u2014a region known for its contribution to cognitive control and regulation \u201344, appeWe observed a positive correlation between extinction-induced \u0394FC  and vmPFC activation during memory recall only in the HC group. The vmPFC plays a key role in inhibiting threat response , 20, 49.We specifically focused our analyses on the connectivity during CS+ processing since our previous study on healthy controls showed that connectivity during CS+ processing increased from early to late extinction learning, and predicted the magnitude of extinction memory . The ideWe observed abnormal connections extensively involved CON and DMN in the PTSD group when comparing it with either the non-exposed controls or trauma-exposed controls. This result suggests that the connectivity alterations in the PTSD group are not merely a result of the traumatic exposure. There is evidence showing that traumatic exposure per se may alter activation and functional connectivity , 53, 54.The dynamic nature of extinction learning-induced neural plasticity is overlooked to some degree in prior studies as many neuroimaging studies average functional brain activation across extinction learning. However, a few prior studies suggested the dynamic changes of activation during the fear conditioning and extinction paradigm in PTSD and healthy participants , 31. SpeSupplemental material"}
+{"text": "Positive affect is important for physical health, well-being, and relationships. Yet, most studies of dementia care dyads have focused on negative outcomes, such as depression and caregiver burden. We present findings from studies that address this important research gap. The first two speakers present findings from actor partner interdependence models using secondary data from a randomized controlled trial of persons with early-stage dementia (PWD) and their spouses. Specifically, Dr. Monin will show that actor quality of life is significantly related to positive affect cross-sectionally, controlling for functional status of each partner and PWD behavioral symptoms. Ms. Piechota will present longitudinal findings demonstrating that when spouses were high in difficulty regulating emotions, the PWD\u2019s positive affect decreased over three months, controlling for intervention arm and covariates. The second two speakers will present findings from two different studies of persons living with behavioral-variant frontotemporal dementia (bvFTD), Alzheimer\u2019s disease (AD), and controls that engaged in laboratory conflict discussions. Dr. Brown will show that caregivers of individuals with bvFTD reported greater decreases in positive emotion across the discussion relative to caregivers of individuals with AD and language variants. She will also discuss how caregivers who reported greater decreases in positive emotion had higher levels of depressive symptoms, controlling for their partner\u2019s diagnosis and level of cognitive impairment. Finally, Dr. Chen will provide evidence that bvFTD caregivers had lower emotional well-being according to the SF-36 than AD caregivers and controls, and this effect was fully mediated by bvFTD caregivers' lower positive emotional connections."}
+{"text": "Increasing travel times to the nearest diagnostic facilities and cancer centers are correlated with decreasing prevalence of breast cancer diagnosis and increasing stage of cancer at diagnosis. Moi Teaching and Referral Hospital (MTRH), in Uasin Gishu County, houses the only public cancer center in western Kenya. A MTRH program, the Academic Model Providing Access to Healthcare Breast and Cervical Cancer Control Program (ABCCCP) hosted health fair breast cancer screening events and mentored nurses at local health facilities to complete clinical breast exams (CBEs). The objective is to understand the effect of the ABCCCP in reducing geographic barriers for breast cancer screening/early diagnosis.This is a retrospective review of the 61,392 patients who underwent breast cancer screening at a ministry of health facility in western Kenya from 2017-2021. ABCCCP hosted health fairs targeted at communities and mentored nurses at health facilities to complete clinical breast exams (CBEs) to target individual patients. Facility distances from MTRH were mapped via Google Maps. Descriptive analyses were performed to a significance of \u03b1 < 0.05.Two-thirds of the screening/early diagnosis CBEs occurred in five of the 22 counties in western Kenya: Busia, Uasin Gishu, Trans-Nzoia, Bungoma, and Kakamega. However, these five counties only had 25% of all ABCCCP screening sites in western Kenya. Only Uasin Gishu and Kakamega provided chemotherapy while Busia and Trans-Nzoia had additional programming promoting preventative healthcare through integration of community health volunteers. In these five counties, no association between the distance of the ministry of health facilities from MTRH and number of CBEs completed existed.ABCCCP programming reduced some geographic disparities in breast cancer screening/diagnosis in the top five counties. It may be result of the number of mentored nurses and health fair events. Further work should be completed to understand if a relationship between geographic distance from MTRH and the stage and treatment patterns of these patients is also reduced by ABCCCP."}
+{"text": "Research from across the globe has consistently shown that young sexual and gender minority individuals  are at a higher risk for depression, anxiety, and suicidal thoughts and behaviors when compared to heterosexual youth, including during early childhood and later adolescence. A sizeable body of research has attributed the elevated risk to increased exposure to specific social stressors related to navigating a stigmatized minority identity, including stressors such as victimization and other interpersonal and social difficulties in, for example, the school environment. Yet, relatively less is known about the early developmental timing of such disparities in childhood and how LGBT+ youth navigate school climates. As a sensitive developmental period, childhood and adolescence may be a particularly challenging time for sexual and gender minority youth to navigate cisnormative and heteronormative school contexts. Exposure to oppressive norms, particularly in school environments, has only recently become the subject of research. Additionally, research has been limited on how supportive school climates may be protective but stigmatizing school environments may drive LGBT+ trajectories towards suicidal behaviors and shape how they may navigate self-disclosure of cooccurring identities and mental health status in school settings, particularly when such stigmas may prevalently intersect. This workshop aims to further explore these novel aspects around developmental and school-based risk and protective factors shaping the mental health of sexual and gender minority children and adolescents. This workshop includes five empirical presentations that span from examining the developmental timing of mental health disparities, the role school-based experiences play in shaping and driving these disparities, to how sexual and gender minority youth may navigate their school context and how supportive climates may be protective for mental health. First, Arjan van der Star will present longitudinal evidence on how sexual identity formation precedes the onset of sexual orientation-based mental health disparities and the role that peer difficulties play in driving these as early as pre-teen years. Next, Niolyne Jasmin Bomolo will present findings from a qualitative study that unravel how school-based experiences shape individual trajectories toward suicidal attempts among LGBT+ adolescents. Third, Wouter Kiekens will explore how normative cultures in school environments may drive sexual attraction-based mental health disparities among a large sample of adolescents. Fourth, Lourdes Cantarero Ar\u00e9valo will present findings on how LGBT+ adolescents living with mental conditions navigate self-disclosure in school environments. Finally, Sandra Sevic will present results on how supportive school environments may be protective for gender minority mental health.\u2022\u2002Negative school-based experiences put sexual and gender minority youth at elevated risk for adverse mental health as early as middle childhood.\u2022\u2002Intersecting stigmas around minority identities and mental health problems may further complicate how sexual and gender minority children and adolescents navigate their school environments."}
+{"text": "In recent years, targeting tumor specific metabolism has gained an interest as a promising therapeutic strategy. We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is highly prevalent in ovarian carcinoma patients and contributes to elevated mitochondrial metabolism in ovarian tumor models. The SDHA overexpressing tumor cells are highly metabolically active, relying on both glycolysis and oxidative phosphorylation in mitochondria to meet their energy requirements. Further, we found that those cells are particularly vulnerable to deprivation of essential nutrients such as glucose and glutamine, which led to a substantial reduction of ATP yield. Lastly, we identified an anti-metabolic compound shikonin, which demonstrated a potent anti-tumor efficacy against SDHA overexpressing ovarian cancer cells. Overall, we strive to advance scientific knowledge by uncovering the previously unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which holds untapped opportunities for therapeutic intervention.We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact on ovarian cancer metabolism has never been investigated, emphasizing the need for further research. We investigated the functional consequences of SDHA overexpression in ovarian cancer. Using proteomics approaches and biological assays, we interrogated protein content of metabolic pathways, cell proliferation, anchorage-independent growth, mitochondrial respiration, glycolytic function, and ATP production rates in those cells. Lastly, we performed a drug screening to identify agents specifically targeting the SDHA overexpressing tumor cells. We showed that SDHA overexpressing cells are characterized by enhanced energy metabolism, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. In addition, SDHA-high phenotype was associated with cell vulnerability to glucose and glutamine deprivation, which led to a substantial reduction of ATP yield. We also identified an anti-metabolic compound shikonin with a potent efficacy against SDHA overexpressing ovarian cancer cells. Our data underline the unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which represents a new opportunity for therapeutic intervention. The reprogramming of cellular metabolism is a hallmark of cancer allowing tumor cells to survive and proliferate. The Warburg effect is an established signature of cancer metabolism and refers to the observation that tumor cells preferentially use glucose via glycolysis pathway rather than oxidative phosphorylation (OXPHOS) in mitochondria for energy production . The relSDHA gene amplification or overexpression is highly prevalent in ovarian carcinoma patients  compared to other tumor types, which indicates its potential importance in reprogramming of ovarian cancer metabolism.To gain a greater insight into the ovarian cancer metabolism, we interrogated metabolic phenotypes of patient-derived xenografts (PDXs) developed from patients\u2019 ovarian tumors . We usedSuccinate dehydrogenase (SDH) also known as mitochondrial complex II, couples oxidation of succinate to fumarate with reduction of ubiquinone to ubiquinol, thus directly connecting the mitochondrial electron transport chain (ETC) with the tricarboxylic acid (TCA) cycle . SDH conIn this work, using various in vitro and in vivo ovarian cancer models, we investigated the biological consequences of SDHA overexpression and its impact on tumor phenotype. Our findings revealed that SDHA overexpression is associated with the improved ability of cells to survive and generate colonies in anchorage-independent conditions. This is an important feature of metastatic ovarian tumor cells that are able to survive and spread in peritoneal fluid (ascites) within the abdominal cavity. Further, we showed that the overexpression of SDHA enhanced ovarian cancer metabolism reflected as increased mitochondrial respiration and ATP production rate. Lastly, we performed a drug screening and identified an anti-metabolic compound shikonin known to disrupt glycolysis and amino acid metabolism ,20. We sAltogether, our study demonstrated that SDHA upregulation frequently occurs in ovarian cancer and contributes to reprogramming of energy metabolism towards highly metabolically active phenotype. Importantly, we showed here that SDHA overexpressing tumor cells can be effectively targetable by anti-metabolic compounds such as shikonin, which represents a new opportunity for therapeutic intervention in ovarian cancer.2 and 95% O2 atmosphere. Cell lines were tested for Mycoplasma by Idexx BioAnalytics and were found negative for any contamination. Human fallopian tube tissues and established PDX tumor models were obtained from the PDX-PCT core facility at OMRF ..29]. We In conclusion, this study demonstrated that the SDHA overexpression contributes to metabolic enhancement associated with significantly increased mitochondrial respiration as well as glycolysis in some of the cell lines leading to increased ATP production rate.As another approach to assess the impact of SDHA upregulation on cellular metabolism, we tested ovarian cancer dependence on nutrients essential for tumor growth. We deprived ovarian cancer cells of selected metabolic nutrients such as glucose or glutamine, or replaced glucose with galactose in culture medium. Glucose is required by cells to produce ATP via glycolysis, and to fuel TCA cycle with pyruvate. Replacing glucose with galactose forces cells to rely almost exclusively on mitochondrial OXPHOS for ATP production . GlutamiTo determine if SDHA overexpression redirects cellular metabolism in response to nutrient deprivation, we cultured selected ovarian cancer cell lines in low glucose, low glutamine or galactose medium  and assessed cellular respiration by the Seahorse XF Cell Mito Stress Test . We obseTo better understand cellular energetics in SDHA overexpressing ovarian cancer cells deprived of nutrients, we quantified ATP production rate. We observed that ovarian cancer cells showed substantial metabolic plasticity, which enabled the cells to switch between glycolysis and oxidative phosphorylation to adapt to changing nutrient conditions during experiment . Our datFurther, we analyzed a total ATP production rate in OVCAR3 cell lines in conditions with low glucose or low glutamine supply. Following glucose deprivation, OVCAR3 cells were capable to fully compensate for a loss in glycolytic ATP production by increasing their mitochondrial ATP production rate E. Such mCollectively, these findings indicate that SDHA overexpressing cell lines are not able to fully compensate for the loss of ATP production following glucose or glutamine deprivation, which results in a significant drop in a total ATP yield. In contrast, the corresponding SDHA-low cells demonstrated an improved metabolic capacity allowing them to better maintain a constant ATP production rate in nutrient deprived conditions. These data also suggest that SDHA overexpressing cells can be more sensitive to a deficiency in essential nutrients or cellular stress.We reasoned that SDHA overexpressing cells could be particularly vulnerable to drugs disrupting glucose and/or glutamine metabolism. To identify agents specifically targeting the SDHA overexpressing ovarian cancer cells, we utilized a custom compound library (from Seleckchem) composed of 64 anti-metabolic compounds . First, Lithospermum erythrorhizon plant) is a Chinese herbal medicine that has been known for its anti-inflammatory and anti-microbial activity [Next, we selected 7 the most potent anti-metabolic compounds and evaluated their efficacy in SDHA-high vs. SDHA-low cell lines. We observed that both shikonin and methotrexate significantly reduced viability of SDHA-high cell lines when compared with SDHA-low counterparts, however the shikonin was the most effective agent in specifically killing SDHA overexpressing cells B. Furtheactivity . More reactivity ,20. NextCollectively, we identified a highly potent compound shikonin that effectively kills SDHA overexpressing ovarian cancer cells. The SDHA overexpression strongly sensitized cancer cells to shikonin, which exhibited a profound anti-tumor efficacy superior that seen with traditional chemotherapy.The reprograming of cellular metabolism is an essential mechanism of tumorigenesis. The metabolic plasticity allows cancer cells to adapt to various unfavorable microenvironmental conditions and sustain uncontrolled cell proliferation, which promotes tumor progression and metastasis ,41. In tSuccinate dehydrogenase has been previously studied in the context of its deficiency in some rare disorders and malignancies ,15,16,17In the present study, our initial findings highlighted a potential importance of SDHA upregulation in ovarian cancer and set the stage for further more rigorous research. First, we performed an analysis of SDHA expression in a collection of healthy fallopian tubes and HGSOC PDX models, which showed that SDHA protein levels are significantly lower in fallopian tubes than in PDX tumors. Further, we observed that ovarian PDXs and established ovarian cancer cell lines exhibit a range of SDHA expressions. Importantly, the percentage (23.5%) of SDHA-high PDX tumors in our data set is consistent with the percentage (19%) of ovarian tumors harboring amplification and/or overexpression of SDHA in patients population (TGCA data set) . Our finTo evaluate the SDHA biological functions in ovarian cancer, we assessed the effect of SDHA overexpression on cell proliferation and in vivo tumor growth. The in vitro experiments revealed that SDHA upregulation is associated with a reduced cell proliferation in some cell lines, while in other cell lines the proliferation of cells is only marginally affected. In vivo data showed a tendency towards reduced tumor growth rate in mice bearing OVCAR3 tumor model. Our findings are in agreement with published studies. For instance, Xu et al., reported that the overexpression of SDHA in renal carcinoma cells inhibited cell proliferation in vitro and suppressed tumor growth in a nude mouse model in vivo . DiffereFurther, our work demonstrated that SDHA overexpression is associated with a generation of significantly more and larger cancer cell colonies in anchorage-independent conditions. It has been shown that aggressive and metastatic tumor cells are able to survive and rapidly propagate in the absence of anchorage to the extracellular matrix, while less tumorigenic or normal cells undergo growth inhibition and/or apoptosis (a process known as anoikis) . These dIn the present study, we set out to investigate the differences in bioenergetic profiles of ovarian cancer cell lines overexpressing SDHA vs. their respective SDHA-low counterparts. The cell lines showed a substantial diversity in their bioenergetic requirements, which was associated with the SDHA overexpression status. Our data consistently demonstrated that the cell lines with SDHA overexpression showed a significantly higher mitochondrial respiration, and tended to have higher maximal and reserve glycolytic capacity. This highly metabolically active phenotype of SDHA overexpressing cells was reflected by significantly increased total ATP yield. Variability in bioenergetic profiles and metabolic plasticity have been previously described in ovarian cancer and other tumor types by others ,32,48,49In our study, we also noted that all cell lines regardless of SDHA status preferentially used glycolysis pathway to fulfill their energy requirements as assessed by higher rates of ATP production from glycolysis than from OXPHOS, which is also in agreement with published data ,51,52. SIn different sets of experiments, we deprived ovarian cancer cells of glucose or glutamine to determine if SDHA overexpression redirects cellular metabolism in response to nutrient deficiency. The cells showed substantial metabolic plasticity switching between glycolysis and oxidative phosphorylation to adapt to changing nutrient conditions. We observed that glucose limitation significantly reduced ATP production from glycolysis that has been compensated with a higher ATP yield from OXPHOS, while glutamine deprivation increased glycolytic ATP yield suppressing ATP production via mitochondrial respiration. Such metabolic flexibility allows cells to become more resilient in variable conditions of tumor microenvironment ,9,32,53.In summary, our work provided novel insights into the role of SDHA upregulation in reprogramming of energy metabolism in ovarian cancer. We showed that SDHA overexpressing cells are highly metabolically active, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. While this phenotype may not drive a higher proliferation rate, it improves cells\u2019 ability to survive anchorage-independent conditions. Importantly, we found that ovarian cancer cells with elevated SDHA are more vulnerable to deprivation of both glucose and glutamine, which is associated with a substantial reduction of ATP yield in those cells. Lastly, we implemented a drug screening strategy and identified anti-metabolic compound shikonin, which demonstrated a specific and potent efficacy against SDHA overexpressing ovarian cancer cells. Our future directions will be focused on pre-clinical testing of shikonin as a promising therapeutic approach for SDHA-amplified tumors. This work is a major step towards our long-term goal, to develop innovative ways to precisely target ovarian cancer-specific metabolism to improve treatment options for ovarian cancer patients."}
+{"text": "Starter Lactic Acid Bacteria (LAB) are responsible for converting lactose to lactic acid during cheese manufacturing and, as a result, play a critical role in defining the attributes of the final product. There is great interest in isolating novel starter LAB strains to provide alternatives to existing industry cultures or to help enhance the quality and safety of cheeses traditionally made without starter cultures addition [1].The Fast-Slow Differential Agar (FSDA) medium was developed in 1984 and still remains the standard to rapidly differentiate fast and slow milk-coagulating lactic streptococci and thus avoid screening a large number of isolates for acid production capacity [2]. However, we found that FSDA was unable to selectively isolate fast acid-producing strains from young, traditional, starter-free Izmir Brined Tulum cheeses, due to the presence of a diverse microbiome including Non-Starter LAB and spoilage Gram-negative microbiota .\u2022Nalidixic acid is an antibiotic that primarily inhibit Gram-negative bacteria [4].\u2022Ascorbic acid and yeast extract stimulate the growth of lactic streptococci [5] and were added to complement skim milk in creating an environment favoring the growth of lactose-positive, casein peptides-utilizing LAB.\u2022The pH indicator bromocresol purple enabled the chromogenic discrimination between LAB with different acid production capability.Here, we describe a modified FSDA (mFSDA) with increased selectivity and recovery efficiency towards lactic streptococci, which was successfully used to rapidly isolate potential starters from Tulum cheeses [1] and could similarly outperform FSDA in raw milk cheeses and other varieties containing high levels of \u201cbackground\u201d microbiota. The main differences between FSDA and mFSDA media consist in the presence of nalidixic acid, ascorbic acid and yeast extract in mFSDA. These targeted additions provide mFSDA with a two-prong selectivity that (I) suppresses unwanted microbiota, and (II) increases the recovery efficiency of lactic streptocci adept to using milk nutrients. Specifically:  Specifications tableThe composition of mFSDA medium is provided in For mFSDA bromocresol purple was chosen over litmus as it was reported to be equivalent to litmus by the developers of the FSDA medium Schleiferilactobacillus harbinensis, while most potential spoilage microorganisms were unable to grow on mFSDA except for Bacillus subtilis. Most of the LAB species tested also produced acid, except for some species normally associated with the Non-Starter LAB microbiota, such as Levilactobacillus brevis, Lentilactobacillus parabuchneri and Latilacobacillus curvatus.The mFSDA medium was initially validated using a bank of 27 Gram-positive and Gram-negative bacteria isolated from raw milks, dairy plants and cheeses during previous projects and stored in the Teagasc DPC culture collection . ResultsFollowing this successful validation, we tested the ability of mFSDA to isolate potential starter streptococci strains from young Izmir Brined Tulum cheeses. Due to the absence of starter addition during manufacturing, young samples of this traditional cheese variety can accumulate spoilage Gram-negative microbiota A key trait of a starter culture for cheese production is the ability to grow rapidly in milk and reduce the pH to \u2264 5.3 in 6 hours. On the other hand, non-starter LAB grow slowly in milk and do not cause such a pH reduction as they are generally lactose-negative and use peptides and free amino acids released from casein by the action of the starter LAB and residual chymosin in the cheese as their nitrogen source Streptococcus infantarius subsp. infantarius and Streptococcus macedonicus, were confirmed to be good acid producers when grown in 10% reconstituted skim milk.In agreement with this, results of the related study In conclusion, the newly developed mFSDA medium affords the same rapid and direct selection of fast acid-producing strains of lactic streptococci as the original FSDA medium while enhancing the recovery efficiency in environments containing background Gram-negative microbiota.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Eosinophilic esophagitis (EoE) is a complex, chronic, allergic disease that commonly presents as dysphagia in young adults. Co-occurring allergic or atopic disease, including food allergies and asthma are seen in approximately 70% of cases. Allergy to house dust mite (HDM) tropomyosin, Der p 10, and cross-reactivity to shrimp has been well described. We discuss a presentation of EoE in the setting of positive HDM skin prick testing that subsequently improved with dietary elimination of shrimp, that has never been described in the literature.To highlight an underlying mechanism in EoE and the importance of a multidisciplinary approach to this disease.A 45-year-old male with a medical history significant for ulcerative colitis  and asthma  was seen by his outpatient gastroenterologist following three weeks of new-onset dysphagia and subjective intermittent food bolus impaction. The patient was pre-emptively started on daily proton pump inhibitor prior to endoscopy, but discontinued this within less than two weeks as he felt like it induced loose bowel movements. Esophagogastroduodenoscopy (EGD) was performed and revealed proximal esophageal furrows. Histology of esophageal biopsies was compatible with EoE: distal esophagus >100 eosinophils/hpf with eosinophil degranulation, mid and proximal esophagus >25 eosinophils/hpf with eosinophil degranulation. The patient self-identified that his episodes of dysphagia and food bolus impaction were associated with shrimp ingestion, thus he eliminated shrimp from his diet.Dermatophagoides pteronyssinus and farina) but negative testing to shrimp, despite clinical improvement with dietary shrimp elimination. Thus his EoE was attributed to HDM cross-reactivity, specifically to the Der p 10 antigen. Follow-up EGD and biopsy to confirm endoscopic and histologic remission with shrimp elimination is scheduled in two months.Two-month clinical follow-up demonstrated symptomatic remission despite no other active treatment or additional food elimination. Consultation with an allergist demonstrated the patient had positive skin prick testing to HDM  shrimp, but often only demonstrate positive skin prick testing to HDM (with negative testing to shrimp). This case demonstrates a role for involvement of an allergist and skin prick testing in select cases of EoE, as this may result in a relatively simple food elimination and avoidance of further therapeutic interventions.NoneNone Declared"}
+{"text": "Prehospital airway devices are often classified as either basic or advanced, with this latter category including both supraglottic airway (SGA) devices and instruments designed to perform endotracheal intubation (ETI). Therefore, many authors analyze the impact of SGA and ETI devices jointly. There are however fundamental differences between these instruments. Indeed, adequate airway protection can only be achieved through ETI, and SGA devices all have relatively low leak pressures which might compromise both oxygenation and ventilation when lung compliance is decreased. In addition, there is increasing evidence that SGA devices reduce carotid blood flow in case of cardiac arrest. Nevertheless, SGA devices might be particularly useful in the prehospital setting where many providers are not experienced enough to safely perform ETI. Compared to basic airway management  devices, SGA devices enable better oxygenation, decrease the odds of aspiration, and allow for more reliable capnometric measurement by virtue of their enhanced airtightness. For all these reasons, we strongly believe that SGA devices should be categorized as \u201cintermediate airway management devices\u201d and be systematically analyzed separately from devices designed to perform ETI. Prehospital airway management devices are often classified as either basic or advanced. According to many recent prehospital studies, both supraglottic airway (SGA) devices and devices designed to perform endotracheal intubation (ETI) represent the advanced category and are therefore analyzed jointly ,2,3,4. IThere are fundamental differences between SGA and ETI devices. While mastering ETI requires considerable clinical expertise , even moIn addition, in studies differentiating ETI from SGA device insertion, clinical outcomes are often different between groups. For instance, a recent study reported the highest mortality and the lowest rate of good neurological performance after out-of-hospital cardiac arrest when SGA devices were used . The reaFurther supporting the separate categorization of SGA devices to explore cardiac arrest related outcomes, a recent simulation study unexpectedly discovered that chest compressions were significantly shallower when ventilation was performed when SGA devices were in place than when bag-valve mask devices were used . Should Even though we are of the opinion that systematically categorizing SGA devices separately from ETI and BVM  devices is scientifically sound and could help optimize prehospital care protocols, fellow authors and researchers may disagree with us for diverse reasons. Indeed, researchers working in systems where ETI capacities are always available may consider that analyzing SGA devices separately is not worthwhile. However, many prehospital providers are neither allowed nor trained to perform prehospital ETI, and SGA devices represent the next best option in such situations. In addition, other researchers might consider that almost all emergency prehospital providers should have been taught and allowed to use SGA devices by now. While we are convinced that enabling the vast majority of prehospital providers to use SGA devices is an important objective since these devices readily improve oxygenation and ventilation in many situations, certified paramedics are still not allowed to use such devices in certain regions of the world .We are aware that acknowledging a new category of airway management devices could be considered controversial since different opinions regarding airway management devices have been expressed in the literature, and some authors may even consider our position as provocative. Nevertheless, given the aforementioned differences and the impact they may have on clinical outcomes, we strongly believe that an intermediate airway management category incorporating all SGA devices should be acknowledged. By allowing the specific appraisal of the clinical impact of these devices, policy changes could subsequently be considered in certain settings where airway management resources are scarce."}
+{"text": "Cognitive control decline is a major manifestation of brain aging that severely impairs the goal-directed abilities of older adults. Magnetic resonance imaging evidence suggests that cognitive control during aging is associated with altered activation in a range of brain regions, including the frontal, parietal, and occipital lobes. However, focusing on specific regions, while ignoring the structural and functional connectivity between regions, may impede an integrated understanding of cognitive control decline in older adults. Here, we discuss the role of aging-related changes in functional segregation, integration, and antagonism among large-scale networks. We highlight that disrupted spontaneous network organization, impaired information co-processing, and enhanced endogenous interference promote cognitive control declines during aging. Additionally, in older adults, severe damage to structural network can weaken functional connectivity and subsequently trigger cognitive control decline, whereas a relatively intact structural network ensures the compensation of functional connectivity to mitigate cognitive control impairment. Thus, we propose that age-related changes in functional networks may be influenced by structural networks in cognitive control in aging (CCA). This review provided an integrative framework to understand the cognitive control decline in aging by viewing the brain as a multimodal networked system. Over the past 20 years, the proportion of older adults in the population has expanded rapidly . AdvanceTo date, a major focus in neurocognitive aging research was linking cognitive control declines to specific regions . From thAccumulating evidence has suggested that CCA can arise from changes in connectivity among brain networks . NetworkMultiple large-scale networks facilitate specialized mental functioning for cognitive control . These nDecreased functional segregation occurs with aging . FunctioPreliminary evidence has suggested that decreased functional segregation of the TPN is associated with a decline in cognitive control with age. For example, in older adults, lower intra-connectivity within frontoparietal and attention network indicates worse cognitive control, and enhanced inter-connectivity between the frontoparietal and dorsal attention networks is associated with cognitive control decline . FunctioFunctional integration  reflects the integrated processing of information during tasks and usually manifests as enhanced functional connectivity . EnhanceFunctional integration among the frontoparietal network may be an important neural indicator of the cognitive control ability during aging. In older adults, functional connectivity between prefrontal and parietal cortex, i.e., within the frontoparietal network, positively predicts their performance during tasks requiring cognitive control . FurtherFunctional integration between frontoparietal network regions  and task-specific regions is associated with CCA (as illustrated in Finally, functional integration, as measured by network efficiency properties, declines with aging. Network integrative processes can be viewed as the communication efficiency measured by graph-theoretic properties . In addiCognitive control relies on functional antagonism between large-scale networks. Functional antagonism differs from functional segregation. Functional segregation usually refers to positive functional connectivity, where blood-oxygen dynamics between regions are predominantly positively correlated, whereas functional antagonism refers mainly to negative connectivity, where the blood oxygen level-dependent signals between paired regions are predominantly negatively correlated . FunctioDeclines in functional antagonism are important neurological indicators of the decreased cognitive control in older adults (as illustrated in Aging-related changes in the functional connectivity of large-scale networks are important contributors to CCA. Specifically, decreased functional segregation, integration, and antagonism are associated with worse behavioral performance measured by control-based tasks in older adults . DespiteAnatomically, a large number of isotropic axons are \u201cbundled\u201d together to form white matter fibers. These fibers form a structural network that ensures the transmission of electrical signals across brain regions . In healAge-related structural changes in the white matter involve both decreases in white matter volume and impairment of structural connections . Voxel-bBoth white matter loss and structural disconnection suggest a decrease in neural signaling capacity and are associated with decreased cognitive control . In oldeFunctional networks may serve as mediators of the cognitive control decline triggered by structural network damage. The impairment perspective proposes that damage to structural connections can weaken functional connectivity. Studies have shown that structural connections support functional connectivity in healthy older adults. For example, However, the damage perspective cannot explain some of the existing empirical results and may lead to a view of functional connectivity compensation (A relatively intact structural network may be a prerequisite for functional connectivity compensation, while severe lesions in the structural network can trigger reduced functional connectivity. When considering a network as a whole, a marked similarity between functional and structural networks can be observed . StructuStructural and functional networks show complex interactions affecting CCA. Because structural connections support and constrain functional connections, it could be concluded that structural connection damage triggers cognitive control decline by weakening functional connectivity. However, when the structural network is locally damaged but globally preserved, the effects on functional connectivity may be compensated through third-party structural pathways and may counteract the cognitive control decline associated with the structural damage. Functional compensation determined by preservation of the structural network should be considered in future explorations of network mechanisms underlying CCA.Aging-related changes in structural and functional connectivity among networks are involved in decreased CCA. However, to date, CCA-related network mechanisms have been established based on correlative evidence . In the Common and unique network mechanisms underlie cognitive control. Cognitive control can be divided into three core subcomponents: working memory, inhibitory control, and cognitive flexibility . All thrAging-related network mechanisms underlying the different subcomponents of cognitive control may be both shared and unique. Declines in functional connectivity within the frontoparietal network are associated with decreased CCA ; howeverpriori variable. In future, researchers should systematically collect multimodal imaging data, select targeted connections or networks, and construct mediating and moderating multivariate models to clarify how structural and functional networks interact and influence CCA.Multimodal network mechanisms for CCA are mostly theoretical, and empirical studies are rare. The impairment perspective suggests that CCA follows the pathway of \u201cstructural connectivity impairment \u2192 functional connectivity impairment \u2192 cognitive control decline.\u201d However, the compensation view suggests that if the structural network is mostly preserved, the compensation of functional connectivity can be occurred through third-party structural pathways, as manifested by increased functional connectivity and cognitive control maintenance. When the structural network is severely disrupted, the functional network will be damaged and result in declines in cognitive control. Thus, structural and functional networks act together in a complex way in CCA, and the degree of structural network impairment may be an important a Notably, communication models and multilayer network analyses that emerge from network science would offer approaches to explore the structure\u2013function coupling of brain networks . By formWhether changes in dynamic functional connectivity are involved in decreased CCA should be examined. Dynamic functional connectivity refers to the time-varying fluctuations of functional networks . CognitiCognitive control decline is a salient feature of aging. Abnormalities in the functional segregation, integration, and antagonism of functional networks suggest that disrupted spontaneous network organization, failed information co-processing, and increased endogenous interference in cognitive control are related to reduced CCA. Severe damage to the structural network can induce cognitive control decline by weakening functional connectivity. Nevertheless, a relatively intact structural network can ensure the compensation of functional connectivity, to delay the decline in CCA. Future research should introduce network neuroscience approaches and investigate the multimodal network mechanisms of aging-related cognitive control decline.HX: writing and revising the article, drafting, and proofreading references. QH and AC: reviewing and revising the manuscript and giving critical comments. All authors contributed to the article and approved the submitted version."}
+{"text": "Arthropod bite mastitis is rarely encountered in imaging practices but can occur in all regions of the world. Diagnosis is often challenging as the offending agent is rarely identified. While most manifestations are self-limited, severe presentations can mimic malignant processes such as Paget\u2019s disease and inflammatory breast cancer (IBC). This case demonstrates the diagnostic challenges sometimes encountered with arthropod bite mastitis as well as imaging findings both prior to and after interventions. While insect and arachnid bites occur worldwide, mastitis resulting from these arthropod bites remains a rare clinical entity with few case reports described -3. ArthrA 56-year-old woman presented with a three-month history of a right breast erythematous macular rash with scaling, which persisted despite the application of a topical antibiotic. The patient reported no antecedent trauma as well as no associated drainage, fever, or chills. During this time, she worked in a grocery store and began handling boxes of produce. At times, she noted occasional spiders and insects around the produce containers.Initial diagnostic mammography demonstrated an asymmetry with architectural distortion and skin thickening in the inferior right breast, with associated non-specific hypoechoic tissue on targeted ultrasound Figure . Punch bA short-term follow-up mammogram in four months demonstrated progressive skin thickening and an enlarging asymmetry in the inferior right breast, with a questionable underlying mass on targeted ultrasound Figure . The finAlthough clinical presentations are rare, arthropod bite mastitis can occur worldwide and should be considered in breast imaging workups ,4. In maNo specific diagnostic imaging criteria are available for arthropod bites, although superficial edema and inflammation are expected . DiagnosIf arthropod bite mastitis is expected, clinical follow-up and possible short-interval follow-up imaging (three to six months) may be suggested to ensure a benign clinical exam or resolution of imaging findings. Specific treatments depend upon the arthropod responsible for the bite, with pharmacologic and nonpharmacologic approaches providing relief . When clSevere presentations of arthropod bite mastitis can mimic breast malignancy, including Paget\u2019s disease and inflammatory breast cancer. Diagnosis is often challenging, and a biopsy may be needed to exclude an underlying malignant process. Awareness of this entity and reliable clinical information such as symptom onset and duration are key to preventing unnecessary additional interventions."}
+{"text": "Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for new therapeutics that otherwise have shown significant successes in disease control. Hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and is widely targeted in drug development. We found that resistance to the HGF-neutralizing antibody drug candidate rilotumumab in glioblastoma cells was acquired through HGF overproduction and misfolding, which led to stress-response signaling and redirected transport inside cells that sequestered rilotumumab and misfolded HGF from native HGF and activated Met receptor. Resistant cells were more malignant but retained their sensitivity to Met kinase inhibition and gained sensitivity to inhibition of stress signaling and cholesterol biosynthesis. Defining this rapidly acquired, multisystem scheme improves our understanding of drug resistance and suggests strategies for early detection and intervention.MET and HGF genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention.Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of  MGMT which encodes an alkyltransferase capable of repairing the DNA damage. The issue has become even more vexing with the development of highly selective agents such as those targeting the epidermal and hepatocyte growth factor  pathways. Acquired resistance to gefitinib or erlotinib in lung adenocarcinomas is a prevalent response to prolonged treatment and occurs through HGF pathway activation and other molecular mechanisms , often through increased expression of hanisms . Ant. AntMGMTHGF and MET genes are expressed in human glioma and medulloblastoma, where their increased relative abundance frequently correlates with tumor grade, tumor blood vessel density and poor prognosis . Quantitative PCR analysis showed that the mRNA transcript levels for HGF v1 and v3, the full-length variants, were more than 600- and 100-fold more abundant in the resistant cell line relative to the parental, respectively  and the most significant IPA \u201cMolecular and Cellular Function\u201d identified was \u201cCellular Growth and Proliferation\u201d . Twenty-six IPA \u201cCanonical Pathways\u201d were identified as having significant overlap with the dataset by right-tailed Fisher\u2019s Exact test and the Benjamini\u2013Hochberg (B\u2013H) multiple test correction , and group 6 pathways are consistent with a cellular origin of GBM. Phenotypic groups 1 and 2 however\u2014stress signaling and immune-related pathways\u2014suggested processes and pathways by which autocrine HGF/Met activation could evade contact with rilotumumab.P. pastoris) provide low yields of active protein unless they are specifically engineered to overexpress protein disulfide isomerase(s) to facilitate the correct disulfide bond pairing required for proper folding  or smaliewed in ,69,70,71HGF and MET gene amplification and HGF protein super-production; (2) downregulation of ER-resident disulfide isomerases contributing to significant HGF protein misfolding; (3) induction of ER stress-response signaling and intracellular HGF and Met protein retention; and (4) dramatically increased rilotumumab uptake and degradation through a shift to caveolar endocytosis and activation of antigen presentation pathways. Together, these changes provided intracellular seclusion of properly folded HGF and Met proteins from rilotumumab and maintained HGF/Met signaling dependence for cell growth and survival.Acquired drug resistance obstructs the effective treatment of many cancers and occurs through various mechanisms, often involving the elimination of drug from target cells or new defects in proto-oncogenes or tumor suppressors that revitalize essential growth and survival signaling pathways. Here we report a novel route to acquired resistance. In glioblastoma cells that require autocrine hepatocyte growth factor (HGF)/Met signaling for proliferation and survival, resistance to the HGF neutralizing monoclonal antibody rilotumumab was acquired through a complex interplay of several intracellular systems: (1) Unlike other acquired drug-resistance mechanisms, mutation of the gene encoding the drug target, loss of critical negative regulators downstream of the drug target, and/or activation of alternative mitogenic pathways parallel to the target were not observed. Despite the number and diversity of the subcellular systems involved, resistance developed rapidly in GBM cells in which HGF is an important oncogenic driver. Defining this mechanism also revealed targetable co-acquired dependencies for survival in resistance cells: cholesterol synthesis needed for caveolar uptake and ER-stress signaling as well as continued sensitivity to small-molecule Met tyrosine kinase inhibitors. These findings suggest strategies for the early detection of this form of resistance and for effective intervention."}
+{"text": "The COVID-19 pandemic impacted predoctoral psychology training at the graduate, practicum, and internship levels including a greater reliance on telehealth and evolving learning needs. However its unique impact on geropsychology training has not been explored. The Building Bridges workgroup for predoctoral training faculty levels, we describe opportunities and barriers to address evolving geropsychology training needs during the pandemic as determined through working group discussion. Negative impacts to training identified include: decreased opportunities for 1) face-to-face patient care and 2) telehealth care due to disparities in telehealth access and utilization in older adults. Other impacts on the geropsychology pipeline include declining opportunities to see older adults at practicum sites. Conversely, increased media attention to the impact of COVID on older adults\u2019 physical and mental health may lead to graduate students\u2019 having greater interest in geriatric mental health and reinforcing a geropsychology career. Recommendations for training programs to address the long-term ramifications of the pandemic will be offered."}
+{"text": "The continued demographic shifts in population aging are coupled with an increase in self-identified, LGBTQ+ individuals entering older age. While they share some common age-related experiences with non-LGBTQ+ individuals, they also face unique challenges as they age, including additional intersectional pressures beyond their sexual or gender identity. These challenges are exacerbated by pre-existing health inequities and heteronormative social support systems. Of particular concern is the ability to locate affirming and accessible social and health services. Gerontologists have a critical role in assisting older LGBTQ+ individuals in navigating complex social systems. To do so requires they have the appropriate education to develop the cultural humility needed to understand and assist these individuals. It necessitates the engagement of gerontology and geriatric education programs in educating future gerontologist professionals about LGBTQ+ older individuals. Critically, it requires the identification of appropriate instructors who are equipped to educate on LGBTQ+ aging topics."}
+{"text": "Social support from family provided benefits for coping during the COVID-19 pandemic; however, not all older adults had access to family. The present study investigates how older adults without access to traditional family ties conceptualized their social relationships throughout the first two years of the pandemic. A subsample of eight older adults without direct access to traditional family ties were identified from a larger 5-wave interview study conducted between April 2020 and June 2022. Transcripts were holistically coded and three overarching themes emerged: constraints of place, redefining family, and feelings of isolation and closeness. The first theme addressed having family members living far away and uncertainty of when they would get to see them again. However, these distance barriers could be overcome through technology. The second theme illuminated that during the pandemic, those without access to traditional family ties redefined their social relationships by developing fictive kin from neighbors, colleagues, and friends. The third theme highlighted that some older adults felt they were lacking strong social networks and were concerned they had nobody to contact if they needed help, while others felt that despite limitations, their social relationships grew closer due to connection through alternative forms of communication (e.g. texting). Results from this study clarify how traditional family ties were challenged and strengthened during physical distancing for some older adults. These findings extend the literature on how fictive kin forms in older adulthood during temporary crises and suggests potential avenues for social connection for older adults lacking traditional family support."}
+{"text": "Recent investigations of the mechanisms through which stress may impact cardiometabolic health point to the potential importance of cognitive tendencies  in this relationship. This study examined the associations between vigilance and stress coping with metabolic risk, and whether these associations varied by race and life course socioeconomic status (SES). Data come from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, a cohort of urban adults . Vigilance was measured by the MacArthur Reactive Responding subscale; stress coping was measured by the Brief Cope scale. Metabolic risk was operationalized by metabolic syndrome z-scores (MetS-Z). Linear mixed models were used to examine longitudinal associations between cognitive tendencies and MetS-Z; interaction terms were used to examine effect modification by race and life course SES. Black participants reported higher adaptive coping; participants experiencing persistent poverty or downward mobility reported higher vigilance and avoidant coping and lower adaptive coping. Overall, vigilance was not associated with metabolic risk. Avoidant and adaptive coping were inversely associated with baseline MetS-Z and further varied by sociodemographic factors. Higher adaptive coping was associated with lower MetS-Z among White adults, while higher avoidant coping was associated with lower MetS-Z among Black adults. Lower stress coping were associated with higher MetS-Z among White participants with low lifecourse SES or downward socioeconomic mobility. In sum, stress coping may modulate the stress-health relationship, but these associations must be interpreted within the intersection of contextual factors."}
+{"text": "Enterobacterales (CRE) presents a major threat to public health. CRE employ two molecular mechanisms to evade carbapenems: 1) expression carbapenemases (CPases), which efficiently hydrolyze carbapenems or 2) disruption of porins, which reduces carbapenem influx to levels that can be hydrolyzed by certain beta-lactamases. Diagnosing mechanisms underlying carbapenem resistance is important for infection control and to administer appropriate treatments.The global spread of carbapenem-resistant Enterobacterales isolated from hospitals in Massachusetts and California using broth microdilution assays at 14 inocula spanning four orders of magnitude. They represented 30 isolates encoding CPases and intact porins, 46 isolates with disruptions in one or both of the porins responsible for carbapenem influx (OmpC and OmpF), 25 encoding CPases with disrupted porins, and two controls encoding intact porins and no CPases.We measured Meropenem and Ertapenem minimum inhibitory concentrations (MICs) for 103 clinical We observed that the two mechanisms result in distinct profiles; first the carbapenem MICs of CPase-encoding strains show a strong inoculum dependence , whereas the MICs of porin deficient strains remain largely constant at all inocula . The synergistic action of these two mechanisms leads to high-level resistance that we termed \u201chyper-CRE\u201d . Together these factors explain the level of resistance in nearly all our CRE isolates. To validate the hyper-CRE phenotype, we successfully employed CRISPR-based gene editing to show that knocking out the major porin in CPase-producing strains elevates their carbapenem resistance to hyper-CRE levels.in vitro AST assays but are truly resistant in vivo.We also determined 18% of our isolates changed susceptibility classification within the Clinical Laboratory and Standards Institute (CLSI) recommended inoculum range. This is worrisome for the treatment of infections with strains that are deemed susceptible via Overall, our approach has demonstrated that measuring MICs at different inoculum can yield crucial diagnostic information about mechanisms of resistance which has important implications for patient care, infection control, and surveillance of emerging CPases.All Authors: No reported disclosures."}
+{"text": "A growing body of literature suggests that inclusion of ultra-processed foods (UPFs) in the diet may be associated with various non-communicable diseases, including obesity, cardiometabolic diseases, and increased mortality. However, one of the most underrated research topics is represented by the potential role of diet for mental disorders. The aim of this study was to explore whether there was an association between UPF consumption and mental health outcomes in a cohort of southern Italian individuals.Demographic and dietary data from 1572 adults living in southern Italy was collected. Food items were categorized by the level of processing according to the NOVA classification. Multivariate logistic regressions were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between UPF intake and mental health outcomes, including sleep quality and depressive symptoms.Individuals in the highest quintile of UPF intake were more likely to have low sleep quality compared to those with the least intake . Among the main component of sleep quality, high UPF intake was associated with sleep latency and efficacy individually. No apparent associations were found between UPF intake and depressive symptoms. However, when considering different age groups, younger individuals (age <40 y) consuming more UPF were more likely to have depressive symptoms than low consumers .These findings show a potential association between UPF consumption and mental health outcomes. Further studies are needed to understand whether the retrieved relation depends on alteration of the physiological feeding patterns leading to food-anticipatory and binge-type behaviors or on nutritional  and non-nutritional factors  triggering pro-inflammatory pathways.\u2022\u2002Ultra-processed food consumption is associated with worse sleep quality and depressive symptoms in Italian adults.\u2022\u2002The detrimental associations between ultra-processed food consumption and depressive symptoms seem stronger among younger individuals."}
+{"text": "We conducted participatory design research for long term care (LTC) socially assistive robotic activities comprised of social, cognitive and physical components and enhanced human-robot (HRI) and human-human interactions (HHI). Repeated sessions were conducted with 10 geriatric experts  and 12 LTC residents (ages 70\u201392). Two robots, animal and humanoid, were used in combination with virtual reality. Four collaborative activities for paired older adults were designed and evaluated: playing drums to music, completing paintings, a fishing game, and training a dog with simple commands. Within each activity, three levels of difficulty were designed. Stakeholder feedback was obtained through observations and interviews. Numerous modifications were made following each session that addressed hardware, software and activity issues. Modifications were necessary both for the HRI and HHI aspects of the activity. Our experience demonstrates the necessity for participatory design in the deployment of technology for LTC settings."}
+{"text": "The Age-Friendly University (AFU) initiative aims to increase the participation of age-diverse older adults in higher education communities. The present study investigated age-friendly practices across 23 institutions in the United States. The ICCS Inventory , which identifies 192 potential age-friendly campus practices was completed by administrators representing major campus units. A heat map was used to graphically represent age-friendly practices and identify where universities differed in the presence of those practices. Heat map findings indicated campuses are low in some auxiliary services that assist retired faculty and staff. However, campuses consistently gave retired faculty and staff access to university library services. Campuses also had limited age-friendly teaching and learning services. None of the campuses reported having resources to help faculty deliver teaching materials in formats specifically geared toward older learners. In addition, none of the campuses reported having teaching and learning staff visiting campus departments to provide resources for older learners, and very few campuses offered courses that focused on aging and age diversity issues. Common age-friendly practices were seen with respect to providing instructional technology support for faculty/staff/students and community partnerships for intergenerational activities. Physical environment and personnel evidenced the most frequent age-friendly practices likely because they are mandated by the ADA . Overall, the present study highlighted the areas where college campuses are most age inclusive, while also revealing areas for improvement in age inclusive practices."}
+{"text": "Markers of functional aging can be used to track biological aging longitudinally and how it changes in response to the environment, e.g., drugs. We aimed to investigate how different drug classes may alter functional aging trajectories using data from the National E-infrastructure of Aging Research (NEAR) in Sweden. Data were harmonized across several longitudinal cohorts of aging for general cognitive performance, grip strength, walking speed, sensory ability , lung function and assessment of frailty using the accumulation deficit model known as the frailty index. Selected drug classes were lipid lowering, glucose lowering and blood pressure lowering medications that are commonly used in old adults. Preliminary analysis using data from one longitudinal cohort shows that using glucose lowering drugs was associated with lower frailty. Additional analyses are ongoing to increase sample sizes. We anticipate that several drug classes may be important for changing functional aging trajectories in late life."}
+{"text": "The cornea is a transparent avascular structure located in the front of the eye that refracts light entering the eyes and also serves as a barrier between the outside world and the internal contents of the eye. Like every other body part, the cornea may suffer insult from trauma, infection, and inflammation. In the case of trauma, a prior infection that left a scar, or conditions such as keratoconus that warrant the removal of all or part of the cornea (keratoplasty), it is important to use healthy donor corneal tissues and cells that can replace the damaged cornea. The types of cornea transplant techniques employed currently include: penetrating keratoplasty, endothelial keratoplasty (EK), and artificial cornea transplant. Postoperative failure acutely or after years can result after a cornea transplant and may require a repeat transplant. This minireview briefly examines the various types of corneal transplant methodologies, indications, contraindications, presurgical protocols, sources of cornea transplant material, wound healing after surgery complications, co-morbidities, and the effect of COVID-19 in corneal transplant surgery. The cornea is an avascular tissue that is transparent due to the arrangement of its component cells, its avascularity and the metabolic processes its endothelium carries out . It measWe searched the Pubmed database using the following search criteria; \u201ccorneal transplantation\u201d [MeSH Terms] OR  OR \u201ccorneal transplantation\u201d [All Fields] OR (\u201ccornea\u201d [All Fields] AND \u201ctransplantation\u201d [All Fields]) OR \u201ccornea transplantation\u201d [All Fields]. Given that this study was focused on CT in the last decade, we narrowed the search criteria to 2012 to 2023, resulting in a return of 3021 results. The search words using only \u201ctransplant\u201d or \u201ckeratoplasty\u201d or other single words were not considered in our minireview to avoid an overabundance of potentially impertinent studies. This search strategy was limiting and could have potentially and unintentionally excluded opinion leaders in this field of research. A Prisma Table was also generated, showing further stratification steps.Corneal transplantation (CT) is indicated via any processes leading to loss of corneal transparency, with neuroretinal integrity and optimal visual potential otherwise preserved . CT is uCTs are among the most common procedure performed in many tertiary eye centers worldwide ,10,11,12Proper patient selection is key to yielding reasonable CT outcomes. A thorough corneal, anterior and gross posterior segment evaluation, in addition to a systemic workup, should ideally be carried out prior to qualifying all potential CT candidates. With regard to preoperative corneal evaluation, the depth of corneal tissue scarring and evidence of corneal ectasia should be determined. Detection of keratic precipitates  indicates active or latent migration and deposition of immune moieties. The resultant hyperimmune sensitization disrupts the ocular immune privilege, decreasing the chances of post-graft tissue survival by more than four-fold . EstabliWhen significant corneal stromal haze or widespread leucomatous scarring impairs intraocular evaluation, imaging modalities such as anterior segment-ocular coherence tomography (AS-OCT), ultrasound biomicroscopy (UBM), and B scan ultrasonography can be respectively utilized to gain a gross outline of individualized intraocular integrity. Corneal central thickness (CCT) measurements with pachymetry have, in the past, been correlated with corneal endothelial cell (CEC) loss , mostly Under normal circumstances, the trilaminar cornea is devoid of lymphocytes. The cornea\u2019s innate defense systems are provided by bacteriostatic enzymes in the tear film, the equilibrium of microbiome/normal flora on the ocular surface and the corneal epithelial barrier attributes . This inStandardized procedures of donor corneal tissue viability analysis are usually followed prior to harvesting and cryopreservation with corneal banks . With reRooij et al. conducted a comparative analysis of three standard methods of CT for the management of Fuchs endothelial dystrophy. They found that there was no significant difference between improvement using conventional PK, inverted mushroom PK and DSAEK .Globally, the need for donor corneal tissue to ease the burden of avoidable corneal blindness far outweighs the availability of viable graft tissue for CT . The demSafe strategies for extending the viability period of donor tissue before allografting have been explored . GlyceroAutologous graft sourcing also represents a viable strategy in rare cases where healthy corneal tissue on the contralateral side may not be of great functionality due to late comorbid ocular disease . HomonymCorneal transplantation of autologous tragal perichondrium with an amniotic membrane overlay has been reported to yield symptomatic relief among patients with bullous keratopathy compared to controls . CulturiA common complication of wound healing is neovascularization. Topical bevacizumab application post-CT four times daily for 24 weeks was found to statistically reduce the occurrence of neovascularization . Better Immune rejection after CT has been successfully managed via donor-derived, tolerogenic dendritic cells . A blockIn cases where there is a severe corneal ulceration threatening the integrity of the globe, a penetrating keratoplasty can be the last chance of saving that eye . The keyCorneal donation involves identifying a potential donor eye, preparing the eye for removal of the graft, extraction of donor tissue and storage. Therefore, the preparation of corneal grafts takes up a critical stage in this regard due to the high demand for cornea tissue and relatively lower supply ,48. IntrHagenah and Winter reviewed recent trends in globe disinfection before graft extraction . They su2 in 14% of its participants and co-morbidities in corneal transplant medicine.The ECD can be a very important indicator of the eventual viability of the graft. Gupta and Gupta examined 100 eyes that received corneal transplants within a two-year period over periodic intervals. They reported that the most endothelial cell loss was seen in patients undergoing a repeat graft, while keratoconus-grafted eyes showed the lowest loss . AnotherThis relative scarcity of corneas for transplant puts their storage on the front burner for many researchers. The numbers of overall grafts properly stored and the eventual viability of the grafts when needed for eventual transplant are two key indices that can advise on the progress of corneal tissue storage development. Garcin et al. developed an active storage device which they called a bioreactor and compared its preservation abilities versus the organ culture storage technique. They published results showing that the bioreactor had a 23% higher rate of endothelial cell survival than the organ culture technique . They alFailure of the cornea graft (PGF).Immunological reaction by the host to the graft .Non-immunological factors such as spontaneous decompensation, glaucoma and diseases ,61. WounOther distinct factors .Generally, the causes of CT failure have been classified into:The cornea endothelium is an inner barrier to edematous damage from aqueous humor breaching into the cornea. Endothelial cell count (CEC) is therefore essential to assess the ability of the eye to retain this protective ability. Studies have shown that the CEC is significantly reduced when corneas are extracted for grafting . Jafarinp = 0.815).Cytokine elevation has also been observed in eyes that suffered CT failure , althougWound dehiscence is a common complication post-CT. A study was conducted in the Riyal Eye and Ear hospital to assess the incidence and clinical demographic of 72 eyes who visited a center for surgery . PeriopeCorneal opacities impede intraoperative visualization during cataract extraction and vitreoretinal surgery . PerformClinicians should also note that patients receiving immune checkpoint medication are at risk of CT rejection . Common Another study at a different center reported an incidence of microbial keratitis in 4.77% of 1508 eyes that had undergone CT . NatamycNon-infective unforeseen events can also complicate the CT process. Jarstad et al. reported a case of cardiac failure in an otherwise healthy young adult during CT surgery that was successfully managed . AnotherRare conditions like monoclonal gammopathy of undetermined significance are also implicated, especially in the presence of elevated levels of abnormal M proteins . Paniz-MAs with any grafting procedure, immunologic interactions between the host and donor tissue can be problematic. However, non-immunologic factors can also be a factor in the loss of CEC, even with patients receiving autologous CT . Repeat The avascularity and degree of sensory innervation of the cornea ensure the maintenance of its structural integrity and function. A deviation from the regular structural integrity and outline precipitated by cornea diseases is the fourth leading cause of blindness worldwide. Most visual impairments resulting from cornea morbidities are avertible and reversible. Cornea transplantation is a required surgical intervention in cornea diseases which results in a deep lamellar cornea structural deformity; however, as with most solid-organ transplants, the risk of transmission of infectious diseases to the handlers of donor tissues and recipients cannot be overlooked. The Eye Bank Association of America (EBAA) released updated recommendations and policy changes with the advent of the COVID-19 pandemic .The COVID-19 pandemic resulted in acute and chronic shortages of donor corneas in a healthcare system that already had a long list of patients waiting ,99. A stSeveral questions regarding the spread and transmission of SAR-CoV-2 in tears and ocular tissues have been asked. The first was to identify the presence of SAR-CoV-2 in tears which may enable its transmission and subsequent infection of ocular tissues . In a stThe shortage of donor tissue during the COVID-19 pandemic also had positive results. Clinicians reported an innovative procedure and were able to use a single donor cornea for four different recipients undergoing CT for different conditions . AnotherA 15-year review of corneal donations in southern Africa revealed that cultural beliefs have led to a marked reduction in donation numbers . HoweverGain et al. conducted a systematic review of reports on corneal transplant medicine and eye banks. They then conducted interview series among specialists spanning 148 different countries. In total, they reviewed 184,576 surgeries using 283,530 corneas obtained from 742 cornea banks. Their work concluded that there was indeed a scarcity of corneas worldwide. Their calculated availability was estimated at only one cornea for every 70 eligible transplant patients. They suggested an acceleration of alternative/artificial solutions such as keratoprostheses .The first CT took place in 1884 using a bovine cornea . CT has Amagai et al. reported the successful development of a novel tissue carrier for donor graft tissue . They vaTissue-engineered construct models for corneal endothelial keratoplasty have shown greater pharmacoeconomic potentials than those working with donor tissue . UltraviAzithromycin treatment regimen has been reported to reduce the incidence of high-risk allograft rejection in murine models . PreoperSteroid therapy after ocular surgery is indicated for the prevention of inflammation and also for its immunosuppressive properties. Poinard et al. conducted a study to assess the adherence of cornea transplant receivers to prescribed postoperative steroid therapy . SteroidTrone et al. also conducted a pilot study (Phase II) as part of a clinical trial to assess the safety of a new dropless PK which incorporated a subconjunctival steroid implant . FourteeAs already stated, conventional keratoplasty involves allogeneic transplantation of corneal tissue: tissue-specifics depending on the disease section of the cornea . NotablyKeratoprestheses require a clear central optic zone to enable refraction onto the retina. Historically, early KPro material consisted of convex glass sheets which served as optics surrounded by metallic rims made of silver, quartz, platinum and like materials . AttemptRetrospectively, the Boston type-1 KPro (with its phakic and aphakic models) and the Osteo-odonto KPro have reportedly recorded proven highest success rates. The use of the temporary Eckardt KPro and other retrievable soft contact lens media has been successfully trialed for posterior segment visualization during vitreoretinal procedures with combined keratoplasty ,143. EyePreoperative preparation requires ocular imaging and biometric analysis to determine anterior chamber depth; gross morphological iridocorneal angle integrity; crystalline lens presence/position; also, and retinal function and integrity (which may require electrophysiology in doubtful cases).Major complications reported post-KPro implantation include glaucoma, persistent autoimmune reaction with cases of coexisting system autoimmune disease -driven responses can help to avert further sight loss following KPro implantation.Corneal specialist surgeons should be globally incentivized to encourage uptake, training, and retraining in modern techniques of allograft transplantation. The major impediment to optimal management of corneal blindness aside from donor shortage remains post-CT rejection/graft failure. Finding solutions may depend on the rate of progress regarding the incorporation of either biological material or procedural modulation of stem cell differentiation to avascular corneal-like tissue, especially for immune-mediated graft failure. There will certainly be limitations to this approach, specifically in the exploitation of totipotent embryonic stem cells. Strategies to prolong the viability time of donor grafts would also serve to minimize cost effectiveness preoperatively. Demand for CT may also decrease if current advances in local ocular stem cell application and amniotic membrane transplantation reduce the incidence of corneal scarring following chemical injury and deep corneal ulceration."}
+{"text": "There is a huge resource gap in mental health service provision & service utilisation in LAMIC including Pakistan. SOUL Programme has been established in the City of Larkana, on charitable donations, which utilises principles of home-based outreach and produces clinical and functional outcomes.SOUL programme focuses on collaborative working with patients & families. The objectives include recognition, treatment, family education & psychosocial support to maximize clinical, functional & occupational outcomes.Single cohort intervention  with innovative service structure and culturally relevant open label intervention design developed with local academic psychiatric unit in Larkano, Pakistan. Training was provided to local mental health professionals on diagnosis, delivering care & use of recognized clinical outcome measures.We have recruited a cohort of 160 patients on continual basis over time. Our analysis show a higher BPRS and lower GAF ratings for men in comparison to female cohort at the baseline. Our Ten year follow up has demonstrated statistically significant clinical / functional improvement on BPRS, CGI & GAF measures. The mean differences recorded for the individual measures after 12 months were BPRS, CGI-I and GAF and were all statistically significant. Innovative home-based community mental health intervention shows significant improvements in clinical and functional outcomes (with good effect size).SOUL Programme is a highly effective and cost-efficient intervention model for treatment of schizophrenia in a developing country setting. Our 10 year follow up study confirms the feasibility of this intervention model through close working with families of our patients.No significant relationships."}
+{"text": "Yet, the relationship in humans between maternal overweight/obesity during pregnancy and fetal hypothalamic development remains largely unknown. Here, using an international  multi-site diffusion tensor imaging (DTI) dataset, we test the hypothesis that maternal pre-pregnancy BMI is associated with newborn offspring HTH mean diffusivity .An extensive body of animal literature supports the premise that maternal obesity during pregnancy can alter the development of the fetal hypothalamus  with implications for offspring obesity risk  using a high-resolution atlas-based definition of HTH. A total of n\u2009=\u2009231 mother-child dyads were available for this analysis . The association between maternal pre-pregnancy BMI and newborn offspring HTH MD was examined separately in each cohort using linear regression adjusting for gestational age at birth, postnatal age at scan, sex, whole white matter mean diffusivity, and DTI quality control criteria. In post hoc analyses, additional potentially confounding factors including socioeconomic status, ethnicity, and obstetric risk were adjusted where appropriate.HTH MD was independently quantified in two separate BMI-matched cohorts  and remained significant after adjusting for cohort-relevant covariates.The distribution of maternal pre-pregnancy BMI was comparable across sites but differed by ethnicity and socioeconomic status. A positive linear association between maternal pre-pregnancy BMI and newborn offspring HTH MD was observed at both sites (These findings translate the preclinically established association between maternal obesity during pregnancy and offspring hypothalamic microstructure to the human context. In addition to further replication/generalization, future efforts to identify biological mediators of the association between maternal obesity and fetal HTH development are warranted to develop targeted strategies for the primary prevention of childhood obesity.The online version contains supplementary material available at 10.1186/s12916-023-02743-8. Childhood obesity is a major global public health challenge as it increases the likelihood of adverse obesity-related disorders in later life as well as their development at earlier ages  and withObesity is a highly multi-factorial phenotype , and theAnimal models suggest that the HTH exhibits developmental plasticity during the fetal period as it develops in the context of, and adapts to, variation in maternal overnutrition \u201320, whichuman HTH in the context of interindividual variation in maternal overnutrition remains limited, it is supported by at least two recent studies. First, we recently reported on an association between maternal circulating saturated free fatty acid concentration (sFFA) during pregnancy and newborn offspring HTH microstructure indexed using diffusion tensor imaging (DTI)-based mean diffusivity (MD), that, in turn, was prospectively associated with early childhood adiposity ) difference in infant HTH MD (HTH MD weighted average across cohorts). While the HTH MD phenotype used here is non-specific to the underlying microstructure, the observed direction of association  is consistent with several microstructural phenotypes of obesity that reduce barriers to diffusion including reduced axonal outgrowth , gliosisThe U.S. Endocrine Society has argued that obesity should be conceptualized as a disorder of the energy homeostasis  system , rather The two cohorts analyzed here differed in maternal age, gestational age at delivery, and pre-pregnancy BMI. Cohort differences in maternal age and gestational age at delivery were in the expected direction \u201341, and Several potentially confounding factors were associated with offspring HTH MD above and beyond maternal pre-pregnancy BMI, and these warrant further discussion. Within site 2, OB risk, maternal education, and maternal ethnicity were all associated with HTH MD. Notably, OB risk and maternal education were not associated with HTH MD within site 1, suggesting that these are not replicable and/or robust observations in the context of this study . However, because site 2 demonstrated a substantially higher prevalence of OB risk, and because maternal education measures may reflect different socioeconomic pressures in different settings, these issues likely warrant further investigation. Relatedly, while significant at both sites, the effect sizes of postnatal age at scan and global measures of MD were markedly different across sites despite similar central tendencies. One explanation for this discrepancy could be differences in sample homogeneity  where a larger proportion of variance is available for attribution to variance in maternal BMI. Alternatively, this observation could simply be due to differing approaches to handling low quality data wherein one excelled at removing measurement error relative to the other. Finally, the association between maternal ethnicity and offspring HTH MD suggesting lower neonatal HTH integrity among Hispanic neonates could not be tested at site 1 due to a high degree of ethnic homogeneity. However, because the direction of effect is consistent with higher rates of pediatric obesity among the Hispanic community , and becThe importance of identifying the role of BMI in the intergenerational transfer of obesity lies in its potential use as a screening tool for risk management . In addition, from the perspective of a developing fetus, BMI is representative of the diverse metabolic gestational milieu  in which the fetal brain develops. However, what BMI contributes in terms of representation, it lacks in specificity. That is, apart from generically informing policy and public awareness about the importance of maintaining a healthy pre-conceptional weight, this work provides limited insight into targeted interventions on the biological pathways of obesity risk transfer from mother to her offspring. For this reason, and because BMI alone is not always perfectly reflective of metabolic status , future efforts should aim to identify the specific ligands and conditions sufficient and necessary for the intergenerational transmission of obesity.Weight stigma is among the most pervasive forms of discrimination within society, and is associated with adverse psychological (depression) and physiological (stress) conditions linked to increased weight  gain. ItLimitations of this study include the focus on a relatively healthy population, lack of gestational biological data, limited spatial resolution, and lack of specificity provided by the outcome (MD). Class I obesity represented roughly 10% of the study population and thus this study is likely underpowered to draw obesity-specific conclusions. To address this shortcoming, future studies would benefit from oversampling class I obesity and above to further identify consequences for fetal development specific to the obese condition. The current study did not collect or consider several developmentally important maternal ligands including the feeding-related hormones leptin  and ghreIn conclusion, the findings from the current study represent a significant conceptual advance to the literature by providing translational evidence of a robust association between maternal pre-pregnancy BMI and newborn offspring hypothalamic microstructure . Importantly, because maternal BMI is potentially modifiable (at least in the short term) through diet, exercise , and/or Additional file 1: Table S1. More Parsimonious Model Site Comparison: Maternal Pre-pregnancy BMI and Offspring Hypothalamic (HTH) Mean Diffusivity (MD). Maternal Pre-pregnancy BMI is associated with offspring HTH MD in a more parsimonious model excluding adjustment for white matter mean diffusivity. Table S2. Parsimonious Model With Sex Interaction Site Comparison: Maternal Pre-pregnancy BMI and Offspring Hypothalamic (HTH) Mean Diffusivity (MD). No evidence for a sex-specific association between maternal pre-pregnancy BMI and offspring infant HTH MD at either site (p\u00a0>\u20090.1)."}
+{"text": "Epichlo\u00eb endophytes from mutualistic to parasitic. The change in symbiosis outcome would be explained by the negative effects of the plant physiological responses on the endophyte performance. Furthermore, we posit that endophytes may protect the mutualism by the induction of plant defence hormone responses and antioxidants.Plants commonly form mutualistic associations with fungal endophytes. We put forward the hypothesis, with supporting evidence, that certain plant physiological responses to stress [i.e. phytohormones and reactive oxygen species (ROS)] change the symbiosis between plants and Epichlo\u00eb  caused by the disruption in the endophyte-derived benefits and growth of the symbionts within plant tissues . We descEpichlo\u00eb-based production of alkaloids, diminish the herbivore resistance of symbiotic plants, and compromise the mutualism   phenotypes in symbiotic plants  than non-symbiotic plants exposed to the same treatment (whereas the endophyte did not affect the reproductive effort of plants not exposed to ozone)  that increase the fitness of symbiotic plants in situations of stress by phytopathogens (Achnatherum inebrians against the phytopathogen Blumeria graminis was increased by the presence of endophytes that boosted plant defences by inducing SA-related responses (Curvularia lunata pathogen was documented in A. sibiricum plants associated with endophytes that induced plant JA-related defence responses (Alternaria solani was shown in Solanum lycopersicum plants symbiotic with Serendipita indica root endophytes that primed JA/ethylene host defence responses (athogens . The resEpichlo\u00eb can also enhance antioxidant levels that generally increase the fitness of symbiotic plants under stressors that increase ROS-associated oxidative damage (Elymus dahuricus plants was increased by the presence of endophytes that enhanced contents/activities of several antioxidants that reduced the oxidative damage within plant tissues (L. perenne plants was also increased by endophytes that enhanced the contents/activities of several antioxidants within symbiotic plants (e damage  (Ueno et tissues . SimilarHere we have highlighted that the effects of environmental stressors can compromise the mutualism between plants and endophytes by the induction of plant physiological responses. Whereas phytohormone- and ROS-related responses were considered independent here, in reality the whole-plant response to stresses involves the interaction between both pathways ("}
+{"text": "Although a large number of studies have shown brain volumetric differences between men and women, only a few investigations to date have analyzed brain tissue volumes in representative samples of the general elderly population.We investigated differences in gray matter (GM), white matter (WM) and intracranial volumes (ICVs) between sexes in individuals above 66 years old using structural magnetic resonance imaging (MRI).Using FreeSurfer version 5.3, we automatically obtained the ICVs, GM and WM volumes from MRI datasets of 84 men and 92 women. To correct for interindividual variations in ICV, GM and WM volumes were adjusted with a method using the residuals of a least-square-derived linear regression between raw volumes and ICVs. We then performed an ANCOVA comparing men and woman including age and years of schooling as confounding factors.Women had a lower socioeconomic status overall and fewer years of schooling than men. The comparison of unadjusted brain volumes showed larger GM and WM volumes in men. After the ICV correction, the adjusted volumes of GM and WM were larger in women.After the ICV correction and taking into account differences in socioeconomic status and years of schooling, our results confirm previous findings of proportionally larger GM in women, as well as larger WM volumes. These results in an elderly population indicate that brain volumetric differences between sexes persist throughout the aging process. Additional studies combining MRI and other biomarkers are warranted to identify the hormonal and molecular bases influencing such differences."}
+{"text": "Although rural-to-urban migration has been well researched, how gender shapes processes and outcomes, including later life health outcomes, has not been thoroughly investigated. Guided by a life course perspective, this study explores gender differences in rural-urban migration patterns and its association with mental health in later life among Chinese older adults. Exploiting rich life history data from the China Health and Retirement Longitudinal Study, we employ sequence analysis to identify the typical migration trajectories of Chinese older adults. Moderated mediation analysis is then used to examine gender-specific health pathways linking migration trajectories and later-life mental health. The results indicate that: men and women follow different migration trajectories across the life course. Men are more likely to migrate between rural and urban areas, and to migrate multiple times. Rural migrants who settled in urban regions have better mental health in later life than return migrants or rural non-migrants; the gender gap in mental health is marginally smaller among early urban settlers than rural non-migrants. Household income and Hukou conversion mediate the relationship between migration trajectories and later-life mental health among older people of rural origin. Household income in later life has stronger mediation effects for migrant men than for migrant women. The study suggests that a life course perspective and awareness of gender dynamics should be incorporated in policymaking to reduce the rural-urban divide and gender-based inequality in mental health."}
+{"text": "Prejudice, stigmatization and discrimination behaviors causes social stress and lead vulnerability to mental and physical health problems in Transgender and Gender Nonconforming (TGNC) individuals. The prevalence of mental disorders that can be associated with \u201cminority group stress\u201d, especially major depression and anxiety disorders, are known to be higher in the TGNC group in comparison to general population.The aim of this study was to reveal the impact of minority stress on TGNC individuals\u2019 mental health. Resilience factors like gender identity pride, social support, community connectedness expected to diminish the negative impact of stigmatization and discrimination.The study sample consisted of 48 volunteered participants who consulted to Psychiatry Department for gender transition process. After semi-structured interview, applicants were given Gender Minority Stress and Resilience Scale-Turkish Form (GMSR-Tr), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Perceived Stress Scale (PSS), Multidimensional Scale of Perceived Social Support (MSPSS).s= .727), BAI , PSS . For psychological resilience, the strongest positive relationship was found with the community connectedness subscale ; the strongest negative relationship was observed with the internalized transphobia subscale .Analysis revealed a negative correlation between the stress subscales of GMSR-Tr scale and BDI (p< .001; rOur study presented the importance of internalized transphobia and protective effect of resilience factors for mental health outcomes of TGNC individuals exposed to minority stress. The depression, anxiety and stress scores decreases with increasing psychological resilience."}
+{"text": "Given the onset of COVID-19, older adults who recently lost their significant others feel more stressed. There yet exist a study utilizing smartphones for web-based delivery of mindfulness intervention among bereaved older adults. Therefore, this study aimed to test the initial efficacy of an app-based mindfulness-meditation (AMM) to alleviate stress and depressive symptoms and improve stress resistance, social support, and self-esteem in Korean older adults experiencing bereavement. Participants included 22 Korean older adults who had been bereaved within the preceding year. AMM involved sound therapy, breathing exercises, and narrated meditation sessions, and the program was conducted over eight weeks. The linear regression results showed that stress level among participants was significantly lower after the intervention, with decreased scores from the baseline. By confirming that AMM is an effective way of reducing stress, more active usage of devices like smartphones should be promoted to develop mental health interventions for older adults."}
+{"text": "We later discuss the necessity to update the current GEA models to predict both regional- and local- or micro-habitat\u2013based adaptation with mechanistic ecophysiological climate indices and cutting-edge GWAS-type genetic association models. Furthermore, to account for polygenic evolutionary adaptation, we encourage the community to start gathering genomic estimated adaptive values (GEAVs) for genomic prediction (GP) and multi-dimensional machine learning (ML) models. The latter two should ideally be weighted by de novo GWAS-based GEA estimates and optimized for a scalable marker subset. We end the review by envisioning avenues to make adaptation inferences more robust through the merging of high-resolution data sources, such as environmental remote sensing and summary statistics of the genomic site frequency spectrum, with the epigenetic molecular functionality responsible for plastic inheritance in the wild. Ultimately, we believe that coupling evolutionary adaptive predictions with innovations in ecological genomics such as GEA will help capture hidden genetic adaptations to abiotic stresses based on crop germplasm resources to assist responses to climate change.Leveraging innovative tools to speed up prebreeding and discovery of genotypic sources of adaptation from landraces, crop wild relatives, and orphan crops is a key prerequisite to accelerate genetic gain of abiotic stress tolerance in annual crops such as legumes and cereals, many of which are still orphan species despite advances in major row crops. Here, we review a novel, interdisciplinary approach to combine ecological climate data with evolutionary genomics under the paradigm of a new field of study: genome\u2013environment associations (GEAs). We first exemplify how GEA utilizes Letter to Karl Freiesleben, June 1799.\u201cI shall endeavor to find out how nature\u2019s forces act upon one another, and in what manner the geographic environment exerts its influence on animals and plants. In short, I must find out about the harmony in nature\u201d Alexander von Humboldt\u2014 Crop wild relatives (CWR) and landraces are well known for providing new alleles for plant breeding . They alVigna subterranea), chickpea (Cicer arietinum), cowpea (V. unguiculata), grass pea (Lathyrus sativus), groundnut (Arachis hypogaea), marama bean (Tylosema esculentum) (Lupinus mutabilis) (Phaseolus acutifolius) , sorghum (Sorghum bicolor), and finger millet (Eleusine coracana) or pearl and proso millets . Many of these crops have interesting drought-tolerance traits and some capacity to grow in compacted soils. Cowpeas, groundnuts, and lesser known cereals are already traditional food sources and biocultural components for vulnerable areas, especially in Sub-Saharan Africa and parts of Asia and Latin America  , tarwi (tabilis) , and tepifolius)  constitu America .Yet, despite their tolerance to drought and heat plus their high nutritional quality, the utilization of these orphan crops is limited partly because of the poor characterization of their genetic background . TherefoStill, a major question to harness crop prebreeding for climate change pressures is whether there is enough heritable variation in traits associated with tolerance to abiotic stress. In this context, genomic characterizations of reference collections comprising CWR, landraces, and orphan crops that span contrasting habitats offer a straightforward scenario to identify natural standing adaptation to abiotic pressures .The spirit behind this novel approach is to detect genomic regions that correlate with habitat heterogeneity as an indication of the natural selection imprint to environmental gradients . Since tGlycine  WCR; or For orphan crops, rather than nondomesticated natural plant species, fewer GEA studies have been undertaken. Although still limited to the easier-to-grow annual grain species compared to perennial and root/tuber crops, GEA is starting to make important contributions to genetic analysis of landraces and WCR germplasm, often richly represented in the world\u2019s major gene banks for crop species. The analytical pipeline for GEA studies is shown in Historically, based on the technological improvements in sequencing and SNP detection and as a means to improve GEA, the field has moved from the candidate gene approach  into fulin situ ecological georeferencing of accessions, and by 2) revealing the genomic architecture of adaptation via cutting-edge predictive models  using georeferencing and statistical downscaling  and machine learning (ML) , capableOverall, CWR and landraces undeniably harbor unique adaptations to abiotic stresses, rarely present in the cultivated and improved genepools . HoweverGP works either on the basis of shared relatedness  or on the basis of linkage disequilibrium (LD) between the SNP marker loci and the genetic variants that underlie phenotypic variation . The relThe predictive ability of GP models may be further biased depending on whether the entire SNP set is used, or the most predictive SNP data are chosen after the GWAS-type analysis , the latde novo GWAS-based GEA estimates gathered from other (or even the same) panels (Better approaches to be implemented and reported include 1) weighted GP models using ) panels  and 2) o) panels . GP can ) panels . GEAVs c) panels  would be) panels , high-th) panels , and ML-) panels .Next-generation GEA models and GEAVs will allow the use of \u201cexotic\u201d parents for targeted predictive prebreeding in crop species. They offer feasible methodologies to trace the sources of abiotic stress adaptation and tolerance targeting crop resources in low-income countries, which are also the most vulnerable to climate change. Here, we have discussed strategies to implement the latest-generation predictive e.g.,  and genoModern GEA approaches will allow further studies of evolutionary conservatism, parallelism, and convergence in the genetic architecture of adaptation to various types of abiotic stresses across a wide range of environments, landraces, and wild accessions . ApproacHow genetic diversity and genomic divergence arise and are shaped based on ecological pressures is one of the main questions in molecular evolution  and has ST statistic (A). Once the potential confounding demographic patterns have been accounted for, it is then feasible to disentangle genuine signatures of environmental adaptation (B) from spurious concurring genetic drift due to genomic constraining features. Finally, these combined summary statistics  can ultimately redound in prebreeding efforts aiming to introgress exotic adaptive variation into elite lines (C), for instance, via backcrossing (BC) schemes for abiotic and biotic stresses.Therefore, GEA efforts can be enhanced by exploring SNP density and statistics of site frequency spectra  in associated vs. nonassociated regions . Figure ad hoc multiple hypotheses  to which scale epigenomic marks  regulatand sRNA , and mayeritance , eventuaeritance .e.g. GEAVs), as well as the identification of underlying factors that may facilitate or constrain future adaptive responses to changing climate.Ultimately, GEA is empowering the understanding on how plant genomes interact with their environment while shaping adaptive phenotypes. Such mechanistic insights of the genome functionality in the wild promise leveraging the characterization of landraces and CWR to assist prebreeding efforts through multi-dimensional adaptive scores (Lastly, GEA studies offer new possibilities to efficiently unlock crop diversity for climate adaptation . Unexplo"}
+{"text": "In preclinical animal models, researchers can, within the same thin slice of tissue, probe activity within neurons [e.g., immediate early gene protein products  and deprivation  on stria terminalis white matter  and function  have a reciprocal relationship that facilitates global and integrative brain processes  and found connection features that distinguish preterm and term-born infants. Their approach revealed novel insights into the global manner in which preterm birth impacts neurodevelopment, identifying local intra-network functional connections and long-range inter-network structural connections that differentiate between pre-term and term-born infant brains.In this current Research Topic, authors demonstrated the breadth of how multimodal neuroimaging can surpass unimodal neuroimaging across developmental, clinical and methodological domains. Zhu et al. presented new methodology featuring brain network construction under a unified framework of joint fMRI and DWI . Their method considered relationships between multiple brain regions and a PageRank algorithm that extracts significant node information from the unified network. Zhu et al. applied their method to a clinical problem\u2014classifying epilepsy diagnoses, comparing normal controls (NC), frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). Their methods achieved the highest classification accuracy compared to unimodal methods when classifying against NC and achieved among the highest accuracies when classifying FLE v. TLE.Tang et al. developed a new interpretable hierarchical graph representation learning framework for brain network regression analysis using multimodal MRI data. They used this approach to predict a variety of affective, somatic, cognitive and behavioral measures and found that the proposed framework achieved the best performance compared to baseline methods; this was attributed to extraction of graph local structures as low-level features and preservation of these into high-level space hierarchically.Sun et al. developed new methods that capitalize on synergies between PET and DWI data, using DWI-derived structural connectivity and PET intensity to denoise PET images. Their CONNectome-based Non-Local Means (CONN-NLM) filter provides more informative denoising by weighting similar-intensity PET voxels and highly connected voxels more heavily. This yielded greater PET image quality and lesion contrasts and produced superior denoising effects compared to filters not utilizing DWI data.Babaeeghazvini et al. reviewed the convergence of structure and function with associations between white matter microstructure and electro-encephalography (EEG). They note that white matter microstructure may influence the velocity of communication between brain regions and across hemispheres, and that amplitudes and latencies of event-related potential components may reflect pathological differences in structure; yet, the diversity of findings calls for more standardization of EEG analysis.Finally, To conclude, the field would benefit significantly from effective use of multimodal approaches in the methods development space and in basic, clinical and translational research. This requires open science and enhanced accessibility of tools that process and analyze multimodal neuroimaging data. Future directions can include enhanced integration of \u201cneurochemical\u201d imaging modalities  with structural and functional modalities. The reports highlighted in this topic are an excellent demonstration of how multimodal approaches can improve methodologies, predictive power and clinical classification abilities to ultimately identify neural markers of psychopathology risk and guide more targeted treatments.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-03727-5, published online 20 December 2021Retraction of: The Editors have retracted this Article.there is insufficient justification for the grouping of the patients who belong to clinically heterogeneous cohorts with multiple different psychiatric disease presentations;the study lacks objective outcome measures; andthere are concerns about the validity of the therapeutic intervention tested\u2014specifically that Tenoten contains antibodies diluted beyond the point at which any active molecules are expected to be present and there is no molecular analysis to support the presence of molecules at these dilutionsAfter publication of this Article concerns were raised regarding the design of the study and the robustness of its central conclusions. Post-publication peer review has confirmed that:The Editors therefore no longer have confidence in the conclusions presented.Vladimir Anatolevich Parfenov, Dina Rustemovna Khasanova, Pavel Rudolfovich Kamchatnov and Alexey Borisovich Glazunov disagree with this retraction. Enver Ibragimovich Bogdanov, Tatiana Markovna Lokshtanova, Aleksandr Vitalevich Amelin, Natalya Nikolaevna Maslova, Nataliia Vyacheslavovna Pizova, Galina Nikolaevna Belskaya, Evgeny Robertovich Barantsevich, Gulsum Abdurahmanovna Duchshanova, Saltanat Ualihanovna Kamenova and Oleg Vladimirovich Kolokolov did not respond to correspondence from the Editors about this retraction."}
+{"text": "Racial and ethnic health disparities are fundamentally connected to neighborhood quality. For example, racial and ethnic minorities are more likely to live in neighborhoods with signs of physical disorder , and physically disordered environments have been noted to associate with increased risk for chronic illness. Given that older adults may spend more time in their neighborhoods than younger adults as they transition out of the workforce, examining associations between neighborhood physical disorder and health among older minorities is of critical importance. Using 2016-2018 Health and Retirement Study (HRS) data, a representative sample of US adults aged 51 years and older , we conducted a series of weighted linear regressions to examine links between neighborhood disorder as rated by third parties and both participant-perceived neighborhood safety and self-rated health. Study results indicated that higher neighborhood physical disorder was significantly related to more neighborhood safety concerns among non-Hispanic White and Hispanic residents, but not among non-Hispanic Blacks. On the other hand, neighborhood physical disorder was significantly associated with poorer health among all racial/ethnic groups. These patterns persisted after adjusting for education, sex, age, and census tract concentrated disadvantaged, population density, and racial/ethnic diversity. Our results indicate that community level interventions targeting neighborhood physical disorder may improve community health and minimize racial/ethnic health disparities."}
+{"text": "Additional abnormal uptake in the right axillary artery, aortic arch, and left femoral artery corresponded to the insertion sites for arterial inflow during cardiopulmonary bypass. Knowledge that FDG accumulation may occur at the insertion sites of an extracorporeal-circulation device enables unnecessary tests to be avoided.A 37-year-old man with previous heart transplantation for dilated cardiomyopathy underwent screening for malignancy under posttransplantation immunosuppression."}
+{"text": "Health inequalities partially remain due to differences in diet between socioeconomic groups. Examining the association between socio-ecological factors and the diet of socioeconomically disadvantaged (SED) individuals can enhance the development of interventions to decrease health inequalities.In total, 278 SED adults residing in two Flemish municipalities completed a survey addressing sociodemographics, diet, health and their perceptions of the food environment. The objective food environment was examined by assessing food retailer information in street network-based buffers of 500m and 1000m around participants\u2019 addresses. Linear regression was used to test assumptions.Individual factors such as poor subjective health , food insecurity  and living alone  were negatively associated with healthy dietary habits such as daily fruit and vegetable (FV) consumption. Positive perceptions on the availability of FV were positively associated  with daily FV consumption. Objective food environmental factors showed a stronger association with unhealthy dietary habits. A greater amount of retailers within 1000m walking distance was negatively associated with fast-food  and sugar-sweetened beverages (SSB) consumption . More supermarkets within 500m distance was negatively associated  with SSB consumption, while more convenience stores within a 1000m distance was positively associated  with SSB consumption.Our findings suggest that factors associated with the diet of SED adults differ according to food and drink items. Interventions focused on this population should take these differences into account.Individual and food environmental factors are both associated with the diet of socioeconomically disadvantaged adults but differ according to food and drink items.Individual factors and perceptions of the food environment more likely associated with a healthy diet. Objective factors of the food environment were more likely associated with an unhealthy diet."}
+{"text": "Impaired reproductive health is a worldwide problem that affects the psychological well-being of a society. Despite the technological developments to treat infertility, the global infertility rate is increasing significantly. Many infertility conditions are currently treated using various advanced clinical approaches such as intrauterine semination (IUI), in vitro fertilization (IVF), and intracytoplasmic injection (ICSI). Nonetheless, clinical management of some conditions such as dysfunctional endometrium, premature ovarian failure, and ovarian physiological aging still pose significant challenges. Stem cells based therapeutic strategies have a long-standing history to treat many infertility conditions, but ethical restrictions do not allow the broad-scale utilization of adult mesenchymal stromal/stem cells (MSCs). Easily accessible, placental derived or amniotic stem cells present an invaluable alternative source of non-immunogenic and non-tumorigenic stem cells that possess multilineage potential. Given these characteristics, placental or amniotic stem cells (ASCs) have been investigated for therapeutic purposes to address infertility in the last decade. This study aims to summarize the current standing and progress of human amniotic epithelial stem cells (hAECs), amniotic mesenchymal stem cells (hAMSCs), and amniotic fluid stem cells (hAFSCs) in the field of reproductive medicine. The therapeutic potential of these cells to restore or enhance normal ovarian function and pregnancy outcomes are highlighted in this study. Over the past few daces, a substantial decline in fertility rate is observed around the world . Both ecDespite the availability of cutting-edge therapies to restore or enhance infertility, some pathological conditions such as the dysfunctional uterus, persistent atrophic/thin endometrial lining, and loss of regeneration capacity of endometrial tissue lower the success rate of these treatments. For instance, successive embryo implantation failure due to a dysfunctional uterus or immune rejection remains the main reason for IVF treatment failure. Similarly, the inefficient process of endometrial tissue regeneration due to the loss of stem cells in the basalis layer of endometrium leads to pathological conditions such as intrauterine adhesion (IUA) or endometrial atrophy. Stem cell-based regenerative therapies hold the great capability of replenishing the functional deficit cell reservoir to address such pathological conditions .Due to the differentiation ability into germ cells and oocyte-like cells, stem cells may adopt the following mechanisms to repair ovarian functions; i) heal injured reproductive tissues by replenishing healthy cells, ii) restore or increase the number of secondary and mature follicles, iii) improve microenvironment by secreting paracrine factors and ameliorate ovarian function, iv) immune regulation by secreting anti-inflammatory factors, and v) regulate the hormonal levels that maintain estrous reproductive cycles and stimulate ovulation such as E2 (Estradiol), AMH (Anti-M\u00fcllerian hormone), and FSH (Follicle-stimulating hormone). Despite the great success of stem cell therapeutics in reproductive disease management, the ethical concerns, heterological nature, low yield, and lower ex-vivo proliferation rate of adult stem cells limit their clinical translation . ConversStem cells isolated from the umbilical cord have well-established therapeutic uses and are discussed in literature excessively . Other eMesenchymal stromal/stem cells (MSCs) derived from the avascular mesenchymal matrix of the human amniotic membrane (hAM) offer a beneficial option to replace adult MSCs \u201311. LimiThe studies that explored the role of hAMSCs to promote ovarian function in natural or premature ovarian aging (NOA or POA) or premature ovarian failure/inefficacy (POF/POI) mouse models are listed in Table \u03b3, TNF\u03b1), induction of anti-inflammatory molecules (TGF-\u00df), and regulation of the Treg cell population were found critical in improving the number of glands and reducing fibrotic areas in ovaries [Yin et al.  and Gan  ovaries .In vivo studies demonstrated that hAMSCs harbor the great ability to colonize uterine tissue and ovarian stroma which helps achieve the utilization rate of hAMSCs thus the desired outcomes. However, various strategies were adopted and compared to improve the homing of stem cells, e.g., repeated vs. single transplantation of hAMSCs , direct In a few comparative studies, the therapeutic potential of hAMSCs in recovering ovarian functions was found superior to other cells such as hAECs , 26 or aThese inherent characteristics of hAMSCs suggest multiple clinical applications in the field of reproductive biology. However, due to the lack of human studies, clinical uses of hAMSCs are mostly theoretical until now and need further optimization in the preparation and banking procedures.Human amniotic epithelial stem cells (hAECs) have been entertained as another possible source of endometrial regeneration or restoring ovarian function. The hAECs comprise a major portion of the epithelial cell layer of the basement membrane of hAM. The stem cell markers expression profile of hAECs, i.e., CD73, CD90, and CD105 positive, while negative for hematopoietic markers CD34 and CD45) is remarkably similar to MSCs. However\u03b2/Smad signaling pathway that resulted in a reduction of cell apoptosis thus improving follicle formation [Wang et al.  performeormation \u201334.Until now, only two studies have assessed the therapeutic efficiency of hAECs for the treatment of IUA Table . Li et aInfertility or obstetrical infertility complications may occur after cesarean section due to injury to the endometrium and subsequent collagen deposition. In a recent study, the hAECs were used to treat cesarean scar defect (CSD) conditions in a rat uterine scar model . After 3Amniotic fluid is enriched with different types of stem cells in all three phases of pregnancy. Stem cells derived from human amniotic fluid (hAFSCs) are characterized by well-established stem cell surface markers , 40. AFSWhile still in an early stage of development, hAFSC-based in vivo studies show promising results to preserve follicle cells and prevent ovarian dysfunction Table . In a stIn a recent study, mesenchymal stem cells from amniotic fluid (hAFMSCs) were explored to study their potential and mechanism to rescue ovarian senescent cells . The amnGiven the ease and availability of placental membranes, which are considered a medical waste following delivery, unexpectedly no clinical studies have been published evaluating the role of amniotic-derived stem cells in restoring ovarian functions in humans. Similar to other fields of medicine, the inherent properties of ASCs warrant their success in the setting of endometrial-driven, chemotherapy-induced, or age-related infertility. However, based on studies reported so far, significant challenges still exist before the translation of these cells in clinical studies. Such as addressing the successful differentiation of ASCs in germ cells in culture, defining the route and time of administration of cells to increase effectiveness, use of precise animal models, and addressing long-term fertility benefits. Future studies should continue to elucidate regulatory mechanisms induced by the amniotic stem cells in ovarian recovery for successful manipulation of these cells in treating infertility.Amniotic tissue or fluid-derived human amniotic cells  exhibit stem cell properties with low immunogenicity or tumorigenesis making them theoretically superior to other stem cells. Many studies were performed using mouse models of chemotherapy treated premature ovarian failures, age-related ovarian failure, or other related infertility pathological conditions. These in vivo investigations reported the fundamental findings to understand the mechanisms of actions of ASCs in restoring fertility outcomes. These studies suggest that ASC transplantation promotes follicle formation, endometrial regeneration, glandular development, and restores hormone levels . These physiological improvements are carried out due to paracrine, anti-inflammatory, and immune regulatory properties of ASCs. Although these studies provide a theoretical foundation for their application in infertility-related health issues, future studies are warranted to confirm these results for their successful translation into clinical applications."}
+{"text": "An 80-year-old Caucasian female patient presented with a two-year history of intensively itching skin rash located on her left lower leg and mild swelling of the proximal interphalangeal and metacarpophalangeal joints, accompanied by morning stiffness around these joints, lasting at least one hour before maximal improvement . She repPresence of intensively pruritic erythematous papules located on the left pretibial surface was established clinically . SymmetrImmunological testing for antinuclear antibody (ANA) and Scl 70 was negative. The cutaneous pathological changes presented required a wide spectrum of differential diagnoses, including pretibial myxedema, necrobiosis lipoidica, the small papular form of cutaneous sarcoidosis, T-cell lymphoma, lichen ruber planus and Arndt-Gottron scleromyxedema. Histopathological evaluations on skin biopsies revealed hyperkeratosis, focal acanthosis, subepithelial structures that stained pink with hematoxylin-eosin and mild to moderate mononuclear infiltrate around single vessels . SubepitThe findings were characteristic of amyloid deposition and a diagnosis of lichen amyloidosis was made. No clinical or laboratory evidence of systemic amyloidosis was presented. Systemic therapy consisting of bilastine (20 mg daily) and acitretin (15 mg daily) was started, with topical application of 0.1% mometasone furoate cream, which produced a satisfactory therapeutic response. The patient was referred to a rheumatological unit for further therapy with biological agents.Localized cutaneous amyloidosis encompasses several conditions characterized by deposition of amyloid or amyloid-like proteins in the dermis, including macular amyloidosis and lichen amyloidosis.Lichen amyloidosis is a primary form of localized cutaneous amyloidosis that is clinically manifested through hyperkeratotic erythematous to brownish papules, while amyloid deposition can be seen via specific histological staining in previously normal skin without any evidence of visceral involvement.Although cutaneous lesions may be seen in up to 40% of patients with primary and myeloma-associated systemic amyloidosis, their presence results from tissue deposition of immunoglobulin light chain material derived from a circulating paraprotein.,Although the etiology is not fully understood, chronic irritation to the skin has been proposed as possible etiological factor.,,Treatment options include potent topical steroids under occlusion, intralesional steroids, topical dimethylsulfoxide and etretinate.We have described a rare association between lichen amyloidosis and rheumatoid arthritis in an 80-year-old female patient, without evidence of systemic amyloid involvement. To the best of our knowledge, this is the first reported case of primary cutaneous amyloidosis in a patient with rheumatoid arthritis, in contrast to the much more frequent association of rheumatoid arthritis with systemic amyloidosis, the pathogenetic relationship remains unclear. It is also unclear whether lichen amyloidosis might be the first clinical manifestation of the initial systemic involvement, in which cutaneous lesions can be seen in up to 40% of the patients,"}
+{"text": "The use of selectiveserotonin reuptake inhibitors (SSRIs) is an independent risk factor for bleeding events. Antidepressants and oral anticoagulants (OACs) are often prescribed together as depression and anxiety often coexist with cardiovascular diseases, atrial fibrillation and thromboembolic disorders. Serotonin is released from platelets in response to vascular injury, promoting aggregation. Inhibition of serotonin transporter (responsible for the uptake of serotonin into platelets) can lead into a reduced ability to form clots and a subsequent increase in the risk of bleeding. Direct oral aticoagulants (DOACs), rivaroxaban, apixaban and edoxaban are primarily metabolized via CYP3A4. The co-administration of antidepressants with inhibitory effects on CYP3A4 may theoretically interact with them.Presentation of a case of upper gastrointestinal bleeding after initiation of Apixaban in a patient taking Sertraline and literature review.We carried out a literature review in Pubmed electing those articles focused on bleeding risk between newer direct oral antigulants and selective serotinin reuptake inhibitors.A 66-year-old woman sought medical assistance for generalized ecchymosis and melena. She was diagnosed with atrial fibrillation treated with apixaban 7 days ago. Concomitant treatment between apixaban and sertraline was the possible cause of upper gastrointestinal bleeding and ecchymosis. We had to switch sertraline into vortioxetine (with less dregree of serotonin reuptake inhibition) and add proton-pump inhibitor (Omeprazole) in order to decrease the risk of bleeding.SSRIs increase the risk of gastrointestinal bleeding, much more in case of concomitant use of oral anticoagulants. If SSRI use cannot be avoided, monitor closely and prescribe proton pump inhibitors."}
+{"text": "Past research shows that discriminatory experiences may reduce sense of purpose among older adults, though these associations are inconsistent across groups. Work is needed both to understand the nuanced role discrimination plays on individuals\u2019 sense of purpose, whether it leads to feeling derailed from life goals, and if effects differ for younger versus older adults. The current study asked 354 American adults (age 19-74) to complete daily surveys over the course of two weeks, to examine whether experiencing discrimination during that two-week period led to a decline in purposefulness. Overall, findings suggest marked stability in sense of purpose during this short timeframe. However, greater daily discrimination predicted decreases in sense of purpose, and increases in derailment over the two weeks. While these associations were similar across age, older adults did report less discrimination at baseline. Findings will be discussed with a focus on successful aging among marginalized groups."}
+{"text": "Individuals with substance use disorders are considered unpredictable and violent by the public. Besides, health care workers (HCW) may have negative attitudes towards them, despite their knowledge about addiction; which is related to lower quality of care. In Turkey, addiction service users are predominantly male, over ninety percent; while women make up a large percentage of psychiatrists.The present study aims to evaluate if the HCWs level of stigma towards individuals with substance use disorder changes due to gender and mental health sector experience of the HCWs.Within an online survey, participant HCWs answered Attitudes Towards Treatment of Substance Use Disorders Scale, Substance Addiction Stigmatization Scale, Alcohol Addiction Stigmatization Scale; in addition to sociodemographic questions.Three hundred ninety-eight HCWs were included in the analyses. 22.7% of them (n=91) were recruited in mental health sector. Mental health care workers had lower levels of stigma towards individuals with alcohol use disorders  and substance use disorders  and, lower levels of stigma towards addiction treatments . Among mental health care workers, women scored higher numbers of stigmatization towards alcohol use disorder and addiction treatments . On the other hand, women and men in other HCWs groups did not differ from each other in terms of stigmatization measurements The gender of mental health care workers may be related to stigmatization towards addictive disorders. Future research should evaluate underlying factors.No significant relationships."}
+{"text": "Despite well-recognised benefits, Irish breastfeeding rates remain suboptimal. Although associations between breastfeeding and allergic disease are well-researched in younger children, evidence for continued effect in older children is sparse. This Irish prospective cohort study investigated associations between breastfeeding and allergic disease at age nine.The study sample included all nine-year-old children enrolled in the Growing Up in Ireland Infant Cohort Study whose mothers had participated in both Wave 1 and Wave 5. Mothers self-reported infant feeding practices at nine months and allergic diseases at nine years. Multiple logistic regression was used to generate adjusted odds ratios (aOR) for associations between breastfeeding and allergic diseases; re-weighting was applied to enhance generalisability.Response rate was 72% . Most mothers (53%) had ever-breastfed their child; younger mothers, smokers and those of lower socioeconomic status were significantly less likely to have ever-breastfed. Compared to never-breastfeeding, ever-breastfeeding was protective against asthma  and eczema  at age nine. Ever-breastfeeding increased the risk of atopic rhinitis ; the association with food allergy was inconclusive . Breastfeeding \u22656 months was protective against asthma  and any allergic disease . Exclusive breastfeeding (3-5 months) was protective against asthma  and eczema .This study provides new evidence suggesting breastfeeding may be protective against asthma and eczema but may increase the risk of atopic rhinitis in older Irish children. Results must be considered in light of high Irish allergic disease prevalence and action in support of breastfeeding prior to and following birth prioritised accordingly.Findings lend support to a protective association between breastfeeding and asthma and eczema in later childhood and indicate breastfeeding may play a role in allergic disease prevention.Breastfeeding may reduce the risk of asthma and eczema in Irish children: findings should be used to drive impactful breastfeeding promotion and reorientate cultural norms in favour of breastfeeding."}
+{"text": "Medicaid home and community-based services (HCBS) provide integral health-related and personal care to support community-dwelling older adults. Growing literature suggests that states with more generous HCBS expenditures may delay or substitute costly nursing home care, but evidence is limited on the impact of HCBS spending on transitions to residential care settings like assisted living. This study determines the association of state Medicaid HCBS generosity\u2014HCBS spending as a percent of total long-term services and supports expenditure\u2014on the probability of incident transitions to residential care settings or nursing homes. Publicly available HCBS expenditure data was linked to a nationally representative sample of 7,197 community-dwelling older adults participating in the National Health and Aging Trends Study from 2011-2018. A discrete-time, competing risk regression model estimated the association between HCBS generosity and transitions from community to residential care settings or nursing homes, adjusting for sociodemographic, socioeconomic, and health factors. Most older adults remained in the community (93.7%). Incident transitions into residential care settings were twice as likely to occur compared to transitions to nursing homes . Older adults residing in states with higher HCBS generosity (one percentage point increase) are less likely to transition to nursing homes . Greater HCBS generosity was not associated with transitions to residential care setting. Assessing HCBS generosity on transitions elucidates important contextual factors affecting the movement of older adults across the care continuum."}
+{"text": "Physical intimacy is assumed to benefit well-being through stress-buffering and mood-improving processes. Although partnered older adults often report wishing for and experiencing physical intimacy, inquiries about how intimacy is linked to affect and stress in older couples\u2019 daily lives remain scarce. We examined self-report and salivary cortisol data from 120 German couples  obtained up to seven times per day over seven consecutive days. In moments when participants experienced more physical intimacy, women reported less negative affect, and men more positive affect. Experiencing more overall physical intimacy was associated with more positive affect and less negative affect in women, and lower daily cortisol in men. More overall intimacy wished was related to more negative affect in women and men, and to higher daily cortisol in men. We conclude that physical intimacy relates to indicators of well-being in older couples\u2019 daily lives and consider routes for future inquiry."}
+{"text": "These neuroinflammatory processes serve to protect or remove degenerative cells and attempt to clean out amyloid plaques. Can AD-affected neurons contribute with a malfunctioning protein degradation mechanism to this process? A recent elegant study by Lee and coworkers5 has analyzed in several genetic mouse models of AD the major cytoplasmic recycling process of cells termed autophagy.Alzheimer\u2019s Disease (AD) with synaptic dysfunction and cognitive decline is a devastating age-associated neurodegenerative disease accounting for about two thirds of all cases of dementia.5 which subsequently fuse with endosomes and eventually lysosomes (autolysosomes) for content degradation and its release for recycling  and expand the cellular membranes to blebs. Such PANTHOS-containing neurons were identified by the authors in post-mortem human AD brain samples as well.\u03b2-peptide deposition, is transported to the membrane through the secretory pathway along the endomembrane system,1 thus ER incorporation into PANTHOS structures provides these autophagic vacuoles with significant amounts of APP that can be proteolytically processed in endosomes/lysosomes. Strikingly, Lee et al. demonstrate that PANTHOS structures contain amyloid plaques with increasing levels of maturation over time concomitant with a compromised neuronal morphology.APP, the source of AEarly PANTHOS-containing neurons are not associated with reactive astrocytes or activated microglia. Therefore, initial autophagic defects, deacidified autolysosome accumulation, PANTHOS build-up and initial plaque formation evades detection by inflammation-mediating neighboring cells. Only when PANTHOS-containing neurons lose structural integrity, they are surrounded by activated astrocytes/microglia. At this advanced stage PANTHOS-containing neurons merge to larger structures likely giving rise to extracellular senile plaques that are eventually released into the extracellular space of the brain.4 Consequently, plaque formation should be viewed primarily as a cell-autonomous rather than a non-cell autonomous process.These findings of the authors imply several ground-breaking new insights into the possible mechanism of AD-associated plaque formation. Foremost, amyloid plaque formation considered to occur extracellularly due to APP proteolysis turns into an intracellular process followed by a release of already formed and matured plaques into the extracellular environment.The generation and accumulation of deacidified autolysosomes occurs long before histological signs of plaque formation and at stages when neurons appear to be healthy at large. This cellular metabolic signature could probably be exploited for diagnostic purposes of initiating AD or related neurodegenerative diseases at stages when preventive measure would still have major effects.Based on the author\u2019s finding the view on neuroinflammatory mechanisms in association with AD may be seen from a different perspective. The first contribution of reactive glia to AD progression may be a late one, when amyloid plaques have already formed and matured inside PANTHOS-containing neurons. But by promoting neuronal cell death of late-stage PANTHOS-neurons, glia might serve as a can opener causing the release of plaque material into the brain environment. This would promote plaque spread, turns further plaque growth from an intracellular into an extracellular process and enables plaque contact and influence possibly with glia.Besides providing crucial novel insights into cell biological processes of amyloid plaque formation, like any exciting research new important question arise. What is so far missing, is a careful assessment about the role of neuroinflammation, since the authors did not elucidate precisely when neuroinflammation starts and what it contributes to the observed phenotype. It also remains unclear which mechanism mediates reduction in vATPase-activity, and why some autophagosomes are poorly acidified, while others show a properly acidic pH-milieu. Autophagy is a process common to all cells. Why are cholinergic neurons of the forebrain affected first by AD, are they more sensitive to PANTHOS formation? Reestablishing proper acidic conditions in poorly acidified autolysosomes in AD mouse models at early stages should prevent PANTHOS-formation and subsequent establishment of histological features as well as AD symptoms in these animals. Such a rescue would further provide evidence that amyloid plaque formation is initiated in a cell-autonomous process by autophagy defects in neurons themselves. This could trigger a plethora of new drugs or even the development of preventive strategies.Neurofibrillary tangles as a hallmark of late AD stages do not appear in PANTHOS-neurons until stages of their destruction. Are these deficits inherent to the genetic mouse models that are unable to phenocopy NFT formation like in human AD brains? To investigate the relationship between PANTHOS-forming processes and neurofibrillary tangle appearance will be an interesting area of research.1 strongly support the notion that, months before plaques develop, A\u03b2 accumulates in faulty lysosomes neurons, and that this finally disturbs neuronal functioning and might cause neuronal death, leaving behind amyloid plaques. This supports therefore the hypothesis that lysosome dysfunction is an early, causal, and, most importantly, pathogenic process in AD.Overall the findings described in Lee et al."}
+{"text": "Surgical boot camps are becoming increasingly popular in Otolaryngology\u2013Head and Neck Surgery (OHNS) residency programs. Despite pioneering virtual reality and simulation-based surgical education, these boot camps have lacked critical appraisal. The objective of this article was to examine the adoption and utility of surgical boot camps in OHNS residency training programs around the world.Ovid Medline and PubMed databases were systematically searched in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for scoping reviews. Additionally, a grey literature search was performed.Inclusion criteria were peer-reviewed publications and grey literature sources that reported on OHNS boot camps for the novice learner. The search was restricted to human studies published in English. Studies were excluded if they were not examining junior trainees.. Following removal of duplicates, screening, and full text review, 16 articles were included for analysis. Seven major boot camps were identified across various academic sites in the world. Most boot camps were one-day intensive camps incorporating a mixture of didactic, skill specific, and simulation sessions using an array of task trainers and high-fidelity simulators focusing on OHNS emergencies. Studies measuring trainee outcomes demonstrated improvement in trainee confidence, immediate knowledge, and skill acquisition.A total of 551 articles were identifiedSurgical boot camps appear to be an effective tool for short term knowledge and skill acquisition. Further studies should examine retention of skill and maintenance of confidence over longer intervals, as little is known about these lasting effects. Upon completing medical school, junior trainees enter post-graduate training programs with dramatically increased responsibilities. To address the concern regarding trainee skill inadequacy, surgical boot camps were developed to help develop skillsets from interpreting diagnostic imaging to performing surgical procedures .The educational design of most surgical boot camps is a combination of didactic learning and small group simulation sessions. Both governing medical educational bodies of Canada  and the United States  have embraced competency-based educational frameworks for post graduate medical education (PGME) . These fLiterature examining the role of surgical boot camps has been extensively covered over the past decade. The majority of studies have examined the following outcomes: knowledge and technical skills acquisition, team communication skill development, and individual confidence improvement \u20136. MoreoA scoping review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis scoping review (PRISMA-ScR) guidelines was performed in February 2021 . The resFour reviewers  independently screened all abstracts to identify studies that fulfilled the predetermined eligibility criteria. Any disagreement between the reviewers was resolved by consensus. Qualitative data from each included study was extracted using standardized data forms including the study\u2019s title, author(s), year of publication, education themes, and outcomes assessed.A total of 21 articles were identified by Ovid Medline, 527 articles by PubMed, and 3 articles from a grey literature search. Following the removal of the duplicate records, 530 abstracts were screened , acute airway obstruction from angioedema (43%), and facial/neck trauma (29%). The most common task trainers were surgical airway (71%), epistaxis (57%), peritonsillar abscess drainage (43%), and bag mask ventilation with tracheal intubation (29%). High fidelity cadaveric and mannequin-based task trainers for task specific procedures appear to be the current trend. All studies that used high fidelity simulation scenarios used the Laerdal  SimMan\u00ae adult simulator. SimMan\u00ae offers a highly realistic training model with real time neurological and physiological function.Despite some of the diversity in task trainers and simulations used across the world, the principal theme in all boot camp curricula appeared to be management of emergency situations and on-call scenarios. The goal was to have junior trainees leave the camp equipped with the skillset to identify and triage acute emergencies, perform basic minor airway procedures, and communicate and activate emergency protocols. We noted that trainee participation in introductory boot camps appears to improve their confidence, immediate knowledge acquisition, and immediate improvement in procedural skills in comparison to traditional didactic methods of learning , 91, 93.Despite strongly positive outcomes from boot camps and simulation training, criticisms of the lack of evidence to suggest long-term retention exist , 67. ThrAlthough boot camps are typically delivered at the beginning of OHNS programs because they are introductory, consensus on when they should be offered is lacking. When surveying American OHNS program directors, a slight majority felt boot camps should be offered within the first few months of residency . InteresBoot camp style training programs for junior OHNS are becoming widely adopted across the world. Fuelled by the utilization of simulation technology to deliver time-effective education for common OHNS emergencies, these programs embrace the educational shift towards competency-based accreditation standards for residency programs. A number of studies have justified this form of education to improve trainee\u2019s performance, confidence, and skill in the short term. However, current literature has failed to examine a number of important long-term outcomes. Future studies that examine the effect of OHNS boot camps on long term outcomes will play a critical role justifying widespread adoption of boot camps for resident education."}
+{"text": "Without comprehensive accountability for citizen values, divergent stakeholder interests complicate rather than address problems. Second, the oral health community remains disconnected from the broader health community. Although oral diseases and noncommunicable diseases share common risk factors and sequelae, oral health systems rarely benefit from innovations in other areas of health care.Therefore, a complex systems problem exists, characterized by limited accountability for incorporating citizen values and research evidence on the effectiveness of oral health programmes and interventions at systems level; for seeking greater integration with broader health systems; and for identifying the critical junctures where path dependencies can be overcome. Inertia and inaction will leave us with a persistent, albeit largely preventable, burden of oral diseases. A different approach is needed to improve oral health systems. Evidence-informed deliberative processes provide one promising approach. Citizen panels can gather citizens with diverse backgrounds and experiences to collectively deliberate about key oral health-system problems, options to address them and key implementation considerations. The gathered citizen values can then be used in policy-making processes to counter narrow stakeholder interests that perpetuate a separation of oral health from the broader health system and that block efforts to improve governance, financial and delivery arrangements.Recent studies describe the role of citizen deliberations for context-specific health policy-making.,Deliberative processes can also be leveraged at the community level.On the clinical practice level, citizens with experience as patients can be involved in deliberations about quality improvement. Iterative reflective learning based on patient feedback can spur quality improvement.Lancet Commission on Oral Health and the World Dental Federation\u2019s Vision 2030 reportIn the oral health context, however, take-up of deliberative approaches as outlined above is currently limited. To ensure access to essential oral health care for everyone without causing financial hardship, the oral health community needs to commit to harnessing citizen values via evidence-informed deliberative processes. Describing the problem without identifying actionable solutions and implementation strategies is no longer an option. Recent developments such as the WHA74.5 Resolution,"}
+{"text": "The outcome of first-episode psychosis (FEP) varies and may be predicted by several baseline measures. In the Helsinki Early Psychosis Study, young adults with FEP (n=97) from the Helsinki area in Finland were broadly assessed as soon as possible after first psychiatric contact for psychosis. Age- and gender-matched population controls were also assessed (n=62). The participants were followed up via appointments and medical records. We present both published and unpublished results on predictors of 12-month clinical, functional, and metabolic outcomes. More severe cognitive deficits at the beginning of treatment predicted several outcomes such as occupational status and functional level \u2013 beyond baseline positive and affective symptom levels, but not when negative symptoms were accounted for. More severe baseline obsessive-compulsive symptoms were predictive of a lower rate of remission, whereas a higher level of anxiety symptoms predicted better functional outcome, when the severity of positive symptoms was adjusted for. Adverse childhood experiences measuring cumulating psychosocial stress did not predict occupational status or functional level when positive and negative symptoms and neurocognition were controlled for, whereas in controls having experienced school bullying was associated with lower functioning. Insulin resistance in early psychosis appeared as an early marker of increased vulnerability to weight gain and abdominal obesity in young adults with FEP. Further, increased waist circumference predicted worsening low-grade inflammation, increasing further the cardiovascular risk. In sum, we have found different types of prognostic markers in FEP. Identifying the individuals at risk of less favorable outcomes could affect treatment choices in FEP.No significant relationships."}
+{"text": "Lipid droplets (LDs) are spherical, single sheet phospholipid-bound organelles that store neutral lipids in all eukaryotes and some prokaryotes. Initially conceived as relatively inert depots for energy and lipid precursors, these highly dynamic structures play active roles in homeostatic functions beyond metabolism, such as proteostasis and protein turnover, innate immunity and defense. A major share of the knowledge behind this paradigm shift has been enabled by the use of systematic molecular profiling approaches, capable of revealing and describing these non-intuitive systems-level relationships. Here, we discuss these advances and some of the challenges they entail, and highlight standing questions in the field. Lipids constitute essential building blocks for cell membrane structures, powerful sources of energy through \u03b2-oxidation, and modulators of cell compartment transactions and cell signaling and behavior . Howeverlipid bodies; or adiposomes in early studies\u2014constitute a safe and efficient means to store lipids, particularly for organisms exposed to environments with intermittent nutrient availability. They appeared early in evolution and can be found across all eukaryotic phyla studied, and in virtually all cell types of higher metazoans  are localized to the crowded surface of the LD, through mechanisms still undergoing characterization . Recent The particular ultrastructure of LDs, with a spherical core devoid of any molecules apart from triacylglycerides and cholesterol species, favored their long-standing view as relatively inert inclusions floating in the cytoplasm, passively subject to growth and consumption cycles . This viWhile relatively labile under routine immunolabeling procedures involving cell permeabilization with detergents, LDs are cell structures particularly amenable for imaging and extraction of rich multiparametric information . Their characteristic spherical morphology and the availability of highly specific cell/tissue permeable dyes for neutral lipids  facilitate automated segmentation routines and the computing of their number, size and relative position across extensive datasets  Figure . This kiBecause LD formation and function are significantly conserved across eukaryotic phyla , differeSaccharomyces cerevisiae is a first prominent example: the versatility and ease of use of this model unicellular eukaryote allows for the combinatorial interrogation of genetic interactions across the whole genome, using different readouts\u2014from subcellular imaging to relative survival across different limiting growth conditions\u2014; this allows for the precise mapping of genetic networks and enzyme complexes to as yet unparalleled resolution   ; or the o below) . Innovato below) , have alCaenorhabditis elegans is a multicellular model system whose use in research largely developed during the birth of molecular biology  to exert its function. Recent C. elegans screening studies have also provided insights onto the regulation of the formation of nuclear LDs (nLD); apart from COPI components and the seipin homolog SEIP-1, the authors identified the nuclear inner membrane NEMP-1/Nemp1/TMEM194A as a required gene for nLD formation  as an important regulator of lipid accumulation in adult flies .A recent genome-wide siRNA screen was performed for regulators of LD biogenesis in THP1 human macrophages . This stAn emerging subfield in cell biology is the study of interorganelle communication through specialized structures, commonly referred to as membrane contact sites (MCSs), which allow for the regulated interchange of molecules and information to achieve coordinated functioning . Studyinbona fide LD proteins are indeed specific substrates for ERAD E3 ligases (see below)  organizing LD distribution through their cooperation with the LD-ER linker seipin  . Systemae below) . Anotherr seipin . Interesr seipin , and ther seipin . All ther seipin ; its molWhile the close apposition of LDs to mitochondria and its link with fatty acid consumption had been early suggested , specifiPeroxisomes enable \u03b2-oxidation of very long chain fatty acids in metazoans, and participate of fatty acid catabolism to its completion in yeast or plants . Recent Contacts between LDs and subcompartments of the endosomal system have also been described , but theDrosophila ; this particular study demonstrated the recruitment of RNA binding proteins participating in viral RNA replication to LDs . Histones, which can be toxic for cells when mislocalized or secreted ; ERAD appears coordinated with lipid metabolism (particularly cholesterol biosynthesis) through the control of different enzymes  for each protein across different cell compartments, as located by specific bona fide markers. These correlative approaches have been rather successful on describing the proteomes of different cell compartments including LDs, especially in studies using machine-learning approaches to describe distribution changes across conditions  can be nditions .in vitro and in vivo; after subsequent affinity purification, mass spectrometry allows for the identification of labelled cell proteome subsets. A variety of applications have been also derived to inform of specific events such as posttranslational modification or interorganelle communication  nication . A relatm radius . Becausem radius . These msee previous section).Bersuker, Olzmann and collaborators fused the APEX2 ascorbate peroxidase  to inertThese studies have provided reference lists of \u2018core\u2019 LD proteins, extremely valuable to understand how responsive this subproteome is, what stimuli regulate their localization to LDs, and what molecular mechanisms underpin such localization . Surprisde novo biosynthesis and triacylglycerol conjugation, respectively)\u2014and LD tethering to replication factories through the RAB18 GTPase and accessory proteins such as Annexin A3 (ANXA3) , induce LD formation and engage in complex interactions through their surrounding phagophore with these organelles, presumably to utilize their resources  also induce the formation of LDs in the host cell, can liberate lipases to obtain free lipids from host LDs, and actively uptake these free lipids for the completion of their biological cycle  . Other F (ANXA3) . Intraceesources . Eukaryoal cycle .However, this model of LDs as solely \u201ccomforting pantries\u201d for intracellular invaders does not fit with different lines of evidence. First, formation of LDs is actively promoted in the cell by the activation of pathogen pattern recognition receptors (PRRs) by their microbial invader product , such as bacterial surface lipopolysaccharides (LPS) and glycolipids  or nucleUsing an experimental system where LD formation is induced in liver upon starvation and LPS administration in mice (thus minimizing effects from reduced food intake upon exposure to LPS), we applied multiplexed isobaric labeling and tandem mass spectrometry to profile the proteome of purified hepatic LDs, and its response to PRR activation . We obseLeveraging on variability across biological replicates, which can capture relevant biochemical relationships , hierarcListeria monocytogenes or herpes simplex virus type 1  is an amphiphilic peptide with prominent roles in innate defense against bacterial infection . Its preDrosophila antimicrobial defense upon recruitment by the Jabba protein  support these are general principles  Figure . Howeverbacteria . The ovebacteria  and conttb types .C. trachomatis-infected epithelial cells found changes associated with LD metabolic reprogramming (both increased lipid usage and anabolism), and identified PLIN2 as a perilipin protein specifically enriched upon infection , a report on the proteomic composition of LD-rich fractions purified from nfection . Of note helices ; studiesWhile cell-based high-content screenings on LD biology have been fruitful, recent developments of these technologies could allow for the systematic interrogation of how these structures are regulated in contexts closer to physiological conditions, and how they relate to many other tissue components and markers. Automated culture and high-content analyses of organoids that capture tissue microenvironment properties have been reported . Recent de novo phospholipid synthesis are important parameters determining the size and coalescence of LDs (4P) species accumulate in large LDs of cells depleted of the ORP5 regulator, which has been proposed to supply phosphatidylserine from PI4P  constitute a versatile means to modify the function, localization, stability, and interactions of proteome subsets in a coordinated manner. Protein phosphorylation comprises a large share of PTMs, driving signaling pathways for the transduction of different cues, including several modulating LD functions. An example is the regulation of LD growth and dynamics by different nodes of nutrient state sensing networks in the cell . FastingThe advancements brought by functional genomics and molecular profiling to all fields in cell biology are particularly prominent in LD research, as their characterization may have lagged as compared to other cell compartments, and some of their emerging functions  were particularly unexpected. Novel unbiased technologies will surely contribute to uncover new systems-level aspects of the roles of LDs in cell function and their emerging relationships with other cell structures, such as the nucleus and the secretory apparatus."}
+{"text": "Demands of caregivers of persons living with dementia (PLWD) are often influenced by the context of their caregiving situation. This study examines factors associated with caregiving burden in terms of task time and task difficulty among paid and unpaid caregivers of PLWD. Cross-sectional baseline survey data were analyzed from 110 paid and unpaid caregivers of PLWD participating in a larger NIH-funded study assessing the feasibility of using a novel in-situ sensor system. Oberst Caregiving Burden Scale constructs of task time and task difficulty served as dependent variables. Two least squares regression models were fitted, controlling for contextual items related to the caregiver, care recipient, and caregiving logistics. Caregivers whose care recipients were female , had more chronic conditions , and had lower Mini-Mental State Exam scores  reported higher task time burdens. Caregivers whose care recipients had other paid caregivers  and spent more months/years caring for their care recipients  reported higher task time burdens. Caregivers\u2019 task time burden was positively associated with their emotional stress level . Caregivers\u2019 task difficulty burden was positively associated with their emotional stress  and depressive symptomatology . Results reinforce the relationship between caregiver burden and mental health. While the care recipient\u2019s disease profile and needs were drivers of task time burden, which may also require coordination with other paid caregivers, task difficulty was emotionally driven. Findings highlight the importance of caregiver support services and programming for mental health."}
+{"text": "Certified community forests combine local governance with forest certification and aim to serve multiple objectives including forest protection, restoration, human wellbeing and equitable governance. However, the causal pathways by which they impact these objectives remain poorly understood. The ability of protected area impact evaluations to identify complex pathways is limited by a narrow focus on top-down theoretical, quantitative perspectives and inadequate consideration of local context. We used a novel mixed-methods research design that integrates the perspectives of multiple actors to develop a generalized conceptual model of the causal pathways for certified community forests. We tested the model using a combination of statistical matching, structural equation modelling and qualitative analyses for an agroforestry landscape in Tanzania. We found certified community forests positively impacted human wellbeing, equitable governance and forest restoration. Equitable governance had the largest impact on wellbeing, followed by crop yield and forest resource availability. Timber revenues varied widely between villages and the average effect of financial benefits did not impact wellbeing due to the immature stage of the certified timber market. We identified positive interactions and trade-offs between conservation and agriculture. Our findings suggest that no simple solution exists for meeting multiple objectives. However, developing understanding of the pathways linking social and conservation outcomes can help identify opportunities to promote synergies and mitigate negative impacts to reconcile competing objectives.This article is part of the theme issue \u2018Understanding forest landscape\u00a0restoration: reinforcing scientific foundations for the UN Decade on Ecosystem Restoration\u2019. However, over the last 50 years the roles of PAs have expanded to include human wellbeing and equitable governance objectives ,2. Some Certified Community Forests (CFs) represent a new generation of PAs seeking to meet the expanding role of PAs, by combining two recent trends in forest PA governance: (i) decentralization\u2014transferring governance responsibility from central governments to local actors in efforts to enhance equitable governance; (ii) forest certification to increase the financial benefits and equitable benefit sharing to incentivize sustainable management . Forest Analysis of causal pathways can be used to explain the complex processes by which PAs impact outcomes . Win-winHowever, the presence of negative interactions between social and ecological outcomes would result in trade-offs between PA objectives. For example, if conservation governance is perceived as being unfair, this could lead to conflicts and local resistance , as occuAdvances in the field of impact evaluation have seen the mainstreaming of statistical matching to exclude alternative explanations and attribute observed differences to the intervention . Howevera priori hypotheses of how PAs impact wellbeing or conservation using exclusively quantitative approaches. This top-down framing of a study system excludes local perspectives and has been described as creating a \u2018bottleneck\u2019 in dialogue [Secondly, impact evaluations tend to test dialogue , which mdialogue ,26. GreaWe aim to advance methods to evaluate the success of conservation and restoration interventions. We identify and test the causal pathways by which certified CFs impact human wellbeing and forest restoration for a case study in Tanzania. Specifically, we evaluate win-win assumptions of PA governance by testing pathways of (i) equitable governance, (ii) financial benefits, (iii) interaction effects and (iv)\u00a0trade-offs.We advance on existing evaluation methodologies by (i)\u00a0combining statistical matching with a conceptual model (ii) integrating top-down theoretical perspectives with bottom-up perspectives of local actors to promote inclusive consideration of alternative explanations from marginalized actors. We thereby contribute to two key knowledge gaps of the United Nations Decade on Restoration: (i) methods for designing interventions, and monitoring restoration success; (ii) linkages between the health of ecosystems and the flow of services to communities .. 2 (a)Tanzania provides an excellent test case of the challenges to reconcile forest restoration and human wellbeing objectives as national development policies aim to expand both agricultural and PA land uses, while CFs are often established on forests already considered to be degraded and economically marginal . We focu (b)Our conceptual model aimed to integrate actor perspectives with hypothesized pathways derived from conservation science literature . We consA thematic analysis of transcripts was then undertaken to identify actor perspectives of the main pathways linking certified CFs with conservation and human wellbeing impacts by identifying logical causal statements that were similar between independent consultation sessions. Identified pathways were then converted into a connected sequence of indicators linking CF governance via one or more causally linked mechanisms to human wellbeing and conservation impacts . The overall conceptual model was then composed of these main pathways. Indicators may be connected to more than one pathway if the causal logic suggested interactions between indicators from different pathways.All indicators in the conceptual model were included in a quantitative questionnaire to collect data on community perceptions of all indicators, which were then used to test the model. Our conceptual model emphasizes measuring \u2018bottom-up\u2019 community perceptions, rather than externally measured data sources because perceptions are important drivers of local behaviour and success of conservation interventions . (c)To improve the causal inference of our study we used statistical matching to compare certified CFs to control villages that represent the counterfactual situation\u2014what would have happened in the absence of the intervention . This apThe questionnaire was undertaken with 955 people from the nine villages with certified CFs and 10 matched control villages, with at least 50 respondents per village stratified by gender, local elite status  and wealth category . The questionnaire was undertaken at the scale of individuals rather than whole households since the concept of wellbeing contains subjective elements which cannot be generalized across households . (d) (i)Multidimensional human wellbeing provides a comprehensive measure of social impacts. Wellbeing indicators were identified following the Wellbeing Indicator Selection Protocol  by a sub (ii)Miombo woodlands were the dominant forest type in the study landscape. Normalised difference vegetation index (NDVI) correlates with ground vegetation biomass and productivity under low to medium vegetation density conditions such as the Miombo woodlands . NDVI ch (iii)Equitable governance concerns notions of fairness , in rela (e)We tested the conceptual model by structural equation modelling using PiecewiseSEM in R . Latent We included socio-economic indicators for local elite status and gender in models to account for any systematic perception biases between actors. To account for residual imbalances in the distributions of confounding variables between treatment and control groups we included orthogonal sets of confounding variables as predictors of response variables . We thenr2 values (the variance explained by fixed effects).For continuous variables, we report standardized path coefficients, which estimate the expected change in the response variable (e.g. wellbeing) as a function of the change in the explanatory variable (e.g. equitable governance), in units of standard deviation. For categorical variables (e.g. governance treatment versus control group), we report the model-estimated means for each factor level . For allp < 0.05). Finally, we critically reviewed the conceptual model through triangulation with the qualitative data to assess whether the identified pathways and trends were representative of different village cases and actors sampled. This served as a verification check to ensure inclusive representation of pluralistic perspectives, particularly potentially marginalized or minority actors whose perspectives might otherwise be masked by reporting normative trends.We assessed the overall model fit by Shipley's test of d-separation, accepted when Fisher's C statistic is higher than a significance level , with mean scores of all equitable governance indicators  higher in villages with certified CFs than control villages. In turn, equitable governance positively impacted human wellbeing both directly (standardized estimate = 0.18) and indirectly . The indWe have a lot of forest here and we work to manage it. But we have a limited number of customers and so the villagers here have not yet felt the actual benefit of this forest. But if we could get many customers to buy our timber then every member of this village could realize the importance of managing the forest - Village Natural Resource Committee Secretary, village 11.Second, a financial benefits pathway blue, , wherebyHowever poor economic performance was not the case in all villages. Annual timber revenue was highly variable between certified CFs . The size of certified CFs was also highly variable , with larger CFs generating more revenue. Some differentiation in timber revenue spending was observed between villages; the highest timber producing village able to undertake additional, larger-scale and more diverse community development projects, including (i) building new village government offices, (ii) installing primary school sanitation facilities, (iii) improved village healthcare provision targeting facilities for pregnant women and disabled patients and health insurance for village natural resource committee members, (iv) building a village-run guesthouse, (v) payment for forest patrols, planning meetings and patrol equipment, (vi) payment for professional forestry and governance training services from the supporting NGO MCDI and the district government forest office. An FSC-certified sawmill factory run by a sustainable timber production company called Sound and Fair had also been established in this village in 2017 to further up-scale timber production and revenue generation, providing additional employment opportunities.Third, a conservation pathway green,  showed tWe are funding our own forest management activities. We pay even from our own village basket for meetings and patrols - Village Natural Resource Committee member, village 2.Fourth, positive interaction pathways were hypothesized from social to conservation outcomes yellow,  with posThe government extended the national forest reserve boundary and so we have been left with a small area for farming. That land, it was very fertile, it was supporting us to have high production and we had a lot of food surplus. But now we have little food because we harvest very little \u2013 Community member, village 1.Fifth, trade-off pathways were hypothesized between conservation and agriculture red, . Focus gLarger certified CFs were also suggested by MCDI to have more economic potential for timber revenue, creating a trade-off between land uses. However, testing of our conceptual model did not show an impact of certified CFs on perceived land availability or knock-on impacts of perceived land availability for farming on crop yield or timber revenue.. 4We found evidence of both win-win and trade-off pathways from certified CF governance to forest recovery and human wellbeing. Certified CFs positively impacted (i) equitable governance and (ii) forest recovery and both pathways positively impacted wellbeing, supporting win-win assumptions that positive social and conservation outcomes can occur together and are causally linked. However, additional hypothesized win-win pathways of (iii) financial benefits from certified CFs and (iv) improved attitudes towards conservation did not impact either wellbeing or forest restoration, suggesting that the importance of these pathways was limited in our case study. The limitation of the economic pathway linking forest governance to wellbeing may be due to the FSC timber market being at an early stage of development and operating sub-optimally. While some villages were able to generate significant FSC timber revenue, which was used to deliver integrated programmes to improve human wellbeing, concerns were raised by other villages about the challenges of accessing timber markets. Nevertheless, these findings agree with other research suggesting that equitable governance can be a more important driver of successful conservation than financial incentives . FinallyBy disaggregating the impacts of PA governance into multiple pathways it is possible to identify which aspects of an intervention are performing well and which aspects are failing. In our case study, the governance equity component of certified CFs had a positive impact, in contrast to other CF programmes in Tanzania . HoweverBy comparing quantitative and qualitative findings it is possible to explore how variation in contextual factors can lead to alternative outcomes. Not all CFs showed poor financial performance. The village that\u00a0 established the largest CF, was also generating the most timber revenue, which was spent on diverse community projects, including additional income generation schemes such as a village-run guesthouse. The economic potential of this village had also attracted the establishment of an FSC-certified sawmill, in contrast to other villages which struggled to attract timber buyers. This more economically successful village, contrary to the general trend identified by modelling analyses, suggests that improved financial performance may require villages to dedicate significant land area to CFs and that strategies are needed to improve engagement with timber markets.The positive interaction pathways suggest the potential for virtuous cycles to occur over time , where pThe trade-off pathways, whereby forests provide both ecosystem benefits and costs for agriculture and potential agricultural land-shortages caused by expansion of PAs, suggest that the study landscape represents a microcosm of global challenges to reconcile forest conservation with rural development objectives ,5. We diOur research design sort to embrace a complex systems perspective. However, several simplifications were necessary to aid interpretation. To support a statistical comparison, we employed a binary distinction between the governance approaches of certified CFs and control villages. However, we recognize that within this overarching governance grouping, varying governance arrangements exist. To move beyond a coarse binary description of governance approaches, we employed qualitative methods to highlight outlying cases that contrasted with the normative quantitative trends reported. However further exploration of the within-group variation in governance approach would be possible through more in-depth case study research . Both huOur novel methodology illustrates the utility of a mixed methods approach for developing and testing theory of complex systems, with quantitative analyses showing overall trends, while qualitative analyses identifying alternative pathways missed by normative analyses. The integration of multiple actor perspectives provided a more comprehensive and contextualized understanding of pathways that balanced assumed positive and negative impacts of forest governance on people and forest recovery. By integrating views of actors from the global south our methodology makes progress in operationalizing calls for a pluralistic perspective of conservation challenges , to impr"}
+{"text": "Xenopus laevis, have revealed that efference copies (ECs) of the spinal motor program that generates axial- or limb-based propulsion directly drive compensatory eye movements. During fictive locomotion in larvae, ascending ECs from rostral spinal central pattern generating (CPG) circuitry are relayed through a defined ascending pathway to the mid- and hindbrain ocular motor nuclei to produce conjugate eye rotations during tail-based undulatory swimming in the intact animal. In post-metamorphic adult frogs, this spinal rhythmic command switches to a bilaterally-synchronous burst pattern that is appropriate for generating convergent eye movements required for maintaining image stability during limb kick-based rectilinear forward propulsion. The transition between these two fundamentally different coupling patterns is underpinned by the emergence of altered trajectories in spino-ocular motor coupling pathways that occur gradually during metamorphosis, providing a goal-specific, morpho-functional plasticity that ensures retinal image stability irrespective of locomotor mode. Although the functional impact of predictive ECs produced by the locomotory CPG matches the spatio-temporal specificity of reactive sensory-motor responses, rather than contributing additively to image stabilization, horizontal vestibulo-ocular reflexes (VORs) are selectively suppressed during intense locomotor CPG activity. This is achieved at least in part by an EC-mediated attenuation of mechano-electrical encoding at the vestibular sensory periphery. Thus, locomotor ECs and their potential suppressive impact on vestibular sensory-motor processing, both of which have now been reported in other vertebrates including humans, appear to play an important role in the maintenance of stable vision during active body displacements.Vertebrate locomotion presents a major challenge for maintaining visual acuity due to head movements resulting from the intimate biomechanical coupling with the propulsive musculoskeletal system. Retinal image stabilization has been traditionally ascribed to the transformation of motion-related sensory feedback into counteracting ocular motor commands. However, extensive exploration of spontaneously active semi-intact and isolated brain/spinal cord preparations of the amphibian  Gaze stabilization during both self-generated and passive motion is essential for constantly maintaining retinal image acuity as a prerequisite for stable perception of the visual world . During While the sensory-motor transformations subserving gaze stabilization are well documented for passive head/body motion, the processes operating during self-generated movements have remained more elusive. Over the last decade, however, evidence has accumulated that intrinsic copies of the actual motor commands responsible for an animal\u2019s propulsive axial or limb movements may also provide a source of neuronal signals for retinal image stabilization . Due to Xenopus laevis, consisting of the head\u2014including inner ears, eyes and eye muscles\u2014along with the still-attached and isolated spinal cord  may provide a functional blueprint that extends to other vertebrates, including humans.Here, we review evidence for the involvement of this novel mechanism during rhythmic undulatory and limb-based swimming in larval and juvenile Xenopus, which occurs mostly in the horizontal plane, both eyes oscillate in conjugation during left-right head excursions resulting from undulatory tail movements  pathway that is known to be involved in producing conjugate eye movements , the ocular motor performance remains exclusively coordinated with the tail undulations, without any evident VOR contributions to eye motion . The strThe suppression of vestibular afferent influences during high-intensity larval swimming might be spatially specific to inputs from the horizontal semicircular canals, or might represent a generalized filtering process that applies to all vestibular signals irrespective of their peripheral origin. To distinguish between these two possibilities, the influence of locomotor ECs on inputs from vestibular endorgans other than the horizontal semicircular canals was tested during passive motion around the longitudinal (roll) axis. In fact, an imposed left-right head roll motion caused a strong modulation of the LR nerve discharge that increased and decreased in strength during contra- and ipsiversive movements, respectively. The directionality of these evoked ocular motor responses and the low frequency (0.1 Hz) of the motion stimulus were consistent with the activation of vestibular signals predominantly arising from the gravitoinertial stimulation of utricular hair cells . SignifiXenopus tadpoles can be conferred by locomotor ECs rather than by VOR-producing sensory-motor transformations, this mechanism also has hitherto unsuspected implications for issues ranging from the evolution of the horizontal semicircular canals to the maintenance of postural stability during locomotion in human patients with vestibular disorders  synapse in the vestibular nuclei, or peripherally, at the synaptic connection between hair cells and vestibular nerve afferent fibers in the inner ear endorgans themselves  at which the suppression of spatially-specific signals in the VOR circuitry occurs, nor the underlying neurophysiological mechanism(s), have been fully established. Such an understanding requires identifying the anatomical pathways that convey the intrinsic CPG-derived signals and the suppressive processes operating at single or multiple synaptic levels. In principle, establishing these underlying features benefits from the simple organization of the VOR circuitry, which is comprised of a three-neuronal reflex arc for integrating angular and translational/gravitoinertial sensory signals . This shemselves .Xenopus, such an efferent neuron activation was indeed revealed by multi-unit recordings from the central severed ends of the anterior and posterior branches of a vestibular  nerve  nerve . During l) nerve , that thl) nerve .2+ transients were recorded in practically all efferent neuronal somata (of which there are 10\u201315 per side located in rhombomere 4), with onsets and durations that were strictly correlated with those of the accompanying spinal Vr bursting  burst discharge recorded in vestibular nerve branches indicated that the latter activity precisely encodes swim episode duration and any changes in Vr burst cycle frequency and intensity. This faithful coupling thereby ensures that the major parameters of propulsive motor commands are conveyed to the sensory periphery.The proportion of efferent neurons that are activated during locomotion was assessed by somatic calcium imaging during episodes of fictive swimming monitored by spinal Vr recordings. During swim episodes, Cabursting . FurtherXenopus preparations with intact vestibular endorgans and preserved peripheral and central nerve connections (en passant during rotational stimuli applied in different spatial planes alone, and during the occurrence of spontaneous fictive swimming (The impact of locomotor-related efferent neuron bursting on vestibular sensory encoding of head/body motion was evaluated in semi-intact larval nections . Vestibuswimming . In the swimming , left. Hswimming , the measwimming . HoweverThe functional significance of the differential effects of efferent neuronal activity on the spontaneous firing of vestibular afferents and their sensitivity to motion stimuli might be related to the push-pull operation of the vestibular system itself. Here, the encoding of immobility relies on bilaterally-balanced population resting discharge rates throughout the afferent neuronal assemblage . AccordiAnother potential site for a suppressive action of locomotor ECs on sensory-motor processing resides within the central circuitry of the vestibular nuclei . Since vAlthough the selective suppression of ocular motor output in tadpoles during horizontal, but not vertical, head rotation is based on a spatial specificity, likely related to the plane of head undulations during axial swimming, an alternative explanation might involve a difference in the dynamic spectrum of activated vestibular afferent units during motion in the two rotational planes. Roll motion stimulation in the vertical plane activates sensory elements in the vertical semicircular canals but is also a highly effective gravito-inertial stimulus for the utricle, thereby activating a large proportion of hair cells/afferent vestibular fibers with more tonic response dynamics . This isAn involvement of cerebellar and local vestibular circuits in the gating of body motion-related sensory signals during locomotion would not be unexpected given previous knowledge of their roles in the control of gaze stabilization . In contIn an evolutionary context, locomotor EC-driven eye movements might constitute a vestige of an ancestral mechanism, appearing in early vertebrates before rotational motion-encoding semicircular canals had appeared . AlthougXenopus laevis, considerably less is known for such a role in other vertebrates. In lamprey, an extant jawless vertebrate species, the use of semi-intact, head-immobilized preparations after optic nerve transection and labyrinth ablation has very recently provided direct evidence that spinal CPG-derived ECs contribute to compensatory eye movements, coordinated with swimming undulations in the horizontal plane (Xenopus. This idea has been further supported by experimental galvanic stimulation of bilateral inner ear endorgans in human patients, which caused smaller trajectory deviations during running than walking (While the functional processes and underlying neuronal pathways by which locomotor ECs can stabilize gaze have been unequivocally demonstrated in the amphibian al plane . Howeveral plane . Furtheral plane . The remal plane  or pre-pal plane  and animal plane . In addial plane  and humaal plane , resultaal plane , then ECal plane , 2022. A walking , again c walking , 2022.ex vivo brain-spinal cord preparations of neonatal mice with spatio-temporal characteristics reminiscent of those described in Xenopus. This ocular motoneuronal pattern complied with rhythmic eye movements, mostly in the horizontal plane, which occurred in phase with the forelimb gait pattern during treadmill-elicited locomotion in decerebrated animals. Moreover, the ascending locomotor signals were likely to derive from cervical cord neurons that connect directly with abducens motoneurons, similar to the situation found in amphibians (More direct evidence for locomotor EC-driven eye movements has recently been discovered in mice, where the existence of a comparable spino-ocular motor coupling has been established by multi-methodological approaches . Brieflyphibians . Thus, sphibians .in vitro experiments on larval and young adult Xenopus laevis provided the initial demonstration that efference copies of axial- as well as limb-based locomotor commands are able to elicit retinal image-stabilizing eye movements. This intrinsic feed-forward mechanism is spatio-temporally specific, functionally appropriate and dynamically adaptive, being capable of initiating gaze-stabilizing eye movements according not only to the immediate strength of ongoing locomotion but also to its mode, even throughout the transitional period of metamorphic development as one locomotor strategy progressively replaces the other. The ability to provide retinal image stability during the change in body format, propulsive motion profile and associated visual demands derives from a remarkable rewiring plasticity of spino-ocular motor coupling pathways that co-exist in the metamorphosing animal. While the impact of predictive locomotor efference copies matches the specificity of reactive sensory-motor transformations, the two fundamentally different signals do not simply summate in the production of image-stabilizing ocular motor commands. Rather, depending on the intensity of spinal CPG activity, the horizontal VOR is selectively suppressed, at least in part by an attenuation of the motion signal encoding at the sensory periphery in the inner ear. Significantly, this gaze-stabilizing mechanism that relies on locomotor EC signaling is not merely idiosyncratic to amphibians with their simpler and more stereotyped locomotor movement profiles, but evidently is also employed by other vertebrates, including humans. Recent studies in both Xenopus and mice (Maintaining visual world stability during locomotion is a major challenge for all vertebrates. Avoiding retinal image slip due to passive or self-generated head/body motion is traditionally ascribed to the transformation of mechanosensory feedback signals into ocular motor commands that offset perturbing head movements to ensure stable eye position in space. However, this generally acknowledged concept has been challenged over the past decade by increasing evidence that ascending neuronal pathways enable the propulsive CPG circuitry in the spinal cord to directly access and drive the brainstem ocular motor system during locomotion. Various types of and mice  suggest and mice . This meHS and JS wrote the first draft of the manuscript. FL made the figures. HS, FL, and JS reviewed and edited the final version of the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "Due to antibiotic overutilization, development of antimicrobial stewardship (AMS) in the outpatient setting has become a necessary focus for AMS programs. The cornerstone of AMS is utilization of antimicrobial prescribing data to provide feedback to individual providers and compare providers to each other in order to promote improved prescribing practices. Respiratory infections, especially conditions that never require antimicrobials, are a common target for this feedback. We aimed to create interactive data visualization dashboards of end-users prescribing for these respiratory and otic conditions in order for AMS and urgent/quick care program staff to identify potential areas of intervention.A multidisciplinary work group consisting of data analysts, infectious diseases physicians, urgent/quick care physicians, and infectious diseases pharmacists determined dashboard content, layout, and comparison charts. Graph types were tested to determine optimal visual output. Using the electronic medical record ICD10 and antimicrobial prescription data was extracted for the encounter with focus on ICD10 codes for respiratory and otic conditions which never require antimicrobials. Rates were calculated as number of antimicrobial prescriptions over total number of visits for these conditions.A multi-faceted dashboard was developed in Tableau\u00ae to view antimicrobial prescribing rates. Dashboard capabilities include the option to view individual provider prescribing rates compared to other de-identified providers, overall clinic prescribing rate, or individual rate compared to clinic rate. This allows for quick direct comparison of antimicrobial prescribing on the same graph by clinic to identify outliers  and allows visualization of trends in prescribing rates by clinics and providers over time .Never Antimicrobial Prescribing Rate ComparisonScatter plot comparing individual prescribers rate of prescribing for never antimicrobial eventsClinic Antimicrobial Prescribing Rate TrendClinic prescribing rate trend over time for never antimicrobial eventsPrescriber and Clinic Antimicrobial Prescribing Rate TrendIndividual prescriber rate compared to clinic rate over time for never antimicrobial eventsWe developed an interactive outpatient AMS dashboard to visualize prescribing of antimicrobials for never respiratory and otic conditions. These dashboards can be used by providers along with AMS and clinic leadership to determine areas of intervention in the urgent/quick care setting.Kelly M. Percival, PharmD, Gilead Sciences Inc: Advisor/Consultant Patrick M. Kinn, PharmD, MPH, Gilead Sciences: Advisor/Consultant Dilek Ince, MD, Evergreen: Member of data monitoring board|Gilead Sciences: Grant/Research Support|Leidos: Grant/Research Support|Moderna: Grant/Research Support."}
+{"text": "Pelvic fractures are common in cases of blunt trauma, which is strongly associated with mortality. Transcatheter arterial embolization is a fundamental treatment strategy for fatal arterial injuries caused by blunt pelvic trauma. However, vascular injuries due to blunt pelvic trauma can show various imaging findings other than arterial hemorrhage. We present a pictorial review of common and uncommon vascular injuries, including active arterial bleeding, pseudoaneurysm, arteriovenous fistula, arterial occlusion, vasospasm, and active venous bleeding. Knowledge of these vascular injuries can help clinicians select the appropriate therapeutic strategy and thus save lives. Pelvic fractures are not rare and account for approximately 3% of skeletal injuries . Pelvic Transcatheter arterial embolization (TAE) is the fundamental treatment strategy for patients with fatal arterial injuries caused by blunt pelvic trauma , 5. HoweTAE is the fundamental treatment strategy for active arterial bleeding due to pelvic fractures . Embolizn-butyl cyanoacrylate (NBCA) is useful for both selective and non-selective embolization; however, an experienced operator is desirable to prevent NBCA-related complications, such as reflux and non-target embolization . Ant. Ant8]. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an important method for treating severe hemorrhagic shock due to pelvic trauma. In this procedure, occlusion of the aorta with a balloon catheter is conducted to increase proximal arterial pressure and maintain organ blood flow while controlling downstream bleeding . HoweverThe formation of pseudoaneurysms in patients with blunt pelvic trauma, although rare, may occur immediately after the injury or later in the clinical course . PseudoaEndovascular treatment of traumatic pseudoaneurysm is usually effective Fig.\u00a0 16]. Th. Th16]. AVF is an abnormal anastomosis between arteries and veins and does not involve capillaries. Traumatic AVF can develop if arterial bleeding influxes into an adjacent injured vein . On radiBecause traumatic AVF can cause heart failure after highly variable latency periods , AVFs shThe middle layer of blood vessels is made up of smooth muscles, and smooth muscle cells may contract and become spasmodic following external compression, stretching, or endothelial injury due to trauma . Active Arterial occlusion is caused by transmural injury or dissection with a thrombus . Active Traumatic occlusion of the main trunk of the common/external iliac artery can cause critical lower limb ischemia, making recanalization crucial . VasculaBleeding due to pelvic fractures occurs more frequently from veins (80%) than from arteries (20%); the main venous sources of bleeding are the presacral plexus and prevesical veins . PeritonActive venous bleeding can be visualized using CT as the extravasation of contrast material in venous phase images without extravasation in arterial phase images Fig.\u00a0 20]. Il. Il20]. Transcatheter venous embolization with NBCA can potentially control critical bleeding from the iliac vein. However, it may cause some complications, such as leg swelling, deep vein thrombosis, and pulmonary embolism by obstruction of venous flow . EndovasWhen surgical treatment is chosen for a venous injury, balloon catheters can reduce bleeding and help obtain the necessary visualization of the operative field by occluding the proximal and distal portions of the injury .Endovascular treatment is effective for vascular injuries due to blunt pelvic trauma. Knowledge of the various forms and imaging findings of vascular injuries is essential for the astute planning of treatment strategies and life-saving maneuvers."}
+{"text": "Events that occur in utero set the trajectory for later-life diseases and longevity. Compelling data exist for interactions between developmental programming and aging, but the underlying mechanisms are not clearly defined. Fetal exposure to glucocorticoids (GC) is associated with alteration in hepatic enzymes and metabolic function in later life. We previously reported increased hepatic lipid accumulation and obese phenotype in middle-age male baboons exposed to GC as fetuses. The mitochondria play significant roles in cellular processes including stress responses and possibly a nexus between developmental programming and aging. The present study investigated the long-term effects of in utero GC exposure on mitochondrial bioenergetics using hepatocytes derived from aging baboons . Mitochondrial bioenergetics of both left and right lobe liver hepatocytes were examined as well as potential sex differences in mitochondrial function. Cell viability following isolation was similar among sexes and liver lobes but hepatocytes from males were highly energetic compared to females. Significant bioenergetic differences were observed in hepatocytes isolated from female baboons\u2019 left and right liver lobes, with higher basal, maximal, and ATP-linked respiration in left lobe hepatocytes compared to the right lobe. These lobe-specific bioenergetic differences were absent in males. Interestingly, H2O2-induced oxidative stress significantly modified male baboon hepatocyte bioenergetics but females were unaffected, suggesting mitochondrial resilience in females compared to males. These data demonstrate that early life exposure to GC elicits a sex-specific effect on mitochondrial function. These mitochondrial differences might drive differences in cell senescence between males and females."}
+{"text": "This survey study uses 2020 American Hospital Association data to assess strategies of US hospitals serving vulnerable populations in addressing social needs during the COVID-19 pandemic. We used 2020 American Hospital Association (AHA) survey data to assess such strategies among rural hospitals, critical access hospitals (CAHs), and safety-net hospitals (SNHs) in the US.Hospitals may play a critical role in alleviating health inequities by addressing underlying social determinants of health (SDOH). Public interest in addressing social needs during the COVID-19 pandemic has been accompanied by substantial health system investments in SDOH.AAPOR reporting guideline.The Harvard School of Public Health Institutional Review Board approved this survey study. The AHA obtained respondent informed consent, with the agreement that hospitals would remain anonymous. The study followed the We used the 2020 AHA Annual Survey Social Determinants of Health Supplement, which surveyed hospitals\u2019 efforts across 3 domains: screening for SDOH, programs/interventions to address SDOH, and community partnerships to address SDOH. The first domain assessed whether hospitals screened across 9 SDOH types. The second domain reported on whether hospitals had programs and/or interventions to address these SDOH. The third domain assessed whether hospitals worked with 14 types of external community partners to address SDOH, participate in community health needs assessments, and implement SDOH initiatives. We created 3 index scores across each domain  responded to the SDOH items . In adju6The results of this survey study suggest that rural hospitals, CAHs, and SNHs are not doing more and, in some cases, are engaging in fewer strategies to address the SDOH of their vulnerable populations, especially regarding community partnerships. This finding may be attributable to limited financial resources, workforce constraints, limited community resources and institutional partnerships, and lack of incentives.Study limitations include limited granularity of categorial responses of hospital efforts, potential variability and unreliability of respondent accuracy, and limited generalizability. The AHA survey also does not validate whether hospitals implemented the reported strategies or their effectiveness. Addressing resource barriers that hospitals serving vulnerable populations may face in implementing SDOH initiatives should be considered a key state and federal policy strategy for improving health equity."}
+{"text": "In humans, various dietary and social factors led to the development of increased brain sizes alongside large adipose tissue stores. Complex reciprocal signaling mechanisms allow for a fine-tuned interaction between the two organs to regulate energy homeostasis of the organism. As an endocrine organ, adipose tissue secretes various hormones, cytokines, and metabolites that signal energy availability to the central nervous system (CNS). Vice versa, the CNS is a critical regulator of adipose tissue function through neural networks that integrate information from the periphery and regulate sympathetic nerve outflow. This review discusses the various reciprocal signaling mechanisms in the CNS and adipose tissue to maintain organismal energy homeostasis. We are focusing on the integration of afferent signals from the periphery in neuronal populations of the mediobasal hypothalamus as well as the efferent signals from the CNS to adipose tissue and its implications for adipose tissue function. Furthermore, we are discussing central mechanisms that fine-tune the immune system in adipose tissue depots and contribute to organ homeostasis. Elucidating this complex signaling network that integrates peripheral signals to generate physiological outputs to maintain the optimal energy balance of the organism is crucial for understanding the pathophysiology of obesity and metabolic diseases such as type 2 diabetes. In most mammalian species, the size of the brain and adipose depots are inversely correlated, indicating compensatory buffering strategies to protect against starvation . HoweverThis review highlights the coordinated reciprocal signaling between the CNS and white adipose tissue. We are discussing the integration of afferent signals from the periphery in neuronal populations of the mediobasal hypothalamus as well as the efferent signals from the CNS to adipose tissue and its implications for adipose tissue function. Furthermore, we are focusing on central mechanisms that regulate resident immune cell function in adipose tissue depots and subsequently contribute to organ homeostasis.The brain interacts with white adipose tissue depots through distinct efferent sympathetic nerves, releasing the catecholamine norepinephrine (NE) from their nerve terminals. In white adipose tissue (WAT), sympathetic nerve terminals are located adjacent to >90% of adipocytes, forming a dense network of sympathetic arborizations . Importa\u03b1- and \u03b2-adrenoceptors (\u03b1- and \u03b2-ARs) on adipocytes (s protein and activation of adenylate cyclase (AC), which increases intracellular cAMP levels. High cAMP levels activate protein kinase A (PKA), which phosphorylates hormone-sensitive lipase (HSL) and perilipin-A (PLIN1). This initiates a signaling cascade that leads to the activation of lipases, such as adipose triglyceride lipase (ATGL) and monoglyceride lipase (MGL) or \u03b1/\u03b2 hydrolase-domain 6 (ABHD6), allowing triglycerides to be hydrolyzed sequentially into fatty acids (FA) and glycerol , which is co-stored with NE, is released from sympathetic nerve terminals and inhibits lipolysis by binding to its receptor NPYR1 . NPY recvia afferent sensory feedback in order to maintain thermoregulation.Lipolysis increases the availability of free fatty acids which in turn activate local WAT afferents that mediate acute induction of thermogenesis in distant BAT depots . This davagus efferent axis regulates fat mass gain , the ventromedial hypothalamus (VMH), the dorsomedial hypothalamus (DMH), the lateral hypothalamus (LH) and the paraventricular nucleus of the hypothalamus (PVH) . These nThe most well-defined neurocircuit in the context of integrative physiology is the melanocortin system, which consists of the functionally antagonistic anorexigenic proopiomelanocortin (POMC)-expressing neurons and the orexigenic agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) of the mediobasal hypothalamus . POMC neImportantly, both AgRP and POMC neurons express receptors for leptin, insulin and other energy-state communicating hormones and are therefore subject to feedback regulation .PVH) dynamically regulates the sympathetic innervation downstream of leptin-sensitive AGRP and POMC neurons in the ARC  in white adipocytes enhances sympathetic activity  mRNA . Pharmacvia the circulation, but also through sensory innervation of adipose depots. Sensory nerve endings allow for the detection of local leptin levels directly in the adipose tissue depot  . ATMs frvia the production and secretion of acetylcholine, which acts on adipocytes via acetylcholine receptors, stimulating the PKA pathway and subsequently inducing thermogenic gene expression  has been shown to decrease food intake in mice and inhibit adipocyte development . NPFF isin vivo and in vitro studies have shown anti-inflammatory effects mediated by melanocortin agonists acting on macrophages  expressed in adipose tissue resident immune cells . Severalrophages . For exarophages . Activatrophages . Howeverrophages . These lrophages .via neurotransmitter release.It is clear that ATMs impact the innervation of adipose tissue in numerous ways and vice versa the adipose tissue innervation directly impacts ATM functions via the neuroregulatory receptor RET, which ultimately leads to an increased cytokine secretion , thereby regulating adipocyte function and energy expenditure  were recently shown to be indirectly regulated by the SNS . Activatenditure . Mice wienditure . Notablyenditure .via the IL-17F effector cytokine (The neurotransmitter acetylcholine (ACh) is an important contributor to immune cell function [for review see  and Cox] and B ccytokine . TGF\u03b21 pcytokine . CollectUnderstanding the complex signaling networks that integrate energy availability signals from adipose tissue in the CNS to generate physiological outputs is crucial for understanding the pathophysiology of obesity and metabolic diseases such as type 2 diabetes. The findings discussed in this review clearly highlight the importance of the melanocortin system in the CNS-adipose crosstalk. However, specific neuronal populations in the mediobasal hypothalamus modify the activity of melanocortin neurons. Defining the exact molecular nature of these regulatory neurons has proven challenging. Owing to their structural and functional diversity, our current understanding of the neurocircuits involved in the control of adipose tissue is still limited. Recent technical advances in neuroscience have led to the possibility of identifying and characterizing the neurocircuits involved in the control of adipose tissue homeostasis. Identifying druggable targets on these specific neuronal populations is a prerequisite for developing novel interventions and therapeutic approaches for obesity and associated metabolic diseases."}
+{"text": "Cognitive reserve (CR) refers to adaptability allowing for better cognitive outcomes given the degree of brain changes or other risk factors for cognitive decline. Despite significant research efforts, our knowledge of cognitive reserve proxies remains limited. Studies predominantly use a single sociodemographic variable  as a proxy measure when CR can manifest in multiple domains. Studies also tend to rely on older samples, whereas adversity factors of cognitive performance may have differing onset ages, suggesting different risk or protective mechanisms at different ages. We examine two cohort datasets spanning from early adolescence  up to the cusp of mid-adulthood  to evaluate the role of CR proxies across over 100 variables. Defined as a moderator between a cognitive outcome and structural brain measure, these variables cover behavioral, environmental, physical and mental health, and psychological trait domains. Using cross-validated regularized regression, we identified dozens of factors acting as CR proxies . We then use a within-family design to examine the moderation effect over and above genetic and environmental covariates. For example, adolescents who read more tend to show better cognitive performance given their gray matter volume . This study aims to identify factors that could be targeted with scalable prevention and intervention efforts earlier in life to maximize cognitive functioning."}
+{"text": "Cartilage diseases affect a large population worldwide and are associated with a significant burden to patients and society. Osteoarthritis (OA) is the most common chronic joint disorder and the fastest growing cause of disability. Cartilage focal defects, predisposing to early OA and degeneration impair the function of many joints, including the articular joint, intervertebral disc and temporomandibular joint. Presently, no effective therapy is available, except for palliative care primarily used to delay invasive and often suboptimal surgical interventions. Regenerative medicine therapies directed at the early stage of osteoarthritis, and tissue engineering approaches to reconstruct cartilage defects provide great potential for cartilage and joint repair in the future. This current research topic represents a collected series of articles in this field. Highlights are summarized below.Liu et al. provided a timely review describing the factors that affect cartilage homeostasis and function, and the emerging regenerative approaches that are informing the future treatment options. Tissue engineering approaches combining cell and biomaterial strategies to reconstruct the complex and functional cartilage tissue are still under active research. Two review articles in the current topic have described the use of 3D printing technology in cartilage tissue reconstruction in general  and for irregularly shaped cartilage in particular . Electrospun gelatin/polycaprolactone (GT/PCL) nanofiber membranes at optimum GT/PCL ratio were used to support in vivo cartilage regeneration from autologous chondrocytes in a swine model . Also xenogeneic acellular cartilage matrix (ACM) materials encapsulated with autologous chondrocytes showed capacity to promote cell proliferation and cartilage formation in goat, with only a minor immune-inflammatory response . This provides scientific evidence for future clinical application of ACM in cartilage tissue engineering. Next to biomaterials, appropriate cell sources are important for cartilage repair. Combined physioxia and fibronectin adherence have shown to select and propagate a meniscus progenitor population that can potentially be used to treat meniscal tears or defects . Additional stimuli can further enhance the cartilage repair potential of cells. For example, a magnetic field applied to magnetic nanoparticles-loaded cells decreased cellular senescence and enhanced chondrogenic capability of adipose-derived mesenchymal stem cells . Senescence can also be targeted using a senolytic peptide, fork head box O transcription factor 4-D-Retro-Inverso (FOXO4-DRI), which removed the senescent cells among chondrocytes .Bi et al. have established an model combining transection of the anterior and posterior cruciate ligaments, and the meniscus, and a cartilage defect in rhesus macaques, which closely resembled the pathophysiological processes of spontaneous knee OA in humans.Last but not least, appropriate animal models for OA are still lacking and play a pivotal role in the development of regenerative therapies."}
+{"text": "Whole-exome and targeted sequencing are widely utilized both in translational cancer genomics and in the setting of precision medicine. The benchmarking of computational methods and tools that are in continuous development is fundamental for the correct interpretation of somatic genomic profiling results. To this aim we developed synggen, a tool for the fast generation of large-scale realistic and heterogeneous cancer whole-exome and targeted sequencing synthetic datasets, which enables the incorporation of phased germline single nucleotide polymorphisms and complex allele-specific somatic genomic events. Synggen performances and effectiveness in generating synthetic cancer data are shown across different scenarios and considering different platforms with distinct characteristics.https://bitbucket.org/CibioBCG/synggen/.synggen is freely available at Bioinformatics online. The interrogation of next-generation sequencing (NGS), principally whole-exome (WES) and targeted sequencing (TS), is rapidly becoming a preferred approach for the exploration of large tissue and liquid biopsy-based cohorts, especially in the context of precision medicine. In this setting, a precise benchmarking of the large collection of computational tools that are continuously developed is fundamental for the correct interpretation of somatic genomic profiling results. Although many simulators of synthetic cancer genomes and NGS data have been developed in the last years  combine these reference models and a set of user-specified germline and somatic genomic profiles to create synthetic sequencing files (FASTQ format).Synggen is a tool written in C programming language to generate synthetic NGS files, in the form of WES or TS experiments, representing heterogeneous cancer genomes and matched controls. The tool provides two execution modes which allow to (i) exploit a set of control (non-cancer) NGS sequencing files (BAM format) to generate three Read Depth Model (RDM), which measures the average intra-sample depth of coverage variability by calculating the probability, across all input files, of observing sequencing reads at any captured genomic region and position; only reads aligning at the lowest genomic coordinate are considered when paired-end data is used; (ii) a Quality Model (QM), which measures the distribution of base qualities across sequencing read positions; (iii) Position-Based Error (PBE), which measures for each captured genomic position [not representing a common single nucleotide polymorphism (SNP)] the probability of observing platform-specific systematic errors supported by high quality reads and bases  and point mutations (PMs). Phased SNPs are used to realistically represent the genetic background of specific individuals and to generate both cancer and matched control samples. Somatic CNAs are defined as allele-specific copy numbers  and are incorporated across all affected WES/TS captured regions to modulate the RDM distribution and to adjust SNP allelic fractions. Of note, both overlapping and nested somatic copy number alterations can be represented  samples (BAM files) available from The Cancer Genome Atlas dataset, focusing on patients having high (>80%) tumor content WES (Sure Select All Exome v3) cancer tissue samples. Generation of synthetic NGS cancer data was instead tested for increasing number of sequencing reads produced. A cancer sample was generated with tumor content at 80% and incorporating patient-specific germline SNPs and patient-specific somatic CNAs and PMs (details in the To demonstrate the effectiveness of synggen in generating benchmarking datasets, we simulated two liquid biopsy cfDNA scenarios considering data produced in We developed synggen to perform fast and scalable generation of cancer and matched control WES and TS synthetic data without the need for intermediate FASTA files generation and exploiting multi-threaded computation. Synggen allows to emulate platform-specific NGS data characteristics and allows to incorporate germline-phased SNPs and complex somatic allele-specific copy number alterations and point mutations. In addition, it allows to create clonal and sub-clonal events across different tumor content scenarios enabling the generation of large-scale complex benchmarking datasets. Synggen is easy to use and is provided with a collection of additional scripts to simplify further its usability.Conflict of Interest: none declared.btac792_Supplementary_DataClick here for additional data file."}
+{"text": "Both pain and mental illness associate with work disability. However, few studies have examined the association of concurrent pain and mental distress with sickness absence (SA). We examined separate and joint associations of chronic pain, multisite pain, and mental distress with total and long-term all-cause SA among young and midlife municipal employees.As part of the Young Helsinki Health study, baseline data were collected in 2017 from 19-39-year-old employees of the City of Helsinki, Finland. Chronic (\u22653 months) pain, multisite (\u22652 body sites) pain and mental distress  were reported by 3911 respondents. Register data on total (>1 day) and long-term ((>11 workdays) SA for the following year were obtained from the employer and the Social Insurance Institute of Finland with respondents\u2019 informed consent. Negative binomial regression analyses were performed with sociodemographic, socioeconomic, and health-related factors as confounders. The interaction of gender was examined.Chronic pain, multisite pain, and mental distress were associated with total SA. Chronic multisite pain was associated with long-term SA , and chronic pain  and multisite pain  with long-term SA among those with mental distress. For women, there was a synergistic interaction of multisite pain to the association with total SA .Chronic and multisite pain associate with SA among young and midlife employees. The associations are generally stronger among women and particularly among those with concurrent mental distress. Interventional studies are needed to confirm if early symptom recognition and support could reduce sickness absence.\u2022\u2002Chronic pain and pain at multiple body sites associate with sickness absence among young and midlife employees, particularly among women and those with concurrent mental distress.\u2022\u2002Interventional studies are needed to confirm if sickness absence could be reduced by early recognizing pain and mental distress among employees and providing preventive and therapeutic services."}
+{"text": "Although research has shown that food insecurity may lead to sleep problems due to mental illness, it remains unclear whether physical health also mediates this relationship in addition to poor mental health. We investigated whether frailty and depressive symptoms mediated the association of food insecurity with sleep deficiency  among community-dwelling older adults. We analyzed the baseline data of the Longitudinal Study of Ageing and Health in the Philippines, a study with national representative sample of adults aged 60 years or older . Sleep deficiency was conceptualized as self-reported sleeping less than 6 hours, complaining about trouble with falling asleep and staying asleep, and/or having non-restorative sleep. Food insecurity was defined as being hungry and not having enough food in the past three months in the household. Frailty was operationalized using modified definitions under Fried\u2019s criteria. Depressive symptoms were assessed using the Center for Epidemiological Studies-Depression Scale. Covariates included socio-demographics , health , and lifestyles . Mediation analysis was performed using PROCESS macro. The results from bootstrapping showed that the indirect effects from food insecurity through frailty  and depressive symptoms  onto sleep deficiency were significant, but the direct effect from food insecurity to sleep deficiency was not . The results suggested that the effects of food insecurity on sleep deficiency were fully mediated through frailty and depressive symptoms among community-dwelling older Filipinos. Preventing frailty and depression may help improve sleep health among individuals being food insecure."}
+{"text": "The incidence of Anti-NMDA receptor encephalitis is 1.5 per million population per year but it has only been described sporadically in the paediatric population. The median age of onset is 21 years old. In children, seizures, abnormal movements, insomnia, and irritability are more frequently identified than psychosis or abnormal behavior. Early detection and treatment can improve treatment outcomes.Presentation of a case of a paediatric patient with Anti-NMDA receptor encephalitis displaying homicidal behavior towards her family membersCase reportA 12 year old with no significant past psychiatric and medical history, was brought in by police to the hospital after she attempted to stab her mother with a knife. She had low grade fever, headaches and lethargy prior to presentation. Organic workup revealed serum and CSF anti-nmda receptor to be positive. She received early treatment with steroids and intravenous immunoglobulins and no longer harboured further homicidal ideations.Initial suspicion of anti-NDMA receptor encephalitis should be raised and early auto-immune workup performed in paediatric patients presenting with acute change in behavior especially in young females with no past medical or psychiatric historyNo significant relationships."}
+{"text": "The importance of resilience factors in the positive adaptation of refugee youth is widely recognised. However, their actual mechanism of impact remains under-researched. The aim of this study was therefore to explore protective and promotive resilience mechanisms on both negative and positive mental health outcomes. Promotive resilience is seen as a direct main effect and protective resilience as a moderating effect.Cross-sectional study with 160 Syrian youth aged 13-24 years, who recently resettled in Norway. A multi-dimensional measure for resilience was used to explore the potential impact of resilience factors on pathways between potentially traumatic events from war and flight (PTE), post-migration stress, mental distress and health-related quality of life (HRQoL). Analyses included regression, moderation and moderated mediation using the PROCESS macro for SPSS.A direct main effect of resilience factors (promotive resilience mechanism) was found for HRQoL and general mental distress, but not for post-traumatic stress disorder (PTSD). No moderating effects of resilience factors (protective resilience mechanism) were found. Post-migration stressors mediated the effects of PTE, and this indirect effect was present at all levels of resilience. Relational and environmental level resilience factors and combined amounts had more impact than individual level factors.Despite high risk exposure and mental distress, resilience was also high. The direct main effect of resilience factors and less impact on PTSD, suggests universal resilience building interventions may be beneficial, compared to exclusively targeting groups with high symptom levels. These interventions should target relational and environmental resilience factors as well as individual coping techniques. Additionally, reducing current stress and symptoms could increase the efficacy of resilience factors already present.\u2022\u2002Refugee youth may have both high levels of risk and high resilience.\u2022\u2002Universal resilience interventions should focus on relational and environmental support, as well as individual resilience."}
+{"text": "In the setting of structural heart disease, ventricular tachycardia (VT) is typically associated with a re-entrant mechanism. In patients with hemodynamically tolerated VTs, activation and entrainment mapping remain the gold standard for the identification of the critical parts of the circuit. However, this is rarely accomplished, as most VTs are not hemodynamically tolerated to permit mapping during tachycardia. Other limitations include noninducibility of arrhythmia or nonsustained VT. This has led to the development of substrate mapping techniques during sinus rhythm, eliminating the need for prolonged periods of mapping during tachycardia. Recurrence rates following VT ablation are high; therefore, new mapping techniques for substrate characterization are required. Advances in catheter technology and especially multielectrode mapping of abnormal electrograms has increased the ability to identify the mechanism of scar-related VT. Several substrate-guided approaches have been developed to overcome this, including scar homogenization and late potential mapping. Dynamic substrate changes are mainly identified within regions of myocardial scar and can be identified as local abnormal ventricular activities. Furthermore, mapping strategies incorporating ventricular extrastimulation, including from different directions and coupling intervals, have been shown to increase the accuracy of substrate mapping. The implementation of extrastimulus substrate mapping and automated annotation require less extensive ablation and would make VT ablation procedures less cumbersome and accessible to more patients. These dynamic changes may play a critical role in the tachycardia mechanism when conduction velocity slows and tissue refractory periods lengthen. Dynamic substrate changes lie mainly within regions of myocardial scar or the SBZ and can be identified as functional delay in electrograms by introducing timed extrastimuli.The fundamental hypothesis of substrate mapping for scar-mediated VT is that surrogates of the isthmus can be identified. These surrogates include electrocardiographic indications for electric discontinuity such as fractionation, split potentials, LPs, and long potentials, also evident as sites displaying activation slowing.,Myocardial scar definition is a key step of any substrate-based ablation approach.High-density, multielectrode catheters can also enhance the possibility of detailed activation mapping of even poorly tolerated VTs because a complete map is faster to obtain. Recently, it has been shown that there is higher freedom from VT recurrence in patients with a fully mappable diastolic pathway recording after an ablative procedure.The use of high-resolution mapping technologies may have a role in improving clinical outcomes.,The advantages of multipolar catheters  are (1) higher mapping density and better substrate definition; (2) higher detection of LAVAs and voltage channels; and (3) higher accuracy in identifying and delineating near-field component (LAVAs) and differentiating from far-field signals.Ripple mapping is a mapping tool that shows both voltage and propagation channels into the scar in a single dynamic display. This technology has the advantage of displaying complex or continuous fractionated local EGMs as time-dependent propagation, rather than choosing a single annotation for timing. Jamil-Copley and colleagues,,Fractionated EGMs are recorded in regions where infarct healing causes wide separation of individual myocardial fibers while distorting their orientation. These anatomic changes likely cause slow and inhomogeneous activation.In the setting of post\u2013myocardial infarction cardiomyopathy, specific EGM signatures are expressions of distinct electrophysiological phenomena. De Bakker and colleaguesMartin and colleagues,,Pace mapping is a technique used to localize the exit site of postinfarct re-entry VT circuits.,De Chillou and colleaguesCharacterization of scar regions is important for the initiation and maintenance of VT re-entry circuits, known as conducting channels (CCs).,Isochronal crowding is defined as local deceleration of propagation in a region within scar with bunching of isochrones (>2 isochrones within 1-cm radius).As re-entrant VT requires fixed or functional localized conduction slowing, Brunckhorst and colleaguesFunctional block has also been defined as an area of the myocardium that is not electrically excitable at shorter coupling intervals but is excitable at relatively long cycle lengths.Among all identified LP in a given substrate, it is not known which zone of late activation most commonly provides the substrate for re-entry. In addition, LPs may be unrelated to any VT circuits and may represent unnecessary ablation targets. The most delayed LPs are not necessarily most functionally specific for re-entry.The insight that decrement precedes unidirectional block was first described in atrial tissue sections in studies undertaken by Lammers and colleagues.,Jackson and colleaguesAcosta and colleaguesFunctionally guided substrate modification approaches that consider both activation and voltage patterns guided by extrastimuli (sense protocol) have been described as alternatives to extensive ablation required to homogenize scar , Video 1Porta-S\u00e1nchez and colleagues,EGM annotation methods based on the maximal negative derivative of the extracellular potential or maximal voltage may be inaccurate in nonuniform anisotropic tissue. Detected EGMs are strictly dependent on electrode orientation, respective to wavefront propagation, which rapidly changes directions resulting in a changeable recording according to the vector line of assessment. As a result, catheters may not identify low-voltage EGMs propagating orthogonal to their orientation, potentially missing critical arrhythmic substrate.,Arenal and colleaguesIn the study by Martin and colleagues,Brunckhorst and colleagues reported that changing the activation sequence  produced a >50% change in EGM amplitude at 28% of sites and a >100% change at 10% of sites, but only 8% of sites had an EGM amplitude classified as abnormal (\u22641.5 mV) with one activation sequence and normal (>1.5 mV) with the other activation sequence. Electrically unexcitable scar (6% of sites) was associated with lower EGM amplitude but could not be reliably identified based on EGM amplitude alone for either activation sequence.,SURVIVE-VT (Substrate Ablation versus Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia) has shown that a substrate-based catheter ablation procedure was associated with a significantly lower rate of implantable cardioverter-defibrillator shocks, cardiovascular death, and hospitalization for worsening heart failure.It remains to be seen whether functional substrate mapping may further improve patient outcomes in an early ablation strategy, but as a technique, it would be optimally placed to be used as a first-line safe strategy for substrate guided VT ablation.Additionally advances in mapping technology continue to play a key role in improving resolution of functional signals. Multipolar electrode catheters with 1-mm electrodes and variable interspacing have been introduced to overcome limitations in mapping in a unidirectional manner. The Advisor HD Grid Mapping Catheter (Catheter Sensor Enabled) is a multipolar catheter with electrodes equally interspaced along each spline and arranged in a grid configuration. The catheter simultaneously records EGMs along and across different orthogonal vectors when point acquisition is set in the bidirectional WAVE configuration. As well as enabling an increase in the near-field-to-far-field signal ratio, it can provide omnipolar EGMs that are independent of the incident wavefront and the fixed interelectrode spacing along and across splines, allowing calculation of conduction velocities.Current substrate modification procedures employing extensive substrate modification covering the entirety of the abnormal substrate are associated with long procedural times and may be unfeasible in unstable patients with limited cardiac reserve and large substrates."}
+{"text": "Agave . Today Agave cultivation, primarily for beverage production, provides an economic engine for rural communities throughout Mexico. Among known dryland-farming methods, the use of rock piles and cattle-grazed areas stand out as promising approaches for Agave cultivation. Identifying new cultivation areas to apply these approaches in Arizona, USA and Sonora, Mexico warrants a geographic assessment of areas outside the known ranges of rock piles and grasslands. The objective of this study was to predict areas for dryland-farming of Agave and develop models to identify potential areas for Agave cultivation. We used maximum entropy (MaxEnt) ecological-niche-modeling algorithms to predict suitable areas for Agave dryland farming. The model was parameterized using occurrence records of Hohokam rock piles in Arizona and grassland fields cultivated with Agave in Sonora. Ten environmental-predictor variables were used in the model, downloaded from the WorldClim 2 climate database. The model identified potential locations for using rock piles as dryland-farming methods from south-central Arizona to northwestern Sonora. The Agave-grassland model indicated that regions from central to southern Sonora have the highest potential for cultivation of Agave, particularly for the species Agave angustifolia. Results suggest that there are many suitable areas where rock piles can be used to cultivate Agave in the Sonoran Desert, particularly in the border of southeastern Arizona and northwest Sonora. Likewise, cattle-grazing grasslands provide a viable environment for cultivating Agave in southern Sonora, where the expanding bacanora-beverage industry continues to grow and where different Agave products  can potentially strengthen local economies.For centuries, humans occupying arid regions of North America have maintained an intricate relationship with  Agave genus and indigenous groups and rural communities in arid regions has been crucial to creating sustainable agroecosystems in arid regions in Mexico and North America .The area highlighted in grey was the study area used to create suitability models for (TIF)Click here for additional data file.S2 Fighttps://gadm.org/index.html].The shapefiles and data used to construct the map were obtained from GADM [(TIF)Click here for additional data file.S3 FigPublished under a CC BY license, with permission from Michael T. Searcy, original copyright 2022.(TIF)Click here for additional data file.S4 FigHighlights in red indicate the variables selected for the study.(TIF)Click here for additional data file."}
+{"text": "Accumulating evidence suggests asymmetrical responses of cerebral blood flowduring large transient changes in mean arterial pressure. Specifically, theaugmentation in cerebral blood flow is attenuated when mean arterial pressureacutely increases, compared with declines in cerebral blood flow when meanarterial pressure acutely decreases. However, common analytical tools toquantify dynamic cerebral autoregulation assume autoregulatory responses to besymmetric, which does not seem to be the case. Herein, we provide the rationalesupporting the notion we need to consider the directional sensitivity of largeand transient mean arterial pressure changes when characterizing dynamiccerebral autoregulation. Cerebral autoregulation (CA) has commonly been described as the ability of the cerebralvasculature to react to steady-state (static CA) or transient (dynamic CA: dCA) arterialblood pressure (ABP) changes. The roles of these physiological responses are to maintaincerebral perfusion to meet the brain\u2019s demand and minimize blood flow variations.Therefore, the extent of the vessels\u2019 vasomotion (i.e. vasoconstriction or vasodilation)will be proportional to the ABP magnitude change, whether ABP increases or ABPdecreases. The hypothesis behind the presence of directional sensitivity of the cerebralpressure-flow relationship resides in the role brain blood vessels play against ABPtransient surges to protect the microcirculation from overperfusion. Therefore, it isthought dCA would be more efficient when ABP acutely increases in comparison with acuteABP decreases. Using an autoregulatory gain calculation between middle cerebral artery meanblood velocity (MCAv) and MAP, Tzeng et\u00a0al. demonstrated a smaller gain when MAP acutelyincreased compared with MAP decreases. We demonstrated a directional sensitivity of the cerebral pressure-flowrelationship by examining changes in MCAv in response to transient increases anddecreases in MAP induced by repeated squat-stands .24 Initially, these changes werecalculated from a seated baseline, an approach that has been criticized. This calculation was further refined byusing the largest concurrent MAP oscillations without an independent resting baseline,and by adjusting for time intervals. In addition to demonstrating a directional sensitivity in the MCA4 and in the posterior cerebral artery using this novel calculation, we suggested the hysteresis-like pattern isfrequency-dependent .4 Abetter autoregulatory capacity was also demonstrated during the squatting phase(transient increase in MAP) of repeated squat-stands using the autoregulatory index.There is growing evidence of cerebral pressure-flow relationship directional sensitivityduring large transient mean arterial pressure (MAP) oscillations. In healthyindividuals, the first observation of a directional sensitivity was reported whencomparing acute increases and decreases in ABP with drugs infusions. The activation of cerebral SNA in response to an acute elevation in MAP wouldserve to protect the brain microcirculation from overperfusion and to reduce the risk ofhemorrhagic stroke. Another potential mechanism underlying this hysteresis-like patterncould be a differing intrinsic myogenic activity when ABP increases, compared with ABPdecreases. However, previous work suggests intrinsic myogenic activity influences dCAduring oscillations below 0.07\u2009Hz and calcium-channel blockade impairs dCA in humans during oscillatory lower bodynegative pressure at frequencies between 0.03 and 0.08\u2009Hz.Differences in cerebral sympathetic nervous activity (SNA) in response to transient MAPincreases, compared with MAP decreases, could potentially explain this directionalsensitivity of the cerebral pressure-flow relationship. Indeed, data in sleeping lambsindicate SNA recorded in the superior cervical ganglia is activated during acute ABPincreases but not acute ABP decreases.9. Interestingly, Katsogridakis et\u00a0al. usedthigh-cuffs inflation and deflation to induce large transient MAP changes. This method has been shown to have extremely large variations in dCA metrics,even when tests are performed just minutes apart. Nonetheless, whether specific methodsto induce significant MAP changes are partly responsible for the directional sensitivityof the pressure-flow relationship remains to be elucidated. Further research will thusbe necessary to ensure this phenomenon is not method-dependent.Of note, there are studies reporting the absence of asymmetry in the cerebralpressure-flow relationship Nonetheless, further studies are needed, as we still do not know whether thishysteresis-like pattern remains present in other physiological and pathological states.In addition, all studies focusing on the directional sensitivity of dCA to date includedmeasures of cerebral blood velocity and MAP. The monitoring of volumetric cerebral bloodflow and cerebral perfusion pressure  in future studies is encouraged to provide more meaningful results not only inregards to the directional sensitivity of the cerebral pressure-flow relationship, butalso for all the other metrics quantifying dCA.Directional sensitivity could be highly relevant to consider while studying CBFregulation in diverse populations. Since there are many physiological contexts  and clinical/pathological states involving acute and large changes in MAP, the direction of MAP has the potential ofbeing an important variable to consider when examining dCA. We have recently reportedthat directional sensitivity of the cerebral pressure-flow relationship is present insedentary and endurance-trained participants, but absent in resistance-trained individuals.It becomes clear there is asymmetrical sensitivity of the cerebral pressure-flowrelationship during large transient MAP changes. We now need to better understand itsunderlying mechanisms and refine the current analytical tools to assess dCA, in order toeventually optimize the management of ABP in clinical populations. Replication ofstudies in various centers using different models of forced ABP oscillations (e.g.oscillatory lower body negative pressure) will also be crucial. The presence ofasymmetrical sensitivity has important implications on quantification of dCA usingstandard analysis on forced ABP oscillations. For example, transfer function analysis, acommon analytical tool to quantify dCA, assumes autoregulatory responses to be linearand symmetric, which is not the case. From now on, we consider we cannot solely useanalytical methods that do not consider the direction of large transient MAP changeswhen characterizing dCA. It will remain crucial the scientific and medical community isaware of this important characteristic of the cerebrovasculature until a global changeis undertaken by our community to take MAP direction into account in the assessment ofdCA and acute manipulation of ABP within the clinical setting."}
+{"text": "HIV-positive patients with schizophrenia spectrum disorders experience burden of double stigma. Comorbid pathology may alter structure of stigma and shall be considered in development of individual destigmatization programs.Study of psychiatric stigma features in HIV-positive and HIV-negative patients with schizophrenic disorders.ISMI , PDD  \u2013 to study stigma in 70 patients divided into three groups with respect to their diagnosis ; BPRS  \u2013 to assess psychiatric status, RSAS  \u2013 to assess anhedonia. Dispersion analysis , Spearman and Pearson correlation were used.Patients with comorbid HIV-infection showed increased level of perceived stigma, although they resisted the stigma internalization better than others did (Table 1).Patients with schizotypal disorders and patients at early stages of HIV infection experienced the most alienation and frailty to internalization of stigma .Correlation relationship between social anhedonia and perceived stigma  observed in patients with HIV infection.Comorbid HIV infection in psychiatric patients contributes to the psychiatric stigma structure. Differentiated approaches in rehabilitation of HIV-positive mental patients should be used."}
+{"text": "Schizophrenia spectrum disorders are among the most debilitating mental disorders and evidence on its pathophysiological underpinnings is scant. The brain-derived neurotrophic factor (BDNF) appears to be involved in the pathophysiology of these complex psychiatric disorders.The present study investigates the longitudinal variation of serum BDNF levels in a 24-month observational cohort study of Sardinian psychotic patients (LABSP). This study assessed the variation in BDNF serum levels and its relationship with psychopathological and cognitive changes. Further, we also examined if genetic variations within the BDNF gene could moderate these relationships.Every six months 105 LABSP patients were assessed for their BDNF serum levels, as well as for a series of psychopathological, cognitive, and drug-related measures. Four tag single nucleotide polymorphisms (SNPs) within the BDNF gene were selected and analyzed using Polymerase Chain Reaction (PCR). Longitudinal data were analyzed using mixed-effects linear regression models (MLRM).Analysis showed significantly lower peripheral BDNF levels in psychotic patients with depressive and negative symptoms. BDNF levels were also decreased in patients scoring lower in cognitive measures such as symbol coding and semantic fluency. In addition, Val66Met polymorphism within the BDNF gene significantly moderated the relationship between the severity of negative symptoms and BDNF levels.Our findings are consistent with previous literature suggesting that peripheral BDNF levels are associated with some cognitive domains and mood disruption in major psychosis. The results also suggest the lack of association between most BDNF genetic variants, except Val66Met polymorphism, with the severity of negative symptoms.No significant relationships."}
+{"text": "The present review is a historical perspective of methodology and applications using inert liquids for respiratory support and as a vehicle to deliver biological agents to the respiratory system. As such, the background of using oxygenated inert liquids (considered a drug when used in the lungs) opposed to an oxygen-nitrogen gas mixture for respiratory support is presented. The properties of these inert liquids and the mechanisms of gas exchange and lung function alterations using this technology are described. In addition, published preclinical and clinical trial results are discussed with respect to treatment modalities for respiratory diseases. Finally, this forward-looking review provides a comprehensive overview of potential methods for administration of drugs/gene products to the respiratory system and potential biomedical applications. Aerosol drugs have been delivered to the lungs for several thousand years . The useDuring the last 20\u00a0years, the combination of nanocrystal technology combined with an inert perfluorochemical vehicle has demonstrated the efficacy of large volume drug delivery to the entire lung because of the vehicle physical-chemical properties  . FurtherThe use of liquids for respiratory support is reviewed in this section, as well as the physical properties of fluid used and the rationale for using specific liquids.2; CO2) and diffusion gradients at atmospheric conditions limited the functional use of saline solution to provide adequate gas exchange  was investigated as respiratory media; however, these oils, although having high gas solubility, also demonstrated toxic effects . Perfluo2 and CO2 are specific to respiratory gas exchange and carried only as dissolved gases with solubilities ranging as much as 16 and three times greater, respectively, in PFC than in saline. Oxygen solubilities range from 35 to 70\u00a0ml gas per deciliter at 25\u00b0C . It is noteworthy that perflubron  is the only medical grade perfluorochemical approved by the FDA for emergency medical use. While many properties of PFC liquids vary, they do provide relatively low surface tension and viscosity, and are more dense than both water and soft tissue.Please refer to  at 25\u00b0C . The carVariations in specific physicochemical properties of the PFC liquids are significant to their use as respiratory media and as vehicles for the administration of biological agents. Fluids of higher vapor pressure may volatilize from the lung more rapidly than liquids having lower vapor pressure. Fluids with greater spreading coefficients (dependent on surface tension) may distribute more easily in the lung than fluids whose spreading coefficients are lower  . Fluids The initial preclinical studies in liquid spontaneous breathing and ventilation support were directed at breathing in unusual environments such as deep sea diving, zero gravity, and space travel . It was Subsequently, several separate investigational new drug applications were approved by the FDA to investigate the safety and efficacy of PFCs, mainly PFOB, as a liquid breathing media in neonates. While animal studies over the years showed significant efficacy and safety of liquid breathing, clinical studies using several techniques in humans  had mixed outcomes. The findings from non-clinical and clinical studies are summarized below.2 requirements that are characteristics of ventilator-induced lung injury . These studies supported the use of liquid ventilation as a superior source of respiratory support when compared with gas media with spontaneous breathing or conventional mechanical ventilation (CMV). Various studies also demonstrated short-term beneficial physiologic responses in lung function because of improved alveolar recruitment and significant preservation of normal histological structure of the lung . Non-clig injury .Recent studies continue to show PFOB improves oxygenation  in animaAnimal studies consistently support the safety of PFOB, as few negative effects have been reported. Studies show PFOB is not absorbed systemically and causes no long-term harm . SeveralEarly clinical studies demonstrated that infants with severe RDS, meconium aspiration, and CDH tolerated liquid PFC in their lungs and were able to effectively exchange gas and maintain cardiovascular stability .Consistent with those studies and animal studies, additional published reports indicated PFOB increased gas exchange  in adultMost importantly, the utility of PFOB was demonstrated in a multicenter study of premature infants with severe RDS refractory to other available treatments  . ThirteeMore recently, lavage with PFC has been shown to be safe for treatment of persistent and difficult-to-treat lung atelectasis . BronchoFollow-up imaging studies up to 20\u00a0years after treatment with PFOB in humans demonstrated no negative effects from this treatment . The stuIn early liquid ventilation studies, it was reported that PFOB usage in adults increased lung compliance , which iSystemic administration of therapeutics to target the lung is faced with numerous challenges secondary to potential degradation by serum and hepatic enzymes and rapid renal clearance. Compromised pulmonary blood flow in the injured lung may further limit passive diffusion of the drug from the blood into the lung parenchyma. Retention of the therapeutics in the lung is also often suboptimal. These challenges can be mitigated by local administration of therapeutics through inhalation or airway instillation . HoweverSome studies have successfully demonstrated that lungs filled with PFC liquid have the ability to deliver active and inactive agents for the diagnosis and treatment of respiratory disorders.Respiratory infections affect distally located alveoli with bacteria and viruses multiplying in the alveolar cells. Distal lung distribution of intra-tracheally delivered anti-infective agents is essential to halt disease progression. In a newborn lamb model of acid lung injury, gentamicin administration during tidal liquid ventilation using PFC resulted in significantly higher lung gentamicin levels compared with intravenous administration . This teIn an animal model of meconium aspiration syndrome, partial liquid ventilation improved regional distribution of intratracheally administered radio-labelled surfactant compared with conventional mechanical ventilation. There was more uniform distribution of surfactant between the lungs as well as between both ventral and dorsal regions of the lungs. Such uniform distribution was associated with improved systemic oxygenation . PFC wasInhalational smoke-induced acute lung injury is characterized by airway epithelial injury leading to excess leakage of plasma substrates into large airways and the formation of fibrin casts. Interventions to prevent or treat airway casts are limited. In this regard, PFC has been used for intratracheal administration of plasminogen activators (tissue plasminogen activator [tPA] and single-chain urokinase plasminogen activator [scuPA]) for management of airway clot and fibrinous cast formation associated with smoke-induced acute lung injury. Enzymatic activities of the plasminogen activator following dispersion and storage in PFC were preserved, and PFC administration alone did not impact physiologic or histological differences. In contrast, PFC-facilitated plasminogen activator delivery resulted in significantly better physiologic and histologic outcomes. PFC-facilitated delivery of plasminogen activator demonstrated improved outcomes than achieved by nebulization of plasminogen activators alone .2 during liquid ventilation potentially could be different compared with the gas-filled lung.Drug delivery during PFC PLV respiratory support has been demonstrated with other soluble gases in PFOB such as inspired nitric oxide (NO). NO administration with PLV in surfactant-depleted adult pigs resulted in a significant improvement in gas exchange and decrease in pulmonary artery pressure, most notably without deleterious effects on systemic hemodynamic conditions . In a coTwenty-two percent of all pediatric hospital admissions are due to respiratory illness. Genetic lung diseases account for increased morbidity and mortality . GeneticCRISPR-Cas9 gene editing provides an unprecedented opportunity to manipulate genes in somatic cells. Editing technologies have demonstrated clear therapeutic promise in non-human primates and early human clinical trials . New appThe postnatal lung presents important limitations to airway delivery because of the substantial mucus and surfactant barrier at the air-epithelial interface, repulsive charge interactions at the cell membrane, and unequal reagent distribution due to the heterogeneity of lung disease with some areas being overinflated and others collapsed . Further2 and CO2 solubility of PFC liquids allows effective gas exchange, even in lungs filled with fluid. PFCs also reduce surface tension, which assists lung volume recruitment at reduced inspiratory pressures by eliminating the air-liquid interface. Importantly, PFC liquids effectively penetrate collapsed regions of the lung to facilitate access to under-ventilated regions. This is particularly important in non-homogenous lung diseases such as surfactant protein diseases, in which PFC liquids could simultaneously facilitate delivery of therapies, increase gas exchange, and improve pulmonary function. Several groups have exhibited the superior effectiveness of PFC liquids as vehicles for pulmonary distribution of genetic cargo (The fluid-filled fetal lung physiology could be partially mimicked in postnatal lungs with PFC liquids because of their high spreading coefficients and intriguing properties for pulmonary distribution of biological agents. The high Oic cargo . PFC liqic cargo . Use of ic cargo . Many stic cargo . As suchic cargo . By adapThe fact that aqueous solutions are not readily soluble in PFCs is an important consideration for PFC drug delivery. Some research projects have circumvented this barrier by relying on bulk flow turbulent mixing . HoweverWhen lung parenchymal disease and/or injury are present in the lung, pulmonary ventilation and perfusion are compromised. Ventilation can be irregular and perfusion may be inhibited by ventilation-perfusion mismatch. The route of therapy administration is hindered by these abnormalities, rendering standard intravenous and aerosol/endotracheal tube delivery ineffective in delivering therapeutic agents to the affected area.Liquid ventilation with an inert respiratory gas solubility is a revolutionary mode for respiratory support, as well as delivery of drug/gene product to the respiratory system. As noted, inert perfluorochemical liquids have low viscosity and high oxygen and carbon dioxide capabilities . The phyThe use of PFC liquid in the respiratory system enhances ventilation and perfusion matching, boosting exposure of the drug/gene product to the circulation, successfully reaching required therapeutic serum drug levels . Studies"}
+{"text": "The Management and Supervision Tool (MaST) helps NHS mental health care professionals identify patients who are most likely to need psychiatric hospital admission or home treatment, due to severe mental illness, through a Risk of Crisis (RoC) algorithm driven by electronic health record (EHR) data analytics. We describe the derivation and validation of the MaST RoC algorithm, and its implementation to support preventative mental healthcare in the NHS.The RoC algorithm was developed and evaluated with EHR data from six UK NHS trusts using Ordered Predictor List propensity scores informed by a priori weightings from pre-existing literature, as well as real-world evidence evaluating the associations of clinical risk factors with mental health crisis using NHS EHR data. Mental health crisis was defined as admission to a psychiatric hospital or acceptance to a community crisis service within a 28-day period. Predictor variables included age, gender, accommodation status, employment status, Mental Health Act (MHA) status (under section or Community Treatment Order), and previous mental health service contacts . Data were analysed using Ordered Predictor List propensity scores. The algorithm was derived using structured EHR data from 2,620 patients in a single NHS trust and externally validated using data from 107,879 patients in five other NHS trusts. Qualitative and quantitative data on feasibility, acceptability and system efficiency impacts of MaST implementation were obtained through staff surveys and local audits.The factors associated with greatest propensity for mental health crisis included recent previous crisis, multiple previous crises, higher number of mental health service contacts in recent weeks, MHA section, accommodation status and employment status. The RoC algorithm identified 64% and 80% crises in its top quintile. Sentiment analysis of staff surveys suggested that the use of MaST improved productivity by reducing time taken to access patient information to support caseload management that was previously difficult to obtain through manual review of EHRs. The systems efficiency audit revealed a reduction in duration of crisis and inpatient admissions following MaST implementation.The MaST RoC algorithm supports the identification of people more likely to use crisis services in NHS mental health trusts, is feasible to implement, and improves systems efficiency. EHR-derived algorithms can support real-world clinical practice to improve outcomes in people receiving NHS mental healthcare."}
+{"text": "Aedes-borne flaviviruses. Domestic dogs may be useful sentinels for West Nile virus.We tested 294 domestic pet dogs in Mexico for neutralizing antibodies for mosquito-borne flaviviruses. We found high (42.6%) exposure to West Nile virus in Reynosa (northern Mexico) and low (1.2%) exposure in Tuxtla Gutierrez (southern Mexico) but very limited exposure to  Aedes spp. and Culex spp. mosquitoes, the endemicity of human arboviral diseases is incongruent with these vector distributions . Canine exposure to WNV was widespread, and we found a higher prevalence of neutralizing antibodies to WNV in dogs from Reynosa  than in those from Tuxtla Gutierrez . The lower reported numbers of WNV cases in Mexico might be in part because of the high seroprevalence of antibodies for other flaviviruses, which have been shown to protect against severe clinical infection from WNV, thus leading to reduced testing (Culex mosquitoes in the study area. Our data suggested substantial WNV enzootic activity in Reynosa and corroborated prior observations of high use of dogs as blood meal hosts by Aedes-borne flaviviruses suggests not an absence of these viruses circulating in these communities but that dogs are likely insensitive sentinels of the viruses\u2019 transmission in Mexico. In Chiapas, 7,972 human cases of dengue and 763 cases of Zika had been reported during 2016\u20132020 (Ae. aegypti in southern Texas and northern Mexico feed on dogs (,The relative lack of canine exposure to Cx. quinquefasciatus mosquitoes, a primary vector of WNV, use high numbers of dogs for blood meals. Therefore, domestic pet dogs may be useful sentinels of WNV transmission, as previously suggested in other regions (Our study suggests substantial WNV enzootic activity in Reynosa, Mexico and corroborates observations that Additional information about the usefulness of domestic dogs as sentinels for West Nile virus."}
+{"text": "Efforts to find disease-modifying treatments for Alzheimer\u2019s disease (AD) have been largely unsuccessful. The relative lack of progress and the age-related incidence of AD suggest that modulation of aging per se may be a useful alternative treatment approach. Therapeutics aimed at preventing or reversing aging should be effective in preventing or reversing dementia and the pathology associated with progressive AD. Epigenetic dysregulation of neuronal gene expression occurs with age, propagating deficits in cellular homeostasis. Regulators of epigenetic processes, such as histone deacetylases (HDACs), are well documented and may represent promising therapeutic targets. HDAC activity becomes dysregulated with age and in AD. An intriguing concept is that HDAC inhibition effectively forestalls AD pathology measured more broadly, addressing the notion that rectifying homeostatic gene expression may be the critical step in ameliorating AD pathogenesis at the earliest stage of disease initiation. HDAC inhibitors target several pathways associated with aging and AD neuropathology including loss of synaptic function, mitochondrial dysfunction, increased oxidative stress, and decreased autophagy activity. Since transcriptional levels of numerous genes are shown to decrease with increasing age, a recovery of their transcriptional activity through HDAC inhibition could prevent or delay age-associated declines in neurological function and provide pathways for treating AD. The prevalence of neurodegenerative diseases is expected to soar with the number of elderly individuals in both developed and developing countries now rising dramatically. Efforts to find disease-modifying treatments have been largely unsuccessful. These efforts have focused mainly on identifying pathogenic mechanisms specific to each disease process. The relative lack of progress with these approaches and the age-related nature of neurodegenerative disease incidence suggests that modulation of aging per se may be a useful alternative approach for delaying the onset or retarding the progression of neurodegenerative conditions ,2. This AD is a complex heterogeneous pathology that impacts multiple aspects of neuronal physiology. The predominant hypothesis guiding AD therapeutic development for the last two decades has been that amyloid initiates a cascading series of events, including phosphorylation and aggregation of tau protein, that lead to pervasive neuronal degeneration. The repeated observation that rare early-onset familial AD mutations increase pathogenic amyloid through perturbations of beta/gamma-secretase function, promoted the notion that targeting amyloid is a potential therapeutic approach. Unfortunately, failures of a number of clinical trials have called into question amyloid as the primary therapeutic target. This demands careful reconsideration of AD disease etiology and justifies why alternative strategies for therapeutic development should be explored.Epigenetic dysregulation of neuronal gene expression occurs with age, propagating deficits in cellular homeostasis. Regulators of epigenetic processes, such as histone deacetylases (HDACs), are well documented and may represent promising therapeutic targets. The gradual and escalating dysfunction of essential cellular processes could link all of the cellular AD phenotypes into a complex cascade, in which amyloid is either a late-stage effector or simply a biomarker of the disease process. In support of this view, numerous transcriptional analysis studies have examined genetic dysregulation in AD and found metabolic processes, oxidative stress, protein degradation, synaptic function and transcriptional regulation to be impacted ,6. Gene HDAC inhibition is a powerful approach to stimulate transcriptional changes within neurons. HDAC activity becomes dysregulated with age and in AD and has been shown to decrease synaptic plasticity in mouse models ,14. The Our published observations that phenylbutyrate (PBA), an HDAC inhibitor, attenuated amyloid plaque development in the PS1delta9/APPswe double transgenic mouse line and partially restored cognitive function , set theHDAC inhibitors target several pathways associated with aging and AD neuropathology. Synaptic pathology is increasingly of interest in assessing AD pathology and is linked to normal aging as well ,20. GeneClosely linked with synaptic pathology, mitochondrial dysfunction leading to decreased ATP production and increased ROS resulting from impaired electron transport chain function appears prominently in both aging and AD \u201330. The Autophagy plays a key role in neuronal physiology and pathology. It degrades cell organelles and misfolded proteins by fusing autophagosomes with lysosomes to prevent buildup of wastes within the cell and promote homeostasis and organelle self-renewal. Misfolded proteins can induce autophagy in primary neurons and this induction can be impaired under neurodegenerative disease conditions ,33. ExprThere is now a growing consensus that increased histone acetylation with globally elevated transcription might be beneficial at older ages as it contributes to reversion of age-dependent decline in expression of metabolic, stress response, and reparative genes involved in homeostasis and health span. There is thus a rationale for targeting deacetylation with inhibitors to activate expression of specific genes. Since transcriptional levels of numerous genes are shown to decrease with increasing age, a recovery of their transcriptional activity through HDAC inhibition could prevent or delay age-associated declines in neurological function and enhance intervention of AD."}
+{"text": "Esophageal atresia, diaphragmatic hernia and abdominal wall defects provide examples of congenital anomalies which have been shown to have poorer neurodevelopmental outcomes in the face of prematurity, with associated increased surgical complexity, higher relative cumulative doses of medications, longer hospital and intensive care stay and increased rates of feeding difficulties, compared with infants who experience either prematurity or congenital anomalies alone.Preterm infants are more likely to be born with congenital anomalies than those who are born at full-term. Conversely, neonates born with congenital anomalies are also more likely to be born preterm than those without congenital anomalies. Moreover, the comorbid impact of prematurity and congenital anomalies is more than cumulative. Multiple common factors increase the risk of brain injury and neurodevelopmental impairment in both preterm babies and those born with congenital anomalies. These include prolonged hospital length of stay, feeding difficulties, nutritional deficits, pain exposure and administration of medications including sedatives and analgesics. Congenital heart disease provides a well-studied example of the impact of comorbid disease with prematurity. Impaired brain growth and maturity is well described in the third trimester in this population; the immature brain is subsequently more vulnerable to further injury. There is a colinear relationship between degree of prematurity and outcome both in terms of mortality and neurological morbidity. Both prematurity and relative brain immaturity independently increase the risk of subsequent neurodevelopmental impairment in infants with CHD. Non-cardiac surgery also poses a greater risk to preterm infants despite the expectation of normal  Congenital anomalies which require surgery during the neonatal period predispose infants to brain injury and subsequent neurodevelopmental impairment, including both cardiac and non-cardiac lesions . Contribin utero or ex utero status. The impaired in utero environment may compromise brain growth and development due to placental dysfunction, uterine dysfunction, maternal ill health, infection, or injury  is a risk to term-born neonates, then the additive impact of prematurity is potentially cumulative. Hunt et al. reported the 8-year-old outcomes of three cohorts of extremely preterm infants who underwent a surgical procedure during their NICU admission . They foWalsh et al. specifically excluded congenital anomalies from a group of preterm infants less than 30\u00a0weeks gestation included in a study comparing MRI at term-equivalent age and 2-year outcome between those who did and did not receive surgery and anesthesia . A relatMost major neonatal surgery is time-critical such that pre-operative MRI is very challenging to obtain. Those researchers who have managed to obtain such images are subject to extreme bias as the more complex or unwell infants are least likely to have been able to access the MRI scanner prior to surgery. Fetal imaging would be the obvious solution to exploring brain growth prior to non-cardiac surgery but has not yet been widely explored to date.Congenital heart disease (CHD) makes up the largest cohort of infants with congenital anomalies requiring neonatal surgery and has provided a helpful model to understand the impact of impaired fetal development on the growing brain. Fortunately, cardiac anomalies often have a slightly longer window of opportunity to allow pre-operative imaging than non-cardiac surgical anomalies. Furthermore, there is an extensive literature exploring fetal MRI in this population.per se. This potential link has been confirmed by MRI studies linking cerebral oxygenation with impaired growth in fetuses with CHD  and neurodevelopmental impairment in CHD, even in early term-born infants. A study of 971 consecutive neonates with critical CHD was stratified by gestational age and adjusted for severity of lesion, against a reference group of neonates born at 39\u201340\u00a0weeks gestation. The risk of cerebral injury increased 2-fold in the 37\u201339\u00a0week gestation group; 8-fold in the 34\u201337\u00a0week gestation group and 25-fold in infants less than 34\u00a0weeks gestation at birth . In the  surgery . Ortinau surgery , but Bel surgery .There has been much debate regarding optimal timing of surgery for infants born prematurely with critical CHD . IntentiBoth critical CHD and non-cardiac congenital anomalies which require neonatal surgery, increase the risk of brain injury and subsequent neurodevelopmental impairment compared with healthy infants. MRI patterns of impairment suggest different mechanisms are at play between the two surgical groups, with myelination delay more prominent in the cardiac group and gyral maturation delays more common in the non-cardiac group. However, both types of lesions place the neonate at risk of further brain injury throughout their peri-operative and intensive care course. The additive burden of prematurity is complex but combines the vulnerable states of both prematurity and relative immaturity such that an increased risk of brain injury and subsequent neurodevelopmental impairment is inevitable.Many studies (including my own) have attempted to simplify and homogenize research findings, by excluding preterm infants from explorations of congenital anomalies on injury and outcome, when in fact this is exactly the group who needs the most attention. Rather than excluding infants with anomalies from studies of preterm neurodevelopment and preterm infants from studies of congenital anomalies, future studies should focus specifically on minimizing risk to preterm infants with comorbid congenital anomalies. This could include health-service research exploring the multidisciplinary team requirements to merge best practices across clinical craft groups with a patient-centered focus. Studies of the impact of developmental care practices in preterm infants could be extended into the surgical and cardiac environment. Further studies should provide gestation-based dosing for commonly used anesthetic and analgesic agents. Follow-up programs should incorporate later preterm infants than historically included, to allow for the potentially additive impact of surgical complexity.A more concerted focus on these high-risk infants should obviate the increased risk of impairment through improvements in patient-centered, developmentally appropriate care, which carefully balances pain management, nutritional support and brain-protective strategies from fetal or neonatal diagnosis to childhood and beyond."}
+{"text": "Benefits of the stay-at-home order imposed in Italy to prevent SARS-CoV-2 transmission need to be weighed against its impact on citizens\u2019 health. In a country with a solid familial culture and where welfare relies on households, confinement drastically decreased support provided by elder relatives, which may have worsened mental health.A web-based cross-sectional study  was conducted on a representative sample of Italian adults during lockdown (27th of April-3rd of May 2020). We asked 3156 subjects to report on reduced help in housework and childcare from retired parents to assess confinement impact on mental health through validated scales before and during the lockdown.Overall, 1484 (47.0%) subjects reported reduced housework help from parents, and 769  diminished babysitting support. Subjects reporting reduced housework help had worsened sleep quality  and quantity , depressive  and anxiety symptoms , compared to those reporting unreduced help. Worsening in sleep quality  and quantity , depressive  and anxiety symptoms  was also associated with reduced babysitting help. In subjects with poorer housing and teleworking, mental health outcomes were worse.Confinement came along with reduced familial support from parents, negatively impacting mental health. Social networks and support within families provided by older relatives act as a resilience factor and a potential vulnerability that affects mental health outcomes. Health and social services response should be designed to address mental health needs and mitigate long-term health costs caused by the pandemic's unprecedented stressfulness and unknown duration.National lockdown measures came along with reduced housework help supply for a large proportion of adult parents who presented increased mental health symptoms with unsatisfactory quality of life.A global, multi-level socioeconomic interdisciplinary approach is needed to inform evidence-based family and welfare policies and prevention strategies centred on population wellbeing."}
+{"text": "The topic of older adult loneliness commands increasing media and policy attention around the world. Are surveys of aging equipped to measure it? We assess the measurement of loneliness in large-scale aging studies in 31 countries. In each country, we document available loneliness measures, examine correlations between different measures, and assess how these correlations differ by gender and age group. There is substantial heterogeneity in available measures of loneliness across countries. Within countries with multiple measures, the correlations between measures are high (range .38-.78). Differences by age and gender group are relatively small. Correlations between loneliness measures and living alone and being without a spouse are positive and similar in magnitude across countries, supporting construct validity. We establish that even single-item measures of loneliness contribute meaningful information in diverse contexts, with reliable and consistent measurement properties within many countries."}
+{"text": "In utero exposure to maternally-derived antigens following chronic infection is associated with modulation of infants \u2018immune response, differential susceptibility to post-natal infections and immune response toward vaccines. The maternal environment, both internal (microbiota) and external  also modulates infant's immune response but also the clinical phenotype after birth. Vertical transmission of ubiquitous respiratory pathogens such as influenza and COVID-19 is uncommon. Evidence suggest that in utero exposure to maternal influenza and SARS-CoV-2 infections may have a significant impact on the developing immune system with activation of both innate and adaptive responses, possibly related to placental inflammation. Here in, we review how maternal respiratory infections, associated with airway, systemic and placental inflammation but also changes in maternal microbiota might impact infant's immune responses after birth. The clinical impact of immune modifications observed following maternal respiratory infections remains unexplored. Given the high frequencies of respiratory infections during pregnancy , the impact on global child health could be important. On the other hand, a decreased expression of placental TLR mRNA (TLR 6 and 7) was observed along with suppression of pro-inflammatory placental cytokines production (IL-1 and TNF). Different knock-out experiments using TLR deficient mice suggest a critical role of maternal TLR signaling in the protection against asthma in their progeny.The factors associated with farm exposure and modulation susceptibility to atopic disease is likely multifactorial . Animal  progeny . This prOverall these data indicate that prenatal exposure to a specific maternal microbial respiratory environment is associated with modification of immune responses at birth with a potential clinical impact during infancy.Lactobacillus exposure through maternal supplementation led to decreased Th2 cytokines and lung inflammation following RSV infection in their neonates . Fetal immune cells show signs of activation as assessed by TNF-\u03b1 and IFN-\u03b3 production. Immune activation is probably non-specific as no sign of SARS-CoV-2 sensitization, has been observed , possibly related to alveolar macrophages dysfunction . StudiesWe have reviewed the different mechanisms associated with acute maternal respiratory infections that could possibly impact infant's immune responses.Previous research in the field of allergy and chronic maternal infections have highlighted the impact of maternal exposure to specific microbial respiratory environment and immune modulation related to chronic infections on infant's immune responses. Susceptibility toward infection and response to vaccines in infancy are modulated after exposure to chronic maternal infection, without vertical transmission while susceptibility toward immune-mediated diseases  is impacted by the respiratory maternal environment , 8, 19.in utero sensitization seems infrequent after exposure to maternal respiratory infections such as influenza and COVID-19.In this mini-review, we show that part of these mechanisms are also observed during maternal respiratory infections, namely induction of innate immune responses and placental inflammation. On the other hand, Maternal microbiota editing may also have an impact on infants \u2018immune responses. During pregnancy, disturbance in the mother microbiota either as a result of infection or stress linked to sexual hormones might influence infant health through several ways. Following lung-gut microbiota crosstalk, additional effects may be associated with upper respiratory infections during pregnancy. Alterations in the lung microbiota profile have been associated with several respiratory diseases such as pneumonia or viral infection . DysbiosMaternal respiratory infections such as influenza and COVID-19 are associated, beside upper and respiratory tract inflammatory responses, with systemic and placental inflammatory responses. Studies performed during the COVID-19 pandemic indicate that neonates exposed to respiratory infections have distinct innate but also adaptive responses, independently of virus-specific immune activation, as sensitization appears infrequent \u201333. ResuModulation of placental TLR responses is associated with differential risk of atopic diseases during infancy. The impact of maternal influenza or COVID-19-induced placental inflammation on the risk of atopic diseases during infancy is undetermined.Finally, responses to vaccines at birth or during infancy, might also be impacted following disturbances of both adaptive and innate immune responses, as previously shown following chronic maternal infections with protozoans or helminths , 7. NotaMost of the literature reviewed here was related to influenza and COVID-19. Other respiratory infections such as RSV and human metapneumovirus (HMPV) are highly prevalent worldwide and also reported during pregnancy as causes of acute respiratory illnesses \u201356. MoreMaternal vaccination is recommended during pregnancy for both influenza and COVID-19; whether maternal vaccination is associated with dampening of inflammatory immune response following respiratory infection remain to be demonstrated."}
+{"text": "The task switching paradigm is widely used to examine cognitive switching, a critical subcomponent of cognitive control. Studies on aging suggest that switching is particularly vulnerable to age-related changes in cognition. However, the effects of manipulating the stimulus dimension on task switching performance is relatively understudied. In this study, 13 younger adults  and 13 older adults  completed a novel cued task-switching paradigm requiring speeded same-different judgments based on a perceptual (color) or conceptual  dimension of the stimuli. Task switching performance was measured using switch cost, which is the difference in accuracy between switch and repeat trials. Overall both YA and OA exhibited switch costs, indicating increased cognitive demand when switching between judgments compared to repetition of the same judgement. In regard to group differences, YA and OA performed similarly when performance was collapsed across the stimulus dimensions; however, when examined separately, OA exhibited worse performance than YA when making conceptual judgements. These results highlight the importance of examining carefully manipulated stimulus-related factors in task switching paradigms to advance our understanding of cognitive control and aging."}
+{"text": "Health-related behavior correlates in critical ways with the current epidemic of chronic diseases. Modifiable behaviors increase the risk of chronic disease. Despite there are well-identified behaviors, efforts at behavior change are clinically-challenging and frequently ineffective.We aim to establish how the current evidence and latest neuroscientific knowledge about behavioral change allow the most reliable assessment of patients with refractory health-related behaviors that negatively impact health outcomes.We performed a literature review using Pubmed databases and UpToDate. The search included \u201cbehavioral change\u201d and \u201chealth-related behavioral change\u201d[MeSH Terms].Habitual behavior consists of behavioral patterns operating below conscious awareness and acquired through context-dependent repetition. Behavioral change is a complex multi-level field of intervention. The Health Belief Model allows a careful description of the patient\u2019s perceived vulnerability, perceived disease severity, self-efficacy, and change motivation. The identification of social variables is critical since they correlated with poor health outcomes, particularly in chronic diseases. Temperament and character traits can have a strong influence on the difficulty of changing habitual behavior. Psychopathology, if present, must be addressed because it can be a notable factor of behavior instability and correlates negatively to health outcomes. Assertive and efficient communication skills in the clinical context are imperative. Motivational interviewing skills can allow effective behavioral change.Interventions addressing behavior change require careful, thoughtful work that leads to a deep understanding of the nature of what motivates people. Intervention based strategies focused on behavioral change must undergo further investigation in the future.No significant relationships."}
+{"text": "Lo non-classical monocytes promotes resolution of perinatal liver injury in a murine model of perinatal hepatic inflammation. Our research also identifies a potential co-regulatory role between neutrophils and non-classical monocytes. Further work is needed to understand how neutrophils regulate other myeloid populations during perinatal liver inflammation. Elucidating the mechanisms that govern perinatal liver injury and repair may lead to the development of immune-directed therapies that can be used to mitigate the devastating effects of diseases like BA.Perinatal liver inflammation can have life-threatening consequences, particularly in infants and young children. An example of a hepatic inflammatory disease during infancy is biliary atresia (BA), an obliterative cholangiopathy that rapidly progresses to hepatic fibrosis and liver failure. The aggressive nature of BA in neonates compared to the pathogenesis of inflammatory liver diseases in adults, suggests that the mechanisms responsible for restoring tissue homeostasis following inflammation are impaired in affected infants. This article reviews our recent findings demonstrating that the relative abundance of Ly6c The maturation of the immune system is a complex process that undergoes major transitions during fetal and neonatal development . ThroughLo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation,\u201d we demonstrate the importance of monocyte subsets in mitigating inflammatory insults to the perinatal liver. Using a rhesus rotavirus (RRV) model of perinatal liver injury, we investigated changes in composition of the hepatic myeloid immune compartment in late-gestation fetuses and in neonatal pups [Lo non-classical monocytes observed at this time. Since Ly6cLo non-classical monocytes exert anti-inflammatory and pro-reparative functions [In our recent study, \u201cLy6ctal pups . Our iniunctions \u20137, we hyLo non-classical monocytes. Using anti-Ly6g targeted neutrophil depletion [Hi classical monocyte depletion [Lo non-classical monocytes within RRV-injected neonatal livers. Importantly, antibody-mediated depletion of neutrophils and Ly6cHi classical monocytes increased both the percentage and the absolute number of Ly6cLo non-classical monocytes, indicating both a proportional and numerical expansion of these cells. Furthermore, the rise in Ly6cLo monocytes was associated with disease resolution in the neonate, supporting the idea that Ly6cLo non-classical monocytes play a role in resistance to perinatal liver injury and resolution of disease. To confirm Ly6cLo non-classical monocytes are responsible for disease resolution and resistance [Lo non-classical monocyte function in the setting of neutrophil and classical monocyte depletion [Lo non-classical monocytes mitigate perinatal liver inflammation [To test this hypothesis, we manipulated the myeloid compartment within the neonatal liver to resemble the fetal environment, thereby establishing an abundance of Ly6cepletion , and antepletion , we expasistance , we usedepletion \u201312. Blocammation .Lo non-classical monocytes [Lo non-classical monocytes reveals a co-regulatory relationship between these two cell populations that are important for tissue repair and healing [Recent evidence suggests that neutrophils play a vital role in regulating and orchestrating inflammation and tissue repair through their interaction with the innate and adaptive immune systems \u201316. Seveonocytes , suggest healing .An intriguing mechanism by which neutrophils may influence other myeloid populations during inflammation may involve the regulation of myeloid precursors and hematopoietic progenitors . We haveThe liver is known to serve as the primary hematopoietic organ throughout fetal life as it harbors the hematopoietic stem cell (HSC) niche . Soon afHi myeloid cells, and Ly6cLo and Ly6cHi monocytes in the setting of tissue injury and systemic disease [In addition to the liver, the spleen can also contribute to the overall hematopoietic activity during neonatal development and inflammation via EMH ,36. Howe disease ,38. ThesUnderstanding the immune response to liver injury during perinatal development is particularly important as the dynamic transitions in hematopoiesis during this time may establish a unique environment that is susceptible to injury and inflammation. Since the liver and spleen are believed to contribute to hematopoiesis in the setting of perinatal liver inflammation, it is important to understand the kinetics of neonatal emergency hematopoiesis to highlight the possible mechanisms by which myeloid populations may contribute to liver injury and repair. Insights gained into perinatal liver inflammation mechanisms will undoubtedly lead to tailored therapies for infants and children who suffer from the devastating consequences of perinatal liver injury."}
+{"text": "Immune checkpoints are small molecules present on the cell surface of T-lymphocytes. They maintain self-tolerance and regulate the amplitude and duration of T-cell responses. Antagonism of immune checkpoints with monoclonal antibodies (immune checkpoint inhibitors) is a rapidly evolving field of anti-cancer immunotherapy and has become standard of care in management of many cancer subtypes. Immune checkpoint inhibition is an effective cancer treatment but can precipitate immune related adverse events (irAEs). Thyroid dysfunction is the most common endocrine irAE and can occur in up to 40% of treated patients. Both thyrotoxicosis and hypothyroidism occur. The clinical presentation and demographic associations of thyrotoxicosis compared to hypothyroidism suggest unique entities with different etiologies. Thyroid irAEs, particularly overt thyrotoxicosis, are associated with increased immune toxicity in other organ systems, but also with longer progression-free and overall survival. Polygenic risk scores using susceptibility loci associated with autoimmune thyroiditis predict development of checkpoint inhibitor associated irAEs, suggesting potentially shared mechanisms underpinning their development. Our review will provide an up-to-date summary of knowledge in the field of thyroid irAEs. Major focus will be directed toward pathogenesis (including genetic factors shared with autoimmune thyroid disease), demographic associations, clinical presentation and course, treatment, and the relationship with cancer outcomes. Immune checkpoint inhibitors (ICIs) are a rapidly expanding class of medications. At present, over 2000 clinical trials have been completed or are in progress to evaluate more than 30 different ICIs . The maiImmune checkpoints are small molecules present on the cell surface of T-lymphocytes . NormallThe etiology of irAEs is yet to be fully elucidated. Potential mechanisms include activation of polyclonal T-cell populations, loss of regulatory T-cell function, and expansion/activation of self-reactive, antigen-specific T-cells . IrrespeThyroid irAEs are the most common endocrine toxicity related to ICI-treatment . From clThyroid irAEs are typically identified incidentally during routine monitoring of thyroid function as part of ICI-treatment protocols . Most thOnset of thyrotoxicosis usually occurs within 3 months of first ICI-exposure , 7. OverIsolated hypothyroidism without a preceding thyrotoxic phase can occur. Most cases of isolated hypothyroidism are biochemically subclinical and may be related to non-ICI factors such as non-thyroidal illness syndrome. Subclinical hypothyroidism without a preceding thyrotoxic phase typically normalizes spontaneously without need for thyroid hormone replacement , 15. OveIdentification of reliable thyroid irAE risk factors has been elusive. To date, no reliable risk factors of thyroid irAEs have been identified, although clinical and biochemical associations have been documented in retrospective cohort studies . Female The etiology and biological drivers of irAEs remain elusive. It is possible that patients who experience irAEs may share a premorbid immunological state prior to ICI-initiation. A recent study using mass cytometry time of flight analysis identified higher levels of activated CD4+ memory T-cells and increased diversity in the T-cell receptor as pretreatment predictors of severe irAEs irrespective of the organ involved . These svia multiple mechanisms as evidenced by phenotypic differences in presentation, antithyroid antibody positivity rates, and differential association with cancer survival outcomes  thyrotoxicosis to biphasic thyroiditis to isolated overt and severe hypothyroidism. This indeed may be the case, although more likely thyroid irAEs arise outcomes .Genetic factors associated with lifetime risk of autoimmune thyroid disease have been implicated in the risk of developing thyroid irAEs during ICI-treatment , 22. Keyvia and therefore thyroid dysfunction is more rapidly progressive following ICI-treatment than in other autoimmune thyroid conditions  should have TSH-receptor antibody level (TRAB) measured to exclude Graves\u2019 disease . In sevePatients with established hypothyroidism may experience transient effects on thyroid function following ICI-treatment . Compensde novo related to ICI-treatment, is unmasked by ICI-treatment, or is a coincidental occurrence remains unknown. Similarly, thyroid eye disease (TED) has been reported (Graves\u2019 disease (GD) has been reported following ICI-treatment . Whetherreported . ReactivObservational studies repeatedly document an association between irAEs and improvement in cancer outcomes , 30. OwiInterestingly, abnormal TSH level (elevated or low) prior to initiation of ICI-treatment has been associated with inferior cancer outcomes irrespective of thyroid function changes post-ICI initiation in one study . HoweverFurther research is required to better inform our understanding of thyroid irAEs and their relationship to thyroid autoimmune conditions occurring outside the cancer immunotherapy setting. Enhanced characterization of the immune phenotype and T-cell subsets driving thyroid irAEs may allow for identification of patients at risk of thyroid (and other) irAEs and inform future research to uncouple the efficacy of ICIs from the risk of developing treatment related irAEs. Understanding the effects of immune checkpoint inhibition on the thyroid gland could also inform use of these agents for treatment of primary thyroid malignancies and prevention of autoimmune thyroid disease.Thyroid irAEs are a frequent complication of anti-PD-1 based ICI-treatment. Recent work has begun to unravel the molecular mechanisms underpinning development and their relationship to other autoimmune thyroid conditions. Regular monitoring of thyroid function during ICI-treatment is required, as although most cases of thyroid irAEs are asymptomatic and manageable, severe presentations with thyroid storm or myxedema can occur. Development of thyroid irAEs is associated with improved PFS and OS, especially overt thyrotoxicosis which may be a surrogate marker of patients experiencing a more robust immune response to ICI-treatment. When hypothyroidism occurs, it is usually permanent and treatment with thyroid hormone replacement will be required. Familiarity with thyroid irAEs among health professionals is important to facilitate efficient diagnosis and appropriate treatment of this increasingly common thyroid disease.All authors listed have made a substantial, direct, and intellectual contribution to the work. All authors approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Systemic amyloidosis is a diseased condition where misfolded proteins deposit in various organs in the form of amyloids, and transthyretin deposition, termed ATTR amyloidosis, can be either an age-related amyloid formation from misfolded wild-type TTR (ATTRwt) or by hereditary TTR malfunction due to mutation in the TTR gene (ATTRv). Although ATTRwt amyloidosis can cause various diseases, such as cardiac failure, conduction disturbances, arrhythmias and carpal tunnel syndrome, it is still under-recognised considering its clinical significance. Here the authors report a case of ATTRwt amyloidosis leading to carotid stenosis requiring surgical intervention. To the best of our knowledge, the current report is the first that described histopathological evidence of amyloid deposition in the carotid artery due to ATTRwt amyloidosis. TTR gene (ATTRv) [Systemic amyloidosis refers to a diseased condition where misfolded proteins deposit in various organs in the form of amyloids . Various (ATTRv) . Althoug (ATTRv) . Here thA 77-year-old Japanese male with a past medical history of acute cardiac infarction was diagnosed with a right carotid artery stenosis which progressed in three years . A digitThe hematoxylin and eosin-stained surgical specimen revealed carotid intima\u2019s eccentric fibrosis, compatible with arteriosclerotic change . Masson\u2019Amyloid cardiomyopathy refers to the myocardial deposition of amyloid fibers causing cardiac dysfunction, and it comprises AL  amyloidosis and ATTR amyloidosis . AlthougOn the other hand, ATTR amyloidosis was considered a much infrequent rare condition compared with AL amyloidosis. However, extensive research has been pursued on ATTR amyloidosis due to its clinical significance in heart failure and it has recently been reported that amyloid deposits derived from plasma transthyretin are present in the heart of up to 25% of elderly individuals . Tafamid"}
+{"text": "Bi-directional associations between depression and cognitive functioning are magnified among aging individuals, challenging behavioral health providers who treat older adults experiencing clinical and subsyndromal depression. This symposium contributes to the science and practice of assessing and treating later-life depression while also attending to issues in professional training. The first paper presents pre-treatment data from the multi-site Optimum Study of older adults experiencing treatment-resistant depression (n = 529). The relevance of positive psychological constructs is supported with analyses showing important relationships among cognitive functioning, social participation, and psychological well-being. The second paper describes the development of an updated measure to assess behavioral health providers\u2019 knowledge of later life depression, including brain health concerns. Psychometric data for the measure were generated from a random pool of licensed social workers (N=900) who were mailed the survey packet. The third presentation features an experimental study demonstrating that foundational information about aging, including debunking misconceptions about cognitive aging, influenced continuing education preferences of generalist Licensed Professional Counselors (LPCs). Among the randomly generated pool of LPCs (N = 120), participants who received aging-specific information were more likely to later choose an aging-specific continuing education option. The fourth paper highlights recommendations for mental health practitioners working in primary care and general medical settings with older adults who have co-existing depressive symptoms and cognitive concerns. The fifth and final presentation describes cognitive behavioral clinical tools to address brain health concerns in the context of later-life depression, using the new Brain Health module of a published client workbook."}
+{"text": "While a growing body of evidence points to potentially modifiable individual risk factors for Alzheimer\u2019s Disease and Related Dementias (ADRD), the contexts in which people develop and navigate cognitive decline are largely overlooked. Geographic variation in ADRD rates suggest that environmental risk and protective factors may be important in cognitive aging and dementia caregiving. Community hazards are often heavily concentrated in underserved and underrepresented neighborhoods. This symposium aims to identify specific built, social, and natural environmental features associated with cognitive aging outcomes. The papers provide much-needed evidence on the role of neighborhoods and community networks for cognitive health and well-being among diverse older adults. First, Godina finds significant associations between neighborhood greenspace and microstructural indicators of brain health. Second, Westrick investigates the role of neighborhood disadvantage on long-term memory aging of older adults with and without a cancer diagnosis in later-life. Third, Finlay presents a new concept of Cognability to demonstrate which constellation of positive and negative neighborhood features may contribute most to healthy cognitive aging. Fourth, Nkimbeng identifies community networks and resources needed to inform dementia education and support care among African immigrants. Fifth, expert discussant Besser will share how these findings may inform upstream health promotion and reduce ADRD risk. She will discuss critical future research directions and methods to investigate environments of cognition. The symposium advances research assessing contexts of aging, and may inform public health and policy efforts to ameliorate community barriers and create more equitable opportunities to promote healthy aging in place."}
+{"text": "Fall risk assessment traditionally focuses on objective physical performance. Balance confidence, a subjective measure of physical function, may provide important information to better predict fall risk and guide assessment and intervention strategies. This study examines the associations of balance confidence congruency with physical performance measures and fall occurrence. One-hundred-fifty-five community-dwelling adults aged 60 and over completed a comprehensive fall risk assessment including physical performance tests , activities-specific balance confidence (ABC) scale, and self-reported falls in the past year. Four groups were created based on congruency between balance confidence (low vs. high) and each physical performance measure or overall fall risk category . Poison regression analyses, adjusted for age and gender, tested the association between group membership and number of falls in the past year. Participants with high balance confidence and at fall risk based on 4-stage balance performance , or high balance confidence and at fall risk following the STEADI screening algorithm  were at increased risk of more falls compared to participants in the group with high balance confidence and not at fall risk. These results suggest that older adults who overestimate their balance relative to their physical performance may be at increased fall risk, and that participant subjective reporting of physical performance should be paired with objective physical performance measures to better identify older adults at fall risk."}
+{"text": "Maintaining a sense of purpose promotes mental and physical well-being in older adults . Drawing on one\u2019s sense of purpose is thus important for late life resilience. How older adults\u2019 sense of purpose manifests in their everyday lives remains understudied. This study used qualitative methods to amplify older adults\u2019 voices regarding purpose and resilience through analysis of their life stories. This study 1) explored what factors contribute to maintaining purpose in older adulthood, and 2) identified how older adults draw on their purpose during major challenges, particularly in the context of the COVID-19 pandemic. Eighteen older men and women  participated in semi-structured life story interviews that asked about participants\u2019 individual interpretations of purpose in their lives and their experiences navigating the COVID-19 pandemic. Thematic analysis was conducted using established methods . To address the first research question, analyses revealed that older individuals largely maintain their purpose through engaging in acts of service to others, fostering connections with close others, and actively setting and achieving goals. Regarding the second question, older adults described how drawing on purpose through acts of service and connections with others fostered resilience through the COVID-19 pandemic. Overall, older adults\u2019 own expressions of their life stories illuminated how they are guided by purpose. Findings demonstrate the functionality of purpose in late life and how purpose can be practically fostered, specifically within the context of universally challenging experiences such as the COVID-19 pandemic."}
+{"text": "Despite the benefits of palliative and end-of-life (PEOL) care for individuals with life-limiting illness, barriers to accessing this care persist among older adults experiencing homelessness. A number of studies have identified barriers to PEOL care from the perspectives of unhoused individuals and other relevant stakeholders; however, few empirically studied interventions exist to support evidence-based guidelines for PEOL care for this population. This scoping review aimed to identify PEOL interventions for adults experiencing homelessness. The search was conducted in May 2021 and yielded 480 results, from which 50 full-text articles were closely reviewed for inclusion. Sources were included if they reported findings of original, empirical research or quality improvement projects evaluating PEOL services tailored for individuals experiencing homelessness. A total of 13 articles representing 12 studies published between 2006-2021 were included in the review. Over half (n = 7) of the studies described interventions to promote advance care planning documentation, five described interventions embedding PEOL services within homeless shelters, and one described a community outreach program to increase access to PEOL services. Nearly all studies reported positive outcomes on participant perspectives, advanced directive completion rates, or cost analysis. None of the studies included clinical palliative care outcomes. Although most studies reported promising results, service and healthcare providers expressed concerns about continuing challenges and longevity of the programs. The body of literature encompassing PEOL interventions for people experiencing homelessness is limited but growing. Future research may benefit from the inclusion of clinical outcomes and efforts to reduce structural barriers to providing care."}
+{"text": "Healthcare systems have become complex and fragmented, negatively affecting healthcare access and navigation. This is especially the case for socio-economically vulnerable people, who encounter organisational and administrative hindrances trying to access care. These difficulties have worsened during Covid-19. Scholarly literature recognises that - by moulding navigation practices - social capital may mediate between potential and realised access to healthcare. However, little is known about how this mediating work practically unfolds.This case study aimed to understand how social capital might affect healthcare navigation practices. To do so, we investigated how the People\u2019s Health Lab (PHL), a community-based organisation, supported socio-economically vulnerable people in navigating healthcare during the Covid-19 pandemic in Bologna, Italy. Nine months of participant observation were conducted both in person and digitally from July 2020 to March 2021. Twelve semistructured interviews were also conducted with volunteers of the organisation. Fieldnotes and interview transcripts were analysed through Thematic Analysis.PHL support activities addressed barriers to healthcare navigation by vulnerable people, which were found to be services fragmentation, bureaucracy and Covid-19 restrictions. Volunteers of the PHL connected vulnerable individuals to health services in manifold, flexible ways, working without standard operative protocols and relying on informal personal contacts within public services. This was found to be key in enabling navigation of healthcare during the first three waves of the pandemic.Our study provides evidence about how structural, linking social capital - the material and nonmaterial resources mobilised through the relationships between heterogeneous groups  - can mediate access to fragmented healthcare systems by shaping navigation practices.\u2022\u2002Contemporary healthcare systems \u2013 including universal ones \u2013 have become complex and fragmented, posing access and navigation challenges to their users, especially those socio-economically vulnerable.\u2022\u2002Linking social capital can mediate access to fragmented healthcare systems by flexibly mobilising material and nonmaterial resources through informal relationships between heterogeneous groups."}
+{"text": "Cancer immunotherapy has gained significant attention in recent years and has revolutionized the modern approach to cancer therapy. However, cancer immunotherapy is still limited in its full potential due to various tumor immune-avoidance behaviors and delivery barriers, and this is seen in the low objective response rates of most cancers to immunotherapy. A novel approach to immunotherapy utilizes image-guided administration of immunotherapeutic agents directly into a tumor site; this technique offers several advantages, including avoidance of potent toxicity, bypassing the tumor immunosuppressive microenvironment, and higher therapeutic bioavailability relative to systemic drug administration. This review presents the biological rationale for locoregional image-guided immunotherapy administration, summarizes the existing interventional oncology approaches to immunotherapy, and discusses emerging technological advances in biomaterials and drug delivery that could further advance the field of interventional oncology. Immunotherapy with immune checkpoint inhibitors has revolutionized cancer care by stimulating the body\u2019s adaptive immune system to detect, engage, and eliminate cancerous cells . Recent The field of interventional radiology is well-poised to drive innovation in cancer immunotherapy. Image-guided interventions have already been used to establish several novel and minimally invasive approaches to cancer treatment, including radiofrequency/thermal tumor ablation, trans-arterial chemoembolization, and targeted delivery of yttrium-90 (Y-90) emitting microspheres . These tThe basis of cancer immunotherapy lies in transforming the adaptive immune system to be able to recognize and eliminate previously unrecognizable tumor tissue, resulting in sustained antitumor activity from the body\u2019s natural immune mechanisms. Current approaches utilize immunotherapy alone as well as in conjunction with conventional chemotherapeutics/radiation depending on the type and stage of tumor . In a tyA significant barrier to this natural process is the ability of tumor cells to evade detection by the immune system and downregulate the cellular immune response. Various mechanisms are utilized by cancers to prevent immunogenicity, ranging from intrinsic regions of hypoxia and elevated lactate levels to production of immunosuppressive cytokines that directly deactivate T cell responses . AdditioLocoregional delivery of immunotherapy utilizing interventional oncology approaches can avoid many of the obstacles associated with current immunotherapy approaches. Using image guidance from X-ray fluoroscopy, ultrasound, magnetic resonance imaging, or computed tomography, an interventional radiologist can utilize a vascular or percutaneous approach to a tumor site and selectively administer immunotherapy directly within a tumor. One significant benefit to this approach is limited off-target effects/systemic toxicity as the therapeutic remains localized within the tumor site. This also allows for lower therapeutic doses to be delivered while concurrently achieving a higher drug concentration within tumors. Another major advantage is the ability to effectively handle metastatic lesions by individual targeting of tumors and immune system potentiation, potentially sparing the patient from systemic effects . The objAs previously described, the immunosuppressive tumor microenvironment poses a significant challenge to both traditional anticancer and novel immunotherapy approaches, so the key goal of immuno-oncology remains to induce the immune system despite these barriers. Tumor ablation and the resulting immune activation from the necrosis-associated DAMPs has proven to be a viable mechanism for this strategy and several techniques are already widely utilized in clinical practice by interventional radiologists to cause tumor immunogenic cell death. Endovascular therapies such as trans-arterial chemoembolization (TACE) and trans-arterial radioembolization (TARE), percutaneous methods including radiofrequency ablation (RFA) and cryoablation, and stereotactic laser-guided approaches have demonstrated tumor volume reduction with consequent immune activation, and immunotherapy can be utilized similarly alongside these techniques for synergistic therapeutic effects .Oncolytic virotherapy is a novel technique that re-engineers human viruses for cancer destruction and DAMP production. The drug talimogene laherparepvec  is the first and at present only FDA approved intratumoral immunotherapy and is used to treat advanced melanoma. TVEC utilizes an attenuated herpes simplex virus, type 1 (HSV-1) which has been engineered to produce granulocyte-monocyte colony stimulating factor (GM-CSF); the double stranded DNA virus can directly and preferentially lyse tumor cells, producing DAMPs and activating the previously latent adaptive immune system. TVEC has demonstrated a well-tolerated and durable response rate in a 2015 Phase III clinical trial, although 5-year survival remained low with monotherapy . ClinicaAdditionally, several other viruses have been identified to have oncolytic properties, including adenovirus, poliovirus, measles virus, and coxsackievirus; though these therapeutics are still in early clinical trials, they have demonstrated oncolytic ability in preclinical models and could open up new therapeutic avenues against a wide range of malignancies . NotablySystemic administration is the conventional approach for oncolytic virus delivery but therapeutic outcomes against solid tumors continue to be modest . The maivia intratumoral delivery as well.Checkpoint inhibitors have proven to be one of the most transformative advances in modern immunotherapy. The immunosuppressive checkpoints mentioned earlier  can be blocked by therapeutics to allow for a more potent immune response, and several drugs have received FDA approval for use against various solid and hematologic malignancies . Pembrolvia the cyclic GMP\u2013AMP synthase (cGAS) \u2013 stimulator of interferon genes (STING) pathway. Activation of these pathways promotes transcription of pro-inflammatory cytokines and interferons which can allow for more potent antitumor responses   cells can contribute to tumor elimination by phagocytosis and cytotoxic mechanisms. The innate immune system is especially sensitive to external antigens, with dedicated sensing pathways for bacterial toxins  and nucleic acids esponses . Therape2668770) . Similar2668770) . HoweverCAR-T cells, which are T cells engineered for anti-cancer activity, have demonstrated significant activity against various types of hematological malignancies. Multiple formulations of systemic CAR-T cell therapeutics have received FDA approval for use against B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma . HoweverNanoparticle-mediated drug delivery is rapidly gaining popularity in clinical applications and may offer solutions to delivery limitations imposed by the immunosuppressive tumor microenvironment. Nanoparticles are defined as materials with a size range between 1 and 100 nm and can be synthesized from a variety of materials, including lipids, polysaccharides, and inorganic compounds. These structures can encapsulate therapeutics and be engineered to navigate biological barriers and deliver their payload to a disease site in a controlled, targeted fashion . Though via T cell targeting nanoparticles achieved stronger T cell activation than systemic administration of the therapeutic in mouse models. Lipid nanoparticles containing a TGF-\u03b2 inhibitor were synthesized with anti-CD8 antibodies conjugated to the particle surfaces and injected into mice expressing B16 melanoma, achieving high concentrations in tumor sites. The group further demonstrated the ability to specifically target tumor reactive lymphocytes by conjugating anti-PD-1 antibodies to the particle surfaces  against the fibrinogen-like protein (FGL1) gene; the nanoconstructs aimed to deliver metformin to block PD-L1 to prevent T cell suppression while simultaneously using siRNA against FGL1 to block another anti-inflammatory pathway. Of note, a pH trigger was utilized in these nanoparticles as the reaction of metformin with CO2 results in the low-pH-activated endosomal escape of the nanoparticle payload. l groups .in vitro and in vivo cellular penetration in preclinical studies, and clinical trials may soon be possible with these novel therapeutics (These studies highlight the ability to engineer nanosystems for targeted delivery and demonstrate a clear potential for applications of nanoparticle technology in cancer immunotherapy. Basic science and clinical research in nanoparticles is highly active with many promising developments on the horizon. Magnetic biomaterials such as iron oxide nanoparticles are being explored for magnetic hyperthermia, a technique which oscillates nanoparticles in an alternating magnetic field to cause heat-induced death and DAMP generation of tumor tissue. Magnetic nanoparticles can also be engineered for highly precise targeting to tumor sites along with magnetic-mediated drug delivery and cellular uptake . CRISPR-apeutics . Technolapeutics . Image-gThe field of interventional oncology as a whole is burgeoning with technological and clinical advancements, and many of the discipline\u2019s most impactful discoveries are just starting to show their promise. Intratumoral administration of cancer immunotherapy in particular has significant potential to alter the landscape of cancer treatment in the coming years, both independently and in conjunction with conventional treatment strategies. Many treatment-resistant or difficult-to-reach malignancies could become accessible with further advances in locoregional therapeutic administration. Moreover, the exciting developments in biomaterials and biotechnology will further enhance the precision and efficacy of locoregional immunotherapy. It is important to keep in mind that many of these technologies are still being validated in preclinical models or early-stage clinical trials and are still several years away from seeing widespread therapeutic applications in humans. However, the promising results demonstrated by the various studies covered in this review and beyond signal high and rapidly growing interest and expectations for a revolutionary approach to cancer treatment from scientists, clinicians, and patients.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Worse physical and mental health are risk factors for cognitive decline in older adults. In Puerto Rico, existing healthcare services are lacking, further exacerbating this risk. This study examines how mental and physical health factors affect subjective cognitive decline for older adults in Puerto Rico. Data comes from the 2020 Behavioral Risk Factor Surveillance System, restricted to adults age 60+ residing in Puerto Rico (n = 1603). Subjective cognitive decline was measured with two dichotomous variables (no/yes): increases in confusion or memory loss and difficulty making decisions in the past year. Multivariate logistic regression models were run for each outcome variables. Predictor variables were number of days in past month with poor mental health, diagnosis of depression or mood disorder, self-rated health, and access to healthcare services, along with covariates. Higher number of days with poor mental health , diagnosis of depression or mood disorder , and cost barriers to accessing healthcare  were associated with increased odds of increased confusion or memory loss. Significant predictors of increased odds of decision-making difficulty included higher number of days of poor mental health , diagnosis of depression or mood disorder , and worse self-rated health . To promote better cognitive health, intervention efforts should focus on those with poor mental and physical health, including identify strategies to improve access to healthcare services."}
+{"text": "Normal respiratory functioning is essential for survival. Injuries or obstructions to airways, lungs or respiratory neural networks can have catastrophic consequences. Every breath places the lungs at the mercy of environmental air quality, which can contain pollutants, noxious gasses, and pathogens, driving or exacerbating acute and chronic respiratory conditions. Airway inflammatory diseases can compromise airflow through excessive mucus and airway wall edema, remodeling, and/or bronchoconstriction. Glottic proximity to the esophagus makes aspiration  a constant threat. Indeed, aspiration frequently causes pneumonia and can lead to sudden, lethal airway obstructions. Neurological trauma or pathology may interfere with respiratory processes, with dire consequences for breathing and airway clearance. While impaired sensory function is problematic, so too is hypersensitivity, contributing to conditions such as chronic cough.It is therefore unsurprising that the respiratory system is equipped with many precise defensive mechanisms that collectively safeguard against risks, but our understanding of these processes is incomplete. This research topic brings together established experts and emerging future leaders to describe the state-of-the-art understanding of pulmonary defenses in health and disease, paving a direction for future research.Lin et al.). Interestingly, select RARs responded immediately, an effect mediated by 5-HT3 receptors, known to be expressed by some vagal sensory neurons .The respiratory system contains diverse sensory nerve fibers that monitor the physical and chemical environment of the airways and lungs. Subsets of mechanosensitive fibers, the slowly (SARs) and rapidly (RARs) adapting receptors, respond to changes in airway smooth muscle tone and distension and lung volume, providing essential volume-related feedback to brainstem neural networks governing breathing and autonomic neural control. Lin et al. performed single unit RAR and SAR recordings in anesthetized rats, observing that serotonin administration profoundly altered RAR firing, although the response was often delayed and hypothesized to occur secondary to serotonin-induced changes in pulmonary mechanics . Mazzone et al. presented new insights into the potential role of neuroimmune mechanisms in sensory nerve plasticity: a mouse model of severe respiratory viral infection showed vagal sensory neuron mobilization of the alarmin HMGB1 (High Mobility Group Box protein 1) and provided evidence that HMGB1 can act on vagal sensory neurons via its cognate receptor RAGE (receptor for advanced glycation end-products) to induce neuronal firing and increased sprouting of neurites . This provides a potential mechanism for altered sensory neuron sensitivity and structure in pulmonary diseases and may suggest a previously unrecognized target for anti-HMGB1 therapy, currently being developed for use in patients.Airway sensory nerve plasticity may induce further respiratory pathology and morbidity. The state-of-the-art review by Drake and colleagues summarizes evidence that such plasticity occurs in asthma and chronic cough. Biopsy samples from both patient groups show increased nerve fiber density and changes in neurochemical phenotype, while advances in RNA sequencing, 3D microscopy and physiological assays are beginning to shed light on possible mechanisms involved and eventual functional implications . Sood et al. investigated deep breath-induced bronchodilation in patients with chronic cough versus patients with classic asthma, cough-variant asthma and healthy controls. Their surprising finding was that the deep inspiration index was significantly lower in cough with normal airway sensitivity versus individuals with either asthma or healthy controls, suggesting that the bronchodilating effect of deep inspiration is impaired in chronic cough without asthma . Bai et al. provided an overview of the perplexing problem of why women are more likely to develop chronic cough than men and disproportionately prone to poor quality of life resultant from cough. Evidence for mechanistic and sociological differences is presented, providing a strong interrogation of sex- and gender-differences in a common respiratory condition and highlighting the need for more research into this important clinical observation . Sykes and Morice reviewed the state of play in chronic cough and cough hypersensitivity clinical research, including the current pipeline of antitussives. They contrasted this with the topic of cough hyposensitivity, highlighting the \u2018two faces\u2019 of cough presented to clinicians and the challenge of developing effective antitussives that suppress unwanted coughing while preserving defensive cough needed to protect against aspiration (Sykes and Morice).Coughing is a critical defensive mechanism for keeping the airways clear from potentially dangerous inhaled, aspirated or locally produced substances. However, altered cough sensitivity leading to excessive coughing is a common, often-debilitating problem. Conversely, insufficient coughing predisposes to early death from aspiration pneumonia. Olsen et al. investigated the cough-suppressing actions of two centrally antitussive drugs (GABA agonist baclofen and opiate codeine) in cats. They showed that neither appears to suppress spinal circuits involved in chest wall and abdominal motor drive, but likely exert their antitussive effects via the brainstem (Defense of the pulmonary system is inarguably essential; however, more research is required to fully elucidate the mechanisms and consequences of pulmonary defensive processes. In submissions originating from four continents and reflecting the efforts of established experts and emerging researchers, this research topic describes the cutting-edge understanding of pulmonary defenses in health and disease. Readers are provided with insight into processes including cough hyper and hypo -sensitivity, sensory neural mechanisms, and sex differences in pulmonary defense, providing strong foundations for future inquiry."}
+{"text": "There are two common hypotheses to explain such high comorbidity between nicotine dependence and schizophrenia (SZ): self-medication for decreasing psychiatric symptoms or common environmental risk factors can predispose to both nicotine dependence and other risky behaviors in SZLittle is known about the influence of cigarette smoking comorbidities such substance use disorder (SUD), criminal history, or risky decision among patients with SZ.The Iowa Gambling test (IGT) was administered to thirty-nine patients with SZ of whom 69% reporting cigarette smoking. Both groups were evaluated using a socio-demographic questionnaire and clinical assessment using PANSS and self-report questionnaire the Barratt Impulsiveness Scale (BIS-11). To evaluate decision making was evaluated with the Iowa Gambling Task (IGT).The full SZ sample performed worse on the IGT then normal population. Smokers with SZ performed significantly worse than nonsmokers on the IGT primarily because they preferred \u201cdisadvantageous\u201d decks to a greater degree. The PANSS and impulsivity tendencies (BIS-11) did not predict overall performance on the IGT. Smokers with SZ had impaired affective decision-making. Behavior suggested preferential attention to the frequency amount of gain and inattention to amount of loss suggesting impairments in risk/reward decision-makingThis study is the first to compare IGT in smokers and nonsmokers with SZ with adjustment of SUD, criminal history, and existing tattoo to further examine IGT performance. These results support the hypothesis that comorbidities between nicotine dependence and SZ can be linked to other common factor that is associated with other externalizing behaviors in SZ.No significant relationships."}
+{"text": "Certain percentage of the first-episode schizophrenia patients presents with negative symptoms, which persists over the year and influence treatment outcomes . Treatment of negative symptoms has been a significant continuous clinical challenge. Majority of recently published guidelines recommend antipsychotic monotherapy as the standard of care, recommending antipsychotic combination therapy only after a failed trial with clozapine . However, real-life forces clinicians to look for possible combinations of medications early on, especially to tackle negative symptoms. The systematic review of global prescribing practices covering four decades found the pooled median rate of antipsychotic combination therapy approximately 20% . One of the largest retrospective studies every conducted  assessed rehospitalisation rates and the long-term use of antipsychotic polypharmacy in schizophrenia. Antipsychotic combination treatment was associated with an approximate 10% lower relative risk of psychiatric rehospitalisation compared with antipsychotic monotherapy . Real-world effectiveness study of antipsychotic monotherapy vs. polypharmacy in schizophrenia from Eastern Europe is also supporting this approach . At the same time antipsychotic combination therapy can increase the total antipsychotic dose burden, frequency of adverse effects, potential drug-drug interactions and incur additional costs. In our recent naturalistic study in schizophrenia outpatients (n=120) with insufficient effectiveness of previous antipsychotics therapy on negative symptoms, we were able successfully switch therapy form several different antipsychotic combinations to monotherapy and gain clinical benefits .No significant relationships."}
+{"text": "Sleep complaints and disorders are two of the most common disturbances to health and well-being in later life. This study examined how evening electronic media use and daytime sedentary behaviors affect subsequent sleep hours and perceived sleep quality, and whether consistent sleep hours  moderate these associations. Data were drawn from 241 older adults (Mage = 74.02) from the Daily Experiences and Well-being Study who completed ecological momentary assessments and wore an accelerometer for four days on average. A series of conditional fixed-effects models indicated that older adults reported more sleep disturbances on nights following the evening computer use. Sedentary behaviors and evening television viewing were not associated with sleep quantity and quality. Older adults with more consistent hours of bedtime reported better sleep quality regardless of their evening electronic media use and daytime sedentary behaviors, thereby highlighting the importance of sleep regularity in later life."}
+{"text": "Background: Diversion of resources from infection prevention activities, personal protective equipment supply shortages, conservation (extended use and reuse) or overuse with multiple gown and glove layers, and antimicrobial prescribing changes during the COVID-19 pandemic might increase healthcare-associated infection (HAI) incidence and antimicrobial resistance. We compared the incidences of Clostridioides difficile infection (CDI), methicillin-resistant Staphyloccocus aureus bloodstream infection (MRSA BSI), and vancomycin-resistant enterococci bloodstream infection (VRE BSI) reported by California hospitals during the COVID-19 pandemic with incidence data collected prior to the pandemic. Methods: Using data reported by hospitals to the California Department of Health via the NHSN, we compared incidences in the second and third quarters of 2020 (pandemic) to the second and third quarters of 2019 (before the pandemic). For CDI and MRSA BSI, we compared the standardized infection ratios , and we calculated the P values. No adjustment model is available for VRE BSI; thus, we measured incidence via crude incidence rates . We calculated incidence rate ratio (IRR) with 95% CI for VRE BSI. To examine the possible effect of missing data during the pandemic, we performed a sensitivity analysis by excluding all facilities that had incomplete data reporting at any time during either analysis period. Results: Incidence measures and numbers of facilities contributing data in prepandemic and pandemic periods are shown in Table P = .05 for either MRSA BSI or CDI between the prepandemic and pandemic periods . Crude VRE BSI incidence increased during the pandemic compared to the prepandemic period . Excluding facilities with incomplete data had minimal effect. Conclusions: We found insufficient evidence that MRSA BSI or CDI incidence changed in California hospitals during the pandemic relative to the prepandemic period; however, there was a significant increase in the crude incidence of VRE BSI. Next, we will include interrupted time series analyses to assess departure from long-term trends, including a risk-adjusted model for VRE BSI. Additionally, we will evaluate for changes in central-line\u2013associated bloodstream infection incidence and antimicrobial resistance among HAI pathogens.Funding: NoDisclosures: None"}
+{"text": "Using 2018 Medicare data, we examined the relationship between dual eligibility and injury-related emergency department use among a cohort of assisted living residents . We fit multilevel models with random intercepts at the assisted living community and license type levels. The baseline rate of injury-related emergency department emergency department use was 0.17. After controlling for resident characteristics , license type characteristics , and assisted living community characteristics , being dually eligible for Medicare and Medicaid was associated with a 12% increase in the probability of having an injury-related emergency department visit . Assisted living communities that serve duals may have fewer resources and staff to provide personal care, potentially leading to increased rates of injuries."}
+{"text": "Immunotherapy for allergy has been practiced for over 100 years. Low-dose repeated exposure to specific allergen extracts over several months to years can successfully induce clinical tolerance in patients with allergy to insect venoms, pollen, house dust mite, and domestic animals. Different regimens and routes for immunotherapy include subcutaneous, sublingual, oral, and intralymphatic. Food allergies have been difficult to treat in this way due to high anaphylactic potential and only recently the first immunotherapy for peanut allergy has received regulatory approval. Several clinical trials have indicated high efficacy in desensitisation of peanut-allergic individuals using oral immunotherapy, which allows for safer administration of relatively high allergen concentrations. Still, the risk of adverse events including serious allergic reactions and high anxiety levels for patients remains, demonstrating the need for further optimisation of treatment protocols. Here we discuss the design and outcomes of recent clinical trials with traditional oral immunotherapy, and consider alternative protocols and formulations for safer and more effective oral treatment strategies for peanut allergy. Arachis hypogaea) is an immunoglobulin E (IgE)-mediated hypersensitivity, which tends to develop early in life and is typically lifelong with resolution in only 20% of affected children ..13].4 and IgA and initial increase followed by a decrease in serum food-specific IgE . Th. ThLactoesponses , 40, andThe long-term follow-up study PPOIT2 published in 2017  aimed toAnother Australian interventional study (ACTRN12617000914369)  will assIn addition to whole peanut protein preparations and adjunctive therapeutics, alternative allergen forms for immunotherapy are being researched and trialled to overcome the associated adverse events of exposing the gastrointestinal tract to whole allergenic protein. DNA vaccines and peptide therapeutics are under investigation for other routes of administration and could be considered for OIT. Hypoallergenic preparations also offer an alternative. These interventions potentially could decrease treatment duration, the need for strict medical supervision and may lead to higher patient adherence.A novel immunotherapeutic approach utilises intradermal administration of plasmid DNA encoding peanut allergens and is currently being tested for safety, tolerability, and immune response in a Phase 1 trial (NCT03755713)  in 20 paVaccination with plasmid DNA will need further proof against apprehensions about the safety of this vaccine type, categorised as gene therapy. Issues have been raised due to the hypothetical risk of integration of the vaccine itself into the genome or long-term persistence of the administered plasmid DNA that could lead to triggering the production of anti-DNA antibodies . These aOther vaccination approaches are currently undergoing pre-clinical testing in animal studies. A study performed by Storni et al. used peanut-sensitised mice to demonstrate a protective effect of vaccination with extracts of roasted peanut or the single allergens Ara h 1 or Ara h 2 coupled to immunologically optimised Cucumber Mosaic Virus-derived virus-like particles (CuMVtt) . ModifieThe alteration of allergenic protein structure and function influences immunoreactivity and allergenicity . Amongstin vitro basophil reactivity to PVX108, providing further support for an improved safety profile of PVX108 over whole allergen immunotherapies [An alternative approach to prevent IgE-mediated adverse events is to utilise T-cell reactive peptide fragments of the allergen that are not recognised by antibodies . Australherapies .OIT enables the administration of much higher doses of allergen with greater safety than other routes of administration of AIT. The recently approved peanut OIT product PALFORZIA represents a promising treatment option for peanut-allergic patients to increase the threshold of clinical tolerance for protection from accidental ingestion and possibly achieving sustained unresponsiveness. Clinical data collection of healthcare providers in the REMS program will help ongoing research in assessing the effectiveness of PALFORZIA in the real-world setting and guide future clinical trial design for OIT.This and other new strategies to enhance the safety and efficacy of immunotherapy for peanut allergy are currently under clinical exploration. Promising trends amongst different protocols and methods to improve OIT success with decreased adverse events are to alter OIT protocols regarding timing and dosing: a lower allergen delivery dose and a slow, delayed escalation rate in OIT treatment seem approachable in the near future.Adjunctive therapy with biologics in parallel to OIT protocols may help to mitigate risk and improve tolerability, especially in highly allergic individuals. Many trials using the biologic Omalizumab as adjunctive treatment in OIT have shown a raised threshold tolerance dose of OIT treatment, thereby reducing the risk of severe adverse reactions. Other biologics such as Abatacept are not optimal for extended use, which limits their application in OIT protocols. Dietary supplements such as probiotics have been shown to improve treatment tolerability with decreased adverse effects over longer periods of time, presenting a cost-effective adjunct treatment with OIT.Alternative formulations that circumvent exposure of the gastrointestinal tract to IgE-reactive, whole allergenic proteins, such as peptides, DNA vaccines, and other hypoallergenic preparations, could present a safer, more cost-effective approach for OIT for peanut-allergic individuals.More studies are needed to fully elucidate the best protocol to achieve sustained unresponsiveness. Most current clinical trials include objective laboratory biomarker analysis in patients undergoing OIT protocols . The rap"}
+{"text": "Gos is a declarative Python library designed to create interactive multiscale visualizations of genomics and epigenomics data. It provides a consistent and simple interface to the flexible Gosling visualization grammar. Gos hides technical complexities involved with configuring web-based genome browsers and integrates seamlessly within computational notebooks environments to enable new interactive analysis workflows.https://github.com/gosling-lang/gos), and documentation with examples can be found at https://gosling-lang.github.io/gos.Gos is released under the MIT License and available on the Python Package Index (PyPI). The source code is publicly available on GitHub ( Existing genomic visualization tools are tailored towards specific tasks and as such are limited in terms of expressiveness .clinvar.ipynb notebook contains a custom visualization to view human genetic variants from the ClinVar database (We provide a set of Jupyter notebooks (doi: 10.5281/zenodo.7321052) demonstrating how genomics visualizations may be created, combined and controlled with Gos. The getting-started.ipynb and navigation.ipynb notebooks introduce a basic concepts of the Gosling grammar through the declarative Python API, with sections detailing data-binding, creation of custom Tracks and Views  and programmatic viewer navigation. The data-loading.ipynb notebook displays an identical visualization for a dataset hosted remotely, on the local filesystem, as well as a Pandas DataFrame, demonstrating the versatile data capabilities of our library.The Gos is a Python library for authoring interactive genomics visualizations via the Gosling grammar. Instead of editing deeply nested and repeated JSON data structures, users write simple Python programs which emit valid Gosling JSON specifications. Python scripts may therefore be repurposed to accommodate new data sources, offering a convenient utility to produce custom visualizations as a part of traditional bioinformatics pipelines.Beyond this core functionality, Gos provides a unified framework to iteratively visualize genome-mapped data within interactive computational notebooks. Responsive genomics visualizations are woven between code and prose, and optional utilities host local and in-memory datasets without requiring users to exit the analysis environment or save intermediate results to disk. Gos connects flexible web-based genomics visualization with the larger scientific Python ecosystem, and we anticipate this integration can foster the use of numerical and machine learning libraries to actualize higher-level genomics visualization tools such as recommendation systems ("}
+{"text": "Maintaining a sense of purpose promotes mental and physical well-being in older adults . Drawing on one\u2019s sense of purpose is thus important for late life resilience. How older adults\u2019 sense of purpose manifests in their everyday lives remains understudied. This study used qualitative methods to amplify older adults\u2019 voices regarding purpose and resilience through analysis of their life stories. This study 1) explored what factors contribute to maintaining purpose in older adulthood, and 2) identified how older adults draw on their purpose during major challenges, particularly in the context of the COVID-19 pandemic. Eighteen older men and women  participated in semi-structured life story interviews that asked about participants\u2019 individual interpretations of purpose in their lives and their experiences navigating the COVID-19 pandemic. Thematic analysis was conducted using established methods . To address the first research question, analyses revealed that older individuals largely maintain their purpose through engaging in acts of service to others, fostering connections with close others, and actively setting and achieving goals. Regarding the second question, older adults described how drawing on purpose through acts of service and connections with others fostered resilience through the COVID-19 pandemic. Overall, older adults\u2019 own expressions of their life stories illuminated how they are guided by purpose. Findings demonstrate the functionality of purpose in late life and how purpose can be practically fostered, specifically within the context of universally challenging experiences such as the COVID-19 pandemic."}
+{"text": "Dear Editor,Airway protection and maintaining patency during neurosurgical cases requiring prone positioning, is of paramount importance. Due to complexity of procedure , it becomes difficult to manipulate an airway once the surgery commences: With provision of video laryngoscopes (VDL) it becomes easier to identify airway edema and other related abnormalities."}
+{"text": "The bi-directional relationship between mental and physical illness is well established. Therefore, in order to lower the already high mortality rates associated with psychiatric disorders, physical health issues must be closely monitored in this population . A recent Lancet commission highlights emerging strategies and recommendations for improvement of physical health outcomes in patients with chronic mental disorders. These strategies involve better integration of physical and mental health care, combined with broader implementation of lifestyle interventions to reduce elevated cardiometabolic risk and attenuate medication side-effects [3].To assess psychiatrists\u2019 confidence levels in physical healthcare competencies; to explore whether confidence was related to learning opportunities.Physical healthcare learning objectives were extracted from the Irish College of Psychiatrists\u2019 training curriculum. An electronic questionnaire was sent to 50 psychiatrists in one Irish healthcare region with a catchment area of c. 450,000. Participants had to rate confidence levels for each competency on a five-point Likert scale and the availability of learning opportunities for attaining each competency.66% response rate was achieved. A majority reported confidence in cardiovascular examination, interpreting blood results and evaluating comorbidities. A minority reported confidence in interpreting imaging, electrocardiograms and recognising medical emergencies. This corresponds to a relative paucity of learning opportunities.Clinical implication Programmes for trainee doctors and CME opportunities for consultant psychiatrists would benefit from an emphasis on physical health examination and modules on interpreting investigations and the recognition of medical emergencies."}
+{"text": "Airborne aerosols reduce surface solar radiation through light scattering and absorption , influence regional meteorology, and further affect atmospheric chemical reactions and aerosol concentrations. The inhibition of turbulence and the strengthened atmospheric stability induced by ADEs increases surface primary aerosol concentration, but the pathway of ADE impacts on secondary aerosol is still unclear. In this study, the online coupled meteorological and chemistry model  with integrated process analysis was applied to explore how ADEs affect secondary aerosol formation through changes in atmospheric dynamics and photolysis processes. The meteorological condition and air quality in the Jing-Jin-Ji area  in January and July 2013 were simulated to represent winter and summer conditions, respectively. Our results show that ADEs through the photolysis pathway inhibit sulfate formation during winter in the JJJ region and promote sulfate formation in July. The differences are attributed to the alteration of effective actinic flux affected by single-scattering albedo (SSA). ADEs through the dynamics pathway act as an equally or even more important route compared with the photolysis pathway in affecting secondary aerosol concentration in both summer and winter. ADEs through dynamics traps formed sulfate within the planetary boundary layer (PBL) which increases sulfate concentration in winter. Meanwhile, the impact of ADEs through dynamics is mainly reflected in the increase of gaseous-precursor concentrations within the PBL which enhances secondary aerosol formation in summer. For nitrate, reduced upward transport of precursors restrains the formation at high altitude and eventually lowers the nitrate concentration within the PBL in winter, while such weakened vertical transport of precursors increases nitrate concentration within the PBL in summer, since nitrate is mainly formed near the surface ground. They pe3) concentration. Atmospheric aerosols cause significant attenuation of ultraviolet radiation and affect photolysis rates and species chemical cycles   . In 2013nditions . The airnditions . But und22.5 concentration is shown in The overall modeling methodology for the study is detailed previously in Following our previous analyses , three sTo further explore these impacts, process analysis (PA) technology  was appl3\u22122 in January and July, respectively. Decreased solar radiation weakens surface turbulence and reduces the daily maximum PBL height. The perturbation of ADEs on solar radiation and the PBL is presented in To provide insight into how ADEs affect sulfate concentration, the vertical distribution of sulfate concentration and related process responses to ADEs is presented in 2 concentration and sulfate formation. Compared with winter, ADED changes sulfate by promoting sulfate formation in July , resulting in weakened nitrate formation at around 900 m in winter. Conversely, the transport direction of nitrate is bottom up in July. Therefore, restrained upward transport of NOx increases the formation of nitrate in the near-surface layer.The ADE impacts on nitrate are then investigated. The vertical profile of nitrate affected by ADEs is presented in The vertical distribution of the nitrate IPR response to ADEs is presented in 42.5 and its components. (2) ADEs through the photolysis pathway inhibit sulfate formation during winter in the JJJ region and promote sulfate formation in July. The differences are attributed to the alteration of effective actinic flux affected by aerosol optical depth (AOD), solar zenith angle, and SSA. (3) ADEs through the dynamics pathway act as an equally or even more important route compared with the photolysis pathway in affecting secondary aerosol concentration in both summer and winter. (4) ADEs through dynamics traps formed sulfate within the PBL, which increases sulfate concentration in winter. Meanwhile, the impact of ADEs through dynamics is mainly reflected in the increase of gaseous-precursor concentrations within the PBL, which enhances secondary aerosol formation in summer. (5) Reduced upward transport of precursors restrains the formation of nitrate at high altitude and eventually lowers the nitrate concentration within the PBL in winter, while such weakened vertical transport of precursors increases nitrate concentration within the PBL in summer, since nitrate is mainly formed near the surface ground.In addition to directly deteriorating air quality, aerosol diminishes solar radiation due to light scattering and absorption, thereby influencing regional meteorology and further modulating air quality. The impact of ADEs on secondary aerosol is more complicated than primary aerosol. This study quantified the impacts of ADEs on secondary inorganic aerosol using the two-way online coupled meteorology and atmospheric chemistry model (WRF\u2013CMAQ) with integrated process analysis. The main pathways through which ADEs affect aerosol concentrations were examined. The key conclusions are the following. (1) ADEs reduce solar radiation and decreases PBL height, concentrating aerosol in the near-ground layers. In this analysis, ADEs improved the model performance for simulating PMSupplement1"}
+{"text": "The normal decline in skeletal muscle mass that occurs with aging is exacerbated in patients with chronic obstructive pulmonary disease (COPD) and contributes to poor health outcomes, including a greater risk of death. There has been controversy about the causes of this exacerbated muscle atrophy, with considerable debate about the degree to which it reflects the very sedentary nature of COPD patients vs. being precipitated by various aspects of the COPD pathophysiology and its most frequent proximate cause, long-term smoking. Consistent with the latter view, recent evidence suggests that exacerbated aging muscle loss with COPD is likely initiated by decades of smoking-induced stress on the neuromuscular junction that predisposes patients to premature failure of muscle reinnervation capacity, accompanied by various alterations in mitochondrial function. Superimposed upon this are various aspects of COPD pathophysiology, such as hypercapnia, hypoxia, and inflammation, that can also contribute to muscle atrophy. This review will summarize the available knowledge concerning the mechanisms contributing to exacerbated aging muscle affect in COPD, consider the potential role of comorbidities using the specific example of chronic kidney disease, and identify emerging molecular mechanisms of muscle impairment, including mitochondrial permeability transition as a mechanism of muscle atrophy, and chronic activation of the aryl hydrocarbon receptor in driving COPD muscle pathophysiology. Chronic obstructive pulmonary disease (COPD) patients are often affected by more severe limb skeletal muscle atrophy than is typical of normal aging , with moIn addition to skeletal muscle atrophy, there are many other manifestations of adverse limb muscle impact in COPD  . It is iTo further test for manifestations of mitochondrial dysfunction in COPD limb muscle, in one of our prior studies we used a histochemical diagnostic approach to identify muscle fibers with severe mitochondrial respiratory capacity impairment and observed a markedly elevated abundance of muscle fibers exhibiting depletion of mitochondrial complex IV activity but relatively normal (or elevated) mitochondrial complex II activity in vastus lateralis muscle biopsies of COPD patients . This phIt is noteworthy that muscle fibers with complex IV deficiency typically exhibit a compensatory upregulation of mitochondrial biogenesis and mtDNA copy number in a futile attempt to restore the bioenergetic capacity of the muscle fiber (futile because the high burden of mutated mtDNA templates precludes biogenesis of properly functioning mitochondria). Whereas in age-matched control subjects fibers with complex IV deficiency and normal or elevated complex II activity (Cox-/SDH+) exhibited greater than 2-fold higher levels of mtDNA copy number compared to normal muscle fibers (Cox+/SDH+), this was not seen in COPD patient muscle  and thisFurther to the relevance of specific mitochondrial enzymatic abnormalities in COPD, a recent study using a mouse model of pulmonary emphysema observed a down-regulation of subunit c of complex II (SDH) that was associated with lower muscle respiratory capacity and greater muscle fatigability. In addition, genetic gain of function experiments to rescue complex II in mice with emphysema improved muscle respiratory capacity and reduced fatigability . Amongstvia actin cleavage , and inflammation, amongst others. These consequences are further compromised during acute exacerbations of disease severity, which can occur secondary to bacterial or viral infections . As a re2 supply through modulation of bioenergetic stress . Their results showed that hypoxia further exacerbated both the decline of muscle mass and shift towards type IIx fibers seen with bed rest  exposure in the etiology of COPD muscle impairment, there is growing evidence that long-term cigarette smoking plays a key role in initiating the muscle impairments with COPD (as summarized in in vitro recapitulates the muscle atrophy (The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with a wide variety of endogenous and exogenous ligands that leads to increased transcription of detoxifying pathways, including cytochrome P450 enzymes such as Cyp1A1  Figure , above.  atrophy  and mito atrophy . Finally atrophy  , and the histone H2A variant gamma-H2AX (\u03b3H2AX). These senescence markers were recently evaluated in the context of aging human skeletal muscle using immunolabeling of muscle cross-sections from young (18\u201335\u00a0years) vs. old (>70\u00a0years) subjects. The authors noted that despite using numerous commercially available antibodies for each senescence marker, \u03b3H2AX was the only one detectable in human muscle, and strikingly it did not evidence an increase with aging and instead was elevated exclusively in myonuclei of obese vs. lean subjects . KeepingAnother biomarker of aging that has received some attention in the context of COPD skeletal muscle impairment is the anti-aging hormone \u03b1-klotho (hereafter referred to as klotho). Klotho serves as a co-receptor for fibroblast growth factor 23 to activate a variety of fibroblast growth factor receptors throughout the body , and is Skeletal muscle of COPD patients is characterized by an exacerbated degree of atrophy relative to age-matched healthy subjects. They also exhibit other manifestations of skeletal muscle impairment, including exacerbated fatigue, weakness, a fast fiber shift, mitochondrial dysfunction, and an accumulation of denervated muscle fibers that is associated with a failed reinnervation transcriptional profile. Notably, COPD patient skeletal muscle exhibits evidence of an increased frequency of mitochondrial permeability transition events, where recent evidence identifies mitochondrial permeability transition as a mechanism of muscle atrophy operating through mitochondrial ROS and caspase 3. There are likely multiple contributing factors underlying the skeletal muscle alterations in COPD, including chronic TS exposure, systemic hypoxia, systemic hypercapnia, and inflammation. Notably, smoking mouse models show that chronic TS exposure without overt lung disease can cause muscle atrophy, mitochondrial impairment, and neuromuscular junction alterations, underscoring the likely role of long-term TS exposure in initiating the muscle impairment in COPD. Furthermore, recent evidence suggests that chronic activation of the AHR in skeletal muscle is likely to play an important role in driving these TS-induced muscle alterations as constitutive activation of the AHR without TS exposure recapitulates many of the same muscle phenotypes induced by chronic TS exposure. In addition to TS-mediated AHR activation, the higher circulating level of the tryptophan metabolite kynurenine seen in COPD patients, which is likely a consequence of impaired renal function, can also activate the AHR. This suggests multiple pathological insults involved in COPD may converge upon the AHR in causing skeletal muscle toxicity. Although an exacerbated accumulation of senescent cells in COPD muscle seems unlikely to underlie the exacerbation of aging muscle phenotypes , reduced circulating levels of the longevity-promoting klotho protein have been reported in COPD and some evidence suggests this may contribute to the adverse muscle phenotypes. In conclusion, COPD patient skeletal muscle alterations are likely to be driven by a combination of factors, some of which precede COPD disease diagnosis , and others that are part of the COPD patient\u2019s systemic milieu  and disease comorbidities . Based upon emerging evidence, preclinical models examining the potential of approaches targeting the mitochondrion  and the aryl hydrocarbon receptor may be valuable in seeking new targeted therapies for treating and preventing adverse skeletal muscle impact in COPD patients."}
+{"text": "There is a growing consensus on brain networks that it is not immutable but rather a dynamic complex system for adapting environment. The neuroimaging research studying how brain regions work collaboratively with dynamic methods had demonstrated its effectiveness in revealing the neural mechanisms of schizophrenia.To investigate altered dynamic brain functional topology in first-episode untreated schizophrenia patients (SZs) and establish classification models to find objective brain imaging biomarkers.Resting-state-functional magnetic resonance data for SZs and matched healthy controls were obtained(Table1).Power-264-template was used to extract nodes and sliding-window approach was carried out to establish functional connectivity matrices. Functional topology was assessed by eigenvector centrality(EC) and node efficiency and its time-fluctuating was evaluated with coefficient of variation(CV). Group differences of dynamic topology and correlation analysis between Positive and Negative Syndrome Scale(PANSS) scores and topology indices showing group differences, which also were used in establishing classification models, was examed.The CV of node efficiency in angular and paracingulate gyrus was larger in SZs. There are 13 nodes assigned into several brain networks displaying altered CV of EC between groups. Fluctuation of EC of the node in DMN, which was lower in SZs, showed negative correlation with PANSS total scores. Dynamic functional topology of above nodes was used to train classification models and demonstrated 80% and 71% accuracy for support vector classification(SVC) and random forest(RF), respectively.Dynamic functional topology illustrated a capability in identifying SZs. Aberrated dynamics of DMN relevant to severity of patient\u2019s symptoms could reveal the reason why it contributed to classification.No significant relationships."}
+{"text": "Left ventricular rupture following prosthetic mitral valve replacement might be avoided by valve-sparing techniques and vigilance at the time of debridement to maintain or support annular integrity.See Article page 48.,DavidAlthough performing prosthetic MVR is not usual, few surgeons have had the misfortune of having to deal with LV rupture. Bright red blood emanating from the posterior pericardium upon separation from cardiopulmonary bypass following MVR is universally accompanied by a sinking feeling in the operator. Should an ill-prepared surgeon attempt lifting the heart to locate the bleeding source in this setting, the maneuver may prove fatal. As outlined by David,,Predispositions to this complication include female patients, a small LV cavity, advanced age, severe mitral annular calcification, and implantation of higher-profile bioprosthetic valves. Vigilance and patch correction at the time of annular debridement may avoid type 1 LV disruption, whereas avoiding deep debridement involving the papillary muscles can mitigate type 2 LV disruption. Posterior leaflet and total leaflet sparing MVR operations have nearly eliminated this complication.Greek mythological reference to Achilles' heel symbolizes that despite overall strength, a focal vulnerability may lead to downfall. Surgeons are well versed in the reproducible techniques of prosthetic MVR. Valve-sparing methods and adaptive strategies to address mitral annular calcification are the established necessary standards to avoid this potential vulnerability and circumvent this pitfall. Vigilance can often save patients from this often fatal problem."}
+{"text": "The Building Our Largest Dementia (BOLD) Infrastructure for Alzheimer's Act (PL115-406) supports public health agencies to develop a uniform dementia infrastructure across the US. Applying a robust public health approach to ADRD that emphasizes data driven decision-making and action along with primary, secondary, and tertiary prevention strategies  for persons living with dementia and their caregivers. Recipients of the BOLD Public Health Programs funds are expanding jurisdiction Dementia coalitions, updating, or creating Dementia Strategic Plans, and implementing strategies from those plans that address a wide variety of life-course strategies for brain health and dementia, including risk reduction. This presentation will explain how risk reduction is integrated and provide examples of several activities being planned and implemented by recipients."}
+{"text": "Ectodermal dysplasias (ED) are inherited disorders involving congenital abnormalities of different ectodermal structures, the most prominent presentation being adontia/hypodontiaIn this article, we present a brief overview of several pediatric cases of ED with a short review of the odontological manifestations.We report several cases of children consulting in the pediatric department for abnormal teeth, with or without systemic manifestations.The clinical examination of these patients revealed insufficient and abnormal dentition, with rare beveled teeth and thin and rare hair, as well as eyelashes and eyebrows.Also, parents reported episodes of hyperthermia without sweating from an early age.Dental radiography confirmed the diagnosis of ectodermal dysplasia.Ectodermal dysplasias (EDs) are a group of various inherited disorders involving abnormal congenital development of at least two ectodermal structures . The management of these rare disabling conditions is still mainly symptomatic. The traditional removable prosthesis can be an option to replace missing teeth. However, implants provide the best long-term results and prognosis. In particular, dental implants are commonly used in oral reconstruction of ED patients, but long-term data on bone augmentation and bone resorption, aesthetic outcomes, and implant success are needed.in utero.EDs are a myriad of heterogeneous conditions encompassing several inherited embryopathies affecting teeth and other ectoderm-derived structures Diagnosis is essentially clinical, confirmed by radiology and genetics which can specify the causal mutation; treatment is mainly conservative."}
+{"text": "This presentation will review the current state of knowledge about severe maternal perinatal mental illness. Severe disorders are associated with a higher prevalence of somatic difficulties during pregnancy, poorer quality of pregnancy follow-up and potential impairment of infant care. These children are therefore very vulnerable and require specific care. We will present how graduated care coordinated and above all integrated between psychiatry, obstetrics, neonatal pediatrics and child protection services allows for early and effective preventive interventions, both for the child\u2019s development and maternal mental health. The concept of shared parenting will be particularly developed.No significant relationships."}
+{"text": "Editorial on the Research TopicDevelopmental origins of health and disease: Impact of preterm birthin utero environment that precipitates the early birth. Further, preterm birth has been associated with impaired structural and function development of organ systems in the offspring, thus making preterm birth a unique predisposing factor for adult disease  scores, but late preterm birth mothers had even higher depressive symptoms; both of which may affect the care provided to their respective infants.\u201d Both Motte-Signoret et al. and Gonzales-Garcia et al. studied small for gestational age or intrauterine growth restricted (IUGR) infants. Motte-Signoret measured growth factor (GF), insulin growth factor 1 (IGF1), and insulin resistance in small for gestational age (SGA) infants. SGA infants demonstrated resistance to GF and IGF1 with insulin resistance. These findings could explain initial defects in early catch-up growth, risks for later catch-up growth, and higher prevalence of metabolic syndrome in later life. Gonzales-Garcia compared the Fenton 2013 growth charts to those from the International Fetal and Newborn Growth Consortium for the 21st Century (Intergrowth 21st) Project (IW-21) for assessing to intra-(IUGR) and extrauterine (EUGR) growth restriction in very low birthweight infants. There was concordance between the charts for IUGR growth trajectories but not for EUGR infants. The dynamic IW-21 was more restrictive but better predicted morbidities in EUGR infants.Reports on the negative effects of preterm birth included identifying predictors of severe necrotizing enterocolitis (NEC) and impaired neurodevelopmental outcomes and indicated that early identification of risk factors might ultimately lead to improved outcomes. Lin et al. sought to identify predictive indicators of necrotizing enterocolitis (NEC) by comparing biomarkers between NEC with portal venous gas (PVG) and NEC without PVG. C-reactive protein (CRP), fibrinogen degradation product, and blood glucose demonstrated predictive value for NEC-PVG. Current outcomes of the Neuroprem 2 cohort study were reported by Lugli et al. Out of 502 very preterm infants 9.6% had severe disability and 5.4% had cerebral palsy. Gestational age and periventricular hemorrhage were most highly associated with severe disability. Along these same lines, Wibowo et al. measured bone mineral content in newborns and found it lower in underdeveloped countries, higher in males, and negatively correlated with maternal cigarette usage. Hole et al. utilized a preterm piglet model to study early motor development. Preterm piglets took shorter steps than term piglets in early stages of walking but rapidly adapted with no differences within 3 days. Overall conclusions from the combined studies were that early interventions are needed to prevent later delays.Khasawneh et al. retrospectively analyzed determinates of late hospital discharge. The majority of all preterm births analyzed were late preterm infants. While several parameters such as gestational age and maternal and neonatal morbidities were correlated with length of stay , there was no correlation between length of stay after birth and later readmission.In summary, growth restriction and small birth weight can have permanent consequences on the metabolic health of the infant. Furthermore, the morbidities associated with preterm birth such as NEC, and motor and neurodevelopmental disabilities are likely to contribute to deficits in the quality of life once these infants reach adulthood. Prematurity and SGA should be considered overall risk factors for adult health and quality of life."}
+{"text": "Understanding how trajectories of positive and negative affect relate to dementia risk and underlying structural brain variables is important for dementia prevention. We examined associations between annually assessed Positive and Negative Affect Scale subscales and dementia risk (2000-18) among cognitively-intact community-dwelling women  from the Women\u2019s Health Initiative Study of Cognitive Aging (years 2000-2010) and Magnetic Resonance Imaging Study (2005-2006). Joint latent class mixture models were constructed to identify latent classes of women with similar trajectories of affect and dementia risk over time. Multinomial and logistic regressions examined whether structural MRI measures predicted latent class membership . Two latent classes of positive affect (high stable:88% and decreasing:12%) and four classes of negative affect  were identified. With the high stable trajectory as referent, women with decreasing positive affect were more likely to develop dementia . The odds of being classified as this high-dementia risk group were increased among women with more (per SD) global small vessel ischemic disease , deep white matter SVID , and smaller parahippocampal volumes . For negative affect, with minimal stable negative affect as referent, women with smaller hippocampal volumes were more likely to be classified as having moderate decreasing negative affect  while emerging negative affect was associated with higher dementia risk . These findings highlight the importance of changes in affect in later-life with dementia risk and potential underlying role of cerebrovascular disease and medial temporal lobe structures."}
+{"text": "Adenoviruses are commonly used as efficient high-capacity vectors and excellent gene delivery vehicles. Their applications range from basic molecular research to gene therapy and recombinant viral vector vaccines. Adenoviral vectors are currently used in regenerative and cancer therapies, and as first-generation COVID-19 vaccines. Despite their widespread use and constant progress, various challenges and safety concerns still limit the application of adenoviral vectors to their fullest potential. Our Special Issue, \u201cNew Aspects of Adenoviral Vaccine Vectors and Adenoviral Gene Therapy\u201d, presents five excellent original research articles and reviews on adenoviral vector development, recent trends in adenovirus-mediated oncolytic therapies, and lessons learned from current large-scale adenoviral vector vaccination programs.An in-depth review article by Erwan Sallard and colleagues provides the latest insights into adenoviral vector design and reiterates lessons learned from adenovirus-based COVID-19 vaccines [A research article by Xiang Du and colleagues summarizes an in vivo proof of concept for a replication-competent adenovirus vector vaccine against a morbillivirus of veterinary importance . They shNora Bahlmann and colleagues contribute new data on improved adenovirus vectors for oncolytic and gene therapies . Their rA thorough review by Wen-Chien Wang and colleagues  recapituPaola Blanchette and Jose Teodoro comprehensively review the characteristics of oncolytic adenoviruses that are currently undergoing clinical trials for cancer therapy . Their oThis collection of articles provides valuable new insights into various properties of adenoviral vectors in vaccine and gene therapy settings\u2014a topic that has been studied for decades but is more relevant than ever, as there have never been so many individuals injected with a recombinant adenovirus vector."}
+{"text": "Communication is fundamental for dementia care and identifying evidence for strategies that facilitate or impede communication is needed. We analyzed 221 videos from a randomized controlled trial of a family caregiver telehealth intervention (FamTechCare) using Noldus second-by-second behavioral coding of communication behaviors and breakdowns in interactions between 53 caregiver-person with dementia dyads. Coded data from 3,642 30-second observations were first analyzed using penalized regression for feature selection  to identify strategies most important for predicting prevention and successful repair of communication breakdown. Bayesian mixed modeling was then used to identify communication strategies associated with successful versus unsuccessful prevention and repair of communication breakdown taking into account of the dyadic structure of our data. Results showed that given our data, communication breakdown was associated with caregivers changing topic , ignoring , making commands  and taking over the task . Successful repair of breakdown was associated with caregivers verbalizing understanding , tag questions, , and silence  while ignoring and changing topic were associated with unsuccessful repair . These results provide evidence for development and testing of evidence-based communication strategy training for family caregivers of persons with dementia. Future analyses will identify effects of dementia stage, diagnosis, and dyad characteristics on associations."}
+{"text": "Mycobacterium tuberculosis DNA present in their stool samples, which can augment current diagnostic gaps. Optimizing extraction of DNA from stool for analysis via sequencing technologies is a paramount initial step to ensure accuracy of downstream sequencing applications.Next generation sequencing (NGS) is quickly coming to the forefront of diagnostic tools to provide efficient, highly informative information from patient samples. Recently, it was established that patients with pulmonary Tuberculosis (TB) have Mycobacterium bovis derived from BCG were used as a model for Mtb. Human stool samples were spiked with varying known concentrations of BCG and extracted with four different DNA extraction kits . Each sample was subjected to quantitative polymerase chain reaction using designed primers and probes specific for identifying Mtb infection from stool. The samples underwent further analysis to assess overall DNA yield (Qubit fluorometer), DNA fragment length (Agilent tape measure), and DNA purity (Nanodrop spectrophotometer).Attenuated strains of Overall, the Fast DNA Spin Kit for Soil extraction kit showed the most optimal results. DNA isolated via this method showed the lowest cycle thresholds of Mtb amplification, indicating the most preserved amount of BCG specific DNA. In addition, this method showed the highest overall DNA yield and highest proportion of long DNA fragment lengths. Fluorometric analysis showed significant contamination in the 230 nm wavelength range, which was amended with an additional AMPure bead cleanup step.Quantiative PCR of Spiked BCGQuantitative PCR Cycle Threshold Values by Different DNA Extraction KitsThe MPFast Soil Extraction kit, when compared to three other DNA extraction kits, performed the best on stool samples for isolating BCG DNA. Overall DNA yield, DNA length, and amount of specific BCG DNA were best optimized with this method and provided the best samples for sequencing analysis. This critical step is the first of many to realize the promise of stool-based NGS.DNA QuantityQuantity of Total DNA by Different DNA Extraction KitsSpectrophotometric AnalysisAnalysis of Absorption of Extracted DNA by Different DNA Extraction KitsSpectrophotometric ResultsSpectrophotometry Results of DNA Samples Extracted by Different DNA Extraction KitsLennard A. Meiwes, n/a, German Center for Infection Research (DZIF): Grant/Research Support."}
+{"text": "Inner strength is a person\u2019s internal process of moving through challenging circumstances, such as receiving a diagnosis of Mild Cognitive Impairment (MCI). This study describes experiences of inner strength using qualitative methodologies to identify themes within semi-structured dyadic and individual interviews with persons diagnosed with MCI within 12 months at a Memory Center and their care partners. We analyzed data in NVivo using reflexive thematic analysis methods. Trustworthiness was maintained through vetted interview guides, verbatim transcription, field notes, peer group analysis, and audit trails. One overarching theme and three subthemes explained inner strength. An overarching theme, Finding Ways to Live with It, described how participants live within the circumstances of MCI. Three subthemes were Defining Strength by Recalling the Past, Seeking Relief and Dwelling in It, and Finding Purpose & Meaning. Implications include supporting inner strength at the time of MCI diagnosis through reminiscence therapy and meaning making interventions."}
+{"text": "There is growing interest in whether linked administrative data have the potential to aid analyses subject to missing data in cohort studies. We aimed to identify predictors of cohort non-response in linked administrative data and examine whether inclusion of these variables in principled methods for missing data handling can help restore sample representativeness.Using linked 1958 National Child Development Study (NCDS) and Hospital Episode Statistics (HES) data, we applied a multi-stage data-driven approach to identify HES variable which are predictive of non-response at the age 55 sweep of NCDS. We then included these variables as auxiliary variables in multiple imputation (MI) analyses to see if they helped restore sample representativeness in terms of early life variables which were essentially fully observed in NCDS  and relative to external population data .We took as our starting point 57 variables derived from HES data based on the presence or number of different types of appointments/admissions, diagnostic codes and treatment codes. After application of our multi-stage data-driven approach we identified five HES variables that were predictive of non-response at age 55 in NCDS. For example, cohort members who had been treated for adult mental illness were almost 3 times as likely to be non-respondents . Inclusion of these variables in MI analyses did help restore sample representativeness. However, there was no additional gain in sample representativeness relative to analyses using only previously identified survey predictors of non-response (i.e. NCDS rather than HES variables).In our applications, inclusion of HES predictors of NCDS non-response in analyses did not improve sample representativeness beyond that possible using survey variables alone. Whilst this finding may not extend to other analyses or NCDS sweeps, it highlights the utility of survey variables in handling non-response."}
+{"text": "The Art of WarRecent technological advances have expanded our understanding of how artificial stimulation interacts with the living nervous system . Song and Martin found that cathodal tsDCS can selectively target voltage-dependent calcium channels to modulate motoneuron activity, informing therapeutic treatment strategies to achieve rehabilitation goals after injury; in particular, to increase muscle force.Significant research efforts have focused largely on developing non-invasive or minimally invasive stimulation techniques  in discriminating the MI condition from rest. Moreover, they showed that st-SES influences functional connectivity of the fronto-parietal network, but through different frequency bands for different subjects. These findings can potentially help to optimize guidance strategies to adapt to different types of MI-BCI users.In addition, motor imaginary (MI)-based brain-computer interface (BCI) must overcome multiple issues to be commercially usable, especially related to signal quality and subject-variation  for severe treatment-resistant depression. Steele et al. proposed a fronto-medial ECT electrode placement that would maximize the EF in specific sagittal brain regions, whilst minimizing EF in sub-regions of the bilateral hippocampi. Such outcomes suggest electrode location can significantly reduce cognitive and non-cognitive side-effects.An optimal implantation region improves not only stimulation performance but also the long-term stability of implantable microelectrodes, as well as reducing side effects  features and joint angles as inputs. A similar idea has been used historically in other neuromodulation fields since various stimulation parameters have been shown to evoke distinct neurological and physiological responses. Conversely, elicited physiological effects, both for targeted and untargeted neurons, can guide stimulus parameter tuning for many neural systems, including the brain  et al. have proposed a new biophysical model of myelin ultra-structures by simulating cytoplasmic channels in the myelin sheath as a low-impedance route, while previous models approximate the myelin sheath as an insulation layer  et al. further investigated how cytoplasmic channels affect EF across the myelin sheaths, concluding that the externally applied EF can control myelin growth. These new findings indicate the possibility of using electrical modulation to treat degenerative neural diseases. Neurodegenerative progression can affect the neuroprosthetic performance  using a biophysically detailed computational model of the human cochlea (Bai et al., Electrical stimulation performance cannot be significantly improved by only optimizing the device in isolation without considering the biophysical complexity of the target nerve system (Abbasi and Rizzo, The Chinese characters shown in the Editorial refer to the origin of each subtitle in the ancient literature The Art of War by Sun Tzu.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."}
+{"text": "Adequate reproductive and maternal healthcare services utilization are significant in reducing maternal deaths, however, the prevalence rate of contraceptive use remains low, with inadequate maternal health services utilization among rural women in Nigeria. This study examined the influence of household poverty-wealth and decision-making autonomy on reproductive and maternal health services utilization among rural women in Nigeria.The study analyzed data from a weighted sample of 13,151 currently married and cohabiting rural women. Descriptive and analytical statistics including multivariate binary logistic regression were conducted using Stata software.An overwhelming majority of rural women (90.8%) have not used modern contraceptive methods, with poor utilization of maternal health services. About 25% who delivered at home received skilled postnatal checks during the first 2 days after childbirth. Household poverty-wealth significantly reduced the likelihood of using modern contraceptives , having at least four ANC visits , delivering in a health facility  and receiving a skilled postnatal check . Women's decision-making autonomy regarding their healthcare significantly increased the use of modern contraceptives and the number of ANC visits, while women's autonomy on how their earnings are spent positively influenced the use of maternal healthcare services.In conclusion, the use of reproductive and maternal health services among rural women was associated with household poverty-wealth and decision-making autonomy. Government should formulate more pragmatic policies that will create awareness and promote universal access to reproductive and maternal healthcare services. In the context of global health priority, the levels of utilization of reproductive and maternal health services are parts of the indicators in measuring the level of healthcare performance, delivery system and developmental indices . The useMaternal healthcare including optimal ANC visits, delivery in a health facility and skilled postnatal check after delivery are significant mediations required during pregnancy and after childbirth for positive maternal and child health outcomes . AlthougIn sub-Saharan Africa, which Nigeria is part of, previous studies have shown the existence of urban-rural disparity in the use of maternal and reproductive health services by demonstrating that urban women tend to use modern contraceptives and maternal health services compared to rural women \u201314. NotwThis study examined household poverty-wealth and decision-making autonomy as predictors of reproductive and maternal health services utilization among rural women in Nigeria. The outcome is expected to provide up-to-date information, relevant policy and programmatic recommendations towards achieving sustainable development goals targets of universal access to quality reproductive and maternal health services; and reducing maternal and child deaths.The study utilized data obtained from the 2018 Nigeria Demographic and Health Survey (NDHS). The survey is a cross-sectional study and data were generated using standardized interviewer-administered questionnaires from a nationally representative sample of women aged \u201349 on soThe outcome variables selected for this study were based on empirical evidence which includes; 1) the use of contraceptive methods, 2) the number of ANC visits, 3) facility delivery services and 4) the postnatal check provider. Information on these outcome variables as generated from the 2018 NDHS was re-categorized from their original frequency ranges in the dataset. Therefore, women who used a modern contraceptive method, had at least four ANC visits during their most recent pregnancy, delivered in a public or private hospital and skilled postnatal check of a mother during the first 2 days after childbirth/before discharge from a doctor, nurse/midwife or auxiliary nurse/midwife were categorized as \u20181\u2019 and \u20180\u2019 if otherwise.The main explanatory variables in this study are household poverty-wealth and women's decision-making measures including the following three subjects: 1) decision on respondent's healthcare, 2) decision on large household purchases, and 3) decision on how to spend respondent's earnings. Therefore, women who made independent decisions on any of the three subjects represent decision-making autonomy and may influence seeking healthcare for themselves . In thisp<0.05 and measures of association were expressed as odds ratio with 95% confidence intervals.Data analysis was conducted with Stata software (version 15) at univariate, bivariate and multivariate levels. The dataset was carefully checked for missing values which were excluded and weighted with the appropriate sampling weights as per the Demographic and Health Survey sampling scheme. At the bivariate level, unadjusted logistic regression as shown in Description of the study population: The weighted descriptive statistics of the women as presented in Reproductive and maternal healthcare services utilization: Unadjusted and bivariate analysis: The unadjusted and bivariate results as presented in p<0.05. However, except for employment status and health insurance coverage, all the main explanatory variables and other covariates are significantly associated with receiving postnatal care from a skilled provider during the first 2 days after childbirth at p<0.05.Adjusted multivariate analysis of the utilization of reproductive and maternal healthcare services by explanatory variables: The adjusted logistic regression analysis results presented in This study examined the influence of household poverty-wealth and decision-making autonomy on reproductive and maternal health services among rural women in Nigeria. The findings of this study revealed that despite the efforts in encouraging the use of modern contraceptive methods, the prevalence of modern contraceptives among rural women is still alarmingly low corroborating different studies in Congo  and EthiThe findings further revealed that rural women found in poor households were less likely to use modern contraceptive methods relative to those in rich households. This corroborates previous studies in sub-Saharan Africa including Nigeria that the poverty-wealth dimension in rural areas is a big factor contributing to the lack of modern contraceptive use \u201331. AlsoThis study showed that rural women's decision-making autonomy regarding their healthcare is a significant predictor of using modern contraceptive methods and having at least four ANC visits during pregnancy. The findings corroborate previous studies that women who can make independent decisions on their reproductive health were more likely than those whose husbands solely made such decisions to use modern contraceptives , 35 and The findings of this study further confirmed an observation that younger women were less likely to use modern contraceptives compared to their older counterparts . PlausibIn conclusion, this study found that the prevalence of modern contraceptives is still alarmingly low, while optimal ANC visits during pregnancy and delivery in health facilities are poorly utilized among rural women. Some rural women who delivered at home subsequently sought skilled medical attention from health facilities. Generally, reproductive and maternal health services utilization were negatively influenced by household poverty-wealth. Women's decision-making autonomy regarding their healthcare and earnings are significant predictors of reproductive and maternal health services utilization. There is a need for some unified skilled postnatal home-visit services outside health facilities through linkages with healthcare providers. Also, the government should formulate more pragmatic policies that will create awareness, educate and promote adequate reproductive and maternal healthcare services utilization among disadvantaged women.The study has some limitations including the use of secondary data from a cross-sectional study which restricts study variables. As a result, the cause-effect association between the explanatory and outcome variables is rather temporary and may not be ascertained. However, the findings are essential for the formulation of more pragmatic policies geared toward achieving universal access to reproductive and maternal healthcare services."}
+{"text": "Previous research has demonstrated that self-concealment of sexual orientation may negatively affect the wellbeing of lesbian, gay, and bisexual (LGB) adults . Additionally, studies have indicated that internalized homophobia significantly predicts depressive symptoms in LGB older adults . The present study examined how internalized homophobia may mediate the predictive relationship between self-concealment on depression symptoms in LGB older adults. As part of a larger study, participants (Nf301) responded to several questions and measures including the Sexual Orientation Self-Concealment Scale, The Internalized Homophobia Scale, and the Center for Epidemiological Studies Depression Scale. Using the Baron and Kenny\u2019s Method for Mediation (1986), the data analysis indicated that internalized homophobia fully mediates the relationship between self-concealment and depression severity (ps < .05). These results suggest that older adults who self-conceal their sexual orientation may experience an increase in depressive symptoms because of internalized homophobias. These findings may help clinicians better understand the mechanisms contributing to the high rates of depressive symptoms within the older LGB population. Furthermore, the findings suggest that cognitive restructuring of thoughts related to internalized homophobia and self-concealment may improve depressive severity in older LGB adults."}
+{"text": "Molecular Cancer, Wang and his colleagues have now placed seven types of tumors in a unified analytic framework [Circular RNAs (circRNAs) are a subgroup of single-stranded endogenous RNAs which exert differential expression pattern between normal and cancerous tissues and function as important regulators in cancer initiation and progression. However, comprehensive characterization of circRNA landscape across cancer types is still lacking. In a recent article published in ramework , all wit, demonstrating circLIFR may serve as a therapeutical target in metastatic cancer. Consistently, the RNA-seq results suggested the ability of circLIFR to alter the expression pattern of some metastasis-related genes involved in cell adhesion and epithelial-mesenchymal transition (EMT). Collectively, this study by Wang et al. certainly illustrates the comprehensive circRNA profiles in multiple solid tumors and highlights the potential of circRNAs as important diagnostic tools or therapeutic targets.Through rRNA depleted transcriptome sequencing, the authors identified a total of 59,056 circRNAs, the majority of which were lowly expressed, while a subset of circRNAs exhibited much higher abundance than their cognate linear transcripts, indicating their biological significance in homeostasis. Using stringent criteria, the authors pictured the distinct circRNA expression signatures among seven types of solid tumors. The dysregulated circRNAs exhibited cancer-specific expression or shared common expression pattern across cancers, implying their diverse functions in cancer progression and their diagnostic potential in multiple cancers. Among the aberrant circRNAs, circLIFR showed an overall downregulation in tumors. Significantly, circLIFR was experimentally validated as a bona fide circRNA which inhibited tumor metastasis in vitro and in vivo"}
+{"text": "The derivative was shown to be non-toxic and safe, upon consumption  position in polysaccharides led to the development of various molecules exhibiting remarkable inhibition against anti-HSV in vitro  derived from a herbaceous perennial plant Radix Cyathulae officinalis Kuan demonstrated dramatic viral inhibition after phosphorylation as compared to unphosphorylated RCPS . Intereal., 2010). Anotheal., 2017). This hin vitro . An in-in vitro and has been shown to be effective against HPV by direct binding to viral capsomeres and further downregulating PI3K/Akt/mTOR pathway  on the cell surface. In an attempt to investigate this behavior, 3,6 O sulphated chitosan was explored al., 2018 [This isal., 2020 [This isal., 2020 [This isal., 2020; Woo et al., 2020). in vitro, and in vivo along with promising clinical trials are needed for better outcomes. Since future viral outbreaks are quite predictable, it is important to design a non-immunogenic, non-toxic and targeted drug delivery system to effectively deliver polysaccharide based antviral drugs to the infected population without any serious side effects and quicker recovery. The benevolent nature, biocompatibility, ease of availability, low cost and non-toxic profile of polysaccharides, claim their anti-viral potential with enhanced therapeutic response. The development and discovery of polysaccharide-based drugs, antibodies and vaccines may prove beneficial in arresting episodes confronted during acute respiratory distress syndrome, particularly in COVID 19 pneumonia. Chemical modification further ameliorates the challenges faced with unmodified polysaccharides. In fact, a combination of chemically modified polysaccharides and anti viral therapeutics, with a change in route of administration may play a decisive role in combating pandemics and epidemics. In a time where viral genome sequencing has unraveled sophisticated molecular pathways responsible for the survival of viruses, genomic epidemiology along with microfluidics can also play a crucial role in mapping evolutionary behaviour and understanding the virulent nature of mutating strains. Despite significant advances in the use of polysaccharides as excipients in recent years, the exact mechanism of viral interaction and signaling pathway is not clear. This necessitates delving into high throughput screening strategies for these dangerous viral infections for tangible patient outcomes. In fact, an amalgamation across different pharma sectors along with the latest AI  tools can fully leverage the antiviral potential of polysaccharides. Identifying potent biomarkers may also help, design polysaccharide-based anti-viral drug candidates to further gain an in-depth understanding and dynamics of infection.Polysaccharides can be future candidates for mitigating viral infections, but more Rabab Fatima, Parteek Prasher and Kamal Dua contributed equally.The authors declare no conflict of interest."}
+{"text": "This article outlines the evolving definition of rejection following kidney transplantation. The viewpoints and evidence presented were included in documentation prepared for a Broad Scientific Advice request to the European Medicines Agency (EMA), relating to clinical trial endpoints in kidney transplantation. This request was initiated by the European Society for Organ Transplantation (ESOT) in 2016 and finalized following discussions between the EMA and ESOT in 2020. In ESOT\u2019s opinion, the use of \u201cbiopsy-proven acute rejection\u201d as an endpoint for clinical trials in kidney transplantation is no longer accurate, although it is still the approved histopathological endpoint. The spectrum of rejection is now divided into the phenotypes of borderline changes, T cell-mediated rejection, and antibody-mediated rejection, with the latter two phenotypes having further subclassifications. Rejection is also described in relation to graft (dys)function, diagnosed because of protocol (surveillance) or indication (for-cause) biopsies. The ongoing use of outdated terminology has become a potential barrier to clinical research in kidney transplantation. This article presents these perspectives and issues, and provides a foundation on which subsequent articles within this Special Issue of Transplant International build. The approved histopathological endpoint for clinical trials of kidney transplantation is the presence or absence of biopsy-proven acute rejection (BPAR) . This enOver time, the spectrum of rejection has broadened, with distinctions made between two major subtypes: T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR) . Deeper Furthermore, the strategy of performing protocol biopsies in the early years following transplantation has been adopted by several European centers, to detect subclinical rejection and guide ongoing patient management . It has \u2022 Suspicious (borderline) for acute TCMR (henceforth simplified to \u201cborderline changes\u201d)\u2022 Acute TCMR \u2022 Chronic active TCMR (caTCMR)\u2022 Acute/active antibody-mediated rejection (aAMR)\u2022 Chronic antibody-mediated rejection (cAMR)\u2022 Chronic active antibody-mediated rejection (caAMR).The classification of allograft rejection has often been modified over the years, such that six histological rejection phenotypes are widely described , 6:\u2022 SusBorderline changes represent less severe inflammation scores than aTCMR. The threshold of inflammation used for diagnosis of borderline changes  varies among centers, because between 2005 and 2017 the Banff Classification stated that retaining the i1 threshold for borderline changes with tubulitis (t) > 0 was permitted . In addiIn the 1990s, a diagnosis of aTCMR was based on a clinical definition  and/or a clinicopathological definition  , 13. TheThe impact of inflammation in atrophic areas (i-IFTA) on graft outcomes has been widely demonstrated , 14\u201316, per se. The response of caTCMR to increased doses of immunosuppressive therapy has not been studied function. Protocol (surveillance) biopsies are performed, per definition, at the time of stable graft function to detect subclinical inflammation  . IndicatFinally, although molecular diagnostics of kidney transplant rejection has been validated prospectively in a multicentric fashion  and is cESOT has come to the following conclusions:\u2022 The use of BPAR as an endpoint for clinical trials in kidney transplantation is no longer accurate.\u25cb Using outdated and/or non-specific definitions, such as BPAR, compromises the future of high-quality clinical research, especially for interventions that are targeted at one rejection subtype.\u2022 Kidney transplant rejection should be classified by its phenotypes\u2014borderline changes, TCMR, and AMR (the two latter having subtypes), and in relation to the nature of graft (dys)function .\u2022 The CHMP acknowledged that histological subclassifications of rejection have evolved during the last decade.\u2022 The CHMP agreed that the histological subtype of rejection is a useful specification and noted that this detailing might be very informative in profiling efficacy of immunosuppression.\u2022 The CHMP commented that the reason for undertaking a protocol or indication biopsy should be taken into consideration when defining endpoints for clinical trials."}
+{"text": "Crop domestication is a co-evolutionary process that has rendered plants and animals significantly dependent on human interventions for survival and propagation. Grain legumes have played an important role in the development of Neolithic agriculture some 12,000\u2009years ago. Despite being early companions of cereals in the origin and evolution of agriculture, the understanding of grain legume domestication has lagged behind that of cereals. Adapting plants for human use has resulted in distinct morpho-physiological changes between the wild ancestors and domesticates, and this distinction has been the focus of several studies aimed at understanding the domestication process and the genetic diversity bottlenecks created. Growing evidence from research on archeological remains, combined with genetic analysis and the geographical distribution of wild forms, has improved the resolution of the process of domestication, diversification and crop improvement. In this review, we summarize the significance of legume wild relatives as reservoirs of novel genetic variation for crop breeding programs. We describe key legume features, which evolved in response to anthropogenic activities. Here, we highlight how whole genome sequencing and incorporation of omics-level data have expanded our capacity to monitor the genetic changes accompanying these processes. Finally, we present our perspective on alternative routes centered on de novo domestication and re-domestication to impart significant agronomic advances of novel crops over existing commodities. A finely resolved domestication history of grain legumes will uncover future breeding targets to develop modern cultivars enriched with alleles that improve yield, quality and stress tolerance. Domestication refers to an evolutionary process causing remarkable changes in plant morphology and physiology in response to the selection pressures created by anthropogenic activities . The proPisum sativum L.), faba bean (Vicia faba L.), lentil (Lens culinaris L.), grass pea (Lathyrus sativus L.) and chickpea (Cicer arietinum L.) are some of the world\u2019s oldest domesticated crops and arose in the Fertile Crescent of Mesopotamian agriculture. These legumes accompanied cereal production and formed important dietary components of early civilizations in the Middle East and the Mediterranean (Glycine max L.) and adzuki bean (Vigna angularis L.) accompanied cultivation with rice (Oryza sativa L.) in China, whereas domestication of common bean (Phaseolus vulgaris L.) and cowpea (Vigna unguiculata L.) occurred in Andes/Mesoamerica and sub-Saharan Africa, respectively. Other pulse crops such as pigeonpea (Cajanus cajan L.), mungbean (Vigna radiata L.) and urdbean (Vigna mungo L.) were domesticated in India  and barley (Hordeum vulgare), along with the grain legume crops such as pea and lentil. Wheat and barley were claimed to be originated in slightly drier, open parkland steppes along with wild grasses, while pulse crops including lentil, pea, chickpea and Vicia spp. originated in the clearings of nearby woodlands and rocky talus slopes , it has been suggested that soybean domestication occurred simultaneously at multiple sites  to its current status as a South Asian and spring-sown Mediterranean crop  has become a standard approach to study crop domestication and evolution. Linkage disequilibrium (LD) encompasses alleles at two or more loci having non-random association, and patterns of LD decay reflect recombination rates in the population. For instance, resequencing of 302 soybean accessions including wild, landraces and breeding lines revealed the extent of LD decay , with wiGenome sequencing of multiple accessions has revealed a loss of genetic diversity in breeding improved cultivars in different grain legume crops. For instance, the genome sequencing of pea and Pigeonpea revealed the most diverse single nucleotide polymorphisms (SNPs) in wild accessions in comparison to landraces and cultivars . The genC. reticulatum has early domesticated into desi type (common in South Asia and sub-Saharan Africa), whereas kabuli (common in West Asia and Mediterranean regions) were subsequently derived  involved in snare membrane traffic, wound-inducible protein and an amino acid transporter  and PAVs but lower CNVs as compared to kabuli . These f derived . The rolnsporter . Similartication . CNVs artication .FLP, MYB12) as the adaptive changes during shifting environments  influencing the two key flowering-related genes SOC1 and FT. The growing sequence data on whole genomes of diverse accessions will likely enrich the knowledge about the genetic underpinnings of the plant phenotypes that were changed during domestication and improvement of grain legume crops.The genomic evolution rate profiling (GERP) score reveals the genomic regions that remain evolutionarily constrained (GERP\u2009>\u20090) and indicates purifying selection, such as 29 Mb in chickpea  and 237.ronments . In commronments . With a ronments . The stuThe potential of CWRs and landraces has been historically recognized for supplying new genetic variation to plant breeding programs . The valCWRs often encounter broad and contrasting environmental conditions across their native range. Over evolutionary time, these exert differential selection pressure that leads to the formation of specifically adapted ecotypes. Drought is one of the main abiotic stresses acting in the Mediterranean and Middle East region, where progenitors of many cultivated crops occur and have to cope with water availability during the vegetation period.CWRs provide a key to counteract the effects of climate change on the world\u2019s food supply. To fully understand and exploit this process, studies in the geographical centers of origin are needed that combine ecology, physiology and genetics. With modern genomics tools, geospatial analysis combined with systematic phenotyping, it is highly desirable to revisit wild accessions and prioritize their use for breeding tolerance to various stresses. In particular, some local adaptations found in CWRs might maximize fitness in specific habitats, especially in the current climate change context .Environmental conditions such as soil salinity, cold and drought stress represent a major constraint on agricultural productivity. Water availability is a primary factor controlling the distribution of vegetation over the earth\u2019s surface. Crop yields are more dependent on an adequate supply of water than on any other single factor, and environmental stress  represents the primary cause of crop yields losses . Many otGmCHX1-conferring salt tolerance to wild soybean G. soja (Lens odemensis and Lens tomentosus) were identified as displaying tolerance to drought (Arachis duranensis) maintains a relatively high rate of transpiration and photosynthesis rate under dehydration treatment  mapping revealed a novel gene- G. soja . Similar drought , and ada drought . Reduced drought . Variati drought , and roo drought . Similarreatment . Adaptivreatment , where treatment . Wide vareatment . Recent ted crop .rhg1 and Rhg4 have been identified from wild soybean controlling resistance against the soybean cyst nematode (SCN), which is one of the major threats limiting soybean production  and drought was evident in a recent research (AsECHI) from Arachis stenosperma reduced the infection rate by 30% as well as accelerating post-drought recovery. In pigeonpea, CWRs are known to possess resistance against a variety of biotic and abiotic stresses  encompasses features that are absent in the wild progenitors or \u2018differentially\u2019 manifested in cultivated species, such as changes in seed retention, seed size, inflorescence and plant architecture and flowering synchronization. There is an ongoing debate about the number of domestication events and centers for a given crop. Two domestication centers have been reported for common bean: Central America and the Andes , and potGmHs1-1, encoding a calcineurin-like metallophosphoesterase transmembrane protein, was found to influence seed coat permeability in soybean  gene was implicated in seed coat permeability in common bean , and this gene not only represses Dt1 that prevents terminal flowering but also activates genes that promote flowering  is common and well conserved in legumes and cereals  and pea (Dpo) demonstrated it to be a monogenic trait; however, later several QTLs affecting this trait were also discovered  underlying flowering time are also known to affect flowering in soybean  in order to promote flowering. In course of narrow-leaf lupine domestication, this requirement has been removed and widely exploited by plant breeders to develop early-flowering varieties of L. angustifolius. It has been shown that the loss of vernalization requirement in narrow-leaved lupin is associated with a deletion in the promoter and de-repressed expression of a Flowering Locus T (FT) homolog , encoding a dirigent-like protein expressed in the sclerenchyma of differentiating endocarp and modulating the mechanical properties of the pod through lignin biosynthesis (C. arietinum ICC 4958\u2009\u00d7\u2009C reticulatum ICC 17160) and intra- (ICC 4958\u2009\u00d7\u2009C. arietinum ICC 8261) specific recombinant inbred lines revealed major QTL for flowering time in chickpea (GI (GIGANTEA) ortholog during chickpea domestication through conferring flowering time adaptation.In the legumes, single locus control of pod dehiscence was found in lentil , pea We and chicynthesis . Table 2chickpea . Like otchickpea , pea  and seed length (AhDPB2) , 62 SNPs showed association with frost tolerance and provided superior haplotypes associated with the frost damage (A genome-wide association study (GWAS) is an alternative approach to associate genomic variations with domestication phenotypes in diverse germplasm collection. GWAS of 203 accessions combined with transgenic and RNA-Seq experiments in groundnut facilitated the identification and validation of genes for seed weight ((AhDPB2) . Likewis(AhDPB2)  and a to(AhDPB2) . By usint damage . The cont damage  and PAV t damage  in soybet damage  correspot damage . Other Gt damage  and commt damage  and flowt damage , pod indt damage , pod mort damage  and seedt damage  in commot damage . The stuC. reticulatum supported its contribution to early phenology, crucial to transitioning from winter to summer crop  led authors to report a significant loss of diversity during domestication, and most of the diversity (87%) was found in the wild  than G. max . Decades of research have enlightened the impact of SVs  in crop evolution and agricultural adaptations. Compared to SNPs, SVs can directly alter the genic expression by modifying the copy number and can cause large-scale perturbations of cis-regulatory regions (CHS) gene expression in yellow soybean  and Arachis kempff-mercadoi ICG 8164\u2009\u00d7\u2009Arachis hoehnei ICG 8190), respectively , and the QTL analysis identified 42 potential QTL governing significant PVs for plant growth habit, height, plant spread and flower color (P. fulvum or P. elatius) in the genetic background of P. sativum offer a valuable resource for genetic research and breeding  by using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) editing of key domestication loci such as fas, lc, CLV3 , an orphan Solanaceae crop, showed the potential of CRISPR\u2013Cas9 editing for de novo domestication by altering one  was achieved by Vigna stipulacea.V. stipulacea, resulting in the recovery of mutants with notable reductions in seed dormancy and pod shattering. Given the species-rich legume family, there is large potential to domesticate novel legume crops for both human food and animal feed. This effort has been recently demonstrated in hairy vetch (Vicia villosa)  . Anothervillosa) , these pvillosa) .While legume CWRs have not yet been subjected to de novo domestication, several traits that could be targeted in these species spring to mind. Perhaps the first of these is seed shattering, which in e.g. common bean  as in ceThe process of redomestication represents an important opportunity for cultivated species to adapt to new ecotype. Besides de novo domestication that could deliver entirely new crops, the wild species or existing crops can be redomesticated by changing the artificial selection pressures toward plant traits catering to future requirements . At the Since the beginning of agriculture, grain legumes have been important ingredients as protein complement sources to starch-rich cereal diets. The domestication of cereal crops has been intensively researched, resulting in the identification and cloning of domestication genes. In recent years, carbonized remains and genetic studies have helped establishing the role of grain crops in old as well as new world agriculture. A very recent example of this is the identification of a WD40 gene as being important in the domestication of grain yield in both rice and maize with a wide range of other genes putatively also following this trend . As suchDomestication of cereals and grain legumes has shown different trajectories as exemplified from the time lines of grain size enlargement . GeneticIndeed, we are convinced that combined evidence from archeobotanical, pangenomes, multi-omics science and cultural shifts will enlighten future crop improvement strategies to rapidly develop modern cultivars of grain legume crops. That said, this will be no easy task and will certainly require both multi-disciplinary and multi-national approaches; however, in principle, the necessary technologies are all in hand and studies concerning the adaptation of our major crops to novel environments will undoubtedly help in efforts to create a more sustainable global agriculture that is more resistant to extreme climacteric events.pcac086_SuppClick here for additional data file."}
+{"text": "Curricular intervention studies have examined if instruction in aging and gerontology affects undergraduates\u2019 attitudes, knowledge, and perceptions towards older adults. However, less is known about curricular impact on undergraduates\u2019 intentions to work with older adults. By identifying factors that increase undergraduates\u2019 intentions to work with older adults we may elucidate meaningful points of intervention to enhance pursuit of careers in the geriatric workforce. The current study examined baseline data from a longitudinal study examining the impact of an upper-level adult development psychology course on student attitudes towards working with older adults. It was hypothesized that there would be positive associations between attitudes towards working with older adults, knowledge about aging, and positive attitudes towards older adults. Participants were 19 undergraduate students enrolled in upper-level undergraduate psychology courses. Participants completed validated, self-report questionnaires related to their attitudes towards working with older adults, ageism attitudes, and attitudes and knowledge about aging. Bivariate correlation analyses were used to examine cross-sectional associations among main outcome variables. More positive explicit attitudes towards older adults were significantly associated with more willingness to work with older adults . Additionally, knowledge of aging was positively correlated with perceived social norms around working with older adults . These initial findings suggest that knowledge and positive attitudes about aging may positively impact attitudes towards working with older adults. Future work will assess curricular impact on undergraduates\u2019 intentions to work with older adults, as well as evaluate predictors of change in intentions."}
+{"text": "Transcatheter aortic valve replacement (TAVR) has transformed the treatment of aortic stenosis and should ideally be performed as a totally percutaneous procedure via the transfemoral (TF) approach. Peripheral vascular disease may impede valve delivery, and vascular access site complications are associated with adverse clinical outcome and increased mortality. We review strategies aimed to facilitate TF valve delivery in patients with hostile vascular anatomy and achieve percutaneous management of vascular complications. Minimally-invasive transcatheter aortic valve replacement (TAVR) has supplanted surgical aortic valve replacement (SAVR) as the preferred mode of treatment in the majority of patients with severe aortic stenosis ,2. The tFailure of vascular closure devices (VCD) to achieve access site hemostasis following valve implantation and sheath removal may lead to severe bleeding, as well as limb ischemia . PercutaCalcified, stenosed and tortuous ileofemoral arteries characterize patients with \u201chostile\u201d vascular anatomy and may impede valve delivery and increase susceptibility to vascular injury during TAVR. In such patients, SAVR may potentially enable valve replacement without the need for instrumentation of the peripheral vasculature. However, patients with peripheral vascular disease often have co-morbidities which are associated with increased surgical risk and may therefore benefit from percutaneous valve delivery. Alternative vascular access approaches  were developed in order to enable TAVR in patients with hostile vascular anatomy in whom TF valve delivery was considered technically challenging. No randomized trials have compared these different approaches; however, the TF route is considered the least invasive. The aim of the present review is to summarize novel techniques which may facilitate totally percutaneous TF valve delivery.Peripheral vascular disease (PVD) is common in patients referred for TAVR ,12, and Vascular calcification ,24,25, tUse of VCD to achieve hemostasis decreases wound complications and duration of hospitalization compared to surgical cut-down ,31,32,33Early detection and rapid management of VC is crucial. Manual compression may achieve hemostasis in cases of minor access site bleeding, and protamine sulfate may be safely administered to reverse anticoagulation . Severe Percutaneous management of VC and vascular repair may be facilitated by placement of a 0.014\u2033 300-cm length \u201csafety\u201d wire within the femoral artery prior to puncture of the primary vascular access site . The safety wire is delivered via a secondary vascular access site  and is uThe contralateral femoral artery was traditionally used for secondary vascular access in TF TAVR procedures. Alternative secondary access sites include the ipsilateral distal branches of the femoral artery  ,41,42, rThe CFA is subject to repetitive stress and flexion at the hip joint. Implantation of balloon-expandable stents within the CFA is unsafe due to risk of stent fracture, compression, restenosis and branch occlusion ,47. NitiStents grafts (SG), which are covered with impermeable membranes such as polytetrafluoroethylene, may be used for excluding vascular tears and perforations and maintaining arterial integrity. Balloon-expandable SG, which were previously used for endovascular repair of iatrogenic vascular injury , have beStents were implanted in 10\u201324% of patients undergoing TF TAVR and achieved hemostasis in 98\u2013100%. During follow-up, the stents maintained near-universal patency with a low rate of asymptomatic strut fracture. Anecdotal data suggests that repeat vascular access and deployment of a VCD may be possible within a vessel that was previously treated by SG implantation . A liberThe CFA should be punctured at least 1 cm above the bifurcation in order to enable SG implantation without compromising outflow to the superficial femoral artery or profunda. Decision to implant SG is usually made following sheath removal, when control angiography reveals evidence of VCD failure. Long sheaths  may be used for SG delivery; however, they require upsizing of the secondary vascular access . Alternatively, SG may be delivered by a sheathless technique in order to minimize vascular trauma at the secondary access site. Stent grafts are typically delivered antegradely, from the contralateral femoral artery . Alternatively, ipsilateral distal vascular access within the superficial femoral artery or profunda ,41,42 anPre-procedural assessment of the femoral artery anatomy may show that the vascular anatomy is unsuitable for deployment of a VCD. In some patients, attempts to perform pre-closure with a suture-based VCD at the beginning of the TAVR procedure, prior to sheath insertion, may fail. Performing TF TAVR despite the inability to utilize a VCD may necessitate surgical vascular repair of the femoral artery. Patients at increased risk for complications of vascular surgery may benefit from a percutaneous method for achieving access site hemostasis following valve implantation and sheath removal. We assessed the feasibility of a strategy of planned stent graft implantation within the femoral artery for achieving access site hemostasis in a cohort of patients undergoing TF TAVR, in whom vascular pre-closure was not possible  60]..60].These patients were considered at increased risk for complications of vascular surgery due to advanced age, frailty, co-morbidities, or immobility. Stent graft implantation achieved access site hemostasis in all patients. During follow-up, 30-day mortality was zero, one-year mortality was 27%, and none of the patients required additional vascular interventions.Recent evolution of techniques and devices for treating severely diseased ileofemoral occlusive vascular disease, as well as novel strategies for utilizing SG for management of access site vascular complications, offer the opportunity to expand the role of totally percutaneous TF TAVR to patients with PVD . A systematic approach to procedural planning and management of vascular complications increases the likelihood of procedural success .Development of TAVR systems with lower device profiles, as well as novel VCD designs with improved efficacy, may expand the role of TF TAVR and decrease the need for alternative vascular access in patients with hostile vascular anatomy."}
+{"text": "Mitochondria regulate numerous cellular processes including metabolism, gene expression, motility and migration, as well as cell division, repair and death. Due to their ability to dynamically remodel, distribute throughout the cell, and interact with other organelles, mitochondria can perform its functions by acting locally or globally. The field of mitochondrial dynamics has thus grown from simple textbook observations of a static \u201ckidney-bean\u201d like energy producing structures to an organelle that works by dynamically changing its architecture and association with other organelles. The importance of the dynamic mitochondrial network and how integral it is to cellular function is highlighted by a growing list of diseases associate with defects in this process . This ReYu et al.). These data identify selective binding dynamics of DRP1 adapter proteins to explain their non-overlapping roles in DRP1 recruitment to mitochondria in healthy cells that gets disrupted in disease caused by the loss of adaptor proteins  to mitochondria by adaptor proteins . In theiproteins .2+ mobilization from ER to mitochondria. This was supported in cells from patients carrying OPA1 GTPase or GED domain mutations. Their study substantiates the role of OPA1 in modulating ER-mitochondrial coupling and shows even when mutant and WT OPA1 proteins are present together in patient cells, ER-mitochondrial Ca2+ homeostasis is disrupted, contributing to autosomal dominant optic atrophy .Unlike DRP1-mediated outer mitochondrial membrane (OMM) fission, Optic atrophy-1 (OPA1) regulates inner mitochondrial membrane (IMM) dynamics, mutations in which leads to dominantly inherited optic neuropathy that causes vision loss . Both OMBonjour et al. examined how the mitochondrial ultrastructure changes during mouse eosinophil maturation and in inflammatory disease. They performed high-resolution mitochondrial ultrastructure analysis using transmission electron microscopy (TEM) and 3D tomography. This uncovered a reduction in mitochondrial area by 70% during eosinophil development that was attributed to increases mitophagy in immature eosinophils. They show that mitochondria form extensive contacts with other mitochondria and cellular organelles at a higher frequency in immature versus mature eosinophils. During asthma-induced inflammation, mitochondrial cristae remodeling occurs and mitochondrial contacts with granules increases. This highlights cell-specific mitochondrial ultrastructure remodeling that is responsive to increased inflammation, expanding the growing body of work highlighting mitochondrial ultrastructural changes in immune cell activity.Complimenting the mechanistic studies of mitochondrial shape change, Willingham et al. review subcellular specialization of mitochondrial structure and function in skeletal muscle and how plasticity of these mitochondrial features regulates function and physiological adaptations of skeletal muscle . The review by Pangou and Sumara explore the connection between mitosis and cell division by discussing the regulation of mitochondria by mitotic machinery and how in turn mitochondrial function and inheritance regulates mitosis. They discuss the mitochondrial dynamics during mitosis and how its dysregulation is linked to diseases (Pangou and Sumara 2022). The discussion of mitochondrial involvement in cell division is also covered by Madan et al., who examine this for polarized epithelium and how mitochondrial dynamics and metabolism play a role during epithelial-mesenchymal transition and cell migration for wound healing, inflammatory responses and tissue remodeling . Extending this discussion to the pathological condition of tumor metastasis, Boulton and Caino have explored how the molecular mechanisms of mitochondrial dynamics affect the growth, metabolism, and invasiveness of tumor cells. They discuss how mitochondrial fission machinery regulates growth factor and ROS signaling that drive metastasis through regulation of tumor cell and its microenvironment (Boulton and Caino. 2022).Expanding on the Original Research, Review Articles included in this Research Topic provide a comprehensive overview of contributions of mitochondrial dynamics to various physiological functions. In their minireview, Together the primary research articles and reviews collected in this Research Topic highlight how control over the mitochondrial spatial, temporal and structural changes drive cell-type specific signaling, to support cellular function in healthy and diseased states. We thank the authors for their contributions and expert insights, the collection of which in this Research Topic will add new insights into the growing recognition of mitochondrial dynamics and its subcellular architecture in driving diverse physiological processes."}
+{"text": "As working family caregivers navigate work and care responsibilities, the work environment may contribute to their psychological well-being and physical health outcomes. Working caregivers who provide multi-generational care  experience greater vulnerability when compared to non-sandwiched caregivers . This vulnerability could be mitigated by supportive work characteristics . Informed by the life course perspective, this study compared the psychological well-being and physical health of working sandwiched and filial caregivers, and the moderating role of work characteristics (decision authority and supervisor support). Sandwiched  and filial  caregivers from the Midlife in the United States (MIDUS-II) Survey provided information about their background, caregiving, employment, well-being, and health via a set of questionnaires and phone interview. Regression analyses showed that sandwiched caregivers exhibited lower levels of generativity than filial caregivers. Moderation analyses revealed that sandwiched caregivers with greater decision authority trended toward exhibiting greater autonomy than other caregivers. Sandwiched caregivers with greater decision authority also exhibited significantly less difficulty with instrumental activities of daily living (IADLs) than other caregivers. Finally, sandwiched caregivers with greater than average supervisor support trended toward exhibiting higher level of generativity as compared to other caregivers. Results highlight the impact of sandwiched caregiving on autonomy, generativity, and IADLs in the context of decision authority and supervisor support. Findings may inform workplace programs and policies aimed at enhancing caregivers\u2019 sense of decision making and increasing supervisor support in order to promote caregivers\u2019 psychological well-being and physical health."}
+{"text": "Automatically synthesizing consistent models is a key prerequisite for many testing scenarios in autonomous driving to ensure a designated coverage of critical corner cases. An inconsistent model is irrelevant as a test case ; thus, each synthetic model needs to simultaneously satisfy various structural and attribute constraints, which includes complex geometric constraints for traffic scenarios. While different logic solvers or dedicated graph solvers have recently been developed, they fail to handle either structural or attribute constraints in a scalable way. In the current paper, we combine a structural graph solver that uses partial models with an SMT-solver and a quadratic solver to automatically derive models which simultaneously fulfill structural and numeric constraints, while key theoretical properties of model generation like completeness or diversity are still ensured. This necessitates a sophisticated bidirectional interaction between different solvers which carry out consistency checks, decision, unit propagation, concretization steps. Additionally, we introduce custom exploration strategies to speed up model generation. We evaluate the scalability and diversity of our approach, as well as the influence of customizations, in the context of four complex case studies. Motivation. The recent increase in popularity of cyber-physical systems (CPSs) such as autonomous vehicles has resulted in a rising interest in their safety assurance. Since existing tools and approaches commonly represent CPSs as (typed and attributed) graph models )."}
+{"text": "Lower extremity ischemia due to extrinsic arterial compression by venous stent placement is a rare but increasingly recognized occurrence. Given the rise of complex venous interventions, awareness of this entity is becoming increasingly important to avoid serious complications.A 26-year-old with progressively enlarging pelvic sarcoma despite chemoradiation developed recurrent symptomatic right lower extremity deep venous thrombosis due to worsening mass effect on a previously placed right common iliac vein stent. This was treated with thrombectomy and stent revision, with extension of the right common iliac vein stent to the external iliac vein. During the immediate post-procedure period the patient developed symptoms of acute right lower extremity arterial ischemia including diminished pulses, pain, and motorsensory loss. Imaging confirmed extrinsic compression of the external iliac artery by the newly placed adjacent venous stent. The patient underwent stenting of the compressed artery with complete resolution of ischemic symptoms.Awareness and early recognition of arterial ischemia following venous stent placement is important to prevent serious complication. Potential risk factors include patients with active pelvis malignancy, prior radiation, or scarring from surgery or other inflammatory processes. In cases of threatened limb, prompt treatment with arterial stenting is recommended. Further study is warranted to optimize detection and management of this complication. Lower extremity ischemia due to extrinsic arterial compression by adjacent venous stents is a rare occurrence. Given the rise of complex venous interventions, awareness of this entity is becoming increasingly important to avoid serious complications including amputation. This case report describes a patient with pelvic sarcoma who developed lower extremity ischemia after the external iliac artery became compressed by an adjacent venous stent. Existing literature including risk factors and potential mechanisms are highlighted.A 26-year-old with progressively enlarging spindle cell sarcoma of the right pelvis despite multiple rounds of systemic and radiation therapy developed deep venous thrombosis and pulmonary embolism due to mass effect on the right iliac vein. This was treated with mechanical thrombectomy, inferior vena cava (IVC) and bilateral kissing common iliac vein stents, as well as initiation of therapeutic anticoagulation. The patient responded well until approximately two months after the procedure, where he presented to the emergency department with 1\u00a0week of worsening lower extremity swelling and pain. Physical exam was notable for diffuse pitting edema of the right lower extremity. Although the swelling limited mobility, there were no focal motor or sensory deficits. The extremity was warm and well perfused with 2\u2009+\u2009doppler signals from the popliteal, posterior tibialis, and dorsalis pedis arteries. The left lower extremity was normal.Right lower extremity ultrasound demonstrated acute deep venous thrombosis of the common femoral vein extending to the calf veins. Computed tomography (CT) venogram demonstrated thrombus throughout the right iliac vein and IVC stents with compression of the external iliac vein by the enlarging pelvic mass Fig.\u00a0. Given tWhile in the interventional radiology suite, posterior tibial vein access was obtained to infuse alteplase and perform venography, which demonstrated flow-limiting thrombus extending from the right popliteal to the common iliac vein. There was minimal flow to the IVC with extensive filling of collaterals Fig.\u00a0. The popWhile in the recovery unit, the patient\u2019s leg appeared mottled. Bedside doppler revealed diminished signals in the right popliteal, posterior tibialis, and dorsalis pedis arteries. After approximately 4\u00a0h the patient reported pain, decreased sensation to the dorsum of the foot, and impaired motor movement of the toes and ankle.A CT angiogram was performed, demonstrating high grade narrowing right external iliac artery adjacent to the newly placed right external iliac vein stent Fig.\u00a0. There wThe patient returned to interventional radiology for arterial angiography. The left common femoral artery was accessed and a 7 French destination sheath was advanced proximal to the right external iliac artery. Angiogram demonstrated severe focal narrowing along the right external iliac artery adjacent to the external iliac vein stent Fig.\u00a0. Two ovePost-procedure, there was return of 2\u2009+\u2009doppler signals throughout the right lower extremity. The previously noted acute motor and sensory deficits resolved. In addition to continuing therapeutic lovenox, the patient was started on 75\u00a0mg of clopidrogel daily to maximize arterial stent patency. The patient experienced significant improvement of lower extremity swelling and pain. Comfort care measures were ultimately pursued given progression of cancer.There has been a growing interest in complex venous interventions, owing to device improvements and increasing evidence to support catheter-based therapies for appropriately selected patients (Vedantham et al. Early recognition of this entity is important, as long-term sequelae from untreated limb ischemia can be devastating. One report describes the need for transfemoral amputation and subsequent issues with wound healing which required additional surgery (Trinidad et al. In almost all published cases where ischemia was detected early, endovascular stenting of the compressed artery was effective for revascularization. We thus recommend angiography and stenting as the primary initial therapy. Since delayed diagnosis can have serious morbidity, there should be a low threshold to bring the patient to the angiography suite. If the situation is not emergent and the clinical picture is unclear, CT angiogram can be considered to rule out other potential causes of ischemia, such as hematoma or distal thromboembolism. Vascular surgery should also be engaged early if there is suspicion for compartment syndrome or the need for open revascularization (Filtes et al. Although the risk factors for this phenomenon have not been rigorously studied, there are common themes within the published literature. Case reports have described this complication among patients with active pelvic malignancy, previously irradiated fields, prior pelvic surgeries, or other inflammatory processes (Filtes et al. While there is no clear trend, use of certain stents may contribute to the occurrence of this complication. Case reports have described this complication in the presence of both covered and uncovered stents, as well as self-expanding and balloon-expandable stents (Filtes et al. This complication was also observed when using Viabahn self-expandable stents during a similar case at our institution, as well in another case report (Subramaniam et al. The most frequently reported location of arterial compression after iliocaval stenting is the external iliac artery (Filtes et al. This case report raises the question of whether routine assessment of lower extremity arterial supply should be performed prior to any iliac vein intervention. In our case, checking pulses prior to our venous intervention was valuable for rapidly diagnosing an arterial problem, since a dramatic loss of arterial doppler signal should not occur after a venous intervention. Since this is easy to perform, we recommend routine perioperative pulse checks for patients who undergo complex venous interventions. Intra-procedural pulse-oximetry monitoring of the toes may also be useful to quickly assess for decreased arterial perfusion and guide whether immediate angiography should be performed (Kwasnicki et al. Although severe stenosis may manifest with clinically overt signs of threatened limb, more subtle effects of ischemia may go undiagnosed or misattributed to other etiologies, such as post-thrombotic syndrome. Thus, more objective assessments of arterial perfusion using non-invasive vascular studies including ABIs, PVRs, and doppler ultrasound should be considered in high risk patients. Rigorous peri-procedural evaluation of patients with peripheral artery disease or diabetes may also be beneficial to identify subclinical cases of decreased arterial perfusion, so that future issues with wound healing can be minimized. Ultimately, more research is warranted to effectively diagnose and manage this complication.Extrinsic arterial compression secondary to venous stent placement is a rare but increasingly recognized complication following iliac vein stenting. Potential risk factors include patients with active pelvis malignancy, prior radiation, or scarring from surgery or other inflammatory processes. In cases of threatened limb prompt treatment with arterial stenting is recommended minimize serious long-term sequelae. Further study is warranted to optimize detection and management of this complication."}
+{"text": "Persons with newly diagnosed Alzheimer\u2019s disease and related dementias (ADRD) and their care partners confront multiple challenges. These challenges have been even greater during the COVID-19 pandemic, where supportive resources often are limited or even discontinued. We conducted semi-structured interviews with 21 care partners of persons who were recently diagnosed with ADRD (2019-2020) to explore their lived experiences of adjusting to the new role. Directed and conventional content analyses were used and were informed by the life course theory. Care partners perceived difficulty in accessing medical and social services for their loved ones, particularly during the pandemic. Despite experiencing distress, some care partners chose not to seek help for fear of contracting COVID-19. This study provides insights on the unmet needs of care partners during a pandemic and highlights that effective, long-term strategies are needed to continue providing person-centered care to persons with ADRD and their families."}
+{"text": "Treatment of acute ischaemic stroke (AIS) focuses on rapid recanalisation of the occluded artery. In recent years, advent of mechanical thrombectomy devices and new procedures have accelerated the analysis of thrombi retrieved during the endovascular thrombectomy procedure. Despite ongoing developments and progress in AIS imaging techniques, it is not yet possible to conclude definitively regarding thrombus characteristics that could advise on the probable efficacy of thrombolysis or thrombectomy in advance of treatment. Intraprocedural devices with dignostic capabilities or new clinical imaging approaches are needed for better treatment of AIS patients. In this review, what is known about the composition of the thrombi that cause strokes and the evidence that thrombus composition has an impact on success of acute stroke treatment has been examined. This review also discusses the evidence that AIS thrombus composition varies with aetiology, questioning if suspected aetiology could be a useful indicator to stroke physicians to help decide the best acute course of treatment. Furthermore, this review discusses the evidence that current widely used radiological imaging tools can predict thrombus composition. Further use of new emerging technologies based on bioimpedance, as imaging modalities for diagnosing AIS and new medical device tools for detecting thrombus composition in situ has been introduced. Whether bioimpedance would be beneficial for gaining new insights into in situ thrombus composition that could guide choice of optimum treatment approach is also reviewed. Occlusion of a cerebral artery by a thrombus results in acute ischaemic stroke (AIS). Treatment of AIS aims to recanalise the occluded artery, promptly and efficiently, either by intravenous thrombolysis via recombinant tissue plasminogen activator (r-tPA) or mechanical removal of the thrombus via endovascular thrombectomy (EVT). In most countries, less than 15% of AIS patients are able to avail r-tPA treatmentUntil recently, there was limited availability of the thrombi that cause strokes. Available samples were mainly limited to occasional postmortem tissue and the clots removed in the course of thrombectomy device clinical trials. Since the success of clinical trials demonstrating effectiveness of mechanical thrombectomy in AIS patients with large vessel occlusions, more occluding thrombi removed during EVT procedures are available for analysis, allowing us to gain insights into thrombus composition.Perhaps the most characteristic feature of AIS thrombi retrieved by thrombectomy is the marked heterogeneity observed. A range of studies have described gross characteristics such as size, shape, morphology, consistency .Using H&E staining, AIS thrombi can be broadly classified into three subtypes, RBC rich, fibrin rich, or mixed. H&E staining cannot differentiate between fibrin and platelets. Nonetheless, using H&E staining, initial studies found that the composition of AIS thrombi is highly variable .6\u201310et al demonstrated that MSB staining can reliably identify platelet-rich areas.Some studies have employed Martius scarlet blue (MSB) staining, which provides better differentiation between fibrin and platelet components.CD42b immunohistochemical staining was used to study the platelet organisation within thrombi. Platelets were observed covering the fibrin layers, located at the periphery of RBC-rich arteriogenic thrombi or were clustered within fibrin rich cardioembolic thrombi.Activated neutrophils release histones and granule proteins embedded in web-like assembly of DNA filaments called neutrophil extracellular traps (NETs), for killing pathogens. Recent data have shown that NETs actively take part in thrombus formation by interacting with RBCs, platelets and platelet adhesion molecules such as fibronectin, fibrinogen and vWF, aiding formation of the thrombus scaffold with fibrin meshwork.Although rare, occasionally AIS thrombi have components found in atherosclerotic plaques such as calcification, cholesterol crystals and arterial wall components.Other methods such as scanning electron microscopy (SEM), atomic force microscopy, fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy have also recently been used to study AIS thrombi.The TOAST  classification categorises ischaemic stroke based on aetiology into five subtypes: (1) large-artery atherosclerosis (LAA), (2) cardioembolism (CE), (3) small-vessel occlusion, (4) stroke of other determined aetiology and (5) stroke of undetermined aetiology/cryptogenic.The composition and structural arrangement of a thrombus, is governed by the local haemodynamic conditions during clot formation.Several studies have suggested that cryptogenic strokes are primarily cardiogenic in origin, based on histological analysisIt has been also observed that extent of WBCs in AIS thrombi can varyThrombus composition can influence the efficacy of thrombolysis by r-tPA. Previous research has shown that RBC-rich thrombi respond better to r-tPA than platelet-rich or white thrombi.A recent study that investigated arrangement of thrombus components speculated that RBC-rich areas which have thin fibrin arrangements might be most prone to degradation by r-tPA.SEM has advanced understanding of the characteristics of thrombolysis-resistant clot which was shown to have a thick, compact outer shell made of densely compacted thrombus components including fibrin, vWF and aggregated platelets and this made the thrombi less susceptible to thrombolysis.et al did not find any correlation of thrombus components with recanalisation after EVTThrombus composition may play an important role in successful removal of thrombus via EVT. A study by Ahn The mechanical characteristics of thrombi are related to composition. An in vitro study with clots prepared from human blood found that thrombi with RBC content of 20% or above have increased viscosity and elasticity compared with clots with low RBC content.Higher WBC percentage in thrombi has been shown to negatively correlate with recanalisation and clinical outcome such as National Institutes of Health Stroke Scale (NIHSS) score at discharge and modified Rankin Scale score upto 90 days.et al found a trend suggesting the presence of vascular wall components was associated with lesser recanalisation success.Calcified emboli are quite rare in AIS patients with large vessel occlusions, but when present, calcification is associated with poor recanalisation and higher mortality.Patients have the best outcomes after EVT if the entire thrombus is retrieved in a single pass.AIS thrombus can be identified by CT and MRI. However, studies investigating the association of thrombus imaging with recanalisation have largely utilised CT imaging . CT is mIsodense clots on non-contrast CT (NCCT) correlate with a high fibrin/platelet content and are more resistant to thrombolysis and EVT.The vessel sign observed on gradient eco imaging (GRE) in AIS patients is called SVS. The SVS on GRE imaging is defined as a hypointense signal that spreads outside the actual thrombus periphery. The SVS is observed in 50%\u201385% of AIS patients with large vessel occlusion, particularly in RBC rich thrombus, while a lack of SVS usually suggests presence of fibrin-rich thrombus .35Thrombus permeability or perviousness is the degree to which blood is able to flow through a thrombus structure. Thrombus perviousness is the residual flow that is quantified using simultaneous measurement of thrombus attenuation on NCCT and single-phase CT angiography, called \u2018thrombus attenuation increase\u2019 (TAI). Increased perviousness gives high TAI.Imaging characteristics such as HAS and SVS have been linked to stroke aetiology. Some single centre studies have correlated SVS with cardioembolic aetiology in AIS.The prognostic value of SVS for recanalisation is debatable. SVS has been variously shown to be a negative predictor of early recanalisation after IV r-tPA treatmentThrombus permeability is potentially an important predictor of AIS treatment. It has been associated with better functional outcome, smaller final infarct volume, and higher recanalisation following IA r-tPA or IV r-tPA.Imaging techniques are the best way of visualising thrombus in situ, and the only way to visualise thrombi in in vivo environments. In the case of thrombi dissolved by r-tPA or thrombi not retrieved via EVT, clot imaging is the only resource for characterisation. While post thrombectomy analysis of clot composition is very valuable to improving our understanding, EVT can damage or cause structural changes in the thrombus during the removal procedure.Intraprocedural devices with dignostic capabilities or new clinical imaging approaches are needed for better guidance of device selection prior to EVT.Biological tissues possess electrical properties and these properties are dependent on morphological, physiological and pathological conditions of the tissue and the frequency of the applied electrical signal.The bioimpedance measured with applied alternating current varies with the frequencyElectrical Impedance Spectroscopy (EIS) is carried out by measuring the electrical impedance of biological tissues over a frequency range. Since the electrical response of tissues is determined by their cellular components and the dimension, internal structure and arrangements of the constituent cells, tissues with different morphological and physiological properties give rise to characteristic impedance spectra.Based on EIS principles, clinical applications have been developed, especially in the field of oncology. SciBase, Dilon Technologies, Zilico, are some of the companies that developed medical devices with CE and/or FDA (US Food and Drug Administration) approval. These devices  can discriminate healthy tissues from cancerous tissues  with high sensitivity and specificity.et al demonstrated that based on EIS measurements, blood clot analogues can be classified into RBC rich or platelet and fibrin rich clots.EIS-based sensors are being developed for blood components such as WBCsSome studies have also demonstrated the feasibility of utilising balloon catheters mounted with microelectrodes for EIS measurements. The integration of four microelectrodes onto a catheter is made possible using a flexible and ultralight polyimide foil. Using such a system in atherosclerotic animal models, intravascular EIS measurements differed significantly in aortic plaques compared with normal aortic tissues.In recent years, mechanical thrombectomy has facilitated the analysis of thrombi retrieved during the EVT procedure and marked heterogeneity has been observed. Restricted availability of thrombi other than ones found in LVOs that are easily retrievable limits the current knowledge of AIS thrombi. Further studies will improve understanding of aetiology and its correlation to thrombus composition and clinical outcome. New emerging methods such as EIS, could be beneficial for gaining new insights into pathophysiological mechanisms of thrombus formation and identifying clot characteristics in situ in the acute care setting, aiding in selection of better treatment options for the AIS patients."}
+{"text": "Subjective age has traditionally been considered by comparing felt age to chronological age, with those who feel younger reporting more adaptive developmental outcomes. Here we consider a new approach: subjective age discordance, which compares felt ages to the ideal ages of participants. Across eight study days, 116 older and 107 younger adults reported their daily felt and ideal ages. On the majority of days, both older and younger adults idealized ages younger than they felt. The opposite pattern, idealized ages older than felt ages, was rare and primarily seen in younger adults. Days when felt ages were less discordant from ideal ages were characterized by higher levels of positive affect than days with greater subjective age discordance. These findings suggest that positive developmental outcomes can occur not only from feeling younger, but through a greater alignment of ideal and felt ages."}
+{"text": "Pressure overload hypertrophy of the left ventricle is a common result of many cardiovascular diseases. Androgens show anabolic effects in skeletal muscles, but also in myocardial hypertrophy. We carefully reviewed literature regarding possible effects of androgens on specific left ventricular hypertrophy in pressure overload conditions excluding volume overload conditions or generel sex differences. Pressure overload hypertrophy (POH) of the left ventricle is a common result of diseases like arterial hypertension, aortic valve stenosis, hypertrophic obstructive cardiomyopathy or aortic coarctation and is associated with increased morbidity and mortality \u20134. Thus,via the enzyme 5 alpha reductase (via androgen receptors (AR), but DHT shows twice the affinity for the AR and a ten-fold more potent effect on signalling pathways when compared to Testosterone (Testosterone in the human body is mainly produced by the gonads (by the Leydig cells in testes in men and by the ovaries in women) and in smaller amounts by the adrenal glands in both sexes. Conversion to DHT takes place eductase . Both hoosterone . Both hoosterone . In humaosterone , 16. Totosterone . A thirdosterone .via androgen receptors (AR) and induce myocardial hypertrophy via two different ways: 1) in a DNA binding-dependent manner (genomic pathway) where androgens bind to the AR, translocate into the nucleus and act like a transcription factor or 2) in a non-DNA binding-dependent manner  where androgens bind to the AR and activate rapid 2nd messenger signalling cascades, for example . Next to low serum levels of DHT these patients showed low degree of left ventricular muscle mass despite severe aortic valve stenosis and pressure overload . Our finData from animal studies and the few existing human data suggest that anti-androgenic therapy has the potential to improve cardiac function and remodelling in heart failure and to reduce or prevent cardiac hypertrophy in pressure overload conditions. Next to the detrimental pro-hypertrophic cardiac effects, Testosterone replacement therapy has been associated with prostate cancer, polycythemia and obstructive sleep apnea and many long-term effects are still unknown , 45. ThuOn the other hand, excessive reduction of serum androgen levels should be prohibited, especially in male patients. Very low levels of Testosterone in elderly men with Testosterone deficiency have been associated with increased cardiovascular risk and mortality and positive cardiovascular effects have been described for Testosterone replacement therapy in these patients \u201349. TestThe study situation currently remains controversial and future studies are required to determine, whether and if yes what kind of anti-androgenic therapy might be a treatment option at least for time-restricted therapy in patients with severe AS waiting for surgical or interventional relieve of pressure overload.Testosterone and/or its active metabolite DHT increase the hypertrophic response of left ventricular myocardium to pressure overload in animal models and associations were seen in human subjects. Anti-androgenic treatment to lower Testosterone and/or DHT levels should be discussed as a possible treatment option to reduce cardiac hypertrophy; however, possible negative effects of low serum levels of Testosterone onto vascular and metabolic health have to be taken into consideration. Future studies should focus on cardiac-specific anti-androgenic therapy in order to prevent myocardial hypertrophy in pressure overload conditions without negatively affecting general patient health in women and men.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication."}
+{"text": "There is literature describing unilateral or focal pulmonary edema due to mitral regurgitation. The proposed mechanism is a regurgitant jet propelling blood towards the orifice of a particular pulmonary vein within the left atrium, which selectively pressurizes that vein. The increased hydrostatic pressure is transmitted to the pulmonary capillaries that drain into that vein, causing focal consolidation. A 62-year-old female presented with acute hypoxic respiratory failure. Her dyspnea started suddenly and she was unresponsive when she arrived at the emergency department via emergency medical services. Her initial oxygen saturation was 23% and she was immediately intubated. Sequential chest radiographs demonstrated dense consolidation in the right upper lung field and then opacification of the right hemithorax. These asymmetric lung findings were suspicious for infectious etiology but she was afebrile with no respiratory secretions and had normal inflammatory markers. Echocardiography showed a ruptured anterior papillary muscle causing a flail mitral valve leaflet with severe mitral regurgitation. The patient developed cardiogenic shock; she had an intra-aortic balloon pump placed for afterload reduction and was taken to the operating room for an emergency mitral valve replacement. Her clinical status rapidly improved and she made a full recovery. As in this case, acute mitral regurgitation can present with sudden life-threatening respiratory failure and cardiogenic shock so prompt diagnosis is critical. This is often misdiagnosed as pneumonia or other respiratory illnesses. Awareness, early diagnosis, and treatment of this entity could provide significant morbidity and mortality benefits for patients. Shortness of breath is a common chief complaint seen in the emergency department and carries a broad differential diagnosis. Chest radiography, a valuable and commonly used tool, can help clinicians narrow differential diagnoses and provide appropriate patient care. Unilateral infiltrates on chest radiography, often seen in bacterial pneumonia, may evoke an infectious etiology of dyspnea. However, focal or unilateral pulmonary edema has been described in patients with mitral regurgitation from numerous causes, including spontaneous valve perforation , valve pA 62-year-old female presented to the emergency department with acute respiratory failure. Her past medical history included obstructive sleep apnea with the use of bilevel positive airway pressure at night, obesity hypoventilation syndrome, systemic hypertension, pulmonary hypertension, mild to moderate mitral regurgitation complicated by pulmonary edema, asthma, and the use of home oxygen . A transthoracic echocardiogram performed five months before the presentation during hospitalization for dyspnea showed normal biventricular size and function, mild left atrial dilation, normal mitral valve structure with mild to moderate regurgitation, and a mildly elevated pulmonary artery systolic pressure. A chest radiograph performed one month before the presentation showed no evidence of pulmonary edema. Her home medications included furosemide, losartan, inhaled fluticasone and vilanterol, promethazine syrup, nebulized albuterol, and benzonatate.Per the patient\u2019s husband, she was in her normal state of health until awakening in the morning and feeling short of breath after using the restroom; the shortness of breath was refractory to albuterol nebulizer treatments self-administered at home for a presumed asthma exacerbation. At that time, she appeared to have labored breathing, prompting the patient and her husband to call emergency medical services (EMS). In the ambulance, she was initially alert and awake with a normal mental status but suddenly became unresponsive; her oxygen saturation dropped to 20% and her heart rate increased to 160 beats per minute. She arrived at the emergency department via EMS, unresponsive, with an oxygen saturation of 23% and sinus tachycardia; initial examination revealed diffuse rhonchi and a Glasgow Coma Scale (GCS) score of six. She was immediately intubated; she required high ventilator settings (fraction of inspired oxygen (FiO2) at 100%, positive end-expiratory pressure (PEEP) at 16 mbar), and neuromuscular blockade to achieve adequate oxygenation.Initial chest radiography demonstrated mild cardiomegaly, background interstitial pulmonary edema, and a dense consolidation in the right upper lobe with a patchy opacity at the right lung base. Figure .A subsequent chest radiograph showed nearly complete opacification of the right hemithorax and progressive opacification of the left lung base Figure .These asymmetric lung findings were suspicious for an infectious etiology, including coronavirus disease 2019 (COVID-19) and bacterial pneumonia. She tested negative for COVID-19 . She had a mild leukocytosis without neutrophilic predominance, and inflammatory markers were not consistent with severe infection  confirmed severe mitral regurgitation and showed a ruptured anterior papillary muscle Figure .The TEE showed severe systolic flow reversal in the right upper pulmonary vein and only mild systolic flow reversal in the other three pulmonary veins. Figure\u00a0The pulsed-wave Doppler images demonstrate pulmonary vein flow reversal, noting the highest degree of flow reversal in the right superior pulmonary vein Figures -9.She was taken to the operating room for emergent bioprosthetic mitral valve replacement. Afterward, her clinical status improved; she began to void, her pulmonary artery pressures were corrected, and she was extubated 72 hours after the presentation. Subsequent chest radiography showed rapid resolution of the asymmetric infiltrates Figure .This was a dramatic presentation of spontaneous, non-ischemic papillary muscle rupture, causing severe acute mitral regurgitation and respiratory failure from the resulting flash pulmonary edema. The patient was critically ill within one to two hours of symptom onset. Of particular interest is the initial chest radiograph showing asymmetric opacification with dense consolidation of the right upper lobe. This appearance was initially concerning for an infectious etiology, which could have delayed the diagnosis.Focal or unilateral pulmonary edema has been described in patients with mitral regurgitation from numerous causes, including spontaneous valve perforation , valve pSchnyder et al. found that 9% of patients with severe mitral regurgitation had chest radiography findings that were \"localized or predominant\" in the right upper lobe . Attias There is a proposed mechanism for localized pulmonary edema due to mitral regurgitation. Typically, systolic or diastolic left ventricular failure leads to increased pressure within the left atrium, which is transmitted symmetrically to each of the pulmonary veins. This leads to increased hydrostatic pressure within pulmonary capillaries, causing a uniform degree of pulmonary edema throughout the lungs. It is thought that asymmetric pulmonary edema is due to a mitral regurgitant jet that propels blood selectively towards the orifice of a particular pulmonary vein within the left atrium. If a regurgitant jet causes increased pressure within that pulmonary vein, it would transmit increased hydrostatic pressure selectively to the pulmonary capillaries that drain into that pulmonary vein, causing focal edema.This mechanism is supported by Kashiura et al., who described two cases of unilateral pulmonary edema from severe acute mitral regurgitation. The first case involved an eccentric jet blowing towards the right side of the left atrium and a patient who presented with right-sided opacities. The second case involved a jet blowing towards the left side of the left atrium and a patient who presented with left-sided opacities . In thisAs in this case, acute mitral regurgitation can present with sudden life-threatening respiratory failure and cardiogenic shock, so prompt diagnosis is critical. This is often misdiagnosed as pneumonia or other respiratory illnesses. Patients with unilateral lung opacification due to mitral regurgitation have delays in diagnosis and worse outcomes compared to similar patients with bilateral pulmonary edema. In this case, the key to the diagnosis was the reported history of sudden-onset dyspnea that rapidly progressed to respiratory failure.In conclusion, acute mitral regurgitation should be considered in the differential diagnosis for patients with focal pulmonary opacities or complete opacification of a hemithorax in the appropriate clinical context, such as sudden-onset hypoxic respiratory failure, especially if vitals, examination, and laboratory biomarkers are inconsistent with severe infection. Awareness, early diagnosis, and treatment of this entity could provide significant morbidity and mortality benefits for patients. In this case, the findings support the previously proposed mechanism of a regurgitant jet selectively pressurizing a pulmonary vein, leading to focal consolidation."}
+{"text": "It is often challenging to engage and retain rural Latinx and Native Americans in psychosocial interventions after stroke, despite the fact that these populations tend to experience poorer health outcomes. Although strategies for effective patient-provider communication exist, few studies focus on the cultural aspects of engagement and retention of diverse dyads in a rural context. The aim of this study is to describe barriers to engagement and retention of diverse rural dyads in post-stroke psychosocial interventions, as well as to elucidate specific strategies to address these barriers. Semi-structured interviews were conducted with Nf14 clinical providers with extensive experience serving diverse rural couples and families. Qualitative data were analyzed using interpretive description methods. Seven key barriers were identified, grouped broadly into: 1. Those presented by providers  and 2. Those existing within dyads themselves . Providers offered specific culturally-informed strategies to overcome barriers which in turn may increase engagement and minimize attrition. Providers and researchers may benefit from these insights as they work to communicate with, build trust, and meet the unique needs of these populations."}
+{"text": "More specifically, they found that university students are more likely to update beliefs concerning grade expectations following positive rather than negative prediction errors.Behavioral results suggest that learning by trial-and-error  relies on a teaching signal, the prediction error, which quantifies the difference between the obtained and the expected reward. Evidence suggests that distinct cortico-striatal circuits are recruited to encode better-than-expected (positive prediction error) and worst-than-expected (negative prediction error) outcomes. A recent study by Villano et al. Virtually all animals use past rewards and punishments to modify their future course of actions (a process referred to as reinforcement learning). Behavioral and computational theories suggest that reinforcement learning relies on a teaching signal, the prediction error (PE), which quantifies the difference between the obtained and the expected reward. PE minimization across trials and repetitions enables  to efficiently learn and adapt their behavior accordingly.2. A direct implication of these neurobiological observations is that learning from positive and negative PEs could be independently modulated at the behavioral level3.Neurophysiological studies across rodents, monkeys and humans collectively suggest that reinforcement learning processes are largely underpinned by dopamine-mediated neural plasticity of the cortical-subcortical connections and that positive and negative PEs are encoded across dissociable circuits that recruit different cortical and subcortical structures of the brainUntil recently, however, prior studies were carried out in relatively constrained and \u201caseptic\u201d experimental settings. Most of the tasks employed implemented quite artificial learning scenarios, which potentially casts doubt on the ecological and real life validity of these findings.1 has overcome this limitation by investigating how humans integrate positive and negative PEs when updating their belief concerning consequential real life outcomes. More specifically, in a large scale study, they asked 625 university students to predict their grades during four consecutive semesters.A recent study from Villano et al.At the macroscopic level, participants learned to modify their expectations concerning future grades in a manner compatible with prediction error minimization. However, a more fine-grained analysis showed signs that could be considered as an \u201coptimistic\u201d bias: on average participants learned more following positive as opposed to negative PEs. The results support the idea of distinguishable neural networks for positive and negative prediction errors by showing an optimistic bias manifesting at the behavioral level.4.The authors also report that participants who presented symptoms consistent with anxiety and depression, also showed a reduction in optimistic learning bias. This finding is consistent with prior evidence showing similar learning rate modifications in depression and anxietyAltogether, this study provides evidence for prediction error-based learning outside of the laboratory, in real life scenarios. It also provides evidence for the fact that learning from positive and negative prediction errors are functionally dissociable. Both findings are consistent with decades-long neurobiological investigations of the computational mechanisms underlying reinforcement learning."}
+{"text": "Certain neuropsychiatric symptoms (NPS), namely apathy, depression and anxiety demonstrated great value in predicting dementia progression representing eventually an opportunity window for timely diagnosis and treatment. However, sensitive and objective markers of these symptoms are still missing.To investigate the association between automatically extracted speech features and NPS in early-stage dementia patients.Speech of 141 patients aged 65 or older with neurocognitive disorder was recorded while performing two short narrative speech tasks. Presence of NPS was assessed by the Neuropsychiatric Inventory. Paralinguistic markers relating to prosodic, formant, source, and temporal qualities of speech were automatically extracted, correlated with NPS. Machine learning experiments were carried out to validate the diagnostic power of extracted markers.Different speech variables seem to be associated with specific neuropsychiatric symptoms of dementia; apathy correlates with temporal aspects, anxiety with voice quality and this was mostly consistent between male and female after correction for cognitive impairment. Machine learning regressors are able to extract information from speech features and perform above baseline in predicting anxiety, apathy and depression scores.Different NPS seem to be characterized by distinct speech features which in turn were easily extractable automatically from short vocal tasks. These findings support the use of speech analysis for detecting subtypes of NPS. This could have great implications for future clinical trials.No significant relationships."}
+{"text": "To protect themselves from contracting the SARS-CoV-2 virus, many older adults managing multiple medical conditions experienced increased social isolation. The objective of our qualitative research study was to describe how older Veterans receiving care from the United States (US) Department of Veterans Affairs (VA) healthcare system, and their caregivers, managed increased social isolation during the pandemic. We recruited Veterans and their caregivers residing in rural and urban areas who received care from either a tele-palliative care or a tele-geriatrics clinic connected to one VA Medical Center, inviting them to participate in phone interviews. From May-September 2021, we interviewed N=23 participants (n=9 Veterans and n=14) caregivers. We applied a deductive and inductive approach to thematic analysis to analyze interview data. Findings revealed that while caregivers experienced increased anxiety, which they attributed to pandemic-related changes, they also expressed solidarity in that others were experiencing similar stressors. Many caregivers and Veterans shared experiences of increased loneliness, which some found difficult to manage as communication with their social networks was sparse. At the same time, the pandemic made them value relationships with others more than before. Some Veterans noted they kept busy with hobbies and did not feel much loneliness despite increased isolation. Caregivers caring for Veterans with dementia stated they experienced confusion about their narrower social networks because they could not remember reasons why they were not regularly spending time with them. Findings demonstrate the need to identify strategies and policies to better support caregivers and older Veterans during times of crisis."}
+{"text": "Hospitalizations for severe injection related infections (SIRI) amongst persons who inject drugs (PWID) are often complicated by patient directed discharge (PDD), incomplete antibiotic treatment and 90-day readmission. Despite a strong association with improved clinical outcomes, medications for opioid use disorder (MOUD) remain significantly underutilized in this patient population. Beginning in January of 2022, our institution revised several key policies that had limited inpatient use of MOUD while also implementing a new order set to facilitate MOUD inductions. This study seeks to quantify the clinical impact of these interventions in PWID admitted with SIRI.We first performed a retrospective analysis of all PWID hospitalized with SIRI between January 2018 and December 2020 to establish baseline rates of PDD, antibiotic completion and 90-day readmission in patients who received MOUD compared to those who did not. Subsequent analyses will utilize a quasi-experimental design to compare the same clinical outcomes in patients admitted before and after institutional guideline revision and MOUD order set implementation.A total of 97 patients were included in our baseline assessment, of which 21 (21.6%) received MOUD while hospitalized. Of patients receiving MOUD, 11 (52.4%) were new inductions. Use of MOUD was associated with significantly lower rates of PDD  and significantly higher rates of antibiotic completion .Our baseline data agrees with existing literature in finding MOUD to be an effective way of reducing PDD and increasing antibiotic completion in PWID admitted with SIRI. However, overall MOUD utilization was low, particularly after accounting for the effect of individuals prescribed MOUD prior to admission. Forthcoming data will assess the impact of institutional guideline revision and MOUD order set implementation on PDD, antibiotic completion and hospital readmission in PWID admitted with SIRI.All Authors: No reported disclosures."}
+{"text": "Many existing Alzheimer\u2019s disease (AD) caregiving interventions focus narrowly on thechallenges and needs of a primary caregiver rather than the family systems in which they areembedded. We advance a family systems framework by invoking convoys of caregiving to adaptan existing AD caregiver intervention to Middle Eastern/Arab American families in metroDetroit (N=56). The composition of caregiving networks is described, followed by assessment ofcare burden, depressive symptoms, care satisfaction and family conflict. Results show thatsiblings and children are the predominate support network members who accompanied theprimary caregiver to the program. Paired t-tests show that care burden and family conflictdecreased while caregiving satisfaction increased following program participation. Depressivesymptoms did not change. Findings illuminate how convoys of care may serve as valuablesupport resources, yet may also be the source of stress and conflict."}
+{"text": "The various application markets are facing an exponential growth of Android malware. Every day, thousands of new Android malware applications emerge. Android malware hackers adopt reverse engineering and repackage benign applications with their malicious code. Therefore, Android applications developers tend to use state-of-the-art obfuscation techniques to mitigate the risk of application plagiarism. The malware authors adopt the obfuscation and transformation techniques to defeat the anti-malware detections, which this paper refers to as evasions. Malware authors use obfuscation techniques to generate new malware variants from the same malicious code. The concern of encountering difficulties in malware reverse engineering motivates researchers to secure the source code of benign Android applications using evasion techniques. This study reviews the state-of-the-art evasion tools and techniques. The study criticizes the existing research gap of detection in the latest Android malware detection frameworks and challenges the classification performance against various evasion techniques. The study concludes the research gaps in evaluating the current Android malware detection framework robustness against state-of-the-art evasion techniques. The study concludes the recent Android malware detection-related issues and lessons learned which require researchers\u2019 attention in the future. Since this study focused on Android malware obfuscation, we had selected \u2018Android malware, \u2018malware obfuscation\u2019, and \u2018malware evasion\u2019 as our search terms. The search results in 511 research from journals and conferences\u2019 proceeding database. The search results mainly records are from IEEE, journals and conferences distributions as per The list of collected articles represent the Android malware obfuscation and detection frameworks. It included the three types of the malware analysis techniques static, dynamic and hybrid techniques in the last decade from 2011 to early 2021. Hence, we collected Android malware frameworks for the last decade and innovative contributions that appeared in high-ranked journals or conferences such as IEEE, ACM, and Springer.Since, this paper explored the last 10 years\u2019 research to evaluate the Android detection frameworks against evasion techniques, we focused on experimental malware detection articles using static, dynamic and hybrid analysis techniques, excluding the unrelated articles. We excluded articles that are not Android specific malware detection such as IOS and Windows based operating system. In addition, we excluded all other languages and include only English language research to avoid translation overhead in future.As shown in We scrutinise Android malware detection academic and commercial frameworks while a large portion of the past work concentrated on commercial anti-malware solutions. This study examines different evasion techniques that hinder detecting malicious parts of applications and affect detection accuracy by reviewing state-of-the-art Android malware studies and issues limiting the detection of evasion techniques. It is worth noting that this work differs from related works that examine detection methods, as we go through evasion techniques that let malware evades detection methods.In the section, we discussed the Android application architecture. Subsequently, we investigate the Android operating system (OS) weaknesses. This background highlights the seriousness of some drawbacks to rationalize the necessity of establishing this review and explain the essential terms to support the readers of this study.Android application, Android app, or APK refers to the Android application from now on and throughout this paper. APK is a compressed file; an unzipping program extracts its files and folders. This segment explains the APK components and their contents, as some terms are essential in this study. APK developers use development tools that occasionally require simple programming experience from young developers. The Android app runs on Dalvik or ART equivalent to Java Virtual Machine (JVM) in a desktop environment. The APK structure consists of many files and directories; the main file is Classes.dex Java bytecode; it includes the classes and is packed together in a single .dex file. The AndroidManifest.xml file contains deployment specifications and the required permissions from Android OS. Resources .arsc is compiled resources, and Res folder is un-compiled resources.The Android system must install the APK file so that the end-user can utilize the application\u2019s functionalities. The Android system only accepts APK with a valid developer certificate, called developer identifier. Individual developers keep their certificate keys; there is no Central Authority (CA) server to maintain developers\u2019 keys, and thus no chain of trust between app stores and developers.a)Activities: The user interface that end-users interact with and that communicates with other activities using intents.b)Services: Android application component runs as a background process and bonds or un-bonds with other Android system components.c)Broadcast and Receivers Intents: send messages that all other applications or individual applications receive.d)Content Providers: It is the intermediate unit to share data between applications.End-users need to run the installed applications, while other apps run as a service in the OS background. Therefore, the Android application\u2019s main components are as follows:(a) Open Source:The advantage of Android source code\u2019s openness helps developers\u2019 communities enhance the OS and add more features. Therefore, the Android community improves Android OS daily. But, this contradicts with the security concerns when malware writers take this advantage. It makes their job more straightforward than in closed source firmware, which commonly triggers new vulnerabilities and malware attacks .(b) End-users Security Awareness:End-users understanding malware\u2019s seriousness plays a vital role in early prevention and detection when using feedback and reviews. However, the end-users feedback system is insecure and easily polluted by fake comments . End-use(c) Third-party Apps Market:via tools such as the ADB tool in Android SDK, which increases the probability of installing malicious apps  The Coarse Granularity of Android Permissions:i.e., one permission that provides access to entire Internet protocols and all sites. There is no competent permission administration or sufficient permission documentation, leading to excess permissions  Developers\u2019 Signatures:Android application developers have to sign their apps with their developer key before uploading the developed application to the market. There is no external party to authenticate developers\u2019 signatures and thus no confidentiality or integrity . Hence, (f) Application Version Update:Android applications usually enhance their functionalities in the form of version updates. The security frameworks analyze the application during installation, and the update process downloads new services/features without security precautions or checks .(g) USB Debugging:USB debugging is a valuable feature for Android Application development; it helps developers be more productive and efficiently troubleshoot applications. It allows direct installation of an application to the Android device using Android SDK tools such as the ADB tool. In addition Expo framework  has the (h) Dynamic Code Loading (DCL):DCL is an Android OS feature that enables benign Android applications to call another APK or malicious code to compile and execute it in real-time. However, malware developers use this feature to load their malicious codes dynamically after the detection framework ranked the malicious app as benign.(i) Inter-application Communication (intent):Android OS uses the inter-application intent system to deliver a message from and to applications. Malware developers sniff, modify, or gain knowledge, compromising data integrity and privacy . The intWith some insight into the Android applications\u2019 development design, we list the Android system\u2019s weaknesses and definitions for the readers of this study. The following is a list of Android flaws and characteristics that malware authors and attackers abuse.This section represents our taxonomy of the currently used evasion techniques and research studies on detecting obfuscated malware. Our taxonomy focuses on classifying the related studies with the same objectives and goals to harvest a comprehensive collection of material and comparative conclusions. When scrutinizing many existing studies, we find it more appropriate to study the evasion detection capabilities of each studied framework after introducing the evasion techniques that hinder malware analysis and detection. This section presents the taxonomy of detection techniques for the ground truth relation between the detection methodology and the evasion ability. Android applications have powerful tools and techniques to secure and protect their applications from being reverse-engineered. Conversely, malware authors are using obfuscation tools and techniques to evade detection. Therefore, evasions, or in other terms, transformation techniques, are techniques that try to defeat Android malware detection and rank the malware applications as benign.As displayed in Polymorphic malware is the malware category that keeps changing its characteristics to generate different malware variants evading malware detectors. Polymorphic malware encrypts part of the code embedding malicious code. The polymorphic malwares encrypt itself with variable encryption keys but maintaining the malicious code body unaltered. Polymorphic malware is an advanced version of oligomorphic malware. The oligomorphic malware encrypts the malicious code to defeat source code static analysis based malware detection. Usually, the malware decrypts the malware using the same techniques. However, the oligomorphic malware decrypts the encrypted malicious code using different deyrptor to make decryptor analysis more difficult. The static analysis analyze the decryptor to find the encryption key that enable the detection of the malware. Hence, the static analysis approach is not effective with oligomorphic malware. Polymorphic malware continuously change the decryptor technique to make it more difficult to the source code static analysis approach. These symptoms are indications of the presence of malicious code in an application. In this section, we discuss the polymorphism evasions subcategories, which are package transformation and encryption.(a) Repacking (RPK): It is the process of unpacking the APK file and repacking the original application files but signing the APK file with a developer security key . This wa(b) Package Renaming (PKR): Every Android application has a unique package name. For instance, com.android.chrome is the package name of Google Chrome. PKR uses multilevel techniques to obfuscate the application classes except for the main Class, for instance, \u201cFlattenPackageHireachey\u201d or \u201cRepackageClass\u201d options . As showThis algorithm is applied relatedly to form the multilevel PKR obfuscation. The GinMaster family contains a malicious service that can root devices to escalate privileges, steal confidential information. Later, it receives instructions from a remote server to download and install applications without user interaction. The malware can successfully avoid detection by mobile anti-virus software by using polymorphic techniques to hide malicious code, obfuscating class names for each infected object, and randomizing package names and self-signed certificates for applications. Therefore, PKR evades the malware detection technique and causes false negatives, proven by (c) Identifier Renaming (IDR): Identifier is another APK parameter representing the application developer\u2019s signature. Classes, methods, and fields consider bytecode identifiers, as a signature is generated based on. Malware authors change developer identifiers using many obfuscation tools such as ProGuard  and DexGIn this section, we study types of package transformation, which are Repacking (RPK), Package Renaming (PKR), and Identifier Renaming (IDR).Data Encryption as DEN, Bytecode Encryption as BEN, and Payload Encryption as PEN. This paper examines the following types of evasions:a)Data Encryption (DEN): This evasion technique tends to encrypt specific data vital for the malicious action and decrypt the encrypted data later, which modifies the malware application characteristics to evade the detection techniques . The datb)Bytecode Encryption (BEN): using ProGuard  or DashOc)Payload Encryption (PEN): Malware authors use payload encryption as in DroidDream  malware Some Android malware families encrypt data values inside the code, compiled code or payload, and decrypt the payload whenever desirable. This paper refers to Metamorphic malware is more complex than polymorphic malware that shows a better ability to evade detection frameworks. Malware authors adopt metamorphic malware so to make metamorphic malware detection harder than leveraging polymorphic malware. The metamorphic malware writes new malicious code that varies in each iteration using the same encryption and decryption key. For example, Opcode ngrams  adopts tCode Reordering (CRE), Call Indirection (CIN), and Dead Code Insertion (DCI).a)Code Reordering (CRE): This transformation changes the order of the code by inserting the standard \u201cgoto\u201d command to maintain the proper program instruction order.b)Call Indirections (CIN): CIN is an object-oriented feature used dynamically to reference specific values inside the code; CIN creates code transformation evasion, obfuscating the call graph detection techniques . Malwarec)Dead Code Insertion (DCI): Malware inserts junk code into the sequence of the application to ruin its semantics. This type of transformation makes the malware more difficult to analyze . AnDarwiCode obfuscation is an evasion technique initially used to protect applications from piracy and illegal use by many obfuscation techniques. Conversely, malware authors use code obfuscation techniques to evade malware detections. In this study, we highlight three types of code obfuscation the Native Exploits (NEX), Function Inlining and Outlining (FIO), Reflection API (REF), Dynamic Code Loading/Modification (DCL/DCM), and Anti-debugging (ADE).a)Native Exploits (NEX): Android applications call native libraries to run system-related functions. The malware uses a native code exploit to escalate the root privilege while running . Unfortub)Function Inlining and Outlining (FIO): Inlining and outlining are compiler optimization techniques options. Inlining replaces the function call with the entire function body, and the outlining function divides the function into smaller functions. This type of transformation obfuscates the call graph detection technique by redirecting function calls and creating a maze of calls .c)Reflection API (REF): Reflection API is a technique to initiate a private method or get a list of parameters from another function or class, whether this class is private or public. Android developers legitimately use it to provide genericity, maintain backward compatibility, and reinforce application security. However, malware authors take advantage of this feature and use it to bypass detection methods. Reflection evasion facilitates the possibility to call private functions from any technique outside the main class. Recently few studies highlighted the reflection effect on code analysis and considered reflection during the analysis process .d)Dynamic Code Loading/Modification (DCL/DCM): Since Java has the capability of loading code at runtime using class loader methods, Android malware application dynamically download malicious code using the dynamic code loading (DCL). The DCL and DCM techniques provide advanced evasion capability to malware authors, and improper use can make benign applications vulnerable to inject malicious code. For instance, the Plankton malware family uses dynamic code loading to evade detection methods. As being the first malware with DCL that stealthy extend its capabilities on Android devices. It installs an auto-launching background application or service to the device, collecting device critical information to a server. The server sends the malicious class payload URL link to the background service using an HTTP_POST message containing a Dalvik Bytecode jar malicious payload file. In the following trigger of \u201cinit\u201d event of the main application, the malicious payload is invoked using the \u201cDexClassLoader\u201d class. Due to the unavailability of the dynamically loaded code during Android malware static analysis, the DCL and DCM evasion technique is another transformation technique that is a big challenge for static analysis . Althouge)Anti-debugging (ADE): The malware developer presumes the limitation of Android that only one debugger can be attached to a process using ptrace functionality . Hence, This section explains the advanced code transformation techniques that are more sophisticated in hindering the malware detection frameworks. We include advanced evasion techniques, such as Virtual Machine Aware (VMA). Another side of anti-emulation evasion is detecting automatic user interaction emulation, which refers to as Programmed Interaction Detection like the monkeyrunner tool used in many frameworks, for instance, the Droidbox (a)Virtual Machine Aware (VMA): The dynamic analysis requires either an Android virtual machine emulator or a physical device to install the suspected application. Scientists studied the possibility of detecting the running environment fingerprints to differentiate between an emulator and a physical device . Androidb)Programmed Interaction Detection (PID): Android malware is an event-driven application that needs a particular series of user interactions to launch malicious actions. Therefore, dynamic analysis requires a running environment user/gesture interaction. Malware writer refers to PID obfuscation as code coverage. Some researchers have tried to address code coverage; however, it remains a challenge to detect it.The primary objective of anti-emulation evasion is to detect the running environment of the sandbox and benignly masquerade as a clean application instead of launching the malicious code, which we refer to as Droidbox  sandbox Droidbox .a)VirtuRepacking (RPK), Package Renaming (PKR), and Identifier Renaming (IDR). Encryption transformation includes Data Encryption (DEN), Bytecode Encryption (BEN), and Payload Encryption (PEN). The metamorphism subcategories are obfuscation transformation, advanced code transformation, and anti-emulations transformation. The code obfuscation subcategory includes Code Reordering (CRE), Call Indirection (CIN), and Dead Code Insertion (DCI). Advanced code transformation includes Native Exploits (NEX), Function Inlining and outlining (FIO), Reflection API (REF), Dynamic Code Loading/Modification (DCL/DCM), and Anti-debugging (ADE) evasion techniques. Last but not least, anti-emulation transformation includes Virtual Machine Aware (VMA) and Programmed Interaction Detection (PID).We scrutinize the top Android malware detection frameworks against the two main evasion categories based on the introduced definitions of Android malware evasion techniques. The first category is polymorphism, which consists of package transformation and encryption transformation. Package transformation includes Many researchers  examine first category is logic-based techniques  classification algorithms to classify the application as benign or malware Vulnerability Check: The vulnerability check method scans all existing Android apps and Android system versions against common security threats. APSET  collectsb)Monitoring Logs: Android systems use process monitoring tools and network monitoring tools. Mobile-Sandbox  uses theThis section explains the Android vulnerability check and monitors the system logs after installing the application. Therefore, post-installation analysis reports the security issues and malicious activity to the end-users.Android malware detection frameworks perform static, dynamic, or hybrid analyses to analyze features for malware detection techniques, which classify the apps as benign or malware. Hence, we identify the following application analysis methodologies.a)Signature-based: This paper classifies the signature-based method under static analysis detection because the signature-based detection approach builds its frameworks with static Android application characteristics. As such, DroidAnalytics  uses a sb)permission-based detection castoff decompressing the APK package; it extracts the malicious symptoms using permission and signature matching analysis. Likewise, Triggerscope (Permission-based: APK Auditor  is a stagerscope  uses pergerscope .c)Androidmanifest file and source code; it scrutinizes the code by listing the native calls, API calls, and URL addresses. It uses machine learning classification to discriminate between malware and benign apps. Likewise, DroidMat  or a scanning agent on an Android smartphone/device. Next is opening a suitable Android operating environment in a physical device or emulator, which we hereafter refer to as a sandbox. The sandbox isolates the application to protect the analysis device from possible malicious attacks. Later, the dynamic analysis starts system logging and network monitoring tools and captures the default system logs.Sandbox Emulator: Most researchers  Supervised Model:Supervised machine learning bases its model on a labelled dataset. The framework splits the dataset into two subsets; first subset is for training and creating the classification model, and the second subset is for testing and validating the trained classification model. Most researchers split the data into 70% training and 30% testing subsets, but some split the data into 50% for training and 50% for testing .(b) Unsupervised Model:In the unsupervised model, apps are unlabeled. The unsupervised model recognizes the class of the applications without knowing which App is malware or benign. Researchers use unsupervised models to learn the covert pattern of the unlabeled data .(c) Reinforcement Learning:The machine exposes itself to an environment where it trains itself continually using trial and error. This machine learns from experience and tries to capture the best possible knowledge to make accurate business decisions. An example of reinforcement learning is the Markov Decision Process .Based on collected characteristics or so-called features , differeTo understand the supervised model classification performance, ML introduces the confusion matrix to calculate the performance measures as per True Positive (TP) represents the number of malware correctly classified.False Positive (FP) accounts for the number of benign apps classified erroneously as malware.True Negative (TN) represents the number of correctly classified benign apps.False Negative (FN) accounts for the number of malware apps classified erroneously as benign.The ML performance measures represent the accuracy of the Android malware detection classification frameworks. y-axis and FPR is the x-axis. Every point in the ROC curve represents one confusion; it is all based on TP and FP values. Area Under the Curve (AUC) is the area under the ROC curve representing the aggregation of the ML trained model (The Receiver Operating Characteristic (ROC) curve plots the TPR against FPR where TRP is the ed model .Researchers or commercial companies have developed the evasion test benches to study the robustness of the currently available anti-malware applications or protect their software packages from piracy issues. The first test benches trials were ADAM  and DroiWe have explored the last 10 years\u2019 research to evaluate the Android detection frameworks against evasion techniques discussed in evasion techniques section. We studied Android malware detection frameworks for the last decade from 2011 to early 2021, as listed in vs polymorphism evasions. We examine the three main static, dynamic, and hybrid frameworks (a) Package Transformation:\u2013 RPK - Repacking Evasion Detection:Detecting repacking evasion is possible using static analysis and detection techniques; Dempster\u2013Shafe  investig\u2013 PKR - Package Renaming Detection:Static analysis frameworks such as DroidoLytics  and Droi\u2013 IDR Identifier Renaming Evasion Detection:DroidOlytics , AndroSiIn summary, most Android malware detection frameworks based on static analysis can detect package transformation techniques . However, most detection frameworks based on dynamic and hybrid analysis inadequately evaluate or report their resilience against IDR evasion techniques. The study spotted 20 papers that scrutinized the RPK evasion using static analysis, and only 10 papers scrutinized IDR. The study spotted nine papers that scrutinized the IDR evasion using static analysis, and only one paper scrutinized IDR using dynamic analysis.(b) Encryption Transformation Evasion Detection:Static analysis detects encryption evasion techniques; many studies, such as DexHunter , DroidKi(a) Code Obfuscation Detection:Code obfuscation consists of CRE, CIN, and DCI; we explain each evasion detection framework in the following list:\u2013 CRE - Code Reordering Evasion Detection:ResDroid , AnDarwi\u2013 CIN - Call Indirections Evasion Detection:As shown in \u2013 DCI - Dead Code Insertion Evasion Detection:AnDarwin  conducte(b) Advanced Code Transformation Detection:It consists of NEX, FIO, REF, DCL, and ADE evasions explained in this section.\u2013 NEX Evasion Detection:DroidAPIMiner  uses sta\u2013 FIO Evasion Detection:vs function inlining and outlining FIO evasion, as shown in AAMO  evaluate\u2013 REF Evasion Detection:As shown in \u2013 DCL Evasion Detection:Some Android malware detection frameworks propose and evaluate their methods to detect DCL evasion, for instance, DroidAPIMiner , PoeplauADE Evasion Detection: Only the static analysis DexHunter  consider\u2013 Anti-emulation DetectionAnti-emulation evasions consist of VMA and PID evasion techniques; the following is the insight of detection framework analysis:\u2013 VMA Evasion Detection:As a countermeasure for the VMA evasion technique, researchers  equip anIn general, the dynamic analysis framework Q-floid  introduc\u2013 PID Evasion Detection:Programmed Interaction Detection is fortunate to evade automated dynamic analysis using the inherent difference between key runner and human interaction patterns . InsteadSingh  enhancesIn this section, this paper synthesizes the last decade\u2019s Android malware detection framework using three methodologies. First is identifying the evasions techniques requiring more attention from the research community. The second represents the potential evasion resilient detection techniques by reporting each framework\u2019s number of considered evasion techniques. The third summarizes the three types of Android application analysis with the number of frameworks that evaluated evasions techniques by bubble plot chart. Finally, we provide a to-do list and learned lessons from all the examined frameworks.The static analysis radar graph shown in etc. Besides each point number representing the number of Android malware detection frameworks that evaluated its proposed model against this evasion technique or point in the radar graph. For example, 15 malware detection frameworks consider the RPR evasion technique; thus, the RPK label points to 15, as displayed in We selected the Radar graph to demonstrate that static detection studies could detect package transformation evasions and basic code obfuscation; however, advanced transformation techniques and anti-emulation were neither studied nor evaluated. Concerning DCL, Pektas , in 2014Until today, many static analysis researchers depends on permissions ; howeverResearchers assume that dynamic analysis covers all the simple obfuscations and transformation techniques. Hence many of the dynamic analysis frameworks  ignored However, a few researchers evaluate their frameworks against specific evasion techniques, as reflected in the radar graph of the hybrid malware detection frameworks, as shown in Most of the recent dynamic analysis researches  confirmeThe Hybrid analysis techniques are suggested by many researchers and have been set in their future plan to overcome the resiliency issue of complex obfuscation techniques. However, it is a shocking fact that the examined 26 Android malware detection frameworks using hybrid analysis, that only nine frameworks just consider few evasion techniques such as RiskRanker  that hasThe systematic evasion detection map is illustrated in Researchers have concentrated on Android malware static analysis in the last few years, which requires less time and effort than dynamic analysis. They tried to overcome the static analysis weaknesses against evasion attacks, which is why many researchers evaluated their frameworks to check the anti-obfuscation capabilities, as presented in (a) Obfuscation datasetAndroid malware development is always one step ahead of malware detection techniques, which means malware detection still requires many efforts to catch up with malware development. To achieve this objective, we share several insights drawn from our analysis.(b) Obfuscation detection framework performanceOne of the most important is to keep on updating and standardizing obfuscated malware datasets. We recommend standardizing this dataset by the research community trusted institutions and being available upon validated requests for research purposes. Despite some available obfuscated datasets such as PRAGuard  sharing (c) Metamorphism evasion:The performance of the Android malware framework degraded over time since new malware variants, and obfuscations techniques were generated PetaDroid . Hence, (d) Standard Evasion Benchmarking:Static detection is unable to detect most of the metamorphism evasion techniques because of the dynamic characteristics of metamorphism. However, there is still a lack of dynamic and hybrid frameworks to detect metamorphism evasions. It is therefore beneficial to focus more on developing dynamic and hybrid methods.(e) Android Exploits:We suggest building a comprehensive and collaborative benchmarking framework for Android malware detection evasion techniques that aims to improve the quality of research and add to the body of knowledge in Android malware detection studies. The benchmark consists of a list of evasion techniques based on the detection methods that have been evaluated. As a result, detection methods are tested against a standardized list of malware evasion techniques to determine whether they are capable of detecting malware evasions.(f) Code Integrity Verification:As mentioned earlier, Android is based on Linux OS; it has inherited Linux exploits. Recently, malware authors developed and published the Android exploit code Dirty-Cow CVE-2016-5195 . The Dir(g) Process Authentication:Verification means that the application integrity is authenticated against repackaging by guaranteed third-party authentication authorities. (h) Triggering Malicious Code Assurance:Some researchers leverage the process of model authentication to eliminate the need for an external Certification Authority (CA) that protects the system from many exploits . HoweverThe process of ensuring the malicious code runs during the dynamic analysis sandboxing. TriggerScope  staticalGlobal evasion techniques make Android malware more advanced and sophisticated, which was our motivation for this study. We aim to highlight the most critical weaknesses of Android malware detection frameworks, mainly when malware uses different evasions techniques. Therefore, this study scrutinizes top Android malware detection frameworks against 18 evaluation test benches to evaluate the effectiveness of the evasions detection techniques in Android malware detection frameworks. Therefore, the study introduces a new evasion taxonomy that categorizes the evasion techniques into two main groups, polymorphism and metamorphism, where each group has branches; the polymorphism group includes package transformation, and the encryption metamorphism group contains code obfuscation, advanced transformation, and anti-emulation branches. The study also pointed out the lack of research in evaluating the malware detection against different evasion techniques; hence we scrutinized the frameworks based on every evasion technique and categorized the evaluations based on the malware detection methods. Our analysis results conclude a lack of research evaluating the current Android malware detection framework robustness against state-of-the-art evasion techniques. We also concluded that static analysis based detection is easily evaded with simple obfuscation.On the contrary, dynamic and hybrid analyses address advanced code transformation techniques and other advanced evasions. However, preliminary studies have evaluated their frameworks against evasion techniques. The missing framework evaluations are due to the lack of standard benchmark evasion datasets with updated standard malware datasets and the lack of comprehensive test benches tools to assess the efficiency of the existing and future frameworks. This study advises the research community to exert more effort into detecting anti-emulation evasion as indicated in the map of evasions and detection techniques. We also plan to create a standard evaluation framework to include all types of evasion techniques and consider the new generation of malware that combines multiple evasion techniques.10.7717/peerj-cs.907/supp-1Supplemental Information 1It is the process of unpacking the APK file and repacking the original application files but signing the APK file with a developer security key.Click here for additional data file.10.7717/peerj-cs.907/supp-2Supplemental Information 2Click here for additional data file."}
+{"text": "Social withdrawal is an early and common feature of psychiatric disorders. Hypothalamic-pituitary-adrenal (HPA)-axis activation through increased salivary cortisol (sC) and sympathetic activation through increased salivary alpha-amylase (sAA) may play a role.We aimed to study whether the link between increased sC and sAA on the one hand and depression on the other hand is mediated by social withdrawal.In this cross-sectional, observational study, sC and sAA measures were measured in seven saliva samples in 843 participants . Social withdrawal was assessed through the Brief Symptom Inventory (BSI)-, the Short Form 36-, and the Dutch Dimensional Assessment of Personality Pathology social withdrawal subscales, and analyzed using linear regression and mediation analyses. On average, participants were 44.0 years old .Basal and diurnal sAA were unrelated to any social withdrawal scale and depression. Certain sC measures were positively associated with the BSI social withdrawal subscale . We found limited support for statistical mediation by social withdrawal  on the relationship between evening sC and depression.Thus, although we found no support for a role of basal and diurnal sAA in social withdrawal, HPA-axis activation may partly aggravate social withdrawal in depressive disorders."}
+{"text": "Dysfunction of both microglia and circuitry in the medial prefrontal cortex (mPFC) have been implicated in numerous neuropsychiatric disorders, but how microglia affect mPFC development in health and disease is not well understood. mPFC circuits undergo a prolonged maturation after birth that is driven by molecular programs and activity-dependent processes. Though this extended development is crucial to acquire mature cognitive abilities, it likely renders mPFC circuitry more susceptible to disruption by genetic and environmental insults that increase the risk of developing mental health disorders. Recent work suggests that microglia directly influence mPFC circuit maturation, though the biological factors underlying this observation remain unclear. In this review, we discuss these recent findings along with new studies on the cellular mechanisms by which microglia shape sensory circuits during postnatal development. We focus on the molecular pathways through which glial cells and immune signals regulate synaptogenesis and activity-dependent synaptic refinement. We further highlight how disruptions in these pathways are implicated in the pathogenesis of neurodevelopmental and psychiatric disorders associated with mPFC dysfunction, including schizophrenia and autism spectrum disorder (ASD). Using these disorders as a framework, we discuss microglial mechanisms that could link environmental risk factors including infections and stress with ongoing genetic programs to aberrantly shape mPFC circuitry. The medial prefrontal cortex (mPFC) controls complex cognitive and emotive functions, including decision making, memory, social interactions and mood . These fMicroglia are increasingly recognized as key players in synapse development and refinement . Microglvia membrane-bound receptors. This represents one key mechanism by which microglia engulf synaptic compartments  and C4B recently shed light on the molecule\u2019s role in synaptic refinement within the retinogeniculate system  provided new insight into mechanisms through which C4-dependent pathways sculpt synapses . In thisvia aberrant microglial pruning. It is possible that yet undiscovered genetic variation in other pruning-relevant molecules  also contributes to disease risk or etiology. As such, we need a more precise understanding of how and when these molecules shape microglial pruning. It will be important to determine whether biological events can elevate C4 expression during adolescence or provoke C4 production outside of its developmentally appropriate time window, leading to pathological circuit modifications via microglial effectors. Individuals with a higher C4A copy number may exhibit particularly strong increases in C4 in certain situations, and, therefore, experience increased vulnerability in particular contexts. These findings also raise the intriguing possibility that an individual\u2019s risk of developing schizophrenia might be mitigated via interventions that modify microglial pruning activity. Along this vein, minocycline, an antibiotic previously shown to reduce synapse pruning in rodent models  during which activity increases dendritic spine density in the dLGN . During In the past decade, numerous studies have corroborated the idea that microglia sculpt developing neuronal circuits . AligninNew work indicates that microglia use different signaling pathways to regulate dendritic spines depending on the stage of development . In bothMECP2 from all GABAergic interneurons recapitulated most behavioral features of Rett\u2019s syndrome, a form of ASD, while deletion in specific regions or other broad cell types only recapitulated some features \u2014non-toxic viruses that are commonly used to manipulate gene expression in the brain. To advance the field, new approaches are needed for spatially restricted manipulation of these cells. In the meantime, as we learn more about the molecular mechanisms guiding neuron-glia interactions in mPFC, we can use neuronally-targeted AAVs to manipulate their interactions in a spatially and temporally restricted manner. With such tools in hand, we can determine when and how microglia regulate specific classes of mPFC synapses. Future studies can investigate to what extent microglia play simultaneous roles in pruning and synaptogenesis within mPFC\u2014potentially at different classes of synapses\u2014and whether microglia may toggle between states that promote synapse formation vs. pruning.When investigating the roles of microglia in mPFC and sensory circuit development, it will also be important to consider potential contributions from astrocytes. Astrocytes shape circuit development in similar ways to microglia. Astrocyte-secreted proteins regulate synaptogenesis  and promIn addition to directly modulating synapse development, astrocytes signal to microglia to alter microglial function. For example, astrocyte-derived IL-33 signals to microglia to promote microglial synapse engulfment and neural circuit maturation in the thalamus and spinal cord . AstrocyStudies from the past decade corroborate the notion that microglia and other immune system factors sculpt developing neuronal circuits . The worAll authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication."}
+{"text": "Inflammatory or kidney-related metabolic biomarkers have been correlated with cognition and risk for developing dementia among older adults. Using the China Health And Retirement Longitudinal Study, we investigated the cross-sectional correlations between metabolic biomarkers and cognitive outcomes that were ascertained in the same wave, as well as measures lagged by data collection waves. After excluding participants with diagnoses of dementia, we analyzed the association of each biomarker  with scores from cognitive tests. We then identified biomarkers that showed consistent associations across waves. Having elevated CRP (1-3 mg/L) was positively associated with cognitive test scores; whereas abnormal levels of Creatinine  were associated with poorer outcomes. These results provide biomarker evidence of the importance of kidney function and inflammation in dementia research."}
+{"text": "In 2020, we observed an increase in inpatient postoperative patient deteriorations. Preliminary case reviews suggested gaps in sepsis care.To identify key drivers associated with effective care escalation and sepsis care in the inpatient surgical setting as part of the initial planning phase of a large improvement initiative.Our multidisciplinary team included surgical nurses, surgical providers, medical providers, patient safety experts, subject matter experts in pediatric sepsis, and subject matter experts in escalation of care. This team formally reviewed cases involving postoperative deterioration to identify causes of gaps in sepsis care and applied its learnings to the development of a key driver diagram. Themes from the key driver diagram included (1) Enhance recognition of deterioration and subsequent escalation of care and (2) Optimize postoperative patient placement. The team hosted a mini-Kaizen event with frontline team members focused on the first theme, the output of which included consensus agreement on two focus areas  and a fishbone diagram to identify/prioritize opportunities in postoperative care escalation.Causes of gaps in sepsis care included barriers to care escalation that could limit generalizability of sepsis resources to the inpatient surgical setting. Figure 1 shows the key driver diagram.We aim to highlight challenges associated with postoperative sepsis care in an inpatient pediatric surgical setting."}
+{"text": "Reports have documented national and state-level increases in drug overdose\u2013related emergency department visits, emergency medical services incidents, and deaths among racial and ethnic minority groups in the United States during 2020 amid the COVID-19 pandemic , compared with 119.7% (from 66 to 145) among Hispanic persons . By sex To improve evidence-based drug overdose prevention and response efforts among persons who use opioids in Nevada, particularly among young male Hispanic persons who have experienced overdoses involving illicitly manufactured fentanyls, a better understanding of the underlying risks for the recent increase in overdose deaths is needed. Naloxone can reverse the effects of overdose from opioids, such as illicitly manufactured fentanyls. Although evidence of naloxone administration for opioid-involved deaths was higher among Hispanic persons in 2020, only approximately one in three of those Hispanic decedents had evidence"}
+{"text": "Recent reports are indicating an inverse association between lithium in drinking water and suicide mortality  observeThe inverse ecological association should be verified by individual data on the biological monitoring of lithium exposure, such as between the serum concentration of lithium and the number of suicide events. Case-control studies analyzing this have been reported. Kanehisa et al. (2017) reporteFinally, Szklarska and Rzymski (2019) reporteThe author declares no conflict of interest.None."}
+{"text": "The extraction and exploration of cellulose-based polymers is an exciting area of research. For many years, wood  was considered the main source of cellulosic compounds because of its abundance in nature ,2. HowevRizal et al., in a very compelling and critical overview of the worlds\u2019 current situation regarding cotton waste fibers and their ineffective processing mechanism to mitigate their environmental impact, provided evidence of new work being conducted to employ these wastes in functional products. Indeed, different pre-treatment techniques were identified for their efficiency in extracting cellulose nanocrystals from cotton wastes, and many applications in the packaging and biomedical fields were highlighted . Neto etNano-fibrillated cellulose extracted from waste peels of citrus sinensis by a chemical method involving alkali and acid hydrolysis and modified with silver nanoparticles also synthesized using extract of citrus sinensis skins as a reducing agent were engineered for heavy metal sorption. Data found these isolates and nanoparticles especially effective in removing cadmium and chromium particles from pharmaceutical effluent samples . Rizal eWang et al., engineered a flexible SERS substrate based on regenerated cellulose fibers, obtained from wastepaper, modified with gold nanoparticles through dry-jet wet spinning method, an approach turned eco-friendly by using ionic liquids. The gold nanoparticles were incorporated on the regenerated fibers through electrostatic interaction. The SERS scaffolding system was found very effective for identifying toxins and chemicals like dimetridazole in aqueous solutions . RecycleIn the field of drug delivery, Al-Rajabi et al., explored a green synthesis method for developing a thermo-responsive cellulose hydrogel using cellulose extracted from oil palm empty fruit bunches. The thermo-responsiveness was guaranteed by the incorporation of Pluronic F127 polymer onto the hydrogels. A sustained release of silver sulfadiazine was observed over time. In the end, it was seen that the thermo-responsive cellulose-based hydrogel could give rise to cost-effective and sustainable drug delivery systems using abundantly available agricultural biomass ["}
+{"text": "GSA\u2019s revised KAER Toolkit for Primary Care Teams  provides useful information for referring individuals and families to community resources following a neurocognitive disorder diagnosis. Mental health practitioners must develop competencies and professional identities within integrated care teams to facilitate this process. This presentation outlines post-assessment suggestions for clinicians across disciplines  in building such teams. There may be needs for serial assessment of specific individual capacities, treatment plans to facilitate shared decision-making between individuals and family care partners, and evaluations of the family care partner\u2019s capacity to provide care. Behavioral health providers assist patients, families, and health care teams across a range of residential settings in understanding and implementing treatment recommendations. Emerging science indicates the value of initiating planning discussions with lifestyle modifications to enhance functioning within dyads. Culturally responsive strategies will be suggested for engagement in planning for future care."}
+{"text": "Somatic mutations are DNA variants that occur after the fertilization of zygotes and accumulate during the developmental and aging processes in the human lifespan. Somatic mutations have long been known to cause cancer, and more recently have been implicated in a variety of non-cancer diseases. The patterns of somatic mutations, or mutational signatures, also shed light on the underlying mechanisms of the mutational process. Advances in next-generation sequencing over the decades have enabled genome-wide profiling of DNA variants in a high-throughput manner; however, unlike germline mutations, somatic mutations are carried only by a subset of the cell population. Thus, sensitive bioinformatic methods are required to distinguish mutant alleles from sequencing and base calling errors in bulk tissue samples. An alternative way to study somatic mutations, especially those present in an extremely small number of cells or even in a single cell, is to sequence single-cell genomes after whole-genome amplification (WGA); however, it is critical and technically challenging to exclude numerous technical artifacts arising during error-prone and uneven genome amplification in current WGA methods. To address these challenges, multiple bioinformatic tools have been developed. In this review, we summarize the latest progress in methods for identification of somatic mutations and the challenges that remain to be addressed in the future. Previoulifespan . Somaticlifespan . Once filifespan . The scalifespan .Somatic mutations have increasingly been implicated in various diseases. Somatic mutations in oncogenes and tumor-suppressor genes are the major cause of cancer . Accumulet al. analyzed the tri-nucleotide sSNV profiles across 30 cancer types and successfully identified 27 mutational signatures (Different mutational processes generate distinct profiles of mutational genomic contexts, termed \u201cmutational signatures,\u201d and the landscape of somatic mutations observed in tissue samples or single cells often reflects the combined impact of multiple mutational processes . The largnatures . The catgnatures . A similgnatures  as well gnatures .Theoretically, sequencing reads from reference and mutant alleles of a given mutation should follow a binomial sampling process, where the expected number of mutant reads is positively correlated with total depth and mutant allele fraction. The mutant allele fraction is one of the key variables for somatic mutation detection, which is largely determined by the timing of the occurrence of the mutation and the selective pressure acting on the cell carrying the mutation . SomaticEarly attempts on somatic mutation calling were made in cancer studies, where the sequencing data from a tumor sample were typically compared to a matched normal control sample obtained from the same donor. Strelka  and VarSAlthough clonal expansion events led by driver mutations are not rare in healthy tissues, they usually involve relatively small clones, making it hard to attain high allele fractions in bulk tissue sequencing . MoreoveTargeted ultra-deep sequencing has been widely used as a cost-efficient strategy to increase sequencing depth and thus improve sensitivity in detecting somatic mutations, especially for screening mutations in cancer-related genes . HoweverSomatic mutation in single-cell data has emerged as a powerful endogenous marker to comprehend underlying mutational mechanisms across different cell types , and to Early pioneering works have demonstrated success in applying bulk-sequencing-based methods to sSNV calling in single cells , despitein silico mixture of multiple single cells, and outperformed other tools on calling clonal mutations.Single cells may share some somatic mutations if those mutations occurred in their common ancestral cell . CompareSomatic mutations can also be called from other types of sequencing data beyond DNA sequencing data. RNA-MuTect identified exonic somatic mutations from bulk RNA-seq data by comparing mutation calls against DNA sequencing of a matched control sample . SomaticMany bioinformatic methods have been developed to study somatic mutation in healthy and diseased human samples using bulk or single-cell sequencing . In bulkIn the past decade, genomic studies have benefited from the development of single-molecule sequencing technologies that can directly read nucleotide sequences from DNA or RNA molecules and deliver much longer reads than previously available NGS technologies . Long se"}
+{"text": "Organized by the Alzheimer's disease and related dementias (ADRD) Interest Group, this symposium aims to highlight unique approaches to address 1) ADRD risk reductions through social and biological factors, and 2) quality of life of those with dementia. The first two presentations introduce remote communication technologies used for behavioral interventions, one for preventing social isolation and the resultant cognitive decline using video-chats by recruiting socially isolated older adults with mild cognitive impairment (MCI). The results of the recently completed randomized controlled trial provide evidence of a positive effect on cognition suggesting enhanced cognitive reserve. Another is for delivering a behavioral symptom intervention for community-dwelling persons with ADRD using telehealth. Researchers will highlight the feasibility, opportunities, and challenges of remote behavioral interventions. The third presentation focuses on micro-level communication between persons living with dementia and their family caregivers. By examining video-recorded home care observations, findings suggest caregiver education on positive interactions could facilitate more meaningful interaction with persons with ADRD. The fourth presentation explores pain among those with ADRD, a multifaceted phenomenon with health and functional consequences. Using the NHATS dataset, researchers show a continued need to detect and address pain in clinical settings particularly among persons with ADRD. The symposium concludes with a presentation using the CHARLS study to investigate correlations between inflammation or kidney-related metabolic biomarkers and cognition. Results provide longitudinal evidence of an association of kidney function and inflammation with cognitive test scores supporting the need to broaden dementia etiology research beyond the amyloid-cascade theory."}
+{"text": "This cross-sectional study investigates trends in out-of-pocket costs for unmixed and novel glucagon formulations among patients with Medicare Advantage and commercial insurance from 2010 to 2020. We assessed trends in wholesale acquisition cost (WAC), an estimate of the manufacturer\u2019s list price, for glucagon formulations over time using the AnalySource drug pricing database. Next, we examined trends in OOPCs paid by patients using the Optum deidentified Clinformatics Data Mart, which includes administrative claims from large commercial and Medicare Advantage (MA) health plans. Analyzed claims included any formulation of glucagon from January 1, 2010, through September 30, 2020. Given that there were only 24 prescription fills of novel premixed liquid glucagon injection, it was excluded from analysis . There are multiple possible reasons that may underly this trend, including MA plans passing on higher WAC to beneficiaries or beneficiaries choosing plans with more cost sharing over time.Our study has several limitations. Results may not generalize to patients who are insured through traditional Medicare or Medicaid or are uninsured. In addition, we were unable to assess instances in which high OOPCs prevented patients from filling the prescription (primary nonadherence) or the association of manufacturer patient-assistance programs and coupons with OOPCs for commercial beneficiaries.Cost-sharing should not serve as a major barrier to accessing glucagon for MA and commercially insured patients. Further work should assess other barriers to guideline-concordant glucagon uptake among patients at risk of severe hypoglycemia. Such barriers may include awareness among patients and primary care, emergency, and diabetes clinicians of the availability of this potentially life-saving treatment. In addition, future studies may examine the association of novel glucagon formulations, which had similar OOPCs to those of unmixed glucagon and may be easier to administer, with uptake in the coming years."}
+{"text": "Lower socioeconomic status African American older adults living with dementia and their family caregivers face unique advance care planning challenges, including achieving appropriate preference-consistent healthcare near the end of life. The purpose of this project within a larger multi-stakeholder study is to assess community stakeholder perspectives on the needs of African American older adults living with dementia and their family caregivers. Diverse community-based organization leaders (n=9) were interviewed and identified the following thematic needs: Reframing of Advance Care Planning, Clarification of Misinformation, and Expansion of Available Resources. Community leaders expressed strong desires to assist families with advance care planning. The use of creative, culturally-tailored, non-traditional approaches to this process offers innovative ways to promote advance care planning through community engagement. This will change the narrative on advance care planning from a cultural perspective while embracing diversity, enriching discovery, and reimaging aging in the community"}
+{"text": "Vitiligo is an autoimmune disease of the skin that results in localized or disseminated white macules. One common feature of several existing classification protocols is the distribution of the disease into two main subtypes, non-segmental vitiligo (NSV) and segmental vitiligo (SV). SV is characterized by depigmentation spreading within one or more skin segments while NSV is widespread. Several clinical-epidemiological observations suggest that SV has distinct autoimmune pathophysiology compared to NSV. Furthermore, the clinical distribution pattern of SV lesions closely resembles other melanocyte mosaicism diseases. These observations led us to hypothesize that SV is caused by a localized autoimmune reaction targeting epidermal mosaicism melanocytes. Here, we proposed examples of experimental approaches to assess mosaicism in SV patients. According to an international consensus, vitiligo is classified into three main groups: Segmental (SV), Non-Segmental (NSV), and mixed vitiligo (coexistence of SV and NSV).Reports suggest differences in the biological mechanisms underlying the pathogenesis of SV as compared to NSV. For example, serum levels of TWEAK (Tumor Necrosis Factor-like Weak inducer of Apoptosis) were significantly higher in SV compared to NSV patients.17de novo mutation or retrotransposition occurred delineates the extent of tissues/cells involved in the mosaicism. The hypothesis to be tested suggest that genetic mosaicism in SV occurred at some point during skin/melanocyte differentiation. Different approaches can be applied to test the mosaicism hypothesis in SV, each aiming to detect a distinct type of mosaicism. Here we proposed examples by adapting designs applied to study the host response to infections, detect somatic mutations in cancers and evaluate embryonic development.23Mosaicism designates individuals encompassing at least two cell populations derived from a single zygote but with distinct genotype or epigenetic profiles.de novo mutation occurred during skin differentiation in one segment, a contralateral healthy skin could be used to establish the melanocyte\u2019s \u201cnormal\u201d profile  would be performed using DNA extracted from melanocytes from hypochromic and contralateral skin from the same individuals. Variants detected in contralateral tissues would be used to exclude germline variants. Algorithms designed to detect tumor cells, such as MuTect2,None declared.Gerson Dellatorre: Study concept, writing and approval of the final manuscript.Vinicius Medeiros Fava: Study concept, writing and approval of the final manuscript.Marcelo T\u00e1vora Mira: Writing and approval of the final manuscript.Caio Cesar Silva de Castro: Study concept, writing and approval of the final manuscript.None declared."}
+{"text": "Developing efficient cognitive training for the older population is a major public health goal due to its potential cognitive benefits. A promising cognitive training target is executive control, critical for multitasking in everyday life. The aim of this pilot study was to establish the feasibility and acceptability of the Breakfast Task in older adults, a new web-based cognitive training platform that simulates real-life multitasking demands. Research Design andA community-based sample of 24 cognitively healthy participants aged between 60 and 75  underwent an online 5-session training protocol. Each session lasted 40 minutes and occurred twice a week at participant\u2019s homes. Game performance was recorded, and participants completed questionnaires at baseline and after the intervention.Feasibility metrics showed overall high recruitment (82.7%), adherence and retention rates (100%). Acceptability was considered good based on participant`s quantitative and qualitative responses. On average, participants rated the game as interesting, enjoyable and did not report difficulties in accessing the game online or in understanding the instructions. Moreover, participants showed a learning curve across sessions, improvement in most game outcomes and benefits from the emphasis change approach. Discussion and Implications: The findings provide preliminary support for the feasibility and acceptability of the Breakfast Task training platform with community-dwelling older adults and demonstrate potential cognitive benefits. Results suggest the value of further research investigating the Breakfast Task features and dose-response relationship, as well as its efficacy in older adults via larger randomized controlled trials."}
+{"text": "Acipenser fulvescens), during the early larval period in response to weekly treatments using chemotherapeutants commonly used in aquaculture  relative to untreated controls. The effects of founding microbial community origin (wild stream vs. hatchery water) were also evaluated. Gut communities were quantified using massively parallel next generation sequencing based on the V4 region of the 16S rRNA gene. Members of the phylum Firmicutes  and Proteobacteria were the dominant taxa in all gut samples regardless of treatment. The egg incubation environment (origin) and its interaction with chemotherapeutant treatment were significantly associated with indices of microbial taxonomic diversity. We observed large variation in the beta diversity of lake sturgeon gut microbiota between larvae from eggs incubated in hatchery and wild (stream) origins based on nonmetric dimensional scaling (NMDS). Permutational ANOVA indicated the effects of chemotherapeutic treatments on gut microbial community composition were dependent on the initial source of the founding microbial community. Influences of microbiota colonization during early ontogenetic stages and the resilience of gut microbiota to topical chemotherapeutic treatments are discussed.Antibiotics, drugs, and chemicals (collectively referred to as chemotherapeutants) are widely embraced in fish aquaculture as important tools to control or prevent disease outbreaks. Potential negative effects include changes in microbial community composition and diversity during early life stages, which can reverse the beneficial roles of gut microbiota for the maintenance of host physiological processes and homeostatic regulation. We characterized the gut microbial community composition and diversity of an ecologically and economically important fish species, the lake sturgeon ( Developing therapeutic regimes that limit stress-induced microbial infection or that reduces the occurrence of high mortality events in aquaculture is essential to successful fish production ,2,3. In 2O2), and sodium chloride (NaCl2)  diversity measures in the lake sturgeon larval GI tracts as a function of egg origin (wild vs. hatchery). The test was performed instead of parametric tests that assume a normal distribution. Next, the effects of chemotherapeutants and egg origin on measures of microbial gut community diversity were estimated based on a generalized linear model (GLM) using suitable probability distributions  in R program (v3.0.2) using glm. The GLM method has been shown to have high efficiency when estimating parameters, yielding interpretable estimates that also avoid transformation bias ,54. p-vaWe included several packages implemented in program R to estimate (beta [\u03b2]) diversity measures quantifying bacterial community compositional differences between samples and ecological statistics at the bacterial OTU level. Briefly, vegan  was usedNext, we performed multivariate hypothesis testing to quantify differences in community composition among samples originating from different groups based on locations of egg origins and exposed to different chemotherapeutant treatments using the adonis function  in progrAnalyses investigated whether host origin and/or chemotherapeutant treatment had a significant effect on microbial community structure. NMDS and PERMANOVA were performed on fish gut communities within each origin group to determine whether chemical treatments had effects on fish gut microbiota. Under the null hypothesis, chemotherapeutant treatments were not expected to significantly affect fish gut community taxonomic composition within an origin group, in part because eggs from both hatchery and wild origins were exposed to peroxide during incubation that was believed to reduce and taxonomically homogenize samples for all treatments and both origins. PERMANOVA analyses that indicated significant treatment effects were then analyzed using post hoc tests using betadisper and permutest functions followed by a Tukey test to determine which treatment(s) differ significantly in larval lake sturgeon gut bacterial taxonomic composition.To determine the operational taxonomic units (OTUs) that most likely explained differences in microbial larval lake sturgeon gut community composition between fish from different origins and among different chemotherapeutant treatment groups, we next employed linear discriminant analysis (LDA) effect size (LEfSe) methods . In geneThe algorithm first identified features (OTUs) that were statistically different among origin groups based on the nonparametric factorial Kruskal\u2013Wallis (KW) rank sum test. Additional tests assessed the consistency of differences using unpaired Wilcoxon rank sum tests. In the final step, LEfSe used LDA to rank each differentially abundant taxon in order of the difference in abundance based on an LDA Score . Results represent a scale indicating \u201cimportance\u201d of an OTU in origin group differences in microbiota composition .https://huttenhower.sph.harvard.edu/galaxy/, accessed 20 November 2014).To run LEfSe, a tabular file was generated from a shared file that contained no singletons in the program mothur v.1.39.5. The tabular file consisted of taxonomic relative abundance in gut community samples from the four different origin samples that were all exposed to four chemotherapeutant treatments. This tabular file was transferred using an online bioinformatics toolkit developed by the Huttenhower lab to perform LEfSe analyses . Phyla detected in the remainder of the gut community included Acidobacteria, Bacteroidetes, and Verrucomicrobia that collectively comprised 30% of gut communities. A total of 144 samples were retained after quality filtering was performed in the sequence pipeline analyses. Comparisons of lake sturgeon larvae gut microbial community composition at the level of phyla indicated that three major phyla dominated more than 65% of total community abundance across all fish samples . One exception was WB larvae exposed to salt (mean 58%) and WC fish exposed to peroxide (mean 50%) that were relatively low compared to other treatments  had a lower percentage of Firmicutes (mean range from 51\u201366%). Proteobacteria relative abundance was likewise relatively uniform across treatments  with the exception of WB fish that were treated with chloramine-T, CT (6%). Actinobacteria were present at 1% in fish that were not exposed to any chemotherapeutant (control) and only in fish from HA and WC origin groups. At the genus level, Firmicutes were represented by two genera, Clostridium_sensu_stricto & unclassified genera from family Clostridiaceae. We found that Clostridium_sensu_stricto were the most dominant genus  for all fish of hatchery origin (except for HA fish exposed to peroxide), whereas all fish of wild origin had unclassified taxa from Clostridiaceae family (mean range: 29\u201362%) as the most abundant genus across any treatment  and WC control fish (mean 1.4%).The relative abundance of the most dominant phylum, eatments a. When creatment b. Generaeatments b. The onp > 0.05). Statistical analyses based on the generalized linear model (GLM) indicated that gut communities of individuals exposed to certain treatments  had significantly different levels of taxa richness, but not on the inverse Simpson indices  ordination of BC dissimilarities in microbial taxonomic composition of gut communities was performed to visualize community compositional relationships among larval gut samples associated with fish from different egg origin and exposed to different chemotherapeutant treatments. Four NMDS plots were generated, including To quantitatively test for gut community compositional differences among chemotherapeutant treatment and origins, PERMANOVA was performed. Comparisons of microbial OTU beta diversity across samples from the controlled groups indicated that gut microbial communities from control groups were not significantly influenced by the egg origin . Subsequp = 0.012). However, the effect of chemotherapeutant treatment was not evident between fish from eggs collected in different regions of the stream , although a significant interaction was observed between origin group and treatment . Chemotherapeutant treatments had significant effects on larval gut microbiomes between individuals from different hatchery families  as indicated by PERMANOVA test results  and Methylocystis (Phylum Proteobacteria). Both genera were present in high abundance in the guts of fish exposed to the peroxide treatment, and for genus Clostridium_XVIII. The taxa were also abundant in the guts of fish from the salt treatment  in high abundance, while fish exposed to the salt treatment had Peptoniphlus and Luteimonas that were in higher abundance compared to individuals from other treatments  to other chemotherapeutant treatment groups . LEfSe analyses performed with fish from the wild group detected two differentially abundant taxa associated with genus ents see c.Understanding interactions between microbes and the host surfaces they colonize is important to aquatic animal health and aquacultural production ,35. PoteIn this study, we found little evidence for the influence of commonly used chemotherapeutant treatments applied topically in water baths to larval lake sturgeon prophylactically on gut microbiome composition. Data did indicate greater influence of microbial founder effects (hatchery vs. wild stream origin), which may be explained by exposure to environmental sources during earlier life stages or influences of genetic effects ,74. ResuAll chemotherapeutants used in our study are commonly used for the treatment of external pathogens rather than orally administered to fish. In fish aquaculture, prophylactic treatments are widely used to control pathogenic bacteria disease outbreaks that commonly occur in hatcheries during vulnerable early life stages. Chloramine-T and peroxide are widely used to control and eliminate infection associated with flavobacteriosis . OverallThere are several potential explanations for the comparatively small effects of chemotherapeutant treatments on larval gut microbial communities. One explanation is that the externally administered treatment did not enter the digestive tract in significant enough concentrations or duration to alter the gut community. When larval fish are provided chemotherapeutants prior to feeding, rather than during feeding, microbial compositional stasis suggested that the chemicals may not enter the gastrointestinal tract. Alternatively, the effect of the treatment may not have been evident due to the short treatment duration (15\u201360 min bath immersion) and weekly periodicity of chemotherapeutant treatments. Exposure to chemotherapeutants, consistent with our methodology, may not have been of sufficient concentration to result in quantifiable changes in gut community composition. In addition, fish were returned into their tank partition after treatments, and that may have allowed rapid recolonization of gut microbiota from the surrounding water. Further, chemotherapeutant treatments were administered at seven-day intervals, potentially allowing community recovery. The microbial communities may have exhibited resiliency to chemotherapeutant treatment; returning to a similar compositional state during the several day period between the timing of treatment and sampling for gut interrogation. Further studies are warranted to quantify the amount of any compound entering the gut during the treatment period to ascertain causal relationships.Thymus vulgaris essential oil (TVEO) on microbiota composition, compared with a control diet without TVEO over a 5 week period. Their study indicated high similarities between gut microbiota in treated and non-treated fish, and TVEO induced negligible changes in gut microbiota profiles. Essential oils include volatile liquid fractions produced by plants that contain the substances usually responsible for defenses against pathogens and pests due to their antibacterial, antiviral, antifungal, and insecticidal activities [In the LEfSe analyses, three out of thousands of microbial taxa appeared to be tied to differences between untreated fish in a hatchery and the wild. After fish were exposed to chemical treatments, different taxa were reported to be differentially abundant. Those taxa, however, are not among the dominant taxa. It is unclear how treatment differentially affected the relative abundance of these taxa. Results could indicate that the gut microbiota were either resistant or exhibited resilience in community composition, where treatment-based changes were short-lived and communities rapidly returned to their original state . The comtivities . We concFirmicutes, Proteobacteria, and Actinobacteria, that dominated the lake sturgeon larval gut community across all samples  are Gram-negative bacteria. Many studies have shown that Gram-negative bacteria are resistant to commercially available antibiotics partly due to their thick cell wall structure compared to Gram-positive bacteria [Enterobacteriaceae include a group of bacteria known as extended-spectrum beta-lactamase (ESBL) Enterobacteriaceae that can confer resistance to antibiotics via production of the \u03b2-lactamase enzyme, which can inactivate certain \u03b2-lactam antibiotics [We detected three major phyla  samples . The mosbacteria ,78. Enteibiotics .Firmicutes that were detected in fish guts across all families and treatments was primarily represented by Unclassified Clostridiaceae1 and taxa Clostridium sensu stricto. Although Clostridia are Gram-positive, these bacteria have been identified as part of commensal gut microbiota that plays major roles in the maintenance of the gut homeostasis. Several features associated with Clostridium spp. could explain why this taxon can thrive in the gut and can likewise be resistant to prophylactic treatments administered in our study. In humans, Clostridium spp. are involved in defenses inside the intestinal microecosystem along with gut-associated lymphoid tissue (GALT), and confer resistance against pathogen infections. This taxon is thought to have immunological tolerance [Clostridium spp. exhibit the ability to form endospores, which offers this bacteria ecological advantages for survival under adverse conditions [Another major phylum, olerance . In addinditions ,81.Comprehensive studies on adverse effects of antibiotic use to the gut microbiomes were reported in other fish species ,37,39 anCarassius auratus gibelito) [Aeromonas. The results were consistent with findings from another study conducted to evaluate the effects of orally administered antibiotics to gibel carp [Relatively few studies have been conducted addressing the effects of chemotherapeutants administered topically in water baths on fish gut microbial communities as conducted in this study. Most studies have been conducted on salmonids or tilapia ,45,75 anibelito) , and havibelito)  reportedbel carp . ImportaA prerequisite for developing a strategy for microbial pathogen control is a knowledge of resident aquatic microflora associated with fish larvae, and how interactions between larvae and microflora occur. De Schryver & Vadstein  suggesteFish produced from wild eggs show greater community diversity compared to artificially produced fish in the hatchery b. Thus, In fishes, microbial binding to host cell surfaces is often mediated through the interactions of bacterial carbohydrate binding proteins (lectins) with host cell surface carbohydrates ,85. StreSeveral studies of gut microbiota in fish with different genetic backgrounds have documented that host genotype (broadly defined) may contribute to compositional heterogeneity among individuals in fish gut microbiota, at least to some extent. Abdul Razak et al.  studied Coregonus spp.) species pairs and their reciprocal hybrids were reared in captivity under a controlled environment. Analyses revealed significant effects of the host genetic background on the taxonomic composition of the transient microbiota. Navarrete et al. [Onchorhynchus mykiss). Full-sibling fish from four non-related families were fed two diet regimes in comparison to the control group. Results showed that some relative abundance of several bacterial taxa differed among trout families, indicating that the host genotypes may influence gut microbiota composition. In addition, the authors reported that the effect of diet on microbiota composition was dependent on the trout family. Studies on other organisms, such as chickens, also showed that under a common diet and husbandry practices, gut microbiota composition differed between two lines  [Another study  demonstre et al.  assessedght, LW) . Findingght, LW)  indicateFindings in this study detail observed differences in microbial founding sources  and chemotherapeutic treatments to developing microbial communities during early ontogenetic stages. These results provide an insight into the consequences of prophylactic treatments and host-microbe interactions. Our study serves as a baseline providing information on the indirect effects of chemotherapeutant intervention that could either positively or negatively affect the normal gut microbiota. Results of minor effects associated with use of chemotherapeutants prophylactically suggest that topical use at the ontogenetic stage and concentration used may not have negative indirect effects on resident gut microbial communities. Thought should be given to the selection of locations to collect gametes to bring into culture. Future work could profitably focus on identifying microbial taxa that colonize the external surfaces of the fish  to see how external treatments impact the colonization of external microbes. Further studies are also warranted that would compare the effects of treatments when administered following pathogen infection."}
+{"text": "Transgender and gender-independent individuals (TGI) encounter myriad barriers to accessing affirming healthcare. Healthcare discrimination and erasure exposure among TGI individuals is vital to understanding healthcare accessibility, utilization behaviors, and health disparities in this population. Exposure to gender identity-related healthcare discrimination and erasure in childhood may contribute to TGI adults\u2019 healthcare utilization behaviors. The commonality of childhood exposure to gender identity-related healthcare discrimination and its relationship to healthcare avoidance during the early months of the COVID-19 pandemic among TGI adults were explored. TGI adults aged 18 to 59 (N = 342) in the United States were recruited online during the summer of 2020. Among individuals who reported childhood exposure to gender identity-related healthcare discrimination, 51% reported experiencing two or more distinct forms of discrimination. Hierarchical logistic regression indicated that exposure to healthcare discrimination in childhood significantly increased the odds of healthcare avoidance during the early months of the COVID-19 pandemic, after accounting for demographic factors and self-reported COVID-19 symptoms . These findings suggest that childhood exposure to gender identity-related healthcare discrimination is a prominent barrier to the utilization of healthcare for TGI adults, even during a global pandemic. Gender identity-related stigmatization, discrimination, and erasure in healthcare settings serve as central barriers to the accessibility and utilization of healthcare for individuals who embody transgender and gender independent (TGI) identities ,2. TGI iTerminology. The term transgender and gender nonconforming (TGNC) is umbrella terminology used to refer to individuals whose gender identities, gender roles, and gender expressions do not align with or conform to the gender norms associated with their sex assigned at birth , significantly predicted healthcare avoidance during the early months of the COVID-19 pandemic over and above the covariates. For each one-point increase in the childhood healthcare discrimination measure, respondents were 30% more likely to have avoided needed healthcare in the early months of the COVID-19 pandemic due to anticipation of gender identity-related discrimination.A hierarchical logistic regression analysis  was condThis study expands the literature about TGI individuals\u2019 healthcare experiences and utilization behaviors ,10,12,18Independent of an individual\u2019s age, race/ethnicity, income level, disability/neurodivergent identity, and health insurance coverage status, lifetime exposure to healthcare discrimination predicted avoiding needed healthcare in the past year when they anticipated encountering gender identity-based discrimination, even despite this past year including pandemic conditions. Findings indicate that higher levels of lifetime exposure to varied forms of healthcare discrimination significantly increase the likelihood that TGI individuals will avoid needed healthcare due to anticipation of gender identity-based discrimination in healthcare settings. These findings demonstrate the considerable toll that healthcare discrimination has on TGI individuals in instances when they must consider the potential risks of seeking or avoiding healthcare beyond gender-affirming care  when it is needed. These findings demonstrate the considerable toll that healthcare discrimination has on TGI individuals in instances when they must consider the potential risks of seeking or avoiding healthcare beyond gender-affirming care  when it is needed. The postponement and avoidance of healthcare have been found to have detrimental outcomes ,24. As oHealthcare institutions and providers can work to ensure that these barriers of cisgenderism  and cisnormativity  are replaced with affirmation and a conceptualization of gender as a more expansive, nonbinary construct . It is iInclusive forms and records would also support TGI individuals in conveying the manner in which their gender identity intersects with their bodies to healthcare providers. TGI individuals may conceal their gender identities to avoid discrimination in healthcare settings which has healthcare accessibility  and outcome  implications . The useTGI individuals, particularly youth, their families, and their doctors, are being increasingly targeted by legislation and executive orders issued by governors that restrict the accessibility of gender-affirming care in states across the U.S. . DespiteCausal inferences could not be made in this study due to its cross-sectional design. Longitudinal cohort studies should be employed to expand knowledge regarding TGI identity development and healthcare accessibility barriers. This study used an online and non-probability sampling method, thereby lessening its representativeness of the diversity that exists among the TGI population. Despite the geographical representativeness of the U.S, the most marginalized tier  of this population were unable to be accessed; as such, these results cannot be generalized to all TGI individuals. Future studies should strive to utilize probability sampling. While this study captured the reported prevalence of healthcare discrimination and healthcare avoidance behaviors associated with the discrimination faced in healthcare settings by this population, it did not investigate exposure to discrimination in specific healthcare settings . Future studies should assess exposure to erasure and discrimination within specific healthcare specialties. This study garnered information about respondents\u2019 disabilities/neurodivergence but did not inquire about participants\u2019 diagnoses of specific chronic health conditions.Notwithstanding these limitations, this study provides information that is critical to understanding the health behaviors and subsequent health implications for the TGI population. This study provides evidence of the persistence of myriad institutional, structural, and ideological barriers to transgender and gender-independent individuals\u2019 abilities to access healthcare, with associations of deleterious health behaviors  generally, amidst a global pandemic, and has articulated numerous clinical and policy implications for future consideration."}
+{"text": "Background: Autosomal-dominant facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy with associated retinal abnormalities such as retinal vessel tortuosity, focal retinal pigment epithelium defect and large telangiectasia vessels. Methods: Case report of an FSHD 16-year-old female referred for blurred vision in both eyes (20/40), evening fever and shoulder muscle weakness over the past month preceding assessment. A multimodal assessment including visual acuity (VA), microperimetry (MP), multifocal electroretinogram (mfERG), optical coherence tomography (OCT), fluorescein angiography (FA) and fundus autofluorescence (FAF) was performed. Results: OCT showed pseudocyst macular abnormalities and disruption of the photoreceptor layer with no signs of macular ischemia/exudation. Macular function showed foveal impairment recorded by mfERG and MP as a reduction of the response amplitude density and retinal sensitivity, respectively. No medical treatment was prescribed. After three years, patient\u2019s VA slightly improved to 20/32. OCT showed resolution of bilateral pseudocyst macular changes and persistence of photoreceptor disruption. By contrast, mfERG recordings remained abnormal for impaired foveal function and microperimetry mean sensitivity was reduced as well. Conclusions: This multimodal assessment showed persistent VA impairment at three years follow-up associated to abnormal foveal function and reduced retinal sensitivity, with spontaneous resolution of morphological macular changes, suggesting a retinal neurodegenerative process on the basis of the disease. After three years, the patient\u2019s visual acuity slightly improved to 20/32 in both eyes. The repeated SD-OCT scans showed spontaneous resolution of bilateral pseudocyst macular changes and persistence of photoreceptor disruption , morphological  and functional (mfERG and microperimetry) assessment for studying the macular area.This multimodal assessment allowed for the finding of a persistent visual acuity impairment at three years follow-up that is associated to abnormal foveal function and reduced retinal sensitivity, with resolution of morphological macular changes, thus suggesting that visual acuity changes can be associated to foveal outer layers of retinal neurodegeneration, similarly to that found by our group in several neurodegenerative diseases .Bilateral visual impairment in a case of FSHD followed for three years was secondary to macular degeneration trait and not associated to vascular retinal barrier damage. The self-resolved macular abnormalities lead us to think that the pseudocyst changes could be an epiphenomenon of FSHD disease, possibly due to retinal vacuolization, whose pathogenic mechanisms need to be clarified by larger studies correlating signs of supposed vasculopathy and macular dystrophy appearance."}
+{"text": "Severe childhood malnutrition impairs growth and development short-term, but current understanding of long-term outcomes is limited. We aimed to identify studies assessing neurodevelopmental, cognitive, behavioural and mental health outcomes following childhood malnutrition.We systematically searched MEDLINE, EMBASE, Global Health and PsycINFO for studies assessing these outcomes in those exposed to childhood malnutrition in low-income and middle-income settings. We included studies assessing undernutrition measured by low mid-upper arm circumference, weight-for-height, weight-for-age or nutritional oedema. We used guidelines for synthesis of results without meta-analysis to analyse three outcome areas: neurodevelopment, cognition/academic achievement, behaviour/mental health.We identified 30 studies, including some long-term cohorts reporting outcomes through to adulthood. There is strong evidence that malnutrition in childhood negatively impacts neurodevelopment based on high-quality studies using validated neurodevelopmental assessment tools. There is also strong evidence that malnutrition impairs academic achievement with agreement across seven studies investigating this outcome. Eight of 11 studies showed an association between childhood malnutrition and impaired cognition. This moderate evidence is limited by some studies failing to measure important confounders such as socioeconomic status. Five of 7 studies found a difference in behavioural assessment scores in those exposed to childhood malnutrition compared with controls but this moderate evidence is similarly limited by unmeasured confounders. Mental health impacts were difficult to ascertain due to few studies with mixed results.Childhood malnutrition is associated with impaired neurodevelopment, academic achievement, cognition and behavioural problems but evidence regarding possible mental health impacts is inconclusive. Future research should explore the interplay of childhood and later-life adversities on these outcomes. While evidence on improving nutritional and clinical therapies to reduce long-term risks is also needed, preventing and eliminating child malnutrition is likely to be the best way of preventing long-term neurocognitive harms.CRD42021260498. High mortality risk and impaired growth are well-recognised short-term risks of childhood malnutrition.While there is increasing appreciation of longer-term risks for survivors, notably adult cardiometabolic non-communicable disease, other longer-term risks have been poorly described.There is strong evidence that malnutrition impairs neurodevelopment and academic achievement in childhood which has significant implications for future well-being and prospects of those affected.Childhood malnutrition is associated with impaired cognition and behavioural problems with evidence of effects through to adolescence and adulthood but the effect of nutritional treatment and interplay with childhood adversity, coexisting illness such as HIV and environmental factors in influencing these outcomes is unclear.Study findings imply that there are likely to be long-term effects of childhood malnutrition on cognition and well-being lasting through adolescence and adulthood.Long-term needs of malnutrition survivors need to be carefully considered in treatment programmes. Further research is needed on the effects of nutritional therapy, adversity and environmental factors to tailor future interventions, particularly with regard to mental health which has been little researched.Severe childhood malnutrition is widespread and has a high disease burden concentrated in low-income and middle-income settings.5Understanding long-term outcomes following child malnutrition is especially important because improved treatment has thankfully resulted in more children with malnutrition surviving into adolescence and adulthood.Causal pathways linking malnutrition with neurodevelopment, cognition, behaviour and mental health are complex. Previous studies have found children admitted to hospital with severe malnutrition often have severe developmental delays with significant implications for ongoing development, well-being and potential future capital.10A 1995 review found school-age children who suffered from early childhood malnutrition generally had poorer IQ levels, cognitive function, school achievement and greater behavioural problems than matched controls and, to a lesser extent, siblings.We searched MEDLINE, EMBASE, Global Health and PsycINFO for studies published between 1 January 1995 and 6 January 2022 using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.10.1136/bmjgh-2022-009330.supp1Supplementary dataWe included studies from low-income and middle-income countries reporting neurodevelopmental, cognitive, school/academic achievement, mental health or behavioural outcomes in children under five exposed to malnutrition compared with children without malnutrition . We defined childhood malnutrition as undernutrition using standard definitions (definitions which are commonly measured in research and often related to severe adverse outcomes)14 15We included cross-sectional, cohort, case-control and controlled trial study designs which had a comparator group not exposed to childhood malnutrition. We excluded conference papers and reviews which did not include original data. We excluded studies which failed to define how malnutrition, child neurodevelopment, cognition, school/academic achievement, mental health or behaviour were measured. We also excluded studies looking at specific sub-populations of children . No language restrictions were placed on studies.Titles and abstracts were screened by two independent reviewers . The full texts of titles and abstracts chosen by any reviewer were then independently reviewed by two reviewers  against our selection criteria. We also screened reference lists of included studies. Data extraction of included studies was done by one of AK or MGo into a standard template . Data extraction was subsequently checked by a second separate reviewer . Disagreements regarding inclusion of full texts and data extraction were resolved through mutual discussion.We assessed study quality using the National Institute for Health and Care Excellence (NICE) quality appraisal checklist.We grouped studies into three outcome areas: neurodevelopmental, cognition/academic achievement and mental health/behavioural outcomes (with some studies reporting outcomes from more than one category). We differentiated tools which measured general neurodevelopmental outcomes  from those which specifically measured only cognition or academic language tests. We undertook a narrative synthesis of results within each of these areas as diverse outcomes and measurement tools precluded meta-analysis. We followed the Synthesis without meta-analysis (SWiM) reporting guidelines for analysing and reporting results.17For neurodevelopmental studies we grouped studies and compared results by neurodevelopmental assessment tool used. For studies investigating cognition/academic achievement, we grouped those that measured IQ or executive function and those that measured either school or language performance/assessment results. For mental health/behaviour studies, we grouped studies that used behavioural assessment tools and then into groups by mental health condition or domain assessed.For each study outcome where available, we recorded the unadjusted and adjusted results in cases and controls, reported effect sizes, and results from any statistical significance tests. When synthesising results by the groupings described above, we used vote counting by direction of effect to assess the number of studies which recorded differences between cases and controls. We summarised results in tables showing the number of studies with an effect on each outcome area. We also recorded the age group  at which outcomes were measured to compare results between studies. Using SWiM guidelines we used vote counting in conjunction with study quality scores  to summarise the strength of conclusions.Thirty studies met our selection criteria .18\u201347 FuStudy quality scoring is included in We identified nine studies assessing neurodevelopmental outcomes of malnutrition . A summaWe identified 12 studies (three from BNS) assessing cognitive outcomes of malnutrition . A summaEleven studies investigated cognition using several tools assessing intelligence and executive function . Eight oWe identified 14 studies (8 from BNS) assessing mental health and behavioural outcomes of malnutrition . A summaSeven studies (five from BNS) investigated different mental health outcomes .19 26 39Our review finds strong evidence that exposure to malnutrition in childhood impairs neurodevelopment and academic achievement. There is moderate evidence that childhood malnutrition is associated with impaired cognition and is associated with more behavioural problems throughout childhood and adolescence. However, there is uncertainty around the relative contributions of malnutrition and other associated factors  to these outcomes. Research investigating mental health outcomes in children with malnutrition is inconclusive and there are few studies investigating specific mental health domains such as depression. These results have implications for policy-makers surrounding the long-term care needs of those treated for childhood malnutrition and there is a need for research exploring how nutritional therapies and social interventions affect these outcomes.Due to study heterogeneity, we were unable to perform a meta-analysis of any results. We therefore, used published guidelines to synthesise results and determine the strength of evidence for each outcome area. Despite this, there are still limitations given potential publication bias of positive associations between malnutrition and the outcomes investigated. Our review, however, builds on previously published evidence which has suggested links between malnutrition and poorer IQ levels, cognitive function, school achievement and greater behavioural problems.48Impaired neurodevelopment in childhood is likely linked to subsequently poorer academic achievement in childhood and adolescence and may also be linked to increased behavioural problems seen in some studies.While there is still uncertainty around the relative contributions of associated medical and social factors, there is increasing evidence from this review that the early impacts of malnutrition are related to worse academic, cognitive and behavioural outcomes compared with well-nourished peers. Preventing and decreasing childhood malnutrition is therefore of key importance to prevent serious long-term neurocognitive issues in affected children, particularly given the ongoing high malnutrition prevalence in many low-income and middle-income settings. Further research is needed on how to optimise treatment and to best support ongoing care for survivors to improve outcomes in the long term."}
+{"text": "Monoclonal Gammopathy of Undetermined Significance (MGUS) is an understudied precursor of multiple myeloma (MM), the second most prevalent hematologic malignancy in the US. MGUS is incidentally diagnosed, and its significance is unclear as only 1% per year transition to MM. MGUS is highly prevalent among adults aged \u2265 50 years. In this presentation, we will review mixed-method approaches. Using healthcare claims and electronic health records from patients in central Massachusetts, we applied group-based trajectory modeling and conditional Poisson regression. These analyses were complemented by a qualitative analysis of in-depth interviews with providers and MGUS patients. Together, these methodologies provided a comprehensive evaluation of the impact of MGUS on healthcare utilization in older adults. The qualitative analysis provided a better understanding of the patient and provider factors influencing healthcare utilization after an MGUS diagnosis. The presentation will highlight how the use of these methodologies provide different perspectives among understudied premalignant conditions."}
+{"text": "Urban residency benefits cognition in later life. In China, the household registration system (hukou) creates another place-based advantage/disadvantage for cognitive aging. We exam the interplay of rural/urban residence and hukou across the life-course in creating cumulative advantage/disadvantage in cognitive aging trajectories using longitudinal data from the 2011-2018 China Health and Retirement Longitudinal Study and its Life History Survey. Results from linear mixed effect models show that always urban dwellers with urban hukou exhibited the highest level of cognitive function and the slowest decline, and the always rural dwellers with rural hukou had the worst cognitive function and experienced a faster decline. Rural-to-urban shifts had better cognitive health than always rural dwellers, but the advantages depend on urban hukou attainment and specific mechanisms. This research suggests cumulative advantage/disadvantage in cognitive aging by residence and hukou throughout life and demonstrates that institutional discrimination and exclusionary policy may create inequality in aging processes."}
+{"text": "The current study addresses how cancer and aging influence older adults' health trajectories differently. The unique cross-sequential design allowed the study to compare the health changes between long-term (5 years +) older cancer survivors  and demographic-matched older adults without a history of cancer in the same geographic area within the same period by merging two longitudinal studies. The study also captured comprehensive information on health disparities over time. General linear models were employed. The findings showed that neither previous cancer experience nor aging affects health trajectories in later life. Conversely, comorbidities, being African American, female, having less than a college degree, and living alone significantly decreased the health trajectory in later life for all older adults. Moreover, when compared to other groups, older African American cancer survivors reported low scores in self-reported health after controlling for other conditions."}
+{"text": "Pure cutaneous recurrence after breast-conserving surgery is rare and presents a unique challenge to clinicians. Some carefully selected patients may be amenable to further breast-conserving therapy. We present the case of a 45-year-old female with a cutaneous recurrence of previously treated right breast cancer along the operative scar in the upper outer quadrant. The patient underwent a further wide local excision with lateral intercostal artery perforator flap with a skin paddle reconstruction. We achieved volume replacement with this technique, disease control, and a pleasing cosmetic result. Breast-conserving surgery (BCS) is a well-established treatment modality for patients with early breast cancer and offers good cosmesis, low rates of recurrence, and survival outcomes comparable to mastectomy ,2. In paA 45-year-old female was diagnosed with a cutaneous breast cancer recurrence in the upper outer quadrant of her right breast approximately 10 years after a lumpectomy for early breast cancer Figures . At the BCS with adjuvant treatment achieves survival rates equivalent to those seen in patients treated with a mastectomy, while also achieving favorable cosmetic outcomes and low rates of locoregional recurrence . The risA completion mastectomy is usually the treatment modality of choice for ipsilateral breast cancer recurrence. More recently, further BCS has emerged as a feasible option in select patients. Alpert et al. published outcomes of completion mastectomy versus further BCS in 146 patients with ipsilateral breast cancer recurrence . After aOncoplastic techniques have continued to develop and offer patients good oncological outcomes with excellent cosmesis. In 1979, anatomical studies by Kerrigan and Daniel provided a sound understanding of intercostal vessels and skin flaps in the surgical repair of large trunk defects . FocusinHamdi et al. elaborated on the utility of intercostal perforator (ICAP) flaps in breast reconstructive surgery in 2006 . The conThe modified LICAP flap with a skin paddle is a novel way to replace volume and associated cutaneous defects in the breast tissue. Examples include cutaneous recurrence of breast cancer, as described, in patients who have had previous scar retraction or even skin necrosis where skin and volume replacement is required. It is not limited to just cutaneous recurrences, which are rare in themselves. The procedure offers both excellent oncological margins and cosmetic results and is suitable in carefully selected patients who participate in multidisciplinary treatment planning."}
+{"text": "The purpose of this study was to identify the association between physical/mental health problems and depressive symptoms among older Black Americans (age \u2265 65) using the 2018 Health and Retirement Study (N = 812). People with multiple medical conditions face substantial emotional difficulties including depressive symptomatology. The study of depressive symptoms among older Black Americans is an emerging area of research. Several existing studies reported a higher prevalence of depressive symptoms among this population. They also experience a disproportionate burden of multimorbidity, both physically and mentally. For statistical analysis, depressive symptoms were measured with the eight-item CES-D scale . Physical multimorbidity was measured by asking whether respondents had ever been diagnosed with seven diseases . Mental multimorbidity was measured by asking whether they had ever been diagnosed with three diseases . Covariates included gender, marital status, and income (logged). A negative binomial regression showed that (a) higher numbers of physical health problems were associated with higher depressive symptoms ; (b) higher number of mental health problems were also related to higher depressive symptoms among older Black Americans . These findings underscore the importance of identifying and managing depressive symptoms among older Black Americans, who present with greater physical/mental health multimorbidity."}
+{"text": "Personal networks are a key component in the provision of social support for older adults. Such support is particularly critical during the COVID-19 pandemic, when traditional avenues of social engagement or assistance are disrupted. Here, we use nationally representative data from the National Social Life, Health, and Aging Project that assesses older adults\u2019 pre-pandemic personal networks and receiving instrumental help and emotional support during the pandemic. We find that larger pre-pandemic confidant networks predict higher odds of receiving needed help and support, higher odds of receiving help and support more often than before the pandemic, and lower odds of being unable to get help. Denser pre-pandemic networks also predict higher odds of receiving instrumental help and support during the pandemic, while having a greater proportion of kin in pre-pandemic networks predicts higher odds of receiving pandemic help for non-white older adults only. Together, results suggest that features of older adults\u2019 pre-pandemic confidant network structure and composition can provide underlying conditions for receiving social support during the pandemic."}
+{"text": "Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse cystic lung disease that occurs almost exclusively in young adult smokers. High-resolution computed tomography of the chest allows a confident diagnosis of PLCH in typical presentation, when nodules, cavitating nodules, and cysts coexist and show a predominance for the upper and middle lung. Atypical presentations require histology for diagnosis. Histologic diagnosis rests on the demonstration of increased numbers of Langerhans cells and/or specific histological changes. PLCH is one of the few diseases in which bronchoalveolar lavage (BAL) has a high diagnostic value and can in some circumstances replace lung biopsy. We present a case of PLCH in an elderly non-smoker. Chest imaging revealed the presence of advanced interstitial lung disease with a fibrocystic pattern. BAL cellular analyses disclosed a macrophage pattern with CD1a phenotype that strongly supports the PLCH diagnosis, even in the setting of atypical clinical presentation and a lack of smoking exposure. PLCH is extremely rare in non-smokers and could represent a distinct phenotype. BRAF-V600E mutation on the BAL cytology specimen and/or whole blood NGS for mutations and fusions in genes of the MAPK-ERK and related pathways provide supplementary diagnostic evidence, especially for atypical PLCH, and could stratify different pathological phenotypes [PLCH is a rare disorder (<5% of ILD cases) of unknown etiology that occurs predominantly in young smokers (>90% of patients) . PLHC beenotypes . The limenotypes . Unfortu"}
+{"text": "Conventional structural neuroimaging methods can identify changes in cortical thickness but cannot relate these changes to specific cortical layers due to a lack of sensitivity. However, several indirect measures sensitive to changes specifically occurring in supragranular cortical layers were developed recently .The aim was to assess the ability of these novel measures to detect cortical layers thickness characteristics potentially associated with risk or resilience to developing schizophrenia.43 first-episode schizophrenia (FES) male patients, 29 non-converted individuals at ultra-high risk of psychosis , and 43 matched healthy controls (HC) underwent structural MRI at 3T Philips scanner. Images were processed via FreeSurfer and MATLAB to derive two markers specific to supragranular thickness change: gyral-sulcal thickness differences (GSTD) and gyral-sulcal intrinsic curvature differences on pial surface (GSCD).GSCD measures were increased in temporal, parietal and occipital cortices, whereas both GSTD and GSCD were increased in the right frontal cortex in FES compared to HC. No GSTD or GSCD were changed in ncUHR compared to HC, and GSCD was decreased in the frontal cortex compared to FES.Our findings from the indirect measures indicate a potential predominance of supragranular thinning in FES and suggest that a supragranular thinning in the right frontal lobe might be associated with precipitating risk and/or illness effects of schizophrenia. At the same time, no clear supragranular markers directly associated with resilience or risk mechanisms were identified. The work was supported by RFBR grant 20-013-00748."}
+{"text": "Our first objective is to investigate how between subject differences in the likelihood of record linkage consent and record linkability determine the composition of and so risks of biases in estimates from linkable business datasets. The utility of datasets linking information from multiple sources is compromised by such non-linkage biases, but both components of the linkage process have rarely been considered. Our second objective is to introduce methods for evaluating non-linkage bias risks in datasets. Such evaluations can inform linkage method choice and assessment of the validity of linked dataset findings. Previous work, often lacking non-linked subject information on non-sample dataset covariates, tends to utilise overall linkage rates as quality measures, but in the related area of survey non-response correlations between analogous response rates and non-response biases are weak.We utilise the UK 2010 Small Business Survey (SBS) dataset. If a survey subject consents to record linkage, an attempt is made to append their Inter-Departmental Business Register (IDBR) identifier (if one exists), enabling linkage to other surveys etc. Given this, we evaluate bias risks arising from variation in subject linkage consent and identifier appendability, as well as its product, overall linkability, utilising representativeness indicators developed to evaluate survey non-response bias risks. These measure risks in terms of sample-subset similarity (representativeness) given an attribute covariate set obtained from the sample dataset, based on variation in subject inclusion propensities estimated by logistic regression, and are decomposable to assess correlates of inclusion propensity variation. Specifically, we use the CV (the standard deviation of inclusion propensities divided their mean), computed given nine attribute covariates describing business demography and perceived performance.We give full details in our presentation. Briefly, overall CVs suggest the linkable dataset exhibits substantial non-representativeness and non-linkage bias risk. Decompositions suggest main impacts on the linkable dataset are under-representation of very small businesses , due to being both less likely to consent and less likely to have an identifier appended, and under-representation of businesses unable / refusing to respond to survey items, due to being less likely to consent.Our analyses provide evidence of non-linkage bias risks in linked SBS datasets caused by under-representation of several sample subgroups. Each is explicable given known IDBR under-coverage or knowledge of business response processes. We also conclude that representativeness indicators are an easily applied method by which such risks can be evaluated."}
+{"text": "Driven by the aim of realizing functional robotic systems at the milli- and submillimetre scale for biomedical applications, the area of magnetically driven soft devices has received significant recent attention. This has resulted in a new generation of magnetically controlled soft robots with patterns of embedded, programmable domains throughout their structures. This type of programmable magnetic profiling equips magnetic soft robots with shape programmable memory and can be achieved through the distribution of discrete domains (voxels) with variable magnetic densities and magnetization directions. This approach has produced highly compliant, and often bio-inspired structures that are well suited to biomedical applications at small scales, including microfluidic transport and shape-forming surgical catheters. However, to unlock the full potential of magnetic soft robots with improved designs and control, significant challenges remain in their compositional optimization and fabrication. This review considers recent advances and challenges in the interlinked optimization and fabrication aspects of programmable domains within magnetic soft robots. Through a combination of improvements in the computational capacity of novel optimization methods with advances in the resolution, material selection and automation of existing and novel fabrication methods, significant further developments in programmable magnetic soft robots may be realized. Variation of the material distribution and magnetic profile has enabled MSRs to demonstrate shape-forming and navigational abilities far beyond those of current soft robots (Programmable magnetic soft robots (MSRs) are typically formed through the combination of magnetic particles with soft elastomeric materials, and are controlled wirelessly t robots . Their pt robots  presentst robots , shape-ft robots  and origt robots .An idealized approach to the development of programmable MSRs is illustrated in This review aims to highlight the most significant developments and challenges specific to the optimization and fabrication of programmable domains for biomedical MSR applications. Following a review of programmable MSRs presented in the literature, we first consider specifically recent developments in optimization procedures, including physics-based modelling, deep learning and genetic algorithm protocols. This is followed by examination of novel fabrication methods across lithographic patterning, direct ink writing and direct laser writing that both support fabrication of optimal designs and limit optimization flexibility. We conclude the review with a discussion focused on the main current challenges and future directions of optimization and fabrication methods for the advancement of programmable MSRs.Many MSR designs rely on magnetic profiling approaches, as depicted in via UV curing, which fixed characteristic magnetization properties to individual target domains. Early research into MSR profiling was largely limited to non-programmable  materials with heterogeneous magnetic distributions, typically restricting shape-forming and navigational abilities to planar deformations . More rein vivo environments such as the endometrium . Another key challenge remains in capturing the MSR\u2019s underlying physics at high fidelity and across a range of voxel scales. This includes interpreting viscous and frictional forces and self-interaction between magnetic regions at submillimetre scales. It is therefore pertinent to investigate methods with reduced computational burden and integration with realtime predictive model data, such that programmable MSR behaviours may be optimized with ever-increasing accuracy and reliability .Deep learning optimization integrates statistical modelling with iterative neural network computation to derive voxel configurations for desired deformation. The integration of deep learning algorithms with MSR fabrication has potential to significantly improve the selectivity and computational reach of MSR optimization, in turn paving the way for a new generation of optimized programmable MSRs.via experiment, which is arduous, or via simulation, which reintroduces the aforementioned errors in modelling assumptions. This presents a significant challenge to adoption in deep learning-based optimization of programmable magnetic domains  to impart varied magnetic properties between cured layers. LP realizes exceptional applicability for single and multidirectional voxel magnetization, ranging from binary magnetization patterning in 1D to arbitrary multi-layer encoding in 3D programmable materials. It has therefore played an integral role, alongside studies into magnetic, complex 3D shape configurations, for biomedical MSR prototypes (In terms of programmable MSR fabrication, LP comprises a family of additive methods which involve embedding magnetic particles within curable substrates, followed by selective magnetization and composite curing (ototypes .via selective curing of a UV resin. Embedded particles were first magnetized with an external magnetic field. A template was then utilized to expose particular composite regions to UV light, locking in the embedded particle magnetizations. This automated process was used to fabricate 2D elastomeric MSRs with programmable magnetic anisotropies and facilitated the development of a bio-inspired undulatory swimming robot which utilized encoded travelling wave motion along its length to achieve flagellar motion, commonly observed in spermatozoa and bacterial cells. This may hold promising applications for minimally invasive navigation throughout complex vasculature or cerebral spinal fluid (A digital light processing lithographic method was developed by al fluid .In contrast, A lithographic approach was also taken by in vivo application (Current challenges for LP voxel-encoding lie in the limited availability of biocompatible materials . Future lication .DIW couples digitally-driven methods of fused deposition modelling with programmable magnetization to produce voxelated structures with readily encoded magnetic anisotropies . DIW incA similar method was developed by At present, DIW suffers from deteriorating print quality at submillimetre scales, largely as the scale of embedded magnetic particles is approached. Additionally, shorter voxel lengths at the submillimetre scale induces weaker magnetic densities between adjacent voxels. Both of these issues reduce the MSR\u2019s overall sensitivity to external magnetic actuation, as well as its ability to achieve deformations of greater complexity . Future via optical additive manufacturing. A magnetic field programs anisotropies throughout each printed voxel layer, whilst a laser scans across target regions for localized encoding of magnetic anisotropies. The application of heat by laser scanning prevents thermal diffusion of magnetic particles to non-target regions, whilst rapid cooling fixes the selected magnetization patterns before consecutive layers are printed. The integration of DLW with pre-existing fabrication methods presents promising opportunities for the rapid, automated fabrication of programmable domains at micrometre scales (Direct laser writing couples digitally-driven laser curing with programmable magnetization to selectively encode magnetic anisotropies at submillimetre scales. Similar to previous methods, DLW involves embedding magnetic particles within curable elastomeric matrices, often e scales .via global laser heating and individual voxel-programming at resolutions of 30\u00a0\u00b5m. The method was used to encode various magnetization profiles on a flower-inspired six-arm gripper robot (er robot . The sixCurrently, limitations in laser penetration depth remain a significant challenge in DLW, in turn limiting the method\u2019s expansion to rapid 3D fabrication and programming . Future in vivo drug delivery. To support flexible, rapid fabrication of MSRs, Other fabrication methods, including injection molding and magnetic spraying, have also played an essential role in the development of programmable MSRs for biomedical applications. Low-pressure injection molding methods for soft continuum MSR fabrication have recently been presented . Lloyd eIt is evident that, even within a short period, significant developments in the optimization and fabrication of programmable domains have played an integral role in miniaturizing and improving the functionality of bio-inspired MSRs. As indicated in via the integration of reliable and computationally efficient optimization procedures with flexible fabrication methods. To maximize this potential, it is therefore pertinent to address the resolution, material, computational and automation challenges that affect the presented optimization and fabrication methods.As outlined, the field holds exceptional potential via experimental data integration due to difficulty of reliable data collection at such scales. At present, optimization via genetic algorithms remains the most promising method, largely due to its operation with model-free experimental arrangements, capability of unlimited search space sizes and potential for increased adoption across various digitally-driven programmable MSR fabrication methods.The computational capacity of physics-based modelling remains a significant hurdle in determining optimal voxel behaviours at submillimetre scales and across the full spectrum of underlying physical interactions which influence programmable MSR actuation. With the identified need for improved models to capture the dynamics, material properties and interaction forces, the required current and potential computational burden of physics-based modelling is significant. The integration of real data to tune adaptive models may be pursued to reduce the computational burden of future physics-based model methods. In deep learning methods, the trade-off between experimental data and simulation data use remains a significant challenge to widespread adoption. Efforts to reduce modelling assumption errors, particularly within underlying FEM models, may be applied for improved reliability of simulation-driven deep learning methods. The choice to utilise experimental data within future optimization procedures may depend on the voxel scale and resolutions applied throughout MSR geometry, with submillimetre scales less likely to be optimized Additionally, significant challenges in the resolution, material selection and automation of current fabrication techniques must also be addressed. The limited availability of biocompatible materials remains a significant hurdle for current LP methods, however, additional research into the use of gelatin and hydrogel-based materials may improve the method\u2019s potential as a widely adopted programmable MSR fabrication procedure. Furthermore, several LP and other fabrication techniques comprise a series of manual steps, reducing the efficiency of the overall MSR fabrication process and hence limiting both its reproducibility and scalability for high-volume fabrication. These manual processes, however, bring greater flexibility for precise domain assembly, as observed in It is widely anticipated that improvements in the capacity of both statistical and physics-based optimization coupled with further improvements to the resolution, material selection and automation of existing and novel fabrication methods will pave the way for further novel programmable MSRs. If an appropriate voxel resolution can be achieved across both optimization and fabrication aspects of MSR development, extended shape-forming abilities and improved biocompatibility hold the potential to unlock novel applications at the milli- and submillimetre scales."}
+{"text": "Each local authority in England must develop a Health and Wellbeing Strategy (HWS) in collaboration with NHS partners to plan and support delivery of local improvements in health and wellbeing. HWSs often draw on diverse sources but few are informed by consultative exercises involving citizens. South Tyneside Council in Northern England sought to ensure their new HWS was community-informed, specifically including seldom-heard groups and individuals. Specific objectives of this community insights research were to:1.Target sampling and recruitment activities at typically marginalized, vulnerable or otherwise underrepresented groups2.Explore the health and wellbeing-related views and priorities of these groups to address health inequalitiesA mapping exercise was undertaken to identify organisations who might act as gatekeepers to accessing participants from underrepresented groups. Focus groups were held in settings-based venues where members would be comfortable and known to one another. Representatives of voluntary and community sector (VCS) organisations often helped to co-facilitate the discussions.119 participants took part in 16 group discussions. Three were held online, two were outdoors, while 11 involved community venues where the groups regularly met. We reached older and younger people, minority ethnic groups, and vulnerable men and women, including residents who had experienced homelessness, mental health issues, substance misuse, offending, domestic violence and learning disabilities. Participants were largely concerned with the wider determinants of health , shifting the narrative away from individual lifestyle factors that tend to be the focus of much public health discourse.Gatekeepers from the VCS were essentially gateways, enabling us to include underrepresented voices in local consultation processes and generate new insights to inform the South Tyneside HWS.Public health strategy development can address health inequalities through community-informed consultative exercises involving seldom heard members of vulnerable communities.Community consultations seeking to reach typically underrepresented groups require gatekeepers acting as gateways, and meeting participants where they are comfortably located at community venues."}
+{"text": "End-stage renal disease (ESRD) causes age-accelerating disease and disproportionally affects older and minority patients; the preferred treatment is kidney transplantation (KT). Rates of KT have risen 5-fold for older adults since 1990 but there is great heterogeneity in KT outcomes by frailty and waitlist status. The person-environment fit theory posits that improving a person\u2019s lived environment will facilitate optimal individual functioning. We recruited a balanced sample of 20 participants  with respect to their frail/ pre-frail and inactive/ active waitlist status to explore personal experience and the lived environment through the use of photovoice, gaining insight into the person-environment fit of those older adults awaiting KT. We will discuss IRB issues, recruitment and logistical tips with using Photovoice. This work will help to inform what vulnerable and marginalized older adults awaiting KT must be prepared for psychologically and physically, including modifications needed to their lived environments."}
+{"text": "Metabolic acidosis, a common complication in patients with chronic kidney disease (CKD), results in a multitude of deleterious effects. Though the restoration of kidney function following transplantation is generally accompanied by a correction of metabolic acidosis, a subset of transplant recipients remains afflicted by this ailment and its subsequent morbidities. The vulnerability of kidney allografts to metabolic acidosis can be attributed to reasons similar to pathogenesis of acidosis in non-transplant CKD, and to transplant specific causes, including donor related, recipient related, immune mediated factors, and immunosuppressive medications. Correction of metabolic acidosis in kidney transplantation either with alkali therapy or through dietary manipulations may have potential benefits and the results of such clinical trials are eagerly awaited. This review summarizes the published evidence on the pathogenesis and clinical consequences of chronic metabolic acidosis in kidney transplant recipients. CalcineRejection can cause tubulitis and ischemic tubular dysfunction, affecting H + ATPase activity and anion exchanger leading to RTA . HoweverLastly, hyperkalemia, a common occurrence post kidney transplantation  also contributes to development of acidosis. Hyperkalemia decreases ammonia generation and transport in proximal tubule and collecting duct respectively, leading to impaired ammonia excretion and subsequent metabolic acidosis . Of the 2 level less than 22\u00a0mmol/L at three months post-transplant was associated with increased risk of graft loss and death censored graft failure , metabolic acidosis defined as the serum total CO failure . Similar failure ; however failure . This poPost transplantation anemia is common in kidney transplant patients with prevalence being reported around 30\u201350% of the patients . The pat2 vitamin D3 by proximal tubule, increasing calcium excretion and serum PTH levels, thus promoting bone resorption sorption . In vitreoclasts . Additioeoclasts , therefoeoclasts .Individuals with advanced kidney disease often have reduced muscle mass and exercise tolerance . PhysicaMetabolic acidosis has been shown to be an independent risk factor for all-cause mortality in CKD . These fThere is a paucity of evidence attesting to the benefits of metabolic acidosis correction in kidney transplant recipients. In fact, in a large retrospective study of 4741 kidney transplant recipients sodium bicarbonate therapy was associated with higher risk of graft failure . HoweverIn a small randomized controlled trial aimed to investigate the effect of sodium bicarbonate therapy on vascular endothelial function in 20 kidney transplant recipients , the sodData on dietary fruits and vegetable consumption as a measure of metabolic acidosis correction in kidney transplant recipients is even scarcer. In CKD, a diet rich in fruits and vegetables favorably affects acid-base metabolism, neutralizes diet-induced acid, and has been shown to be cardio-protective . In a prMetabolic acidosis is an understudied, highly prevalent complication in kidney transplant recipients. In addition to mechanisms described in metabolic acidosis of CKD, calcineurin inhibitors play a central role in its development and maintenance, through dysregulation of tubular transport proteins involved in acid load handling. Additional research aimed to unfold the mechanisms and consequences of metabolic acidosis present post kidney transplantation will help inform future large intervention trials designed to correct it, in an attempt to prevent allograft loss and improve overall survival in kidney transplant recipients."}
+{"text": "Do physician group practices participating in bundled payments among Medicare beneficiaries exhibit similar or different changes in episode outcomes compared with participating hospitals?This cohort study with a difference-in-differences analysis found that physician group practices participating in bundled payments had associated savings with surgical but not medical episodes, whereas participating hospitals had savings associated with both episode types.The findings of this cohort study suggest that policy makers should consider the comparative performance of participant type when designing and evaluating future bundled payment models. Hospital participation in bundled payment initiatives has been associated with financial savings and stable quality of care. However, how physician group practices (PGPs) perform in bundled payments compared with hospitals remains unknown.To evaluate the association of PGP participation in the Bundled Payments for Care Improvement (BPCI) initiative with episode outcomes and to compare these with outcomes for participating hospitals.This cohort study with a difference-in-differences analysis used 2011 to 2018 Medicare claims data to compare the association of BPCI participation with episode outcomes for PGPs vs hospitals providing medical and surgical care to Medicare beneficiaries. Data analyses were conducted from January 1, 2020, to May 31, 2022.Hospitalization for any of the 10 highest-volume episodes  included in the BPCI initiative for Medicare patients of participating PGPs and hospitals.The primary outcome was 90-day total episode spending. Secondary outcomes were 90-day readmissions and mortality.The total sample comprised data from 1\u2009288\u2009781 Medicare beneficiaries, of whom 696\u2009710  received care through 379 BPCI-participating hospitals and 1441 propensity-matched non\u2212BPCI-participating hospitals, and 592 071  received care from 6405 physicians in BPCI-participating PGPs and 24 758 propensity-matched physicians in non\u2212BPCI-participating PGPs. For PGPs, BPCI participation was associated with greater reductions in episode spending for surgical  but not for medical episodes . Hospital participation in BPCI was associated with greater reductions in episode spending for both surgical  and medical  episodes.This cohort study and difference-in-differences analysis of PGPs and hospital participation in BPCI found that bundled payments were associated with cost savings for surgical episodes for PGPs, and savings for both surgical and medical episodes for hospitals. Policy makers should consider the comparative performance of participant types when designing and evaluating bundled payment models. This cohort study evaluates the association between bundled payments and episode outcomes per medical and surgical episodes for physician groups compared with hospitals participating in the Medicare bundled payments initiative. Along with hospitals, PGPs participated in model 2 of Medicare\u2019s Bundled Payments for Care Improvement (BPCI) initiative,10 assuming accountability for the quality and costs of medical and surgical episodes spanning hospital admission and up to 90 days of postacute care. Although PGP participation in BPCI was associated with reduced Medicare payments and improved quality for joint replacement episodes,11 data are lacking for the hundreds of groups participating in other medical and surgical episodes.Although hospital participation in bundled-payment programs has been well studied,12 We addressed this knowledge gap by evaluating the association between PGPs and hospitals participating in BPCI model 2 on episode outcomes and comparing PGP vs hospital performance.To coordinate participation in future payment models, policy makers must understand the dynamics of PGP vs hospital performance, particularly given the evidence from other payment models indicating that physician groups may perform differently than hospitals in managing quality and costs.STROBE) reporting guideline.13This study was approved by the University of Pennsylvania Institutional Review Board and informed consent was waived because only historical data with minimal risk of harm were used. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology  and a subsequent intervention period . The study sample included Medicare fee-for-service beneficiaries receiving care through BPCI PGPs and hospitals for 1 of 10 episodes, each defined by a set of Medicare Severity-Diagnosis Related Group codes: the top 5 highest-volume medical episodes  and the top 5 highest-volume surgical episodes . We excluded beneficiaries with end-stage kidney disease or insurance coverage through Medicare Advantage, as well as beneficiaries who had any non-Inpatient Prospective Payment System claims, lacked continuous primary Medicare fee-for-service coverage during or in the 12 months preceding the episode, or died during the index hospital admission.3 We excluded episodes between January 1, 2013, and September 30, 2013, to account for the transitional period during which PGPs and hospitals may have implemented care process changes in anticipation of BPCI.We constructed episodes beginning with hospital admission and spanning 90 days after hospital discharge, capturing episodes beginning on or before September 30, 2017. To avoid bias arising from Medicare precedence rules for overlapping episodes between participating PGPs and hospitals, we followed prior methods and constructed naturally occurring episodes by assigning overlapping ones to the earlier hospitalization.12 and those with any BPCI PGPs or BPCI hospitals were defined as BPCI Markets. We categorized patients based on hospitalization for 1 of 10 episodes of interest through BPCI PGPs, non-BPCI PGPs, BPCI hospitals, or non-BPCI hospitals. Patients receiving care through BPCI PGPs and hospitals were categorized as \u201cBPCI-both.\u201dWe used Medicare claims data (2011-2018) to identify BPCI PGPs and BPCI hospitals. Groups and hospitals that never participated in any of the 48 episodes in BPCI were categorized as non-BPCI PGPs and non-BPCI hospitals. We used propensity scores to match BPCI with non-BPCI PGPs and BPCI with non-BPCI hospitals , and other responses were classified in the \u201cother\u201d category.The study exposures were dichotomous indicators of PGP participation and hospital participation in BPCI. To reflect participant entry into BPCI at different times, participation indicators were time-varying and specific to each PGP or hospital. Groups and hospitals were considered as participants after enrolling in BPCI, regardless of subsequently dropping out. Covariates were chosen based on prior studies and included patient demographic and clinical variables, such as age, sex, and disease severity (defined using Elixhauser comorbidities), as well time-varying market variables, such as Medicare population size and Medicare Advantage penetration.The study\u2019s primary outcome was 90-day total episode spending . Secondary outcomes were 90-day readmissions and 90-day mortality. We also evaluated a number of exploratory spending and utilization outcomes (eMethods 2 in 18 We used a difference-in-differences (DID) method to mimic a 2\u2009\u00d7\u20092 factorial experiment comparing BPCI participation among hospitals and PGPs. Per the factorial design, we classified the treatment groups to reflect patient exposure to BPCI hospitals, BPCI PGPs, both (BPCI-both), and neither (non-BPCI). This approach enabled the comparison of episode performance for BPCI PGPs (vs non-BPCI) and BPCI hospitals (vs non-BPCI), as well as between BPCI PGPs and BPCI hospitals).Characteristics between the propensity-matched BPCI and non-BPCI PGPs and BPCI and non-BPCI hospitals were compared using standardized differences of means and proportions.19 Nonparticipating PGPs and hospitals were assigned the same treatment indicators as their propensity matched organizations. We evaluated medical and surgical episodes separately because they involve different care processes that may have different associations with outcomes.19In adjusted analyses, DID models included PGP- and hospital-specific indicators of BPCI participation as treatment to reflect the time-varying nature of BPCI participation\u2014that is, the fact that PGPs and hospitals could start participating at different times. This approach contrasted with traditional DID models, in which the baseline and treatment periods are fixed regardless of timing of actual contract initiation.We used generalized linear models with identity links and normal distributions for all outcomes. All models included episode (Medicare Severity-Diagnosis Related Group code) and market  fixed effects to generate within-episode type, within-market estimates that addressed time-invariant episode type, and geographic differences. Models also included time  fixed-effects to account for secular trends. Robust standard errors were clustered at the hospital level.20 we assessed the relationship between the primary outcome and potentially time-varying market-level covariates and how those covariates changed over time across the 4 study groups .Final model specifications for the primary outcome included only covariates deemed as potential confounders according to this process  as being in the BPCI PGP group. Finally, we repeated analyses for the mortality outcome by including individuals who died during index hospitalization.In response to an association observed between BPCI participation and differential changes in mortality that, to our knowledge, has not been previously described in the literature, we conducted post hoc analyses to explore robustness. First, we described selection based on observable and unobservable patient characteristics. Second, we tested approaches to mitigate bias from unobserved clinical severity of patients. Third, we repeated analyses using our modeling approach, but using data from that earlier time period, to assess the ability to replicate those mortality results.The total study sample comprised 2011 to 2018 Medicare claims data for 1\u2009288\u2009781 beneficiaries, of whom 696\u2009710 patients  received care through 379 BPCI hospitals and 1441 propensity-matched non-BPCI hospitals; and 592\u2009071 patients  received care from 6405 physicians in BPCI PGPs and 24\u2009758 propensity-matched physicians in non-BPCI PGPs.Compared with non\u2212BPCI-participating hospitals, participating hospitals tended to be larger, nonprofit, teaching hospitals located in urban areas and markets with larger populations and smaller proportions of low-income individuals . In contrast, there were no differential changes in spending between BPCI PGP and non-BPCI groups  or between BPCI-both and non-BPCI groups . The BPCI hospitals had differentially greater reductions in total episode spending compared with BPCI PGPs .In adjusted analysis of medical episodes , but not between BPCI PGP and non-BPCI groups . Compared with the non-BPCI group, there were differential decreases in mortality for BPCI PGPs  and BPCI hospitals . The BPCI hospitals and BPCI PGPs did not exhibit comparatively differential changes in mortality or readmissions. The BPCI hospitals differed from nonparticipants with respect to exploratory outcomes for medical episodes , BPCI PGP group , and BPCI-both  compared with the non-BPCI group. The magnitude of spending changes did not differ between BPCI hospitals and PGPs .In adjusted analysis . In contrast, there were no differential changes in readmissions for the BPCI hospital or BPCI-both groups compared with the non-BPCI group .Compared with patients in the non-BPCI group, those in the BPCI PGP group had differentially greater changes in 90-day readmissions  and BPCI hospitals  compared with patients in the non-BPCI group. The magnitude of these changes was not different for BPCI hospitals vs BPCI PGPs . Compared with nonparticipants, BPCI hospitals and PGPs differed in exploratory surgical episode outcomes (eTable 10 in Mortality changed differentially for patients cared for through BPCI PGPs (difference, \u20130.5 pp; 95% CI, \u20130.8 to \u20130.2 pp; 3 that found no association between BPCI hospital participation and differential mortality changes.Compared with the main study analyses, results of sensitivity analyses were qualitatively similar (eFigures 7-12 in In this cohort study with DID analysis, participation of PGPs and hospitals in BPCI was associated with cost savings for surgical episodes; however, only hospital participation was associated with cost savings for medical episodes. Hospital and PGP participation were associated with different patterns of changes in postacute utilization and mortality. For example, for medical episodes, hospital participation in BPCI was significantly associated with reductions in length of stay at skilled nursing facilities, whereas PGP participation was not. For surgical episodes, PGP participation in BPCI was associated with reductions in home health use, whereas hospital participation was not. These findings pose 3 implications.11 Although it is only one aspect of a payment model\u2019s success, spending reductions are critical because policy makers increasingly judge the viability of bundled payment programs by their cost savings.22First, these findings underscore the benefit of engaging PGPs in episode-based payment models. This analysis adds to prior work by describing the association of PGP participation in BPCI with cost savings for multiple surgical episodes, extending beyond hip and knee replacements.12 demonstrating that PGPs may be more successful than hospitals at reducing spending in population-based payment models, such as acute care organizations. Future work should elucidate drivers underlying this distinction. For example, hospitals may be better positioned to coordinate with postacute care organizations such as skilled nursing facilities given their high volume of shared patients. These strategies may be particularly important for medical conditions where the episode cost savings come from reductions in postacute care facility length of stay rather than reductions in the proportion of individuals discharged.3 Policy makers may consider these facets of performance when considering participant types in future alternative payment models.Second, these study findings affirm the suitability of hospitals to bundled payment models, specifically highlighting their relative advantage over PGPs in achieving cost and potential quality outcomes for medical conditions. These findings contrast with prior researchThird, these study findings emphasize the need for future research on the drivers of cost savings and quality improvements under bundled payments. Our results regarding BPCI-participating PGPs point to the importance of changes in readmissions and postacute care utilization in determining episode savings. Yet as observed from BPCI-participating hospitals, different patterns of utilization changes may drive savings for different episode types. Specifically, in these findings medical episode savings were associated with reductions in length of stay within skilled nursing facilities, whereas surgical episode cost savings came from fewer discharges to skilled nursing facilities.Additional work is also needed to assess the relationship between bundled payments and quality improvements. Although differential mortality reductions were observed by this study, there was also evidence of observable and unobservable favorable patient selection under bundled payments. This makes definitive conclusions regarding changes in health care quality challenging. Clarity on whether apparent quality changes represent true improvements, patient selection, or measures of both is highly relevant to policy and should be the focus of future studies.This study had some limitations worth noting. Findings may have been subject to residual confounding; however, we mitigated concerns by using a DID design that accounted for unobserved heterogeneity and patient and hospital characteristics. We evaluated the highest-volume episodes under a single program; however, BPCI model 2 was the direct basis for ongoing PGP and hospital participation in BPCI Advanced. Also, we did not include more recent data from BPCI Advanced because physician group participation files were not available. Moreover, we were unable to match physicians or identify episodes using tax identification number-level information owing to a lack of data availability. However, our approach using all episodes per National Provider Identification number and any participation in BPCI was conservatively biased toward the null hypothesis. Furthermore, to our knowledge, mortality reductions have not been previously described, and although we tested the robustness of the findings using a range of sensitivity and post hoc analyses, the analyses suggested the presence of unobservable patient selection that precluded definitive conclusions regarding any changes in health care quality. Despite conducting sensitivity analyses using alternative modeling approaches for episode spending as the primary outcome, future work should assess the use of modeling approaches beyond ordinary least-squares for other outcomes.This cohort study with DID analysis found that PGP participation in BPCI was associated with cost savings for surgical episodes but not for medical episodes, whereas hospital participation in BPCI was associated with savings for both episode types. Policy makers should consider the comparative performance of participant type when designing and evaluating future bundled payment models."}
+{"text": "Bronchopulmonary sequestration (BPS) and hybrid lesion of congenital pulmonary airway malformation (CPAM) are congenital lung lesions typically presenting with systemic vascular connection. We describe and categorize this atypical systemic vascular anatomy in congenital lung lesions.In a medical chart review from 2005 to 2020 patients with systemic vascular connection of congenital lung lesions were identified. Clinical and radiological data were collected and compared. Two experienced pediatric radiologists reviewed postnatal thoracic contrast-enhanced computed tomography scans to describe and categorize atypical vascular anatomy. We completed our findings with a review on vascular anatomy in congenital lung lesions.A total of 21 patients with congenital lung lesions  had systemic arterial supply; with seven of these additionally having systemic venous drainage. Origin of the feeding arteries from the aorta or aortic main branches was described as supra-diaphragmatic (descending thoracic aorta) in nine and infra-diaphragmatic in ten patients . In two patients with hybrid lesions both supra- and infra-diaphragmatic arterial feeders were found. Additional systemic venous connection of supra-diaphragmatic type drains into the azygos-hemiazygos system (4/21) while the infra-diaphragmatic type (3/21) drains into caval vein, portal or splenic vein.Various variants of systemic arterial and venous connection of congenital lung lesions can be found. Classification of systemic arterial connection as well as venous drainage of congenital lung lesions as supra-diaphragmatic and infra-diaphragmatic types is intuitive, simple and may be important for the surgeon to avoid unanticipated situations and to perform safe resections. Congenital pulmonary lesions are occasionally detected in prenatal ultrasound examinations. The most common lesions are congenital pulmonary airway malformation (CPAM) and bronchopulmonary sequestration (BPS). Atypical systemic blood supply is a characteristic feature of BPS, but there is also a number of CPAMs presenting with systemic vascular connection referred to as hybrid lesions . PrenataThis is a retrospective chart review performed in a tertiary perinatal center in a large Austrian city. After institutional review board approval, all patients with BPS and CPAM were identified in prenatal, neonatal and surgical database from 2005 to 2020. Only patients with systemic vascular connection  of congenital lung lesion were included. Medical records were reviewed for pre- and postnatal clinical data; complications and outcome of treatment were assessed. Two experienced pediatric radiologists reviewed postnatal CECTs (iodixanol) to precisely describe the atypical anatomy of both arterial and venous systemic connection of congenital pulmonary lesions. We focus on description and categorization of vascular anatomy of these congenital lung lesions. A literature review on vascular characteristics in congenital lung lesions completes our data.From 2005 to 2020, 48 patients  with either BPS or CPAM were treated at our department of pediatric surgery in a tertiary university hospital. In 39 cases these congenital lung lesions were identified in prenatal ultrasound examination. Postnatal CECT scan did not depict systemic vascular supply in 25 of 48 patients with congenital lung lesions\u2014these were \u201cclassical\u201d CPAM. In two patients, prenatally diagnosed congenital lung lesion was not confirmed postnatally: one child had a normal CECT scan and the other showed small vascular connections between the thoracic aorta and the pulmonary artery in the absence of a lung lesion.In 21 cases postnatal CECT depicted systemic vascular connection of congenital lung lesions: nine extralobar bronchopulmonary sequestrations (EBPS), five intralobar bronchopulmonary sequestrations (IBPS) and seven hybrid lesions. CECT scans were performed with general anaesthesia at a median age of 95 days (range 1\u2013218 days) in all patients. In seven of these 21 patients, systemic vascular supply had been identified prenatally .n = 4) and the abdominal aorta (n = 6). Further possible supra- and infra-diaphragmatic types of arterial feeders in congenital lung lesions are presented in n = 2) or infra-diaphragmatic types (n = 1). Maximum diameter of the arterial systemic branches ranged from 1.0 to 5.0 mm (median = 2.3 mm).Arterial blood supply of the congenital lung lesion was categorized as supra-diaphragmatic and infra-diaphragmatic, depending on the origin of the arterial branch . Supra-dSeven of twenty-one cases of congenital lung lesions with systemic arterial supply additionally had atypical systemic venous drainage . Supra-dOpen surgical resection of BPS and hybrid lesion was performed in all 21 patients with congenital lung lesion and systemic vascular supply. Postoperative complications were found in three patients (3/21). In two patients pneumothorax urged chest tube insertion in the postoperative phase. One patient had postoperative hemothorax due to blood oozing from injured intercostal vessels necessitating revision surgery within 8 h. No bleeding occurred from the ligated atypical systemic arteries or veins. At follow up 6 months after surgery all patients presented without any complaints.In congenital lung lesions, systemic vascular connection of the lesion is a frequent and characteristic finding. Atypical arterial and venous vessels play an important role in diagnosis and classification of these lesions. BPS may be diagnosed prenatally by depiction of a lung mass with systemic arterial connection. It is well-known that intralobar and extralobar bronchopulmonary sequestration  may be distinguished by venous return of the lesion: IBPS drains via pulmonary veins while EBPS drains systemically. An overlap between BPS and CPAM has been found and this congenital lung lesion has been described as hybrid lesion\u2014a CPAM with systemic vascular connection . It is nSystemic arterial supply in congenital lung lesions seems to frequently originate from the thoracic or abdominal aorta . NeverthIn our series five patients had more than one systemic artery. As described in the sparse literature on this subject, this may not be a rare finding  and evenThe most distal systemic arterial feeder in our series originated from the celiac trunk; but even arterial supply coming from a renal artery has been described . In thisAtypical systemic venous drainage occurs less frequently than atypical arterial supply in congenital lung lesions, as the majority of intralobar BPS show normal venous drainage via pulmonary veins. Nevertheless, systemic venous drainage may also be found in IBPS . Supra-dIn congenital lung lesions, atypical systemic vascular connection is a major cause of morbidity: high output cardiac failure, congestive heart failure or hemoptysis may occur . AlthougThe high degree of variability of systemic vascular anatomy necessitates clear and intuitive classification of this systemic arterial and venous connection in congenital lung lesions. Based on the origin of systemic arteries and veins we differentiate supra-diaphragmatic and infra-diaphragmatic vascular types of congenital lung lesions. This differentiation has practical-surgical relevance: as the diaphragm separates abdominal and thoracic cavity, vascular injury during surgery in congenital lung lesion with infra-diaphragmatic arterial supply may cause fatal intraabdominal bleeding. Therefore, our classification may contribute to correct preoperative evaluation to avoid unanticipated vascular complications.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.SK: study conception and design. FS, MS, and JK: data collection. SK, FS, MS, and JK: analysis and interpretation of results and draft manuscript preparation. All authors reviewed the results and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Medial prefrontal cortex (mPFC) interacts with distributed networks that give rise to goal-directed behavior through afferent and efferent connections with multiple thalamic nuclei and recurrent basal ganglia-thalamocortical circuits. Recent studies have revealed individual roles for different thalamic nuclei: mediodorsal (MD) regulation of signaling properties in mPFC neurons, intralaminar control of cortico-basal ganglia networks, ventral medial facilitation of integrative motor function, and hippocampal functions supported by ventral midline and anterior nuclei. Large scale mapping studies have identified functionally distinct cortico-basal ganglia-thalamocortical subnetworks that provide a structural basis for understanding information processing and functional heterogeneity within the basal ganglia. Behavioral analyses comparing functional deficits produced by lesions or inactivation of specific thalamic nuclei or subregions of mPFC or the basal ganglia have elucidated the interdependent roles of these areas in adaptive goal-directed behavior. Electrophysiological recordings of mPFC neurons in rats performing delayed non-matching-to position (DNMTP) and other complex decision making tasks have revealed populations of neurons with activity related to actions and outcomes that underlie these behaviors. These include responses related to motor preparation, instrumental actions, movement, anticipation and delivery of action outcomes, memory delay, and spatial context. Comparison of results for mPFC, MD, and ventral pallidum (VP) suggest critical roles for mPFC in prospective processes that precede actions, MD for reinforcing task-relevant responses in mPFC, and VP for providing feedback about action outcomes. Synthesis of electrophysiological and behavioral results indicates that different networks connecting mPFC with thalamus and the basal ganglia are organized to support distinct functions that allow organisms to act efficiently to obtain intended outcomes. The ability to act based on the current incentive value of action outcomes is a defining feature of purposive or goal-directed behavior, one that distinguishes goal-directed responses from stimulus-elicited habits that are unaffected by changing outcome values . Goal-diWe focus on behavioral and electrophysiological studies that allow direct comparisons between mPFC, the basal ganglia, and thalamus. Rodent mPFC corresponds to regions of primate cingulate cortex . It is aGoal-directed responses are guided by the incentive value of anticipated action outcomes . Much ofAlthough questions remain about their precise roles it seems clear that PL, IL, and MO are important for anticipating the incentive value of potential action outcomes. Neurophysiological recordings of brain activity have confirmed that neurons in these areas fire in anticipation of action outcomes and provided evidence that this information is also represented in other areas that give rise to goal-directed behavior. Human functional magnetic resonance imaging (fMRI) studies show that anticipation of monetary awards is associated with cortical activation in midcingulate/supplementary motor and insular areas distinct from areas of anterior and posterior cingulate cortices activated during award delivery . Electron = 50) in rats performing a dynamic DNMTP task (n = 63) exhibited increased activity within 0.2 s after reward delivery began and lasted until 1 s after it ended. They did not respond following unrewarded incorrect choices. It is unclear from timing data whether these responses are related to consummatory activity or reward delivery. Other studies have provided evidence that neurons in orbitofrontal cortex and mPFC encode information about the identity and subjective value of rewards  analyses have revealed two levels of organization in learned action sequences: actions initiating learned sequences or chunks of learned sequences have elevated RTs reflecting the cost of planning an organized sequence ahead of time while actions later in sequences (or chunks) exhibit reduced RTs reflecting the benefits of performing a practiced sequence . Bailey While fMRI analyses have revealed preparatory activity in multiple brain regions, including motor, somatosensory, and parietal regions, only signals originating in contralateral supplementary motor and premotor regions consistently predict the type of sequential finger movement executed . AC cortAdaptive responding requires constant updating of sensory information to guide ongoing actions in dynamic environments. M2 plays a critical role in flexibly mapping sensory signals to motor actions, consistent with its prominent connections to sensory and association cortices and motor control areas . EarlierConvergent evidence indicates that cingulate areas of mPFC monitor current actions and outcomes, provide error feedback and information about reward value and manage conflict when there is competition between potential actions or strategies . ContingLesions or inactivation of mPFC affect the ability of organisms to adapt when contingencies between stimuli, actions, and outcomes are changed during extinction learning . ElectroTo respond adaptively in dynamic contexts organisms must constantly update information about environmental conditions and action-outcome contingencies across short and long timescales. mPFC is interconnected with important memory systems and has functional properties that seem well suited for this purpose see . mPFC isLonger-term memories promote adaptive responding by gradually integrating information across time, a function that allows organisms to adjust to lasting changes in the external environment or response contingencies. All areas of mPFC receive projections from the hippocampal-entorhinal cortex network and the BLA , importaAll areas of mPFC have afferent and efferent connections with multiple nuclei in central thalamus . These aThe central lateral (CL), paracentral (PC), and central medial (CM) rostral intralaminar nuclei project to distinct areas of mPFC and striatum that are connected by corticostriatal projections. These appear organized to control cortical-basal ganglia networks and thus the selection of goals, actions, and sensory signals . The venLesion and inactivation studies have confirmed the dependence of mPFC function on distinct contributions of different thalamic nuclei see . MD lesiLesions damaging the rostral intralaminar nuclei  have effects comparable to mPFC lesions on DMTP and DNMTP: producing delay-independent deficits for egocentric DMTP and DNMTP that affect both speed and accuracy of choice responses with more limited effects on allocentric radial maze DNMTP . IntralaThe anterior thalamic AM and IAM nuclei are important nodes in pathways linking the hippocampal system with PL and AC areas of mPFC . AM and Striatum, the input side of the basal ganglia, receives projections from virtually all areas of cerebral cortex and the limbic system . These cLesion studies have demonstrated functional specialization at the level of the broad channels of information flow in dorsolateral, dorsomedial, and ventral striatum. Dorsolateral and dorsomedial striatum have also been dissociated for tasks used to distinguish goal-directed and habitual action control. Treatments disrupting dorsolateral striatum increase sensitivity to outcome devaluation and contingency degradation, interfere with execution of species-specific and learned sequential actions, and bias animals toward spatial rather than response-related cues in navigation while disruption of dorsomedial striatum blocks sensitivity to outcome devaluation and contingency degradation, decreases dependence on spatial navigation cues and increases reliance on habit learning . These fThe multiple striatal subnetworks revealed by large-scale mapping studies indicate that striatal specialization extends beyond the broad division into dorsomedial, dorsolateral, and ventral domains. Ventral striatum is considered an important link between limbic systems encoding reward and aversion and motor circuits . It receLesions or inactivation of ventral pallidum produce delay-dependent impairment of RT and accuracy of DMTP, comparable to effects of mPFC, central thalamic, and ventral striatal lesions . Cross-iMedial prefrontal cortex is organized as a hub for multiple large-scale neural networks that give rise to prospective, concurrent, and retrospective processes that support adaptive goal-directed behavior . ElectroAnatomical evidence indicates that mPFC is organized along a dorsal to ventral gradient, with more dorsal areas closely linked to sensory and motor cortices and ventral areas of mPFC receive more prominent connections with amygdala and limbic areas of cortex, including hippocampal and parahippocampal areas . Lesion Medial prefrontal cortex has reciprocal connections with multiple central thalamic nuclei that have distinct effects on adaptive goal-directed responding . This inMediodorsal is the main source of focal thalamic projections to middle layers of mPFC and accordingly is often emphasized in treatments analyzing the role of thalamus in mPFC function. Recent studies have elucidated a role for MD regulating signal processing properties of mPFC neurons and stressed its importance for rapid trial-by-trial learning and complex decision making . LesionsDorsal and ventral areas of striatum are comprised of distinct subdomains defined by open loop projections from functionally specific areas of cerebral cortex and the limbic system, closed loop projections from subregions of prefrontal cortex, and thalamostriatal projections primarily from midline and intralaminar nuclei. Both electrophysiological and behavioral findings (reviewed above) are consistent with the hypothesized distinction between ventral striatum processing reward signals and facilitating the motivational control of performance and dorsal striatum forming associations between sensory, motor, and limbic inputs to guide action selection and support the acquisition of goal-directed actions . Large-sThalamus serves as an important integrative center for cortico-basal ganglia networks as nodes connecting basal ganglia to cortex and as the source of thalamostriatal projections that terminate on medium spiny neurons in striatum . MD is a(1)Medial prefrontal cortex (mPFC) interacts with the basal ganglia and thalamus to support functions that allow organisms to control actions intended to obtain desired outcomes . These include prospective anticipation of potential action outcomes, selection and maintenance of motor goals, and motor preparation; concurrent control and monitoring of ongoing actions; and retrospective updating of information and strategies to guide future behavior.(2)Medial prefrontal cortex is organized with dorsal regions prominently connected with sensory and motor cortices controlling motor planning, prospective decision making, motor response memory, and flexible responding based on trial-specific sensory cues. Ventral areas have more prominent connections with hippocampus, amygdala, and limbic areas of cortex and are important for anticipating action outcomes, fear learning and extinction, and systems memory consolidation.(3)Electrophysiological recordings during DNMTP reveal neurons with responses related to actions and outcomes distributed throughout mPFC. Although there is no sudden transition apparent when electrodes are driven ventrally through mPFC, there are significant trends for neurons with responses related to motor preparation, lever press actions, and movements between levers to be distributed in dorsal mPFC and neurons with responses related to reward anticipation, movements toward reinforcement, and memory delay to be more frequent in ventral mPFC. Inactivation of central thalamus affects the expression of action- and outcome-related responses in mPFC. The inclusion of choice responses during DNMTP trials engages mPFC neurons to respond to task-relevant information.(4)Lesion studies indicate that dorsal striatum is important for associative and sensorimotor control and ventral striatum for reward and motivational control of goal-directed behaviors. Deficits produced by striatal lesions parallel the effects of lesions damaging anatomically related areas of mPFC. Large scale mapping studies have described extensive reconfiguration and integration of corticostriatal projections into striatal subnetworks that provide a structural basis for information processing and functional heterogeneity within striatum.(5)Multiple thalamic nuclei have afferent and efferent connections with mPFC that appear organized to control different aspects of goal-directed responding. The mediodorsal nucleus (MD) is the main source of focal thalamic input to middle layers of mPFC. Recent evidence indicates that MD amplifies and sustains activity in mPFC neurons that encodes information about actions and outcomes important for rapid trial-by-trial learning, complex decision making, and working memory. The intralaminar nuclei have thalamostriatal and thalamocortical projections that control transmission of information in cortico-basal ganglia networks. Behavioral studies have confirmed that intralaminar lesions have broad effects on functions that depend on mPFC and striatum. The ventral medial nucleus has prominent connections with dorsal regions of mPFC and adjacent sensorimotor cortex that support integrative motor responses. The ventral midline reuniens and rhomboid nuclei provide a critical link between mPFC and hippocampus and play a critical role in spatial and contextual memories and systems memory consolidation. The interoanteromedial (IAM) and anterior medial (AM) nuclei are nodes in pathways linking mPFC with hippocampus important for allocentric spatial learning and memory. While lesion studies indicate that mPFC lesions do not impair allocentric spatial memory, reciprocal connections with AM and IAM provide a link between mPFC and hippocampal-related systems that mediates this function.(6)Comparisons of neuronal activity in mPFC, MD thalamus, and ventral pallidum (VP) reveal important similarities and differences for information represented in these areas in rats performing a dynamic DNMTP task. Neurons in mPFC exhibit responses related to motor preparation, reward anticipation, and prospective memory delays not observed in VP. Responses related to motor preparation and prospective memory delays are also not observed in MD. Although reward anticipation responses are observed in MD, these are delayed and less robust. This suggests that mPFC exerts top-down control of prospective processes anticipating action outcomes, selecting motor goals, and preparing to execute action sequences. VP, by contrast, is dominated by neurons with responses related to reward delivery and reward-related actions consistent with evidence that VP provides feedback about action outcomes and affects the vigor of outcome-related responses.RM was primarily responsible for writing the article. MF, EK, and BG contributed to the writing and discussion. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Population aging in Singapore has encouraged the development of ambient smart communities to support healthy aging. Poor understanding of the living activities that address both clinical and biological concerns may plague efficient aging service designs and community health programs. We have designed a new computational workflow to identify important living activities for older adults in Singapore. We investigated innovatively three pillars of human life aspects: activities, clinical health, and biological health to identify living activities that are significantly associated with both clinical health and biological health. Cross-sectional data analyses were performed on 1356 community-living Chinese older adults of 65\u201380 years old in the Singapore Longitudinal Aging Study II (SLASII) cohort. 7 out of 29 living activities were found significantly associated with clinically healthy aging and showed improved prediction accuracy towards health status in machining learning schemes. Furthermore, biological age has been computed by screening and modeling 66 biomarkers. 15 out of the 29 living activities were found significantly associated with biologically healthy aging. Checking the overlapping living activities, we have found that physical exercise and cognitive-simulating activities are the most important activities for healthy aging: such as jogging regularly and reading, writing, and doing puzzles often. We regroup participants into active and non-active groups according to these two activities. The Keplan-Meier survival analysis showed statistically significant differences in survival time between the active and non-active groups (p < 0.001) in an 8-year longitudinal study. The workflow, results and biomarkers may provide references for future health program design improvement."}
+{"text": "Disparities in vaccination uptake among migrant populations are well documented. WHO and ECDC have sought renewed focus on participatory research that engages migrants in co-producing tailored initiatives to address vaccination inequities and increase coverage.This community-based participatory research study aims to engage Congolese migrants in co-developing a tailored approach to increase vaccine uptake. Phase 1 used poster walls and in-depth interviews with Congolese migrants (n = 32) to explore COVID-19 vaccination beliefs, experiences, and preferred information sources and communication methods, analysed iteratively and thematically in NVivo.Institutional distrust has shaped this population\u2019s interpretation of the pandemic response and enabled vaccine misinformation and conspiracy theories to take hold. We found complex information networks and preference for Francophone, African and social media. Limited English proficiency and preference for the oral tradition restricted engagement with official public health messaging. Suspicion of government motives, low knowledge, and culturally specific perceptions about vaccination contributed to belief that breakthrough infections and need for COVID-19 boosters imply the vaccine is not effective. The population felt coerced by vaccination reminders and mandates, and were resultantly more hesitant to accept COVID-19 vaccination.The population\u2019s specific characteristics suggest that existing and trusted interpersonal networks and oral communication in first languages should be harnessed to spread credible information and encourage vaccine uptake, and mandate policies are unlikely to be effective. Training local role models to facilitate vaccination dialogues and myth-bust may be effective at changing behaviour. The next phases will gather more information from key stakeholders and engage migrants in workshops to co-design insight-driven, tailored interventions.\u2022\u2002Global policy-setting organisations have called urgently for participatory research that engages migrants in the co-production of tailored initiatives to address vaccination inequalities.\u2022\u2002Populations with strong interpersonal networks and low trust in public institutions may be receptive to tailored, community-centred dialogue approaches using local messengers and role models."}
+{"text": "Pulmonary vein thromboses (PVT) is a complication of lung malignancy and can be complicated by arterial embolic phenomenon. Patient is a 69-year-old female with a history of coronary artery disease and recent pneumonia seen on chest x-ray who presented with progressive headache, left arm numbness and abdominal pain. She was found to have numerous bilateral strokes, bilateral renal infarction and splenic infarction. CT Chest showed a right upper lobe mass compressing the pulmonary veins with filling defects concerning for thrombus. Diagnosis of PVT is made with CT angiogram, echocardiogram and MRI. Treatment consists of anticoagulation and treatment of underlying factors. Pulmonary vein thromboses (PVT) is a described complication of lung malignancy , lung re2Patient is a 69-year-old female with history of coronary artery disease, ulcerative colitis, hypothyroidism, hyperlipidemia and recent pneumonia seen on chest x-ray who presented with progressively worsening headache, transient left arm numbness and abdominal pain. CT head was negative for acute hemorrhage. National Institute of Health Stroke Scale was 1. Neurology was consulted who recommended MRI brain. MRI showed multifocal acute and subacute infarcts in the supratentorial and infratentorial brain; in the bilateral frontal parietal cortical regions; occipital temporal regions; right thalamus and bilateral cerebellum. CT abdomen and pelvis showed bilateral renal infarctions and numerous splenic infarctions. The morning after admission the patient developed acute onset facial droop and slurred speech. CT head showed subacute right middle cerebral artery (MCA) and bilateral posterior cerebral artery (PCA) infarcts without hemorrhage, herniation or mass-effect/midline shift. CT angiogram of the neck was negative for any acute narrowing or aneurysm. CT perfusion showed a moderate sized area of ischemia in the left occipital and right temporal occipital lobes with large surrounding penumbra. CT angiogram of the head showed interval development of two noncalcified, soft thrombi located in the right MCA bifurcation and left MCA. Patient was taken for mechanical thrombectomy of the left MCA with good angiographic results with Thrombolysis in Cerebral Infarction score of 2c. Patient had worsening neurological exam overnight with increased somnolence which prompted repeat imaging. CT head overnight showed subacute right MCA/PCA, left MCA and left cerebellar infarctions, increasing edema with a 2 mm midline shift, no signs of herniation and subarachnoid hemorrhage. Transthoracic echocardiogram was negative for left atrial or left ventricular thrombus. CT Chest showed large right upper lobe mass with associated mediastinal and right hilar lymphadenopathy. The mass was compressing the pulmonary veins with filling defects concerning for thrombus. Due to the extensive stroke burden the patient was unable to receive systemic anticoagulation and the patient was transitioned to comfort measures. Transesophageal echocardiogram, biopsy of the mass and thrombophilia workup were deferred because of the family's decision to transition to hospice care.3PVT can be an unfortunate complication of malignancy, especially pulmonary malignancy. The case demonstrates a large right upper lobe lung mass compressing the pulmonary veins. External compression likely caused stasis and coupled with a hypercoagulable state in the setting of malignancy led to the development of pulmonary vein thrombosis. Subsequent thromboembolic phenomena led to diffuse infarction in multiple organ systems. Due to the acuity of the patient's symptoms and clinical deterioration, the gold standard imaging tests were unable to be obtained. Diagnosis can be challenging but detection of PVT is increasing with improvements in imaging technique. Typically, a combination of imaging techniques are used to best diagnose PVT. CT scan with IV contrast with timing for the pulmonary venous system is the best diagnostic technique . Transes-Patients with diffuse arterial emboli should be evaluated for pulmonary vein thrombosis, left atrial thrombus, left ventricular thrombus and systemic shunts-Workup includes CT imaging with timing of contrast to evaluate the pulmonary veins, MRI/MR venogram, transthoracic echocardiogram and transesophageal echocardiogram-Systemic anticoagulation should be initiated when diagnosis is suspected to avoid diffuse arterial embolizationThis work was performed as part of employment under Naples Community Hospital Healthcare System. The authors listed above are all employed within this system.The authors listed above certify that they have no financial or non-financial interest in the subject matter or materials discussed in this manuscript."}
+{"text": "Impaired cognitive ability and its misperception contribute to poor decision-making of older adults; yet their impact on health-related decisions is less known. We examined how self-perceived and actual cognition were associated with chronic disease awareness using a nationally representative sample of Chinese older adults. Blood biomarkers data were collected in 2015 to identify participants\u2019 dyslipidemia and diabetes status. Among participants with identified dyslipidemia or diabetes, disease awareness was defined as self-reported diagnosis of the conditions as of 2018. Objective and subjective cognition were respectively assessed using the Mini-Mental State Examination and self-rated memory. The associations of subjective and objective cognition with chronic disease awareness were determined by weighted logistic regressions. Among 4,578 adults aged 60 and older with complete measurements, 1,442 and 759 individuals were identified having dyslipidemia and diabetes, with proportions of disease awareness being 38.0% and 58.1%, respectively. Individuals with mild  or severe cognitive impairment  had lower odds of dyslipidemia awareness; and those with severe cognitive impairment had lower odds of diabetes awareness  than cognitively intact counterparts. However, adjusting for objective cognition, older adults with better subjective cognition had lower odds of dyslipidemia  and diabetes  awareness. Such associations were stronger for individuals with rural status, lower education, or living without children. Our findings highlight the great challenges deteriorated cognitive function and misperception may pose to chronic disease awareness, as well as the importance of targeted supports particularly for those more disadvantaged."}
+{"text": "The incidence and societal burden of cancer is increasing globally. Surgery is indicated in the majority of solid tumours, and recent research in the emerging field of onco-anaesthesiology suggests that anaesthetic-analgesic interventions in the perioperative period could potentially influence long-term oncologic outcomes. While prospective, randomised controlled clinical trials are the only research method that can conclusively prove a causal relationship between anaesthetic technique and cancer recurrence, live animal (in vivo) experimental models may more realistically test the biological plausibility of these hypotheses and the mechanisms underpinning them, than limited in vitro modelling. This review outlines the advantages and limitations of available animal models of cancer and how they might be used in perioperative cancer metastasis modelling, including spontaneous or induced tumours, allograft, xenograft, and transgenic tumour models. In 2020, an estimated 18 million cancer cases were newly diagnosed (excluding nonmelanoma skin cancer), accounting for approximately 10 million cancer related deaths ,4.The original hypothesis that the anaesthetic technique during primary cancer resection surgery of curative intent might influence the risk of cancer recurrence or later metastasis was first proposed over a decade ago . This inTo ultimately prove these hypotheses, large prospective randomised-controlled clinical trials are required to establish if a causal relationship exists between anaesthetic techniques and the risk of cancer recurrence following primary cancer surgery. However, pre-clinical laboratory models, primarily in vivo animal models, retain an important role in translational cancer research for several reasons . FirstlyThe emergence of onco-anaesthesiology as a distinct clinical subspecialty has driven the exploration of translational research utilising animal models of cancer, traditionally undertaken by oncology researchers. Therefore, we aimed to summarise animal models of cancer commonly encountered within in vivo translational cancer research and how they may be applied to ongoing research in onco-anaesthesiology.Animal models of cancer may be classified in a variety of ways. Most simply, they are either spontaneous or induced and mammalian or non-mammalian. Alternatively, they may be categorized by the method of inducing cancer occurrence. However, spontaneously occurring cancers may occur in genetically engineered animal strains or such genetic-engineering may be induced following exposure to various carcinogens, so there is some cross-over in these descriptions. Non-mammalian animals such as zebrafish benefit from being high-throughput and low-cost, ideal for molecular investigation and chemical screening studies, however, significant phenotypical differences limit their usefulness for translational research so they will not be discussed further . Table 1A xenograft model  involvesThe advantages of xenograft models are that they are relatively inexpensive when using commercially available cancer cell lines and attractive for translational research due to the ability to mimic cancer cell biological traits and the direct evaluation of therapeutic targets in human derived cancer tissue ,16. HoweAn allograft model  involvesThe main advantage this has over xenograft models is the ability to evaluate the host animal\u2019s cancer-related immune response when assessing the effect of potential therapeutics. Compared to xenografts, allografts produce larger tumours that metastasize more quickly and reliably, enabling consistency when assessing for clinically relevant endpoints . They doThe preservation of the host immune response underpins why these models are often favoured for investigation in onco-anaesthesiology, where immunomodulation by anaesthetic drugs is one of the most frequently proposed mechanisms to explain how differences in perioperative pharmacotherapy may influence cancer outcomes ,25,26 A Testing potential therapeutics on spontaneous cancers that develop in household pets  is an ofTransgenic models  of canceTransgenic cancer models may play a significant role in onco-anaesthesiology research as they allow for testing of drug effects on the onset and progression of an expected cancer in immunocompetent animals, such as what has already been performed with morphine, which had no effect on the onset of cancer development but did hasten cancer progression . HoweverIn conclusion, there are several in vivo animal models of cancer that may be utilized for conducting translational research in onco-anaesthesiology. Whilst xenograft models are attractive for the ability to tailor the cancer cell biology around the human cancer under investigation, a lack of any representative immune response severely hinders its suitability for onco-anaesthesiology research. Transgenic models demonstrate significant promise in providing representative animal cancers and may be used alone or as donors for allogenic models. Multiple transgenic mouse colonies and cancer cell lines are commercially available to enable rapid integration of in vivo mouse models into novel research, however, due care must be taken to ensure the model chosen is most appropriate for the hypothesis under investigation."}
+{"text": "The COVID-19 pandemic highlighted the significance of vaccination for older adults (OA), however, more health benefits could be gained with vaccination against influenza, pneumococcal disease, herpes zoster and tetanus as their uptake remains rather low. As healthcare professionals (HCP) play an important role in the vaccination decision making of OA, this study identifies obstacles in vaccination communication between HCP and OA.80 in-depth structured interviews have been conducted with HCPs in Hungary (HU), Italy (IT), the Netherlands (NL) and France (FR). Participants were general practitioners, medical specialists, public health physicians, occupational physicians, pharmacists, geriatricians, specialists elderly care and nurses. The interview included questions on HCPs\u2019 perceptions regarding information provision to OA on vaccines. Data were analyzed cross-country, using thematic analysis.Preliminary results reveal that a factor hindering HCPs to initiate conversations with OA on vaccines was lack of time . In hospitals this was often due to (acute) clinical problems taking precedence over discussing vaccines . In ambulatory settings the high number of patients waiting to be seen prevented discussing vaccines with OA (HU). Moreover, HCPs sometimes forgot to discuss vaccines with OA . Patient factors hindering the conversation of HCPs on OA vaccines were a negative attitude  and lack of understanding the information provided . Also, misinformation on vaccines , as well as anti-vax beliefs from patients (NL) or their relatives  hampered the conversation on vaccines. HCPs mentioned their need to learn communication skills to convince OA on vaccines .HCPs encounter various obstacles in communicating with OA about vaccines. Lack of time and not recognizing the opportunity to discuss vaccines are important barriers for initiating vaccine conversations.\u2022\u2002Providing HCPs with communication strategies is important to support HCPs in discussing vaccines with OA.\u2022\u2002Reminder systems are important to help HCPs remember address vaccination."}
+{"text": "Many of the competencies that trainees in psychiatry are required to achieve can be linked to leadership in the broadest sense, yet specific training is not often systematically provided. The West Midlands Psychiatry Leadership Development Programme aims to support the acquisition of important leadership skills already set out in the curriculum through provision of high-quality specialist leadership content within the existing programme. Here we present the findings of a scoping exercise exploring the views and attitudes towards leadership training held by higher trainees in psychiatry within the West Midlands.All psychiatry higher trainees within West Midlands Deanery were invited to complete an anonymous online survey using Survey Monkey in November 2021. This survey incorporated questions about their preferred learning styles, confidence in their leadership skills and barriers to accessing leadership opportunities, generating both quantitative and qualitative data.37 responses were received. All subspeciality training programmes were represented. Almost half of respondents (46%) were ST6 or above and most were in training full time (84%).Trainees expressed a preference for experiential learning about leadership (87%) as well as small group teaching (62%) and interactive workshop style content (62%).Awareness of leadership opportunities was typically via their peer group (81%) or clinical supervisor (60%). Only 52% of trainees were aware of leadership opportunities within the Deanery.Only 54% felt that existing leadership training met their curriculum requirements. Less than half of trainees (46%) felt confident to evidence their leadership experience within their training portfolio.One-fifth of trainees (21%) reported experiencing barriers to leadership development. These included: inadequate awareness of opportunities, lack of senior support, time constraints and difficulty matching interests with available opportunities.Key results included:Trainees expressed interest in the redevelopment of a regional leadership training programme which would support them to achieve their curriculum competencies and prepare them for life as a consultant psychiatrist. The new multi-faceted regional leadership programme will offer resources in a variety of formats including webinars, podcasts, optional interactive workshops and action learning sets. It is hoped that this flexible programme, linked to the Medical Leadership Competency Framework, will better meet the needs of higher trainees as they pursue their own personal leadership journeys."}
+{"text": "Previous studies have found relatively good physical health in doctors, whereas several studies now report relatively high levels of stress and burnout among them. With the exception of higher suicide rates, we have less evidence of poorer mental health among doctors than among other professionals. The elevated suicide rate may represent the tip of an iceberg of frustration and inadequate mental health care among medical doctors. There are very few longitudinal studies that can identify possible risk factors and causality. The Longitudinal Study of Norwegian Medical Students and Doctors (NORDOC) has since 1993/94 followed repeatedly two cohorts of medical students (N=1052) in seven waves during 25 years (Facebook: @docsinrush). Outcomes presented here are on mental health, burnout and problematic drinking. There are two main hypotheses with regard to possible risk factors. First, it may be due to individual factors such as personality traits, past mental health problems etc. Second, contextual stress may influence mental health among doctors, whether this be unhealthy working conditions or negative life events (i.e. stress outside of work). The presentation will give and overview of both individual and work-related predictors of stress and mental health problems among Norwegian physicians. Individual and organizational interventions to reduce stress and physician burnout will also be dealt with.No significant relationships."}
+{"text": "Evidence suggests that besides having stigmatizing misconceptions towards people with mental illness, medical students and doctors often resist seeking help for their own mental issues. This is a vulnerable group for stress and other mental health problems, due not only to professional burden but also high perfectionism and low self-compassion.To analyse the relationship between mental health stigma (MHS) and other variables related to personality and emotional states in a sample of medical students.634 medicine and dentistry students  answered to a survey including sociodemographic data, self-perception of psychological health/SPPH and the Portuguese validated versions of: Link\u2019s Perceived Discrimination and Devaluation (PDD) scale to assess MHS and its two dimensions - social stigma/SocS and self-stigma/SelS; Depression Anxiety Stress Scale (DASS-21); Neff\u2019s Self-Compassion Scale (SCS); and Big Three Perfectionism Scale (BTPS). Correlations, t-student tests and linear regressions were performed with SPSS 27.0.Stigma correlated negatively to SPPH and positively to DASS, the negative poles of SCS  and BTPS second-order factors . No gender differences in MHS were observed. Participants with higher mean levels of total and SelS had significantly higher scores in all DASS dimensions and lower SPPH; participants with higher SocS also scored higher in DASS, but didn\u2019t reveal lower SPPH. Isolation was a significant predictor of SocS ; isolation and narcissistic perfectionism were significant predictors of SelS .Our results highlight the importance of including MHS as a main need in the curricula of future doctors.No significant relationships."}
+{"text": "Mental disorders, such as depression, anxiety, and autism, have become one of the leading causes of disability worldwide with a high lifetime prevalence. Individuals with these disorders exhibit marked social and cognitive impairments, which are often closely associated with brain alterations both structurally and functionally. However, success rates of pharmacological and behavioral interventions vary widely and affected individuals often suffer from residual symptoms. Further, some of these interventions are characterized by severe side effects and induce high drop-out rates. Therefore, innovative brain modulation approaches that can directly target and regulate the involved brain circuits are of great translational potential for these disorders.Kerr et al. explored an innovative dyadic rt-fMRI NF protocol in which mothers attempted to down-regulate the anterior insula activity of their children. Based on an independent support vector machine-based classifier, Pereira et al. trained patients with depression to match their own neural activity with the neural activity corresponding to the \u201chappiness emotional brain state\u201d of a healthy participant via rt-fMRI NF training and found improvement in clinical symptoms associated with training success. Orth et al. conducted a systematic review of rt-fMRI NF studies targeting brain activations within the frontostriatal circuitry given that it is a common target for the treatment of aberrant behaviors in various psychiatric and neurological disorders. Their overview emphasizes the relevance to address network connectivity rather than localized excitability only.Our Research Topic aimed to improve our understanding of how innovative brain modulation approaches affect human behavior and neural responses and provide an overview on recent progress in the field. The articles that were published in this Research Topic bring us new insight on how brain modulation approaches such as real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback (NF) training, transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) can be applied to modify emotion regulation and brain activity/connectivity in healthy or clinical populations. More specifically, in a proof-of-concept study on emotion regulation Cheng et al. investigated the asymmetric role of the bilateral ventrolateral prefrontal cortex (VLPFC) in cognitive reappraisal and found that while the left VLPFC is responsible for the semantic process of generating and selecting appraisal strategies based on the goal of emotion regulation, the right VLPFC is mainly involved in inhibiting inappropriate negative emotions and thoughts. Huang et al. demonstrated that a 4-week intervention of high-frequency repeated TMS on the left dorsolateral prefrontal cortex (lDLPFC) decreased the temporal variability of resting-state functional connectivity (rsFC) in the cortico-thalamo-cerebellar circuit (CTCC), with higher alteration in rsFC temporal variability between the left DLPFC and right posterior parietal thalamus predicting a higher remission ratio of negative symptom severity. Importantly, in the support vector regression analysis the pattern of rsFC temporary variability within the CTCC predicted the efficacy of high-frequency rTMS intervention on negative symptoms of schizophrenia. By combining tDCS with TMS, Alkhasli et al. revealed that excitatory intermittent theta-burst (iTBS) to a tDCS-inhibited lDLPFC yielded more robust functional connectivity to various areas as compared to excitatory iTBS to a tDCS-enhanced DLPFC. This suggests feasibility of using tDCS to modulate subsequent TMS effects on the DLPFC which may be of translational potential for the treatment of depression. In addition to these direct brain modulation approaches, Wang et al. demonstrated that open motor skill training (table tennis experts vs. matched non-experts) may be associated with greater activation in brain regions involved in visual processing during language processing tasks (word and semantic judgement tasks). These findings bridge the complex interplay between short- and long-term neuromodulation and behavioral training effects.Using the online single-pulse TMS technique, In conclusion, studies in the Research Topic applied highly innovative approaches to modulate human brain functions in healthy or clinical populations, with some of them reporting promising improvement in clinical symptom severity. We believe findings from these studies does not only improve our understanding of neural mechanisms underlying these brain modulation approaches, but also inspire future studies aiming to translate neuromodulatory approaches from different disciplines into clinical applications.SY and KM drafted the manuscript. JZ and XZ critically revised the manuscript. All authors contributed to the article and approved the submitted version."}
+{"text": "Evidence documents racial/ethnic disparities in access, quality of care, and quality of life (QoL) among nursing home (NH) residents who are Black, Indigenous and persons of color. Yet, little is known about mechanisms for these disparities. This presentation examines the mechanisms for racial/ethnic disparities in QoL in high-proportion BIPOC facilities while highlighting variability in QoL disparities across these facilities. The presentation uses data from a 5 year mixed-methods project involving 96 resident interviews; 61 staff interviews; and 614 hours of observations in high proportion BIPOC facilities in MN, coupled with resident clinical Minimum Dataset assessments linked with survey data on residents\u2019 QoL. The findings show significant racial/ethnic disparities in QoL with need for system level changes. Given the increasing racial/ethnic diversity of NHs, ensuring equity in QoL for BIPOC residents is an urgent priority for NHs to remain relevant in the future."}
+{"text": "The process of matching skeletal muscle blood flow to metabolism is complex and multi-factorial. In response to exercise, increases in cardiac output, perfusion pressure and local vasodilation facilitate an intensity-dependent increase in muscle blood flow. Concomitantly, sympathetic nerve activity directed to both exercising and non-active muscles increases as a function of exercise intensity. Several studies have reported the presence of tonic sympathetic vasoconstriction in the vasculature of exercising muscle at the onset of exercise that persists through prolonged exercise bouts, though it is blunted in an exercise-intensity dependent manner . The collective evidence has resulted in the current dogma that vasoactive molecules released from skeletal muscle, the vascular endothelium, and possibly red blood cells produce local vasodilation, while sympathetic vasoconstriction restrains vasodilation to direct blood flow to the most metabolically active muscles/fibers. Vascular smooth muscle is assumed to integrate a host of vasoactive signals resulting in a precise matching of muscle blood flow to metabolism. Unfortunately, a critical review of the available literature reveals that published studies have largely focused on bulk blood flow and existing experimental approaches with limited ability to reveal the matching of perfusion with metabolism, particularly between and within muscles. This paper will review our current understanding of the regulation of sympathetic vasoconstriction in contracting skeletal muscle and highlight areas where further investigation is necessary. As mentl muscle . Consisteceptors .1-adrenergic receptor agonist, phenylephrine, was only reduced during heavy-intensity exercise, whereas the vascular response to the selective \u03b12-adrenegic receptor agonist, clonidine, was diminished during mild- and heavy-intensity exercise. P2X-receptor responsiveness was attenuated during heavy-intensity exercise, whereas NPY-Y1 receptor responsiveness was blunted across exercise intensities -adrenergic receptors, it is theoretically possible that NE binding to \u03b2-adrenergic receptors may oppose SNS mediated vasoconstriction. However, sympathetic vasoconstrictor responsiveness was not augmented following \u03b2-adrenergic receptor blockade in male and female rats, indicating that \u03b2-adrenergic receptors do not oppose sympathetic vasoconstriction in contracting skeletal muscle or contribute to functional sympatholysis .Collectively, the available data related to changes in receptor responsiveness during exercise suggest that the distribution of post-synaptic receptors between muscles and in different vascular segments combined with muscle recruitment patterns may result in local modulation of vascular resistance that would serve to distribute blood flow between and within muscles and facilitate perfusion to metabolism matching during exercise. However, the definitive study to demonstrate this has not been completed.2 catalyzed by the enzyme NO synthase (NOS), which exists in endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) isoforms . Tetrahydrobiopterin (BH4) is an essential cofactor required for NO production by NOS enzymes (4 administration. A reduced ability to inhibit sympathetic vasoconstriction during muscular contraction has been reported in humans with duchenne muscular dystrophy (The cellular mechanism(s) responsible for a decline in receptor responsiveness during exercise has not been fully elucidated, however the vasoactive molecule nitric oxide (NO) and intravascular adenosine triphosphate (ATP) have been the focus of investigation . NO is p enzymes . eNOS anisoforms . Tetrahy enzymes . Several enzymes . In cont enzymes . Acute uystrophy  and in gystrophy  that do ystrophy .Exercise training has also been used to investigate sympatholysis . In ratsGiven that NOS enzymes are expressed differentially across skeletal muscles , it seem+ channels) does not alter the ability of exogenous ATP to blunt \u03b1-adrenergic receptor mediated vasoconstriction , contrast enhanced ultrasound (CEU), and diffuse correlational spectroscopy (DCS/NIRS).NIRS-ICG has been applied to investigation of blood flow in skeletal muscle and the results compare favorably with dye dilution MRI methods during knee extension exercise . The tecContrast enhanced ultrasound requires infusion of microbubbles which are smaller than red blood cells to allow them to pass through the skeletal muscle microcirculation. As described by Diffuse correlational spectroscopy (DCS) is an emerging noninvasive technology that has been applied during exercise by several laboratories . CombiniAn example of how these techniques might be employed would be to apply DCS/NIRS sensors bilaterally to one limb that remains resting and the other limb which performs contractions across a range of exercise intensities. Sympathetic nerve activity could be activated reflexly to both limbs by using lower body negative pressure (LBNP) or cold pressor stimuli. Greater vasoconstriction in inactive skeletal muscle compared to active skeletal muscle would support redistribution of blood flow.The above example suggests an experimental approach to demonstrate redistribution of blood flow between muscles. Finding a method to study redistribution of blood flow within a muscle to more active fibers is more problematic. The fundamental problem is that microvascular units are not precisely aligned with muscle motor units. Constriction of a terminal arteriole reduces perfusion to all the capillaries supplied by that arteriole which means that perfusion cannot be exclusively directed to active muscle fibers or a single fiber type .Although not discussed in this focused review, there is ample evidence that aging, sex, obesity and various disease states modulate sympatholysis and impairments in sympatholysis have functional consequences for exercise performance. Further exploration of the effects of sympatholysis in these populations/conditions is warranted.Our current understanding is that the matching of skeletal muscle blood flow to metabolism involves a complex interplay between local vasodilation and sympathetic vasoconstriction that restrains local vasodilation and directs blood flow to active muscles, while also maintaining total peripheral resistance and blood pressure.The presence of tonic vasoconstriction in inactive tissue and exercising limbs is well established, and some studies have demonstrated that tonic vasoconstriction contributes to the distribution of blood flow within the limb during exercise. Numerous studies in a variety of experimental models have also demonstrated that sympathetic vasoconstriction is blunted in contracting muscle (sympatholysis). While investigators have done outstanding work to characterize the phenomenon of sympatholysis and identify some potential mechanisms involved in the process, direct experimental evidence that sympatholysis is involved in the matching of perfusion to metabolism is lacking.Despite the sound logic that sympatholysis would facilitate the distribution of blood flow between and within muscles during exercise, currently available technology and experimental approaches make the definitive study to demonstrate that sympatholysis contributes to the matching of perfusion to metabolism infeasible in the dynamically exercising animal or human. Until there is new evidence provided, researchers should refrain from speculating that functional sympatholysis can redirect blood flow to active fibers within a muscle."}
+{"text": "Invasive\u00a0hemodynamic assessment of patients with an LVAD may improve readmission rates, but early detection of nonresponders-to-therapy can lead to earlier LVAD therapy and transplant listing.18.See Article page Left ventricular assist devices (LVADs) constitute important advanced therapy for patients with heart failure. Despite improvements in LVAD technology, optimal hemodynamic management remains challenging. In addition, frequent readmission, hemocompatibility-related adverse events, and thromboembolic complications limit the effectiveness of LVAD therapy.3The development of implantable hemodynamic monitoring (IHM) allows continuous, remote measurement of pulmonary artery pressure, which is known to improve outcomes in patients with heart failure.Utilization of IHM technology for ongoing monitoring and optimization of LVAD therapy in the outpatient setting is reviewed. A patient vignette describes IHM use in a patient before and after LVAD therapy to demonstrate improvement in pulmonary artery pressures after LVAD implantation, thereby allowing cardiac transplant listing. However, limited evidence to date does not support a recommendation for routine use of IHM in patients with an LVAD. Further study of IHM in this patient population is suggested.,Current era LVAD complications that limit transplant potential include pulmonary hypertension  but are increasingly related to gastrointestinal bleeding, blood transfusion, and sensitization events or debilitating stroke.Increased adoption of IHM in patients with an LVAD (and advanced heart failure) has the potential to alter the transplant landscape by improving listing candidacy or status justification for patients in outpatient settings. These benefits may potentially lower waitlist time and mortality with earlier transplantation, obviating the need for prolonged hospital admission before cardiac transplantation.Lambert and Teuteberg"}
+{"text": "Venous anomalies are typically asymptomatic and may be discovered unexpectedly at the time of implantation of a cardiac implantable electronic device. We report a case of leadless pacemaker implantation in a patient with hypoplasia of the left brachiocephalic vein who had previously undergone multiple interventions for relapsing right-sided breast cancer. The prevalence and etiology of this anatomic variant remain unknown. However, awareness of its existence may prevent complications during left-sided interventions. such as placement of a central venous line or a cardiac implantable electronic device. Alternative diagnostics and implantation strategies are discussed. Venous anomalies  are typically asymptomatic and may be discovered unexpectedly at the time of implantation of a cardiac implantable electronic device. Rarely, venous anomalies result from chemotherapy or radiotherapy. We report a case of leadless pacemaker implantation in a patient with a severely hypoplastic left brachiocephalic vein who had previously undergone multiple cycles of radiotherapy for relapsing right-sided breast cancer.A 78-year-old woman with symptomatic transient third-degree atrioventricular block was referred for dual-chamber pacemaker implantation. The patient had a history of 2 right-sided breast cancer relapses, for which she underwent repeated surgeries and radiation therapy cycles between 1983 and 1993. A venogram at the time of implantation showed the absence of a left brachiocephalic vein, with drainage of the left jugular and subclavian veins into a left hemi-azygous vein (,,The prevalence of this anatomic variant remains unknown, and the etiology of an absent or hypoplastic brachiocephalic vein remains speculative.\u2022An absent or hypoplastic left brachiocephalic vein is rare, but this possibility should be kept in mind when performing left-sided interventions.\u2022The major tributaries of the superior and inferior vena cava derive from distinct embryologic veins.\u2022Venous anomalies are most often solitary. When a venous anomaly is discovered, alternative transvenous implantation strategies should be considered.\u2022Leadless pacemaker implantation can be successfully performed in patients with abnormal upper-body venous drainage as an alternative to surgical epicardial leads.We report a rare case of brachiocephalic vein hypoplasia discovered at the time of left-sided pacemaker implantation. Although this anatomic variation is rare, knowledge of its existence may allow avoidance of vascular complications. In this patient with a history of repeated right breast cancer surgery, alternatives included implantation of a leadless pacemaker, a transvenous femoral pacemaker, or epicardial leads. Investigation of the lower-body venous drainage anatomy revealed no further anomalies, and a leadless pacemaker was implanted."}
+{"text": "An 85-year-old male who had been prescribed prasugrel presented to the emergency department (ED) after a motor vehicle collision and developed progressive neurological deficits. Computed tomography imaging demonstrated epidural thickening from the second through seventh cervical vertebrae, and magnetic resonance imaging was notable for a cervicothoracic epidural hematoma. The patient underwent emergent decompression with a favorable outcome.Cases of traumatic spinal epidural hematomas are rarely seen in the ED. These are part of a small subset of operative neurological emergencies that benefit from urgent surgical intervention. An 85-year-old male presented to the emergency department (ED) after a motor vehicle accident with abdominal pain, neck pain, and stool incontinence. The patient\u2019s medication list included prasugrel, but it was unclear whether he was taking it. Exam was notable for cervical and thoracic spine tenderness, decreased rectal tone, decreased bilateral upper extremity sensation, and mild weakness of the right lower extremity. Cervical spine computed tomography (CT) demonstrated dorsal epidural thickening from the second through seventh cervical vertebrae .On reassessment, the patient had loss of sensation below the seventh thoracic dermatome and markedly diminished bilateral lower extremity strength and reflexes concerning for ascending paralysis due to spinal cord compression. Magnetic resonance imaging (MRI) of the complete spine showed a cervicothoracic epidural hematoma .Orthopedic spine surgery performed emergent decompression, and the patient experienced rapid postoperative improvement in strength and sensation.A spinal epidural hematoma is a collection of blood between the spinal canal dura and vertebrae.3Given the non-specific clinical findings, spinal epidural hematomas are challenging to diagnose.5What do we already know about this clinical entity?A spinal epidural hematoma is a collection of blood between the spinal canal dura and vertebra that presents as back or neck pain with progressive neurological deficits.What is the major impact of the image(s)?Cases of traumatic spinal epidural hematomas are part of a small subset of neurological emergencies that benefit from early recognition and surgical intervention.How might this improve emergency medicine practice?Correlation of presentation with computed tomography and magnetic resonance imaging is essential to diagnose spinal epidural hematomas."}
+{"text": "The no-touch saphenous vein with surrounding pedicle tissue harvesting techniquepreserved endothelium and vessel wall integrity and demonstrated improvedlong-term saphenous vein conduit patency that was comparable to internalthoracic artery conduit patency. Despite improved saphenous vein conduit patencyrates, there is a possibility that no-touch saphenous vein harvest may increasewound complication rates by increased tissue disruption, including venous andlymphatic channels. Comprehensive strategies to minimize leg wound complicationsafter no-touch saphenous vein harvest are discussed. An elasticated bandage was applied to the legwound after surgery and was replaced by a compression stocking from the2nd postoperative day. The compression stocking was kept in placefor 1 to 2 months postoperatively for prevention of leg swelling. TheJackson-Pratt drain was removed when the amount of drained fluid decreased to< 10 mL daily. Leg wound complications in the SV harvesting site were definedas infection or wound disruption that needed additional repair or secondaryintention healing. Leg wound complications developed in eight of 518 patients(1.5%) who received no-touch SV graft and underwent wound closure using theaforementioned strategies from 2017 to 2021 (unpublished data). All eightpatients recovered after secondary intention healing.After protamine administration to normalize the prolonged activated clotting timeat the end of CABG, a Jackson-Pratt drain was inserted into the SV harvestingsite and the leg wounds were closed in layers: interrupted 3-0 absorbablesutures to the subcutaneous tissue, interrupted 4-0 subcuticular absorbablesutures, and additional staples or zip surgical closure method for the skin. Zipskin closure  is a noninvasive skin closure system, and it has several advantages forwound healing such as providing better cosmetic results, facilitating woundhealing, and reducing infection riskThe rate of wound complication after not-touch SV harvest may be minimized bypreoperative evaluation of lower limb vascular status, selection of an adequatevein, creation of a precise skin incision, careful harvesting of the vein, placementof a drain in the vein harvest site, and meticulous closure of the skin wound."}
+{"text": "Physical activity contributes to the prevention of chronic illness as well as promotion of physical and mental health, but most adults remain inactive. Chronic illness affects mainly middle aged and older adults, and very little objectively measured data on physical activity behaviours and associated health outcomes of this population is published. The aims of this study are to: 1. Objectively measure physical behaviour outcomes of adults participating in the Move for Life study; 2. Develop distinct activity profiles based on six behaviour variables; 3. Investigate whether health outcomes differ across the activity profiles.Participants were Irish adults aged 50 years and older. Using the activPAL, objectively measured data were collected on average daily: light intensity physical activity (hours); moderate to vigorous intensity physical activity (minutes); step count; time in bed (hours); standing time (hours); and waking sedentary time (hours). Data were obtained on chronic illness and health service utilisation. Validated questionnaires were used to collect data on wellbeing, loneliness and social isolation. Hierarchical cluster analysis using squared Euclidian distance was used to cluster behaviours based on similarity, using SPSS version 26. Regression models explored associations between health outcomes and activity profiles, adjusted for age and sex.Data from 485 participants were analysed, and four activity profiles were identified: sedentary , low active , moderate active  and higher active . We will present the differences across the activity profiles for chronic illnesses, multi-morbidity, health service utilisation and validated health tools, comparing to data from the Irish Longitudinal Study on Ageing (TILDA) and the English Longitudinal Study on Ageing (ELSA).The use of physical activity behaviour clusters may identify people with multi-morbidity and higher utilisation of health services. These findings could be factored into the development of future targeted physical activity interventions."}
+{"text": "Coastal wetlands are not only among the world\u2019s most valued ecosystems but also among the most threatened by high greenhouse gas emissions that lead to accelerated sea level rise. There is intense debate regarding the extent to which landward migration of wetlands might compensate for seaward wetland losses. By integrating data from 166 estuaries across the conterminous United States, we show that landward migration of coastal wetlands will transform coastlines but not counter seaward losses. Two-thirds of potential migration is expected to occur at the expense of coastal freshwater wetlands, while the remaining one-third is expected to occur at the expense of valuable uplands, including croplands, forests, pastures, and grasslands. Our analyses underscore the need to better prepare for coastal transformations and net wetland loss due to rising seas. Landward migration of coastal wetlands under rising seas will transform coastlines but not compensate for seaward losses. Societal perspectives of the value of coastal wetlands have changed greatly in the past century  coasts . Of the Our analyses indicate that freshwater forested wetlands and freshwater marshes collectively represent two-thirds of the total area available for wetland migration across the conterminous United States . Upland One of the critical limitations of prior landward migration studies is that they have focused exclusively on tidal saline wetlands without explicit consideration of adjacent freshwater wetlands . AlthougSome freshwater wetlands can migrate landward along river corridors into adjacent freshwater wetlands. However, that migration does not result in new wetland formation because it occurs at the expense of other freshwater wetland classes. Coastal freshwater wetlands that cannot migrate landward into uplands due to topographic barriers are particularly vulnerable to rising sea levels that lead to the landward migration of tidal saline wetlands . For exaTo complicate matters, there is much uncertainty regarding the long-term stability and potential extent of tidal saline wetland migration into adjacent freshwater wetlands. Many of these freshwater wetlands are positioned at elevations that may be equivalent to, below, or just slightly higher than tidal saline wetlands. Thus, these coastal freshwater wetlands are also highly vulnerable to coastal drowning under higher sea level rise rates. Further, in areas with organic-rich biogenic soils, there are critical questions regarding the likelihood of landscape-scale tidal saline migration given the potential for peat collapse and conversion of freshwater wetlands to open water that is too deep for plant establishment and the landward migration of tidal saline wetlands  through biogeomorphic feedbacks between inundation, plant growth, and sedimentation. The second process involves the landward migration  of wetlands into adjacent upslope or upriver lands. Our analyses focus exclusively on the second process\u2014the landward migration of wetlands.https://coast.noaa.gov/slr), the NOAA Office for Coastal Management has produced several related products including national-scale tidal datum data, derived from NOAA\u2019s vertical datum transformation tool , and Coastal Change Analysis Program (C-CAP) land cover class migration data at 0.1524-m net sea level increments. We obtained these data, which we used in combination with other land cover, elevation, and levee data sources, to identify areas available for the landward migration of tidal saline wetlands and freshwater wetlands.Our landward migration analyses examine the upslope and upriver movement of two broad wetland classes: (i) tidal saline wetlands and (ii) freshwater wetlands. To our knowledge, there is not a national-scale dataset that quantifies the migration potential of these two broad wetland classes into adjacent freshwater wetland and upland land cover classes. However, as part of the NOAA Sea Level Rise Viewer  effort  the inland limit of the MSLRMM-derived future estuarine land cover classes  to define the upper boundary of the future tidal saline wetland zone (table S3) and (ii) the MSLRMM-derived future freshwater wetland classes  to define the upper boundary of the future freshwater wetland zone (table S4). However, for some areas , we developed complementary analyses using the MSLRMM approach in combination with elevation data and MSLRMM-derived future MHWS data (tables S5 and S6).To define the lower boundary of the future tidal saline wetland zone, we used the upper boundary of the current estuarine land cover classes , which was determined using NOAA\u2019s 2016 C-CAP data . The state and estuary-scale data are available as a U.S. Geological Survey Date Release ("}
+{"text": "Applications of dual-energy computed tomography and virtual non-contrast technique in neuroimaging are still emerging. While the role of DECT in differentiating parenchymal hemorrhage and contrast media after mechanical revascularization is well recognized, the value of DECT in evaluation of brain ischemia in post resuscitation patients who have received intravenous (IV) iodinated contrast is not well documented. We present a challenging case where DECT helped explain hyperattenuation in cortical grey matter and deep grey nuclei as well as cerebellar hemispheres in a comatose patient post cardiac arrest following massive pulmonary embolism. Applications of dual-energy computed tomography (DECT) and virtual non-contrast (VNC) techniques in neuroimaging are still emerging. While the role of DECT in differentiating between brain parenchymal hemorrhage and leaked contrast media after mechanical revascularization is well recognized 19-year-old female with no significant past medical history with only reported medication intake of oral contraceptive pills initially reported increasing dyspnea for 1-2 weeks preceding collapse with initial return of consciousness following bystander cardiopulmonary resuscitation. She subsequently lost consciousness, and Emergency Medical Services found her to be in ventricular fibrillation followed by pulseless electrical activity. She underwent pan-CT scanning with IV contrast earlier in the management which demonstrated massive pulmonary embolism resulting in right heart strain and manifestations of multi-organ failure. Within 24-hours of presentation the patient underwent percutaneous pulmonary artery thrombectomy and inferior vena cava filter placement. Serial head CTs performed are discussed below. Patient expired, following a short course, from multisystem failure.Serial CT imaging of the head was obtained  that demDECT facilitates material differentiation based on different peak voltage acquisitions (high and low). Materials demonstrating equal Hounsfield densities at 120 kVp imaging can be distinguished by assessing energy dependent changes of attenuation of respective materials In our case, serial non-contrast CTs of the head demonstrated progressively increasing attenuation of the subarachnoid spaces that was attributed to pseudo subarachnoid hemorrhage appearance (vascular engorgement) secondary to severe diffuse cerebral edema and recent resuscitation from cardiopulmonary arrest, as has been previously described The VNC technique proved 2 things. First, the subarachnoid hyperattenuation was from contrast retention within the vasculature, and second and more importantly, the extensive hyperattenuating brain parenchymal areas that were bright on iodine maps were hypodense on the subtracted VNC images representing ischemic tissue retaining contrast. The VNC images confirmed underlying areas of brain infarction with extensive hypoattenuation in a pattern typical of diffuse hypoxic/ischemic insult. Hence DECT helped reveal widespread cerebral and cerebellar infarctions by confirming contrast retention in the areas of infarction.In conclusion, DECT with VNC is valuable in assessing brain parenchymal hyperdensities seen on a non-contrast CT in the setting of post resuscitation hypoxic/ischemic injury with prior history of IV iodine contrast administration. It differentiates contrast retention from hemorrhage and reveals underlying parenchymal infarction.Written informed consent for all pertinent details of this case was obtained from patient's representative."}
+{"text": "The sympathetic nervous system maintains metabolic homeostasis by orchestrating the activity of organs such as the pancreas, liver and white and brown adipose tissues. From the first renderings by Thomas Willis to contemporary techniques for visualization, tracing, and functional probing of axonal arborizations within organs, our understanding of the sympathetic nervous system has started to grow beyond classical models. In the present review, we outline the evolution of these findings and provide updated neuroanatomical maps of sympathetic innervation. We offer an autonomic framework for the neuroendocrine loop of leptin action, and we discuss the role of immune cells in regulating sympathetic terminals and metabolism. We highlight potential anti-obesity therapeutic approaches that emerge from the modern appreciation of SNS as a neural network vis the historical fear of sympathomimetic pharmacology, while shifting focus from post- to pre-synaptic targeting. Finally, we critically appraise the field and where it needs to go. Anatomical dissections in the 17 Oxford)  and subs Oxford) . Jacques Oxford) . Neurons Oxford) . By the esponse)  and the The canonical model of bivalent and oppositional autonomic function is inadequate in describing metabolic control, as some metabolic tissues receive innervation exclusively from sympathetic neurons, including brown adipose tissue (BAT) and white adipose tissue (WAT), and in others like the liver, the sympathetic innervation seems to play the crucial role in hepatic homeostasis. While the SNS has long been acknowledged as an essential arm of metabolic control, the modern experimental toolkit has afforded a more consolidated appreciation of the sympathetic contribution to metabolic homeostasis. In this review, we first outline how sympathetic neurons control the metabolic activity of the pancreas, liver, and adipose tissues. Then, we describe how these processes are related to immune function and dysregulated by the inflammatory responses that characterize metabolic diseases. Finally, we highlight emerging therapeutics targeting key sympathetic processes to reverse metabolic disease.Sympathetic innervation is crucial for the regulation of pancreatic insulin and glucagon release and the control of glucose homeostasis, particularly by protecting against hypoglycemia during fasting and by increasing blood glucose during periods of elevated demand, such as by physical, inflammatory or psychological stress.panel A). Preganglionic sympathetic fibres in the greater thoracic splanchnic nerves provide inputs to coeliac ganglia neurons, which in turn provide postganglionic fibres to the pancreas. In addition, the vagus nerve provides preganglionic parasympathetic supply to a network of intrapancreatic ganglia. Neurons from the intrapancreatic ganglia then provide postganglionic cholinergic innervation to the exocrine and endocrine pancreas. Both vagal and spinal sensory fibres carry afferent sensory information from pancreas with their cell bodies in the nodose and dorsal root ganglia, respectively.Gross anatomical dissections and histological analyses of fixed pancreatic tissue, primarily in dogs and cats, provided an early anatomical framework for sympathetic, parasympathetic and somatic pancreatic innervation  Figure , panel AMethodological limitations in classic histology \u2013 namely poor stain tissue specificity and inadequate image resolution \u2013 led to conflicting reports regarding the distribution of sympathetic nerve fibres within pancreas . Improvepanel B). Still, tissue sectioning an entire organ is laborious and tracing filamentous structures across serial sections is both time consuming and prone to artefacts. Tissue clearing, light sheet microscopy and image analysis have enabled the best 3-dimensional imaging and quantification of pancreatic innervation to date. Studies applying these methods in mice highlight sympathetic innervation to intrapancreatic ganglia, islets and vasculature (panel B). Quantification of TH+ innervation across hemipancreata confirmed relatively even distribution through the pancreas but suggested TH+ innervation is enriched in mouse islets compared to the exocrine pancreas, representing 3% of islet volume + sympathetic fibres allowed for 3D reconstruction and quantification of sympathetic innervation across the entire pancreas. In mice, such studies showed TH+ fibres distributed evenly throughout the pancreas  and the culature . Sympathculature  , together with neuropeptides such as galanin  and neurStudies examining the roles of pancreatic sympathetic nerves on glucagon release have been more consistent. Splanchnic and pancreatic nerve stimulation increased pancreatic glucagon release into either the portal or systemic circulation in many species, including humans . In someHowever, splanchnic nerve stimulation and pharmacological studies do not specifically target pancreatic innervation, and it is possible that effects on other organs innervated by the coeliac ganglia, such as the liver, or modified by systemic adrenergic receptor antagonists may indirectly alter pancreatic insulin release. An additional challenge is discerning which changes to beta cell function are due to direct sympathetic neuronal signalling, and which are secondary to changes in islet blood flow, as evidence amounts for the parallelism of insulin secretion and vasodilation . FurtherSome studies have assessed whether sympathetic innervation also regulates the exocrine functions of the pancreas. Early studies in guinea pigs suggested so since NA administration potentiated cholecystokinin-induced amylase release . HoweverRecent intriguing work has suggested that pancreatic sympathetic innervation may play a role in the development, maintenance and remodelling of islet structure. Genetic or pharmacological ablation of sympathetic innervation in mice altered pancreatic islet structure reduced plasma insulin and impaired glucose tolerance. The effects on islet structure were partly reversed by beta-adrenergic receptor agonists . In addiUnlike the liver or adipose tissue, the pancreas receives dense parasympathetic innervation and islet expression of cholinergic receptors M2 and M3. Studies using electrical stimulation of the efferent vagus nerve lowered blood glucose  while acdb/db mice, recent work reported remodelling of pancreatic ducts close to islets and increased sympathetic innervation of the islet-duct boundary  nerves, but not the vagus branch innervatin the liver (parasympathetic), would inhibit this effect . Followial cells . Electroal cells . In addial cells .T. Belengeri, Forssman and Ito used fluorescence microscopy to show sympathetic nerve fibres in close apposition to hepatocytes in the peripheral zone of the lobule where parenchymal cells, sinusoidal lining cells and Kupffer cells also appeared to be innervated  specific staining suggested cholinergic hepatic input to hepatic vessels, bile ducts and intralobularly in close apposition to hepatocytes and sinusoids . In modenervated . Auto-ra Mulatta . However Mulatta .Retroviral PRV tracing studies have mapped the neuroanatomical origin of hepatic sympathetic nerves. Two studies report sympathetic neurons originating from the coeliac superior mesenteric complex, aorticorenal and suprarenal ganglia, which are in turn innervated by splanchnic preganglionic neurons located in the intermediolateral column of the spinal cord (T7\u2013T12)  Figure . PerhapsSince Claude Bernard\u2019s early lesion studies, a more consolidated appreciation on the function of hepatic autonomic innervation has been sought. In the 1960s, Shimazu and colleagues established that electrical stimulation of rabbit splanchnic nerve was sufficient to increase the hepatic gluconeogenetic enzymes glycogen phosphorylase and glucose-6-phosphatase . FurtherDespite the evidence that the liver is strictly innervated by the sympathetic nervous system, recent functional studies defend different perspectives. In one study, it was shown that surgical resection of the hepatic branch of the vagus nerve in rats would prevent the effects of brain-infused insulin on hepatic glucose production . Since ten passant fibres related to the sympathetic nervous system, impacted afferent signals, or have influenced surrounding organs, such as the adrenal glands or the pancreas. Even though the authors show no changes in corticosterone and glucagon one hour after the illumination, blood glucose increased quickly (within 15 min) and it is possible that hormone levels were affected in the first minutes.Another study used optogenetic approaches to identify the circuit by which pro-opiomelanocortin (POMC) neurons control blood glucose . In a fiBrown Adipose Tissue (BAT) performs non-shivering thermogenesis by dissipating the mitochondrial H+ gradient across the mitochondrial inner membrane while circumventing ATP synthase. Metabolic substrate is thus oxidised without generating chemical stores of energy, instead generating heat . BAT is BAT was recognised as relevant to the physiology of rodents and human infants as their large surface area to volume ratios required additional support in maintaining core body temperature . Only wiBAT has an impressive ability to use energy \u2013 it consumes more glucose per gram than any other peripheral tissue when stimulated, except perhaps the brain  and estiSympathetic innervation has emerged as an important regulator of BAT thermogenesis - since the initial descriptions of the central role of sympathetic stimulation for maintenance of body temperature upon cold exposure  and its Ucp1 mRNA , increases weight without affecting feeding behaviours and inhibits physiological responses to cold challenges. In denervated subjects - all of these processes can be acutely resolved via NA injection . More recp1 mRNA , but theUnderstanding structural, functional, and molecular changes associated with upregulated BAT thermogenesis could help unearth important pathways for potentiating its activity in humans. Imaging studies utilizing sectioning methods reported that cold exposure increases sympathetic nerve density and arborisation of BAT  but modebeiging in WAT  premotor neurons expressing POMC/CART in the hypothalamus , DMH and VMH nuclei) and in the brainstem, ii) spinal cord and iii) stellate ganglion . Additio obesity . By cont outflow , suggestGiven the complexity of hypothalamic networks, the precise signalling involved in downstream activation of sympathetic activity still needs to be further understood - however, it should be noted that its investigation has been focused on central pathways and assumed noradrenergic signalling as the single effector mechanism responsible for the observed phenotypes, a major caveat also present in studies investigating sympathetic functions in other tissues.(Nrg4) was significantly upregulated with BMP8b overexpression, and down-regulated in BMP8b knockouts. Exogenous application of NRG4 promoted sympathetic axon growth and branching, suggesting BAT could dynamically remodel surrounding tissue in response to BMP8b  in mice increases sympathetic innervation and BAT vascularisation, even in mice housed at warm temperatures . Transcrto BMP8b . Similarto BMP8b . CLSTN3\u00dfto BMP8b . AdipocyFinally, emerging evidence suggests BAT is an integrated metabolic tissue with endocrine functions  and roleNoradrenergic signalling has long been known to cause WAT lipolysis. Challenges presented by imaging adipose tissues and manipulating its function have meant that an understanding of how NA is supplied and regulated within WAT has been elusive until recently. Early imaging studies suggested that WAT received some innervation  but the Only with recent advances in two-photon imaging and tissue clearing it has been possible to visualise entire sympathetic arborizations as well as confirm the presence of neuro-adipose junctions. In 2015, Zeng and colleagues used optical projection tomography approach to reconstruct 3D images of entire inguinal fat pads. Two photon microscopy of catecholaminergic reporter mice labelled with lipophilic dye showed that 50% of all neurons innervating fat pads were sympathetic, and bouton-like structures innervated 8% of adipocytes. Advanced tissue clearing preparations have allowed for direct imaging of entire fat pads . In 2017More macroscopically, retrograde tracing techniques have aimed to map the neuroanatomical origin of pre- and post-ganglionic fibres innervating WAT and suggest that distinct fat pads receive innervation from distinct populations of neurons. Early fluorogold retrograde tracing studies in Siberian Hamsters claimed dense cell bodies projecting to inguinal WAT (iWAT) from T13 abdominal sympathetic ganglion, although the study did not provide representative micrographs of ganglia . More moet al. likely caused tracer to diffuse via the inguinal canal to infect abdominal organs, highlighting a common pitfall in retrograde viral tracing studies.While most neuroanatomical studies tend to present harmonious findings, a 2017 study received a lot of attention and offered a different framework of iWAT neuroanatomy. The authors used an Alexa-dye-conjugated Cholera Toxin Subunit B (CTB) injection into iWAT and reported labelled neurons almost exclusively in the coeliac ganglia \u2013 a structure providing visceral sympathetic innervation to kidney, liver and GI organs. The authors reported very few cells innervating iWAT originating from either the spinal cord or lumbar dorsal root ganglia . These rSome deeper adipose pads also appear to be supplied by post-ganglionic neurons that synapse not in the paravertebral sympathetic chain but in mid-line autonomic ganglia. Using a green fluorescent protein labelled adeno-associated retrograde virus tracing technique, Cardoso et al observed cell bodies of the efferent sympathetic nerves innervating gonadal WAT (gWAT) in the aorticorenal ganglion . In addiIndirect evidence of sympathetic-induced lipolysis has existed for over 60 years - plasma free fatty acid concentrations were noted to increase with noradrenaline administration in rats and with electrical stimulation of adipose nerves in dogs, and these changes were inhibited by trimethaphan camphorsulfonate ganglionic blockade and peripheral \u00df-adrenergic antagonism . The anaDirect evidence that sympathetic activation was sufficient to drive lipolysis has only emerged since the advent optogenetic and chemogenetic techniques that can stimulate or inhibit the activity of molecularly defined neuronal populations. By crossing TH-Cre mice to a Cre-dependent ChR2 line, Zeng et al showed optogenetic activation of tissue specific sympathetic neurons released NA (as measured by ELISA assay) and chronic stimulation depleted fat mass in illuminated areas . SimilarSimilarly, the functional spatial control of SNS signalling is poorly understood. The apparatus for spatially restricted control of lipolysis is present \u2013 WAT is innervated from discrete spinal levels and sympathetic ganglia and local SNS-WAT communication is performed at the Neuron-Adipose Junction. Functional evidence based on limited NATO methods do support the notion of some regional specialisation in lipolysis. In response to a 16 hour fasting challenge, sympathetic outflow is significantly higher in iWAT over epididymal WAT (eWAT) , while iFinally, ambiguity still surrounds the morphological changes to sympathetic axons during cold and fasting challenges \u2013 namely, whether sympathetic arborisations change their density or localisation to facilitate lipolysis. Earlier studies suggested an increase in neuronal arborisations and increases in TH+ neuron density in WAT after cold acclimatization but these observations were based on analysis of tissue sections that poorly represent the entire fat pad . Whole t2 of iWAT per sample, while Chi\u2019s protocol lasted only for 7 days and analysed ten cubic \u2018representative\u2019 areas of unspecified size. In addition, Blaszkeiwicz used the pan-neuronal marker PGP9.5 for neuronal quantification, whereas Chi used TH, specific for sympathetic neurons. Recently, Willows and colleagues quantified neurite densities across entire adipose tissues using mechanical compression method, and found a non-significant increase in neurite densities in cold adapted mice, but only examined four mice in a proof-of-concept study  that appears to play important roles in the regulation of metabolism. Because BeAT exhibits increased mitochondriogenesis and expresses a significant amount of UCP-1, it is thought that it has the capacity to generate heat through uncoupling of the electron transport  expression which could be replicated by \u03b23 adrenoceptor agonism . UCP-1 p beiging .beiging and thermogenesis. 3D imaging of tissue cleared iWAT shows adipocyte-specific PRDM16 knockouts are unable to keep the regional differences in SNS density within the different sub-regions in iWAT, whereas the WT control showed a notable regional difference in medial vs lateral sub-regions of iWAT , a transcriptional regulator, is sufficient to initiate differentiation of beige adipocytes in subcutaneous WAT , and imp of iWAT ; this re of iWAT . BidirecHomeostatic neuroendocrine feedback loops maintain homeostasis via afferent (sensory) signals that are integrated and processed centrally to generate efferent (motor) outputs. In the context of metabolism, leptin is the primary afferent signal, information regarding metabolic state is computed primarily in the hypothalamus, and the SNS signalling acts as the effector arm .Leptin is an adipokine synthesised proportionally to adipose tissue mass. Global increases in fat mass raise plasma leptin concentrations to increase energy expenditure and reduce food intake . ConversImmediately following leptin\u2019s discovery , the preSympathetic signalling is an important mechanism by which leptin increases energy expenditure. Early studies noted that chronic \u03b23-adrenergic agonist treatment mimicked leptin application, reducing adipose tissue mass and leptin expression while sparing lean tissue mass in mice . Some muBy deduction, SNS signalling was the most likely mediator of leptin\u2019s effects on energy expenditure. This was bolstered by studies showing intravenous (IV) infusion or intra-hypothalamic delivery of leptin increases nerve activity to BAT. These measurements came from extracellular electrodes implanted over local neurovascular peduncles, so the activity of non-sympathetic neurons was also measured . Similaret al. (Leptin crosses the blood\u2013brain barrier (BBB) to bind to Leptin receptors (LepR), predominantly in the ARC, VMH, DMH and medial preoptic nuclei (MPO)  and latet al. . Functioet al. . Also, cet al. . In addiet al. . Intereset al. , and thoet al. . Specifiet al. ), regulaMPO LepR+ neurons have recently been implicated in regulating both energy expenditure and thermogenesis in response to internal energy state . SimilarThe advent of techniques that allow tissue-specific control of neurons has yielded direct evidence of the necessity of SNS function to elicit leptin-induced energy expenditure. In 2015, Zeng and colleagues found tissue-specific genetic ablation of sympathetic neurons within a fat depot inhibited the lipolytic effect of leptin . SimilarLeptin resistance \u2013 a blunted response to leptin signalling, a weakened effector arm of this neuroendocrine homeostatic feedback loop \u2013 has emerged as an important pathological change in the development of obesity . This stInsulin resistance and hyperinsulinemia are associated with obesity and are connected with hypertension problems in obese subjects. However, similarly to leptin resistance, the mechanisms involved in the dysregulation of this neuroendocrine loop are still under study. Insulin resistance and hyperinsulinemia are associated with obesity and are associated with hypertension problems in obese subjects. However, similarly to leptin resistance, the mechanisms involved in the dysregulation of this neuroendocrine loop are still under study.Central insulin signalling is another important afferent signal in the metabolic feedback loop. There is accumulating evidence that insulin crosses the BBB into the brain and regulates different peripheral tissues and systemic metabolism  and deletion of insulin receptors in the brain increases food intake and promotes obesity . ICV insHowever, other studies have shown the opposite. Insulin action in the brain is a critical regulator of WAT metabolism with inhibitory effects on sympathetic output. Thus, in lean rats, the sympathetic outflow to fat tissue is reduced and lipolysis suppressed after central insulin administration; but, like an inverse regulation, mediobasal hypothalamus insulin increases de novo lipogenesis in adipose tissue . NeverthStudies with neuron-specific insulin receptor knockout models have postulated some neuron populations as key players integrating the insulin signal. Thus, insulin signalling in POMC and NPY/AgRP neurons has an important role in regulating energy balance . InsulinSympathetic innervation of metabolic tissues is essential for maintaining metabolic health, but metabolic dysregulation increase the propensity for neuropathy within these tissues. Such an autonomic neuropathy may trigger or exacerbate metabolic diseases, initiating a positive feedback cycle seemingly difficult to break.Peripheral sensorimotor neuropathies are common in patients with metabolic syndromes, especially diabetes. While obese adipose tissue takes on a fibrotic quality that is difficult to image , 3D imaget al to observed liver neuropathy  or in leptin deficiency . Liu anduropathy . In aliguropathy . In thisuropathy .Understanding the mechanisms by which SNS signalling to metabolic tissues is altered in disease states remains an important question in designing effective therapeutics. In recent years, the interactions between SNS, metabolic organs and local immune cells have emerged as a key contributor to pathological signalling changes. The central role of these interactions have led to the development of the growing field of neuroimmunometabolism, which investigates how these systems are interconnected and how these connections can be explored for therapeutic interventions.The presence of the relevant apparatus for SNS signalling, immune cells and adipokines to interact has been known for some time. All primary and secondary immune organs are innervated by postganglionic sympathetic nerves  and bothAlbeit only a few studies have investigated the interplay between sympathetic signalling and immune modulation in the pancreas, recent work has supported a role for pancreatic sympathetic innervation in immune modulation and protection from autoimmune diabetes in mice . In one et al. used three-dimensional immunoimaging to evaluate the liver sympathetic innervation in samples from NAFLD patients, and revealed increased sympathetic axonal sprouting associated with mild nerve degeneration in the early stages of disease and a significant loss of sympathetic innervation in advanced steatohepatitis  specialized in phagocytosis and participating in the innate responses. Interestingly, these cells were shown to be innervated by sympathetic fibres and to express adrenergic receptors . Evidencepatitis . They al  increase from 10% of the adipose tissue resident immune cells to 50% and tend to change from M2 anti-inflammatory to a M1 pro-inflammatory phenotype, producing proinflammatory cytokines including IL-6, IL-1\u03b2 and TNF-alpha and paracrine factors. Proinflammatory ATMs were indirectly associated with insulin resistance, vascular remodelling, and increased adiposity, but over the last decade their role as architects of lipolytic signalling has been increasingly accepted. Indeed, among the tissues discussed in the present review, the adipose tissue is the one in which immune populations and their interplay with autonomic signaling are most extensively described .beiging of WAT and causing a significant and sustained weight loss in obese mouse models  . Cruciale models . Likewise models  reportede models .et al.  onto adipocytes and incubated with Met-Enk to onserve an upregulation of Ucp1  data from WAT  . Paralelipocytes . Ultimatutgrowth . Thus, bCollectively, these findings establish a novel homeostatic role of tissue macrophages and other immune cells that can control sympathetic innervation. Any disruption between this neuroimmune crosstalk might impact the nerve integrity and tissue function with a considerable final effect on metabolism.Obesity is a leading cause of morbidity and mortality globally, but until recently, anti-obesity pharmaceuticals have had poor therapeutic efficacy and tolerance. The prolipolytic signalling of the sympathetic nervous system has attempted to be exploited by sympathomimetics - compounds that stimulate sympathetic nerves by inhibition of MA uptake or direct stimulation of peripheral adrenoceptors . They haClassically, the mechanism of action of sympathomimetic-induced weight loss was thought to be central, by suppressing appetite and promoting locomotion. The addictive properties of sympathomimetic are due to nigrostriatal monoamine release; cardiovascular toxicity is thought to be caused by a combination of central and peripheral stimulation. This view was challenged by Mah\u00fa and colleagues, who brought attention to the contribution of the brain on the peripheral readouts of sympathomimetics , while p\u00df3-adrenoceptor agonists have also received attention due to their ability to promote BeAT differentiation and formation in rodents, but poor selectivity and systemic administration of early \u00df3 agonists caused intolerable side-effects .Recent attention emerged surrounding Mirabergon, a specific \u00df3 agonist already used to treat urinary urge incontinence. In 2015, Cypess and colleagues measured 18F-FDG uptake in PET scans to show a 200mg dosing regimen of Mirabegron increases human BAT metabolic activity, while also increasing BAT glucose uptake and increasing resting metabolic rate by 230\u00b140 kcal/day . SubsequRelative to brain research, sympathetic neuroscience is lagging several decades behind - owing to the dispersed and difficult anatomical access and technical limitations that the developments we envision will likely surpass. These will be necessary to overcome the conceptual barrier that stagnated in the era of adrenergic receptor pharmacology, which solely accounts for post-synaptic adrenergic targeting in organs. Although such models account for the action of a few adrenergic drugs that are routinely used in the clinic , sympathetic nerves are seldom considered as a neural circuit, whereby pre-synaptic manipulations of a node within the network might not be predicted by post-synaptic adrenoceptor agonism or centrally acting sympathomimetics which have a widespread top-down action. Moreover, the assessment of adrenoceptor subtype expression across cell types mainly originates from bulk tissue techniques that do not account for expression by resident immune cells. Only single nuclei sequencing has parsed apart tissue heterogeneity, particularly that of WAT&BAT, which cannot be analyzed by conventional cell sorting.Moreover, the linearity of post-synaptic agonism falls apart as adrenoceptors are also expressed in sympathetic neurons, suggesting that feedforward or feedback circuits may exist among ganglia. Whether intra- and inter ganglionic circuitry exists is an open question, despite the highly suggestive TH+ axon bundles between every two ganglia along the paravertebral sympathetic chain. Such ganglionic circuits can be influenced by resident immune cells that cleanse norepinephrine or produce neuromodulators such as opioids. Thus, the field needs to rise from the era of post-synaptic adrenoceptor pharmacology to that of neural networks. As such, the classic view that SNS is responsible for the \u2018fight or flight\u2019 response antagonised by the PNS is an incomplete description of autonomic metabolic control in light of the modern neuronal network theory. Not only do adipose tissues and liver  receive innervation exclusively from the SNS, but PNS in the heart can act as a cardioprotective buffer whilst sympathofacilitator drugs exert effective control of metabolic tissues to facilitate weight loss and restore the homeostasis of the neuroendocrine loop of leptin action.Current molecular genetic technologies widely used in the brain have had limited success with SNS circuits. Dissections of the murine paravertebral sympathetic chain of ganglia are complicated, and retrograde tracing with a non-replicative non-polysynaptic virus has low transduction efficiency, perhaps due to the cleansing of viral particles by immune cells resident in sympathetic tissues. PRV retrograde tracing pioneered mapping the efferent postganglionic sympathetic innervation of BAT, which seems consensual across species. However, the innervation of WAT is more variable across species and the location of the fat depot. Similarly, the origin of the sympathetic innervation of the liver is inconsistent and seems restricted to the perivascular space. Unlike liver and adipose tissues, and more aligned with conventional autonomic paradigms, the pancreas possesses both sympathetic innervation and parasympathetic innervation with opposing effects. Differential sympathetic activation would be advantageous for selective targeting and treatment of organ-specific dysfunction, including immune and metabolic pathologies. Except for central leptin action, it is debatable whether manipulations of upstream brain circuits would recruit a top-down response that is cardioneutral and specific to metabolic organs. Centrally acting sympathomimetics such as amphetamines and MCR8 agonists recruit widespread and cardiotoxic sympathetic drive, indicating that higher-order manipulations may not be more targetted than those of lower order at the postganglionic level. Drawing a parallel with the organization of other descending axes such as sensory-motor circuits: lesions or stimulations of higher order brain structures produce effects that are more widespread relative to peripheral manipulations, for instance, when comparing the sensory-motor deficits originating from the stroke of the central medial artery to those arising from peripheral lesions. This organizational principle could also apply to the sympathetic axis, whereby peripheral postganglionic targeting may be more specific than higher-order pre- sympathetic central circuits. Thus, manipulations of sympathetic postganglionic neurons may be a means to achieve metabolic control while identifying neural circuits, or nodes within them, that preserve cardiovascular health. Critical to this endeavour will be to generate transgenic CRE/DRE driver lines for subpopulations of neurons that could be systematically used as molecular handles for remote activation/inhibition via minimally invasive technologies, such as chemogenetics or magnetogenetics, for a causal assessment of the exact neuronal pathways of the sympathetic-metabolic axis. Realistic maps with single-neuron resolution akin to the MouseLight Project are still missing. A functional understanding of SNS circuitry in-vivo will require the development of non-invasive genetically encoded activity reporters that can be sensed in deep-seated sympathetic ganglia \u2013 possibly capitalizing on optoacoustic as an enabling technology.Obesity-induced sympathetic neuropathy is a cause and effect of metabolic disease \u2013 weakening the sympathetic efferent arm in the neuroendocrine loop of leptin action. Reversing obesity-induced sympathetic neuropathy may be a step towards re-establishing body weight homeostasis, and this will require deciphering the cross-talk among sympathetic-resident immune cells. This prospect promises \u201csympathoprotective\u201d immunotherapeutic targets and could offer a new generation of safe and effective anti-obesity treatments."}
+{"text": "Colorectal cancer (CRC) represents the third most prevalent cancer worldwide and a leading cause of mortality among the population of western countries. However, CRC is frequently a preventable malignancy due to various screening tests being available. While failing to obtain real-time data, current screening methods (either endoscopic or stool-based tests) also require disagreeable preparation protocols and tissue sampling through invasive procedures, rendering adherence to CRC screening programs suboptimal. In this context, the necessity for novel, less invasive biomarkers able to identify and assess cancer at an early stage is evident. Liquid biopsy comes as a promising minimally invasive diagnostic tool, able to provide comprehensive information on tumor heterogeneity and dynamics during carcinogenesis. This review focuses on the potential use of circulating tumor cells (CTCs), circulating nucleic acids (CNAs) and extracellular vesicles as emerging liquid biopsy markers with clinical application in the setting of CRC screening. The review also examines the opportunity to implement liquid biopsy analysis during everyday practice and provides highlights on clinical trials researching blood tests designed for early cancer diagnosis. Additionally, the review explores potential applications of liquid biopsies in the era of immunotherapy. According to the GLOBOCAN database, colorectal cancer (CRC) is the third most prevalent cancer worldwide, representing the second leading cause of cancer-related mortality around the globe . Albeit Despite the high mortality rates observed in the advanced stages, CRC is frequently a preventable malignancy through screening methods . The vasEven with the various screening technologies available, with colonoscopy representing the gold standard, adherence to CRC screening programs remains suboptimal among some populations ,10. EndoThe aim of this article is to review the existing data on liquid biopsies and their clinical application in detecting early-onset CRC. In addition, the review discusses the available methods for implementing liquid biopsies in everyday practice and offers highlights on clinical trials investigating blood tests designed for screening and early cancer detection. The review also discusses the challenges met during the analysis of liquid biopsy components and its potential future applications in the era of immunotherapy.Recent research has been shedding light on a new diagnostic approach suited for cancer patients, the liquid biopsy. Liquid biopsy comes as a simple, minimally invasive diagnostic tool, attempting to overcome the limitations of conventional tissue biopsy by providing more comprehensive data on tumor heterogeneity and dynamics at different junctures in cancer development . Liquid Originally described in 1869, CTCs are now gaining clinical importance in the management of patients with cancer . Tumor cCTCs can be successfully enriched through various procedures that exploit the dissimilarities observed between tumor cells and other circulating blood cells. These methods attempt to isolate CTCs based on their particular physical characteristics and their contrasting expression of cell surface proteins .Positive enhancement methods, also known as label-dependent, use specific antibodies targeting molecular markers expressed by CTCs (cell-surface antigens). The membrane protein most commonly used during positive enhancement selection is the epithelial cell adhesion molecule (EpCAM), however, other cytoplasmic markers expressed by CTCs may be exploited  . EpCAM iOnce the sample has undergone enrichment processes, CTCs require individual recognition. CTC detection can be achieved through immunocytology, molecular biology, or functional assays . The mosCTCs can be extensively characterized using a range of techniques. Profiling proteins expressed by CTCs represents one of the most commonly used methods and it requires immunostaining with antibodies to specific markers of cell proliferation and apoptosis . A diffeThe available scientific data showed the importance of CTCs in different CRC stages. In the nonmetastatic setting, the CTCs count was found to be lower, therefore, the cutoff for many of the clinical trials conducted was set for \u22651 CTC/7.7 mL of blood, while in the metastatic setting, the cutoff was set higher (\u22655 CTCs/7.5 mL of blood) . Even ifIn this regard, a prospective clinical study was presented at ASCO GI 2018 . The stuMoreover, CTCs were shown to evaluate patients\u2019 prognoses and predict metastasis and recurrence. A meta-analysis including 1847 patients from 11 studies revealed that an increased CTC baseline count represents an independent and strong prognostic factor for OS  and PFS  in metastatic CRC . By analHowever, despite promising results reported by clinical trials, the scientific community will have to overcome several limitations in order to further use the information provided by CTCs in clinical practice.The analysis of circulating nucleic acids (CNAs) represents a novel minimally invasive approach, able to assess the tumor and its molecular characteristics while allowing a more accurate description of tumor heterogeneity and evolution in time. CNAs, more specifically, circulating tumor DNA (ctDNA) and circulating microRNA (miRNA), are generally isolated from blood; however, other biological fluids could represent a source of CNAs  . CNAs enNumerous amounts of cell-free DNA (cfDNA) fragments are detected in blood plasma as a result of cellular death, with sizes ranging between 180 and 200 base pairs . It has The blood samples collected require a series of manipulations in order to identify ctDNA and then further analyze the material for genetic aberrations. Firstly, samples are subjected to sequential centrifugation, isolating plasma as the main source for cfDNA . ctDNA iExtensive research focusing on circulating DNA (cDNA) analysis has successfully discovered its clinical utility in CRC screening. A series of markers indicative of aberrant DNA methylation have been described and utilized to detect CRC in early stages and precancerous lesions  Table 1Table 1.Tumor suppressor gene septin-9 (SEPT9) is one of the most widely researched methylation markers in CRC pathogenesis. A study conducted by Warren et al.  evaluateSeveral multi-cancer detection tests have been thoroughly analyzed as potential screening tools in a new era of preventive medicine . CancerSCirculating miRNAs represent the purpose of extensive research focusing on cancer biomarkers. miRNA can be identified in biological fluids as a result of tissue injury and apoptosis or following active selective secretion by CTCs and tumor cells from the primary site or metastases ,93. The Even though the interest in miRNA as a liquid biopsy biomarker is relatively novel, research has already found its potential value for CRC screening .Several miRNA clusters appear up-regulated in CRC , of whicPresent in all biological fluids, exosomes represent cell-derived nanovesicles with sizes ranging from 30 to 150 nm in diameter . ExosomeAn increasing amount of evidence has identified exosomes as essential participants in cancer development processes. Exosomes secreted by tumor cells have been found responsible for alterations in the immune response that lead to suppression of antitumor response . In addiExosome concentration in biological fluids is relatively low, thus making their isolation, detection and further analysis relatively challenging. Isolation of exosomes can be achieved based on their physical properties (size and density), electromagnetic characteristics, or according to their immunological properties . IsolatiExosomal microRNAs have been attracting considerable attention as promising biomarkers suitable for cancer diagnosis. Multiple exosomal miRNAs have been studied, with some of them showing substantial value in identifying early cases of CRC .Research has identified several significantly up-regulated miRNAs in the setting of CRC, including cases of early-stage disease. One study found miRNA-23a to have an important diagnostic accuracy with an area under the curve (AUC) of 0.953, while miRNA-1246 and miRNA-21 also showed encouraging results . OverexpOver the past few years, immunotherapy has changed the treatment paradigm for many cancer types. In CRC, the MSI-high phenotype was associated with a significant response to immune checkpoint inhibitors (ICIs) . MoreoveTo date, liquid biopsies are investigated for use as biomarkers to predict and evaluate the response to immunotherapy. CTCs, circulating DNA (cDNA), circulating RNA (cRNA) and exosomes hold a generous amount of tumor-related information. Moreover, liquid biopsies may provide a more comprehensive and dynamic overview of the tumor microenvironment and heterogeneity than single-site tissue biopsies . The utiA better selection of the patients receiving immunotherapy could be guided by specific somatic mutations detectable in cDNA. In this regard, a genomic mutation signature was developed to characterize immunophenotypes and predict response to immunotherapy in gastrointestinal cancers . As mentRAS assessment in mCRC is essential to select patients suitable for anti-EGFR therapy. The concordance between tissue detection and somatic mutations detected in ctDNA appeared high in patients with advanced tumors, supporting blood-based testing. Moreover, ctDNA was shown to be highly useful for monitoring treatment response. However, some clinicopathological features, including tumor histology (mucinous) and metastatic sites , negatively influenced RAS detection in ctDNA . Along wImmunotherapy and targeted therapy are major therapeutic breakthroughs in cancer care, and one of the most challenging concerns is proper patient selection. To overcome these shortcomings, liquid biopsy-based biomarkers represent a promising tool, hence they require detection methods with sufficient specificity, sensitivity and predictive power .Despite many pieces of scientific evidence highlighting the potential benefits of liquid biopsies in cancer care, numerous limitations remain for their clinical use.CTCs have great potential as diagnostic, prognostic, predictive, as well as monitoring tools. However, their translation into clinical practice is still restricted amid their isolation from the bloodstream . To corrFor exosomal segregation, ultracentrifugation is thought to be the most efficient method. Although convenient and requiring reasonable costs, ultracentrifugation encounters several limitations. A significant concern is the co-purification of lipoproteins and protein aggregates along with EVs . Hence, ctDNA is a small fraction representing about 0.01% of cfDNA. One of the main logistical reasons limiting the extensive use of cDNA-based analysis is represented by their feasibility outside the academic cancer centers . The avaEven if several logistic and biological limitations are encountered at the present moment, liquid biopsies will more likely become a fundamental tool in the management of CRC patients in all stages of disease-related interventions. Evaluation of ctDNA levels in patients with stage II CRC has led to a decrease in adjuvant chemotherapy administration while maintaining a favorable recurrence-free survival (DYNAMIC II study) . AdditioDespite the implementation of extensive programs designed to diagnose CRC in the early stages, the adherence of the general population to screening protocols remains unsatisfactory. Liquid biopsy comes as a novel, minimally invasive tool, adequate for early diagnosis of malignancy while also attempting to overcome the limitation showed by traditional CRC screening and tissue sampling methods. Research has proved that liquid biopsy analytes and biomarkers offer valuable information regarding carcinogenesis and could indeed single out individuals at risk for developing CRC or those presenting early-stage CRC otherwise undetected during conventional screening tests.Since FDA has taken the necessary steps to approve CellSearch System for CTC detection and enhancement during clinical studies, the scientific community could soon implement the test in everyday clinical practice. In addition, studies have identified numerous methylation markers indicative of malignancy. In this regard, the detection of SEPT9 gene methylation in DNA fragments derivative from tumor masses is the most widely explored sequence and therefore experiences more promising results. As a result of thorough research, the SEPT9 methylation model comes within reach of validation for current practice, with tests such as Epi proColon expressing significant diagnostic values for CRC early detection. Several extensively researched miRNAs are also approaching clinical utility in everyday practice. miRNA-92a proves relevant sensitivity and specificity values in detecting early CRC cases, as well as advanced adenomas, while panels including multiple miRNAs show improved accuracy when compared to single markers. Additionally, exosomal miRNA-23a has been shown to differentiate patients with early-stage disease with high accuracy, indicating that protocols defining its clinical applicability could be imminent.However, in order to successfully isolate compelling biomarkers, blood samples require complex manipulation techniques that often show unsatisfactory efficiency and prove to be time-consuming and costly. Studies conducted thus far have demonstrated encouraging accuracy, yet further research is critical in order to validate liquid biopsy as a screening and early diagnostic technique. Furthermore, the utility of liquid biopsies in the era of precision medicine is an important frontier that demands thorough inquiry."}
+{"text": "Elder abuse by family caregivers is an often-overlooked phenomenon that affects many older adults. Especially, retirement-aged children caring for their oldest-old parents with dementia may be at greater risk of engaging in harmful or abusive behaviors, given their own age-related health issues and other competing caregiving demands. Most of the elder abuse literature has focused on general demographic predictors of elder abuse, regarding the caregiver, care recipient, and the care environment. Less attention has been paid towards relationship factors, which may play a large role among these parent-child dyads. This study examined how relationship factors are associated with potentially harmful caregiver behaviors , which have been identified as \u201cearly warning signs\u201d for elder abuse. Relationship factors of interest include positive and negative relationship quality measured by caregivers\u2019 mean scores on the support and conflict subscales on the Quality of Relationship Inventory (QRI). We conducted in-depth interviews with 88 caregivers (65+) who are caring for their parents with dementia (90+) as the part of the Boston Aging Together Study. Regression models revealed that relationship conflict was significantly associated with higher levels of PHCB, accounting for caregiver, care recipient, and care environment characteristics. The creation of screeners to identify \u201chigh conflict\u201d care dyads could prove useful in the early detection and intervention of potential elder abuse cases, given that caregivers may be more willing to report negative aspects of their relationship  than more obviously harmful or abusive behaviors."}
+{"text": "Vascular risk factors including hypertension, diabetes and dyslipidaemia promote diverse pathological mechanisms in the brain leading to cerebral hypoperfusion and ultimately cognitive decline in people. Medial temporal, medial frontal and anterior cingulate atrophy has been closely associated with diabetes and medial temporal lobe atrophy is associated with hypertension in people with Alzheimer\u2019s disease (AD).To assess if hypertension, diabetes and dyslipidaemia have differential effects on different brain locations using brain imaging in people with AD.18F] fluorodeoxyglucose- positron emission tomography (FDG-PET) data of 970 participants from two large Phase III multi-centre clinical trials of a novel tau aggregation inhibitor drug Leuco-Methylthioninium (LMTX)meeting research criteria for mild to moderate AD. Vascular risk factor data including hypertension, diabetes and dyslipidaemia were collected and quantification of FDG PET hypo-metabolism was done by calculating Standardized Uptake Value Ratio(SUVR).The current study is based on [Hypertension, diabetes and dyslipidaemia were found to have differential effects on brain locations in people with AD. When people with hypertension, diabetes and dyslipidaemia were compared to those without, mean SUVR was increased significantly in both left and right parietal and occipital lobes and decreased in left and right anterior cingulate gyri in hypertensives. SUVR was significantly higher in both left and right temporal lobes in diabetics andlower in both left and right anterior cingulate gyri in people with dyslipidaemia.Vascular risk factors including hypertension, diabetes and dyslipidaemia have differential effects on different brain regions, measured using SUVR analysis of FDG-PET.The FDG-PET data was taken from participants of two large phase III clinical trials sponsored by TauRx Therapeutics (Singapore). TauRx Therapeutics has contributed towards my studentship during my PhD but the data related to drug used in the clinical tria"}
+{"text": "Novel opportunities to examine how life experiences connect to health and mortality through biological aging have increased due to the affordability of genomic analysis. Although epidemiological studies suggest associations between stress and accelerated biological aging, most if not all measures in the past have been global, data cross-sectional, and from primarily white samples. As part of a completed measurement study, a diverse sample  provided detailed stress measures, including EMA and lifetime stress assessments, and consented to future analysis of their blood samples. We successfully used decade-old blood samples to estimate methylation-based epigenetic clocks and examined them within the context of various stress measures as a preliminary phase of a future longitudinal study. Additional whole genome sequencing will also allow for future work that incorporate continuous measures of genomic ancestry when examining lifetime discrimination-related stress, rather than simply testing for demographic group differences."}
+{"text": "Electrocardiography and high-sensitivity cardiac troponin testing are routinely applied as the initial step for clinical evaluation of patients with suspected non-ST-segment elevation myocardial infarction. Once diagnosed, patients with non-ST-segment elevation myocardial infarction are commenced on antithrombotic and secondary preventative therapies before undergoing invasive coronary angiography to determine the strategy of coronary revascularisation. However, this clinical pathway is imperfect and can lead to challenges in the diagnosis, management, and clinical outcomes of these patients. Computed tomography coronary angiography (CTCA) has increasingly been utilised in the setting of patients with suspected non-ST-segment elevation myocardial infarction, where it has an important role in avoiding unnecessary invasive coronary angiography and reducing downstream non-invasive functional testing for myocardial ischaemia. CTCA is an excellent gatekeeper for the cardiac catheterisation laboratory. In addition, CTCA provides complementary information for patients with myocardial infarction in the absence of obstructive coronary artery disease and highlights alternative or incidental diagnoses for those with cardiac troponin elevation. However, the routine application of CTCA has yet to demonstrate an impact on subsequent major adverse cardiovascular events. There are several ongoing studies evaluating CTCA and its associated technologies that will define and potentially expand its application in patients with suspected or diagnosed non-ST-segment elevation myocardial infarction. We here review the current evidence relating to the clinical application of CTCA in patients with non-ST-segment elevation myocardial infarction and highlight the areas where CTCA is likely to have an increasing important role and impact for our patients. It accounts for 6% of all Emergency Department attendances in the UK, resulting in approximately 350,000 hospitalisations each year. In contemporary practice, the application of high-sensitivity cardiac troponin assays for the diagnosis of myocardial infarction is central to clinical pathways for acute chest pain. This has resulted in marked improvements in the detection of not only myocardial infarction but also myocardial injury, substantially altering the prevalence of the diagnoses of unstable angina and myocardial infarction. Moreover, high-sensitivity cardiac troponin assays can expedite the exclusion of myocardial infarction through so-called \u2018rule-out\u2019 pathways. Indeed, less than one in five patients are ultimately diagnosed with an acute coronary syndrome. However, because of their high sensitivity, these assays also have issues of specificity, and a large proportion of cardiac troponin elevations are unrelated to atherosclerotic plaque disruption or even not myocardial infarction.Acute chest pain is one of the commonest presentations to the Emergency Department, with half of the patients subsequently being hospitalised for assessment of suspected acute coronary syndrome. Furthermore, neither cardiac troponin concentration thresholds nor background cardiovascular risk factors are sufficient to identify underlying mechanisms of myocardial injury nor determine the subtypes of myocardial infarction. Therefore, invasive coronary angiography plays a pivotal role in the management of high-risk patients with acute chest pain, including those with cardiac troponin elevation.The differentiation between the various mechanisms responsible for myocardial injury and distinctive subtypes of myocardial infarction is critical because those with a classic or Type 1 myocardial infarction attributable to atherosclerotic plaque disruption are more likely to benefit from intensive pharmacotherapy and coronary revascularisation. Interestingly, only a half or less of patients admitted with cardiac troponin elevation are diagnosed with Type 1 myocardial infarction. Moreover, CTCA is cost-effective and reduces length of stay in patients with acute chest pain and without cardiac troponin elevation. To exclude underlying obstructive coronary artery disease, the European Society of Cardiology guidelines recommend CTCA for those with chronic coronary syndrome and a lower likelihood of the presence of haemodynamically significant stenosis, and for those with suspected acute coronary syndrome and a normal or inconclusive cardiac troponin concentration. However, it remains unclear whether patients with non-ST-segment elevation myocardial infarction would also benefit from CTCA by improving their downstream management and treatment. This review will examine the latest advances in CTCA in patients with acute chest pain, discuss the potential application of CTCA in those with suspected non-ST-segment elevation myocardial infarction, and highlight potential future developments in this area.Computed tomography coronary angiography (CTCA) has diagnostic accuracy and prognostic performance comparable to invasive coronary angiography in the diagnosis of obstructive coronary artery disease. It is associated with enhancing clinical diagnosis, better targeting of treatments, and improving clinical outcomes in patients with stable chest pain. Finally, an elevation in cardiac troponin in the absence of symptoms or signs of ischaemia is termed myocardial injury and can be acute  or chronic (persistently elevated). Although non-ischaemic aetiologies account for the majority of cardiac troponin elevations, differentiating and classifying myocardial injury and myocardial infarction are not always straightforward even among a panel of experts with pre-specified guidance.Any elevation of a cardiac troponin concentration above the 99th centile upper reference limit defines myocardial injury. Under such a pre-requisite, myocardial infarction is diagnosed by a rise and fall in cardiac troponin in the context of clinical symptoms or electrocardiographic signs suggestive of myocardial ischaemia. Based on underlying pathophysiology contributing to oxygen supply\u2013demand imbalance, myocardial infarction is further subclassified into five types: atherothrombosis (Type 1), acute mismatch between oxygen supply and demand unrelated to atherosclerotic plaque disruption (Type 2), cardiac death presumably due to myocardial ischaemia (Type 3), and consequences of coronary procedures (Types 4 and 5). Currently, cardiac magnetic resonance imaging is recommended in patients with cardiac troponin elevation of undetermined aetiology. Based on the pattern of injury and dysfunction, it may distinguish myocardial infarction from myocardial injury, or alter a location of the infarct-related artery in non-ST-segment elevation myocardial infarction. However, the pattern of myocardial injury on imaging is not always specific for a disease or pathophysiological process, and the availability of cardiac magnetic resonance imaging service is limited.The presence of coronary atherosclerosis is a pre-requisite for Type 1 myocardial infarction and a common observation in Type 2 myocardial infarction. Although assessing coronary artery anatomy may aid in the distinction between myocardial injury and myocardial infarction, invasive coronary angiography has many limitations, especially when the infarct size is small. In those with cardiac troponin elevation in the absence of obstructive coronary artery disease, CTCA has greater sensitivity for the detection of atherosclerotic plaques and the identification of the infarct-related artery than invasive coronary angiography. Conversely, CTCA demonstrates that three-quarters of patients with cardiac troponin elevation and low clinical suspicion for acute coronary syndrome have no or minimal atherosclerotic plaques. Consequently, the likelihood of Type 1 myocardial infarction is extremely low when all coronary arteries are free from atherosclerotic plaques. Finally, it also offers an opportunity to evaluate other cardiothoracic structures and recognise alternative causes of myocardial injury. Therefore, CTCA provides important information to help guide the diagnosis and classification of aetiologies for myocardial injury  trial. In this trial, 1023 out of 2147 patients with non-ST-segment elevation acute coronary syndrome  underwent CTCA before invasive coronary angiography. Using invasive coronary angiography as the gold standard, the negative-predictive value for CTCA to exclude any diameter stenosis \u226550% was 91%. Among 24 patients who were falsely excluded by CTCA, only three had a lesion with diameter stenosis \u226550% in a major epicardial coronary artery by invasive coronary angiography. The positive-predictive value for CTCA to identify diameter stenosis \u226550% was 88%. Among 92 patients who were falsely included by CTCA, 17 had a non-diagnostic scan and 19 had previous coronary stenting. The negative-predictive value for patients with cardiac troponin elevation, an ischaemic electrocardiographic change, and a GRACE score >140 was 89%, 95%, and 95%, respectively. The overall negative- and positive-predictive values of CTCA remained similar when considering diameter stenosis \u226570% as the cut-off. Thus, CTCA has very similar diagnostic performance to invasive coronary angiography in the setting of non-ST-segment elevation myocardial infarction. It has excellent negative-predictive value and rarely misses an obstructive atherosclerotic lesion in a major epicardial coronary artery.CTCA has excellent diagnostic performance compared to invasive coronary angiography in patients with stable chest pain and a low-to-intermediate pre-test probability of coronary artery diameter stenosis \u226550%.Non-ST-segment elevation myocardial infarction represents three-quarters of all contemporary myocardial infarctions, but many do not have obstructive coronary artery disease at the time of invasive coronary angiography. Implementation of CTCA was associated with a slight increase in the immediate use of invasive coronary angiography. However, around 50% of patients were directly discharged from the Emergency Department after CTCA, and fewer patients required subsequent non-invasive functional testing for myocardial ischaemia, resulting in shorter lengths of stay and a reduced cost at the Emergency Department. Similarly, compared with routine functional ischaemia testing, CTCA was associated with a higher rate of invasive coronary angiography and subsequent coronary revascularisation but again shorter lengths of stay.Prior to the advent of high-sensitivity cardiac troponin testing, randomised controlled trials of low-risk patients with acute chest pain reported that rates of invasive coronary angiography and coronary revascularisation within usual clinical care were low at less than 6 and 3%, respectively .42 ImpIn the era of high-sensitivity cardiac troponin testing, three randomised controlled trials have evaluated the clinical effectiveness of CTCA in patients presenting with suspected or diagnosed non-ST-segment elevation myocardial infarction . The Bet In the overall RAPID-CTCA trial population, the rate of invasive coronary angiography was lower with CTCA than with standard of care (54% vs \u200961%) although there was no difference in the rates of coronary revascularisation. For those with cardiac troponin elevation in the RAPID-CTCA trial, the findings remained consistent, suggesting CTCA allows for the better selection of patients for coronary revascularisation even in higher risk patients. In the CARMENTA trial, both cardiac magnetic resonance imaging and CTCA reduced the proportion of patients referred to invasive coronary angiography during index hospitalisation  and at one year (88 and 70% vs \u2009100%). In contrast, the diagnostic yield for the presence of diameter stenosis \u226570% was greater with CTCA than with cardiac magnetic resonance imaging or standard of care . Thus, these three trials demonstrate that CTCA reduces the requirement for invasive coronary angiography without affecting the use of coronary revascularisation especially in patients with suspected non-ST-segment elevation myocardial infarction. This has implications for resource management in hospitals where CTCA can help efficiently identify those who require invasive coronary angiography and access to coronary revascularisation.Reflecting the lower risk trial population, only a minority of patients in the BEACON trial underwent invasive coronary angiography (13\u201317%) or coronary revascularisation (7\u20139%), and the 30-day rates of these procedures were unaffected by CTCA.There is always a concern that the introduction of new tests will lead to so-called test inflation where new or incidental findings will lead to further testing. Indeed, in low-risk and asymptomatic populations, this is an inherent concern. However, in general, CTCA was associated with a reduced need for downstream or layering of testing in patients with non-ST-segment elevation myocardial infarction. In keeping with the rates of invasive coronary angiography, CTCA was associated with a reduced requirement for downstream non-invasive ischaemia testing. This was seen across all three trials and resulted in similar lengths of stay. Overall, these trials would suggest that CTCA has no or minimal impact on length of stay but does reduce the need for downstream non-invasive ischaemia testing without impacting on overall healthcare costs  in the RAPID-CTCA trial and 0.64  in the CARMENTA trial.Downstream clinical event rates are clearly determined by the length of follow-up and the risk of patients included in the trials. The follow-up duration of the BEACON trial was 30 days, and there was only one death and four possible recurrent acute coronary syndromes in 500 patients. The one-year event rate of death or myocardial infarction was comparable between the RAPID-CTCA (6%) and the CARMENTA (4%) trials. Nevertheless, patients with cardiac troponin elevation in the RAPID-CTCA trial appeared to have the highest risk as the one-year rate of death or myocardial infarction reached 8%.Overall, contemporary trials enrolling higher risk patients including those with non-ST-segment elevation myocardial infarction have suggested that early CTCA can lead to accelerated management and tailored investigations and treatments but does not have a major impact on near- and short-term major adverse cardiovascular events. The high sensitivity and negative-predictive value of high-sensitivity cardiac troponin assays have meant that there is little scope for CTCA to identify unrecognised cases of non-ST-segment elevation myocardial infarction. Thus, there is no opportunity to prevent recurrent immediate or intermediate clinical events for those already diagnosed with non-ST-segment elevation myocardial infarction. However, CTCA does have a role in identifying those with cardiac troponin elevation who do not have Type 1 myocardial infarction and thereby improves on specificity for the diagnosis of non-ST-segment elevation myocardial infarction. However, those clinical variables may not always represent a target that could be modified to improve outcomes, and the recommended risk scores and models do not always have good long-term discriminative performance. In contrast, cardiac imaging can potentially identify treatable targets, recommending treatment selection, as well as providing more powerful risk stratification.Initial risk stratification is essential in the clinical pathway for non-ST-segment elevation myocardial infarction in order to allocate appropriate therapies proportionate to the projected risk. Currently recommended risk stratification schemes using clinical variables offer good predictive value for near- and short-term outcomes. a finding that was recently reaffirmed in the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial. For patients with suspected or diagnosed non-ST-segment elevation myocardial infarction, similar excellent risk prediction is seen with CTCA. In the VERDICT trial, the long-term (a median of 4.2 years) follow-up of 978 patients who underwent CTCA suggested that the presence of diameter stenosis \u226550% by CTCA was associated with an increased risk of major adverse cardiovascular events independent of cardiac troponin elevation. In addition, the presence of diameter stenosis \u226550% in left main coronary artery, proximal left anterior descending artery, or two or more vascular territories by CTCA identified patients at the highest risk of long-term adverse outcomes. Finally, among those without diameter stenosis \u226550% by CTCA, the subsequent findings of invasive coronary angiography did not further distinguish patients at increased risk.In patients with stable chest pain, CTCA-defined risk stratification is superior to functional testing for myocardial ischaemia, On the other hand, most cardiac troponin elevations are related to either Type 2 myocardial infarction or myocardial injury. Again, the differentiation between Type 1 myocardial infarction, Type 2 myocardial infarction, and myocardial injury can be challenging, and the optimal investigations and treatments for these conditions remain to be established. This has led to the design of several clinical studies investigating the use of CTCA in patients with suspected or diagnosed non-ST-segment elevation myocardial infarction  is currently recruiting patients with intermediate risk and a cardiac troponin concentration within three times upper reference limit to evaluate the effect of coronary calcium scoring on diagnosis and management for patients in the observe zone. Another two studies, the Coronary CT Angiography for Improved Assessment of Suspected Acute Coronary Syndrome With Inconclusive Diagnostic Work-up  and the Prospective RandOmised Trial of Emergency Cardiac CT  will throw light on the effectiveness of CTCA in patients with a \u2018non-diagnostic\u2019 cardiac troponin concentration under the current clinical pathway.The atherosclerotic plaque burden measured by calcium score is a simple gauge for long-term cardiovascular outcomes independent of diameter stenosis, Beyond qualitative assessment, semi-automated quantification allows for a reproducible and detailed breakdown of atherosclerotic plaque morphology  study showed that two-thirds of patients with Type 2 myocardial infarction had coronary artery disease of any severity, of which half had not been identified previously. In addition, many of them were not treated with preventative therapies, suggesting missed treatment opportunities. Further substudies of the DEMAND-MI study and the DEFINing the PrEvalence and Characteristics of Coronary Artery Disease Among Patients With TYPE 2 Myocardial Infarction Using CT-FFR  study will use CTCA-based techniques to explore the prevalence of coronary artery disease, haemodynamically significant stenosis, and plaque characteristics among patients with Type 2 myocardial infarction. This information will increase our understanding of pathogenesis of Type 2 myocardial infarction and suggest potential treatment opportunities.Additional computational fluid dynamics and advanced molecular imaging may enhance the identification of adverse features that are culprit for incident acute coronary syndrome. the specificity of CTCA in discriminating anatomical (\u226550% diameter stenosis) or functional  obstruction remains imperfect. Fractional flow reserve derived from CTCA is a promising approach that improves discrimination of those at higher risk for future events. However, its use has not resulted in further improvement of major adverse cardiovascular events in patients with stable chest pain. The CArdiac cT in the treatment of acute CHest pain-2 (CATCH-2) trial showed that additional computed tomography perfusion imaging further reduced the utilisation of invasive coronary angiography in low-risk patients with acute chest pain, but it was underpowered to evaluate clinical outcomes. These findings are not definitive, and the role of CTCA-derived fractional flow reserve or computed tomography myocardial perfusion remains to be established in non-ST-segment elevation myocardial infarction. Ultimately, any advanced computed tomography-based functional assessment will need to demonstrate incremental diagnostic and prognostic value over CTCA in the value-based health care.Although CTCA is excellent at identifying normal coronary arteries and avoiding unnecessary invasive coronary angiography, Thus, the greatest opportunity for CTCA to improve long-term clinical outcomes in those with acute chest pain may be in those who have myocardial infarction excluded but may still be at a high risk of future long-term cardiovascular events. Two ongoing randomised controlled trials, the Randomized Evaluation of Coronary Computed Tomographic Angiography in Intermediate-risk Patients Presenting to the Emergency Department With Chest Pain  and the Troponin in Acute Chest Pain to Risk Stratify and Guide EffecTive Use of Computed Tomography Coronary Angiography  trials, will determine the effectiveness of CTCA on long-term (\u22653 years) major adverse cardiovascular events in such patients.The principal advantage of CTCA is to identify unrecognised coronary atherosclerosis regardless of stenosis severity as an opportunity to apply preventative interventions, such as antiplatelet and statin therapies. The benefit of such interventions take many years to accrue as demonstrated in patients with stable chest pain.In patients with suspected non-ST-segment elevation myocardial infarction, electrocardiography and high-sensitivity cardiac troponin testing will remain the initial step for clinical evaluation, and invasive coronary angiography is still the routine clinical tool to determine the strategy of coronary revascularisation. CTCA has an increasingly important role in avoiding unnecessary invasive coronary angiography and reducing downstream non-invasive functional testing for myocardial ischaemia especially among those with low or intermediate risk. Moreover, CTCA is an excellent gatekeeper for the cardiac catheterisation laboratory, provides complementary information for patients with myocardial infarction in the absence of obstructive coronary artery disease, and can highlight alternative or incidental diagnoses for patients with non-ST-segment elevation myocardial infarction. There are several ongoing studies evaluating CTCA and its associated technologies that will define and potentially expand its application in patients with suspected or diagnosed non-ST-segment elevation myocardial infarction."}
+{"text": "Men using cholesterol-lowering statin medications have been found to have lower risks of both advanced and fatal prostate cancer in multiple registry-based studies and prospective cohort studies. Statin use has also been associated with longer survival among men already diagnosed with prostate cancer. Mechanisms responsible for purported anti-cancer effects of statins are not well understood but may offer insight into prostate cancer biology.We summarise epidemiological data from studies of statins and prostate cancer and discuss to what extent these findings can be interpreted as causal. Additionally, lipid-mediated and non-lipid-mediated mechanisms that may contribute to potential anti-cancer effects of statins are reviewed. Finally, we consider treatment settings and molecular subgroups of men who might benefit more than others from statin use in terms of prostate cancer-specific outcomes.Data from prospective observational studies generally reported a lower risk of fatal prostate cancer among statin users. There is some evidence for serum cholesterol-lowering as an indirect mechanism linking statins with advanced and fatal prostate cancer. Window-of-opportunity clinical trials show measurable levels of statins in prostate tissue highlighting potential for direct effects, whilst observational data suggest possible statin-driven modulation of prostate microenvironment inflammation. Additionally, emerging data from registry studies support a potential role for statins within the context of androgen deprivation therapy and anti-androgen treatment.Prospective and registry-based studies support a lower risk of advanced and fatal prostate cancer in statin users relative to non-users, as well as better outcomes among prostate cancer patients. The few randomised-controlled trials conducted so far have short follow-up, lack identified molecular subgroups, and do not provide additional support for the observational results. Consequently, additional evidence is required to determine which men may experience greatest benefit in terms of prostate cancer-specific outcomes and how statin effects may vary according to molecular tumour characteristics. Statins are competitive antagonists of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, whose activity is rate-limiting for the biosynthesis of cholesterol and derivatives via the mevalonate pathway. While the evidence supporting the role for statins in cardiovascular disease prevention is unequivocal , mountinThis review discusses epidemiological evidence supporting a potential role for statins in prostate cancer prevention, particularly prevention of fatal disease. Whilst underlying mechanisms behind statin effects in cancer are currently unclear, we review evidence from epidemiological studies that may support existing theories and provide greater understanding of prostate cancer biology. This is followed by an evaluation of data exploring the timing of statin use alongside, and potential synergy with, androgen deprivation therapies (ADT). Finally, we review current data regarding which patients may benefit more from statin use. Our companion review discusses mechanistic evidence of anti-tumour effects of statins from laboratory studies .Following the first report of a stronger association of pre-diagnosis statin use with advanced, metastatic and fatal prostate cancer , the majTwo prospective cohort studies addressed this question by following cancer-free men long term. Findings from the Health Professionals Follow-up Study, with 801 fatal prostate cancers diagnosed amongst 44,126 men during 24 years of follow-up, showed a 24% lower rate of fatal prostate cancer in pre-diagnosis statin users vs. non-users (hazard ratio (HR) 0.76; 95% CI 0.60\u20130.96) [In addition, registry-based studies have explored effects of pre- and post-diagnosis statin use on prostate cancer-specific mortality. A UK registry study reported that the association between post-diagnosis statin use and prostate cancer-specific mortality was strongest amongst pre-diagnosis statin users  . In contGiven that any clinical trial of statins is more feasible among men already diagnosed with prostate cancer, it is informative to evaluate the effect of post-diagnosis statin use on prostate cancer-specific outcomes. Indeed, all three aforementioned studies reported similar magnitudes of association between post-diagnosis statin use and reduced prostate cancer-specific mortality. Specifically, the Finnish Randomised Study of Screening for Prostate Cancer showed that post-diagnosis statin use was associated with a 20% (95% CI 0.65\u20130.98) lower rate of prostate cancer-specific mortality, with stronger associations among those using higher doses of statins and for longer durations . The magBefore taking next steps, a central question is whether bias from confounding and other sources may affect reported associations between statin use and prostate cancer outcomes as they do in studies of other commonly used medications . For exaAppropriate analytic methods as well as prospective study designs help reduce potential sources of bias. Prospective cohort studies address confounding through adjustments for detailed measures of modifiable and non-modifiable risk factors for prostate cancer and competing causes of death, with registry studies using medical diagnoses and medications as proxies. As it is ultimately unknowable if confounding and bias was successfully controlled in observational studies, results from existing randomised trials need to be considered.The Cholesterol Treatment Trialists\u2019 Collaboration pooled data from 27 major randomised-controlled trials of statin therapy, including 1877 incident prostate cancers and 211 prostate cancer deaths over a median follow-up of 4.8 years, with null results  . A doublIdentification of mechanisms linking statins and prostate cancer could provide a biological rationale to support epidemiological associations. Unfortunately, the mechanisms responsible for purported statin anti-cancer effects are still unclear though two broad categories have been proposed: lipid-mediated and non-lipid-mediated, for which we have summarised the epidemiological evidence below. Our companion review considers mechanistic evidence from laboratory studies .Statins have a pronounced effect on serum lipid levels, reducing low density lipoprotein (LDL) cholesterol by 30\u201360%, total cholesterol by 23\u201328% , and triIn a meta-analysis of six studies, the association between high versus low categories of total serum cholesterol and high-grade or advanced prostate cancer  tended to be slightly more pronounced than for total prostate cancer  . SeveralAn additional consideration is that serum lipid levels may not reflect tumour lipid levels. In a randomised-controlled trial, 160 men were treated with radical prostatectomy after randomisation to high-intensity atorvastatin (80\u2009mg daily) or placebo for at least 28 days . MetabolOne approach to teasing apart the mechanism is to compare associations of statin versus non-statin cholesterol-lowering drugs with prostate cancer, though this can be challenging due to the overlap in use of statin and non-statin cholesterol-lowering medications and therefore necessitates large studies. A registry study from the Canadian province of Saskatchewan  found thSeveral studies have found measurable statin levels within the prostate tissue itself. The ability of statins to access the prostate supports the potential for direct physiological effects of statins unrelated to systemic lowering of circulating cholesterol and other lipid species. Two window-of-opportunity trials measured statin concentrations in prostate tissue after roughly 4 weeks of statin treatment. A Canadian pilot trial randomised men with localised prostate cancer to 80\u2009mg fluvastatin for 4\u201312 weeks prior to their scheduled radical prostatectomy. Fluvastatin was detected in prostate tissue of 10 (36%) of 28 patients evaluated, and mean intraprostatic fluvastatin concentration in these ten patients was 9.7\u2009ng/g or 24\u2009nM, while mean serum fluvastatin levels were tenfold higher (200\u2009nM) . AnotherReduction of systemic and local inflammation is one of the best described non-cholesterol-lowering effect of statin use. Results from secondary analyses of cardiovascular disease clinical trials demonstrate that statins lower plasma levels of the inflammatory biomarker C-reactive protein , 35 in aTwo prostate cancer chemoprevention trials, REDUCE and the Prostate Cancer Prevention Trial (PCPT), provided opportunities for assessing the association of statin use with benign prostate inflammation among men undergoing study-mandated, PSA-independent prostate biopsies. REDUCE, which recruited men with elevated baseline PSA but a negative prostate biopsy, found lower risk of chronic histological inflammation of negative biopsies in statin users versus non-users  and suggested lower odds of severe acute histological inflammation  . By contA window-of-opportunity clinical trial which administered atorvastatin to 158 men scheduled to undergo radical prostatectomy in Finland examined intraprostatic inflammation as a secondary endpoint. Among men with high-grade disease randomised to atorvastatin, histological inflammation score was slightly lower . FinallyAlthough potential mechanisms discussed above are grouped into lipid-mediated and non-lipid-mediated categories, it is important to note that statins have pleiotropic effects, and so these may not be mutually exclusive. Mechanisms are challenging to tease apart in epidemiological studies, and country-specific prescribing patterns and differences in treatment protocols may hinder direct comparison of findings from various studies.One major consideration is whether it is appropriate to analyse statins together as a class or whether their effects and mechanisms need to be considered according to the statin type or subgroup. While many studies reported the prevalence of use of various statin types and doses (previously summarised in ), most wIn addition to statin type, few observational studies have been able to accurately account for variations in serum cholesterol levels throughout statin therapy. The previously mentioned ARIC study by Mondul et al. performed a stratified analysis by pre-statin serum cholesterol level  and found similar associations between statin use and fatal prostate cancer in both groups . MurtolaGiven a cardiovascular risk profile that places most men with prostate cancer at high cardiovascular event risk , these mAs a first step towards answering this question, several studies explored the association between post-diagnosis statin use and prostate cancer-specific mortality, stratified by tumour characteristics at diagnosis. An analysis of the Health Professionals Follow-up Study reported that post-diagnosis statin use was not associated with lower prostate cancer-specific mortality overall , but found an inverse association among men diagnosed with higher stage prostate cancer , not present among men with stage T1 disease  . An obseTMPRSS2:ERG fusion (ERG) status [Examining associations with subgroups defined by pathological and molecular features could highlight not only the most statin sensitive prostate tumours but could also bring to light new molecular targets that may be susceptible to other treatment modalities. Efforts to identify molecular biomarkers of prostate tumours that may be particularly susceptible to statins are now underway, which would enable more precise identification of men predicted to benefit. Within the prospective Health Professionals Follow-up Study, we reported a lower risk of PTEN-null prostate cancer among cancer-free men who used statins compared to non-users  and no association between statin use and PTEN-intact prostate cancer  . The ass) status . As ERG ) status , height ) status , physica) status , and lyc) status  further As statins are associated with reduced risk of advanced prostate cancer and androgen deprivation therapy (ADT) is the main treatment for this patient subgroup, it is not surprising that recent investigations have focused on statins in the context of patients managed with ADT Table\u00a0. A 2017 By inhibiting androgen synthesis in the testes, ADTs lower systemic androgen levels, limiting androgen signalling pathways driving prostate cancer survival and proliferation. However, tumour progression inevitably occurs in spite of low availability of circulating androgens through a variety of documented mechanisms including intratumoral androgen synthesis from cholesterol . As suchWith a view to understanding which point in clinical progression that the tumour may be most sensitive to statins, a number of studies reporting lower prostate cancer-specific mortality in statin users Table\u00a0 performeAside from blocking intratumour cholesterol ester accumulation, which may primarily affect advanced tumours with the necessary enzymatic machinery to synthesise intratumoral androgens, an alternative hypothesis as to why statins may synergise with ADT lies in their potential effect on adrenal androgens such as dehydroepiandrosterone (DHEAS), a precursor to the more potent dihydroxytestosterone (DHT) and testosterone. As adrenal androgens continue to be synthesised despite orchiectomy or pharmaceuticals that modulate gonadotropin-releasing hormone, which largely target testicular androgen synthesis, they are thought to be one of the mechanisms of tumour resistance to ADT . A pre-sSecond generation anti-androgens, including abiraterone acetate, interfere with the androgen signalling axis in multiple organs including the adrenal glands as well as the prostate itself. As such, the aforementioned downregulation of adrenal androgens by statins suggests a mechanism whereby statins could complement downregulation of adrenal androgens by abiraterone to improve prostate cancer outcomes. As statins compete with abiraterone for SLCO-mediated influx there were initial concerns that statins may be antagonistic to abiraterone and therefore interfere with treatment efficacy. However, a US hospital-based cohort study found a trend towards longer duration of abiraterone response among men with CRPC using statins  . The retTo date, the observational data summarised in our review shows a narrowing of focus for the promise of statin for prevention of all prostate cancer to prevention of fatal prostate cancer. Results showing an inverse association between statins and fatal prostate cancer risk are promising. While this is particularly encouraging given these patients currently have limited effective treatments and shorter survival times, biomarkers may help identify and subsequently target the molecular subgroups that are most likely to benefit from statin therapy. Given that statins are comparatively safe, in addition to support for improved prostate cancer-related outcomes in statin users, it could be argued that most men with prostate cancer should receive a statin. A central consideration here is that men with prostate cancer, particularly those receiving ADT , are at It is critical that these questions be evaluated using randomised-controlled trials. With advances in molecular profiling of prostate cancer, resulting biomarkers may aid in more efficient selection of participants for clinical trials of statins as well as become appropriate intermediate endpoints in such trials.As one of the world\u2019s most prescribed medications, statins are well-established and clinically safe drugs. For prevention and treatment of prostate cancer, as summarised in this review, the most pronounced and robust associations have been observed between statin use and outcomes related to advanced prostate cancer. A key consideration is the high burden of cardiovascular disease among men with prostate cancer , 71, witOur review shows that statins are not a cure-all, but the hype surrounding this class of drugs is understandable. Prostate cancer research motivated by potential statin effects has advanced our understanding of prostate cancer biology with regards to both cholesterol and lipid metabolism (see partner review of mechanistic data)  as well With many observational studies supporting the hypothesis that statins may protect against fatal prostate cancer, there is hope that statins could form part of a multipronged therapeutic strategy. Ultimately, the focus should be on testing this hypothesis in patients using randomised-controlled trials. Furthermore, translational research integrating epidemiological data and lab-based investigations could help identify biomarkers of statin sensitivity. Such biomarkers would be beneficial to define molecular subgroups for subsequent examination in observational and trial-based settings."}
+{"text": "Exercise intensity has been suggested to influence acute appetite-regulating gut hormone responses after exercise. High intensity interval training (HIIT) with near maximal to maximal intensity or sprint interval training (SIT) with supramaximal intensity might induce greater effects on gut hormones compared to moderate intensity continuous training (MICT), while current findings were inconsistent regarding the effects of these popular training methods.This systematic review and meta-analysis aimed to synthesis the findings in the literature and explore the impact of exercise modality on acylated ghrelin (AG), glucagon-like peptide-1 (GLP-1) and peptide YY (PYY).After searching the major databases  to find articles published up to May 2022, twelve studies that compared hormone responses to HIIT/SIT and MICT were identified and included in the analysis.A random-effects meta-analysis showed that HIIT/SIT and MICT decreased AG concentration and increased GLP-1 and PYY concentration compared with no exercise control group, while interval training protocols, especially SIT protocols, elicited greater effect sizes in suppressing AG levels at all of the analysed time points and PYY immediately post-exercise compared to MICT.Acute SIT with lower exercise volume appears to be a more advantageous approach to decrease plasma AG concentration and potentially suppress hunger to a greater extent compared to MICT, despite the similar effects of HIIT/SIT compared to MICT in increasing anorectic hormones . Future studies are needed to further investigate the impact of moderators  on the variability of changes in gut hormones after interval trainings."}
+{"text": "Immunization programs are key preventive interventions and have largely contributed to reducing the burden of infectious diseases and decreasing related morbidity, mortality and healthcare costs. The study aimed to investigate coverage regarding diphtheria, tetanus, and acellular pertussis (dTap) - Inactivated Poliomyelitis Vaccine (IPV) and Human Papilloma Virus (HPV) vaccine and attitudes towards vaccinations among undergraduate university students in Southern Italy.This cross-sectional study was conducted among 327 students through an anonymous online questionnaire and included socio-demographic characteristics, attitudes towards vaccinations overall and specifically on dTap-IPV and HPV, reasons for having received or not vaccinations and willingness to receive vaccinations.One third of the students were concerned about serious adverse effects of vaccines and 95% believed that vaccines for uncommon diseases are useless. During adolescence, 89% of the sample received the mandatory dTap-IPV vaccine booster. Among unvaccinated students, 45% were unwilling to get vaccinated against dTap-IPV because they believed not to be at risk of infection (59%) and had lack of recommendation (35.3%). Regarding vaccination against HPV, 67% had received the recommended schedule. Among those who did not receive it, 34% were unwilling to get vaccinated because they did not feel at risk of HPV infection (41%). Interestingly, 16% of the sample disclosed some barriers to access vaccination centers. Moreover, 30% declared that HPV vaccination was discouraged by healthcare professionals (HCPs).Vaccination uptake is worryingly low and national objective coverage seems not still achieved. Likewise, risk perception of vaccine-preventable diseases was low and it seems negatively impact on the intention to get vaccinated. Improving vaccine confidence among HCPs is crucial as they have been shown to have the potential to influence patient vaccination uptake.Skilled communication with a trusted HCP could increase acceptance of vaccine during adolescence and address vaccine hesitancy.Strategies to disseminate information on vaccines should be established to increase mandatory and recommended vaccines coverage."}
+{"text": "The Appalachian region is often characterized by poor health outcomes and economic depression. Health centers (HCs) are community-based and patient-directed organizations that deliver comprehensive, culturally competent, high-quality primary healthcare services in high need areas, including Appalachia, where economic, geographic, or cultural factors can hinder access to healthcare services.The study compares the clinical quality performance in preventive care and chronic disease management between Appalachian HCs and their non-Appalachian counterparts.Using 2015 Uniform Data System (UDS) health center data, bivariate and multivariate linear regression analyses examine the association of Appalachian HC with performance on preventive and chronic care clinical quality measures (CQMs).In the multivariate analysis, patients served at Appalachian HCs are more likely to receive colorectal cancer screening and pediatric weight assessment and counseling than at non-Appalachian HCs. No statistically significant differences in performance observed among other CQMs. The percentage of Medicaid patients and total physician FTEs have positive associations with preventive care in colorectal and cervical cancer screening, pediatric weight assessment and counseling, and tobacco screening and cessation intervention as well as chronic disease management of aspirin therapy for ischemic vascular disease and hypertension control in the multivariate model.Overall Appalachian HCs perform as well as or better than non-Appalachian HCs in delivering preventive and chronic care services. Further examination of clinical quality improvement programs, insurance payer mix, and practice size among Appalachian HCs could advance the replication of clinical quality success for clinics in similar underserved communities. The Appalachian region is a geographically and culturally distinctive region of the U.S. extending from New York to Alabama characterized by largely rural geography and resiliency assets that include strong social cohesion, family ties, social support, and spiritual belief.7Health centers (HCs) are community-based and patient-directed organizations that deliver comprehensive primary health care services and receive federal grant funding from the Health Resources and Services Administration (HRSA). HCs provide services in high-need areas, including Appalachia, where economic, geographic, or cultural factors hinder access to affordable primary care services. Annually, HCs are required to report clinical quality measures (CQMs) into HRSA\u2019s Uniform Data System (UDS). This study uses the national 2015 UDS data to examine the differences in clinical quality performance in preventive care and chronic disease management between the Appalachian HCs and their non-Appalachian counterparts.The HRSA\u2019s 2015 UDS data contain health center organizational-level data for patient sociodemographic, services provision, workforce, clinical quality measures, cost, and revenues.This cross-sectional study examines six preventive care and three chronic care CQMs reported in the UDS. The preventive measures consist of the following:cervical cancer screening: percentage of women aged 21\u201364 years who received timely Pap tests to screen for cervical cancer;colorectal cancer (CRC) screening: percentage of patients aged 50 to 75 years who had appropriate screening for colorectal cancer, which could be a colonoscopy within the last 10 years, a flexible sigmoidoscopy within the last 5 years, or an annual fecal occult blood test (FOBT), including the fecal immunochemical (FIT) test;body mass index (BMI) screening and follow-up plan: percentage of patients aged 18 and older with a documented BMI during the most recent visit or within the 6 months prior to that visit and when the BMI is outside of normal parameters, a follow-up plan is documented;weight assessment and counseling for nutrition and physical activity for children and adolescents: percentage of patients aged 3\u201317 years who had evidence of BMI percentile documentation and who had documentation of counseling for nutrition and who had documentation of counseling for physical activity during the measurement year;tobacco use and screening and cessation intervention: percentage of patients aged 18 years and older who were screened for tobacco use at least once during the measurement year or prior year and who received cessation counseling intervention and/or pharmacotherapy if identified as a tobacco user; andscreening for depression and follow-up plan: percentage of patients aged 12 years and older screened for clinical depression using an age appropriate standardized tool and follow-up plan documented.The chronic disease management clinical quality measures are as follows:aspirin therapy for patients with ischemic vascular disease;blood pressure control (as defined by hypertensive patients with a blood pressure less than 140/90); andrate of uncontrolled diabetes, that is, diabetic patients with a hemoglobin A1c (HbA1c) > 9%.Bivariate and multivariate linear regression analyses examined the association between being an Appalachian health center and performance on preventive and chronic care clinical quality measures. Other covariates in the regression model include patient characteristics, total number of physician full-time equivalent (FTE) as a proxy for practice size, and patient-centered medical home (PCMH) recognition status. HRSA has supported HC\u2019s implementation of PCMH practice transformation to improve clinical quality through effective care coordination and holistic care. Patient characteristics were composed of percentage of racial/ethnic minority patients, percentage of patients at or below 100% of the federal poverty level (FPL), and percentage of Medicaid patients. Statistical analyses were conducted using SAS version 9.3.In In the multivariate linear regression analysis as exhibited in Our findings demonstrate that patients receiving health care in Appalachian HCs experience quality of preventive and chronic care on par with patients served at non- Appalachian HCs. In particular, receiving care at Appalachian HCs is not associated with lower cervical cancer screening rate, which suggests Appalachian HCs are making strides towards addressing risk factors associated with receipt of cervical cancer screening such as lack of routine source of medical care, self-image insecurity, cultural stigma, as well as misperceptions about health and cancer.10Of particular interest are findings of positive associations between Appalachian HC and preventive CQMs of CRC screening and pediatric weight assessment and counseling. The CRC screening CQM performance in Appalachia HCs may reflect targeted clinical quality improvement initiatives by HCs and professional organizations to expand CRC screening modalities beyond colonoscopy, address financial barriers, and enhance trust in patient\u2013provider relationships towards screening recommendation adherence.The primary limitation of this study is that findings from 2015 UDS cross-sectional data do not allow for causal inferences. In addition, the Appalachian HC definition includes any HC with a clinical service delivery site in an Appalachian county, which may potentially lead to the inclusion of primary care service sites in border counties incorporated into CQM data reported at the HC organizational level.Overall, Appalachian HCs perform better than or comparable to their non-Appalachian counterparts in delivering preventive and chronic care services. Additionally, study findings suggest that HCs may be providing effective primary care that helps offset health care related disparities expected in Appalachia communities. In particular, barriers to Appalachian health disparities can be overcome by culturally competent care delivered in organizations such as HCs that utilize PCMH model of care with strong care coordination and case management to improve CQMs in Appalachian communities.What is already known about the subject? Health disparities in the Appalachian region reflect broader trends in rural America, which include higher prevalence of obesity, diabetes, hypertension, cancer mortality, lower life expectancy, and lower adoption of preventive screening.What is added by this report? The Appalachian health centers performed better or comparable than their non-Appalachian counterparts in delivering high quality primary care in preventive and chronic disease management.What are the implications? Future research on clinical quality improvement programs, insurance payer mix, and practice size among Appalachian health centers could advance the replication of clinical quality success for clinics in similar underserved communities."}
+{"text": "Individuals differ in the extent to which they represent their goals as hoped-for versus feared states. We examined the role of such goal representations for how everyday affective experiences and goal pursuit are intertwined. When goals are represented as hoped-for states, we expected stronger associations between daily positive affect and goal pursuit. In contrast, when goals are represented as feared states, we expected stronger associations between daily negative affect (particularly fear) and goal pursuit. We used seven days of repeated daily life assessments from 238 older individuals . At baseline, participants reported three goals they planned to pursue over the study period and the extent to which each goal referred to something they hoped-for or feared. During the daily life assessments, participants reported their current affective states and momentary goal pursuit  three times per day . Multilevel analyses regarding participants\u2019 most salient goal provide initial evidence supporting the expected interactions of goal representations on everyday affect\u2013goal pursuit links. Specifically, individuals with a strong hope-focus in their goals engaged in more goal pursuit when positive affect was up than individuals whose goals were low in hope-focus. In contrast, those with feared goals engaged in more goal pursuit when reporting increased fear. Findings are discussed in the context of the possible selves literature. Future analyses will examine lead-lag effects to address the temporal order underlying affect-goal pursuit associations."}
+{"text": "Despite concerns regarding the risks of ionizing radiation from computed tomography (CT) imaging, the rates of abdominal pelvic CT (APCT) utilization in the emergency department (ED) continues to increase for patients with inflammatory bowel disease (IBD).To determine the factors that drive decisions on when to perform APCT imaging in the ED for patients with IBD and to determine if differences exist between physician specialties.We performed a quantitative, web-based survey between November 2021 and August 2022. Structured questions for Crohn\u2019s disease (CD) and ulcerative colitis (UC) were developed with input from stakeholders in gastroenterology, surgery, and emergency medicine. Surveys were disseminated to Canadian physicians in each of the three specialities through personal emails, and by newsletter from national specialty organizations. Between specialty comparisons were performed by Chi-squared and Fisher exact tests where appropriate.A total of 208 participants responded to our survey: median age 44 years (IQR 37-50), 132 (63%) male, and 141 (68%) in an academic practice. Survey participants included 81 (39%) gastroenterologists, 35 (17%) surgeons and 92 (44%) emergency physicians.There were significant differences between specialties in the perceived rates of positive findings from APCT imaging. In UC, gastroenterologists felt inflammation alone was more common than emergency physicians and bowel obstruction and septic complications less common than surgeons and emergency physicians. In CD, surgeons felt bowel obstructions, septic complications and bowel perforations were more common compared with gastroenterologists and emergency physicians.There were significant differences between specialties in the types of clinical presentations that drove decisions to arrange APCT imaging . In UC, gastroenterologists were less likely to order APCT imaging for diarrhea with rectal bleeding, abdominal pain without peritoneal findings and fever than surgeons and emergency physicians. In CD, there were similar practice patterns between specialities except gastroenterologists were less likely to order APCT imaging for diarrhea with rectal bleeding than surgeons.Our survey identified key differences between physician specialties in the perceived rates of positive findings from APCT imaging and practice patterns of CT utilization. These findings will help to guide the development of future multidisciplinary consensus guidelines for the appropriateness of CT imaging in the ED for patients with IBD.NoneNone Declared"}
+{"text": "Antenatal depression and antenatal anxiety adversely affect several obstetric and foetal outcomes, and increase the rate of postnatal mental illness. Thus, to tackle these challenges the need for social support during pregnancy is vital.This study examined the association between domains of social support and antenatal depressive and anxiety symptoms among Australian women.Our study used data obtained from the 1973\u201378 cohort of the Australian Longitudinal Study on Women\u2019s Health (ALSWH), focusing upon women who reported being pregnant (n=493). Depression and anxiety were assessed using the Center for Epidemiological Studies Depression (CES-D-10) scale, and the 9-item Goldberg Anxiety and Depression scale (GADS) respectively. The 19 item-Medical Outcomes Study Social Support index (MOSS) was used to assess social support. A binary logistic regression model was used to examine the associations between domains of social support and antenatal depressive and anxiety symptoms.After adjusting for potential confounders, our study found that the odds of antenatal depressive symptoms was about four and threefold higher among pregnant women who reported low emotional/informational support  and low social support   respectively compared with their counterpart. In addition, the odds of antenatal anxiety symptoms was seven times higher among pregnant women who reported low affectionate support/positive social interaction .Low emotional support and low affectionate support have a significant association with antenatal depressive and anxiety symptoms respectively. As such, targeted screening of expectant women for social support is essential.No significant relationships."}
+{"text": "Despite efforts by the WHO to support local surveillance strategies in developing countries, there is a lack of robust public health surveillance frameworks. As a result, early infectious disease outbreak detection and response remain a significant challenge for local health systems in low-resource settings such as sub-Saharan African countries. In contrast, the growing digital infrastructure, especially in the mobile phone sector, and the global availability of extensive digital data offer promising solutions to enhance and strengthen epidemiological surveillance. Yet, there is little insight into concepts of utilisation and transfer into local public health practice. Using Tanzania as an example, a novel electronic surveillance and early outbreak alert framework is being developed that links signals on emerging diseases with relevant contextual Open Data for rapid outbreak risk assessment. The concept focuses on haemorrhagic fever diseases, specifically dengue virus disease, which is increasingly spreading in sub-Saharan Africa. A data stack framework forms the core of the system, which augments electronic information on the occurrence of acute haemorrhagic fever syndrome, e.g., collected via mobile phone-based surveillance tools, with openly available socio-ecological context data specific to dengue. Preliminary results on the data and information flow within the surveillance framework are presented and strategies for an automated indicator-based risk assessment for dengue outbreaks will be discussed, supplemented by an agent-based simulation framework to model possible short-term outbreak scenarios. In addition, adequate data inputs, identified through an appraisal of various data sources available for Tanzania, are outlined. The framework could serve as a blueprint for designing locally implementable early warning and decision support systems integrated with existing digital surveillance infrastructure.\u2022\u2002Digital health surveillance and Open Data offer great potential for early outbreak detection and supporting health decisions but require tailored solutions to benefit low-resource settings.\u2022\u2002Building on existing digital surveillance infrastructure, the framework may serve as a blueprint for designing an enhanced surveillance and decision support system for infectious disease outbreaks."}
+{"text": "Coping styles refer to cognitive and behavioral patterns used to manage the demands of stressors. This study aimed to characterize associations between coping styles and cognitive functioning across non-Hispanic Black and non-Hispanic White older adults. Cross-sectional data comes from the Michigan Cognitive Aging Project . Coping styles are measured with COPE inventory. Global cognition was a composite of five cognitive domain factor scores derived from a comprehensive battery. Results show that Black older adults reported more emotion-focused coping than Whites, but there were no differences in problem-focused coping. Less emotion-focused and greater problem-focused coping were each more strongly associated with better global cognition among Black older adults, who showed disproportionately worse cognitive performance in the context of less adaptive coping. Coping style may be a particularly important psychosocial resource for cognitive health among Black older adults who may have less access to compensatory resources than Whites."}
+{"text": "Cell senescence and inflammation are interconnected mediators of aging and age-related disease. Recent advances in molecular and cellular profiling methods and research models are aiding in our ability to decipher mechanisms through which senescent cells drive inflammatory dysfunction, and inversely, to discover mechanisms through which aging immune cells may drive senescence, inflammation, and pathology. This symposium will feature exciting advances that span the emerging conceptual framework of how senescence and inflammation influence mammalian aging. Dr. Birgit Schilling will discuss the use of advanced mass spectrometric methods for profiling the senescent cell proteome, which reveal new insights into protein pathways and mechanisms of aging and disease. Dr. Matt Yousefzadeh will share how endogenous DNA damage can invoke cellular senescence, which enhances inflammation in both a cell autonomous and non-autonomous manner to drive tissue dysfunction and impact health. Dr. Daniel Tyrrell will discuss discovery of a novel population of age-associated CD8 T-cells that enhance local tissue senescence and inflammation and promote atherosclerosis. Dr. Xu Zhang will share a characterization of senescent cells in skeletal muscle using single-cell RNA-sequencing and the potential recruitment of immune cells by senescent fibroadipogenic progenitors. Dr. Marissa Schafer will discuss cell senescence as a mediator of age-related brain inflammatory cell composition and senescent cell targeting as a strategy to prevent cognitive decline. Importantly, discoveries discussed in this symposium may reveal new avenues for therapeutic development, to ultimately improve human healthspan."}
+{"text": "We can understand the ecology and evolution of plant thermal niches through thermal performance curves (TPCs), which are unimodal, continuous reaction norms of performance across a temperature gradient. Though there are numerous plant TPC studies, plants remain under-represented in syntheses of TPCs. Further, few studies quantify plant TPCs from fitness-based measurements , limiting our ability to draw conclusions from the existing literature about plant thermal adaptation. We describe recent plant studies that use a fitness-based TPC approach to test fundamental ecological and evolutionary hypotheses, some of which have uncovered key drivers of climate change responses. Then, we outline three conceptual questions in ecology and evolutionary biology for future plant TPC studies: (i) Do populations and species harbour genetic variation for TPCs? (ii) Do plant TPCs exhibit plastic responses to abiotic and biotic factors? (iii) Do fitness-based TPCs scale up to population-level thermal niches? Moving forward, plant ecologists and evolutionary biologists can capitalize on TPCs to understand how plasticity and adaptation will influence plant responses to climate change. Variation in plant performance across temperatures are illustrated with a thermal performance curve (TPC), where performance peaks at a benign temperature and decreases to zero as temperature becomes cooler or warmer. Thermal performance curves have been useful for understanding evolution and plasticity, especially in response to climate change. However, most plant TPCs in the literature are based on physiological traits of single leaves, rather than individual fitness which would more directly approximate how populations might respond to changes in temperature. We describe what has been done and necessary next steps that utilize TPCs to determine how plants will respond to climate change. Temperature is among the most important global drivers of productivity and biodiversity  to geothThermal performance curves are unimodal, continuous reaction norms of performance, defined as any metric of an organism\u2019s ability to function, across a temperature gradient ; Fig. 1AHere, we convey the value of fitness-based TPCs for addressing key questions in plant ecology and evolutionary biology. By fitness-based TPCs, we mean TPCs that are quantified through performance traits that are measured at the individual level or above . We do not discuss TPCs characterized by short-term, subindividual traits (e.g. photosynthesis) or the physiological or molecular mechanisms underlying such TPCs as these topics are already well-studied (Mollugo verticillata (Mimulus), species with broader TPCs experienced greater temperature variation across their ranges relative to species with narrower TPCs  evolved narrower thermal performance breadth  rely on measurements of the same individuals across multiple temperatures and can take only a few minutes to quantify e.g. , fitnessGiven that these fitness proxies typically do not encompass the full life cycle, a key knowledge gap is whether fitness-based TPCs capture the relationship between temperature and the long-term growth rates of natural populations . M. verticillata. Second, using populations spanning the northern half of the geographic range of M. cardinalis, Two studies have combined species distribution models (SDMs) with TPCs to investigate the hierarchical nature of niche breadth and predict how plant populations and species will respond to climate change. First, Mimulus species with greater genetic variation for thermal tolerance have evolved broader TPCs. They were unable to fit TPCs to each genotype (represented by full-sibling seed families) to evaluate whether species with greater genetic variation for TPC parameters have evolved broader TPCs, because hierarchical TPC models that could simultaneously estimate multiple genotype-level TPCs from a population-level average TPC were not yet available. Rather, they focused on genetic variation for thermal reaction norms at the two lowest and the two highest experimental temperatures. They found that species with broader TPCs had greater among-genotype variation in slopes of reaction norms at both the cold (15\u201320 \u00b0C) and hot (40\u201345 \u00b0C) ends of the temperature gradient. Future work is needed to evaluate whether plant populations have sufficient genetic variation for TPC parameters to respond to climate change, and to further develop modelling approaches that can account for variation at multiple biological levels  is \u22651, indicating demographic stability or growth, whereas a TPC describes a performance metric for a biological entity . While extreme temperature events may drive short-term acclimation responses at the subindividual level (In the strictest sense, the thermal niche represents the set of temperatures across which population growth rate (Daphnia (Previous work has estimated TPCs using population growth rate as the response variable in short-lived organisms including Daphnia . Such stin situ. Ultimately, we hope that this viewpoint paves the way for including plants in future syntheses of TPCs and deepening our understanding of the ecological and evolutionary determinants of plant responses to climate change.Thermal performance curves are an ideal tool for fundamental and applied research in plant ecology and evolution. Here, we have described plant TPC studies that have tested hypotheses about plant adaptation and plasticity, with important implications for predicting responses to climate change. Several hypotheses, however, remain untested, including those about the roles of genetic variation in the evolution of niche space at the population level and beyond, controls of biotic interactions on realized niche space, and whether fitness-based TPCs determined in experimental settings can be scaled up to represent population-level niche space"}
+{"text": "This symposium uses data from the National Social Life, Health & Aging Project to examine how and for whom older adults\u2019 social relationships and experiences changed with the advent of the COVID-19 pandemic. Zhang et al. examine video call usage among older adults with hearing impairment and how this might mitigate loneliness. They find that although this population reported greater loneliness during the pandemic, video calls attenuated this relationship in a dose-response manner. Wilder et al. evaluate 2015 resilience and socioeconomic status as predictors of older adults\u2019 reports that the pandemic led to a positive change in their lives. Results revealed greater odds of reporting a positive impact of the pandemic for those with higher education, adjusting for resilience. Compernolle et el. assess differences by cognitive status in changes in mental health from pre- to during the pandemic. Higher 2015 cognitive functioning was associated with greater pandemic loneliness, with decreased pandemic emotional support partly explaining this association. Copeland & Liu investigate the role of 2015 personal networks in receiving instrumental and emotional support during the pandemic, finding that larger and denser pre-pandemic confidant networks each predicted higher odds of receiving various types of support during the pandemic. Wong et al. explore whether and for whom relationship quality changed since the pandemic started. Two-thirds of partnered respondents reported unchanged relationship quality, and Black respondents were more likely to report improved relationship quality. These investigations highlight sub-group differences in older adults\u2019 changes in experiences, behavior, and well-being since the pandemic began."}
+{"text": "Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. Due to an increased risk of developing colorectal cancer, regular surveillance for dysplastic lesions via colonoscopy is recommended. Invisible dysplasia is the abnormal development of cells noted on pathology with no visible lesion seen during colonoscopy. Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease leading to progressive stricturing and fibrosis of the bile ducts. There is significant association between PSC and IBD, as up to 80% of patients with PSC having underlying IBD. Drug induced liver injury (DILI) is a common cause of acute liver failure in most Western countries. Most cases of DILI are self-limited, with resolution of laboratory and clinical findings after cessation of the offending agent.To describe a case of invisible colonic malignancy and possible idiosyncratic drug-induced liver injury from vedolizumab (VDZ) in a patient with ulcerative colitis (UC), PSC and autoimmune hepatitis (AIH) overlap syndrome.Patient consent was obtained. Information from electronic records was extracted, including admission notes and procedural reports. A literature review was performed using Pubmed.A 32-year-old Caucasian female with UC on VDZ with PSC and AIH had multiple colonoscopies performed demonstrating multifocal low-grade dysplasia. However, she remained resistant to surgery. She presented to clinic with tea-coloured urine, fatigue, and scleral icterus. Investigations revealed conjugated hyperbilirubinemia with elevation in hepatocellular liver enzymes. Imaging was consistent with large duct PSC, and liver biopsy showed grade 2 chronic hepatitis raising the possibility of large bile duct obstruction. She underwent liver transplant assessment and VDZ was held. Her bilirubin and liver enzymes recovered. Given multiple colonoscopies showing multifocal dysplastic changes and the patient declining other biologics, she would ultimately undergo total proctocolectomy with end ileostomy. Pathology demonstrated mucinous adenocarcinoma with a signet ring component.Both mucinous adenocarcinoma and signet ring carcinoma are more aggressive malignancies associated with poor prognosis. Found more often in younger patients, they are often diagnosed in later stages with lymphovascular invasion. Here, there was no evidence of metastases in any of the 40 lymph nodes examined, which indicated more favourable prognosis.The mechanism by which VDZ potentially causes liver injury is unknown. Multiple therapies for PSC-AIH overlap and IBD were entertained as causative agents. However, significant improvement in clinical symptoms and serologic parameters following cessation of VDZ was temporally suggestive.This case simultaneously highlights the importance of both timely colectomy in IBD patients with high-risk features during surveillance and early recognition and cessation of potential causative medications which induce liver injury.NoneNone Declared"}
+{"text": "Within Ohio\u2019s MyCare demonstration, two distinct care management models were selected by the participating MyCare Ohio health plans (MCOPs): fully-delegated waiver care management and waiver service coordination. The purpose of this presentation is to describe the components of care management operating in MyCare Ohio. Qualitative interviews with n=91 Area Agency on Aging (AAA) and n=131 MCOP care management personnel were audio-recorded, transcribed, and checked for accuracy prior to thematic coding in Dedoose. Results indicate that comprehensive care management is the core element of MyCare Ohio. Fully-delegated care management models were viewed by participants as beneficial to reducing confusion for members however \u2018scope creep\u2019 challenged the already strained AAAs. Effective teamwork was identified for waiver service coordination models but the division of labor and communication needed between the AAA and MCOP care management personnel created tensions. The discussion will focus on practice recommendations for training, caseloads, and support staff."}
+{"text": "Teaching Point: Intravertebral venous collateral formation can occur in thoracic venous obstruction syndrome and mimic metastatic bone lesions on contrast-enhanced imaging: vanishing bone metastases. Intravertebral venous collateral formation can occur in thoracic venous obstruction syndrome and mimic metastatic bone lesions on contrast-enhanced imaging.A 60-year-old man was admitted to the emergency department complaining of headaches, dyspnea and deterioration of consciousness during the past few days. He has a history of esophageal cancer treated with surgery and adjuvant radiochemotherapy. Clinical examination revealed swelling of the face, neck and upper limbs, as well as turgidity of the jugular veins and stridor.A contrast enhanced computed tomography (CT) scan of the neck and chest was performed. It showed a superior vena cava obstruction with various venous collaterals  and 2 11.Multiple high-density bone lesions were also detected in several cervical and thoracic vertebral bodies . These fSpine magnetic resonance imaging (MRI) performed two days later didn\u2019t reveal any vertebral signal abnormalities . Nor werTherefore, we can conclude that the dense intravertebral images on the contrast-enhanced CT imaging resulted well from contrast accumulation in intravertebral venous collaterals .Venous dilatation and relative blood stagnation can be present when the superior vena cava is obstructed. Most frequent venous collateral pathways are via the azygos, hemiazygos, intercostal veins and vertebral venous plexuses. In some cases, intravertebral collaterals can also be involved. These intraosseous venous collaterals are located in the vertebral bodies and drain into vertically oriented veins in the spinal subarachnoid space 45.4Therefore, stagnation of intravenous contrast material in these intravertebral collaterals can mimic condensing bone metastases on CT scans after contrast administration , hence tIn literature, there are limited number of case reports describing such vanishing bone metastases. One of the first descriptions of this peculiar aspect was in 2009 by Jesinger and colleagues .Vanishing metastases appear to be an underdescribed entity and should not be confused for malignant lesions."}
+{"text": "Anxiety disorders (ADs) are pervasive, detrimental, and associated with numerous psychiatric disorders; however, their etiology and effective treatment strategies are not yet fully explored.We aimed to study whether the symptom severity of ADs is related to mindfulness and metacognition among adults. In addition, we wanted to compare metacognition and mindfulness between patients with ADs and healthy controls (HC).Two hundred participants were enrolled in this study. Structured clinical interview, sociodemographic form, Five Facet Mindfulness Questionnaire-Short Form (FFMQ-S), Metacognition Questionnaire-30 (MCQ-30), and Hamilton Anxiety Rating Scale (HAM-A) were administered. Multivariate analysis of covariance (MANCOVA) was conducted to compare the groups in terms of mindfulness and metacognition. Correlation and multiple linear regression analyses were performed to measure the association between anxiety symptom severity, mindfulness, and metacognition.The main finding indicates that Positive Beliefs about Worry are associated with reduced symptom severity of ADs. Furthermore, the results suggest that HC have more Positive Beliefs about Worry and Nonjudging of Inner Experience compared to patients with ADs, who use Negative Beliefs about Uncontrollability and Danger and Need to Control Thoughts to a greater extent.This study suggests that dysfunctional metacognitive beliefs may influence symptom severity of ADs among adults. We advise that focusing on reducing maladaptive metacognitions may be beneficial while treating ADs in adultsNo significant relationships."}
+{"text": "The pancreas exhibits remarkable inherent cellular plasticity in response to injury. To prevent inflammatory injury or death, acinar cells can undergo transient acinar-to-ductal metaplasia (ADM) by suspending normal cell functions and adopting characteristics of ductal cells. However, persistent ADM in the setting of chronic pancreatitis predisposes to pancreatic cancer. Less frequently, acinar cells have also been found to undergo acinar-to-adipocyte transdifferentiation, but the mechanisms and clinical significance of this process are largely unknown. Recent studies have identified that the Hippo signaling pathway and its effectors are vital for pancreatic development and function.YAP is highly expressed in normal pancreatic ducts and transiently in acinar cells undergoing ADM, suggesting a dual role for YAP in (1) the homeostatic maintenance of pancreatic ductal cells, and (2) the regenerative response to injury in acinar cells. However, little is known about the cell type-specific effects of YAP/TAZ on pancreas homeostasis and regeneration.Yap/Taz in both acinar cells and ductal cells using the previously described CluCreERT mouse line. We also established a pancreatic ductal cell-derived organoid system. The efficiency of in vitro Cre recombinase induction was confirmed in Yapfl/fl;Tazfl/fl;CluCre-ERT;LSL-tdTomato (YTKO) ductal organoids.We investigated the homeostatic functions of Yap and Taz in the pancreas by conditionally ablating We observed severe atrophy and a pancreatitis-like phenotype in the pancreata of YTKO mice following tamoxifen induction. At later time-points, YTKO pancreata were progressively remodeled \u2013 the exocrine pancreas was almost entirely replaced by adipose tissue and large hyperplastic ductal structures. We will perform further lineage tracing experiments to determine whether infiltrating adipose cells derive directly from transdifferentiating acinar cells. YTKO pancreatic ductal organoids exhibited disrupted survival and proliferation, evidenced by increased expression of cleaved Caspase3 and decreased EdU incorporation compared to vehicle-treated controls.Although some flexibility in cell fate potential is beneficial for the regenerative capacity of the pancreas, dramatic changes in cellular identity can have disastrous consequences. Overall, this study revealed that disruptions in Hippo signaling in the adult murine pancreas led to failure of regeneration and the complete remodeling of the exocrine pancreas, and has shed light on the previously uncharacterized role of Hippo signaling in acinar-to-adipocyte transdifferentiation. The potential contribution of fatty infiltration of the pancreas to the pathogenesis of diabetes mellitus and pancreatic cancer merits further exploration.CIHR, OtherFonds de recherche du Quebec - Sante (FRQS)None DeclaredCELLULAR & MOLECULAR GASTROENTEROLOGY"}
+{"text": "The coated alloy was co-cultured with bone marrow mesenchymal stem cells and showed excellent biocompatibility and osteoinductivity in vitro. A further exploration of the underlying mechanism by quantitative real-time polymerase chain reaction and western blotting revealed that the enhancement effects are related to the upregulation of genes and proteins  involved in the Wnt/\u03b2-catenin pathway. In vivo experiments showed that the TiCu/TiCuN coating significantly promoted osteoporotic fracture healing in a rat femur fracture model, and has good in vivo biocompatibility based on various staining results. Our study confirmed that TiCu/TiCuN-coated Ti promotes osteoporotic fracture healing associated with the Wnt pathway. Because the coating effectively accelerates the healing of osteoporotic fractures and improves bone quality, it has significant clinical application prospects.Osteoporosis results in decreased bone mass and insufficient osteogenic function. Existing titanium alloy implants have insufficient osteoinductivity and delayed/incomplete fracture union can occur when used to treat osteoporotic fractures. Copper ions have good osteogenic activity, but their dose-dependent cytotoxicity limits their clinical use for bone implants. In this study, titanium alloy implants functionalized with a TiCu/TiCuN coating by arc ion plating achieved a controlled release of copper ions   Osteoporosis is a common orthopaedic disease characterized by bone microstructure destruction and bone loss. As the bone quality declines, the bone microstructure is destroyed. The bones become very fragile over time, and eventually, fractures can occur in response to minimal external force. Osteoporotic fractures are difficult to treat. Because of the decline in bone quality, postoperative fractures that do not heal or delayed healing can occur. Fracture healing generally occurs in three phases: inflammation, osteogenesis and bone remodelling . Bone reThe implants currently used to fix fractures are mainly made of stainless steel, medical titanium alloy or cobalt chromium molybdenum alloy, and have high mechanical strength, excellent biocompatibility and maintain optimal stability , 6. HoweCopper is an indispensable trace element in the human body and is involved in most metabolic reactions as an important coenzyme . In addiin vitro corrosion resistance tests. Further in vitro and in vivo studies are needed to assess osteogenic activity.Titanium nitride (TiN) is a very hard and stable material , 18, witin vivo by promoting Wnt/\u03b2-catenin signalling pathway, and promote the formation of callus at the fracture site, thereby accelerating fracture healing ; the Science and Technology Commission of Shanghai Municipality [22YF1422900 and 21002411200]; the Shanghai Municipal Key Clinical Specialty, China [shslczdzk06701]; Huangpu District Industrial Support Fund [XK2020009]; the National Facility for Translational Medicine (Shanghai), China [TMSZ-2020-207]; and the Shanghai Engineering Research Center of Orthopedic Innovative Instruments and Personalized Medicine Instruments and Personalized Medicine [19DZ2250200].Conflicts of interest statement. The authors have no conflicts of interest relevant to this article.rbac092_Supplementary_DataClick here for additional data file."}
+{"text": "Acute upper limb ischemia in a patient with thoracic outlet syndrome is a rare but serious clinical disorder. If the disease is not treated promptly due to underdiagnosis, it could lead to distal artery embolization and limb-threatening ischemia. Revascularizing upper extremity arteries in a timely manner could rescue ischemic limbs and improve the patient\u2019s quality of life. We reported here a case of a patient who presented with bilateral upper limb ischemia caused by arterial thoracic outlet syndrome.A 63-year-old woman who presented with sudden bilateral upper extremity cold, numbness, pulselessness, and altered temperature sensation was first diagnosed with arterial thoracic outlet syndrome. The patient had performed a lot of pull-up and lat pull-down exercises in the 2 months prior to the onset of the above symptoms. Color Doppler ultrasonography showed thrombosis in the right axillary artery and left subclavian and axillary artery. The patient received Rotarex mechanical thrombectomy combined with drug-coated balloon percutaneous transluminal angioplasty (PTA) to complete revascularization of the upper extremities and achieved a full recovery finally.Complete endovascular revascularization for treating arterial thoracic outlet syndrome is a minimally invasive and effective method, especially for upper extremity ischemic lesions caused by nonbone compression. Arterial thoracic outlet syndrome (TOS) is a group of disorders manifested with upper extremity ischemia or aneurysmlike disease caused by external compression of subclavian or axillary arteries at the thoracic outlet . ArteriaDecompression of the thoracic outlet is the classic therapy, including cervical rib excision, release of scalenus, and vascular thrombectomy and reconstruction . HoweverWe report a rare case of acute ischemia of bilateral upper extremities caused by arterial thoracic outlet syndrome. Rotarex mechanical thrombectomy combined with a drug-coated balloon was used to reconstruct the upper extremity blood flow, and finally, the patient fully recovered.A 63-year-old female patient presented with acute bilateral upper extremity cold, pulselessness, and altered temperature sensation. The patient described that she had performed a lot of pull-up and lat pull-down exercises in the 2 months prior to the onset of the above symptoms. The physical examination showed that typically marked bilateral upper extremity ischemia manifesting with radial and ulnar artery blood flow were out of palpable and cold sensation in upper limbs. The patient was diagnosed with arterial thoracic outlet syndrome after clinical provocation tests  and computed tomography (CT)  results The patient received anticoagulant and antiplatelet therapy after hospitalization. An 8F Rotarex  mechanical thrombectomy system was used to reduce the thrombus burden in the axillary artery and the subclavian artery. To decrease the risk of ectopic embolization, we adopted a strategy of slowly pushing the Rotarex catheter from proximal to distal end of the artery. Before the aspiration of thrombus in the distal artery, we performed repeated aspiration in the proximal artery aiming to reduce the amount of thrombus fully. Then, 3-, 5-, and 8-mm Mustang balloon catheters   were useArterial thoracic outlet syndrome is usually present with upper extremity ischemia or aneurysm caused by chronic external compression of the subclavian artery or axillary artery when passing through the defined anatomical space called thoracic outlet. Bony abnormalities such as abnormal cervical rib and first rib, anomalous development of anterior scalene muscle, and other soft tissues contribute to subclavian/axillary artery stenosis, occlusion, thrombosis, and aneurysm. The innovation of endovascular technology makes it possible to treat arterial thoracic outlet syndrome through a more minimally invasive surgical approach.First, the diagnosis of arterial TOS needs to be carefully distinguished. Patients with arterial TOS usually present with obvious symptoms of limb ischemia such as cold feeling, pulseless, and altered temperature sensation. In addition to pain, numbness, and paresthesia, some neurogenic TOS patients also manifested intermittent finger paresthesia, discoloration, and coldness in the absence of thromboembolism in the subclavian artery. The ischemic manifestations of the upper extremities are mainly attributed to vasospasm mediated by sympathetic nerve plexus compression rather than true arterial TOS , 13. ColThe congenital abnormality of anterior scalene muscle, cervical rib, the first rib, and other factors lead to the compression of the subclavian/axillary artery, resulting in intimal hyperplasia, thrombosis, and aneurysm in arterial TOS. Traditional surgery requires thoracic outlet decompression, artery release, thrombectomy, and subclavian\u2013axillary artery bypass grafting, causing extremely traumatic injury and bleeding. The advancement of endovascular intervention provides new treatment possibilities. Pantoja et al.  comparedRotarex thrombectomy combined with drug-coated balloon dilation achieved good initial clinical results and a satisfactory arterial patency rate in treating arterial TOS; however, a strict case screening is required. For arterial TOS caused by bone compression, it is still necessary to decompress the neurovascular bundle first . Further"}
+{"text": "This study examined Alzheimer\u2019s disease (AD) knowledge and its predictors among Korean Americans (KAs). A total of 268 KAs in the Greater Washington metropolitan area participated in the study and completed a cross-sectional survey. Using the Alzheimer\u2019s Disease Knowledge Scale (ADKS), overall and domain knowledge was assessed. Multiple regression analyses were conducted with predictors including exposure to AD, social engagement, sources and frequency of health-related information, stigmatic beliefs , English proficiency, and education. KAs reported 59% accuracy in overall AD knowledge. They were most knowledgeable about assessment and diagnosis domain and least knowledgeable about caregiving domain. Regression analyses showed that having more education is associated with greater overall and certain domain knowledge. Having more pity stigmatic beliefs is related to greater knowledge in both life impact and caregiving domains while having less pity stigmatic beliefs is associated with more risk factor knowledge; having less social distance stigmatic beliefs is associated with greater life impact knowledge; and having less antipathy stigmatic beliefs is related to better caregiving knowledge. Our findings revealed areas of misconceptions and knowledge gaps in KAs which need to be addressed in educational interventions. Different knowledge status across the domains demonstrates a multi-dimensional nature of AD knowledge. Multivariate findings confirmed the robust role of education in AD knowledge. Effect of different AD stigmatic beliefs on certain AD knowledge domains suggests ways of how stigma change can be efficient for the purpose of increasing AD domain knowledge in KAs."}
+{"text": "COVID-19 raises serious concerns regarding its unknown consequences for health, including psychiatric long term outcomes. Historically, influenza virus has been responsible for pandemics associated with schizophrenia. Epidemiological studies showed increased risk for schizophrenia in children of mothers exposed to the 1957 influenza A2 pandemic. Controversy remains concerning the mechanisms of pathogenesis underlying this risk.We aim to review the evidence for the association between influenza infection and schizophrenia risk, the possible pathogenic mechanisms underlying and correlate these findings with the schizophrenia hypothesis of neurodevelopment.We reviewed literature regarding evidence from epidemiological, translational animal models and serological studies using medline database.The biological mechanisms likely to be relevant account to the effects of infection-induced maternal immune activation, microglial activation, infection-induced neuronal autoimmunity, molecular mimicry of the influenza virus, neuronal surface autoantibodies and psychosis with potential infectious antecedents. Influenza infection may fit into the theory of the neurodevelopment of schizophrenia as a factor that alters the normal maturation processes of the brain (possible second or third hit).Influenza infection has multiple pathogenic pathways in both pre and post natal processes that might increase the risk of schizophrenia or psychosis. The existing evidence regarding the relationship between influenza virus and psychosis might help us draw similar long-term concerns of COVID-19.No significant relationships."}
+{"text": "Little is known how adults\u2019 memories of parental acceptance-rejection in childhood influence their behavior toward their aging parents. Grounded in interpersonal acceptance-rejection theory (IPARTheory), this study attempts to better understand how early parent-child relationships affect adult offspring who provide care to their parents in later life. Data were collected from 41 adult offspring. Findings revealed that adults who felt rejected by their parents in childhood reported fewer positive caregiving behaviors toward their now aging parents, were less satisfied with social activities with their parents, spent less time with them or visited them less frequently, and revealed less overall concern for their aging parents. Results were consistent with IPARTheory\u2019s expectations that if parents reject their children, then parents place their own dependent old age at the risk of counter rejection: As you sow, so shall you reap. Such findings may help researchers, clinicians, and practitioners better understand the well-being of aging adults."}
+{"text": "Pain is endemic for residents of long-term care homes, with many residents experiencing pain daily. Given that healthcare aides provide most daily care for residents, they are ideally situated to deliver timely assessment and non-drug interventions for managing resident pain. In this Cochrane-style systematic review, we searched 7 databases to identify intervention studies that included long-term care residents aged \u226560 years who received interventions to reduce chronic pain. Interventions were either delivered by healthcare aides at the resident level or were directed at healthcare aides to improve their pain management practices. We screened 400 titles/abstracts and 152 full-text articles. Nine studies met inclusion criteria and were included in a narrative review. Due to the limited number of studies and variety of study designs, data were insufficient to perform meta-analyses or thematic analysis. Three studies described pain interventions delivered by healthcare aides at the resident level reporting significant improvement of pain. Six studies described pain interventions delivered to healthcare aides. Results of these interventions were inconsistent; 2 reported significant improvements in pain-related outcomes , 3 reported insignificant changes, and 1 reported a positive correlation between measured pain and pain medication use. We concluded that despite the paucity of research in this area, this systematic review provides preliminary support for pain interventions by healthcare aides for long-term care residents. Future research exploring interventions for healthcare aides to take greater roles in pain management could unlock further improvements in resident care."}
+{"text": "Although clinical parameters such as unexplained syncope or a family history of WPW may correlate with increased risk, most commonly the risk is estimated based on parameters observed during episodes of clinical tachycardia or variables measured during electrophysiology study (EPS).This case involves a 16-year-old female patient with WPW and episodes of supraventricular tachycardia since the neonatal period. Owing to increasingly frequent and prolonged episodes of supraventricular tachycardia with symptoms including severe chest pain and near-syncope, she was referred for EPS and catheter ablation. Her baseline ECG demonstrated ventricular pre-excitation with a pattern consistent with left anterolateral accessory pathway .Figure\u00a01At diagnostic EPS, local ventricular pre-excitation with earliest activation was identified at the distal coronary sinus catheter. Ventricular pacing also demonstrated eccentric and nondecremental ventricular-atrial conduction at the anterolateral aspect of the coronary sinus. The antegrade accessory pathway effective refractory period was 270 ms with 600 ms cycle length drive train. There was persistent antegrade accessory pathway conduction with rapid atrial pacing at 260 ms. Induced orthodromic reciprocating tachycardia converted into atrial fibrillation with a single-interval SPERRI of 228 ms; however, the majority of R-R intervals were in the range of 350\u2013400 ms . Atrial In patients with WPW, it is generally accepted that the risk of sudden death is related to the characteristics of the accessory pathway(s). The mechanism of sudden death is reported as atrial fibrillation with rapid antegrade accessory pathway conduction leading to ventricular fibrillation.For adult patients with WPW, high-risk is defined as the SPERRI during atrial fibrillation \u2264250 ms, the presence of multiple accessory pathways, an accessory pathway refractory period \u2264240 ms, or atrioventricular reentrant tachycardia precipitating pre-excited atrial fibrillation.Atrial flutter and atrial fibrillation are proposed to be related entities and may transform into one another, as demonstrated with our patient.Invasive risk stratification for pediatric patients with WPW is imperfect. The relationship of atrial fibrillation  and atrial flutter  may offer an explanation for sudden death or life-threatening events in children who have low-risk pathways by invasive electrophysiologic testing. Catheter ablation should be considered at the time of EPS if safe and feasible."}
+{"text": "Physical therapists often treat pain and functional limitations associated with chronic musculoskeletal conditions common in aging adults. While patient report improvement after physical therapy, these results do not translate to sustained physical activity. This is a lost opportunity to support aging adults in adopting behaviors proven to improve quality of life and reduce comorbidity burden. We conducted semi-structured interviews with 30 physical therapists to understand how they support adoption of physical activity and identify what is needed to improve uptake. Physical therapists endorse physical activity as essential in the management of MSK conditions. Eliciting motivation, addressing psychosocial needs, and empowering patients to actively engage in solutions were identified as significant challenges in the effort to change physical activity. At the clinician level, physical therapists identified the need for improved skills in motivational interviewing and person-centered communication. Improved coordination with mental health providers and community resources were identified as environmental needs."}
+{"text": "Amidst global shifts in the distribution and abundance of wildlife and livestock, we have only a rudimentary understanding of ungulate parasite communities and parasite-sharing patterns. We used qPCR and DNA metabarcoding of fecal samples to characterize gastrointestinal nematode (Strongylida) community composition and sharing among 17 sympatric species of wild and domestic large mammalian herbivore in central Kenya. We tested a suite of hypothesis-driven predictions about the role of host traits and phylogenetic relatedness in describing parasite infections. Host species identity explained 27\u201353% of individual variation in parasite prevalence, richness, community composition and phylogenetic diversity. Host and parasite phylogenies were congruent, host gut morphology predicted parasite community composition and prevalence, and hosts with low evolutionary distinctiveness were centrally positioned in the parasite-sharing network. We found no evidence that host body size, social-group size or feeding height were correlated with parasite composition. Our results highlight the interwoven evolutionary and ecological histories of large herbivores and their gastrointestinal nematodes and suggest that host identity, phylogeny and gut architecture\u2014a phylogenetically conserved trait related to parasite habitat\u2014are the overriding influences on parasite communities. These findings have implications for wildlife management and conservation as wild herbivores are increasingly replaced by livestock. They arHistorically, sampling limitations have impeded community-level multi-host/multi-parasite analyses. Gastrointestinal nematodes parasitize many different large mammalian herbivore species, yet accurate taxonomic identifications\u2014necessary to quantify diversity and identify host-sharing networks\u2014typically requires retrieving adult specimens from dead hosts or culturing larvae. Moreover, while several databases document host-species\u2013parasite relationships ,13, dataFor diverse large-herbivore assemblages, such as those found in African savannahs, such approaches could address knowledge gaps about patterns and determinants of parasite prevalence, diversity and sharing in locations where wild and domestic hosts overlap . SeveralThree host-specific predictors are often proposed as correlates of parasite species richness across systems and species: body size , geographical range size , and population density (and thus intraspecific transmission opportunities) ,26. A reBecause sympatric herbivores share many of the same food and water resources that serve as transmission routes for gastrointestinal parasites , studiesWe used DNA metabarcoding of the ITS-2 region to analyse gastrointestinal nematode DNA (Strongylida) in fecal samples from a diverse community of wild and domestic large herbivores  in an East African rangeland. Strongylida are among the most common metazoan parasite groups in large herbivores and infect various parts of the digestive tract, including the stomach and intestines. While taxonomic reference data for nematodes remain limited, DNA metabarcoding enables comparative analysis of diversity and composition by clustering sequences by similarity even when taxonomic names are lacking, as has been validated for both parasitic and free-living nematodes ,35 ), richness and phylogenetic diversity? We hypothesized that, in addition to strong effects of host species identity on parasite assemblages , hosts t. 22 of semi-arid thorn-scrub savannah managed for wildlife conservation and livestock production ) (b)a,b; electronic supplementary material, figure S9), demonstrating the role of a few generalists in connecting the network. The high centrality of giraffe and camel\u2014intriguing given that each is the only local member of its family and that both feed overwhelmingly in the overstorey\u2014suggest that these species are infected by generalist parasites and may play an important role in cross-species transmission depending on their movement and density. One clear management implication is that regularly deworming camels, as done successfully for sheep and goats at our site, might help limit parasite transmission to wildlife . The same is true for donkeys, which had the highest centrality of the three equids and are likely to share parasites with the endangered Grevy's zebra and near-threatened plains zebra.Our finding that host\u2013parasite links were highly aggregated aligns with previous studies showing that most parasites specialize on few hosts while only a few have broad host ranges ,81. Parafigure 3Our finding of phylogenetic influence on network centrality metrics is consistent with the likelihood that closely related hosts share ecological, anatomical and immunological traits that shape host\u2013parasite coevolution. Indeed, models based on herbivore parasite records  suggest  (c)While the DNA barcode we sequenced can effectively distinguish parasitic nematode species across a wide range of hosts , it is lOur raw data contained low-abundance mOTUs that generated a highly interconnected host\u2013host sharing network, but filtered data using mean RRA greater than or equal to 2% per species were more concordant with prior studies ,13. WhilWe could not identify 48% of parasite mOTUs to species due to gaps in genetic resources for many wildlife parasites . While t. 5We show that host phylogeny and digestive strategy explain a high degree of variance in parasite community composition and sharing across a diverse community of wild and domestic large herbivores. While additional work is needed to maximize the value of parasite metabarcoding data, this approach holds enormous promise to shed light beneath the tip of the biodiversity iceberg. Use of these methods in studies with spatially or temporally stratified sampling designs will allow researchers to capture multi-host parasite dynamics that have long remained elusive. Our finding of substantial parasite sharing at the livestock-wildlife interface suggests that regularly deworming camels and donkeys could be an effective local management intervention to reduce transmission between livestock and several globally threatened and near-threatened ungulates. More broadly, our results suggest that changes to domestic animal communities or their parasite loads  will impact parasitism in sympatric wild hosts."}
+{"text": "The minimal dimension of critical isthmus regions may be less than 1 cm in more than 25% of circuits mapped.A 73-year-old man with history of dilated cardiomyopathy and left ventricular (LV) ejection fraction of 39%, complete heart block status post permanent pacemaker placement 15 years ago with upgrade to biventricular implantable cardioverter-defibrillator 2 years ago, presented with recurrent episodes of VT and appropriate implantable cardioverter-defibrillator therapies despite antiarrhythmic drug therapy with sotalol. Cardiac magnetic resonance imaging showed midmyocardial delayed enhancement with full-length midmyocardial scar from the basal anteroseptum to inferoseptum . He undeIn anticipation of mapping a septal VT, a linear multielectrode catheter  was placed in the septal right ventricular outflow tract (RVOT) and an ablation catheter  was positioned on the LV basal anterior septum via transseptal approach. A diagnostic 2F microcatheter  was placed into the distal coronary sinus to record within the AIV and SPV . During d, proving critical circuitry confined within the interventricular septum , a balloon technique was not implemented. However, VT remained reinducible at a faster rate and therefore additional ablation were performed at 50 W from the LV and RV septum. VT has not recurred for 9 months at the time of this report.A second VT with left bundle branch block morphology with VLMNA and TTN, are associated with VT recurrence rates that are among the highest in structural heart disease.LMNA variants in particular have been shown to have high rates of arrhythmia recurrence, progression of cardiomyopathy to end-stage heart failure, and high mortality.Catheter ablation for drug-refractory VT in patients with dilated cardiomyopathies, particularly in those with genetic mutations such as ,,Lamin cardiomyopathy classically involves the septum and periaortic region and seems to be predominantly related to reentry in and around regions of scar. Periaortic VTs have been increasingly described with regard to reentrant mechanism and circuit characteristics.,Prior studies have not demonstrated localized reentry completely confined within the intramural septum, which is the novelty of this report. These descriptions reiterated the propensity of LMNA to predominantly involve the septum,Strategies such as substrate modification via transcoronary venous ethanol may warrant further consideration, particularly when a full-length septal scar is present on magnetic resonance imaging, which portends a poor prognosis.Owing to high rates of recurrent VT associated with lamin cardiomyopathies, early collaboration and consultation with a heart failure team is warranted to discuss advanced management options, given modest outcomes from ablation and high risk of mortality from progression of heart failure. This case provides further mechanistic insights into the nature of septal VTs in this challenging patient population that may be entirely missed by traditional endocardial and epicardial mapping techniques.In midmyocardial septal scar substrates, SPV recordings may provide critical intramural information to elucidate the spatial dimensions and location of circuit-challenging VTs. Localized reentry recorded from a single bipole pair can be confined completely within the septum, which cannot be fully characterized from either endocardial surface."}
+{"text": "Grandparent-headed families in South Korea have been growing prominent in the country\u2019s cultural landscape. Approximately 153,000 Korean grandparent-headed households existed in 2015; this number is expected to double by 2035. This qualitative study explored Korean custodial grandparents\u2019 experiences of raising grandchildren and the cultural significance of multigenerational caregiving in Korea. Using a phenomenological approach, semistructured interviews with 22 custodial grandparents were conducted. Significant functions of patrilineality and stigma surrounding divorce for Korean grandparent-headed families were found. Considering the complicated cultural factors, social/family service programs must pay attention to the unique needs of grandparent-headed families and consider the circumstances related to grandparents\u2019 positions in the family . Korean government programs and policies could better help marginalized grandparent-headed families with an empowerment approach to help marginalized grandparent-headed families gain positive attitudes toward their caregiving situation."}
+{"text": "Keratosis obturans is estimated to occur among 4 to 5 patients among 1000 new otological cases.A previously healthy 22 year-old Malay gentleman presented to our clinic with a two-month history of worsening left otalgia with bloody otorrhea. There was also left sided reduced hearing followed by asymmetry on the left side of face for the past 1 week. Patient claimed that there was no recent or any recurrent upper respiratory tract infection prior to this.Further history from patient revealed that he had similar complaints a year ago involving the right ear with no facial asymmetry. Patient was diagnosed with right aural polyp and polypectomy was done under local anaesthesia in another government hospital. However, patient defaulted his follow-up as the problem resolved completely.Upon examination, patient was comfortable, not septic looking and afebrile. Facial nerve examination revealed House\u2013Brackmann Grade III lower motor neuron palsy as there was loss of left nasolabial fold and drooping of left angle of lip. Otoscopic examination revealed a polypoidal mass occluding the entire left ear canal covered with bloody, foul smelling otorrhea . Right eA high-resolution computer tomography (HRCT) scan of temporal was obtained, which revealed non-enhancing soft-tissue mass occupying left external auditory canal, left Prussak's space and middle ear with erosion of left scutum. The left inner ear was intact with normal right ear structures. There was no evidence of facial canal dehiscence or erosion; however signs of inflammation over the tympanic segment of facial canal were noted .Figure 2Patient underwent microscope-guided examination under anaesthesia which revealed polypoidal mass occupying entire lateral third of ear canal with whitish keratin-like debris noted medial to the mass. Polypectomy and aural toileting was commenced. As tympanic membrane appeared bulging, myringotomy and grommet insertion was performed. Histopathologic examination revealed cyst wall covered with stratified squamous epithelium containing lamellated keratin flakes suggestive of keratosis obturans  Post-opeKeratosis obturans can be of two types: Inflammatory type or silent type.Keratosis obturans usually affects younger age group, occurs bilaterally and manifests as severe otalgia, conductive hearing loss and widened ear canal.Computer tomography typically demonstrates soft tissue plug in bilateral external ear canal with evidence of ballooning of the osseous part. In our patient, his main complaint was severe otalgia and otorrhea which was followed by unilateral facial weakness and hearing loss. Although rare, few cases of keratosis obturans, presenting with facial weakness have been reported.Clinical differential diagnosis for mass in aural canal with facial nerve palsy includes external auditory canal cholesteatoma, neoplasms of external canal and malignant otitis externa. It is important to distinguish the diagnosis, as management of each of the differential diagnosis is notably different. Hence, thorough and detailed history, physical examination, radiological examination and most importantly histopathological examination is crucial prior to a diagnosis. Histopathological examination of the biopsied or excised mass is the main modality of diagnosis, more so when there is an atypical or rare presentation.As for management, keratosis obturans usually requires frequent aural toileting to remove the keratin plug and topical medication. This may be done under general anaesthesia especially among non-cooperative patients. Split skin graft and canalplasty method have also been reported for refractory keratosis obturans.Albeit commonly regarded benign, keratosis obturans may result in devastating complications including facial nerve palsy as in our patient. Hence, high clinical suspicion and prompt management among clinicians are of dire importance as absence of typical clinical features usually lands both the attending physician and patient in dilemma.The authors declare no conflicts of interest."}
+{"text": "The COVID-19 pandemic caused severe disruptions in healthcare systems and societies and exacerbated existing inequalities for women and girls across every sphere. Our study explores health systems responses to gender equality goals during the COVID-19 pandemic and which role these goals play in pandemic recovery policies.We apply a qualitative comparative approach. Country case studies  were collected in March/April 2022. The sample comprised Australia, Brazil, Germany, United Kingdom and USA, reflecting conditions of high to upper-middle income countries with established public health systems, democratic political institutions and gender equality policies. Selected topics: maternity care/reproductive services, violence against women, and gender equality/female leadership.All countries tried to keep essential maternity and reproductive services open, but strong limitations applied especially for prevention and counselling services; at the same time, digitalisation/telemedicine supported service expansion. Violence against women and children strongly increased during the pandemic. Routine services were partly kept open and new helplines occasionally established, but no action was taken to scale-up mental health support and respond to new demand. A push-back of gender equality was observed across countries in all areas of health and social care, often coupled with strong increase in intersecting social inequalities; participation of women in decision-making bodies was generally weak and not monitored.Across countries, gender equality policies cracked under the pressure of the COVID-19 pandemic; this is true for countries with male and female political leaders, and for different areas of SDG5 and health. There is an urgent need for more effective intersectional gender equality policies and improved participation of women in global health and in health system recovery plans.\u2022\u2002Health systems failed to take action to protect SDG5 goals; gender and intersecting inequalities strongly increased during the pandemic.\u2022\u2002Building back better after COVID-19 will only be possible with an intersectional gender equality programme and feminist policy approaches."}
+{"text": "Observational studies suggest psychosocial factors such as social support and loneliness are associated with vulnerability for frailty in older adults, but less is known about the generalizability of these putative psychosocial mechanisms in underrepresented groups. Thus, we evaluated whether better telecommunication social support and lower levels of loneliness were associated with decreased frailty and increased functional ability using a unique longitudinal cohort of rural South African older adults. We conducted generalized estimating equation and robust regression analyses using cross-sectional data from 347 participants in the HAALSI  Dementia Cohort. Social support via telecommunication and self-reported loneliness were measured using standard assessments and modeled as exposure variables. Outcomes were frailty (measured using Fried\u2019s frailty phenotype) and functional status . Lower level of telecommunication social support was associated with higher impairment in ability to perform IADLs. This association persisted after additional adjustments for depression  and vascular risk factors . No associations were observed in relating telecommunication social support and loneliness with frailty. Among rural South African Black older adults, lower telecommunication-based social support was associated with greater risk of impairment in functional ability. Although further validation is required for possible reverse causality, our findings suggest that future intervention studies focused on promoting telecommunication-based social support to preserve independent functioning may be merited."}
+{"text": "Poor physical function has been linked to greater depressive symptoms among older adults. On the other hand, older adults\u2019 perceptions of positive and negative age-related changes provide personal strength and vulnerability to stressful events, respectively. We therefore expected that positive self-perceptions of aging (SPA) would be associated with fewer depressive symptoms, while negative SPA would be related to greater depressive symptoms, beyond the effect of physical function. We further tested the hypotheses that positive SPA would buffer the association between physical function and greater depressive symptoms, whereas negative SPA would exacerbate this association. This study used data from 108 older adults (mean age = 81.09) in independent-living or retirement communities. Results from a linear regression revealed that more positive SPA  and less negative SPA  were associated with fewer depressive symptoms, even after controlling for physical function, both types of SPA, and other covariates. In contrast, physical function was no longer significantly associated with depressive symptoms , after controlling for both types of SPA. There were no significant moderating effects of positive and negative SPA. Findings suggest that how positively and negatively older adults perceive their own aging may be important for their mental health while experiencing less physical function in late life."}
+{"text": "Most children with developmental disabilities (DD) live in resource-limited countries (LMIC) or high-income country medical deserts (HICMD). A social contract between healthcare providers and families advocates for accurate diagnoses and effective interventions to treat diseases and toxic stressors. This bio-social model emphasizes reproductive health of women with trimester-specific maternal and pediatric healthcare interactions. Lifelong neuronal connectivity is more likely established across 80% of brain circuitries during the first 1000 days. Maladaptive gene-environment (G x E) interactions begin before conception later presenting as maternal-placental-fetal (MPF) triad, neonatal, or childhood neurologic disorders. Synergy between obstetrical and pediatric healthcare providers can reduce neurologic morbidities. Partnerships between healthcare providers and families should begin during the first 1000 days to address diseases more effectively to moderate maternal and childhood adverse effects. This bio-social model lowers the incidence and lessens the severity of sequalae such as DD. Access to genetic-metabolomic, neurophysiologic and neuroimaging evaluations enhances clinical decision-making for more effective interventions before full expression of neurologic dysfunction. Diagnostic accuracy facilitates developmental interventions for effective preschool planning. A description of a mother-child pair in a HIC emphasizes the time-sensitive importance for early interventions that influenced brain health throughout childhood. Partnership by her parents with healthcare providers and educators provided effective healthcare and lessened adverse effects. Effective educational interventions were later offered through her high school graduation. Healthcare disparities in LMIC and HICMD require that this bio-social model of care begin before the first 1000 days to effectively treat the most vulnerable women and children. Prioritizing family planning followed by prenatal, neonatal and child healthcare improves wellness and brain health. Familiarity with educational neuroscience for teachers applies neurologic diagnoses for effective individual educational plans. Integrating diversity and inclusion into medical and educational services cross socioeconomic, ethnic, racial, and cultural barriers with life-course benefits. Families require knowledge to recognize risks for their children and motivation to sustain relationships with providers and educators for optimal outcomes. The WHO sustainable development goals promote brain health before conception through the first 1000 days. Improved education, employment, and social engagement for all persons will have intergenerational and transgenerational benefits for communities and nations. Accurate clinical decisions require serial assessments across developmental time beginning before conception . A dual Accurate clinical decision-making is particularly crucial for children who have increased risks for neurologic sequelae such as those with developmental disabilities (DD). DD consist of a constellation of functional deficits that are expressed beginning early in life, adversely affecting a child\u2019s physical, learning, or behavioral performance . ChildreA maternal-child pair medical case history is discussed to highlight the importance of time-sensitive diagnostic assessments from pre-conception through adolescence for successful interventions. Maternal and childhood adverse effects were addressed. Revised educational plans through her school years integrated maternal-pediatric healthcare histories into successful educational experiences. A dual diagnostic approach is discussed that teaches recognition of the maturational potential of any child according to principles of developmental neuroplasticity applied to clinical decision-making and therapeutic interventions. All healthcare providers and educators require knowledge and skills to implement the same diagnostic and educational approaches for the most vulnerable children in LMIC and HICMD.This child was previously included in a discussion of a diverse group of children who were diagnosed with genetic disorders . NeuroloThis maternal-child pair presented to healthcare providers and educators in a HIC. A serial diagnostic approach considered recognition of clinical phenotypes expressed by this woman, MPF triad, neonate, and child. Systems science application applied an understanding of etiopathogenesis pathways to the child\u2019s neurologic sequelae. Time-dependent medical and scholastic resources were offered to preserve health while she completed high school education. Joint attention by her mother and healthcare providers addressed adverse childhood effects that potentially could reduce long-term benefits from interventions in response to early life expression of DD.Mother was a 28-year-old gravida 2 para 1\u20132 woman with asymptomatic Sjogren\u2019s Disease and class 3 obesity  prior to conception. She followed a weight reduction plan which included bariatric surgery before pregnancy and achieved a lower body mass index. Her healthcare providers noted the inherited risks for this pregnancy consisting of an older child with autism spectrum disorder and parental anxiety disorders. Mother received behavioral interventions to manage her anxiety both before and during her pregnancy. A high-risk maternal fetal medicine service managed her autoimmune disease. No immunosuppressive medications were recommended given she remained asymptomatic for Sjogren\u2019s disease after conception.An AV block on a fetal EKG was later documented during third trimester abdominal sonography at 28 weeks GA. Despite maternal treatment with digitalis, this dysrhythmia progressed to nonimmune hydrops fetalis at 32 weeks\u2019 gestation secondary to cardiac failure. Labor induction and delivery was electively performed without complications after antenatal dexamethasone administration. No fetal distress occurred during delivery with a clinically stable female preterm newborn. She received 1- and 5-min Apgar scores of 6 and 7 without the need for advanced resuscitative interventions. Her anthropometric measurements were within appropriate gestational age ranges.The child subsequently required neonatal intensive care for multiple system-specific complications. Multiple cardioversions for cardiopulmonary arrest and severe hypotension/bradycardia were required to treat repetitive sudden heart block during her first week of life until effective digitalis dosing was established. Pulmonary disease, anemia and nutritional supplementation required medical interventions during the neonatal time. Neonatal cranial sonography did not document intraventricular hemorrhage or periventricular leukomalacia.Histological examination of the placenta at 10 days of life documented chronic villitis and maternal malperfusion lesions consisting of underdevelopment of the placental vasculature including decidual necrosis. These microscopic findings were supplemented by gross descriptions of a hyper coiled umbilical cord (2/cm) with a 1 cm marginal insertion.The child initially expressed hypotonia which later resolved with expression of age-specific developmental reflexes. Bulbar dysfunction initially required gavage feedings because of poor oropharyngeal function. Gradual transition to oral feeding was achieved during her early months of infancy.She required a permanent cardiac pacemaker at 11 months for persistent heart block for continued episodes of hypotension that remained unresponsive to medication adjustments. Cardiogenetic testing confirmed a long QT syndrome type II (G604S-KCNH-2), which was also confirmed for one parent.Developmental delay with borderline microcephaly (5%) was documented on serial assessments during her first 2 years of life. Vision and hearing evaluations were normal. No seizures occurred. Early intervention therapies were provided to supplement and support parental care. Primary care included social work support to address adverse childhood effects. Developmental testing documented cognitive, motor, social and language deficits. Sufficient skill acquisition was achieved during her preschool yea to matriculate into mainstream classes. She advanced through primary and middle school grades assisted by individual educational planning.She presented with status epilepticus associated with an acute hypertensive event at age 10 years. Brain lesions consistent with posterior reversible encephalopathy syndrome were noted on neuroimaging. Her pediatric intensive care successfully controlled seizures after stabilization of severe hypertension. With resolution of her encephalopathic state and renal dysfunction, she was discharged to home on antiepileptic medication. No neurologic regression occurred without further seizures. Antiepileptic medication was discontinued after a three-year interval.She experienced cognitive and behavioral challenges into adolescence. Cooperation between family and the school\u2019s multidisciplinary team of teachers and therapists offered revised interventions at school and home to address all medical challenges based on information provided to healthcare providers. Mental health care addressed her generalized anxiety and socialization challenges with educational accommodations and counselling. Functional neurological disorders included psychogenic seizures during adolescence were addressed with resolution. Dysautonomic symptoms of postural orthostatic tachycardia syndrome were recognized and managed with preventive interventions.Individualized educational plans (IEP) accommodated this child\u2019s expressive language delay, reading disability, hyperkinesis with short attention and lower limb spasticity, beginning during her preschool and primary school grades. Ambulation without ankle supports was achieved before her middle school years. She received psychotropic medications to manage anxiety without the use of stimulant medications. Serial neuropsychometric testing after age five years documented cognitive abilities within the normal range with subtest deficiencies in attention, reading and executive planning. She received educational accommodations through high school graduation. Behavioral interventions addressed her anxiety and socialization challenges which challenged her into adolescence. She successfully graduated high school with plans to pursue a nursing career.This next section reviews the systems science associated with the prenatal expression of diseases affecting this maternal-child pair. Applicability for effective horizontal and vertical approaches to diagnosis and treatment for a comparable woman in a LMIC and HICMD will be compared with the healthcare delivery received by this mother-child pair. Advocacy by healthcare providers regarding healthcare resources must consider diversity and inclusion to achieve optimal outcomes for healthcare and school readiness.Any child with a genetic disorder exemplifies G x E interactions that can begin before conception with time-dependent expression that are influenced by adverse maternal and childhood acquired conditions. Phenotypic presentations may first appear during pregnancy or after birth . For thiInteractions between familial genetic risks and acquired conditions affected this maternal-placental fetal (MPF) triad and neonate with adverse consequences into early childhood. Etiopathogenetic pathways across developmental ages during her first 1000 days altered phenotypic expressions of her brain disorders. Global developmental delay with borderline microcephaly were early phenotypes. A hypertensive disorder was a later childhood expression of this genetic disorder. Cognitive/behavioral and mental health disorders became more dominant phenotypes during her adolescent development.This child\u2019s fetal presentation at 28 weeks GA with heart block occurred after activation of an inherited channelopathy by maternal autoantibodies despite mother\u2019s asymptomatic Sjogren\u2019s disease . AutoantWithout clinical symptoms and the risk for adverse effects of corticosteroid use, mother received no treatment after conception. She alternatively was followed by a high-risk obstetrical service that monitored her based on maternal levels of care relevant to the this HIC health system.Pregnancy management for a woman in a LMIC or HICMD with asymptomatic Sjogren\u2019s disease might advocate for more proactive medical interventions to maximize chances for favorable outcomes despite less available prenatal and neonatal services. Earlier steroid treatment despite no maternal clinical signs may be the more practical therapeutic option. Treatment prior to conception or early first trimester for any woman identified with autoimmune disease might avoid or lessen the severity of fetal cardiac disease, hydrops fetalis and prematurity. Long QT syndrome may still present at older postnatal ages. However, with greater brain maturity, less severe neurologic sequalae may result because of increased resilience to brain injury. Benefit from immunomodulators other than steroids  in the fPreventive healthcare training for maternal care by physicians, nurse practitioners and midwives in a LMIC and HICMD must prioritize preventive care to offset less access to expensive high-risk maternal fetal medicine and neonatal intensive care services. WHO guidelines for maternal and neonatal levels of care , have emOther non-infectious inflammatory conditions accompanied this mother\u2019s Sjogren\u2019s disease. Her obesity and anxiety worsened similar inflammatory disease pathways subserved by this autoimmune disorder. Suboptimal placental implantation and development began 2\u20138 days after conception given this exaggerated pro-inflammatory state. The placenta\u2019s shared genetic endowment between parents and fetus  more likUse of corticosteroids, weight reduction and treatment for anxiety before conception in LMIC and HICMD could help delay or avoid trimester-specific placental diseases for a percentage of MPF triad This preventive approach could avoid fetal cardiac failure, hydrops fetalis and prematurity.Prematurity is a complex adverse outcome. Trimester-specific G x E interactions to the MPF triad involve placental dysfunction resulting in prematurity . SuboptiCurrent fetal surveillance tests cannot fully document placental disease pathways affecting many MPF triads. Training of healthcare providers particularly in LMIC and HICMD must anticipate these adverse effects of placental-cord pathology without the availability of fetal surveillance testing to document abnormalities. Chronic or acute diseases are often undetectable using fetal sonographic assessments of fetal heart patterns, Doppler flow indices and biophysical scores to assess fetal well-being. Appropriate measures of fetal growth and function does not exclude risks from placental disease with adverse outcomes to the fetal nervous system.Training of placental-cord development and pathogenesis enhances the provider\u2019s understanding of time-dependent etiopathogenesis that contributes to sequelae such as DD. Placental-cord disease pathways are associated with diseases expressed by the woman, MPF triad and neonate. This perspective improves clinical decision-making, effective interventions, and prognosis. Despite normal fetal surveillance testing, postnatal pathological examinations may document trimester-specific disease pathways. Future prenatal structural and functional placental imaging studies will offer more effective diagnosis and interventions to improve outcomes for affected MPF triads  before fThree placental disease mechanisms cumulatively contribute to an understanding of adverse effects to the fetal brain. Knowledge of these disease entities are essential for maternal-pediatric healthcare providers to advocate for improved medical delivery particularly in LMIC and HICMD.Maternal immune activation (MIA) was the initial pathologic process that presented shortly after conception for this MPF triad. MIA represents immune intolerance between the embryo and the mother . SuboptiMIA is associated with reduced energy substrate delivery, waste removal, and deprivation of essential growth factors as embryonic-fetal maturation advances into second and third trimesters . MIA conIschemic placental syndrome (IPS) was the second placental disease that developed later during this pregnancy given postnatal gross and histological placental-cord findings. Prenatal sonographic measurements described preserved fetal growth for this child without fetal growth restriction. However, abnormal placental angiogenesis from IPS can still reduce placental blood flow to the fetus without current fetal surveillance detection. Defective spiral artery remodeling after 12 weeks GA results from abnormal precursor trophoblastic cellular development that begins during early first trimester ,21 with Marginal cord insertion  with hypFetal inflammatory response (FIR) is a third pathologic mechanism that potentially affected placental structure and function in addition to MIA and IPS . Often uMaternal autoantibodies , the metabolic syndrome  and elevated endogenous steroid and norepinephrine production  cumulatively contributed to this mother\u2019s non-infectious pro-inflammatory state into the third trimester.FIR type I is the more predominant etiopathogenetic mechanism closer to delivery. Two disease pathways have been identified with FIR Type I, contributing to fetal brain injuries. Asphyxia occurs from inflammatory mediator-induced vasoconstriction within the placenta/cord and fetal brain blood\u2013brain barrier vasculature resulting from direct effects by pathogens and abnormal cytokines on blood vessel caliber size and contractile responsivity. A second cytokine-associated mechanism with FIR Type I contributes to this asphyxial neuronal damage. Mitochondrial dysfunction within the cytosol and altered genetic expression within nuclei result in injury from cytokines with cell death or dysfunction in surviving neurons .Fetal brain maldevelopment and/or injury therefore potentially result from the cumulative effects of MIA, IPS and FIR to a vulnerable MPF triad across three trimesters. Altered embryonic-fetal brain structures during the first trimester impair multiple neuronal cell precursors within transient region with abnormal proliferation, differentiation, and migration. Abnormal neuronal connectivities later alter the cortical mantle during the second and third trimesters  with abnBalanced development of excitatory and inhibitory neuronal precursor activities is required for normal fetal brain maturation and function. An altered excitatory/inhibitory ratio resulting from these placenta-cord diseases contribute to altered brain circuitries expressed as DD, mental health disorders and epilepsy .Present standards of maternal levels of care  for thisFour \u201cgreat neonatal neurological syndromes\u201d comprise most children who require neonatal neurocritical care . NeonataG x E vulnerabilities of this maternal-child pair exemplified how prenatal and postnatal diseases contributed to EP and later DD.Developmental and destructive brain processes define EP with trimester-specific disease pathways that later influenced postnatal disease factors . Risks fOver 80% of nearly 15 million preterm children are born in LMIC . IncreasThese efforts will lower the prevalence and severity of EP for vulnerable MPF triads such as those exposed to healthcare disparities in LMIC and HICMD.Postnatal complications of prematurity further increased risks for EP following fetal cardiac failure with hydrops fetalis. An elective premature delivery with later postnatal medical complications occurred. Multiple pointes de torsade required emergent cardioversions during her first week of life to treat her cardiac decompensation. These events represented cumulative postnatal risks for injury from cerebral hypoperfusion. Additional adverse conditions of prematurity included pulmonary disease, anemia and gastrointestinal immaturity which contributed to reduced oxygen and nutrient delivery.Current conventional postnatal cranial sonography and conventional brain MRI studies  documentSuch diagnostic and therapeutic advances will be first available to MPF triads and neonates in HIC where there is greater access to research protocols. Research protocols in LMIC and HICMD require strategies for best practices to deliver technologies to those who are most vulnerable with healthcare disparities. Maternal-pediatric hospitals in these countries and regions require research efforts that compare different preventive, clinical and wellness study protocols to best deliver healthcare to women and children  to reducDevelopmental delay during this child\u2019s first 1000 days represented postnatal clinical expression of previously acquired fetal and neonatal brain disorders. Early interventions supported by parental commitment offered greater healthcare and educational opportunities. Preschool expression of DD was replaced during school years with neurocognitive and mental health challenges as she matured into adolescence.Primary pediatric care partnering with early intervention programs need to offer all children opportunities to address medical and developmental needs. Support for early diagnosis and rehabilitative interventions must begin during the first 1000 days. Challenges are greater with more limited access to preventive, clinical and wellness resources in LMIC and HICMD. Community-based primary care with the ability to provide early intervention programs must be accompanied by wellness programs to minimize adverse childhood effects.Communicable and non-communicable diseases during childhood further complicate healthcare with adverse effects educational achievement. An acute hypertensive crisis with a cerebrovascular complication for this child at 10 years of age presented a new medical challenge. Her neurologic presentation of posterior reversible encephalopathy syndrome  was assoSudden systemic hypertension potentially alters cerebral blood flow preferentially to posterior brain regions where cerebral vasculature is highly susceptible to the adverse effects of increased systemic blood pressure. Persons with hypertensive disorders throughout their lifespan can experience brain injuries from this disease. The etiopathogenesis responsible for the clinical presentation of encephalopathy and seizures impairs function within the neurovascular unit . Risks for stroke and/or hemorrhage are known complications. A percentage of affected persons, however, exhibit transient or reversible neuroimaging findings as the acute clinical symptoms resolve. This child fortunately did not experience permanent injuries expressed by more severe sequelae.Intensive care management for this child included emergent treatment for status epilepticus and acute hypertensive crisis. Seizures were successfully controlled with resolution of neuroimaging findings on follow-up brain MRI images. Medication discontinuation without seizure reoccurrence after a three-year course of antiepileptic drug treatment was achieved. No apparent regression of her neurologic abilities resulted from these medical events.Healthcare systems in LMIC and HICMD need to prioritize continuity of medical delivery when childhood diseases present that require hospitalizations. Management of childhood medical complications present greater challenges when there is less access to advanced hospital-based medical care. WHO guidelines offer suggestions for improved hospital services for children confronted with acute illnesses in LMIC and HICMD . HealthcBrain maturation during adolescence involves accelerated synaptogenesis that reflects adaptative or maladaptive neuroplasticity. More complex brain connectivities are needed for optimal adult neurologic function. Increased neural network complexity is required to achieve sophisticated cognitive reasoning and social intelligence  requiredMental health challenges accompany DD which may intensify during adolescence. This child\u2019s anxiety, mood instability, and problems with social interactions were adolescent expressions of abnormally increased synaptogenesis which potentially could further limit her adult performance. She experienced functional neurologic disorders and mental health challenges at home and in school despite lessening of earlier life DD. Continuity of psychiatric interventions and social supports by her family helped her through graduation. Continued mental health care by family and healthcare providers will be needed as she prepares for a career, establishes social relationships, and confronts life challenges .Mental illness expressed during childhood more likely is associated with brain disorders during the first 1000 days. Children in a LMIC or HICMD may not experience the same degree of recovery as the child presented for this discussion. Neuron-specific cell processes may result in atypical brain development starting during fetal life with more severe expressions of childhood neurocognitive/behavioral disorders including mental health disorders into adulthood. Public health resources must recognize the importance of mental health care and social problems to address childhood adverse effects. These risks are greatest for those with DD who experience healthcare disparities .Two longitudinal/cross-sectional cohorts present results applicable to the importance of preclinical diagnosis of mental health disorders. Comparisons of neuroimaging and genetic data sets suggested more accurate prediction of mental health disorders prior to clinical expression. Region-specific growth of the cerebral cortex was documented using detailed neuroimaging protocols based on large pediatric cohorts. These studies preceded mental illness and general psychopathology as expressed throughout childhood . These MThese neurodiagnostic advances will benefit children with DD who may also present with mental disorders. Availability for such diagnostic testing is needed in LMIC or HICMD for children at highest risk for mental health disorders accompanying DD.Healthcare policy therefore must advocate for mental healthcare in these vulnerable populations. Unfortunately, cultural misperceptions of DD and mental illness impede these efforts. Criminalization and religious demonization of people with these disorders result in exclusion of children with DD from receiving adequate healthcare and education. Support for families must respect religious, ethnic, and racial perspectives to properly direct interventions. Appropriate services need to be prioritized by community-religious leaders, policy makers, healthcare providers, and educators.The maternal-child pair used for this discussion stresses the continuum of prenatal and postnatal risks that began with maternal autoimmune disease, obesity, and anxiety. Fetal cardiac disease and complications of prematurity were adverse outcomes associated with these conditions. MPF triad phenotypes more broadly reflect multiple maternal diseases  pandemic . SeventeLawmakers and health policy leaders in both HIC and LMIC must adopt bio-social models of care that advocate for optimal care for all persons across the lifespan. This social contract by healthcare providers ,85 benefThe mother-child pair chosen for this review represented a family living in a comparatively resource-rich community. Her parents\u2019 access to the internet and community services provided information and guidance to receive maternal and pediatric healthcare, minimize adverse childhood effects and plan educational interventions as their daughter\u2019s medical and school challenges were identified. Teachers and therapists effectively applied knowledge of educational neuroscience applicable to her specific scholastic needs. Healthcare and educational services remained available for this family throughout high school.Healthcare strategies must address cultural, financial, and political barriers to care  beginninPrinciples of ontogenetic adaptation help explain long term effects of positive and negative neuroplasticity . Time-deWith advances in medical care into adulthood, longer life expectancy for older survivors with DD requires a greater priority for inclusion regarding optimal educational attainment during childhood to achieve better employment and societal interactions as adults . There iAs estimates for life expectancy increase for people with DD, acute and convalescent medical services and quality home care delivery must be anticipated to assist aging families and their proxies. Adults with moderate intellectual disability and cerebral palsy may potentially live into their fifties, assuming stable health without accidents or chronic illnesses. Milder clinical expressions of disability now experience similar life expectancy estimates as healthy populations without DD ,92,93.Communicable and noncommunicable diseases disproportionately affect more women and children in LMIC and HICMD. Maternal health consequences after genitourinary infections, hypertensive disorders, and diabetes mellitus are examples of prevalent maternal conditions that adversely affect fetal brain health presenting as diseases of the MPF triad and neonate. The great neonatal neurologic syndromes of encephalopathy, seizures, stroke, and EP are postnatal expressions of trimester-specific diseases after birth. Childhood neurologic disorders such as DD are further influenced by ongoing diseases or adverse conditions.Diversity and inclusion for healthcare and education delivery are essential for optimal outcomes. Integrating developmental origins and life course theories into clinical and public health practices  will serThe WHO sustainable development goals advocate for all women and children. Transactional models to achieve these goals require healthcare policies that integrate the continuity of maternal and pediatric healthcare beginning before conception when first addressing a girl\u2019s reproductive health. These goals are later integrated with advocacy for pregnancy planning and optimal maternal preventive care during and between pregnancies. Communities require resources provided by public health programs for effective nutrition, health care, housing, and sanitation to maximize life-course health during and between each pregnancy.Preventive healthcare education and resources require support by a nation\u2019s public health infrastructure that can effectively provide medical and educational services to children and families that recognize and overcome geographic-cultural barriers. With public health efforts, effective educational plans can be initiated at the earliest ages to optimize the school performance of a child with DD, applying educational neuroscience by teachers recognizing ethnic, racial, and cultural context. These actions will benefit the most vulnerable with healthcare disparities in LMIC and HICMD.While these efforts potentially have significant global impact, wide gaps remain between preclinical diagnosis of DD and implementation of interventions for women of reproductive age between and during their pregnancies. The WHO sustainable development goals recently highlighted brain health across the lifespan to promote adaptive neuroplasticity starting during critical-sensitive periods. This emphasis on brain health must advocate for women, children, and adolescent health, with interventions that begin during the first 1000 days and continue into adulthood .Every Newborn Action Plan presented by the WHO further emphasizes strategies to reduce neonatal morbidity and mortality. Success of this plan also advocates for prenatal health of women and MPF triads to maximize the benefits for neonates who require resuscitation, transport, and neonatal intensive care .International cooperation among government and nongovernmental organizations must advocate for a woman\u2019s right for optimal health care and educational services for her children within their community. Such advocacy must be maintained from childhood through adulthood for healthy children and those with DD. Future research protocols need to address maternal and pediatric health disparities by applying public health initiatives that educate women and families to advocate for resources to sustain health into adulthood. Effective partnerships will improve the woman\u2019s health and quality of life throughout life beyond her reproductive years as well as for her children and successive generations.Future biomarkers can potentially apply genetic-metabolomic, neurophysiologic and neuroimaging technologies  for pre-"}
+{"text": "Peer support complements traditional models of chronic kidney disease (CKD) care through sharing of peer experiences, pragmatic advice, and resources to enhance chronic kidney disease self-management and decision-making. As peer support is variably offered and integrated into multi-disciplinary CKD care, we aimed to characterize healthcare providers\u2019 experiences and views on peer support provision for people with non-dialysis-dependent CKD within Canada.In this concurrent mixed methods study, we used a self-administered online survey to collect information from multi-disciplinary CKD clinic providers  on peer support awareness, program characteristics and processes, perceived value, and barriers and facilitators to offering peer support in CKD clinics. Results were analyzed descriptively. We undertook semi-structured interviews with a sample of survey respondents to elaborate on perspectives about peer support in CKD care, which we analyzed using inductive, content analysis.We surveyed 113 providers from 49 clinics. Two thirds (66%) were aware of formal peer support programs, of whom 19% offered in-house peer support through their clinic. Peer support awareness differed by role and region, and most referrals were made by social workers. Likert scale responses suggested a high perceived need of peer support for people with CKD. Top cited barriers to offering peer support included lack of peer support access and workload demands, while facilitators included systematic clinic processes for peer support integration and alignment with external programs. Across 18 interviews, we identified themes related to peer support awareness, logistics, and accessibility and highlighted a need for integrated support pathways.Our findings suggest variability in awareness and availability of peer support among Canadian multi-disciplinary CKD clinics. An understanding of the factors influencing peer support delivery will inform strategies to optimize its uptake for people with advanced CKD.The online version contains supplementary material available at 10.1186/s12882-022-02776-w. Chronic kidney disease (CKD) is a complex condition that affects 13% of the population globally and, in its most advanced stage, can result in kidney failure requiring dialysis or transplantation as life-sustaining therapy , 3. PeerPeer support may augment traditional models of multi-disciplinary CKD care by enabling peer validation of patients\u2019 experiences and exchange of pragmatic resources for living well with their disease \u20138. Peer Limited research on peer support for people with kidney disease suggests that variability in awareness and promotion within kidney care programs poses a barrier to peer support uptake . While aWe used a concurrent mixed methods approach to understand how peer support is perceived and delivered in multi-disciplinary CKD clinics across Canada . This inEligible participants included healthcare providers  from multi-disciplinary CKD clinics across Canada. We purposively sampled eligible providers through the CKD Clinic Network, a pan-Canadian organization of providers and managers from multi-disciplinary CKD clinics who care for persons with advanced, non-dialysis-dependent CKD , 26. A nA self-administered online survey was developed by the investigators based on findings from previous work and related peer support and self-management literature  experienced in qualitative research and with no prior relationships with participants completed all interviews, which were audio-recorded and lasted approximately 30-40\u2009min. A question guide was used to prompt discussion about the promotion and integration of peer support programs in CKD clinic care and their perceived need to address identified care gaps   groups are in silos\u201d limited their availability to a broader range of people with CKD. Despite the potential value of integrating peer support within CKD clinics as an \u201cadjunct\u201d to existing support services, providers considered it critical to clarify the scope of services through clear boundaries and expectations.Ranked barriers and facilitators from survey responses and those reported in interviews with supporting quotes are compared in Table\u00a0Survey respondents emphasized inconsistent awareness of peer support among clinic providers as a main barrier to integrating peer support. Interviews identified additional challenges posed by recent increases in virtual technology use. The latter issue made it difficult to identify patients who might benefit from peer support during clinic encounters and to offer peer support virtually to patients with limited access to technology. Interview and survey participants also identified barriers of workload demands, competing priorities, and lack of adequate time and resources to discuss or offer peer support.Across surveys and interviews, participants underscored having systematic approaches to offering peer support in clinics as a facilitator. This included processes for routine staff education about available programs and clear role definitions among team members as to who discusses peer support with patients. The importance of close relationships with external organizations to foster collaboration in peer support delivery was highlighted more frequently in interviews than surveys. Although leadership and management support were ranked highly as facilitators in the survey, participants did not emphasize this during interviews.Integrated findings across quantitative and qualitative phases suggest that despite variable awareness of peer support availability, participants appreciated the value of peer support for people with CKD. A lack of systematic processes for introducing peer support within and across CKD clinics meant that many providers were unable to consistently offer it to their patients. Participants expected that attempts at integrating peer support within CKD clinics would be met with challenges, including high workload demands and competing priorities for CKD clinic staff. The importance of addressing accessibility challenges through tailored peer support options was also emphasized across participants. Despite anticipated difficulties, providers offered suggestions for integrating peer support into CKD clinic care with appropriate organizational supports and collaboration.Participants across roles recognized that provider awareness of peer support was necessary to effectively promote programs to their patients. However, awareness was lower than anticipated and varied by role and region, which may point to variability in how CKD clinics operate and in peer support availability across the country. Although our results differ from other studies reporting higher awareness of peer support among staff in kidney care programs, poor knowledge of peer support practicalities has been identified as a major barrier to uptake of peer support programs among people with varying stages of kidney disease , 14, 33.In our study, peer support referral and embeddedness with other clinic support offerings were inconsistent given both limited resources and lack of formalized practices. Participants also described a lack of role clarity related to offering and/or integrating peer support within their clinics. Whereas nephrologists and nurses commonly assumed that social workers were the most appropriate team member to discuss peer support, social workers indicated it should be a shared responsibility. In contrast, respondents from other studies suggested peer support referral fit within the nursing scope of practice , 33. TakParticipants emphasized the importance of tailoring peer support delivery to their local context as a way of addressing lower receptivity and access to peer support among CKD patients, yet faced challenges in doing so in the clinic setting. As Canadian CKD clinics operate under regional health authorities and comprise different models of care and resources , 27, 35,Wood et al. recently reported on experiences related to the adoption of a national peer support program for patients across various kidney disease contexts, including dialysis, in the United Kingdom (UK) . In thisFindings from our study offer practical considerations for the provision of peer support as part of routine CKD care. CKD clinics may provide an optimal setting for offering or embedding peer support due to their provision of longitudinal care using a multi-disciplinary, team-based approach \u201322. Our Our study was strengthened by its inclusion of healthcare providers and CKD clinics from across Canada and exploration of complementary aspects of an important care issue for patients with CKD . HoweverIn this study we noted variability in how healthcare providers from CKD clinics across Canada promoted and offered peer support opportunities to patients and their caregivers. Our findings suggest that factors such as streamlined referral processes, collaboration between programs, and program adaptation to fit local contexts could encourage peer support awareness and uptake. A clearer picture of how peer support is currently offered to patients with non-dialysis-dependent CKD and providers\u2019 needs related to peer support delivery can inform strategies to optimize its integration into CKD care. Future work to establish and evaluate systematic approaches to peer support in comprehensive CKD care are needed.Additional file 1. Consolidated Criteria for Reporting Qualitative Research (COREQ): completed checklist reporting on qualitative results according to recommended guidelines.Additional file 2. Peer support in CKD survey: questions included in the online survey.Additional file 3. Interview guide: questions used in the semi-structured interviews with a subset of healthcare providers.Additional file 4. Characteristics of in-house peer support: description of integrated peer support programs from respondents indicating peer support delivery within their clinic.Additional file 5. Characteristics of peer support processes: description of clinic processes from respondents indicating peer support awareness.Additional file 6. Likert scale responses: responses to Likert scale questions about perceived need, interest, and impact of peer support."}
+{"text": "Halophyte [Cynodon plectostachus (K. Schum.) Pilg.] and non-halophyte grasses (Lolium perenne L. and Panicum maximum Jacq.) clustered along increasing soil salinity. Halophytic grasses [Panicum antidotale Retz. and Dicanthum annulatum (Forssk.) Stapf] congregated with Medicago sativa L., a non-halophytic legume along a gradient of increasing photosynthesis. Halophytic grasses  had strong yield-salinity correlations. Medicago sativa L. and Leptochloa fusca L. Kunth were ubiquitous in their forage biomass production along a continuum of medium to high salinity. Forage crude protein was strongly correlated with increasing salinity in halophytic grasses and non-halophytic legumes. Halophytes were identified with mechanisms to neutralize the soil sodium accumulation and forage productivity along an increasing salinity. Overall, halophytes-non-halophytes, grass-forbs, annual-perennials, and plant-bacteria-fungi synergies were identified which can potentially form cropping systems that can ameliorate saline soils and sustain forage productivity in salt-affected arid regions.Soil salinity limits crop productivity in arid regions and it can be alleviated by crop synergies. A multivariate analysis of published data ( Forage crops and rangeland species have immense potential to rehabilitate and improve the natural ecosystem services besides providing forage supply to livestock and wildlife. They maintain soil health by regulating environments against the effect of climate change and pollution. In arid regions, these benefits from vegetation have been jeopardized by adverse environmental conditions, particularly endemically marginal precipitation . Traditi\u20131 and sodium accumulation greater than 15%  ions which replace potassium (K+) ions in plant biochemical functions  how consistent are mechanisms of tolerance to salinity among forage species in different habitats, (ii) do species converge in their salinity tolerance mechanisms, (iii) what are the possible synergies among species in their adaptation to saline soils, and (iv) how can mechanisms of species tolerance and synergies be used to design forage cropping systems adapted to saline soils. Hence this article reviews and reanalyzes published data to determine crop yield loss to soil salinity, species mechanisms of salinity tolerance and ecosystem services, and their potential synergies which can be used to design forage cropping systems for sustainable and resilient agroecosystems.\u20131). Subsequently, crop species were categorized according to their ecosystem services reported in saline soils in arid and semi-arid habitats across continents. These involved studies spanning 1\u20135 years conducted in field conditions, each with a non-saline soil control besides an increasing magnitude of treatment to strongly saline soils. The criteria of + ion accumulation in crop biomass and their role in reducing soil salinity (bioremediation). Lastly, supporting services were crop microbe interactions that support nutrient cycling in forage cropping systems. The identified synergies were used as indicators to illustrate the model cropping systems that can alleviate soil salinity and enhance forage crop productivity and nutritive value.This article provides a synthesis of correlations between salinity tolerance mechanisms and ecosystem services of forage crops. The first stage was to determine forage crop yield losses to soil salinity and discuss its tolerance. Thereafter, attempts were made to determine if forage crop species converge in their mechanisms of salinity tolerance and what this implies to forage productivity. In this regard, tolerance was considered the ability to maintain photosynthesis and dry matter yields with increasing salinity up to 200 mM NaCl concentrations in the propagation medium . Salinite (saturated paste extract), and crop duration and cited authors. Additional variables including accumulated soil organic carbon, forage dry biomass, forage crude protein, soil EC change, and Na+ ion uptake. Data were subjected to the multivariate analysis procedure to determine correlations between variables and accordingly relationships among forage crop species. In doing so, the FactoMiner package was deployed to conduct principal component analysis (PCA) which also involved standardizing data according to the deviation of individual variates from the sample mean divided by sample standard deviation  Thwaites and Panicum antidotales Retz. have been reported to retain similar shoot moisture with increasing salinity levels from 0 to 140 mM NaCl (+ ions in the media around roots (Imperata cylindrica (L.) P. Beauv., Eragrotis amabilis (L.) Wight and Arn., Cynodon dactylon (L.) Pers., and Digitaria ciliaris (Retz.) Koeler  Thwaites grown in saline environments up to 140 mM NaCl  Kunth which enhanced photosynthesis up to 400 mM NaCl (+ and Cl\u2013 ions as well as their role in generating reactive oxygen species. This is exemplified in enhanced exudation of Na+ and Cl\u2013 ions by Sporobolus spicatus (Vahl) Kunth at 400 mM NaCl  Koeler , Festuca mM NaCl , and Agr mM NaCl . Under itabolism . Potassitabolism . Potassiectively . In thise shoots . In the  mM NaCl . In addi mM NaCl . Maintai mM NaCl . Species mM NaCl . Festuca mM NaCl , which d2 and O2 . These mCynodon plectostachyus (K. Schum.) Pilg.), a halophytic grass, clustered together with non-halophytes including perennial ryegrass (Lolium perenne L.) and guinea grass (Panicum maximum Jacq.) and less proximately with Setaria sphacelata (Schum.) Stapf and Hubb. and Pennisetum hybridus, all of which had close associations with increasing soil salinity. Alfalfa which is a non-halophyte clustered with halophytes namely marvel grass (Dicanthum annulatum (Forssk.) Stapf) and blue panicum grass  along increasing photosynthesis. Saltgrass (Sporobolus spicatus (Vahl) Kunth) which is a halophyte, stood alone with strong and near equitable contribution to increasing relative yield, photosynthesis and salinity. Saltgrass is reported to restrict the Na+ uptake with increasing soil salinity and secrete excess salts at night (Lotus corniculatus L.), a non-halophytic legume, congregated with halophytic grasses including intermediate wheatgrass , and blue panicum grass  associated with reducing salinity, photosynthesis, and relative yield. Intermediate wheatgrass has C3 photosynthetic machinery  and wheat (Triticum aestivum L.) which are considered marginal halophytes. These annual grain crops are commonly diversified with annual legumes in time or space. Nevertheless, their proximal grouping with birdsfoot trefoil suggests a potential coexistence, for instance, in living mulch or in prolonged rotations. Living mulch refers to maintaining a perennial legume crop in an annual cropping system. Oat (Avena sativa L.), a halophytic annual grain, and Pennisetum purpureum Schumach., a non-halophytic grass, had near neutral contribution to salinity, photosynthesis, and relative yields hence potential candidates for long perennial annual rotations. Overall, the results of PC indicate a convergence of halophytes and non-halophytes in their physiology and yield response to salinity. This suggests possibilities for synchrony of diverse species functional groups in their adaptation to salinity stress which can support synergies that enhance overall forage productivity. In broad sense, such coexistence and facilitation can compensate for generally low forage productivity of halophytes as It is of primary significance that grass and forb species mechanisms of salinity tolerance translate to sustainable forage biomass production and resilience to further exposure to salt stress. at night . This inachinery  and is lSynergies refer to the simultaneous increase or decrease in the provisioning of ecosystem services . Forage \u20131  to 41 dS m\u20131  are analyzed in sections \u201cProvisioning Ecosystem Services of Forage Production\u201d to \u201cSupporting Ecosystem Services for Soil and Animal Health.\u201dOverboard, crop diversification to mimic the stability of primary production and resilience of natural vegetation to disturbances is increasingly appealing to the design of sustainable agroecosystems . For exa\u20131. Blue panicum grass and Rhodes grass followed a similar pattern.As shown in + over Na+ ions in grass  and lower crude protein than legumes. As depicted here, grasses are versatile in their range of crude protein concentration, some of which march that of legumes. A combination of grasses and forbs to generate forage of NDF \u2264 50% and crude protein \u2265 20% of dry matter is recommended to support animal and ruminal microbial energy needs which invigorate animal health and reproduction . The balvia improved soil structure and therefore enhanced infiltration of Na+ ions down the soil profile , a halophyte, can extract an estimated 1 ton of Na+ ions ha\u20131 year\u20131. This subsequently enhanced plant water and K+ ion retention together with shoot biomass in succeeding barley (Hordeum vulgare L.). Saltwort has similar potential, for instance, accumulating up to 125 g of Na+ ion kg\u20131 of dry matter within a span of 1 year , saltmeadow cordgrass (3 dS m\u20131), and blue panicum grass (2 dS m\u20131) are reported to have intermediate effects  on biological N fixation by sweet clover (\u223c100%) and alfalfa (90\u201370%) except at 20 dS m\u20131 . It is suggested that N fixing bacteria release indole acetic acid at levels that safeguard the symbiotic process and plant growth from severe levels of soil salinity  with annual grain-legume mixtures in a sequence that extends through fallow periods. The halophyte is designed not only to adapt in marginal weather conditions but also able to absorb Na+ ions and supply surface mulch for the next annual grain-legume crop mixture. The fourth system is an annual grain monocrop-legume monocrop in rotation. This system advances the benefits of optimum forage productivity and cover crops over at least 3 years of rotation. Overall, the cropping systems suggested here are designed to exploit the ecosystem services that enhance N and P supplies and optimize forage productivity and nutritive value. These systems are also developed to sequester carbon and alleviate salt buildup and toxicity in a gradual process that leads to sustainable forage production in areas prone to salinity.All of the above information showed that there is overwhelming evidence that soil microbes are ingredients of ecosystem sustainability by virtue of their roles in soil nutrient cycling. Soil microbial communities rely on energy from their plant hosts, and when established, they can revitalize crops against the effects of soil salinity and support forage productivity and nutritive value. This potential has not been fully exploited in orchestrated cropping systems to alleviate soil salinity and its effects on ecosystem health. This article explored species mechanisms and synergies that can be incorporated in cropping systems to alleviate the challenges of soil salinity and sustain forage productivity in arid regions. It is clear that halophytic and non-halophytic forage crop species have convergent mechanisms of salinity tolerance manifested in enhanced photosynthesis and productivity. There are indicators of ubiquity of ecosystem services of both halophyte and non-halophytic species along a continuum of increasing soil salinity. Potential grass-forb, annual-perennial, halophytes-non-halophytes, and plant-bacteria-fungi synergies against effects of soil salinity were identified. These synergies can be harnessed in designing sustainable forage cropping systems that ameliorate saline soils and improve nutrient cycling to sustain optimum forage productivity.The original contributions presented in the study are included in the article/DA and AN conceived and designed the study. AN supervised the work. DA, EA, AH, and AE collected and analyzed the data. DA drafted the manuscript. AH, LK, KD, and AN validated the data analysis and reviewed all the versions of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Post-traumatic stress disorder (PTSD) and abnormal spirometry are highly prevalent mental and health conditions in World Trade Center (WTC) responders. We tested the hypothesis that PTSD symptomatology and abnormal spirometry are conjointly and synergistically associated with poorer cognitive performance. A total of 1,326 responders  from the WTC Health Program took part in the study. PTSD symptomatology was assessed using the PCL-IV, and we calculated the FEV1/FVC ratio to measure pulmonary function. Cogstate assessments measured cognitive performance. Linear regressions were employed to evaluate PTSD and pulmonary function on cognitive performance while adjusting for age, sex, education, smoking status, and comorbidity. Higher PTSD symptomatology and lower pulmonary function were independently and conjointly negatively associated with cognitive performance. Further, a significant synergistic effect was present in that higher severity of PTSD symptomatology in the presence of lower pulmonary function was associated with poorer cognitive performance . Results suggested that chronic stress and lung damage might share underlying biological mechanisms, including inflammatory and oxidative stress pathways, which may also be affecting the brain. Early intervention efforts to mitigate preventable cognitive decline in high-risk populations should be studied."}
+{"text": "Background: Many patients suffering from schizophrenia spectrum disorders continue having distressing auditory hallucinations and paranoid ideations despite receiving current treatment. Virtual reality assisted treatment offers the potential of advancing current psychotherapies for psychotic symptoms by creating virtual environments that can elicit responses  mirroring real-world settings. In two large-scale randomised clinical trials, we are investigating whether targeted virtual reality assisted psychotherapy can reduce psychotic symptoms and increase daily life functioning and quality of life. The CHALLENGE trial examines whether nine sessions of virtual reality-assisted psychotherapy is superior to nine sessions of standard treatments in reducing the severity, frequency, and distress of auditory hallucinations in patients with psychosis. In the Face your Fears trial we are investigating whether virtual reality assisted cognitive behavioral therapy (CBT) is superior to standard CBT in reducing levels of paranoid ideation in patients with psychosis spectrum disorders. Methods: The CHALLENGE and Face your Fears trials are randomised, assessor-blinded parallel-groups superiority clinical trials, allocating a total of 266 and 256 patients, respectively to either the experimental intervention or a control condition. The trials are currently enrolling patients; thus, no quantitative data is available yet. The main objective of this presentation is to give a qualitative account of this new psychotherapeutic methods as it is applied in both trials. Results: Qualitative data comprising case descriptions and video material will be presented at the conference. Discussion: The preliminary findings indicate great potential for these innovative treatments albeit important concerns regarding implementation will be raised.No significant relationships."}
+{"text": "Research has repeatedly demonstrated that greater affective reactivity to daily stressors is associated with detrimental health outcomes . However, most research has only considered linear effects, which precludes an examination of whether moderate levels of stress reactivity may be beneficial. Using daily diary data from the National Study of Daily Experiences  we fit multilevel SEMs to simultaneously model daily within-person associations between stress and negative affect , and individual differences in the linear and quadratic associations between stress reactivity and life satisfaction, psychological distress, and chronic conditions. Significant quadratic effects were found for each of the three outcomes , indicating a U-shaped pattern where both low and high levels of stress reactivity were associated with poorer health, whereas moderate levels of daily stress reactivity predicted better health outcomes. The results suggest that some affective response to daily stressors can be beneficial."}
+{"text": "Medication nonadherence is associated with numerous negative health outcomes among older adults, including myocardial infarction, stroke, preventable hospitalizations, and increased risk of decline in self-reported health status. Maintaining continuous use and access to needed medications in later life has important implications for quality and length of life. A primary barrier shown to interfere with medication adherence in older adults is an inability to pay for medication. Relative to their younger counterparts, older adults have more financial protections that increase access to needed prescription medication through health insurance coverage. Despite these added protections, older adults are more likely to experience financial insecurity, with some evidence suggesting that COVID-19 accentuated existing vulnerabilities. Data are derived from the Health and Retirement Study (HRS), leveraging data drawn from the 2016, 2018, and 2020 study waves . Logistic models were used to evaluate the association between five COVID-19 related financial setbacks , and medication nonadherence among adults 60+. Results show that net of pre-COVID financial vulnerabilities and socioeconomic status, individuals who reported being unable to pay medical bills and those unable to pay rent/mortgage after the start of the pandemic reported higher odds  of not taking/filling their prescription medication due to cost. Results suggest that greater financial protections for housing and medical bills among financially vulnerable older adults will increase medication adherence."}
+{"text": "Computed tomography angiography (CTA) has been the gold standard imaging modality for vascular imaging due to a variety of factors, including the widespread availability of computed tomography (CT) scanners, the ease and speed of image acquisition, and the high sensitivity of CTA for vascular pathology. However, the radiation dose experienced by the patient during imaging has long been a concern of this image acquisition method. Advancements in CT image acquisition techniques in combination with advancements in non-ionizing radiation imaging techniques including magnetic resonance angiography (MRA) and contrast-enhanced ultrasound (CEUS) present growing opportunities to reduce total radiation dose to patients. This review provides an overview of advancements in imaging technology and acquisition techniques that are helping to minimize radiation dose associated with vascular imaging. Patient radiation exposure is a known consequence of several common forms of medical imaging but has been deemed acceptable in a variety of conditions where the benefit of diagnosing or excluding an underlying medical condition outweighs the potential adverse effects of patient radiation exposure. Computed tomography (CT) and CT angiography (CTA) are the medical imaging methods with the highest radiation exposure, accounting for approximately half of the total radiation exposure in the United States  Report No. 184) [Current generations of CT scanners generate peak energies between 80 to 140 kV, with the majority using a tube potential of 120 kV, according to the International Commission on Radiological Protection (ICRP) Publication 135 [A single CT examination can range anywhere from 1\u201330 mSv in adult patients depending on the type of scan, CT scanner, and the region of the body measured, while CTAs can reach 100 mSv in some cases . While avol). Some example reference values of CTDIvol include 25 milligray (mGy) for the adult abdomen, 15 mGy for the pediatric abdomen, and 75 mGy for the adult head [vol and the scanning length in centimeters (cm). Facility registries, such as the CT Dose Index Registry, as well as the development of guidelines (including the ACR Appropriateness Criteria), have been implemented to promote further radiation reduction throughout the medical imaging field [Commonly accepted radiation exposure limits for various examinations are developed by the ACR and must be validated regularly for accreditation for each CT scanner used at a given facility, termed the Computed Tomography Dose Index Volume (CTDIult head . Dose Leng field . Even wiT), a relative measure of the radiosensitivity of organs to radiation, include the stomach, colon, lung, bone marrow, and breast [Patients who undergo surveillance or postoperative scans are exposed to additional radiation even after the initial identification and intervention of the underlying medical condition. While ongoing surveillance scans are often indicated, the lifetime cumulative radiation exposure of continued surveillance scans may breach even the highest lifetime radiation exposure recommendations. Intraoperative exposure to radiation by fluoroscopy is another source of considerable radiation exposure used in a wide variety of procedures, including the guidance of intravascular catheters and for confirmation of orthopedic hardware placement. Organs with the highest tissue weighting factor  is commonly used to evaluate coronary artery disease (CAD) and is preferred over invasive coronary angiography for patients with low\u2013intermediate risk of CAD . The useAs radiation reduction techniques continue to evolve in other areas of CT imaging ,14,15,16A literature search was performed using the PubMed database and Google  search engine. Databases were searched using the keywords \u201cradiation reduction techniques\u201d, \u201cmagnetic resonance angiography radiation reduction\u201d, and \u201ccomputed tomography angiography radiation reduction\u201d. Some specific searches for relevant topics such as the new MAGNETOM FreeMax  magnetic resonance imaging (MRI) system was performed using Google, as well as further exploration of topics around the use of AI in radiation reduction techniques.The most efficacious strategies for radiation reduction adhere to the as low as reasonably achievable (ALARA) principle in which acquisition techniques are optimized to answer the clinical question, while reducing patient radiation exposure as much as possible .A simple but often overlooked method of radiation reduction includes reducing and/or optimizing the scan length, which has proven especially effective for radiation reduction in coronary CTA (CCTA) scans ,18. ScanAutomatic tube current modulation (ATCM) enables CT scanners to alter tube current based on density differences in tissue attenuation, utilizing lower tube current when possible and subsequently resulting in lower radiation exposure . Larger New, sophisticated CT image reconstruction techniques require less patient radiation exposure to produce diagnostic level imaging quality. Advances in imaging reconstruction due to increased computer processing speeds allow for increased image processing complexity while retaining acceptable processing times.Iterative reconstruction (IR) is one such example that reduces radiation exposure from 40\u201363% when compared to using filtered back projection (FBP) techniques for CCTA; new hybrid IR techniques are expected to further reduce dose exposure in the future ,21,22,23Other methods of radiation exposure reduction take advantage of the increased processing power now possible with modern computers, such as electrocardiogram (ECG)-controlled tube current modulation (ECTCM), a technique that reduces radiation exposure during periods of the cardiac cycle when the resulting image would be unused . More soAI shows promise as another method of radiation reduction through various methods but most notably in image reconstruction. Convolutional neural networks (CNN) are AI algorithms developed to recreate standard-dose images from low-dose computed tomography (LDCT) scans . Deep leAI is also able to reduce radiation exposure by automating CTA tube voltage by dynamically selecting the appropriate voltage based on the patient\u2019s anatomy and size, all while maintaining adequate image quality . AnotherRadiation dose exposure reduction is also possible via the implementation of a dual-source CT (DSCT), which allows for faster image acquisition due to two detectors acquiring perpendicular images simultaneously while maintaining temporal resolution. DSCT is particularly effective in patients who cannot remain still . Using DAnother advancement in the field of CT is dual-energy CT (DECT). DECT is particularly advantageous in the assessment of pulmonary embolus (PE) and the evaluation of chronic thromboembolic pulmonary hypertension (CTEPH) . StudiesImportantly, the photon counting detector in DECT machines can apply a threshold that enables the filtering of unwanted noise, allowing the scans to be performed at lower radiation doses . Some stVirtual monoenergetic images (VMI), acquired using DECT, involve using either the projection domain or image domain to generate superior, blended images of high and low energy acquisitions, taking advantage of the high contrast offered in low keV scans while also benefitting from the low noise of the high keV acquisition . VMI+, cDECT also offers an alternative to traditional contrast scans through virtual non-contrast images. These DECT scans are used to calculate the calcium score (CaSc) for coronary artery disease risk stratification. In the past, the level of radiation exposure via traditional angiographic imaging modalities led to this risk stratification method being downgraded . CalciumDECT is also under investigation as a method of evaluating myocardial ischemia. Using color-coded-iodine perfusion maps, DECT scans can serve as an indirect perfusion marker and provide functional information regarding the patient\u2019s coronary artery disease. Such information further increases the utility of DECT when compared to traditional CCTA, which only includes anatomic information . Other sWhile many methods to reduce radiation exposure from CT or CTA scans have successfully limited radiation exposure, alternative imaging methods using non-ionizing imaging techniques can supplement, and in some cases replace, traditional irradiating scanning modalities. The ACR Appropriateness Criteria offers clinicians radiologist-approved imaging recommendations for various clinical indications, including a qualitative assessment of the amount of radiation exposure for a given technique, allowing clinicians to select viable alternative imaging methods which result in less or no radiation exposure .Magnetic Resonance Angiography (MRA) is a notable radiation-free alternative to CTA. Radiation exposure from CTA scans is significant, delivering some of the highest radiation dose exposure on a per scan basis of any medical imaging modality. MRA is capable of high-resolution cross-sectional, multiplanar imaging (often without contrast) in a wide variety of applications. In a meta-analysis comparing MRA with CTA, the results show that the two imaging modalities have the same diagnostic value for intracranial aneurysm evaluation, albeit with a limited sample size .Both non-contrast MRAs (NC-MRAs) and contrast-enhanced MRAs (CE-MRAs) offer unique utility based on acquisition methods. Advantages of non-contrast studies include the absence of concern for nephrogenic systemic fibrosis (a condition associated with some of the gadolinium-based contrast agents that may be used in contrast-enhanced MRA), the relative simplicity and non-invasive nature of the scanning procedure compared to scans with contrast, and rapid repeatability of the scans which is particularly beneficial if initial scans are nondiagnostic due to motion artifacts or technical issues . The abiWithin the MRA imaging modality, multiple non-contrast techniques are available based on the region of interest. Flow-independent MRA is often utilized for imaging slow blood flow through veins and diseased arteries with a tradeoff in imaging quality from artifacts generated by off-resonant regions . Flow-deFor patients with renal dysfunction, QISS was developed to evaluate peripheral artery disease (PAD) without the need for contrast material. Requiring only 7 to 8 min on average for a whole-leg exam, QISS drastically reduces scan time when compared to the time of flight (TOF) methods that frequently take an hour or more for a whole-leg exam. QISS is also less prone to artifacts than TOF-MRA, and portions of the exam acquired with motion artifacts can easily be repeated when identified, resulting in only a 1-to-2-min prolongation of the exam time. QISS has also shown promise as a non-contrast, radiation-free imaging technique in diagnosing pulmonary embolism with a sensitivity and specificity of 86.0% and 93.3%, respectively, in a recent study . The priA third non-contrast MRA technique is subtractive 3D MRA. The cardiac-gated subtractive 3D fast spin-echo technique provides image quality comparable with CTA without the off-resonance artifacts that are prominent with flow-dependent MRA techniques. Other subtractive methods include flow-sensitive dephasing (FSD) and arterial spin labeling (ASL). FSD takes advantage of flow-dependent signal reductions between peak systole and end-diastole, resulting in arterial contrast after dephasing gradients are applied along the vessel length. ASL, another subtraction-based imaging acquisition method, is most commonly used as an MRA equivalent of x-ray digital subtraction angiography (DSA) for perfusion imaging of the brain but is also capable of imaging the extracranial carotid arteries. New developments in ASL imaging, such as 3D pointwise encoding time reduction MRA (PETRA-MRA), are in closer agreement with DSA when compared to TOF-MRA in the evaluation of intracranial stenosis . AdditioThe final two notable techniques of non-contrast MRA acquisition include velocity-selective 3D MRA and phase contrast MRA. Velocity-selective MRA is beneficial in slow flow settings where alternative methods such as IFDIR and ASL-based MRA techniques may result in low penetration of tissues. A primary limitation of this method is that artifacts are prominent in a non-uniform magnetic field setting. Phase contrast is an advantageous technique in cardiac imaging, providing quantitative values for shunts and valvular disease. Phase contrast is unique amongst imaging modalities in that the more complex 4D (otherwise known as 3D cine) acquisitions are capable of simultaneously displaying vessel anatomy and flow rates. Like many other MRA techniques, phase contrast is primarily limited by lengthy scan times and the need for complex image processing.In some scenarios, contrast-enhanced MRA (CE-MRA) is a helpful technique for imaging flow-related phenomena . CE-MRA Cardiac MR (CMR) is an imaging modality commonly used for long-term surveillance of adult congenital heart disease (ACHD), which is preferred over alternative methods due to the lack of radiation as well as the ability to avoid the rib spaces  . CompareRegarding MRA performance, a systemic meta-analysis demonstrates sensitivity and specificity of 91% and 88%, respectively, for TOF-MRA of the extracranial arteries . HoweverOne common barrier to utilizing MRA as an alternative to CTA revolves around the availability and/or accessibility of scanners, as well as the relative difficulty that many claustrophobic patients experience due to the traditional scanner design. The prolonged scanning times of MRAs compared to CTAs create additional difficulty for some patient groups. With recent advancements in MR design and reconstruction, new scanners are attempting to mitigate many of the issues associated with MR, including increasing the bore size to accommodate larger patients and reduce claustrophobia. For example, the FDA recently approved a 0.55 Tesla (T) magnet with a larger bore design (80 cm). Importantly, this product has substantial cost savings compared to other scanners due to the lower field power, which allows the scanner to be lighter and easier to transport . AdditioWhile poor resolution has traditionally been associated with lower-powered magnets, some aspects of a low-field strength are beneficial to the image acquisition process . Low-fieContrast-enhanced ultrasound (CEUS) has many advantages over other imaging modalities, including low-cost, non-nephrotoxic contrast agents and a low rate of complications compared to iodinated contrast agents . CEUS isDynamic feedback, a feature unique to the ultrasound (and CEUS) modality, allows for real-time feedback that is particularly advantageous in targeted biopsies where examiners can distinguish between vascularized and non-vascularized tissue . This tyImportant limitations of CEUS include the intralesional gas formation, which limits the utility of ultrasound. Ultrasound utility is limited in areas where the acoustic window may be obstructed by rib shadows which may be further complicated by an intervening bowel gas as well as patient respiration and immobility . FurtherAs discussed previously, a variety of techniques have been developed to reduce radiation exposure that focus on the scanning modality itself. While these methods have been well-studied, other methods of radiation reduction that are unrelated to the imaging modality are effective and may be more easily to implement, especially when financial limitations are a limiting factor when attempting to reduce radiation exposure.In cases where regular surveillance of vascular pathology is required, performing surveillance scans using an approach that alternates between irradiating (CTA) and non-irradiating (MRA) imaging modalities may be a reasonable method to reduce radiation exposure in high-risk patients. As previously described in a publication regarding endovascular repair surveillance , alternaThe creation and implementation of CT imaging protocols requires a team approach, often made up of radiologists, physicists, and CT technologists. Studies have shown that the more individuals involved in the process, the more variable the radiation dose. Employing external medical physicists is associated with increased radiation exposure in lung cancer screening (LCS) exams compared to internal medical physicists, while using any type of medical physicist is associated with lower radiation exposure overall . FurtherPatients at risk of high lifetime radiation exposure should receive special consideration regarding imaging modality selection, as many may require long-term, regular screening for potentially life-threatening pathology.In children, radiation reduction is of paramount importance due to the detrimental effects that cumulative radiation exposure may have on a child\u2019s development and risk of cancer. Kawasaki disease, which requires monitoring for evaluation of coronary aneurysms, can result in high radiation exposure in children as coronary CTA has been the predominant surveillance method . The JapGenetic aortic syndromes, the most common of which is Marfan syndrome, are genetic conditions that require regular imaging for monitoring of the aortic diameter, which is an important predictor of potentially life-threatening aortic aneurysms and aortic dissections . As a reVascular Ehlers-Danlos (previously Ehlers-Danlos type IV) is another aortic syndrome that requires special consideration because of the potential for high radiation exposure. Although no evidence-based guidelines have been developed, institutions have a range of screening recommendations for patients with Vascular Ehlers-Danlos, ranging from regular screening for vascular abnormalities of the arterial tree to a single transthoracic echo in adults with no further follow-up ,52. DoppLoeys-Deitz syndrome, another aortic syndrome, overlaps with Marfan syndrome and/or Vascular Ehlers-Danlos, depending on the specific subtype . Due to Turner syndrome is another condition in which cardiovascular imaging is recommended for bicuspid aortic valve and aortic isthmus stenosis, two congenital cardiovascular malformations that are commonly seen with Turner syndrome . The recBicuspid aortic valve, independent of patients with Turner syndrome, is the most common cardiovascular malformation with a prevalence of 1000\u20132000/100,000 . PatientOutside of genetic conditions, many patients may have more common conditions that require special consideration regarding lifetime radiation exposure. Radiation therapy can be a life-saving treatment for patients with a variety of malignancies, however the impact of cumulative dose should be considered when imaging these patients . Other pThrough various advancements both in imaging acquisition and processing, the average radiation dose has drastically fallen over the last decade. Various institutions have successfully established protocols that reduce radiation through a combination of decision-making algorithms and careful coordination amongst multiple clinicians involved in the individual\u2019s care. CT technique remains the modality of choice for most indications related to vascular imaging. However, several advancements both with CT technology as well as alternative imaging modalities have contributed to opportunities for significant reductions in radiation exposure .DECT allows for more accurate tissue characterization while at the same time requiring lower maximum energy ranges when compared to traditional CT scans. Through this novel technique, a wide range of clinical applications show promise when imaged with DECT, including lung and myocardial perfusion studies, calcium subtraction imaging for coronary artery disease evaluation, detection of portal and deep vein thrombosis, and PE detection, all with benefits of lower or equivalent radiation exposure without the need for exogenous contrast administration.The development of the low-field MRI offers a radiation-free alternative that will gradually become more accessible to a larger subset of the population. By reducing setup costs and other barriers through the novel design of new scanners, MRI may become the imaging modality of choice in the coming years for a wide variety of clinical indications and various screening exams. In specific situations, such as the intensive care unit (ICU) and ED, smaller, portable MRI systems have been shown to be effective, improving efficiency by reducing personnel required due to the portability of the scanner while also improving patient care with a bedside solution that negates the potentially detrimental transportation of the patient that would have previously been a necessity.MRA has proven to be a reliable alternative for radiation reduction, particularly in scenarios where CTA may be traditionally deployed. Multiple studies have found that MRA is comparable to CTA in diagnosing various vascular pathology while offering superior image quality in certain situations such as in the setting of severe atherosclerosis and some metallic artifacts. New techniques allow for the dynamic assessment of blood flow in evaluating pathologic changes in the vessels. Other methods reduce scan time, further reducing the time discrepancy that remains a predominant critique of MRA compared to CTA\u2019s rapid scan times. While CTA will likely remain the predominant modality of choice, advancements in MRA acquisition techniques continue to narrow the gap between MRA and CTA, offering a capable and radiation-free alternative for a variety of indications.Another promising radiation reduction development is deploying AI and scanner learning to acquire low-dose, diagnostic quality scans. With rapid advancements in DL algorithms, AI can reduce radiation exposure by improving the image quality of low-dose images while also reducing processing times compared to traditional iterative reconstruction techniques. Outside of the image quality domain, AI can improve patient positioning during the scan, optimizing the patient\u2019s location within the scanner which reduces radiation exposure. The diagnostic yield of various exams can also be enhanced through AI, allowing clinicians to improve their decision-making process by leveraging the large volumes of data available.While reducing radiation exposure through various hardware and software advancements will continue to reduce total exposure, improving the decision-making process of ordering scans and reducing unnecessary scans is another method of reducing radiation exposure that should be considered. Making decision-making support systems using information technology available for clinicians increases the diagnostic yield of the scans ordered while also reducing both the exposure to the patient and the volume of scans at the medical center .Unfortunately, many medical imaging facilities continue to utilize legacy scanners that limit access to modern radiation reduction techniques. DECT-capable scanners have not been widely adopted as many facilities continue to use legacy CT scanners. MRI accessibility is even more limited due to the higher cost associated with this technology. The development of new image acquisition methods that could be applied to existing scanners to improve the diagnostic quality of low-dose scans may prove useful in situations where new equipment may be cost-prohibitive or financially impractical.Numerous benefits of CT often prevent consideration of other modalities. These benefits include the widespread availability of CT scanners in most hospitals  as well as other factors such as staffing and scan duration ,55. ThisGiven the widespread availability of CT and a variety of other factors already discussed, many trials and research studies have focused on CTA\u2019s diagnostic performance and efficiency rather than MRA or other techniques. For example, CTA was the predominant imaging modality used to identify proximal large-artery occlusion in various trials where mechanical thrombectomy was shown to be superior to noninterventional approaches . CTA alsThe development of AI for widespread use also raises some concerns. Lack of verifiability across imaging platforms, as well as the subjective human ratings that are relied upon during the approval process for AI deployment, have been called into question . CollaboVascular imaging constitutes a robust volume of imaging in many modern radiology practices, ranging from smaller private practice settings to larger referral centers. Traditional methods for evaluating vascular pathology often involved high levels of radiation exposure to patients; however, modern techniques and advances in vascular imaging have significantly reduced radiation doses associated with this segment of diagnostic imaging. A variety of dose reduction techniques and strategies have been developed and applied to CTA imaging which remains the most accessible method to evaluate vascular pathology. Recent advances in alternative non-ionizing imaging modalities have either reduced and/or eliminated differences in sensitivity and specificity between CTA and alternative modalities. However, cost and accessibility remain potential obstacles to realizing the widespread use of these alternative modalities. In particular, technological advances in the sector of MRA imaging have been so rapid that research evaluating performance compared to CTA has been slow to catch up. As researchers further evaluate and confirm the performance of these advances in vascular imaging for both ionizing and non-ionizing radiation imaging techniques, radiologists and clinicians should expect patient radiation exposure associated with imaging of vascular pathology to continue to decrease."}
+{"text": "A number of recent studies have shown that human exposures to a wide range of endocrine-disrupting chemicals (EDCs) may increase the risk of disease across the lifespan by altering the homeostasis or action of endogenous hormones, or other signaling chemicals of the endocrine system. Commonly investigated EDCs include chemicals widely applied in commercial and industrial products, such as per- and poly-fluoralkyl substances (PFAS), polychlorinated biphenyls (PCBs), bisphenol A (BPA), phthalates, and certain pesticides. Our understanding of human health risks associated with exposure to EDCs remains limited. The early development period  might be more vulnerable to exposures to EDCs, but depending on the outcomes, relevant exposure windows may include several periods throughout the entire lifespan. In this Special Issue, we include seven epidemiological studies that address different aspects of human health risks associated with exposures to EDCs.Two epidemiological studies assessed potential associations between EDCs exposure and human reproductive health effects. First, an Italian study considered serum and follicular level of phthalates and BPA among 122 women undergoing oocyte retrieval for in vitro fertilization [Next, a cross sectional study of 1058 Danish men age 18\u201321) evaluated whether the use of personal care products (PCPs) that potentially contain multiple EDCs affected semen quality [1 evaluatThe following two studies published in this issue evaluated the effect of EDCs on maternal health, including preeclampsia and adiposity. The risk of developing preeclampsia in pregnancy was evaluated in relation to exposure to PFAS in a case-control study from Sweden. The study includes 296 cases diagnosed with preeclampsia and 580 controls pregnancies without preeclampsia identified through the Swedish medical birth register . PFAS waA study in a population with a high prevalence of obesity from the Pacific Island nation of Samoa evaluated the association of dietary BPA exposure and adiposity among 399 mother\u2013child pairs . The stuNext, we have also included two articles that assessed associations between EDC chemical exposures and neurological outcomes in children. A California study evaluated whether maternal pregnancy exposure to agricultural pesticide compounds affects offspring\u2019s risk for cerebral palsy (CP) . CP is tAnother study from Taiwan examined childhood urinary levels of multiple EDCs, including several phthalates metabolites, para-hydroxybenzoic acids, and BPA, on the susceptibility to attention-deficit/hyperactivity disorder (ADHD) . ADHD isFinally, this issue also included a methodological study that explored the challenges when distinguishing the confounding or mediating role of obesity in epidemiological analyses that aim to estimate EDCs exposure effect on other chronic health outcomes . The stuIn summary, the seven manuscripts included in the present Special Issue highlight the complexity when studying human health effects associated with endocrine-disrupting chemicals. The included papers demonstrated small steps in our continued understanding of the exposure effects of various EDCs on human health. This area of research is far from complete and greater efforts would be needed from the scientific community to understand whether and how these extremely widespread chemicals may influence health and disease risk in the populations."}
+{"text": "Ex vivo mitral models are fundamental to mitral research and this diligently designed study provides an apt reminder of the strengths of this modelling modality in enhancing our understanding of mitral disease processes and spawning research hypotheses especially in areas where the evidence base is limited such as PM rupture. This commendable hypothesis generating work suggests the presence of sub-phenotypic groups within those with PM rupture, the characterization of which could allow for more precise and efficacious interventional strategies and sets the stage for further study in this challenging research area. Given the acuity and rarity of PM rupture, such information would be difficult to derive from clinical studies.The anatomical and functional complexities of mitral valve pathologies render clinical decision-making and intervention challenging particularly in emergent settings such as acute papillary muscle (PM) rupture. Although rare since the advent of percutaneous coronary intervention, PM rupture carries a dismal prognosis, with a recent multicentre study published in this journal revealing an in-hospital mortality of 24.9% in those undergoing surgical intervention . Given tex vivo mitral modelling are also apparent. Indeed, porcine models are not patient specific and do not fully emulate the complex biomechanics and anatomical variations of human mitral tissue nor would they simulate the various aetiologies of PM rupture and the concomitant sequalae such as left ventricular dysfunction and arrhythmia. Validation of such models is difficult, thereby limiting their translational value to only experimental use. Large-scale use of animal tissue within ex vivo simulators may also be costly and carry ethical implications.Despite the robust study design, the limitations of ex vivo platforms, therefore enhancing their effectiveness. Indeed, it is unlikely that ex vivo platforms will be rendered obsolete with the advent of these novel technologies.The advent and rapid evolution of disruptive technologies in medicine\u2014namely three-dimensional (3D) printing, computational modelling, machine learning and extended realities\u2014and advances in cardiac imaging have the scope to revolutionize mitral modelling. Moreover, they bear the translational potential to facilitate \u2018personalized\u2019 cardiac care and improve clinical outcomes by offering patient-specific procedure planning, surgical simulation training and procedural augmentation. Such technologies are also capable of being integrated with et al. [By integrating volumetric cardiac imaging, material technologies and software engineering, 3D printing transforms digital objects into 3D replicas through multi-layered material deposition over a digitally defined geometry. Advances in cardiac imaging\u2014notably in cardiac CT and 3D transoesophageal echo (TOE)\u2014enable rendering of highly accurate 3D images of cardiac structures. Progress in software engineering, particularly with the integration of machine learning (ML), now enables highly accurate and rapid delineation of anatomical boundaries in a process known as segmentation [et al. . Such plThe domain agnostic nature of ML enables identification of complex associations within big data with the efficacy of such models increasing with volume of inputted data. The quantitative nature of structural heart imaging naturally lends itself to ML and such methods have found a myriad of applications in mitral modelling particularly in automating and enhancing mitral segmentation to rapidly produce accurate 3D mitral replicas in the quest for point of care 3D printing. ML methods and 3D printing have also been successfully integrated to produce a hyper-realistic simulation platform for training in minimally invasive mitral valve surgery .et al. where augmented reality optimized intraprocedural TOE guidance facilitated more safer NeoChord implantation in a porcine model [Extended realities technologies harbour promise in the arena of mitral valve modelling and intervention particularly in surgical training, virtual proctoring and procedure planning . There ine model .Despite the rapid evolution of disruptive technologies, there is cause for caution amidst this riot of innovation. These technologies are relatively nascent, costly and carry their own inherent limitations. Indeed 3D-printed mitral replicas are as yet unable to accurately model mitral tissue and the complexities of mitral biomechanics such as deformation. The accuracy of 3D-printed replicas is also dependent on the quality of cardiac imaging from which they are derived and despite significant advances in this area, important limitations still apply. Computational flow dynamics offer high fidelity simulation of stress and deformation, but widespread clinical application is stifled by cost and complexity. Meanwhile, extended reality technologies face technical challenges associated with interfacing high volume multimodality data and issues associated with motion induced sickness in operators. Headsets can be cumbersome and could cause procedural hindrance. Much of the research with these technologies comprises of small proof of feasibility studies and comparison between studies is challenging given their heterogeneity.In essence, disruptive technologies look set to continue their rapid evolution and play an instrumental role in the quest for personalized cardiac care; however, careful consideration is required to their limitations when contemplating widespread clinical translation. Pragmatism would dictate that hybrid modelling through integration of these technologies\u2019 may optimize their efficacy and this may represent the next translational step in this exciting field."}
+{"text": "Empathizing with others\u2019 pain appears to recruit the whole pain matrix, including a collection of frontal regions involved in the affective, motivational, cognitive, and attentional dimension of pain.This research explored how the modulation of interoceptive attentiveness (IA) can influence the frontal  activity related to the emotional regulation and sensory response of observing pain in others.22 healthy participants were required to observe face versus hand, painful/non-painful stimuli in an individual versus social condition while brain hemodynamic response (oxygenated [O2Hb] and deoxygenated hemoglobin [HHb] components) was measured by functional Near-Infrared Spectroscopy (fNIRS). The sample was divided into experimental (EXP) and control (CNT) groups and the EXP group was explicitly required to focus on its interoceptive correlates while observing the stimuli.In the individual condition, higher brain responsiveness was detected for painful confronted to non-painful stimuli, and a left/right hemispheric lateralization was found for the individual and social condition, respectively. Besides, both groups showed higher DLPFC activation for face stimuli displayed in the individual condition compared to hand stimuli in the social condition. However, face stimuli activation prevailed for the EXP group, suggesting the direct interoceptive phenomenon has certain features, namely it manifests itself in the individual condition and for pain stimuli.We can conclude that IA modulation promoted the recruitment of internal adaptive regulatory strategies engaging both DLPFC and somatosensory regions towards emotionally relevant stimuli . Therefore IA could be trained for promoting emotion regulation and empathic response."}
+{"text": "Sentinel lymph node biopsy (SLNB) has been the standard of care for clinically node-negative women with invasive breast cancer (IBC) and is also performed for women with ductal carcinoma in situ (DCIS) with high-risk features undergoing breast conservation surgery (BCS). Despite national guidelines, there is still controversy on whether to perform SLNB when the risk of metastasis is low or when it does not affect survival or locoregional control.National guidelines indicate that SLNB should not be routinely performed in women over 70 years of age with early-stage hormone receptor-positive (HR+) Her2 negative IBCSimilarly, one-third of ASBrS surgeons surveyed recommend SLNB for DCIS with high-risk features when guidelines advocate against it. Surgeons in academic settings were less likely to perform SLNB in this setting.Despite national guidelines, most surgeons favor SLNB in older patients with early-stage HR+ Her2 negative IBC. Clinical factors such as tumor grade, stage, and histology may be used to predict nodal positivity in this population to tailor the omission of SLNB to the subset with low-risk features."}
+{"text": "Cancer among older adults is pervasive, putting excessive strain at the individual, caregivers, and wider society levels. In our symposium, we bring together researchers from varied disciplines\u2014with a focus on easing the strain of cancer on older adults by identifying important gaps in care and developing and implementing innovative methods for improving health services. First, Carrion will discuss the multifactorial experience of fears and beliefs about cancer and cancer prevention in 57 older Latino men. Krok-Schoen will discuss the longitudinal association between religiosity and cognitive functioning among older adults with hematological cancers. Next, Seaman will discuss engaging hard-to-reach patients and those who underutilize the health system. Blackberry will then describe an implementation and impact framework of a five-year research program to improve care in older people with cancer. Lastly, Halpin will discuss the 36-month implementation of a video-based patient education program for patients with multiple myeloma who are preparing for autologous stem cell transplant. Understanding the development and implementation of programs aimed at improving health services among older adults with cancer will help improve understanding potential methods for identifying and addressing health services challenges in these populations."}
+{"text": "Interactions between species above- and belowground are among the top factors that govern ecosystem functioning including soil organic carbon (SOC) storage. In agroecosystems, understanding how crop diversification affects soil biodiversity and SOC storage at the local scale remains a key challenge for addressing soil degradation and biodiversity loss that plague these systems. Yet, outcomes of crop diversification for soil microbial diversity and SOC storage, which are key indicators of soil health, are not always positive but rather they are highly idiosyncratic to agroecosystems. Using five case studies, we highlight the importance of selecting ideal crop functional types (as opposed to focusing on plant diversity) when considering diversification options for maximizing SOC accumulation. Some crop functional types and crop diversification approaches are better suited for enhancing SOC at particular sites, though SOC responses to crop diversification can vary annually and with duration of crop cover. We also highlight how SOC responses to crop diversification are more easily interpretable through changes in microbial community composition . We then develop suggestions for future crop diversification experiment standardization including (1) optimizing sampling effort and sequencing depth for soil microbial communities and (2) understanding the mechanisms guiding responses of SOC functional pools with varying stability to crop diversification. We expect that these suggestions will move knowledge forward about biodiversity and ecosystem functioning in agroecosystems, and ultimately be of use to producers for optimizing soil health in their croplands. Because soil microbes drive soil functioning, their diversity is a major target for improving agricultural soils, which have lost between one-third and one-half of their organic carbon relative to natural vegetation due to conventional management practices . Crop diLessons learned from plant and microbial ecology of natural/unmanaged systems is helpful in explaining site-level differences in relationships among plant diversity, microbial diversity, and ecosystem functioning of managed agroecosystems. In a grassland biodiversity experiment, positive effects of plant diversity on soil fungal diversity occur through increased aboveground biomass production and thus supply of organic substrates . This meZea mays L.), likely because corn produces higher amounts of biomass with low C:N ratio, which can contribute considerably to SOC accumulation  and/or soybean (Glycine max L.)  as a focal crop, (3) use Illumina next-generation sequencing to generate sequence data for bacterial and/or fungal communities in bulk soil, and (4) provide sequencing data publicly or by request. We specifically use studies that provide next-generation sequencing data, following the recent movement toward DNA-based analyses of microbial communities as a metric for soil health  crop diversification experiment in corn and soybean cropping systems in the southeastern United States . Along wJuglans regia L.)-based agroforestry on bacterial diversity are positive overall  alone or in a six-species mixture decrease SOC by about 20% relative to a fallow control  or wheat (Triticum aestivum L.) cover crop in the winter fallow corn-soybean cropping systems significantly decreases soil bacterial diversity  plots. One way to optimize sampling effort is to increase subsamples collected and homogenized for each plot. In the 2, and thus the numbers of composited subsamples for SOC  soils of a long-term tillage experiment , within- for SOC  should b for SOC  and coul for SOC . VerticaFigure 1K). We performed an additional power analysis to identify how many replicates it would take to detect a significant effect after only 5 years of agroforestry given the observed effect size, and found that replication would have to increase by two orders of magnitude  can prevent detection of significant changes in SOC and microbial community diversity. Soil microbial diversity, in particular, can vary significantly at local or field-scales . Howeveragnitude . Thus, wagnitude , 2H.diversified\u2013meansimplified)/pooled standard deviation. Using these observed effect sizes and an alpha level of 0.05, we determined the achievable statistical power given a range of sample sizes from 2 to 100 +  is one factor to consider to robustly measure diversity of soil microbial communities. To determine how soil sample size influences the ability to detect crop diversification effects on soil microbial diversity, we conducted a power analysis of results from to 100 + . This anto 100 +  to detecAdditionally, when characterizing soil microbial communities, it is important to consider optimizing sequencing depth  and accounting for relic DNA. Inadequate sequencing depth would lead to underestimation of actual diversity, whereas excess sequencing depth would be a resource intensive effort. The case studies highlighted here obtained paired end sequence read lengths of 250\u2013300 bases per sequence, which should be sufficient for 16S gene regions and for most ITS gene regions . However(A) indicates sufficient sampling depth. The absence of leveling off in (B) indicates insufficient sampling depth, which may hinder insights gained from this dataset about how soil microbial diversity responds to crop diversification. Given this variation in apparent soil microbial diversity in agroecosystems, future studies would benefit from pilot tests to determine the adequate sequencing depth for overall diversity in the systems.Sequencing depth for soil microbial characterization. To illustrate the importance of sequencing depth in understanding soil microbial diversity, we plotted species abundance curves of fungal amplicon sequence variants (ASVs) identified in Identifying coordinated changes (or lack thereof) in SOC and soil microbial diversity can advance our understanding of diversity-ecosystem functioning relationships in agroecosystems, but determining the mechanisms that underlie SOC changes can help us to explain such relationships. Carbon cycling frameworks have increasingly understood microbial influences on SOC storage, but reconciling this framework with changes to SOC under crop diversification remains a major challenge. That is, we have seen a common pattern where corn production systems accumulate more SOC than soybean systems. However, according to the Microbial Efficiency-Matrix Stabilization (MEMS) framework, higher-quality  litter (such as that of soybean) decomposes more quickly, thereby increasing readily available carbon , which can then be stabilized and protected through associations with the mineral soil matrix . This miTwo case studies presented here measure readily available fractions of SOC , which cRecent global analysis has identified strong positive linkages among plant diversity, soil microbial diversity, and SOC in agroecosystems, but these linkages at the site level are quite idiosyncratic. Here, we have discussed contingencies upon plant functional type, number of crop species, field location, and experimental duration in determining how soils respond to crop diversification. Overall, we have described the role of crop functional type (more so than number of species) in how soils respond to crop diversification, with corn contributing more to SOC accumulation in agroecosystems compared to soybean and wheat. Still, higher microbial diversity is not always an outcome of crop diversification or an indicator of increased SOC, and site-to-site and year-to-year variation can introduce significant inconsistency in the effectiveness for any one crop diversification strategy. Though crop diversification does not have consistent effects on soil microbial diversity, it does consistently shift microbial community composition. Further, soil microbial diversity has no strong associations with SOC within sites, but SOC is generally a significant predictor of soil microbial community composition. Thus, despite the limited scope of our analysis of five case studies, we find strong evidence that microbial diversity is a less important mediator of crop diversification effects on SOC compared to microbial community composition. Moving forward, given a combination of more subtle effects that occur in early years of implementation of crop diversification and inherent spatial and temporal variation in SOC and soil microbial communities, we need to optimize sampling efforts and sequencing depths that aid robust estimates of change. We also need to integrate agroecosystems into current theory on soil microbe-carbon interactions. Such efforts will improve our understanding of plant diversity-ecosystem functioning in agroecosystems.RW, SK, and SJ conceived the project. RW acquired and processed the raw sequence data with substantial input from SK. RW conducted statistical analyses. All authors contributed to writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Digital Mental Health holds strategic potential in fulfilling populations\u2019 mental healthcare unmet needs, enabling convenient and equitable access to mental healthcare. However, despite strong evidence of efficacy, uptake by mental healthcare providers remains low and little is known about factors influencing adoption and its interrelationship throughout the Digital Mental Health adoption process.This study aimed at gaining in-depth understanding of factors influencing adoption and mapping its interrelationship along different stages of the Digital Mental Health adoption process.This work adopted a qualitative approach consisting of in-depth semi-structured interviews with 13 mental healthcare professionals, including both psychologists and psychiatrists. The interviews were transcribed and analysed thematically, following Braun and Clarke\u2019s method.In this communication, we will describe how digital technology is currently used by clinicians to deliver mental healthcare. We identify potential factors influencing Digital Mental Health adoption and characterize the different identified stages inherent to this appropriation process: i) Pondering appropriate use; ii) Contractualizing the therapeutic relationship; iii) Performing online psychological assessment; iv) Adapting and/or developing interventions; v) Delivering Digital Mental Health interventions; and vi) Identifying training unmet needs. A discussion on how different factors and its interrelationship impact the adoption process will also be performed.By characterizing mental healthcare providers journey throughout the Digital Mental Health adoption process, we intend to inform ecosystem stakeholders, such as researchers, policy makers, societies and industry, on key factors influencing adoption, so policies, programs and interventions are developed in compliance with this knowledge and technology is more easily integrated in clinical practice."}
+{"text": "Salmonella typhimurium were shown to exhibit increased MNase sensitivity specifically at genes implicated in immune responses. Increased sensitivity at the \u22121-nucleosome permitted transcription factor and RNA Pol II binding events. This system illustrates how cytoplasmic signals induce altered chromatin states to produce a specific cellular response to a stimulus. Innate immune activation is a longstanding model for inducible promoters, transcriptional activation, and differential nucleosomal sensitivity in response to immune activation and offers a model that may be largely applicable to other specific cellular responses including viral infection and cancer. Previous work has shown that early transformation events are associated with prolonged nucleosome occupancy changes that are not observed later in cancer progression. Herein, we propose a model in which we suggest that detailed studies of nucleosomal occupancy and sensitivity in response to specific stimuli will provide insight into the regulation of nuclear events in cancer and other biological processes.The nucleosome, consisting of ~150bp of DNA wrapped around a core histone octamer, is a regulator of nuclear events that contributes to gene expression and cell fate. Nucleosome organization at promoters and their associated remodeling events are important regulators of access to the genome. Occupancy alone, however, is not the only nucleosomal characteristic that plays a role in genome regulation. Nucleosomes at the transcription start sites (TSSs) of genes show differential sensitivity to micrococcal nuclease (MNase) and this differential sensitivity is linked to transcription and regulatory factor binding events. Recently, lymphoblastoid cells treated with heat-killed  The nucleosome has long been considered a regulator of nuclear events. Consisting of ~150bp of DNA wrapped 1.65 times around a histone octamer, the nucleosome serves as the functional subunit of chromatin \u20134. SimilThe availability of massively parallel sequencing technologies in the early 2000s allowed for more detailed studies that mapped nucleosome occupancy in a highly time-resolved manner and provided insights into the dynamics of nucleosome remodeling. Time-resolved studies demonstrated widespread transient changes in nucleosome occupancy in response to reactivation of Kaposi\u2019s sarcoma associated herpesvirus (KSHV) to produce a transient intermediate chromatin conformation favorable to an immune response followed by a return to the basal state . SimilarThis type of transient remodeling may also play a role in response to other stimuli including viral infections and resulting immune-mediated pathologies like those seen in acute SARS-CoV-2 infections and persistent systemic symptoms classified as Post-Acute Sequelae of COVID-19 (PACS). Chromatin remodeling complexes are essential for viral infection and replication indicating a direct role for chromatin dynamics during viral infection . InitialSalmonella typhimurium. However, increased sensitivity at the \u22121 nucleosome in highly expressed genes is observed 20 minutes after stimulation which is consistent with the timeframe for the innate immune response to bacterial stimulation [Nucleosome mapping is often achieved by digesting crosslinked chromatin in micrococcal nuclease (MNase) to produce ~150bp fragments which correspond to nucleosome-protected immune-specific regions  Figure . Biochemmulation ,26. MNasmulation . The posGenomic instability and altered chromatin organization are the hallmark of the transformed phenotype and are associated with cancer progression. Features of chromatin organization  are regulated by ATP-dependent chromatin remodeling complexes . MutatioSalmonella example above. The longer-lived nucleosome sensitivity changes explain differential gene activation through altered regulatory factor accessibility in conditions, such as high-grade cancers, where nucleosome occupancy appears largely static.Early grade adenocarcinomas show widespread nucleosome depletion at transcription start sites particularly in genes associated with chromatin structure and cancer progression. While it is unknown exactly how long this remodeled state persists, an appealing explanation is that this remodeled state persists longer than physiologically expected due to dysregulation of ATP-dependent chromatin remodeling complexes. Consistent with this explanation, differential occupancy is reduced in higher grade tumors , hintingThe above observations suggest that measurements of nucleosome occupancy and sensitivity will provide valuable insights into gene expression and cell fate outcomes in cancer progression. We propose a model to explain these relationships . In this"}
+{"text": "Person-centered care (PCC), or delivery of care consistent with preferences, can improve outcomes for residents in long-term care (LTC). However, PCC has not been universally adopted. Few studies focus on measuring specific barriers to meeting resident preferences, hindering identification of actionable targets to improve PCC delivery. The purpose of this study was to develop and test the content validity of a survey that measures staff barriers to fulfilling resident preferences for daily care and activities. Item sets comprised of barriers and preferences were informed by a review of literature and a descriptive, qualitative study with 19 LTC staff. An expert panel (n=8) was convened to test content validity, and content validity indices (CVI) were calculated. The initial survey consisted of 12 item sets assessing whether knowledge gaps, resident characteristics , family, facility rules/policies, availability of options, or staffing/workload functioned as barriers to meeting resident preferences for daily care and activities . Revisions informed by expert feedback resulted in a total of 17 items sets. Second round testing with experts (n=10) revealed overall improved item sets . These findings indicate that the survey items have initial content validity in measuring staff barriers to meeting resident daily care and activity preferences. Further psychometric testing with LTC staff is needed prior to implementing the survey, which will represent the first tool of its kind for supporting measurement of staff-derived targets for PCC interventions and policy change."}
+{"text": "Socioemotional selectivity theory postulates that limited future time perspective (FTP) motivates older adults to prioritize emotionally meaningful goals, explaining documented age advantages in emotional well-being. During the early months of the COVID-19 pandemic, we collected data from 945 community dwelling adults and 156 assisted living facilities residents living in the United States . Participants reported their FTP using the scale developed by Carstensen and Lang (1996), as well as the frequency and intensity of sixteen positive and thirteen negative emotions. Age association with limited FTP was comparable to past studies. Contrary to our hypotheses, limited FTP was associated with lower emotional well-being across ages and suppressed (rather than mediated) a general trend towards higher emotional well-being in older ages. Findings suggest that there may be conditions under which perceptions of limited time horizons have negative implications. Theoretical implications are discussed."}
+{"text": "Medicaid Accountable Care Organizations (ACO) are increasingly common, but the network breadth for maternity care is not well described. The inclusion of maternity care clinicians in Medicaid ACOs has significant implications for access to care for pregnant people, who are disproportionately insured by Medicaid.To address this, we evaluate obstetrician-gynecologists (OB/GYN), maternal-fetal medicine specialists (MFM), certified nurse midwives (CNM), and acute care hospital inclusion in Massachusetts Medicaid ACOs.Using publicly available provider directories for Massachusetts Medicaid ACOs (n = 16) from December 2020 \u2013January 2021, we quantify obstetrician-gynecologists, maternal-fetal medicine specialists, CNMs, and acute care hospital with obstetric department inclusion in each Medicaid ACO. We compare maternity care provider and acute care hospital inclusion across and within ACO type. For Accountable Care Partnership Plans, we compare maternity care clinician and acute care hospital inclusion to ACO enrollment.Primary Care ACO plans include 1185 OB/GYNs, 51 MFMs, and 100% of Massachusetts acute care hospitals, but CNMs were not easily identifiable in the directories. Across Accountable Care Partnership Plans, a mean of 305 OB/GYNs , 15 MFMs , 85 CNMs , and half of Massachusetts acute care hospitals  were included.Substantial differences exist in maternity care clinician inclusion across and within ACO types. Characterizing the quality of included maternity care clinicians and hospitals across ACOs is an important target of future research. Highlighting maternal healthcare as a key area of focus for Medicaid ACOs\u2013including equitable access to high-quality obstetric providers\u2013will be important to improving maternal health outcomes. Accountable Care Organizations (ACOs) are a payment and delivery model designed to incentivize the provision of high-quality care at lower cost. Evidence of reduced spending in Medicare ACOs compared to traditional payment models has prompted states to experiment with the use of ACOs in their Medicaid programs \u20134. PreliDistinct in structure from Medicare ACOs where Medicare enrollees with traditional Medicare assigned to ACOs can visit any primary care or specialist clinician accepting Medicare , MedicaiAs of 2020, over half of physicians nationally are participating in at least one ACO of any type with just over a quarter of physicians participating in a Medicaid ACO . PhysiciMost research on clinician participation in Medicaid ACOs has focused on primary care clinicians , but theAs alternative payment models, including ACOs, become more common in all insurance types, understanding the differences in provider network breadth in Medicaid ACOs is increasingly important to ensure patient access to care. In Medicaid ACOs, adequate networks of OB/GYN providers are essential to ensuring high quality care for women. In this study, we quantify maternity care provider inclusion in Massachusetts Medicaid ACOs, implemented starting in March 2018, and analyze differences in provider inclusion by specific Medicaid ACO type.Using publicly available provider directories for Massachusetts Medicaid ACOs and data on provider supply, we quantified inclusion of obstetrician-gynecologists (OB/GYN), maternal-fetal medicine (MFM) specialists, certified nurse-midwives (CNM), and acute care hospitals with obstetrics departments in Medicaid ACOs. We then compared the number and type of providers across ACO types, across ACOs within ACO type, and to the total number of providers within Massachusetts.In Massachusetts, Medicaid ACO models were implemented starting in March 2018 with two ACO distinct models available as of 2021 , 28. TheWe analyzed obstetric provider inclusion in the 13 ACPP ACOs and three PCACOs operating in Massachusetts Medicaid in January 2021. We analyzed the inclusion of OB/GYNs, MFMs, and CNMs using ACO provider directories available online between December 2020 and January 2021. Five ACPP ACOs provided print directories generated directly from online directories located on the ACO websites. Eight ACPP ACOs provided separate, distinct printed directories available on the ACO websites. The three PCACOs utilized the MassHealth provider network for specialists, and we used the MassHealth online directory for these ACOs. Enrollment data for each ACO is determined as of July 2018 .For ACPP plans, clinicians included in the analysis were those listed in the categories of obstetrician, obstetrician/gynecology, gynecology, or maternal-fetal medicine within the provider directories. For certified nurse midwives (CNM), the directories which included CNMs had a separate section listing those who were included. For directories including a provider identification number (such as an NPI), the identifier was extracted, and duplicates were removed to determine the total number of providers included in that plan. For all others, duplicates were removed manually based on clinician name. If provider directories included practice names, we did not count these practices towards the number of included clinicians; we checked a number of these by hand in each directory to ensure that the majority of clinicians practicing in those organizations were included in the provider directory and discuss in the results where there were any deviations from this. We were not able to include family medicine physicians who provide maternity care due to the difficulty of systematically identifying these specific physicians.For the PCACO plans, we searched the online provider directory by specialty for \u201cObstetrics (OB/GYN)\u201d and included individual clinicians in the count. MFMs were not classified separately in the online provider directory but were included within OB/GYN provider listings. To determine MFM inclusion, MFM providers listed within the 2019 Massachusetts Registration of Provider Organizations Physician Roster (MA RPO) were manually identified within the covered Medicaid OB/GYN providers . The MA The Medicaid waiver implementing the Medicaid ACOs includes a policy that PCACOs may designate a \u201creferral circle\u201d of ACO-preferred specialists that patients may visit without a required PCP referral ; howeverThe total number of OB/GYNs and CNMs in Massachusetts for comparison to provider directories is based on estimates from the Area Health Resources File from the Health Resources and Services Administration . We calcWe used the MassHealth Enrollment Guide (January 2019) to determine hospital inclusion for each ACO, limited to in-state acute care hospitals with an obstetrics department that conducts deliveries . Acute cThe primary outcomes of this study are the number of 1) Maternity care clinicians including OB/GYN physicians, MFM physicians, and CNMs and 2) acute care hospitals with obstetrics departments included in each of the Massachusetts Medicaid ACO plan types.Descriptive statistics for ACO provider inclusion were calculated; these statistics give equal weight to each ACO. Comparisons were made between ACO types and to the number of practicing physicians in MA. For ACPPs, which have different numbers of included physicians, we compare the number of included clinicians to the ACO enrollment. All analyses were conducted using Microsoft Excel.Across Accountable Care Partnership Plan ACOs, there was substantial variation in number of providers included . The meaPrimary Care ACOs utilize the full Massachusetts Medicaid specialist network, and therefore all ACOs of this type have the same OB/GYN inclusion of 1185 OB/GYNs and MFM inclusion of 51 . In addiWe compared these included clinician numbers to the total practicing obstetric clinicians in Massachusetts according to the AHRF. The AHRF notes there are 1,046 OB/GYNs, which is higher than the number of OB/GYNs included in any ACPP provider networks; however, it is smaller than the number of OB/GYNs listed in the PCACO network. The number of practicing Maternal-Fetal Medicine from the MA RPO is 61. The number of practicing CNMs in Massachusetts from AHRF is 345.The percentage of hospitals with obstetrics departments included also varied substantially within and across ACO types . AccountFinally, we examine variation in provider inclusion in ACPP ACOs by enrollment. First introduced in 2011, Medicaid ACOs are a relatively new value based payment model, and there is limited prior research characterizing the breadth of provider networks in these ACOs . In thisThe few prior studies on Medicaid ACOs in maternal health care show Medicaid ACO participation resulted in an improvement of the timeliness of prenatal care initiation in the first trimester but did not increase the total receipt of adequate prenatal care ; state MAnother important finding is that some Medicaid ACOs did not include any CNMs, and the PCACOs did not easily identify any included CNMs. CNMs attend over 17% of births in Massachusetts, including almost 20% of births covered by Medicaid . MidwifeACPPs that had high numbers of member enrollment had correspondingly high levels of provider and hospital inclusion. However, among plans that had lower member enrollment, provider and hospital inclusion varied widely. MFMs are crucial for managing maternity care for high-risk patients, yet fewer than 10 MFMs were included in a majority of ACPP ACOs, particularly in ACPP ACOs with low member enrollment. This has important implications regarding access to care for Medicaid insured individuals. As many ACOs with low levels of enrollment are located outside of major metropolitan areas, a smaller network could lead to increased distances to the nearest provider, as well as fewer options in selecting a specific clinician. Maternity care availability (including providers and insurance coverage) in rural areas is critical for ensuring adequate perinatal care, and reduced access is an ongoing issue throughout the nation .The study had several limitations. First, given the known limitations of online provider directories , 62, ourIn this study, we examine variation in the maternity care provider inclusion in Medicaid ACOs in Massachusetts, which is critically important for access to care for Medicaid enrollees. We find substantial differences across ACO types and within ACO type. Understanding the role of maternity care provider inclusion in Medicaid ACO contracts and Medicaid risk adjustment and payment policy may be an important area of future research to understand incentives of Medicaid ACOs that improve maternal health care and health outcomes. Additionally, measuring the quality of included obstetric clinicians and hospitals, particularly for maternal healthcare, is an important area for ensuring equitable health care for Medicaid enrollees. As Medicaid ACOs expand nationally, ensuring that maternal healthcare is an area of focus\u2013including sufficient and equitable access to high quality maternity care providers\u2013will be important to ongoing efforts to improve maternal health outcomes.S1 TableNote: Directories were accessed in December 2020/January 2021. Links updated as of November 2022. Due to a change in insurer ownership, BMC HealthNet provider directories are no longer available online.(DOCX)Click here for additional data file."}
+{"text": "This cross-sectional study examines the association between the complexity of consumer guidelines for COVID-19 vaccination and identification of eligibility. The US Centers for Disease Control and Prevention also released guidance on prioritization.2 The survey measured demographic factors, COVID-19 vaccine eligibility criteria, and perceived eligibility for vaccination. States a priori selected for this analysis based on having greater than 75 participants were the 5 largest states by population and Georgia (Georgia was oversampled). To determine participant vaccine eligibility, vaccine prioritization guidelines of each state were extracted from government communications  identified as female; mean age was 45 years . The In this study, higher guideline complexity was negatively associated with correct identification of COVID-19 vaccine eligibility during vaccine scarcity in the US. When developing guidance, health agencies must balance precision and clarity. Increased precision may lead to greater complexity and lower target audience comprehension. Our findings suggest potentially large public health implications for complex guidelines. This study is limited owing to ecological design, social desirability bias, and potential misclassification of vaccine eligibility owing to self-reported data.More complex vaccine guidelines were associated with lower participant comprehension, potentially hindering eligible persons from seeking vaccines during a period of scarcity. To optimize public health communication, brevity and simplicity should not be undervalued."}
+{"text": "It has been reported that diabetes mellitus affects 435 million people globally as a primary health care problem. Despite many therapies available, many diabetes remains uncontrolled, giving rise to irreversible diabetic complications that pose significant risks to patients\u2019 wellbeing and survival.In recent years, as much effort is put into elucidating the posttranscriptional gene regulation network of diabetes and diabetic complications; RNA binding proteins (RBPs) are found to be vital. RBPs regulate gene expression through various post-transcriptional mechanisms, including alternative splicing, RNA export, messenger RNA translation, RNA degradation, and RNA stabilization.Here, we summarized recent studies on the roles and mechanisms of RBPs in mediating abnormal gene expression in diabetes and its complications. Moreover, we discussed the potential and theoretical basis of RBPs to treat diabetes and its complications. \u2022 Mechanisms of action of RBPs involved in diabetic complications are summarized and elucidated.\u2022 We discuss the theoretical basis and potential of RBPs for the treatment of diabetes and its complications.\u2022 We summarize the possible effective drugs for diabetes based on RBPs promoting the development of future therapeutic drugs. According to a survey by the International Diabetes Federation (IDF), DM is a major health problem affecting 435 million people worldwide . In 20212O2) are important factors in pancreatic \u03b2-cell, functioning in cellular signaling processes and regulation of glucose-stimulated insulin secretion (GSIS) ; the National Natural Science Foundation of China ."}
+{"text": "Physical activity is beneficial for older adults to maintain health and help manage chronic diseases but relies on routine participation. Some older adults continue with physical activity behaviors as they age, whereas others are negatively affected by impaired functional abilities, physical disabilities, and unmet psychosocial needs. This symposium presents quantitative and qualitative data on physical and psychosocial factors that can influence physical activity among older adults with varying levels and types of physical abilities. The first presentation will focus on aging into the disability associated with knee osteoarthritis, the leading cause of mobility decline among older adults that generally onsets after the fifth decade of life. The second presentation will focus on aging with a disability, specifically how health perspectives evolve when aging with a spinal cord injury. The third presentation will highlight how the COVID-19 pandemic has influenced outdoor physical activity among older adults when indoor activities became limited. The fourth presentation shifts perspectives to clinicians, specifically physical therapists, to explore the needs for addressing physical activity in the clinic. The fifth presentation outlines a physical activity intervention program and its implementation for community-dwelling older adults. Together, these presentations will provide practical insights for designing a person-centered program to improve physical activity for older adults including those aging into disability or aging with disability."}
+{"text": "Bothersome urinary symptoms plague many older adults and disproportionally affect women. Underreporting of symptoms and general stigma/embarrassment associated with incontinence has negatively impacted the availability of treatments, as research cannot be championed if the severity of the problem is not apparent. Available therapeutics have limited efficacy and are often not recommended in aged patients. Lower urinary tract function has a long and rich history in animal studies; while much of the underlying anatomy has been described, including neural control mechanisms, the impact of aging has only just begun to be addressed. Recent work has provided strong evidence that neural control over micturition is significantly impacted by aging processes. This mini review discusses recent findings regarding how aging impacts the neural control mechanisms of micturition. With increasing age comes an increased incidence of lower urinary tract symptoms (LUTS), most prevalent in women and institutionalized populations . The sevThe bladder demonstrates complex neural regulation of its function despite a seemingly simple design. Control over the urinary bladder occurs as both an involuntary reflex and a conscious process. In cortical regions of the central nervous system (CNS), cortical function acts to suppress the voiding reflex until micturition is desired . Conversvia both somatic (conscious) and autonomic (unconscious) pathways and has been previously well reviewed   as the bladder expands, and the level of afferent nerve firing is proportional to bladder volume. The PAG relays this information to the cerebral cortex in humans, allowing for conscious input over the voiding reflex  . The autg reflex . Higher Functional changes in the urinary bladder are common in older adults, regardless of if they are symptomatic. The phenomena of overactive bladder (OAB) and underactive bladder (UAB) describe symptom complexes; diagnosis of detrusor underactivity (DU) or detrusor overactivity (DO) require clinical urodynamic assessment . DU and Like many other faculties, the CNS suffers in the aged environment. Functional MRI (FMRI) studies have demonstrated decreased blood flow, brain shrinkage, and metabolic dysfunction in the brains of older adults . In oldeDuring urine storage, adrenergic (sympathetic) inputs from the hypogastric nerve act on beta-adrenoceptors in the bladder wall, inducing relaxation, and act on alpha-adrenoceptors in the urethra, inducing contraction. Together, this allows for accommodation of increasing bladder volumes while maintaining relatively low pressure. Adrenergic and cholinergic receptor expression decreases with aging at both the mRNA and protein levels . EmptyinLUTS are a common, costly problem: billions of dollars are spent annually on the treatment and management of incontinence and related urinary problems. Nearly half of women over 65\u00a0years experience urinary incontinence\u2014allowing for acceptance of LUTS as \u201cthe new normal\u201d with aging\u2014yet many remain continent throughout their lives, implying simply possessing an old bladder is not the sole prerequisite for developing urinary dysfunction and/or symptoms. LUTS significantly decrease quality of life and are a driving force in institutionalization. Available pharmacologic therapeutics pose many unfortunate and undesirable side effects: anticholinergic medications, for example, have been associated with increased cognitive symptoms with little improvement in LUTS. Surgical interventions can be challenging in older adults, limiting the realistic use of neuromodulatory devices for sacral nerve stimulation.Aging negatively impacts function across many systems, including the CNS. Vascular deficits are observed with aging: ischemia in the brain and bladder have been demonstrated, undoubtedly affecting urinary function . Alterat"}
+{"text": "JCI, Hindy and colleagues report on their evaluation of a multi-ethnic cohort of over 5,000 participants without known CVD. High suPAR levels correlated with incident CVD and atherosclerosis. Genetic analysis revealed two variants associated with the suPAR-encoding gene (PLAUR) with higher plasma suPAR levels. Notably, a mouse model with high suPAR levels possessed aortic tissue with a proinflammatory phenotype, including monocytes with enhanced chemotaxis similar to that seen in atherogenesis. These findings suggest a causal relationship between suPAR and coronary artery calcification and have clinical implications that extend to inflammatory disorders beyond CVD.Atherosclerosis contributes to the majority of deaths related to cardiovascular disease (CVD). Recently, the nonspecific inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) has shown prognostic value in patients with CVD; however, it remains unclear whether suPAR participates in the disease process. In this issue of the  Despite decades of research and improvement in outcomes, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide . AtherosAtherosclerosis is a diffuse, slowly progressing disease that in most cases remains asymptomatic for decades. It begins with subendothelial accumulation and retention of low-density lipoprotein particles, triggering an inflammatory response . CirculaOver the last 10 years, soluble urokinase plasminogen activator receptor (suPAR) has emerged as a nonspecific inflammatory biomarker with predictive and prognostic value in patients with CVD . suPAR iJCI, Hindy et al. (PLAUR) gene associated with higher plasma suPAR levels. One variant (rs4760) was confirmed experimentally in vitro and in vivo to lead to higher suPAR levels. The authors very nicely demonstrate that expression of the rs4760 PLAUR missense variant in human embryonic kidney (HEK) cells in in vitro and in in vivo mouse experiments resulted in an approximate seven-fold increase in suPAR levels, providing strong evidence that the rs4760 variant caused the high suPAR levels observed in humans. Through Mendelian randomization, the authors found that suPAR levels, predicted by the specific missense variant rs4760, were causally linked to atherosclerotic phenotypes in the UK Biobank, notably coronary artery disease, myocardial infarction, and peripheral arterial disease  mice that exhibited increased circulating levels of suPAR to mimic increased suPAR levels observed in the clinic. Genetic overexpression of suPAR in a murine model of atherosclerosis using Pcsk9-AAV coupled with a Western diet led to a two-fold increase in atherosclerotic plaque size with large necrotic cores and macrophage infiltration in the TgsuPAR mice compared with WT mice. The authors determined that, prior to atherosclerosis, the aortic tissue isolated from TgsuPAR mice secreted higher levels of C-C motif chemokine ligand 2 (CCL2)  and exhibited higher numbers of monocytes. Furthermore, monocytes isolated from the circulation and aortic tissue of TgsuPAR mice exhibited a proinflammatory phenotype with enhanced chemotaxis, which contributes to atherogenesis ..suPAR trThe clinical data demonstrating the causal relationship between suPAR and coronary artery calcification and the data for cumulative incidence of CVD events presented by Hindy and authors are powerful and striking . The aut"}
+{"text": "The authors had 5 indications for PLLA injections and used subjective before and after photographs to evaluate its effectiveness. It would have been powerful to see a more objective assessment of volume retention such as three-dimensional imaging or patient reported outcome metrics using validated survey instruments (Video). The authors present a retrospective review of 241 patients who underwent facelift surgery with fat grafting, associated with Poly-L-Lactic Acid (PLLA) injections for facial volume maintenance after surgery.An important detail of this study was that the authors used an off-label dilution of PLLA, a common practice in facial aesthetics, reporting no complications or nodule formation in this series. Integrating facial fillers into postsurgical maintenance regime is especially helpful in patients with very low body mass index and inadequate fat donor sites. This paper reflects current clinical facial aesthetic surgery practices on facial volumization. In addition to PLLA, in our practice and many others, the use of different filler types such as hyaluronic acid (HA) and calcium hydroxyapatite is also very helpful for ongoing facial volumization and rejuvenation."}
+{"text": "Walking ability is a robust predictor of health outcomes in aging. Compelling evidence supports meaningful interrelations between walking and cognition, notably when the former is performed under dual-task conditions that place increased demands on attention and executive control resources subserved by the prefrontal cortex (PFC) . Indeed,2) and deoxygenated hemoglobin (Hb) and is uniquely suited to examine task-related changes in brain hemodynamic responses during active walking [Due to the limitations inherent in traditional neuroimaging methods such as magnetic resonance imaging (MRI), our ability to understand and quantify how the brain is functionally involved in gait control during active walking has been limited. Nonetheless, recent studies using functional Near-Infrared Spectroscopy (fNIRS), a noninvasive optics-based neuroimaging modality, have begun to shed light on the functional brain correlates of walking. This technology uses light in the near infrared range (650-950nm) to quantify changes in oxygenated  . Our stu2 levels in the PFC across experimental conditions were assessed during active walking using fNIRS Imager 1100 . Magnetic resonance imaging was performed in a 3 T Phillips scanner . The scanner was equipped with a 32-channel head coil. FreeSurfer software package (http://surfer.nmr.mgh.harvard.edu/) was used to extract cortical thickness measures in 68 brain regions (34 in each hemisphere). The results revealed that thinner cortex in specific regions in the frontal, temporal, parietal and occipital lobes as well as the cingulate cortex and insula was associated with inefficient increases in fNIRS-derived HbO2 from single to dual-task walking conditions, notably the analyses controlled for several covariates including gait and cognitive performance. These findings indicate that multiple brain regions are involved in volitional control of walking in older adults. Furthermore, reduced cortical thickness maybe an important causal factor implicated in neural inefficiency in aging and possibly in other clinical populations.Cortical thickness and gray matter volume are genetically and phenotypically distinct. Therefore, our recent investigation was designed to determine the effect of cortical thickness on changes in the hemodynamic response in the PFC across walking task conditions to further elucidate interactions between structural and functional brain systems of locomotion . Communi"}
+{"text": "Teaching Point: Cystic dystrophy of the duodenal wall is often associated with underlying heterotopic pancreas and easily assessed with advanced and noninvasive imaging modalities such as CT scan and MRCP. A 56-year-old man presented with recurrent epigastric pain, projectile vomiting, and weight loss. He had a history of chronic alcohol abuse and acute necrotizing pancreatitis one year prior.Physical examination revealed a tenderness with sensation of induration in the epigastric region.Laboratory tests showed high level of lipase 870 U/L; (870 UI/L) other results were unremarkable.Contrast-enhanced computed tomography (CT) scan  showed aCDDW is a rare condition characterized by the presence of cysts within thickened duodenal wall. It often reflects cystic and inflammatory changes of aberrant pancreatic tissue into the duodenal wall, also referred to as pancreatic heterotopia . CDDW ocContrast-enhanced CT scan and magnetic resonance imaging (MRI) are helpful for this challenging diagnosis. Demonstration of mural thickening, stenosis of duodenal lumen, and cysts within the duodenal wall or in the paraduodenal groove are the key features. Small remnants of pancreatic tissue within duodenal wall having the same morphological and hemodynamic behavior as normal pancreas parenchyma may be detected. MRCP is superior in demonstrating dilatation of small pancreatic ducts into pancreatic remnants .ERCP remains the modality of choice in confounding cases. It may confirm the intramural location of the cysts and demonstrate signs of chronic pancreatitis. Using a fine-needle aspiration, ERCP may rule out duodenal adenocarcinoma, which is the main differential diagnosis of CDDW. Groove pancreatitis still the main complication of CDDW. in such cases, conservative treatment is recommended. However, surgical options such as pylorus-preserving pancreatectomy and the Whipple procedure are necessary to alleviate recurrent symptoms ."}
+{"text": "Widowhood is associated with decreased emotional well-being, particularly increased depression. Prior research suggests that religiosity may help improve mental health among widowed individuals. However, longitudinal studies exploring the role of religiosity on emotional well-being among widowed older adults is lacking, as are studies which examine different dimensions of religiosity. This longitudinal study analyzed data from the 2006-2018 waves of the nationally representative Health and Retirement Study (HRS). Ordinary least squares (OLS) regression analysis was used to examine the relationship between widowhood and depression as well as the role of religiosity as a moderator of this association. Analysis was stratified by gender to further explore these interactions. Results show that men and women show similar levels of depression at widowhood, but men are far less likely to be depressed prior to widowhood. Women also show a better recovery pattern over time post-widowhood. Furthermore, religiosity (particularly attending church) is an effective way of coping with widowhood and mitigating depression for both genders. However, men are significantly less religious than women. This study highlights the long-term effects of widowhood on depressive symptomology among older adults. Practical implications of this study include intervention development around increased screening and treatment for depression for widowed older adults  as well as connecting this vulnerable population with resources. These findings may also inform program outreach (such as hospice bereavement services) that aim to facilitate healthy grieving among widowed older adults."}
+{"text": "Dyadic coping is a daily interpersonal process that married couples use to manage stress and maintain their marriage. However, little is known about its mediating role in the association between empathic response and marital quality among same-sex and different-sex couples. This study aimed to examine the extent to which dyadic coping mediates the association between empathic response and marital quality, focusing on middle-aged men and women in same-sex and different-sex marriages. We used dyadic data from the Health and Relationships Project (HARP), including 124 gay, 171 lesbian, and 124 straight couples. Results from the actor-partner interdependence mediation model (APIMeM) showed that dyadic coping within couples mediated the association between empathic response and marital quality for all couple types . More empathic response was associated with better dyadic coping, which led to higher marital quality. While such mediated paths did not differ significantly between gay and lesbian couples, direct associations between empathic responses and marital quality were only significant among lesbian couples. Additionally, there were gendered patterns within straight couples; while female spouses\u2019 empathic response was associated with their and their male spouses\u2019 marital quality through the couple\u2019s dyadic coping, such a mediated path was not significant for male spouses\u2019 empathic response. These findings suggest dyadic coping as an effective strategy for enhancing marital quality among same-sex and different-sex married couples, but the mediating role of dyadic coping is gendered in different-sex marriages."}
+{"text": "With a rapidly aging global population, declines in cognition and functional abilities are an increasingly salient challenge and fear among many older adults. Researchers and clinicians often study changes in cognition and changes in functional limitations as separate trajectories although they frequently co-occur. In this study, we used two-stage structural equation modeling (SEM) to estimate longitudinal trajectories of cognitive and functional limitations using data from the Health and Retirement Study (2010-2016) . First, individuals\u2019 longitudinal factor scores  were estimated for cognition  and functional limitations . A bivariate latent trajectory model was then fit to these scores. Model fit was acceptable . Parameter estimates showed that, on average, cognition declined slightly (-.08SD/decade) and functional limitations increased gradually (0.38SD/decade). Importantly, individual cognitive declines were significantly correlated with increases in functional limitation . This study fills an important research gap by using advanced statistical modeling (bivariate latent growth models) to examine the joint trajectory of cognition and functional decline which underscores the need to consider the interplay of these two abilities. Methods that quantify both individual and group trajectories can aid in better identification of aging patterns and lead to new ways of thinking about interventions to reduce the burden of concurrent decline."}
+{"text": "Accumulating evidence indicates the existence of cancer stem cells (CSCs) sub-populations which fuel cancer growth and maintain stemness in different cancers. In addition to the genetic and phenotypic variabilities that differentiate CSCs from non-CSCs counterparts, CSCs adopt a flexible metabolic strategy to sustain their oncogenic and stemness properties, in order to survive and propagate in a hostile tumor microenvironment (TME). TME factors and metabolites exert context-dependent influence on cancer stemness. In addition, the metabolic landscape in TME is complicated by the crosstalk between CSCs and tumor-infiltrating cells. In this review, we will summarize the metabolic interaction between CSCs and various microenvironmental factors and review how this interplay regulates cancer stemness and tumorigenesis.An increasing body of evidence suggests that cancer stem cells (CSCs) utilize reprogrammed metabolic strategies to adapt to a hostile tumor microenvironment (TME) for survival and stemness maintenance. Such a metabolic alteration in CSCs is facilitated by microenvironmental cues including metabolites such as glucose, amino acids and lipids, and environmental properties such as hypoxic and acidic TME. Similarly, metabolites uptake from the diet exerts critical imprints to the metabolism profile of CSCs and directly influence the maintenance of the CSC population. Moreover, CSCs interact with tumor-infiltrating cells inside the CSC niche to promote cancer stemness, ultimately contributing to tumor development and progression. Understanding the underlying mechanisms of how CSCs employ metabolic plasticity in response to different microenvironmental cues represents a therapeutic opportunity for better cancer treatment. Emerging evidence has suggested that tumor cells inside a tumor bulk are heterogenous with variable genetic, phenotypic and functional profiles . Among wCSCs reside in the tumor microenvironment (TME) where heterogeneous cell populations interact with one another . The intReprogramming cellular metabolism is considered as one of the core hallmarks of cancer ,16, by wExtracellular metabolites could exert either tumor-promotive or -suppressive effect in different cancers . Their a+CD117+ CSCs isolated from epithelial ovarian cancer patients showed increased glucose uptake while CSC phenotype could still be maintained under glucose deprivation environment [+ liver CSCs [Glucose, as the primary energy-producing metabolite, has been shown in different cancers to either promote or suppress CSCs. A study observed that hyperglycaemia resulted in enhanced invasion and stemness of breast CSCs by reducing the tumor suppressing microRNA miR-424 . Howeverironment . Similarver CSCs . These sAmino acids are another important group of metabolites which influence CSC stemness . GlutamiExtracellular lactate impacts cancer cells and CSCs through diverse mechanisms ,32,33,34In addition to glucose, amino acids and lactate, lipids also play critical roles in regulating the stemness trait of CSCs. In ovarian CSCs, the provision of exogenous fatty acid sources such as palmitoleic acid and oleic acid rescued CSCs from ferroptosis-induced cell death which was resulted from the inhibition of fatty acid lipogenesis enzyme stearoyl-CoA desaturase (SCD1) . In relaCSCs consume metabolites in the TME, at the same time CSCs also actively remodel the TME by their altered metabolite secretome in order to establish a supportive ecosystem for tumor initiation and progression . Under hKetone bodies, comprising of acetone, acetoacetate and beta-hydroxybutyrate (\u03b2-HB), possess both pro-tumor and anti-tumor properties . IncreasMetabolic plasticity could be observed in CSCs exhibiting flexible energy metabolic strategy, that enables them to cope with energy demands in response to changing nutrient availability and environmental stress  54,55,5,555,56. Under hypoxia, CSCs rely on glycolysis rather than OXPHOS to maintain their survival . Zhou etAcidic extracellular microenvironment, termed acidosis, is another physical environmental factor that influences CSC metabolism and functions ,69,70,71In addition to the alteration of physical properties of the TME, extracellular metabolites also contribute to the reprogramming of CSC metabolism. High glucose concentrations in the culture media promoted glucose metabolism in pancreatic and ovarian CSCs as evident by the activation of glucose transporter 1 (GLUT1) . In anotThe reprogrammed metabolic strategies in CSCs represent therapeutic opportunities. Drugs targeting glucose metabolism exert effect on glycolytic CSCs, as exemplified by the use of 2-DG ,78,79. ODiet determines the nutrient availability in the microenvironment where CSCs are exposed to, that in turn alters CSC metabolism .+ intestinal stem cell pool through the activation of peroxisome proliferator-activated receptor-related signaling pathway [+ CSCs pool and promoted tumorigenesis through JAK2/STAT3 signaling in colon cancer [+ CSCs [High fat diet has been correlated with higher cancer incidence and worse prognosis , and it  pathway . In oral pathway . In high pathway . Similarn cancer . Moreove [+ CSCs .Increased dietary intake of cholesterol and high cholesterol level have been implicated to facilitate tumor development and progression . Ehmsen Other types of diets have also been implicated in regulating CSCs. For example, a fasting-mimicking diet was observed to lower the glucose level and reduce the expression of stemness markers in breast CSCs . AccumulResults from the above studies indicate that dietary metabolites possess either promotive or suppressive role in the maintenance of CSC phenotypes in various types of cancers. Deciphering the mechanisms of such dietary effects on CSCs would shed light on novel therapeutic opportunities.The presence of heterogeneous cell populations within the tumor bulk are well characterized in different cancers ,94. CSCsCancer associated fibroblasts (CAFs) are fibroblastic cells residing in the TME that possess regulatory functions on cancer cells and CSCs . CAFs fu+ liver CSCs induced tumor angiogenesis [Endothelial cells (ECs) are functional cells that line the vascular system and are recruited to the TME for angiogenesis ,107. Unlogenesis . Wang etogenesis . Similarogenesis . In glioogenesis . Despite+ tumor-infiltrating T cells shifted their metabolism from glycolysis towards fatty acid catabolism [Immune evasion is one of the major hallmarks of CSCs . The mettabolism . Furthertabolism . The inttabolism . Proteintabolism ,125,126.tabolism . HoweverThe TME is comprised of various cellular and non-cellular components which reside with CSCs in the tumor bulk and continuously affect and modify the behaviors of CSCs. Metabolic plasticity displayed by CSCs enables flexible switching of their metabolic strategies to accommodate and survive in the hostile TME. In reverse, CSCs produce and secrete various proteins and metabolites to influence the neighboring microenvironment. This bidirectional interaction not only sustains the aggressive tumor behaviors but also protects and enhances tumor survival in response to stress and environmental insults.Given the importance of metabolic reprogramming in the maintenance of cancer stemness, elucidating the underlying molecular mechanisms which drive the metabolic plasticity of CSCs will likely reveal novel metabolic vulnerabilities and therapeutic targets to combat CSC-driven tumor development and progression. Current research efforts have been put to identify activated or mutated metabolic enzymes which play roles in promoting certain metabolic pathways to support cancer development and progression. Clinical trials with the use of small molecular inhibitors to target different metabolic enzymes has been underway . MetformDespite the enthusiasm of the development of metabolic therapies to target CSC metabolism for cancer treatment, concern and criticism were raised regarding the validity of experimental results using in vitro culture which deviates from the physiological environment . In part"}
+{"text": "The aim of this study was to investigate the role of a synthetic dermal matrix, Biodegradable Temporising Matrix (BTM), for coverage of complex wounds. The authors defined complex wounds as wounds not amenable to reconstruction with skin grafting alone due to an inherent avascularity of the wound bed, such as the presence of exposed bone, tendinous or neural structures.A retrospective review of a prospectively maintained database of complex wounds as defined above was carried out. Clinical and operative notes were reviewed along with review of an extensive photographic database demonstrating wound healing progress using staged dermal matrix (BTM) and autologous skin graft reconstruction.55 patients were identified who underwent staged dermal matrix and autologous skin graft reconstruction for complex wounds affecting a wide variety of patient demographics, treatment indications and body sites. Wound aetiology varied between burn injury, non-burn related trauma including degloving injury and infective complications. We discuss caveats relating to successful application of a dermal matrix, technique tips, prevention and management of complications.Dermal substitutes play an integral role in providing biological wound cover for avascular wound beds which may otherwise require complex distant flap or microsurgical free flap reconstruction. BTM is a completely synthetic dermal matrix comprised of a 2-mm-thick sheet of biodegradable polyurethane foam bonded to a non-biodegradable polyurethane sealing membrane. Our department has developed significant expertise in the use of BTM throughout its development from initial animal studies through to recent human clinical trials. The synthetic composition of BTM does not require rapid neo-vascularisation for its integrity or survival. As such, two-stage BTM reconstruction has proven robustness in the face of unfavourable wounds compared with other popular dermal matrices, physiologically covering avascular structures, allowing for early graft take, expediting rehabilitation and mobilisation with excellent scar cosmesis and limited contracture formation.Dermal matrices such as BTM play an important role in complex wound healing, frequently achieving excellent results with a low complication profile. BTM has been used successfully in cases where biological matrices would not routinely be considered as demonstrated by this clinical series. It has provided a valuable alternative to free-tissue transfer in patients with significant co-morbidities, vascular insufficiency and/or those for whom long operations are undesirable."}
+{"text": "The COVID-19 pandemic in NYC, the epicenter of the US crisis, revealed indisputable evidence that social determinants of health  and disparities in comorbid health risk factors produce higher burdens of disease and death among racial and ethnic populations. We conducted a needs assessment of SDoH among 1400 patients in several ambulatory care clinics to explore the impact among older adults, across different clinical populations. Among older adults with HIV (OAH), we found lower rates of food and housing insecurity compared to older adults without HIV. Despite higher levels of COVID knowledge and prevention adherence, we also found significantly higher levels of isolation, loneliness, depressive symptoms, and anxiety among OAHs compared to those without HIV. Access to Ryan White entitlements did buffer some impacts but preexisting high burdens of mental health issues were exacerbated, perhaps due to heightened perceptions of increased vulnerability to COVID-19."}
+{"text": "There is an abundance of evidence for the widespread presence of this spinal reflex arch originating from virtually every visceral organ and thus having a substantial role in blood pressure control. Additionally, this review highlights specific endogenous eicosanoid species, which modulate the activity of afferent fibers involved in this reflex, through their interactions with transient receptor potential (TRP) cation channels.The spinal cord is an important integrative center for blood pressure control. Spinal sensory fibers send projections to sympathetic preganglionic neurons of the thoracic spinal cord and drive sympathetically-mediated increases in blood pressure. While these reflexes responses occur in able-bodied individuals, they are exaggerated following interruption of descending control \u2013 such as occurs following spinal cord injury. Similar reflex control of blood pressure may exist in disease states, other than spinal cord injury, where there is altered input to sympathetic preganglionic neurons. This review primarily focuses on mechanisms wherein visceral afferent information traveling  Physiological mechanisms of blood pressure control involve complex interactions between neural and humoral factors, which work hand-in-hand to ensure optimal delivery of nutrient rich blood to all the cells of the body. In regulating blood pressure, particularly important are the effects of the sympathetic nervous system. Sympathetic postganglionic neurons innervate blood vessels to regulate vascular smooth muscle tone and peripheral resistance. The rostral ventrolateral medulla is arguably one of the most critical cites for establishing baseline blood pressure as it sends tonic impulses to sympathetic preganglionic neurons located within the intermediolateral cell column of the thoracic spinal cord. Although the spinal cord is often described as a mere relay station between the brainstem and the periphery, clinical and experimental evidence highlights the important role of intraspinal reflex circuits in blood pressure regulation.via spinal nerves influences sympathetic nerve activity and blood pressure. Special emphasis is placed on descending inhibitory control of sympathetic preganglionic neurons and how interruption of this inhibition, as occurs following spinal cord injury, leads to aberrant spinal reflex control of blood pressure. Additionally, we propose that the spinal sensory input may contribute to tonic control of blood pressure in able bodied individuals. Finally, we highlight endogenous modulators of this neurocircuitry and their potential roles in regulation of blood pressure in healthy and diseased states.In this review we summarize available evidence that suggests intraspinal reflex circuits can directly and independently orchestrate profound reflex-mediated changes in blood pressure, especially when descending inhibitory pathways are interrupted, as in patients with spinal cord injuries. We primarily focus on mechanisms wherein visceral afferent information traveling via a spinal reflex arc \u2013 independent of central processing within the brain. The effect of visceral stimulation on systemic blood pressure was first empirically demonstrated in seminal works by Sir Charles Sherrington. He showed that distension of hollow visceral organs such as the urethra, bile duct or rectum in spinalized or decerebrate animals led to moderate increases in blood pressure, which were associated with a series of involuntary motor responses  and spinal pathways. Stimulation of cranial afferent nerve fibers is generally associated with cardiovascular depressor responses, while spinal afferent stimulation generally evokes pressor responses  within and surrounding visceral organs, are relayed to the central nervous system esponses . First oesponses . Within nal cord  , the lower visceral organs are arguably less innervated by vagal afferent fibers and are densely innervated by thoracolumbar and/or sacral (pelvic) afferent fibers, whose cells bodies are located within dorsal root ganglia. The nerve bundles of these spinal sensory neurons are composed of thinly myelinated A\u03b4 and unmyelinated C fibers ,b. TheseVisceral mechano sensation has been extensively studied and mechanosensitive afferent fibers arising from the viscera are important drivers of sympathetic reflexes .Low threshold mechanosensitive afferent fibers innervate mucosal membranes and muscle layers of the visceral organs and are tonically active . They arHigh threshold mechanosensitive afferent fibers innervate blood vessels in the mesentery and mucosal membranes and muscle layers of visceral organs. These fibers are involved in detecting urgency, changes in mesenteric arterial pressure and mechanically induced pain.Silent mechanosensitive afferent fibers are mostly involved in signaling pathological visceral changes . These fIt is well established that mechanosensitive A\u03b4 and C-fibers drive sympathetic responses to mechanical stimulation of the viscera . HoweverThe above described functional organization for processing of afferent information exists within most spinal segments and highlights potential of intraspinal circuitry to influence spinal visceral reflexes originating from various spinal segments.As described above, the viscero-sympathetic reflex, similar to spinal motor reflexes, is integrated at the level of the spinal cord. Various visceral reflex arcs are contained within the spinal cord and are involved in normal gastrointestinal and urogenital physiology. As indicated below, activation of most spinal visceral reflexes is preserved following upper thoracic spinal cord injury and is associated with increases in systemic blood pressure.Micturition reflex: During the storage phase of the micturition reflex, pelvic sensory afferents send slow impulses into the spinal cord, which drive involuntary contraction of the internal urethral sphincter and relaxation of the detrusor muscle, both of which are needed to facilitate urine retention and are mediated via sympathetic efferent fibers. Importantly, bladder filling is associated with a progressive increase in activity of other regional sympathetic efferent fibers and in systemic blood pressure  results in reflex increases in sympathetic nerve activity and blood pressure . Sympathetic fibers innervating the bladder neck, prostate, seminal vesicles, and vas deferens are activated and drive the emission phase of ejaculation  across the plasma membrane. TRP channels are activated by a wide range of physiological and pathophysiological signals and respond to both chemical ligands and physical stimuli. In addition, many of the mammalian TRP channels are thermo-sensitive and can be directly activated by cold or hot temperatures  family. To date, 28 mammalian TRP channels have been identified  salt-sensitive hypertension  or can be indirectly activated  via three major enzyme systems: the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) pathways. Eicosanoid molecules play a critical role in inflammatory signaling (2 (PGE2), clearly indicate that binding of PGE2 to its G protein coupled receptors (EP1-4) on the surface of TRP channel expressing neurons promotes hyperalgesia by driving phosphorylation of TRP channels thereby increasing excitability to mechanical, thermal and chemical stimuli (reviewed in via direct interactions (Eicosanoids are bioactive metabolites derived from polyunsaturated fatty acids (PUFAs) and generated ignaling , and theractions . Such inractions .Interestingly, many of the eicosanoids that promote afferent hyperexcitability through interactions with TRP channels are derived from \u03c9-6 PUFAs, which are abundant in Western diets. This has led us and others to hypothesize that dietary PUFA content may directly influence the excitability of TPR expressing C and A\u03b4 fibers. Evidence to support this hypothesis was recently published by the laboratory of K.M. Hargeaves . Specifivia intraspinal circuitry. However, it is important to highlight that similar sympathetic responses can be generated by spinal afferent information arising from somatic afferents   . As in t reflex) . While i reflex) . However reflex) . This lein vivo electrophysiology recording will be an important tool for understanding the role of eicosanoids in altering spinal afferent excitability. Furthermore, additional studies into the role of dietary PUFA content and eicosanoid-TRP interactions in regulating baseline sympathetic nerve activity are needed.We have briefly highlighted the potential role of eicosanoid-TRP interactions in modulating the afferent limb of the viscero-sympathetic reflex circuitry. However, many mechanistic issues remain to be resolved and via chronic activation of the viscero-sympathetic reflex circuitry. Consistent with this notion, a large Danish cohort study found the risk for developing hypertension was significantly reduced among patients undergoing surgical colectomy when compared to patients undergoing other surgical procedures (It is notable that inflammatory conditions involving the viscera, such as inflammatory bowel disease, lead to the development of visceral afferent hyperexcitability . Interesocedures . Future ZM and CR: idea, writing, and editing. DO\u2019L: idea and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Kefir is an easy to administer per feeding tube probiotic yogurt that does not contain the risk of powdered probiotics, which may contaminate patient wounds or intravenous lines. Previous studies show patients taking probiotics may decrease hospital-acquired infections (HAI) although kefir has not been well studied. We hypothesized that kefir would be well tolerated and prevent infections among critically injured patients including patients with burn injury on enteral nutrition (EN).We performed a retrospective review of adult critically injured patients at a level 1 trauma and burn center from January 2018 to March 2021 who received EN. Patients with a history of clostridium difficile (C. diff) were excluded. Patients who received kefir were given 120ml twice daily. The kefir protocol was improved with input from clinical stakeholders. The rate of C. diff, catheter-associated urinary tract infection (CAUTI), and central line-associated blood stream infection (CLABSI) were compared between patients who received kefir and those who did not. Incidence rate ratios (IRR) and corresponding 95% confidence intervals were calculated to assess differences in these rates.3,814 patients met criteria, 545 of whom received kefir (14%). Suggested improvements to the kefir protocol by stakeholders were changing flavored to plain kefir to decrease the amount of carbohydrate, change to lactose-free kefir to improve usage in lactose intolerant patients, and educate nurses on flushing feeding tubes to avoid clogs.None of the incidence rates of HAI were significantly different between patients who received kefir and those who did not (Table 1). Crude IRRs suggest that C. diff infections may have occurred less frequently among patients who received kefir while the reverse occurred for CLABSI infections, though these results are not significant.The kefir implementation was refined by stakeholder feedback. Although no clear benefit of kefir was observed with HAI reduction, future research should investigate the potential association between kefir use and C. diff."}
+{"text": "Background: Numerous studies have shown that trauma-focused psychological treatments for PTSD are effective .Results: Were preceded by changes in for most measures, changes in cognitive factors preceded changes in PTSD symptoms, but not vice versa.Study 2 Methods: Patient and therapist ratings of working alliance were taken repeatedly. Autoregressive, cross-lagged models were used to examine whether working alliance predicted PTSD symptom severity at the next assessment point and vice versa.Results: Higher patient and therapist working alliance was associated with lower PTSD symptoms. Crossed-lagged associations were found for therapist-rated alliance, but not for patient-rated alliance. A better working alliance at the start of treatment predicted treatment outcome. For most measures, changes in cognitive factors preceded changes in PTSD symptoms, but not vice versa.Conclusions: Study 1 extended previous findings that that cognitive and behavioural processes suggested by theoretical models of PTSD play a key role in driving symptom improvement during trauma-focused CBT. Changes in cognitive factors preceded symptom change. This result suggests that monitoring these processes during therapy may help therapist in maximising treatment outcomes in individual patients, and may also point to further ways of optimising treatments in general. Study 2 suggested that working alliance may be an important factor in setting the necessary conditions for effective treatment, but did not find evidence of a temporal precedence of changes in working alliance driving symptom change."}
+{"text": "The ultimate goal for vaccination is the generation of a safe and effective immune response that protects against diseases. Adjuvants are included to enhance and direct vaccine responses. Precisely how adjuvants and indeed vaccine formulations influence the innate immune response and the subsequent cell- and antibody-mediated arms of the adaptive immune system are being characterized and clarified. Identification of safe but potent vaccine adjuvants, particularly those directed at mucosal sites, which generate long-lasting immunological memory and are effective against intracellular and extracellular pathogens is a high priority for public health and the health of veterinary species. After they are identified, tremendous amounts of work must be done to fine-tune adjuvant production, stabilization, and purification before commercialization. We launched this special issue to highlight recent basic research in vaccine formulation for infectious diseases and assess the adjuvant mechanism of action.Alcaligenes spp. that inhabit Peyer\u2019s patches in the gut [Alcaligenes lipid A may be a safe and effective Th17-type adjuvant.The following is a synopsis of the results reported in seven original articles. Systemic or mucosal adjuvants that promote T helper 17 (Th17)-type immunity are being investigated. Chaffey et al., 2021) assessed whether an intramuscular injection of adjuvants with ovalbumin in mice could induce an antigen-specific Th17-type immune response [021 asses the gut . Ex vivoMucosal vaccines need potent mucosal adjuvants to be effective. Razim et al. developed and characterized nanoadjuvant candidates (NACs) composed of silicon oil and cationic detergents and organic solvents for intranasal application . They idAssessing whether FDA-approved drugs can be repurposed as vaccine adjuvants is an important way to potentially fast-track adjuvant approval. Miltefosine (MTF) is an FDA-approved anti-leishmaniasis drug. Lu et al. assessed its adjuvant potential by immunizing mice via an intraperitoneal injection with hemagglutinin from influenza followed by intranasal challenge . The micAvian metapneumovirus (aMPV) is a virus that is the causative agent of turkey rhinotracheitis in turkey flocks and swollen head syndrome in chickens leading to significant morbidity and mortality throughout China. Bao et al. performed intramuscular injections of inactivated aMPV/B strain LN16 formulated with commercially available immune-stimulating complexes  and measured the resultant immune response . They deFour review articles in this issue highlight the production, purification, and formulation of interferon-based biopharmaceuticals  , the effTaken together, this special issue contains 11 relevant research and review articles focused on various aspects of the adjuvant mechanism of action and novel vaccine formulations that should be explored further for use in human and veterinary vaccines."}
+{"text": "FGFR inhibitors evolved as therapeutic options in cholangiocarcinoma and urothelial malignancies. Given the implications of FGFR pathway in various physiological functions, FGFR inhibitors are known to cause unique toxicities. In this review, we summarized the physiology of FGF/FGFR signaling and briefly discussed the possible mechanisms that could lead to FGFR inhibitor resistance and side effects. In addition, we proposed treatment guidelines for the management of FGFR-inhibitor-associated toxicities.FGFR2 fusions or rearrangement, and erdafitinib in metastatic urothelial carcinoma with FGFR2 and FGFR3 genetic aberrations, lead to their accelerated approval by the United States (USA) FDA. Along with these agents, many phase II/III clinical trials are currently evaluating the use of derazantinib, infigratinib, and futibatinib either alone or in combination with immunotherapy. Despite the encouraging results seen with FGFR inhibitors, resistance mechanisms and side effect profile may limit their clinical utility. A better understanding of the unique FGFR-inhibitor-related toxicities would invariably help us in the prevention and effective management of FGFR-inhibitor-induced adverse events thereby enhancing their clinical benefit. Herein, we summarized the physiology of FGF/FGFR signaling and briefly discussed the possible mechanisms that could lead to FGFR inhibitor resistance and side effects. In addition, we proposed treatment guidelines for the management of FGFR-inhibitor-associated toxicities. This work would invariably help practicing oncologists to effectively manage the unique toxicities of FGFR inhibitors.Fibroblast Growth Factor receptor (FGFR) pathway aberrations have been implicated in approximately 7% of the malignancies. As our knowledge of FGFR aberrations in cancer continues to evolve, FGFR inhibitors emerged as potential targeted therapeutic agents. The promising results of pemigatinib and infigratinib in advanced unresectable cholangiocarcinoma harboring  FGFR gene aberrations have been implicated in human malignancies . In . In 8]. TP53 gene thereby activating the cancer-associated fibroblasts promoting the tumorigenesis in FGFR aberrations . Given this expanding role of FGFR inhibitors in cancer care, a thorough knowledge on their unique side effects will aid in preventing unnecessary dose reductions and interruptions. It is important that patients be educated about these FGFR-inhibitor-related unique side effects and possible preventive mechanisms. Along with effective management of drug-related toxicities, a special focus is to be made on expanding our knowledge on resistance to FGFR-inhibitors. As determined in preclinical models, combination regimens such as synergistic inhibition of FGFR inhibitors and mTOR or MAPK pathway inhibitors may further be evaluated to bypass the resistance mechanisms.FGFR inhibitors are a unique class of emerging targeted therapies that have shown promising results in tumors harboring"}
+{"text": "Myocardial infarction leads to pathological changes in the heart, including loss of cardiomyocytes and degradation of the cardiac extracellular matrix (ECM). These changes result in wall thinning, infarct enlargement, and development of scar tissue. Such remodeling ultimately leads to end-stage heart failure ,2. To adIn order to address these limitations, Silveira-Filho et\u00a0al.  investigMany studies in the field of cardiac tissue engineering address remodeling timepoints immediately after ischemic wounding. However, this acute approach is not realistic because most of the remodeling in clinical ischemic heart disease occurs undetected over long periods of time, leading to extensive ventricular thinning, scarring, and progressive heart failure. The experimental time course followed in this study attempted to recapitulate extensive remodeling in the validation of PECUU-ECM patches by addressing ischemic wounds 8\u00a0weeks after myocardial infarction. This study found PECUU-ECM patches were efficacious in reversing the negative remodeling seen in advanced stages of ischemia, offering great potential for clinical translation. Additionally, the authors\u2019 rationale for incorporating PECUU patches within the biohybrid patch was its slower degradation rate relative to that of poly(ester urethane)urea (PEUU). This slower degradation rate ultimately led to better remodeling outcomes in post-infarcted rats given a PECUU patch compared to those given a PEUU patch over their infarcted hearts. Despite the slower rate of degradation, PECUU patches favorably did not form encapsulations typically caused by nondegradable material. These findings point to the importance of polymer selection in the development of cardiac patches. Notably, there are still some challenges this study needs to address in the future. The biohybrid patch used is mechanically compatible with rat myocardium, yet how these patches may influence the contractility and electrophysiology of human myocardium and whether the patches will withstand the pressures of a full adult human cardiac load upon implantation remain to be investigated . If implRecent advances in the field of cardiac tissue engineering include the use of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to produce engineered heart tissue (EHT) . In the The PECUU-ECM technology engineered by Silveira-Filho et\u00a0al.  shows prThe authors have reported that they have no relationships relevant to the contents of this paper to disclose."}
+{"text": "In mucosal barrier interfaces, flexible responses of gene expression to long-term environmental changes allow adaptation and fine-tuning for the balance of host defense and uncontrolled not-resolving inflammation. Epigenetic modifications of the chromatin confer plasticity to the genetic information and give insight into how tissues use the genetic information to adapt to environmental factors. The oral mucosa is particularly exposed to environmental stressors such as a variable microbiota. Likewise, persistent oral inflammation is the most important intrinsic risk factor for the oral inflammatory disease periodontitis and has strong potential to alter DNA-methylation patterns. The aim of the current study was to identify epigenetic changes of the oral masticatory mucosa in response to long-term inflammation that resulted in periodontitis.ROBO2, PTP4A3), cell adhesion (LPXN) and innate immune response . Enrichment analyses implied a role of epigenetic changes for vesicle trafficking gene sets.Genome-wide CpG methylation of both inflamed and clinically uninflamed solid gingival tissue biopsies of 60 periodontitis cases was analyzed using the Infinium MethylationEPIC BeadChip. We validated and performed cell-type deconvolution for infiltrated immune cells using the EpiDish algorithm. Effect sizes of DMPs in gingival epithelial and fibroblast cells were estimated and adjusted for confounding factors using our recently developed \u201cintercept-method\u201d. In the current EWAS, we identified various genes that showed significantly different methylation between periodontitis-inflamed and uninflamed oral mucosa in periodontitis patients. The strongest differences were observed for genes with roles in wound healing (Our results imply specific adaptations of the oral mucosa to a persistent inflammatory environment that involve wound repair, barrier integrity, and innate immune defense.The online version contains supplementary material available at 10.1186/s13148-021-01190-7. Genetic studies of chronic inflammatory diseases focused primarily on identifying DNA variants  that confer disease risk through genome-wide association studies . MorThe oral masticatory mucosa locates to the alveolus/tooth complex and the hard palate and comprises all parts of the oral mucosa that are involved in chewing. Its position at the entrance to the gastrointestinal tract and respiratory systems entails its direct exposition to a diverse microbiota and various other environmental stressors such as tobacco smoke. If the mucosal barrier is impaired, pathogens can invade into subjacent tissue layers and promote periodontal inflammation. Persisting inflammation causes gingival bleeding and leads to the loss of connective tissue and alveolar bone with subsequent tooth loss, which determines the clinical characteristics of the common oral inflammatory disease periodontitis. In the etiology of periodontitis, persistent gingival inflammation is the most important risk factor , followeCYP1B1 (cytochrome P450 family 1 subfamily B member 1) and AHRR (aryl-hydrocarbon receptor repressor). Several EWAS have identified these associations for cells of the alveolar  for the top 10 differentially methylated genes in the GO term \u201csynaptic vesicle cycle\u201d."}
+{"text": "Traumatic brain injury (TBI) is common among older adults, with significant public health costs, and advanced age is a risk factor for poor outcomes after TBI. Older Veterans with TBI-related cognitive and emotional dysfunction without dementia may benefit from cognitive rehabilitation, particularly executive function training, and technology may promote optimal functioning for these patients by increasing access to such treatments. Dr. Kornblith will present pilot data on one such promising group intervention, Goal-Oriented Attentional Self-Regulation (GOALS), administered via in-home video telehealth. Themes gleaned from qualitative feedback collected throughout the intervention and post-treatment feedback questionnaires include the importance of communication and a smooth process with clear instructions for joining study sessions. Preliminary data suggest that only minor adaptions to the existing GOALS protocol are required for telehealth delivery and that delivering group-based executive function training to older TBI-exposed older Veterans with cognitive complaints via telehealth is feasible and acceptable."}
+{"text": "Long-lasting changes in neural pain circuits precipitate the transition from acute to chronic pain in patients living with inflammatory bowel diseases (IBDs). While significant improvement in IBD therapy has been made to reduce inflammation, a large subset of patients continues to suffer throughout quiescent phases of the disease. Peripheral and central mechanisms contribute to the transition from acute to chronic pain during active disease and clinical remission. Lower mechanical threshold and hyperexcitability of visceral afferents induce gliosis in central pain circuits, leading to persistent visceral hypersensitivity (VHS). In the spinal cord, microglia, the immune sentinels of the central nervous system, undergo activation in multiple models of VHS. Using the Dextran Sodium Sulfate (DSS) model of colitis, we found that microglial G-CSF was able to sensitize colonic nociceptors that express the pain receptor TRPV1. While TRPV1+ nociceptors have been implicated in peripheral sensitization, their contribution to central sensitization via microglia remains unknown.Here we investigated the mechanisms of microglia activation to identify centrally acting analgesics for chronic IBD pain.Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) expressed in TRPV1-expressing visceral neurons that sense colonic inflammation, we tested whether neuronal activity was indispensable to control microglia activation and VHS. We then investigated the neuron-microglia signaling system involved in visceral pain chronification.We found that chemogenetic inhibition of TRPV1+ visceral afferents prevents microglial activation in the spinal cord and subsequent VHS in colitis mice. In contrast, chemogenetic activation, in the absence of colitis, enhanced microglial activation associated with VHS. We identified a purinergic signaling mechanism mediated by neuronal ATP and microglial P2RY12 receptor, triggering VHS in colitis. Inhibition of P2RY12 prevented microglial reactivity and chronic VHS post-colitis.Overall, these data provide novel insights into the central mechanisms of chronic visceral pain and suggest that targeting microglial P2RY12 signaling could be harnessed to relieve pain in IBD patients who are in remission.CCC"}
+{"text": "Retaining older adults in clinical trials has often been a challenge for researchers. Clinical trial procedures, aimed at improving fidelity, often offer barriers to frail older adults who have challenges traveling to medical centers and enduring long clinical assessment visits. During the COVID-19 pandemic, we modified the procedures of two randomized controlled trials. COMPASS: A novel transition program to reduce disability after stroke is a clinical trial examining the efficacy of a transition home program that provides home modifications and self-management strategies compared to stroke education. HARP: Removing home hazards for older adults living in affordable housing is a pragmatic trial examining the effectiveness of a home hazard removal program for residents of low-income housing. Modifications to the trials were designed to reduce human contact but in some cases reduced the burden on trial participants. Modified procedures addressed retention, assessment of endpoints and intervention methods."}
+{"text": "Tumor heterogeneity is one of the hallmarks of glioblastoma multiforme (GBM). Morphology within a given GBM tumor can be extremely variable where some regions of the tumor have a soft, gel-like structure while other areas are dense and fibrous. Abnormal mechanical stress and tissue stiffening caused by cancer proliferation are believed to affect vascularity by compressing structurally weak blood vessels and restricting the supply of nutrients and oxygen to the tissue. These effects contribute to a hypoxic microenvironment that promotes disease progression and chemoresistance. The genetic and molecular mechanisms that govern tissue stiffness within GBM tumors, however, are largely unknown. Magnetic Resonance Elastography (MRE) is an emerging technique for quantifying tissue stiffness non-invasively.We have evaluated 10 GBM patients by MRE imaging obtained prior to surgical resection. During surgery, 2\u20137 stereotactically navigated biopsies were collected from locations within the tumor with varying degrees of measured stiffness. Biopsies were processed to extract RNA, proteins, polar metabolites and lipids. Biomolecules were analyzed on relevant -omics platforms .Differential expression and gene set enrichment analysis of patient paired biopsies indicate an overall increase in macrophage infiltration and extracellular matrix re-organization associated with increased tumor stiffness. Among the most highly upregulated genes in stiff tumor tissue were lymphatic endothelial hyaluronic acid receptor 1 (LYVE-1) and macrophage receptor with collagenous structure (MARCO), both of which have been associated with immune cell infiltration and tissue stiffness.Our preliminary findings offer novel insights into tumor morphology in GBM that can be inferred from imaging prior to surgery. This can be used to identify tumor regions with high risk of progression and infiltration, thereby informing and guiding surgical strategy and may ultimately lead to novel treatment strategies."}
+{"text": "Roney et al. review recent advances in how axonal endolysosomal trafficking, distribution, and functionality maintain distal degradation capacity in neuronal health and become disrupted in several neurodegenerative diseases. Lysosomes serve as degradation hubs for the turnover of endocytic and autophagic cargos, which is essential for neuron function and survival. Deficits in lysosome function result in progressive neurodegeneration in most lysosomal storage disorders and contribute to the pathogenesis of aging-related neurodegenerative diseases. Given their size and highly polarized morphology, neurons face exceptional challenges in maintaining cellular homeostasis in regions far removed from the cell body where mature lysosomes are enriched. Neurons therefore require coordinated bidirectional intracellular transport to sustain efficient clearance capacity in distal axonal regions. Emerging lines of evidence have started to uncover mechanisms and signaling pathways regulating endolysosome transport and maturation to maintain axonal homeostasis, or \u201caxonostasis,\u201d that is relevant to a range of neurologic disorders. In this review, we discuss recent advances in how axonal endolysosomal trafficking, distribution, and lysosomal functionality support neuronal health and become disrupted in several neurodegenerative diseases. Lysosomes are dynamic, membrane-bound, acidic organelles that play a central role in the degradation of intracellular and extracellular cargos. More than 60 hydrolytic enzymes that are active under acidic environments within the lysosomal lumen facilitate degradation of complex biological macromolecules, including proteins, lipids, nucleic acids, and carbohydrates . LysosomNeurons are highly polarized cells consisting of a cell body, complex dendritic arbors, and a single long axon with extensive branches and terminals that can span several tens to hundreds of centimeters in length. Given this extended morphology, neurons require efficient bidirectional transport mechanisms to coordinate clearance of endocytic and autophagic cargos generated distally by lysosomes that are relatively enriched in the cell body. Efficient transport is critically important in maintaining neuron growth, survival, and function but particularly challenging in distal axons and terminal branching regions. Accumulation of autophagic vacuoles (AVs) and lysosome-like organelles characterizes axonal pathology in several neurodegenerative diseases associated with lysosome dysfunction, reflecting disruptions at various steps in the maturation and trafficking of endolysosomal and autophagic organelles . In thisLysosomes serve as terminal degradation hubs for endocytic and autophagic components. Extracellular materials internalized by endocytosis, intracellular components sequestered by autophagy, and newly synthesized lysosomal proteins reach endolysosomes through highly regulated trafficking routes. Endolysosomal trafficking from early endosomes (EEs) to late endosomes (LEs) and finally to mature lysosomes is essential for delivering target endosomal proteins for degradation . TransitThe unique compartmental features of neurons add yet another layer of complexity to lysosome maturation. As in other cell types, neuronal lysosomes receive cargos through the endocytic, autophagic, and biosynthetic pathways. Because of their extreme morphological features, neurons require coordinated bidirectional transport mechanisms to maintain a steady-state distribution of the endolysosomal system in the axon, dendrites, and cell body. Degradative lysosomes are predominantly located in the cell body , represeEarly work measuring the pH of axonal endocytic cargos demonstrated an increasing frequency of acidic organelles as cargos moved from distal to proximal , suggestL-phenylalanine 2-naphthylamide  in neurons showed enriched hCTSD puncta in somatodendritic regions of layer 5 cortical neurons and hippocampal CA1 neurons . AlthougNeurons require efficient transport mechanisms to maintain a steady-state distribution of endolysosomes throughout the cell. Kinesin and dynein motors drive long-distance transport along microtubule (MT) tracks in axons and dendrites, whereas myosin motors mediate short-range movement along actin filaments enriched in growth cones and synaptic regions . BidirecBorcs7 (encoding a BORC subunit) develop progressive axonal dystrophy and motor dysfunction, indicating a critical role of BORC-dependent axonal lysosome transport for maintaining axon integrity and neuron function in vivo  mouse dystrophic axons contain immature lysosomes with low levels of proteases, representing a population of lysosomal intermediates distinct from mature lysosomes in the cell body  and thus facilitates retrograde LE transport from axonal terminals toward the soma . Deletinradation  and enharadation . Interesradation  that is radation , althougGlued  transport and positioning responds to alterations in cytoplasmic pH. Acidification of the cytosol causes lysosome dispersal into neuronal processes, whereas cytosolic alkalization shifts LE/LY distribution to the cell body , suggestDegradation of autophagic cargos depends on their dynamic interactions with endolysosomes, which supply the hydrolytic enzymes needed for substrate degradation . Both thIn axons, autophagosomes predominantly form at distal terminals , then suThus, the maturation of these distal AVs into autolysosomes is tightly linked to their retrograde transport. Scaffolding proteins, including JIP1, HTT-associated protein 1 (HAP1), and JIP3 , regulatAlthough dynein-driven retrograde transport of autophagosomes was suggested, a fundamental question remained as to how autophagosomes generated at distal axons acquire dynein motors for retrograde transport toward the soma. Using live rat dorsal root ganglion neurons combined with molecular disruption of autophagosome fusion with LEs or impairment of dynein\u2013snapin (motor\u2013adaptor) coupling, a study revealed a motor-adapter sharing model in which LE-loaded dynein\u2013snapin complexes are shared by autophagosomes upon their fusion . BlockinRecent evidence further revealed the role of lysosomes in axonal autophagosome maturation and clearance. Lysosomes that transport from the soma into axons target autophagic cargo to facilitate local AV maturation and cargo degradation. These lysosomes contain active lysosomal enzymes and are continuously delivered to distal axons from the cell body . DisruptLysosome dysfunction and impaired trafficking are linked to the pathogenesis of rare and common neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD), Alzheimer\u2019s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington\u2019s disease (HD), Parkinson\u2019s disease (PD), and lysosomal storage disorders (LSDs) such as Niemann-Pick disease type C NPC; . In thesTMEM106B, encoding a transmembrane protein primarily localized on LEs and lysosomes, have been linked to several neurodegenerative diseases, including FTLD  interacts with DIC  leads to enhanced recruitment of JIP4 to AV membranes, inducing abnormal activation of the anterograde motor kinesin  be differentially regulated in response to certain stimuli and signaling pathways; (2) associate with unique endolysosome subpopulations at different maturation stages or with specific functions; (3) selectively target to organelles within different segments of long axons; (4) play cell type\u2013specific roles depending on their expression levels within a given neuronal subtype; or (5) serve overlapping or partially redundant functions. Therefore, further work is needed to examine these possibilities, which will conceptually advance our understanding of how these motor\u2013adaptor transport complexes are regulated and coordinated to sustain efficient clearance capacity in distal regions under physiological conditions and become disrupted under pathological conditions.Moreover, many other important issues also need to be addressed in future studies. For example, do neuronal lysosomes in the periphery or distal regions serve as environmental or metabolic sensors to activate transcriptional pathways in the soma and promote lysosomal adaptation to stress? What are the upstream signaling events that regulate neuronal lysosome trafficking within axons and positioning at sites of high axonostatic demand or under autophagic stress? What role do cytoskeletal modifications play in modulating axonal lysosomal movement? How do interactions with other organelles such as the ER or mitochondria contribute to lysosome positioning and local degradation capacity in axons? Do these dynamic events change throughout development and aging? Addressing these questions will help advance our understanding of neuronal endolysosomal transport and lysosomal functionality under physiological conditions and how impaired trafficking and lysosomal dysfunction contribute to neurodegenerative diseases. Understanding the disease-linked mechanisms underlying axonostatic failure is critical for designing potential therapeutic strategies that target axonostatic restoration to support neuronal survival and function."}
+{"text": "Theories suggest that with increasing age, adults more effectively regulate their emotions and seek to limit high physiological arousal. Prior research indicates physical activity attenuates negative affect reactivity to stress, but also increases physiological arousal. The present study extends prior work by examining age-related differences and changes over time in the extent of attenuation. Participants , from the National Study of Daily Experiences completed 8 end-of-day assessments of their negative emotions, stress, and physical activity across 3 measurement bursts spaced approximately 10 years apart. Results from three-level multilevel models suggest that when full random effects are specified, physical activity does not attenuate negative affect reactivity to stress. Additionally, extent of attenuation did not differ with age or change over time. Discussion pertains to how these findings advance theoretical understanding of socioemotional development and to methodological nuances of random effects and non-normally distributed data."}
+{"text": "Prior studies of caregiving characteristics by type of caregivers are inconsistent, particularly those who are spouses and adult children. This study examined caregiving characteristics between spouses and adult children of cognitively impaired older adults. We analyzed phone-screening data from an ongoing trial of a dyadic sleep intervention program for persons with dementia and their caregivers. Data included spouse caregivers (n=52) and adult child caregivers (n=24). Nearly all participants (95%) lived with their care recipients (91% with dementia). Types of caregiving activities were measured by activities of daily living [ADLs] and instrumental ADLs [IADLs] with their levels of intensity . Care recipients\u2019 sleep was measured by the Neuropsychiatric Inventory-Nighttime Behavioral Subscale (8 items). Analyses included Pearson correlations and t-tests. Adult child caregivers helped their care recipients at significantly higher levels as indicated by their measure of dependence in dressing , continence , laundry , and transportation  than spouse caregivers. Adult child caregivers also reported their care recipients having more difficulty falling asleep  and having more numbers of sleep problems than spouse caregivers . The findings suggest that adult child caregivers may involve higher levels of caregiving responsibilities during daytime and nighttime, compared to spouse caregivers. Further research needs to explore complimentary ways to involve spouse and adult child caregivers in the care of this vulnerable population."}
+{"text": "ABSTRACT IMPACT: This study advances our understanding of potentially key drivers in the early formation of pancreatic cancer, a disease with few treatment options and poor patient outcomes. OBJECTIVES/GOALS: Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) have a 5-year survival rate of \u02dc9%. A key driver of poor patient outcomes is late-stage diagnosis. A better understanding of PDAC onset is needed. This study was developed to understand how extracellular vesicles may be involved in the early formation of PDAC. METHODS/STUDY POPULATION: Extracellular vesicles (EVs) were isolated from several human PDAC and normal pancreatic cell lines, using ultracentrifugation with filtration or size exclusion chromatography. We next treated normal pancreatic cell lines with cancer cell EVs (cEVs). Next generation sequencing was used to measure global gene expression changes after treatment. Validations were performed using qPCR and luciferase activity assays. Multi-omics characterization of EVs was accomplished using mass spectrometry based proteomics, metabolomics and lipidomics analysis. RESULTS/ANTICIPATED RESULTS: We found that normal cells upregulated a variety of stress response pathways in response to cEVs. Lipid synthesis was also severely downregulated in these cells. We further validated activation of the unfolded protein response (UPR) in normal cells treated with cEVs. Multi-omics characterization of cEVs identified several enriched proteins, lipids and metabolites which may play a role in the activation of the UPR. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our results indicate that cEVs induce stress, and in particular the UPR, in normal pancreatic cells. Long-term UPR can impact a variety of cancer hallmarks. The UPR can mediate progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. Our results highlight a potential role for cEVs to alter the function of normal cells, aiding disease onset."}
+{"text": "Few studies have explored the underlying pathways between environment cognition  and mental health in older adults. We tested the mediation effects of physical activity and place attachment in the relationship between environmental cognition and mental health, based on a survey study of 1,553 older adults in Hong Kong using structural equation model. The results showed that significant relationship between negative environmental cognition  on access to convenient stores, leisure facilities, clinics, community centers, religious places and lower mental health can be explained by lower daily average physical activity time. Place attachment can significantly mediate the positive effect of positive environmental cognition  towards all types of services on mental health. Findings from this study have policy implication for urban planning and age-friendly community design"}
+{"text": "Studies have demonstrated a link between sensory impairment and dementia risk, but little is known about the presence of beta-amyloid plaques in individuals with single and multisensory impairments. Sensory function  and amyloid PET imaging were measured in 170 BLSA participants  from 2012 to 2019. Log-binomial regression models were used to examine the prevalence ratios (PR) of amyloid positivity for individual sensory impairments and across categories of impairments. While crude associations indicate associations of vision impairment  and impairments in all four senses  with amyloid positivity, these associations were insignificant after adjusting for age, sex, race, and education. There were no other crude and adjusted associations. These results suggest sensory impairments may be related to dementia independent of AD pathology. Future studies with larger sample sizes are warranted."}
+{"text": "Aging is the most prominent risk factor for cognitive decline, yet behavioral symptomology and underlying neurobiology can vary between individuals. Certain individuals exhibit significant age-related cognitive impairments, while others maintain intact cognitive functioning with only minimal decline. Recent developments in genomic, proteomic, and functional imaging approaches have provided insights into the molecular and cellular substrates of cognitive decline in age-related neuropathologies. Despite the emergence of novel tools, accurately and reliably predicting longitudinal cognitive trajectories and improving functional outcomes for the elderly remains a major challenge. One promising approach has been the use of exosomes, a subgroup of extracellular vesicles that regulate intercellular communication and are easily accessible compared to other approaches. In the current review, we highlight recent findings which illustrate how the analysis of exosomes can improve our understanding of the underlying neurobiological mechanisms that contribute to cognitive variation in aging. Specifically, we focus on exosome-mediated regulation of miRNAs, neuroinflammation, and aggregate-prone proteins. In addition, we discuss how exosomes might be used to enhance individual patient outcomes by serving as reliable biomarkers of cognitive decline and as nanocarriers to deliver therapeutic agents to the brain in neurodegenerative conditions. Age-related cognitive decline remains a prominent public health concern, with Alzheimer\u2019s Disease (AD) accounting for the majority of dementia diagnoses  . DespiteAging is the most prominent risk factor for cognitive decline, but behavioral symptomology and underlying neurobiology can vary between individuals. Indeed, some individuals exhibit significant cognitive impairments in comparison to age-matched controls, while others maintain intact cognitive functioning or display only minimal decline . AlthougAPOE, APP, PSEN1 etc.) as well as rare  genetic variants  whose primary function is to translocate biological substrates  between cells . Exosomethe cell . While tthe cell . Of notethe cell . Regardithe cell .in vitro supernatant vs. clinical plasma/serum), processing generally involves isolation  and characterization  followed by biological interpretation of exosomal quantity and contents utilizing complementary biochemical techniques    . Renewedys etc.) . Given tys etc.) . The capys etc.) . It shouys etc.) ; howeverys etc.) .Attempts have been made to categorize exosomes according to their net advantages or disadvantages for CNS homeostasis, yet such a dichotomous distinction may be misleading. For instance, accumulating evidence illustrates exosomes facilitate symbiotic dynamism between neurons and oligodendrocytes, whereby activity dependent synaptic transmission triggers exosomal secretion from oligodendrocytes that contain essential myelin components ; subsequently, internalization of these exosomes amongst proximal neurons enhances cellular viability . ConversA large quantity of exosome research has focused on their capacity to incorporate and transport microRNAs (miRNAs). These short  non-coding RNAs function as post-transcriptional regulators of gene expression by binding to complementary pairing sites on mRNA  across various locations within a cell, including the nucleus, cytoplasm and subcellular compartments, such as stress granules . Such biin silico analysis linked these miRNAs to stress response and neurotrophic signaling pathways, findings suggested miRNA mediated regulation of these biological processes may increase risk for cognitive decline . While a large set of miRNAs showed significant positive correlations with age, another set maintained significant negative correlations with cognitive performance, including those miRNAs selectively expressed in the brain. In turn, functional annotation of miRNAs associated with poor performance revealed several biological pathways, including neurotrophin signaling, whose miRNA-mediated regulation may be important mediators of cognitive decline . Further decline . Interes decline .To gain more reliable insights into the neurobiological mechanisms of cognitive decline, additional investigations have interrogated the role of miRNAs from brain derived exosomes. After isolating neural exosomes from AD plasma samples, researchers recently identified a set of significantly upregulated  and downregulated  miRNAs which were predicted to regulate several homeostasis pathways in the CNS, including steroid biosynthesis and mTOR signaling . In anotin vivo delivery via exosomes was capable of ameliorating memory deficits in rodents  otherwise induced by intracerebral application of A\u03b2 oligomers; furthermore, researchers inferred these benefits may be attributed to the increased synaptic phosphorylation of calmodulin-dependent kinase II   whose inase II . Similarpathway) .To expand our understanding for the role of exosomal miRNAs in mediating the underlying mechanisms of cognitive decline, several lines of inquiry require elucidation, some of which are addressed below. For one, we currently lack a comprehensive understanding of the mechanisms within recipient cells that are modulated by exosomal miRNAs. Previous evidence suggests miRNAs released by exosomes remain functional in their recipient cells, capable of directly downregulating the expression of target transcripts, similar to endogenous effects in parent cells . Interesinflamm-aging, is a common feature of normal aging. Higher levels of neuroinflammation are a risk factor for age-related cognitive decline and the accumulation of neuropathological hallmarks , which ultimately resulted in the disruption of plasma membrane integrity as well as elevated neurotoxicity ; increase anti-inflammatory cytokines ]; in turn, this is associated with the mitigation of pathological peptides  and the preservation memory capacities . Interestingly, such beneficial effects on cognition and neuroinflammation were comparable when exosomes were specifically targeted to the brain or administered systemically, highlighting the capacity of these EVs to exert their effects across the BBB , 2019. FTo enhance our understanding of exosomal-mediated neuroinflammation and associated risk for cognitive decline, several lines of evidence require further interrogation. Most prominently, further studies are needed to characterize the contents of exosomes which are responsible for alterations in CNS inflammation. Along with pathogens , a variety of molecules can induce immune responses in the brain, including reactive oxygen species (ROS), purine metabolites , calcium-binding proteins and lipotoxic ceramides . In addiEvidence indicating the association between aggregate-prone proteins  and age-related cognitive decline is abundant, with increasing data suggesting their spread between CNS cells can be facilitated through exosomes . It shou1\u201342, pTau-181 and pTau-S396 in neuronal exosomes isolated from blood samples could differentiate AD patients from controls, as well as those patients with MCI who remained cognitively stable from those who illustrated progressively declining MMSE scores. Furthermore, intracerebral injection of such exosomes into healthy adult mice induced a significant accumulation of pTau in CA1 pyramidal neurons, compared to those exosomes from stable MCI participants , individuals who illustrated higher exosomal A\u03b21\u201342 levels maintain an 11.1- and 8.5-fold increased risk for significant cognitive deterioration at 2 and 3 year follow-up assessments, respectively, compared to MCI participants who remained cognitively stable  via exosomes is capable of increasing translation of these proteins in recipient cells; such exploitation of host cell gene expression machinery could facilitate the accumulation of protein aggregates in otherwise healthy CNS cells  may synergistically compromise CNS homeostasis . Such a NS cells . AnotherNS cells . FurtherPredicting individual cognitive trajectories in aging can be important for diagnostic purposes, and the adoption of exosomes as biomarkers may prove particularly useful in this respect. Clinical assessment alone can fail to discriminate those individuals who maintain cognitive resilience from those who develop MCI, as well as those MCI patients who go on to develop dementia . AlthougNumerous studies have used miRNAs isolated from blood-derived exosomes as biomarkers to classify individuals who are exhibiting late life cognitive dysfunction. Compared to blood samples, available evidence suggests measures of exosomal miRNAs obtained from CSF samples offer similar accuracies in distinguishing individuals with age-related cognitive impairment . HoweverAlthough there is no consensus on which individual miRNAs or groups of miRNAs from exosomes best predict cognitive impairment, some consistent evidence has emerged. For example, levels of miR-342-3p in plasma exosomes were significantly lower in AD participants compared to controls and correlated with poor cognitive performance  among elderly, cognitively unimpaired individuals in a separate study . SimilarIn addition to cross-sectional investigations, several studies have used exosomes as biomarkers to predict longitudinal variation in cognitive decline. Using neurally derived exosomal concentrations of aggregate-prone peptides, researchers can predict individuals who progress from MCI to AD-dementia within 36 months , as well as cognitively sound individuals who develop dementia up to 10 years later  . IncreasTo enhance the utilization of exosomes as reliable and valid biomarkers, several important limitations should be considered. When examining their associations with cognitive decline, researchers should take steps to differentiate the tissue-specific  as well as the cell-specific origin of exosomes. Indeed, data indicate exosomes from the CNS contain significantly different molecular contents depending on an individual\u2019s cognitive capacities  as well as their cellular origin , while such differences in content can subsequently induce distinct functional consequences for recipient cells . InvestiDespite limitations, the implementation of exosomes as biomarkers for age-related cognitive decline offers several advantages. As mentioned previously, exosomal sampling is more cost effective and less invasive than currently available biomarkers . Furthermore, exosomes derived from the CSF and blood offer similar accuracy for identifying individuals exhibiting cognitive decline, while neuroimaging and blood derived exosomes exhibit similar specificity for distinguishing dementia cases from healthy controls . Meanwhiin vitro   . For inseatment) . Researceatment) . Similareatment) .Perhaps the greatest advantage offered by exosomes is their capacity to transverse the BBB due to their small size, endogenous biological properties, and low immunogenicity, which has otherwise been a major obstacle in treatment development for cognitive decline . This ha1\u201340, A\u03b21\u201342, plaques)  can reliably improve performance on cognitive tasks  and inhibit biological processes associated with cognitive impairment, including the dysregulated expression of pro- and anti-inflammatory cytokines (IL1-\u03b2 and IL-10), the activation of CNS immune cells  and the deposition of A\u03b2 (A\u03b2plaques) . Additioplaques) . Togetheplaques) .1.While the clinical development of therapeutic interventions faces a variety of hurdles, the consideration of exosomes as a novel delivery vehicle for future nanotherapeutics may prove to enhance outcomes for those individuals vulnerable to age-related cognitive pathologies. In this context, the use of un-modified exosomes isolated from adipose mesenchymal stem cells is currently being investigated for AD-dementia in clinics (NCT04388982). Although the study is only exploring the safety and efficacy of exosome treatment in patients, data from secondary outcome measures that include AD biomarkers based in A\u03b2 plasma/CSF measures, PET scans, and neuropsychological tests, may further encourage the development of engineered vesicles for the treatment of age-related cognitive decline. The current composition proposes exosomes are uniquely suited to improve our mechanistic understanding as well as enhance patient outcomes for the growing public health challenge of age-related cognitive decline. We highlight how the analysis of exosomes can improve our understanding of varying mechanisms in age-related cognitive decline, including the role of miRNAs, neuroinflammation and aggregate-prone proteins . Despite these contributions, we suggest specific areas of inquiry that warrant further interrogation, including the elucidation mechanisms in recipient cells that are modulated by exosomal miRNAs, the characterization of exosomal contents that are responsible for alterations in neuroinflammation and the examination of other aggregate-prone peptides  in exosomes that may synergistically increase risk for late life cognitive impairment. Moreover, we discuss how exosomes might be used to enhance outcomes for elderly individuals by serving as reliable biomarkers and therapeutic agents.To improve the reliability of studies going forward, consistent nomenclature coupled with protocol modifications that enhance the discrimination of EVs could be particularly effective. Due to similar biophysical properties , isolation techniques developed for exosomes can inadvertently lead to results that are derived from samples containing a variety of different EVs . SimilarSeveral additional limitations hinder the further application of exosomes discussed herein. Notably, it remains unknown whether concurrent variation in exosomes and cognitive capacities is reflective of a causal or reverse-causal association. In other words, it is difficult to determine if exosomal differentiation contributes to divergent cognitive trajectories, or if such differences are secondary to other biological processes that otherwise increase risk for cognitive deterioration in aging. A lack of data measuring time-dependent variation in the profiles of neuronal exosomes contributes to this lack of understanding, and potentially inhibits researchers from adequately controlling for the effects of aging. Although a limited set of investigations have employed longitudinal designs , future MD and VP conceived and designed the study. MD and AL conducted the literature search. MD, AL, and VP wrote the manuscript. TF and MW edited the final manuscript. All authors have read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "One of these involve a de novo heterozygous variant in an X-linked gene (ARHGEF9) in a female individual. We hypothesize the skewed X-inactivation may result in primarily expression of the pathogenic variant. We anticipate identifying additional candidate variants in coding regions of genes previously not associated with EMAS or pediatric epilepsies as well as in noncoding regions of the genome. DISCUSSION/SIGNIFICANCE OF IMPACT: Despite the genetic heterogeneity of EMAS, our initial analysis identified de novo pathogenic or likely pathogenic variants in 15% (6/40) of our cohort. As the cost continues to decline, short read genome sequencing represents a promising diagnostic tool for EMAS and other pediatric onset epilepsy syndromes. CONFLICT OF INTEREST DESCRIPTION: The authors have no conflicts of interest to disclose. SD has consulted for Upsher-Smith, Biomarin and Neurogene on an unrelated subject matter. GLC holds a research collaborative grant with Stoke therapeutics on unrelated subject matter.OBJECTIVES/GOALS: Epilepsy with myoclonic-atonic seizures (EMAS) is a childhood onset epilepsy disorder characterized by seizures with sudden loss of posture, or drop seizures. Our objective was to use short-read genome sequencing in 40 EMAS trios to better understand variants contributing to the development of EMAS. METHODS/STUDY POPULATION: Eligibility for the cohort included a potential diagnosis of EMAS by child neurology faculty at Children\u2019s Hospital Colorado. Exclusion criteria included lack of drop seizures upon chart review or structural abnormality on MRI. Some individuals had prior genetic testing and priority for genome sequencing was given to individuals without clear genetic diagnosis based on previous testing. We analyzed single nucleotide variants (SNVs), small insertions and deletions (INDELs), and larger structural variants (SVs) from trio genomes and determined those that were likely contributory based on standardized American College of Medical Genetics (ACMG) criteria. RESULTS/ANTICIPATED RESULTS: Our initial analysis focused on variants in coding regions of known epilepsy-associated genes. We identified pathogenic or likely pathogenic variants in 6 different individuals involving 6 unique genes. Of these, 5 are"}
+{"text": "Teaching point: The probable mechanism of pseudoaneurysm formation related to metastatic neoplasm is a tumor embolus penetrating and destroying the vessel wall.Pulmonary artery pseudoaneurysm (PAP) related to metastatic neoplasm is rare. We describe a unique case of multiple PAPs secondary to metastatic uterine leiomyosarcoma and demonstrate the serial chest computed tomography to support the theory that the tumor begins as a tumor embolus, followed by infiltration and breakdown of the vessel wall, leading to aneurysmal dilatation and invading the perivascular tissue. Figure 1). Computed tomography pulmonary angiography (CTPA) was performed to rule out acute pulmonary thromboembolism and showed innumerable heterogeneously enhanced masses scattered in both lungs, surrounding segmental branches of pulmonary arteries. Multiple fusiform pulmonary artery pseudoaneurysms surrounded by soft tissue masses were also noted . A review of serial chest computed tomography (CT) revealed tumor emboli in the peripheral branches of pulmonary arteries , which finally developed into pseudoaneurysms with surrounding soft tissue masses .A 49-year-old female with known uterine leiomyosarcoma and lung metastasis with multiple tumor thrombi in pulmonary arteries was receiving palliative chemotherapy. Prior to her fourth chemotherapy session, the patient developed acute-onset dyspnea. Chest radiograph revealed a larger size of the multiple well-defined pulmonary masses scattered in both lungs; therefore, progressive pulmonary metastasis was suspected . The serial chest CT also showed gradual dilatation of peripheral branches of right pulmonary arteries ; this could be due to tumor growth and continued destruction of vessel walls.A similar mechanism of pathogenesis is thought to have occurred in this case. From the serial chest CT, the PAPs with surrounding soft tissue masses had previously shown intraluminal thrombus and dilated pulmonary artery, which resembled tumor thrombus (Abnormal dilatation of the pulmonary arteries and veins was also observed in the patient\u2019s CTPA with similar findings previously described in a reported case of metastatic uterine sarcoma . The onlIn conclusion, PAPs caused by metastatic neoplasm may firstly begin as tumor emboli, later progressing into pseudoaneurysms as we elucidated in the serial chest CTs and CTPA findings in this case."}
+{"text": "Previous studies have shown that engaging in musical activities throughout the lifespan may buffer age-related decline in auditory and motor function, as well as in general cognitive function. MRI studies have demonstrated that individuals with musical training and experience exhibited greater grey matter volume and functional connectivity in extensive brain regions, especially in auditory and motor systems, compared to matched controls with no particular musical training or experience. Therefore, musical activity is a potential protective factor for brain health across lifespan. However, how lifespan musical experience shapes functional connectivity in older adults is still unknown. The current analysis investigated whether general musical experience (Goldsmith Music Sophistication Index) is associated with functional connectivity in older adults , focusing on seed regions in primary motor areas  and primary auditory regions  and their functional connectivity towards other areas throughout the whole brain. We found that older adults with more musical experience showed greater functional connectivity between anterior superior temporal gyrus and insula , and between posterior superior temporal gyrus and cerebellum . However, musical experience and music-related functional connectivity was not significantly correlated with general cognitive functions in our sample. Overall, our findings suggest that older adults with more musical experience might be more efficient in some aspects of auditory processing and auditory-motor skills, but this may not transfer towards domain-general cognitive tests. Our results support the notion that even non-professional engagement in musical experiences may afford benefits to the aging brain."}
+{"text": "Dear Editor,we read with great interest the study by Vetrugno et al.  where thWe propose a brief case to suggest taking Inferior Vena Cava Filter (IVCF) placement into account as a prevention tool for recurrent fat embolism (FE) in selected patients. A 16-years old male was involved into a motor-scooter accident reporting right femoral shaft fracture and left tibia shaft fracture. External fixation was provided as a bridge treatment to surgery. A few hours later he suddenly developed respiratory failure and coma and was admitted to our Intensive Care Unit (ICU) for supportive care. Cerebral Computed Tomography (CT) was normal; total body CT scan with contrast excluded pulmonary thromboembolism (PTE) and showed diffuse interstitial and alveolar edema; electroencephalogram identified status epilepticus for which antiepileptic drugs were started. Cerebral magnetic resonance imaging revealed a \u201cstarfield\u201d pattern compatible with the diagnosis of cerebral fat embolism. Patent foramen ovale was excluded. He was treated conservatively with mechanical ventilation with gradual improvement of his respiratory status, whereas neurologic impairment needed prolonged sedation. During his stay in the ICU he underwent sudden unexplained respiratory distress episodes, suggesting that embolization was possibly recurring. When stable, on day 7 of hospitalization, the patient was scheduled for surgical treatment. An IVCF was placed the day prior to surgery with the aim of stopping more fat emboli from spreading during intramedullary nailing of femur and tibia (Fig. Although IVCF insertion is discouraged for primary prevention of PTE in both orthopaedic surgery  and majoDespite scarce evidence, we reckon that IVCF could improve prognosis in selected patients with FES, especially those presenting high risk factors, after accurately weighing risks and benefits. This measure may also help to earlier stabilize the patient so that definitive surgical treatment of the fractures is promptly provided.In conclusion, the study by Vetrugno et al. shed light on risk factors related to FES. However, further research is necessary to identify the best treatment and prevention strategies. Structured studies and prospective evaluation are needed to establish the effective benefits of IVC filter placement in similar cases."}
+{"text": "Given the frequent overlap between biological plant invasion and ecological restoration efforts it is important to investigate their interactions to sustain desirable plant communities and modify long-term legacies both above- and below-ground. To address this relationship, we used natural reference, invaded and created vernal pools in the Central Valley of California to examine potential changes in direct and indirect plant effects on soils associated with biological invasion and active restoration ecosystem disturbances. Our results showed that through a shift in vegetation composition and changes in the plant community tissue chemistry, invasion by non-native plant species has the potential to transform plant inputs to soils in vernal pool systems. In particular, we found that while invasive plant litter decomposition was driven by seasonal and interannual variability, associated with changes in precipitation, the overall decomposition rates for invasive litter was drastically lower than native species. This shift has important implications for long-term alterations in plant-based inputs to soils in an amplifying feedback to nutrient cycling. Moreover, these results were independent of historic active restoration efforts. Despite the consistent shift in plant litter decomposition rates and community composition, we did not detect associated shifts in below-ground function associated with invasion by non-native plants. Instead, soil C:N ratios and microbial biomass did not differ between invaded and naturally occurring reference pools but were reduced in the manipulated created pools independent of invasion levels. Our results suggest that while there is an observed invasive amplifying feedback above-ground this trajectory is not represented below-ground, and restoration legacies dominated 10 years after practices were applied. Restoration practices that limit invasive plant feedbacks and account for soil legacy recovery, therefore offer the best solution for disturbed ephemeral ecosystems. Applications of restoration practices in wetland systems frequently must contend with plant invasion by non-targeted species, and these invading plants can undermine restoration goals through impacts both above- and below-ground. In this study we examined the impacts of invasive plants among natural and created vernal pools in California and found that invasion had a large effect on the plants present in the community and especially influenced plant litter decomposition rates. These invasive species caused changes can have implications for long-term alterations in plant-based inputs to soils; however, we did not detect associated shifts in below-ground function associated with invasion by non-native plants. The vegetation community has a key role in influencing soil properties through increased soil physical stabilization , alterinThe impact of changes in plant\u2013soil feedbacks associated with plant invasion on ecosystem processes is varied  as well In restoration ecology, a common response to increased threat from invasive species is to implement management strategies to reduce the prevalence and spread of the incoming plant species ; howeverseeVernal pools are shallow ephemeral wetlands found in flat to low slope grasslands with poorly draining soil that facilitates ponding. They are predominately precipitation-fed and defined by abrupt edges delimited by locations of ponding . HistoriTo examine the consequences of invasion in the context of restoration through plant\u2013soil feedbacks on ecosystem processes, we examined a series of natural reference pools dominated by native species, naturally occurring pools invaded by non-native plants and created vernal pools dominated by non-native plants all located in a grassland site in central California. Among these contrasting restoration and invasion legacies we asked three primary questions: (i) How does invasion and restoration in vernal pool systems influence above-ground litter decomposition? (ii) How might shifts in above-ground community composition impact litter inputs to soils? (iii) Have shifts in above-ground community composition prompted changes in below-ground ecosystem function? Within this framework we hypothesize that ecosystem processes being driven by the above-ground presence of invasive plants will increase both carbon and nitrogen into the soil through altered plant litter and decomposition rates causing positive feedbacks, yet the plant material chemical ratios will favour increased nitrogen and thus increase microbial biomass in the invaded sites regardless of restoration status. Alternatively, active restoration, such as creating a disturbance of scraping the topsoil layer, has the potential to expose new soil layers lowering overall carbon and nitrogen content and increasing C:N ratios, pH and altering soil texture thereby producing lasting effects below-ground that could potentially overshadow the impacts of biotic invasion.seeseeWe conducted our experiment in the Central Valley of Solano County, CA, USA . This region experiences a strong seasonality, with most precipitation falling during the winter months between November and February, a mean annual temperature of 20.1 \u00b0C, and mean annual rainfall of 500 mm . In our study site located at the Travis Air Force Base, Solano County, CA, both naturally occurring \u2018reference\u2019 vernal pools, that have existed in a single grassland meadow for decades, as well as pools created for restoration purposes are present across the 15-ha study site. This meadow contains a network of pool basins and upland grassland vegetation representative of regional vernal pool and grassland systems see. To examseeOver time (approximately in years 2006\u201308), a subset of the naturally occurring pools in this landscape also became dominated by invasive non-native annual grasses (hereafter \u2018invasive\u2019) while other pools eluded invasion, maintaining native species see. Given tWe also assessed variation in the chemistry of plant tissues from 18 vernal pool species as well as upland dominant species common to the site and surrounding grassland communities, to examine community-scale changes in stoichiometry and tissue chemistry from individual plants distributed across the site. These metrics were selected to target potential plant inputs on nutrient and carbon cycling among the three different vernal pool types. Specifically, we measured plant tissue concentrations of nitrogen (N), cellulose, lignin and carbon (C), and calculated the associated ratios between these components carbon:nitrogen (C:N) and lignin:nitrogen (L:N). All plant species were collected during peak biomass in 2011 coinciding with species composition surveys as measurement of growing season standing pools of plant chemistry. Cellulose and lignin, which are important components in litter decomposition and photodegradation . Plant Cin situ above-ground plant decomposition rates through the utilization of litter bags. While using vegetation from peak biomass prevents the potential for nutrient translocation and resorption and consequently influences tissue chemistry, plant inputs in this system do not commonly undergo full senescence prior to mowing and deposition on the landscape, similar to N = 72 litter bags above field-collected invasive litter and N = 72 litter bags below). While 1 cm of litter has been shown to impact vernal pool vegetation structure ; thus, we used recently cut foliage, collected from both upland and pool areas across the larger research site, for key species during spring peak biomass the season prior to field implementation to determine tructure , placingTo examine environmental and biotic drivers of vernal pool litter decomposition we installed litter bags for two winter wet seasons during the period when ponding is expected and one summer dry season, as well as comparing species effects on decomposition for the first wet season. We installed \u2018wet season\u2019 litter bags in the fall prior to any substantial precipitation (2011\u201312 and 2012\u201313) and removed them in the spring after pools dried down and the annual vegetation had bolted. These field incubations for the winter wet decomposition studies lasted from September to April. We placed the \u2018dry season\u2019 litter bags (2013) in the field just after spring drydown and removed them before any substantial autumn rains (April\u2013September).Lolium multiflorum, an non-native invasive annual grass species that is ubiquitous in both created and invaded reference pools at the study site , only the invasive grass L. multiflorum was used in the sequential litter bag deployments (wet season 2012\u201313 and dry season 2013) due to low site-level abundance of the native grass P. californicus.For the first year of the study, we were able to include litter bags for both the dominant native and invasive species for the wet season 2011\u201312 sampling period to test for species-level non-native invasive versus native decomposition differences. The invasive species litter was composed of pure udy site . The natN = 72 at 125 cm3 each) were placed on dry ice immediately upon sampling. Samples were kept cold at 4 \u00b0C until processed, with the majority of soil analyses  completed within 1 month of field collection .We collected bulk soil samples during peak flowering and peak above-ground plant biomass (April) in 2011 as the annual plants are dependent on soil processes while active during this brief period of highest productivity. Three soil samples were collected per pool, with one sample at each of three elevational plot locations within each pool . Soil samples (We obtained soil moisture through the gravimetric soil moisture method (% soil moisture = 100 * (fresh weight \u2212 dry weight)/dry weight). We measured soil pH using a 1:3 soil to water ratio  on soil subsamples, where the pH subsample was measured three times to calculate a mean value for each elevational location within each pool. We used a subset of the pool bottom soils to obtain soil texture  using a modified version of For all univariate data analysis, we used linear mixed-effects models in R version 4.0.0  in the lFor our multivariate analyses, we examined differences among pool types based on community-scale chemistry traits, including tissue C, N, lignin and cellulose. Community composition was used to scale chemistry traits based on abundance of dominant plant species present in vegetation plots during the same year as tissue sample collection for chemical analysis (2011). We created species traits matrices based on multiplying species counts by species-level chemical traits, thereby creating four independent species trait matrices scaled by species presence, in addition to the community composition matrix of species counts that included all species present in each plot. These trait and composition matrices were examined for differences among pool types using a permutational multivariate analysis of variance (perMANOVA) test based on a Bray\u2013Curtis dissimilarity matrix (R package Adonis). Multiple comparisons among pool types were conducted using the function pairwiseAdonis, which accounts for multiple comparisons and uses a Bonferroni correction . We applF2, 69 = 4.9, P < 0.01) with different compositions in reference pools from pools created through creation  or affected by invasive species , N , lignin  and cellulose , suggesting differences in the drivers of decomposition linked with invasion.Finally, decomposition differed substantially associated with species selection  where the created pools (C:N-10.7) were significantly lower than the reference (C:N-11.7) and invaded pools (C:N-11.8). We found that soil microbial biomass C when compared across pool types also varied . The lowest average microbial biomass was found in the created pools and was significantly lower than the reference pools based on effect size.Many of the fundamental physical soil properties we measured did not differ among vernal pool types associated with invasion or creation ; howeverThe introduction of invasive species can alter the ecosystem through a variety of pathways creating amplifying feedbacks that exacerbate further ecosystem changes . To combseePhragmites australis, however, shows a similar decrease in decomposition rates driven by higher C:N ratios and higher concentrations of lignin ultimately promoting nutrient competition for native plant species (Invasive species can alter ecosystems through a wide variety of pathways, ranging from shifts in community interactions to changes in nutrient cycling and physical ecosystem properties  and this species .While we observed that invasive non-native decomposition was slower than native species in our study, an alternate positive feedback to soil nutrients associated with invasive effect on the ecosystem has been noted in this vernal pool system . Here thLong-term averages of litter decomposition are driven largely by climate and microbial biomass  and the Restoration ecology focused on evaluating restoration success in depressional wetlands more generally has suggested that the nutrient composition of vegetation is an important metric in evaluating long-term restoration success .Differences in plant community composition, tissue chemistry and decomposition rates can have a cascade of effects on the below-ground, such as speed of nutrient cycling, microbial community composition (While a direct effect of a restoration legacy was observed below-ground in soil C:N and generally in extracted microbial biomass C, not all soil metrics tested demonstrated this artefact of restoration nor demonstrated a change solely due to invasion, in contrast to studies comparing reference and restored pools with greater differences in vegetation community structure (i.e. woody plants; Similar interacting processes likely influenced our findings for differences in soil pH among pool types that were not connected to either invasion or restoration independently. Invasive plants have been shown to alter the soil pH, both increasing and decreasing depending on the invasion type and magnitude , and we In summary, despite strong changes in above-ground plant contributions the soil metrics directly linked to plant inputs did not show the same response to the plant invasion. Instead, organic soil components exhibited a legacy of vernal pool active restoration from the decade prior. This study demonstrates that while above-ground vegetation may vary strongly in its abundance and composition and produce conditions that facilitate further invasion, this signal does not necessarily translate below-ground even after multiple years of invasion. The success of a restoration project is often based solely on the above-ground vegetation, and in this regard, further restoration efforts to minimize invasive species presence is required for our vernal pools. However, this study illustrates an opportunity to limit long-term effects of altered above-ground plant\u2013soil feedbacks on below-ground processes should additional restoration occur. The importance of this time lag in establishing altered community feedbacks within the ecosystem provides a window of opportunity for adaptive management practices aimed at ecosystem recovery.The following additional information is available in the online version of this article\u2014plab042_suppl_Supplementary_Figure_S1Click here for additional data file."}
+{"text": "ABSTRACT IMPACT: Identifying factors associated with opioid overdoses will enable better resource allocation in communities most impacted by the overdose epidemic. OBJECTIVES/GOALS: Opioid overdoses often occur in hotspots identified by geographic and temporal trends. This study uses principles of community engaged research to identify neighborhood and community-level factors associated with opioid overdose within overdose hotspots which can be targets for novel intervention design. METHODS/STUDY POPULATION: We conducted an environmental scan in three overdose hotspots\u2019\u2018 two in an urban center and one in a small city\u2019\u2018 identified by the Rhode Island Department of Health as having the highest opioid overdose burden in Rhode Island. We engaged hotspot community stakeholders to identify neighborhood factors to map within each hotspot. Locations of addiction treatment, public transportation, harm reduction programs, public facilities , first responders, and social services agencies were converted to latitude and longitude and mapped in ArcGIS. Using Esri Service Areas, we will evaluate the service areas of stationary services. We will overlay overdose events and use logistic regression identify neighborhood factors associated with overdose by comparing hotspot and non-hotspot neighborhoods. RESULTS/ANTICIPATED RESULTS: We anticipate that there will be differing neighborhood characteristics associated with overdose events in the densely populated urban area and those in the smaller city. The urban area hotspots will have overlapping social services, addiction treatment, and transportation service areas, while the small city will have fewer community resources without overlapping service areas and reduced public transportation access. We anticipate that overdoses will occur during times of the day when services are not available. Overall, overdose hotspots will be associated with increased census block level unemployment, homelessness, vacant housing, and low food security. DISCUSSION/SIGNIFICANCE OF FINDINGS: Identifying factors associated with opioid overdoses will enable better resource allocation in communities most impacted by the overdose epidemic. Study results will be used for novel intervention design to prevent opioid overdose deaths in communities with high burden of opioid overdose."}
+{"text": "In retrospect, the yet to be resolved refractory nature of adult cardiomyocytes with respect to cell cycle progression and cell division necessitates the need for an innovative approach to promote adult cardiomyogenesis.Cardiomyocyte loss followed by scar formation is the leading cause of heart failure upon pathological injury, chronic or acute stress, and aging. Despite decades of investigation, therapeutic development to enhance cardiomyocyte turnover and restore the structural and functional integrity of the heart has been limited due in part to the inherent lack of proliferative capacity within adult cardiomyocytes. A therapeutic solution to the conundrum of post-mitotic cardiomyocytes has long been sought after, leading to a range of pre-clinical interventional approaches including (but not limited to) overexpression of cell cycle proteins, induction of systemic hypoxemia, as well as transcriptional and hormonal regulation. The consensus outcome reveals dedifferentiation rather than proliferation potential of adult mammalian cardiomyocytes based upon phenotypic changes such as (1) loss of myofibrillar structure; (2) expression of stem cell markers; and (3) exhibition of immature metabolic functions. In an effort to illustrate the myocardial therapeutic significance of PR, Chen et al., demonstrated that short-term myocardial introduction of OSKM reprograms cardiomyocytes to a fetal phenotype evidenced by (1) transcriptome resembling neonatal and embryonic developmental stages; (2) expression of \u03b1-SMA; and (3) morphological rearrangement and cell cycle re-entry in vitro. Regardless of the time of induction, in vivo OSKM expression promoted structural recovery of the heart following myocardial infarction; however, functional results varied among induction regimens.Cellular reprogramming via the four pluripotency factors, OCT4, SOX2, KLF4, and MYC (OSKM), is a promising approach to epigenetically remodel somatic cells of various lineages into an induced pluripotent stem cell state. Partial reprogramming (PR) via the transient introduction of OSKM reverses age-associated phenotypes and promotes the regenerative potential of adult tissues such as skeletal muscle. From cardiomyocyte-specific overexpression of cyclins to transdifferentiation of fibroblasts into myocytes, to differentiating induced pluripotent stem cells (iPSCs) into cardiomyocytes, time and again, the results indicate that such approaches are unlikely to translate directly into clinically relevant therapies. And yet, each new insight into cardiomyocyte biology increases the knowledge base necessary to design better informed regenerative therapies. The current findings by Chen et al. reveal a threshold of cardiomyocyte dedifferentiation in adult mice, after which cardiac function declines and cardiac tumors form, in contrast to lower vertebrates and neonatal mammals, which tolerate greater cardiac plasticity.Driving cell cycle progression to achieve true proliferation in adult mammalian cardiomyocytes represents a longstanding goal in the ongoing effort to repair damaged myocardiumet al. highlight the challenge of associating clinically relevant cardiac repair with endogenous cardiomyocyte cell cycle progression. All of the partial reprogramming regimens result in reduced scar size in infarcted hearts, and post-injury therapeutic treatment yields the most 5-Ethynyl-2\u2032-deoxyuridine (EdU) + cardiomyocytes. However, the best functional outcomes are observed in the pre-injury treatment group, whereas no functional improvement is observed in the post-injury therapeutic treatment cohort. Salvage, cell cycle progression, and function appear disconnected in this repair model.Creating pre-clinical models of cardiac repair that reflect clinically therapeutic scenarios remains an ongoing challenge in cardiac research. Differentiation of cardiac progenitor cells, iPSCs, or reprogrammed cardiomyocytes into functional, mature myocytes remains a major roadblock for translational applications. Experimental treatments that coincide with myocardial injury tend to represent cardioprotective salvage models rather than therapies that replace damaged myocardium post-injury. Functional outcomes may be improved; however, cardiac patients are unlikely to receive regenerative treatment at the time of a cardiac event. Interestingly, the infarction injury results presented by Chen . Reagents that track cell cycle in real-time, such as various transgenic fluorescence ubiquitination cell cycle indicator reporter animal models, can provide dynamic readouts of cell cycle status in vitro and in vivo. Perhaps the most convincing data demonstrating cardiomyocyte proliferation in the current publication are live imaging videos tracking tagged cells going through karyo and cytokinesis. Of course, the next crucial step in the regenerative process is to convert these dedifferentiated reprogrammed proliferating cardiomyocytes into functional adult cells that contribute to cardiac function. Whether comparable division and re-differentiation occur in damaged reprogrammed hearts remains to be demonstrated.Identifying true cardiomyocyte replication represents another point of contention among researchers. Mature cardiomyocytes are generally post-mitotic; however, their nuclei can undergo changes that appear to reflect proliferation, such as DNA synthesis in response to stress, binucleation or karyokinesis without cytokinesis, or increases in ploidy during aging. Measures of cell cycle re-entry such as EdU, phospho histone H3, even aurora B kinase, are insufficient to definitively prove full cardiomyocyte cellular division\u20138. Reprogrammed cardiomyocytes in an adult heart are not equivalent to developing cardiomyocytes maturing in concert with associated systemic postnatal hormonal changes. Studies have shown that the paracrine, metabolic and structural milieu of an adult mammalian heart favor cellular hypertrophy or senescence over cardiomyocyte proliferation. The myocardial environment in most heart disease patients is probably even less conducive to proliferation and repair, underscoring the challenge of transforming reprogrammed cells into new functional new myocytes. Nonetheless, while the gap between basic research findings and clinically relevant cardiac therapies remains unbridged, cumulative research findings are essential to successful development of those therapies.Systemic context plays a crucial role in myocardial regenerative potential. Metabolic and paracrine factors, and the state of the extracellular matrix all have an enormous impact on cardiomyocyte cell cycle activityet al., represent substantial translational hurdles. How can cardiomyocyte reprogramming be administered safely and titrated to avoid the deleterious effects observed in over-reprogrammed hearts? Would this be possible given the enormous variability among human cardiac patients? Perhaps the real takeaway lesson from this and similar studies investigating cardiomyocyte proliferation lies in understanding what makes an adult cardiomyocyte healthy and capable of cell cycle re-entry to the point of replication. From a preventative medicine point of view, a more realistic approach may be to identify lifestyles and habits that support the more youthful and proliferative cardiomyocyte phenotypes identified in partial reprogramming models. Transcriptomic and proteomic profiling studies comparing youthful and diseased or senescent cardiac phenotypes may provide therapeutically relevant targets for suppressing senescence-associated secretory phenotype, inflammation, or oxidative stress in a time and a dose-dependent way to encourage myocardial healing. Evaluating signaling pathways associated with youthful or proliferative phenotypes could also reveal safer, more reliable targets. Ultimately, combinatorial therapies incorporating multiple restorative strategies probably hold the most promise for improving cardiac patient outcomes.Many questions about cardiomyocyte proliferation remain unanswered from the basic and clinical perspectives, perhaps the most important being: can adult human cardiomyocytes be coaxed to divide in response to injury on a therapeutically relevant level, and is it possible to quantify this proliferation in recipient human patients? Experiments performed in young adult mice in no way reflect the systemic profile of human heart patients, many of whom are elderly or have underlying comorbidities such as hypertension, diabetes, or other metabolic dysregulation. Timing and dosage of a hypothetical reprogramming therapy, in light of the results presented by Chen In summary, the holy grail of physically mending damaged human hearts remains elusive. Considerable time, resources, and effort have gone toward understanding myocardial injury, repair, aging, and possible regeneration in vertebrate animal models. Approaches including cell therapy, tissue engineering, and driving adult mammalian cardiomyocytes to proliferate in response to damage as documented in neonatal hearts, or adult fish and reptile systems, have yielded valuable new insights into cardiac biology. Moreover, although a marketable therapy to repair pathologically challenged human hearts has not yet materialized, this goal has inspired incredible scientific creativity and a deeper understanding of cardiac cellular and molecular biology. Put another way, research findings cannot be valued solely on their immediate translational relevance, or unduly influenced by increasing pressure to produce therapies and cures. However, clinically driven studies that build on collective basic and translational research findings bring cardiac medicine closer to curing or even preventing heart disease altogether."}
+{"text": "The COVID-19 pandemic posed new challenges for caregivers. This study examines the prevalence of pandemic care challenges  and their associations with caregiver mental health and interpersonal well-being in a nationally representative sample of 311 caregivers who participated in the June 2020 National Poll on Healthy Aging. We consider seven care challenges and supports as key predictors of caregiver mental health  and interpersonal well-being  in bivariate tests and ordinary least squares regressions. Each care challenge/support was endorsed by between 13-23% of caregivers. Difficulty getting needed medical care was the most predictive challenge associated with increased caregiver stress, depressive symptoms, and worsened interpersonal well-being. All care challenges predicted an increase in caregiver stress. Effective caregiver tools and supports must consider changing policies and care needs, especially during a pandemic."}
+{"text": "Self-reported cognitive difficulties are common in older adults and may be an early indicator of future cognitive decline or dementia. In past retrospective reports, cognitive difficulties have been linked with differences in social engagement or social relationships among older adults. However, little is known about how self-reported cognitive difficulties in daily life, such as memory lapses, relate to older adults\u2019 daily social experiences. This study examined how self-reported cognitive difficulties were related to older adults\u2019 daily social interactions and loneliness. Data were drawn from 312 community-dwelling older adults (aged 70 to 90 years) who reported their social interactions and loneliness throughout the day (five times) as well as cognitive difficulties  at the end of each day for 14 days. Multilevel models revealed that participants reported fewer memory lapses on days when they reported more frequent interactions with family members (p=.041). Higher levels of disruptions to daily activities caused by cognitive difficulties, in turn, predicted higher levels of loneliness the next day (p=.006), but not changes in social interactions the next day. At the between-person level, more memory lapses in daily life were associated with less frequent social interactions with friends, but more frequent unpleasant social interactions and higher levels of loneliness on average. These results suggest that older adults\u2019 self-reported cognitive difficulties were dynamically associated with their social interactions and loneliness at the daily level and played an important role in older adults\u2019 social life and well-being."}
+{"text": "ABSTRACT IMPACT: This study provides insights on how to replicate a successful initiative for preventing unintended teen pregnancy. OBJECTIVES/GOALS: Reducing unintended teen pregnancy is a national health priority, and a recommended strategy is to increase awareness and availability of long-acting reversible contraception (LARC). The Rochester LARC Initiative did this, and teen LARC use rose from 4% to 24%. The goal of this study is to determine key elements for replicating the intervention. METHODS/STUDY POPULATION: Our initiative used an innovative approach we call \u2018community detailing\u2019 to deliver education about LARC to adults working with teens. We analyzed the intervention goals, design components, implementation strategies, and public health outcomes. Our analysis was informed by the CDC model for Promoting Science-Based Approaches to Teen Pregnancy Prevention Using Getting to Outcomes (PSBA-GTO), Diffusion of Innovations, and RE-AIM framework for implementation outcomes. We compared our model with characteristics of LARC-promotion efforts, as well as successful health education campaigns. We tabulated the components of our intervention across theoretical domains, aiming to determine essential elements of effective design, adaptation, and dissemination & implementation. RESULTS/ANTICIPATED RESULTS: The initiative incorporated multiple components common to successful health education programs: measurable behavior-change outcomes; formative research before roll-out; tailored communications for different audiences; speakers who were credible, knowledgeable and skilled communicators; content that was new to recipients and essential for decreasing barriers to desired behaviors. It included elements of successful LARC promotion/teen pregnancy prevention programs, such as organizing information by effectiveness of methods and using youth-empowering messaging. It differed from other successful programs by offering discussions to adults who work with teens in both medical and community settings. This analysis also highlights unintended positive ripple effects. DISCUSSION/SIGNIFICANCE OF FINDINGS: These results establish how community detailing is effective for disseminating actionable information about the safety, efficacy and availability of LARC. These insights could inform other prevention initiatives. An anticipated practical product of this study will be a user-friendly manual for replicating the LARC Initiative in other locations."}
+{"text": "Drug-induced myocarditis is a rare, but underrecognized complication of clozapine therapy for schizophrenia. We present a case of clozapine-induced myocarditis with recovery of cardiac function after drug cessation and summarize the literature to highlight the variable presentation of this condition. A 29-year-old man presented from a psychiatric hospital with 2 days of sudden onset, progressive chest pain, and troponin elevation after recently initiating clozapine therapy.The patient had a history of alcohol abuse and treatment-resistant schizoaffective disorder with multiple suicide attempts. After intentional ingestion of acetaminophen and lithium, he was involuntarily hospitalized for intensive treatment, including initiation of clozapine therapy.The differential diagnosis included acute coronary syndrome, myopericarditis from viral or drug-induced etiology, pulmonary embolism, and pneumonia. The patient first noted substernal chest pain worse with deep inspiration 8 days after clozapine initiation. Symptoms worsened over the following two days. Electrocardiogram (EKG) demonstrated ST elevations most prominent in V2-V3 . Serum lChest pain persisted, and he was transferred to the cardiology service. Cardiovascular exam was notable for tachycardia without murmurs or rubs. He had no peripheral edema or elevated jugular venous pressure. Lungs were clear. Cardiac magnetic resonance (CMR) imaging showed global hypokinesis with a left ventricular (LV) ejection fraction (EF) of 45% Figure  and subtMyocarditis was suspected based on a clinical syndrome of chest pain and elevated troponin in the setting of a known causative medication and low pretest probability for coronary artery disease. CMR confirmed the diagnosis by the updated Lake Louise Criteria . This caClozapine-induced myocarditis (CIM) is a drug-related myocarditis with variable presentation ranging from mild symptoms to fulminant myocarditis. The mechanism of toxicity to cardiomyocytes is unclear. In animal models, clozapine induces serum catecholamine excess that causes cardiac inflammation and myocyte apoptosis through tumor necrosis factor-alpha-mediated pathways . At autoThe true incidence of CIM is difficult to ascertain due to underdiagnosis of subclinical or mild presentations and may be underrecognized; thus, a high index of suspicion is required . ShortneCardiovascular complications resulting from antipsychotic medications are not limited to myocarditis. Patients with schizophrenia treated with antipsychotics are at higher risk of sudden unexplained death than the general population . CardiovWhen CIM is suspected, cardiology consultation should be obtained with inpatient monitoring for arrhythmia and heart failure. Aside from drug withdrawal, no specific treatment for CIM has been identified. Patients with LV systolic dysfunction warrant guideline-directed medical therapy (GDMT) in the absence of contraindications. Close cardiology follow-up and repeat echocardiography after clozapine cessation and initiation of GDMT should be individualized.Intriguingly, published literature reports cases of clozapine reinitiation in patients with severe schizophrenia refractory to alternate antipsychotics despite prior drug withdrawal due to CIM. Rechallenge with clozapine can be successfully achieved with intensive monitoring with swift discontinuation of the drug for any sign of myocardial injury . In one The patient was not reinitiated on clozapine and instead was treated with lithium and electroconvulsive therapy. Repeat echocardiography 2 weeks later demonstrated recovery of LV function Figure .Patients with schizoaffective disorders treated with antipsychotics are at higher risk for sudden unexplained death. CIM is a rare but likely an underrecognized complication of clozapine therapy and a mechanism of sudden cardiac death. Treating psychiatrists and consulting cardiologists must maintain high index of suspicion for CIM with withdrawal of clozapine in the acute setting to reduce poor outcomes. In the long term, care must be patient-centered with consideration of underlying psychiatric and cardiovascular disease severity.To recognize the clinical presentation of drug-induced myocarditis, associated with the use of clozapineTo illustrate the role of noninvasive testing in diagnosis of clozapine-induced myocarditisTo understand the importance of a multidisciplinary approach involving both psychiatry and cardiology specialists in managing clozapine-induced myocarditis"}
+{"text": "Visual representation of the community in materialsPositive FramingStatistics and graphs should be minimalAppropriate reading level and minimizing jargonABSTRACT IMPACT: Advanced spatial analysis techniques are used to target a community education intervention for Immigrant and African American women to increase breast cancer screening. OBJECTIVES/GOALS: We are addressing breast cancer screening disparities through the development of the COmmuNity kNowlEdge to aCtion Toolkit (CONNECT). CONNECT implements a mixed-methods approach using GIScience, community education, and social media to mitigate the impact of breast cancer screening disparities for Immigrant African and African American women. METHODS/STUDY POPULATION: We used advanced spatial analysis techniques, Spatially Adaptive Filters (SAF) to reveal mammography screening rates below the state level. SAF create screening maps of This new information allows lay health educators to identify and engage their communities in the Breast Cancer Champions program. We transformed and curated existing cancer educational material into culturally relevant educational training for lay health educators. Lay health educators participate in educational trainings and receive stipends for conducting formal and informal breast cancer education and screening events. RESULTS/ANTICIPATED RESULTS: We have identified four principles for designing culturally relevant education materials.Due to COVID-19, our breast cancer champions are engaging with their community in socially responsible ways . Our social media campaign, which began in October has already attracted over 1000 followers. DISCUSSION/SIGNIFICANCE OF FINDINGS: Despite the disruption of COVID-19, our project continues reduce breast cancer screening disparities. We have developed and created culturally appropriate materials and are currently training Champions. By incorporating an online presence into our community outreach, we are increasing the ways we connect with our community."}
+{"text": "The local vascular inflammation is not only caused by SARS-CoV-2 infection but also accelerated by gut dysbiosis-caused systemic inflammation and decreased anti-inflammatory mechanisms.On the other hand, brain pathological changes could further increase gut dysbiosis. It has been well demonstrated that the gut-brain axis has bidirectional effects.An appreciation of the role of intestinal dysbiosis in the cytokine storm in COVID-19 neurological comorbidity has therapeutic implications. Modulation of gut dysbiosis to improve gut microbiota could be achieved by various approaches such as probiotics, prebiotics, faecal microbiome transplantation and dietary modification.Data sharing is not applicable to this article as no new data were created or analysed.The authors report no competing interests."}
+{"text": "Bladder cancer is a heterogeneous disease that is composed of epithelia with varying transcriptional, mutational and lineage signatures. The epithelia of bladder tumors can also undergo pronounced changes in transcriptional and phenotypical qualities in response to progression, treatment related stresses and cues from the tumor microenvironment (TME). We hypothesize that changes in epithelial tumor heterogeneity (EpTH) occur due to the evolving content of epithelial subpopulations through both Darwinian and Lamarckian-like natural selection processes. We further conjecture that lineage-defined subpopulations can change through nongenomic and genomic cellular mechanisms that include cellular plasticity and acquired driver mutations, respectively. We propose that such processes are dynamic and contribute towards clinical treatment challenges including progression to drug resistance. In this article, we assess mechanisms that may support dynamic tumor heterogeneity with the overall goal of emphasizing the application of these concepts to the clinical setting.Acquired therapeutic resistance remains a major challenge in cancer management and associates with poor oncological outcomes in most solid tumor types. A major contributor is tumor heterogeneity (TH) which can be influenced by the stromal; immune and epithelial tumor compartments. We hypothesize that heterogeneity in tumor epithelial subpopulations\u2014whether de novo or newly acquired\u2014closely regulate the clinical course of bladder cancer. Changes in these subpopulations impact the tumor microenvironment including the extent of immune cell infiltration and response to immunotherapeutics. Mechanisms driving epithelial tumor heterogeneity (EpTH) can be broadly categorized as mutational and non-mutational. Mechanisms regulating lineage plasticity; acquired cellular mutations and changes in lineage-defined subpopulations regulate stress responses to clinical therapies. If tumor heterogeneity is a dynamic process; an increased understanding of how EpTH is regulated is critical in order for clinical therapies to be more sustained and durable. In this review and analysis, we assess the importance and regulatory mechanisms governing EpTH in bladder cancer and the impact on treatment response. Tumor heterogeneity (TH) has been referred to as the \u201cRosetta Stone\u201d of cancer progression and therapeutic response ,2. The iWithin a single tumor, TH encompass both the tumor microenvironment, including stromal and immune cells, as well as the cell autonomous epithelial compartment. TH is also regulated by acellular components such as stromal and connective tissues. Together, such elements form a plastic tumor milieu which can change dynamically during tumor progression and in response to therapeutic challenges.When considered on a patient population scale, TH is typically extensive and contributes towards the complexity of understanding for when and how often to administer a drug for optimal clinical response. In some instances, drugs that are considered beneficial on a population scale can induce adverse disease progression on certain tumor types, thus highlighting the need for assigning tumor-specific treatments.While bladder cancer presents as a mutational disease, genetic changes continue to occur in pretreated tumor progression and in response to therapy. Thus, the mutational landscape not only has implications for immune cell infiltration but contributes towards the pool of cells capable of clonal expansion, treatment resistant disease and metastasis. Growing evidence supports that lineage transdifferentiation is an important mechanism for cancer cells to adapt to the stress of therapy ,10 incluRecently, single-cell technologies have greatly leveraged our ability to understand the remarkable transcriptional diversity present in bladder cancers. Such technologies provide opportunities to understand the evolutionary changes in tumor cell composition commencing from pretreated primary tumors through to post-treatment, resistant metastasis. We will address the importance of single-cell technologies to increase our understanding of EpTH both with respect to bulk changes in subpopulations as well as single-cell changes in cellular identity (lineage transformation). Improved single-cell techniques will provide the sensitivity and spatial information needed to address critical questions of whether EpTH can be experimentally manipulated to enhance treatment and reduce lethal phenotypes including bladder cancers with neuroendocrine-like (NE-like) signatures. While such processes have proven to be reversible under certain experimental conditions ,13, the As the importance of TH and relevance for tumor progression encompass a large body of information, our discussion and analysis will focus on the tumor epithelial compartment.Clinical bladder cancer typically presents with substantial pathological heterogeneity and a high mutational burden . MultiplIn an effort to reconcile previously published MIBC classification schemes, large-scale studies conducted by Kamoun et al. analysed 1750 transcriptomic profiles from 18 datasets and have identified a consensus molecular classification of MIBC that includes six molecular subtypes: luminal papillary (LumP), luminal nonspecified (LumNS), luminal unstable (LumU), stroma-rich, basal/squamous (BaSq) and NE-like .In this instance, consensus classifiers were associated with distinct mRNA signatures which strongly associated with clinical outcome and overall survival . The utiStrikingly, only approximately 30% to 40% of residual bladder tumors following NAC or immunotherapy were of the same lineage subtype as the pretreatment tumors ,24. In aMolecular analysis using bulk RNA seq data has increased our understanding of TH and the potential clinical utility in selecting patients for different systemic treatment . HoweverThe use of single transcriptomic technologies such as single-cell RNA sequencing (scRNA-seq), single-cell DNA seq (scDNA-seq) and spatial sequencing (sp-seq) in research will prove superior for defining clinically viable information, over bulk molecular analysis, by allowing the ability to study TH and to characterize rare cell epithelial subpopulations ,29. HoweIntratumoral molecular and genetic heterogeneity have been associated with poor prognosis in multiple cancers including lung cancer, head and neck cancers and chronic lymphocytic leukemia ,30,31,32Together, these findings demonstrate significant intratumoral heterogeneity in bladder cancer and suggest that categorical molecular subtyping may not be adequate for optimal therapeutic outcomes.Mechanisms promoting Intra-EpTH in pretreated bladder tumors can be broadly divided into mutational and nonmutational. Mutational mechanisms induce heterogeneity in genomic DNA which in turn can translate to phenotypic heterogeneity. Nonmutational mechanisms of heterogeneity induce phenotypic variability without any genetic modifications . The prePretreated urothelial carcinoma is characterized by a high mutational burden that contributes to TH. With a median of 8.1 mutations per mega base pair, bladder cancer ranked 11th in terms of mutational burden when compared with 166 other cancer types . PhylogeMultiple genetic driver mutations are associated with bladder cancer carcinogenesis and progression . Cells wDrivers of bladder cancers with high mutational burden remain poorly understood. Although DNA replication occurs with high fidelity, occasional transcriptional errors still occur even in the absence of mutagens, thereby introducing de novo genetic mutations. This stochastic mutational process is involved in tumorigenesis and disease progression . ExposurThe apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) can induce tumoral genetic heterogeneity leading to an APOBEC mutational signature present in urothelial cancers and other solid tumors . Using wThe genetic heterogeneity in tumor epithelial plays a significant role in disease progression and development of drug resistance largely due to either de novo or acquired therapy-resistant clones . High inAlthough mutational burden has been associated with response to immune checkpoint inhibitors (ICI), recent evidence suggests that tumors with high Intra-TH have decreased response to ICI. Using a preclinical melanoma mouse model, investigators evaluated the association of total mutational burden and intra-TH with respect to antitumor immunity . They shAs opposed to mutational mechanisms where variability in cellular DNA is the source of heterogeneity, nonmutational drivers of tumoral heterogeneity do not involve modification in the cellular genetic code. Embryological development is an example of nonmutational process of changing heterogeneity where cells with the same DNA code differentiate into multiple cellular phenotypes. Different from genetic heterogeneity, tumor cells contributing toward nonmutational heterogeneity can be highly plastic and have important contributions towards tumor development ,58.At a baseline or pretreatment setting, fluctuating cellular transcription constitutes a source of cellular heterogeneity. Upon the exposure to drugs, cells meeting a threshold of resistance-related gene expression will survive and be selected for ,60. For Cellular plasticity represents the capacity of cells to adopt different phenotypes and switch between different lineage identities . TogetheIn bladder cancer, cellular plasticity has been observed by Yang et al. using single-cell sequencing to demonstrate that nonstem cells, in urothelial cancers, can acquire stem-like properties and develop self-renewal capabilities . CellulaEMT is a tightly regulated process involved in embryonal development and in tissue healing and represents the most studied example of cellular plasticity . EMT shoThe formation of epithelia with neuroendocrine qualities constitutes another lineage occurring frequently during therapeutic stress  Figure B. For exTaken together, this suggests that plasticity is important in the evolution of bladder cancer. We conjuncture that plasticity represents a clinically important resistance mechanism as cells switch from a treatment-sensitive lineage to treatment-resistant lineages in order to accommodate the stress of therapy.While mounting evidence supports that lineage plasticity is a bona fide mechanism for cancer cells to adapt to therapy, less is understood as to whether plasticity can be reversed in a controlled manner. Due to its important role in tumor progression and aggressiveness, EMT represents an attractive target for the development of targeted therapies. Multiple pathways regulating EMT are being investigated as potential treatment targets with clinical trials investigating drugs capable of targeting EMT being conducted in solid tumors such as breast cancer, lung cancer and colorectal cancer ,97. InteIn response to drug exposure, a subpopulation of cancer cells termed drug-tolerant persisters (DTPs) will acquire a poorly differentiated phenotype and enter a dormant, slow-cycling and drug tolerant state  Figure C. DTPs cAlthough tolerant cells may pre-exist in the tumor, it has been shown that some cells become DTPs through EMT and phenotype plasticity following drug exposure ,102,103.In basal-like breast cancer cell lines, exposure to MEK and PI3K/mTOR inhibitor resulted in development of DTPs through epithelial plasticity driven by therapeutic challenge . In EGFRTumor heterogeneity is a dynamic process that serves an important role in tumor progression and response to therapies. Changes in TH through clinical evolution are likely a consequence of both changing proportions of lineage defined subpopulations as well as processes of cellular plasticity. Understanding how clinically approved therapies regulate these processes on a temporal scale will help define therapies. Adaptive therapy is an example of a novel treatment approach that incorporates these concepts and aims to maintain a population of treatment-sensitive cells to prevent the expansion of treatment-resistant cell populations B.Using mouse models of breast cancer, Enriquez-Navas et al. showed that low doses of paclitaxel are effective in controlling tumor volume and preventing unopposed proliferation of treatment-resistant cell populations . AdaptivA better understanding of cancer cell heterogeneity and plasticity will allow clinicians to consider tumor heterogeneity in a dynamic and adaptive fashion, rather than in a static manner in the elaboration of new treatment approach.Tumor heterogeneity and cellular plasticity are hypothesized to play important roles in the evolution and management of bladder cancer. The limitations of homogenous and static classifications of urothelial cancer need to be acknowledged. The heterogeneous and dynamic nature of this disease should be emphasized paving the way for further research on specific mechanisms regulating the dynamics of tumor subpopulations and cellular plasticity."}
+{"text": "Dislocation of inferior vena cava filter (IVCF) is a rare complication with potential IVC perforation and other life-threatening risks requiring early diagnosis and in-time retrieval. Most of dislocation IVCF in the past have been shelved or removed by open surgery. It is very difficult to retrieve the filters by interventional technology.Here we report a 49-year-old man suffering from dislocation of IVCF implanted due to deep vein thrombosis (DVT) in the right femoral vein. Successful retrieval of the IVCF using double sheaths docking technique was done soon after confirmation of the dislocation. Importance of monitoring and early detection of dislocation of IVCF should be emphasized to avoid further complications.The double vascular sheaths docking technique can be considered as a preferential option in difficult operative situation. DVT in lower extremities occurs under conditions of venous endothelial damage, blood hypercoagulation, and stasis. The main risks of DVT include early fatal pulmonary embolism (PE) and late pulmonary hypertension. For patients with anticoagulation contraindications and recurrent DVT, IVCF should be implanted to prevent fatal PE. Furthermore, monitoring on IVCF status is critical to guarantee its\u2019 thrombus capture effect and reduce filter-derived complications.IVCF-derived adverse events have been reported as placement issues 45.1%), IVC penetration (29.9%) and IVC filter fracture (27.1%) [%, IVC peWe report an insidious case of IVCF leg dislocation, potentially leading to perforation of the vena cava. Double sheaths docking technology was used to successfully retrieved the IVCF, verifying the importance of timely handling of IVCF migration.A 49-year-old man with DVT in right femoral vein following ruptured cerebral aneurysm underwent retrievable IVCF  implantation to prevent fatal PE. Pharmoco-mechanical thrombectomy was performed with angiojet system . During the surgery, a leg of the filter was found to be dislocated Fig.\u00a0A, which IVCF is an absolutely therapeutic choice for avoiding fatal PE when conventional anticoagulation is contraindicated or deemed ineffective . A retriThis case revealed filter leg dislocation and axial migration of the filter. The dislocated filter leg may not only causes perforation of the inferior vena cava, resulting in retroperitoneal hematoma , and cauDislocation of the IVCF is a rare and serious complication, calling for our sufficient attention. Monitoring on IVCF status is critical to guarantee its\u2019 thrombus capture effect and reduce filter-derived complications. The double vascular sheaths docking technique can be considered as a superior method."}
+{"text": "OBJECTIVES/GOALS: Clinical trials are the gold standard for developing evidence-based medicine. However, 20% of pediatric randomized clinical trials are discontinued and about 30% of completed trials go unpublished.  Although patient recruitment is the most cited barrier to completing clinical trials, trials funded by academia are more likely discontinued compared to those funded by industry. This study is an attempt to gain additional insights into clinical trials in academic pediatrics. METHODS/STUDY POPULATION: Junior pediatrics faculty (Instructors and Assistant Professors) were recruited to participate in an online survey through RedCAP. The physicians were asked if they had prior experiences with clinical trials and whether they have interest in participating in clinical trials. Those interested were asked three additional questions: what role they were interested in, barriers to participating and interventions they thought would educate them about participating in clinical trials. RESULTS/ANTICIPATED RESULTS: Ninety two (92) out of 119 (77%) junior pediatrics faculty completed the survey. Twenty (20) pediatric subspecialties were represented and respondents were on various academic pathways. A third of the respondents (35%) had previously participated in clinical trials. A majority of the faculty respondents  are on the clinical educator pathway. The 13 respondents who were not interested in clinical trials indicated their preference for patient care, education and quality improvement. Of those interested in clinical trials, the top three preferred roles were site co-investigator (68%), help designing future protocol (47%) and site principal investigator (44%). Other than time, the top barriers to participation were a lack of awareness of what it takes to lead or engage in clinical trials (53%) and a lack of training on clinical trials (45%). Mentoring from an experienced clinical trialist emerged as the top preferred intervention (78%). DISCUSSION/SIGNIFICANCE OF IMPACT: Although limited to one institution, the findings of this study provide insights into pediatric faculty interest in clinical trials. If academic pediatricians are provided with mentoring, there could be an uptick in completed and published clinical trials involving pediatric populations."}
+{"text": "Through leveraging the known advantages of musical engagement and socialization, choir interventions are known to facilitate psychological and cognitive benefits for persons with dementia (PwD). Surprisingly, no research has explored whether social singing may also confer neurological advantages. In this study, we employed functional near infrared spectroscopy (fNIRS) to investigate the cortical correlates of both social and solo singing in PwD (n=13). Paired-sample t-tests were used to evaluate within-person differences in frontal cortical activation between the social vs solo singing. Results showed significant activation differences in three frontal channels, with social singing requiring comparatively less frontocortical activation. These findings indicate potential neural benefits of social singing \u2013 with less frontal activation being a proxy for greater reliance on intact proceduralized systems \u2013 and serve to highlight the utility of fNIRS in better understanding the neural correlates underlying the benefits of social singing interventions for PwD."}
+{"text": "In 2017, the United States Comprehensive Addiction and Recovery Act (CARA) expanded authorization to prescribe buprenorphine for opioid use disorder (OUD) to nurse practitioners (NPs). Compared to physicians, NPs were required to complete 16 additional hours of training on controlled substance prescribing before a buprenorphine waiver application. As this differential additional education mandate was seen as a potential barrier, we evaluated the impact of this requirement on both NP waiver acquisition and prescribing of controlled substances, comparing NPs who obtained waivers to those who had not.Through 2016\u20132018 Oregon Prescription Drug Monitoring Program and linked NP licensure data, we identified factors associated with waiver acquisition at baseline (2016) and evaluated changes in controlled substance prescribing before (2016) and after waiver acquisition (2018). Using chi-square and Mann-Whitney U testing, we calculated and described controlled substance prescribing types, rates, and patient level quantities including co-prescribing of benzodiazepines and opioids by NPs. Multivariable linear regression compared prescribing by waivered and non-waivered NPs for significant changes in non-buprenorphine controlled substance prescribing.Waivered NPs were more likely to have a psychiatric certification, have prior disciplinary action, and have generally higher levels of non-buprenorphine controlled substance prescribing than their non-waivered counterparts. While there was a significant increase in opioid prescriptions per patient among waivered NPs, following CARA implementation, co-prescribing of benzodiazepines and opioids significantly declined among waivered NPs relative to non-waivered NPs.Although educational requirements were rescinded in 2021 for most applicants, enhanced opioid prescribing training should be incorporated into professional educational offerings regardless of regulatory mandate. We recommended continued focus on education regarding avoidance of high risk prescribing such as co-prescribing of opioids and benzodiazepines. NPs who acquire waivers may take on higher risk patients already using opioids, and these findings may represent transitions in practice and patient setting. United States federal law and regulation expanded access to buprenorphine for treatment of opioid use disorder (OUD). In 2016 Congress passed the Comprehensive Addiction and Recovery Act (CARA) which extended prescriptive authority for office-based treatment with buprenorphine to nurse practitioners (NPs) for up to 30 patients beginning in 2017 . StudiesUnlike physician assistants, who are required to practice with a supervising physician, NPs have autonomous practice in many states. As of December 2021, 24 states and the District of Columbia confer full scope of practice to NPs without a requirement for physician involvement in prescribing decisions . States NPs are granted full prescriptive authority for scheduled drugs in the state of Oregon, which was among states with the largest increase in NP prescribing of buprenorphine, particularly in very rural areas after implementation . NPs in In late 2020, the Trump administration promulgated rule changes to remove the DEA waiver requirement for physicians who prescribe buprenorphine to fewer than 30 patients . AlthougThe effect of these additional educational requirements on non-buprenorphine controlled substance prescribing has not been evaluated. It is critical to examine how and if expanded educational requirements impacted prescribing of controlled substances overall. While OUD is the target of buprenorphine therapy, prescribers authorized to provide it are not restricted from continued prescribing of opioids or other controlled substances such as benzodiazepines which can create risk for patients, and a history of substance abuse diagnosis is associated with high dose benzodiazepine prescribing by primary care providers .Characteristics of NPs who prescribe buprenorphine and where they practice likely differ from those who prescribe controlled substances generally. County level variables which facilitate buprenorphine prescribing include treatment capacity, overdose rate, and percentage of male non-Hispanic white population . PrescriThe objectives of this study were: 1) to describe characteristics of NPs who obtained a waiver in Oregon to prescribe buprenorphine (waivered) compared to those who did not (non-waivered) and 2) to evaluate changes in non-buprenorphine controlled substance prescribing following CARA implementation between waivered and non-waivered NPs. We hypothesize that increased educational components for waivered NPs would change controlled substance prescribing as measured by key variables associated with patient use and dispensing patterns.n\u2009=\u2009396,385) prescriptions. This dataset includes information on drug name, strength, quantity dispensed, days\u2019 supply, date dispensed, and prescriber. NP characteristics were determined through a Drug Enforcement Agency (DEA) number linked demographic and licensure database from the Oregon Board of Nursing. The Board of Nursing licensure database contains demographic and practice information such as age, NP specialty certifications, licensure date, and prior professional disciplinary action.We excluded all non-NP prescribers from this study as well as any prescriptions for buprenorphine products . We included all NPs with one or more prescriptions for either an opioid or benzodiazepine prescription dispensed by a pharmacy and entered into the Oregon Prescription Drug Monitoring Program (PDMP) database from January 1, 2016 to December 31, 2018  and licensure time was categorized into five-year increments by the Oregon Health Authority prior to data release. For professional certification, we identified if NPs had a psychiatric or mental health specialty certification. DEA waiver-status was provided by Oregon\u2019s PDMP program.Our first objective was to identify factors associated with NP waiver acquisition. We compared demographic and licensure characteristics between NP who ultimately received an waiver and those who did not. We also used PDMP dispensing data to compare controlled substance prescribing patterns between these two groups of NPs using 2016 (pre-CARA) as the baseline year. For each NP, we calculated the number of unique patients to whom they prescribed opioid analgesics, the average number of opioid prescriptions they prescribed to each patient, the number of patients to whom they prescribed long-term opioid therapy, and the number of patients who received at least one opioid prescription at or above 90 morphine milligram equivalents (MME) per day . We consP-values less than 0.05 were considered statistically significant. All analyses were performed using Stata/SE 15.1 .Our second objective was to evaluate changes in controlled substance prescribing among waivered NPs relative to those who were not. Using the prescribing metrics described above, we used multivariable linear regression to compare changes in prescribing patterns in 2018 relative to 2016 (prior to CARA waiver acquisition) across groups. In each regression model, the dependent variable was operationalized as the within NP difference in each prescribing metric; independent variables included waiver status, age, years in practice, psychiatric specialty, prior discipline, and the prescribing metric at baseline (2016). p\u2009<\u20090.001) and have had prior discipline  than non-waivered NPs.Of the 3321 NPs identified in the Board of Nursing licensure data, 187 were identified as acquiring a wavier by the Oregon Health Authority. Demographic and prescribing characteristics for these NPs are summarized in Table p\u2009<\u20090.001). Prior to waiver acquisition, waivered NPs wrote significantly more opioid prescriptions per patient than non-waivered NPs  and had more patients with long-term opioid therapy . NPs who became waivered also prescribed benzodiazepines to more patients  and with higher intensity  than those who did not. Waivered NPs co-prescribed opioids and benzodiazepines to more patients than those who were not .Of the NPs included, 1450 had one or more controlled substance prescription in Oregon\u2019s PDMP in 2016. At baseline (2016 pre-CARA), waivered NPs were more likely to have prescribed controlled substances than non-waivered NPs , initial waiver acquisition required additional training above and beyond that which was required by physicians. Although continuing education can improve performance, its link to patient outcomes is tenuous . While tHowever, additional support is needed to engage other healthcare professionals who might facilitate or limit buprenorphine access. For example, a recent study found 20% of pharmacies limited buprenorphine access for patients with OUD . InclusiOur results found that waivered NPs significantly changed their practice regarding the high-risk co-prescribing of benzodiazepines and opioids as compared to non-waivered NPs. Given the removal of the educational mandate to become a waivered prescriber, consideration should be given to multiple methods of continued support and interprofessional education regarding not only safer provision of controlled substances but also effective ongoing treatment of substance use disorders."}
+{"text": "Spinal cord injury (SCI) leads to irreversible functional impairment caused by neuronal loss and the disruption of neuronal connections across the injury site. While several experimental strategies have been used to minimize tissue damage and to enhance axonal growth and regeneration, the corticospinal projection, which is the most important voluntary motor system in humans, remains largely refractory to regenerative therapeutic interventions. To date, one of the most promising pre-clinical therapeutic strategies has been neural stem cell (NSC) therapy for SCI. Over the last decade we have found that host axons regenerate into spinal NSC grafts placed into sites of SCI. These regenerating axons form synapses with the graft, and the graft in turn extends very large numbers of new axons from the injury site over long distances into the distal spinal cord. Here we discuss the pathophysiology of SCI that makes the spinal cord refractory to spontaneous regeneration, the most recent findings of neural stem cell therapy for SCI, how it has impacted motor systems including the corticospinal tract and the implications for sensory feedback. Traumatic spinal cord injury is most commonly caused by compression, laceration and contusions which lead to severe impairment of motor/sensory function below the level of injury . The magThe initial traumatic event that may comprise fractures and/or dislocation of the vertebral column results in disruption of the vasculature, neurogenic shock and alterations in ion and neurotransmitter release. Ultimately this will set the stage for the secondary phase of injury ,5,6,7 inThe lack of repair following spinal cord injury is due to both cell intrinsic factors and the extrinsic injury environment . NeuronsWhile the first traumatic damage leads to immediate and often serious impairment of neurological function, the secondary phase usually dictates the full magnitude of injury. Inflammatory cells and resident glia including astrocytes and oligodendrocyte progenitor cells become reactive at the lesion that culminates in a permanently remodeled tissue ,26,27 F. As a heAnother main component that limits axonal growth is the physical barrier formed at the lesion site. SCI usually results in a breakdown of the blood spinal cord barrier (BSCB) and vascular permeability . FollowiIn efforts to increase axonal regeneration and recovery of function, experimental approaches targeting the environment at the injury site such as inhibiting molecules associated with scar and myelin debris ,31,44 haOne strategy to restore functional connectivity between severed spinal cord segments is the transplantation of neural progenitor cells (NPCs). NPCs have high therapeutic potential for reconstruction of the injured spinal cord tissue, since they can proliferate and differentiate into neurons and glia ,53. In aA major issue in these earlier techniques was a lack of retention of neural tissue within the injured spinal cord parenchyma that resulted in poor cell survival and failure of axonal growth. Later studies successfully overcame this issue by providing a more appropriate source or substrate for axonal growth. An experimental model using a peripheral nerve inserted into the lesion in the CNS showed extensive growth of axons from transplanted neurons along the \u201cneuron-free conduits\u201d . Later, Although experimental studies in the 1980s showed a gradual improvement of cell survival, integration and axonal growth, there was no evidence of functional improvements. Only in the 1990s did intraspinal fetal grafts placed into the site of SCI in adult and newborn rats show some improvements in functional outcomes ,58,64. TThe concept of neuronal relays is applicable when new neural circuits support and establish new connections across the site of injury. Specifically, descending host motor axons that project into stem cell grafts ,69,70 esAs previously discussed, SCI usually results in a large lesion area that damages not only the central gray matter, but also the surrounding white matter axon tracts that connect the brain with the rest of the body. Although damage of local spinal cord gray matter neurons primarily affects local segmental functions, disruption of white matter axon tracts is the major cause of neurological deficits below the level of injury ,78. UnliNeural stem/progenitor cell transplants have the potential to reconnect damaged axons since transplant-derived neurons can function as neuronal relays for disrupted pathways. First, transplant-derived neurons can serve as new neuronal targets attracting injured host axons that regenerate into and innervate the graft. A typical example is the robust regeneration of corticospinal (CST) axons into neural progenitor cell grafts . Second,In order to successfully generate neuronal relays by transplanted neural stem/progenitor cells in the injured spinal cord, a continuous transplant that completely fills the lesion site is needed. Excellent tissue integration with the surrounding host parenchyma and direct contact of transplants with the host tissue are additional pre-requisites for the ingrowth and outgrowth of axons . Large aAs an alternative approach, neural stem/progenitor (NSC/NPC) cells have been transplanted into remaining spared portions of the spinal cord, rostral and caudal to the lesion epicenter rather than in the lesion epicenter itself ,84. MostIn order to function as neuronal relays, a large proportion of transplanted NSC/NPC must differentiate into neurons that can reconnect injured circuits. Freshly dissociated rodent embryonic spinal cord-derived neural stem/progenitor cells usually differentiate into ~30% neurons and ~50% glia when embedded in a growth factor cocktail containing fibrin matrix within 7 weeks after transplantation . In contFor the formation of neuronal relays, propriospinal neurons and interneurons might be ideal as these neurons serve as natural \u201crelays\u201d in the intact spinal cord . In precIn general, transplant-derived neurons share many similarities with developing neurons. This includes a high intrinsic growth capacity allowing for axon extension into surrounding areas and remote regions. Transplanted neural stem/progenitor cells supported by fibrin-containing growth factors survive and differentiate into healthy neurons that can robustly extend their axons into host white matter over very long distances to innervate host gray matter. As many as 29,000 axons were shown to emerge from rat NPC grafts in caudal direction  in the rat . Graft-dThe traditional source of neural stem/progenitor cells from the developing CNS contains various stages of NSCs and progenitor cells. Fetal CNS tissue, such as brain and spinal cord, can either be directly transplanted without prior dissociation , dissociAn alternative means to generate neural stem cells or neural progenitor cells is the use of pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). ESCs are derived from the inner cell mass of the early blastocyst and have unlimited proliferative potential, therefore providing an unlimited resource of stem cells. In addition, ESCs are able to differentiate into a variety of cell types including neural cells . iPSCs hIn order to replace lost neurons and glia and to generate functional neuronal relays for CNS repair, pluripotent stem cells need to be induced to differentiate into neural cell lineages, especially to neural stem/progenitor cells or even early-stage neurons through a process called neural induction and differentiation. Early studies used a method of embryoid body (EB) formation and manual selection of neural rosettes after spontaneous differentiation or neural induction using growth factors or co-culture with PA6 stromal cells. Recent studies have focused on manipulation of specific signaling pathways such as inhibition of BMP, TGF beta  and WNT pathways by proteins and/or small molecules for neural induction. In addition, the early stage neuroectoderm can be patterned by different morphogens to produce distinct rostro-caudal, dorsoventral and mediolateral neurodevelopmental lineages ,93.Interestingly, in caudal spinal neurodevelopment, neural progenitors are derived from transient neuro-mesodermal progenitors that are capable of generating both spinal cord neural and mesodermal progenitors . This prAdditional studies with human ESC- or iPSC-derived neural stem/progenitor cells in animal models of SCI are needed to support the safety, feasibility and potency of these cells for clinical translation.An alternative approach and short-cut is direct conversion of somatic cells into induced neural stem cells (iNSCs) ,96. InteDescending motor tracts represent key elements to voluntary motor control in humans. One such pathway, the corticospinal tract (CST), commands its voluntary motor control not due to its connections with the motor cortex, but its immediate and direct access to spinal and motor interneurons within the spinal cord . In humaTo address this, we and others have used neural progenitor cell transplantation into a lesion cavity to provide a fortuitous substrate for axon regeneration and reinnervation ,104,110.This concept of neural relays was further supported when rhesus monkeys with a cervical spinal cord injury received a human caudal neural progenitor cell graft and showed CST axons growing into the graft for up to 500 \u00b5m . Other aInterestingly, more modern techniques have revealed the molecular signature of the adult corticospinal neuron as it regenerates after injury. Surprisingly, translational profiling indicated that during an early time after injury, CST neurons reverse back towards an immature developmental state and take on a gene expression profile similar to embryonic day 18 CST neurons . This prOne might ask if this strategy is feasible to establish the primordial circuits of the CST required for appropriate interneuron and motoneuron innervation within the spinal cord, leading to restored cortico-motor circuits for precise motor control. In the developing CST circuit in infant rhesus monkeys, CST fibers terminate within the intermediate zone of the spinal grey and no CST fibers innervate the motoneuron pools of the ventral horn . During Given that modern tools of neuroscience have unveiled that adult regenerating CST neurons regress back towards an embryonic fate while undergoing active regeneration, one can hypothesize that activation of this intrinsic developmental program can be harnessed to drive new CST circuit formation, and that in combination with training-induced adaptation, projections towards the appropriate targets within the spinal cord can be achieved.Most studies examining NSC-mediated behavioral improvements and formation of novel circuits have focused on descending motor systems, whereas restoration of sensory function from levels below a site of SCI has not received the same attention. Without doubt, there is a good rationale to focus on motor systems and specifically CST axons, one of the most important pathways for fine motor control. However, without any sensory feedback, precise supraspinal motor control will be difficult to achieve. Besides the important role of sensory feedback in motor control, regaining sensory function in areas below the lesion site could prevent or reduce some of the worst secondary complications from spinal cord injury including life threatening autonomic dysreflexia, detrusor sphincter dyssynergia that can lead to kidney failure, and pressure skin lesions, one of the leading secondary complications after SCI. In addition, pain at or below a site of SCI is highly prevalent in the SCI population, particularly in patients with incomplete injuries, severely impairing the quality of life ,122. ThuAscending sensory projections include the dorsal column system, which is mainly responsible for fine discriminative touch and conscious proprioception. It is the only system with direct long primary sensory neuron projections from ipsilateral DRGs to dorsal column nuclei (Nucleus gracilis/Nucleus cuneatus) and one of the most investigated systems in spinal cord regeneration. It has long been appreciated that the intrinsic regenerative capacity of these neurons can be enhanced by lesions of their peripheral axons ,124. TheEvidence for synaptic connections between sensory axons and different types of NSC graft-derived neurons also comes from several more recent studies. In mice with dissociated E13 fetal NPC grafts in lesions at level C4, retrograde transganglionic labeling of DRG neurons was observed as low at the upper lumbar spinal cord . As the These data raise the question whether sensory innervation of graft-derived neurons is a random process or whether formation of synapses between sensory axon and graft-derived neurons is more selective and specific. In studies examining sensory axon regeneration into syngeneic E14 rat NPC suspension grafts in a dorsal column lesion, neurons expressing dorsal horn markers  were not only clustered but also aligned in laminae-like patterns similar to the mature spinal cord . This unTaken together, the studies described above strongly suggest that mouse, rat and human NSC grafts are innervated by host sensory projections and therefore fulfill the first major prerequisite for functional sensory relays. There is also ample evidence for the second prerequisite, namely that primary sensory axons extending into NSC grafts form functional synapses, and that there is at least a preference if not some specificity in the graft-derived neuron population that receives sensory input. Regarding the third requirement for a sensory relay, namely innervation of relevant host sensory target nuclei by graft-derived axons, information is sparser, although NSC graft-derived axons extend into rostral direction in virtually every study. In immunodeficient rats with hiPSC-derived NSC grafts to C5 lateral hemisections, GFP-labeled graft-derived axons were found in dorsal column nuclei, medulla and midbrain and cerebellum, all sensory target nuclei . WhetherAt level and below level pain after spinal cord injury is highly prevalent, in particular in SCI patients with incomplete injuries. An area of potential concern is the possibility that NSC transplantation worsens or induces pain symptoms either by inappropriate new connections or by influencing the pain circuitry in the surrounding host spinal cord. Most studies have not reported any potential sensory adverse effects of NSC grafts but specific functional tests that can detect nociceptive sensitization were not always conducted. On the contrary, using stem cells differentiated towards inhibitory lineages, amelioration of pain-like behaviors has been reported. While SCI-related neuropathic pain has many underlying mechanisms, spinal disinhibition (loss of inhibitory activity) resulting in hyperactivity of the pain circuitry plays an important role in the pathophysiology of pain. Thus, a localized increase in inhibitory neuronal activity or innervation by transplants of inhibitory interneurons could be an effective means of modulating pain.Inhibitory neuronal progenitors obtained from the medial ganglionic eminence have been the focus of one set of studies. In animal models of peripheral neuropathies, grafting embryonic MGE-derived precursors into the lumbar spinal cord profoundly reduced pain-like behavior . TranssyDespite the detrimental outcomes after SCI, there is no effective treatment to restore functional connectivity of the injured spinal cord. One promising strategy is to reconstruct the lesion site with neural stem/progenitor cell grafts (NSC/NPC) as transplanted cells can differentiate into neurons that may re-connect disrupted spinal neural circuitry. Recent studies from our and other groups support the concept of neuronal relay formation by transplant-derived neurons.First, embryonic and pluripotent stem cell-derived NPCs can be transplanted into a lesion cavity and differentiate into neurons and glia. These developmentally early stage grafts integrate with the host tissue without generating a glial \u201cscar\u201d between host and graft , where gSecond, recent work not only demonstrates successful regeneration of both descending supraspinal motor axons and ascending sensory axons into NSC/NPC transplants, but also the formation of functional synaptic connections. Corticospinal optogenetic stimulation in the motor cortex showed a clear calcium response in graft-derived neurons in the spinal cord, indicative of action potentials initiated by host motor circuitry . TranssyThird, host axons growing into these NSC/NPC grafts within the lesion cavity appear to have at least some specificity. Regenerating motor circuits extended their axons into the graft and formed synapses with premotor interneurons and motor neurons, avoiding sensory interneuron clusters within the graft . In turnFourth, NSC/NPC grafts support functional improvements after injury. NSC/NPCs with spinal identity placed into clinically relevant models of SCI resulted in functional improvement in hindlimb ,110 and Although the above studies support the role of NSC/NPC grafts as a potential therapeutic intervention for SCI, meaningful functional improvements in the clinic will likely require additional advances. While a large proportion of corticospinal axons penetrate into NSC/NPC grafts in the lesion site, most of these axons are located within the first 1 mm of the rostral host/graft interface. Intensive rehabilitation can strengthen and even reshape newly formed circuitry to promote functional outcomes after injury as rehabilitation can strengthen synapses , lead toFinally, potential adverse effects associated with NSC/NPC transplantation need to be addressed before clinical translation, including possible over-growth or tumor formation and transplant-induced pain. Consistent and reproducible protocols for the production of a sufficiently large number of cells under defined conditions have to be generated. Potency assays and cellular characterization with minimum acceptance criteria need to be established, and in vivo dose\u2013response curves for efficacy and toxicity have to be completed. Parallel progress in the generation and transplantation of neuronal subpopulations most relevant for the formation of neuronal relays may further enhance the formation and efficacy of novel neuronal circuits. Thus, additional preclinical studies are warranted to support and improve the safety and efficacy of NSC/NPC therapy. Progress over the next years is likely to advance neural stem cells for the generation of neuronal relays in SCI towards clinical trials."}
+{"text": "The continuing COVID-19 pandemic has necessitated changes to research protocols and approaches to mitigate health risks to both study participants and researchers. This is particularly true of studies exploring the biopsychosocial well-being and personal perspectives of older adults and those at elevated risk of COVID-19 complications. While videoconferencing platforms have enabled remote work and social activities, reliance on them may potentially exclude some individuals . Persons living with dementia (PLWD) may experience difficulties navigating videoconferencing systems and building rapport with interviewers, though the inclusion of PLWD in research is necessary to ensuring their equitable representation. This presentation disseminates promising practices and lessons learned from a longitudinal study conducting remote interviews on sensitive topics with PLWD and their care partners (CP). Findings are drawn from a case study of the Better Together Dementia Care Study, an 18-month longitudinal study of PLWD (N=8) and their CPs (N=13), which implemented remote interviewing in Summer 2020 to gather data on the quality-of-life, resilience, relationship quality, adverse childhood experiences, mistreatment, and health status of PLWD. Researchers were able to interview most enrolled PLWD (n=7) via videoconferencing. Paper surveys were mailed to phone-interviewed participants, enabling them to view questions and answer choices in concordance with verbal queries. Researchers also tested a protocol asking CPs to leave the room while PLWD answered questions on sensitive topics. Findings support the use of remote interviewing with PLWD and provide insights to guide replication of these approaches."}
+{"text": "Similar to humans and laboratory animals, reproductive aging is observed in wild species-from small invertebrates to large mammals. Aging issues are also prevalent in rare and endangered species under human care as their life expectancy is longer than in the wild. The objectives of this review are to (1) present conserved as well as distinctive traits of reproductive aging in different wild animal species (2) highlight the value of comparative studies to address aging issues in conservation breeding as well as in human reproductive medicine, and (3) suggest next steps forward in that research area. From social insects to mega-vertebrates, reproductive aging studies as well as observations in the wild or in breeding centers often remain at the physiological or organismal scale (senescence) rather than at the germ cell level. Overall, multiple traits are conserved across very different species (depletion of the ovarian reserve or no decline in testicular functions), but unique features also exist . There is a broad consensus about the need to fill research gaps because many cellular and molecular processes during reproductive aging remain undescribed. More research in male aging is particularly needed across all species. Furthermore, studies on reproductive aging of target species in their natural habitat (sentinel species) are crucial to define more accurate reproductive indicators relevant to other species, including humans, sharing the same environment. Wild species can significantly contribute to our general knowledge of a crucial phenomenon and provide new approaches to extend the reproductive lifespan. Reproductive aging is a process involving a combination of multiple intrinsic and extrinsic factors affecting the whole organism and more directly the reproductive organs as well as the quality of germ cells. Reproductive aging in human and laboratory animals has been studied for decades at the physiological, hormonal, cellular, and molecular levels. As gamete quality declines more rapidly in women than in men, reproductive aging leads to infertility, increased miscarriages, and birth defects . The menCaenorhabditis elegans and Drosophila melanogaster has conserved properties in the process of mammalian ovarian aging  during aging are associated with declining reproductive performance. This can be used as a predictor of fertility longevity in cattle; however, it still remains largely unexplored in sheep and other farm species . DomestiCoturnix japonica) males demonstrated that similar to mammals, plasma androgen levels decline gradually, being accompanied by a loss of reproductive behavior . For instance, aging in the drosophila model still remains understudied in males. However, recent reports have shown that, not only sperm, but also seminal fluid are both qualitatively and quantitatively affected by age with each component making distinct contributions to declining reproductive performance in older males . Studiesbehavior . Interesbehavior .Antechinus sp.) to negligible reproductive senescence   . Even th glaber) . This isThe objectives of this review are to (1) present conserved as well as distinctive traits of reproductive aging in different wild animal species (2) highlight the value of comparative studies to address aging issues in conservation breeding as well as in human reproductive medicine, and (3) suggest next steps forward in research.The study of reproductive senescence in free-ranging populations is invaluable as it allows to better understand fundamental aspects, such as mate choice, sperm competition, or environmental impact. Furthermore, short- and long-lived wild species exhibit unique characteristics that inform our understanding of aging processes. An overview of the impact of aging on reproductive traits (including some observed in humans) in selected wild mammalian species (from rodents to non-human primates) is presented in Meles meles), there is strong evidence for a gradual decline in sex-steroid levels with age in both sexes, which is even followed by over 2 years of post-reproductive life (Acinonyx jubatus) after the age of 9, which is even older than the average life expectancy (In carnivores like the European badger (ive life . Interespectancy .Cervus elaphus) stags show a faster decline in annual breeding success than females that went through successive gestations and lactations (Canis rufus), reproductive aging in males also is observed while there is no evidence for reproductive aging in wild female wolves , there is no consequence of early life reproduction; however, for a given number of offspring, females that weaned more sons than daughters experience earlier senescence (In bighorn sheep (nescence . OffspriPan troglodytes), females with high number of years spent gestating and lactating during their reproductive lives have a delayed ovulatory attrition (Papio sp.) also suggested that reproductive senescence occurs later in females than males , calf survival decreases with maternal age because of less maternal investment , although reproduction does not entirely cease until the age of 65 year old, females have a relatively long post-reproductive life     or the f glaber) .Castor fiber), earlier breeding opportunities lead to earlier senescence through resource-dependent mechanisms , chimpanzees (Pan troglodytes), and chamois (Rupicapra rupicapra). Notably, some species rather show an increase in fertility as they age   . As seenconomus) . Lastly,An overview of the knowledge about the impact of aging on reproductive traits (including some observed in humans) in selected wild non-mammalian species  is presented in Somniosus microcephalus), reptiles , and some birds   .Gryllus campestris) investing more in early reproduction may senesce faster and die younger (Setophaga caerulescens) older males tend to have longer sperm cells, which may be advantageous in post-copulatory sexual selection  (Leucopsar rothschildi)   or birdsschildi) .Zoo animal populations represent an ideal model to study reproductive aging process since lifespan is frequently longer than in the wild, so repeated observations under controlled conditions are possible. Reproductive aging also represents a major issue in conservation breeding, especially for genetically valuable individuals that are too often not reproducing .Heterocephalus glaber) colonies has generated intriguing data. Unusually large ovarian reserve in naked-mole rat provides one mechanism to account for this species\u2019 protracted fertility. However, whether germ cell nests in adult ovaries contribute to the long reproductive lifespan remains to be determined (Research on naked mole rat (termined .Mustela nigripes), has revealed that even modest aging decreases sperm production and libido while abnormal sperm number increases (Arctictis binturong) show that males of advanced ages still produce good quality semen  and cheetahs (Acinonyx jubatus)  . As repojubatus) .Ailuropoda melanoleuca) cub by artificial insemination with frozen-thawed semen in one of the oldest females in captivity . A good illustration is the recent birth of a giant panda (aptivity . While aAcinonyx jubatus), uterine environment in aging females is the real issue while oocyte quality is not affected (in vitro fertilization (IVF) on oocytes from old donors and transfer the resulting embryos into young recipient females  that quickly dies after the breeding season (As highlighted in g season . Except Acinonyx jubatus), nothing is known about the influence of aging in gamete quality (success of fertilization and early embryo development) or uterine environment  reported above could suggest some research areas or questions in humans, for instance:\u2022Understanding rapid vs. absence of decline in fertility.\u2022Exploring sustained oocyte quality in felids (and other species having induced ovulations).\u2022Examining the influence of parental age on offspring reproductive health .\u2022Characterizing the impact of allostatic load  known for very long lifespan.\u2022Using the systems biology approach to better understand and mitigate reproductive aging.Regarding mitigations and treatments, expanding reproductive life could be achieved through, hormonal treatments  also are crucial to define more accurate reproductive metrics that are relevant to species, including humans, sharing the same habitats. We must keep building bridges between the ecology of senescence and areas of research in reproductive science. Repeated observations in zoo animals also will remain invaluable sources of information to decipher the mystery of reproductive aging.In sum, wild species can potentially contribute to the general knowledge of a crucial phenomenon. Comparative models will help to understand the fundamental mechanisms underlying reproductive aging and then develop new approaches to extend the length and the quality of reproductive lifespan, which will ultimately impact overall health.PC and MA contributed equally to the preparation and the writing of the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "ABSTRACT IMPACT: This study aims to advance the understanding of the biological mechanisms associated with feeding disturbances in infants born to diabetic mothers through non-invasive salivary gene expression analyses and body composition measurements at birth. OBJECTIVES/GOALS: To determine if non-invasive salivary gene expression analyses and body composition measurements at birth could elucidate biological mechanisms associated with aberrant feeding behaviors and disrupted metabolic profiles commonly seen in infants born to diabetic mothers. METHODS/STUDY POPULATION: This prospective cohort study enrolls subjects born at \u226535 weeks\u2019 gestation without a history of intrauterine growth restriction or major congenital anomalies. The diabetic cohort is defined as infants born to mothers with gestational diabetes or type 2 diabetes. The primary outcome is salivary expression of the hunger signaling genes, AMPK and NPY2R. Secondary outcomes include infant body composition measurements, obtained by skinfold measurement and/or air displacement plethysmography, and salivary expression of the adipokines, leptin, ghrelin, and adiponectin. Multiple logistic regression will be used to determine which factors are associated with AMPK and NPY2R expression. RESULTS/ANTICIPATED RESULTS: We propose that poor oral intake seen in infants of diabetic mothers may be due to alterations in the expression of hunger signaling genes  resulting in a diminished feeding drive in these large for gestational age infants. In addition, infant adiposity and the expression of genes involved in the adipoinsular axis will be inversely proportional to feeding volume intake. Namely, increased neonatal fat mass will be associated with increased expression of leptin and decreased expression of ghrelin and adiponectin. DISCUSSION/SIGNIFICANCE OF FINDINGS: Infants of diabetic mothers are at higher risk of poor oral feeding in the newborn period. This study aims to elucidate the link between neonatal body composition, adipoinsular axis, and hunger signaling to explain this unique feeding phenotype."}
+{"text": "Hematopoietic cells and their microvesicles have recently emerged as novel markers of cardiovascular risk. The crosstalk between these vesicles and endothelial dysfunction or vascular damage is a field of continuous progress. Additionally, thromboinflammation represents an emerging concept in cardiovascular diseases. In hypertension, the role of signaling pathways in hypertension remains also under investigation. Realizing the unmet needs of increased awareness of treating physicians and active researchers in this complex setting, we launched our Special Issue on \u201cMolecular Advances in Hypertension and Blood\u201d. Our issue has addressed both sides of the coin by publishing four articles that are summarized in this editorial. Firstly, we published an experimental study providing evidence that certain molecular pathways may be involved in myocardial remodeling in the settings of arterial hypertension and chronic kidney disease. Secondly, an in vitro study revealed a novel immune-modulatory effect of Ticagrelor, which is widely used in patients with hypertension and cardiovascular disease. Thirdly, another translational study assessed endothelial injury and pro-coagulant activity using circulating microvesicles in survivors of allogeneic hematopoietic cell transplantation, compared to a control population matched for traditional cardiovascular risk factors. Lastly, a review article delineated the role of Toll-like receptors in the pathogenesis of essential hypertension.Hematopoietic cells and their microvesicles have recently emerged as novel markers of cardiovascular risk ,2,3. TheAll articles submitted to us for this Special Issue underwent a rigorous peer review process. Ultimately, four articles were published. Three of these articles detail original research into (i) signaling pathways in arterial hypertension and chronic kidney disease, (ii) evidence suggesting a novel immune-modulatory effect of Ticagrelor, and (iii) endothelial injury and pro-coagulant activity in survivors of allogeneic hematopoietic cell transplantation. This Special Issue also includes one review that discusses the role of Toll-like receptors in essential hypertension. These four articles are discussed below.(i) Bodganova and colleagues aimed to delineate the pathophysiology of myocardial remodeling in arterial hypertension and chronic kidney disease. The authors induced early chronic kidney disease in spontaneously hypertensive rats and compared myocardial remodeling with controls. Chronic kidney disease in these rats was associated with increased FGF23 and decreased renal a-Klotho, along with increased systolic blood pressure, myocardial mass index, cardiomyocyte diameter and myocardial fibrosis. Myocardial remodeling was correlated with increased expression of calcineurin/NFAT and \u03b2-catenin. TRPC6 protein levels and mRNA expression were also elevated. Therefore, the authors concluded that Wnt/\u03b2-catenin and TRPC6/calcineurin/NFAT signaling pathways may be involved in myocardial remodeling of arterial hypertension and chronic kidney disease, potentially mediated by the FGF23 and \u03b1-Klotho axis [(ii) Mitsios and colleagues investigated the effects of Ticagrelor on inorganic polyphosphates released by thrombin-activated platelets and stent-induced neutrophil extracellular traps (NETs) in ST elevation myocardial infarction (STEMI). The authors stimulated neutrophils from healthy individuals and patients receiving Ticagrelor to produce NETs, and further incubated them with plasma from the infarct-related artery of STEMI patients. Then, they assessed the effects of Ticagrelor on NETs and tissue factor loading. Ticagrelor attenuated NETs induced by inorganic polyphosphates and inhibited stent-induced NET release. Considering the clinical need for novel antithrombotic strategies targeting inflammation, their findings highlighted an important and novel immune-modulatory effect of Ticagrelor .(iii) Gavriilaki and colleagues studied 45 survivors of allogeneic hematopoietic cell transplantation  without established cardiovascular disease and 45 control individuals matched for traditional cardiovascular risk factors. Circulating microvesicles (MVs) of different cellular origins (platelet and erythrocyte) were increased in alloHCT compared to controls. Endothelial MVs were increased only in recipients of a myeloablative conditioning. These results suggested that endothelial dysfunction and increased thrombotic risk in alloHCT survivors, independently of traditional cardiovascular risk factors .(iv) Lazaridis and colleagues reviewed the role of Toll-like receptors into essential hypertension considering that subclinical inflammation has been implicated in the pathogenesis of the disease. Toll-like receptors have emerged as novel effectors in the inflammatory background, which is evident from the very early stages of hypertension. This review has highlighted the contribution of innate immunity in the pathogenesis of hypertension and clarified the role of TLR signaling in promoting inflammation and hypertensive vascular damage .Taking into account the multi-disciplinary character of this Special Issue, we hope that it will inspire researchers and clinicians to continue their explorations into novel advances in blood and hypertension."}
+{"text": "Upper motor neuron (UMN) is a term traditionally used for the corticospinal or pyramidal tract neuron synapsing with the lower motor neuron (LMN) in the anterior horns of the spinal cord. The upper motor neuron controls resting muscle tone and helps initiate voluntary movement of the musculoskeletal system by pathways which are not completely understood. Dysfunction of the upper motor neuron causes the classical clinical signs of spasticity, weakness, brisk tendon reflexes and extensor plantar response, which are associated with clinically well-recognised, inherited and acquired disorders of the nervous system. Understanding the pathophysiology of motor system dysfunction in neurological disease has helped promote a greater understanding of the motor system and its complex cortical connections. This review will focus on the pathophysiology underlying progressive dysfunction of the UMN in amyotrophic lateral sclerosis and three other related adult-onset, progressive neurological disorders with prominent UMN signs, namely, primary lateral sclerosis, hereditary spastic paraplegia and primary progressive multiple sclerosis, to help promote better understanding of the human motor system and, by extension, related cortical systems. Upper motor neuron (UMN) is the term traditionally used for motor neurons within the central nervous system proximal to the spinal motor neuron. Dysfunction of the upper motor neuron in neurological diseases manifests with well-recognised clinical features, including (i) increased muscle tone at rest and in response to passive velocity-dependent muscle stretch , (ii) pyDysfunction of upper motor neurons is well recognised in several inherited and acquired neurological diseases. Inherited disease with prominent clinical features of UMN dysfunction include hereditary spastic paraplegia, leukodystrophies, such as Alexander\u2019s and Krabbe disease, and craniovertebral junction anomaly. Acquired disease of the central nervous system with prominent features of UMN dysfunction include neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), inflammatory disorders such as primary progressive multiple sclerosis (PPMS) and paraneoplastic encephalitis, chronic infection with human T lymphotrophic virus-1 (HTLV)-1 and syphilis, cerebrovascular events such as ischemic and haemorrhagic stroke or cerebral palsy and rare spinal cord ischemia due to vascular malformation.The pathophysiology of neurological diseases where UMN dysfunction predominates may yield novel insights into the complexity and division of function of the pathways that subserve motor control ,4, incluAmyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disorder of the human nervous system, exhibiting prominent features of upper motor neuron dysfunction . The terAmyotrophic lateral sclerosis is characterised by preferential patterns of muscle wasting and weakness. Specifically, the split hand , split hClinical UMN signs are variably manifest in ALS phenotypes. The extensor plantar response is evident in approximately half of ALS patients , while bDespite varying ALS phenotypes , the hisThe initial utility of imaging in neurological disease of the brain and spinal cord was for structural assessment of tissue, which was clinically difficult to visualise. Brain and spinal cord imaging in ALS diagnosis was used for exclusion of other disorders with characteristic imaging features . Though Reconstructing fibre pathways using tractography, detecting metabolite markers of neuronal integrity or cell turn-over using magnetic resonance spectroscopy (MRS), assessing cortical networks using resting-state functional MRI (R-fMRI) techniques and assessing grey matter perfusion with arterial spin labelling (ASL) are newer technologies being developed to assess functional changes in the upper motor neuron in disease  which maThe technique of electrical stimulation of the motor cortex to record motor evoked potentials in target upper limb muscles was developed  in the eA consistently reported neurophysiological abnormality in ALS, is the phenomenon of cortical hyper excitability thought to result from a loss of inhibitory pathways mediated via GABA-A receptors ,39,40. HA receptors and enhanced by glutamatergic and noradrenergic pathways [Several other neurophysiological measures also provide insights into upper motor neuron pathology in ALS. The motor-evoked potential (MEP) amplitude reflects a summation of complex corticospinal volleys  and the pathways . An incrpathways ,47 earlyCentral motor conduction time (CMCT) represents the time from stimulation of the motor cortex to the arrival of the corticospinal volley at the spinal motor neuron . CMCT isB receptors in the latter part [Cortical silent period (CSP) designates the interruption in EMG generated by voluntary motor activity in a target muscle following stimulation of the contralateral motor cortex. CSP is mediated by spinal mechanisms in its early part and cortical inhibitory mechanisms acting via GABAter part . Reductiter part ,39,53 anThe motor threshold (MT) reflects the ease of stimulation of the corticomotor neuron and reflects the density of projection of corticomotorneurons on the spinal motor neuron ,54. MT iPrimary Lateral Sclerosis (PLS) is an adult-onset, sporadic, slowly progressive neurodegenerative disorder of the upper motor neuron. The term is attributed to Charcot , who desDemographically, PLS is a non-familial disorder with slight male preponderance, low incidence ,61 and sHistopathology in PLS has been obtained in a few clinically well-defined cases , showingNeuroimaging in PLS has been limited and is usually undertaken in PLS as a subset of ALS cohorts. No clear diagnostic neuroimaging markers have been identified in PLS. MRI changes reported in PLS have included (i) atrophy specifically of the precentral gyrus , (ii) reCortical neurophysiology studies using transcranial magnetic stimulation reveal motor cortex inexcitability in PLS  with inaHereditary spastic paraplegia (HSP) is a genetically diverse group of inherited disorders resulting in length-dependent dysfunction primarily of the corticospinal axons, though other spinal tracts such as the posterior columns may also be involved. They are now understood to be a family of genetic disorders causing dysfunction primarily of extremely long corticomotor axons due to a variety of genetic mutations, affecting pathways involved in the maintenance of axonal health and integrity . The inhHereditary spastic paraplegia (HSP) has been categorised based on genetic inheritance into autosomal dominant, autosomal recessive or X-linked  primary Histopathology in HSP is limited due to the relatively normal lifespan of patients with pure HSP . NeuropaNeuroimaging in HSP was initially a tool to exclude mimic causes of spastic paraplegia. Atrophy of the spinal cord without anteroposterior flattening measured most often at the cervical cord level is the most reported finding in pure and complicated forms of HSP . StudiesCortical changes were not noted in a group of patients with the autosomal dominant (AD) genetic HSP when using the transcranial magnetic stimulation technique to probe motor cortex hyperexcitability  with motPrimary progressive multiple sclerosis (PPMS) has been studied under the category of inflammatory disorders of the central nervous system. PPMS is clinically an insidious-onset slowly progressive pure upper motor neuron disorder presenting with gait dysfunction . FeatureInterestingly, a case report of a patient with a clinical diagnosis of PPMS and a family history of Pelezaeus\u2013Merzbacher disease revealed a point mutation in the proteolipid protein1 (PLP-1) gene . PLP-1 cThe role of inflammatory cells causing pathological changes in the cerebral cortex and spinal cord in PPMS has been well described , with B Along with the wider subject of multiple sclerosis, PPMS has been extensively studied using neuroimaging modalities, and current diagnostic criteria require the presence of typical brain or spinal cord lesions for the diagnosis of PPMS . The lesCortical excitability using transcranial magnetic stimulation technique  did reveThis review summarises the salient features of four adult-onset neurological diseases with progressive and prominent upper motor neuron signs, with emerging key differences in their pathophysiological mechanisms. An improved understanding of the upper motor neuron has been promoted by studies exploring the pathophysiology of these disorders.Amyotrophic lateral sclerosis (ALS) is now recognized as a TDP-43 proteinopathy . HoweverPrimary lateral sclerosis (PLS) is also thought to be a TDP-43 proteinopathy , though Hereditary spastic paraplegia (HSP) is emerging as a disorder of a heterogenous family of genes which code for proteins involved in axonal transport, resulting in a length-dependent motor disorder affecting primarily the lower limbs ,77. OthePrimary progressive multiple sclerosis (PPMS) is increasingly being recognized as a neurodegenerative disorder, with neuroinflammation being the pathogenetic mechanism for neurodegeneration ,95. Nota"}
+{"text": "The spinal cord (SC) is a complex structure containing several neuronal circuits related with motor function of the upper and lower limbs, operating under the influence of higher centres. Central nervous diseases can change the responses of the spinal motor circuits leading to its dysfunction. Over the last decade, there has been a growing interest in the study of trans-spinal direct current stimulation (tsDCS) as a potential therapeutic tool to modulate spinal circuits through the application of electric currents delivered non-invasively . ComputaA literature narrative review was carried out through Pubmed database and manual search, considering the following selection criteria: research papers published in journals with impact factor in the areas of neuroscience, neurophysiology and biomedical engineering from 2008 to 2018; use of keywords related with the topic ; written in English. A qualitative analysis was performed over the literature selected considering the following items: electrode montage; tsDCS protocol; methods for assessing motor responses; observed changes; computational results; induced electric field (EF) distribution.Discussion and conclusions: Literature review indicates that experimental findings mainly depend on electrode polarity and position over the SC. tsDCS is a tool amenable to modulate motor circuits excitability in the spinal cord. This intervention can have clinical implications in the treatment of conditions like spasticity. However, future studies should consider EF magnitude and its orientation relative to spinal neurons. We propose that future clinical protocols should be guided by computational modelling to increase the chances of consistent positive results [Published studies showed different neuromodulation effects on the motor responses of the lower limb. Whereas some studies reported a reduction of spinal motoneurons excitability using anodal tsDCS, others described higher motor unit recruitment with cathodal stimulation T10\u2013T12), suggesting modulation of Ia-motoneuron (MN) synapse. Other authors failed to replicate a modulatory effect applying tsDCS . Modelli, suggest results ."}
+{"text": "Hope has been associated with increased pain tolerance  and has been incorporated in interventions targeting chronic pain . Research suggests that African Americans with osteoarthritis (OA) pain experience greater pain severity and disability compared to non-Hispanic White individuals . Although the literature is limited, there is some evidence to suggest racial/ethnic differences in hope . The current study examined race as a moderator of the association between hope and pain in a sample of older adults. Experience sampling (ESM) data was used from a multi-site study examining non-Hispanic White and African American individuals with knee osteoarthritis (OA). Participants completed the Adult Hope Scale  during baseline interviews and self-reported momentary pain during 28 ESM calls. Multilevel models revealed a significant interaction between hope and race (p = .04). Specifically, greater hope was associated with decreased momentary pain, and this association was stronger for African American compared to non-Hispanic White individuals. Results suggest that high levels of hope may be particularly protective for African American chronic pain patients. These findings can help inform existing and future interventions focused on enhancing hope in chronic pain populations."}
+{"text": "Spinal cord injury (SCI) results in multiple pathophysiological processes, including blood\u2013spinal cord barrier disruption, hemorrhage/ischemia, oxidative stress, neuroinflammation, scar formation, and demyelination. These responses eventually lead to severe tissue destruction and an inhibitory environment for neural regeneration.cAMP signaling is vital for neurite outgrowth and axonal guidance. Stimulating intracellular cAMP activity significantly promotes neuronal survival and axonal regrowth after SCI.However, neuronal cAMP levels in adult CNS are relatively low and will further decrease after injury. Targeting cAMP signaling has become a promising strategy for neural regeneration over the past two decades. Furthermore, studies have revealed that cAMP signaling is involved in the regulation of glial cell function in the microenvironment of SCI, including macrophages/microglia, reactive astrocytes, and oligodendrocytes. cAMP-elevating agents in the post-injury milieu increase the cAMP levels in both neurons and glial cells and facilitate injury repair through the interplay between neurons and glial cells and ultimately contribute to better morphological and functional outcomes. In recent years, combination treatments associated with cAMP signaling have been shown to exert synergistic effects on the recovery of SCI. Agents carried by nanoparticles exhibit increased water solubility and capacity to cross the blood\u2013spinal cord barrier. Implanted bioscaffolds and injected hydrogels are potential carriers to release agents locally to avoid systemic side effects. Cell transplantation may provide permissive matrices to synergize with the cAMP-enhanced growth capacity of neurons. cAMP can also induce the oriented differentiation of transplanted neural stem/progenitor cells into neurons and increase the survival rate of cell grafts. Emerging progress focused on cAMP compartmentation provides researchers with new perspectives to understand the complexity of downstream signaling, which may facilitate the clinical translation of strategies targeting cAMP signaling for SCI repair. Spinal cord injury (SCI) is a devastating neural trauma with an incidence of 54 patients per million people in the United States , the subacute phase (2 days to 2 weeks), the intermediate phase (2 weeks to 6 months), and the chronic phase (>6 months) , which include nine transmembrane members  and one soluble member . tm-ACs are downstream effectors of G-protein coupled receptors (GPCRs) that are activated by extracellular molecules, AC1 and AC8 are also directly activated by Ca2+. sAC is activated by intracellular bicarbonate, Ca2+, and ATP , and oligodendrocyte-myelin glycoprotein (OMgp)  and thereby induce Arg-1 (an M2 macrophage biomarker) expression  tend to exhibit lower GFAP expression and a preserved nonreactive morphology with slender processes, indicating that the increase in Epac2 activity might attenuate the activation of astrocytes. As observed in ex vivo SCI models, S-220-treated spinal cords show a closer relationship between neurite profiles and astrocyte processes, whereas nontreated spinal cords exhibit collapsed growth cones when confronted with RAs  are activated to become reactive astrocytes (RAs) that exhibit cellular hypertrophy and extended processes. RAs subsequently migrate to the periphery of the lesion site, express cell adhesion molecules, and ultimately transform into scar-forming astrocytes (SAs) that adhere to each other to form the glial scars , neural stem and progenitor cells (NSPCs), bone marrow stromal cells (MSCs), and olfactory ensheathing cells (OECs). These cell grafts provide permissive matrices to synergize with the cAMP-induced inherent growth capacity of neurons. Researchers previously injected Schwann cells and db-cAMP into the lesion site of SCI models and delivered rolipram subcutaneously for 2 weeks. The combination treatment significantly promoted axonal regeneration growth and myelination, leading to improved motor function recovery  further investigating the roles of cAMP signaling in different cells, particularly glial cells, under physiological and pathological conditions; (2) promoting the entry of combination strategies into preclinical or clinical trials to further confirm their safety and efficacy; and (3) comprehensively elucidating cAMP compartmentalization to more precisely modulate spatiotemporal intracellular cAMP signaling. All of these efforts will promote the development of new therapeutic strategies for SCI and ultimately benefit the patients.GZ and JG wrote the manuscript. ZW drew the figures. SH and YL helped write the manuscript and reviewed the manuscript. All authors reviewed and approved the final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Determining ways to improve hip fracture recovery in older adults is important, however recruitment of this target population into clinical trials is challenging. Multimodal interventions that target multiple mechanisms of recovery may improve outcomes, but each component presents unique recruitment barriers. While exercise interventions have been shown to be beneficial for hip fracture recovery, offering exercise following completion of conventional physical therapy can be viewed as a burdensome time commitment. Hormone replacement therapy may hold promise for overcoming anabolic resistance, but concern about adverse side effects can also deter participation. STEP-HI is a multisite trial testing whether exercise and testosterone can improve hip fracture recovery in older women. In this talk, recruitment barriers experienced in STEP-HI and strategies employed to overcome these barriers will be discussed. Strategies include: partnering with hospitals, skilled nursing facilities and orthopedic surgeons. providing talks and education materials; and featuring past participant testimonials in recruitment materials."}
+{"text": "Researchers are encountering increasing challenges in recruiting participants for healthcare research. We conducted semi-structured individual interviews to identify participant barriers to research and recommendations for overcoming these challenges. We recruited 17 patients and eight caregivers who were approached to participate in a randomized control trial. We also recruited 31 primary care physicians. Using grounded theory, three researchers independently coded the transcripts and then met to compare codes and reconcile discrepancies. Themes from patient and caregiver interviews included time constraints, privacy concerns, lack of research familiarity, disconnect with research institution, self-perceived health status, and concerns with study randomization and repetitive questions. Physician-identified barriers focused on time constraints and study randomization. Patient and caregiver recommendations for study recruitment included various recruitment techniques. Physician recommendations were related to incentives. Although patients and caregivers prefer that their physicians recruit them for health-related research studies, physicians identified time constraints as a barrier to research involvement."}
+{"text": "This systematic review aims to evaluate the effect of nicotine replacement therapies (NRTs) on measures of agitation amongst nicotine-dependent adult psychiatric inpatients.Since the introduction of the smoke-free policy for all psychiatric facilities, a psychiatric admission is likely to upset a nicotine-dependent individual's normal routine of nicotine consumption. In addition to the physiological effects of nicotine withdrawal (NW), the interpersonal dynamic which nurse-led guardianship of nicotine products constructs presents stressors to the nicotine dependent patient.Several systematic reviews evaluating changes in objective measures of agitation amongst smoking patients in medical critical care units have found varied results, with some demonstrating worsening agitation with NRT use. We therefore believe that there is sufficient equipoise in the use of NRT to prompt a review of studies amongst psychiatric inpatients.This review identified English language studies through developed search strategies in PubMed/MEDLINE, EMBASE, PyschINFO, PSYCHLit, Cochrane databases, and Google scholar. The bibliographies of notable papers were explored. Hand searches of five major psychiatric journals were conducted. Peer reviewed studies of any study design were included if they reported primary data of adult psychiatric inpatients. Studies were extracted from 1990 \u2013 present, this was felt appropriate as nicotine replacement patches became available in 1992.Search strategies were informed by MeSH search terms and included multiple conceptions of \u201cagitation\u201d, including variations on; agitation, irritability, and arousal to capture the concept from broad academic constructions. The quality of studies was assessed with the Newcastle-Ottawa and Cochrane Collaboration tools.This review follows PRISMA guidelines, and an application for PROSPERO registration has been submitted pending acceptance.Two studies were identified which matched inclusion criteria. A double-blinded randomised placebo-controlled trial of 40 nicotine-dependent inpatients from Allen et al. reported a significant 23% reduction in Agitated Behaviour Scores at 24 hours following NRT administration on admission compared to their matched placebo controls. Yet a retrospective cross-sectional analysis from Okoli using scores for NW identified more severe withdrawal symptoms including \u201crestlessness\u201d and \u201canger/irritability\u201d than nicotine-dependent patients not provided with NRT.Despite considerable commentary within literature there is presently only one study providing moderate evidence of a positive benefit to measures of agitated behaviour from the use of NRT amongst nicotine-dependent psychiatric inpatients. There is currently very low evidence whether NRT improves or exacerbates the agitation associated with NW amongst nicotine-dependent psychiatric inpatients."}
+{"text": "Robust evidence of fetal programming of adult disease has surfaced in the last several decades. Human and preclinical investigations of intrauterine insults report perturbations in placental nutrient sensing by the mechanistic target of rapamycin (mTOR). This review focuses on pregnancy complications associated with placental mTOR regulation, such as fetal growth restriction (FGR), fetal overgrowth, gestational diabetes mellitus (GDM), polycystic ovarian syndrome (PCOS), maternal nutrient restriction (MNR), preeclampsia (PE), maternal smoking, and related effects on offspring birthweight. The link between mTOR-associated birthweight outcomes and offspring metabolic health trajectory with a focus on sexual dimorphism are discussed. Both human physiology and animal models are summarized to facilitate in depth understanding. GDM, PCOS and fetal overgrowth are associated with increased placental mTOR, whereas FGR, MNR and maternal smoking are linked to decreased placental mTOR activity. Generally, birth weight is reduced in complications with decreased mTOR  and higher with increased mTOR . Offspring display obesity or a higher body mass index in childhood and adulthood, impaired glucose and insulin tolerance in adulthood, and deficiencies in pancreatic beta-cell mass and function compared to offspring from uncomplicated pregnancies. Defining causal players in the fetal programming of offspring metabolic health across the lifespan will aid in stopping the vicious cycle of obesity and type II diabetes. Decades of research have revealed that many diseases diagnosed over a lifetime have fetal origins. As a response to various exposures during the developmental period, such as maternal over/under-nutrition, chemicals, and stresses, fetal organs may be mal-programmed due to their inherent plasticity during development. The concept of fetal programming suggests that nutritional and environmental events that occur during critical periods of pregnancy cause permanent effects on the fetus and the long-term health trajectory of the offspring. A robust and important area of research investigating the developmental origins of health and disease (DOHAD) hypothesis has made huge strides in understanding the fetal programming of adult chronic and non-communicable diseases. Myriad epidemiological studies provide evidence of this association as it relates to risk for obesity, hypertension, cardiovascular disease, and diabetes ,2. HowevMechanistic target of rapamycin (mTOR) is a serine/threonine kinase that serves as a core component of mTOR complex 1 and mTOR complex 2. mTOR is activated by growth receptors, such as insulin growth factor (IGF) and insulin receptors, via IRS and the PI3K cascade. Direct downstream targets phosphorylated by mTOR include ribosomal protein S6/S6K1 and 4E-BP1, both involved in protein synthesis, ULK1, which inhibits autophagy, and others see . Newer sMaternal-placental-fetal units act in coordination to meet the needs of the fetus and to support the mother simultaneously. Within this coordinated system, mTOR senses and integrates nutrient signals ,8. As suThis narrative review will focus on the relationship between alterations in placental mTOR signaling associated with intrauterine complications and offspring metabolic health. First, placental mTOR signaling and associated birth weight outcomes will be reviewed for each pregnancy complication, with a special focus on sexual dimorphism within each pregnancy complication if data are available. Subsequently, the offspring metabolic health trajectory will be evaluated through discussions of obesity, insulin sensitivity, and pancreatic beta-cell mass and function. Human pathophysiology is reviewed with discussion of important animal studies to better facilitate readers\u2019 understanding.Fetal growth restriction (FGR) is defined as fetal weight below the 10th percentile for gestational age. FGR affects up to 10% of all pregnancies in the United States and carries an increased risk of perinatal mortality and morbidity. Long-term FGR complications include higher risk for hypertension, cardiovascular disease and type II diabetes . FGR invIn human pregnancies, mTOR activity has been shown to be decreased in placentas of FGR/growth-restricted babies . AlteredFGR itself is biased toward males in the human context . In factMaternal obesity during pregnancy elevates the risk of pregnancy complications and large-for-gestational-age babies . SituatiA Swedish study revealed a positive correlation between maternal BMI during the first trimester of pregnancy, birth weight, and placental insulin and mTOR signaling. These findings were accompanied by an inverse correlation between birth weight and AMPK signaling . These dMale sex has been defined as an independent risk factor for macrosomia or fetal overgrowth in humans , perhapsmTOR signaling is a key pathway in mediating maternal-fetal nutrient transport as described above . BrieflyA study of human GDM placentas showed increased mTOR signaling as determined by phosphorylated p70S6K (downstream mTOR target) in GDM compared to normal term placentas . Other sMetformin treatment for GDM introduces another aspect to placental mTOR regulation during pregnancy. Metformin is an anti-diabetic medication commonly prescribed to women with GDM that targets AMPK and subsequently blunts mTOR signaling. Metformin can be transported into fetal blood circulation. Therefore, mTOR signaling in the placenta and developing fetus can be reduced in response to metformin treatment for GDM. In human studies, metformin-exposed offspring are at increased risk for fetal growth restriction and catch-up growth during mid-childhood . In a muGDM is associated with higher birth weight and increased risk for macrosomia , with 15Polycystic ovary syndrome (PCOS) is an endocrine disorder that commonly affects women of reproductive age. Obesity and insulin resistance commonly characterize PCOS and can present PCOS mothers with an increased risk for GDM and hypertension . PCOS moLimited human studies have assessed the direct relationship between placental mTOR, PCOS and pregnancy outcomes. One study addressed whether mTOR signaling was increased in PCOS placentas from uncomplicated pregnancies. However, this study found no effect on mTOR signaling in the PCOS placenta versus controls . In a stHuman and preclinical studies segregating results by sex are lacking in PCOS.Maternal nutrient restriction (MNR) is a phenomenon leading to placental insufficiency and FGR. MNR captures both low protein diets and calorie restriction. Perhaps the most striking evidence linking human MNR to placental insufficiency is the 1944\u20131945 Dutch Famine, where severe calorie restriction during critical periods of pregnancy resulted in low birth weights and reduced placenta masses .In a baboon model, MNR reduced fetal weights by 13%. This reduction in weight was accompanied by a decrease in placental mTOR signaling  and AKT/insulin signaling  as determined by Western blot analysis . A rat sRoseboom et al., 2011 reported sexual dimorphic effects in severity of reduction of placental size and area in the Dutch Famine cohort. The effect of MNR during the Dutch Famine on the placental area was more severe for male offspring compared to female . PreclinPreeclampsia (PE) is a hypertensive disorder that occurs during pregnancy. Human studies have presented mixed results surrounding the relationship between PE and birth weight.Human placentas from pregnancies complicated by PE exhibit a mild decrease in phosphorylated mTOR but an increase in downstream phosphorylated 4E-BP1 . A signiMild PE has been associated with normal fetal growth of male offspring and growth restriction of female offspring at neonatal stage . A potenThe Centers for Disease Control and Prevention estimate that 12% of women smoke during pregnancy in the United States. Maternal smoking is associated with lower birth weight. For example, an analysis of the Tasmanian Infant Health Survey revealed that maternal prenatal smoking was associated with lower placental and birth weight . The HeaA preclinical model determined that dams exposed to secondhand smoke for 4 days had offspring with decreased placental and fetal weights (FGR), decreased trophoblast invasion, and decreased activation of placental phospho-mTOR, phospho-p70 and phospho-4E-BP1 .Maternal smoking during pregnancy has adverse impacts on fetal programming and offspring health. However, there is a lack of preclinical models of smoking, which limits our understanding of causal factors. In addition, a need for stratification by sex in human investigations and mechanism-driven studies with sex as a biological variable are needed to determine whether there is a sexual dimorphic effect of maternal smoking on offspring metabolic health and resilience.The relationship between birth weight and risk for obesity across the lifespan is well-established. Several findings indicate higher BMI in childhood and adulthood in the offspring of mothers with pregnancy complications. Placental mTOR has been implicated in programming offspring tissues to be more sensitive to a metabolic challenge .Observational studies suggest that the offspring of GDM mothers are more likely to develop childhood obesity (or higher BMI) compared to offspring not exposed to maternal hyperglycemia. This finding has been repeated in several studies across the globe . HoweverSeveral epidemiological studies have reported an association between maternal smoking and childhood/adolescent obesity ,71, possYoung adult males from the Dutch Famine cohort were at greater risk of developing obesity following exposure to nutrient restriction in utero. This finding was specific to enduring severe under-nutrition during first half of pregnancy . SimilarDirect mTOR deletion in the placenta resulted in offspring with obesity outcomes that were different between sexes. Neither male nor female offspring with placental mTOR knockout developed obesity when subjected to a normal chow diet  for 12-weeks. However, when metabolically challenged with a high-fat diet , females became more obese as compared to littermate controls, whereas male offspring on a high-fat diet did not develop obesity [Multiple pregnancy complications are associated with reduced placental mTOR signaling and low birth weight. Low birth weight also has a connection to insulin resistance in adulthood. Due to the timescale needed to study the development of insulin resistance in adulthood, there are limited human studies investigating this relationship in a longitudinal manner. However, evidence from the Dutch Famine cohort and preclinical models have substantiated this relationship .Individuals from the Dutch Famine cohort have reported low birth weight due to prenatal exposure to under-nutrition. In adulthood, this cohort displays impaired glucose tolerance and insulin resistance possibly related to inadequate insulin secretion or action . AnotherA 2002 study was the first to link maternal smoking to development of early adult-onset diabetes . Since tFemale offspring with placental mTOR knockout in utero displayed high-fat diet-induced insulin intolerance in adulthood, accompanied by hyperinsulinemia. On the other hand, male offspring with placental mTOR knockout had comparable glucose and insulin tolerances to littermate controls .Determining the relationship between placental mTOR and offspring pancreatic beta-cell mass and function comprises a newer area of research. Direct placental mTOR knockout gives rise to sexually dimorphic effects on beta-cell mass compensation, discussed in more detail below. The relationship between intrauterine insults such as preeclampsia and nutrient restriction, which have previously been associated with altered mTOR signaling in the placenta, have been studied in the RUPP model of preeclampsia and in maternal low-protein diet investigations ,59.In the gestational hypertension RUPP model, increased beta-cell death, reduced beta-cell area, and decreased mTOR protein level in the offspring fetal pancreas were reported . In respDirect ablation of placental mTOR reduced placental weight in the female offspring but did not alter beta-cell mass in both male and female neonates. Adult female and male offspring showed normal glucose homeostasis under a normal chow diet. While adult female offspring with mTOR knockout in utero demonstrate high-fat diet-induced insulin resistance, they have normal beta-cell mass and function compared to littermate controls .Differences in placental and fetal gene expression, epigenetic mechanisms, and hormone levels have been identified early in fetal development. Dearden et al., in 2018, elegantly reviewed several mechanisms mediating sexual dimorphic programming leading to adult metabolic disruption . DespiteThe importance of mTOR signaling in the placenta to regulate fetal development and programming of metabolic organs is gaining momentum. The link between perturbed placental mTOR and adverse birth weight outcomes has been assessed in several pregnancy complications, and a robust relationship between birth weight and offspring metabolic health trajectory has been defined. However, longitudinal studies and mechanistic investigations are lacking in the current body of research. Longitudinal human studies, as well as preclinical studies designed to follow mother and offspring from pre-conception, through gestation, and across the lifespan are needed to draw causal conclusions. Mechanistic studies investigating molecular changes occurring in response to placental mTOR perturbations both locally in the placenta and systemically throughout the developing fetus will be necessary to understand the sexual dimorphic metabolic outcomes observed. In addition to those highlighted in the previous section, several other mechanisms mediating sexual dimorphism include alterations in inflammation, nutrient transport, and hypoxia in the placenta and developing fetal tissues."}
+{"text": "In 2016, catastrophic flooding in south Louisiana claimed 13 lives with billions of dollars in damage to homes and communities in the decade after Hurricanes Katrina and Rita devastated the US Gulf Coast. In this study, we tested the inoculation hypothesis which predicts that older adults will be less distressed than younger adults due to their prior experience with severe weather events. Participants were 218 predominately middle-aged and older adults who varied in current and prior flood experience: less than half (40%) did not flood in 2016, 31% had flood damage, and 29% had relocated permanently inland after catastrophic losses in the 2005 Hurricanes Katrina and Rita and they flooded again in 2016. Depression symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9). Emotion regulation strategies were measured using the Cognitive Emotion Regulation Questionnaire-Short Form. Results indicated that the older adults had fewer symptoms of depression and were less likely to report self blame for flood-related adversities compared to younger adults. The two age groups did not differ significantly on the emotion regulation strategies of acceptance, reappraisal, positive refocusing, other blame, and perseveration. Age was inversely associated with symptoms of depression and the maladaptive strategies of self blame for flood-related misfortune and perseveration over losses. These data support the inoculation hypothesis and suggest that prior severe weather experiences, which are likely for older adults living in hurricane prone areas, are important for post-flood resilience. Implications of these findings for disaster planning and age-sensitive interventions to mitigate adversity are considered."}
+{"text": "Bilateral giant inguinoscrotal hernia (GIH) is rare and creates significant challenge in surgical management. The main concern of hernia reduction to abdominal cavity is development of abdominal compartment syndrome (ACS). Different approaches for prevention of ACS after surgery have been suggested.We report a case of 68-year-old male with bilateral inguinoscrotal hernia for 20\u00a0years reaching just below midpoint of thigh. He presented with difficulty in micturition and mobility. Preoperative investigations were normal. He underwent bilateral mesh repair without any preoperative or intraoperative adjunct measures. No significant complication occurred in postoperative period.Bilateral GIH is rare and the patients usually present late. GIH has been classified into three types on the basis of extension. Type I GIH can be managed with simple hernioplasty, in both unilateral and bilateral cases. Measures like resection of hernia contents and measures to enlarge intraabdominal space are warranted in type II and III GIH. Abdominal volume can be increased by utilising techniques like Pre-operative Progressive Pneumoperitoneum (PPP), injection of Botulinum toxin A (BTA) in the anterior abdominal wall, and rotation of viable tissue. The measures can be used either alone or in combination.Type I GIH can be treated with simple hernioplasty with safety with monitoring for features of ACS and respiratory complications postoperatively. However, additional measures like resection of hernia contents or procedures to enlarge intra-abdominal space are warranted for type II and III GIH. \u2022Surgical management of bilateral giant inguinoscrotal hernia is challenging as reduction of hernia contents to abdominal cavity may lead to development of abdominal compartment syndrome (ACS) and cardiorespiratory complications.\u2022We report a case of bilateral GIH managed with bilateral mesh repair with postoperative monitoring for features of ACS and cardiorespiratory complications.\u2022There was no significant complication in the postoperative period and no recurrence in six month follow-up period. This case report has been reported in line with the SCARE Criteria 2A 68-year-old male, known case of bilateral inguinoscrotal hernia for 20\u00a0years presented to our center with complaint of increasing difficulty in micturition for past two years. He had multiple episodes of acute urinary retention that required catheterization. The patient couldn't walk and sit properly. The swelling had become irreducible with time. He didn't have abdominal pain, distension, and vomiting. He didn't have any co-morbidities.Physical examination revealed bilateral massive inguinoscrotal swelling that descended to just below midpoint of inner thigh in the standing position . There wPatient underwent elective exploration via inguinoscrotal approach in tertiary care hospital by a team of general and gastrointestinal surgeons and mesh hernioplasty performed on bilateral inguinal region. Intra-operatively, large hernia sac was present containing omentum and small bowel with only the proximal ileum A and B. A double-layered closure by prolene surgical mesh was done followed by reconstruction of the wall. This was followed by exploration of contralateral left inguinoscrotal hernia. Intraoperatively, we found hernia sac containing omentum and small bowel with only the proximal jejunum lying within the sac. Adhesiolysis was done and manual reduction of hernia content was done through the deep inguinal similar to left inguinal hernia. Closure was done with Prolene Mesh followed by reconstruction of wall and bilateral inguinal drain was placed .Fig. 3ClPostoperatively, there was early return of bowel movement and mobilization. His intraabdominal pressure was monitored routinely to avoid abdominal compartment syndrome. No respiratory complication was seen during his stay in hospital. On the seventh postoperative day, the drain was removed before discharge. Small postoperative inguinal seroma developed which resolved within few weeks without surgical intervention. There was no evidence of recurrence at six months during follow up.3Giant inguinoscrotal hernia (GIH) is defined as hernia extending below the midpoint of inner thigh of a patient in erect position In 2013, Akpo conducted a study focusing on psychosocial aspects of bilateral GIH. The patients visited medical facility either due to inability of penetration or denial of sexual intercourse by partners. They presented late because of financial constraint or neglect of the disease despite understanding that surgery is necessary for treatment. These patients also experience difficulty in movement like our patient and at times face acute complications like bowel obstruction and acute retention of urine. These consequences significantly impair their quality of life. Our patient also experienced multiple episodes of acute retention of urine which can possibly be due to constrictive effect of enlarged scrotum on buried penis. In the same study, Akpo also gave classification of bilateral GIH for the first time Considering the rarity of the disease and unavailability of standard approach, dilemma exists among healthcare providers for management of GIH Trakarnsagna A et al. classified GIH into three types on the basis of extent of hernia sac, based on which management principles differ. In type I GIH (hernia that extends between midpoint of inner thigh and the midpoint of the mid-inner thigh and suprapatellar margin), hernioplasty with forced reduction with post-operative intra-abdominal and intra-thoracic pressure monitoring is considered enough. However, in other types, resection of contents or increased intra-abdominal volume procedures is warranted to prevent intra-abdominal hypertension One study conducted among 32 patients with type I GIH including a case of bilateral GIH showed that laparoscopic surgery using Transabdominal Pre-peritoneal (TAPP) approach with negative pressure drain can be performed with safety and low post-operative complications In type II and type III GIH with loss of domain, additional procedures to prevent ACS should be considered. Various approaches used for prevention are resection of hernia contents and procedures to enlarge intra-abdominal volume The techniques mentioned earlier are either used alone or in combination for GIH  as mentioned in some recent studies Despite emergency surgical intervention, a rare case of fatality in bilateral GIH has been reported in an obese patient presenting with respiratory distress 4Type I GIH, including bilateral GIH, can be treated safely with simple hernioplasty. However, patient should be monitored vigilantly for features of ACS and respiratory complications during the postoperative period. In type II and type III GIH, additional measures like resection of hernia contents or procedures to enlarge intra-abdominal space are required.The case report is exempt from ethical approval in our institution.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Sunil Basukala (SB), Sabina Rijal (SR), Narayan Thapa (NT), Rakesh Kumar Gupta (RKG) = Study concept, Data collection, and surgical therapy for the patientSB, SR, Bishnu Deep Pathak (BDP) = Writing - original draft preparationRM, SR, BDP = Editing and writingNT and RKG = senior author and manuscript reviewer.All the authors read and approved the final manuscript.Sunil Basukala.Not applicable.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Not commissioned, externally peer-reviewed.None."}
+{"text": "Previous research suggests depressive symptoms and loneliness are increasingly prevalent among older adults living in lower-income neighborhoods. The purpose of this study was to examine the extent to which neighborhood socioeconomic status (SES) was associated with depressive symptoms and loneliness among a sample of older adults from the Healthy Heart and Mind Study ; 66.7% women; 40.6% African American). It was hypothesized that older adults living in neighborhoods with greater socioeconomic disadvantage would report more depressive symptoms and loneliness than those residing in neighborhoods with less socioeconomic disadvantage. Depression was assessed with the Beck Depression Inventory-II (BDI-II), and loneliness was assessed using the Revised University of California, Los Angeles (UCLA) Loneliness scale. Neighborhood SES was measured with the Area Deprivation Index (ADI), which allows rankings of neighborhoods by SES disadvantage both statewide and nationally. After controlling for demographic variables , linear regression analyses showed that greater neighborhood SES disadvantage was associated with higher depression scores  and higher loneliness scores . These findings highlight the importance of neighborhood context on mental health in older adults, as underserved populations are more likely to experience declines in mental health under strenuous circumstances. Future research should investigate the impact of neighborhood SES on mental health in aging adults."}
+{"text": "Aging elicits dramatic changes to DNA methylation (DNAm), however the causes and consequences of such alterations to the epigenome remain unclear. The utility of biomarkers of aging based on DNAm patterns would be greatly enhanced if in vitro models existed that recapitulated physiological phenotypes such that modulation could garnish mechanistic insights. Using DNAm from serially passaged mouse embryonic fibroblasts, we developed a marker of culture aging and asked if culture phenotypes, like exhaustive replication, are epigenetically analogous to physiological aging. Our measure, termed DNAmCULTURE, accurately estimated passage number and was shown to strongly increase with age when examined in multiple tissues. Furthermore, we observed epigenetic alterations indicative of early cultured cells in animals undergoing caloric restriction and in lung and kidney fibroblasts re-programmed to iPSCs. This study identifies culture-derived alterations to the methylome as physiologically relevant and implicates culture aging as an important feature in known epigenetic aging phenomena."}
+{"text": "Researchers worldwide are repeatedly warning us against future zoonotic diseases resulting from humankind\u2019s insurgence into natural ecosystems. The same zoonotic pathogens that cause severe infections in a human host frequently fail to produce any disease outcome in their natural hosts. What precise features of the immune system enable natural reservoirs to carry these pathogens so efficiently? To understand these effects, we highlight the importance of tracing the evolutionary basis of pathogen tolerance in reservoir hosts, while drawing implications from their diverse physiological and life-history traits, and ecological contexts of host-pathogen interactions. Long-term co-evolution might allow reservoir hosts to modulate immunity and evolve tolerance to zoonotic pathogens, increasing their circulation and infectious period. Such processes can also create a genetically diverse pathogen pool by allowing more mutations and genetic exchanges between circulating strains, thereby harboring rare alive-on-arrival variants with extended infectivity to new hosts . Finally, we end by underscoring the indispensability of a large multidisciplinary empirical framework to explore the proposed link between evolved tolerance, pathogen prevalence, and spillover in the wild. Plasmodium knowlesi (Rattus norvegicus) and domestic  species that are known to share more zoonotic pathogens with humans than other animal taxa  can remain infected with the Marburg virus for 7 months after inoculation , a small number of individuals can shed Brucella abortus, the causative agent of brucellosis, persistently at a high level for more than 2 months . Growing evidence suggests that besides causing severe flu-like symptoms in humans , host-pathogen interactions have been traditionally viewed as purely antagonistic. Consequently, studies on pathogen defense have primarily focused on mechanisms that host typically use to resist infections by activating immune responses . This biIn this review, we are primarily addressing how disease tolerance in reservoir species can be intrinsically linked to the maintenance and transmission of pathogens and their spillover. We first discuss why and how tolerance might naturally evolve during long-term association between natural hosts and pathogens as an effective strategy. We then outline the favorable ecological and evolutionary contexts vis-\u00e0-vis host-pathogen tolerogenic interactions that may maximize the spillover risk  where individuals can harbor high viral titers without showing any significant morbidity, suggesting features of infection tolerance (Hemignathus virens) from low-elevation regions show a reduced rate of weight loss and better physiological condition even during the acute-phase infection with Plasmodium relictum than their high-elevation counterparts, indicating their higher tolerance to pathological effects of avian malaria (Microtus agrestis), mature males can maintain better body condition than immature males while harboring very high macro- and micro-parasite loads, again indicating a higher tolerance (Bufo americanus) and green frogs (Rana clamitans) also show characteristics of relatively higher tolerance to Echinostoma trivolvis, a locally abundant trematode species, compared to younger tadpoles , the natural reservoirs for the Marburg virus, lack the induction of several pro-inflammatory genes that are classically implicated in primate filoviral pathogenesis such as CCL8, FAS, and IL6  and African green monkeys (Chlorocebus aethiops) infected with SIV show acute early inflammation, but they also possess regulatory mechanisms to rapidly control such responses; for example, they use anti-inflammatory inhibitory cytokines such as transforming growth factor-\u03b2 (TGF-\u03b2) and IL-10  infected with Sin Nombre virus (SNV) also upregulate cytokines that correspond to Treg responses, prolonging the viral presence (R. norvegicus) infected with Seoul virus (SEOV) not only reduce the pro-inflammatory mediators such as interleukin-6 (IL-6) or TNF-\u03b1 in their lungs but also increase the expression of regulatory factors TGF-\u03b2  proliferation, tolerating the effects of viral infection  populations performed by Hayward and coworkers  from two locations with a different coevolutionary history of infection by bacterium Mycoplasma gallisepticum was particularly helpful here  and higher levels of anti-inflammatory cytokine (IL-10)  isolated from regions with longer exposure to heartworm (Dirofilaria immitis) also showed higher tolerance compared to populations with little exposure to the parasite  . In anotparasite . These rparasite . In rode strongly supports this possibility where small isolated populations had a higher abundance of henipaviruses and extended within-host latency  and chikungunya  virus (CHIKV)  possibly derived from a bat-isolated orthoreovirus (Perameles bougainville), which exhibited genomic properties of both the Papillomaviridae and the Polyomaviridae family of viruses (Rousettus leschenaultii bats for 2 years found recombinants of RdRp (RNA-dependent RNA polymerase) and p10 genes in Ro-BatCoV GCCDC1 within as early as 5 months since the initial surveillance began  and SIV (retrovirus) might persist together in their natural hosts sooty mangabeys , which s (CHIKV) . Althoug (CHIKV) . For exa (CHIKV) . This is (CHIKV) . Also, ireovirus . In thisreovirus . Another viruses . These oce began .Pathogens, especially viruses, can evolve much faster than their hosts, presenting numerous mechanisms to avoid immune sensing . SIV, foConversely, host-pathogen tolerogenic interactions over an evolutionary timescale might also lead to progressive loss of immune evasion mechanisms in the pathogen, potentially reducing their infectivity to future hosts. Perhaps, one of the best-documented examples includes Myxoma virus (MYXV), which is highly pathogenic to European rabbits, with a case fatality rate close to 100% . The samFinally, recent vaccination studies in poultry birds can also offer some important clues on how tolerance can in principle influence the pathogen persistence and diversity. This is particularly true for vaccines that operate by reducing the disease symptoms , rather than preventing the infection, pathogen replication, and transmission . InfectiAnother example is live vaccination with attenuated strains of porcine reproductive and respiratory syndrome virus (PRRSV), which prevents the development of disease symptoms in pigs but does not protect them against contracting the infection . In factHost immune strategies, ecology, and pathogen prevalence all play instrumental roles in facilitating spillover, but studying them in isolation is far from ideal given the complex interactions that are involved therein. Costly immune responses might evolve to act at suboptimal levels in the wild due to constraints from available resources and physiological states . AlthougOur understanding of emerging diseases from natural reservoirs has increased substantially over the past two decades , but unfTransmission dynamics might also be contingent on intermediate hosts and vector populations . UnderstLong-term tracking of pathogens and disease with altered species interactions is perhaps most relevant for rapid land-use changes in recent decades  \u2013 deforehttps://www.globalviromeproject.org; https://ibol.org/programs/bioscan), the extension of the International Barcode of Life Program . Finally, proactive programs aimed at pandemic prevention also critically need more spatial and temporal information describing key changes in ecological communities  and environmental parameters  to better understand why circulation and transmission risk of zoonotic pathogens might vary across ecosystems. A recent web-based application \u2018SpillOver\u2019 is particularly useful to gain some of these insights , was operational until recently to identify broad patterns of emerging pathogens with pandemic potential in geographical regions that are disease hotspots such as the Republic of Congo, China, Egypt, India, and Malaysia . However Program , and theinsights . In addiAn integrated program to catalog pathogens across species, populations, and locations will prepare a unique stage to subsequently ask more mechanistic questions; for example, explaining the macro-scale structural variations, using diverse metrics of host immunological, ecological, and physiological parameters. However, multiple challenges need to be overcome to conduct any meaningful analyses. Below, we describe the indispensability of accepting the challenges and testing the natural variation in immune strategies and their complex interplay with life-history to explain EID prevalence and emergence.Batrachochytrium salamandrivorans that usually infects amphibian skins  as a proxy in a wild population of cyprinid freshwater fish  , tolerance was quantified by assessing eye cataract formation as a degree of pathology against increasing burden of eye fluke Diplostomum pseudospathaceum (Ovis aries) populations to distinguish how natural selection acts separately on three functionally distinct isotypes of antibodies  against a prevalent nematode parasite Teladorsagia circumcincta  . In Atlaathaceum . All theumcincta . Future Anolis sagrei lizards also used body condition, locomotor performance, and survival to the end of the breeding season as a function of infection with Plasmodium parasites  feeding on a low protein diet showed increased tolerance to Photorhabdus luminescens , however, found increased tolerance to skin penetrating nematode Aplectana sp. when maintained on proteinaceous insect diets  found multiple such highly polymorphic sites in the receptor regions, which interacts with the spike proteins of a coronavirus isolated from the same species of bats named as SARSr-CoV  rapidly evolved to antagonize host restriction factor tetherin by acquiring mutations in the accessory protein Vpu within merely four passages through an atypical HIV-1 host species pigtailed macaques  can help us to partially overcome the uncertainties associated with quantifying parasite burden and estimating fitness traits in the wild .Yet it might be challenging to answer some of the most fundamental questions, such as do hosts actually evolve tolerance to their natural pathogens? If so, how do we track such evolutionary processes? Besides gathering clues from comparative studies using various host populations, laboratory experimental evolution using tractable animal models (with known biology and genomic information) can be an excellent alternative to test these possibilities . They caArmigeres subalbatus is a natural vector for the zoonotic filarial worm Brugia pahangi whom they can tolerate, but not the morphologically and biologically similar pathogen Brugia malayi , which is crucial for their tolerance and survival against chikungunya virus and dengue virus, respectively (Aedes populations lacking (or with inherently lower) viral tolerance; (2) impose long-term viral selection to directly test whether stronger tolerance is correlated with increased vDNA synthesis; and (3) finally, test whether such evolved tolerance can be reversed by reducing vDNA synthesis (using reverse genetics) to verify its functional role  and the dynamics of noninfectious diseases (e.g., increased risk autoimmune disorders in geographical regions where improved hygiene has reduced pathogen burden;"}
+{"text": "In the immediate postoperative period, cell-free hemoglobin (CFH) and lactate dehydrogenase (LDH) were significantly lower in the study group than in the control group . Moreover, patients treated with the magnetic levitation pump showed lower creatinine and indirect bilirubin  [Increased plasma concentrations of circulating cell-free hemoglobin (CFH) are supposed to contribute to the multifactorial etiology of acute kidney injury (AKI). In their recent article: \u201cThe role of cell-free hemoglobin and haptoglobin in acute kidney injury in critically ill adults with ARDS and therapy with VV ECMO.\u201d, Graw et al. identified a cohort of 1044 ARDS patients with CFH and haptoglobin measurements before initiation of ECMO therapy. They concluded that in critically ill patients with ARDS requiring therapy with VV ECMO, increased plasma concentration of CFH were an independent risk factor for AKI. Among patients with increased CFH concentrations, higher plasma haptoglobin concentrations might protect from CFH-associated AKI ["}
+{"text": "During the publication process of the original article  an errorUn Jung KangThe correct corresponding authors are:Luis Concha-Marambio, Roland G. Heym, Claudio Soto, Byron Caughey and Un Jung KangThe incorrect corresponding author was:The publisher apologizes for the inconvenience caused to the authors and readers."}
+{"text": "Standard treatment of Parkinson\u2019s disease involves the dopaminergic medications. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an important neurosurgical intervention often used as alternative treatment to drug therapy; however, it can be associated with increase of impulsive behaviors. This descriptive review focused on studies investigating the correlation between Deep brain stimulation of the subthalamic nucleus and impulsivity in Parkinson\u2019s disease patients, arguing, the action\u2019s mechanism and the specific role of the subthalamic nucleus. We searched on PubMed and Web of Science databases and screening references of included studies and review articles for additional citations. From initial 106 studies, only 15 met the search criteria. Parkinson\u2019s Disease patients with and without Deep Brain Stimulation were compared with healthy controls, through 16 different tasks that assessed some aspects of impulsivity. Both Deep brain stimulation of the subthalamic nucleus and medication were associated with impulsive behavior and influenced decision-making processes. Moreover, findings demonstrated that: Impulse Control Disorders (ICDs) occurred soon after surgery, while, in pharmacological treatment, they appeared mainly after the initiation of treatment or the increase in dosage, especially with dopamine agonists. The subthalamic nucleus plays a part in the fronto-striato-thalamic-cortical loops mediating motor, cognitive, and emotional functions: this could explain the role of the Deep Brain Stimulation in behavior modulation in Parkinson\u2019s Disease patients. Indeed, increase impulsivity has been reported also after deep brain stimulation of the subthalamic nucleus independently by dopaminergic medication status. Deep brain stimulation of the sub-thalamic nucleus (STN-DBS) is an important neurosurgical intervention that could determine, as well as dopaminergic medication, relevant side effects such as increased impulsivity.The studies analyzed in this review showed that after the surgical intervention, impulsivity improves independently by dopamination medication status. These findings could help to individuate contrasting data about the role of DBS on impulsivity in PD patients.Future research should include the study of other factors, such as genetic predisposing, direct effect on limbic part of STN, cognitive outcome or depression scores, and should conduct larger, prospective, controlled trials to better clarify how different subcomponents of impulsivity can be modulated both by dopaminergic drugs and STN-DBS.decisional forms, including delay discounting ;reduced sensitivity to adverse outcomes (negative prediction errors) during learning;reflection impulsivity (rapid decision-making);risk-taking and response conflict (slowing and errors with competing responses);motor forms, such as response inhibition  .Parkinson\u2019s disease (PD) is a neurodegenerative disorder due to loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and it is characterized by tremor, rigidity, and bradykinesia . AlthougDeep brain stimulation (DBS) is an adjunctive therapy to reduce some of the symptoms of an advanced stage that responds to levodopa Deep brain stimulation (DBS) is an adjunctive therapy in reducing some of the symptoms of advanced, levodopa-responsive. It improves motor disability by 33%\u201467%, motor fluctuations by 73%\u201483%, and dyskinesias caused by levodopa \u201315. DBS This descriptive review focuses on the studies that investigated the effect of STN-DBS on impulsivity in PD patients and argued its possible mechanisms of action.The sample population included PD patients with STN DBS;Studies provided a neuropsychological assessment of impulsivity and neurocognitive performances;Data compared the performance of PD patients on/off stimulation and on/off medication and healthy controls (HC);We excluded studies on PD patient with dementia or affected by other neurological or major psychiatric disorders;Animal studies and published in non-peer reviewed research were excluded;We excluded case studies.Studies were identified in PubMed  and Web of Science databases (November 2007 \u2014 January 2020). The search combined the following terms: (\"impulsive behavior\" [MeSH Terms] OR (\"impulsive\" [All Fields] AND \"behavior\" [All Fields]) OR \"impulsive behavior\" [All Fields] OR \"impulsive\" [All Fields]) AND (\"deep brain stimulation\" [MeSH Terms] OR (\"deep\" [All Fields] AND \"brain\" [All Fields] AND \"stimulation\" [All Fields]) OR \"deep brain stimulation\" [All Fields]) AND (\"parkinson disease\" [MeSH Terms] OR (\"parkinson\" [All Fields] AND \"disease\" [All Fields]) OR \"parkinson disease\" [All Fields] OR \"parkinsons\" [All Fields]). The search terms were identified in the title and abstract. We selected only English texts. After duplicates had been removed, articles were evaluated based on the title, abstract, and text. Studies that examined impulsivity in PD patients were included, after they fulfilled the following criteria:Of 108 studies identified, 15 met the inclusion criteria  task , 28 and Reference  examinedThe effects of DBS on impulsivity were also investigated by other tasks involving inhibitory control or response selection under conflict. In Simon task, that produced conflict from response impulses in patients with PD and HC, responses were faster and more accurate when relevant (color) and irrelevant  features of an imperative stimulus corresponded to the same response, but slower and less accurate when these features signaled conflicting responses . STN-DBSSince it is not yet clear what aspects of PD are actually caused by Basal Ganglia (BG) dysfunction,  investigStimulation of the ventromedial STN through its close connection to the nucleus accumbens loop potentially induces ICD . These cSTN plays a key role in inhibition processes, which permit the suppression of premature actions and to block interference from irrelevant stimuli. Altered decision-making is associated with cognitive impulsivity, which is considered the inability to weigh the consequences of immediate and future events and, consequently, delay gratification . Lesion Two studies hypothesized that STN DBS selectively improves inhibitory functions , 41. ThiStudies on impulsivity in PD patients highlighted conflicting results. DA seems to represent the main risk factor that leads to \u201creflection impulsivity\u201d. Indeed, ICDs predominantly occurred subsequent to treatment initiation or dosage increase particularly related to the effects of the DA , 25. HowContrasting data suggest that STN-DBS significantly improves the proficiency of reactive inhibitory control , 41 and The etiology and pathogenesis of treatment-induced impulsivity in PD remain unknown , though"}
+{"text": "While spinal interbody cage options have proliferated in the past decade, relatively little work has been done to explore the comparative potential of biomaterial technologies in promoting stable fusion. Innovations such as micro-etching and nano-architectural designs have shown purported benefits in in vitro studies, but lack clinical data describing their optimal implementation. Here, we critically assess the pre-clinical data supportive of various commercially available interbody cage biomaterial, topographical, and structural designs. We describe in detail the osteointegrative and osteoconductive benefits conferred by these modifications with a focus on polyetheretherketone (PEEK) and titanium (Ti) interbody implants. Further, we describe the rationale and design for two randomized controlled trials, which aim to address the paucity of clinical data available by comparing interbody fusion outcomes between either PEEK or activated Ti lumbar interbody cages. Utilizing dual-energy computed tomography (DECT), these studies will evaluate the relative implant-bone integration and fusion rates achieved by either micro-etched Ti or standard PEEK interbody devices. Taken together, greater understanding of the relative osseointegration profile at the implant\u2013bone interface of cages with distinct topographies will be crucial in guiding the rational design of further studies and innovations. Solid bony fusion is an essential requirement for successful spinal arthrodesis surgery that allows for stability of adjacent vertebrae \u20134. A comEnhancements to implant topography and architecture, including surface treatments and porous technologies, can putatively accelerate osseointegration and osteoconduction, which is key to long-term biomechanical function of interbody devices , 14, 15.The purpose of this article is to critically assess the tissue engineering potential of modified implant surfaces in spinal surgery, in particular with respect to the ability of activated surface and scaffold designs to accelerate or enhance osseointegration and structural stability following spinal instrumented arthrodesis procedures. We review a new imaging modality, dual-energy computed tomography (DECT), which allows for additional image post-processing and material characterization not possible with conventional systems. Finally, we discuss the rationale for two recently initiated randomized clinical trials designed to evaluate the rate of early osseous fusion using DECT within either activated Ti or PEEK lumbar interbody cages. Taken together, we believe that new insights will soon be gained to help elucidate the potential relative efficacy of microscopic lattice structures in accelerating the process of osseointegration and fusion.While current lumbar interbody cage designs are generally associated with favorable radiologic and clinical outcomes \u201323, fullA recent in vitro evaluation showed that implants bearing a trabecular scaffolded topography enhance cellular proliferation, bone matrix formation, and mineralization with increased mechanical strength by 20% for compression strength and 60% for compressive modulus . FurtherOne critical implant property that can play a role in osteoconduction and osseointegration is the three-dimensional geometry and intricately designed porosity. Specifically, interbody cage porosity accommodates bone ingrowth with the potential to yield improved implant fixation , 31. A mImplant surface roughness and surface finish also may play a significant role in promoting osseointegration . An earlAnother study compared osseointegration when alumina and a multiphase calcium phosphate (MCD) were used as the blast media. Blasted Ti alloy (Ti6Al4V) cylinders were implanted into rabbit tibiae and then evaluated two and four weeks after implantation. The histologic results showed the MCD to elicit significantly greater volume of new bone formation . A more Intriguingly, the combination of nanostructures onto microroughened surfaces may synergistically enhance the production of osteoblast differentiation markers and local factors important for bone formation compared to unmodified microrough controls . Indeed,Yet another factor that can influence the biomimetic properties of the bone\u2013implant interface is the modulus of elasticity. Specifically, 3DP can design implants with an elasticity modulus resembling natural or cadaveric tissue. As a result, a better elastic recovery, biodegradability and cytocompatibility is expected , 46. MorA number of activated Ti cages are commercially available but with no long-term clinical evidence supporting their relative efficacy in promoting early osseointegration and fusion , 49. A r\u00ae or Trial 2: straight-shaped Medtronic AdaptixTM) versus PEEK cages.Clinical confirmation of enhanced osseointegration or bony fusion through activated Ti cages remains lacking. As such, the principal author (HFF) has designed two separate randomized double-arm single-blinded studies in patients undergoing either single- or double-level instrumented arthrodesis procedures  to compare radiologic and clinical outcomes using either activated Ti cages  implanted at each level of single- or contiguous double-level lumbar arthrodesis procedures. Both cages will be used in conjunction with milled local autograft bone generated as part of the spinal decompression portion of the procedure. Clinical and radiographic outcomes are being collected at regular intervals post-operatively. The primary outcome measure of effectiveness is radiographic bony fusion as assessed by an independent neuroradiologist at 6 months post-operatively, which grossly corresponds to the early phase of expected fusion following lumbar interbody cage placement. Radiographic bone fusion will be graded by the method of Brantigan and Steffee as modified to describe the Fraser definition of locked pseudoarthrosis  with a Grade BSF-3 being considered successful bone fusion. Grade BSF-3 is defined by radiographical fusion presenting bone bridges within at least half of the fusion area with at least the density originally achieved at surgery  Figs. \u20134 54\u201359\u20135954\u201359.With current X-ray tube technology, it is not possible to generate monochromatic spectra for scanning and greater artifact is expected with a polychromatic beam. As such, the potential for diminished artifact stems from the ability of VMIs to simulate what would be expected with a monochromatic X-ray beam. Furthermore, VMI images can be generated at a wide range of energies with unique advantages depending on the problem at hand and material of interest Fig. . By geneFinally, DECT scans can be used to generate basis material decomposition maps. While the feasibility depends on the specific material of interest and its physical properties, these maps can be used to estimate the distribution and concentration of certain materials, which is not possible using conventional CT imaging. One such example, virtual non-calcium maps, are used to demonstrate marrow edema , 68, 69.Enhanced implant-bone integration and fusion rates may have significant clinical benefits, particularly in more complicated clinical scenarios where fusion may be delayed, such as in osteoporosis, smokers, or with concomitant immunosuppressant use. The results of these two trials should provide relevant information regarding the relative efficacy of activated Ti surfaces  in accelerating the process of osseointegration and fusion. Novel insights in this regard are likely to be gained with DECT imaging, whose potential advantages include enhanced artifact reduction. Our conclusions should also assist in the design of further multicenter studies evaluating potential clinical benefits, either for similar degenerative conditions or for more complex reconstructions such as in adult spinal deformity."}
+{"text": "COVID-related safety concerns mandated suspension of our ongoing trial testing the effects of movement and social engagement in older adults with early-stage dementia and their caregivers (dyads). Participant vulnerability and the requirement for group social interaction complicated intervention resumption. We present results from a successful pilot to rapidly and iteratively optimize study interventions for remote delivery targeting intervention mediators  based on participant feedback. Three-dyad groups  completed cycles of intervention via Zoom immediately followed by an interview with open-ended and quantitative feedback. Cycles were repeated until no new information was solicited, then repeated with new participants. Optimization revealed needs for technological support, more intensive movement, and social connection. Specifically, the inability to make eye contact, see others\u2019 full body, and technology-associated timing asynchronies impeded social connection in the movement group. We will present practical tips for crafting remote group interventions for caregiver/person living with dementia dyads."}
+{"text": "Voriconazole is a broad-spectrum triazole antifungal used to treat invasive fungal infections. It is commonly used prophylactically in immunocompromized patient cohorts, including transplant recipients. Diffuse periostitis is a very rare complication of chronic voriconazole use. It is associated with diffuse bone pain, elevated serum alkaline phosphatase and fluorine levels. Characteristic imaging findings include periosteal thickening with a dense, nodular, irregular and often bilateral pattern. We describe the case of a 71-year-old female who presented with multifocal bone pain six years following double lung transplantation. Her post transplantation course had been complicated by a life threatening episode of sepsis secondary to Scedosporium apiospermum, a rare invasive fungal infection following which lifelong prophylaxis with oral Voriconazole was commenced. We discuss the characteristic clinical and imaging manifestations of this rare condition. A 71-year-old female presented with diffuse bone pain involving the shoulders and multiple ribs. On examination there was slightly reduced strength in both upper extremities, full although painful range of motion in the shoulder joints and diffuse tenderness at both shoulders and over multiple left-sided ribs. Her history was significant for double lung transplantation for emphysema six years previously. The post-transplantation course was complicated by severe sepsis due to Scedosporium apiospermum, a rare invasive fungal infection, requiring critical care admission. The patient was subsequently commenced on oral voriconazole as prophylaxis to mitigate against further fungal infection.). A diagnosis of voriconazole-induced periostitis was made based on these characteristic imaging appearances, in combination with the patient's history. This was supported by a significantly elevated serum alkaline phosphatase value of 220 U/L , a characteristic laboratory finding in voriconazole induced periostitis.Radiographs of the chest and shoulders were obtained . ChangesThe patient was commenced on an analgesic regime which resulted in significant symptom improvement. The possibility of discontinuing voriconazole prophylaxis was considered, but ultimately the significant benefit in terms of mitigation against fungal infection was considered to outweigh symptoms which were now well-controlled and the patient continued on lifelong voriconazole.Immunosuppression post-transplantation increases patients susceptibility to infection, which may be life-threatening. Voriconazole is commonly used in both the treatment and prophylaxis of fungal infections in organ transplant recipients.Frequently reported side effects of voriconazole include nausea and vomiting, visual disturbances, rash, abnormal liver function tests, QT prolongation, headaches and hallucinations. In 2009 the first cases of voriconazole induced periostitis were reported in 5 lung transplant patients receiving long-term prophylactic treatment with voriconazole Voriconazole is a tri-fluorinated compound. Several studies have shown that this increased fluoride level may play a role in the mechanism of how voriconazole causes periostitis Characteristic imaging features of periostitis include periosteal thickening, with new bone formation which tends to be dense and irregular. This is generally bilateral but may be asymmetric. Nuclear medicine imaging techniques such as bone scintigraphy or single photon emission computed tomography (SPECT) demonstrate radiotracer uptake at affected sites. The differential diagnosis for periostitis is broad, including entities such as hypertrophic osteoarthropathy, hypervitaminosis A, venous stasis and infection. The patient's clinical history (as well as the distribution of periositis) are crucial to accurate diagnosis.Voriconazole induced periostitis typically resolves following medication discontinuation (or in some cases dose reduction) In summary, though uncommon, voriconazole-induced periostitis is an important diagnosis for radiologists to be aware of in the post-transplant or otherwise immunocompromized patient. Accurate diagnosis requires assimilation of the relevant imaging characteristics and patient history.Informed consent has been obtained for the publication of this case report.None."}
+{"text": "This multicenter care innovation program wassupported by a Centers for Medicare & Medicaid Services (CMS) Health CareInnovations Award. It includes transitional care nurses (TCNs) and social workers (SWs)who staff the GEDI WISE level 1 GEDs and conduct geriatric assessments , engage in conversationsabout goals of care, and assist with care coordination.JAMA Network Open, Hwang et al3 measured the cost savings associated with TCN orSW evaluations at GEDI WISE sites. Using entropy balancing, they compared the totalMedicare costs for 30 and 60 days after the index ED visit among an intervention groupof fee-for-service Medicare beneficiaries who received a TCN or SW evaluation and acontrol group of fee-for-service Medicare beneficiaries who did not. Whereas the priorGEDI WISE studies evaluated the association of this care model with ED visits andhospital admission rates, in this study Hwang et al3 conducted a more comprehensive evaluation of costs of care bylooking at total Medicare costs\u2014including inpatient, outpatient, home health,hospice, and skilled nursing facilities claims. In doing so, they not only quantifiedthe cost savings related to avoidance of hospitalization and ED revisits but alsodetermined whether the cost savings were offset by increased care costs related to homehealth referrals or transfer to skilled nursing or acute rehabilitation facilities.Hwang et al3 found that after entropybalancing, patients who received the TCN or SW intervention had a mean 30-day savings of$2436 per beneficiary at 1 site and $2905 per beneficiary at the other site. The costsavings persisted at 60 days, with a mean savings of $1200 at 1 site and $3202 at thesecond site.Elsewhere in This study provides important evidence demonstrating the cost efficiency of thisenhanced care model for geriatric emergency care. Evidence that higher-quality models ofcare, such as GEDs, can reduce health care costs should catalyze the adoption of thesemodels. This is more likely to happen when the savings generated benefit the entityshouldering the costs. However, in the GEDI WISE program, the savings went to the payer,in this case Medicare, while the costs of sustaining this intervention beyond thegrant-funded period were borne by the hospitals. Asking hospitals to spend their ownmoney to save Medicare money is unlikely to be sustainable. Growth of this care modelrequires that health care systems also benefit financially from the cost savings.6 In these advanced ACO reimbursement models, theorganization receives additional revenue when savings are generated and quality of careis maintained or improved. Another mechanism for funding advanced geriatric emergencycare models is through collaboration with Medicare Advantage plans, given that theseplans benefit from reducing costs while improving quality of care. Health care systemsshould collaborate with ACOs and/or their local Medicare Advantage plans whenimplementing a GED model of care because these parties all stand to benefit from thesavings demonstrated in this study.The traditional way Medicare has incentivized individual clinicans, hospitals,and health care systems to adopt new services is to directly pay for it\u2014allowingclinicians and health care systems to submit bills for the services they have provided.While this is a mechanism that could be used to reimburse facilities for a TCN or SWconsultation or a similar GED care model, creating new billing codes is an arduous andprolonged process and not likely to create additional revenue for GEDs anytime soon. CMSis encouraging the adoption of value-based care models in which organizations  financially benefit from providing high-value care.CMS is accomplishing this by encouraging organizations to take on financial risk formanaging patient populations in risk-sharing Accountable Care Organization (ACO) models.These models hold organizations responsible for financial risk if they provide low-value care to their patient populations.7 Wemust consider how geriatric care models developed in large academic EDs in metropolitanareas can be disseminated to small EDs in rural locales. Telehealth is an obviousanswer. Through a telehealth platform, a single TCN or SW could conduct consultationsacross multiple EDs, improving efficiency and expanding access to this care model.Home-based care alternatives are another option that is cost saving for payersand revenue generating for hospitals. Instead of admitting an older adult with complexcare needs to the hospital, a GED could admit that patient to a hospital-at-home programor leverage telehealth and/or remote monitoring programs for follow-up. Telehealth mayalso be a viable solution for disseminating GED models of care across the United States.While the GEDI WISE sites are level 1 GEDs in large metropolitan areas, at least 18% ofolder adults reside in rural areas.The next phase of research into models for geriatric emergency care must examinethe association of GEDs with carefully selected, patient-centered outcomes that mattermost to older adults. This research may include evaluation of GED care models onphysical functioning, cognition, and quality of life. For instance, does avoidance ofhospitalization through the GED model of care result in improved physical activity andprevent functional decline? Will GED models of care prevent delirium in older adultswith acute medical care needs? Do GED initiatives improve quality of life in olderadults requiring emergency care? Quality of life is a measure that encompasses anindividual\u2019s physical, mental, emotional, and social functioning and could serveas a composite patient-oriented outcome in future studies evaluating the consequences ofgeriatric emergency care innovations.Now that the cost savings of enhanced geriatric emergency care are clear, we needto consider how we can leverage payer models to increase adoption of these programs anddisseminate them to nonmetropolitan areas. We also need to conduct robust research toevaluate the association of GEDs with outcomes among older adults using apatient-centered approach and focusing on what matters most to this population. Throughthis framework, we can increase access to high-quality, cost-effective,geriatric-centric emergency care in the United States for older adults."}
+{"text": "The development of antimicrobial drug resistance has encouraged scientists to develop alternate methods to combat infectious pathogens associated with dental diseases. Therefore, it is of interest to predict interactions for catechin (a plant derivedcompound) with protein targets in the red complex pathogens using computer aided network tools. However, in vitro and in vivo studies are warranted to confirm the antimicrobial effect of catechin  andgallolyl catechins) on the dental pathogens. Drug resistance to pathogens has reached alarming numbers in recent times. A global burden of antibiotic resistant organisms in the community as well as hospital settings is seen due to indiscriminate use of antibiotics. Oral micro flora is a complexenvironment wherein there is interplay between host and pathogens causing infectious diseases. Several pathogens of the oral cavity such as Enterococcus faecalis, Streptococcus mutans etc. are known to contain proteins responsible for drug resistant phenotypes,2. SelecThe mechanism underlying the anti-microbial activity of catechin against red complex pathogens is investigated using available computer aided predictive tools.The strains of red complex pathogens sich as Porphyromonas gingivalis ATCC 33277, Treponema denticola ATCC 35405 and Tannerella forsythia ATCC 43037 available in the STITCH database were selected for the analysis  virulence factors; (2) information and storage processing; (3) cellular process and (4) metabolism. The virulence factors are identified using a support vector machine (SVM)algorithm, which classifies proteins based on their amino acid composition and sequence pattern .VirulentPred is a yet another SVM based method, used for automated prediction of virulent proteins based on the sequences . The scoCatechin is a major component of green tea known for its antioxidant, anti-inflammatory, anti-proliferative activities. Bai et al. has shown the antimicrobial activity of catechin against a canine dental pathogen . Itis oWe document the predicted interaction targets for catechin (a plant derived compound) with protein targets in the red complex pathogens using computer aided network tools. However, in vitro and in vivo studies are necessary to verify the antimicrobial effectof catechin  and gallolyl catechins) on the dental pathogens."}
+{"text": "Targeted anti-cancer therapies have revolutionised melanoma patient care; however, cures remain uncommon due to acquired drug resistance that results in disease relapse. Recent insights from the clinic and experimental settings have identified a key role for metabolic plasticity, defined as the flexibility to utilise different nutrients and process them in different ways, in both disease progression and response to targeted therapies. Here, we discuss how this plasticity creates a moving target with important implications for identifying new combination therapies.Resistance to therapy continues to be a barrier to curative treatments in melanoma. Recent insights from the clinic and experimental settings have highlighted a range of non-genetic adaptive mechanisms that contribute to therapy resistance and disease relapse, including transcriptional, post-transcriptional and metabolic reprogramming. A growing body of evidence highlights the inherent plasticity of melanoma metabolism, evidenced by reversible metabolome alterations and flexibility in fuel usage that occur during metastasis and response to anti-cancer therapies. Here, we discuss how the inherent metabolic plasticity of melanoma cells facilitates both disease progression and acquisition of anti-cancer therapy resistance. In particular, we discuss in detail the different metabolic changes that occur during the three major phases of the targeted therapy response\u2014the early response, drug tolerance and acquired resistance. We also discuss how non-genetic programs, including transcription and translation, control this process. The prevalence and diverse array of these non-genetic resistance mechanisms poses a new challenge to the field that requires innovative strategies to monitor and counteract these adaptive processes in the quest to prevent therapy resistance. Cancer cells must continuously reprogram their metabolism in order to maintain proliferation and survival in response to changes in the surrounding microenvironment. Metabolic reprogramming in cancer is therefore rarely static but instead a highly dynamic process that allows rapid adaptability. This demand for metabolic adaptability requires both the flexibility to utilise different metabolic substrates and the ability to process metabolic substrates in different ways . CollectMetastasis is the leading cause of all cancer-related deaths and involves the elaborate reprogramming of many distinct cellular processes that allows cellular extravasation and invasive dissemination, circulation, and subsequent colonisation of distant tissues by cancer cells . The metThe first clear evidence of metabolic plasticity in melanoma metastasis comes from an elegant study by Piskounova and colleagues using melanoma patient-derived xenotransplant (PDX) models . Using aFurther evidence supporting a role for metabolic plasticity during melanoma progression and metastasis comes from a study investigating the role of peroxisome proliferator-activated receptor \u03b3 coactivator \u03b1 (PGC1\u03b1), a master regulator of mitochondrial function . During Metabolic plasticity has also been linked with the development of site-specific melanoma metastases. Analysis of a large melanoma patient cohort identified significant upregulation of OXPHOS specifically in brain metastases when compared to patient matched extracranial metastases  Figure A. AnalysReprogrammed fatty acid metabolism has also been extensively linked with melanoma progression and metastasis . FurtherFlexibility in fuel usage has also emerged as a major factor that can facilitate melanoma metastasis. Melanoma cells of varying oncogenic backgrounds display highly glycolytic phenotypes in which 60\u201380% of glucose is converted to lactate, and this activity is enhanced to 90% or more in hypoxia . Using iThere is also clinical and experimental evidence supporting a role for alterations in lipid uptake in melanoma progression and metastasis. Analysis of melanoma patients in The Cancer Genome Atlas (TCGA) identified a gene signature that includes fatty acid uptake genes caveolin-1 (CAV1) and cluster of differentiation 36 (CD36), and the fatty acid oxidation (FAO) gene carnitine palmitoyltransferase 1C (CPT1C), that predicts for significantly worse overall survival . A clearOverall, these studies highlight the inherent plasticity of melanoma metabolism and how this can directly promote metastatic progression of disease. Importantly, these data also highlight that these events can occur independently from acquisition of new genetic events, indicated by the reversible nature of metabolome alterations observed in metastatic cells derived from different tissue origins. They also reveal the diversity of fuel sources melanoma cells can utilise to survive in different microenvironmental niches, another key feature of plasticity. As such, this inherent metabolic plasticity creates a moving target for therapeutic interventions and consequently poses a major challenge to effective therapy. Indeed, metabolic plasticity has emerged as a key feature of adaptive response and resistance to current standard-of-care oncogene targeted therapies for melanoma, and this aspect of metabolic plasticity in melanoma is discussed in detail below.V600 melanoma patients, and the Food and Drug Administration (FDA) has approved three combination therapies; dabrafenib/trametinib, vemurafenib/cobimetinib and encorafenib/binimetinib. Exceptional response rates and low toxicities are two major advantages of these targeted therapies over other anti-cancer therapies currently available in melanoma. However, despite their success in improving overall survival, persistence of a residual disease that eventually acquires resistance and drives disease relapse is a major barrier to achieving cures. Indeed, the dabrafenib plus trametinib combination in BRAF mutant melanoma patients has a 34% 5-year overall survival rate [Activating mutations in BRAF (V600) occur in approximately 40% of all melanoma patients and have led to the development of molecular targeted therapies directed against BRAF and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK), two kinases in the mitogen-activated protein kinase pathway (MAPK) . BRAF anHistorically, genetic drivers of resistance to targeted therapies have been the major focus, and more than 20 genetic mechanisms of acquired resistance have been identified in melanoma so far . The preGlucose is a major fuel source for melanoma, and in general, melanoma cells display an elevated glycolytic phenotype at the expense of oxidative mitochondrial respiration ,50,51. IV600 also regulates the microphthalmia-associated transcription factor (MITF), a melanocyte lineage transcription factor, which is a crucial determinant of the response to BRAFi. Treatment with BRAFi leads to MITF dependent regulation of PGC1\u03b1, which subsequently promotes mitochondrial biogenesis, OXPHOS and response to oxidative stress in BRAFV600 melanoma cells  tRNA (U34 enzymes) are key players of rewired protein synthesis observed upon resistance to MAPK targeted therapy in melanoma [34 enzymes promote glycolysis through direct translational regulation of HIF1\u03b1 mRNA that consequently maintains high levels of HIF1\u03b1 protein to facilitate reactivated glycolytic networks in MAPKi resistant melanoma cells. Together, these data clearly show a role for glucose metabolism in acquired resistance, in addition to its role in the early MAPKi response.In addition to glucose consumption being a useful biomarker of the early targeted therapy response in melanoma (discussed above), reactivation of glucose uptake and glycolysis has also been observed upon acquisition of BRAF inhibitor resistance. Following early suppression of glucose consumption upon treatment with the BRAF inhibitor vemurafenib, subsequent increases in glucose uptake as assessed using FDG uptake in treated tumours tightly correlated with emergence of resistance . Consistsistance , restorent cells . Translamelanoma . MechaniFurther to glucose, increased dependence on glutamine has also been demonstrated in cells with acquired resistance to single agent BRAF inhibitors , and theThe ability to utilise alternative fuel sources such as glutamine and lipids is concordant with elevated mitochondrial biogenesis and oxidative metabolism signatures identified in MAPKi resistant melanoma patients ,58. IndeAltogether, these studies highlight a key role for metabolic plasticity across all major phases of the targeted therapy response and development of resistance in melanoma.The inherent plasticity of melanoma metabolism and the flexibility to use diverse fuel sources provides a survival advantage necessary to colonise harsh microenvironments and survive inhibition of metabolic pathways. Consequently, this creates a moving target for therapeutic interventions and poses a major challenge to effective therapy. While some activity with single agents has been observed in preclinical models, metabolic inhibitors will likely be most useful in combination with current anti-cancer targeted therapies. Indeed, targeting mitochondrial oxidative metabolism in melanoma has been shown to cause metabolic compensation through both glucose and glutamine utilisation in mouse models . MoreoveStrategies that target multiple metabolic pathways at the same time have shown some success. As discussed above, co-inhibition of mitochondrial metabolism with MAPKi, which effectively suppresses glycolysis, can improve the response and overcome acquired resistance to targeted therapies ,55,57,58Targeting metabolic features of drug tolerant cells that persist following treatment with anti-cancer therapies also represents a therapeutic opportunity to overcome acquired resistance and tumour relapse. Further characterisation of SMC populations that transiently emerge following exposure to therapy in melanoma tumours may therefore prove useful therapeutically. If the SMCs are precursors to other drug tolerant cellular states , then idAnother approach that warrants further investigation is targeting regulatory pathways underpinning plasticity in the metabolic network, and the available data suggests this occurs at the transcriptional and translational level. An extensive list of transcription factors has been directly linked with metabolic plasticity during melanoma metastasis and adaptive resistance to MAPKi . However, in general, therapeutically targeting transcription factors remains a challenge, and most efforts in melanoma have been directed at targeting downstream activated pathways (see above). Targeting translational mechanisms may offer an alternative approach, and multiple aspects of selective and global mechanisms of translational regulation are under investigation and have proven useful in preclinical settings. Silvestrol is a naturally occurring member of the flavagline family of compounds that inhibits cap-dependent translation by targeting eIF4A ; howeverA growing body of evidence now highlights the inherent plasticity of melanoma metabolism and how this can directly promote metastatic progression of disease and response to anti-cancer therapies. Importantly, adaptive metabolic reprogramming can occur independently from acquisition of new genetic events. This is indicated by the reversible nature of metabolome alterations observed in metastatic cells derived from different tissue origins and in melanoma cells that show transient and reversible activation of metabolic pathways as they acquire therapy tolerance and resistance. These studies also reveal the diversity of fuels melanoma cells can utilise to survive in different microenvironmental niches during both metastasis and response to anti-cancer therapies, which is another key feature underpinning metabolic plasticity. Targeting metabolic plasticity is therefore predicted to have therapeutic benefit in melanoma patients; however, the maximal benefit is likely to be achieved by combining therapies directed against metabolic plasticity with current anti-cancer therapies directed against MAPK signalling. Moreover, because plasticity creates a moving target for therapeutic interventions, an attractive approach would be to exploit the specific regulatory molecules that facilitate plasticity in the metabolome."}
+{"text": "Thermal therapies such as radiofrequency ablation (RFA) are gaining widespread clinical adoption in the local treatment of skeletal metastases. RFA has been shown to successfully destroy tumor cells, yet the impact of RFA on the quality of the surrounding bone has not been well characterized. RFA treatment was performed on femora of rats with bone metastases (osteolytic and osteoblastic) and healthy age matched rats. Histopathology, second harmonic generation imaging and backscatter electron imaging were used to characterize changes in the structure, organic and mineral components of the bone after RFA. RFA treatment was shown to be effective in targeting tumor cells and promoting subsequent new bone formation without impacting the surrounding bone negatively. Mineralization profiles of metastatic models were significantly improved post-RFA treatment with respect to mineral content and homogeneity, suggesting a positive impact of RFA treatment on the quality of cancer involved bone. Evaluating the impact of RFA on bone quality is important in directing the growth of this minimally invasive therapeutic approach with respect to fracture risk assessment, patient selection, and multimodal treatment planning. Skeletal bone metastases occur in one third of all cancer  with freIn its use, a radiofrequency (RF) generator supplies an alternating current to a probe inserted into the tissue to be treated. Frictional heat induced by the electric current creates a thermal ablation zone. The RF circuit may be completed using grounding pads in unipolar designs  or with RFA leads to a coagulative necrosis within seconds to minutes and distinct defined tissue changes are visible after RFA dose delivery . TypicalArchitecture and tissue level material properties of bone impact its strength and are regulated through the mineral  and organic (primarily collagen) components of their ultrastructure \u201316. The In the organic component of bone tissue, the distribution and orientation of collagen type I fibrils are responsible for bone\u2019s ductility and toughness . The recPrevious work by our group demonstrated different effects of various types of metastases on rat bone quality , 29\u201331. Foxn1rnu rats  through intracardiac injection under general inhalation anaesthesia. The intracardiac injection of luciferase transfected human ZR-75-1 (ATCC\u00ae CRL-1500\u2122) breast cancer cells resulted in the development of osteoblastic metastases within 56 days. Intra-cardiac injection of 1.5 x 106 luciferase transfected HeLa cells . Th. Th38]. BMDD of healthy and metastatic bone is modified post-RFA. In healthy bone, regardless of the age of the model (Day 21 or Day 84), average mineral content is unchanged post-treatment. However, younger healthy bone (Day 21), demonstrates greater heterogeneity post treatment which may be due to the shorter recovery period. In the osteolytic bone metastases model, due to the aggressive nature of tumor growth, longer observation periods are not possible. In comparison to older healthy bone (Day 84), which is monitored for 28 days post-treatment and hence undergoes several remodeling cycles; age-matched younger healthy bone (Day 21) is only monitored for 7 days post-treatment  . SeveralPost-RFA treatment, osteoblastic bone tissue demonstrated an enhanced mineralization profile with improved homogeneity. Higher mineralization values (CaPeak) and elevated mineral content (CaMean) are observed post-RFA . It is eOur earlier work evaluating bone quality secondary to skeletal metastatic involvement has considered Raman spectroscopy in addition to SHG and BSE to assess changes in bone quality in pathologic vertebrae . In thisIn this study, the impact of RFA on the mineral and organic components of healthy and metastatic bone were assessed. In the context of skeletal metastases, RFA resulted in a more homogenous bone tissue by replacing the diseased bone with more mature, highly mineralized bone. RFA treatment was shown to be effective in targeting tumor cells and promoting subsequent new bone formation. RFA did not negatively impact healthy bone tissue. The positive impact of RFA on bone quality in metastatically involved bone is important in directing the utilization of this growing local minimally invasive therapeutic approach with respect to fracture risk assessment, patient selection and multimodal treatment planning."}
+{"text": "Mobility, physical activity and social engagement are important to healthy aging and independent living among older adults. This symposium includes four related studies on these issues. Dr. Lien Quach and her team examined racial and ethnic disparities in social engagement among community-living older adults using data from the national Health and Retirement Study. The analysis found that Asians and Hispanics had significantly lower social engagement score compared with non-Hispanic Whites, advocating for further investigations of the causes of racial disparities in social engagement. Dr. Su-I Hou\u2019s study examined the impact of physical activity and social relationship on social engagement. The study found positive impacts of more physical activity, better social relationships and volunteers on social engagement. The results have important implications to promotion of social engagement among older adults participating in aging-in-community programs. Dr. Ladda Thiamwong\u2019s study demonstrated the benefits of using assistive health technology (AHT) to assess the relationships between fall risks, body compositions and objectively measured physical activity in older adults. Dr. Thiamwong\u2019 will discuss the research protocol and preliminary results. Dr. Li\u2019s Health Aging and Neighborhood Study examined variations of older adults\u2019 driving behaviors by sex, age, race, income, health status and housing density of the neighborhoods. The study found substantial differences in mobility and driving patterns by both personal characteristics and neighborhood living environment. The findings have important implications to community programs that support older adults aging in place."}
+{"text": "Although researchers have identified medications that relieve symptoms of Multiple Sclerosis (MS), none are entirely effective and some persons with multiple sclerosis (PwMS) use alternatives. Our study compared cannabis use among PwMS (N=135) and persons diagnosed with arthritis (N=582) or cancer (N=622) who participated in the Illinois medical cannabis program. We tested for significant differences across psychological well-being, quality of life and three behavioral outcomes, and also considered effects of co-occurring prescription opioid use. A majority of all individuals used cannabis to address pain and improve quality of sleep. PwMS reported lower levels of productivity, exercise and social activity, and cannabis was less helpful with improving these particular outcomes. Most persons used cannabis for sleep or digestive problems and we found no differences across groups in terms of well-being and quality of life. This comparative evaluation suggests cannabis mechanisms are not specific as much as they impact common processes."}
+{"text": "Previous research suggests a decline in body mass index (BMI) among older adults is associated with negative health outcomes, including mild cognitive impairment (MCI) and incident dementia . However, few studies have examined BMI longitudinal trajectories and how they change after MCI diagnosis among older African Americans. To characterize trajectories of change in BMI among older African American participants with no cognitive impairment at baseline we used data from the Minority Aging Research Study, MARS . We constructed piecewise linear mixed-effects models that included a random intercept and two random slopes. The first slope began at baseline. The second slope began at MCI diagnosis allowing for acceleration in the rate of decline after the diagnosis. The results showed BMI declined over time , and there was a faster decline after MCI . In a second model controlling for age, higher education was associated with a lower BMI at baseline  but slower decline before MCI . However, after MCI the decline of participants with higher education was faster . These results suggest an accelerated decline in BMI following MCI diagnosis, with higher education related to an even faster BMI decline, possibly a consequence of cognitive reserve."}
+{"text": "Humans require a plethora of higher cognitive skills to perform executivefunctions, such as reasoning, planning, language and social interactions, whichare regulated predominantly by the prefrontal cortex. The prefrontal cortexcomprises the lateral, medial and orbitofrontal regions. In higher primates, thelateral prefrontal cortex is further separated into the respective dorsal andventral subregions. However, all these regions have variably been implicated inseveral fronto-subcortical circuits. Dysfunction of these circuits has beenhighlighted in vascular and other neurocognitive disorders. Recent advancessuggest the medial prefrontal cortex plays an important regulatory role innumerous cognitive functions, including attention, inhibitory control, habitformation and working, spatial or long-term memory. The medial prefrontal cortexappears highly interconnected with subcortical regions  and exerts top-down executive control over various cognitivedomains and stimuli. Much of our knowledge comes from rodent models usingprecise lesions and electrophysiology readouts from specific medial prefrontalcortex locations. Although, anatomical disparities of the rodent medialprefrontal cortex compared to the primate homologue are apparent, current rodentmodels have effectively implicated the medial prefrontal cortex as a neuralsubstrate of cognitive decline within ageing and dementia. Human brainconnectivity-based neuroimaging has demonstrated that large-scale medialprefrontal cortex networks, such as the default mode network, are equallyimportant for cognition. However, there is little consensus on how medialprefrontal cortex functional connectivity specifically changes during brainpathological states. In context with previous work in rodents and non-humanprimates, we attempt to convey a consensus on the current understanding of therole of predominantly the medial prefrontal cortex and its functionalconnectivity measured by resting-state functional MRI in ageing associateddisorders, including prodromal dementia states, Alzheimer\u2019s disease,post-ischaemic stroke, Parkinsonism and frontotemporal dementia. Previouscross-sectional studies suggest that medial prefrontal cortex functionalconnectivity abnormalities are consistently found in the default mode networkacross both ageing and neurocognitive disorders such as Alzheimer\u2019sdisease and vascular cognitive impairment. Distinct disease-specific patterns ofmedial prefrontal cortex functional connectivity alterations within specificlarge-scale networks appear to consistently feature in the default mode network,whilst detrimental connectivity alterations are associated with cognitiveimpairments independently from structural pathological aberrations, such as greymatter atrophy. These disease-specific patterns of medial prefrontal cortexfunctional connectivity also precede structural pathological changes and may bedriven by ageing-related vascular mechanisms. The default mode network supportsutility as a potential biomarker and therapeutic target for dementia-associatedconditions. Yet, these associations still require validation in longitudinalstudies using larger sample sizes. Jobson et al. convey that the medial prefrontal cortex functional connectivity inman exhibits disease-specific alterations across dementia associated disorders.These abnormalities appear to precede structural changes and may be driven byageing-related vascular mechanisms. This mainly affects the large-scale defaultmode network, thus providing potential biomarkers and therapeutic targets.  Greater understanding of the significance of the prefrontal cortex (PFC) is probablyowed to the serendipitous discovery after the unusual accident suffered by PhineasGage in 1848. The iron-tamping rod he had used on the railroad had pierced throughhis orbitofrontal lobe and changed him forever from once a respectable family manquickly into an ill-tempered irrational individual. We now know that a plethora ofhigher cognitive skills in order to perform crucial executive functions, such asreasoning, planning, language and social interactions, are regulated predominantlyby the PFC which contains the orbitofrontal region.Brodmann gave the first topographical description of the \u2018frontal\u2019 and\u2018precentral\u2019 regions of the primate frontal lobe, which possessed adefinitive granular pyramidal layer IV as a prominent characteristic. Although theanterior cingulate cortex (ACC), which contains agranular   needed to performvarious complex cognitive tasks.,Electrophysiological evidence in rodents recording multiple single cells usingtetrodes has equally resulted in a mixed picture of changes in neuronal ensemblefiring rates and patterns in that only a few mPFC neurons discharge spatialworking memory transient signals differently during delay periods of maze tasks,with some cell assemblies predicting spatial locations.Non-human primate studies have instead largely suggested the dlPFC is essentialfor working memory, as early influential lesion studies exhibited evidence thatdlPFC damage, particularly involving the principal sulcus  is a key executivefunction mediated by the PFC and can be defined as the ability to adaptbehaviour with changing environmental contingencies.,Set-shifting ability is typically assessed in the clinic by utilizing theWisconsin Card Sorting Test (WCST), which ultimately involves a shiftingresponse by the individual switching their attention between variable perceptualcategories based upon changing card-sort rules.,Set-shifting procedures have additionally been modified for testing ofstructure\u2013function relationships in rodents with substantial similarityto non-human primates. For example, Birrell and Brown designed a seminalset-shifting task for rats, which included extra-dimensional, intra-dimensionaland reversal learning stages akin to the monkey version. However, findings inrats were different from those in monkeys because mPFC lesions demonstratedsimilarly impaired extra-dimensional set-shifting, whilst ACC lesions impairedintra-dimensional set-shifting.,Human studies assessing cognitive flexibility processes have largely implicatedsimilar PFC subregions compared to the animal literature, thus emphasizing thesuitable translatability of the models. Specifically, individuals largely withdlPFC and mPFC damage have reported difficulties performing set-shifting duringthe WCST, such as inabilities to switch to a new rule as well as random andperseverative errors.,,,,,,Lesion studies of the mPFC have also been shown to play a role in impairedreversal learning, specifically when rodents are presented with complex imagesusing touchscreens.,,,,As with other domains of executive function, attention is a complex cognitiveprocess with various components that seem to depend on differing PFC subregions.Attention enables the brain to allocate sensory resources efficiently for theimmediate goal whilst ignoring alternative irrelevant inputs.The apparent agreement of findings from rodents to humans is perhaps undeniableas the 5-CSRTT was initially developed by Carli et al.,,It has been debated over several years whether rodent mPFC studies are relevant todefine human dlPFC functions, whilst others have suggested that rodent mPFC mightbetter represent the ACC.,Animal behavioural tasks of cognition adapted from human versions have enableddetailed investigation of brain areas by utilizing naturalistic paradigms. However,limitations arise if factors are not controlled such as food restriction, lack ofmotivation, susceptibility to stress and malaise or sense/locomotor impairments,which may be apparent for the prior studies analysing executive functions. Beforeanimals perform behavioural tasks, it may therefore be necessary to ensure that theycritically assess the cognitive function under investigation precisely, asexemplified by modified T-maze or operant procedures developed for working memory orcognitive flexibility respectively.,,In man, there is a clear deterioration in cognitive function during normal ageing,often with an observable reduction in information processing speed, which is notdependent on executive functioning.Studies utilizing rodent models have thus not only suggested that mPFC cognitivefunctioning is substantially affected by ageing in seemingly complex ways but haveadditionally aided in elucidating the underlying pathophysiology ofageing-associated neurological disorders that are susceptible to dementia.Specifically, authors demonstrated with a photothrombosis model   that revealed significant differences between ageing anddementia-associated disorders in terms of mean connectivity to brain regionsinvolving the mPFC. The current data present 41 published studies totalling 2473subjects with an average of 60 per study . The mos,There is a consistent decrease in mPFC\u2013PCC FC in healthy aged individuals. Althoug,,,Furthermore, the PCC-insula reduced FC association has been positively correlatedto cognitive tests including those for executive function, along with decreasedFC with ageing in ACC connections to the insula as part of the salience network , which is predominantly characterized by executivedysfunction. Indeed, svMCI subjects exhibit significant declines in numerousDMN-associated regions compared to controls, which may result structurally fromsubcortical WM lesions that directly and indirectly impair fibre tractsessential for transmitting cerebral FCs. These regions specifically include thePCC/precuneus, mPFC, ACC, hippocampus, parietal cortices and superior frontalgyrus/middle frontal gyrus.,,,Approximately 30% of elderly stroke survivors develop delayed dementia(known as post-stroke dementia), with most cases closely resembling criteria forVaD diagnosis.,,,,However, lowered mPFC/ACC-precuneus FC was conversely demonstrated by utilizingsimilar group ICA/region-of-interest methodologies and rather reflects theimpact upon structural damage facilitating cognitive disturbances as adisconnection syndrome.,,Parkinson\u2019s disease as a neurodegenerative disorder is typicallycharacterized by progressive motor dysfunction, but patients also show cognitivedecline with executive deficits, memory impairment and often dementia inadvanced stages.,,,However, similar disparities in trends as demonstrated in the prior vascularstudies, are prevalent within the Parkinson\u2019s disease studies. As mPFC FCchanges compared to controls did not appear in two studies, which instead onlyshowed significant FC decreases that associated with cognitive performance orlower GM volume  structurally between the precuneus/PCC and subcortical/motor areas ormedial temporal gyrus.,,Despite stringent Parkinson\u2019s disease clinical criteria, there remains asubstantial misdiagnosis rate with atypical Parkinsonian disorders (APDs), suchas multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), eventhough APDs account for 10\u201320% of Parkinsonism subjects.The most common form of FTD is the behavioural variant, which has previously beenshown to account for approximately half of all frontotemporal lobar degeneration. Learning and plasticity are supported and shaped byneurotransmitter systems in the brain. Cholinergic neurotransmission playsimportant roles in synaptic plasticity, glial remodelling and the regulation ofinflammation. In addition, dopamine, and tonic GABAergic signallingNevertheless, it is still arguably difficult to ascertain confidently that the FCdysfunctions  are valiThe role of the mPFC within cognition, ageing and dementia is diverse, yet seeminglyfundamental for a range of critical cognitive operations. Animal work utilizinglesions and electrophysiology paired with behavioural tasks has refined ourunderstanding by demonstrating precise mPFC subregions perform distinct executivefunctions. However, much of the equivalent rodent functions lack direct anatomicalhomology to primates, which implicates the lPFC instead. Such a disparity mayreflect inconsistencies in mPFC terminology across studies as well as inadequaciescontrolling cognitively influential factors; therefore, further clarification of PFCterminology and rs-fMRI methodologies across the field is likely necessary.Moreover, rodent models of ageing have exhibited substantial decline in the abilityto perform tasks assessing mPFC-related executive functioning. Whilst rodent modelsof dementia-associated pathophysiological processes in PIS, VaD as well asadditional neurodegenerative disorders have distinguished crucial inabilities toperform several behavioural paradigms tasking the mPFC. Studies examininglarge-scale brain connections have comprehensively shown that the mPFC\u2019slinks to heteromodal brain areas are integral for effectively coordinating numerousyet explicit cognitive paradigms, with the DMN exemplifying an extensively reportedinterconnectivity network that contains the mPFC as one of its central nodes.Existing rs-fMRI studies implicate mPFC FC variances during ageing anddementia-linked conditions between pairwise regions and globally within large-scalenetworks. Aberrations involving the DMN anterior and posterior sub-systems have beenpersistently reported across disorders, along with distinct patterns ofneuropathological changes that may preclude structural defects and subsequentcognitive deterioration. In addition, some findings remain uncertain within thedisorders due to methodological or sample inconsistencies, future validation couldthus enable translation into effective biomarkers for earlier diagnosis ortherapeutic intervention against pathological cognitive decline.Accordingly, future work is essential for deciphering if the identified trends ofreorganized FC intensity across disorders remain by replicating the rs-fMRIprotocols whilst utilizing larger cohort sample sizes, which likely would remove anyconfounding effects of detected chance observations. Future rs-fMRI studiestargeting the mPFC should also be conducted upon a longitudinal basis, which wouldenable a clearer understanding of how the disorders progressively worsen cognitionthrough modifying mPFC FCs over the entire clinical course of an individual\u2019slifetime. This would clarify the remaining knowledge gap concerningstructure-functional relationships and if FC changes definitively precede or evenaugment atrophy of the GM and WM tract changes, thereby further elucidating theunderlying pathophysiological sequalae of these disorders. Moreover, conductingfuture rs-fMRI studies that focus specifically upon the impact of ageing anddementia-associated disorders within PFC-associated networks other than the DMNwould better clarify how this important region is more broadly affected. Perhaps,future studies should also have a closer selection of individuals with comparablecognitive performances and clinical features that may further remove any patientheterogeneity effects responsible for divergent results. Detailed biochemical andmolecular biology assessment of circuit-level receptors responsible mechanisticallyfor the mPFC connectivity alterations would be most helpful, perhaps through use ofagonists/antagonists targeting these receptors within rodent models, thereby furtherenabling the elucidation of refined pharmacological targets as a therapeuticintervention. Ultimately, use of network-based techniques may reconcile differencesthat remain within the field of mPFC cognitive function across species from a globalintegrated perspective by surveying the entire PFC and brain as a whole. Suchdeductions are particularly important considering the FCs between the mPFC withextra-frontal areas including the dlPFC are consistently implicated as necessary forcognition within both health and disease states.Data sharing is not applicable to this article as no new data were created oranalysed. The summarized data incorporated in the review are however available inBrain Communications online.This work was supported by previous grants from the Alzheimer\u2019s Research UK(ARUK PG2013\u201322) and Medical Research Council, UK .The authors report no competing interests.fcab125_Supplementary_DataClick here for additional data file."}
+{"text": "Background Despite the development of geriatrics surgery process quality indicators (QIs), few studies have reported on these QIs in routine surgical practice. Even less is known about the links between these QIs and clinical outcomes, and patient characteristics. We aimed to measure geriatrics surgery process QIs, and investigate the association between process QIs and outcomes, and QIs and patient characteristics, in hospitalized older vascular surgery patients. Methods This was a prospective cohort study of 150 consecutive patients aged \u2265 65 years admitted to a tertiary vascular surgery unit. Occurrence of geriatrics surgery process QIs as part of routine vascular surgery care was measured. Associations between QIs and high-risk patient characteristics, and QIs and clinical outcomes were assessed using clustered heatmaps. Results QI occurrence rate varied substantially from 2% to 93%. Some QIs, such as cognition and delirium screening, documented treatment preferences, and geriatrician consultation were infrequent and clustered with high-risk patients. There were two major process-outcome clusters: (a) multidisciplinary consultations, communication and screening-based process QIs with multiple adverse outcomes, and (b) documentation and prescribing-related QIs with fewer adverse outcomes. Conclusions Clustering patterns of process QIs with clinical outcomes are complex, and there is a differential occurrence of QIs within older vascular surgery patients, suggesting process QIs alone may be unreliable targets for quality improvement. Prospective intervention studies are needed to understand the causal pathways between process QIs and outcomes to help prioritize care processes that are most clearly linked to improved outcomes."}
+{"text": "This session will provide updates on how the pandemic led to horrific situations in long-term care facilities and how the pandemic influenced major federal efforts to address elder abuse, neglect, and exploitation."}
+{"text": "Peripheral arterial disease (PAD) is a vascular condition disproportionately affecting adults > 60 and the leading cause of disability for adults > 50. Because PAD is marked by severe leg pain and sometimes lower extremity amputation, quality of life (QOL) and wellbeing may be compromised however, we understand little about these constructs in this population. Furthermore, surgical care providers lack a comprehensive understanding of how individuals think about wellbeing and what is important to individuals during surgical care. We conducted a qualitative photographic elicitation study (n = 60) in one academic multidisciplinary PAD clinic to understand specific aspects of QOL of older individuals with PAD. Guided by interpretive description, a methodology pioneered in nursing, we analyzed data within and across five clinical symptom severity categories to examine for QOL constructs, impact on everyday life, understanding of disease, and desired treatment. Results demonstrate that individuals do not fully understand PAD diagnosis or its implications . Disease-specific knowledge was prevalent among patients experiencing lower extremity amputation but those suffering from wounds or gangrene had limited understanding. Furthermore, patients\u2019 descriptions of QOL conflicted with the conceptualization of QOL in clinical practice and research. That is, many participants describe QOL based on activities they are capable of performing despite limitations. Results demonstrate the need for integrating gerontological knowledge into clinical care to improve quality of care for older adults."}
+{"text": "Pennisetum glaucum) is a staple cereal crop for semi-arid regions. Its whole genome sequence and deduced putative gene sequences are available. However, the functions of many pearl millet genes are unknown. Situations are similar for other crop species such as garden asparagus , chickpea (Cicer arietinum) and Tartary buckwheat (Fagopyrum tataricum). The objective of the data presented here was to improve functional annotations of genes of pearl millet, garden asparagus, chickpea and Tartary buckwheat with gene annotations of model plants, to systematically provide such annotations as well as their sequences on a website, and thereby to promote genomics for those crops.Pearl millet  counterparts identified by BLASTX. Conserved domains in protein sequences of those species were identified by the HMMER scan with the Pfam database. The resulting data was deposited in the figshare repository and can be browsed on the Terse Genomics Interface for Developing Botany (TGIF-DB) website (http://webpark2116.sakura.ne.jp/rlgpr/).Sequences of genomes and transcripts of pearl millet, garden asparagus, chickpea and Tartary buckwheat were downloaded from a public database. These transcripts were associated with functional annotations of their  Pennisetum glaucum) is a staple cereal crop for semi-arid regions. Its whole genome was sequenced and putative gene sequences were deduced [Asparagus officinalis), chickpea (Cicer arietinum) and Tartary buckwheat (Fagopyrum tataricum) [Arabidopsis thaliana and rice (Oryza sativa) are dicot and monocot model species, respectively, and have better functional annotations for each gene  sequences that were deduced from the genome sequences of pearl millet, garden asparagus, chickpea and Tartary buckwheat as well as genome annotation files in the general feature format (GFF) were downloaded from the International Pearl Millet Genome Sequencing Consortium (IPMGSC) website , the Asp Arabidopsis or rice.Some proteins of the species used do not appear to have conserved domains and/or any close homolog in eitherSome pearl millet genes have been characterized by targeted analyses (,3; for e"}
+{"text": "Research suggests that social resources positively influence the health and well-being of lesbian, gay, bisexual, and transgender (LGBT) aging adults, but their access to social resources may vary according to LGBT identity. Using data from Aging with Pride: National Health, Aging, and Sexuality/Gender Study , multivariate models tested how access to social resources varied by LGBT identity and whether the effect of LGBT identity showed additional variations by sociodemographic characteristics  among aging LGBT adults. Lesbian respondents had larger social networks than gay respondents, while gay respondents had smaller networks than transgender respondents. Lesbian respondents had more social support and community belonging than other identity groups. Bisexual male respondents and transgender respondents had less support than gay respondents and bisexual male respondents reported less community belonging than gay respondents. Education and age moderated the association between LGBT identity and social support. Findings highlight the importance of considering social support separately from social network size with the understanding that large social networks do not necessarily provide ample social support and this distinction was particularly relevant for transgender respondents who had larger social networks, but less social support than gay respondents. Results also suggest that feelings of LGBT community belonging vary among LGBT identity groups. Health and human service professionals should not only consider the sexual and gender identity of their aging LGBT clients, but also consider the clients\u2019 additional sociodemographic characteristics when assessing their access to social resources."}
+{"text": "Personal social networks play a fundamental role in the daily lives of older adults. Although many studies examine how life course factors and personal preferences shape network formation, fewer consider how the places in which older adults live present opportunities and obstacles to cultivate social relationships. In the present study, we explore how geographic context is associated with the ability to interact with non-overlapping social groups within one\u2019s personal network . This unique network formation offers older adults access to diverse social stimuli, non-redundant information, and social autonomy. By analyzing data from the Person-to-Person Health Interview Survey (N=709), we found that a minority of respondents reported the ability to bridge social groups within their networks. Respondents residing in rural and semi-rural counties engaged in fewer non-overlapping social groups compared to those residing in urban counties. These findings suggest that the communities in which older adults live condition opportunities for accessing unique social resources. Identifying the link between geographic residence and personal network structure has important implications for how individuals navigate the uncertainty and elevated support needs of later life. Additional research adopting a social network perspective is needed to provide insight into geographic health disparities occurring among the older population."}
+{"text": "Middle-aged and older adults with mental health conditions have a high likelihood of experiencing comorbid physical health conditions, premature nursing home admissions, and early death compared with the general population of middle-aged and older adults. An emerging workforce of certified older adult peer support specialists aged 50 years or above is one of the fastest growing mental health workforces and may be a suitable community-based workforce to simultaneously support the mental health, physical health, and aging needs of middle-aged and older adults with a serious mental illness. Older adult peer support specialists are people with a lived experience of aging into middle age and older adulthood with a mental health condition. This presentation will present three single-arm pilot studies examining how certified older adult peer support specialists\u2019 incorporate technology, including text messaging, ecological momentary assessments, and smartphone applications into practice and clinical outcomes among older adults with serious mental illness."}
+{"text": "Increasing research points to the relevance of educational attainment for positive emotional experiences and physical functioning across adulthood. However, little is known about how age-related developments in positive affect and physical functioning differ by educational attainment. This study used longitudinal data of 10,893 individuals (60\u201380 years) from the Health and Retirement Study to examine whether educational attainment moderates trajectories of positive affect and physical functioning and their interrelations over 12 years. Initial results from multiple-group bivariate growth models revealed that individuals with less formal education have lower positive affect and poorer physical functioning at baseline. There was, however, no evidence that longitudinal changes in positive affect, longitudinal changes in physical health, and coupled changes between both variables varied with educational attainment. These initial findings suggest that lower educational attainment is primarily related to lower levels of positive affect and physical functioning, but not to greater age-related declines or their interrelations."}
+{"text": "This symposium brings together four papers that address racial health disparities by investigating stressful aspects of social relations at different points in the life course. Cleary and colleagues focus on racial disparities in psychological health by testing cross-sectional effects of intergenerational stress over time. In particular, they investigate effects of network composition on the relationship between mothers' stressors and their children's depressive symptoms at three time points over 23 years. Camacho and colleagues use longitudinal data from the National Social Life, Health and Aging Project to examine cognitive decline among U.S. African-American, Latino, and White adults aged 60 and above. Results indicate loneliness predicted greater global cognitive decline over time in all groups. However, race differences in this association were found across cognitive function domains. Turner and colleagues consider dementia caregiving challenges among non-Hispanic Blacks. Data from five focus groups were analyzed to reveal distinctive challenges to caregiver health during the COVID-19 pandemic including increased burden and barriers to service access. Finally, Sol and colleagues examined the bidirectional association between loneliness and self-rated health over time among a racially diverse sample. Findings illustrate racial patterns in how loneliness at midlife influences health in later life. Antonucci will discuss the role of stress from social relations as a means to fully understand racial disparities in health across the life course."}
+{"text": "It remains challenging to quantify the pace of aging across lifespan due to lack of comprehensive longitudinal measurements across wide range of age. In Baltimore Longitudinal Study of Aging, we have measured the longitudinal trajectories of more than 30 phenotypes across four pre-identified domain - body composition, energy regulation, homeostatic mechanisms and neurodegeneration/neuroplasticity, among participants with age between 20+ and 90+. We implemented a two-stage approach to summarize the longitudinal trajectories of these phenotypes across four domains into a summarized score. We demonstrated that higher summarized score  is associated with slower decline in both cognitive and physical functions, across different stages of adulthood. Our results imply that deep longitudinal profiling contains rich information and may potentially replace diseases as an early endpoint in trials targeting at aging. Further, understanding the underpinning of longitudinal phenotypic trajectories may provide clues to the biological mechanisms of aging."}
+{"text": "Antiphospholipid syndrome is an antibody mediated pro-thrombotic state leading to various arterial and venous thromboses. The syndrome can be either primary or secondary to other autoimmune diseases, commonly systemic lupus erythematosus. Cardiac involvement, in particular valvular disease is common in patients with antiphospholipid syndrome, occurring in about a third of these patients. Valvular diseases associated with antiphospholipid syndrome often occur as valve thickening and non-bacterial vegetation or Libman-Sacks endocarditis. Deposits of antiphospholipid immunoglobulin and complement components are commonly observed in the affected valves, suggesting an inflammatory process resulting in valvular vegetation and thickening. Libman-Sacks endocarditis has a high propensity towards mitral valve, although haemodynamically significant valvular dysfunction is rare.We present a successful aortic valve replacement with cardiopulmonary bypass in a 48\u2009years old lady with antiphospholipid syndrome, who has severe aortic regurgitation as a result of Libman-sacks endocarditis. Antiphospholipid antibodies were positive and the clinical data showed both negative cultures and infective parameters. Surgically resected vegetations revealed sterile fibrinous and verrucous vegetations on aortic valve. Valve replacement and the course of cardiopulmonary bypass was uneventful, and the patient was discharged well.Classically Libman-Sacks endocarditis is often and more commonly associated with autoimmune diseases such as systemic lupus erythematosus, although it can occur in both primary and secondary antiphospholipid syndrome. It is not a common entity, and it is a frequent underestimated disease as most clinicians do not routinely screen for valvular lesion in patients with antiphospholipid syndrome unless they are symptomatic. However, due to its high prevalence of cardiac involvement, clinicians should have a high index of suspicion in the attempt to minimize cardiovascular and haemodynamic complications. Valve surgery in patients with antiphospholipid syndrome carries considerable early and late morbidity and mortality, usually caused by thromboembolic and bleeding events. The perioperative anticoagulation management and haemostatic aspect of antiphospholipid syndrome present an exceptional challenges to clinicians, surgeons, anaesthetists and laboratory personnel. Antiphospholipid syndrome (APS) is a rare coagulative disorder with antiphospholipid antibody mediated pro-thrombotic state mainly characterised by hypercoagulable complications. Cardiac manifestations of APS include arterial or venous thromboses, valve diseases, coronary artery disease, intracardiac thrombus, pulmonary hypertension and dilated cardiomyopathy, with the functional impairment of heart valves being the most common manifestation, which commonly associated with Libman-Sacks endocarditis. Libman-Sacks endocarditis, also known as non-bacterial thrombotic, verrucous, or marantic endocarditis, originally described in patients with systemic lupus erythematosus, is a well-known complication of APS. We present a successful aortic valve replacement in a 48\u2009years old lady with aortic valve Libman-sacks endocarditis and APS who presented with acute pulmonary oedema.A 48\u2009years old lady was admitted to cardiology ward complaining of progressively worsening breathlessness, orthopnoea and chest discomfort for 1\u2009month. Coexisting medical conditions include chronic hypertension on treatment, with 2 episodes of spontaneous miscarriages previously and 1 episode of transient ischemic attack 3\u2009years ago.Clinically, she was haemodynamically stable with a wide pulse pressure. Finger clubbing was noted with livedo reticularis rashes over bilateral upper and lower limbs without ulcers or thrombophlebitis. Her peripheral pulses were bounding with water-hammered pulse, and a grade III diastolic murmur was heard during cardiac auscultation. In addition, she has elevated jugular venous pressure, crepitation over both lung bases, and bilateral pedal oedema.2 was seen on aortic valve  and Erythrocyte sedimentation rate (ESR). Otherwise the reports were not suggestive of occult infection with normal white cell count, C-reactive protein (CRP), and negative blood cultures. D-dimer was positive but there was no features suggestive of deep venous thrombosis or pulmonary embolism. Further serological investigations revealed positive antinuclear antibody (1:640), Lupus anticoagulant (LA), anti-smith antibodies, direct and indirect coombs\u2019 test. Subsequent bone marrow aspiration and cytogenetic study showed a grossly normal specimen. She was thus treated as acute pulmonary oedema secondary to severe aortic regurgitation, precipitating by aortic valve vegetation with newly diagnosed antiphospholipid syndrome. Therapeutic enoxaparin therapy was initiated perioperatively.She underwent aortic valve replacement, and intraoperative exposure of aortic valve revealed verrucous thickening of aortic leaflets with vegetations involving all three cusps, with rolled edge on left coronary cusp. No perforation or destruction of cusp tissue was identified. A mechanical valve was implanted following the excision of aortic valve. The course of cardiopulmonary bypass was uneventful. Subsequent microscopic findings of the valve specimen confirmed the diagnosis of Libman-Sacks endocarditis Fig.\u00a0.Fig. 2EPostoperatively, oral anticoagulation therapy was started with international normalized ratio (INR) target of 2.5 to 3.5 with subcutaneous enoxaparin as bridging therapy. There was no excessive bleeding or major thromboembolic complications occurred during in-patient stay. Corticosteroid therapy was started at 2\u2009months postoperatively by Hematology team. She was well and free of complications at 6\u2009months and 1\u2009year follow-up. Clinical examinations and echocardiography demonstrated satisfactory aortic valve function. The microbiological culture of the excised vegetations revealed sterile specimens.Antiphospholipid syndrome (APS) is a multi-system disorder of autoimmune aetiology. This syndrome is defined clinically by arterial and venous thrombotic events as well as recurrent pregnancy loss, with serologically positive antiphospholipid antibodies including lupus anticoagulant (LA) and anticardiolipin antibodies (aCL). It was originally described and most often found in patients with systemic lupus erythematosus (SLE), however, even patients without features of autoimmune disease may harbour antiphospholipid antibodies and suffer from thromboembolic events, thus leading to the distinction of primary and secondary APS. APS affects 2% of population and SLE is found in 40% of patients with APS . The preAPS comprises a wide array of clinical features such as venous and arterial thromboses, recurrent pregnancy loss and even thrombocytopenia. Heart valve disease is the most common cardiac manifestation in patients with APS, and it is defined in the absence of rheumatic and infective endocarditis. It was reported as high as 32\u201338% of valvular lesion occur in patients with APS by transthoracic echocardiography , 5. WhenThe role of antiphospholipid antibodies in the pathogenesis of Libman-Sacks endocarditis remained unclear, probably the result of autoimmune antibodies being directed against the negatively charged phospholipids on the endothelial membranes, either due to micro injuries secondary to stress or turbulence, or induction of autoantibodies by molecular mimicry caused by infectious agents , 10. MicPatients with APS often present with thromboembolic events from other systems rather than cardiac manifestation, most commonly cerebrovascular ischemic events, which is apparent in this case study where patient had transient ischemic attack years ago. These thromboembolic episodes might be due to direct effect of antiphospholipid antibodies or intermittent dislodgement of Libman-Sacks vegetations. Majority of valvular impairment associated with Libman-Sacks endocarditis are mild with minor insignificant haemodynamic disturbance without clinically overt disease , 14. OnlDiagnosing Libman-Sacks endocarditis often necessitates the exclusion of rheumatic valve disease and infective endocarditis. Most clinicians do not routinely screen for valvular lesion in APS patients unless the patient is symptomatic or in the presence of new murmur. Recently, the international consensus committee has revised the definition of APS associated cardiac valve lesion with the following criteria: Coexistence of laboratory criteria of APS along with echocardiography detection of lesions, and/or regurgitation and/or stenosis of mitral or aortic valve, with the defining valve lesions of thickness more than 3\u2009mm, localized thickening involving the leaflet\u2019s proximal or middle portion, and irregular nodules on the atrial face of the edge of the mitral valve, and/or the vascular face of the aortic valve . HoweverUnlike infective endocarditis where the valve needs to be completely excised to remove infected tissue, repair and preservation of the valve is possible in selected patients with Libman-Sacks endocarditis, thus eliminating the need for lifelong anticoagulation therapy. The indications for surgery remain dispute, and the outcomes of surgical valvular replacement have been limited to case reports or series. However, we agreed on the clear indications for surgical intervention, which include severe valvular dysfunction, large vegetations and recurrent embolization despite therapeutic anticoagulation. Furthermore, non-bacterial thrombotic endocarditis may have much greater surgical risk for vegetation embolization than infective endocarditis due to the risk of thromboembolism . To dateAortic valve replacement is deemed necessary due to severe valvular regurgitation causing significant symptomatic ventricular dysfunction. The selection of mechanical valve in this case was based on the existing unavoidable need for lifelong anticoagulation therapy. A mechanical valve may be theoretically more advantageous over a tissue valve considering the younger age of patients at the time of surgery in regards to the risk of structural valve deterioration, and the need for lifelong anticoagulation. However, the use of tissue valve has increased progressively over the years to allow for easier and safer monitoring and management of anticoagulation therapy, with regards to prevention of thromboembolic events and bleeding complications, compounded by the complex monitoring of anticoagulation due to presence of antibodies, and the possible coexisting thrombocytopenia . This isIt is well recognized that patients with APS undergoing surgical valve replacement surgery with cardiopulmonary bypass are at much greater risk of thrombotic and bleeding episodes. Perioperative management of patients with APS undergoing cardiac surgery is a major concern and remains challenging due to significant risk of thrombosis with the cessation of anticoagulation therapy; as well as bleeding secondary to excessive anticoagulation or coagulation factor deficiency . FurtherLibman-Sacks endocarditis is not a common entity and is frequently underestimated as majority valvular involvement in patients with APS are asymptomatic and often diagnose incidentally. It is difficult to detect Libman-Sacks endocarditis, and the diagnosis often requires strong clinical suspicion with exclusion of more common valve lesions such as rheumatic or infective endocarditis. We hope that this case study is able to emphasize Libman-Sacks endocarditis as a cause of valvular heart disease not only in systemic lupus erythematosus, but also in primary APS. Early detection and prompt treatment of valvular disease in APS may halt the progression of valvular dysfunction since valve replacement surgery in APS carries significant perioperative morbidity and mortality."}
+{"text": "Twenty-eight states have provided nursing homes (NHs) with immunity from legal liability related to COVID-19. This study places these provisions in the context of prior actions protecting NHs from legal action and explores factors influencing the adoption of such immunity provisions across states. It uses cross-sectional data to examine patterns of policy adoption and to assess states\u2019 likelihood of adopting immunity provisions using multivariate methods. Variables of interest include information on state political, socioeconomic, programmatic, and COVID-19-related characteristics as well as data on campaign contributions and lobbying activity at the state level. Factors significantly related to NH immunity provision adoption included measures of state fiscal health (unemployment), ideology (percent legislators Democrat), governing capacity (unified government), and NH characteristics . Population density and Medicaid as a percentage of state general fund expenditures proved significant as well. Against these complex influences, organizations lobbying on behalf of NH residents and their families have found themselves ineffectual in creating avenues for accountability. Results indicate that enforcing accountability for NH deaths during the COVID-19 pandemic is a complex process, constrained by available policy tools and made more complicated by factors external to the NH environment that contributed to high death rates. Historically, the NH industry has been successful in avoiding consequences for poor quality care, a pattern that has persisted in that NHs have generally been successful in avoiding liability for negligence during the COVID-19 pandemic."}
+{"text": "Pregnant patients may present with multiple complex comorbidities that can affect peripartum management and anesthetic care. The preanesthesia clinic is the ideal setting for early evaluation of high-risk pregnant patients. Comorbidities may include cardiovascular pathology such as valvular abnormalities, septal defects, aortopathies, arrythmias and cardiomyopathies. Additional comorbidities\u00a0include pulmonary conditions such as obstructive sleep apnea as well as preexisting neuromuscular and skeletal disorders that may impact anesthetic management. Hematologic conditions involving both bleeding diathesis and thrombophilias may present unique challenges for the anesthesiologist. Patients may also present with endocrinopathies including diabetes and obesity. While not as common, high-risk patients may also have preexisting gastrointestinal conditions such as liver dysfunction, renal failure, and even post-transplant status. Ongoing and prior substance abuse, obstetric conditions such as placenta accreta spectrum disorders, and fetal conditions needing ex utero Intrapartum treatment also require advanced planning. Preanesthesia evaluations also help address important ethical and cultural considerations. Counseling patients regarding anesthetic considerations as well as addressing concerns will play a role in reducing racial and ethnic disparities. Anticipatory guidance by means of pre-anesthetic planning can facilitate multidisciplinary communication and planning. This can allow for an impactful and meaningful role in the care provided, allowing for safe maternal care and optimal outcomes. While caring for pregnant patients, current anesthesia guidelines emphasize the importance of a communication system between obstetric providers, anesthesiologists, and members of multidisciplinary teams .\u00a0Women aEarly evaluation of high-risk pregnant women in preanesthetic clinics can enable optimal care. Preanesthetic clinics facilitate comprehensive patient assessment and optimization and provide education regarding obstetric management and anesthetic options for labor and delivery . The AmeCardiovascular systemThe physiological changes of pregnancy can aggravate preexisting cardiac disease. Cardiovascular disease is a leading cause of maternal mortality. The severity of the maternal condition should not be underestimated and attributed to the \u201cnormal\u201d symptoms of pregnancy . A multiPatients with cardiac disease typically fall into the following broad categories-congenital versus acquired, valvular (stenotic versus regurgitant), septal or shunt lesions, pulmonary hypertension, ischemic heart disease, cardiomyopathies, aortopathies and arrythmias. Risk stratification models may be used to determine the best hospital for antenatal management and delivery ,34.\u00a0For Improvements in cardiac surgery have resulted in female babies with previously fatal congenital conditions surviving to reach sexual maturity .\u00a0AcquireThe effects of valvular disease in pregnancy vary based on several factors including type of lesion and severity. Ventricular dysfunction due to regurgitant valves can lead to heart failure and arrhythmias. Aortic regurgitation during pregnancy can be tolerated in the absence of left ventricular dysfunction. Stenotic valves are typically more concerning and when combined with the decreased systemic vascular resistance and increased blood volume in pregnancy, it can lead to syncope and congestive heart failure respectively. Echocardiographic measurement of valve areas is usually preferred to flow gradients during assessment since the latter can be expected to increase in pregnancy because of increased cardiac output and may not give as accurate an assessment  . Mitral Mortality due to pulmonary hypertension remains high during pregnancy despite advanced therapies. Vaginal delivery under appropriate analgesia is generally recommended. To avoid a rapid decrease in systemic vascular resistance that can cause cardiopulmonary decompensation, incremental epidural-only anesthesia with careful titration of local anesthetics is suggested, as general anesthesia with positive-pressure ventilation could increase pulmonary vascular resistance and right-to-left shunt .\u00a0GeneralHypertrophic obstructive cardiomyopathy is frequently inherited and presents with left ventricular outflow obstruction. Tachycardias, hypovolemia and vasodilatation are poorly tolerated. Peripartum cardiomyopathy is the development of heart failure in the last month of pregnancy or within five months of delivery . A smallFor patients with syndromic (e.g. Marfan\u2019s syndrome) and non-syndromic (e.g. ACTA2 gene mutations) familial aortopathies, monitoring blood pressure, symptomatology and surveillance imaging should be done throughout pregnancy to reduce risk of aortic dissections ,39. For Creation of a delivery plan, discussion of anesthetic and analgesic options, and discussion regarding invasive hemodynamic monitoring are part of the preanesthetic evaluation. Patients with severe left-sided obstructive heart disease including coarctation of the aorta and stenotic valvular lesions, pulmonary hypertension, and cardiomyopathies may have particularly poor outcomes and difficulty tolerating labor, surgery, and anesthesia -35. HighFor most cardiac patients, vaginal delivery remains the safest option, barring obstetric indications for cesarean delivery. Vaginal delivery is associated with decreased blood loss and hemodynamic changes and reduced risk of thrombosis and infection . A \u201ccardAnxiety and pain during labor can lead to increased afterload, decreased uteroplacental perfusion, and potential cardiovascular collapse. Neuraxial labor analgesia results in greater cardiopulmonary and hemodynamic stability and should be initiated as early as possible during labor.As mentioned, parturients with cardiac disease may require invasive monitoring that includes placement of arterial, central venous and pulmonary artery catheters and transthoracic echocardiography. Central venous access allows for infusion of vasoactive drugs . PulmonaRespiratory systemPregnant women with obstructive  or restrictive  lung diseases may be seen in the preanesthetic clinic .\u00a0Asthma The physiological changes of pregnancy worsen sleep-disordered breathing, a spectrum of conditions of increasing severity from loud snoring to obstructive sleep apnea (OSA). All obstetric patients should be assessed for OSA as it increases the risk of adverse maternal, fetal, and neonatal outcomes . If OSA Cystic fibrosis patients begin pregnancy with mixed obstructive and restrictive lung disease, often with chronic lower respiratory tract infections . PulmonaRestrictive lung disease can occur secondary to intrinsic (e.g. sarcoidosis) or extrinsic (e.g. kyphoscoliosis) factors. Antenatal assessment should also include determination of respiratory reserve and functional status including exercise capacity testing and home oxygen requirements .\u00a0Neurological, neuromuscular and skeletal disordersPregnant patients with neurological disorders  neuromuscular disorders  or musculoskeletal disorders  may also be encountered. Early consultation allows accurate documentation of any pre-existing neurological deficit and management. Delivery should be done in a tertiary care center with access to services such as neurology, neurosurgery, and radiology.\u00a0Pregnant women with epilepsy face several challenges. Increased seizure frequency is observed in some due to the pharmacokinetic and hormonal changes of pregnancy. Anticonvulsant drug levels can decrease during pregnancy which is explained by decreased plasma protein binding and the greater drug clearance . MaternaMultiple sclerosis is a chronic autoimmune inflammatory demyelinating disease with an onset commonly occurring during the childbearing years. A lower relapse rate is thought to occur during pregnancy, with an increased relapse rate in the first three months postpartum. Patients should be counseled about this risk that exists irrespective of the type of anesthetic . AssessmArnold-Chiari malformations (ACM) are congenital anomalies in which the cerebellum herniates through the foramen magnum, displacing the lower pons and medulla. Of the four types described, type I is the most common. The condition is associated with an impaired flow of cerebrospinal fluid (CSF) from the fourth ventricle and dynamic or static herniation of brain tissue. It has been shown that cerebrospinal fluid pressure increases with uterine contractions by a mean of 2.5 mmHg, and that the elevation of intracranial pressure (ICP) is much greater during the second stage of labor. While neuraxial techniques have been found to be a safe and viable anesthetic option, correct interpretation of imaging tests and multidisciplinary input, including that of neurology and neurosurgery, should be elicited before deciding on anesthetic management in patients with known increases in ICP ,48.Women with cerebral aneurysms or intracranial space-occupying lesions  present unique peripartum challenges. For patients with unruptured cerebral aneurysms, while mode of delivery does not seem to alter the incidence of rupture, most women tend to undergo cesarean delivery . EpiduraIdiopathic or benign intracranial hypertension  is a common condition, characterized by raised intracranial pressure without related pathology in either the brain or the composition of cerebrospinal fluid. The main symptom is headache, and the cardinal sign is papilledema . TreatmeSpinal dysraphisms are neural tube closure birth defects that may be open or closed and are commonly seen in the lumbosacral area. In patients with surgically corrected open spinal dysraphisms, the terminal portion of the spinal cord typically lies at a vertebral level lower than normal. Dysraphisms may be inherently associated with the tethered cord syndrome. Patients often\u00a0develop minor sensory, motor, and functional deficits of the lower limbs, bowel and bladder. Closed defects may or may not be associated with cutaneous stigmata. A tethered spinal cord has implications for neuraxial anesthesia with increased risk due to its association with a low-lying spinal cord, need for imaging, and often abnormal preanesthetic neurological status . If spinWith improvements in management and rehabilitation, more women with spinal cord injury are conceiving children. Women with spinal cord injuries may give birth vaginally. Patients with spinal cord injury at the level of T6 or above are at risk of developing autonomic hyperreflexia. Although pain perception is impaired in these women at or above T10, neuraxial anesthesia is the treatment of choice for pain arising from the pelvic organs. Early neuraxial labor analgesia is advisable. Continuous intraarterial blood pressure monitoring should also be considered during the peripartum period .\u00a0Myasthenia gravis is an autoimmune disorder characterized by episodes of skeletal muscle weakness that are made worse by activity. The course of disease during pregnancy is highly variable. The maternal physiological changes of pregnancy may require adjustments in the doses of anticholinesterase drugs. Patients may experience progressive respiratory compromise secondary to diaphragmatic elevation during pregnancy. Preanesthetic evaluation should assess the extent of bulbar and respiratory involvement and overall baseline muscle strength. Pulmonary function testing should be done if there is respiratory compromise. Since the uterus consists of smooth muscle, the disorder generally does not affect the first stage of labor. The second stage of labor requires the use of striated muscle, so an assisted vaginal delivery may be required . Early nRare neuromusculoskeletal disorders that have multisystem manifestations include myotonic dystrophies, neurocutaneous syndromes like neurofibromatosis and tuberous sclerosis, and Guillain-Barre syndrome. In muscular dystrophies, cardiorespiratory involvement may be varied. Neuraxial techniques are preferred for labor analgesia and cesarean delivery. Severe disease may result in both airway and spinal abnormalities presenting challenges . In neurMusculoskeletal disorders including the inflammatory arthritides rheumatoid arthritis and ankylosing spondylitis can affect perioperative planning for the obstetric patient. Systemic manifestation involving the cardiovascular and respiratory system should be ruled out. Neuraxial anesthesia may also be technically challenging do to calcified interspinous ligaments and osteophyte formation limiting the patient\u2019s ability to flex forward. Unexpectedly high blocks have been reported . ChallenScoliosis is a lateral deviation in the vertical axis of the spine with severity being determined by measurement of the Cobb angle. Most cases of scoliosis are idiopathic; however, some are associated with neuromuscular conditions such as myotonic and muscular dystrophies, Marfan\u2019s syndrome, rheumatoid disease, osteogenesis imperfecta and achondroplasia. Pregnancy exacerbates the severity of the spinal curvature and cardiopulmonary abnormalities including restrictive lung disease and pulmonary vascular resistance. Neuraxial anesthesia may be offered, however it may be technically difficult with increased possibility of complications such as aberrant local anesthetic spread. Patients with achondroplasia are often delivered by cesarean delivery due to an inadequate maternal pelvis outlet with a normal-sized fetus. The small stature and spinal stenosis in these patients necessitate a reduction in the dose of local anesthetic required, therefore an epidural or combined spinal-epidural anesthesia may allow for better titration of the local anesthetic dose .Parturients who have had prior back surgeries may also have scar tissue or removal of the ligamentum flavum that could pose an anatomic challenge for epidural placement and for anesthetic administration . If a paHematological disordersCommon causes of thrombocytopenia during pregnancy include gestational thrombocytopenia, autoimmune  thrombocytopenic purpura, and hypertensive disorders of pregnancy. Gestational thrombocytopenia is a benign self-limiting condition and accounts for most of the thrombocytopenia seen during pregnancy . In most6/L is likely to be very low in obstetric patients with thrombocytopenia secondary to gestational thrombocytopenia, immune thrombocytopenia (ITP), and hypertensive disorders of pregnancy in the absence of other risk factors [If thrombocytopenia is discovered during pregnancy, an assessment of bleeding history and etiology is necessary. The risk of spinal epidural hematoma associated with a platelet count \u226570,000 \u00d7 10 factors . For pat factors .Congenital coagulopathies include von Willebrand\u2019s disease which is divided into several subtypes based on quantitative and qualitative defects in the von Willebrand factor (vWF), which binds to collagen at sites of vascular injury, mediates platelet adhesion and aggregation, and serves as a carrier protein for coagulation factor VIII. A hematology consultation should be obtained early in pregnancy. These parturients should be tested for functional VWF and factor VIII concentration, as low levels are often be treated prior to delivery with therapies including desmopressin and von Willebrand factor concentrates. Case series have demonstrated safe spinal, epidural, and combined spinal-epidural anesthesia, and neuraxial anesthesia is considered an option for patients with normalized VWF:RCo, factor VII, and VWF antigen concentrations .Common thrombophilias diagnosed in pregnancy include Factor V Leiden deficiency and protein C and S deficiency. ACOG has recommended thromboprophylaxis for pregnancies complicated by inherited thrombophilias, which present challenges for neuraxial anesthesia about which the patient should be counseled . The SocEndocrine disordersGestational diabetes accounts for the majority of women with diabetes, followed by type I diabetes and type 2 diabetes . MaternaPatients with obesity are at a higher risk of anesthetic and obstetric complications and should have a formal preanesthesia evaluation . A thoroPregnant women likely exhibit overt or symptomatic hypothyroidism at a much lower rate than nonpregnant women. However, the required replacement of thyroid hormone in clinically hypothyroid patients often increases during pregnancy and is titrated to serum TSH levels. Patients with hyperthyroidism are treated with methimazole and propylthiouracil. Radioactive iodine is contraindicated in pregnancy. Patients with severe, untreated hyper- or hypothyroidism may present with unexplained tachycardia (hyperthyroidism) or bradycardia (hypothyroidism), abnormal weight gain for gestational age, or a visible or palpable goiter . This caGastrointestinal disordersPregnant patients with chronic liver disease or end-stage liver disease who are pre-transplant are at increased risk for both obstetric and anesthesia-related complications . They arParturients with chronic kidney disease or end-stage renal disease are anemic, experience hemodynamic alterations and electrolyte imbalances and are at increased risk for gastric aspiration. Although uncommon, pregnancy has been reported in women undergoing hemodialysis . AnticoaSubstance abuse disordersTobacco and alcohol are among the most commonly used substances during pregnancy and can cause anesthetic complications in addition to their teratogenic effects . AnestheThere is a high prevalence of opioid use during pregnancy, with risks of maternal withdrawal, neonatal abstinence syndrome, and increased analgesic needs due to opioid intolerance or opioid-induced hyperalgesia . ParturiHigh-risk obstetric and fetus-related considerationsPatients with placenta accreta spectrum disorders benefit from an early preanesthetic consultation. These cases involve multidisciplinary care and coordination involving maternal-fetal medicine, gynecology-oncology, obstetric anesthesiology, urology, general and trauma surgery, interventional radiology and neonatology, with potential need for massive transfusion . The obsEx utero intrapartum treatment is a specialized surgical technique developed to establish cardiopulmonary support safely and efficiently at delivery while maintaining placental bypass. The technique involves planned partial delivery of the fetus via hysterotomy while maintaining uterine relaxation and placental support, allowing for the establishment of neonatal cardiopulmonary stability in a controlled manner . Early aWe have included the following tables for further guidance. Tables Anesthesiology consultations for complex obstetric patients foster\u00a0optimal outcomes. They can help facilitate multidisciplinary care and enable shared decision-making. Furthermore, understanding the physiologic changes during pregnancy and the complex interplay between systemic comorbidities can improve the care provided. Finally, improved communication with patients regarding expectations, and anesthetic and peripartum planning can improve parturients\u2019 satisfaction with their delivery experience and potentially reduce maternal morbidity and mortality."}
+{"text": "Struvite stones represent the most common cause of the rapidly growing staghorn calculiwhose predisposing factors include female sex, stasis from urinary tract malformationsor obstruction, neurogenic bladder, among othersWe read with great interest the work of Danilovic et alThe authors found a similar frequency of metabolic abnormalities in 24-hour urine testsbetween groups, but only important for hypocitraturia. There was no significantdifference in new events between groups, and treatment of metabolic abnormalities amongpatients with MAP stones rendered them prone to the same risk for a new event as thosewithout any metabolic disturbance.2, especially concerninglower rates of urinary calcium, due to secondary hyperparathyroidism, as alreadydemonstrated in primary struvite urolithiasis populationsAlthough metabolic abnormalities in pure struvite stone formers indeed appear to be morecommon than previously reported, the profile of metabolic alterations differ amongreports. Iqbal et alNevertheless, the study by Danilovic et al"}
+{"text": "Hip dislocation after hip arthroscopy is an uncommon postoperative complication. We report a case of a 51-year-old woman who underwent right hip arthroscopy and presented with an anterior hip dislocation on postoperative day five. The index surgery involved capsulotomy, cam lesion debridement, and femoroplasty for an anterosuperior labral tear and cam-type femoroacetabular impingement. The patient underwent an uneventful recovery course until eight weeks postoperatively she developed iliopsoas bursitis. Her symptoms were managed conservatively with activity modification and physical rehabilitation. Complete resolution of symptoms was reported by the six-month follow-up visit, and no further dislocations or instability had been reported at 12 months. Anterior hip dislocation is a rare complication following hip arthroscopy and patients may experience persistent iliopsoas bursitis several months following successful reduction. Hip arthroscopy (HA) is a surgical procedure increasing in popularity in recent years due to its relatively low complication rate and less invasive approach compared to traditional hip surgery ,2. Hip dThe patient is a 51-year-old woman who underwent right hip arthroscopy with labral repair and femoroplasty with cam lesion debridement. After failing years of conservative management for unremitting right hip and groin pain, she elected to undergo right hip arthroscopy. Following surgery, she was made partially weight-bearing with an early range of motion to assist in recovery. She experienced an uneventful postoperative course until day five. While cleaning her kitchen, she extended and externally rotated her operative leg resulting in sudden and severe right hip pain accompanied by a fall to the ground and an inability to bear weight.Upon presentation, her right leg was shortened and externally rotated with intact neurovascular function. Radiographs revealed right anterior hip dislocation without evidence of acute fracture Figure .She was consciously sedated, closed reduced, and placed in a knee immobilizer Figure .Postreduction computed tomography (CT) revealed an impaction-type fracture in the anterior aspect of the femoral head Figure .Magnetic resonance imaging (MRI) was also obtained, which revealed an impaction fracture involving the anterior margin of the right femoral head and neck junction Figure .Surgical pathology of the cam resection and femoroplasty ruled out the presence of bony pathology. By one week postoperatively, she was able to ambulate with a walker. Physical examination revealed painless hip flexion greater than 100 degrees, extension to neutral, internal rotation to 35 degrees, and abduction to 45 degrees. However, she still experienced a sensation of anterior hip popping and had crepitus anteriorly. Initial MRI and CT scan were re-reviewed, and the labral repair appeared to be intact. She was advised to limit external rotation and hyperextension of the hip with protected weight-bearing and crutch use.By six weeks postoperatively, her preoperative anterior hip popping and crepitus had entirely resolved. She experienced no pain in the anterior hip capsule and no apprehension with hyperextension or external rotation. The patient had a stable gait without the use of assistive devices and was able to perform a full crouch without difficulty.The patient did not remain symptom-free during her continued follow-up visit. By eight weeks postoperatively, she experienced a re-intensification of her right hip pain that she characterized as a deep ache in the joint. Her hip occasionally locked and was accompanied by a sense of instability. She denied a history of trauma - other than the recent hip dislocation - or inciting events. Physical examination revealed palpable crepitus in the anterior acetabular margin at 60 degrees to 90 degrees of flexion. Both internal and external rotation aggravated these symptoms. The patient could ambulate, although she preferred to take small steps with her right lower extremity to reduce pain. Radiographs of the right hip revealed a well-maintained joint surface and joint line architecture with no gross bony abnormalities.Subsequent MRI revealed right iliopsoas bursitis with filling defects in the joint recesses and the iliopsoas bursa suspicious for synovial proliferation and small intra-articular bodies Figure .Additionally, new-onset small focal cartilage loss and osteochondral impaction injury in the femoral head secondary to microtrauma and instability were identified.\u00a0Her symptoms were managed conservatively with activity modification and physical rehabilitation. Complete resolution of symptoms was reported by a six-month follow-up, and no further dislocations or instability had been reported at 12 months.HA is a low-risk, minimally invasive procedure with numerous indications, including acetabular labral tears, FAI, chondral lesions, osteochondritis dissecans, ligamentum teres injuries, snapping hip syndrome, iliopsoas bursitis, and loose bodies .\u00a0Hip artWith such an exceedingly low complication rate, post arthroscopic hip dislocation has not been well documented. The majority of cases of hip dislocation after HA reported have been anterior hip dislocations -13. AlteOur patient underwent a transverse limb capsulotomy of the anterior joint capsule without repair, rim trimming of the acetabular margin, and femoroplasty with cam lesion resection. Interestingly, our patient experienced anterior hip dislocation only five days post arthroscopy. The patient also sustained a femoral head fracture, intra-articular loose bodies, and focal cartilage loss that resulted from the original injury. We can postulate from our experience that intraoperative distension and stretching of the anterior joint capsule may create instability and thus the risk for dislocation and subsequent injuries. Prior studies reported dislocation events that occurred immediately in the recovery room , on postInciting mechanisms vary depending on the activity level of the individual. Less active individuals frequently report a low energy twist or fall ,10,11. AOur patient was diagnosed with new-onset iliopsoas bursitis eight weeks following closed reduction of her post arthroscopic anterior hip dislocation. Six other cases describe further complications that required additional surgery: residual pain and apprehension treated with arthroscopic capsular plication , gross hAnterior hip dislocation after HA is an uncommon postoperative complication of an otherwise safe and well-regarded procedure. Surgeons must be aware of the surgical and patient-specific risk factors that contribute to postoperative hip instability in order to optimize patient safety in both the acute and chronic stages of recovery. Furthermore, the presence of iliopsoas bursitis, degenerative arthritis, and other causes of continued hip pain following closed hip reduction is an important topic that requires further investigation as the incidence of these complications is likely to rise with a growing number of hip arthroscopy procedures. This case emphasizes the need to investigate safer techniques to minimize postoperative complications, avoid dislocation after hip arthroscopy, and successfully manage resulting pathology."}
+{"text": "Implementing intergenerational programming amidst the COVID-19 pandemic has required creativity, partnership, and dedication to the work. Most intergenerational programs involving in-person meetings or events are accompanied by guidelines to protect participant health and safety. Programming is routinely cancelled or postponed due to poor weather or contagious illness, particularly when a vulnerable population is involved. The needs for safety precautions and continued intergenerational contact were both amplified during the pandemic, leading many to modify or innovate ways to engage generations rather than eliminate contact for extended periods. Technology has afforded new approaches to engage young people and older people with each other; non-technological ways have also proven effective. This symposium will address strategies used to implement intergenerational programs during the pandemic. Authors will highlight lessons learned and strategies they expect to retain in the future. The first paper describes a pivot in nutrition programming designed for a shared site with preschool children and frail older adults. In paper two, authors discuss their partnership-based approach shifting to remote offerings of Cyber-Seniors programming. Paper three addresses how MentorUp Service-Learning expanded its reach by adaptations to virtual programming for older adults in retirement communities. The final paper presents evaluation data comparing arts programming delivered in-person pre-pandemic and again virtually during the pandemic. In each case, researchers and community partners learned techniques to maintain their programmatic foci. Some projects developed strategies they plan to maintain post-pandemic. Donna Butts, Executive Director of Generations United serves as the symposium discussant."}
+{"text": "This session examines innovative approaches to effectively address the aging services workforce needs in rural, Midwestern settings. Presenters will explore career pathways and transfer opportunities in gerontology education, as well as best practices for addressing the educational, professional and personal needs of diverse student populations."}
+{"text": "Objectives are to detail the model, pilot funding mechanism, early research findings and infrastructure investments. METHODS/STUDY POPULATION: The health research system has widely acknowledged challenges that can delay research translation to systems that advance health for chronically disadvantaged health disparity population groups. MSM\u2019s vision is to lead the creation and advancement of health equity. The vision-aligned strategic plan prioritized formalization of a TX TM implementation priority. The study population was the institution\u2019s research faculty and leaders, research administration, and communication arm. Through a cross-institutional working group, a plan was deployed to 1) assess the institutional landscape, 2) review the grey and peer reviewed literature on translational research and 3) invest in a pilot research funding mechanism. RESULTS/ANTICIPATED RESULTS: Over $700K has been invested in TX TM implementation. Over half of research faculty completed an institutional landscape assessment to identify translational research expertise, interests and points of interest in new collaboration. The most frequently cited collaborative research interests were clinical research with human subjects, patient-centered outcomes and laboratory-based research with human subjects/specimens. Funded multidisciplinary and/or community-engaged pilot studies investigate the role for circadian rhythms and shift work, cultural variables influencing mental health among Haitians living in the US and integrating prescription reconciliation telehealth in primary care. DISCUSSION/SIGNIFICANCE OF IMPACT: TX TM requires interdisciplinary collaboration across translational research spheres and beyond the academy. Institutional investment, infrastructure support and senior-level champions are central to awareness and rewarding such scholarship towards scaling approaches that advance health equity. CONFLICT OF INTEREST DESCRIPTION: Coined at Morehouse School of Medicine (MSM), Tx TM symbolizes an approach and scientific philosophy designed to intentionally promote and support convergence of interdisciplinary approaches and scientists to stimulate exponential advances for the health of diverse communities.OBJECTIVES/GOALS: Morehouse School of Medicine (MSM), T"}
+{"text": "Inpatient falls are a persistent problem and despite research efforts during the last decade, inpatient fall rates have not significantly decreased. Older adults have an estimated 50% greater inpatient fall rate than younger adults. How older adults perceive their own fall risk affects their adherence to fall prevention recommendations. The aim of this phenomenological study was to gain a deeper understanding of the lived experiences of being at risk for falling in the hospital among older adults aged 65 years and older (N=9). Participants  were interviewed twice using video conferencing within two weeks of hospital discharge. The audio-recorded interviews were transcribed, and then analyzed using van Manen\u2019s interpretive phenomenological method. The Health Belief Model expanded with the concepts of independence, fear of falling, embarrassment, dignity, and positivity effect served as the theoretical framework. Five major interpretive themes emerged: Relying on Myself, Managing Balance Problems in an Unfamiliar Environment, Struggling to Maintain Identity, Following the Hospital Rules, and Maintaining Dignity in the Relationships with Nursing Staff. These themes describe how the participants thoughtfully planned their mobilization to avoid falls. This process was influenced by their struggling to remain independent, following the hospital fall prevention rules out of politeness, and experiencing both positive and negative relationships with nursing staff. Hospitalized older adults employed their self-efficacy to manage balance problems in the hospital. These findings have not been previously documented in the literature. Fall prevention interventions supporting hospitalized older adults\u2019 self-management of fall risk are needed."}
+{"text": "The 2019 Global Assessment Report (GAR2019) on Disaster Risk Reduction , the ideThe current special issue primarily focuses on how cascading disaster risk can be analyzed and modeled\u2014to support decision-making about disaster mitigation, preparation, and response. The special issue covers cascading impacts triggered by multiple hazard types, cascading impacts triggered by extreme rainfall events and by ground deformation, and the cascading impacts of business and infrastructure disruptions. Specific issues concerning the risk of cascading hazards for oil storage infrastructure and for underground railways are also analyzed, alongside potential mitigation measures. Other papers outline the importance of organization within social networks and of public health provision for cascading disaster management.Mignan and Wang  analyzedHuggins et al.  focused Cando-J\u00e1come et al.  used an Dubaniowski and Heinimann  used an Zhang et al.  developeWang et al.  analyzedChen et al.  focused Harada et al.  providedThe current special issue on Cascading Disaster Modelling and Prevention includes several examples of how cascading disaster analysis supports a more preventative and pro-active approach to cascading disaster risk. Case study reviews and other data analyses have illustrated how cascading impacts are triggered by multiple hazard types, and can be characterized by severe infrastructural and organizational disruptions. Relevant analyses have been conducted for specific sites, namely oil depots and underground railway systems. In both cases, innovative approaches to analytical modeling have identified key targets for cascading hazard mitigation. The remaining pair of special issue papers highlight the potential to learn from prior disasters, which have already affected large populations and broad geographical areas. Flexible and well-networked capacities remain paramount, especially where mitigation has not been achieved or where key targets for mitigation have not yet been identified. Analytical efforts are ongoing to help ensure that larger scale cascading disaster management can leverage more of the analytical precision that characterizes site-specific analyses."}
+{"text": "Theoretical and empirical evidence suggests the existence of a general perceived stress factor overarching different life domains. The present study investigated the general perceived stress relative to domain-specific perceived stress as predictors of 26 diverse health outcomes, including mental and physical health, health behaviors, cognitive functioning, and physiological health indicators. A bifactor exploratory structural equational modelling approach was conducted in two samples from the Health and Retirement Study. Across the two samples, perceived stress was well-represented by a bifactor structure where there was a robust general perceived stress factor representing a general propensity towards stress perception. Meanwhile, after controlling for the general factor, specific factors representing perceived stress in different life domains were still clearly present. The general perceived stress factor was the most robust predictor of the majority of health outcomes. Age, sex, personality traits, and stressor exposure were found as possible diathesis underlying the general perceived stress factor."}
+{"text": "Peak intra-articular load distribution for active squatting was lateral-heavy, contrasting to the medial-heavy distribution observed in passive intraoperative measurements, for all specimens. These aspects should be given due consideration while assessing intraoperative and postoperative joint stability following TKA.Ligament balancing during total knee arthroplasty (TKA) often relies on subjective surgeon experience. Although instrumented tibial trays facilitate an objective assessment of intraoperative joint balance through quantification of intra-articular joint loads, postoperative clinical assessment of joint balance relies on passive stress tests quantifying varus\u2013valgus joint laxity. This study aimed at correlating the intraoperative and postoperative metrics used to assess joint balance while also comparing joint loads obtained during passive assessment and active functional motions. Four experienced surgical fellows were assigned a fresh-frozen lower limb each to plan and perform posterior-stabilised TKA. An instrumented tibial insert measured intraoperative intra-articular loads. Specimens were then subjected to passive flexion\u2013extension, open-chain extension, active squatting, and varus\u2013valgus laxity tests on a validated knee simulator. Intra-articular loads were recorded using the instrumented insert and tibiofemoral kinematics using an optical motion capture system. A negative correlation was observed between mean intraoperative intra-articular loads and corresponding mean postoperative tibial abduction angle during laxity tests (medial: R = \u22120.93,  Total knee arthroplasty (TKA) is an established surgical procedure to treat severe osteoarthritis in the knee; however, joint instability has been reported as a major cause of postoperative patient dissatisfaction . Soft-tiVerasense , a smart tibial tray compatible with already existing TKA designs, facilitates the quantitative measurement of soft-tissue balancing during TKA by measuring intraoperative loads in situ in the medial and lateral compartments at the points of contact between the femoral condyles and tibial plateaux ,7. With While intra-articular loads are used to achieve joint stability intraoperatively, clinical assessment of postoperative joint stability typically relies on passive tests, such as the stress tests quantifying the varus\u2013valgus laxity of the knee at multiple flexion angles , performMoreover, while this manual passive postoperative assessment of joint stability is performed at constant flexion angles, the aim is to have desired postoperative joint stability for dynamic activities of daily living, such as walking, over the entire range of knee flexion. Active motions differ from their passive counterparts primarily owing to active muscle force production, as well as their often closed-chain nature resulting in higher joint contact forces .Therefore, the primary aim of this in vitro study was to correlate intraoperative intra-articular loads to the postoperative tibiofemoral abduction measured during the varus\u2013valgus stress tests, hypothesizing a negative correlation between the two parameters. The secondary aim of this study was to compare intra-articular loads measured intraoperatively to those measured postoperatively during passive and active motions, with the hypothesis that active motions would alter load distribution between the medial and lateral compartments owing to a change in joint dynamics and muscle force production.Four fresh-frozen cadaveric specimens  were obtained from the institute body donation programme following ethical approval by the local ethics committee. None of the specimens had signs of lower limb disorder or prior surgical intervention.Magnetic resonance imaging and full leg radiographs were obtained for each specimen to design specimen-specific cutting blocks for the TKA surgery using the VISIONAIRE protocol . Rigid marker frames with reflective spheres (diameter = 12 mm) were attached to the femur and tibia using bicortical bone pins. Computed-tomography (CT) scans  obtained for each frozen specimen in full extension were used to identify the location of the markers relative to anatomic landmarks  in order to define a joint coordinate system for the femur and tibia .Each lower limb was thawed for 24 h before resecting it 32 cm proximally and 28 cm distally to the knee joint. Care was taken to preserve the joint capsule, ligaments, and tendons while dissecting the surrounding skin and subcutaneous tissue. The femur and tibia were embedded in metal pots using acrylic resin  in a physiologic orientation. Tendons of the quadriceps and the hamstrings were carefully exposed and prepared to be attached to an electromechanical actuator for dynamic control and passive springs for constant tensile load application, respectively.Each of the four specimens was randomly allotted to one of four experienced surgical fellows  scores > 85%) ,12. SurgFollowing implantation, each specimen was mounted on a previously validated physiological knee-joint simulator  and subjThe specimen was kept moist during experimental testing with phosphate-buffered saline solution to mitigate tissue-drying effects. The order of tasks performed was randomized to avoid potential bias. Each task was performed in triplicate by a single operator.A six-camera motion capture system  was used to track the motion of the femur and tibia. Intra-articular loads in the medial and lateral compartments of the knee were recorded during all tasks using the custom company software .p < 0.05). Peak intra-articular loads in the medial and lateral compartments were calculated for passive flexion\u2013extension, open-chain extension, and active squatting, and compared to values obtained intraoperatively.The recorded trajectories of markers on the femur and tibia were processed further  to calculate tibiofemoral kinematics for each specimen using a custom code  based on joint coordinate systems defined using anatomical landmarks obtained from CT. The relationship between postoperative joint laxity, measured using the tibial abduction angle during varus\u2013valgus stress tests, and intraoperative intra-articular load was assessed for each specimen using the Pearson correlation test   than in flexion (4.4 \u00b1 2.4\u00b0) postoperatively . Mean po = 0.04) .Peak total intra-articular load across the range of knee flexion was higher for actively loaded tasks\u2014open-chain extension and squatting\u2014as compared to passive measurements, with the peak load during squatting being the highest amongst all tasks for three out of the four specimens . For allIn the case of peak loads for intraoperative measurements, passive flexion\u2013extension, and open-chain extension, loads in the medial compartment were higher than those in the lateral compartment for three out of the four specimens; however, for active squatting, loads in the lateral compartment were higher than those in the medial compartment for all specimens .Ligament balancing is vital in the successful outcome of TKA ; howeverOne of the highlights of this study was the participation of four experienced surgical fellows, each performing specimen-specific TKA. The same implant was used by all fellows to avoid implant-specific variability in postoperative biomechanics; however, specimen-specific cutting guides were based on the preoperative surgical planning performed by each fellow. Moreover, although trained at different institutions globally, the fellows followed standard surgical norms of joint balancing during TKA ,3. This Intra-articular loads measured during TKA revealed that all specimens were tighter in extension, thereby leading to higher loads, than in flexion . MoreovePostoperative joint laxity largely corroborated with intraoperative intra-articular loads, since it was ensured that implant sizes and/or component alignments were not altered following intraoperative joint balancing assessment with the instrumented tibial trays. Postoperative tibial adduction and abduction during the varus and valgus stress tests, respectively, were higher in flexion than in extension , therebyPeak total intra-articular load over the range of knee flexion was higher for dynamic loaded tasks as compared to static measurements , with thHowever, this was not the case for one specimen (Spec 2), which exhibited such high intra-articular loads during intraoperative measurements already that the differences in peak loads between passive and active motions were minimal, as compared to those observed in other specimens . MoreoveAlthough this unique cadaveric simulator study included state-of-the-art instrumented sensors, one of the main shortcomings of the study was the small sample size. Future studies should not only look to include a larger number of specimens but also increase the number of static flexion angles used to test intraoperative intra-articular loads and corresponding postoperative joint laxity, thereby facilitating a better correlation analysis of the two parameters with statistical and clinical significance. Another limitation was the underlying assumption that Verasense sensors could sustain intra-articular pressure encountered during the actively loaded squatting motion, often reaching ~16 MPa , withoutA conformance between intraoperative intra-articular joint loads and postoperative joint laxity was observed, although the correlation between these parameters was not statistically significant for all specimens. Moreover, there was a stark discrepancy in peak joint load distribution across the medial and lateral compartments between passive tasks and active functional motions. These aspects should be given due consideration while performing a joint balancing procedure during TKA, as well as clinically assessing postoperative joint stability."}
+{"text": "Entrapment peripheral neuropathies are clinically characterized by sensory impairment and motor deficits. They are usually caused by mechanical injuries, but they are also a frequent manifestation of metabolic diseases, toxic agent exposure, or systemic fibrotic disorders. Here we describe the clinical, radiological, and histopathological features of a novel progressive fibrotic disorder characterized by progressive multifocal fibrosing neuropathy. We identified two patients who presented with severe and progressive peripheral neuropathic symptoms sequentially affecting multiple sites. These patients presented with severe and progressive multifocal, sequentially additive peripheral neuropathic symptoms. Extensive nerve conduction and radiological studies showed the sequential development of multifocal motor and sensory peripheral neuropathy in the absence of any exposure to known infectious, inflammatory, or fibrotic triggers and the lack of family history of compression neuropathies. Extensive clinical and laboratory test evaluation failed to support the diagnosis of any primary inflammatory or genetic peripheral neuropathy and there was no evidence of any systemic fibrosing disorder including Systemic Sclerosis, lacking cutaneous fibrotic changes and cardiopulmonary abnormalities. The clinical course was progressive with sequential development of motor and sensory deficits of upper and lower extremities displaying proximal predominance. Histopathological study of tissues obtained during nerve release surgeries showed severe perineural fibrosis with marked accumulation of thick collagen bundles encroaching the peripheral nerves. There was no evidence of vasculitic, inflammatory, or vascular fibroproliferative lesions. We suggest that the clinical findings described here represent a previously undescribed fibrotic disorder affecting peripheral nerves, and we propose the descriptive term \"Progressive Multifocal Fibrosing Neuropathy\" to refer to this novel disorder. Despite the inherent limitations of this early description, we hope this is would contribute to the identification of additional cases. Peripheral neuropathies caused by nerve compression or entrapment syndromes manifest clinically by sensory impairment and motor deficits. They most commonly result from chronic mechanical injuries of nerve tracts in fibro-osseous canals or compression by other tissue structures, including tendons, ligaments, and muscles , 2. SlowHere, we describe two patients who developed a novel disorder characterized by severe and progressive peripheral neuropathy with multifocal and sequential involvement of multiple sites. Extensive neurological and histopathological studies demonstrated that this process was caused by encroachment of nerve tracts by the accumulation of large amounts of excessive fibrotic tissue in the absence of genetic or acquired neurological disorders or systemic inflammatory or fibrotic diseases. Therefore, it is suggested that this clinical entity represents a previously undescribed fibrotic disorder affecting the peripheral nerves.Both patients were referred to the Scleroderma Center at Thomas Jefferson University for evaluation of a systemic fibrosing disorder causing progressive neuropathy affecting multiple peripheral nerves. Appropriate laboratory tests for the assessment of SSc and SSc-like disorders, including autoantibody testing, nail-fold video-capillaroscopy, pulmonary function tests, high-resolution chest computed tomography, and echocardiograms were performed. Neurological evaluations, including extensive clinical and electrophysiological assessment, were performed by a neuromuscular neurologist (M.C.D); and radiological studies included resonance imaging (MRI), and ultrasonography. Histopathological studies of biopsies from affected nerves and surrounding tissue obtained during decompression surgeries were performed. The tissues were stained with hematoxylin\u2013eosin (H&E), and Masson\u2019s Trichrome stains, immunohistochemistry studies for inflammatory cell markers including CD3, CD8, CD20, and CD68 were performed. A search for peripheral myelin protein (PMP22) gene mutations to exclude hereditary neuropathy with liability to pressure palsies (HNPP) was performed in both patients .A 37-year-old female presented with three months history of severe pain localized to the left genital area. An initial evaluation was negative for infectious etiologies. Owing to the persistence of symptoms, an MRI was performed. The study disclosed soft-tissue edema surrounding the left pudendal nerve , silica, organic solvents, pesticides, radiation, occupation/hobby exposures, or other identifiable environmental factors. No family history of a similar syndrome was found. Laboratory testing in both cases showed the absence of eosinophilia and tests for antinuclear antibody were negative. Repeated analysis failed to show elevation of inflammatory markers (ESR and CRP). Genetic testing did not disclose any peripheral myelin protein 22 (PMP22) mutations. An echocardiogram did not show signs of pulmonary hypertension or myocarditis, and pulmonary function tests (PFTs) were normal. There was no clinical or laboratory evidence to suggest the diagnosis of diabetes mellitus.Given the fact that the findings of EMG/NC studies correlated with the clinical picture in both patients and provided imaging evidence of entrapment neuropathy, lumbar puncture and CSF analysis were not performed.MRI of the pelvic area showed marked perineural edema surrounding the left pudendal nerve of patient 1 and right pudendal nerve in patient 2  , 18, an Given the fact that several systemic fibro-inflammatory conditions have been related to an exogenous triggering agent, an extensive and detailed inquiry was performed but failed to disclose any toxic exposure. Although patients with more than one neuropathic compressive syndrome affecting the same extremity, usually associated with thoracic outlet syndrome have been described and a \u201cdouble crush mechanism\u201d was proposed for those cases , 22, in An extensive review of the published medical literature indicates that there was no previously described syndrome or disease with the clinical and histopathological findings described in this report and the cases and the cases studied and reported appear to be unique. Therefore, it is suggested that this may represent a novel clinical entity descriptively termed \"Multifocal Progressive Fibrosing Neuropathy\". The most important features distinguishing Multifocal Progressive Fibrosing Neuropathy from SSc, TOS, EF, EMS, and NSF, and other neurological diseases frequently causing neuropathy are listed in Tables Finally, we can hypothesize that owing the absence of inflammation in immunopathological studies but significant fibrosis, these patients could benefit from the use of antifibrotic drugs."}
+{"text": "JCI, Arinze et al. explore the role of tryptophan metabolites in chronic kidney disease\u2013associated (CKD-associated) peripheral arterial disease. The authors used mouse and zebrafish models to show that circulating indoxyl sulfate (IS) blocked endothelial Wnt signaling, which impaired angiogenesis. Plasma levels of IS and other tryptophan metabolites correlated with adverse peripheral vascular disease events in humans. These findings suggest that lowering IS may benefit individuals with CKD and ESKD.Patients with end-stage kidney disease (ESKD) have increased vascular disease. While protein-bound molecules that escape hemodialysis may contribute to uremic toxicity, specific contributing toxins remain ambiguous. In this issue of the  The use of chronic dialysis in patients with end-stage kidney disease (ESKD) is one of the miracles of modern medicine with which we can keep patients with kidney failure alive; however, dialysis does not completely remove the many uremic toxins . PatientJCI, Arinze et al. provide in vivo evidence in mouse and zebrafish animal models that circulating IS (at concentrations found in humans with CKD) blocks Wnt signaling in the endothelium and impairs angiogenesis in a Wnt ligand\u2013independent fashion  . The autWhile the in vivo findings compellingly link IS with PAD, several questions remain unanswered. The hind-limb ischemia model is a comparatively acute model focusing on capillary bed density that may only reflect part of the pathophysiology of PAD associated with CKD. Although increased concentrations of IS have been associated with PAD in hemodialysis patients, IS does not seem to have any substantial association with other cardiovascular outcomes . ConsequTaken together with other published studies, Arinze\u2019s study shows that activation of AhR by IS and other tryptophan metabolites is now implicated in multiple pathophysiologic processes associated with CKD, including glomerular injury, renal fibrosis, atherogenesis and cardiovascular disease, protein energy wasting, renal anemia, loss of bone mineralization, and cognitive dysfunction . Finding"}
+{"text": "A 93-year-old man living in a nursing home presented to our emergency department with altered mental status. Examination revealed hypotension and severe hypoxia. Chest radiograph showed infiltrates in the right upper lobe, and computed tomography of the abdomen and pelvis demonstrated a left femoral neck fracture. A point-of-care transthoracic echocardiogram (TTE) revealed an enlarged right ventricle, severe tricuspid regurgitation, and numerous white floating dots moving toward the right atrium from the inferior vena cava (IVC), leading to the diagnosis of fat embolism syndrome (FES).Although imaging studies can facilitate diagnosis, the diagnosis of FES is typically made by clinical history and presentation, making a swift diagnosis often difficult in those who are critically ill. Recent case reports have described that TTE can detect fat emboli, seen as flowing hyperechoic particles in IVC. This image demonstrates the utility of TTE to diagnose FES. A 93-year-old man living in a nursing home presented to our emergency department with altered mental status, which occurred suddenly over the previous one hour. An initial history elicited from the nursing home staff failed to identify any risk factors. Examination revealed hypotension and severe hypoxia with oxygen saturation of 85% on 15 liters per minute oxygen with a non-rebreather mask. Chest radiograph showed infiltrates in the right upper lobe, but contrast computed tomography (CT) showed no pulmonary embolism. Suspecting an occult organ pathology, we ordered CT of the abdomen and pelvis, which demonstrated a left femoral neck fracture. Further inquiry of the nursing home staff revealed that the patient had fallen earlier on the same day, striking his hip on the floor. A point-of-care transthoracic echocardiogram (TTE) revealed an enlarged right ventricle, severe tricuspid regurgitation, and numerous white floating dots moving toward the right atrium from the inferior vena cava (IVC) , leadingFat embolism syndrome is a rare condition defined by the presence of fat globules in respiratory circulation.What do we already know about this clinical entity?Fat embolism syndrome (FES) is defined by the presence of fat globules in respiratory circulation; its diagnosis is often challenging.What is the major impact of the image(s)?Floating fat emboli can be detected using point-of-care ultrasound, which facilitates the diagnosis of FES.How might this improve emergency medicine practice?Point-of-care transthoracic ultrasound is an essential diagnostic tool to evaluate patients with suspected FES.VideoTransthoracic echocardiogram. The video shows numerous white floating dots moving toward the right atrium (RA) from the inferior vena cava (IVC) suggestive of fat embolism syndrome."}
+{"text": "Delivery of serious illness communication (SIC) is necessary to ensure that all seriously ill patients receive goal-concordant care. However, the current SIC delivery process contains barriers that prevent the delivery of timely and effective SIC. In this paper, we describe the current bottlenecks of the traditional SIC workflow and explore how a hybrid artificial intelligence-human workflow may improve the efficiency and effectiveness of SIC delivery in busy practice settings. High-quality and timely SIC enables and enhances decision-making and care planning through the process of cultivating patients\u2019 prognostic awareness and translating their values and priorities into patient-centered recommendations. The iterative and non-linear process of SIC requires frequent and early conversations to ensure that clinicians accurately understand patients\u2019 evolving goals, values, and priorities and to make patient-centered recommendations throughout the illness trajectory.Serious illness communication (SIC) is an essential component of palliative care that ensures the delivery of goal-concordant care. SIC is often defined as the conversations between clinicians and patients with serious illness about their goals, values, and prioritiesThe traditional SIC delivery process consists of a series of conversations where gathering, interpreting, and integrating SIC data occur within a clinical encounter followed by manual clinician documentation in the electronic health record (EHR) post-visit. This process can be broken down into the following steps: determining patient eligibility for SIC; gathering and interpreting information ; conducting a therapeutic conversation  with the goal of shared decision-making; documenting the conversation; and making SIC documentation accessible to others in the EHR Fig. . However2. Second, patients and/or clinicians may be unclear about the optimal timing and when to make such conversations a priority2. Third, clinicians often lack time to conduct SIC2 and to document these conversations adequately3. Fourth, standards for EHRs to facilitate consistent, accurate documentation that is easily accessible to all care team members are lacking4. Therefore, in addition to training more clinicians to be competent in SIC, a novel workflow that addresses these barriers will be necessary to ensure that all seriously ill patients receive timely and effective SIC that informs their care in real time and naturally results in documentation of patients\u2019 goals and preferences that is visible to others. We propose that a hybrid artificial intelligence (AI)-human workflow can improve this process by helping clinicians identify patients with SIC needs more accurately; promoting upstream data collection to facilitate more efficient in-person shared decision-making; reducing clinician documentation burden by streamlining the SIC documentation process; facilitating seamless sharing of patient goals and preferences via accurate and efficient identification of SIC documentation in the EHR; and providing real-time feedback to clinicians on their SIC skills.First, most clinicians lack SIC training and feel unprepared to have these difficult conversations with their patients5. Moreover, systematic methods to identify patients with palliative care needs are lacking6. To solve this problem, AI researchers have developed machine learning algorithms to generate more accurate mortality predictions to facilitate earlier SIC and palliative care delivery8. Some researchers have demonstrated that coupling AI-generated mortality predictions with behavioral nudges to clinicians can improve SIC frequency9. However, critics have expressed worry about using mortality predictions alone for identifying populations with palliative care needs because a reductionistic interpretation of these results may lead to further propagation of algorithmic or other systemic biases leading to inequitable care and patient harm10. Therefore, others have suggested alternative metrics that identify patients at risk of worsening serious illness to train predictive algorithms\u2014including functional decline, deteriorating quality of life, escalating caregiver burden, or psychosocial or spiritual distress10. Some accountable care organizations are already using claims-based algorithms to identify high-cost patients who would benefit from earlier palliative care11, but greater effort is needed to mitigate algorithmic bias, especially among commercially available products that are widely used12. Moreover, additional methods to identify SIC-eligible patients should be considered since EHR-based algorithms often have performance gaps13.Patients with serious illness often experience delayed SIC because clinicians are poor at prognosticating life expectancy for terminally ill patients, usually erring on the side of optimism16, but the technology to date is mature enough to support its use in SIC as a basic data-gathering agent. One could imagine SIC conversational agents that would collect information about the patient\u2019s prognostic awareness and priorities prior to in-person visits. Doing so would enable clinicians to maximize face-to-face time on higher-order cognitive and emotional tasks  that would lead to earlier shared decision-making. Conversational agents may also give patients time to reflect and discuss issues with trusted persons prior to meeting with the clinician.The use of conversational agents (aka chatbots) has largely been unexplored in palliative care. Conversational agents that are emotionally aware or use unconstrained natural language input are nascent in health care18. In one study, older adults utilized multiple-choice responses to converse with an agent that provided spiritual counseling, which reduced anxiety and increased the intent to create a last will and testament17. In another, machine learning algorithms allowed the agent to collect patient-reported outcome measures and display empathy to the users\u2019 free text responses18. Although conversational agents were well-received in these preliminary studies, some patients will prefer to have the entire SIC with their clinicians directly, obviating the need for a chatbot. Further studies need to be conducted on actual patients with serious illness and should assess if conversational agent-led SIC triggers emotional distress in patients or actually enhances the patient-clinician relationship. Moreover, deploying conversational agents may inadvertently widen inequities in certain populations, particularly patients with limited English proficiency, health information technology literacy, or broadband access.To date, no studies on conversational agents have been conducted on patients with serious illness, but proof-of-concept studies in the general population have demonstrated the acceptability of conversational agents that address palliative care-related topics3. NLP-enabled dictation software has demonstrated the ability to reduce medical documentation time while maintaining documentation quality19 and is already commercially available20. Such technology would reduce the time clinicians spend manually writing notes and minimize recall bias since the content of the conversation is transcribed verbatim during the conversation and not hours later, typical of much documentation. As a result, nuanced details of the conversation are readily captured in real time leading to higher quality notes with less clinician effort.AI can also streamline the SIC documentation process and potentially improve the quality of SIC documentation via natural language processing (NLP)\u2014a form of machine learning designed to understand, interpret, or manipulate human language. Missing or incomplete documentation in the EHR regarding patient preferences for life-sustaining treatment is common and contributes to medical errors related to end-of-life care4. In its current state, identifying SIC documentation in the EHR typically involves a manual chart review that possibly includes a keyword search or utilization of note filters. NLP-enabled software that identifies free text SIC documentation would likely reduce the time and effort clinicians spend looking for this information and prevent inadvertent oversight of patient preferences leading to goal-discordant care. AI-assisted chart reviews have demonstrated higher accuracy and shorter time for extracting relevant patient information compared with standard chart reviews21. Additionally, NLP has demonstrated the ability to identify SIC documentation accurately from EHR data and, in some cases, more accurately than human coders24. However, the accuracy of NLP to identify SIC documentation largely depends on the quality of the gold standard dataset created by human annotation used to train the model. Consequently, widespread implementation of NLP-enabled software to identify SIC documentation likely remain years away since high-quality annotated examples to train generalizable models are lacking, and adapting NLP models between different datasets often require additional training or fine-tuning25. In the interim, some health systems have created a centralized location for SIC documentation in the EHR to improve SIC documentation identification26, but compliance with utilizing these modules will likely remain an issue and additional NLP assistance will optimize the identification of SIC documentation in the EHR27.NLP also has the potential to address barriers resulting from poor EHR design that prevent or inhibit the extraction and flow of meaningful advanced care planning information across the care continuum28. Automated speech analysis and communication feedback will likely take years to manifest because not only do technical and logistical barriers remain 28, but also greater consensus is needed to define and measure basic communication quality and outcomes29. Researchers are currently utilizing NLP to analyze audio recordings of SIC to characterize and understand the naturally occurring features of these complex conversations32, such as identifying intentional pauses that foster empathy, compassion, and understanding, aka \u201cConnectional Silences.30\" This type of research will guide future efforts to develop ways of automating the measurement of SIC quality in real time, allowing for immediate feedback to improve clinician performance.Finally, AI has the potential to improve SIC delivery by providing speech analysis and personalized feedback to clinicians regarding their communication skillsIn conclusion, a hybrid AI-human SIC workflow may improve the efficiency and effectiveness of SIC delivery in busy practice settings. Some of the AI technology are available for widespread use presently , whereas others are emerging technologies that are being developed and studied . This proposed paradigm still requires that clinicians undergo some SIC training to capitalize on the assistance provided by AI, as well as additional research to avoid unintended consequences of AI implementation. That said, a semi-automated approach to SIC delivery holds tremendous promise and would likely improve current SIC workflow by optimizing clinical manpower and efficiency while increasing the likelihood that these critically important conversations will occur effectively and in a timely fashion."}
+{"text": "Alcohol (ethanol) use and misuse is a costly societal issue that can affect an individual across the lifespan. Alcohol use and misuse typically initiates during adolescence and generally continues into adulthood. Not only is alcohol the most widely abused drug by adolescents, but it is also one of the most widely abused drugs in the world. In fact, high rates of maternal drinking make developmental ethanol exposure the most preventable cause of neurological deficits in the Western world. Preclinical studies have determined that one of the most consistent effects of ethanol is its disruption of hippocampal neurogenesis. However, the severity, persistence, and reversibility of ethanol\u2019s effects on hippocampal neurogenesis are dependent on developmental stage of exposure and age at assessment. Complicating the neurodevelopmental effects of ethanol is the concurrent development and maturation of neuromodulatory systems which regulate neurogenesis, particularly the cholinergic system. Cholinergic signaling in the hippocampus directly regulates hippocampal neurogenesis through muscarinic and nicotinic receptor actions and indirectly regulates neurogenesis by providing anti-inflammatory regulatory control over the hippocampal environmental milieu. Therefore, this review aims to evaluate how shifting maturational patterns of the cholinergic system and its regulation of neuroimmune signaling impact ethanol\u2019s effects on adult neurogenesis. For example, perinatal ethanol exposure decreases basal forebrain cholinergic neuron populations, resulting in long-term developmental disruptions to the hippocampus that persist into adulthood. Exaggerated neuroimmune responses and disruptions in adult hippocampal neurogenesis are evident after environmental, developmental, and pharmacological challenges, suggesting that perinatal ethanol exposure induces neurogenic deficits in adulthood that can be unmasked under conditions that strain neural and immune function. Similarly, adolescent ethanol exposure persistently decreases basal forebrain cholinergic neuron populations, increases hippocampal neuroimmune gene expression, and decreases hippocampal neurogenesis in adulthood. The effects of neither perinatal nor adolescent ethanol are mitigated by abstinence whereas adult ethanol exposure-induced reductions in hippocampal neurogenesis are restored following abstinence, suggesting that ethanol-induced alterations in neurogenesis and reversibility are dependent upon the developmental period. Thus, the focus of this review is an examination of how ethanol exposure across critical developmental periods disrupts maturation of cholinergic and neuroinflammatory systems to differentially affect hippocampal neurogenesis in adulthood. This rsee . The devsee (see ). One resee  . Ethanol exposure exerts adverse consequences on the brain throughout the lifespan, with deficits evident from exposure during perinatal development through adulthood. The spectrum of ethanol\u2019s adverse effects produces enormous individual, interpersonal, and societal costs. For example, the robust teratogenic effects of ethanol exposure egnancy)  makes feegnancy) . Of noteegnancy) . Furtheregnancy) . The preegnancy) . Howeverncy) see.Each section of this review will discuss the adult impact of ethanol exposure on these systems during discrete neurodevelopmental windows: perinatal, adolescence, and adulthood. Incubation effects, persistence, and reversibility will be discussed, with sex differences highlighted when applicable. The goal of this review is to highlight the molecular underpinnings of ethanol\u2019s impact on hippocampal neurogenesis across the continuum of the lifespan.in utero and neonatal) development induce long-lasting neurodevelopmental consequences on neurological structure and function due to alterations in development of neurocircuitry and other neurobiological systems, permanently shifting maturational trajectories in both the brain and body. One of the most ubiquitously known teratogens is ethanol, and the consequences of ethanol exposure during perinatal development are devastating. These consequences were first documented in 1968 by Paul Lemoine , therebirth see.see . In addThe myriad of developmental and pharmacological variations in rodent FASD models complicates translation of findings to the human literature, particularly when results vary by experimental design. For example, the characteristic facial dysmorphology evidenced in children with FASD  has been specifically linked to ethanol-induced cell death during early embryonic exposure (mouse embryonic days 7\u20139)  are not see , findinsee see. Althougsee see. As suchsee see. The lacseeHuman studies of FASD indicate prior alcohol exposure results in attenuated age-related increases in hippocampal volume across adolescent development . HoweverseeFuture studies will need to elaborate on these findings, particularly in relation to perinatal ethanol-driven effects on adult hippocampal neurogenesis versus gliogenesis as well as potential sensitivity differences in males versus females. Examination and reporting of both sexes is particularly critical, as some studies have found differences solely in one sex but not the other see. For exaseeThe cholinergic system rapidly develops during the early neonatal period in rodents see, and is 1) ethanol-induced decreases in adult basal forebrain cholinergic neurons may result from caspase-3-mediated apoptotic cell death during critical neonatal developmental windows, and 2) reductions in adult populations of basal forebrain cholinergic neurons after neonatal ethanol exposure do not recover despite long periods of abstinence. These findings have been reproduced across a variety of mammalian species, from mice to primates, suggesting a high level of congruency in this literature. Moreover, neonatal ethanol-induced loss of basal forebrain cholinergic neurons is accompanied by diminished evoked acetylcholine efflux in the adult hippocampus as assessed using in vivo microdialysis, indicating that perinatal ethanol exposure persistently disrupts basal forebrain-hippocampal cholinergic neurocircuitry  the critical role of acetylcholine in neurogenesis, 2) the likely contribution of acetylcholine reductions to loss of neurogenesis in these model, and 3) the therapeutic potential of compounds which target the cholinergic system in FASD.Loss of basal forebrain cholinergic neurons and subsequent diminution of acetylcholine efflux in the hippocampus have critical implications for cognitive and behavioral deficits in FASD and preclinical models of FASD. For example, deprivation of choline, which is an essential nutrient and critical component of acetylcholine synthesis, exacerbates perinatal ethanol-induced deficits in motor development in early life . Conversult rats . This suult rats , furtherOne of the mechanisms by which perinatal ethanol-induced disruption of basal forebrain-hippocampal cholinergic neurocircuitry may affect adult hippocampal neurogenesis is through long-term alterations in cholinergic receptor activation in adulthood. Both muscarinic and nicotinic receptors directly affect neuroprogenitor pools and indirectly regulate the hippocampal environmental milieu. Muscarinic M1 receptors are abundant in the adult hippocampus, where they colocalize with newborn cells in the dentate gyrus to play a key role in hippocampal cell proliferation . In factInterestingly, the sole study reporting that ethanol exposure across gestation decreases adult cell proliferation  parallelIn contrast to muscarinic receptors, nicotinic receptors have received little attention in relation to the lasting effects of perinatal ethanol exposure, with a single study reporting that hippocampal \u03b17 nicotinic receptor density in adulthood is unaffected by perinatal  ethanol exposure . Howeversee . While see . Microglsee . Interessee . Future Specifically, prenatal ethanol exposure increased CCL6, IL-21, IL-10ra, and TNF\u03b1 expression in the developing brain of male and female rats, relative to age-matched controls, on E17 , with feThe effects of perinatal ethanol on innate immune activation are further exacerbated in adulthood. This is in part due to the fact that perinatal ethanol has cascading repercussions on immune regulation of the developing cholinergic system to impact later neuroimmune signaling dynamics in adulthood. For example, some studies suggest perinatal ethanol sensitizes later innate immune gene responses in adulthood, in part due to diminished capacity for cholinergic anti-inflammatory feedback that leads to an exaggerated proinflammatory neuroimmune response. Prenatal ethanol exposure  dramatically exacerbates the adult response to modest innate immune challenges (25\u00a0\u03bcg/kg lipopolysaccharide [LPS]), evidenced by exaggerated hippocampal gene expression of IL-1\u03b2 and IL-6 in male rats but not female rats, relative to controls . SimilarIn addition, persistent increases in CCL2 signaling  by perinseeCollectively, these findings indicate that perinatal ethanol-induced acute induction of proinflammatory signaling cascades may be an early underlying factor in developmental cholinergic deficits by contributing to their programmed cell death during rodent neonatal or human third-trimester development. In adulthood, these developmental deficits in cholinergic function may unmask greater impairments under conditions of neuronal stress, potentially through alterations in muscarinic and nicotinic receptor activation and consequential augmented disruption of the proinflammatory signaling in the hippocampal environmental milieu, reflecting a vicious cycle that may drive both impairments in neurogenesis and greater cognitive deficits in high-complexity tasks see.1) ethanol-induced alterations during perinatal development persistently impact development by changing gene transcription, 2) some consequences of perinatal ethanol will emerge over time in conjunction with developmental changes in epigenetic regulation of gene expression, and 3) pharmacological interventions which aim to reverse perinatal ethanol-induced developmental effects will be most effective if they also reverse perinatal ethanol-induced epigenetic changes.Children with FASD have several complications due to large-scale cell death induced by prenatal alcohol exposure coupled with broad shifts in epigenetic regulation of gene expression. Epigenetics is the modulation of gene expression in the absence of alterations to DNA, making it a master director of brain development by altering gene accessibility to transcriptional machinery across time . For exaThe emergence of ethanol\u2019s cascading consequences on neurodevelopment over time complicates interventions aimed at reversal of neurological and behavioral deficits in models of FASD. In fact, the majority of current pharmacological intervention strategies approved for children with FASD target other neuropsychiatric comorbidities, such as the use of stimulants for the highly co-morbid diagnosis of attention deficit hyperactivity disorder in FASD children, with few treatment strategies aimed to prevent or reverse FASD pathophysiology itself . These cThe positive preclinical effects of choline supplementation on FASD behavioral and neurological outcomes have given it a spotlight in clinical trials, several of which are ongoing . HoweverAdolescence is a period of rapid brain maturation with extensive myelination, synaptic pruning, and neurogenesis, highlighting that remodeling of molecular circuitry is a critical component of this developmental period that parallels rapid behavioral and cognitive growth . Adolesc1) National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), which evaluates the progressive disruption of neurodevelopment and behavioral alterations with alcohol exposure across adolescence in humans, and 2) the Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium, which uses rodent models of adolescent intermittent binge ethanol exposure to examine mechanisms underlying ethanol\u2019s long-term molecular and cognitive-behavioral changes in adulthood (via an intermittent dosing regimen that results in the high BECs (>150\u00a0mg/dl) that are achieved in human adolescents . Findinnts (see ). This sNeurogenesis during adolescent development is on average four-fold greater than during early adulthood , and thisee  a failure to assimilate signals driving successful integration into existing hippocampal circuitry or 2) hypersensitivity to the stimulation of cell death executioner pathways.The enduring loss of hippocampal newborn neurons after AIE most likely involves both subtle disruptions in the neuroprogenitor cell proliferating pool as well as more robust findings involving decreased survival of neuroprogenitors as they differentiate into neurons and integrate into hippocampal circuitry  expression of pNF-\u03baB p65 . This phAdolescent binge ethanol exposure causes a loss of basal forebrain cholinergic neurons immediately following the conclusion of ethanol treatment  that persists well into adulthood , paralleling AIE-induced lasting reductions in hippocampal neurogenesis and proinflammatory induction. The observed 20\u201330% reduction in basal forebrain cholinergic neuron number following adolescent binge ethanol exposure is consistent across both mouse and rat studies  in both 1) concurrent induction of caspase activity of these neurons during critical neurodevelopmental windows during the brain\u2019s growth spurt, and 2) failure to restore ChAT immunoreactivity with pharmacological or environmental interventions . In parorebrain . Similarorebrain .Both HMGB1 and phosphorylation of NF\u03baB p65/p50 have been implicated in pathways that modify epigenetic machinery, although their roles are complex, depending in part on co-activation of other factors. Thus, HMGB1 and NF\u03baB p65/p50 can have distinct functions under normal physiological versus pathological conditions. For example, under normal physiological developmental conditions, nuclear HMGB1 promotes the formation of transcription complexes by overcoming limitations with tightly bent DNA . In contseeEthanol-induced epigenetic silencing shines light on potential mechanisms for recovery with interventions that reverse this epigenetic silencing , and in Despite the loss of basal forebrain cholinergic neuron phenotype, behaviorally-evoked acetylcholine in the hippocampus during reversal learning in adulthood is slightly, but non-significantly, blunted by prior adolescent binge ethanol exposure . This fivia decreased nAChR\u03b17 activation on immunocompetent glia is at the juncture of both persistent inductions in neuroinflammatory signaling cascades, induction of apoptotic executioner caspases, and reductions in survival of adult newborn neurons.Adolescent brain maturation shows developmental reductions in nicotinic cholinergic receptor expression . InteresseeAIE persistent induction of neuroimmune genes as well as reduction in hippocampal neurogenesis corresponds with impairments in a variety of learning and memory tasks, including discrimination learning  and reveDuring the adolescent developmental period, changes are governed by alterations in epigenetic regulation of cholinergic and neuroimmune genes, driving an environmental imbalance in the hippocampal environmental milieu which is unfavorable to the successful adult birth, maturation, and integration of newborn hippocampal neurons. This suggests that in the absence of intervention, both adolescent ethanol-induced loss of neurogenesis , basal fAlcohol use disorder (AUD) is highly prevalent in Western society, with estimates of up to 29% of adults suffering from AUD at some point in their lifetime . This disee , rodentsee . CollectPreclinical studies indicate that adult chronic binge ethanol exposure decreases hippocampal neuroprogenitor cell proliferation and neurogenesis  even in seeAdult ethanol-induced suppression of hippocampal cell proliferation is further complicated by withdrawal periods, as there is some evidence for a brief burst in cell proliferation 1\u00a0week into abstinence . Howeverin vivo microdialysis studies in adults after long-term 3-month ethanol exposure in drinking water, acetylcholine efflux in the hippocampus was significantly reduced by 57%, relative to controls (The basal forebrain cholinergic system is profoundly affected by ethanol during early development, with both perinatal and AIE exposure reducing basal forebrain cholinergic neuron expression in addition to decreasing cholinergic regulation of the hippocampus. However, adult alcohol exposure does not produce as rapid or robust an effect on the basal forebrain cholinergic system. Just as intermittent ethanol exposure across adolescence but not adulthood produces deficits in adult hippocampal neurogenesis , adolesccontrols . This efChronic ethanol exposure in adulthood can also disrupt cholinergic receptors, but this finding is complex and largely depends on subtype. For example, 10 weeks of ethanol consumption decreases hippocampal nicotinic receptor expression independently from altering binding affinity . In contThe loss of hippocampal nicotinic receptor expression could underlie sensitivity to neuroinflammatory induction after chronic ethanol in adulthood, as microglial nicotinic \u03b17 receptors play critical negative feedback role for proinflammatory cascades. Thus, loss of activation at nicotinic \u03b17 receptors is suggestive of a loss of anti-inflammatory feedback and chronic induction of proinflammatory signaling cascades in the brain of individuals with AUD. In support of this concept, an increase in neuroinflammation in post-mortem human brains with AUD is one of the most prevalent clinical findings , and prephox NADPH oxidase subunit, TNF\u03b1, and IL-1\u03b2 as well as greater morphological changes in microglia (The effect of ethanol on hippocampal neuroinflammation can be magnified under conditions which challenge the immune system, such as a LPS or polyI:C innate immune challenge. Ten days of intragastric administration of ethanol in mice potentiates proinflammatory responses in brain to a lipopolysaccharide-TLR4 innate immune challenge which included CCL2, COX-2, gp91icroglia . Similaricroglia . These nicroglia . NeuroimTherapeutics under investigation for AUD often exhibit anti-inflammatory components. Given the critical role of the cholinergic system in regulating anti-inflammatory feedback, it is unsurprising that many of these restorative interventions center around the cholinergic systems. Rodent and human studies suggest successful therapeutic targets at both cholinergic muscarinic M4 receptors  and nicoThese mechanisms linking neuroinflammation and neurogenesis are particularly important when examining sex differences as human females are more likely than men to experience organ damage following long-term alcohol use, including greater brain damage in general and more specifically loss of hippocampal volume , and areThe molecular mechanisms of ethanol-related neuronal damage and related intervention strategies circulate around the cholinergic system, neuroinflammation, and the mechanistic mediators of these systems on hippocampal neurogenesis regardless of developmental window, suggestive of certain central commonalities within the effects of ethanol on these systems. However, across the neurodevelopmental landscape, while the mechanisms may overarchingly be consistent, various systems display differing sensitivities in the magnitude and reversibility of ethanol-related disruptions. For example, in models of FASD, ethanol produces seemingly irreversible deficits in the cholinergic system, and one of the key factors in treatment for FASD focuses on preventing rather than reversing this neuronal damage. If unmitigated, the irrecoverable loss of cholinergic neurons is a hindrance to the functional recovery of ethanol-related damage, and later life consequences of this disruption include greater neuroinflammatory responses and decreases in neurogenesis when neural systems are challenged. As females tend to be diagnosed with FASD later than males, this suggests that intervention strategies may be particularly difficult for this population as females have a greater likelihood of missing early intervention therapeutic windows.In contrast, adolescence is marked by epigenetic-mediated suppression of basal forebrain cholinergic phenotypes, which is exciting from a therapeutic standpoint as reversal of epigenetic machinery in cholinergic neurons similarly restores their phenotypic expression, which consequently also restores the hippocampal neuroinflammatory-trophic balance as well as ethanol-mediated deficits in hippocampal neurogenesis. This balance between persistence and reversibility after adolescent ethanol exposure highlights a shift in the mechanisms driving ethanol-induced loss of hippocampal neurogenesis and neurocognitive impairments from the cholinergic system as the central mediator to neuroimmune dysregulation playing a greater role.This shift becomes more apparent in adulthood, where hippocampal neuroimmune induction in both preclinical models and in human postmortem tissue from individuals diagnosed with AUD persists long after ethanol exposure and seem to drive long-term cellular consequences, including hippocampal damage and deficits in neurogenesis. While abstinence reverses some of these deficits in males, females exhibit greater sensitivity to ethanol-related brain damage, with emerging studies finding that females require more aggressive intervention strategies than males.in utero or in adolescence increases drinking behaviors at later developmental windows (The shifts in vulnerability of cholinergic versus neuroimmune systems over development suggests that efficacy of interventions aimed at restoring ethanol-related damage to hippocampal neurogenesis and cognitive function must take a developmental approach. However, a limitation of preclinical models of FASD, adolescent binge drinking, and AUD is that often alcohol exposure in humans is not isolated to a single developmental period. In fact, prior exposure to ethanol either  windows . Thus, a windows . This do"}
+{"text": "Objective: To examine differential relationships between communication technology use and social connectedness among paid and unpaid caregivers providing care for middle-aged and older adults. Methods: This nationwide study utilized a cross-sectional Qualtrics panel survey from caregivers, ages 50 years and older (n=504) of middle-aged and older adults. About 17% were paid (n=86) and 83% (n=418) were unpaid caregivers. Primary outcomes were caregivers\u2019 sense of belonging to their local community and social bonds. The primary predictor of interest was caregivers\u2019 use of communication technology (texting/communication applications). A multivariable regression analysis was performed to predict each outcome based on communication technology use, separately among paid and unpaid caregivers. Multivariable regression analyses were repeated after including the caregivers\u2019 payment status (paid/unpaid) and the interaction term between the caregivers\u2019 payment status and the use of communication technology. The models were adjusted for caregivers\u2019 age, education, financial status, place of residence, and total weekly hours of caregiving. Results: Use of communication technology had a statistically-significant positive association with sense of belonging only among paid caregivers . The relationship between use of communication technology and sense of belonging was significantly different between paid and unpaid caregivers (p=.005). Use of communication technology was significantly associated with social bonds only among unpaid caregivers . There was no statistically-significant differential association between communication technology use and social bonds. Conclusion: Communication technology may play differential roles in linking paid and unpaid caregivers with their community and interpersonal groups. Additional efforts should examine mechanisms that provide meaningful caregiver support."}
+{"text": "They report optimized diffusion at an intermediate temperature between cryogenic and room temperatures. Most commendably, they combined results from three distinct optical techniques to support their hypothesis for this non-monotonic temperature dependence. Photoluminescence measurements suggested phonon scattering was the predominant impediment to transport at higher temperatures, while Raman characterization of micro strains indicated that a 2D disorder potential was the primary obstacle at lower temperatures. Pump probe experiments and associated theoretical modeling were performed to further corroborate the hypothesis. While open questions remain on exciton transport in TMD monolayers, new and exciting opportunities are emerging for controlling exciton transport in van der Waals heterostructures.Excitons\u2014charge-neutral quasiparticles comprised of bound electron hole pairs\u2014can be formed within a wide range of semiconductors, including monolayer transition metal dichalcogenides (TMDs). The ongoing development towards practical excitonic devices necessitates a fundamental understanding of exciton transport in TMDs. Excitons in TMD monolayers exhibit ultrafast population relaxation times and correspondingly short diffusion lengths. In their article, Qi, Luo, and coworkers investigated how phonon scattering and disorder influence exciton diffusion in a WSe"}
+{"text": "Persistent postoperative pain (PPP) after cardiac surgery is a significant complication that negatively affects patient quality of life and increases health care system burden. However, there are no standards or guidelines to inform how to mitigate these effects. Therefore, in this review, we will discuss strategies to prevent and manage PPP after cardiac surgery. Adequate perioperative analgesia may prove instrumental in the prevention of PPP. Although opioids have historically been the primary analgesic approach to cardiac surgery, an opioid-sparing strategy may prove advantageous in reducing side effects, avoiding secondary hyperalgesia, and decreasing risk of PPP. Implementing a multimodal analgesic plan using alternative medications and regional anesthetic techniques may offer superior efficacy while reducing adverse effects. According to the International Association for the Study of Pain, PPP is defined as pain that persists beyond 3 months after surgery, can be continuous or intermittent, and is attributable to the surgical insult, excluding other potential etiologies. Up to 43% of patients suffer PPP at 3 months after cardiac surgery. A meta-analysis that included 11\u2009057 cardiac surgical patients across 23 studies demonstrated a 37% incidence of PPP in the first 6 months and up to 17% at 2 years after surgery. A retrospective analysis of 35\u2009817 cardiac surgical patients registered in a national administrative claims database of private payers revealed that nearly 1 in every 10 patients who were previously opioid na\u00efve developed opioid use that persisted >3 months after surgery and associated higher oral morphine equivalents prescribed with an increased risk of persistent opioid use. Patients with PPP experience decreased health-related quality of life, effectively rendering the surgical intervention a means to displace the focus of their suffering instead of alleviating it. Beyond suffering, pain impedes critical postoperative rehabilitation, resulting in functional disability that prevents return to work and a normal life. On a larger scale, PPP can result in medicolegal actions, disparate economic impact, and increased medical costs and resource utilization.Persistent postoperative pain (PPP) is a devastating complication that affects both patients and health care systems. The incidence of moderate to severe PPP can vary widely based on surgery type, from <5% to >80% of cases performed. Risk factors for PPP after cardiac surgery include young age, female gender, preexisting pain, anxiety, a catastrophizing mindset, higher body mass index, and a history of osteoarthritis.7 Of note, more intense acute postoperative pain has been associated with a greater incidence and severity of PPP.7Of cardiac surgical patients with PPP, half have reported it to be moderate to severe and most have described it as neuropathic in quality, the primary location of pain in the chest, the next being the leg in patients having undergone saphenous vein harvesting.9 Likewise, aggressive preventive analgesia has been associated with decreased PPP. Therefore, adequate understanding and management of perioperative pain constitutes a fundamental strategy in PPP prevention following cardiac surgery. Risk factors for acute postsurgical pain include young age, longer duration of surgery, and thoracotomy, as compared with surgical access at other sites  receptor blocking activity of methadone, which has been associated with the prevention of opioid-induced hyperalgesia. A perioperative, opioid-sparing strategy utilizing analgesic alternatives and adjuncts may ultimately mitigate the risk of developing PPP and additional opioid-induced side effects, while also conferring additional benefits versus opioids alone.24 It is important to clarify, however, that prevailing evidence and expert opinion support opioid-sparing but not opioid-free techniques. Not only do opioids, when dosed in moderation, have longstanding efficacy, the absolute avoidance of them has actually been shown to cause harm.Cardiac anesthesia has historically relied on significant opioid administration due to their potent analgesia amid a favorable hemodynamic profile,tion see .15 Whe24 Acetaminophen, gabapentinoids, and ketamine have all been previously described as providing both effective analgesia and offering opioid-sparing benefit.28 Rafiq and colleagues conducted a prospective randomized controlled trial (RCT) examining multimodal analgesics versus opioids following cardiac surgery through median sternotomy. The authors found a combined regimen utilizing dexamethasone, gabapentin, ibuprofen, and acetaminophen provided superior analgesia (decreased numeric rating pain scores) through postoperative day 3 and decreased incidence of nausea and vomiting versus morphine and acetaminophen alone. Despite these findings during the acute pain period, a recent systematic review and meta-analysis regarding gabapentinoids observed no clinically significant analgesic effect to support their routine perioperative use. Further literature remains limited or not yet assessed regarding gabapentinoid use in the prevention of chronic poststernotomy pain.30The application of multimodal analgesics may play particular importance in preventing PPP as this more inclusive approach has been described as providing optimal acute pain management with potentially fewer side effects when compared with a traditional opioid-based strategy. With regard to acetaminophen (paracetamol) administration, the authors found 2 of 4 RCTs demonstrating significantly decreased Visual Analogue Scale (VAS) scores and one of these publications demonstrating significantly decreased opioid consumption.3134 Of 3 RCTs examining nonsteroidal anti-inflammatory drug (NSAID) analgesics and cardiac surgery, 2 trials demonstrated decreased VAS, and opioid consumption with NSAID use.36 Although the authors acknowledge the literature remains sparse regarding acetaminophen and NSAID use specific to cardiac surgery, Bignami and colleagues conclude that the use of multimodal analgesia provides synergistic pain relief with fewer adverse effects. Although VAS scores permit readily obtainable data gathering, more comprehensive assessments including functional and disability data may provide more reliable and objective measures in assessing pain. Direct comparisons of differing pain-related studies are often complicated by heterogeneity in outcome assessment and the use of non-patient-centric endpoints such as morphine equivalents. There are numerous validated patient satisfaction and quality of life questionnaires that better capture more meaningful outcomes related to improved pain control rather than relying on VAS scores alone.39A subsequent systematic review conducted by Bignami and colleagues examined perioperative pain management modalities and cardiac surgery including multimodal analgesics. Among the 40 RCTs with analgesics including NSAIDs, gabapentin, pregabalin, lidocaine, steroids, ketamine, NMDA blockers, fentanyl, nitrous oxide, venlafaxine, and the antiarrhythmic mexiletine, only intravenous ketamine provided a statistically significant, albeit modest, reduction in the incidence of postsurgical chronic pain. In a subsequent review of postoperative chronic pain prevention, Reddi similarly concluded that ketamine may reduce chronic pain after surgery while suggesting gabapentin and pregabalin as promising but requiring additional robust studies prior to recommendation. In a recent review of chronic poststernotomy pain, Kleiman and colleagues similarly found no evidence to support the use of transdermal lidocaine, glucocorticoids, or dexmedetomidine in decreasing chronic pain. In contrast, the authors acknowledge the effectiveness of acetaminophen, gabapentinoids, and ketamine in providing opioid-sparing analgesia, but describe their utility in preventing chronic poststernotomypain as limited or not yet examined.Beyond the acute postoperative period, the role of systemic pharmacologic therapies in preventing the development of chronic pain after surgery has also been examined. Chaparro and colleagues conducted a meta-analysis of RCTs with systemic drugs administered perioperatively and evaluated pain 3 or more months following surgery. Multimodal analgesics have often been combined with targeted regional anesthetic techniques to reduce opioid requirements, enhance pain control, and potentially reduce systemic analgesics and their accompanying side effects including delirium, hypotension, bradycardia, bleeding, and sedation. Neuraxial anesthesia serves as one regional technique that may be considered in cardiac surgery via thoracic epidural analgesia (TEA) or spinal anesthesia.44 TEA has been shown to provide effective analgesia with decreased VAS scoring and reduced opioid consumption postoperatively,27 yet no evidence supports a definitive decrease in developing chronic pain following TEA or intrathecal opioid administration. The risk of spinal hematoma has historically been shown to be 1:1528 for TEA and 1:3610 for spinal anesthesia, but the risk for TEA has more recently been shown to be as low as 1:3552. The 2018 guidelines released by the American Society of Regional Anesthesiologists states there is insufficient evidence to determine whether the risk of epidural hematoma with neuraxial procedures is increased with the use of the level of anticoagulation required for cardiopulmonary bypass (CPB). The decision to employ neuraxial anesthesia as part of any opioid-reducing analgesic strategy should always consider a risk-benefit calculation regarding epidural hematoma formation in the vulnerable cardiac surgery patient population.49The application of regional anesthesia provides a diverse array of potentially opioid-sparing pain management methods in accordance with a multimodal analgesic strategy. The ability to administer local anesthetics through regional anesthesia may be particularly favorable in high-risk surgical candidates as these techniques may reduce or outright avoid adverse effects associated with opioid administration.4952 The risk of epidural hematoma formation proves notably relevant within cardiac surgery due to the frequent anticoagulation requirement for patients undergoing cardiopulmonary bypass. Similar to TEA, there exists no evidence to support thoracic PVB in the prevention of chronic poststernotomy pain.Thoracic paravertebral block (PVB) serves as alternative regional anesthetic technique utilized for analgesia related to cardiac surgery. Thoracic PVB consists of a type of peripheral nerve block with option for continuous catheter placement similar to TEA, yet PVB may be performed under direct ultrasound guidance. When compared with TEA, thoracic level PVB has been found to provide comparable analgesic efficacy and improved side effect profile, including theoretically less risk of epidural hematoma formation in the anticoagulated patient.27 without effect on chronic pain development. Similarly, ultrasound-guided parasternal intercostal nerve block performed presternotomy has demonstrated significantly lower postoperative pain scores versus saline injection or nonregional, morphine-based regimen. Studies assessing intrapleural block for sternotomy pain are limited, and similar to continuous wound catheters, have not yet examined their relationship with regard to developing PPP.Various other regional anesthetic techniques including emerging, ultrasound-guided peripheral nerve blocks have been applied for poststernotomy analgesia and cardiac surgery at large. Surgeon administered parasternal block has been shown to provide improved postoperative analgesia and reduced opioid requirements,55 The erector spinae plane (ESP) block presents a novel fascial plane block that was first described in 2016 for thoracic neuropathic pain and has since been applied as an easier to perform alternative to PVB to multiple procedure types involving the chest wall and abdomen.57 Few clinical studies assessing the ESP block for cardiac surgery have taken place, but initial data reveal promising analgesic efficacy and reduction in opioid consumption, while the need for replication via blinded RCTs persists.58 Similar analgesic studies have evaluated both the pectoral nerve and serratus anterior fascial plane blocks with encouraging results. The pectoralis (Pecs) nerve block entails dual interfascial plane injections (Pecs I and Pecs II) with the aim of anesthetizing the chest wall. Kumar and colleagues examined postoperative bilateral pectoralis nerve block following midline sternotomy, demonstrating both significantly decreased duration of ventilator dependence and improved pain scores utilizing the regional technique. Currently, no published evidence exists evaluating the more laterally performed serratus anterior nerve block approach specific to sternotomy pain, yet studies have shown improved pain scores following other thoracic surgical interventions.Promising, emerging peripheral nerve blocks of the chest wall occur most often using direct visualization with ultrasound guidance, potentially adding to their safe application.62 Through incorporation of multiple individuals, a multidisciplinary, perioperative pain team may optimally treat complex pain through specialization, communication, and education among providers and patients. Such a team would be well positioned to combine clinical management with pain research.In addition to the consulting anesthesiologist\u2019s role in managing opioid-sparing, multimodal analgesia, a multidisciplinary approach may provide the ideal strategy in preventing PPP in the cardiac surgery patient.63 Because mediastinitis has been associated with developing chronic pain, the more selective skeletonization harvest may prove warranted, particularly in the diabetic patient population. Minimizing sternal retractor trauma, removing sternal wires posthealing, and prophylactic sternal plating in high-risk individuals has been suggested to minimize chronic pain contributions. Minimally invasive techniques have been used to decrease the degree of tissue traumatization, acute postoperative pain, intraoperative time, perioperative bleeding, and the incidence of sternal wound infections and recovery time. In addition, the removal of chest drainage tubes on the first postoperative day, as compared with days 2 or 3, has been associated with improved pain scores without an increased risk of requiring chest tube reinsertion.Procedural considerations should be discussed with surgical colleagues as multiple operative variables may influence the development of PPP. For example, obtaining bilateral internal thoracic artery grafts via pedicled harvest rather than skeletonization has been associated with an increased risk of developing mediastinitis after coronary artery bypass graft (CABG). exacerbates acute postoperative pain. Despite the likelihood of a link between this altered pathophysiologic state and sensitization to pain signaling, this mechanism has not been investigated. There have been numerous studies comparing patients having undergone CABG surgery performed either with or without CPB, but none have specifically evaluated differences in pain following these techniques.Surprisingly, it is unknown if the well-described state of heightened systemic inflammation associated with the use of CPB68 Interestingly, patients on cannabinoids may have higher tolerance to opioids and NSAIDs, requiring higher doses.There are some classes of home medications that may affect perioperative analgesia. To optimize analgesia while minimizing relapse and overdose, it is recommended for patients taking low-dose buprenorphine and methadone to continue those medications throughout the perioperative period.7074 Early involvement of a pain psychologist or integrative pain team may offer valuable insights to both identify and address these psychological risk factors outside of the cardiothoracic anesthesiologist and surgeon\u2019s area of expertise.75Addressing patients\u2019 psychological comorbidities may also play a key role within a multifaceted approach to PPP prevention after cardiac surgery. Patients may present with preexisting psychological risk factors for the development of chronic pain including anxiety, depression, posttraumatic stress disorder, and pain catastrophizing.7679 Multimodal analgesia has remained central to ERAS protocols as this strategy may offer decreased opioid exposure in addition to potentially reducing recovery times, complications, and improving cost expenditures with surgery.81 Similarly, regional anesthesia has been increasingly implemented as part of a multimodal strategy in cardiac surgery and related ERAS protocols to reduce opioid consumption.83 The addition of emerging truncal fascial plane blocks for pain optimization presents a promising new area within cardiac ERAS.84 Because cardiac ERAS pathways often highlight opioid-sparing strategies and acute pain management optimization,86 implementation of these protocols aligns with addressing the aforementioned factors thought to contribute to PPP.Many of the aforementioned pain management components and multidisciplinary approach relevant to cardiac-related PPP have been integrated as part of comprehensive, enhanced recovery after surgery (ERAS) protocols. ERAS pathways including those specific to cardiac surgery continue to gain popularity and aim to incorporate multiple objective variables to optimize patient experience, perioperative efficiency, and improve outcomes.Although prevention is likely the most impactful strategy to decrease the burden of PPP after cardiac surgery, this may not always be possible. There are a variety of treatment options for PPP including medications see , surgery88 Indeed, the most updated 2015 Food and Drug Administration (FDA) black box warning for non-ASA NSAIDs advises against their use in patients prior to or after CABG, emphasizing the potentially increased risk for heart attack or stroke in patients with underlying cardiovascular disease. Furthermore, the use of non-ASA NSAIDs for cardiac surgical patients has been associated with acute kidney injury, whereas ASA use has been shown to be protective.Medical management of PPP involves targeting the various pathways and mechanisms of pain. NSAIDs decrease the production of inflammatory cytokines and chemokines such as prostaglandins. This may be particularly helpful in the acute phase of injury for patients, but also plays a role in chronic musculoskeletal pain and associated flares. Both the acute and long-term risks of NSAID use needs to be considered, especially in the cardiac surgery population, and the distinction between acetylsalicylic acid (ASA) and other NSAIDs is warranted. Renal injury, increased risk of myocardial infarction and stroke are all potential adverse events that the cardiac surgery population may already have a higher baseline risk for developing when using non-ASA NSAIDs. There is evidence that it inhibits COX centrally and acts through other non-COX mechanisms as well. This agent has a better safety profile without a demonstrated association with hepatic dysfunction, although caution should be taken in patients with acute liver injury.Acetaminophen or paracetamol is a known cyclooxygenase (COX) inhibitor, although it does not exert its effect through peripheral inhibition of this enzyme as the non-steroid anti-inflammatory class of medications.5 These agents have a generally favorable safety profile with nausea, sedation, and dizziness being some of the more common side effects and caution should be taken for patients with baseline renal dysfunction.Gabapentin and pregabalin bind to the alpha2delta subunit of calcium channels and are used in treating many different types of chronic pain. They are most well studied and effective for neuropathic pain. For cardiac surgery patients that have a neuropathic component to their pain, these may be a reasonable treatment option and studies have shown that approximately half of cardiac surgical patients with PPP do have a neuropathic component to their pain. The primary site of action is likely augmentation of the descending inhibitory pathways, although there are likely additional mechanisms of action that provide analgesic benefit. SNRIs including duloxetine have been studied for a variety of neuropathic pain conditions and shown to provide significant benefit. For most patients, SNRIs are better tolerated and have a better side-effect profile when compared with TCAs.Additional neuropathic agents including serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) may also play a role in the management of PPP that has a significant neuropathic component.There is limited evidence regarding the use of dexamethasone specifically regarding the treatment postoperative pain in cardiac surgery patients. One randomized double blinded, placebo-controlled study of 300 postoperative patients who had coronary revascularization surgery did not find a difference in opioid consumption or severity of postoperative pain for the first 2 days after surgery. Patients should have treatment goals that may include pain reduction and functional improvement and they should respond favorably to low doses of opioids. Practically, the number of patients who should require and would benefit from chronic opioid therapy is likely low, although this has not been studied in this population.Chronic application of opioids needs to be carefully weighed with the risks. Chronic use needs to be carefully monitored and the appropriateness of ongoing therapy evaluated by pain management specialists.99 Cryoablation of neural tissue has been utilized for treatment of various painful conditions. The first study of cryoablation of the intercostal nerves was done in 1980 for pain associated with thoracotomy and reported significantly reduced analgesic use in the group that received the intercostal cryoablation. Perhaps the most relevant study pertinent to this review was done in 2000 for patients undergoing minimally invasive cardiac surgery via minithoracotomy. This study reported reduced pain scores, although no difference was seen in analgesic consumption. Neuromodulation is a field that has continued to develop and there are case reports and small studies of patients who may benefit for spinal cord stimulation for chronic, refractory angina or in one case truncal complex regional pain syndrome following sternotomy.103 A limitation of these techniques may be anticoagulation for patients with cardiovascular disease and further research is needed to determine which patients would benefit most from these advanced and more invasive techniques. Surgery can also be an option for a small subset of patients who have a clear mechanical component to their pain. This would include patients with sternal malunion or sternal wire fracture, although these are relatively rare complications and are likely not significant contributors to PPP for most patients.Beyond medical management, interventional pain procedures may be appropriate for certain patients. Patients who have had a minimally invasive procedure performed via thoracotomy may develop intercostal neuralgia or post-thoracotomy pain. Treatment with intercostal nerve blocks, paravertebral blocks, trigger point injections, or thoracic epidural steroid injections may be treatment options. Treatment of chronic pain is an off-label use for most of these therapies given the relatively limited evidence, but for patients with refractory pain they may be appropriate to trial. Depending on the characteristics and location of the patient\u2019s pain, topical agents such as lidocaine, diclofenac, or capsaicin can be considered. In patients with muscle spasms or myofascial pain, muscle relaxants  can provide some symptom relief. Physical therapy is important for recovery in strength and function after surgery, but there can be further benefits for patients who go on to develop chronic pain. Dry needling can target pain with a myofascial component and therapists can work to improve function in patients who are deconditioned due to inactivity from their pain. Psychological therapy in the form of cognitive behavioral therapy, cognitive function therapy, acceptance and commitment therapy, biofeedback, and mindfulness can be helpful for patients with chronic pain, particularly when there are complicating psychosocial factors. The importance of a comprehensive approach to the treatment of chronic pain with therapy , medication, interventions, and adjunctive therapies cannot be understated.For refractory neuropathic pain antiepileptic agents , NMDA receptor antagonists such as memantine and infusions including ketamine or lidocaine are treatment options to consider.PPP and opioid use remain vital pain management concerns in providing optimal anesthetic care surrounding cardiac surgery. Further best practices data are required through future research study in multiple areas including the following:Further studies identifying patient risk factors for the development of PPP after cardiac surgeryResearch needed to assess the effect of cardiac surgical procedure type and intraoperative interventions on pain outcomesResearch examining the inflammatory state and role of intraoperative CPB use in the development of chronic painResearch addressing the consequence of acute pain management and its effect on the development of PPPLarge-scale RCTs assessing systemic, multimodal analgesics in the development of chronic pain following cardiac surgeryLarge-scale RCTs evaluating regional anesthesia applied to cardiac surgery and the development of chronic painHead-to-head comparative studies assessing novel, ultrasound-guided regional anesthetic techniques with cardiac surgeryResearch assessing secondary hyperalgesia therapies as potential preventative measures to developing chronic painResearch needed to assess the effect of psychological and behavioral interventions on the development of chronic postsurgical painLarge-scale RCTs assessing ERAS pathway implementation and the development of chronic painLarge-scale RCTs evaluating neuromodulation and spinal cord stimulator therapy for chronic poststernotomy pain106 Current literature suggests both prevention and treatment of PPP should optimally include multimodal pharmacology, regional anesthesia, and multidisciplinary involvement.62 Future research is required in this vulnerable patient population to confirm best practices in PPP prevention and treatment as part of an enhanced recovery after cardiac surgery pathway.Persistent postoperative pain after cardiac surgery represents a significant complication negatively affecting patients and health care systems. Adequately treating acute pain following cardiac surgery remains paramount as severe postoperative pain and opioid-induced hyperalgesia may increase the risk of developing PPP."}
+{"text": "OBJECTIVES/GOALS: Environmental factors may significantly increase the risk of or buffer against Alzheimer\u2019s disease and related dementias, yet strategies to address cognitive decline and impairment to date largely overlook the role of neighborhoods. This mixed-methods study is the first to examine potential links between access to eateries and cognitive function. The goal is to inform place-specific interventions to help aging individuals reduce risk for cognitive impairment through neighborhood community and design. METHODS/STUDY POPULATION: Following an exploratory sequential mixed-methods design, seated and mobile interviews with 125 adults aged 55-92 (mean age 71) living in the Minneapolis (Minnesota) metropolitan area suggest that eateries, including coffee shops and fast-food restaurants, represent popular neighborhood destinations for older adults and sources of wellbeing. To test the hypothesis that these sites, and the benefits they confer, are associated with cognitive welfare, we analyzed data from urban and suburban dwelling participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study, a national racially diverse sample of older Americans followed since 2003 . RESULTS/ANTICIPATED RESULTS: Qualitative thematic analysis of how older adults perceived and utilized local eateries include sites of familiarity and comfort; physical and economic accessibility; sociability with friends, family, staff, and customers; and entertainment . Quantitative results from multilevel linear regression models demonstrate a positive association between density of eateries and cognitive functioning. Taken together, these results complicate our understanding of fast-food settings as possible sites of wellbeing through social interaction and leisure activities. DISCUSSION/SIGNIFICANCE OF IMPACT: The results contribute new evidence towards an emerging ecological model of cognitive health. Understanding whether and how retail food environments can help buffer against cognitive decline among older adults provides novel opportunities to promote wellbeing in later life through community interventions and neighborhood design."}
+{"text": "Long implicated in aversive processing, the amygdala is now recognized as a key component of the brain systems that process rewards. Beyond reward valuation, recent findings from single-neuron recordings in monkeys indicate that primate amygdala neurons also play an important role in decision-making. The reward value signals encoded by amygdala neurons constitute suitable inputs to economic decision processes by being sensitive to reward contingency, relative reward quantity and temporal reward structure. During reward-based decisions, individual amygdala neurons encode both the value inputs and corresponding choice outputs of economic decision processes. The presence of such value-to-choice transitions in single amygdala neurons, together with other well-defined signatures of decision computation, indicate that a decision mechanism may be implemented locally within the primate amygdala. During social observation, specific amygdala neurons spontaneously encode these decision signatures to predict the choices of social partners, suggesting neural simulation of the partner\u2019s decision-making. The activity of these \u2018simulation neurons\u2019 could arise naturally from convergence between value neurons and social, self-other discriminating neurons. These findings identify single-neuron building blocks and computational architectures for decision-making and social behavior in the primate amygdala. An emerging understanding of the decision function of primate amygdala neurons can help identify potential vulnerabilities for amygdala dysfunction in human conditions afflicting social cognition and mental health. Here weThe amygdala is a collection of nuclei located in the anterior part of the medial temporal lobe. It participates in a range of functions including emotion, learning, memory, attention and reward-guided behavior. Based on its anatomical connections, classical views considered the primate amygdala an interface between (i) hypothalamic and brainstem areas related to endocrine and autonomic functions, and (ii) limbic and neocortical regions related to cognitive functions . The amyEarly lesion studies suggested that amygdala damage in monkeys affects an animal\u2019s ability to identify reinforcing stimuli . SubsequIn the present review, we focus on the neuronal signals mediating the primate amygdala\u2019s more recently acknowledged functions in economic decision-making and in predicting others\u2019 decisions in social contexts. We also consider key factors that influence the reward signals of amygdala neurons, which provide important inputs to decision processes.2Primate amygdala neurons respond to conditioned, reward predicting stimuli and track the changing value of these stimuli during learning . AccordiThese theoretical concepts demand to ask whether conditioned reward processing in amygdala neurons follows reward contingency rather than reward pairing. Lesions in the amygdala make rats insensitive to changes in background reward, indicating a general role in contingency-dependent learning . To follThus, typical reward-conditioned responses in primate amygdala neurons reflect reward contingency rather than stimulus-reward pairing. Such acquired responses to reward-predicting stimuli would constitute useful inputs to neuronal mechanisms underlying informed economic decision-making. The specific mechanisms by which amygdala neurons process reward contingency from comparing stimulus-based reward and background reward remain to be uncovered.3Given that amygdala neurons acquire responses to rewarding events  and thatReward amount scaling is reflected in the responses of primate amygdala neurons to reward receipt : these rThe amygdala neurons reviewed above faithfully identify by their response which reward is the better one in any changing distribution of rewards. This quantitative reward code could provide critical inputs to an economic decision process. An important open question is whether the same amygdala neurons that encode quantitative reward-magnitude information are also sensitive to reward probability. Processing of both reward probability and magnitude in individual amygdala neurons would provide a substrate for computing key statistical properties of reward distributions, including expected value and variance.4The predicted time of future reward fundamentally affects behavior, as evidenced in the temporal difference model of reinforcement learning  and the The forms of sensitivity to temporal reward structure described above would allow amygdala neurons to participate in timing processes underlying learning and decision-making. Recent studies, described below, uncovered time-sensitive amygdala signals in decision tasks that require planning ahead and tracking progress over extended periods ,5. Howev5Neuronal decision processes involve the translation of graded, parametric value signals, reflecting the evidence for the decision, to signals predicting the animal\u2019s categorical choice. Primate amygdala neurons seem well suited to contribute to such reward-based decision processes. As described above, their flexible, context-sensitive value signals provide a substrate for integrating relevant evidence to decision inputs. An explicit choice signal computed from such values could also be broadly distributed by the amygdala, given its diverse efferent connections. Furthermore, lesions studies demonstrated essential amygdala contributions to decision-related processes including reinforcer devaluation ,44, stimIn a series of studies, we examined the activity of primate amygdala neurons in a sequential economic decision-making task ,4,5. In During performance of the save-spend task, a significant number of amygdala neurons predict the monkeys\u2019 save-spend choice on individual trials . These cMore recent findings extend our beginning understanding of the amygdala\u2019s decision functions. One study examined amygdala neurons in monkeys tracking the changing values of multiple visual stimuli and balancing exploration-exploitation decisions . During The data reviewed above suggest that primate amygdala neurons play a much more direct role in decision-making than traditionally thought. Specifically, the observation of explicit value-to-choice transitions in individual neurons  and othe6The best rewards are often distant, requiring careful planning and stepwise, sequential choices to reach internally set goals. In the save-spend task described above , amygdalA distinct type of amygdala neuronal activity observed in the save-spend task explicitly signals the monkeys\u2019 progress through a saving sequence . ProgresThus, the activity of amygdala neurons reflects the value and temporal structure of an animal's plan to obtain distant reward goals, and tracks the stepwise progress toward that goal. By specifying prospective reward goals, these amygdala signals could provide direction for behavioral plans encoded in frontal lobe areas ,55. This7Primates do not only make choices individually but also observe the choices of their social partners. By observing their partners, primates can learn the values of objects to inform own decision-making and to predict their partners\u2019 choices and intentions. The amygdala may play an important role in these social processes. Its neurons process social cues, such as faces  and amygA recent study examined the activity of amygdala neurons in a social situation in which two monkeys observe and learn from each other\u2019s reward-based choices B. BeyondThe observed functional types of amygdala neurons C suggestThe amygdala is unlikely to perform these sophisticated operations in isolation. The anterior cingulate cortex contains neurons that predict partner\u2019s choices during competitive interactions , neuronsThus, recent data suggest important contributions of primate amygdala neurons in social decision-making and predicting others\u2019 choices. These data may help explain the effects of amygdala lesions on social behaviour ,61, the 8The findings reviewed above suggest an emerging account of how amygdala neurons and circuits contribute to individual decision-making and social decision simulation. A role for the primate amygdala in implementing a decision mechanism is consistent with observed value-to-choice conversions in individual amygdala neurons , with adHow do amygdala decision signals relate to decision signals found in other brain structures? The amygdala and orbitofrontal cortex receive prominent sensory inputs from all modalities , which pThe reviewed parallel neurophysiological studies on amygdala decision and social functions also inform the broader question of whether the amygdala is specialized for social behavior, as suggested by the Social Brain Hypothesis , or whetThe decision signals and planning activities in amygdala neurons described above may inform our understanding of amygdala dysfunction in human psychiatric conditions, including mood disorders that impact on the motivation to make decisions and pursue future rewards . The amyNone."}
+{"text": "While the development of communication competencies in medical schools plays a pivotal role in the curriculum, studies show that students\u2019 communication skills and patient-centred attitudes may vary based on gender and ethnicity. The goal of this study was to investigate the socio-demographic factors that influence medical students\u2019 communication abilities and, more specifically, to what extent their attitude toward communication skills learning and patient orientation associate with communication abilities. Our population included medical students admitted in 2017. Used tools included a communication score, the patient-provider orientation and communication skills attitudes scales.. There was a significant association between gender, native tongue, attitudes towards communication skills learning and communication skills OSCE performance. In conclusion, to support medical students to improve their communication proficiency and attitudes towards the importance of clear communication and patient-oriented care, medical educators should consider teaching and assessment strategies that address socio-cultural aspects of communication.Three hundred and sixty-five students participated in the study . Female and German native speaking students had a better communication skills OSCE performance, were more patient-oriented and had more positive attitudes toward communication skills learning than male and non-native speaking students One of the main roles of a physician articulated in national medical curriculum frameworks of learning objectives is being a communicator . DespiteThe main method to assess medical students\u2019 communication skills are the objective structured clinical examinations (OSCEs). Widely used as an outcome measure for academic success in medicine, OSCEs generally assess students\u2019 knowledge and skills in history taking, diagnostic tests interpretation, communication, and physical examinations and were shown to improve students\u2019 communication skills . Given tPhysicians\u2019 competencies are referred to in curriculum documents as medical knowledge, clinical skills and professional attitudes . AlthougMedical students\u2019 declining positive attitudes toward social issues  raise coThe goal of this study was to address this gap and investigate which factors influence medical students\u2019 communication skills OSCE performance and, more specifically, to what extent medical students\u2019 attitudes towards communication skills learning and patient orientation are associated with the communication skills OSCE performance.This is an observational study examining communication competencies of medical students at one German medical school. Students had started studying medicine in 2017 and were in their second or third year of study. At the end of the fourth and fifth semester, students take two in person OSCEs containing ten five minutes stations  , 13 and Socio-demographic data as well as data on attitudes towards communication skills learning and patient orientation were collected as part of a survey conducted electronically at the end of the OSCE.Patient orientation was measured with the patient-provider orientation scale . The insAttitudes towards communication skills learning were assessed with the communication skills attitudes scale (CSAS) . The CSAThe data were collected between July 2019 and February 2020.We report on descriptive analyses of socio-demographic characteristics and communication skills OSCE performance. A one-way between subjects ANOVA/post hoc Bonferroni procedure was conducted to compare the effect of mother tongue on the communication score. We used the T-test to investigate the effect of gender on the communication skills OSCE performance, attitudes towards communication skills learning and patient orientation. Correlation coefficients and backward multiple linear regression models were then calculated to investigate the extent to which gender, mother tongue, attitudes towards communication skills learning and patient orientation are associated with the communication skills score.The sample consisted of 365, 2nd or 3rd year medical students who completed all five stations of the composite communication skills OSCE. Students were aged on average 24.8 (\u00b1\u20093.5) years; the majority were female  and German native speakers .There was a significant effect of mother tongue on students\u2019 communication skills OSCE performance, attitudes towards communication skills learning and patient orientation. The communication skills score of native speakers and bilingual medical students was significantly higher than the communication skills score of non-native speakers. German native speakers reported significantly lower NAS and more positive patient oriented attitudes than bilingual or non-native speakers. Female students scored higher on PAS and the communication skills score, lower on NAS and were more patient oriented than male students. Age seemed to play a role in attitudes development in that older students reported more positive and less negative attitudes towards communication skills learning Table .Table 2DOur regression model explaining 20.7% of the variance revealed that expressing less negative attitudes towards communication skills learning, being a native speaker, and female gender were significantly associated with a higher communication skills score. Positive attitudes, age and patient orientation were excluded from the model due to lack of statistical significance Table .Table 3RA composite OSCE focused on communication skills was developed to investigate associations between medical students\u2019 communication skills OSCE performance, attitudes towards communication skills learning, patient orientation and socio-demographic characteristics.In our study, we found gender differences in the communication skills score in favour of women, a finding which is in line with previous research , 16, 17.Native speakers as well as bilingual students had significantly better communication skills scores than non-native speaking students. This gap in exam results was also observed in studies from the Netherlands and the UK, which showed that students that belonged to specific ethnic minority groups underperformed in communication and clinical problem-solving tests , 18. LanThe communication skills score in our study was associated with less NAS, a finding which is congruent with previous research that indicated a link between poorer communication skills and less patient-centred attitudes . BesidesIn conclusion, medical educators need to consider different curriculum design approaches to address attitudes and socio-cultural aspects of communication skills. Such approaches include: supporting peer assisted learning and assessment methods  to encouThis study was conducted at one university in Germany. However, research results are coherent with previous international findings and therefore relevant to an international audience of medical educators. This is a cross-sectional study on students\u2019 communication skills in the first half of their studies. A longitudinal study design that allows the observation of attitudes and skills evolution could strengthen claims of decline in communication skills as students progress towards graduation. Finally, we used a validated tool for the self-reporting of attitudes towards communication skills learning. A direct observation of attitudes may have yielded a more robust assessment. Future research should address these gaps as well as the effectiveness of curriculum interventions as proposed above by using both quantitative and qualitative research methods."}
+{"text": "As examples, the present commentary tries to integrate responses of AHR and NAD+-consuming enzymes  into infectious and stress-induced inflammatory responses, the latter exemplified by nonalcoholic fatty liver disease (NAFLD). TCDD toxicity models in sensitive species provide hints to molecular AHR targets of energy metabolism including gluconeogenesis and glycolysis. AHR research remains challenging and promising.Aryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of various physiologic AHR functions. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to exert cellular stress-mediated sterile inflammatory responses in exposed human tissues but may be lethal in sensitive species. Inflammation can be thought of as the extreme end of a spectrum ranging from homeostasis to stress responses (sterile inflammation) and to defense against infection (infectious inflammation). Defense against bacterial infection by generation of reactive oxygen species has to be strictly controlled and may use up a considerable amount of energy. NAD Aryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of various physiologic AHR functions. AHR has been characterized as ligand-activated, multifunctional transcription factor and environmental sensor  is known to exert sterile inflammatory responses in exposed tissues  the commentary tries to integrate functions of AHR and NAD+-consuming enzymes in infectious and sterile inflammatory responses. TCDD toxicity models in sensitive species are discussed since they provide hints to molecular AHR targets in energy metabolism.Elucidation of AHR functions is challenged by dependence upon cell type, cellular context, and species differences, the latter suggested by TCDD toxicity in sensitive species leading to wasting syndrome and lethality  or a chain of ADPR units to proteins. PARP1 is the most abundant and best studied enzyme and belongs to the poly(ADP-ribosylating) proteins. It is mostly involved in DNA repair. With regard to cooperation with AHR, TCDD-induced PARP7/TiPARP (TCDD-inducible PARP) has been characterized as repressor of AHR expression   may stimulate anti-inflammatory responses and prevent NASH  and sterile inflammation  as examples.Accumulating evidence suggests that AHR is involved in infectious and sterile inflammatory responses. These processes may use up a considerable amount of energy. Therefore, energy metabolism has to be metabolically adapted  have been demonstrated. In addition, both AHR and CD38 are constituents of a signalsome of neutrophils (Bunaciu et al. Multiple sources of endogenous, phytochemical and microbial AHR ligands have been identified allowing intense interaction of the receptor and sensor between barrier organs and the environment. Connections between AHR and NAD+-consuming enzymes in tissue-dependent inflammatory diseases have been discussed using two examples: infectious colitis and obesity-mediated NAFLD and NASH. In intestinal inflammation, beneficial effects have been discussed in homeostasis, microbial defense and the resolution phase of inflammation, provided that AHR is transiently activated. In NASH, both AHR and CD38 may be involved in anti-inflammatory processes. Therefore, both AHR-activating and CD38-inhibiting phytochemicals and microbial products as well as NAD+ boosting compounds may provide therapeutic options. However, anti-inflammatory tolerance mechanisms bear the risk to facilitate autoimmune diseases and carcinogenesis. Therefore, clinical studies have to evaluate risks and benefits in particular cases. The discussed perceptions may be applicable to inflammatory diseases of other organs including skin and lung.Roles of AHR and NAD+-dependent nuclear SIRT1 and mitochondrial SIRT3 as key regulators of gluconeogenesis and glycolytic enzymes. Hence, AHR research remains a challenging and promising field.TCDD toxicity is known to be species dependent leading to wasting syndrome and lethality in sensitive species (Poland and Knutson"}
+{"text": "Cancer is one of the primary causes of death that can affect any organ of the body. Cancer originates from transforming normal cells to tumour cells that often rapidly propagate and invade into adjoining tissues. Cancer cells spreading into other tissues are so called metastases, which is highly associated with death in humans. As to the World Health Organization, lung, colon and liver cancers are among the top ranked cancer types with high mortalities in recent years. The burden of cancer can be largely reduced with proper prevention, early diagnosis, effective treatment, and appropriate palliative care. Cancer treatment remains challenging, largely due to the complexity of its etiology and frequent occurrence of drug resistance.Targeted therapies are preferably adopted in cancer treatment for years. Such treatment alone or in combination with conventional chemotherapies have improved the survival of many cancer patients including those with tumours considered as incurable. Although clinical successes have been achieved in many cases, the failure rate of cancer targeted therapies remains disappointingly high. This is possibly due to the misapplication of therapies targeting pan-essential genes, the dysfunction of which leads to dose-limiting toxicities and/or the compromised therapeutic efficacy resulted from drug resistance.Drug resistance is either early intrinsic or late acquired . The verDrug resistance is the primary obstacle to achieve satisfactory clinical outcomes in carcer targeted therapies as numerous patients are inherently or adaptively resistant to existing regimens. Furthermore, there are deadly cancers without effective systemic therapies at present, like human uveal melanoma  and gastProteins that play essential roles in cell division, cell cycle progression and/or cell death continue to be valid therapeutic targets in cancer treatment. For instance, histone deacetylases (HDACs) that are enzymes responsible for removing acetyl groups from proteins, are widely involved in cellular processes. Their inhibitors have shown clinical potentials against specific malignancies and are under pre-clinical and clinical evaluations to treat various cancers .As to gastroesophageal cancer , targeted therapies against EGFR/HER signalling have been extensively evaluated. Despite the reduced side effects compared to that of conventional chemotherapies, a panel of tyrosine kinase inhibitors (TKIs) downregulating EGFR/HER signalling yielded unsatisfactory outcomes in clinical trials. Thus, emerging drug targets like the store-operated Ca2+ entry (SOCE) , attractDrug resistance pronouncedly compromises the clinical effectiveness of cancer therapies; there are multiple mechanisms contribute to such therapeutic defect. ATP binding cassette (ABC) transporters are important membrane proteins responsible for cellular efflux of substances including many commonly used drugs. Overexpression of ABCs has been widely observed in tumour cells, which notably leads to clinical failure of cancer targeted therapies . One of In colorectal cancer, irinotecan is clinically used in treating its metastatic disease. It is known that ABCG2/BCRP-mediated drug resistance remarkedly impacts on the pharmacokinetic performance of irinotecan and consequently, limits the clinical applications of this agent . The inein silico analysis have both been adopted to design adjuvant cancer regimens. Overexpressed oncogenes and common biological processes like ubiquitination are preferable targets for adjuvant therapies. Computer modelling-facilitated chemical modification has been widely applied in designing combined therapies in addition to traditional chemotherapies such as cisplatin and doxorubicin with severe side effects. The pre-clinical tests regarding these adjuvant regiments are often conducted on malignant cell lines and tumour xenograft models. However, clinical predictions based on these studies may be suboptimal due to the loss of tumour characteristics in immortalised cell lines and expected species differences between human and animals. Therefore, it is highly desired that confirmative evaluation can be performed on tumour tissue-derived primary cell lines, which better preserve tumour characteristics and genetic variations.Empirical approaches and One emerging area in cancer drug research is the incorporation of machine learning algorithms with the advance of artificial intelligence . With thIt is thought that novel drug delivery carriers can greatly improve effectiveness, safety and targetability of agents. Research has widely investigated unconjugated or conjugated liposomes, polymeric micelles, microspheres and nanoparticles in delivering cancer targeted therapies. The advance in drug delivery technology adds credits to existing cancer targeted therapies with enhanced stability and biocompatibility, improved targeting as well as reduced drug resistance . The draOverall, the ongoing battle against drug resistance associated with cancer targeted therapies is a great challenge in biomedical research. Continuous efforts, multidisciplinary collaborations and long-term monitoring will be required to ensure the progress in this field."}
+{"text": "ABSTRACT IMPACT: Understanding how perceived discrimination affects Asian Americans can help stakeholders target subgroups that are at highest risk of discrimination-related behaviors and design culturally appropriate interventions to ensure equitable access to healthcare. OBJECTIVES/GOALS: The COVID-19 pandemic has exposed longstanding anti-Asian racism in the US. Yet, effects of discrimination on Asian American health are unknown, partly because diverse Asian American populations are analyzed in aggregate. We aim to understand how perceived discrimination affects healthcare utilization among different Asian American subgroups. METHODS/STUDY POPULATION: We examine the association of perceived discrimination with healthcare utilization using the California Health Interview Survey (CHIS). In the CHIS, respondents reported whether they would\u2019ve gotten better medical care if they belonged to a different race. We examine the association between these responses and physician visits within the past year, in the survey years 2003, 2004 and 2016-2017. We adjust for covariates based on the Andersen Health Behavior model. Subsequent modeling examines potential mediating and moderating factors such as limited English proficiency, immigration status, income, and survey year. Asian American subgroups analyzed include Asian Indian, Korean, Chinese, Filipino, Vietnamese, Japanese, and other Asian. RESULTS/ANTICIPATED RESULTS: Results will highlight how perceived discrimination incentivizes or disincentivizes certain Asian subgroups to utilize healthcare. Asian American subgroups have differing and diverse experiences with discrimination due to their historical and cultural differences; results will elucidate how discrimination affects these subgroups. Results will be compared to non-Hispanic Whites, who represent the racial group least likely to experience discrimination in the US. Mediation and moderation analysis will help understand how traditionally cited factors for healthcare utilization interact with perceived discrimination on Asian Americans. DISCUSSION/SIGNIFICANCE OF FINDINGS: Asian American subgroups are understudied, despite Asian Americans being one of the fastest growing racial groups in the US. Understanding how perceived discrimination affects Asian Americans can help stakeholders target subgroups that are at highest risk of discrimination-related behaviors and design culturally appropriate interventions."}
+{"text": "Microbes are routinely engineered to synthesize high-value chemicals from renewable materials through synthetic biology and metabolic engineering. Microbial biosynthesis often relies on expression of heterologous biosynthetic pathways, i.e., enzymes transplanted from foreign organisms. Metallocluster enzymes are one of the most ubiquitous family of enzymes involved in natural product biosynthesis and are of great biotechnological importance. However, the functional expression of recombinant metallocluster enzymes in live cells is often challenging and represents a major bottleneck. The activity of metallocluster enzymes requires essential supporting pathways, involved in protein maturation, electron supply, and/or enzyme stability. Proper function of these supporting pathways involves specific protein\u2013protein interactions that remain poorly characterized and are often overlooked by traditional synthetic biology approaches. Consequently, engineering approaches that focus on enzymatic expression and carbon flux alone often overlook the particular needs of metallocluster enzymes. This review highlights the biotechnological relevance of metallocluster enzymes and discusses novel synthetic biology strategies to advance their industrial application, with a particular focus on iron-sulfur cluster enzymes. Strategies to enable functional heterologous expression and enhance recombinant metallocluster enzyme activity in industrial hosts include: (1) optimizing specific maturation pathways; (2) improving catalytic stability; and (3) enhancing electron transfer. In addition, we suggest future directions for developing microbial cell factories that rely on metallocluster enzyme catalysis. Escherichia coli  cluster; (ii) a catalytic MoFe protein (the \u03b12\u03b22-tetramer NifDK) containing four complex metalloclusters: two M-clusters (or FeMo cofactor), and two P-clusters   hydrogenase (MBH) from Ralstonia eutropha holds a special [4Fe-3S] cluster that enables the enzyme to reduce O2 into harmless water  hydrogenases -hydrogenase-3 (Hyd-3) from its natural electron donor formate. An engineered Hyd-3 covalently attached to a ferredoxin from Thermotoga maritima accepts electron from pyruvate instead, and sustains in vivo hydrogen production when co-expressed with a pyruvate-ferredoxin oxidoreductase (PFOR) [The physical linkage of metalloenzymes with electron carriers can also be employed to engineer alternative electron transfer pathways with improved efficiency. For instance, alternative electron donors have been engineered in e (PFOR) .E. coli. Attachment of a hydrogenase and a ferredoxin on a synthetic protein scaffold improved hydrogen production by three-fold [Since the physical interaction between partner proteins is critical for electron transfer, their spatial organization can be optimized to enhance electron flux through desired metabolic pathways. Optimized spatial organization of electron donor and acceptor proteins increases their chance of physical contact, and reduces cross-talk with other cellular pathways . Moleculree-fold . The useree-fold . Other sree-fold .Eukaryotic organisms, such as yeast or microalgae, are essential hosts in the development of microbial cell factories. As many industrial bioprocesses use eukaryotic microbial hosts, implementing biotechnologically relevant pathways in these organisms is crucial to the large-scale production of chemicals. Unfortunately, attempts of transferring pathways that rely on the activity of bacterial metallocluster enzymes into eukaryotes have encountered limited success. For instance, many bacterial FeS enzymes involved in industrially relevant pathways display little-to-no activity when expressed in yeast, and common synthetic biology interventions have failed to improve their activity . AttemptThe barriers to the functional expression of recombinant metallocluster enzymes in eukaryotic organisms are analogous to those that exist between bacterial species: (i) inefficient maturation and/or electron supply due to incompatibilities between phyla-specific systems; and (ii) oxidative stress. The co-expression of bacterial FeS maturation and reducing pathways in yeast is unfortunately insufficient to enhance enzymatic activity, as demonstrated for the enzymes IspG and IspH . Other sE. coli cell chassis to determine that electron transfer pathways from chloroplasts, but not mitochondria, are capable of supporting bacterial nitrogenase systems [Engineering nitrogen fixation in eukaryotes by expressing bacterial nitrogenases has been a long-sought goal due to the cost of synthetic nitrogen fertilizers; however, nitrogen fixation in plants for self-fertilization has not been achieved due to difficulties in expressing functional nitrogenase systems . Neverth systems . More re systems . This woThe aim of making biology easier to engineer is the central goal of synthetic biology. To this purpose, tools and standardized principles for manipulating DNA have been developed over the past two decades. Genetic engineering technologies have enabled the engineering of a wide range of organisms with novel biological functions, including biotechnologically relevant microbial cell factories. However standard synthetic biology tools focused on genetic manipulation have faced challenges in engineering pathways that rely on many catalytically powerful metalloenzymes. Here, we presented an outline of the obstacles to the functional expression and optimization of heterologous metallocluster enzymes in biosynthetic pathways. We also described novel synthetic biology strategies and investigations that could enable harnessing their full biotechnological potential. Such efforts are focused on overcoming obstacles specific to the functional requirements of catalytic metallocluster enzymes: (i) engineering essential supporting pathways involved in enzyme stability and maturation; and (ii) engineering pathways for electron supply that sustain redox active catalysis. The combination and further development of these strategies could be used to optimize novel microbial cell factories with economically viable yields.However, major challenges to the full exploitation of these engineering approaches remain, as our fundamental knowledge on the biochemistry and barriers to the heterologous expression of metallocluster enzymes is still very limited. Indeed, synthetic biologists cannot easily predict the transferability of a given metallocluster enzyme, nor anticipate what will be required for their activation in heterologous hosts. More studies of phylogenetic compatibility and functional requirements will help develop intuitive rules for harnessing heterologous metallocluster enzymes. To this purpose, original research at the intersection between biochemistry, metabolomics, functional genomics, and synthetic biology is necessary. For instance, large-scale cellular assays could be developed to screen the in vivo functionality of relevant metallocluster enzymes in foreign hosts, and to address the barriers to their transferability and catalytic activity . FurtherMoreover, recent advances in synthetic biology have enabled de novo engineering of artificial metallocluster enzymes by incorporating catalytic metallocofactors (including abiotic cofactors) into designed protein scaffolds. These artificial enzymes catalyze a remarkable range of natural and synthetic reactions , and theBesides their potential for microbial biosynthesis, metallocluster enzymes participate in a wide range of key biological processes across kingdoms, including some of technological importance, such as antiviral  or antib"}
+{"text": "Dear readers,The Journal of Innovations in Cardiac Rhythm Management, Alqam et al.1 assess the discontinuation of anticoagulation after typical flutter ablation. Although retrospective and nonrandomized, their study offers important information that can help physicians managing patients with atrial flutter.In this issue of 2 recommended adherence to AF anticoagulation in patients with a history of AF ablation, regardless of procedural success or failure. Continuous or frequent electrocardiographic monitoring to screen for AF recurrence should also be considered in patients in whom anticoagulation discontinuation is being weighed based on patient values and preferences.2 Some well-designed nonrandomized studies8 have found that catheter ablation for AF reduces the risk of stroke; stopping anticoagulation after successful ablation can also be safely accomplished in some patients if careful rhythm monitoring is performed.Meanwhile, no randomized studies have investigated the continuation versus cessation of oral anticoagulation after catheter ablation for atrial fibrillation (AF). A 2017 expert consensus statement on catheter and surgical ablation of AFThe field of cardiac rhythm monitoring has rapidly expanded in recent years. I believe the discontinuation of anticoagulation after AF ablation can be safely accomplished in selected patients when paired with careful rhythm monitoring; however, randomized clinical studies that consider different monitoring practices and groups of patients remain critical.Sincerely,md, fhrs, faccMoussa Mansour, Editor in ChiefThe Journal of Innovations in Cardiac Rhythm ManagementMMansour@InnovationsInCRM.comDirector, Atrial Fibrillation ProgramJeremy Ruskin and Dan Starks Endowed Chair in CardiologyMassachusetts General HospitalBoston, MA 02114"}
+{"text": "Community-based participatory research (CBPR), a bottom-up approach that community stakeholders and academics are involved equitably, is an effective approach for enhancing relevance and value in public health research and has gained popularity in recent decades. However, little is known about how CBPR can be used in mental health studies with older adults. This systematic review examined the current state of knowledge about how CBPR approach has been adopted in mental health research among older adults in different societies. According to the PRISMA guidelines, we searched five major databases and screened the literature using these criteria: 1) journal articles reporting use of CBPR in mental health research among older adults, 2) articles published in English language, 3) studies conducted in any settings with any mental health research. Initial search found 3,227 articles and preliminary screening identified 23 eligible articles. We found that around 90% of studies were conducted in the West. Most studies adopted CBPR to develop community-based mental health interventions or to revise current interventions or models while addressing the cultural needs of their studied population. Few studies adopted CBPR to evaluate existing mental health workshops or programmes. The extent of involvement of older adults in the CBPR approach varied across studies, from questionnaire design to programme evaluation. Our review uncovered ways of CBPR implementation across different societies and elements of successful implementation in CBPR practices in mental health research among older adults."}
+{"text": "Pathology education conventional methods have been disrupted by the Corona-Virus Disease 2019 (COVID-19) outbreak, compelling a re-evaluation of the means of educational interactions from the undergraduate to the postgraduate level. This commentary explores how the COVID-19 outbreak has challenged pathology education.We reviewed the current challenges and determined the potential implications of virtual technologies on modern pathology education for the future of pathology competency learning and assessment.The challenges are partly due to transferring from in-person teaching to a virtual education. Other reasons are shifting away from discipline-based teaching to organ-system based in medical curriculum and additional pressures on pathology faculties, such as increased demand for pathology services, lack of time, and learning resources. Keeping the national standards in pathology education even in the constant disruptions from pandemic outbreaks are current challenges. Pathology expertise will need to use emergent technologies in providing educational material to ensure quality pathology education. However, virtualization of pathology education produces a value of digital pathology and web-based pathology training materials. Medical students could review clinical cases remotely with their supervisors and gain the pathology competencies necessary for clinical practice. We need new innovative strategies, and we suggested the following steps to take advantage of the current opportunity to meet the challenges: evaluating the available digital training materials for formal pathology education, investing in the virtual infrastructure for competency-based pathology education, expanding student/residents exposure to pathology educational cases through virtual platforms; applying digital pathology solutions for virtual pathology education.  Pathology education conventional methods have been disrupted by the COVID-19 outbreak, compelling a re-evaluation of the means of educational interactions from the undergraduate to the postgraduate level , 3. ThisWorldwide, the health systems confront with a shortage of pathologists .Pathology Education in Modern Medical CurriculaPathology is the vital component of diagnostic strategies and central to medical education , 5. PathThe most medical curriculum has already reformed toward horizontal integration of courses, case presentation in the preclinical phase. The undergraduate medical education shifted away from discipline-based teaching to organ-system based in the medical curriculum. These changes affect pathology education at the undergraduate level. Moreover, forming medical educator teams composed of various medical specialists increasing the role that interdisciplinary teams play in medical education. Integration of disciplines has eliminated formal pathology classes in many medical schools , 6. HoweWith current educational policies to reduce transmission of COVID-19, Pathology departments and multidisciplinary networks should evaluate where the virtual educational technologies fit into their new educational plans in an integrated medical curriculum.Keeping the Competency-based Pathology Education The pathology competencies represent the mini-mum requirements of what the national pathology education board has agreed upon to educate undergraduate medical students for practice and for entry into any residency program.Pathology competency-based education focuses on applying pathology knowledge into practice, clinical reasoning, and pathology diagnostic skills.Keeping the competency-based standards in pathology education even in constant disruptions from pandemic outbreaks are current challenges of pathologists. The ability to gain a broad knowledge of the physiological and pathological processes of each organ system, the competency to apply disease mechanisms to explore the pathobiology, and the competency to improve the pathology diagnostic and therapeutic skills through lifelong learning is essential in becoming a competent physician .Pathology Education Challenges in Shifting to Virtual Learning Pathology education's main general challenges are deciding how much to change the courses, adapting to online education, determining the efficiency and effectiveness of virtual learning, and maintaining student engagement . The othWe Need new Innovative Strategies, and We Suggested the Following Steps to Take Advantage of the Current Opportunity to Meet the Challenges. However, contextual priorities may lead medical education experts to make individualized decisions based on unique circumstances.Evaluating the free available web-based pathology training materials for formal pathology education1) The studies indicate that medical students adopted the online resources as a learning tool, and a combina-tion of supervised small group discussions and the self-directed web-based (online) format improved path-ology teaching , 9. Web-The educational impact-not availability- of pathology web resources is a key for a successful transition to effective virtual pathology education. Therefore, pathology educational experts should evaluate the online videos according to national standards in pathology education whether they contribute to pathology education at the undergraduate and postgraduate levels. Some publicly available websites illustrate pathological principles, present rare disorders that are less relevant to undergraduate education. Some studies indicate that YouTube as a popular online video sharing website is an informative and accurate media of histopathology (cellular pathology) learning for both undergraduates and postgraduates. Moreover, autopsies were present on the site .Besides, Case X is an online platform that provides case-based learning materials and video-based medical cases. Online Case X helps student\u2019s clinical reasoning through self-directed learning . Self-diInvesting in the Virtual Infrastructure and Products for Competency-based Pathology Education and Assessment2) The innovative learning technologies will change the future of pathology education and can facilitate training pathology with interactive simulation learn-ing . The intThe virtual educational products need massive infrastructures, including management software and hardware for clinical simulation, case designing tools, and cloud-based eLearning. Pathology content experts should support the virtual system for developing specific learning objectives, pathologic cases, providing updated educational material, virtual supervision, and support .The virtual reality (VR) platform and interactive virtual learning tools can respond to specific issues for pathology discipline that is practical in training and competency assessment . The Advancements in VR technology make its use as a training and assessment tool in online objective structured clinical examination (OSCEs) and Virtual OSCEs (VOSCEs) possible , 13. The formative \u2018\u2018online OSCE\u2019\u2019 for pathology education could assess the disease recognition skills in pathology residents. A sequence of stations presents high-quality specimen images, and the residents should answer the questions and determine the organ and diagnosis within a time limit. After the deadline, they can find the correct answers and case histories of the specimens .Moreover, this can include standardized virtual patient resembling a real patient encounter in virtual stations. Variety of tools are applied in the health care system such as medical history taking, examination, diagnosis, laboratory/ imaging tests, and treating the VP. The system helps medical students master main pathology competencies, including disease mechanisms, organ system pathology, and diagnostic and therapeutic pathology skills. Besides, automated scoring is complementary to assess their progress. Virtual simulation provides the necessary tools to provide benchmarking, better preparing them for real-world medical practice.Expanding Pathology residents\u2019 Exposure to Educational Cases Through Virtual Platforms3) Previous studies showed that some pathology educational programs should increase the residents\u2019 exposure to pathology cases and practice because pathology subspecialty training programs require residents to apply for fellowships as early as the end of their specialty training. Also, studies indicate that changes in pathology specialty curricula and educa-tional activities have affected resident choices of fellowships , 15..\u00a0Keeping the national standards in pathology education are current challenges. Pathology expertise will need to use emergent technologies in providing educational material to ensure quality pathology educationThe clinical pathology cases presented through a patient\u2019s laboratory data or images by detailed explanations help the learner to understand and apply diagnostic principles and incorporate morphologic or laboratory results for accurate diagnosis and treatment. Virtual discussion forums provide the context for sharing the core educational points to promote clinical reasoning.Applying Digital Pathology Solutions for Virtual Pathology Education4) Virtualization of pathology education produces a value of digital pathology; it also assists medical universities to support the continuing education of pathologists in the COVID-19 crisis.Digital pathology (DP) becomes the necessary components in clinical pathology service and cellular pathology training. Pathologists require innovative DP tools and artificial intelligence for digital-enabled care. Residents need these tools to acquire their pathology competencies necessary for the practice of pathology during their early years and discover which subspecialty areas most interest them .DP provides real-time access to clinical/ pathology cases and virtual simulation-based education technologies provide the necessary tools to review clinical cases remotely with supervisors and discuss cases with a histopathologists consultant through virtual conferencing during this pandemic.Some DP technology products are also ready for deployment on the virtual medical education platforms. England\u2019s national health systems (NHS) partners from Oxford, Belfast, Nottingham Universities, and PathLAKE Features University are creating fully digital cellular pathology laboratories with a database of anonymous scanned slide images. These university diagnostic labs are developing AI algorithms for their generated slides , 17.Pathology education is witnessing a paradigm shift where scientific progress and technological advances are growing faster than pathologists\u2019 workforces. Digital pathology and AI algorithm for image analysis would promote pathologic diagnosis. Such technologies and innovations are still in their early stages, but the future is promising. Applying digital pathology solutions for virtual pathology education will increase the efficiency of individual pathologists.We have described the challenges of keeping pathology education on track during the pandemic, and how virtual education platforms and digital technologies in pathology can provide real-time solutions to pathology competencies development. Pathology aca-demic departments should evaluate new technologies and encourage routine adoption of virtual education for digital native medical students. Moreover, the virtual platforms allowed the pathology educators to use DP with providing a safer and more efficient education during the COVID-19 crisis.The following four steps were suggested for utilizing the formal pathology education (from the undergraduate to the postgraduate) to support uninterrupted learning and assessment: 1) Evaluating the free available web-based patho-logy training materials for formal pathology education. 2) Investing in the virtual infrastructure and pro-ducts for competency-based pathology education and assessment.3) Expanding pathology residents\u2019 exposure to educational cases through virtual platforms. 4) Applying digital pathology solutions for virtual pathology education.The Advancements in DP make it a pathology competencies training and assessment tool. The technologies still need to progress before virtual OSCEs become a comprehensive assessment plat-form. Despite this, the future is promising."}
+{"text": "Hypertensive disorders of pregnancy (HDP) contribute to adverse gene-environment interactions prior to conception and continue throughout pregnancy. Embryonic/fetal brain disorders occur from interactions between genetic susceptibilities interacting with acquired diseases or conditions affecting the maternal/placental fetal (MPF) triad. Trimester-specific pathophysiological mechanisms, such as maternal immune activation and ischemic placental syndrome, contribute to adverse peripartum, neonatal and childhood outcomes. Two diagnostic approaches provide timelier diagnoses over the first 1000 days from conception until two years of age. Horizontal analyses assess the maturation of the triad, neonate and child. Vertical analyses consider systems-biology from genetic, molecular, cellular, tissue through organ networks during each developmental niche. Disease expressions associated with HDP have cumulative adverse effects across the lifespan when subjected to subsequent adverse events. Critical/sensitive periods of developmental neuroplasticity over the first 1000 days are more likely to result in permanent sequelae. Novel diagnostic approaches, beginning during pre-conception, will facilitate the development of effective preventive, rescue and reparative neurotherapeutic strategies in response to HDP-related trimester-specific disease pathways. Public health policies require the inclusion of women\u2019s health advocacy during and beyond their reproductive years to reduce sequelae experienced by mothers and their offspring. A lower global burden of neurologic disease from HDP will benefit future generations.  Two diagnostic approaches assist in the prediction of brain health or disease throughout the life-span.  Over theBoth diagnostic approaches allow the fetal/neonatal neurologist (FNN) to anticipate adverse outcomes from any disease process that may potentially affect the developing nervous system across time-periods. This analytic process can be applied to pathophysiological mechanisms associated with specific categories of disease affecting the MPF triad, such as from hypertensive disorders of pregnancy (HDP). Brain health or disease experienced after HDP during critical/sensitive developmental time-periods over the first 1000 days will more likely remain permanent across the lifespan. Novel diagnostic approaches, starting during pre-conception are required that potentially can be applied to all levels of maternal care across the three trimesters. These advances will lead to effective and timelier neurotherapeutic interventions that combine preventive, rescue and reparative strategies for the developing brain in response to the diseases and adversities  associatThis analytic approach requires a working knowledge by an interdisciplinary team of practitioners regarding the maturing embryonic/fetal brain within the MPF triad across three trimesters in association with HDP. Such an approach will better select the appropriate diagnostic tests and treatment interventions that are patient-centric from a developmental perspective regarding a vulnerable MPF triad.The practitioner is confronted with a spectrum of HDP disorders in women, including hypertensive diseases before conception, gestational hypertension, early and late preeclampsia, HELLP syndrome and eclampsia. For this discussion of potential sequelae after HDP, no single diagnostic test or therapeutic intervention will be effective for all women at all times before and during pregnancy. New obstetrical research will offer the clinician with different options and timing that can be standardized for maximal effectiveness, beginning prior to conception. This will be discussed in HDP affects 5\u20137% of the world population of women and their offspring. In one recent study, as many as 7\u201315% of the world\u2019s population of women will experience HDP when assessed on a per-woman basis . Given sImproved diagnostic algorithms of HDP will help reduce the global burden of neurologic disease. As discussed at the conclusion of this review, this should be a public health priority for women and their offspring given the high prevalence of HDP. International efforts, such as the sustainable development goals proposed by the WHO ,9, must Transgenerational followed by early pregnancy G \u00d7 E influences subject the MPF triad to HDP, with different expressions of neurologic sequelae by the offspring. Pre-conceptional genetic susceptibilities have been identified through investigations such as high-throughput genome-wide association studies (GWAS) and epigenetic studies . ImproveCandidate genes and pathways responsible for sequelae are more accurately identified by integrated bioinformational analysis . DifferiCo-morbidities associated with maternal diseases and adversities further augment genetic/epigenetic effects  beginninCross-species expression of the MPF triad structure and function suggests preserved evolutionary biological processes, with either beneficial and adverse outcomes in humans . This trStructural markers detected by fetal surveillance using sonography and more detailed fetal neuroimaging with magnetic resonance imaging include a wider range of detectable brain lesions, including major malformations with or without lethality to region-specific lesions represented by focal developmental anomalies and destructive lesions. The form and severity of these anatomical biomarkers depend on the trimester-specific timing and specific pathophysiological pathways that were activated by G \u00d7 E interactions associated with HDP as well as other diseases entities with similar harmful effects from hypoxia/ischemia, inflammation and coagulopathy. Early pregnancy anomalies range in severity from neural tube defects, holoprosencephaly and schizencephaly to focal cortical dysplasias. During the latter half or pregnancy, destructive lesions predominate and may accompany earlier anomalous lesions associated with HDP-related effects, such as the maturing MPF triad experiences in on-going disease.G \u00d7 E interactions result in different neurologic sequalae specific to pre-conception and the trimester-specific time-periods when the MPF triad is affected by HDP. Primary prenatal neurologic structural/functional disorders without systemic involvement may occur. Secondary brain lesions alternatively result from multi-systemic conditions that also contribute to adverse neurologic outcomes. Disease processes, such as maternal immune activation  and ischG \u00d7 E interactions associated with HDP continue to be expressed after birth as the great neonatal neurological syndromes (GNNS) of encephalopathy (NE), seizures (NS), stroke (NSK) or encephalopathy of prematurity (EP) . The sevPediatric infections, trauma and multi-systemic diseases later in childhood may further worsen sequelae after HDP, stressing the continuity of risk from G \u00d7 E interactions during postnatal maturation. Both communicable and noncommunicable childhood diseases contribute to adverse outcomes, involving hypoxic/ischemic, inflammatory and hemostatic disease pathways. Biosocial adversities affecting the child within the family and community contribute to the extent and complexity of sequelae. Developmental disorders, such as intellectual disability, autism and cerebral palsy, as well as behavioral/cognitive deficits and epilepsies, are potential sequalae expressed throughout childhood and adolescence. Each disorder may either present independently or as co-morbidities. Associations with HDP need to be considered.Sequalae later present with maturation into adulthood. The aging brain\u2019s pathophysiological mechanisms will result in long-term responses to the prenatal conditions of HDP, as well as to other adverse diseases or conditions affecting the MPF triad. Diverse sequalae include cerebrovascular diseases, dementias, adult-onset epilepsy and neurodegenerative disorders. G \u00d7 E interactions at the end of the lifespan are significantly influenced by permanent maladaptive developmental neuroplasticity that occurred during the first 1000 days.Complex MPF triad G \u00d7 E interactions from HDP early during pregnancy profoundly impairs neuronal and glial progenitor cells within transitory brain structures . DisruptMulti-potential precursor populations undergo proliferation, differentiation and migration during the first twenty weeks within multiple transient structures , such asAltered progenitor cell populations within the neuroectoderm or yolk sac later promote abnormal connectivity during the second half of pregnancy with postnatal neurologic sequelae A, B. AltImpaired brain development during the first half of pregnancy associated with HDP affects the interactions of multiple neuronal, glial, and angiogenic precursors, particularly within the developing neurovascular unit . Deficient pro-angiogenic growth factors, such as placental growth factor  and vascImmune intolerance between the mother and embryo/fetus from abnormal placental implantation and development result in maternal immune activation (MIA), which later influences the expression of multiple psychiatric and neurological disorders over the life-span . SpecifiConsideration of G \u00d7 E interactions over the first 1000 days begins with an understanding of the vulnerability from MIA effects after infectious and non-infectious inflammatory conditions, particularly during early pregnancy. A broad range of diseases and conditions result in MIA, including HDP, and affect the maturing components of the MPF triad, with altered fetal brain connectivity. While prevalence estimates of MIA remain imprecise, a significant percentage of children and adults later express early and long-term neurologic disorders from maladaptive developmental neuroplasticity as a result of MIA associated with diseases such as those from HDP. Improved neurotherapeutic interventions need to be developed in order to apply an understanding of MIA  in relatDisordered cellular migration, dendritic arborization, synaptogenesis and myelination within the developing fetal brain is predominant during the latter half of pregnancy. These developmental fetal brain stages are particularly active within the maturing cortex and subplate zone . AnomaloDi Renzo introduced the term \u201cthe great obstetrical syndromes\u201d (GOS) 2009), referring to abnormal maternal, placental and fetal outcomes as a result of abnormal placental angiogenesis. A growing list of adverse outcomes from GOS can affect the MPF triad. Phenotypes specific to each of the three triad components include preeclampsia, diabetes, morbidly adherent placenta, abruptio placenta, premature rupture of membranes, fetal growth restriction, fetal demise, and prematurity. All these conditions adversely affect MPF triad health, with impairment to fetal brain development specific to the developmental stage. Abnormal placental angiogenesis during the second half of pregnancy consists of incomplete spiral artery remodeling and shallow embedding A,B. This09, referHDP are expressions of abnormal placental angiogenesis associated with IPS . PathophAdverse trimester-specific conditions from HDP can negatively impact peripartum events close to and including labor and delivery . ObstetrAdverse intrapartum events associated with HDP may only later be identified during neonatal or childhood time-periods. Whether sentinel or gradual in onset, presumed fetal distress detected during labor and delivery by surveillance testing is also a poor proxy that cannot reliably identify the presence or timing of brain injury. The peripheral chemoreflex remains primarily an adaptive response, activated during uterine contractions to protect against primarily brain, cardiac and adrenal injuries in most situations as the child descends the vaginal tract. Specific clinical scenarios can result in intrapartum fetal brain injury , particuComplex disease conditions represented by HDP are best interpreted by applying horizontal and vertical analytic perspectives to anticipate risk or occurrence of brain injuries prior to, as well as during, labor and delivery. Interdisciplinary consensus reports periodically update the evolving scientific bases for these analyses ,49. CompComplex phenotypes after birth are expressed collectively as the great neonatal neurological syndromes (GNNS). Similar to the GOS, trimester-specific G \u00d7 E interactions affect the MPF triad during postnatal life, expressed as the GNNS. Differences from GOS include: 1) clinical presentations include events specific to the peripartum and neonatal time-periods; (2) phenotypic expressions of GNNS are not reliably detected across trimesters for all maternal levels of care, particularly with seemingly low-risk pregnancies, (3) early and later pregnancy factors cumulatively affect MPF triad components closer to delivery expressed as the GNNS. NE, NS, NSK, and EP are the four major GNNS categories [ clinicalNegative outcomes associated with the GNNS occur despite adjustments in obstetrical management closer to delivery to conditions associated with HDP. Introduction of resuscitative interventions and neurocritical care may not significantly alter antepartum adverse outcomes ,3. FNN aAcute infections, metabolic-toxic and traumatic etiologies may best explain peripartum or neonatal-acquired encephalopathies and/or brain injuries expressed by the GNNS. Alternatively, trimester-specific MPF triad G \u00d7 E interactions associated with HDP have a varying clinical expression during peripartum and neonatal time-periods, based on the timing and etiologies associated with brain anomalies or injuries superimposed on acute disease. Childhood neurologic disorders may later present, despite neonatal neurocritical care interventions for the GNNS as well as in the absence of early neonatal disease expression. Neonatal evaluations specific to each GNNS have been discussed in more detail elsewhere and are applicable to clinical assessment after HDP . NE, NS,Paradoxically, lower mortalities and adverse neurological outcomes such as periventricular leukomalacia, intraventricular hemorrhage and cerebral palsy have been retrospectively reported in specific studies of extremely and very preterm infant populations when associated with HDP, compared with cohorts without HDP . HDP mayDiagnostic strategies to assess the GNNS requires a time-sensitive interpretation of serial examinations, neuroimaging, electroencephalography and blood/serum studies throughout the neonatal hospitalization . Multi-sOne important diagnostic test regarding the timing and etiology of brain injuries should include gross and microscopic examinations of the placenta, cord and uterus. While the completed pathology report may not be available until after the first week of life, findings often more accurately estimate an antepartum time-period to diseases that precede events closer to delivery. Trimester-specific pathophysiological mechanisms may better explain different disease processes associated with HDP after pathological analyses of the placenta, cord and uterus. This explanation will better assist the family for both diagnostic accuracies, as well as prognosis and anticipatory care. Revised pathological classifications have strengthened these chronic associations . HoweverDuring the first two years of life, the expression of developmental disorders and epilepsies ,58 may bChildren who experienced the GOS and GNNS after diseases such as HDP more likely require earlier medical interventions at older ages. Hospitalizations, may require pediatric neurointensive care  for a moPediatric neurology consultations in the clinic or hospital settings may originate from primary-care practitioner or pediatric subspecialist referrals when communicable and noncommunicable diseases worsen neurologic function associated with organ-specific systemic diseases. Congenital heart disease (CHD) is the most common anomalous organ system disease of childhood that can be associated with HDP, with sequelae including cognitive/psychiatric disorders . ContinuInvolvement during the first 1000 days facilitates continued pediatric neurology consultative input throughout childhood into adolescence. This continuity of care more effectively addresses ongoing or new conditions affecting brain health when clinical disorders are expressed in association with HDP. Clinical expression requires brain maturation.Epileptic, behavioral/cognitive and mental health disorders  are assoNeurologic and mental health disorders associated with HDP may only become clinically apparent with maturation into adulthood . These sCombined developmental origins and life-course approaches to diagnosis and prognosis therefore stress the relevance of the first 1000 days to neurologic/psychiatric diseases presenting across the life-span. Cerebrovascular, cognitive, epileptic and neurodegenerative disorders  into oldCurrent practice guidelines and stress conventional management strategies to control HDP . PregnanAdverse effects by HDP on embryonic and early fetal brain development within the MPF triad requires neurotherapeutic interventions, targeted to immature neuronal populations and connectivities that may be impaired during the first half of pregnancy. Pre-conception testing will target inherited genomic biomarkers associated with hypertensive disorders affecting a future pregnancy . The nexReduced burden of neurologic disorders across the lifespan from conditions associated with HDP should constitute one of multiple sustainable goals required for maternal and pediatric health initiatives . SignifiImprovements in both person-centric and population-based healthcare define a nation\u2019s medical, economic and social well-being. Cooperation between government, industry, and nonprofit entities collectively strengthen healthcare policy for populations specific to resource-rich and poor nations. This advocacy must include medical deserts within resource-rich nations. Health disparity research augments efforts to address prenatal and early childhood brain disorders in association with HDP required by public health programs. This is exemplified by the WHO Millennium sustainable goals , which can more effectively reduce disease burden and financial costs, as well as elevate the quality of life . The sigInterventions need to be offered that are gender-specific and sensitive to sexual-orientation, specifically recognizing the unique aspects of healthcare relevant to women and men . Outcome"}
+{"text": "Stem-cell derived in vitro cardiac models have provided profound insights into mechanisms in cardiac development and disease. Efficient differentiation of specific cardiac cell types from human pluripotent stem cells using a three-step Wnt signaling modulation has been one of the major discoveries that has enabled personalized cardiovascular disease modeling approaches. Generation of cardiac cell types follow key development stages during embryogenesis, they intuitively are excellent models to study cardiac tissue patterning in primitive cardiac structures. Here, we provide a brief overview of protocols that have laid the foundation for derivation of stem-cell derived three-dimensional cardiac models. Further this article highlights features and utility of the models to distinguish the advantages and trade-offs in modeling embryonic development and disease processes. Finally, we discuss the challenges in improving robustness in the current models and utilizing developmental principles to bring higher physiological relevance. In vitro human cardiac models are complimentary tools that allow mechanistic interrogation in a reductionist way. The unique advantage of utilizing patient specific stem cells and continued improvements in generating reliable organoid mimics of the heart will boost predictive power of these tools in basic and translational research. Over the past decade, several strides made in stem cell research has led to unparallel opportunities to study human diseases in vitro. Cardiovascular diseases (CVD) comprising of congenital heart disease, heart failure, stroke and hypertension contribute toward nearly one-third of all deaths worldwide , 2. CardThe heart forms from the mesodermal embryonic tissue from anterior primitive streak. The cardiac specification and differentiation take place after the lateral movement of the anterior region into splanchnic mesoderm. This tissue further self-organizes into three distinct regions where the cardiac crescent or first heart field (FHF) is \u2018sandwiched\u2019 between head folds and second heart field (SHF). During the morphogenetic movements, the heart regions lie in close contact with pharyngeal or foregut endoderm . TranscrFrom a molecular point-of-view, orchestration of T-box containing transcription factors such as TBX20 and TBX5 trigger chamber and septa formation while BMP driven TBX2 and TBX3 driven activation leads to atrioventricular canal and outflow tract. Cardiac neural crest influx into the outflow tract and complete septation is completed around week 12 in humans where it resembles the heart structure morphologically . Heart bIn vitro differentiation of cardiomyocytes (CMs) from iPSCs follow sequential stages observed during embryonic development, wherein heart forming progenitor cells arise from the mesodermal cell layer sandwiched between the ectoderm and endoderm in the primitive streak. Cardiomyogenesis in vertebrates is driven by classes of growth factor proteins such as wingless/INT (WNTs), bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) , 10. ConMost recently, there has been a surge in cardiac \u2018organoid\u2019 models which are self-organized, spatially restricted clusters of cardiac-specific cell types derived from pluripotent stem cells. Some organoid models have been touted as new tools to study several congenital and developmental disorders such as hypoplastic left heart syndrome (HLHS) where the left ventricle fails to form due to mutation in NOTCH1 gene . SeveralDevelopmental cardiac organoid-like models do not serve as an attractive tool to perform investigations in a reductionist manner due to lack of high fidelity in cellular composition and niche. Diseases where the pathophysiology is unclear in vivo due to complex microenvironment could benefit from engineered tissue-like structures that can be manipulated in a modular fashion. Several protocols have been developed in recent years to generate major non-myocyte cell types of the heart from iPSCs such as endothelial cells , cardiacBoth cardiac organoid and heart-on-a chip models are excellent surrogates to understand several important aspects of heart function during development and disease. However, it is important to acknowledge that utility in predicting in vivo functions will remain limited due to stochastic self-patterning variability between every batch of stem cell differentiation. In addition, several factors that currently rely on self-assembly time need to be coupled with controlled delivery of cues. For example, in addition to progenitor-cell types, cardiogenesis is driven by a combination of long- and short-range paracrine interactions, gene regulatory networks and ECM-guided geometrical cues. Efforts toward obtaining blueprints of stage-wise development will enable us to isolate and embed temporal cues in these models to influence multi-axial patterning and cellular organization, rather than focusing on autonomous self-assembly under different conditions. Another important aspect in cardiac models is obtaining innervation and vascular anastomoses which provide feedback on carbon dioxide, dissolved oxygen and fluid pressure. Technical challenges that prevent widespread use of cardiac models can be addressed through standardized characterization of stem cell sources, using well-defined platforms and most importantly choosing the right model in the context of use . With inCurrently, both ECM and ECM-free cardiac models are proving useful as an obligate substitute for pre-clinical animal models, to validate clinical observations and as a screening tool for therapeutics or toxicology. With success through continued efforts in addressing some of the discussed challenges, we must revisit our expectations and utility of the model based on evidence and reproducibility. For example, current 2D and 3D tissue engineered models with limited heart-like features would be useful from a reductionist approach to understand cell specific mechanism or direct pharmacological response. Future availability of morphologically and spatially defined organoid mimics will further assist in mapping direct and indirect interactions due to concerted cellular response and fluidic stress. Such systematic approach toward building complexity will drive utility-based research in cardiovascular organoid biology as a complimentary tool and not a panacea for studying multifactorial cardiovascular diseases."}
+{"text": "To the Editors,Endovascular treatment of carotid artery disease has gone through fast-paced evolution since the advent of balloon angioplasty and stents three decades ago. Nevertheless, it was not until significant improvements in neuroprotection were achieved that carotid artery stenting became a solid contender to the gold standard carotid artery endarterectomy. Embolic protection devices, such as proximal common and/or external carotid artery balloon occlusion devices and internal carotid artery filters paved the way toward a safer and more definitive strategy. The concept of flow reversal in the early 2000s,Carotid artery calcific disease remains a challenge in patients undergoing carotid artery stenting regardless of whether it is done via a transfemoral or transcarotid approach. By far, the most challenging scenario is circumferentially calcified internal carotid artery plaques that can cause inadequate expansion of stents and limited luminal gain despite vigorous pre- and post-dilation of the lesion.The two main strategies use either atherectomy devices or the new intravascular lithotripsy (IVL) balloon. We have reported both use of orbital atherectomy"}
+{"text": "Although loneliness and social isolation are often discussed together, they are mainly examined separately. The few studies examining both concepts simultaneously focus usually on the wider category of older people (65+), with no or little attention to very old age. Our main aim was to investigate loneliness and social isolation in combination among near-centenarians and centenarians. Analyzing data from the Fordham Centenarian Study , we found no or very weak associations between loneliness and social isolation. Combining measures of loneliness  and social isolation  we built a typology with four different groups . The factors that most strongly predicted the distribution among these four groups were gender, widowhood, education, and self-rated health. Findings highlight the importance of jointly studying both concepts to better understand social risks in very old age."}
+{"text": "Fusarium, continue to be a major threat to agricultural crops worldwide. In this issue, Tracanna and coworkers  implement a targeted amplicon sequencing approach to identify conserved domains and specific metabolic pathways shared among soil samples with antagonistic activities against Fusarium culmorum. They also introduce dom2BGC, an open-source annotation platform that builds co-occurrence networks of natural product-associated domains across samples and aids in putative gene cluster reconstruction. When coupled with metagenomics, functional amplicon sequencing and the dom2BGC pipeline can aid in identifying mechanisms and potential metabolites associated with particular microbiome-associated phenotypes.Soil-dwelling microorganisms associated with plant roots carry out essential processes that promote plant growth and productivity. In addition to these beneficial functions, the rhizosphere microbiome also serves as the first line of defense against many plant pathogens. While many rhizobacteria are capable of producing antifungal natural products, fungal pathogens, such as those belonging to the genus  Soils are biologically diverse habitats and represent some of the most complex ecosystems found in nature . As sustInvestigations into the rhizosphere have shown that this is a complex and dynamic environment . Plants Fusarium species being among the most devastating. While a previous study identified soil samples with antagonistic activity against Fusarium culmorum  are a large class of bioactive natural products and are typically biosynthesized in an assembly line-like fashion by nonribosomal peptide synthetases (NRPSs). Adenylation domains are essential components of the NRPS assembly line and are responsible for selecting the amino acid building blocks that get incorporated into the natural product. Using degenerate primers, adenylation domains were PCR amplified from rhizosphere DNA collected from four of the authors\u2019 soil samples possessing activity against programs . Furtherin silico amplicons extracted from the antiSMASH and MIBiG databases. Taxonomic diversity and community structure relationships are calculated across sample sets, and domain co-occurrence networks establish biosynthetic distribution patterns that can be used to explain microbiome-associated phenotypes. While a similar PCR-based targeting approach was used in the discovery of the malacidins, the bioinformatics program eSNaPD (With the adenylation sequences from the rhizosphere microbiomes in hand, the authors developed an automated annotation platform to assist with comparative analyses across the sample sets. Briefly, dom2BGC annotates biosynthetic domains based on similarities with m eSNaPD  that iniF. culmorum.Using the dom2BGC platform, the authors identified community structure overlap between adenylation domain profiles from suppressive rhizobacteria and were able to map the sequences to multiple taxonomic groups. From the co-occurence patterns, dom2BGC was also successful at reconstructing multiple biosynthetic gene clusters. Results from the amplicon clustering were validated using 10\u00d7 metagenome assembly and demonstrated that dom2BGC is a powerful platform for identifying functional elements in complex microbial communities. Detailed analysis of the amplified adenylation domains suggested an enrichment of cyclic and branched lipopeptide-producing biosynthetic clusters in the soil samples possessing antifungal activity, and bioinformatic analysis of the metagenomic data revealed several siderophore, lipopeptide, and 2,4-diacetylphloroglucinol gene clusters. It was speculated that the agents associated with the respective gene clusters could be responsible for the antagonistic activity against Tracanna and coworkers  demonstr"}
+{"text": "Palliative care is included within the universal health coverage goal of the sustainable development goals as an essential health service and is considered a human right.COVID-19 patients and their families report multidimensional symptoms, ranging from those that are physical, to psychosocial, spiritual and existential distress from the threat to survival.In our recent review of African COVID-19 case management guidelines, we found few palliative care approaches and a focus on clinical management to the neglect of important psychosocial and spiritual stressors affecting morbidity and outcomes.The supply of medical products, including palliative medicines, has also been disrupted by the pandemic, even more so in countries still experiencing increased cases, including Kenya, South Africa and Uganda.Before the pandemic strained African health systems, only 5\u201311% of people requiring palliative care had access. The negative impact on services has heightened the risk of unnecessary suffering in patients with COVID-19 and other serious illnesses. Therefore, policy-makers in Africa must try to lessen the impact of the pandemic on palliative care services by integrating palliative care within the COVID-19 response. This integration involves training family caregivers and community health-care workers caring for COVID-19 patients and other seriously ill patients whose home care by specialist teams has been disrupted by pandemic restrictions, and ensuring ongoing funding for palliative care services.African institutions must rapidly expand palliative care training to health-care professionals outside palliative care services and support the training with clear, comprehensive case management guidelines focused on palliative care. Service providers must also urgently collaborate with researchers in adapting palliative care delivery approaches and testing new technology-based service delivery models, such as mobile health applications."}
+{"text": "Knowledge of school attendance problems (SAPs) is needed to inform treatments targeting SAPs and protecting youths from negative outcomes associated with SAPs.This study examined the school absence, absence categories , sociodemographic characteristics, and mental health problems among youths seeking psychological treatment for SAPs.The study used a cross-sectional design. Sociodemographic and clinical characteristics of 152 help-seeking youths with SAPs  and their parents were examined. The data were derived from the baseline assessment conducted before treatment start.Older youths, youths with mental health problems, and youths whose parents had mental health problems exhibited higher levels of absence. Lower levels of non-excused absence were found among youths with highly educated fathers, and youths living with both parents. Many youths had clinical levels of anxiety, depression, or \u2018emotional and behavioral difficulties\u2019.The study highlights the need for early intervention, addressing a broad range of mental health problems.NCT03459677.ClinicalTrials.gov:  School attendance problem (SAP) refers to difficulty attending school or absence from school that is problematic because of its frequency and/or duration  while studies addressing truancy have focused on non-excused absence . Sociodemographic characteristic and mental health problems are often described for distinct subgroups of youths with SAPs  are more likely to be effective for youths presenting high levels of school absence together with a complex clinical presentation including anxiety, depression, and/or behavioral disorders.S1 Table(PDF)Click here for additional data file."}
+{"text": "Previous research indicates volunteering promotes well-being of individuals and communities. Volunteering in later-life may buffer some of the negative health effects experienced during retirement, facilitating opportunities for older adults to engage in meaningful activities and stay active. The current study examined characteristics of older adults who volunteered outside of participation in a regular cognitive monitoring study. All 124 members  of a regular cognitive monitoring study, requiring completion of a 15-minute cognitive online test once a month, with complete data on personal characteristics, volunteer activities, as well as study adherence and dropout rates were included. ANCOVA and logistic regression analyses adjusted for sociodemographic characteristics were used to assess differences between volunteers and non-volunteers. Results indicated that volunteers were less educated (p<.05), and slightly more likely to be younger and women compared to non-volunteers. There were no differences in cognitive performance (ps>.05). Volunteers had lower scores for neuroticism (p=.02) and were marginally higher agreeable and extraverted (ps<.09). Volunteers needed more reminders to complete the monthly test (ps<.01) but had lower dropout rates (p=.001). The most frequent type of volunteer activity reported was religious. Volunteers were motivated mainly by altruism, although most reported multiple reasons such as building social relationships and feeling important. Findings provide information about characteristics that can help identify older adults who are likely to volunteer. Results regarding study adherence may have implications for promoting recruitment and retention among older adult volunteers."}
+{"text": "Inflammatory biomarkers and sex hormones have been investigated as independent risk and resilience factors for cognitive decline in older adults. Many sex hormones are anti-inflammatory and there is emerging evidence that sex hormones may buffer the risk for cognitive decline associated with higher inflammation. However, few studies have included concurrent examination of inflammation and sex hormones in studies of cognitive performance and cognitive aging. A diverse sample of older adults  had blood drawn before and after a two-week measurement burst that included three cognitive tests (6x per day) assessing working spatial memory, perceptual speed, and feature binding. Testosterone, estradiol, estrone, and six basal cytokine concentrations were quantified. Composite scores of basal inflammation were calculated. Multilevel modeling indicated that heightened inflammation related to poorer spatial working memory performance . In addition, sex hormones moderated the association of cytokine concentration with perceptual speed . Decomposition these interactions revealed that heightened inflammation predicted poorer performance, but only among individuals with lower sex-hormone concentrations. This study provides evidence of immune and hormonal-by-immune associations with performance in two cognitive domains in older adults. Examining the functional crosstalk between immune and sex hormone functioning will improve understanding of risk and resilience factors related to cognitive performance and help predict cognitive decline in older adults."}
+{"text": "ABSTRACT IMPACT: Our data identify a novel candidate for combination strategy in melanoma treatment, and can inform clinicians in their decision-making process regarding therapeutic intervention for melanoma patients. OBJECTIVES/GOALS: Soluble adenylyl cyclase (sAC) is a novel source of cyclic AMP (cAMP). In melanoma, nuclear sAC localization has an established diagnostic utility and we newly found that nuclear sAC functions as a tumor suppressor by inhibiting Hippo pathway, which affects treatment response. Here, we examine the effect of nuclear sAC on melanoma treatment response. METHODS/STUDY POPULATION: We developed a doxycycline inducible system for increasing sAC activity only in the nucleus. We assessed whether nuclear sAC activity affects treatment response, using BRAFV600 human melanoma cell lines. Using a clonogenic assay, we examined how nuclear sAC activity affects growth inhibition in the presence of a BRAF inhibitor, vemurafenib. Our findings will be confirmed in vivo using tumor xenografts. After tumor formation in NSG mice, mice will be randomized to be fed normal or doxycycline chow for nuclear sAC induction, then subdivided to receive vehicle or vemurafenib to examine the effect of nuclear sAC activity on treatment response in vivo. We will also compare melanoma biopsies collected before and after treatment with BRAF inhibitors to assess how nuclear sAC staining affects tumor morphology in vivo. RESULTS/ANTICIPATED RESULTS: So far, nuclear sAC activity has rendered SkMel178 and M263 cell lines more susceptible to vemurafenib. Cell viability was inversely correlated both with vemurafenib and with doxycycline concentration. Cell viability after vemurafenib treatment was dramatically reduced when nuclear sAC was activated. It appears that nuclear sAC enhances the sensitivity of BRAF mutant melanomas to vemurafenib in vitro. We anticipate that xenografts of these cells in mice will be more susceptible to vemurafenib when nuclear sAC is activated. We also anticipate that positive nuclear sAC staining will correlate with a favorable response to therapy. DISCUSSION/SIGNIFICANCE OF FINDINGS: Targeted therapy with BRAF inhibitors is used in late-stage melanomas, but its use is limited as patients invariably acquire resistance. Here, we identified nuclear sAC activation as a novel candidate for combination strategy. Our data will also inform clinicians how best to integrate this biomarker into their decision-making regarding therapy."}
+{"text": "There remains a lack of knowledge on marital satisfaction of African Americans generally, but particularly older African Americans. In addition, only a handful of studies investigate satisfaction among couples who are unmarried. With data from the National Survey of American Life, this study examined the correlates of romantic and marital satisfaction among older African Americans. Findings reveal that married older African Americans were slightly more satisfied with their relationship than individuals who were either remarried or unmarried but in a romantic relationship. Among older African American married adults, older age was associated with higher marital satisfaction, and men had higher levels of marital satisfaction than women. Also, married older African Americans with lower family incomes reported higher marital satisfaction. Given the limited research on older African Americans couples, either married or unmarried, this study offers valuable implications for individuals and professionals engaging these couples in practical settings."}
+{"text": "In Japan, care managers engage frail older adults to support their assisted living in long term care insurance system. However, due to the lack of some or all supervision, many care managers face problems such as low work engagement and high turnover rate. This study aims to examine what types of supervision have positive effects on work engagement and turnover intensions of care managers in Japan. The sample of 241 care managers were asked whether they have received individual supervision in the workplace (ISVW), individual supervision in the community (ISVC), group supervision in the workplace (GSVW), or group supervision in the community (GSVC). Independent samples t-tests and one-way ANOVAs were conducted to examine the effectiveness of each types of supervision on work engagement and turnover intension. T-tests showed that only GSVW was significantly related to work engagement . Whereas, only ISVW had a significant effect on turnover intensions . One-way ANOVAs revealed that 28 care managers receiving GSV had significantly higher work engagement than 92 care managers who did not receive any SV . 40 care managers receiving both ISV and GSV showed significantly lower turnover intentions than 92 care managers who received neither ISV nor GSV . Since the results have implications for the importance of supervisions to enhance work engagement or to reduce turnover intension of care managers, a larger sample will need to confirm these effects."}
+{"text": "One of the well reported but difficult to manage symptoms of spinal cordinjury (SCI) is neurogenic lower urinary tract dysfunction (NLUTD). The type ofNLUTD is variable based on location and extent of injury. SCI affects more malesand NLUTD is especially debilitating for men with incomplete injury. This reviewsummarizes the anatomical basis of NLUTD in SCI and discusses current diagnosticand management strategies that are being utilized clinically. The last twosections address new innovations and emerging discoveries with the goal ofincreasing scientific interest in improving treatment options for people withSCI. Areas warranting further investigation are pinpointed to address currentgaps in knowledge and/or appropriate technology. These pThe spinal level of SCI causes distinct neuroanatomical disruption patternsresulting in different treatment strategies. Suprasacral lesions produce neurogenicdetrusor overactivity (NDO) and a noncentralized sacral spinal reflex. Sacral lesions directly involve the spinalmicturition center and cause mixed NLUTD symptoms and detrusor underactivity . Pudenda2.Prompt evaluation of lower urinary tract function is important consideringits cause of increased morbidity and mortality and high prevalence in SCI(70%\u201384%) male victims. Clinical patterns can help determine the presence ofNLUTD and help localize the lesion to guide conservative, pharmacologic, andsurgical therapies. Several guidelines exist for evaluating NLUTD including EuropeanUrological Association, Joint Societe Internationale D\u2019Urologie-InternationalConsultation on Urologic Diseases (SIU-ICUD), and Japanese clinical guidelines\u201312. ConsWorkup begins with a thorough history and physical exam especially with focuson male urologic history regarding benign prostate hypertrophy, urinary infrequency,and any urologic malignancies. Review of the initial trauma and severity of the SCIwith a validated system like the ASIA score is first performed. It is important toconsider factors in a male\u2019s medical history, like severe hypertension orhistory of acute angle closure glaucoma, that may contraindicate the use ofmedications in the treatment in NLUTD . AbladdBladder function can be objectively evaluated using urodynamic studies atleast once within the months following injury and can measure bladder sensitivity.For incomplete SCI, this can help determine return of function. Video urodynamicsserve as the gold standard for those with NLUTD. It is generally recommended toperform the first urodynamic study 3\u20136 month following injury.Electromyography may evaluate external urethral sphincter function. The resultingmorphologies based on the information gained regarding intravesicular pressure,detrusor activity, bladder compliance, bladder sensitivity, and bladder storagecapacity can help diagnose NLUTD, differentiate between the different subtypes, suchas those that involve detrusor overactivity or DSD, localize the level of SCI,identify the extent of injury on ASIA scale, give prognosis, and monitor treatmenteffect.Post-void residuals can be measured using bladder ultrasound or cleanintermittent catheterization. Other non-neurogenic conditions can be ruled out usingrenal and pelvic ultrasonography. MRI or CT of the brain can rule out otherneurogenic causes, particularly in the setting of polytrauma where the brain may beaffected and cause disruption of the pontine micturition center. MRI of the spinecan reveal spinal cord compromise that may be amenable to surgical intervention withpossible subsequent symptom improvement .This isDilation of the ureters, calyxes, and hydronephrosis should be considered inthose with NLUTD. The upper urinary tract can be evaluated using ultrasound andmagnetic resonance urography . Several3.3.1SCI is unique from other NLUTD etiologies in that it is oftenaccompanied by traumatic injuries and spinal shock syndrome. These factorscreate distinct phases of treatment for urologic issues affecting males: theacute recovery phase, post-acute rehabilitation phase, and long-term managementphase . Allowin3.2SCI patients may require indwelling catheterization during the acuterecovery phase until renal and cardiovascular function is optimized andurodynamic parameters improved .Beyond Pharmacological treatments of NLUTD generally target neuromuscularjunctions in the smooth muscle of the detrusor or internal urethral sphincter.Antagonism of alpha-1 adrenergic receptors relaxes the internal sphincter andbladder neck to improve voiding. Terazosin and tamsulosin are two of the mostwell-studied \u03b11 antagonists and both have been demonstrated to reduceautonomic dysreflexia and improve urodynamics, especially in males \u201322. AntaChemodenervation of the detrusor by botulinum neurotoxins (BoNT) hasalso emerged as a minimally invasive treatment for NLUTD in men with incompleteSCI. The most commonly used BoNT serotype is onabotulinumtoxin A (BoNT/A),commercially known as Botox  . Althoug3.3via implantation ofexternally-controlled electrodes at the sacral nerve roots may be considered incases where conservative management fails to adequately control symptoms orproduces unfavorable side effects. The Brindley Procedure, combined sacralanterior root stimulation (SARS) and rhizotomy of dorsal sacral rootsS1\u2013S5 can be considered in NLUTD patients where conservative managementfails [Neurostimulation ntfails . Deafferntfails \u201330. The ntfails \u201332.4.As outlined above, bladder storage and micturition are controlled by acomplex interplay between the smooth muscle of the lower urinary tract, the striatedmuscle of the urethral sphincter, the cerebral cortex, pontine micturition center,sacral micturition center, and both the sympathetic and parasympathetic portions ofthe peripheral nervous system. In incomplete SCI, the range of damage is variable,and, therefore, may affect different elements of these cascades, which explains thedifferent etiologies and presentations of NLUTD after SCI. Despite this complexity,a simplified view of NLUTD after SCI may be described as improper sensory awarenessfor the need to void or improper stimulus delivery to cause the bladder to void.Therefore, new treatment options have focused on the use of sensors to monitorbladder pressure parameters, neuromodulation to deliver precise stimulation to causethe micturition cascade, and combined closed-loop neuromodulation systems to bothsense bladder fullness and void. Some of the key findings were highlighted above incurrent treatments section but the experimental approaches are addressed furtherbelow and may be especially valuable for males with SCI. Outline of promisingapproaches highlighted in Urodynamic testing is a known study that examines the parasympathetic andsympathetic function of the urinary system, enabling examiners to evaluate bladderand urinary sphincter function and integrity . ClinicaMany of the recent innovations have been as a result of improved targetingof electrical stimulation and noninvasive modalities . Traditi5.Technical considerations to improve outcomes of bladder dysfunction andmicturition continue to be explored in experimental animal models of SCI. Thesediscoveries encompass portable and reliable urodynamic monitoring, percutaneous orimplantable devices for specific neuromodulation of bladder control, and thecombination of these elements into biofeedback devices to approach restored bladderfunction after SCI. As described, innovations in urodynamic testing aim to guidecare management in real time for men with incomplete SCI. Several groups haverecently used porcine models of bladder physiology to investigate submucosalimplantation of sensors for localized bladder function . ImplantAmbulatory urodynamic monitoring (AUM) is used to permit specificmeasurement of functional status in clinic. However, sensitivity and portabilityremain significant challenges since the aim of AUM is to reproduce bladderdysfunction in the clinic setting and requires connection to an external powersource. For increased sensitivity, wearable telemetric devices would provide morerelevant functional assessment during the course of a patient\u2019s dailyactivities . Novel dReal-time monitoring, notification, and subsequent intervention forincreased intravesical pressure would enable timely voiding and minimize theincidence of complications in patients with SCI . Treatme6.The management of NLUTD after SCI in males is continuing to evolve. Standarddiagnostic tools are being optimized for widespread applicability. In this review,we highlighted the underlying anatomical contribution and current diagnosticstrategies. We delved into current treatment approaches and highlighted the newinnovations and emerging discoveries. Research is proceeding regarding improvedtreatment options in this patient population both for men with incomplete andcomplete SCI."}
+{"text": "Spatially resolved transcriptomic data demand new computational analysis methods to derive biological insights. Here, we comment on these associated computational challenges as well as highlight the opportunities for standardized benchmarking metrics and data-sharing infrastructure in spurring innovation moving forward. To preserve such spatial information, advances in imaging technologies have enabled high-throughput in situ, targeted transcriptomic profiling of pre-selected RNAs at molecular and single-cell resolution2. In addition, technologies based on spatially resolved RNA capture followed by sequencing have enabled non-targeted, genome-wide transcriptional profiling at the 10-100\u2009\u00b5m pixel resolution3. Though the suitability of each spatial transcriptomics technology in addressing a particular biological question will currently involve balancing the need for experimental throughput versus spatial resolution, with current imaging-based technologies generally\u00a0offering higher spatial resolution but lower experimental throughput and current sequencing-based technologies generally\u00a0offering higher experimental throughput but lower spatial resolution, all of these resulting large-scale spatially resolved transcriptomic data demand new computational methods to take advantage of this new spatial information to derive biological insights.Advances in single-cell sequencing technologies have enabled high-throughput transcriptomic profiling for individual cells, allowing the characterization and discovery of transcriptionally distinct cell types and cell states. However, current protocols require dissociating cells from tissues, thereby losing potentially valuable spatial information that may inform how cell types and cell states are organized within tissues and how such organization may ultimately impact phenotype and function4, generalized linear models5, and spatial autocorrelation analysis6 have been developed to identify genes whose expression exhibits significant spatial variability. Some of these methods can also classify different patterns of spatial variation, such as linear or periodic gene expression4, as well as identify spatial features such as gene expression hotspots7. Such identification of spatially variable genes can lend insight into position-specific phenotypes as well as developmental and migration gradients. Spatial information can also augment the identification of putative cell\u2013cell communication networks. With single-cell sequencing data, cell\u2013cell communication inference has relied on identifying coordinated expression of known ligand\u2013receptor pairs8. Computational methods that leverage the added spatial information from spatially resolved transcriptomic data using graph convolutional neural networks9, optimal transport approaches10, and spatial cross-correlation analysis6 can narrow down candidates to ligand\u2013receptor pairs that are spatially colocalized, potentially indicative of autocrine or paracrine signaling. Furthermore, spatially resolved transcriptomic data with co-registered imaging data present additional sources of heterogeneity, such as morphological variability, which can be used for clustering, as differences in morphology can be a proxy for differences in cell states or other functional phenotypes such as cell cycle position, transformation, or invasiveness. Computational methods that incorporate spatial and morphological information in addition to gene expression information have been applied to further dissect heterogeneity in single-cell populations to identify clusters of single cells that are not only transcriptionally distinct but also morphologically and spatially distinct12. Although these aforementioned computational methods can be applied to both single-cell resolution and multi-cell pixel-resolution spatially resolved transcriptomic data, interpretation of the resulting trends with multi-cell pixel-resolution data will need to take into consideration potential confounding from pixels containing cells of different cell types.Given the nascency of such high-throughput spatially resolved transcriptomic technologies, new computational methods for analyzing the resulting data are still actively being developed. Already, computational methods leveraging Gaussian processes14. Integrating additional information such as cellular transcriptional composition and prior knowledge of cell type-specific gene expression can further enhance segmentation performance, particularly with crowded but transcriptionally distinct cells16. However, for cells with more complex morphologies such as neurons, additional computational methods for reliable cell segmentation are still needed. Beyond ensuring more accurate estimation of single-cell gene counts, reliable segmentation opens the door to additional downstream computational methods to incorporate subcellular spatial information. For example, by accurately accounting for the subcellular location of RNA counts, these downstream methods enable the prediction of future cellular transcriptional states by inferring RNA velocity in situ or the characterization of the subcellular spatial heterogeneity of RNAs and its functional impact18.Data from spatially resolved transcriptomic technologies present unique analytical challenges and opportunities. For spatially resolved transcriptomic data from in situ imaging-based technologies, individual identified RNA molecules must be aggregated into cells to achieve single-cell resolution transcriptomic profiling. Therefore, reliable cell segmentation is needed to fully dissect the heterogeneity of single cells in their spatial context, as well as to probe their morphological features and to characterize their intracellular variability. Several cell segmentation pipelines exist and work well with images of cells in culture or fluorescent labeled cells21 or by applying generative modeling approaches22. Although these deconvolution approaches infer the proportional representation of cell types within multi-cellular\u00a0pixels, additional methods are needed to further dissect the spatial organization of cell types and enable the inference of sub-pixel spatial information.Likewise, spatially resolved transcriptomic data from sequencing-based, pixel-resolution, spatially resolved RNA capture technologies present a different set of unique analytical challenges. In particular for technologies with larger pixel sizes, transcripts from multiple cells may be captured in each spatially resolved pixel. As such, each resulting spatially resolved transcriptomic profile may reflect multiple cells of different cell types, thereby hindering the identification of cell-type-specific spatial organizational patterns. To overcome this challenge, several computational methods have been developed to deconvolve cell-type mixtures within each multi-cellular\u00a0spatially resolved pixel, often by integrating the cell-type-specific transcriptomic profiles derived from a suitable single-cell reference23.Still, additional computational methods for analyzing spatially resolved transcriptomic data are needed. Notably, although computational methods have been developed to identify and characterize spatial gene expression patterns, we find that additional methods to systematically characterize and statistically evaluate how such patterns relate to anatomical features of tissues such as blood vessels or organ borders are still needed to understand the relationship between structure and phenotype. Furthermore, current computational methods generally limit spatial analysis to individual tissue sections or multiple contiguous sections from the same sample. To analyze samples collected from different individuals, time points, or perturbations, we anticipate that additional computational methods for aligning to a common coordinate system will be needed to compare, contrast, and characterize differences in spatial gene expression patterns and cellular organizationAs these spatially resolved transcriptomic technologies become more widely adopted, we anticipate that beyond the development of new computational methods for spatially informed data analysis, such computational methods must be implemented and made accessible as robust and usable software. This is needed to ensure that users can apply these technologies and analyze the resulting data effectively and efficiently. We believe the software developed to preprocess and analyze spatially resolved transcriptomic data should therefore adhere to best practices in open-source software development, such as providing adequate documentation of software functionality and maintaining responsive issue tracking. Further, support mechanisms need to be made available to promote and incentivize such adherence. Adherence to such best practices will be especially critical to ensure that these technologies and tools are accessible to researchers with more limited computational expertise. Moreover, as these spatially resolved transcriptomic technologies and protocols are further developed to enable data collection from larger tissue sections with more genes and cells across more samples, analytical algorithms and software implementations that are scalable with respect to runtime and memory will also be critical to ensure that these technologies and tools are accessible to researchers with more limited computational resources.24, further efforts are needed to encourage adoption by enhancing their ease of use, offering comparable features to existing in-house pipelines, while maintaining flexibility across available technological platforms, as well as demonstrating robustness and reproducibility across use cases.As current spatially resolved transcriptomic technologies continue to mature, we believe standardized metrics and benchmarks will need to be created, to enable comparisons across these technologies, in particular with regards to detection sensitivity, specificity, and capture efficiency. Such standardized metrics and benchmarks will be important for understanding which technologies may be better suited for specific biological questions such as those that demand detection of lowly expressed genes or single-nucleotide variations. Such standardized metrics and benchmarks will also facilitate the development of computational methods for harmonized analysis of data across multiple technologies. In particular for spatially resolved transcriptomic data from in situ imaging-based technologies, standardized metrics for reporting confidence in spot calling, gene identification, and gene-to-cell assignment remain to be established. We anticipate that such specific standardized metrics will be useful in mitigating error propagation to downstream analyses that may lead to incorrect biological interpretations. For example, errors in spot calling, gene identification, and cell segmentation may lead to inaccurate cellular gene expression counts that result in the misidentification of seemingly new, transcriptionally distinct cell types that are the result of propagated technical errors. One challenge towards establishing a set of standardized metrics for spatially resolved transcriptomic data from in situ imaging-based technologies is related to the current dearth of uniform preprocessing pipelines. Many of the current spatially resolved transcriptomic in situ imaging-based protocols rely on in-house image preprocessing pipelines. Although uniform preprocessing pipelines are being established25. Further, it makes readily accessible not only the processed gene counts but also raw sequences, as well as metadata on the machines and organisms used to generate the data and metrics regarding the quality of the data such as base call quality scores. Establishing a similar infrastructure for spatially resolved transcriptomic data from in situ imaging-based technologies may prove to be more complex given the range of protocols and modalities that exist and the sheer size of the raw imaging data as well. However, establishing such an accessible data-sharing infrastructure will be especially important for accelerating the development of computational methods to analyze such spatially resolved transcriptomic data, as it ensures the availability of a wide range of data for method testing and enables the characterization of method performance with respect to data quality. We envision that additional discussion and collaboration from the community will be needed to establish the form of processed data and range of standardized metrics most useful for all invested parties, from those interested in developing new computational methods to those interested in further enhancing the technologies, and those interested in probing deeper into datasets for biological insights.In addition, we find that an accessible and centralized infrastructure is currently still needed for sharing spatially resolved transcriptomic data, in particular from in situ imaging-based technologies. Such an accessible and centralized infrastructure already exists for RNA-sequencing dataIn conclusion, spatially resolved transcriptomic technologies offer an exciting new way of probing the intricate spatial mechanisms at play within tissue ecosystems. Computational methods are needed to enable the characterization of tissue heterogeneity using the high informational content data obtained from such spatially resolved transcriptomic technologies. Still, there remains a need for targeted perturbation, experimental validation, and investigation of generalizability to validate the insights gained from applying these computational methods. For example, although computational methods have been developed to integrate spatial and morphological information in single-cell clustering, further validation is needed to understand if new cell clusters identified through such integrative approaches represent meaningful functional heterogeneity. Furthermore, investigating the extent to which spatial and morphological characteristics of cells are independent of their gene expression can lend insights into other cell intrinsic and cell extrinsic factors that influence cell phenotype. Likewise, intracellular spatial heterogeneity and its functional consequences remain to be characterized. Ultimately, computational methods for analyzing spatially resolved transcriptomic data offer the potential to identify and characterize the heterogeneity of cells within their spatial contexts and contribute to important fundamental biological insights regarding how tissues are organized in both the healthy and diseased settings."}
+{"text": "This session will provide updates on how the pandemic led to horrific situations in long-term care facilities and how the pandemic influenced major federal efforts to address elder abuse, neglect, and exploitation."}
+{"text": "Pseudomonas aeruginosa (PSAR) is challenging to treat due to its multiple resistance mechanisms, limited anti-PSAR agents, and population pharmacokinetic (PK) variances. Beta-lactam antibiotics (BLA) are commonly used to treat PSAR infections and although they have a wide therapeutic index, suboptimal exposures may lead to treatment failure and antimicrobial resistance while high exposure may result in adverse effects. Certain patient populations may benefit from BLA therapeutic drug monitoring (TDM) due to their significant PK variability. The purpose of this study was to compare clinical outcomes in patients with PSAR pneumonia (PNA) or bloodstream infection (BSI) receiving BLA with and without the guidance of TDM.Retrospective, parallel cohort study conducted at UF Shands Gainesville and UF Health Jacksonville evaluating five years of patients with PSAR PNA or BSI. TDM group was defined for routine BLA TDM compared to nonroutine BLA TDM service (non-TDM). Patients were excluded if they died before a culture result, transferred in with a positive PSAR culture, were transplant recipients, cystic fibrosis or burn injury patients. The primary outcome was a composite of presumed clinical cure defined as the absence of the following: all-cause in-hospital mortality, escalation, and/or additional antimicrobial therapy for PSAR infection after 48 hours of treatment with primary susceptible regimen due to worsening clinical status or transfer to a higher level of care.Two-hundred patients were included . The overall primary composite outcome of presumed clinical cure occurred in 73% of patients . A post-hoc multivariate analysis was conducted to assess predictors of not attaining clinical cure.While there was no difference in the primary composite outcome of presumed clinical cure, future studies can use these data to assess TDM patient selection and whether a bundled care approach of BLA regimens with known clinical benefit, early TDM-guided dose optimization, and continued clinical assessment improves outcomes in patients with PSAR PNA or BSI compared to use of each modality individually. All Authors: No reported disclosures"}
+{"text": "Difficulties in parent-child interaction are easily observed and are a potential target for early intervention. This study aimed to assess the utility of observation of parent-child interaction in the first year of life in identifying children at risk of developing later psychopathology, using a rigorous systematic review method.EMBASE, CINAHL, PsycINFO, MIDIRS, MEDLINE and Cochrane Library databases were searched using MeSH terms and keywords, and reference lists screened. Two authors independently reviewed papers for inclusion and completed data extraction. All peer reviewed papers studying the association between an independent observation of parent-child interaction and later childhood psychopathology in community-based samples were included. Studies based on \u2018high risk\u2019 samples  were excluded. Results were synthesised qualitatively due to high heterogeneity.18,226 papers were identified, nine were included in this study. Childhood psychopathology was associated with fewer positive parent-infant interactions, lower parent vocalisation frequency and lower levels of adult speech and activity. Maternal sensitivity was inversely related to separation anxiety and oppositional defiant/conduct disorders were associated with lower shared look rates. Disruptive behaviour disorders were associated with higher frequency of child vocalisation. Pervasive developmental disorders were associated with \u2018abnormal\u2019 maternal infant interactions, as assessed by community health nurses using a standardised measure.Included studies reported small samples, and several of these samples overlapped. Some studies were of poor quality, but were included due to a paucity of available data. The findings may therefore have limited generalisability. Difficulties in parent-child interaction are easily observed and assessments could be made by non-specialists such as health visitors or general practitioners. Such difficulties may be an early indicator of later childhood psychopathology. Childhood psychiatric diagnoses (with the exception of Autistic Spectrum Disorders) appear associated with level of maternal activity . Assessments may identify at-risk families for early intervention, but further work is required to develop and validate reliable methods for risk stratification in community-based practice."}
+{"text": "The emergence of multicellularity is strongly correlated with the expansion of tyrosine kinases, a conserved family of signaling enzymes that regulates pathways essential for cell-to-cell communication. Although tyrosine kinases have been classified from several model organisms, a molecular-level understanding of tyrosine kinase evolution across all holozoans is currently lacking. Using a hierarchical sequence constraint-based classification of diverse holozoan tyrosine kinases, we construct a new phylogenetic tree that identifies two ancient clades of cytoplasmic and receptor tyrosine kinases separated by the presence of an extended insert segment in the kinase domain connecting the D and E-helices. Present in nearly all receptor tyrosine kinases, this fast-evolving insertion imparts diverse functionalities, such as post-translational modification sites and regulatory interactions. Eph and EGFR receptor tyrosine kinases are two exceptions which lack this insert, each forming an independent lineage characterized by unique functional features. We also identify common constraints shared across multiple tyrosine kinase families which warrant the designation of three new subgroups: Src module (SrcM), insulin receptor kinase-like (IRKL), and fibroblast, platelet-derived, vascular, and growth factor receptors (FPVR). Subgroup-specific constraints reflect shared autoinhibitory interactions involved in kinase conformational regulation. Conservation analyses describe how diverse tyrosine kinase signaling functions arose through the addition of family-specific motifs upon subgroup-specific features and coevolving protein domains. We propose the oldest tyrosine kinases, IRKL, SrcM, and Csk, originated from unicellular premetazoans and were coopted for complex multicellular functions. The increased frequency of oncogenic variants in more recent tyrosine kinases suggests that lineage-specific functionalities are selectively altered in human cancers. Tyrosine kinases propagate cellular signals through the phosphorylation of tyrosine residues on protein substrates. Forming a monophyletic group within the larger protein kinase superfamily, tyrosine kinases diverged from serine\u2013threonine kinases prior to the emergence of opisthokonts  , which aA classification of the protein kinome into evolutionarily and functionally related families (here on referred to as the KinBase classification) was achieved two decades ago following the sequencing and comparative genomic analyses of model organism genomes including human , mouse , sea urcIn addition to the uniquely evolved features across different tyrosine kinase families, similarities across some tyrosine kinase families have also been noted. For example, the recently termed \u201cSrc module,\u201d which consists of a tyrosine kinase domain and N-terminal SH3 and SH2 domains, is found across the Src, Abl, Tec, and Csk families, and structural and solution studies have determined that a similar autoinhibitory configuration of the Src module is shared across members of the Src, Abl, and Tec families . BecauseHere, we determine a novel hierarchical, constraint-based classification of the tyrosine kinome that newly identifies three evolutionary subgroupings of tyrosine kinase families based on the selective conservation of sequence motifs in the kinase domain, which encode common autoinhibitory conformations. In addition, we illustrate an evolutionary timeline of how unique kinase functions have expanded on shared subgroup-specific features through duplication events, selection of family-specific motifs, and domain shuffling to give rise to the vast repertoire of tyrosine kinase signaling observed throughout metazoans. A closer examination of tyrosine kinase phylogeny in light of constraint-based tyrosine kinase subgroups reveals new insights into the evolutionary conservation or divergence of subgroups, as well as the unique signaling features that may have emerged from three separate monophyletic clades of receptor tyrosine kinases. In particular, we note the early emergence of two major clades of holozoan tyrosine kinases distinguished by the presence (or absence) of an insert between the \u03b1D and \u03b1E helices of the kinase domain, where tyrosine kinases containing the insert comprise the majority of metazoan receptor tyrosine kinases. Our classification of the tyrosine kinome and the approach used in this study set a new precedent for the classification and evolutionary study of protein kinases and other large protein families.To generate a comprehensive classification of the holozoan tyrosine kinome, we generated a multiple sequence alignment of 44,639 tyrosine kinase sequences spanning 586 species . We then used the Bayesian Partitioning with Pattern Selection (BPPS) algorithm to classify aligned sequences into hierarchical clusters based on the patterns of conservation and variation in aligned tyrosine kinase domain sequences A Neuwal, 2014. ENext, we reclassified 34,954 tyrosine kinase sequences from the UniProt reference proteomes database into the optimized hierarchy by quantifying the extent to which individual sequences match cluster-specific motifs . We define this reclassification as a constraint-based classification because this post-processing step eliminates spurious or divergent sequences from clusters that do not score over an optimal cut-off score due to their lack of cluster-specific patterns. The spurious sequences eliminated from each cluster are categorized within the unclassified family .The new constraint-based hierarchical classification of tyrosine kinases, which is broadly similar to the KinBase classification of the tyrosine kinome, reveals several novel subgroupings. In particular, the constraint-based classification defines three new subgroupings of tyrosine kinase families which account for nearly half of the tyrosine kinome: the Src module (SrcM) subgroup, the insulin receptor kinase-like (IRKL) subgroup, and the fibroblast, platelet-derived, and vascular growth factor receptors (FPVR) subgroup . The SrcBy examining the sequence constraints that define each of the three novel subgroups in light of existing crystal structures, we observe that subgroup-specific motifs are located in known regulatory regions of the kinase domain. For example, the SrcM subgroup conserves a highly distinguishing GxM motif in the \u03b23-\u03b1C loop and a GxKF motif in the activation loop that both form important interactions associated with a common Src-like inactive conformation in the activation loop A Xu et . This SrIn order to infer when each of these tyrosine kinase subgroups and families emerged in evolution, we organized tyrosine kinase subgroups and families based on taxonomic conservation . TyrosinIn order to further explore the functional diversity of SrcM, IRKL, and FPVR tyrosine kinases, we surveyed the diversity of protein domains present across these subgroups and analyzed their conservation across holozoan taxa . As prevThe IRKL and FPVR subgroups encompass the majority of receptor tyrosine kinase families and, despite sharing common kinase domain mechanisms within these subgroups , have diHis260) in the \u03b1E helix which tyrosine kinases selectively lost upon diverging from the serine/threonine kinases . By integrating our constraint-based classification of tyrosine kinases with our phylogenetic tree A, we can kinases  online  group of serine/threonine kinases. Holozoan tyrosine kinases (Group A) also form a monophyletic clade that is distinct from a paraphyletic group of divergent tyrosine kinase sequences found in pre-opisthokonts (Group B), such as those found in the amoebozoans nhardtii  . This correlation between the presence of the longDE insert with the presence of transmembrane and extracellular domains, alongside evidence that the insert plays important roles in kinase activation and protein recruitment for downstream signaling, suggests that the longDE insert evolved as a means to facilitate downstream intracellular signaling upon the activation of receptor tyrosine kinases by extracellular signals. In addition, though the DE insert is difficult to align across families due to the lack of sequence conservation, the DE insert is alignable within families and often conserves sequence motifs including phosphorylatable tyrosine, serine, or threonine residues, suggesting that individual receptor tyrosine kinase families along the longDE clade have rapidly and frequently evolved the longDE insert in family-specific contexts, presumably to carry out family-specific downstream signaling functions. We also note that the longDE tyrosine kinases highly conserve a unique activation loop methionine, which is not observed in shortDE tyrosine kinases C; howeveInterestingly, the shortDE clade in the tyrosine kinase phylogeny, which predominantly consists of cytoplasmic tyrosine kinases, includes two monophyletic clades of receptor tyrosine kinases: the EGFR family of receptor tyrosine kinases and a separate monophyletic clade that includes the Eph and choanoflagellate-specific RTKC families of receptor tyrosine kinases. Thus, our phylogeny suggests at least three independent origins of highly expanded receptor tyrosine clades, with the majority of receptor tyrosine kinases emerging from the longDE clade. That these disparate branches along the tyrosine kinase phylogeny have convergently evolved to include transmembrane and extracellular domains highlights the importance of relaying extracellular signals into intracellular responses across various signaling niches. Although the longDE receptor tyrosine kinases are distinguished by extra functionalities imparted by the longDE insert, the Eph and EGFR families also exhibit unusual signaling functions so far unobserved in other longDE receptor tyrosine kinases. Eph receptor tyrosine kinases have a unique capacity for bidirectional signaling, where the binding of ephrin ligands, which are also membrane bound, can activate signaling both in the receptor-bearing cell, as well as in the ligand-bearing cell . FurtherThe classification of protein kinases into evolutionarily related families has provided the foundation for decades of comparative sequence-structure-function studies on protein kinases . Here, wWe constructed a new representative phylogenetic tree of the holozoan tyrosine kinome which revealed larger evolutionarily related clades of tyrosine kinases associated with additional defining features A. DividiThe expansion and diversification of the tyrosine kinome across the animal kingdom highlights its central role in metazoan biology. Although many previous studies have speculated on the role of tyrosine kinases in the evolution of multicellularity , our finGiven the important roles of tyrosine kinases in multicellular metazoan biology, it comes as no surprise that sequencing efforts have identified many disease-related variants across the tyrosine kinome . MultiplWe sampled alternative classification hierarchies ab initio, using the omcBPPS algorithm  which emPhe43) and ending at the \u03b1I helix (PKALys292). Kinase sequences which did not span from at least the \u03b23-Lys to the DFG-Asp were deemed fragmentary and removed from the alignment. The UniProt sequence set contained 12,137 tyrosine kinase sequences. The nr sequence set was further purged at 98% sequence identity and contained 17,071 tyrosine kinase sequences. We performed hierarchical clustering on both sequence sets using omcBPPS. For both sequence sets, we optimized the \u201cminnats\u201d parameters (minnat\u2009=\u20091 and minnat\u2009=\u20095) which changed the minimum log-likelihood required to form a cluster. All runs were performed twice. To create a consensus of the hierarchical classification schemes found by multiple runs of omcBPPS, we used the mcBPPS algorithm. Clusters which were consistently identified throughout multiple runs were refined using the mcBPPS algorithm  and NCBI nonredundant (nr) proteins database  . Within lgorithm . We ran Using our consensus model, we developed quantitative means of evaluating how well any given sequence fit into each of the clusters defined by our model  which implements NumPy array-based sequence alignment manipulation. All sequence features  were represented as Boolean arrays as a function of the full sequence alignment. More complex queries pertaining to multiple sequence features (such as the presence of a given domain in a given taxon) were constructed by Boolean algebra. These Boolean arrays were applied as filters to our sequence alignment using NumPy indexing routines . SequencAfter we classified our representative set of tyrosine kinase into discrete clusters, we determined the taxonomic conservation of each cluster. We determined the source of each tyrosine kinase sequence using the organism identifier number (OX) provided in the FASTA header of UniProtKB sequences. OX numbers were traced back to their parent node identifiers using the nodes dump file provided in the NCBI taxdump database. All node identifiers were translated to their respective scientific names using the taxonomy names dump file. We determined the distribution of taxa across each cluster of tyrosine kinases and selected an optimal mix to depict diverse taxa ranging from unicellular pre-metazoans to more complex metazoans such as chordates  online. Intron/exon annotations were mapped using Scipio . Intron We produced protein domain annotations for each full-length tyrosine kinase sequence using the NCBI Conserved Domain Database  database of conserved protein domains  one randomly selected sequence from each cluster-taxon pair based on  online etellanii , and 4) tellanii , with Motellanii . Branch tellanii . Resultstellanii  online. The consensus tree with the highest bootstrap support values for the three major tyrosine subgroups was selected as the final tree. The optimal substitution model for our final topology was determined to be LG+R8 based on the Bayesian Information Criterion as determined by ModelFinder . We rootWe compared our tree to previously published phylogenies which also sampled diverse tyrosine kinase families . HoweverMolecular Biology and Evolution online.msab272_Supplementary_DataClick here for additional data file."}
+{"text": "Although clinical guidelines recommend that people showing signs of cognitive decline engage in Advance Care Planning (ACP) while they still have decision-making capacity, too often this opportunity to clarify values and treatment preferences is missed among patients and their families. In reflection of the paucity of empirical data on factors influencing how this planning process begins for families experiencing cognitive decline, this study explored facilitators and barriers to ACP among adult children of parents showing signs of early- to mid-stage dementia, with a particular focus on relationship quality. Among this sample (N = 315), relationship quality positively and significantly predicted advance care planning engagement . Financial burden weakly and positively predicted ACP engagement , while both psychological burden  and financial burden  negatively and significantly predicted relationship quality. This study validates the use of the ACP Engagement Survey (ACPES) adapted for surrogates among adult children of people experiencing cognitive decline and contributes to a scarce literature on the impact of relationship quality on ACP engagement."}
+{"text": "Current 3D cardiac organoid cultures have shown their utility in modelling key developmental hallmarks of heart organogenesis, but the complexity of the organ demands a more versatile model that can investigate more fundamental parameters, such as structure, organization and compartmentalization of a functioning heart. This review will cover the prominence of cardiac organoids in recent research, unpack current in vitro 3D models of the developing heart and look into the prospect of developing physiologically appropriate cardiac organoids with translational applicability. In addition, we discuss some of the limitations of existing cardiac organoid models in modelling embryonic development of the heart and manifestation of cardiac diseases.Medical research in the recent years has achieved significant progress due to the increasing prominence of organoid technology. Various developed tissue organoids bridge the limitations of conventional 2D cell culture and animal models by recapitulating  Congenital heart defects (CHD) affects approximately 0.4\u20135% of live births worldwide, making it the most common form of congenital disease . Despitein vivo (The advent of pluripotent stem cells (PSCs), of both embryonic stem cells (ESC) and induced pluripotent stem cell (iPSC) origins differentiated into various cell lineages, provides novel insights to embryonic development and regenerative biology . Human iin vivo . These fin vitro tissue cultures have been widely used in multiple research fields to model their in vivo organ counterparts. Self-organized from stem cell populations, these organoids have the potency to undergo multiple divisions and differentiate into various appropriate cell types to confer structural and cell composition resembling in vivo organs  o organs . Kidney,o organs . Cell-ceo organs . As suchin vitro model that can capture such a complex system, maintain, and mature the various cell types will be even harder to achieve. While cardiac organoid technology is still in its infancy, a number of research groups have developed methods to generate 3D cardiovascular tissue using either a pure CM starting population or a mixture of CMs, CFs and ECs and aggregating them into Engineered Heart Tissues (EHT) or on scaffolds , epicardial cells, endocardial cells, smooth muscle cells, cardiac fibroblasts (CF) and endothelial cells (EC) with compositions that can vary with age or due to myocardial damage and remodelling . PSC-dercaffolds  (Eschenhcaffolds . A summaEmbryoid bodies (EBs) are aggregate masses of PSCs cultured in suspension and are widely used for differentiation into various tissue lineages. CMs were first derived using EBs generated using murine stem cells . Since tTo overcome the stochastic nature of EB-CM models resulting in widely varied cell compositions and cell number, cardiac spheroids have been aggregated using specific cell composition and number. A number of research groups have explored aggregating tissues of varying compositions appropriate to study specific archetypes of cardiac developmental diseases or health. Hanging drop culture has been used to aggregate CMs, ECs and CFs in a 3:1:6 ratio for spheroids to measure the cardiotoxicity of doxorubicin, a widely used cancer drug . Anotherin vivo early heart and foregut endodermal anlagen of the developing embryo, with layered myocardium and endocardium, vascular network, and anterior-posterior foregut patterning (On the other hand, cardiac organoids are more strictly defined as 3D cardiac structures that were self-organized from either PSCs or multipotent progenitors. This direction is highly popular of late, with many recent works on utilizing either murine and human PSCs to generate cardiac organoids attempting to recapitulate cardiogenesis . Interestterning . By natuA popular method to overcome the maturation limitation of these spheroid and organoid models is long-term culture within bioreactors. Bioreactors supply biochemical signals by improving media circulation around the organoids to ensure higher mass transfer, physiological relevant gradient of nutrients and sufficient removal of waste products . In addiEngineered heart tissues are amongst the oldest and most utilized 3D tissue construct made up of aligned CMs with the ability to propagate contractions along a plane . While tEHTs have also been adapted to contain the appropriate cell composition for modelling specific diseases. ECs and/or CFs have been aggregated to study neovascularization and cardiac fibrosis . PurifieHowever, there are limitations to EHTs as a modelling platform. It requires a high initial cell count for aggregation, within a complex equipment setup that prevents high throughput screens . In addiEHT constructs of 3D CM tissues was popularized alongside several other hydrogel/polymer based matrixes for patterning . ConceptSimilarly, hydrogels and polymers have been utilized to create 3D scaffolds as a biomimetic approach to recapitulate human cardiac tissue . While EWhile cardiomimetic scaffolds have been developed to provide a geometrically and environmentally appropriate 3D architecture for CM seeding, simple folded scaffolds have also been developed to promote cardiac chamber formation . These hAlternatively, precise control of cellular composition and spatial distribution of individual cells can be achieved via 3D bioprinting. Hydrogels and decellularized extracellular matrix have been developed into bioinks that serve as a scaffold for individual cell types to be printed on . Of notein vitro heart models limit research in understanding these disorders. While much effort has been poured into generating the 3D CM models described in in vivo development.Congenital heart defects occurring during the first 8\u00a0weeks of embryonic development are detrimental to the growing embryo\u2019s ever-increasing metabolic demands during embryogenesis. However, inaccuracies in the in vitro models were shown to recapitulate various aspects of cardiogenesis. Earlier work by There have been significant recent advances in the field of developmental cardiac organoids, which were intrinsically formed by taking advantage of the self-organizing and patterning capabilities of either murine or human hPSCs. These Consistently, in vivo heart (in vitro organ/tissue formation to mimic cardiogenesis from the early to mid-gestation stages, and thus does not require complex differentiation protocol. Therefore, the heart organoids represent a promising research tool to study developmental diseases for drug testing.Developmental organoids can also possess the capability to be used as a disease modelling tool, particularly for drug testing. Heart organoids were generated using mouse ESCs by utilizing FGF4 and extracellular matrix, emulating the developmental processes of the vo heart . These hAs mentioned, several organoid platforms have focused particularly on the disease modelling and drug screening purposes of the model . These mvia Wnt signaling modulation, and extensively detailed its capability in modelling cardiac development and diabetes-induced congenital heart disease. These hHOs were mainly comprised of myocardial tissue, with epicardial tissue organized near the exterior surface of the organoids. In addition, these hHOs recapitulate the functional and structural features of the developing fetal heart, exhibiting robust contraction and action potential waves reminiscent of the PQRST waves, and expressed well defined sarcomeres surrounded by gap junctions, mitochondria and t-tubules. As a proof of concept, pregestational diabetes impacted the cardiac development of these hHOs, resulting in irregular arrhythmic contraction, metabolic dysfunction and structural organization in accordance with the phenotype observed in vivo.Of note, Myocardial infarction and drug cardiotoxicity has been recently modelled in a cardiac microtissue organoid model as well . The uniin vivo. However, current cardiac organoid models fall short in developing important structural and morphological elements unique to the heart. Particularly, cardiac architecture, most notably being the heart chambers are absent, and thus related elements such as the septa and valves are also missing. As such, CHD affecting these missing elements in the in vivo developing heart cannot be accurately modelled.Collectively, developments in 3D cardiovascular disease models have demonstrated the ability of patient-derived cardiac organoids to recapitulate developmental processes of cardiogenesis, as shown by ultrastructural, gene expression, histochemical characteristics with resemblance to the developing heart in vivo (Cardiac progenitors within the embryonic heart specifies their subtype early in development, primarily during heart field specification . Howeverin vivo . Furtherin vitro, working in tandem with classical models for accurate phenotyping of disease and drug effects. However, the lack of functional cardiac chambers limits the utility of these organoids in the disease modelling space. The closest model in achieving self-organized chambers currently available is the hHO model by Lewis-Israeli et al., detailed previously in + endocardial cells (Lastly, the missing structural elements of current cardiac models results in the failure to model mechanical functional changes such as myocardial wall thickness, pressure loading and ejection fraction. Heart disease often present with pathological cardiac remodeling, causing hypertrophic growth, irreversible decompensation and thinning of the myocardium and dilatation of the failing heart . Classical cells . Howeveral cells . Such anDrawing from the approaches of the tissue organoid systems currently generated, intrinsically formed chambered cardiac organoids should theoretically be achievable. Judging by the rapid pace of advances in the space of cardiac organoid development in recent years, there is promise that such an organoid model will soon be developed and be scalable for high-throughput disease modelling. Lately, there has been increasing interest in utilizing microfluidic systems such as organ-on-a-chip platforms for use in preclinical analysis. These chip-based systems are the preferred platform for industry-level research\u2014completely automated high throughput derived organ-models are screened within highly reproducible fabricated chips. Organ-chip systems have been adapted to allow for vascularization in a number of tissue types, recently reviewed by in vivo heart in place, future in vitro cardiac modelling will be able to better support downstream preclinical pharmaceutical research in discovering cures and preventing cardiotoxic drugs from slipping through.While 3D CM cultures currently exist and are routinely used for studying development, drug screening and disease modelling, they often portray an incomplete picture of associated effects on a human heart. The strong demand required to bridge the technology and knowledge gap will enable researchers to better study heart development and cardiovascular diseases for research and translational purposes. Hence, future direction for cardiac organoid research is currently focused on generating physiologically appropriate chambered cardiac organoids paired with an appropriate high-throughput modelling platform that can simultaneously assess multiple cardiac functional parameters. With more faithful models of the"}
+{"text": "Socioeconomic status (SES) is one of the most robust predictors of health. The source of SES-health associations is heavily debated; one approach is investigating neighborhood-level environmental characteristics. Challenges include selection effects and the possibility of reverse causation: people choose their neighborhoods. Longitudinal twin research can overcome these issues by assessing location choice over time as well as twin similarity; however, few existing twin studies have incorporated neighborhood-level data, and none of those focus on aging. Using longitudinal data from the Swedish Adoption/Twin Study of Aging, the current study examined the impact of location at various points in life. Location at birth and in 1993 were available for 972 participants. Birth years ranged from 1926 to 1948; mean age in 1993 was 54.55 (range = 35-67). Thirty-nine percent of the sample had moved to a different county between birth and midlife: individuals who moved had significantly higher parental SES and had achieved significantly higher education. Moreover, identical twin concordance for geographic mobility (77%) was significantly higher than fraternal twin concordance (65%), indicating a modest but significant genetic contribution. Geographic mobility did not impact identical twin similarity on a functional aging factor (corrected for age and education), but fraternal twins concordant for mobility were more similar than discordant twins, suggesting genetic contributions to mobility may also impact health. Ongoing retrieval of location information for twins born 1900-1925 and geocoding of location information available at 9 waves of data collection will allow for expanded investigation of the SES-health relationship at the neighborhood level."}
+{"text": "METHODS/STUDY POPULATION: This study involves refractory epilepsy patients with implanted intracranial electrodes and moderate-to-severe traumatic brain injury (m/sTBI) survivors. In epileptic patients, we will identify connectivity of cortical regions via the ANT, which probes components of attention  and a CC task that probes implicit learning. We hypothesize that modulation of attention and learning can be seen at the network level. In TBI we will assess improvement following two attention rehabilitation paradigms behaviorally; and use our results from epileptic patients to guide measurement of treatment-related neuroplastic change via scalp electroencephalography. RESULTS/ANTICIPATED RESULTS: When the proposed objectives are complete, we expect to determine how the implicit learning rate in m/sTBI changes as a result of both direct attention and metacognitive-strategy training, and discern the neuroanatomical networks associated with attention and implicit learning based on connectivity results. We expect to identify intracranial regions and networks that exhibit modulatory effects associated with attention and implicit learning. Additionally, we anticipate that deficits in attention will be mitigated following training and hypothesize that implicit learning rate will improve in TBI patients as a result of both attentional rehabilitation paradigms. DISCUSSION/SIGNIFICANCE OF IMPACT: Characterizing intracranial activity in epilepsy patients will give electrophysiology data unattainable in TBI patients. This intracranial perspective will enable us to propose mechanisms of action that may result from our interventions and enable critique of current rehabilitation treatments.OBJECTIVES/GOALS: 1) Investigate the network level interactions of attention and learning during an attention network task (ANT) and an implicit learning contextual cueing (CC) task. 2) Assess the effect attention rehabilitation strategies have on"}
+{"text": "In the last decade, cold water immersion (CWI) has emerged as one of the most popular post-exercise recovery strategies utilized amongst athletes during training and competition. Following earlier research on the effects of CWI on the recovery of exercise performance and associated mechanisms, the recent focus has been on how CWI might influence adaptations to exercise. This line of enquiry stems from classical work demonstrating improved endurance and mitochondrial development in rodents exposed to repeated cold exposures. Moreover, there was strong rationale that CWI might enhance adaptations to exercise, given the discovery, and central role of peroxisome proliferator-activated receptor gamma coactivator-1\u03b1 (PGC-1\u03b1) in both cold- and exercise-induced oxidative adaptations. Research on adaptations to post-exercise CWI have generally indicated a mode-dependant effect, where resistance training adaptations were diminished, whilst aerobic exercise performance seems unaffected but demonstrates premise for enhancement. However, the general suitability of CWI as a recovery modality has been the focus of considerable debate, primarily given the dampening effect on hypertrophy gains. In this mini-review, we highlight the key mechanisms surrounding CWI and endurance exercise adaptations, reiterating the potential for CWI to enhance endurance performance, with support from classical and contemporary works. This review also discusses the implications and insights (with regards to endurance and strength adaptations) gathered from recent studies examining the longer-term effects of CWI on training performance and recovery. Lastly, a periodized approach to recovery is proposed, where the use of CWI may be incorporated during competition or intensified training, whilst strategically avoiding periods following training focused on improving muscle strength or hypertrophy. Cold water immersion (CWI) is a strategy aimed at enhancing recovery from strenuous exercise, typically involving the submersion up to the waist or mid-torso for ~5\u201320 min in temperatures between ~8 and 15\u00b0C (Versey et al., Meta-analyses and experimental research in general show that CWI can beneficially influence the recovery of physical performance (Montgomery et al., In this mini-review, we have adopted an introspective approach in discussing the molecular mechanisms and rationale surrounding CWI and endurance exercise adaptations. Moreover, we review and discuss key studies which provide information on the applied scenarios where CWI can be utilized to promote physical recovery and adaptation whilst avoiding potential negative effects on hypertrophy and strength gains.Cold stimulus is a physiological stressor capable of triggering primary signals and downstream cascades implicated in exercise-induced improvements in muscle oxidative function (Ihsan et al., Seminal work by Spielgeman's group in the late 90's generated major breakthroughs in the mechanisms underpinning mitochondrial biogenesis (Puigserver et al., Whilst CWI was not conceived as a strategy specifically meant to supplement exercise adaptations, there was substantial interest in examining how recovery-based CWI might influence skeletal muscle adaptations to endurance exercise (Ihsan et al., Although such molecular responses would expectedly improve endurance performance in the longer term, Yamane et al.  reportedIn contrast to Yamane et al.  initial While these findings refute suggestions that CWI might counteract endurance adaptations, it nevertheless questions whether post-exercise CWI is an effective strategy to promote muscle adaptations resulting in improved exercise performance. Indeed, changes in acute signaling response (Ihsan et al., While some studies have shown that CWI can enhance physical recovery following resistance exercise (Vaile et al., 2 supply and utilization (Ihsan et al., Complimenting these mechanisms, we suggest that the attenuated increase in muscle mass observed following CWI and resistance training may be part of a macro-level mechanism protecting the oxidative profile of the muscle. This is supported by D'Souza et al.  demonstrWhile we rationalize that the dampened increase in muscle mass observed following CWI is a compensatory mechanism improving oxidative function, further research is needed to understand how this might influence athletic function and performance. For instance, it is currently unknown if CWI influences the regulation of muscle mass following aerobic exercise, and whether this hypothetical trade-off involving the attenuated increase in muscle mass and strength might be beneficial to endurance performance. On the other hand, co-assessment of muscle aerobic function within these resistance training studies (Frohlich et al., Athletes embark on a variety of training sessions such as cardiovascular conditioning, strength/resistance training, technical, and tactical work. In sports science practice, CWI is likely to be incorporated at various instances to promote recovery, particularly when recovery time between sessions is limited. Caution should be warranted against the regular use of CWI particularly following resistance exercise sessions.Recent work  examininTraining frequency reported within these applied studies surmounts to at least 10 sessions per week . PerhapsAnother key feature of these studies , and perCold water immersion is widely utilized by athletes during training and competition. Given that both a cold stimulus and exercise are independent stressors capable of enhancing muscle oxidative function, there remains substantial interest in examining how this modality might influence adaptations to exercise. Although post-exercise CWI up-regulates mitochondrial-related signaling, longer-term changes in protein content and result in vascular adaptations, these changes do not seem to translate to improved endurance performance. As such, further research is required to elucidate how endurance performance can be improved through its positive molecular signaling outcomes for CWI to be incorporated to enhance exercise-induced oxidative adaptations. It must be re-iterated that CWI does not impair aerobic training adaptations, and can be incorporated as a recovery modality following endurance training if needed. In contrast, regular CWI recovery incorporated into a resistance training program will dampen strength adaptations, and therefore the use of this modality following resistance exercise sessions should be discouraged. However, there is emerging data showing no impairments in strength gains in athletes incorporating regular use of CWI during intensified training periods; this either indicates that the recovery benefits conferred by CWI may outweigh its dampening effects on hypertrophy response, or the negative effects of CWI on strength may be circumvented by programing CWI following technical or aerobic conditioning sessions. In this regard, \u201crecovery periodization\u201d may be an important approach, where the use of CWI may be incorporated during competition or intensified training, whilst strategically avoided following training focused on improving muscle strength or hypertrophy.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The aerial portion of a plant, namely the leaf, is inhabited by pathogenic andnon-pathogenic microbes. The leaf\u2019s physical and chemical properties, combined withfluctuating and often challenging environmental factors, create surfaces that require ahigh degree of adaptation for microbial colonization. As a consequence, specificinteractive processes have evolved to establish a plant leaf niche. Little is known aboutthe impact of the host immune system on phyllosphere colonization by non-pathogenicmicrobes. These organisms can trigger plant basal defenses and benefit the host by primingfor enhanced resistance to pathogens. In most disease resistance responses, microbialsignals are recognized by extra- or intracellular receptors. The interactions tend to bespecies specific and it is unclear how they shape leaf microbial communities. In naturalhabitats, microbe\u2013microbe interactions are also important for shaping leaf communities. Toprotect resources, plant colonizers have developed direct antagonistic or hostmanipulation strategies to fight competitors. Phyllosphere-colonizing microbes respond toabiotic and biotic fluctuations and are therefore an important resource for adaptive andprotective traits. Understanding the complex regulatory host\u2013microbe\u2013microbe networks isneeded to transfer current knowledge to biotechnological applications such asplant-protective probiotics. Microbial colonization of above-ground parts of plants is a dynamic and interactiveprocess that requires a high degree of adaptation. Understanding complexhost\u2013microbe\u2013microbe interactions is key to new strategies for plant protection. This review examines how aerial parts of plants, particularly leaves, are colonized bymicrobes. The first section (\u2018Colonizing leaf surfaces\u2019) dissects biotic and abiotic factorsthat shape leaf microbial communities and determine the quality and quantity ofcolonization. We discuss pre-formed barriers, such as the cuticle, that restrict plant hostcolonization, and environmental conditions that enhance selection pressures. As aconsequence of the extreme conditions on leaves, the properties and generation of biofilmsthrough quorum sensing (QS) are considered. Leaf colonization by microbes is not onlyimpacted by host and environmental factors but also by resident microbes, includingpathogens that can severely perturb microbial communities. The second section(\u2018Microbe\u2013microbe\u2013host interactions\u2019) discusses effects of microbial communities on hostsusceptibility to pathogens and the impact of plant pathogens and endophytes on microbialhost colonization and community composition. A particular focus is on microbe\u2013microbeinteractions that are often mediated via the plant host. Individual plant cells also havethe capacity to steer microbial activities by pre-formed or induced structures and compoundsthat influence microbial growth on the leaf surface. The third section (\u2018Role of the plantimmune system in shaping the phyllosphere microbiome\u2019) considers the role of the plantimmune system on microbial host interactions with a focus on plant leaf colonization,leaf\u2013microbe outputs, and microbial diversity.6\u2013107 cells cm\u20132 of leaf area ,lettuce (Lactuca sativa), and neotropical forest and poplar treesconsists of four major bacterial phyla, namely Proteobacteria,Firmicutes, Bacteroidetes, andActinobacteria , and other treeleaves , and nitrogen fixation (nifH) gene markers,Methylobacterium and Sphingomonas species were highlyabundant in the plant leaf environment of three species, namely A.thaliana, Trifolium repens, and Glycine max fungal infection  andEscherichia coli O157:H7 (EcO157) colonize fresh leafy vegetables suchas lettuce (Lactuca sativa) via damaged leaf tissue and can causefood-borne disease outbreaks  whichregulates colonization as an important priming event in microbial community interactionswith the plant .ResearcPseudomonas syringae pv. syringae B728a strains onbean (Phaseolus vulgaris) leaves indicated that this hygroscopicbiosurfactant increases diffusion of water across a waxy leaf cuticle surface whichattracts moisture and nutrients to benefit the bacteria , ormation . SimilarN-acyl-l-homoserine lactone  and quinolones as QS molecules, whereas modified oligopeptides  are commonly used by Gram-positive bacteria for communication betweencells  enhancedsusceptibility of various Brassicaceae species to fungal mildew pathogens and Erwinia toletana(olive knot cooperator) stabilize the community and exchange QS signals, and thiscooperation results in a more aggressive disease on olive plants (Oleaeuropaea)  leaf-associated strains with QQ activity fordisruption of AHL-mediated QS, by using the biosensor reference strainChromobacterium violaceum CV026. These bacterial quorum quenchers canbe used as effective biocontrol agents against plant pathogens (Endophytes utilize QS to act against pathogenic microbes by expressing QS inhibitors(QSIs) to attenuate the activity of AIs, or quorum quenching (QQ) enzymes to disruptsignaling molecules. For example, AHL lactonase enzyme (a potent quorum quencher) presentin endophytic bacteria has been reported to inhibit the plant pathogens rotovora , 2001, Bngiensis , and Entasburiae . Ma et aInplanta experiments on Phaseolus lunatus have shown that, if apathogen was introduced to the plant on the same day or before inoculation with anendophyte, disease resistance was more strongly reduced than when the endophyte hadalready colonized the host . Similarly, different strains of the pathogenic fungusFusarium oxysporum can act as microbial antagonists against otherF. oxysporum strains  and intracellular receptors which recognize microbial or modified host molecularsignatures and retain plant health and secure plant propagation. Surface immune receptors are members of a diversefamily of ligand-binding proteins that sense microbial, environmental, developmental, andnutritional cues . The intThe activation of plant immune responses by mobilizing a network of defense and stresshormone pathways has been extensively characterized in binary plant\u2013pathogen interactions. High-thIn this section, we consider evidence that abiotic and biotic stress responses modulatemicrobial consortia on leaves and discuss the consequences for plant fitness. It is becomingclear that microbial community structure throughout a plant host\u2019s life cycle is dynamic andmodulated by the innate immune system, which itself is tuned to environmental changes.P. syringae bacteria and riceresistance to the rice blast fungus, Magnapothe oryzae (ethylene-insensitive2 (ein2) mutantdisplayed an altered bacterial leaf community compared with wild-type plants, suggestingthat ethylene signaling is important for modulating the leaf microbiota ] that is defective inPTI and the MIN7 vesicle trafficking pathway (affecting the aqueous apoplasticmicroenvironment) and a constitutively activated cell death1(cad1) mutant had altered endophytic bacterial leaf diversity  in protecting Arabidopsis against infection by afungal necrotrophic pathogen, B. cinerea (Actinobacteria(Strepotmycetes sp.) are able to activate plant biosynthesis ofsalicylic acid (SA) and promote leaf defense responses against fungal pathogens , which favor NLR expression in thephyllosphere , is often mediatedby intracellular NLR receptors which recognize certain pathogen-delivered virulencefactors (effectors) to induce immunity  reduce microbial diversity within leaf habitats and stabilizemicrobial communities among wild plants  in leaf tissues  and grapevine against necrotrophic (B.cinerea) fungi have been studied extensively in vitro (P. syringae pathovar tomato (Pst) to Arabidopsis rootsattracted Bacillus subtilis and led to IP upon Pstinfection  affecting microbial diversity  on crops such as potato against biotrophic(The plant phyllosphere is a highly competitive and challenging habitat for microbes tocolonize. Pre-formed barriers such as the hydrophobic cuticle, stomata, or cell wallstructures require specific adaptation for the microbes, and persistence of microbesstrongly depends on their ability to interact with others. Thus understanding microbiotaassembly and persistence in the plant phyllosphere requires investigating ecological factorsthat shape pre-formed plant structures and therefore directly act on host\u2013microbe andindirectly microbe\u2013microbe interactions. Microbe\u2013microbe interactions in turn not onlyimpact microbial behavior but can impact host fitness by antagonizing plant pathogens.Pathogen invasion generally has a significant negative effect on host fitness caused bytissue damage, nutrient loss to invaders, and reallocation of resources to immuneactivation. Successful pathogenesis on the other hand is a complex process that requiresmultiple steps of host colonization and reproduction, and is generally the result oflong-term co-evolution (The downside is, however, that this pool is highly dynamic and probably requires a stableco-existence of different microbial species in one habitat in order to express beneficialtraits. Interconnected networks between organisms can be an important element in providing abuffer against perturbations since such links help to recruit microbes to fulfill specificfunctions in cases where another organism that, for example, provides importantantimicrobial compounds or enzymes within the network is lost.A main goal to develop strategies to protect the phyllosphere from pathogen invasion, suchas wheat from rusts, is to identify probiotics that can either stabilize the naturalcommunity or become stable on its own. One major effort to develop such probiotics istherefore understanding the multistep process of establishing a niche and defending thisniche. Only once we know how to combine traits for stability with our desired traits such asplant protection will we be able to develop products that can replace the majority of ourcurrent agrochemicals."}
+{"text": "Geum peckii Pursh, Rosaceae) is a globally rare and endangered perennial plant found only at two coastal bogs within Digby County  and at several alpine sites in the White Mountains of New Hampshire (USA). In Canada, the G. peckii population has declined over the past forty years due in part to habitat degradation. We investigated the culturable foliar fungi present in G. peckii leaves at five locations with varying degrees of human impact within this plant species\u2019 Canadian range. Fungal identifications were made using ITS rDNA barcoding of axenic fungal cultures isolated from leaf tissue. Differences in foliar fungal communities among sites were documented, with a predominance of Gnomoniaceae . Habitats with more human impact showed lower endophytic diversities (10\u201316 species) compared to the pristine habitat (27 species). Intriguingly, several fungi may represent previously unknown taxa. Our work represents a significant step towards understanding G. peckii\u2019s mycobiome and provides relevant data to inform conservation of this rare and endangered plant.Eastern Mountain Avens ( Phialocephala scopiformis, produces rugulosin, which inhibits the feeding of the spruce budworm, Choristoneura fumiferana. Consequently, the Canadian forestry industry inoculates spruce seedlings with P. scopiformis to improve host health ..https://Geum peckii. We documented 51 ascomycete fungi from the classes Sordariomycetes, Leotiomycetes, Dothideomycetes, and Eurotiomycetes. Endophytic fungal species richness changed with habitat degradation status, suggesting that this may influence the fungal assemblage present within leaves. A core fungal assemblage was documented for the first time in this plant host, from multiple sites throughout its Canadian range. Additionally, we present new host records for Rosaceae and make valuable linkages between host plants in the habitats and shared endophytes within Geum peckii that warrant further ecological investigation. By approaching plant conservation from a mycological perspective, we provide the first mycobiome assessment of G. peckii, an understudied component of the habitat. This new knowledge aids in ongoing conservation and propagation of this endangered plant species.In summary, we present the first preliminary survey of foliar endophytic fungi from the rare and endangered Eastern Mountain Avens,"}
+{"text": "Objective determination of burn wound healing potential remains elusive and significantly impacts decision making for surgery, the extent of tissue excised intraoperatively and the use of donor site-sparing alternative tissue therapies. Indocyanine green angiography (ICGA) has promise as an adjunct to evaluate healing potential, but feasibility has limited adoption in clinical practice. Delayed fluorescence imaging of indocyanine green (ICG), in a method called second-window ICG (SWIG), is a new technique used intraoperatively to guide tumor resection via increased peritumoral endothelial permeability. The objective of this study is to examine ICGA and SWIG fluorescence in burns requiring excision and grafting, and to correlate SWIG fluorescence to microscopic localization of inflamed and necrotic tissue.ex-vivo to determine the presence of fluorescence in the tissue compared to that remaining within the wound bed. Excised tissue was processed for histologic analysis of cellular architecture, viability, inflammation and necrosis. Macroscopic ICGA and SWIG fluorescence images were compared to the associated microscopic tissue sections to determine the presence of inflammatory infiltrate, localization of non-viable tissue, and co-localization of ICG fluorescence.Deep partial thickness, indeterminate depth or full thickness burns were identified in adult patients scheduled for excision and grafting. 24 hours prior to surgery, baseline bright light and fluorescence images were obtained before the administration of up to 5 mg/kg ICG intravenously. ICGA was performed within 5 minutes of infusion initiation. On the day of surgery, bright light and SWIG fluorescence images were obtained before and after burn excision. The excised tissue was imaged ICGA imaging performed preoperatively demonstrated variable fluorescence throughout the burns without a clear cutoff value to delineate deep partial versus full thickness burns. SWIG imaging revealed a speckled fluorescence pattern prior to burn excision that became diffuse after excision suggesting a potential utility of SWIG to intraoperatively identify excision completion. ICGA and SWIG fluorescence demonstrated an inverse relationship, and SWIG fluorescence was associated with non-viable tissue.ICGA imaging alone was unreliable to delineate the need for surgical intervention. SWIG imaging of burn injuries may represent a valuable tool to guide the extent of excision intraoperatively and reduce unnecessary excision of viable tissue. Further studies are needed to understand SWIG fluorescence at the inflammation-necrosis border and how ICGA fluorescence along with SWIG can synergistically improve detection of healing potential in burn patients."}
+{"text": "Biomolecules, titled \u201cOral Regenerative Medicine: Current and Future\u201d, covers the dental field and focuses on craniofacial tissue regenerative therapy. Dental pulp and periodontal tissue-derived cells are well-known as major cell sources in the dental field. Dental pulp stem cells (DPSCs) are promising cell sources for biomineral tooth complexes [2+-ATPase (PMCA) in rat and human odontoblasts mediates dentin mineralization [2+ homeostasis in odontoblasts. They suggested that PMCA not only plays a critical role in physiological dentin formation but also in the pathological reactionary dentin formation induced by multiple external stimuli. It is also used in the application of high-pH dental materials on the dentin surface. Dental and oral tissues maintain homeostasis through potential reparative or regenerative processes. This native biological regulation ensures appropriate oral function and provides systemic health conditions through ideal digestion and intake of nutrition. Even if some tissues break down, general dental treatment or the administration of growth factors can help them to recover. However, a large disruption of oral tissues due to tooth loss, malignant diseases, and severe trauma can cause irreversible tissue loss in the oral cavity. To compensate for this, artificial materials, such as prostheses and dental implants, support the improvement in human quality of life. We need to consider both native biological elements and biomedical products. This Special Issue of omplexes . Pilbaueomplexes . The automplexes . In thisomplexes . Schmidtomplexes . The autlization . This stAmong oral tissues, the periodontium is also permanently exposed to mechanical forces resulting from chewing, mastication, or orthodontic force. Brockhaus reported on the preservation and remodeling processes within the periodontium through periodontal ligament fibroblasts during orthodontic tooth movement. Tooth movement by mechanical stress initially decelerates the periodontal ligament fibroblast cell cycle and proliferation. After adapting to environmental changes, cells can regain periodontium homeostasis, affecting their reorganization . DieterlThis Special Issue suggests the importance of understanding the relationship between both the cell source and effective regeneration. Physiological functional recovery is the most essential problem and the ultimate purpose of regenerative therapy. A deeper understanding of the pathological background and genetic basis and cellular signaling in local-systemic regulation is essential in dental tissue regeneration."}
+{"text": "Following ischemic stroke, polymorphonuclear neutrophils (PMNs) are rapidly recruited to the ischemic brain tissue and exacerbate stroke injury by release of reactive oxygen species (ROS), proteases and proinflammatory cytokines. PMNs may aggravate post-ischemic microvascular injury by obstruction of brain capillaries, contributing to reperfusion deficits in the stroke recovery phase. Thus, experimental studies which specifically depleted PMNs by delivery of anti-Ly6G antibodies or inhibited PMN brain entry, e.g., by CXC chemokine receptor 2 (CXCR2) or very late antigen-4 (VLA-4) blockade in the acute stroke phase consistently reduced neurological deficits and infarct volume. Although elevated PMN responses in peripheral blood are similarly predictive for large infarcts and poor stroke outcome in human stroke patients, randomized controlled clinical studies targeting PMN brain infiltration did not improve stroke outcome or even worsened outcome due to serious complications. More recent studies showed that PMNs have decisive roles in post-ischemic angiogenesis and brain remodeling, most likely by promoting extracellular matrix degradation, thereby amplifying recovery processes in the ischemic brain. In this minireview, recent findings regarding the roles of PMNs in ischemic brain injury and post-ischemic brain remodeling are summarized. PMNs are first line immune invaders in the ischemic brain. PMN recruitment after experimental ischemic stroke is highly coordinated in a spatio-temporal way. PMNs accumulate within capillaries and venules of the ischemic brain territory within the first hour after ischemic stroke , followeEvidence in humans supports the idea that PMNs have detrimental consequences on stroke outcome. Hence, PMNs of ischemic stroke patients produce and release significant amounts of reactive oxygen species (ROS) and proteases, such as neutrophil elastase, as shown in peripheral blood within the first 6 hours post-stroke . Under ivia which PMNs in peripheral blood aggravate secondary ischemic brain damage are PMN stalls resulting in microvascular occlusions even under conditions of successful arterial reopening  within 6 hours of symptom onset aggravated neurological recovery assessed by the mRS score, increased stroke mortality and increased infection susceptibility . BesidesEx vivo, the treatment of blood clots obtained from ischemic stroke patients with DNAse-1 significantly increased tPA-induced thrombolysis in comparison to tPA alone  and Hertie-Stiftung .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Key challenges include poor graft survival, low donor neuron localization to the host retina, and inadequate dendritogenesis and synaptogenesis with afferent amacrine and bipolar cells. In this review, we summarize the current state of experimental RGC transplantation, and we propose a set of standard approaches to quantifying and reporting experimental outcomes in order to guide a collective effort to advance the field toward functional RGC replacement and optic nerve regeneration.As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs and their axons, which compose the optic nerve. To functionally restore vision, lost RGCs must be replaced. Despite tremendous advancements in experimental models of optic neuropathy that have elucidated pathways to induce  The retina is embryologically derived from central nervous system (CNS) neuroectodermal progenitors. The mammalian retina, therefore, like the rest of the mammalian CNS, lacks inherent regenerative capacity . RetinalRetinal diseases have been pioneering targets for therapeutic cell transplantation in medicine ,12, withendogenous RGCs following experimental injury [Molecular targets relevant to achieving critical milestones in functional RGC replacement, particularly the achievement of RGC survival and axon regeneration, have been elucidated by studying l injury . For exal injury ,20. Insul injury , overexpl injury , inductil injury , deletiol injury ,25,26, al injury  in endogl injury . RGC-extl injury ,29. Morel injury , establil injury .By comparison, in vivo transplantation of exogenous primary RGCs or stem cell derived RGCs remains a field in its infancy. Nonetheless, pioneering transplantation studies have recorded light-evoked electrophysiological responses from donor RGCs  and docuRGC transplantation strategies require generating lineage committed progenitors or terminally differentiated neurons in sufficiently large quantities. The source of donor cells for transplantation  into humBRN3b-dependent tdTomato and murine Thy1.2 have facilitated purification of RGCs and longitudinal cell tracking in transplantation studies [ESCs are derived from the inner cell mass of embryonic blastocysts , and the studies .Adult human somatic cells, after appropriate induction, can dedifferentiate and resemble ESCs in morphology, and have the capacity for multilineage differentiation and self-renewal . When auA limitation to cellular differentiation in two dimensional culture is a lack of multi-cellular organization, which is overcome by three dimensional cultures of self-organizing organoids . These \u201cTaken together, characterization of robust RGC differentiation from multiple cell lineages and culture conditions have paved the way for stem cell-based replacement strategies as a promising approach to optic nerve regeneration. The tools now exist to study, in earnest, RGC transplantation in vivo. In order to maximize generalization of protocols and experimentation worldwide, standard descriptions of donor cell characteristics are critical when reporting RGC transplantation results. Such studies should explicitly describe the parental stem cell line or source, differentiation culture conditions, the stage of RGC or progenitor at harvest, RGC purification technique and yield, and the expression of a standard set of canonical RGC markers. Ideally, critical results should be replicated with multiple independent lines of donor RGCs. Critically, we do not know the developmental state for donor cells\u2014whether fully mature RGCs, developing RGCs, or lineage-committed progenitors\u2014that will yield the best engraftment results. Whether stem cells or organoids are used as a source of donor RGCs, the isolation process should maximize purity in order to limit aberrant tissue overgrowth or teratoma formation from undifferentiated cell populations. Furthermore, RGCs survive poorly in organoids during prolonged culture , presumaA critical prerequisite to studying interactions between donor RGCs and the host retina is robust survival of transplanted neurons. Unfortunately, this has been a formidable obstacle in most studies to date (see below). One of the difficulties in comparing survival rates across multiple methodologies stems from unstandardized methods of reporting survival, either as an absolute number, a percentage of transplanted cells, or by providing the density of surviving cells. The transplantation route plays a critical role in discerning donor cell survival. Administration to the basal (vitreous) side of the retina via intravitreal injection provides the most direct access to the inner retina, without the need for potentially disruptive transparenchymal migration . MoreoveIn nearly all cases, where reported, intraocular transplantation of RGCs has yielded low rates of neuronal survival, far below what would be required to restore visual function in advanced optic neuropathy . Develop2 [2 [Purified postnatal mouse RGCs transplanted into rat recipients survive at a typical rate of about 1% , althoug2 . However2 [2   pathway is particularly relevant to RGC survival and regeneration following injury . DownregBax subfamily of Bcl-2-related proteins is essential for JNK-dependent apoptosis [Dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) are other key sensors in the RGC injury response . Upon dapoptosis , and itspoptosis . Initiatpoptosis . Deletiopoptosis . In addipoptosis , indicatpoptosis . Based on extensive work identifying critical regulators of injury-related RGC death, there are myriad intracellular pathways that could be targeted pharmacologically or transgenically to promote donor RGC graft survival following transplantation in the eye. Although manipulating neuronal survival pathways may seem like an obvious and feasible method to attenuate undesirable death of transplanted cells, we must also acknowledge the importance of these cellular pathways in driving malignant transformation. For instance, deregulation of PI3K/Akt mTOR signaling contributes to the initiation, development, and acceleration of multiple types of cancer . A majorPromotion of donor RGC survival by modulation of neurotrophic factor delivery may be an alternative to or compliment to directly targeting cell-intrinsic death signaling cascades. Soluble neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF), regulate neuron growth and survival . The binBDNF and NGF signal via tyrosine-receptor kinases (Trk) receptors to promote cell survival, or via neurotrophin receptor p75 (p75), which induces neuronal apoptosis. Indeed, the effects of NGF on RGC survival depend on the relative expression of these dueling receptors . SpecifiBDNF is developmentally critical to RGC survival. By binding to the TrkB receptor, BDNF triggers activation of the Ras/MEK/extracellular signal-regulated kinase (ERK) pathway . Under nCNTF belongs to the IL-6 family of cytokines and binds a heterotrimeric membrane receptor complex composed of CNTF receptor-\u03b1, gp130, and the leukemia inhibitory factor receptor (LIF-R) . CNTF prGiven their strong potential for neuroprotection, trophic factors delivered concomitantly with RGC transplantation may substantially improve graft survival. However, clinical translation is limited by inefficient delivery of these agents. Intravitreal protein injection has a short therapeutic duration due to rapid clearance. Slow release formulations are being explored and have yielded promising results . Given tNumerous aspects of the recipient ocular microenvironment into which donor RGCs are transplanted influence their survival, including innate and adaptive immune system reactivity; blood flow, oxygen, and nutrient supply; and reactive gliosis .Autologous cell transplantation is generally well accepted by the recipient, although some genetic manipulations can generate immunological responses . However+ T cells are activated through the binding of MHC class I and T cell receptors, particularly in the presence of non-matching major histocompatibility complex  [Whereas the vitreous cavity and the subretinal space are relatively immune privileged when compared to other sites, damage to the blood ocular barrier and local inflammatory cytokine production can be induced by both neurodegenerative disease and the transplantation procedure itself . Intraocen, HLA) ,125,126.en, HLA) ,127.Editing of individual HLA genes in iPSCs to establish \u201cuniversal donor cells\u201d has been proposed for evasion of both T cell activity caused by HLA mismatching and natural killer (NK) cell activity. Genetic manipulation, such as the transgenic expression of HLA-E or HLA-G on porcine endothelial cells inhibits NK cell cytotoxicity and adhesion . GeneticThe transplantation technique itself is critical to consider when evaluating factors that might affect transplanted RGC survival. To date, the majority of studies have injected cells directly into the vitreous cavity, where the supply of oxygen and nutrients is subject to passive diffusion from the uveal vasculature. During development, the lens and the developing inner retina are first vascularized by the hyaloid canal, composed of the hyaloid artery, vasa hyaloidea propria, and tunica vasculosa lenti, which lie within the vitreous cavity. However, at birth in humans and postnatally in mice, these vessels regress as retinal vessels are prioritized, leaving the vitreous cavity unperfused . In ordeIt is critical to recognize that RGC transplantation will only be necessary because a primary neurodegenerative process caused extensive death of endogenous RGCs. Glaucoma, optic neuritis, and ischemic optic neuropathy are the most common neurodegenerative diseases characterized by RGC loss, but each one has unique pathophysiologies ,133. OncInnate neuroinflammatory processes influence donor RGC survival following injury and are principally mediated by retinal macroglia (astrocytes and M\u00fcller glia) and microglia. Under normal conditions, astrocytes play a key role in maintaining homeostasis in the CNS, controlling angiogenesis, contributing to the extracellular matrix (ECM), and maintaining the blood retinal barrier. Upon disruption or injury, reactive glia undergo complex alterations in gene expression, morphology, and function. Reactive astrocytes are promoted by JAK/STAT signaling, which leads to the release of a variety of soluble mediators that activate inflammation within the CNS ,136. His2 (PGE2) synthesis, which contributes to neuronal death [2+ concentrations and induces CREB-mediated transcription of apoptotic proteins, resulting in cell death [Some of the effectors of neuroinflammatory toxicity have been elucidated. In response to CNS injury or neurodegenerative disease, multiple cell types produce cyclooxygenase-2 (COX-2), leading to prostaglandin Eal death . Anti-inal death . Glial aal death ,145. Nonll death . Thus, nDonor cells arriving at the retina from the vitreous cavity encounter the retinal basement membrane (the ILM), local astrocytic and M\u00fcller glial reactivity, and local inflammatory cells that impede spontaneous cell migration into the retina ,147. EndThe ability of transplanted RGCs to migrate spontaneously into the recipient retina is inconsistent across published studies, which may be related to differences in graft and host species, or to the methodologies of determining graft localization. Our previous ex vivo work has identified that the ILM is a major barrier to both human RGC somal and neurite engraftment; we have found that donor human RGC migration into the host mouse retinal parenchyma rarely occurs spontaneously . DisruptAvailable evidence supporting donor integration is typically derived from en face confocal micrographs illustrating close proximity between donor cells and host RGCs, or from histological sections, again relying on proximity to the endogenous RGCs. However, such demonstration typically lacks the spatial resolution to distinguish the anatomical layers at the vitreoretinal interface. Because the RGCL is in close proximity to the ILM, donor RGCs that are external to the retinal parenchyma (within the posterior vitreous cavity) but juxtaposed to the retina can easily be mistaken for having \u201cintegrated\u201d into the retina, both in retinal flat mounts and in histological sections . TherefoA combination of analyses using histological sections and en face evaluation of retinal flatmounts will provide a compromise between complete topographic imaging and depth resolution;Flatmount microscopy should be performed with high resolution confocal or multiphoton microscopy using a high magnification objective in order to create shallow depth of field;High depth resolution is attained by minimizing slice interval distance and pinhole aperture diameter (if single photon microscopy is employed);Z-stack reconstructions should be assessed using an orthogonal slice viewer to compare the localization of the donor cell to those of nearby endogenous cells;A secondary marker that outlines the boundary of the retinal parenchyma should be included when possible, such as immunofluorescent laminin delineation of the ILM .Although retinal cross sections can clearly demonstrate the relationship between transplanted RGCs and endogenous RGCL, applying this method to completely survey entire eyes is unfeasible. To help meet this challenge, we propose the following considerations for microscopic inspection of donor RGC localization within the host retina : A combiScrutinizing donor RGC integration using this robust approach sets a benchmark for accurate assessment of donor cell localization. The reported outcomes from the localization analyses should include the absolute number and percentage of total surviving RGCs in each of the retinal layers  as well as outside of the retinal parenchyma. Somal localization is important because donor RGCs with cell bodies remaining outside of the host retina can rarely exhibit parenchymal neurite ingrowth, which may be distinguished from fully integrated donor cells.In our experience, we observe negligible spontaneous donor human RGC integration into the host RGCL when the ILM remains intact, whereas somal integration is greatly enhanced by enzymatic disruption of ILM , suggestWe have observed a propensity for transplanted RGCs to cluster when cultured on organotypic retinal explants with intact ILM . ProteolConsidering this challenge, studies of RGC transplantation should include quantitative characterizations of cellular dispersion and retinal coverage. We have employed spatial analytic tools to describe the topography of donor RGCs cultured on the retinal surface ex vivo , and theAfter overcoming barriers to localization of transplanted RGCs within the recipient retina, dendrite targeting of the IPL necessarily precedes synaptogenesis to achieve true functional integration into the visual neurocircuitry. Donor RGCs are unlikely to sprout neurites without specific external cues . One sucThe proper targeting of donor cell dendrites to the mature host IPL is an understudied aspect of RGC transplantation. Developmental studies reveal that RGC dendritic lamination in the IPL is guided by signaling through cell surface receptors, and dendrite localization is reinforced and stabilized by neuronal activity . RGCs utRetinal flatmounts are superior to histological section for characterizing complex dendritic arbors of RGCs within the IPL;Additional secondary tissue samples for histological sectioning can, however, be useful for correlation of sublaminar neurite localization with multiple immunohistochemical markers that define RGC subtype;It is of interest to characterize the topographical spacing among integrated RGCs. Reported metrics may include nearest neighbor and density recovery profiles of integrated donor RGCs;When possible, metrics describing dendritic architecture should be described for individual cells; if individual arbors are not resolvable from overlapping RGCs, then metrics should be normalized to the number of donor RGCs contained within a region of interest;Dendritic architecture and localization within the recipient retina should be assessed using high resolution microscopy; it may be necessary to tile images in order to capture entire dendritic arbors at high resolution;Integrated dendritic arbors can be convoluted and should be resolved and traced using 3D rendering software ;Useful metrics to describe dendritic arbors include total neurite length, number of neurite segments, neurite density, dendritic Sholl analysis , and neuIn order to robustly characterize the dendritic outgrowth of donor RGCs, we raise the following considerations:developing RGCs express both MAP2 and Tau until definitive specification of an axon [If neurite integration is to be evaluated, detailed characterization of neurite identity will be needed. In mature RGCs, dendrites and axons are defined by the expression of MAP2 and Tau, respectively . Neurite an axon . Therefo an axon . This fiThere are over 40 subtypes of RGCs, each having dendritic arbors precisely restricted to specific lamina within the IPL . Such heViral transsynaptic tracers make it possible to decipher complex circuit connectivity. Individual viruses have defined directionalities of travel and benefit from intracellular replication that propagates reporter signal generation . The mosThere are numerous paradigms available to restrict uncontrolled propagation of virus across multiple synapses, to specify neuronal subtypes for primary infection (starter cells), and to not only label but also genetically modify synaptically coupled partner neurons through payload packaging. Typically, viruses used for synaptic circuit tracing are modified and incapable of infectivity and/or replication without helper genes  that are supplied to starter neurons separately. Through the use of Cre-dependent helper gene expression in conjunction with Cre reporter lines, one could, for instance, restrict starter cells to retinal neuronal subtypes of interest and probe donor RGCs for evidence of viral transsynaptic spread following transplantation . A compaLarge scale visualization of neuronal activity can be achieved by imaging genetically encoded fluorescent indicator proteins. Various optical reporters have been devised in response to vesicle release, membrane voltage change , and calElectrophysiology and synaptic histology remain useful for characterizing specific examples of functional synapses. Whole cell patch clamping of donor RGCs facilitates recording of light-evoked electrophysiological responses in retinal flatmount preparations. So long as controls are included to exclude the possibility of recording from intrinsically photosensitive RGCs, electrophysiologic responsivity to light implies stimulus conduction from bipolar cells downstream of photoreceptor transduction. Characterization of specific responses to light permits classification of donor RGCs based on electrophysiological properties.Synapses in retinal neurons are unique in that they require rapid and sustained release of neurotransmitters in order to achieve graded synaptic output in response to a dynamic range of light signal intensity. Consequently, retinal synapses require a several fold higher number of vesicles than conventional synapses that transmit action potentials elsewhere . SynaptiThese techniques may prove useful in future transplantation studies examining factors that regulate synaptogenesis between donor RGCs and the mature recipient retinal neurons. Synthetic synaptic organizers have been developed that are capable of inducing functional excitatory synapses within the CNS . Their fOne major consideration that is required for all transplantation studies is the possibility of intercellular material exchange ,189,190,Using human stem cells in RGC transplantation requires balancing safety and efficacy against potential risks and ethical considerations. Ethics concerns surrounding ESC use has largely been avoided with iPSCs as an alternative stem cell source. However, colonies expanded from a single iPSC display more heterogenous gene expression compared to ESCs , elevatiRecent scientific advances have enabled RGC production from a wealth of human stem cell sources for both disease modeling and RGC replacement within the visual pathway. Developments in stem cell biology and regenerative neuroscience have brought the field of optic nerve regeneration from science fiction to scientific possibility. Nonetheless, tremendous challenges for translating this potential to actual vision restoration for human patients lie ahead. Improving transplant survival remains the primary short-term goal, as it sets the foundation for subsequent study of functional integration. Advanced differentiation protocols may provide reliable RGC subtype specification and expand the donor source repertoire. As imaging techniques continue to improve, we anticipate significant progress in the ability to assess migration, localization, synaptogenesis, and axonogenesis in vivo.It is not well established how closely transplanted human stem cell derived RGCs resemble developing or mature neurons. This distinction may be important because the molecular machinery governing growth and regeneration potentially involves separate sets of regulatory mechanisms . For exa"}
+{"text": "This study explored the role of tested contextual factors  in high Medicaid (under resourced) nursing homes performance. Four nursing homes in geographically diverse states were purposefully selected for site visits based on high and low performance  indicators. Eight nursing home administrators and directors of nursing, and twenty-one nursing staff  and providers of support services were interviewed. Data were analyzed using an inductive thematic approach with NVivo 12 Plus. Within and across case analysis was used to compare participants\u2019 perspectives across nursing homes and across administrators and staff. Several themes provide insight into varied influences of contextual factors on these nursing homes\u2019 performance: focus on quality care, team-based approach, community support and engagement, and staffing retention. Providing quality care to residents was strategic priority in all facilities, which was enhanced by an adopted team-based leadership approach, open-door policy and home-like atmosphere. Community reputation and availability of local training opportunities for CNAs affected nursing staffing which some facilities addressed using creative retention strategies. These research findings will facilitate interventions, such as leadership training and organizational development activities, aimed at improving the performance of low performing facilities in terms of lower costs and better quality."}
+{"text": "The purpose of this study was to examine whether frailty status moderates the association between social participation and attitude towards using gerontechnology. The sample was Korean older adults without cognitive impairment  who completed an online survey. The attitude towards using gerontechnology was measured with two questions from the Senior Technology Acceptance Model , asking whether using technology is a good idea and whether they like the idea of using technology. Social participation was assessed by asking whether the participants engage in social or community activities on a scale of 1\u201310. Frailty status was determined based on the Korean Groningen Frailty Indicator (K-GFI). Covariates were age, gender, marital status, employment status, education level, and household income. Results from regression analyses showed significant interaction between frailty status and social participation on attitude towards using gerontechnology. Specifically, social participation was associated with positive attitude towards using gerontechnology among non-frail older adults. This association was not significant among frail older adults. Our findings suggest that the relationship between social participation and attitude towards using gerontechnology might differ by physical health status. Among older adults who are physically healthy and actively participate in social activities, the attitude towards using gerontechnology might be more positive due to greater exposure to new technology-related information. Future studies need to address alternative ways to enhance technology-friendliness among older adults with poor physical health."}
+{"text": "Caenorhabditis elegans), fruit flies (Drosophila melanogaster), and zebrafish (Danio rerio): prominent model systems in which anatomical and genetic analyses have defined fundamental principles by which epidermal cells govern SSN development.Somatosensory neurons (SSNs) densely innervate our largest organ, the skin, and shape our experience of the world, mediating responses to sensory stimuli including touch, pressure, and temperature. Historically, epidermal contributions to somatosensation, including roles in shaping innervation patterns and responses to sensory stimuli, have been understudied. However, recent work demonstrates that epidermal signals dictate patterns of SSN skin innervation through a variety of mechanisms including targeting afferents to the epidermis, providing instructive cues for branching morphogenesis, growth control and structural stability of neurites, and facilitating neurite-neurite interactions. Here, we focus onstudies conducted in worms ( Why focus on these model systems? Our understanding of patterns and mechanisms of Somatosensory neuron (SSN) innervation in human skin is limited by several challenges. First, human skin exhibits remarkable diversity in its structure across anatomical locations, varying in thickness, permeability, and cellular composition. Single-cell RNA-seq (scRNA-seq) studies demonstrate the presence of multiple distinct subpopulations of fibroblasts, keratinocytes, and other dermal cells at various locations in mammalian skin  provide solutions to many of these problems. Chief among them, these organisms offer transparent skin and ex utero development that renders SSNs optically accessible, providing a direct window into SSN development in vivo. These systems also offer sophisticated genetic toolkits that facilitate manipulation of gene function with single-cell resolution, reagents to simultaneously and independently visualize skin cells and SSNs, and a repertoire of epidermal cells and SSNs whose developmental origins and peripheral morphologies are defined.The model systems discussed here  and motor neurons that traverse the body and receive instructive epidermal cues. The touch receptor neurons (TRNs), sensory neurons PVD and FLP, and motor neurons provide instructive examples of different modes of epidermal signaling that contribute to skin innervation patterns. First, the bipolar mechanosensory TRNs ALM and PLM  extend distinctive anterior and posterior processes, and their polarized outgrowth is controlled by epidermal cues. Epidermal cells ensheath axons of these neurons, providing insight into the developmental origin and function of this specialized epidermis-SSN interaction  and is surrounded on the basal surface by a basement membrane  has served as a powerful experimental system for analysis of SSN dendrite morphogenesis, cell spacing, and dendrite-epidermis interactions that shape innervation patterns. Unlike vertebrate dorsal root ganglion (DRG) neurons, cell bodies of Drosophila SSNs are located in the periphery, where sensory organ precursors delaminate from the ectoderm early during embryogenesis and give rise to neurons in a highly stereotyped spatiotemporal birth order  organs or chordotonal (cho) organs; as discussed below, studies of cho neuron development have revealed roles for epidermal cues in guiding SSN migration and orienting dendrite outgrowth  on the basis of larval dendrite arborization patterns , and muscle.Each larval segment contains >10 different epidermal cell types, transcriptionally specified on the basis of their position along the anterior-posterior (AP) axis within each parasegment  have distinct experimental advantages for the analysis of SSN/skin interactions. Zebrafish are amenable to forward and reverse genetic screens; reverse genetic manipulation is particularly attractive since the large, externally fertilized eggs are easy to inject with antisense morpholino oligonucleotides or CRISPR-Cas9 ribonucleoprotein complexes. The small size of the larvae and automated behavioral assays additionally make high-throughput chemical screens feasible  periderm layer is derived from the enveloping layer  organs contain bipolar mechanosensory neurons that extend a single unbranched dendrite, and a subset of these neurons (v\u2019ch1 and lch5) migrate along the epidermis to their final position, rotating during migration to orient dendrite outgrowth  or frazzled (fra), which encodes an attractive DCC  family Netrin receptor, prevent v\u2019ch1 migration and randomize the direction of dendrite outgrowth  in mouse skin, in which a local secreted factor orients neurite positioning  and Drl2, which signal through the Rho guanine nucleotide exchange factor (GEF) Trio and Rho1 to locally destabilize the actin cytoskeleton and prevent dendrite extension beyond the Wnt5 source  and Wnt (Wingless) ligands illustrate two additional principles of peripheral guidance by secreted cues. First, extrinsic guidance signals can work in concert with intrinsic mechanisms for neurite spacing to fine-tune peripheral arborization patterns. Self-avoidance signaling mediated by the Drosophila homophilic adhesion molecule Dscam1 promotes sister dendrite spacing in da neurons  controls the density of body wall innervation . Third, how are short- and long-range Ret signaling coordinated? Mav exerts short and long-range effects on C4da dendrite growth, yet Mav exhibits limited diffusion, so internalized Mav likely regulates growth throughout the arbor. In vertebrates, internalized Ret-GDNF complexes mediate long\u2013range retrograde signaling from the periphery together with GFR\u03b11\u20133  as well as increased epidermis-ECM adhesion that is thought to reduce the permissivity of the ECM to dendrite growth , NLP-29, triggers this degeneration , which promotes ECM adhesion , whereas non-peptidergic nociceptors project through the SS and innervate the stratum granulosum  likewise regulates dendrite positioning of Many types of cutaneous receptors form specialized terminal structures with epidermal components that contribute to somatosensation -enriched microdomains on epidermal membranes adjacent to sensory neurites  to the cortex of the epidermal membrane surrounding the invaginating neurite  and numerous septate junction proteins  family member, is required for sheath formation, and EPB41 proteins function as interaction hubs that organize specialized plasma membrane domains , controls this developmental restriction of C4da plasticity  and engulf dendrite debris generated via laser-induced damage . What are the cells that mediate engulfment and digestion of neurite debris in the skin? Surprisingly, neither macrophage-like hemocytes in Drosophila, many studies have focused on Draper (drpr), an engulfment receptor, as an important component in both epidermal and non-epidermal phagocytic clearance of axon debris  downstream of engulfment receptors  often rely on the same set of phagocytic machinery to recognize and engulf synapses, cell corpses, or debris . In DrosDrosophila requires the CD36 family member Croquemort  and in human skin samples from patients with atopic dermatitis (AD), epidermal fibers often penetrate through the tight junction barrier and avoid pruning by keratinocytes. These observations raise the interesting possibility that aspects of pathological itch in AD may be due to aberrant SSN pruning by epidermal cells. It is possible that similar mechanisms may be at play in other skin diseases, lending to their pathologies, but this requires more careful investigation.Questions remain about epidermal involvement in neurite pruning and debris removal in adult animals, as well as whether these features are conserved in mammalian systems. Intriguingly, one recent study in mice found that epidermal SSN fibers often reside directly beneath keratinocyte tight junctions that form below the outer, cornified layer  and time? C. elegans presents an appealing system to address these questions, given the morphological stereotypy and limited cellular diversity. Finally, how do different SSNs achieve type-specific innervation patterns in response to similar extracellular cues? Neuron type-specific expression of receptors for these cues has been a focus of recent study, but additional mechanisms likely contribute including cell- and context-dependent signal transduction, as well as spatial tuning of receptivity to signals within SSN arbors.Despite the recent progress, substantial questions remain to be answered about epidermal control of SSN innervation. One pressing question is the extent to which epidermal diversity contributes to innervation patterns. A necessary prerequisite to answering this question is a deeper sampling of epidermal cell types. Even within model systems, this question is understudied, hence leveraging positional information embedding in the CY, EP, JR, and JP wrote this manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Me & My Wishes is a novel systematic approach for long-term care residents living with dementia to record videos about their care preferences that can be shared with staff and families in care plan meetings. To understand how the videos were utilized in Goals of Care (GOC) conversations, we coded and analyzed transcripts of recorded care plan meetings at the time of sharing the video using a priori codes derived from GOC conversation elements. Coding discrepancies were resolved in team meetings; finalized codes were summarized to derive themes. Thirty-four care plan meeting conversations between residents (n=34), family members (n=29) and staff (n=35) were analyzed. Residents appreciated sharing personal histories and preferences via video, while staff members appreciated deeper understanding of residents\u2019 care preferences. Two themes described care plan meeting conversations: Everyday Care - a checklist-style assessment of the resident\u2019s daily care , activities engaged in and satisfaction with care; and Clarifying Care Goals - checking the resident\u2019s treatment preference , explaining hospice, or confirming the resident\u2019s contact person. Several elements of GOC were not discussed  and conversations lacked depth and comfort evidenced by apologetic language and abrupt transitions of topics rather than exploring alignment of goals with care preferences. Me & My Wishes videos are a mechanism for residents to voice preferences. Standardized guidance, which is lacking in long-term care, is needed to help care teams engage in meaningful conversations to ensure alignment of goals and treatment preferences."}
+{"text": "Whether increased formal long-term care (LTC) reduces informal LTC use by serving as a substitute or has a complementary role that boosts both informal and formal LTC use has been an important issue for evaluating LTC policy effectiveness. We described trends in in-home LTC use among older adults and LTC availability in relation to changes in LTC policy in Japan. In addition, we examined whether these trends differ by living arrangements, gender, income, and disability levels. We used five waves of repeated cross-sectional data starting in 1999 to 2017. The use of both informal and formal LTC types combined increased until 2006 and then gradually decreased while remaining higher than in 1999. Although implementing the LTC program may have temporarily contributed to the complementary use of both LTC types, eligibility limitations brought about by LTC reform potentially reduced the effects of formal LTC\u2019s complementary role."}
+{"text": "Microbial communities are constantly challenged with environmental stressors, such as antimicrobials, pollutants, and global warming. How do they respond to these changes? Answering this question is crucial given that microbial communities perform essential functions for life on Earth. Our research aims to understand and predict communities\u2019 responses to change by addressing the following questions. (i) How do eco-evolutionary feedbacks influence microbial community dynamics? (ii) How do multiple interacting species in a microbial community alter evolutionary processes? (iii) To what extent do microbial communities respond to change by ecological versus evolutionary processes? To answer these questions, we use microbial communities of reduced complexity coupled with experimental evolution, genome sequencing, and mathematical modeling. The overall expectation from this integrative research approach is to generate general concepts that extend beyond specific bacterial species and provide fundamental insights into the consequences of evolution on the functioning of whole microbial communities. Microbial communities perform pivotal functions, from the cycling of elements through Earth\u2019s ecosystems to the digestion of complex foods that shape human health and disease. Many of these functions emerge from the interaction of multiple species working as a collective . For exaAchieving such understanding is extraordinarily difficult given that microbial communities are incredibly diverse in terms of numbers of different microbes, genes, and interactions. Progress on this problem requires both top-down studies that deal with the complexity of natural communities and bottom-up research that uses simpler experimental setups . My reseRapid evolution can impact short-term ecological dynamics, and these altered ecological dynamics can feedback to affect subsequent evolutionary change . Eco-evo4\u2013Acinetobacter johnsonii and Pseudomonas putida, two bacterial species that were originally isolated from a polluted aquifer in Denmark   . Thus, bA. johnsonii and P. putida  in natural communities  and different genotypes (evolutionary responses). What is the relative contribution of ecological versus evolutionary processes to mediating responses to change? We previously discussed how adaptive evolution mediated by settings . What resettings , 20. Filsettings . This exOne important ecosystem function is plant litter decomposition, which is performed by microbial communities . I have recently joined a collaboration, The Loma Ridge Climate Change Experiment, aiming to understand how the plant litter microbiome responds to drought in Southern California , 23. We Using an integrative research approach based on evolution experiments of simple microbial consortia, whole-genome sequencing, and mathematical modeling, we have gained general insights into the mechanisms by which microbial communities respond to environmental change. We are currently working to understand how these responses affect community-level functions important for ecosystem functioning. The next exciting research directions will be (i) to study whether natural selection can act on community-level properties  and (ii)"}
+{"text": "ABSTRACT IMPACT: This study is designed to address a critical gap in our understanding of how aging patients and caregivers recognize and respond to clinically important changes in heart failure symptoms during vulnerable transitions. OBJECTIVES/GOALS: Research on family involvement in heart failure (HF) symptom response is limited. Our objective is to examine HF symptom monitoring processes in couples after HF hospitalization, and quantify how coupled symptom assessments predict symptom response, patient clinical events, care strain, and dyad health during the high-risk post-discharge period. METHODS/STUDY POPULATION: This is an ongoing T2 translational study that employs an intensive longitudinal design. Adults aged \u226565 years hospitalized for HF and their caregiving spouse/partner are enrolled. The target n is 48 dyads. Over 5 weeks of follow-up, dyads complete daily diaries assessing patient HF symptoms. Clinical biomarkers of HF severity  are also collected. Primary study endpoints are dyads\u2019 HF symptom response behaviors and caregiver strain; secondary endpoints are dyads\u2019 health status and patient clinical events. Dyadic dynamics of symptom assessment will first be characterized using dyadic autoregressive time series models. Subsequently, we will extract cross-partner effect parameters from the time series models and test whether dyadic effects predict the trajectories of each of our endpoints. RESULTS/ANTICIPATED RESULTS: This study is currently underway. In line with our study hypotheses, we anticipate that couples who assess patient symptoms similarly (dyadic agreement), and whose symptom assessments accurately reflect clinical severity, will be more likely to respond to symptoms appropriately with lower stress to the caregiving partner, and have better trajectories of health . Characterizing dyadic symptom dynamics will provide important insight into the day-to-day process of symptom recognition in couples. Further, quantifying dyadic symptom dynamics in relation to our endpoints will provide information on the clinical value of dyadic symptom agreement, and whether it might be a target for future interventions to support better symptom response and health outcomes for both dyad members. DISCUSSION/SIGNIFICANCE OF FINDINGS: This project innovates on existing paradigms by applying family-level theory and techniques to better understand and support interventions for couples during post-discharge HF transitions - a vulnerable period for older adults that has traditionally been studied almost exclusively at the patient-level, with marginal success."}
+{"text": "A 33-year-old male presented to the emergency department following a motor vehicle collision with complaints of right eye pain after hitting his head on the steering wheel. Point-of-care ultrasound (POCUS) revealed retinal detachment and an anterior lens dislocation.Lens dislocations following blunt head trauma can often be diagnosed using POCUS. Anterior ocular lens dislocation is a rare but vision-threatening result of head trauma. This case highlights how POCUS can facilitate early detection of ocular pathology, such as lens dislocation, and improves patient outcomes. A 33-year-old man with a history of blindness in his right eye from a congenital cataract presented to the emergency department with blunt head trauma sustained during a motor vehicle collision. He complained of right eye pain and foreign body sensation. On examination, a round white object was visualized within the anterior chamber; his head was otherwise atraumatic. The patient stated that the white spot had been present prior to the accident but had now changed in size and appearance, noting that the spot had enlarged following his injury.Fluorescein staining showed no abnormalities, and intraocular pressures were normal . Light perception was not present. Slit lamp examination demonstrated a round, white-speckled object in the dependent portion of the anterior chamber. Bedside ocular ultrasonography revealed a retinal detachment and an anterior dislocation of a cataract lens through the iris \u20133. OphthCrystalline lens dislocation, or ectopia lentis, occurs primarily after blunt head trauma.5Patients can present with eye pain and visual changes ranging from light distortion to loss of vision.What do we already know about this clinical entity?Anterior ocular lens dislocation is a potential result of blunt head trauma. If unrecognized, it can block the anterior chamber causing elevated intraocular pressures.What is the major impact of the images?The sonographic appearance of anterior lens dislocation has not been well described in emergency medicine literature. These are some of the first reported images.How might this improve emergency medicine practice?Because anterior lens dislocation can result in vision loss, accurate diagnosis is important. Point-of-care ultrasound can be used to diagnose lens dislocations.Ultrasonography can aid in the diagnosis of all types of lens dislocations and assess for additional ophthalmologic pathology, including retinal detachment and vitreous hemorrhage."}
+{"text": "The Weathering Hypothesis states BIPOC face more stressors, by which over a lifetime they are subjected to the negative consequences of stress . Using ecological momentary assessments, we examined whether subtle discrimination moderated the within-person stressor slope on positive and negative affect. We predicted emotional wellbeing would be worse at stressor moments, and those with greater discrimination experience would be more impacted by stressors. Participants were 334 diverse adults  from Bronx, New York. Positive affect decreased and negative affect increased significantly at stressor moments (p<.0001). Unexpectedly, subtle discrimination was not a significant moderator for the within-person stressor slope on positive affect and negative affect. Unlike the predictions of the Weathering Hypothesis, these results show that prior discrimination experiences may not exacerbate responses to stressors and entail additional risk in daily life."}
+{"text": "Pain is generally concomitant with an inflammatory reaction at the site where the nociceptive fibers are activated. Rodent studies suggest that a sterile meningeal inflammatory signaling cascade may play a role in migraine headache as well. Experimental studies also suggest that a parenchymal inflammatory signaling cascade may report the non-homeostatic conditions in brain to the meninges to induce headache. However, how these signaling mechanisms function in patients is unclear and debated. Our aim is to discuss the role of inflammatory signaling in migraine pathophysiology in light of recent developments.Rodent studies suggest that a sterile meningeal inflammatory reaction can be initiated by release of peptides from active trigeminocervical C-fibers and stimulation of resident macrophages and dendritic/mast cells. This inflammatory reaction might be needed for sustained stimulation and sensitization of meningeal nociceptors after initial activation along with ganglionic and central mechanisms. Most migraines likely have cerebral origin as suggested by prodromal neurologic symptoms. Based on rodent studies, a parenchymal inflammatory signaling cascade has been proposed as a potential mechanism linking cortical spreading depolarization (CSD) to meningeal nociception. A recent PET/MRI study using a sensitive inflammation marker showed the presence of meningeal inflammatory activity in migraine with aura patients over the occipital cortex generating the visual aura. These studies also suggest the presence of a parenchymal inflammatory activity, supporting the experimental findings. In rodents, parenchymal inflammatory signaling has also been shown to be activated by migraine triggers such as sleep deprivation without requiring a CSD because of the resultant transcriptional changes, predisposing to inadequate synaptic energy supply during intense excitatory transmission. Thus, it may be hypothesized that neuronal stress created by either CSD or synaptic activity-energy mismatch could both initiate a parenchymal inflammatory signaling cascade, propagating to the meninges, where it is converted to a lasting headache with or without aura.Experimental studies in animals and emerging imaging findings from patients warrant further research to gain deeper insight to the complex role of inflammatory signaling in headache generation in migraine. Pain is generally concomitant with an inflammatory reaction of varying intensity at the site where the nociceptive fibers are activated. Migraine is probably no exception; there is ample experimental evidence, mostly from rodents, suggesting that the nociceptive trigeminocervical afferents mediating the headache can be activated by a sterile meningeal inflammatory process . This prProlonged activation and sensitization of primary and central nociceptors within the trigeminocervical complex are thought to underlie the throbbing headache and allodynia during migraine. Rodent experiments suggest that a sterile meningeal inflammation initiated by release of peptides from trigeminocervical C-fibers and activation of resident inflammatory cells  could contribute to sustained activation and sensitization of meningeal nociceptors \u201317. SuppMeningeal nociceptive fibers can release a number of vasoactive peptides including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), substance P and neurokinin-A upon prolonged activation , 21. By 2 PBR28 PET may also provide insight into the relationship between inflammatory signaling and headache in secondary headache disorders. As in migraine, parenchymal inflammation can also play a role in post-seizure headache, as suggested by studies showing activation of the neuroinflammatory cascade in seizure models , 180. SiIn conclusion, experimental studies in animals and emerging imaging findings from patients warrant further research to gain deeper insight into the complex role of inflammatory signaling in headache generation. Research over the past 50\u2009years have revolutionized our understanding of migraine, however, many unanswered questions and controversies remain. We need cutting-edge tools to directly and comprehensively study the complex nociceptive mechanisms in experimental animals and also high-resolution advanced imaging technologies to assess the significance of basic findings in the clinic. Admittedly, current experimental and clinical methods have shortcomings to provide unequivocal evidence for competing hypotheses."}
+{"text": "Panel A) while brain MRI showed no obvious abnormalities in the basal ganglia region. Contrast-enhanced computed tomography showed renal and splenic infarction (Panel B). Moreover, a transoesophageal echocardiogram showed a mobile mass attached to the aortic valve moving back and forth between the ascending aorta and the left ventricular outflow tract . Based on these findings, we concluded that ischaemic stroke due to cardiac mass was the underlying cause of the hemichorea in this patient. During the hospitalization, the patient had an exacerbation of involuntary movements. Repeat echocardiography revealed the reduction in the size of the mass and brain MRI showed acute multiple cerebral infarctions. Therefore, we decided to surgically remove the residual mass to prevent further embolic events. Histopathological examinations with haematoxylin\u2013eosin staining revealed papillary fibroelastoma (Panel D), a rare primary cardiac tumour, with organized thrombus (Panel E). After the surgery, we started anticoagulation with warfarin for the prevention of thrombotic event. His hemichorea disappeared 6 months after the onset of symptoms.A 74-year-old man presented to our hospital with acute onset of right hemichorea. He had no medical history of hereditary disease, inflammatory, or endocrine disorders that could be associated with involuntary movement. Although the patient had no clinical findings suggestive of infective endocarditis, it was not possible to accurately differentiate between tumour, thrombus, and sub-clinical endocarditis. Brain diffusion-weighted magnetic resonance imaging (MRI) revealed multiple cerebellar infarctions  Brain magnetic resonance imaging showing cerebral infarction. (Panel B) Contrast-enhanced computed tomography showing renal and splenic infarction. (Panel C) Echocardiogram showing a mobile mass attached to the aortic valve. (Panels D and E) haematoxylin\u2013eosin staining showing papillary fibroelastoma (Panel D) and organized thrombus (Panel E).(Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance."}
+{"text": "Mycobacterium tuberculosis. It may show wide variability of clinical symptoms and imaging appearance, ranging from asymptomatic with a normal radiographic examination to severe joint pain along with joint destruction, osteomyelitis, and abscess formation. This article presents radiographic and MR imaging appearance from a case of tuberculous septic arthritis with large abscess formation mimicking soft tissue tumor.Tuberculous septic arthritis is an infection that occurs inside the joint or synovial fluid and joint tissues caused by We reported a 32-year-old female with a slowly enlarging lump on her right proximal thigh within the last 4 months along with slowly progressing joint pain. Both radiographic and MR images showed destruction of the femoral head and acetabular roof, with a formation of large rim-enhanced abscess that extending superficially and distally until mid-thigh. The patient underwent open drainage surgery and excisional biopsy. Histopathological examination showed chronic granulomatous inflammation caused by tuberculous infection.MR imaging combined with radiographic and clinical information played a very important role in the diagnosis of tuberculous septic arthritis with abscess, and to differentiate it from soft tissue neoplasms. Tuberculosis; Septic arthritis; Infectious arthritis; Abscess In Indo2We reported a 32-year-old female patient who came to the hospital after being referred from another hospital to have further treatment for a soft tissue tumor of her right thigh. She complained of a slowly enlarging lump on her right proximal thigh in the last 4 months, with intermittent sub febrile temperature and mild but slowly progressing pain. She was unable to walk unsupported. Physical examination showed a large fusiform soft tissue mass in the right thigh with a diameter of 84 cm, limited range of motion, moderately firm in palpation, and tenderness of the right hip . In the 2.1An AP radiograph of the right femur was obtained, showed a large lobulated soft tissue mass on the lateral side of the proximal femoral region and was assessed as a soft tissue tumor . HoweverLaboratory test showed microcytic hypochromic anemia, increased white blood cells (WBC) count, , increased c-reactive protein (CRP) , increased erythrocyte sedimentation rate (ESR)  and increased lactate dehydrogenase (LDH) . Other laboratory findings were unremarkable.2.2The large lobulated cystic mass may be consistent with a large abscess formation, and its connection with the abnormality of the right hip may support the diagnosis of chronic infection. Other potential diagnoses related to fluid-filled mass in musculoskeletal lesions were true cystic lesions (such as seroma) and cystic-appearing solid neoplasm (myxofibrosarcoma and myxoid liposarcoma that contain high mucin component).2.3The patient underwent open drainage surgery and excisional biopsy and the specimens were sent to the Pathology Department.2.4The histopathology examination showed chronic granulomatous inflammation caused by tuberculous infection . The pat3Joint destruction with adjacent tumor-like mass has several differential diagnoses, including tuberculous septic arthritis, malignant soft tissue tumor, and pyogenic septic arthritis. Their clinical appearance may look similar, especially with the formation of a large painful mass. It becomes important to differentiate infection from the formation of tumor-like abscess from malignant soft tissue tumor, as they have completely different therapy. Malignant soft tissue tumors should be evaluated with core biopsy so that the clinicians can give appropriate chemotherapy, whereas infection would need immediate abscess drainage, antibiotics and debridement procedures. Delayed management may cause further destruction of the joint and results in irreversible disability, and worsened prognosis.The potential pitfall in the radiographic interpretation, in this case, is the large size of the soft tissue mass, which may divert the reader's attention from the hip joint abnormality. Another potential misinterpretation is whether these two findings are two separate entities or whether they are associated. Without MR imaging, this can be quite challenging since the extent of the mass is quite huge compared to the degree of hip joint destruction.Tuberculous septic arthritis is a chronic disease with long progressive clinical and radiological changes. Saraf SK et al  has intrFluid-filled mass in the musculoskeletal system may have several differential diagnoses, including true cystic lesions (abscess and seroma) and cystic-appearing solid neoplasm (myxofibrosarcoma and myxoid liposarcoma that contain high mucin component) . Seroma Both cystic appearing solid neoplasm and tuberculous septic arthritis may show the same painful mass-forming lesion, with no apparent local infection signs such as redness or warmth on the lump, but MR imaging and blood examination may help to differentiate them. Cystic-appearing solid neoplasm may show heterogeneous signal intensity with inhomogeneous enhancement but without increased leukocyte and CRP level, whereas tuberculous abscess formation will show thin and smooth wall enhancement with the increased number of leukocytes and CRP. Therefore, tuberculous abscess formation is more likely than cystic-appearing solid neoplasm in this patient.Staphylococcus aureus. As the pathogen produces proteolytic enzymes, pyogenic septic arthritis usually has an acute onset, more rapid, and more progressive [Pyogenic septic arthritis can affect all age groups with no specific range of age. The most common pathogen is gressive . It alsogressive  showed bM.\u00a0tuberculosis does not produce proteolytic enzymes like pyogenic pathogens, it shows less inflammation process and relative joint space preservation compared to pyogenic septic arthritis which is characterized by a more aggressive course, prominent inflammation, and progressive joint space loss [MR imaging and clinical manifestation may help differentiate pyogenic from tuberculous septic arthritis. As ace loss . The mosThe patient had open drainage surgery and excisional biopsy, and histopathology examination showed chronic granulomatous inflammation caused by tuberculous infection. Histopathology examination and good response of clinical condition after the anti-tuberculosis drug combination administration made the diagnosis of tuberculous septic arthritis in this patient.4The presented case was confirmed as tuberculous septic arthritis with large soft-tissue abscess formation. Tuberculous septic arthritis should be considered as one of the differential diagnoses in slow-progressing monoarticular joint pain, especially in endemic countries. As the disease progresses slowly and may cause irreversible joint destruction, early diagnosis is crucial to improve the patient outcome. MR imaging, combined with the radiograph and clinical information, played an important role in the diagnosis of tuberculous septic arthritis and differentiation to pyogenic septic arthritis or other cystic-appearing neoplasms.All authors listed have significantly contributed to the investigation, development and writing of this article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data will be made available on request.The authors declare no conflict of interest.\u2022The case presented shows variability of clinical symptom and imaging appearance, ranging from asymptomatic with the radiographic presentation could mimicking other abnormalities such as pyogenic septic arthritis and soft tissue tumor lesion.\u2022The patient with monoarticular joint pain that has slow progress symptoms, especially in endemic countries, tuberculous septic arthritis should be considered as one of differential diagnosis\u2022MR imaging can be beneficial to differentiate pyogenic from tuberculous septic arthritis with the most significant imaging characteristic to differentiate tuberculosis from the pyogenic abscess is the abscess wall.No additional information is available for this paper."}
+{"text": "Sepsis is a life-threatening syndrome induced by aberrant host response towards infection. The autophagy-lysosomal pathway (ALP) plays a fundamental role in maintaining cellular homeostasis and conferring organ protection. However, this pathway is often impaired in sepsis, resulting in dysregulated host response and organ dysfunction. Transcription factor EB (TFEB) is a master modulator of the ALP. TFEB promotes both autophagy and lysosomal biogenesis via transcriptional regulation of target genes bearing the coordinated lysosomal expression and regulation (CLEAR) motif. Recently, increasing evidences have linked TFEB and the TFEB dependent ALP with pathogenetic mechanisms and therapeutic implications in sepsis. Therefore, this review describes the existed knowledge about the mechanisms of TFEB activation in regulating the ALP and the evidences of their protection against sepsis, such as immune modulation and organ protection. In addition, TFEB activators with diversified pharmacological targets are summarized, along with recent advances of their potential therapeutic applications in treating sepsis. Sepsis is the most common and severe syndrome that can affect a population of critically ill patients . Each yeTranscriptional factor EB (TFEB) is a member of the microphthalmia (MiTF/TFE) transcriptional factor family . TFEB biThe ALP mainly consists of the autophagy machinery and its associated lysosomal degradation processes . This paIt has been extensively demonstrated that the ALP is beneficial for balancing the immune response and protecting organ function during sepsis. A recent review article described autophagy features extensive crosstalk with innate immune cells, thereby exerting influence on phagocytosis in neutrophils, degranulation in mast cells, along with differentiation and migration in NK cells . Researc2+-dependent exocytosis in the lysosomes  bearing the CLEAR element  mRNA has been shown to reduce the expression of TFEB and impair the TFEB-dependent autophagic process , polysaccharides and peptides) can modulate the ALP by activating TFEB . These a2+-calcineurin modulators  agonists  and other natural compounds  have been shown to upregulate the mRNA expression of TFEB, thereby activating the ALP and enhancing the cellular clearance machinery . MoreoveIn addition to small molecular activators, other larger biomolecules, such as polysaccharides, peptides and miRNAs, can also regulate the activity of TFEB. A few recent studies have reported that polysaccharides  and peptides  can activate TFEB and enhance the ALP process by inhibiting mTOR activity  or promoGiven that the impairment of ALP in sepsis results in unresolved infection, inflammation, organ injury, and immunodysfunction, researchers have begun to investigate TFEB modulators in preclinical models to examine their therapeutic efficacy in ameliorating sepsis-induced dysfunction by promoting autophagy and lysosomal functions.Mycobacterium tuberculosis and Salmonella typhimurium). It is notable that opportunistic pathogens, such as mycobacterial species, can commonly induce secondary infection in post-sepsis patients or trigger sepsis in patients who are immunocompromised. Moreover, pathogens like Mycobacterium tuberculosis inhibit autophagy and lysosomal function by inducing miR-33 dependent inactivation of TFEB  instead of endotoxemia models or otherwise tested in clinical settings. Moreover, most TFEB activators target the upstream regulators of TFEB, such as mTORC1 and Car events . Therefor events . Therefo"}
+{"text": "Various few-shot image classification methods indicate that transferring knowledge from other sources can improve the accuracy of the classification. However, most of these methods work with one single source or use only closely correlated knowledge sources. In this paper, we propose a novel weakly correlated knowledge integration (WCKI) framework to address these issues. More specifically, we propose a unified knowledge graph (UKG) to integrate knowledge transferred from different sources . Moreover, a graph attention module is proposed to sample the subgraph from the UKG with low complexity. To avoid explicitly aligning the visual features to the potentially biased and weakly correlated knowledge space, we sample a task-specific subgraph from UKG and append it as latent variables. Our framework demonstrates significant improvements on multiple few-shot image classification datasets."}
+{"text": "Desmosomes are critical adhesion structures in cardiomyocytes, with mutation/loss linked to the heritable cardiac disease, arrhythmogenic right ventricular cardiomyopathy (ARVC). Early studies revealed the ability of desmosomal protein loss to trigger ARVC disease features including structural remodeling, arrhythmias, and inflammation; however, the precise mechanisms contributing to diverse disease presentations are not fully understood. Recent mechanistic studies demonstrated the protein degradation component CSN6 is a resident cardiac desmosomal protein which selectively restricts cardiomyocyte desmosomal degradation and disease. This suggests defects in protein degradation can trigger the structural remodeling underlying ARVC. Additionally, a subset of ARVC-related mutations show enhanced vulnerability to calpain-mediated degradation, further supporting the relevance of these mechanisms in disease. Desmosomal gene mutations/loss has been shown to impact arrhythmogenic pathways in the absence of structural disease within ARVC patients and model systems. Studies have shown the involvement of connexins, calcium handling machinery, and sodium channels as early drivers of arrhythmias, suggesting these may be distinct pathways regulating electrical function from the desmosome. Emerging evidence has suggested inflammation may be an early mechanism in disease pathogenesis, as clinical reports have shown an overlap between myocarditis and ARVC. Recent studies focus on the association between desmosomal mutations/loss and inflammatory processes including autoantibodies and signaling pathways as a way to understand the involvement of inflammation in ARVC pathogenesis. A specific focus will be to dissect ongoing fields of investigation to highlight diverse pathogenic pathways associated with desmosomal mutations/loss. The desmosome is integral for maintaining structural integrity in tissues undergoing constant mechanical stress such as the heart Najor . The carEmerging new evidence has revealed that defects in protein degradation trigger the structural remodeling underlying the desmosomal disease, ARVC  is a multiprotein enzymatic complex consisting of eight subunits (CSN1-8), with known functional roles in controlling ubiquitin-mediated protein degradation as it has been shown to de-neddylate and inactivate cullin RING E3 ubiquitin ligases  and action potential propagation between cardiac muscle cells as a means to synchronize coordinated cardiac muscle contraction  are directly linked to the inherited cardiac arrhythmia, Brugada syndrome  channel to the cardiac intercalated disc -deficient mice, revealing arrhythmogenic pathways in mice distinct from classic desmosomal structural alterations and remodeling  may be an initiating factor to this inflammatory response  resulting in ventricular arrhythmias (ventricular tachycardia) that could be indistinguishable from proven ARVC patients  crossed to the Ribotag mouse as a means to identify ribosome-resident transcriptionally changes in inflammation in cardiomyocytes  to the desmosome and one found in the cytosol ; however, future studies should focus on how these pathways work cooperatively to degrade desmosomal proteins in the context of human ARVC-associated desmosomal mutations. Desmosomes are an essential hub for electrical homeostasis in the cardiomyocyte. Recent work highlights that diverse arrhythmogenic pathways may relate to specific desmosmomal proteins with PKP2 mutations/loss  while other desmosomal proteins, such as DSP may impact classic CX43 channel functions, which may drive electrical dysfunction in the absence of structural disease in ARVC. Further work is required to dissect whether all desmosomal proteins equally impact these distinct channel functions or whether there are adapter proteins associated with the desmosome that may uniquely mediate desmosome-associated arrhythmias. Additional findings suggest that inflammatory signaling pathways may play an important role in the pathogenesis of ARVC associated with desmosomal mutations. Early infiltration of immune cells and autoantibodies provide new evidence for better clinical diagnosis of ARVC; however, there remains limited direct evidence of the relationship  between desmosomal loss/deficiency and recruitment of immune cells in ARVC progression, which should be a focus for future studies."}
+{"text": "Laparoscopic surgery has been undermined throughout the COVID-19 pandemic by concerns that it may generate an infectious risk to the operating team through aerosolization of peritoneal particles. There is anyway a need for increased awareness and understanding of the occupational hazard for surgical teams regarding unfiltered escape of pollutants generated by surgical smoke and other microbials. Here, the aerosol-generating nature of this access modality was confirmed through repeatable real-time methodology both qualitatively and quantitively to inform best practice and additional engineering solutions to optimize the operating room environment. Laparoscopic surgery has been undermined throughout the COVID-19 pandemic by concerns that it may generate an infectious risk to the operating team through aerosolization of peritoneal particles. There is anyway a need for increased awareness and understanding of the occupational hazard for surgical teams regarding unfiltered escape of pollutants generated by surgical smoke and other microbials. Here, the aerosol-generating nature of this access modality was confirmed through repeatable real-time methodology both qualitatively and quantitively to inform best practice and additional engineering solutions to optimize the operating room environment. First, formal smoke studies were used to detail room ventilation dynamics around the operating table during surgical simulation scenarios with and without positive-pressure room ventilation (25 room air exchanges per h). For this, an Air-Trace smoke generator  created low levels of isokinetic, isothermal smoke via a 25-mm duct. The scenarios replicated personnel and equipment conditions for surgical procedures with varying complexity of set-up  with the smoke generator hose positioned at the simulated operative site.Thereafter, flow studies were performed during actual elective operations with varying degrees of intraoperative electrocautery . For this, a light sheet generated by a galvanometer optical laser scanner was used to illuminate a two-dimensional (2D) slice of the surgical airspace during surgery and imaged with an 8\u2009K Ultra-High Definition camera  whose absence of diffraction limitation enabled resolution of droplets larger than 2 \u00b5m (visible as scintillations within the laser sheet). Simultaneous extracorporeal airspace sampling was performed during these operations after investigator training using a particle counter  to measure 30-s periods both at baseline  and then episodically during the procedure by positioning the device\u2019s isokinetic probe inlet 10\u2009cm from the target areaVideo 1 and Appendix S1). Increased crowding of the operating table with people and equipment caused increased local air stagnation. Intraoperative footage during patient operations showed smoke and particles (evidenced as scintillations) moving similarly during surgery, notable even with the instruments in situ, as well as during manoeuvres including trocar instrumentation, and venting and specimen removal . Aerosol and particle leakage into the OR airspace was most evident during the operative phase of intra-abdominal dissection using hook cautery.Smoke studies revealed effective dissipation of smoke by positive-pressure room ventilation with the OR fully empty, as expected. However, during simulated operative scenarios, smoke behaviour was significantly different, with evident upwards drift from the operating site enveloping members of the surgical team . Counts were particularly increased during electrocautery dissection of the gallbladder from the liver bed during cholecystectomy compared with dissection of the mesoappendix during appendicectomy, which in turn was associated with higher counts than were observed during intra-abdominal reduction of a parastomal hernia (done without cautery dissection). Trocar venting caused the highest concentration of particulate effluvium.Particle counts confirmed increasing particulate concentration after initiation of the operation, reaching extracorporeal airspace levels in excess of 1\u00d710This study focused on establishing methods and indicative data regarding the operative airspace particulate contamination occurring during laparoscopy, using open procedures as control in a simulation study as well as in two common general surgical laparoscopic operations that employ electrocautery to different extents (versus a laparoscopic operation without electrocautery). This is important as many surgical teams feel any such occupational hazard to be either theoretical or mitigated anyway by room ventilation and perhaps standard surgical maskshttps://www.gov.uk/government/collections/health-technical-memorandum-disinfection-and-sterilization) is not powerful enough to counteract the local airspace environment created by surgical teams carrying out their work. This means that there is relative stagnation of haze in the operative airspace above the abdomen during laparoscopic operation, with entrainment towards surgical team members likely induced by movement, body heat, and electrostaticityThe evaluations in this study reflect actual workspace conditions of OR teams, corroborating simulation data with live intraoperative flow visualization and sensitive particle counting . Together, these show that the surgical team is exposed to considerable amounts of particles and pollutants during laparoscopy. Indeed, aerosol (containing gas and particles) leaks continuously from the patient during laparoscopic operations, with such flue comprising the constituents of the pneumoperitoneal gas including any noxious components present. The local OR airspace pollution is particularly marked during the cautery dissection phase of the operation, and occurs constantly rather than just at the time of instrument insertion and removal,,,Although investigation of COVID-19 infectivity owing to laparoscopic access is ongoing, the pandemic has already caused considerable reflection regarding the aerosol-generating capability of laparoscopy, and encouraged re-examination of practice and equipment from this new perspectiveThe implications of the present study regarding aerosolization at laparoscopy extend beyond the present pandemic. The results provide insight into both mechanism and degree as well as assessment methodology for future evaluations, including those of mitigation strategies. Although practice adviceznab114_Supplementary_DataClick here for additional data file."}
+{"text": "With the current spotlight on systemic racism and the need to address health inequities, it is critical to develop culturally appropriate strategies for recruiting research study participants from racial/ethnic minority groups. Empirical studies have highlighted that people from racial/ethnic minority groups have poorer health outcomes compared to non-Hispanic Caucasians. However, racial/ethnic minority groups remain underrepresented in healthcare research. Several factors may contribute to the lower participation of racial/ethnic minority groups. Sequelae of atrocities in healthcare research on African American/Black people in the US during slavery and Jim Crow eras were widespread and persistent. Discrimination against people of Hispanic descent and increased anti-Asian discrimination have also been documented. Fear and mistrust of the health system and researchers have been identified as critical barriers to participation in clinical research for these populations. Further, health research teams rarely reflect the racial/ethnic diversity of the US population, hindering diversity in recruiting study participants. Inadequate ethnic/racial minority groups participation in study populations not only weakens external validity of empirical studies, but research interventions and policies being implemented may not be culturally appropriate to all populations. Therefore, systemic strategies to improve recruitment of racial/ethnic minority groups should: 1) increase preferential funding to incentivize research teams becoming more racially/ethnically diverse; 2) increase recruitment of racial/ethnically diverse healthcare researchers; 3) use community-based participatory research designs to build trust among racial/ethnic minority populations; 4) provide training on culturally appropriate research study recruitment strategies to the academic communities; 5) apply a prism of intersectionality for representation throughout the research cycle."}
+{"text": "Indoor room transition is an underexplored real-world activity outcome. We estimated the stability and variability of indoor room transitions and their associations with mild cognitive impairment (MCI) in older adults. Older adults living-alone  from the Oregon Center for Aging & Technology (ORCATECH) and the Minority Aging Research Study (MARS) were included. Room transitions were detected using passive infrared motion sensors in bathroom, bedroom, kitchen, and living room. The hourly number of room transitions was used to calculate the interdaily stability and intradaily variability of room transitions. MCI was operationalized by the Clinical Dementia Rating equaled 0.5. Generalized estimating equations models adjusted for demographics, health, and environmental factors revealed that older adults with MCI had a lower interdaily stability of room transitions than cognitive healthy peers . A pervasive-sensing system deployed in homes can obtrusively measure room transition activities to inform cognitive health in older adults."}
+{"text": "Existential distress is a significant source of suffering for patients facing life-threatening illness. Psychedelic-Assisted Therapies (PAT) are novel treatments that have shown promise in treating existential distress, but openness to providing PAT may be limited by stigma surrounding psychedelics and the paucity of education regarding their medical use. How PAT might be integrated into existing treatments for existential distress within palliative care remains underexplored.The present study aimed to elucidate the attitudes of palliative care clinicians regarding treatments for existential distress, including PAT. We recruited palliative care physicians, advanced practice nurses, and spiritual and psychological care providers from multiple US sites using purposive and snowball sampling methods. Attitudes toward PAT were unknown prior to study involvement. Semi-structured interviews targeted at current approaches to existential distress and attitudes toward PAT were analyzed for thematic content.Nineteen respondents  were interviewed. Identified themes were 1) Existential distress is a common experience that is frequently insufficiently treated within the current treatment framework; 2) Palliative care providers ultimately see existential distress as a psychosocial-spiritual problem that evades medicalized approaches; 3) Palliative care providers believe PAT hold promise for treating existential distress but that a stronger evidence base is needed; 4) Because PAT do not currently fit existing models of existential distress treatment, barriers remain.PAT is seen as a potentially powerful tool to treat refractory existential distress. Larger clinical trials and educational outreach are needed to clarify treatment targets and address safety concerns. Further work to adapt PAT to palliative care settings should emphasize collaboration with spiritual care as well as mental health providers and seek to address unresolved concerns about equitable access.The online version contains supplementary material available at 10.1186/s12904-021-00889-x. Existenlization , 6. Evidlization  and targlization \u201313.Psychedelic-assisted therapies (PAT), which apply psychotherapeutic approaches to altered states of consciousness produced by agents such as psilocybin, 3,4-Methylenedioxymethamphetamine (MDMA) or ketamine, may be potent treatments for patients facing existential distress in the setting of LTI. Randomized-controlled crossover trials using psilocybin have demonstrated reduced depression, anxiety and fear of death in patients with cancer- associated anxiety or depression \u201316, withWhether PAT become broadly implemented within palliative care will depend not only upon the results of larger clinical trials but also the attitudes of health care providers in a position to recommend PAT. Qualitative studies of palliative care providers have identified key themes regarding attitudes toward the use of PAT in palliative settings , 29, as We conducted qualitative semi-structured interviews with palliative care physicians, advanced practice nurses, chaplains, psychologists, and social workers currently working in palliative care settings within the United States.Participants were recruited via email between May 2019 and August 2020 using a combination of purposive and snowball sampling methods. Participants were not selected for knowledge about or known positions regarding PAT. Participants provided informed consent and were not directly compensated; one randomly-selected participant received an online gift card after study completion. Recruitment continued until interviews failed to reveal significant new thematic content.The interview guide was developed by an interdisciplinary team including experts in palliative care (M.L.) and PAT (B.K.) and was directed at two key research questions: (1) How do palliative care providers view their role regarding existential distress and its treatment? (2) What are their attitudes toward PAT as potential treatments for existential distress in LTI? The final interview guide is available in Recorded interviews were conducted by H.N. via phone, Zoom video conferencing software, or in person. Interviews ranged in duration from 32 to 52\u2009min, and concluded once participants had responded to all sections of the semi-structured guide and had been offered the chance to extrapolate further on earlier responses. Recorded audio from each interview was transcribed using Microsoft Word and de-identified prior to qualitative analysis. After the interview, participants completed an online survey covering basic demographics, clinical setting, and health care experience.Transcriptions were uploaded to Dedoose software version 8.3 and coded using a grounded theory approach , 34. IniThemes, subthemes, and representative quotations were then sent to a subset of 5 participants for validation. Criteria for validation was \u2265.78 agreement for each individual theme and subtheme.Thematic saturation was achieved after 19 interviews. Table\u00a0Four major themes and 15 subthemes were identified. All major themes and 13 subthemes met validation criteria, and are featured in Fig. All participants identified existential distress as an important and relevant concept for their clinical palliative care work.Respondents described existential distress as commonly arising both in the anticipation of dying as well as in response to changes in physical and psychosocial capabilities earlier in the course of illness. Existential distress was described as a disruption of, or challenge to, pre-existing sources of meaning or valued identities. Respondents noted a relationship between existential distress and psychiatric illness, though made a clear distinction between the two.The absence of relationships or adequate social support was linked to greater likelihood of a patient meeting difficulty in resolving existential distress. However, concern for unmet emotional, relational, or financial needs for family members was also seen as a source of distress, and LTI was noted to give rise to existential distress through the exacerbation of prior traumas and unresolved interpersonal conflicts.Respondents also described care of patients\u2019 families as a critical part of their clinical role, and noted challenges to identity and meaning among caregivers for those with LTI. Respondents identified their own existential distress as an occupational hazard of working with patients at the end of life.Refractory distress was reported across all types of clinical settings. Factors associated with refractory cases included late referral to palliative care, pre-existing psychiatric illness or trauma history, and young age, especially when the patient was a young parent.Respondents, especially those from smaller hospitals or outpatient groups, pointed to barriers including limited time for visits, absence of specialty interventions and insufficient staffing to meet patient needs. Patient resource limitations were cited as a barrier to effective treatment in all settings.All respondents endorsed existential distress treatment as falling within their scope of practice, with specific roles and degree of involvement differing across professional disciplines.Respondents described existential distress as often overlooked or treated with discomfort by medical practitioners, especially primary consulting teams and oncologists. Physician and advanced practice nursing respondents reported an absence or paucity of training on existential distress treatment prior to specialization in palliative care. Palliative care approaches to existential distress were described as contrasting with a general medical culture focused on biological models of diagnosis and treatment.Participants endorsed therapeutic interpersonal techniques as the primary intervention for existential distress, including active empathic listening and nonjudgmental exploration of patients\u2019 distress. More complicated cases were described as requiring specialist intervention with providers of spiritual care or psychotherapy, of which the most common types were meaning-centered, cognitive behavioral, and mindfulness-based psychotherapies. Helping patients repair or build new personal relationships was seen as integral to reducing existential distress.Respondents expressed interest in expansion of research and clinical access to PAT. However, not all were enthusiastic proponents and reservations or skeptical attitudes were common.PAT was identified as a potentially powerful addition to the palliative care \u201ctoolkit\u201d and respondents described PAT as facilitating meaning-making by allowing patients new perspectives through which to reframe their existential struggle. Respondents endorsed the use of PAT through compassionate use provisions, describing PAT as providing hope for patients experiencing refractory existential distress. Respondents saw PAT as an alternative to controversial interventions for end-of-life distress, such as palliative sedation or physician aid-in-dying.At the same time, participants identified the current evidence base as insufficient and cited a need for further PAT research and greater education on PAT within palliative care departments before they could feel confident in its use. Participants described PAT as late-line interventions to be used only after other therapies had failed.Participants also expressed concerns about stigma for patients receiving PAT, as well as fears about stigmatization from other medical providers for providing PAT. Participants reported concerns that use of PAT would trigger relapse for patients with substance use disorders, and expressed worries about lasting psychological harm from dysphoric psychedelic experiences. Attitudes were more negative toward LSD and positive toward psilocybin and ketamine.Participants expressed confidence in the safety of PAT in properly controlled settings. Respondents emphasized key safety considerations for PAT, including rigorous screening for cardiac disease or history of mania or psychosis, skilled supervision during medication-facilitated sessions, and longitudinal psychotherapy follow-up to integrate these experiences.Providers struggled to identify clearly how PAT could fit into the current treatment paradigm, with fundamental questions unanswered regarding for whom PAT might be an appropriate and accessible treatment.There was no clear consensus around the relative benefits of delivering PAT to patients early in their course of LTI, later while admitted as inpatients, or even while on hospice. Respondents similarly failed to present clear agreement about which palliative care patients should be considered for PAT. Some described psychiatric and trauma histories as important indicators of patients who might benefit most from PAT, while others expressed concern regarding PAT for patients with any psychiatric comorbidity.Providers described interest in PAT as concentrated within specific sociocultural groups, such as younger patients in urban settings. Respondents estimated greater interest in West Coast and Northeastern states than in the Southern US. Participants identified patient groups for whom PAT might not be appealing, such as particular religious groups, and described PAT as cost-prohibitive and likely to exclude poor and underserved communities.The present study reports attitudes toward the treatment of existential distress using PAT within a representative sample of palliative care professionals. PAT were seen as holding promise to improve the treatment of existential distress within palliative care settings, especially in refractory cases. Overall, respondents identified further research and outreach as necessary before PAT can be expanded in palliative care settings, and identified several unresolved barriers to implementation of PAT in palliative care settings.One of the most striking features of these interviews was the emphasis on interdisciplinary collaboration within palliative care, a central cultural tenet of the field. Notably, both subthemes that failed validation touched on questions of role boundaries, and likely were rejected due to perceived violations of this core value.Physicians and advanced practice nurses have limited roles in the treatment of existential distress as compared to chaplains and social workers\u201d (Theme 2) was drawn from descriptions of medical providers serving primary screening roles and triaging cases of existential distress to spiritual care or mental health care providers. However, the language of this subtheme was poorly considered, and respondents in the validation sample emphasized a team-based approach to the treatment of existential distress in which distinct roles are equally valuable.\u201c\u201cPAT would mark a significant change in how and by whom existential distress is treated\u201d (Theme 4). Feedback on this subtheme suggests that while respondents agree PAT would require greater involvement of psychiatrists and other mental health providers, palliative care providers would prefer to expand the umbrella of palliative care rather than referring cases to outside collaborators. This reflects the growing field of psycho-oncology and the greater incorporation of psychiatric and mental health providers into the multidisciplinary palliative care team. Furthermore, respondents reported strong interest in obtaining training in PAT within palliative care departments, despite no explicit question directed at this topic.Similarly, the second unvalidated subtheme dealt with the possibility of PAT marking a greater involvement of psychiatrists and other mental health practitioners in existential distress care: This study, by exploring current standards of care and attitudes toward PAT in a sample reflective of the interdisciplinary culture of palliative care, improves upon and further contextualizes recent investigations of attitudes toward PAT among palliative care providers. Those studies, which addressed perspectives of a diverse group of experts in palliative care, oncology and PAT  and a smExpansion of research into PAT in palliative care settings will be facilitated by the clear identification of a target population. While some participants reported an ideal of offering access to PAT for all patients facing life-threatening illness, PAT were commonly seen as intensive treatments indicated only after conventional methods have failed. Perceptions of PAT as late-line therapies may be reflective of stigma around psychedelics and thus subject to change with greater education about PAT. Still, many participants saw conventional treatments of existential distress as largely adequate, which invites us to consider the exact treatment gap PAT might fill.The greatest need for PAT may be within populations especially likely to suffer from refractory existential distress, such as younger adults or patients with significant trauma histories. Further research would be best directed at identifying risk factors for poor response to conventional psychotherapy and spiritual counseling. Alternatively, referral to PAT could be triggered by specific shifts in the course of treatment associated with significant unmet existential needs, such as cancer recurrence, hospice enrollment, or transition from standard cancer therapies to phase I clinical trials .Notably, the characteristics of patients with refractory existential distress overlapped with those of patients deemed too ill or unstable to be safely considered for PAT. Further studies are needed to clarify which psychiatric comorbidities are contraindications for PAT. Without this, the great challenge is that the window of opportunity \u2013 patients sick enough for PAT but not sick enough to be at risk of destabilization \u2013 may be narrow.Similarly, if treatment for existential distress is more limited in less-resourced settings, PAT is not well-situated to amend this treatment gap. Even if PAT are covered by insurance, the significant time demand of treatments may perpetuate problems of power and access that continue to plague American medicine, with marginalized groups unable to benefit equitably from these therapies. Research efforts to date have failed to adequately include diverse samples, with patients of color underrepresented in PAT studies . FurtherRespondents in our sample described meaning-enhancing interpersonal interventions, including both spiritual care and psychotherapeutic frameworks, as the core of conventional existential distress treatment. That meaning-making specifically mediates benefits of some conventional treatments  underscoOur findings suggest that PAT might be most easily integrated into palliative care practice if delivered in a manner consistent with current first-line meaning-enhancing approaches of psychotherapy and spiritual counseling. As researchers explore synergies between PAT and specific therapeutic modalities in other clinical contexts , 42, effBroader collaboration between PAT and faith traditions will not be without challenges. While psychedelic agents are important sacraments for some spiritual communities , 44, resThese findings also suggest the importance of maintaining emphasis on PAT\u2019s meaning-enhancing effects. Psilocybin\u2019s FDA designation as a breakthrough therapy for major depressive disorder , 46, whiPositive and stigmatizing views toward PAT were both common, often co-occurring within the same interview. This demonstrates the complicated way in which providers integrate new information about the therapeutic potentials of PAT with decades-old understandings of psychedelics as dangerous and illegal agents. While concerns about potential risks of PAT for patients with cardiac comorbidities echoe the exclusion criteria of recent studies, respondents also voiced concerns that do not track with recent evidence. Fears that PAT might trigger relapses among patients with substance use disorders contrasts with observations that psychedelics decrease patterns of problematic substance use in naturalistic settings \u201349; PAT These examples highlight the importance of education to dispel longstanding misconceptions regarding carefully monitored psychedelic use and promote data-driven understandings of the risks associated with PAT. While the present study was underpowered to assess variations in knowledge and attitudes toward PAT across professional classes, further survey-based research should seek to better classify these patterns, as has been demonstrated in larger samples of psychiatrists  and psycConvenience and snowball recruiting methods may have resulted in bias toward the cultures and institutional orthodoxies of included sites. Attitudes may be culturally specific and not necessarily generalizable outside the US. The sample of respondents was skewed toward younger and less experienced clinicians, who may be more likely to have positive views toward psychedelic therapies . While tPalliative care providers describe existential distress as a common source of suffering for patients with LTI. Current treatments emphasize enhancement of sources of meaning and rely on interdisciplinary coordination. Clinicians view PAT as promising treatments for refractory existential distress, though concerns regarding access and exclusionary criteria currently limit their potential scope. Further research and education regarding psychedelic interventions are needed before PAT can be more widely adopted in palliative care settings, especially to address safety concerns and clarify a target population. Close collaboration with spiritual care and mental health providers and adaptations of PAT to existing meaning-focused approaches will facilitate integration into current practice. Educational outreach should address misconceptions regarding risks of substance use and psychological harm. Broader access to PAT research and greater diversity of study samples will improve generalizability and promote equitable treatment outcomes.Additional file 1. Semi-structured interview protocol."}
+{"text": "Identifying preference of older adults supports person-centred care. The most sophisticated instrument is the preference for everyday living inventory (PELI). The PELI has been translated into German language and tested in different care settings. For people who experience difficulties communicating their preference the PELI has been combined with photographs. The voice of older immigrants could lead to an enhancement of the PELI as well other preference tools. Thus, our symposium title: Variety of identifying and assessing preferences of everyday living of older adults. Our symposium includes four presentations: Dr. Bergmann will present data from a preference study in three different care settings  in Germany. The results indicate that the importance of certain preferences distinguishes between the care settings. Dr. Vanessa Burshnic will present data from her content validity study of photographs used to supplement the Preferences for Everyday Living Inventory-Nursing Home (PELI-NH) from the perspective of older adults. Content analysis revealed thematic codes describing participants\u2019 photograph preferences including image quality, context, subject diversity, and relevance to long-term care. Mike Rommerskirch-Manietta will present results from a review to identify Instruments which can be used to assess preferences for everyday living of older adults. Interestingly instruments either represent multiple or only one domain. The study from Viktoria Peters-Nehrenheim does focus on preferences of older immigrants. She will present results how older immigrants (first generation) define preferences and how they can be assessed. Prof. Van Haitsma will be our discussant."}
+{"text": "The drastic demand for geriatrics-trained providers in medical and mental healthcare persists years after the Institute of Medicine first highlighted this need . New innovative approaches must instead optimize the current workforce through leveraging existing geriatric experts\u2019 knowledge and skills related to working aging adults. This symposium will highlight four approaches spanning post-licensure education to using technology to deliver specialized services and training. First, Dr. Gregg will discuss the evaluation of an advanced topics workshop in Geropsychology which has significantly enhanced depth of Geropsychology competencies for psychologists working in primarily rural areas. Next, Dr. Asghar-Ali will describe the multi-modal interactive geriatric educational opportunities for interprofessional staff developed by the South East Texas Geriatric Workforce Enhancement Program (SETx GWEP). He will discuss how these training opportunities have been tailored to address the impact of COVID-19 and healthcare disparities among older adults. Third, Dr. Filips will present an evaluation of a consultation model in which a geriatric psychiatrist provides tele-consultation in a 5-state region to rural aging Veterans with complex medical and behavioral comorbidities. Finally, Dr. Beaudreau will describe adaptations to a national VA Problem Solving Training program for mental health clinicians of older Veterans with complex comorbidities. Dr. Karel, VA National Geriatric Mental Health Director, will serve as discussant and comment on the ways in which these novel approaches are meeting the ever-growing need for competent geriatric mental health providers."}
+{"text": "A 40-year-old man, a laborer from Bihar (eastern India), presented to the surgical department with multiple large nodular swelling and discharging sinuses over the left foot with a duration of six months. These lesions began as small nodules that progressively increased in number and size and developed multiple sinuses. On examination, the swelling was painless and firm. He had no significant medical history. Computed tomography showed extensive osteolytic destruction of the tarsal and metatarsal bones. Magnetic resonance imaging demonstrated involvement of soft tissue with multiple sinus tracts . Gram stMycetoma pedis is used to describe chronic granulomatous disease caused by true fungi (eumycetoma) or filamentous bacteria (actinomycetoma).,The term Madura foot or"}
+{"text": "Recruiting and enrolling older adults with cognitive impairment is challenging under the best of circumstances. This symposium will begin with an introduction to best practices for recruitment of older adults living with cognitive impairment, followed by four presentations describing recruitment successes and challenges across multiple settings. The first presentation describes COVID-19 pandemic-related factors that have influenced recruitment and enrollment of older adults with cognitive impairment in an intervention study of a physical activity smartphone app. Strategies and procedural alterations to facilitate achievement of enrollment goals for technology-based interventions are discussed. The second presentation describes researchers\u2019 recruiting experiences with older adults with mild cognitive impairment (oaMCI)-care partner dyads for a pilot, platform trial of biopsychosocial interventions. There were differences in study disinterest between oaMCI and study partners that may require specialized communication messaging and strategies for dyad engagement. The third presentation features recruitment adaptations for an Internet-delivered behavioral intervention study with oaMCI and insomnia. Anticipated concerns of oaMCI using technology or accessing the Internet were not significant barriers to recruitment, while fewer oaMCI endorsed sleep concerns than expected. The last presentation demonstrates the potential for telephone-based outreach to increase dementia knowledge and cognitive risk. Working with faith-based health educators to reach rural, ethnically-diverse older adults, researchers will describe how to promote inclusivity and successfully recruit oaMCI within the community. Presenters and participants are encouraged to dialogue on how recruitment and retention barriers may be avoided as well as to share success stories from their own research with oaMCI."}
+{"text": "ABSTRACT IMPACT: Successful implementation of this control strategy will result in a commercially available ivermectin-treated birdfeed that the public can use to protect themselves from infection with West Nile virus (WNV) by reducing mosquito survival and thereby suppressing WNV transmission around their homes. OBJECTIVES/GOALS: We assessed the efficacy and feasibility of ivermectin (IVM)-treated birds as a mosquito control strategy for local reduction of West Nile virus (WNV) transmission. We conducted a randomized field trial in backyard chickens and developed a mathematical model informed by field data to predict the impact of treated wild birds on transmission. METHODS/STUDY POPULATION: We placed 48 chickens in four treated and four untreated control flocks in backyards coops across Davis, CA and administered IVM daily in feed to treated flocks (Jul-Sep 2019). We assessed entomological indices weekly  around each coop, monitored serum IVM levels in treated chickens, and tested for WNV antibodies in all chickens. Shifting our focus to wild birds, we developed a spatially-implicit mathematical model of WNV transmission near IVM-treated birdfeeders. Model parameters for bird movement were based on our telemetry of 27 birds in Fort Collins, CO (Aug-Sep 2020). Using the model, we predicted optimal deployment of treated feeders to provide local WNV control. RESULTS/ANTICIPATED RESULTS: WNV seroconversions were reduced in treated vs. untreated flocks, indicating a reduction in WNV transmission intensity at treated coops (P = 0.03). A sustained, but insignificant reduction in number of infected mosquitoes was observed near treated coops (P = 0.59); small sample sizes and below normal WNV prevalence in the study area limited our power. We anticipate that optimal spacing and number of IVM-treated birdfeeders required for effective WNV control in neighborhoods will depend on feeder usage rates by common bird species irrespective of WNV competence; broad availability of IVM-treated bloodmeals to mosquitoes will be more effective in reducing transmission than targeting the few species responsible for viral amplification. DISCUSSION/SIGNIFICANCE OF FINDINGS: IVM is a novel method for controlling zoonotic pathogens in the US and has the potential for targeted mosquito control to reduce pesticide usage. Evaluating spatial deployment of IVM-treated bird feed for local reduction in WNV transmission is a stepping stone to commercial deployment of this WNV control strategy."}
+{"text": "A key challenge for scholars who study aging is identifying a pool of research volunteers willing to participate. Toolkits and strategies acknowledge the differences in recruitment needed for older adults relative to younger adults, but there is little information about variations among older adult research volunteers. Based on a community sample of older adults age 60+, this study evaluates differences across seven specific motivators across three broad categories: values/altruism, personal growth/improvement, and immediate gratification. We then identify and evaluate four typologies of older adult volunteers based on the combinations of motivations the older adults in our sample identify as important to participation in research studies. Based on these analyses, we describe how our results might inform recruitment and retention practices in aging studies. Further, we will discuss how these results will help shape our technology-based reminder system with a greater understanding of motivations."}
+{"text": "Previous studies suggest that falls among community-dwelling older adults living with dementia (OLWD) harm the health and wellbeing of their family/friend care partners. However, little is known about the process through which falls impact care partners. We conducted a grounded theory analysis using 59 semi-structured interviews with care partners of OLWD who were recently hospitalized and had a history of falls. We identified several areas of care partners\u2019 functioning that were affected by falls in positive and negative ways: everyday life, health management for OLWD, and interactions with healthcare providers. Both the fall events and fall risks had negative consequences of reducing care partners' self-care activities and work productivity. Other adverse consequences of fall risks were (1) care partners\u2019 fatigue and conflicts with OLWD due to the intense requirement of daily monitoring, and (2) hesitance to ask healthcare providers for assistance because clinicians frequently did not teach care partners how to address fall risks and might recommend institutionalization. However, OLWD's fall events became a transition point for some care partners to seek support and gain more information and skills about managing OLWD\u2019s health conditions, which might reduce care partners\u2019 burden in the long term. Because OLWD\u2019s falls may have negative and positive consequences for care partners, both problem-solving and strength-based fall management approaches are needed. These strategies focus on developing and sustaining care partners\u2019 self-care, developing collaborative relationships with OLWD, enhancing successful capacity for OLWD\u2019s health management, and cultivating partnerships with healthcare providers."}
+{"text": "Maintaining cognitive function in later life is key to healthy aging because cognitive impairments compromise everyday functional abilities, impeding independent living. Numerous studies have discovered early life experiences and lifestyle behaviors over the lifespan to have substantial influences on cognitive functioning with age. Especially, subtle brain changes related to dementia occur as early as midlife, and lifestyle factors in midlife influence neuropathological development, suggesting that midlife is a critical period for preserving cognitive health in later life. This study investigated the association between lifestyle behaviors in midlife and cognitive performance in later life using 12-year follow-up data from the Korean Longitudinal Study on Aging (KLoSA). Cognitive function was assessed with the Harmonized Cognitive Assessment Protocol (HCAP) for KLoSA. Eight thousand respondents from the KLoSA sample were administered HCAP neuropsychological tests. Hierarchical multiple regression analyses were used to examine whether health-promoting lifestyles at baseline (2006) predicted cognitive function in 2018 after controlling for health-related covariates. We identified a positive influence of health-protective behaviors  at baseline on language abilities in 2018 . In addition, health-promoting behaviors covering interpersonal relationships, social engagement, optimistic outlook, and positive attitudes at baseline were predictive of language abilities , executive function , and the visuospatial ability  in 2018. This study highlights the importance of midlife health-promoting lifestyles in maintaining cognitive health in later life."}
+{"text": "This study focuses on long-term care (LTC) state Medicaid policy and its impact on caregiver decisions and experiences. It examines respondents\u2019 general knowledge of LTC state policies and services, challenges with navigating LTC policies and services, and decision-making pathways based on these factors. Using purposive sampling, 63 family caregivers across eight states participated in open-ended qualitative interviews (2019-2020) until thematic saturation was reached. Questions broadly examined caregivers\u2019 experiences and decisions, focusing on decisions made around type of care setting and experiences with LTC state policy. States were selected to represent variation in Home and Community Based Service (HCBS) expenditures as a percentage of total Medicaid long-term services and support expenditures. While LTC policies and services vary significantly by state, we identified many parallels in caregiver experiences and perceptions across states, as respondents often lacked specific knowledge about LTC policies and services and how to access them. Overarching themes include LTC policy navigation challenges, distrust in state-funded LTC services and supports, and moral expectations of caregiving. To manage these challenges, caregivers employed coping strategies such utilizing informal support networks, hiring care coordination assistance, and \u201cstretching things thin\u201d to fill the policy and service gaps. Study findings highlight potential strategies to improve LTC services across states. There is a need to improve community trust with state services by employing transparent regulatory and evaluation procedures for LTC. Wider access to case management may improve communication and knowledge of available services to maximize benefit from HCBS expansions."}
+{"text": "The longitudinal associations between hearing impairment and higher-level functional measures and the potential confounding role of vestibular function have not been assessed. We investigated these associations in 831 participants of the Baltimore Longitudinal Study of Aging (2012\u20132019). Hearing was measured using pure-tone audiometry and categorized using WHO standards. Physical function was assessed with the Health Aging and Body Composition Physical Performance Battery  and walking endurance with time to walk 400 meters. Multivariable regression models tested the hypotheses that participants with hearing impairment have poorer physical outomes. In a subset, we further adjusted for vestibular function. Hearing impairment was associated with decrements in higher-level physical performance and walking endurance, and faster decline over time, regardless of vestibular function. Among participants with any hearing impairment, hearing aid users were faster in the 400-m walk. Early screening for higher-level functional loss among older adults with hearing loss is warranted."}
+{"text": "Self-determination is a core value of person-centered care. Research has shown residents and families want to be involved in decisions about care. Care conferences are one existing structure where residents and families can engage in decision-making about care goals. However, there are few tools to support effective engagement. To inform future tool development, this study sought to understand what resident and family stakeholders value about engaging in care conferences. In virtual meetings, 16 stakeholders identified 3 key areas of engagement: being informed about health/well-being, influencing care goals, and advocating for needs. They indicated current approaches do not achieve these engagement goals, which is particularly problematic during COVID when families cannot engage in person. Stakeholders offered ideas for supporting engagement such as provision of data before the conference. The study has implications for individualizing care conferences and encouraging resident and family engagement in decision-making both during and beyond COVID."}
+{"text": "This cross-sectional study evaluates the out-of-pocket costs of diagnostic breast imaging services incurred by commercially insured women who underwent additional imaging evaluation and procedures after screening mammography. We performed a retrospective analysis using a national commercial claims database  with individual-level demographic information and inpatient, outpatient, and pharmacy claims for health care plan members residing in all 50 US states. Claims information included both OOPCs for plan members  and total standardized reimbursements.This cross-sectional study was deemed exempt from University of Michigan Institutional Review Board approval owing to use of deidentified data and followed the Strengthening the Reporting of Observational Studies in Epidemiology , ultrasonography (US), magnetic resonance imaging (MRI), and biopsy  were followed by additional breast imaging examinations or procedures. After applying exclusions, the final cohort included 325\u2009900 women with 418\u2009378 additional breast imaging examinations or procedures.Out-of-pocket costs varied substantially across women and type of imaging received and generally increased over time . For exaCost sharing also increased throughout the study period . Among w3Although the ACA largely eliminated OOPCs for screening mammography, our findings suggest that among commercially insured women ages 40 to 64 years, OOPCs for additional breast imaging evaluations and procedures after screening are common, nontrivial, and increasing. This trend coincides with the rapid rise in high-deductible health care plans that has been observed during the same time frame as the study period.This study has some limitations. We did not include OOPCs for related care such as office visits and pathology expenses, likely underestimating the total patient contributions. In addition, we could not distinguish between diagnostic evaluations for abnormal screening vs those for symptoms. We were also unable to discern the number of women who had an abnormal screening but did not undergo a subsequent evaluation or procedure.4 Although the association between OOPCs and receipt of one-time diagnostic testing has not been described (to our knowledge), it is possible that higher cost sharing could deter women from undergoing diagnostic evaluation following screening mammography, thus undermining the goal of the ACA to remove barriers to screening. The benefit design of health care plans must acknowledge that cancer screening often requires multiple steps and remove financial barriers for patients to complete the screening process.Consumer cost sharing is associated with decreased use of evidence-based medical care."}
+{"text": "Although African Americans have lower rates of anxiety in childhood than other racial and ethnic minority groups, they seem to experience escalating rates during emerging adulthood. Despite this, few studies have examined factors associated with anxiety during emerging adulthood among African American populations. The current study investigated the extent to which late adolescent family relationships affect anxiety problems among African American emerging adults. Informed by family development theory, family cohesion was hypothesized to indirectly effect anxiety problems through self-regulation. This model was tested with three waves of data  from African Americans participating in the Maryland Adolescent Development in Context Study. Study findings were consistent with the hypothesized model: family cohesion forecasted decreased anxiety problems, indirectly, via increased self-regulation. This finding suggests that families may be an important promotive process for anxiety problems during emerging adulthood. Prevention programs that target family processes may be able to reduce anxiety problems in emerging adult African Americans. Anxiety is characterized by heightened, relentless fears and worries about everyday events . Clinicafamily cohesion in promoting the development of youths\u2019 autonomy and their ability to navigate new contexts.Racial and ethnic group differences in anxiety rates and severity have been observed. Although African Americans have lower rates of anxiety in childhood than other racial and ethnic minority groups, they seem to experience escalating rates during emerging adulthood , 14. MorFamily cohesion describes nurturant communication, warmth, emotional support, and involvement between family members \u201318. In gAlthough these studies suggest that cohesive families may reduce poor psychological outcomes in emerging adulthood, the extent to which family cohesion is associated with anxiety problems among African American emerging adults is not well studied, despite close family ties being culturally important for many African American families . Data onWe further hypothesized that self-regulation may be a mechanism through which family cohesion affects anxiety problems during emerging adulthood. Self-regulation refers to individuals\u2019 ability to control their emotions, behaviors, and thoughts . EmerginTaken together, theory and extant research suggest that cohesive families may act as an emotional safety net which supports the development of self-regulation during emerging adulthood. With this safety net in place, emerging adults may feel comfortable exploring new opportunities while navigating the potential emotional turmoil of this challenging developmental period. The extent to which family cohesion forecasts self-regulation and reduced anxiety problems among African Americans emerging adults is not well studied. The current study addresses this gap. Informed by family development perspectives and previous research, family cohesion is hypothesized to indirectly effect anxiety problems through self-regulation. This hypothesis was tested via a secondary analysis of three waves of data from African Americans participating in the MADICS Study of Adolescent Development in Multiple Contexts (MADICS) controlling for antecedent family support.Youth and their families were recruited from 23 middle schools in Prince George\u2019s County, Maryland , 46. PriThe MADICS was a longitudinal study investigating psychological and behavioral determinants of developmental trajectories of youth living in Prince George\u2019s County, Maryland, a county located near Washington, D.C. , 46. MAD\u03b1 = .69) and Wave 4 (\u03b1 = .68). Closeness with family members at Waves 3 and 4 were measured using five items from the Iowa Youth and Family Study  indicated that the indirect effect of family cohesion on anxiety problems through self-regulation was significant.Descriptive statistics and bivariate correlations for the 886 African Americans participating in Wave 4 of MADICS are presented in Informed by family development perspectives on emerging adult mental health, this study investigated the effects of family cohesion during late adolescence on self-regulation and anxiety problems as African Americans transition into emerging adulthood. Three key findings emerged. First, family cohesion in late adolescence was significantly related to increased self-regulation in emerging adulthood. Second, self-regulation was significantly related to reduced anxiety problems in emerging adulthood. Third, family cohesion in late adolescence indirectly effected anxiety problems in emerging adulthood through self-regulation.The first finding suggests that family cohesion during late adolescence is an important process for supporting self-regulation during emerging adulthood. This finding is consistent with and extends previous research on family effects among children and adolescents . In addiOur findings suggest that self-regulation is an important factor in reducing anxiety problems among emerging adults. This is in line with similar findings in investigations of children and emerging adults. For example, a study of children between the ages of 8 to 12 found that highly regulated children were able to manage negative emotions such as worry, sadness, and anger, which suggests that self-regulation may be an important promotive factor for anxiety problems . SimilarThe indirect effect finding suggests that self-regulation may act as a mechanism through which family cohesion during late adolescence affects downstream anxiety. Similar results were reported by Brody and Ge  in a stuStudy findings have several implications for prevention. Prevention programs working to reduce anxiety problems in African Americans prior to and during the transition to adulthood should consider targeting enhancing family cohesion. The Adults in the Making (AIM) prevention program is an example of a program that seeks to increase family cohesion in order to improve emerging adult outcomes . FamilieThe current study has several limitations. First, the sample comprised of African American youth living in Maryland, so these findings may not generalize to African American youth living in other cities or regions of the United States. Second, these findings are correlational. Experimental designs using preventive interventions  could beIn summary, family cohesion in late adolescence was indirectly related to changes in anxiety problems in emerging adulthood through self-regulation. This finding suggests that families continue to serve as important promotive processes for self-regulation and anxiety problems during the transition to emerging adulthood. Prevention programs that incorporate the family may be able to reduce anxiety problems in emerging adult African Americans.S1 Table(DOCX)Click here for additional data file."}
+{"text": "Christopher Abbosh and Charles Swanton discuss circulating tumor DNA as a potential biomarker for neoadjuvant treatment response in solid tumors. Three studies presented within this special issue of PLOS Medicine focus on evaluation of circulating tumor DNA (ctDNA) as a response biomarker in early-stage solid tumours. Both Yaqi Wang and Pradeep Chauhan and their respective colleagues evaluate ctDNA as a tool capable of predicting complete pathological response (pCR) in locally advanced rectal cancer (LARC) and muscle invasive bladder cancer (MIBC), respectively ,2. JeannQuantitation of ctDNA kinetics over time can act as a dynamic biomarker of tumour response to targeted therapies, immunotherapy and radiation therapy \u20136. In a In relation to the latter point, Wang and colleagues draw attention to the potential for deferral of surgery in patients exhibiting complete clinical response  following neoadjuvant chemoradiation treatment for LARC . This isThe study from Wang and colleagues supports prior findings from Murahashi and colleagues who also evaluated post-treatment ctDNA kinetics in patients undergoing neoadjuvant treatment for LARC . In MuraLike the application of ctDNA in LARC, Chauhan and colleagues asked whether evaluation of urinary ctDNA (utDNA) could differentiate pCR from non-pCR in patients being treated with neoadjuvant therapy for MIBC . DevelopTie and colleagues explored ctDNA as a curative-therapy response biomarker in CRLM. Within a cohort of patients who underwent neoadjuvant chemotherapy, they noted a median 40.93-fold decrease in ctDNA levels during treatment with 13 of 18 evaluable patients exhibiting absence of ctDNA detection pre-cycle 4 of treatment: all 4 patients with pCR in the resection specimen experienced ctDNA clearance prior to cycle 3 or 4 of neoadjuvant treatment. However, ctDNA clearance during neoadjuvant chemotherapy had no impact on 5-year relapse free survival (RFS) when compared to lack of ctDNA clearance. In contrast, the team identified that ctDNA detection after surgery was a strong predictor of reduced RFS, with patients who were ctDNA positive following curative therapy (surgery +/- adjuvant therapy) exhibiting a 5-year RFS rate of 0% versus 75.6% in ctDNA negative patients. These data highlight the importance of associating ctDNA clearance dynamics during neoadjuvant treatment with post-operative survival endpoints, since in this study ctDNA clearance with neoadjuvant chemotherapy did not translate into reduced risk of disease recurrence following surgery.Supporting ctDNA as a neoadjuvant response biomarker in other tumor types, data in non-small-cell lung cancer (NSCLC) from the neoadjuvant CheckMate-816 study, a randomized, phase III study comparing neoadjuvant platinum chemotherapy with or without nivolumab in stage IB-IIIA NSCLC, highlighted that ctDNA clearance at day 1 cycle 3 post-combination chemotherapy and immune checkpoint inhibitor treatment associates with pCR . Stage IIn conclusion, the findings presented in this special issue add to an emerging literature highlighting a need to explore the translational potential for ctDNA assessment as a response biomarker in the neoadjuvant setting. These data are particularly relevant in LARC and MIBC where treatment response biomarkers that are not reliant on pathological examination of resection specimens are required to guide non-operative management decisions. The data from Tie and colleagues suggest that the capability of neoadjuvant chemotherapy-induced ctDNA clearance to act as a surrogate of long-term survival benefit from curative intent therapy could be absent in CLRM, however the sample size in this study was modest which may have limited ability to detect an association. It is conceivable that the utility of ctDNA as a neoadjuvant response biomarker may vary by therapeutic class and solid tumour type. To address this issue, it will be important for prospective interventional trials to incorporate ctDNA clearance kinetics as an endpoint to determine surrogacy of these measures for survival across solid-tumour types. Finally, to gain understanding of the relative merits and disadvantages of ctDNA-based response metrics versus conventional clinical measures of response , direct comparison of ctDNA clearance with these approaches is warranted."}
+{"text": "Heritability of cognitive ability changes across late adulthood, although whether genetic variance increases or decreases in importance is not understood well. We performed a systematic review of the heritability of cognitive ability derived from longitudinal twin studies of middle-aged and older adult twins. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, articles were identified in APA PsycINFO and Clarivate Web of Science electronic databases. Identified articles were screened by title and abstract; remaining full-text articles were then fully evaluated. Reference sections served as an additional method for identification of relevant articles. In total, 3,106 articles were identified and screened, 28 of which were included and were based on data from 10 longitudinal twin studies published from 1994-2021. There are large genetic influences on an initial level of cognitive performance across domains whereas there are small to moderate genetic influences on change in performance with age. Evidence was less definitive about whether the same or different genetic factors contribute to both level and change. Non-shared environmental influences appeared to drive individual changes in cognitive performance. Heritability tended to either be stable or decline after 65 years, possibly because of the increasing importance of non-shared environmental influences on cognitive ability. Recent studies report increases in heritability across specific subtests and domains. Shared environmental variance accounted for little variance in cognitive ability. Emerging research questions and future directions for understanding genetic and environment influences in the context of gene-environment interplay are highlighted in this review."}
+{"text": "Level\u00a0of Difficulty: Advanced.)We present 3 cases of superior vena cava (SVC) syndrome following percutaneous right ventricular assist device (RVAD) placement. Each case underscores the importance of early recognition of SVC syndrome in patients with percutaneous RVAD insertion via the internal jugular vein and calls for heightened awareness of device-associated complications. (  At present, device-related SVC syndrome accounts for up to 40% of all cases . PatientSVC syndrome can arise in postsurgical settings or as a consequence of iatrogenic obstruction to venous drainage. Currently, heart transplantation and ventricular assist devices may be used in end-stage heart failure that is unresponsive to interventional treatments. Although bicaval anastomosis during heart transplantation is preferred because of anatomic and hemodynamic benefits, this method effectively limits the distensibility of the SVC to the circumference of the suture line and may precipitate SVC syndrome with post-transplant RVAD use . AlthougAlthough both postsurgical and iatrogenic causes of SVC syndrome can develop secondary to a disruption in hemodynamic stability , scant literature has reported the onset of SVC syndrome after percutaneous RVAD cannulation via the right internal jugular vein . As the A 61-year-old man presented with restrictive cardiomyopathy with biventricular failure and underwent orthotopic heart transplantation (OHT). The patient had a dual-chamber implantable cardioverter-defibrillator (ICD) that was removed following OHT. A postoperative transesophageal echocardiogram (TEE) revealed a moderately dilated right ventricle (RV) with normal function. Postoperative day 2, the patient became profoundly hypotensive and unresponsive to vasopressors, and because of high central venous pressure (CVP) and RV dysfunction, the patient underwent RVAD extracorporeal membrane oxygenation. Approximately 30 hours later, the patient had marked swelling of the head and upper extremities and a CVP of 45\u00a0mm\u00a0Hg . The patA 55-year-old man presented with acute decompensated left ventricular systolic heart failure and cardiogenic shock that required an intra-aortic balloon pump; he underwent LVAD and RVAD implantation. One week before LVAD placement, the patient\u2019s biventricular ICD was removed because of sepsis. Shortly after, central RVAD support was switched to percutaneous support with no complications. Approximately 45 hours following placement of the device, the patient exhibited rapidly progressive head and neck swelling suggestive of SVC syndrome. After removal of a preexisting left internal jugular central venous line, the patient experienced improved facial edema, and signs of SVC syndrome resolved.A 50-year-old man with a history of HeartMate II explant for recovery presented with recurrence of heart failure with a reduced left ventricular ejection fraction of 10% and associated RV dysfunction. After implantation of LVAD and RVAD support, the patient experienced facial edema, orbital swelling, and underwent emergent venogram that showed near occlusion of the SVC  and 2. DThe diagnosis of SVC syndrome is accomplished using clinical picture and supplementary imaging modalities like chest radiography, contrast-enhanced computed tomography scanning, duplex ultrasound, conventional catheter-based digital subtraction venography, and magnetic resonance venography . These tFor nonmalignant causes of SVC syndrome, including placement of a dual-lumen cannula, there are several strategies for preventing venous congestion. In the setting of transplant, preoperative SVC imaging can reveal anatomical variance in caval diameters; significant discrepancy between host and donor may increase risk for bicaval stenosis and subsequent venous congestion. Likewise, we suggest performing a venogram before RVAD placement in patients with preexisting leads or central lines because it may reveal subclinical stenosis. Similarly, venous obstruction can be circumvented via imaging of the SVC-RA junction among patients before device placement; however, this approach poses a significant challenge because of poor validation of ranges for cross-sectional radiographic sizing across different imaging modalities .In addition, the SVC is a compliant vasculature, and its sizing is likely dependent on the hemodynamic status at the time of measurement. More informative imaging techniques may be accomplished via computed tomography venography, but this approach carries a substantial radiation dose and is poorly validated because venous size chiefly depends on intrathoracic pressure and volume status . An alteVenous scarring from preexisting intravascular leads may result in reduced distensibility and may precipitate venous congestion after percutaneous RVAD cannulation. For example, SVC syndrome following pacemaker implantation can occur secondary to the formation of vegetations or via thrombosis after endothelial disruption . In all Here, we describe 3 cases of SVC syndrome following percutaneous dual-lumen cannulation for extracorporeal life support. Patients with signs of SVC syndrome, including facial and chest edema, dyspnea and cough, and nonpulsatile distended neck veins, experienced improvement following either device explantation or removal of the accompanying central venous catheter within the left internal jugular and subclavian venous system. By considering multiple etiologies for SVC syndrome, we hypothesize that appropriate RV support and early recognition of SVC syndrome are critical for preventing venous obstruction.The authors have reported that they have no relationships relevant to the contents of this paper to disclose."}
+{"text": "Transgender persons who came of age in the late 1960s are considered LGBTQ+ elders - The Stonewall Generation. These persons experience unique bio-psychosocial challenges, often complicated by a history of a lack of access to good medical care and social supports. Discrimination and bias can influence the provision of care and the protection of privacy for transgender or gender non-conforming persons. Staff training is essential to provide ethical care for aging trans persons who require residential care. This presentation examines current staff training modules of 100 Long Term Care (LTC) facilities, assessing training needs to provide affirming, culturally competent, and ethical care for sexual and gender minorities.Keywords: cultural competence; Long Term Care; staff training; transgender"}
+{"text": "The present study aims to identify personality and socioeconomic  factors that contribute to midlife cognitive functioning across middle adulthood. Specifically, we examined how the growth trajectories of personality and socioeconomic factors across 12 years predict subsequent cognitive functioning, using data from a large sample of Mexican-origin adults . Personality was assessed using the Big Five Inventory, which assesses the Big Five domains as well as specific facets of each domain; economic stress was assessed using measures of negative economic events  and economic hardship . Cognitive functioning was assessed using the NIH Cognitive Toolbox with measures of memory, language, and executive function. Findings from this work will help identify intervention targets for promoting healthy cognitive aging in midlife and beyond in Mexican-origin adults."}
+{"text": "This session will provide updates on how the pandemic led to horrific situations in long-term care facilities and how the pandemic influenced major federal efforts to address elder abuse, neglect, and exploitation."}
+{"text": "Data harmonization methods facilitate further use of existing studies and research resources. Most statistical harmonization methods require pooling data across studies, which is complex and requires careful scrutiny of source data. Most methods  require datasets to have common items for linking a common construct across studies: this necessitates the qualitative process of pre-statistical harmonization. Here, we document pre-statistical harmonization of items measuring behavioral and psychological symptoms  which represent problematic behaviors among people with dementia administered in a national survey (ADAMS), evaluations conducted at Alzheimer\u2019s Disease Research Centers (NACC), and in six randomized trials . We describe our approach to review question content and scoring procedures to establish comparability across items prior to data pooling. We identified 327 items from 15 instruments across these eight studies. We found considerable cross-study heterogeneity in administration and coding procedures for items that measure the same domain. For example, eight items were coded as count variables in some studies but as categorical variables in others. Moreover, of the 359 items, 191 are conditionally dependent on values of another item. These issues around item response heterogeneity and conditional dependency needed to be resolved prior to estimation of item response theory models for statistical co-calibration. We leveraged several rigorous data transformation procedures to address these issues, including re-coding and winsorization. This study provides guidelines for how future research may acknowledge and address similar issues in pooling behavioral and related instruments."}
+{"text": "The Arabidopsis genome encodes ten Argonautes proteins showing distinct expression pattern as well as intracellular localisation during sexual reproduction. Dear Editor,Small RNAs (sRNAs) are key regulators of gene expression. The importance of reproduction-specific sRNAs has been recognized in plants . Beyond Arabidopsis AGOs are detected in mature ovules before fertilization. Within the female gametophyte, their accumulation seems to be particularly enriched in the egg cell compared with the central cell. Preferential AGO expression in the egg cell was confirmed using previously published female gametophyte transcriptome data obtained by laser-capture microdissection , we could detect expression of 8 out of 10 on limit . mCherryon limit . GFP-AGOon limit . Based oon limit . This dion limit  and suggWe then analyzed AGO accumulation patterns in the differentiated zygote at the heart-stage  As previArabidopsis AGO1 and AGO4 have been shown to shuttle between the cytoplasm and the nucleus although their respective steady-state subcellular localizations seem to reflect their involvement in either PTGS  or TGS   . In agreArabidopsis, yet they are often marred by biological incongruities such as the use of overexpression promoters or C-terminal fusions known to affect AGO functions. The uniform set of tools presented in this study might help bridging this gap across the plant RNA silencing community.To conclude, our study reveals a clear asymmetry of AGO expression between the gametes and accessory cells before fertilization and between the embryo and endosperm lineage after fertilization. A summary of their expression pattern in reproductive tissue can be found in  Schematic representation of the constructs used in this study. RT-qPCR results assessing AGOs expression levels in inflorescence of wild-type and complemented lines. Complementation of ago mutants. Additional channels and LUTs corresponding to the pictures of  Additional pictures.\u2002Arabidopsis AGO transcription patterns extracted from microarray data of LCM-dissected female gametophytes (tophytes  confirmi Additional pictures of AGOs expression pattern in mature pollen counter stained with DAPI. AGO accumulation in germinating pollen tube. Paternal expression in the early zygote of AGOs expressed in sperm cells. Additional channels and LUT corresponding to the pictures of \u2002Arabidopsis AGO transcription patterns extracted from microarray data of LCM-dissected seeds at the pre-globular stage (ar stage  confirmi Primers used in this study. Materials and Methods.kiab474_Supplementary_DataClick here for additional data file."}
+{"text": "Pulmonary vein stenosis (PVS) is a known complication after radiofrequency ablation of atrial fibrillation (RAAF) and is often misdiagnosed owing to lack of awareness regarding PVS among noncardiologists. Misdiagnosis results in unnecessary treatment; therefore, greater understanding of PVS can improve the management of these patients.We report the case of a 38-year-old man with a history of RAAF who presented with massive hemoptysis. His symptoms persisted despite undergoing transcatheter bronchial artery embolization on two occasions.Pulmonary computed tomography angiography revealed a completely occluded left superior pulmonary vein. Considering the patient\u2019s history of RAAF, we diagnosed him with RAAF-induced PVS and performed left superior lobectomy after which hemoptysis did not recur.Unexplained massive hemoptysis should alert clinicians regarding the possibility of RAAF-induced PVS. Balloon angioplasty and stent placement are used to treat PVS; however, their efficacy is controversial considering the high recurrence rates associated with these interventions. Hemoptysis is an important clinical manifestation of respiratory diseases. Common causes of hemoptysis observed in clinical practice include bronchitis, bronchogenic carcinoma, bronchiectasis, infections, and tuberculosis.. Additionally, a high-density stripe observed in the left upper lobe suggested chronic inflammation . Medical treatment with vasopressin and hemagglutinin was ineffective. Left bronchial artery angiography revealed an enlarged bronchial artery showing an extensive branching pattern, and contrast agent extravasation was observed in the left upper lung field . We performed transcatheter bronchial artery embolization using polyvinyl alcohol embolization particles , gelatin sponge particle embolic agent  and fibered platinum coils . Hemoptysis was controlled immediately after the procedure; however, massive hemoptysis recurred on the second day. Repeat angiography revealed that an ectopic bronchial artery originating from the left internal thoracic artery was the source of hemorrhage ; therefore, we performed transcatheter embolization of the ectopic bronchial artery. Unfortunately, hemoptysis was controlled only for 2 days after the procedure and recurred thereafter.The patient was referred to the emergency department at our hospital because of massive hemoptysis. He reported a history of catheter ablation performed for atrial fibrillation, 10 days prior to presentation. Chest radiography did not reveal any positive findings. Thoracic computed tomography (CT) scan revealed scattered ground-glass opacities in the left upper lobe, suggesting alveolar hemorrhage A. Additiammation B. Medicang field A. We permorrhage B; theref. Based on his history of RAAF, hemoptysis was attributed to RAAF-induced PVS in this patient. The patient underwent left superior lobectomy after which hemoptysis did not recur.Pulmonary CT angiography was performed to detect potential ectopic bronchial arteries, and complete occlusion of the left superior pulmonary vein was accidently discovered during this examination A and B. ,Since it was first reported in 1998,Most patients with PVS present with dyspnea, recurrent cough, expectoration, chest pain, flu-like symptoms and hemoptysis. Recurrent hemoptysis was the predominant symptom in our patient, and although hemoptysis is not rare in patients with PVS, hemoptysis associated with RAAF-induced PVS is relatively rare when considering the overall common causes of hemoptysis. The pathophysiological mechanism contributing to hemoptysis in patients with PVS remains unclear. We concluded that hemoptysis was attributable to increased pulmonary vascular resistance secondary to PVS. Magnetic resonance imaging and pulmonary vein CT angiography are valuable noninvasive diagnostic tools for PVS. Both modalities provide useful information regarding the site and extent of PVS, but the low spatial resolution associated with these modalities is a limitation; therefore, cardiac catheterization and pulmonary artery angiography remain the gold standard for the diagnosis of PVS.Transcatheter bronchial artery embolization is widely used as a safe and effective treatment to prevent hemoptysis; however, it is ineffective in patients with RAAF-induced PVS because these patients develop hemoptysis secondary to elevated pulmonary vein pressure and reduced venous backflow. Therefore, treatment in these patients is primarily aimed at relieving the obstruction and increasing blood flow through the pulmonary veins. The main treatment modalities for PVS include balloon angioplasty and/or stent implantation. Both methods are known to successfully alleviate symptoms; however, high rates of restenosis have been observed over the long-term follow-up. Compared with balloon dilation, stent implantation is associated with a relatively low restenosis rate, particularly with the use of stents measuring >10\u00a0\u200bmm in diameter. Long-term anticoagulant therapy is necessary after the procedure to avoid pulmonary vein thrombosis. A recent study has reported the use of drug-eluting stents to reduce the restenosis rate,In conclusion, PVS is a complication of RAAF that is often misdiagnosed owing to lack of adequate awareness regarding this condition among noncardiologists. Unexplained massive hemoptysis should alert clinicians regarding the possibility of RAAF-induced PVS in patients with such a clinical presentation. Pulmonary vein CT angiography is a valuable noninvasive method to diagnose PVS. Minimally invasive treatments, such as balloon dilation and pulmonary vein stenting have been used to treat PVS; however, their efficacy remains controversial owing to the relatively high recurrence rates associated with these interventions.Written informed consent was obtained from patients for publication of this case reports and any accompanying images.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."}
+{"text": "Declines of large-bodied herbivorous reptiles are well documented, but the consequences for ecosystem function are not. Understanding how large-bodied herbivorous reptiles engineer ecosystems is relevant given the current interest in restoration of tropical islands where extinction rates are disproportionately high and reptiles are prominent as herbivores.Conolophus subcristatus), large-bodied herbivores known to feed on many plant species. We characterized plant communities on each island by developing high-resolution (<1 cm2) aerial imagery and delineating extent of plant associations and counting individual plants on each.In this study, we measured the ecosystem-level outcomes of long-term quasi-experiment represented by two adjacent islands within the Galapagos Archipelago, one with and the other without Galapagos land iguanas (In the presence of iguanas there was dramatically less woody plant cover, more area with seasonal grasses, and many fewer cacti. Cacti had a more clumped distribution where iguanas were absent than where iguanas were present.This study provided strong evidence that Galapagos land iguanas can substantially engineer the structure of terrestrial plant communities; therefore, restoration of large-bodied reptilian herbivores, such as land iguanas and giant tortoises, should be regarded as an important component of overall ecosystem restoration, especially for tropical islands from which they have been extirpated. ReptileConolophus subcristatus, C. marthae and C. pallidus) and giant tortoises (Chelonoidis spp.) once dominated as the only large-bodied herbivores present in the Galapagos Islands  reproduction while enhancing sexual reproduction via seed dispersal away from adult plants where bird predation on seeds is intense  aerial imagery and delineating extent of plant associations on each. Our study provided an opportunity to ask questions about the role of reptilian herbivores on structuring the plant communities of islands, including impacts on keystone plants, as well as to explore the ramifications of restoring reptile populations on islands to promote ecosystem recovery , Bouteloua disticha (Poaceae), Cyperus anderssonii (Cyperaceae), Panicum laxum (Poaceae), Sporobolus pyramidatus (Poaceae); woody plants\u2014Acacia rorudiana (Mimosaceae), Bursera graveolens (Burseraceae), Maytenus octogona (Celastraceae), Parkinsonia aculeata , and Scutia spicata (Rhamnaceae); succulents\u2014Sesuvium edmonstonei (Aizoaceae), and cactus\u2014Opuntia echios (Cactaceae).The Galapagos Islands are a volcanic archipelago straddling the equator 1000 km west of continental Ecuador . ClimateZalophus wollebaeki) to enter the island for resting. A final biotic difference known to occur between the islands other than presence/absence of land iguanas was the former existence of a small cohort of goats  using the Geospatial Data Abstraction Library for geo encoding, warping and tiling supported with Python 3.4 and Imagemagick software  in R  in R . To measge) in R .versus its extent in the eight neighboring grid cells  and 1,777 grid cells on South Plaza island (iguanas present) . Vegetatid cells  indicateid cells  revealedThis study provides evidence that large-bodied, herbivorous reptiles can substantially engineer the structure of terrestrial plant communities. Not only was woody vegetation far less extensive on the island with land iguanas, the spatial pattern of woody vegetation also differed insofar as it tended to be surrounded by more woody vegetation in the presence of iguanas than in their absence. Land iguana impacts on cactus\u2014a keystone species for the entire vertebrate community\u2014were also substantial, reducing cactus abundance and altering spatial distribution of cactus.We suspect the dramatic contrasts in vegetation between islands were due primarily to herbivory by iguanas. Land iguanas consume fruits, flowers, leaves and shoots of woody plants, including those of species that dominated on the Plazas Islands . TargeteLand iguana herbivory might well have a cascading effect on the biotic community of small oceanic islands, by influencing other terrestrial vertebrates through changes in habitat structure and composition. One important interaction likely resulting from iguana herbivory with impacts on many other species on the Plazas Islands involves marine mammals. Sea lions cannot navigate through woody vegetation when seeking basking sites, and occupy more sparsely vegetated areas facilitated by iguanas. Sea lions deposit prolific amounts of guano with attendant changes in the soil chemistry . Notablyvia trampling and altering soil chemistry through deposition of feces sea lions affecting vegetation. This said, many parts of South Plaza Island remain inaccessible to sea lions and those areas still evidence the general differences observed in vegetation  between North and South Plazas Islands.A primary limitation of our study is that it represents a pseudo-replicated design with one replicate within each treatment. Unfortunately given the widespread extinctions of island forms of large-bodied reptilian herbivores elsewhere in Galapagos and around the world , there aWhy land iguanas do not occur on North Plaza Island is not clear. The species\u2019 habitat is characterized as \u201cdry areas with low growing shrubs and Opuntia cactus\u201d  which deversus absence of land iguanas. We provide evidence that land iguanas substantially engineer the structure of plant communities. This study suggests that the widespread extinction of reptile herbivores, which once served as the dominant herbivore in many tropical oceanic ecosystems, might have profound implications for the status of these ecosystems, and the species that comprise them, today. Restoration of large-bodied reptilian herbivores, such as land iguanas and giant tortoises, should be regarded as an important component of restoration in ecosystems where they have been extirpated.Understanding how large-bodied herbivores engineer ecosystems is relevant today given widespread, current interest in reintroducing extant species back to places from which they were extirpated in historical times . With ma10.7717/peerj.12711/supp-1Supplemental Information 12) aerial imagery and delineating extent of plant associations and counting individual plants on each .Plant communities characterized on each island by developing high-resolution  and North Plaza Island (iguanas absent).Click here for additional data file."}
+{"text": "ABSTRACT IMPACT: This qualitative study describes health system barriers to high-quality care for Latino older adults with Alzheimer\u2019s Disease and Related Dementias OBJECTIVES/GOALS: Compared to non-Latino Whites, Latino older adults are more likely to receive low-quality dementia care such as high-risk medications or services. Caregivers play a critical role in managing medical care for persons with dementia (PWD). Yet little is known about the perceptions and knowledge of dementia quality of care among Latino caregivers of PWD. METHODS/STUDY POPULATION: We used a qualitative research design and conducted interviews with Latino caregivers of PWD and caregiver advocates. We recruited both from community organizations, senior centers, and clinics. Our interview guide focused on experiences of caregiving, interactions with medical system, and knowledge and experiences managing behavioral and eating problems. We used Grounded Theory methodology for coding and analysis, focusing on contrasting and comparing experiences within and between caregivers and caregiver advocates. RESULTS/ANTICIPATED RESULTS: Preliminary results from interviews with two caregivers and two caregiver advocates illustrate that caregivers of persons with dementia have a difficult time receiving high quality care from primary care clinicians. All participants noted that many primary care doctors didn\u2019t know how to diagnose ADRD and dismissed critical symptoms as part of old age. Caregivers also reported that they wished they had more information on what to expect with ADRD disease progression, noting they received little information from the formal medical care system. With respect to behavioral problems, caregiver advocates noted that primary care doctors often did not provide non-pharmacological alternatives to behavioral problems. DISCUSSION/SIGNIFICANCE OF FINDINGS: Findings from our pilot study demonstrate that there is a clear need to train primary care physicians who serve Latino older adults on ADRD care. Improved diagnosis and management could improve outcomes among Latino older adults with dementia."}
+{"text": "COVID-19 upended in-person educational programming in areas such as classroom instruction within academic institutions, engagement of adult learners, and training of direct care workers. In-person educational offerings were forced, as a result of health restrictions, to pivot into either asynchronous or synchronous web-based instruction. This panel discussion will discuss lessons-learned in cyber-pedagogy in three areas: 1) Faculty Consultation: Faculty who teach online regularly and have completed training in quality online educational practices are experts who were called upon to assist others with transitioning courses to an online format. This presentation outlines the ways in which certified online instructors, at one academic center, tutored and assisted faculty in the health sciences with online instruction. 2) Adult Learning: The rapid transition to online learning has implications for adult learners pertaining to accessibility, diverse learning and technology abilities, and course and peer engagement. This presentation will explore strategies that faculty can utilize to offer adult learners differentiated learning and engagement opportunities. This discussion will also highlight the nexus among these pedagogical strategies and the Age-Friendly University Global Network, providing guidance for how universities can connect online learning methods to the Age-Friendly University principles. 3) Workforce Training: The direct care workforce employed in community-based services and support programs and long-term care settings tend to receive little or no training in geriatric care. This presentation will discuss how educational trainings offered through a Geriatric Workforce Enhancement Program transitioned onto web-based platforms in order to accommodate these ongoing educational needs throughout the pandemic."}
+{"text": "Existing research has identified significant risk factors for experiencing social isolation in later life including chronic health conditions, mobility impairments, and living alone among others. Although many older people who live alone maintain active social lives, living alone remains a top predictor of social isolation. Less is known about other types of risk factors, such as place-based risks and social exclusion. Despite calls to examine the role of place and social exclusion in social isolation risk, few studies have investigated the links. Models of isolation risk have often omitted place-based factors and social exclusion and focused largely on individual-level risks. In order to address these gaps, this paper presents the findings of 17 in-depth, qualitative interviews with community-dwelling older people who live alone (aged 65-93). Participants were recruited using a theoretical sampling strategy to ensure that a diverse range of neighbourhood types were represented among the participants . Interview transcripts were analyzed using a constructivist grounded approach resulting in several major themes. Participants described aspects of their local environments as shaping their risk of isolation including infrastructure and amenities delivered in place, and neighbourhood makeup, among others. These themes are further examined through the lens of place-based exclusion and used to conceptualize how dimensions of both place and social exclusion fit into the model of known isolation risk factors. An adapted model of risk is presented to guide future research and intervention planning."}
+{"text": "As COVID-19 lockdowns began in Canada last spring, family caregivers (FCGs) of people living with dementia (PLWD) found themselves facing a catch-22: they and their family members were often most at risk of severe outcomes should they contract the virus, yet the public health measures put in place also detrimentally affected their ability to continue providing care. To understand the nuances of caregiver experiences during the pandemic, we conducted 9 focus groups with 19 FCGs of PLWD in the Calgary region in summer 2020. Caregivers reported negative outcomes resulting from decreased services for both themselves and the PLWD, including increased isolation, poor mental health, and accelerated dementia progression. Caregivers also emphasized the importance thinking beyond the binary of either locking down or opening up; rather, we must find creative solutions to safely continue providing supports to caregivers. This presentation explores FCG suggestions for balancing COVID-19 risk against caregiver needs."}
+{"text": "Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease. Developing axons in the mammalian nervous system can extend very long distances . After rContinuous addition of new membrane is required during axon and dendrite growth ,24, streA schematic representation of membrane expansion during axonal and dendritic growth, stretch growth of integrated axons, myelin formation and repair, sealing of membrane ruptures and axon regeneration. PPV: plasmalemmal precursor vesicles.Membrane expansion in developing axons is mediated by polarized exocytosis of plasmalemmal precursor vesicles that are anterogradely transported to the growth cone ,36. New A schematic representation of the assembly of the exocyst octameric protein complex that controls the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. Soluble N-ethylmaleamide attachment proteins (SNAP), vesicle associated membrane proteins (VAMP) and syntaxis form the core machinery of vesicle fusion also known as the SNARE  complex . WhereasAfter axotomy, rapid sealing of disrupted membranes is necessary to restore boundary integrity of the axonal compartment, to equilibrate ion concentration and to counteract osmotic stress . These sFormation of a new growth cone at the axonal stump also requires insertion of new membrane into the neurolemma ,59. A prAnother recent study in adult CNS neurons has shed light on the specific changes in lipid metabolism that contribute to axon regeneration. After axotomy, expression of the phosphatidic acid phosphatase enzyme lipin 1 increase in retinal ganglion cells . MechaniProm1, which encodes the membrane glycoprotein Prominin-1, acts as a positive regulator of peripheral nerve regeneration in adulthood [Prom1 forced expression enhances axon regeneration via Smad2-dependent signaling and inhibits the expression of genes related to cholesterol biosynthesis [During early stages of development, immature neurons exhibit an extraordinary axon growth and regenerative capacity ,62,63. Adulthood . Prom1 fynthesis . In the adult CNS, the vast majority of cholesterol is present in myelin sheaths and plasma membranes. After SCI, disruption of cellular membranes and myelin sheaths cause an excess of cholesterol to accumulate in the extracellular space. Of interest, cholesterol depletion has been shown to promote axon growth in vitro and regeneration of peripheral nerves in vivo . By loweThe neuronal cell bodies in sensory, sympathetic and parasympathetic ganglia are wrapped by satellite glial cells . The impTogether, experimental evidence suggests that rewiring lipid metabolism can be manipulated for therapeutic gain as it favors axon regeneration both in the central and peripheral nervous systems. Whether pharmacological and molecular strategies lowering cholesterol synthesis promote neurological recovery after SCI is unknown and deserves further attention in future investigations. Drosophila have shown that dendrite expansion in larva neurons relies on cell-autonomous production of lipids [srebp mutant. SREBP acts as a basic helix\u2013loop\u2013helix leucine zipper transcription factor that binds to sterol regulatory elements to control the expression of genes that encode key enzymes of both fatty acid and cholesterol metabolism [srebp mutant larvae. In turn, cell-autonomous production of fatty acids is necessary for correct dendritic development and function. A genetic screen in dendritic arborization sensory neurons of the Drosophila larval peripheral nervous system has identified the easily shocked (eas) gene, which encodes the ethanolamine kinase , as a c mutants , causing mutants . Eas mut neurons ,86. ThusMyelin is constituted by multiple overlapping layers of a specialized membrane spiraling around axons . Myelin During normal brain development, astrocyte-derived fatty acids constitute a significant portion of lipids incorporated into CNS myelin . RemarkaAs result of CNS trauma and disease, myelin sheaths along the axon can be severely damaged. De novo fatty acid synthesis via fatty acid synthase is critical for CNS myelin formation after demyelination injury. Genetic depletion of fatty acid synthase from OPC has no effect on proliferation and differentiation along the oligodendrocyte lineage, yet is necessary for accurate CNS myelination . TreatmeIn mammals, the ability to regenerate and repair the CNS declines with age ,117. In Recent evidence suggests that a delicate balance in lipid synthesis and homeostasis is crucial during myelin formation and remyelination during CNS development, as well as after injury or disease. Strategies targeting lipid composition of the myelin membrane may exert contradictory responses where a lipid-enriched diet may rescue myelination defects while excess lipids trigger oligodendrocyte death and inflammation. Learning how to fine tune lipid composition in myelin membranes via extracellular lipid supply, lowering cholesterol levels or promoting its clearance with spatial precision without causing adverse effects represent important areas of future investigation. As discussed above, lipids are necessary for proper sealing of the plasma membrane, formation of a new growth cone and regeneration after axonal injury. These energy demanding processes require optimal mitochondrial transport and adenosine triphosphate (ATP) production ,122,123.As axons reach their target field during late stages of development, formation of collateral branches and synaptic contacts allow neurons to establish complex connectivity patterns ,131,132.Mitochondria trafficking and anchoring along the axons needs to be tightly regulated to respond to altered energy requirements . To meetMitochondrial positioning along the axon is important as it enables local energy supply . AccumulO-linked \u03b2-N-acetylglucosamine (O-GlcNAc) post-translational modification of serine and threonine residues of proteins acts as a nutrient sensor and metabolic mediator [worms, a decrease in O-GlcNAc levels promotes axon regeneration by adopting glycolysis as the primary source of energy [O-GlcNAc levels fail to regenerate after blocking glucose transport or inhibiting glycolysis, increasing O-GlcNAc levels act on mitochondrial function and enhance axon regeneration in Caenorhabditis elegans through FOXO/DAF-16\u2013dependent mechanisms [O-GlcNAc levels drive distinct branches of the insulin pathway to promote regeneration in worms may help explain these seemingly contradictory results. How does cellular metabolism contribute to neuron repair after axotomy? By linking glucose metabolism to the hexosamine biosynthetic pathway, mediator . One dayf energy . Whilst chanisms . The facAs glial cells are metabolically coupled to axons, they may provide energy metabolites to support axon survival and function ,156,157.Together, the above examples underscore the importance of achieving optimal mitochondrial transport and glial metabolism as they are necessary for energy production to fuel axon growth and regeneration. Whether mitochondrial transport may be linked to nutrient and energy sensing is not known. It is also not clear whether mitochondria have memories, allowing them to respond rapidly to changes in environmental nutrient and energy levels. The extent to which boosting energy metabolism and mitochondria trafficking may be sufficient to promote functionally relevant regeneration and CNS repair under different experimental conditions awaits confirmation. After CNS trauma and disease, altered lipid metabolism and lipid accumulation in neurons and various tissues in the body can be harmful, as it causes permanent cellular damage . To undeUnder normal physiological conditions, excess energy is stored in depots of white adipose tissue (WAT) in the form of triacylglycerides. WAT depots include abdominal and subcutaneous fat ,163 Fig. To mobiGeneration of body heat by external stimuli like temperature or food is called adaptive thermogenesis and is further classified as either shivering or non-shivering thermogenesis. By controlling the non-shivering thermogenic function, brown adipose tissue (BAT) plays a crucial role in maintaining whole-body energy balance. BAT\u2019s unique ability to produce heat relies on the mitochondrial uncoupling protein 1 (UCP1), which disengages oxidative phosphorylation from the electron transport chain to produce heat instead of energy in the form of ATP . IncreasRecent evidence suggests that innervation of adipose tissue may play a critical role in lipid mobilization and endocrine signaling ,170,171.More than 100 years ago, Dogiel reported neurons of unknown origin innervate WAT . DecadesSensory neurons also innervate WAT. In fact, T13-L3 neuronal cell bodies can be visualized upon retrograde tracing in WAT . SimilarUnlike WAT, BAT segments bilaterally . As noreLipolysis and adaptive thermogenesis are necessary to control a healthy energy balance. Neurons that connect the hypothalamic regions and innervate WAT and BAT form a \u2018leptin sensitive\u2019 closed loop. The arcuate nucleus in the hypothalamus is one such CNS region that critically senses leptin levels  to promoIndividuals that sustained an injury to the brain or spinal cord may have lower life expectancy due to chronic secondary complications that develop months and years after injury. Bladder and bowel dysfunction can cause anxiety, social isolation and depression after SCI . SympathIt is important to note that adiposity in SCI individuals and healthy individuals is not exactly the same. Within a year after injury, SCI individuals lose bodyweight, mostly in lean muscle mass . The draAt least half of individuals with SCI has >30% of their total body mass as adipose tissue, indicating SCI individuals are at high risk of developing metabolic syndrome  Figure . AdiposeA rise in triglycerides in the liver may be caused by increased storage after de novo synthesis, reduced breakdown, or impaired secretion in the form of very-low-density lipoproteins (VLDL). Under pathological conditions like obesity, fatty acids are converted into triglycerides. These are stored as neutral lipid droplets as they no longer get converted into energy substrates by oxidation. With more incoming fatty acids adding to the pool of stored lipid droplets in the liver, the de novo synthesis of lipids increases, thereby causing lipid accumulation within the liver ,225. As Proper insulin signaling in the liver orchestrates the critical steps of VLDL secretion . HoweverMore than half of the triglycerides deposited in the liver originates from circulating fatty acids and ~25% of the triglycerides comes from de novo lipogenesis . Given tA gradual rise in whole-body adiposity compromises the balance between fatty acid uptake and secretion with negative impacts on the liver metabolic profile. Despite recent progress, a thorough mechanistic understanding of liver pathology after SCI is still lacking. As the liver represents the primary site for drug metabolism, reducing hepatic metabolic dysfunction may boost efficacy of SCI medications and repair strategies. As circulating free fatty acid levels increase due to adiposity, the glucose-fatty acid cycle, also known as the \u2018Randle\u2019 cycle , destabiCardiovascular complications represent the leading cause of death in chronic SCI individuals ,242,243.We have discussed evidence suggesting that reprogramming lipid metabolism, boosting mitochondrial transport and neuron-glia metabolic coupling promote survival and regeneration of injured axons. Whereas large amounts of lipids are necessary during development to grow axons, dendrites and myelin sheaths, dysregulation of lipid metabolism, impaired mitochondrial functions and excess lipid accumulation through the body including in non-adipose organs can be harmful as they cause lipotoxicity and increased levels of fatty acids. Not only do such detrimental conditions contribute to axon regeneration failure, but also to insulin resistance, cardiovascular disease and metabolic syndrome, thus leading to poor neurological outcomes and a diminished quality of life. In addition, spatial and temporal alteration of circulating fatty acids may compromise CNS function and repair under pathological conditions including CNS trauma and neurodegenerative diseases. Correct positioning of organelles for membrane trafficking, lipid exchange and energy production requires a complex interplay between various organelles and molecular motors . The fab"}
+{"text": "Strong social relationships and social engagement are crucial for both successful aging and successful community re-entry after incarceration. Here, we utilized a mixed methods approach to understand the impact of incarceration on social relationships and social engagement among formerly incarcerated community-dwelling African-American adults aged >50. Participants in the 2012 or 2014 waves of the Health and Retirement Study answered questions regarding prior incarceration, social relationships, and participation in social activities. Additionally, we utilized key informant interviews to further explore how incarceration might impact relationships and social engagement. This presentation will describe quantitative associations between prior incarceration and social relationship structure & function. Further, we will use our qualitative interview data to further explore possible explanations for our findings. Finally, we will describe how MCUAAAR Scientist/Faculty interactions facilitated this work."}
+{"text": "OBJECTIVES/GOALS: People engaging in high-risk substance use or experiencing food insecurity or housing instability are at increased risk to develop end-stage kidney disease. This study will examine associations between these risk factors, patient indicators of socioeconomic position, and hospitalization rates and quality of life after initiation of hemodialysis. METHODS/STUDY POPULATION: The proposed study will leverage a prospective cohort design. We will enroll a convenience sample of 330 participants from the same large dialysis organization. Participants will complete measures of socioeconomic position ; substance use; food insecurity; housing instability; and quality of life at baseline. We will follow participants for 6 months and extract hospitalization counts from the dialysis facility medical record. RESULTS/ANTICIPATED RESULTS: We will generate risk scores  from measures of substance use, food insecurity and housing instability. We will conduct multiple logistic regression to generate odds ratios comparing risk group membership by indicators of socioeconomic position. We anticipate that low or medium-risk groups will differ from high risk groups by indicators of socioeconomic position. We will conduct Poisson regression to generate incidence rate ratios for 6-month hospitalization rates comparing low or medium-risk and high-risk groups. Lastly, we will conduct multiple linear regression to generate beta coefficients for changes in quality of life scores comparing low or medium-risk and high-risk groups. We anticipate that high-risk groups will have higher hospitalization rates and lower quality of life scores. DISCUSSION/SIGNIFICANCE OF IMPACT: As the prevalence of end-stage kidney disease continues to increase, there is a need for tertiary prevention interventions that reduce costly inpatient utilization and improve health-related quality of life. The proposed study will lay groundwork for the development of interventions to improve patient outcomes and reduce Medicare spending."}
+{"text": "Oral health is a global public health concern. The four papers in this symposium capture various understudied risk and protective factors in oral health and dental care among older adults in China. The first paper examined the relationship between social isolation, loneliness, and tooth loss among Chinese older adults, using the Chinese Longitudinal Healthy Longevity Survey. The findings suggest that higher levels of social isolation, rather than loneliness, were associated with fewer remaining teeth and accelerated tooth loss over time. The second paper investigated urban-rural disparities in dental care utilization among Chinese adults aged 18 to 65 years old, using the 2019 New Era and Living Conditions in Megacities Survey. The findings demonstrate urban residents were more likely to visit dentists than rural residents. Besides socioeconomic status, health attitudes/behaviors, and oral health needs, health insurance coverage was considered an important enabling factor to promote dental care use in this population. The third paper examined the relationship between denture use and cognitive decline among Chinese older adults, using data from the Chinese Longitudinal Healthy Longevity Survey. The findings indicate that denture use is protective against cognitive decline over time in later life. The fourth paper examined the prevalence of self-reported orofacial pain symptoms and their correlates at the last year of life among Chinese older adults. Low socioeconomic status, smoking, chronic conditions, oral hygiene practice, and natural teeth condition were associated with such symptoms. This symposium offers valuable insights to improve oral health and dental care in older adults in China."}
+{"text": "ABSTRACT IMPACT: This project aims to better understand mechanisms of sensory and motor deficits in individuals with ASD with the goal of informing diagnosis and treatment development. OBJECTIVES/GOALS: Over-reliance on both visual and proprioceptive feedback have both been observed during motor behavior in persons with Autism Spectrum Disorders (ASD), suggesting that separate sensory feedback processes may be selectively altered during different behaviors. The objective of this study is to clarify sensory mechanisms of fine motor control in ASD. METHODS/STUDY POPULATION: Participants with ASD (N=43) and controls (N=23) matched on age (10-20 yrs) and non-verbal IQ completed tests of precision gripping. Participants were instructed to press on force sensors with their index finger and thumb so that a moving bar corresponding to their force output reached and stayed as stable as possible at the level of a stationary target bar. Visual feedback was manipulated by changing the visual gain of the force bar . The force bar moved more per change in force output at higher gains. Proprioceptive feedback was manipulated by applying 80 Hz tendon vibration at the wrist to induce an illusion of muscle contraction. This was compared to a condition with the tendon vibrator turned off. Force variability (standard deviation) and regularity (sample entropy) were examined. RESULTS/ANTICIPATED RESULTS: Controls showed increased force variability with the tendon vibration on compared to off ; however, the ASD group showed no difference in force variability between the tendon vibration conditions . Individuals with ASD had stronger age-associated reductions in force variability relative to controls across tendon vibrator and gain conditions . The ASD group also had greater age-associated increases in force regularity relative to controls, especially at higher gain levels . Unlike the ASD group for whom regularity increased with age in both tendon vibration conditions, controls only showed these age-related gains when the tendon vibrator was off . DISCUSSION/SIGNIFICANCE OF FINDINGS: Our findings indicate that while controls integrate proprioceptive and visual feedback online to accurately adjust fine motor behavior, persons with ASD rely mostly on visual feedback. Our results suggest delayed development of sensory integration and reduced reliance on multisensory feedback during online fine motor control in persons with ASD."}
+{"text": "Although cognitive decline has previously been associated with mobility limitations and frailty, the relationship between sustained attention and gait speed is incompletely characterized. To better quantify the specificity of the sustained attention and gait speed association, we examined the extent to which this relationship is unique rather than accounted for by executive functioning and physical health characteristics. 58 middle-to-older-aged community-dwelling adults without overt illness or diseases  participated in the study. Each participant completed a 4-meter gait speed assessment and validated neuropsychological tests to examine various domains of executive functions including working memory , inhibitory control , and task switching . Multiple physical and vascular risk factors were also evaluated. Sustained attention was assessed using the gradual onset continuous performance task (gradCPT), a well validated go/no-go sustained attention task. A series of linear regression models were created to examine how different aspects of cognition, including sustained attention and traditional measures of executive functioning, related to gait speed while controlling for a variety of physical and vascular risk factors. Among all predictors, gradCPT accuracy explained the most variance in gait speed  and was the only significant predictor  when accounting for executive functioning and other physical and vascular risk factors. The present results indicate that sustained attention may be uniquely sensitive and mechanistically linked to mobility limitations in middle-to-older adults."}
+{"text": "Inflammaging characterized with increased low grade inflammation in older adults is common determinant of unhealthy aging; and is a major risk factor of morbidity and mortality in older adults. The precise origin of inflammation in older adults is not known, however, emerging evidence indicate that increased intestinal epithelial permeability (leaky gut) and abnormal (dysbiotic) gut microbiota could be one of the key source. However, no preventive and treatment therapies are available to reverse the leaky gut and microbiome dysbiosis in older adults. Here, we presented the evidence that a human-origin probiotics cocktail containing 5 Lactobacillus and 5 Enterococcus strains isolated from healthy human infant gut can ameliorate aging-related metabolic, physical and cognitive dysfunctions in older mice. We show that the Feeding this probiotic cocktail prevented high-fat diet\u2013induced (HFD-induced) abnormalities in glycose metabolism and physical functions in older mice and reduced microbiota dysbiosis, leaky gut, inflammation. Probiotic-modulated gut microbiota reduced leaky gut by increasing tight junctions on intestinal epithelia, which in turn reduced inflammation. Mechanistically, probiotics increased bile salt hydrolase activity in older microbiota, which in turn increased taurine deconjugation from bile acids to increase free taurine abundance in the gut. We further show that taurine stimulated tight junctions and suppressed gut leakiness. Further, taurine increased life span, reduced adiposity and leaky gut, and enhanced physical function in Caenorhabditis elegans. Whether this novel human origin probiotic therapy could prevent or treat aging-related leaky gut and inflammation in the elderly by reversing microbiome dysbiosis requires evaluation."}
+{"text": "Function by Roy et al.\u201cChoose your parents wisely\u201d is a popular adage coined by the British Philosopher Bertrand Russell, and often used when discussing issues such as socioeconomic position and genetic contributions to disease risk. When it comes to vascular function, a predictor of cardiovascular disease risk, the recent study in HCR) and vice versa (HCR-mtLCR). Specifically, HCR female offspring were backcrossed with male LCR  via inbreeding, and this backcross procedure was repeated over several generations to generate the LCR-mtHCR and HCR-mtLCR. The investigators performed echocardiography to assess cardiac function and left ventricular mass, wire, and pressure myography to assess arterial vasodilatory function (with and without PVAT) and mechanics, macroscopic tissue imaging of PVAT, and bioenergetic assays with vascular smooth muscle cells (VSMCs).The investigators studied rats artificially selected (within-family) for intrinsic aerobic endurance running capacity to generate LCR and HCR male rats.HCR) but decreased left ventricular mass and several indices of cardiac performance in HCR-mtLCR relative to HCR.Compared to HCR, LCR rats had higher body mass, epididymal fat mass, and blood pressure. Regarding cardiac measures, HCR rats presented higher left ventricular mass than LCR rats see . CompareHCR), however, it did not reduce vascular function in HCR-mtLCR. Using mesenteric arterioles and plotting internal lumen and external diameters with intraluminal pressure curves, the authors revealed that the arterioles from LCR rats exhibited hypotrophic remodeling . Moreover, mitochondrial swap did not have an effect on either the LCR or HCR phenotype.The key findings were that compared to HCR, LCR rats presented with lower endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilation in mesenteric resistance arteries. Mitochondrial swap rescued endothelium-dependent and endothelium-independent vasodilation in LCR  to what extent intrinsic exercise capacity and mitochondrial DNA influence vascular function in female and older rodents, (2) if the reduced endothelium-dependent vasodilation in LCR rats is mediated by reduced NO synthesis and/or bioavailability or a combination of NO and/or other vasodilators  or prostacyclin), (3) the role of mitochondrial ROS and other vascular sources of ROS  in contributing to the vascular phenotypes associated with HCR and LCR, and (4) determining whether exercise, similar to mitochondrial swapped conplastic strains, can also rescue endothelial dysfunction in LRC rodents .,HCR on LCR rodents demonstrates that mitochondrial DNA is an essential oddment to the protective phenotype conferred by high CRF. These findings will hopefully pave the way for exciting future research to determine mitochondrial-based targets to help prevent and treat cardiovascular disease.At the population level, we cannot do much to improve an individual\u2019s intrinsic CRF. Indeed, the HERITAGE family study established that intrinsic capacity and trainability are genetically heritable in humans."}
+{"text": "The coexistence of expiratory central airway collapse and diaphragmatic paralysis presents a diagnostic and treatment challenge. Both entities are underrecognized causes of dyspnea, cough, sputum production, and orthopnea. Optimal treatment must be individualized and is best achieved by a multidisciplinary team. We present a case of a patient with profound functional impairment from dyspnea and hypoxemia due to expiratory central airway collapse, complicated by bronchiectasis from recurrent respiratory infections, and diaphragmatic paralysis. There are a myriad of causes of dyspnea, hypoxemia, and excessive sputum production. Identifying the relevant contributors to patient's presenting concerns is critical for appropriate management. Expiratory central airway collapse (ECAC) involving either the cartilaginous tracheal wall or the posterior membranous portion may be suggested by computed tomography imaging of the chest obtained during forced expiration and confirmed by dynamic bronchoscopy. Fluoroscopy and diaphragm ultrasound are used to diagnose diaphragmatic paralysis. Surgical management includes tracheobronchoplasty and diaphragmatic plication. ECAC and diaphragm paralysis both compromise gas exchange during surgery but the effect can be mitigated by the use of intraoperative extracorporeal membrane oxygenation (ECMO).A 54-year-old man presented with progressive shortness of breath, cough, and recurrent pneumonia. Chest examination was notable for reduced bilateral lung excursion, coarse breath sounds diffusely, and paradoxical breathing in the supine position. Pulmonary function testing suggested severe restriction with FVC of 27% predicted, FEV 1 28% predicted, normal FEV1/FVC ratio, and respiratory muscle strength < 10% predicted.Computed tomography (CT) of the chest revealed basilar bronchiectasis and bilateral diaphragmatic elevation with associated atelectasis. Dynamic CT showed anterior displacement of the posterior tracheal wall at the distal trachea, bilateral main stem bronchi, and bronchus intermedius. Electromyogram demonstrated bilateral phrenic neuropathy and left brachial plexus neuropathy. Ultrasound confirmed the absence of diaphragm movement bilaterally. He had progressive clinical decline requiring near constant noninvasive positive pressure ventilation (NPPV). Dynamic bronchoscopy showed severe expiratory central airway collapse (ECAC) with >90% collapse of the trachea, main stem bronchi, and bronchus intermedius . A stentThe initial surgery was aborted due to the inability to maintain adequate oxygenation during single lung ventilation. One week later, the procedure was successfully completed through right thoracotomy under venous-venous extra-corporeal membrane oxygenation (VV ECMO) support. Central airway stabilization was achieved by suturing a knitted polypropylene mesh to the posterior membrane of the trachea and bilateral main bronchi. Due to persistent ventilator dependency, left diaphragm plication through a left thoracotomy was performed 5 days postoperatively. He was discharged home on postoperative day #23.At follow-up evaluation, he no longer required NPPV and regained independence in activities of daily living. Pulmonary function testing showed improvement with FVC of 53% predicted, FEV1 42% predicted, and respiratory muscle strength 13% predicted. CT of the chest demonstrated improved lung volumes . DynamicAlthough diagnostic parsimony encourages identifying a single unifying explanation for one's symptoms, this case illustrates the veracity of Hickam's dictum: \u201cA man may have as many diseases as he damn well pleases .\u201d We hypUnilateral or bilateral dysfunction of the diaphragm can result from phrenic nerve dysfunction, neuromuscular junction disease, or myopathy. Paradoxical respiratory efforts and decline in FVC while supine suggest DP with confirmation achieved with fluoroscopy, ultrasound, or phrenic nerve EMG. Symptomatic unilateral disease that cannot be explained by another underlying disease process may be amenable to plication. Bilateral DP can be managed by noninvasive positive-pressure ventilation and treatment, if available, of the underlying cause. Diaphragmatic pacing may be beneficial if phrenic nerve function is intact. The goal of plication is at eliminating the paradoxical upward motion of the paralyzed diaphragm and decreasing the basilar parenchymal compression. Although historically performed via a thoracotomy, plication can also be performed effectively with minimally invasive robotic, thoracoscopic, or laparoscopic techniques . SurgicaRecognition of large airway dysfunction during expiration as a cause of chronic respiratory symptoms is gradually increasing. Two patterns have been described in ECAC: (1) tracheobronchomalacia (TBM) in which the cartilaginous component of the anterolateral tracheal wall collapses on forced expiration and (2) excessive dynamic airway collapse (EDAC) in which there is anterior displacement of the posterior (membranous) tracheal wall during expiration . When clWhen the degree of airway collapse is severe, surgical repair should be considered. A preoperative stent trial with uncovered self-expandable metallic stents is strongly advised to estimate the potential surgical benefit prior to surgical intervention . In our Our technique for tracheobronchoplasty involves plication of the redundant posterior membrane of the trachea and mainstem bronchi and fixation to a semirigid permanent (polypropylene) permeable mesh. The standard approach is through a right thoracotomy, although minimally invasive robotic and thoracoscopic approaches have also been reported to be feasible but with unknown long-term results .We hypothesize that basilar bronchiectasis in this patient was due to inadequate airway clearance from both ECAC and DP resulting in recurrent lower respiratory infections. Medical management of bronchiectasis to improve airway mucous clearance was limited due to compromised large airways from ECAC and weak cough from DP.VV ECMO is used most commonly in acute respiratory distress syndrome and in patients with advanced lung disease requiring transplant either intraoperatively or as a bridge to lung transplantation. As the use of ECMO increases, understanding the surgical implications of this therapy is critical. In a review of 563 patients on ECMO, 269 required noncardiac surgery. There was no difference in outcomes between those needing or not needing surgery . AnticipBoth ECAC and bilateral diaphragmatic dysfunction, with associated bronchiectasis, synergistically lead to dyspnea, cough, respiratory infections, and severe functional impairment in this patient. Demonstration of the improvement in clinical outcomes with an airway stent trial before entertaining surgical correction of ECAC is critical to optimize patient selection. As demonstrated, surgical intervention for both ECAC and diaphragm paralysis can dramatically improve the quality of life and functional capability. Intraoperative ECMO may permit definitive surgical treatment of ECAC in patients with gas exchange abnormalities that would otherwise preclude surgery.This case elucidates three critical concepts to comprehensive patient-centered care. The importance of thoroughly investigating all the relevant contributors to a patient's symptoms, with specific attention to those for which therapy can be offered, is illustrated. Additionally, the novel use of ECMO demonstrates the need to embrace unconventional surgical approaches as mandated by the patient's clinical scenario. Finally, it was only the multidisciplinary team-based approach to care, involving pulmonologists, interventionalists, thoracic surgeons, anesthesiologists, and intensivists that allowed successful management of this patient's complex presentation."}
+{"text": "Racial minorities and educationally disadvantaged experienced more housing loss, unemployment, and financial strain during the 2007-2009 Great Recession. These hardships may heighten stress and amplify persistent and growing health inequities, which were further worsened by the recent COVID-19 pandemic. It is therefore essential to identify factors that contribute to individual differences in vulnerability so that more effective interventions can be implemented, especially in older adult populations who may face unique economic hardships tied to age discrimination. According to the reserve capacity model, higher levels of psychosocial resources, including psychological well-being, can protect against the negative health outcomes related to heightened stress exposure. This study tested the intersections between recession hardship, pre-existing vulnerability defined as racial and educational disadvantage, and psychological well-being as predictors of biological indicators of chronic allostatic load. Chronic allostatic load was assessed with cardiovascular reactivity and recovery to acute mental stress and systemic inflammation . Biological data came from a national sample of adults known as the Midlife in the US Study  that completed assessments after the recession. Multiple regression models revealed that more widespread recession hardship predicted greater biological dysregulation. Tests of three-way interactions revealed that the association between recession hardship and biological dysregulation was strongest among respondents with combined disadvantages of low educational status and low levels of psychological well-being. This study connected a major economic event to individual variation in health vulnerability and identified potential biological pathways to future disease outcomes."}
+{"text": "Compared to non-dementia caregivers, family/friend caregivers of individuals with dementia experience more negative caregiving consequences. One reason is the myriad of negatively impacted life domains including: managing symptoms; family communication; financial and legal matters; and finding and coordinating services. Few psychometrically tested measures exist for assessing the range of potential unmet needs of dementia caregivers. Such a measure would describe the frequency and correlates of unmet needs and provide a key outcome for intervention research. This study tested the psychometric properties of a comprehensive measure of unmet needs, the BRI Unmet Need Instrument. Data from 192 family/friend dementia caregivers was used to test reliability and four validity types. Results showed total unmet needs, as well as its nine subscales, had good reliability . Discriminant validity was confirmed through factor analyses of the 45 unmet needs and items in measures of depression and care-related strain. Unmet need items loaded on separate factors that were deemed acceptable (.72-.38). Predictive validity was assessed by the association with depression, which was significant and an acceptable range . Convergent validity was confirmed by significant associations with three caregiver strain measures, mastery , emotional strain , and relationship strain . Good structural validity for nine predetermined unmet needs subscales was found using principal component analysis (loadings = .82-.39). Results suggest the BRI Unmet Needs Instrument is a ready-to-use, reliable and valid comprehensive measure."}
+{"text": "The extant literature highlights the physiological and psychological benefits of active lifestyles among older adults, though there is a considerable gap in scholarship for sexual minority groups. Utilizing the Social Integration Model, we hypothesize that social activities enhance individual psychological well-being, but those effects differ by one\u2019s social identities. Using a national AARP foundation survey of adults (45+), this study examines whether individuals\u2019 activities predict loneliness and depressive symptoms of heterosexual (n=2905) and LGBTQ adults (n=318). We utilize an index of diverse activities, which includes, social technology use, meeting with friends, and volunteer activities. Multiple linear regression is used to study cross-sectional associations of loneliness and depressive symptoms on the diverse activity index. Results show that a wider array of activities correspond with higher psychological well-being and lower loneliness, and this association is higher for LGBTQ older adults. We discuss implications for counseling and wellness programming for LGBT older adults."}
+{"text": "Although insurance companies are increasingly paying for home-based palliative care (HBPC), enrollment remains low. To identify patient and caregiver perceived barriers to HBPC and their recommendations for overcoming these barriers, we conducted semi-structured individual interviews. Our interview protocol elicited participants\u2019 perspectives on HBPC services; positive and negative aspects of the palliative program explanation; and suggestions for improving HBPC messaging. Seventeen patients and eight caregivers who were eligible for a randomized controlled trial of HBPC were interviewed. Themes related to HBPC referral barriers included reluctance to have home visits, enrollment timing, lack of palliative care knowledge, and patients\u2019 self-perceived health condition. Themes related to recommendations for overcoming these obstacles included ensuring that HBPC referrals come from healthcare providers or insurance companies and presenting HBPC more clearly. Findings reinforce the need for palliative care education among seriously ill patients and the importance of delivering palliative care information and referrals from trusted sources."}
+{"text": "Maternofetal stress induces fetal programming that restricts skeletal muscle growth capacity and metabolic function, resulting in intrauterine growth restriction (IUGR) of the fetus. This thrifty phenotype aids fetal survival but also yields reduced muscle mass and metabolic dysfunction after birth. Consequently, IUGR-born individuals are at greater lifelong risk for metabolic disorders that reduce quality of life. In livestock, IUGR-born animals exhibit poor growth efficiency and body composition, making these animals more costly and less valuable. Specifically, IUGR-associated programming causes a greater propensity for fat deposition and a reduced capacity for muscle accretion. This, combined with metabolic inefficiency, means that these animals produce less lean meat from greater feed input, require more time on feed to reach market weight, and produce carcasses that are of less quality. Despite the health and economic implications of IUGR pathologies in humans and food animals, knowledge regarding their specific underlying mechanisms is lacking. However, recent data indicate that adaptive programing of adrenergic sensitivity in multiple tissues is a contributing factor in a number of IUGR pathologies including reduced muscle mass, peripheral insulin resistance, and impaired glucose metabolism. This review highlights the findings that support the role for adrenergic programming and how it relates to the lifelong consequences of IUGR, as well as how dysfunctional adrenergic signaling pathways might be effective targets for improving outcomes in IUGR-born offspring. Intrauterine growth restriction (IUGR) is the result of fetal developmental programming aimed at increasing the chances of surviving poor intrauterine conditions by promoting thrifty growth and metabolism. Unfortunately, these same developmental changes also diminish metabolic health and quality of life after birth . The linLow birthweight in livestock due to IUGR is a barrier to the economic sustainability of meat production, as these animals exhibit greater early-life mortality and lifelong performance deficits . Severe The establishment and characterization of several animal models for IUGR provides the opportunity to study the fetal programming mechanisms underlying IUGR pathologies in livestock and humans . CurrentThere is a broad range of causes for IUGR in livestock and humans that result in varying degrees of fetal growth restriction, which have been reviewed in greater detail elsewhere . In liveIUGR is necessitated by the increase in nutrient requirements to support normal fetal growth and the inability of the compromised placenta to meet them. Peak placental development occurs from the mid-1st trimester to the late 2nd trimester, which is from approximately day 30 to 100 of gestation in sheep and day 50 to 90 in humans . Most ma2 by the placenta creates chronic fetal hypoxemia and hypoglycemia  muscles from near-term IUGR fetal sheep exhibited 20\u201350% reductions in the proportion of oxidative fibers  relative to glycolytic fibers   . Changestrations . This imtrations .Glucose homeostasis in the IUGR fetus and offspring is further impeded by reductions in pancreatic islet mass and function . \u03b2 cellsgreater-than-normal fat deposition as juveniles , which are expressed in tissue-specific combinations throughout the body  modestly reduces glucose uptake but increases glycogen breakdown, glucose oxidation, and protein synthesis  described in earlier sections. Additional work is warranted to more thoroughly characterize the observed adrenergic programming, but existing evidence indicates that it almost certainly contributes to the persistent deficits in muscle mass and glucose oxidation exhibited by IUGR-born offspring . By 60 days of age, these lambs exhibited substantial improvements in growth, muscle mass, and body symmetry (In vivo and ex vivo metabolic studies showed that daily clenbuterol injections at least partially recovered glucose-stimulated insulin secretion and skeletal muscle glucose oxidation, which was reflected by improvements in early-life whole-body O2 consumption rates (The identification and characterization of adrenergic programming mechanisms in IUGR tissues provides a target for potential treatment and intervention strategies. Indeed, animal studies have begun to provide the fundamental basis for adrenergic manipulation as a strategy to improve growth and metabolic outcomes in IUGR fetuses and offspring. In IUGR fetal sheep, pharmaceutical blockade of elevated adrenergic activity ecretion . Althougecretion . Moreovexidation . Althougon rates . Howeversymmetry . Greateron rates , 2021.2 supplementation was used to improve fetal oxemic status in sheep, metabolic improvements exceeded the impact on apparent adrenergic tone. Specifically, acute fetal normoxia improved insulin secretion in the IUGR fetus prior to reductions in circulating norepinephrine (2 content (The complexity of IUGR programming means that targeting adrenergic dysfunction alone is unlikely to fully recover growth and metabolic deficits in their entirety. For example, adrenal demedullation of IUGR fetal sheep did not improve deficits in pancreatic islet development and only partially corrected insulin secretion . Moreovenephrine , and dai content . Recent  content , glucoco content , and poo content  in the d"}
+{"text": "Polymeric hydrogels are fascinating platforms as 3D scaffolds for tissue repair and delivery systems of therapeutic molecules and cells. Among others, methacrylated gelatin (GelMA) has become a representative hydrogel formulation, finding various biomedical applications. Recent efforts on GelMA-based hydrogels have been devoted to combining them with bioactive and functional nanomaterials, aiming to provide enhanced physicochemical and biological properties to GelMA. The benefits of this approach are multiple: i) reinforcing mechanical properties, ii) modulating viscoelastic property to allow 3D printability of bio-inks, iii) rendering electrical/magnetic property to produce electro-/magneto-active hydrogels for the repair of specific tissues , iv) providing stimuli-responsiveness to actively deliver therapeutic molecules, and v) endowing therapeutic capacity in tissue repair process . The nanomaterial-combined GelMA systems have shown significantly enhanced and extraordinary behaviors in various tissues  that are rarely observable with GelMA. Here we systematically review these recent efforts in nanomaterials-combined GelMA hydrogels that are considered as next-generation multifunctional platforms for tissue therapeutics. The approaches used in GelMA can also apply to other existing polymeric hydrogel systems.  \u2022Physicochemical properties of GelMA hydrogel.\u2022Role of nanomaterials for engineering bio-functional GelMA hydrogel.\u2022Diverse biomedical applications of nanostructured GelMA hydrogel.\u2022Promising directions for nano-inspired GelMA bioink formulation.\u2022Applications and challenges of advanced GelMA-nanomaterial platforms. Compared to other biomaterial platforms used for regenerative purposes, hydrogels have an increasing demand owing to their close resemblance to the cellular microenvironment . These mBulcke et al. synthesized one such representative hydrogel formulation in the year 2000 popularly known as Gelatin methacryloyl or GelMA . GelMA oIn this review we emphasize multifunctional GelMA platforms with nanomaterials from different aspects, including its fabrication, crosslinking, polymeric\u2013nanophase interactions, and its application as tissue therapeutics with future perspectives. The key objective is to provide critical analysis of multifunctional GelMA-nanomaterial platforms as versatile substrates and insights about their current challenges and future directions from a biomaterial point of view to their regenerative applications. Even though, many conceivable applications of these multi-functional materials are known, we focus more on its biomedical applications highlighting its current trends in regenerating tissues.  shows th2Hydrogel formation occurs by the cross-linking of polymer chains dispersed in an aqueous medium through numerous mechanisms, including physical gelation, ionic interactions, and chemical crosslinking . Most of2) and hydroxyl (-OH) groups are mainly involved in this substitution reaction where methacryloyl groups are introduced onto gelatin. The polymerization of GelMA occurs in an aqueous state by a free radical mechanism in presence of a photoinitiator. The UV irradiation of the photoinitiator causes the generation of free radicals by homolytic cleavage which initiates chain-growth polymerization. In the second step chain propagation occurs between methacryloyl groups present on the polymeric chain and finally terminates between a propagating chain and another free radical . M. M83]. Mractions . Polar ac groups ,22,24. Bc groups . Other ic groups . The BGnc groups . This hy3.3The hydrogels integrated with metallic nanomaterials have become an evolving area in developing customized multi-responsive constructs for tissue repair. Nano-biomaterials based on metals and their oxides have been shown to possess desired physical properties such as conductivity of electricity (gold-based) , magnetiNavaei and colleagues reported a photopolymerizable hybrid platform based on GNR encapsulated within GelMA hydrogels . This na3.4Among the multitude of GelMA platforms developed for tissue engineering, polymeric nanomaterial incorporated ones have attained a remarkable interest. These structures are similar to the macromolecule-centered components in the human body and are often considered to be good candidates for drug delivery purposes since they offer spatial and sequential control over drug/gene/growth factor release owing to the tailored physical properties, manageable degradation as well as their capability to resist the degradation of labile biomolecules .Such delivery systems can impact therapeutically advantageous properties of drug delivery and are set to possess clinical importance . CompareSeveral polymeric nanomaterials such as hyperbranched polymers, dendrimers, nanopolysaccharides, proteins like ferritin, etc. have various hydrophobic or hydrophilic units available for conjugation with the functional groups of hydrogels . These pI) acted as the delivery system for VEGF which efficiently transfect myocardial tissues which could facilitate local myocardial neovascularization at the injected sites, reduces fibrosis, and potentially improve cardiac function in an in-vivo AMI model as indicated in (N-isopropylacrylamide-co-acrylamide) nanogels loaded with DOX by entangling it within the GelMA prepolymer before photocrosslinking [A biocompatible injectable hydrogel gene delivery system developed by Paul and colleagues also showed its efficacy in specific delivery of vascular endothelial growth factor (VEGF), a signaling protein that supports angiogenesis that is necessary for the regeneration of damaged cardiac tissues for acute myocardial therapy (AMI) . GelMA icated in . This naslinking . This naslinking ,261,262.4Tissue repair and reconstruction using nano-engineered hydrogels have been developed as a promising medical strategy to the existing replacement therapies for the healing of damaged tissues . Tissue 4.1Many new developments have been made in engineering bone tissues by using hydrogel as a multifunctional platform during the last decade. Even though hydrogel-based materials display excellent bio functionality it possesses demerits such as poor mechanical stability and low processability making it unsuitable for bone tissue regeneration ,290,291.. However, single-layered GelMA hydrogels often fail to regenerate multiple tissue defects such as osteochondral defects possibly due to the mismatched stiffness of the hydrogels relative to cartilage and subchondral bones. On the other hand, bilayered GelMA hydrogels based on mussel-inspired chemistry without nanomaterial engineering have been shown to restore such defects [Owing to many fascinating potential uses of multicomponent GelMA-based materials, their design and synthesis have been a focus of substantial research over the last few years defects ,297.ve and gram \u2212ve bacterial contamination both in-vitro and in-vivo rat cranial bone defects. The overall results show the effective role of nAg/HNTs/GelMA hybrid hydrogels in dealing with infected bone defects. In another study, Xin and co-workers embedded MBGN into GelMA hydrogel by an amide reaction to construct a hybrid membrane that can act as a substitute for periosteum [GelMA-nanomaterial interfaces provide an appropriate matrix environment and facilitate controlled growth factor delivery at different points of bone regeneration. In an early attempt studies using GNP encapsulated GelMA hydrogels (GNP/GelMA) revealed that the presence of GNP might promote cell spreading, osteogenic differentiation, and basic phosphatase activities of ADSCs . In respriosteum . This Geriosteum . The higNaturally occurring hydroxyapatite (HA) incorporated microfabricated GelMA platforms were exploited for modular tissue engineering to mimic native osteons, which are basic structural units of mature bones . These bPrevious studies thus highlight the vital role of inorganic components in regenerating bones by regulating mechanical properties and cellular differentiation. Except for inorganic components, some biodegradable organic components have also been introduced to impart specific functions into the GelMA hydrogel. For instance polylactic acid, a biodegradable polyester was introduced into 3D printed GelMA constructs consists of bioactive GNPs through filament freeform fabrication technique for regenerating diseased bones . It was Many nanocomposites were examined actively for their potential use in soft tissue engineering but these hydrogels cannot often mineralize thereby limiting their usage in engineering bone tissues . Recent 4.2The hydrogel wound dressing is considered as best wound treatment technique because of its excellent biocompatibility, moisture resistance, and ability to activate immune cells to promote wound healing . PolymerMany GelMA-based materials were reported to show tissue adhesiveness. However, due to the poor mechanical properties of GelMA, various functional nanomaterials were mainly added to improve the mechanical properties. Assmann and colleagues developed a highly elastic adhesive hydrogel that could act as tissue sealants . The dev+ released from the hydrogel also concurrently exhibits antibacterial activity. It was shown that the NIH 3T3 fibroblasts cultured on these substrates grow and multiply extensively on soft 15% GelMA hydrogels compared to other sets. AgNPs incorporated within the GelMA matrix even at a higher concentration of 150\u00a0\u03bcg/ml showed no significant toxicity, which agrees to the optimum Ag+ ion concentration required to destroy both gram +ve and gram -ve bacterial strains  also possess enhanced electrical conductivity and superior mechanical properties ,264,360.4.4Nerve tissue regeneration is an advanced and fast-developing area that assures replacement or repairment of injured, diseased nerve tissues or treating major neurological disorders that are difficult to rectify employing a normal clinical approach . Among tDifferent approaches to fabricate NGCs have been introduced in recent years to overcome the typical limitations related to nerve grafting . Differe5The 3D bioprinting arose as an innovative approach that utilizes a computer-aided process to fabricate cell-laden constructs of defined geometries that support soft or hard tissue regeneration or alternate for organ replacements . Self-he. The presence of two independent entwined polymer chains in this bio-ink conjugated themselves via a distinct cross-linking mechanism allows precise control over its characteristics. The presence of nSi enhances the mechanical stiffness and tissue adhesiveness by exerting reversible electrostatic interactions within the hydrogel chains. Being a printable hydrogel formulation this could be utilized for the fabrication of various mechanically robust cellularized structures [Nanoengineered ionic covalent entanglement bio-ink (NICE), a novel smart bio-ink developed by Chimene and colleagues for 3D bone bioprinting is one of a kind . This biructures . Furtherructures . These iructures . The ostructures . This syImproved cytocompatibility and bioactivity are the most essential requirements in nanomaterials intended to be used in developing new bio-ink. Many inorganic ions are capable of inducing cellular differentiation. So there exists massive promise for these ions for effective use in bone regeneration. The role of strontium (Sr) in the remodeling and engineering of bone tissues has been reported in recent years . A low cThe regeneration of cardiac tissues using nanoengineered hydrogels also profusely progressed due to the new insights of converging microscale technologies with stem cell biology. Even though a lot of noteworthy studies have been done focused on developing bio-engineered cardiac constructs or patches for functional tissue replacement, a clinically applicable engineered cardiac structure representing the morphological, physiological, and functional properties of natural myocardium remains the challenge . Surfact3D bioprinting of soft tissue constructs was always a challenge for biomedical researchers since it lacks the desired mechanical properties . Advance6The nano-structured hydrogels of succeeding generations have got potential to transform or replace the existing systems for various tissue engineering applications. The superior characteristics owned by multi-functional hybrid systems, which lack in their hydrogel counterparts enable them for various applications. Being a dominant hydrogel formulation of recent times, the future direction on GelMA-nanomaterial platforms certainly includes balanced optimization in all aspects says physical, chemical as well as biological. Next-generation nano-engineered GelMA is being progressively evaluated for its various clinical applications. Even though the non-functionalized nanomaterial and GelMA interactions could result in useful material characteristics, the resultant hybrid composites lack control over many key properties including stimuli responsiveness and physiological degradation. To overcome these drawbacks different strategies have been introduced in which modifying GelMA hydrogel network by incorporating multifaceted nanomaterials of various types is the most common approach. Our research group also recently focused on developing similar systems by functionalizing antioxidant nanomaterials such as cerium oxide (CeO2) using macromolecules such as dendrimers which would interact with the hydrogel physically or chemically and resulted in multi-responsive scaffolds of better stiffness and microarchitecture. Nowadays more efforts are also made in designing hydrogels with long-term biocompatibility that will aid desired biological behavior. The reviewed literature proposes that the development of novel synthetic routes, functionalizing strategies, and fabrication technologies for GelMA-nanomaterial hybrid systems will continue in the coming years and more priority will be given to research for its personalized applications. Microfabrication approaches for knowing the cell-nanophase communication is one such attempt. Microscale technologies are emerging as a prevailing technology to solve the many existing challenges in tissue engineering. Studies conducted using CNT reinforced hybrid microgels and hyperbranched polyesters have shown the effective utilization of microscale technologies for cell entrapping on pre-defined patterns resulting in different functional tissues of interest. Engineered GelMA hydrogel holds a groundbreaking role in hastening the progress in clinical therapeutics by converging biological and bio-fabrication approaches. Apart from the advances, there are many challenges linked to the clinical translation of photocrosslinkable hydrogels like GelMA. The most important factor is the conversion of various synthetic strategies towards successful regeneration methods and procedures by accepting good manufacturing practices (GMP) while conserving the envisioned capacity for tissue regeneration. Furthermore, evaluations on nano-functionalized constructs are mandatory before the clinical applications to limit the concerns related to biosafety. Certain nanocomposite hydrogels could be applicable only in culturing specific cell types  compared to non-functionalized GelMA hydrogel platforms, due to the intrinsic material characteristics. Consequently integrating universal functionalities is also important to attain tissue engineering applications in a broader range. GelMA-based hydrogel constructs have not been completely applied for clinical applications due to limitations concerning their biosafety associated with using UV radiations used for crosslinking which can damage cellular DNA by oxidation and also could result in sudden inheritable changes. Assessing the biosafety for both cell-free and cell encapsulated GelMA-nanomaterial platforms is thus of utmost importance to ensure safe and effective usage for its future biomedical applications.The authors declare no competing financial interest."}
+{"text": "Malignant paediatric nervous system tumours, such as Medulloblastoma, Neuroblastoma and ATRT commonly harbour tumour cells with stem-like features which are highly tumorigenic and resistant to conventional cancer therapies. These tumours can exhibit high lethality and may result in severe sequelae, including cognitive and motor deficits that significantly affect patients\u2019 quality of life. Oncolytic virotherapy is a novel therapy class that exploits viruses that preferentially infect and destroy tumour cells. These viruses present a unique advantage in targeting highly heterogeneous cancers, such as nervous system tumours, as they possess a secondary mechanism of action through which they induce a tumour-specific immune response. Clinical studies employing oncolytic virotherapy have in general reported low toxicity and minimal adverse effects, deeming oncolytic virotherapy as a potentially attractive and safer intervention against paediatric tumours.The Zika virus (ZIKV) is capable of infecting and destroying neural stem-like cancer cells from human embryonal Central Nervous System (CNS) tumours in vitro and in vivo. Infection of CNS tumour cells with ZIKV effectively inhibits tumour metastasis in mice and, in some cases, induces complete tumour remission. Neuroblastoma arises from immature nerve cells and multiple Neuroblastoma cell lines are susceptible to ZIKV infection and oncolysis. These initial findings have demonstrated the potential for a ZIKV-based virotherapy against paediatric nervous system tumours and warrants examination into the molecular mechanisms through which ZIKV executes its oncolytic ability. My research goal is to elucidate the mechanisms which are of paramount importance for ZIKV-induced oncolysis of brain tumour and Neuroblastoma cells. Utilising global expression omics profiling of ZIKV infection and mapping of viral protein-host protein interactions will identify these mechanisms both at the cellular pathway and molecular levels. These collectively will inform our understanding of how we can employ a future ZIKV-based virotherapy against paediatric nervous system tumours."}
+{"text": "Outpatient peer support groups have been demonstrated to help patients reintegrate with the community and improve self-acceptance following burn injury. Despite this, there is little data examining who desires participation. This is especially true for minority and socio-disadvantaged populations. The purpose of this study is to examine factors that influence desire to participate in burn survivor groups and actual participation rates.Patients attending outpatient clinic were asked about participation in burn survivor group, interest in joining a group, and administered National Institute of Health Patient-Reported Outcomes Measurement Information System (PROMIS) Managing Emotions (ME) and Managing Social Interactions (MSI) questionnaires. Patient demographics, total body surface area burned (TBSA), initial hospital length of stay (LOS), and surgical intervention were collected from the medical record. While controlling for age and gender, indicators of injury severity and scores on PROMIS questionnaires were each examined for associations with survivor group interest using Firth or standard binary logistic regression.70 patients completed surveys in English  and Spanish . Current or past participation in burn survivor group was low , with greater interest in joining burn survivor group . Most patients interested in burn survivor group were Spanish speaking . Interest in joining a burn survivor group was associated with all collected measures of injury severity (Table 1). Scores on ME and MSI were not significantly associated with burn survivor group interest .There is a gap between interest and participation in burn survivor group, particularly among Spanish speaking patients. Patients with increase in TBSA, LOS, and undergoing surgery were more likely to express interest in burn survivor group participation. Interestingly, patients\u2019 self-reported outcomes on emotional distress and interactions with others were not related to interest in burn survivor group."}
+{"text": "For couples affected by HIV, and serodifferent couples in particular, pregnancy desire is often juxtaposed against the risk of HIV transmission between the couple and the potential neonate leading to thinking about measures to minimize risk of HIV transmission. We assess the use of fertility awareness methods [FAM] and evaluate the drivers of alignment between indicators of fertility and sexual behavior among HIV-serodifferent couples desiring pregnancy.HIV-serodifferent couples from Thika, Kenya were enrolled into an open-label pilot evaluation of safer conception strategies. Women responded to daily 7-item short message service [SMS] surveys on FAM and sexual activity. Menstrual cycles were categorized as having condomless sex aligned, not aligned, or partially aligned to the predicted peak fertility. We used binomial logit models with generalized estimating equations to assess alignment between condomless sex during peak fertility days and FAM results. We used Cox proportional hazards to compare pregnancy incidence among months with sex and peak fertility aligned and mis-aligned.A total of 6929 SMS surveys across 252 menstrual cycles of 65 women were included. Reporting \u201csticky\u201d cervical mucus  and positive ovulation prediction kit [OPK] result  were associated with increased likelihood of alignment of condomless sex during peak fertility. Pregnancy incidence was statistically similar among periods with sex aligned and not aligned with peak fertility.Among women engaged in a comprehensive safer conception program, a moderate percentage of women aligned condomless sex and predicted peak fertility days at least once. While FAM, particularly cervical mucus and OPK, are an inexpensive option for couples to consider using as a component of their safer conception strategies, antiretroviral-based strategies remain important to minimize risk. HIV-serodifferent couples are partnerships where one partner is living with HIV and the other is not. For these couples, the desire to become pregnant can be in contrast to the risk of transmitting HIV either to the baby or between the couple. Safer conception strategies can be used to reduce the risk of HIV transmission during pregnancy attempts, and they include fertility awareness methods [FAM] which involve timing condomless sex to the time when a woman is most likely to become pregnant during her menstrual cycle, called the peak fertility window. FAM include tracking menstrual cycles, monitoring cervical mucus, measuring daily body temperature, and using an ovulation prediction kit [OPK].Seventy-four HIV-serodifferent couples were enrolled in a clinical study in Kenya. Each wanted to become pregnant and all were trained to track FAM. Women reported their sexual activity and FAM indicators via text message every day.Sexual activity was better aligned to the peak fertility window when women found their cervical mucus to be \u201csticky\u201d and if they had a positive OPK result. The use of these FAM indicators to align condomless sex with peak fertility did not affect pregnancy outcomes.While FAM indicators are an inexpensive option for HIV-serodifferent couples to consider using as a part of their safer conception strategies, other HIV prevention strategies remain important to minimize risk.For heterosexual couples who desire pregnancy, augmenting the probability of conception by estimating days with peak fertility and having sex on those days is an important method to achieve reproductive goals. Fertility awareness methods (FAM) are used to identify peak fertility days and optimally time condomless sex to these days to improve chances of conceiving . For peoFor couples affected by HIV, and serodifferent couples in particular, pregnancy desire is often juxtaposed against the risk of HIV transmission between the couple and the potential neonate leading to thinking about measures to minimize risk of HIV transmission. HIV-serodifferent couples can employ any number of \u201csafer conception\u201d strategies to reduce HIV risk during pregnancy attempts, including timing of condomless sex to peak fertility and use of condoms at all other times, antiretroviral therapy (ART), pre-exposure prophylaxis (PrEP), and/or reproductive assistance technologies when fertility may be compromised \u201310. TailSeveral studies have assessed the use of FAM indicators to improve the time-to-pregnancy , 13, andThe Safer Conception Intervention for Partners  was an open-label pilot evaluation of a comprehensive safer conception package that enrolled 74 heterosexual HIV-serodifferent couples between March 2016 to April 2018 in Thika, Kenya : 0\u20131), and were in their partnerships for 2\u00a0years (IQR: 1\u20133\u00a0years). Approximately half of the women were living with HIV (47.7% and 53.3% were HIV-negative and in a partnership with a person living with HIV) and, of these women, two-thirds were virally suppressed , similar pregnancy incidence rate pattern was observed across alignment categories Table . Across Among HIV-serodifferent couples engaged in a comprehensive safer conception program to minimize HIV transmission during pregnancy attempts, a moderate percentage (71%) of women aligned condomless sex to predicted peak fertility periods at least once. After training women and couples on the use of FAM indicators, there was high uptake of the use of FAM methods reported via SMS (65 of 74 couples). Across similar settings in Africa, couples and women desiring pregnancy are not often aware of safer conception methods or have low uptake of methods such as timed intercourse \u201323. TherSticky cervical mucus and positive OPK results allow women to self-estimate their peak fertility period and reporting these characteristics was associated with timing of condomless sex in our cohort. Other studies have found that cervical mucus status is the strongest indictor of upcoming fertility days and that self-tracking mucus characteristics reduces the time-to-pregnancy , 24. OurPrevious fecundity studies have demonstrated that tracking FAM improves fertility rates , 12, 13.Our analysis had several limitations including that this was a small sample of couples attempting pregnancy and may not be broadly generalizable. Further, there may be misclassification of the time-varying characteristics since study visits were not timed to menstrual cycles and most data points for time-varying confounding factors straddled two consecutive cycles. We conducted sensitivity analyses to assess whether there was a meaningful effect of misclassification when matching menstrual cycle data to in-clinic interviews, and we found a similar magnitude and same direction for all associations. Finally, the pregnancy incidence rates may indicate misreporting of sexual activity or misclassification of fertility periods since the aligned definition of sex only within the peak fertility period had a lower pregnancy incidence than partial or non-aligned.Safer conception interventions improve reproductive health outcomes of heterosexual HIV-serodifferent couples attempting pregnancy and uphold the reproductive rights of HIV-serodifferent couples to satisfy their desires to attempt pregnancy . The FAM"}
+{"text": "OBJECTIVES/GOALS: Parents\u2019 empathy toward their children affects their parenting, which can in turn impact child outcomes. Although parental empathy is theoretically distinct from trait empathy, current literature relies on largely self-report measures of parents\u2019 trait empathy. Thus, the current study evaluated new analog assessments of parental empathy. METHODS/STUDY POPULATION: One parental empathy analog measure  was created based on parents\u2019 responses to open ended prompts describing scenarios that elicit different emotions  in children. These responses were used to create short scripts. A second analog task  was created using 20 sec audio clips of children expressing the different emotions wherein participants respond with how they feel hearing the emotions and separately, how they believe the child feels. After an initial pilot, both versions of the EMPAT-E were administered to 120 families enrolled in a prospective longitudinal study. Parents completed self-report measures of trait empathy and parental empathy, as well as the EMPAT-ES and EMPAT-EA analog tasks. RESULTS/ANTICIPATED RESULTS: Internal consistency of both the EMPAT-ES and EMPAT-EA tasks are expected to be robust, demonstrating the reliability of these novel assessments of parental empathy. Results are also expected to demonstrate the construct and convergent validity of both analog tasks. These new measures of parental empathy are expected to be significantly associated with measures of trait empathy. Specifically, parents\u2019 responses indicating how they believe the child feels in the analog are expected to be strongly related to their reported emotion recognition abilities and responses indicating how analog items made parents feel are expected to be related to parents\u2019 empathic concern. Finally, parents\u2019 responses to the analog tasks are anticipated to be strongly associated with parents\u2019 self-reported parental empathy. DISCUSSION/SIGNIFICANCE OF IMPACT: Valid, novel assessments of parental empathy can impact the parenting literature as well as community intervention and prevention efforts with parents. Such analog tasks can bolster parenting research but they may also be translated to the community setting as a training tool wherein parents are taught new skills that promote more positive parenting."}
+{"text": "Caregiver self-care may be impacted by the household environment. We evaluated the impact of support quality  and total household occupancy on a validated measure of self-care neglect in caregivers of patients with heart failure. Multivariate regression modeling was used to examine predictors of self-care neglect and we introduced an interaction term between support quality and household occupancy. The main effects model included terms for years of caregiving experience, hours caregiving daily, support quality, and total household occupancy . The interaction term between support quality and household occupancy contributed significantly (p < .05) to the respecified model . We suggest that the potential benefit of total household occupancy on caregiver self-care depends on perceived support quality. Clinicians should assess quality of household resources with caregivers during interactions."}
+{"text": "We report on launching a dental initiative that addresses healthy aging and oral health, focusing on prevention and changing the false belief that aging inevitably involves deterioration in oral health. Our project integrates the age-friendly health system's principles into specialty dental care at Eastman Institute for Oral Health, URMC. We established an oral health-centered framework with project elements of the 4Ms - what matters, medication, mentation, and mobility. We developed pilot 4Ms templates integrated into dental charts to implement healthy-aging key oral health processes, including oral health assessment, treatment planning, and oral hygiene support. We engaged all members of the dental team through educational sessions for providing care for patients affected by Alzheimer\u2019s disease and related dementias. We leveraged on locally available interdisciplinary resources and the collaboration reflecting undergoing efforts at the University of Rochester Division of Geriatrics and the Finger Lakes Geriatric Education Center, a Geriatric Workforce Enhancement."}
+{"text": "TM. The library simulates even complex bio-models and supports deterministic Ordinary Differential Equations; Stochastic Differential Equations; constraint-based analyses; recent SBML and SED-ML versions; exchange of results, and visualization of in silico experiments; open modeling exchange formats (COMBINE archives); hierarchically structured models; and compatibility with standard testing systems, including the Systems Biology Test Suite and published models from the BioModels and BiGG databases.Studying biological systems generally relies on computational modeling and simulation, e.g., model-driven discovery and hypothesis testing. Progress in standardization efforts led to the development of interrelated file formats to exchange and reuse models in systems biology, such as SBML, the Simulation Experiment Description Markup Language (SED-ML) or the Open Modeling EXchange format. Conducting simulation experiments based on these formats requires efficient and reusable implementations to make them accessible to the broader scientific community and to ensure the reproducibility of the results. The Systems Biology Simulation Core Library (SBSCL) provides interpreters and solvers for these standards as a versatile open-source API in Javahttps://draeger-lab.github.io/SBSCL/ and via Maven Central.SBSCL is freely available at Bioinformatics online. TM programming library that numerically solves systems biology models in multiple mathematical frameworks. A popular file format for representing computational models in a standard way and facilitating the exchange of models between different tools is the Systems Biology Markup Language  is an open-source, cross-platform pure JavaDifferential equation solver: The most fundamental feature of SBSCL is simulating ODEs. Version 2.1 adds interpreters and solvers for SDEs to support the latest SBML standards. SBSCL efficiently implements three deterministic numerical solvers (Constrained optimization solver: SBML Level 3 (http://www.scpsolver.org), a linear programming API with support for various solver backends. This lightweight abstraction allows users to define model constraints and an objective function and solve the corresponding optimization problem.Result tables and plots: Since viewing is an essential aspect of understanding the results of a simulation experiment, SBSCL provides experiment output in graphical and tabular form, which it can export in conventional formats such as Comma-Separated Values (CSV).Archival format support: Working toward exchangeability and reproducibility, SBSCL v2.1 supports the Open Modeling EXchange format (OMEX) format as input. These archive files contain the information on running simulation experiments based on SBML and SED-ML (Hierarchical model simulations: The SBML extension package comp enables encoding complex and coupled biological systems that can be distributed or hierarchically structured. SBSCL v2.1 efficiently supports the simulation of this addition, including the automatic assembly of models from multiple and possibly remote input files.Tests against benchmark suites: A crucial part of implementing new features is providing robust testing of the added functionality and use-cases. SBSCL tests all newly added features against the SBML Test Suite in a continuous integration approach. SBSCL provides full testing support against the genome-scale models from the BiGG Models database and kinetic models from the BioModels database.in silico experiment definition SED-ML file or wrapped within OMEX archives. Benchmarks of SBSCL using the SBML Test Suite and a broad range of published models from relevant databases ensure its correctness and reliability (see The open-source library SBSCL simulates complex biological models in various frameworks specified in SBML format, optionally together with their lity see . With thbtab669_Supplementary_DataClick here for additional data file."}
+{"text": "Effective treatment of established tumors requires rational multicombination immunotherapy strategies designed to target all functions of the patient immune system and tumor immune microenvironment. While these combinations build on the foundation of successful immune checkpoint blockade antibodies, it is increasingly apparent that successful immunotherapy will also require a cancer vaccine backbone to engage the immune system, thereby ensuring that additional immuno-oncology agents will engage a tumor-specific immune response. This review summarizes ongoing clinical trials built upon the backbone of cancer vaccines and focusing on those clinical trials that utilize multicombination (3+) immuno-oncology agents. We examine combining cancer vaccines with multiple checkpoint blockade antibodies, novel multifunctional molecules, adoptive cell therapy and immune system agonists. These combinations and those yet to enter the clinic represent the future of cancer immunotherapy. With a cancer vaccine backbone, we are confident that current and coming generations of rationally designed multicombination immunotherapy can result in effective therapy of established tumors. Throughout the 20th century, chemotherapy rapidly evolved from using single agents as a monotherapy to highly integrated multicombination therapy, utilizing multiple chemotherapeutic agents combined with surgery, radiation, molecularly targeted therapies and immuno-oncology agents . Each agTo date, the most mature immuno-oncology agents are immune checkpoint blockade (ICB) antibodies, which enable an already present immune infiltrate to promote tumor killing. While seven ICB agents have been FDA approved in multiple cancer indications as monotherapy , they doengage the immune system through the induction of tumor-antigen specific immunity, expand the specific tumor immune response, enable the immune response to ensure prolonged and persistent antitumor activity, and ensure an evolving immune response, preventing tumor escape . Th. ThQuick"}
+{"text": "This positioning paper aims to discuss current challenges and opportunities for artificial intelligence (AI) in fungal lung disease, with a focus on chronic pulmonary aspergillosis and some supporting proof-of-concept results using lung imaging. Given the high uncertainty in fungal infection diagnosis and analyzing treatment response, AI could potentially have an impactful role; however, developing imaging-based machine learning raises several specific challenges. We discuss recommendations to engage the medical community in essential first steps towards fungal infection AI with gathering dedicated imaging registries, linking with non-imaging data and harmonizing image-finding annotations. Aspergillus species are ubiquitous, saprophytic fungi with airborne conidia that grow on organic matter. Aspergillus fumigatus is the principal causative agent of human aspergillosis, which can range from allergy to invasive aspergillosis (IA), a life-threatening infection in immunocompromised hosts, with a further cohort of susceptible individuals developing chronic pulmonary aspergillosis [Relatively few fungal species can infect humans; however, certain fungi can cause life-threatening systemic infections in susceptible patient populations. gillosis  (CPA). Cgillosis . The agegillosis , 4. CPA gillosis .Individuals with both invasive and chronic pulmonary aspergillosis unfortunately have significant morbidity and high mortality. In part, this relates to challenges in diagnosis, difficulty in distinguishing fungal infection from other infections/illnesses and detecting breakthrough infection or treatment failure . DiagnosWithin clinical medicine, over the last decade there has been significant increased interest in the application of machine learning and artificial intelligence (AI) for complex decision making including diagnosis  and guiding therapeutic decision making .Regarding in vivo medical imaging, AI is transforming radiological diagnosis with mature developments related to oncology in breast  and chesComputed tomography (CT) represents the imaging modality of choice for lung infection diagnosis. AI for lung CT imaging bears some specific risks and challenges due to the lack of image standardization and multiple sources of variability . However, radiological societies are working toward reporting standards for AI tools \u201317 that detection with predictive value for inference of CPA severity or mortality within a time frame rather than mimicking expert precise contouring.CT enables localization of CPA-related pathological signs  such as We have shown , 23 Fig that a wAlthough quantitative scoring algorithms have been developed, further work is needed in defining a standard protocol for reporting radiological findings on CPA lung lesions. This is important to refine future annotation task and to benchmark new imaging AI tool against human radiological scoring . Given tTo progress the field, there is a need to develop a dedicated imaging cohort with a critical size, large diversity , and linked with diagnostic data , and treatment information as possible in international registry datasets  . For iniFor an imaging cohort to be used in AI, it requires some annotation, and here, a concerted community effort will be required from a number of specialists  to agree on the ground-truth expert source  and the granularity of the image annotation . Building large imaging cohorts remains tedious but can have very clear impact for fungal lung disease which currently suffers from two challenges: (1) current diagnostic uncertainty and need for subjective amalgamation of multiple observations with high levels of uncertainty; (2) difficulty in determining treatment response because of challenges in monitoring effects using quantitative radiological markers.Further integration with other omics  and electronic health record data \u201329 is alIn summary, the application of machine learning and AI presents a unique opportunity within fungal lung infection with the potential to improve diagnosis through early detection, standardization of imaging markers and their quantitative longitudinal monitoring , to impr"}
+{"text": "This study describes the development of a prototype bi-spectral microbolometer sensor system designed explicitly for radiometric measurement and characterization of wildfire mid- and long-wave infrared radiances. The system is tested experimentally over moderate-scale experimental burns coincident with FLIR reference imagery. Statistical comparison of the fire radiative power  retrievals suggest that this novel system is highly reliable for use in collecting radiometric measurements of biomass burning. As such, this study provides clear experimental evidence that mid-wave infrared microbolometers are capable of collecting FRP measurements. Furthermore, given the low resource nature of this detector type, it presents a suitable option for monitoring wildfire behaviour from low resource platforms such as unmanned aerial vehicles (UAVs) or nanosats. This could include combining MWIR and LWIR bands in a single camera\u2014for example, by using butcher block filters near the focal plane array, or with a filter wheel. Moreover, the development of a less resource-intensive thermal offset compensation method would likely be required. This could potentially be achieved by using a lightweight mechanical shutter, or by using temperature measurements at strategic points in the camera and correcting the images accordingly."}
+{"text": "Candida, Cryptococcal, Aspergillus and Trichophyton species is described herein, highlighting the need for defined species-specific antifungal breakpoints, and for Malassezia and Wickerhamomyces anomalus species which also have zoonotic potential. Novel compound phendione showed promising antimicrobial activity, with MICs determined for both fungal and bacterial species. The biocidal options investigated also showed potential to act as intermediate-level disinfectants, where peracetic acid proved most effective against fungal spore formers. Fungal skin infections and iatrogenic disease of companion animals continue to be an ongoing issue for veterinarians, where misdiagnosis or inapt medical treatment result in secondary conditions within animals. The widespread use of antifungals in both modern medicine and agriculture has resulted in concomitant resistance in species, where zoonotic transfer poses a risk to public health. Studies described herein assess the resistance of pathogenic species isolated from companion animals to a battery of conventional antimicrobial agents. Levels of resistance were detected using recognised in vitro methods, where additional novel therapeutic and biocide options were also extensively investigated. Results show high levels of resistance to the three main families of antifungal agents, namely caspofungin, Amp B and fluconazole. Resistance in  Microsporum, Trichophyton, and Epidermophyton species. Superficial zoophilic skin infections (dermatomycosis) are also caused by non-dermatophyte fungal species such as Malassezia, Aspergillus and Candida . Dermal tissue may become infected following colonisation of the cutaneous tissue and dermal follicles with opportunistic and pathogenic fungi. Animal mycoses is a common reoccurring issue globally, with zoonosis a risk in companion animals, where humans are continually exposed to infectious propagules . Dermal Invasive and systemic fungal disease can result from movement of the fungal species transdermally via open wounds . SystemiWickerhamomyces anomalus  is a zoonotic and nosocomial yeast, associated with the production of lethal mycotoxins having a mortality rate of 38% in adults and 42% in paediatric patients globally . Student\u2019s T tests were conducted to determine significance levels (p < 0.05) of bacterial susceptibility to treatment using Minitab 16 . All the experiments were performed three times with three plate replicates for each experimental data point, providing a mean result for each test species and antifungal susceptibility (\u00b1standard deviation). The logC. albican to non-albican species, as well as rarer  non-Candida species. This study presents eight examples of specific clinical cases that required greater application of existing fungal diagnostics and improved overall fungal diagnostic capability, where CBPs were lacking for many fungal pathogens. The presence of resistant species in companion animals such as those described herein, represents an often-unrecognised route of disease transmission, where zoonosis poses a significant risk. The development of new treatment options is, therefore, essential for both animal and human medicine, where test agent phendione showed promising potential as both an antifungal and antibacterial agent. Additionally, test biocidal options triameen and peracetic acid both showed high levels of antifungal activity. In particular, the peracetic acid-based disinfectant shows promise for controlling the spread of microbial species in veterinary settings, also being active against spore formers. The phenomenon of immunosuppression  has been recognised as a major contributor of increasing fungal disease, where more and more patients with chronic immunosuppressing conditions require antifungal treatment as part of their treatment plan. This rising rate of infection has been accompanied by increasing levels of antifungal resistance, where fungal pathogens are following the same pattern of exposure-resistance as seen with bacteria in the imminent antibiotic crisis. In order to defeat AMR, accurate and timely diagnosis is of utmost importance, where selection of fungal therapy must now also consider the shift in predominance from"}
+{"text": "Widowhood is associated with decreased emotional well-being, particularly increased depression. Religiosity may help improve mental health among widowed individuals. However, longitudinal studies exploring the role of religiosity on emotional well-being among widowed older adults is lacking, as are studies which examine this relationship using different dimensions of religiosity. This study analyzed data from the 2006-2016 waves of the nationally representative Health and Retirement Study (HRS). Trajectories of depression among older adults >50 years  were examined to explore patterns of depression among those entering widowhood and the potential impact of religiosity on depressive symptoms during widowhood. Ordinary least squares (OLS) regression analysis was used to examine the association between widowhood and depression as well as the role of religiosity as a moderator of this association. Older adults experienced an increase in depressive symptomology after the onset of widowhood, and although the levels of depressive symptomology decrease post-widowhood, they do not return to their pre-widowhood levels. Additionally, high religious service attendance and higher intrinsic religiosity were both associated with lower depressive symptomology. High religious service attendance moderated the relationship between widowhood and depression. The relationship between high religious service attendance and depression was stronger among widowed older adults living alone. This study highlights the long-term effects of widowhood on depressive symptomology among older adults. The findings also suggest that higher religious service attendance can lessen the effects of widowhood on depressive symptoms, especially for those living alone. These findings may inform intervention development around increased screening and treatment for depression."}
+{"text": "Testosterone treatment increases muscle mass, strength, and leg power in menopausal women, hypogonadal men, older men with mobility limitation, COPD and ESRD. Testosterone's effects on muscle mass and strength are augmented by exercise training and growth hormone. Testosterone treatment improves some measures of physical performance, such as stair climbing power and aerobic capacity; the improvements in gait speed have been modest. Testosterone increases muscle mass by inducing the hypertrophy of type 1 and 2 muscle fibers, and by increasing satellite cell number. Testosterone promotes the differentiation of mesenchymal progenitor cells into myogenic lineage and inhibits their differentiation into adipogenic lineage by activating Wnt-target genes, including follistatin that plays an important role in mediating testosterone's effects on the muscle. Testosterone also increases polyamine synthesis in the muscle. Combined administration of testosterone plus multi-component exercise intervention that includes functional training may be needed to improve function and mobility in older adults."}
+{"text": "Crocidura sp.) and a single rodent (Lophuromys sikapusi). Although these cases were only once-off detections, it provided evidence of the first known lyssavirus species has an association with non-volant small mammals. To investigate further, retrospective surveillance was conducted in 575 small mammals collected from South Africa. Nucleic acid surveillance using a pan-lyssavirus quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay of 329 brain samples did not detect any lyssavirus ribonucleic acid (RNA). Serological surveillance using a micro-neutralisation test of 246 serum samples identified 36 serum samples that were positive for the presence of MOKV neutralising antibodies (VNAs). These serum samples were all collected from Gerbilliscus leucogaster (Bushveld gerbils) rodents from Meletse in Limpopo province (South Africa). Mokola virus infections in Limpopo province have never been reported before, and the high MOKV seropositivity of 87.80% in these gerbils may indicate a potential rodent reservoir.The reservoir host of Mokola virus (MOKV), a rabies-related lyssavirus species endemic to Africa, remains unknown. Only sporadic cases of MOKV have been reported since its first discovery in the late 1960s, which subsequently gave rise to various reservoir host hypotheses. One particular hypothesis focusing on non-volant small mammals  is buttressed by previous MOKV isolations from shrews ( Lyssavirus genus, all capable of causing a fatal encephalitic disease  and dogs (Canis familiaris), most commonly reported to be infected with MOKV. This has led to the hypothesis that the reservoir of MOKV might be a prey species that interacts with domesticated animals via a prey-to-predator pathway , four in Nigeria and one in Cameroon  in the Central African Republic , a rabies-related lyssavirus, represents one of 17 recognised species within the Non-volant small mammals were captured and sampled in accordance with the field procedure guidelines of Sikes and Gannon  during tn = 329)  using TRIzol\u2122 reagent , followed by nucleic acid surveillance using a pan-lyssavirus quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay as previously described   were subjected to serological surveillance using a micro-neutralisation test as previously described   were extracted from brain samples (Gerbilliscus leucogaster) tested from Meletse at the cut-off 1:25 serum dilution  between the individual gerbils is expected since previous molecular characterisation assays performed on the Gerbilliscus genus have recorded intra-species genetic variation that range from 1% to 20% (Aghov\u00e1 et al. Of the 36 gerbils showing MOKV seropositivity, only 28 were genetically identified with the CytB barcoding PCR assay . The samGerbilliscus genus are nocturnal and terrestrial, exhibit no sexual dimorphism (Skinner & Chimimba Gerbilliscus leucogaster, however, is less arid adapted and can be found along rivers and drainage lines in open grasslands and wooded savannas (Dempster G. leucogaster rodents are not well-understood, however, studies have reported a communal nature (De Graaff Steatomys and Rhabdomys genera occurring at Meletse.Members of the Dempster . The breMore nucleic acid and serological surveillance studies in non-volant small mammal populations are required to obtain a better understanding of MOKV distribution, prevalence and its potential reservoir species. Brain and serum samples in this study were collected from seemingly healthy small mammals in areas that do not coincide with areas where previous MOKV cases have been reported in South Africa. Surveillance should be expanded to areas where MOKV spillover infections in cats and dogs have previously been reported. Furthermore, because lyssavirus distribution and dynamics might be influenced by seasonality, surveillance efforts should also include samples that were collected in different seasons and over multiple years. This expansion, together with representative sample sizes of certain non-volant small mammal species, will collectively increase the possibility of identifying more of these animals that are infected or that have previously been exposed to MOKV."}
+{"text": "Mountain regions are important places for biodiversity, where organisms could persist throughout prolonged periods and accumulate genetic divergence as well as promote speciation. Roles of mountains for biodiversity have been exclusively discussed in regions that have specifically diverse species or covered with ice-sheets during the Pleistocene glacial periods, whereas the importance of mountainous regions in East Asia has been less disputed. High mountains in the Japanese Archipelago, located at the eastern edge of the Eurasia continent, have one of southernmost populations of alpine and arctic-alpine plants that are also distributed in the northern Pacific and/or the circumarctic regions. Phylogeographic studies on the Japanese alpine plants have excluded their possible ephemeral occurrence during the current warm period, and rather, suggest persistence of alpine plants throughout several cycles of climate changes in the Pleistocene on high mountains in central Honshu, the main island of the Japanese Archipelago. In this review, I look through decade long phylogeographic studies and show complicated patterns of range dynamics of Japanese alpine plants. In addition, I note recent findings of genetic relationships of Japanese populations of alpine and/or arctic-alpine plants with those in northern regions and their possible ecological divergence in the Japanese Archipelago. Taken together, I provide several issues for understanding historical processes that established distribution of alpine plants following climate changes as well as their diversification and propose importance of Japanese populations of alpine plants on biodiversity in alpine communities across broader range, especially in the northern Pacific region. Mountain regions harbour a high terrestrial biodiversity  Gift et Kron et P. F. Stevens ex Galasso, Banfi et F. Conti mostly dominate in the plant communities on the high mountain ridges, whereas snow-bed species occurring in the northern Pacific region including Phyllodoce aleutica (Spreng.) A. Heller, Primula cuneifolia Ledeb., and Sieversia pentapetala (L.) Greene form large communities at moist part of mountains covered with snow until late summer. Accordingly, alpine plants in the Japanese Archipelago have long been recognized to have originated by cold-adapted species in northern regions that spread southward during the Pleistocene cold periods and have survived climatic warming on high mountains , which has small seeds with moderate dispersal ability in capsule, using three inter genetic spacers of plastid DNA   D.Don  A.Heller  strongly supported the scenario of colonization history occurring at least twice during different glacial periods. Such scenario was\u00a0likely\u00a0shared among 11 species including five preliminary investigated species   Fig.\u00a0, whereasC. nipponica and K. procumbens  and only a few alpine plants are distributed  compared to central Honshu (ca. 3000\u00a0m), species exclusively occurring in higher part of mountains such as ens Fig.\u00a0b have li500\u00a0m comComparing geographic patterns of genetic variation enables us to infer a shared history of prolonged refugial isolation and/or postglacial range expansion. In particular, comparative phylogeography would be an efficient approach to identify locations of refugia during the last glacial period and infer postglacial dispersal processes in various temperate and alpine species in Europe and North America  Makino provides the first sufficient evidence for the lack of genetic structure in pDNA haplotypes , which encodes one of red and far-red light receptors, evolved with divergent selection, where amino acid replacements exclusively occurred on a domain for light perception (the PHY domain). In addition, a similar study on A. nana found that natural selection on amino acid changes resulted in clinal patterns of allele frequencies on PHYE between its northern and southern populations (Ikeda and Setoguchi PHYE (Ikeda and Setoguchi C. nipponica) and higher latitude (Cardamine bellidifolia) (Ikeda et al. A. thaliana, this finding implies that light and temperature sensitivity of phytochromes may be involved in ecological divergence between these sister species. In A. thaliana, phyE is involved in regulation of ecologically important traits such as flowering or seed germination at lower temperature (Halliday and Whitelam PHYE truly reflected divergence in ecologically important traits are required to address this issue. Since genome-wide investigations could examine natural selection through genomic scan (Luikart et al. Furthermore, genetic footprints of divergent selection between the northern and southern populations suggest ecological roles for maintaining genetic structure. Ikeda et al.  investigDecades long phylogeographic studies confirmed the importance of high mountains in central Honshu for alpine plants to persist throughout the climate changes in the late Pleistocene. On the contrary, these studies show that genetic uniqueness exclusively in central Honshu is not the single common pattern of genetic structure across Japanese alpine plants. Instead, there are four major patterns of genetic structure including the lack of genetic structure. Owing to the less glaciated history and subsequent possible prolonged persistence of alpine plants in the Japanese Archipelago, genetic structures of Japanese alpine plants were likely shaped by multiple historical events including migrations and/or range separation occurring during different periods. In addition, Japanese alpine plants contain species with various ecological characters as well as habitat preference, which may have influenced genetic structures as well. Thus, assessing demographic history as well as ecological characters is crucial to fully understand historical processes how alpine plants shaped the current distribution patterns in Japan.Notably, the recent phylogeographic studies demonstrated that some alpine plants in Japan could have migrated northward, especially into the northern Pacific region, providing novel insight that alpine plants in Japan are not necessarily relict of cold adapted species distributed around Bering Straits. Further comparative studies could open new avenue for understanding the Pleistocene dynamics of alpine communities across broader ranges encompassing the northern Pacific region. Given potential ecological divergence of alpine plants within Japan, high mountains in Japan may have definitely played important roles for diversification of alpine plants not only in the archipelago but in northern East Asia as well as the northern Pacific region."}
+{"text": "Recent efforts to identify novel bacterial structured noncoding RNA (ncRNA) motifs through searching long, GC-rich intergenic regions (IGRs) have revealed several new classes, including the recently validated HMP-PP riboswitch. The DIMPL (Discovery of Intergenic Motifs PipeLine) discovery pipeline described herein enables rapid extraction and selection of bacterial IGRs that are enriched for structured ncRNAs. Moreover, DIMPL automates the subsequent computational steps necessary for their functional identification.https://github.com/breakerlab/dimpl.The DIMPL pipeline is freely available as a Docker image with an accompanying set of Jupyter notebooks. Full instructions for download and use are available at Bioinformatics online. Discovery and validation of the over 45 known classes of metabolite- or elemental ion-binding riboswitches , 2017. HIn this article, we introduce DIMPL (Discovery of Intergenic Motifs PipeLine), a bioinformatics pipeline which automates the process of total genome analysis by extracting IGRs, filtering them by length and nucleic acid composition, and collecting the data necessary to identify candidate motifs and assign their possible functions. DIMPL also provides reproducible techniques for identifying genomic regions enriched for ncRNA through support vector machine (SVM) classifiers. Although our primary objective in creating DIMPL was to accelerate the discovery of novel riboswitch classes, it can also be used to identify a wide-range of other intergenic nucleic acid and protein motifs such as upstream open reading frames, short open reading frames, ribosomal protein leader sequences, selfish genetic elements and other structured RNA motifs of unknown function.The DIMPL computational pipeline consists of two primary stages: (1) genome analysis and (2) draft motif analysis. For the genome analysis stage of DIMPL, the user begins by entering the Uniprot ID for a microbial genome for which there are Rfam annotations. DIMPL proceeds to automatically request the latest genomic sequence and protein annotations  accessibIn the next step, the tool uses a SVM classifier  to identThe draft motif analysis portion of DIMPL is performed in parallel on all IGRs that have met the selection criteria. The process begins by using Infernal 1.1.3  to searcde novo for each genome analyzed using the IGR %GC content and nucleotide length as the features, the presence/absence of a structured RNA as the class labels and a set of hyperparameters that have been weighted to select a contiguous region of a genome\u2019s %GC versus length plot. The primary purpose of the SVM classifier is to perform an enrichment of IGRs that reduces the number subjected to the more computationally intensive steps in the pipeline. Applying the SVM-RBF algorithm allows DIMPL to accomplish this goal in a systematic and reproducible manner.The SVM enrichment of IGRs in DIMPL uses a radial basis-function (RBF) kernel and is implemented with scikit-learn (www.github.com/breakerlab/dimpl. The DIMPL pipeline is built primarily in Python and is distributed as a Docker image  with allDIMPL provides an integrated collection of tools to streamline the process of identifying novel structured ncRNA motifs, including new riboswitch candidates, on a genome-wide scale. It relies on established methods of enriching bacterial IGRs for ncRNA motif discovery (btab624_Supplementary_DataClick here for additional data file."}
+{"text": "Bone fracture healing and osteoblast differentiation are impaired with advanced age. Using a combination of parabiosis and proteomic models, we identified apolipoprotein E (ApoE) to be an aging factor in bone regeneration. Circulating levels of ApoE increased with age in patients and in mice. ApoE impaired bone fracture healing by decreasing bone deposition in the fracture callus which subsequently decreased the mechanical strength of healed tissue. Osteoblasts serve as the sole bone forming cells within the body. In tissue culture models, ApoE treatment decreased osteoblast differentiation and activity which led to decreased matrix formation and mineralization. This inhibition of osteoblast differentiation relied on down-regulation of the Wnt/\u03b2-catenin pathway. In mouse models, aged bone repair was rejuvenated when we lowered circulating ApoE levels using a hepatotropic AAV-siRNA model \u2013 serving as a proof of concept that ApoE can be targeted to improve bone repair in an older population. While promising, knockdown of circulating ApoE in such a fashion is likely not translatable to patient care. Thus, current work in our laboratory is focused on developing treatment strategies that temporally decrease circulating ApoE levels and consequently improve bone healing after acute injury and/or surgical orthopedic procedure in the geriatric population."}
+{"text": "N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) family. SNARE proteins embedded in opposing membranes spontaneously assemble to drive membrane fusion and cargo exchange in vitro. Evolution has generated a diverse complement of SNARE regulatory proteins (SRPs) that ensure membrane fusion occurs at the right time and place in vivo. While a core set of SNAREs and SRPs are common to all eukaryotic cells, a specialized set of SRPs within neurons confer additional regulation to synaptic vesicle (SV) fusion. Neuronal communication is characterized by precise spatial and temporal control of SNARE dynamics within presynaptic subdomains specialized for neurotransmitter release. Action potential-elicited Ca2+ influx at these release sites triggers zippering of SNAREs embedded in the SV and plasma membrane to drive bilayer fusion and release of neurotransmitters that activate downstream targets. Here we discuss current models for how SRPs regulate SNARE dynamics and presynaptic output, emphasizing invertebrate genetic findings that advanced our understanding of SRP regulation of SV cycling.Membrane fusion is a universal feature of eukaryotic protein trafficking and is mediated by the soluble  Regulated secretion is mediated by a large cohort of SNARE regulatory proteins (SRPs) that control the timing and localization of SNARE assembly , the soluble NSF attachment proteins (SNAPs) and Unc18 function in both constitutive and regulated secretion, others like Unc13, Complexin (Cpx), Synaptotagmin 1 (Syt1), Rab3-interacting molecule (RIM), and Tomosyn (Tom) provide unique temporal and spatial control of regulated secretion.Eukaryotes rely on membrane-bound organelles to organize and transport material between cellular compartments . Transpoassembly . AlthougSaccharomyces cerevisiae, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster   for SV fusion can be approximated by measuring AZ Pr, which varies across neuronal subclasses and within the AZ population of a single neuron  . Followi+ influx . Releasee neuron . Most SV sorting . Reforme release .2+-dependent fusion. After fusion, NSF and SNAPs disassemble the SNARE complex to recharge individual SNARE proteins for further cycles of release. Intrinsic SNARE properties protect SNAREs from spontaneous reassembly post-fusion with help from the SRPs Unc18 and Tomosyn. Finally, RIM and Rab3 cooperate with Unc13 to re-position endocytosed SVs for subsequent docking and priming. Each of these steps provide avenues for modulation of SV release that can impact synaptic strength and plasticity.In this review we examine current models for how SRPs guide SNAREs through their assembly/disassembly cycle, focusing on insights from invertebrate genetic studies of SV fusion. We also highlight biochemical approaches that guided reverse genetic experiments and provided context for interpreting genetic studies. The biochemistry and genetics of mammalian SV fusion have been described in prior reviews . Key invLipids form stable bilayer membranes that innately repel each other through electrostatic forces and hydration repulsion . Bindingtrans-SNARE complex, with transmembrane segments residing on separate compartments and full SNARE assembly being temporarily arrested  are immobile and lack detectable SV release  are embryonic lethal, but retain uncoordinated movements that indicate a low level of residual SV release  in the second SNARE motif of the protein  displays a similar phenotype, indicating multiple t-SNARE mutations can alter SNARE dynamics in a manner that enhances fusion at lower temperatures and blocks release at elevated temperature  have not been characterized electrophysiologically though they display locomotor defects that suggest RIC-4 is essential for normal synaptic function  and enhance SV fusion in C. elegans  is essential for SV fusion, yet strongly inhibits both evoked and spontaneous release when overexpressed  is highly stable and resistant to SDS denaturation, indicating a large input of cellular energy is required to break the complex apart  mediates neuronal SNARE complex disassembly (comatose)  . Many coex apart . Althougaralysis . Accumularalysis  and a praralysis  mirror taralysis , 2001. Tcomatose mutations cause adult paralysis and synaptic transmission defects, the role of NSF at larval NMJs has been difficult to ascertain. NSF1 null mutants are lethal, but die over a developmental window that spans from late embryogenesis to the pharate adult stage  mutants, suggesting SNAPs are not fully redundant  cargo release and for some SVs at a few central mammalian synapses  on the plasma membrane, impaired neurotransmitter release and enlarged SVs  have normal AZ dense body projections and Ca2+ channel clustering, but fail to accumulate SVs that normally surround the AZ due to defective Cpx binding  show a dramatic increase in evoked neurotransmitter release  prevents its ability to inhibit SV availability, thereby enhancing SV release to facilitate plasticity and memory formation . Additioclusters . In Drosclusters . Short iisoforms , suggestBoth authors wrote and edited the manuscript, contributed to the article, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."}
+{"text": "Dementia is an increasingly important public health problem with known vascular contributors. Respiratory function, measured by peak expiratory flow (PEF), may be a novel modifiable risk factor in reducing the risk of dementia along the vascular pathway. We investigated the association between PEF and incident dementia in older adults from the National Health and Aging Trends Study (NHATS). Using NHATS criteria, participants were categorized as having or not having probable incident dementia during NHATS Rounds 2-4, spanning three years. Of 3,622 participants with available PEF and covariate data, 543 (15.0%) had incident cases of dementia. Quartile of baseline PEF was analyzed as a predictor of incident dementia using logistic regression models, while controlling for several health and sociodemographic covariates. The fourth quartile of PEF had statistically significantly decreased odds of incident dementia when compared to the first PEF quartile . Significantly reduced odds of incident dementia were found when comparing the third and second PEF quartiles to the first PEF quartile, as well . These relationships were dose-dependent so that increasing PEF quartile levels were more protective against incident dementia. PEF may be considered as an easily administered, low-cost measure of respiratory function and a possible screening tool for dementia risk. Improving PEF may reduce dementia risk through vascular mechanisms . Future research should explore these potential causal pathways between PEF and dementia."}
+{"text": "The COVID-19 pandemic has led to social distancing protocols, subsequently increasing social isolation for older adults. The purpose of this study was to explore the relationship between social connectedness and mental health outcomes. Leveraging NHATS, a nationally representative study , we examined the association between the method of social connectedness and mental health outcomes. Descriptive analyses revealed older adults are using various methods  to remain connected with their social networks during COVID-19. Findings from all of the linear regression analyses indicated phone or video calls are associated with negative affect, whereas in-person visits are associated with lower levels of negative affect. These findings suggest substituting in-person visits with video calls or phones may not be sufficient to relieve their loneliness and negative affect. Future studies should investigate this effect on physical or emotional health outcomes."}
+{"text": "We developed comprehensive multi-domain profiles of psychosocial stress in urban-dwelling, racially and ethnically diverse adults  and evaluated associations with cognitive function. Participants completed psychosocial stress measures tapping into ten domains and tasks of processing speed, working memory, and episodic memory. Latent profile analyses controlling for age yielded four-profiles: high neighborhood stress, moderate versus high work stress and daily discrimination, and high health and relationship stress. Profiles significantly differed in income, age, and employment status. The profile with moderate work stress and daily discrimination and the profile with high neighborhood stress each had significantly lower working memory than the other profiles. The finding of lower working memory among individuals in the moderate work stress and daily discrimination profile was not due to sociodemographic variables. Results highlight the potentially cumulative influence of different contextual stressors on cognition."}
+{"text": "ABSTRACT IMPACT: As newborn screening is now available for X-linked adrenoleukodystrophy, there is a need to establish meaningful disease markers to detect the onset of the severe demyelinating cerebral form of this disease at the earliest possible stage, and to quantify early disease progression to evaluate the relative efficacy of therapies. OBJECTIVES/GOALS: Longitudinal testing of neurocognitive and motor function using smartphone and tablet-based applications holds promise for early detection and quantification of brain white matter changes in patients with adrenoleukodystrophy (ALD) and other rare demyelinating diseases, but this methodology requires validation in pediatric populations. METHODS/STUDY POPULATION: We developed an iPad application with a game-like interface to assess interhemispheric transfer across the corpus callosum, the brain structure where cerebral demyelinating disease typically begins in patients with ALD. Feasibility data from remote test administrations with healthy children were collected to analyze and speed and timing of finger tapping movements requiring bimanual coordination on a touchscreen. RESULTS/ANTICIPATED RESULTS: Among our pilot sample of healthy school-aged children, age-related improvements in finger tapping speed were observed in both single-hand and alternating-hand conditions. Results indicate that remote testing using iPad applications is a viable way to collect psychometric testing data rapidly in pediatric populations and is feasible during a pandemic. Next steps in this research project will be: (1) evaluating the stability of repeated test administrations (test-retest reliability), (2) assessing agreement between performance on our iPad application and validated measures of interhemispheric transfer and fine motor function, and (3) comparing performance of children with known corpus callosum white matter abnormality to performance of healthy children. DISCUSSION/SIGNIFICANCE OF FINDINGS: Brief neurocognitive tests that can be frequently administered may have the ability to capture subtle brain changes in developing children. Approaches enabling remote  testing will facilitate research during the covid-19 pandemic and are especially well-suited for data collection in rare disease populations."}
+{"text": "Older adults with dementia rely on others to recognize and treat their pain and will ultimately become dependent. Family caregivers (FCGs) play a crucial role in pain management, yet limited data is available regarding the factors that impact their abilities. This qualitative descriptive study sought a deep understanding of FCGs perception of their abilities to manage pain for a loved-one with dementia. A sample of 25 adult family caregivers of community-based older adults with dementia was recruited in central Virginia. Participants were 29 to 95 years old, predominantly white, married, female, and high school graduates. We conducted semi-structured interviews that were audio recorded and analyzed using constant comparative analysis. Participants\u2019 who perceived greater competence with pain management reported less pain for their loved-one, and their level of confidence was influenced by 3 factors: progress and stage of dementia: this increases the complexity of care, affecting FCGs ability to manage pain and engendering a self-perception of incompetence; developing adaptive mechanisms: built self-efficacy and improved FCGs perceived competence;, and support from professionals: a greater degree of support alleviated FCGs concerns and instill new skills, Effective pain management depended on family caregivers\u2019 belief in their own abilities, and perceived competence could be improved by learning new skills or making adaptations. Professional care givers need to routinely assess FCGs abilities and provide adequate interventions."}
+{"text": "We evaluated nucleic acid amplification testing (NAAT) for Zika virus on whole-blood specimens compared with NAAT on serum and urine specimens among asymptomatic pregnant women during the 2015\u20132016 Puerto Rico Zika outbreak. Using NAAT, more infections were detected in serum and urine than in whole blood specimens. Zika virus (ZIKV) infection during pregnancy can cause severe brain and eye malformations and is associated with neurodevelopmental abnormalities in affected infants   within 12 hours of collection, and stored according to Food and Drug Administration and CDC guidelines (https://www.hologic.com) at Vitalant Research Institute   performed quality-control testing by singleplex NAAT   years; specimen collection was evenly distributed by trimester of pregnancy . Of the specimen . A totalAmong 28 women who tested positive by NAAT, 8 were by whole blood, 10 by urine, and 20 by serum . Among tThis study provides information about laboratory testing to maximize detection of ZIKV infection among asymptomatic pregnant women. In this small sample of ZIKV NAAT\u2013positive asymptomatic pregnant women, no additional ZIKV-positive cases were identified by whole-blood NAAT beyond those identified through tests of other samples. This finding contrasts with other studies that note prolonged detection, higher viral load, and greater sensitivity of whole-blood NAAT versus NAAT on other specimens (All asymptomatic ZIKV-positive women had detectable ZIKV in NAAT of urine or serum samples in our study. Although previous studies detected ZIKV RNA in urine more frequently than in serum (This large study comparing NAAT for ZIKV on serum, urine, and whole-blood specimens is unique in that the study population is among asymptomatic pregnant women. Although studies have mentioned lack of overlap between different specimens tested by NAAT (Our detection of acute ZIKV infections by NAAT is likely low because the study occurred 2\u20133 months after the peak of the Puerto Rico outbreak (These findings support CDC guidance to perform NAAT on asymptomatic pregnant women during outbreaks when ZIKV is widely circulating ("}
+{"text": "Pediatric fecal matter transplant (FMT) clinical trials relying on \u201chealthy\u201d donor stool use screened adult donor stool, likely assuming safety and efficacy. However, we consider how adult donor stool could instead be posing risks of atypical development or transmission of early disease, which could be prevented with age-matching donors and recipients for FMT.The gut microbiome has been identified as a potential therapeutic target to combat pediatric intestinal and extraintestinal diseases through FMT. FMT involves the transfer of \u201cnondiseased\u201d stool into the gastrointestinal (GI) tract of an individual with the disease in attempts to replenish the gut microbiota and ameliorate adverse GI symptoms. Currently, no standard methodology exists for clinical trials investigating FMT efficacy. Key elements such as donor selection processes are often based on drastically different criteria but usually involve adult stool donors even in pediatric FMT clinical trials. We consider how the usage of adult donors may be of concern when considering the long-term implications of FMT on pediatric health. The pediatric microbiome plays an important role in immune, GI, and neurological development and to introduce adult donor stool to an already dysbiotic microbiome could lead to atypical maturation. Furthermore, selection of nondiseased stool is based on current screening protocols. Screened and deemed \u201cnondiseased\u201d adult donor microbiota could be showing early disease markers for diseases that are not yet visible with current donor screening protocols, putting pediatric recipients at risk for disease development. Current pediatric guidelines have yet to consider these specific pediatric risks, which could be jeopardizing the long-term health and development of pediatric patients and influencing the future of pediatric therapeutics.The microbiota is largely shaped in early childhood. Antibiotic usage in early childhood has shown to increase the risk of acquiring conditions such as inflammatory bowel disease (IBD), asthma, allergy, and eczema , 2. ThisThroughout childhood, adolescence, and adulthood, age is associated with drastic differences in composition and functional gene potential of the microbiome . Age greIn a pediatric FMT clinical trial, considerations for donor stool should include both microbial factors, such as similarity of microbial species between donor and recipient, as well as factors for host intestinal tolerance toward the donor microbes. Because the gut microbiota of young children, adolescents, and adults are all distinct, the necessary microbiota across development is crucial for typical neurological, immunological, and GI development \u20134, 6. IfClostridioides difficile infection (rCDI) (NCT02134392). In these pediatric trials, the age of the stool donor is listed as either an adult or is not mentioned in study record details.In the pediatric population, active FMT clinical trials include treatment of intestinal colonization of extended-spectrum resistant Enterobacteriaceae (NCT02543866), IBD (NCT03399188), autism spectrum disorder (NCT03426826), ulcerative colitis (NCT03582969), Crohn's disease (NCT03378167), and refractory Methodology within FMT clinical trials vary with donor selection procedures being a particular area of heterogeneity . Fecal dScreening efforts are established to not only ensure stool viability but robustly reduce the chance of transmitting infection or active medical comorbidities from donor to recipient . ScreeniDonor selection methodology is a particularly large area of ambiguity. For example, a systematic review of FMT clinical trials reported before 2017 determined that out of 85 FMT clinical trials, almost 50% of published studies did not report donor selection eligibility criteria in their publications . This reTrial method heterogeneity and uncertainty surrounding true efficacy further exacerbates the concerns for safety in FMT clinical trials. Safe stool is as safe as how it has been screened, and screening can only include testable pathogens already established to directly cause disease. However, the definition of what can cause disease is constantly evolving. For example, FMT has revealed the possibility of transmission of diseases previously assumed as nontransmissible. A patient developed issues with significant weight gain following an FMT from a healthy, but overweight, donor leading to FMT guidelines to suggest screening for donor body mass index . This poCurrent pediatric guidelines suggest donor selection should involve adults aged 18 and older based on medicolegal considerations . While aEarly life disruptions to the microbiota can already increase an individual's susceptibility to a variety of immune, metabolic, neurological, and psychiatric diseases . This phEarly disease markers for a variety of gut microbiome associated diseases have not yet been identified. These early disease markers could be characteristic changes occurring in the gut of an adult donor, years before diagnosis of disease, and invisible with current stool-screening guidelines. It is established that bidirectional communication between the brain and GI tract has been implicated in a variety of neurological diseases. Transmission of early disease markers from a variety of diseases could occur; here, we will illustrate the issue using Parkinson's disease (PD) as an example. PD has characteristic changes in the GI tract including constipation and gut dysbiosis with increased inflammation and reduced short-chain fatty acid production. Adults with REM-sleep behavior disorder, a prodromal stage of PD, already have the same pattern of dysbiosis . ConstipTo contextualize early disease marker transmission using specific evidence from pediatric FMT, a study of the gut microbiome of pediatric recipients following FMT with \u201chealthy\u201d adult donor stool showed the potential for acquisition and persistence of antimicrobial genes from the donor . AlthougWe are concerned that adult donors beginning to generate characteristic microbiome profiles of adult-onset disease could be acting as FMT donors for pediatric FMT trials, potentially generating long-term implications for the recipient child with their GI tract being introduced to characteristic pathogenic changes in childhood. Matching pediatric FMT recipients with pediatric donors could largely reduce the possibility of adult-onset neurodegenerative disease marker transmission and allow for less interruption of age-specific maturation of the gut microbiota.With past efforts focused on the promotion of immediate safety for pediatric FMT recipients, the field is ready for conversations surrounding long-term safety and healthy development in pediatric FMT recipients. Optimal donor selection should be a focus of these conversations, with considerations of matching donors and recipients by age being prioritized. Age-matching could reduce the exacerbation of the child's atypical immune, GI, metabolic, and neurological development to allow for parallel interplay of microbiota development with typical physiological development.The idea of age-matching is not without an introduction of its own novel risks, such as possible transmission of childhood-onset diseases including asthma or allergy to pediatric recipients. However, we argue this phenomenon could still occur with the introduction of adult donor microbiota because it could be affecting typical immunological development. Furthermore, screening for risk factors for allergy and asthma, such as antibiotic usage, mode of delivery, and formula feeding in pediatric donors, could aid to protect against this occurrence.A joint-position paper from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition similarly argues that further research into age-matching is warranted due to concerns of long-term efficacy and safety with adult donors . Age-matCurrently pediatric FMTs are changing children's lives, treating persistent, and sometimes otherwise incurable, diseases, demonstrating the power of the approach. FMT trials explore increasingly diverse applications for pediatric intestinal and extraintestinal diseases and long-term clinical considerations for health and development will be increasingly important. Given the increasingly recognized role of the gut microbiome in adult diseases including neurodegenerative disorders, we believe choosing age-matched donors for pediatric FMTs will likely be the best safe-guard to reduce potential future complications.At time of submission all clinical trials statuses mentioned in the manuscript are listed as: NCT02543866 (recruiting), NCT03399188 (recruiting), NCT03426826 (recruiting), NCT03582969 (recruiting), NCT03378167 (recruiting), and NCT02134392 (recruiting).https://clinicaltrials.gov/.Current trial statuses can be accessed at AM conceived the opinion and drafted manuscript. BF and SA-C contributed expertise to review and critique final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Transposable element sequences are usually vertically inherited but have also spread across taxa via horizontal transfer. Previous investigations of ancient horizontal transfer of transposons have compared consensus sequences, but this method resists detection of recent single or low copy number transfer events. The relationship between humans and domesticated animals represents an opportunity for potential horizontal transfer due to the consistent shared proximity and exposure to parasitic insects, which have been identified as plausible transfer vectors. The relatively short period of extended human\u2013animal contact (tens of thousands of years or less) makes horizontal transfer of transposons between them unlikely. However, the availability of high-quality reference genomes allows individual element comparisons to detect low copy number events. Using pairwise all-versus-all megablast searches of the complete suite of retrotransposons of thirteen domestic animals against human, we searched a total of 27,949,823 individual TEs. Based on manual comparisons of stringently filtered BLAST search results for evidence of vertical inheritance, no plausible instances of HTT were identified. These results indicate that significant recent HTT between humans and domesticated animals has not occurred despite the close proximity, either due to the short timescale, inhospitable recipient genomes, a failure of vector activity, or other factors. Drosophila was the first case of inferred HTT [Transposable elements (TEs) are DNA sequences that can move or copy themselves to new locations in genomes . This prrred HTT , with thrred HTT . While Hrred HTT , evidencrred HTT ,18. Probrred HTT ,19.Despite an increasing number of ancient HTT events being detected, studies evaluating evidence for more recent HTT are lacking. The use of consensus TE sequences when inferring HTT, while necessary for evaluating large-scale transfers across millions of years between many genomes, also prevents the detection of transfers currently in single or low copy numbers in the recipient genome. Human domestication of animals is a ready example of species sharing an environment conducive to HTT on a shorter timescale, on the order of tens of thousands of years or less . FeatureThe existence of high-quality reference genomes for humans and most domesticated animals finally makes the detection of low- and single-copy HTT events possible. Despite the close physical contact and other factors that make HTT more likely to be present, we expected the rarity of successful TE invasion and a lack of adequate time for any transferred TEs to become ubiquitous in the population to result in no detectable HTT events, even when searching millions of individual elements between human and domestic animal genomes. Here, we provide a comprehensive search for individual HTT events between humans and domestic animal species.https://genome.ucsc.edu/ accessed on 30 May 2021). Only intervals longer than 100 bp were included. The search was also limited to retrotransposons based on a lack of evidence for significant DNA TE activity in mammals outside of the Vespertilionidae family of bats for a time period far exceeding the history of animal domestication by humans [https://www.R-project.org/ accessed on 30 May 2021), and reference genomes downloaded from UCSC. TE intervals from non-chromosomal scaffolds were removed for species with chromosomal assemblies, while TE intervals were used in full for genomes without chromosome-level assemblies. A 400 bp decoy sequence (hg38 chr1:1000000\u20131000400) containing no TEs was appended to each retrotransposon multifasta; this sequence served as a positive control to verify that megablast was functional in the event of zero high-identity hits for a given pairwise comparison. Pairwise comparisons of reference mRNA sequences downloaded from UCSC were also performed as a positive control for vertical inheritance in a subset of domestic animal species.Reference genomes and retrotransposon genomic intervals  for human (GRCh38/hg38) and thirteen domestic animal species  were downloaded from UCSC Table Browser using the RepeatMasker (rmsk) track  were performed in the command line using BLAST+ version 2.8.1 . The humper year . Using tper year . Verticaper year .Pairwise megablast queries of 27,949,823 retrotransposons from the reference genomes of humans and thirteen domestic animal species revealed zero insertion events consistent with HTT . InitialThirty-seven human TEs also yielded high-identity hits in two or more domestic animal species ; high idHelicoverpa armigera [For the eight SINE hits initially detected as unique to human and one other species, manual inspection with the 100 Species MultiZ alignment track in UCSC Genome Browser revealed strong conservation across multiple vertebrate genera and orders , providiarmigera . Indicatarmigera ,54. WhilThe lack of HTT between humans and domestic animal species was consistent with the study expectations. We chose domestic species due to humanity\u2019s history of unnaturally close proximity, shared parasitization by plausible HTT vectors (which have served as HTT vectors in other clades), and rapid expansion of human and domestic animal population sizes. An illustrative case is the BovB element, which has proliferated rapidly in species as divergent as bovines and squamates and ultimately makes up 12% of the cattle genome . HoweverOur search demonstrates a lack of evidence for recent HTT between humans and domestic species. Prior identification of HTT events used consensus sequences of transposons derived from multiple paralogs within a species, compared to consensus or individual insertions in an unrelated species. The advantage of our study is in the ability to detect HTT resulting in few or even single insertion events. Still, the use of reference genomes allows for the possibility of HTT detection failure due to population heterogeneity, somatic HT, inadequate genome coverage or errors (particularly over repetitive regions) or other factors. However, the lack of plausible horizontally transferred elements within human and animal reference genomes provides adequate evidence to assume that the phenomenon is not common or widespread."}
+{"text": "This case study explores an employer-initiated biweekly group support call for home care aides implemented by a large New York City-based home care agency during the COVID-19 pandemic. Specifically, we investigate how agency staff used information gathered through these calls to intervene into existing agency communication and support systems for aides. Our single-site case study analyzes detailed notes from almost 100 support calls that took place between April 2020 and March 2021, as well as interviews with agency staff from communications, human resources, nursing, and other departments that support aides. We compare and contrast new communication and support mechanisms advanced in conjunction with these calls with agency systems pre-pandemic. Our findings suggest that while calls were initially targeted toward providing emotional and operational support, staff also advocated for more systemic supports. We discuss the sustainability of these new efforts, as well as ongoing barriers and gaps."}
+{"text": "ABSTRACT IMPACT: Up to 33% of patients of patients who undergo reconstruction have hostile defects with coexisting soft tissue and osseous defects due to prior radiation, prior failed cranioplasty or concurrent infections we seek to identify optimal strategies for these patients based on the experience of a southeastern tertiary referral center. OBJECTIVES/GOALS: Scalp and calvarial defects in patients may result from a number of etiologies including trauma, burns, tumor resections, infections, osteoradionecrosis, or congenital lesions. Our objective was to retrospectively evaluate the use of alloplastic reconstruction alongside autologous reconstruction for high risk cranial defects. METHODS/STUDY POPULATION: An IRB approved retrospective review of patients who underwent cranioplasty of a hostile site at a Southeastern tertiary referal center between January 2008 and December 2018 was performed. The patients were stratified into three groups based on the type of implant used: autogenous (bone), alloplastic , or mixed (combination of both types of graft). The primary outcome metric was a complication in the year following cranioplasty, identified by flap or bone graft failure, necrosis, or infection. Statistical analysis included t-tests and chi-square tests where appropriate using SPSS. RESULTS/ANTICIPATED RESULTS: There were 43 total cases in this time period; 15 autogenous, 23 alloplastic, and 5 mixed. The purely autogenous group had the highest complication rate (85%) and the alloplastic group had the lowest complication rate (38%). When stratified by specific material used for reconstruction , overall complication rate was statistically significant  with PEEK implants having the lowest complication rate (21%). The analysis documented an overall complication rate that was statistically different between the three groups (p=0.012). DISCUSSION/SIGNIFICANCE OF FINDINGS: This analysis interestingly found that in the setting of hostile cranial defects, cranioplasties would benefit from the use of prosthetic implants instead of autologous bone grafts, not only for avoidance of donor site morbidity but also for decrease in overall complications."}
+{"text": "ABSTRACT IMPACT: This study will be used to culturally tailor interventions to reduce maternal and infant health disparities in a Marshallese community. OBJECTIVES/GOALS: Inadequate prenatal care is associated with adverse birth outcomes including preterm births, low birth weight infants, and neonatal mortality. Marshallese Pacific Islanders are less likely to receive early and consistent prenatal care compared to other racial/ethnic groups and are thus at a higher risk for maternal and infant health disparities. METHODS/STUDY POPULATION: This article used a qualitative comparative analysis method to compare and contrast the perceived barriers to prenatal care for the prospective of Marshallese mothers and Maternal Health Care Providers (MHCPs). RESULTS/ANTICIPATED RESULTS: Marshallese mothers and MHCPs identified the same structural barriers to prenatal care: health insurance, transportation, and language. The socio-cultural barriers to prenatal care were depicted quite differently by Marshallese mothers verses MHCPs. DISCUSSION/SIGNIFICANCE OF FINDINGS: While the description of structural barriers were consistent among Marshallese mothers and MHCPs, the socio-cultural barriers and the value assigned to those barriers was quite different. Understanding the perspectives from both lenses is an important step towards addressing the barriers to prenatal care among Marshallese."}
+{"text": "Vulnerable older adults, such as physically impaired or care-dependent individuals, are vastly underrepresented in psychotherapy research. Improving their inclusion in randomized controlled trials is necessary to determine the effectiveness of psychotherapy in this population. This study is the first to systematically evaluate strategies to recruit home-living vulnerable older adults with clinically significant depression into a large randomized controlled psychotherapy trial. Potential participants were approached directly  or via cooperation with gatekeepers .The initiator of the first contact with the study team and successful recruitment strategies were recorded. Referral strategies were compared with respect to number of inquiries and inclusion rates; study personnel\u2019s time investment; and participant characteristics .Most of the N=197 participants were included via gatekeeper-referral  and referral by medical practitioners led to highest inclusion rates =8.964, p<.05). Most participants were referred from a hospital setting (50.3%), whereas referral numbers by medical practices were low (15.9%). Participants who initiated the first contact themselves had higher inclusion rates and were less functionally and cognitively impaired.Including home-living vulnerable older adults into psychotherapy trials requires simultaneous implementation of diverse recruitment strategies. Medical practitioners and psychologists, especially in hospitals, are the most effective recruitment strategy, but self-referral via media is most cost-efficient in terms of time investment."}
+{"text": "Lasionycteris noctivagans (silver-haired bat), Tadarida brasiliensis (Mexican free-tailed bat), and Eptesicus fuscus (big brown bat)  after bat exposures that occurred during August 2021. This increase in bat-associated human rabies deaths in the United States followed only three deaths during the previous 48 months. The cases during fall 2021 occurred in two adults and one child, all male, from Idaho, Illinois, and Texas. Initial symptoms included pain and paresthesia near the site of exposure progressing to dysphagia, altered mental status, paralysis, seizure-like activity, and autonomic instability. All three patients had recognized direct contact  with a bat approximately 3\u20137 weeks before symptom onset and died approximately 2\u20133 weeks after symptom onset. The deaths were associated with three bat species: own bat) . All thrRabies is a zoonotic disease transmitted primarily through virus-laden saliva from the bite of an infected mammal. The typical incubation period from exposure to symptom onset is 3\u201312 weeks. Rabies is nearly always fatal once symptoms develop but nearly always preventable when PEP is administered in accordance with the recommendations of the Advisory Committee on Immunization Practices.Preventing transmission of rabies from bats to humans can be accomplished by 1) avoiding contact with bats, 2) safely capturing and testing bats implicated in human exposures, and 3) seeking rapid evaluation for PEP when direct bat contact occurs and rabies cannot be ruled out. Two of the bat-associated cases in fall 2021 were considered avoidable exposures: one was attributed to a bat roost in the patient's home, the other to the patient picking up the bat with his bare hands. Safely excluding bats from homes and instructing persons not to touch bats can prevent rabies exposures.Bats are ecologically critical species with seasonal activity patterns. Although bat activity is reduced in winter months, increased human-bat contacts often occur again in late spring to early fall ("}
+{"text": "Older adults with mild behavioral impairment (MBI), or the presence of late-life neuropsychiatric symptoms, have a unique cognitive phenotype. However, the neural correlates associated with MBI-related cognitive changes is not well understood. The goal of this study is to examine if specific regions of the brain moderate the relationship between the presence of MBI and performance on tasks of cognition. Data from the National Alzheimer\u2019s Coordinating Center was utilized for this study. Participants  were included in our analyses if they were cognitively healthy or had mild cognitive impairment (MCI). Multiple domains of cognitive performance were evaluated. The neuroanatomical regions included hippocampus, caudal anterior cingulate (ACC), rostral ACC, entorhinal, and parahippocampal gray matter volume; and caudal ACC, rostral ACC, entorhinal, and parahippocampal mean cortical thickness. Hippocampal, entorhinal, and parahippocampal cortical gray matter volume moderated the relationship between MBI and performance on tasks of episodic memory. Left rostral ACC cortical gray matter volume and entorhinal and parahippocampal mean cortical thickness moderated the relationship between MBI and performance on language tasks. Hippocampi cortical gray matter volume also moderated the relationship between MBI and performance on processing speed tasks. Persons with smaller brain sizes in these areas were more negatively affected in these cognitive domains if they had MBI. These results suggest that the association between smaller brain volumes and cognition was stronger among persons with MBI. These findings suggest that older adults with MBI may perform worse on these tasks due to neurodegeneration that is present."}
+{"text": "Institutions of higher education need to become more age friendly. Creating an on-campus lifelong learning program can offer older adults opportunities to audit classes and engage in multigenerational classrooms, but can also promote intergenerational learning when instructors consciously use pedagogy that fosters engagement between learners from various generations. Promoting intergenerational learning to facilitate reciprocal sharing of expertise between generations is also the fourth principle of the Age Friendly University framework. This qualitative interview study examines the perspectives of 27 faculty members who have opened their face to face classrooms to older adult auditors to 1) Explore perceived benefits and challenges associated with having older adults in the college classroom and to 2) Determine what levels of intergenerational learning may be taking place. Compared to lecture-based courses, faculty whose pedagogy promotes discussion, sharing, and small group work reported detailed examples of older adult learners and traditionally-aged college students engaging in course-related discussion. The unique, historical and diverse perspectives of older adults improved the quality of education for students, and fostered in-depth learning. Challenges related to older adult auditors included poor/limited attendance, sharing of strong opinions/dominating class discussion, sensory/mobility and technology accessibility. Recommendations include training to promote intergenerational engagement in college classrooms."}
+{"text": "Bradyrhizobium diazoefficiens . Using gene-level network and duplication functional traits to predict accessory gene distributions across environments, genes predicted to be superfluous are more likely lost in high stress, while genes with multi-functional roles are more likely retained. Genes with higher probabilities of being lost with stress contain significantly higher proportions of codons under strong purifying and positive selection. Gene loss is widespread across the entire genome, with high gene-retention hotspots in close spatial proximity to core genes, suggesting Bradyrhizobium has evolved to cluster essential-function genes  in discrete genomic regions, which may stabilise viability during genomic decay. In conclusion, pangenome evolution through genome streamlining are important evolutionary responses to environmental change. This raises questions about impacts of genome streamlining on the adaptive capacity of bacterial populations facing rapid environmental change.Bacteria have highly flexible pangenomes, which are thought to facilitate evolutionary responses to environmental change, but the impacts of environmental stress on pangenome evolution remain unclear. Using a landscape pangenomics approach, I demonstrate that environmental stress leads to consistent, continuous reduction in genome content along four environmental stress gradients  in naturally occurring populations of  A pervasive challenge in microbial ecology is detecting how natural microbe populations respond to environmental change. Prokaryotes have highly variable intraspecific genome content, described as a pangenome , 2. WithOne approach in detecting changes in evolutionary pressures on genome evolution, such as ecological adaptation, is to determine how natural environmental variation, putative agents of natural selection, predict the distribution of genomic variation. Landscape genomics has been a powerful approach in uncovering the genetic basis of adaptation, traditionally detecting putative adaptive loci or SNPs on a single reference genome, and effectively concentrating adaptive discovery to the core genome of a species. However, little attention so far has been given to uncovering patterns of accessory genome variation across the environment . Here, IGenome reduction represents a major change in the accessory genome. Prokaryotic genomes are thought to be under constant decay due to a mutational bias towards deletion , 13. OneBradyrhizobium diazoefficiens, which was previously sampled across a contiguous and environmentally complex heterogeneous landscape  or low stress [large negative z-score]) appear to be under strong selection  are under stronger selective pressure, having significantly higher proportion of codons under purifying or positive selection compared to accessory genes randomly distributed with respect to environmental stress. Because accessory genes that only occur in extreme ends of the stress gradient  and increase in population differentiation (Fst) with high stress in core genes, when compared to aridity and acidity. The observed decrease in the efficiency of selection provides strong evidence of either weaker selection and/or smaller effective population size in the core genome at high heat and salinity stress. Consistent with this study\u2019s finding, theoretical models predict that increased population differentiation (Fst) can be a result of decreased effective population size through increased population sub-division . The conThe pervasive genome decay along soil and climate-related stress gradients also has implications regarding evolvability in bacterial populations. The observed loss of genetic diversity (at the gene level) with increasing stress prompts future questions and experiments on the upper bounds of genome decay that microbial populations can tolerate with increasing environmental stress. The loss of genetic diversity also raises questions about how genome streamlining impacts the ability for bacterial populations to evolutionarily respond to environmental change when already faced with stressful conditions.Supplemental InformationSupplementary interactive 3D version of Figure 6"}
+{"text": "Nature Photonics (2022)10.1038/s41566-021-00921-9Thermal radiation is commonplace in our everyday life, exemplified by natural sunlight and infrared thermometers. When an object emits thermal radiation, a radiative cooling process carrying away energy from the object occurs spontaneously. Hence, the control of thermal radiation or radiative cooling is beneficial not only to the development of practical cooling techniques, but also to the exploitation of renewable energy resources. An emerging field of thermal photonics provides exciting opportunities for manipulating the radiative process artificially. In this review article, Shanhui Fan from Stanford University and Wei Li from Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences have discussed fundamental concepts involved in radiative cooling and summarized principles for tailoring thermal radiation with photonic structures. The story starts with the demand of daytime radiative cooling and introduces photonic concepts and recent advances in this area. Inspired by the daytime radiative cooling, more scenarios such as solar cell cooling, thermal management of outdoor colored objects and cooling textiles have been proposed. Thermodynamics in radiative cooling is finally discussed for harvesting outgoing thermal radiation. We anticipate these fruitful discussions can help readers walk into thermal photonics and motivate researchers to find novel applications of radiative cooling."}
+{"text": "ABSTRACT IMPACT: This study aims to provide insight into naturally acquired immunity against severe malaria, thereby laying the foundation for the design of novel vaccine candidates to prevent severe disease as well as monoclonal antibody therapies to treat severe malaria. OBJECTIVES/GOALS: Severe malaria is caused by parasite surface antigens that contain high sequence diversity. Nevertheless, P. falciparum-exposed individuals develop antibody responses against these antigens. Our goal is to isolate antibodies with broad reactivity to understand how disease protection is acquired. METHODS/STUDY POPULATION: Our study cohort consists of Ugandan adults living in a malaria-endemic region with high transmission intensity, who are protected against severe malaria. Using fluorescently labeled probes of parasite surface antigens, we have isolated antigen-specific B cells from these donors. We then expressed the corresponding monoclonal antibodies in vitro. These antibodies were screened against a library of variant surface antigens to determine antibody breadth and potential to inhibit interaction of the parasite surface antigen with host receptors, a critical step in pathogenesis. Additionally, using a panel of variant surface antigen mutants, we have predicted the epitopes targeted by the broadest monoclonal antibodies. RESULTS/ANTICIPATED RESULTS: We have identified three monoclonal antibodies with exceptionally broad reactivity and inhibitory activity against our panel of severe disease-inducing variant surface antigens. We have identified two major sites targeted by these broadly reactive antibodies. The first site was associated with the largest breadth, but limited inhibitory potential, while the second site showed high-affinity antibody binding and inhibition of receptor binding. Interestingly, two of these three antibodies were very similar in structure, even though they were isolated from different donors. Isolation of antigen-specific B cells from additional donors will enable us to identify how common such broadly reactive antibodies are and allow the identification of additional epitopes DISCUSSION/SIGNIFICANCE OF FINDINGS: This study is the first to isolate broadly reactive antibodies that are likely to protect against severe malaria in naturally immune individuals. Further characterization of antibody-antigen interactions will inform the development of this surface antigen as a vaccine candidate for malaria."}
+{"text": "Exercise training decreases abdominal fat in an intensity-dependent manner. The fat loss effect of exercise has been intuitively thought to result from increased fat burning during and after exercise, defined by conversion of fatty acid into carbon dioxide in consumption of oxygen. Nevertheless, increasing exercise intensity decreases oxidation of fatty acids derived from adipose tissue despite elevated lipolysis. The unchanged 24-h fatty acid oxidation during and after exercise does not provide support to the causality between fat burning and fat loss. In this review, alternative perspectives to explain the fat loss outcome are discussed. In brief, carbon and nitrogen redistribution to challenged tissues (muscle and lungs) for fuel replenishment and cell regeneration against abdominal adipose tissue seems to be the fundamental mechanism underlying the intensity-dependent fat loss effect of exercise. The magnitude of lipolysis (fatty acid release from adipocytes) and the amount of post-meal carbon and nitrogen returning to abdominal adipose tissue determines the final fat tissue mass. Therefore, meal arrangement at the time when muscle has the greatest reconstruction demand for carbon and nitrogen could decrease abdominal fat accumulation while increasing muscle mass and tissue repair. Exercise decreases abdominal fat mass, especially at high intensity. This outcome is not causally associated with fat burning, but better explained by carbon and nitrogen redistribution. Since abdominal fat tissue constantly releases fatty acids into circulation under post-absorptive condition with natural cell deaths, exercise diverts more post-meal carbon and nitrogen to muscle for energy repletion and cell regeneration after phagocytosis and stem cell homing. This in turn leads to concurrent fat mass loss and muscle mass gain. Respiratory ventilation during high-intensity aerobic exercise amplifies the competition for post-meal carbon and nitrogen against adipose tissues. TherefoLipolysis appears to be more relevant with fat loss than fatty acid oxidation. Exercise increases plasma epinephrine levels at high intensities . EpinephThe physiological significance of the enhanced release of fatty acids from lipolysis without the corresponding increase in fatty acid oxidation during and after exercise remains unclear. However, a proposed role of adipocyte-derived fatty acids in tissue repair has been recently described elsewhere . Fatty aThe first basic assumption of fat burning theory is that fat cell death has no role in fat loss. However, this assumption is unlikely valid since fat cells are continuously dying and regenerating throughout our life. Approximately 8.4% of subcutaneous abdominal adipocytes are renewed annually with an average half-life of 8.3 years in human adults . AbdominThe second basic assumption of the fat burning theory is that muscle and fat cells are not interconvertible in a human body. However, we could not preclude the possibility that the fat mass loss concurrent with muscle mass gain after exercise training is associated with conversion between muscle and fat progenitor cells, derived from circulating bone marrow stem cells. Conversion from muscle satellite cells to an adipogenic lineage contributes the development of obesity and muscle mass loss in animals . GlucoseFurther evidence of this mechanism comes from the wide array of exosomes (containing nucleic acids or peptide) released from exercising skeletal muscle implicating the crosstalk between muscle and fat tissues. Adipose tissues are a major source of circulating exosomes containing a variety of mediators, which may influence muscle development . Some nuThe third assumption of the fat burning theory is that the increased carbon and nitrogen demands for airway epithelial cells regeneration in lungs does not contribute to fat loss during and after exercise. However, the possibility that the fat loss effect of high-intensity aerobic training due to competition for carbon and nitrogen between lungs and adipose tissues cannot be excluded . The lunDuring unfed conditions, visceral adipose tissues continuously releases fatty acids into circulation , togetheStudies employing dual energy X-ray absorptiometry have also provided solid support for the carbon and nitrogen redistribution effect of exercise training by the evidence of concurrent increases in lean body mass and decreases in fat mass . This nuLipoprotein lipase (LPL) attached on the surface of endothelial cells in capillary lumen determines relative partition of circulating triglycerides to muscle and adipose tissues after meals. The molecular size of triglyceride carried by chylomicron and VLDL is too large to transport across cell membrane of adipocytes from blood unless it is locally hydrolyzed by LPL in the adipose and muscle tissues. Relative LPL expression in adipose tissue and muscle tissues thus determines the daily distribution of circulating triglycerides (chylomicron and VLDL) partitioning into adipose tissues and skeletal muscle after meals. This ratio is substantially influenced by exercise training, in which trained women have relatively higher (\u223c8 times) muscle-to-adipose tissue LPL ratio compared to their untrained state . This suFatty acids (from lipolysis) are continuously released from abdominal adipose tissue into the circulation and fat cells are continuously dying in normal human adults. The size of adipose tissue is determined by the magnitude of nutrient competition from muscle and lungs for cell regeneration and energy replenishment after exercise. This is varied by types of exercise (aerobic or resistance exercise). Despite the fact that lower exercise intensity relies more on fatty acid oxidation, high-intensity exercise training (anaerobic in nature) provides a superior abdominal fat loss effect than low- and moderate-intensity exercise training. Given the fact that exercise does not increase 24-h fatty acid oxidation during and after exercise training, the carbon and nitrogen redistribution theory is more suitable to explain the abdominal fat loss outcome of exercise training than fat burning theory. This reasonably explains why low- and moderate-intensity exercise often fail as strategies for fat loss despite the greater percentage of fatty acid oxidation compared with high intensity exercise. Studies on inter-tissue communication during exercise (such as muscle-derived extracellular vesicles) for post-meal carbon and nitrogen redistribution are promising and may provide useful application to normalize body composition and prevent obesity. Furthermore, the role of fatty acids on repairing post-exercise damage deserves further investigation. More data are needed to support the carbon and nitrogen redistribution theory on fat loss effect of exercise.Both authors contributed significantly to this work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Objective: This study aims to identify multiple dimensions of religiosity among young adults at the beginning and end of the transition to adulthood, and describe how transition patterns of religiosity in early adulthood are associated with filial elder-care norms in midlife. Background: There is a broad consensus that religiosity is multidimensional in nature, but less is known regarding transitions in multiple dimensions of religiosity from early to middle adulthood and predicted filial eldercare norms as a function of those religiosity transitions. Methods: The sample consisted of 368 young adults participating in the Longitudinal Study of Generations in 2000 (mean age = 23 years) and 2016 waves. We conducted a latent class and latent transition analyses to address our aims. Results: We identified three religious latent classes among young adults in both 2000 and 2016 waves: strongly religious, weakly religious, and doctrinally religious. Staying strongly religious young adults between 2000 to 2016 waves reported higher filial elder-care norms in the 2016 Wave than those who were in staying weakly religious, staying doctrinally religious, and decreasing religiosity transition patterns between 2000 to 2016 waves. Conclusion: Our findings suggest that religiosity is still an important value for young adults shaping their intergenerational relationships with their aging parents. Keywords: religiosity, filial eldercare norms, young adults, transition to adulthood"}
+{"text": "A major component of The Middle Tennessee GWEP involves delivery of an annual regional geriatrics update conference. Formerly in-person, the planning committee transformed the 34th Annual Update Conference to a virtual platform within a six-month period. The University partner provided a Zoom platform with licensing and training of program staff. National marketing was achieved through professional societies and purchased e-mailings. Participants numbered 79, including 8 disciplines. Presenters were instructed on platform techniques including screen sharing, polling function, and breakout rooms to enhance audience participation. REDCap registration captured demographic information and facilitated evaluations and post-attendance intention-to-change surveys. Lessons learned were shared with community partners and advisory board members who demonstrated changes in service delivery models and training of new staff to support care to greater numbers of clients and participants. Virtual platforms can extend outreach for valuable learning and service outcomes and maintain high levels of satisfaction among target audiences."}
+{"text": "Chronic ocular graft-versus-host disease (oGVHD) is an ocular comorbidity of graft-versus-host disease (GVHD) that usually occurs concurrently with systemic manifestations. Failure to detect and treat oGVHD in its early stages may lead to progression of ocular signs and symptoms leading to oGVHD that is refractory to conventional treatment.We report the clinical course of a 19-year-old male and a 59-year-old female with severe and progressive chronic oGVHD without concurrent systemic signs of chronic graft-versus-host disease (cGVHD). Although their systemic conditions had been stable, both suffered from severe oGVHD and were referred to our clinic. Both cases exhibited marked improvement in conjunctival inflammation and fibrotic changes after amniotic membrane transplantation (AMT). Both cases underwent keratoplasty eventually to stabilize ocular surface conditions and to improve visual function.We reported the clinical outcomes of 2 cases of chronic oGVHD without concurrent systemic comorbidities that were treated with AMT. The clinician should be aware that cGVHD may persist in target organs even in the absence of concurrent systemic comorbidities following seemingly successful systemic treatment. A multidisciplinary team approach is essential in the early detection and therapeutic intervention for chronic oGVHD. Dry eye disease (DED) is the most frequent ocular manifestation after haematopoietic stem cell transplantation (HSCT) , 2, and The human amniotic membrane (AM) is reported to exert anti-inflammatory and anti-scarring actions \u20139, and aIn this article, we report the clinical outcomes of 2 cases of refractory chronic oGVHD without long-term systemic comorbidities, both of which were treated with AMT and keratoplasty to achieve clinical improvement.A 19-year-old Japanese male with a history of acute myelogenous leukaemia (AML) who underwent reduced intensity allogeneic HSCT (mini-transplantation) in March 2005 was referred to the Keio University Dry Eye outpatient clinic in October 2005 complaining of severe ocular pain, difficulty opening his eyes and foreign body sensations after acute and chronic skin GVHD were completely stabilized. Prior to mini-transplantation, no ocular surface abnormality was noted at the previous hospital, and he started to suffer from newly developed symptoms of DED in May 2005, after alleviation of acute skin GVHD. Systemic prednisolone (PSL) had been tapered from 40 to 20\u2009mg/day in July and was discontinued in August 2005. Just after cessation of PSL, bilateral lid swelling and severe ocular pain had emerged. PSL (15\u2009mg/day) was restarted to treat skin chronic GVHD in October 2005. Skin chronic GVHD was well controlled by this treatment. At the first visit to Keio University Dry Eye outpatient clinic in October 2005, severe DED, extensive trichiasis, corneal conjunctivalization, corneal ulcer, spontaneous lacrimal punctal occlusion, and active corneal neovascularization were observed in both eyes  who underwent allogeneic bone marrow transplantation (BMT) without irradiation in May 2010 was referred to the Keio University Dry Eye outpatient clinic in September 2013 as she developed refractory chronic oGVHD. After BMT, she developed acute skin GVHD and was successfully treated with systemic tacrolimus (2\u2009mg/day) and PSL (30\u2009mg/day), which was tapered over almost 1 year. In early 2011, just after tapering of treatment for acute skin GVHD, she developed DED and transient difficulty opening her mouth, which was diagnosed as chronic ocular and oral GVHD. She had been suffering from symblepharon, LSCD and conjunctivalization in her right eye, and she had been previously treated with contact lenses, commercially available eye drops, autologous serum and topical cyclosporine and tacrolimus, yet her ocular surface condition had not improved. At the first visit to Keio University Hospital in 2013, severe conjunctival fibrosis of the upper conjunctiva and fornix shortening, partial LSCD and conjunctivalization of the upper cornea on her right eye were observed (Fig.\u00a0Chronic oGVHD is an immune-mediated fibrotic disease that usually occurs concurrently with systemic comorbidities, and its aetiologies are multifactorial and still largely unknown. Currently available treatments such as eye drops, oral medications or punctal plugs are often insufficient to control severe ocular surface inflammation and excessive fibrosis, and additional therapeutic interventions such as AMT, corneal transplantations, and COMET are indicated for this intractable disease. The availability of such surgical interventions is limited, and the indications for these interventions should be considered carefully. Therefore, it is vital to detect oGVHD in the early phase to prevent severe ocular complications.AMT has been reported to be effective in treating refractory ocular surface diseases, including Stevens-Johnson syndrome and ocular cicatricial pemphigoid , 10. CliIn both cases the fornix was successfully reconstructed and long-term maintenance was achieved after AMT. However, a minor recurrence of corneal conjunctivalization in case 2 and corneal perforation in case 1 were observed after AMT, and both were treated with corneal keratoplasty.Although acute skin GVHD in cases 1 and 2 and transient chronic oral GVHD in case 2 were observed, oGVHD continued to progress rapidly even after stabilization of systemic conditions. Both cases resulted in severe oGVHD during or after tapering of systemic corticosteroids or immunosuppressants and AMT was required to reconstruct the fornix and to prevent corneal conjunctivalization due to LSCD.The limbal stem cell region has been reported to be infiltrated by inflammatory cells based on confocal microscopy observations in chronic oGVHD . FurthercGVHD patients are immunocompromised, and monitoring for ocular surface infections as well as systemic conditions is imperative. However, ocular manifestations may become apparent even after stabilization of systemic GVHD, as we experienced in the two cases reported herein. We suspect that these patients had hidden or latent mucosal or exocrine gland GVHD involving several mucosal surface barrier regions. The clinician therefore should be aware of the possibility of subclinical mucosal inflammation in cGVHD and the possibility of exacerbation of such inflammation especially at cessation or tapering of systemic anti-inflammatory medication. A multidisciplinary team approach is essential in determining the optimal timing for tapering of systemic anti-inflammatory medication in order to minimize the risk of chronic oGVHD."}
+{"text": "To report pooled prevalence of all mental disorders among the general prison population in the United Kingdom (UK). This includes individuals in Young Offender Institutions (YOI), youth custody and adult prisons across all categories. A secondary aim explores possible sources of heterogeneity by performing subgroup and meta-regression analysis across certain covariates (e.g. sex of prisoner). We hypothesise that contemporary estimates of mental disorders are higher than the general population.Prevalence of mental health problems among prisoners are considerably higher than the general population; this poses an important public health concern. Individuals who require diversion to appropriate psychiatric services are becoming embroiled in the revolving door of the criminal justice system. However, there are no up-to-date reviews assessing prevalence of mental disorders across the general prison population in the UK. This study aims to address this gap.We conducted a systematic search of PsycINFO (1923 \u2013 October 2019), MEDLINE (1946 \u2013 October 2019), EMBASE (1947 \u2013 October 2019) and Web of Science  of articles reporting prevalence of mental disorders in UK prison populations (PROSPERO registration number: CRD42019132685). The Joanna Briggs Institute (JBI) Appraisal Checklist for Studies Reporting Prevalence Data assessed study quality and bias. Pooled prevalence of each mental disorder was calculated using Stata statistical software 16.0 via the metaprop command. Forest plots present prevalence estimates with study weights and associated 95% confidence intervals (CI). Overall, 20 studies satisfied inclusion criteria, comprising of 12,335 prisoners across England, Wales and Scotland.We identified higher rates of neurotic disorders , personality disorders , alcohol  and drug dependence . The lowest prevalence rates included schizophrenia , panic disorders , adjustment disorders  and intellectual disability . Meta-regressions for psychotic disorder and personality disorder revealed no significant differences across study year, sample size and gender.Our prevalence estimates of mental disorders in prisons are higher than the general English population. However, we should acknowledge the influence of considerable heterogeneity. These findings demonstrate the need to quantify current prevalence of mental disorders amongst prisoners in the UK. We recommend for the government to consider performing an up-to-date census of psychiatric morbidity to facilitate service provision."}
+{"text": "ABSTRACT IMPACT: This project seeks to identify unique host responses that are biomarkers for specific urethral pathogens, and which can be used in the development of point-of-care (POC) STI diagnostics. OBJECTIVES/GOALS: How Chlamydia trachomatis (CT) and other common STIs, e.g. Neisseria gonorrhoeae, evade immunity and elicit pathology in the male urethra is poorly understood. Our objective is to determine how STI-infected urethral epithelial cells, as well as the uninfected \u2018bystander\u2019 cells with which infected cells communicate, respond to CT and other STIs. METHODS/STUDY POPULATION: We evaluated how immortalized urethral cell lines - including transduced human urethral epithelial cells (THUECs) - respond to increasing doses of CT infectious particles using in vitro one-step progeny assays performed in the presence or absence of cycloheximide, a drug that inhibits eukaryotic protein synthesis. We will perform concurrent single-cell RNA sequencing (scRNA-seq) and multiplex cytokine analyses to determine how different CT doses impact the transcriptomes of infected and bystander urethral epithelial cells and modulate cytokine production of the overall monolayer. Results of these experiments will inform the feasibility of performing similar analyses in situ using urethral swabs from men with clinically diagnosed urethritis. RESULTS/ANTICIPATED RESULTS: Our results demonstrate that immune-competent urethral cell monolayers strongly resist CT infection, unless most of the cells are simultaneously infected. This suggests that uninfected bystander cells sense CT-infected cells and secrete soluble factors that may act to limit CT proliferation in infected cells and to inform remaining uninfected cells that a potential pathogen is present. We anticipate that our scRNA-seq and cytokine analyses will identify both specific effector pathways that protect against CT and intracellular signals that modulate them. We speculate that these pathways and signals may differ during infection with CT and other STIs. Importantly, we anticipate that our in vitro model of CT infection will be highly representative of in situ immune responses observed in urethras of infected men. DISCUSSION/SIGNIFICANCE OF FINDINGS: In men, common STIs including CT are usually managed syndromically due to a lack of POC diagnostics. By determining how STIs elicit urethral inflammation and identifying countermeasures that STIs use to evade urethral immunity, we can identify host responses that serve as biomarkers for urethritis, generally, and for specific urethral pathogens."}
+{"text": "Understanding the neurobiological underpinnings of pedophilic behavior may contribute to a more comprehensive characterization of these individuals on a clinical ground, a pivotal step forward for the development of more efficient therapeutic rehabilitation strategies.Pedophilia is a disorder of public concern because of its association with child sexual offense and recidivism. Previous neuroimaging studies of potential brain abnormalities underlying pedophilic behavior, either in idiopathic or acquired  pedophilia, led to inconsistent results. This study sought to explore the neural underpinnings of pedophilic behavior and to determine the extent to which brain alterations may be related to distinct psychopathological features in pedophilia. To this aim, we run a coordinate based meta-analysis on previously published papers reporting whole brain analysis and a lesion network analysis, using brain lesions as seeds in a resting state connectivity analysis. The behavioral profiling approach was applied to link identified regions with the corresponding psychological processes. While no consistent neuroanatomical alterations were identified in idiopathic pedophilia, the current results support that all the lesions causing acquired pedophilia are localized within a shared resting state network that included posterior midlines structures, right inferior temporal gyrus and bilateral orbitofrontal cortex. These regions are associated with action inhibition and social cognition, abilities that are consistently and severely impaired in acquired pedophiles. This study suggests that idiopathic and acquired pedophilia may be two distinct disorders, in line with their distinctive clinical features, including age of onset, reversibility and The online version contains supplementary material available at 10.1007/s11682-020-00442-z. Pedophilia is a paraphilic disorder included within the Diagnostic and Statistic Manual of Mental Disorder  identify the brain regions consistently impaired in idiopathic and acquired pedophilia; (ii) determine whether the two forms of pedophilia are associated with overlapping or distinct brain networks; (iii) link topographically defined regions with corresponding psychological processes, testing which kind of experiments are most likely to activate a given region, to give a cognitive/psychological meaning to the detected alterations.In order to identify brain regions consistently impaired in idiopathic pedophilia, a coordinate based meta-analysis using the Activation Likelihood Estimation (ALE) method was performed  AND . A search for studies in review and meta-analysis articles and a reference tracing were also performed.To be included in the analysis, studies had to meet the following criteria: (i) use structural (sMRI) or functional (fMRI) MRI; (ii) perform a whole brain analysis  analysis were excluded); (iii) be original peer-reviewed data; (iv) include both pedophilic individuals and a healthy control group (HC) or pedophilic individuals who committed and who did not commit sexual abuse; (v) have a sample size of at least five individuals per group; (vi) report results in a standardized coordinate space .Literature screening and selection was performed according with the PRISMA guidelines  method  version 3.0.2. This algorithm treats activated foci of brain regions as three-dimensional Gaussian probability distributions centered at the given coordinates  ; therefore, they did not present a spatially defined lesion that could be outlined. In order to identify the neural structures consistently impaired in bvFTD, a coordinate based meta-analysis was run on papers presenting structural or functional abnormalities in patients with bvFTD vs. healthy controls  on the axial image of a standardized template using the MRIcron software  of patients with lesions functionally connected to each individual voxel. A stability analysis was performed by replicating the analyses using three different control groups, each with 25 healthy subjects . Analyses were performed using SPM-CONN (2018b) adopting standard preprocessing and denoising steps.Second, traced lesions were used as individual seeds in a seed based connectivity analysis, using resting state fMRI data from one hundred healthy subjects randomly selected from a freely available dataset: http://www.brainmap.org/), to reveal the Behavioral Domain and Paradigm Classes consistently associated with these regions.To link topographically defined brain regions with the corresponding psychological process, we ran a behavioral profiling approach across databases of aggregation from activations experiments  was impaired in nine patients, spared in four, while no data were available for the remaining six cases.Lesion localization was very heterogeneous, as reported in Table Though the individual lesions had different locations, the lesion network mapping analysis revealed that 95% of them were part of a single brain network defined by functional connectivity with posterior midline structures , including the posterior cingulate cortex (PCC) and precuneus; the bilateral OFC ); the right inferior temporal gyrus , the left calcarine gyrus  and the left fusiform gyrys   identify consistent alterations associated with acquired and idiopathic pedophilia; (ii) understand whether and to what extent the two forms of pedophilia may share the same biological substrate; (iii) investigate whether consistent brain abnormalities may explain psychopathological features typically detected in pedophiles.Of relevance, the lesion network mapping technique revealed that the neural bases of acquired pedophilia localize to a common resting state network, despite the high spatial heterogeneity of the individual lesions. Overall, these data support a shared neurobiological substrate in acquired pedophilia, as they reveal that the lesions chronologically associated with acquired pedophilic behavior are all functionally connected with a network involving the OFC areas, the posterior midline structures, the right inferior temporal gyrus and the left fusiform gyrus.On the contrary, the ALE meta-analysis of whole brain neuroimaging studies in idiopathic pedophilia revealed no spatially convergent findings across studies, suggesting that idiopathic pedophilia does not have consistent brain alterations that may be detected by structural or functional neuroimaging investigations. However, when lowering the statistical threshold, a few clusters of spatial convergence emerged in the superior frontal gyrus, middle cingulate and middle occipital gyrus. The different findings obtained from the analyses in idiopathic and acquired pedophilia may suggest that the two conditions may not rely on a shared neural base. Of note, the amygdala, which had been reported to be consistently impaired in pedophilia , specifically theory of mind (posterior midline structures), emotion recognition (right OFC), impulse control (right OFC), semantic interpretation of cues . It is noteworthy that these results match well with the aberrant behavior pattern described in acquired pedophiles. The observation of altered activity in a key region for impulse inhibition fits perfectly with previous evidence from single case description of patients with acquired pedophilia, in whom dis-inhibition is invariably present  model of causation . Results of neuroimaging analyses, however, strongly reflect cognitive/behavioral deficits observed in those patients, corroborating the plausibility of our analysis. Second, the lesion network analysis was run using only a relatively small sample of healthy controls (one hundred subjects). The additional analyses we run, however, corroborated the robustness of the results, which remained stable using different control groups of 25 healthy controls. Finally, in the lesion network mapping analysis we could not take into account potential medication effects in the individual patients. However, the original papers indicate that drugs were usually administered after symptoms insurgence, thus the impact of pharmacotherapy for the purposes of the current study is limited. Future studies should assess potential effects of pharmacotherapy.In summary, the results of this study pinpoint aberrant brain activity related to acquired but not to idiopathic pedophilia. All the lesions causing acquired pedophilia localized to a shared resting state network including the posterior midlines structures, the right inferior temporal gyrus and the bilateral OFC, regions consistently involved in social cognition, theory of mind, emotion recognition and action inhibition. Alterations of these neuropsychological functions have been consistently described in individual reports of acquired pedophiles, in line with the observed results. Interpreting these findings in light of the INUS model of causation is relevant to better characterize these patients and to develop novel therapeutic and rehabilitative strategies ESM 2(PDF 370 KB)ESM 3(DOC 92.5 KB)ESM 4(PDF 486 KB)ESM 5(DOC 47.0 KB)"}
+{"text": "The optimal blood pressure (BP) management in acute ischaemic stroke (AIS) and acute intracerebral haemorrhage (ICH) remains controversial. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist physicians in their clinical decisions regarding BP management in acute stroke.The guidelines were developed according to the ESO standard operating procedure and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available to provide recommendations based on the GRADE approach. Despite several large randomised-controlled clinical trials, quality of evidence is generally low due to inconsistent results of the effect of blood pressure lowering in AIS. We recommend early and modest blood pressure control (avoiding blood pressure levels >180/105\u2009mm\u2009Hg) in AIS patients undergoing reperfusion therapies. There is more high-quality randomised evidence for BP lowering in acute ICH, where intensive blood pressure lowering is recommended rapidly after hospital presentation with the intent to improve recovery by reducing haematoma expansion. These guidelines provide further recommendations on blood pressure thresholds and for specific patient subgroups.There is ongoing uncertainty regarding the most appropriate blood pressure management in AIS and ICH. Future randomised-controlled clinical trials are needed to inform decision making on thresholds, timing and strategy of blood pressure lowering in different acute stroke patient subgroups."}
+{"text": "Social support exchanges are an integral part of older adults\u2019 well-being. Yet, we know little about how older adults' marital status may influence their support exchanges with different social partners in everyday life, and whether the effect of support exchanges on daily well-being vary by marital status. Adults aged 65+ (N = 278) completed an initial interview about their background and close social networks; then, participants reported whether they provided or received support from their close social partners and rated their psychological well-being for 5 to 6 days. Multilevel logistic models revealed that married older adults were more likely to provide or receive daily support from their close partners than widowed or divorced older adults. However, with respect to specific non-spousal ties, married older adults were less likely to provide support to siblings, friends or others  compared to divorced older adults. Although married older adults were more likely to receive support from children than divorced older adults, they were less likely to receive support from siblings and friends compared to widowed or divorced older adults. Furthermore, receiving support from other familial ties  was associated with reduced daily well-being for widowed older adults whereas married older adults were able to maintain their daily well-being in such situation. Findings highlight the central role siblings and friends play in unmarried older adults' daily support networks and suggest that receiving support could have differential impact on daily well-being depending on older adults\u2019 marital status."}
+{"text": "As prevalence decreases in pre-elimination settings, identifying the spatial distribution of remaining infections to target control measures becomes increasingly challenging. By measuring multiple antibody responses indicative of past exposure to different pathogens, integrated serological surveys enable simultaneous characterisation of residual transmission of multiple pathogens.Here, we combine integrated serological surveys with geostatistical modelling and remote sensing-derived environmental data to estimate the spatial distribution of exposure to multiple diseases in children in Northern Ghana. The study utilised the trachoma surveillance survey platform  to collect information on additional identified diseases at different stages of elimination with minimal additional cost. Geostatistical modelling of serological data allowed identification of areas with high probabilities of recent exposure to diseases of interest, including areas previously unknown to control programmes. We additionally demonstrate how serological surveys can be used to identify areas with exposure to multiple diseases and to prioritise areas with high uncertainty for future surveys. Modelled estimates of cluster-level prevalence were strongly correlated with more operationally feasible metrics of antibody responses.This study demonstrates the potential of integrated serological surveillance to characterise spatial distributions of exposure to multiple pathogens in low transmission and elimination settings when the probability of detecting infections is low. Following implementation of successful interventions, one of the primary challenges for neglected tropical disease programmes is identifying areas with remaining disease transmission. As disease prevalence decreases, these infections become increasingly rare and hard to detect. Serological assays measure long-lived disease-specific antibody responses indicating past exposure to pathogens and increase the probability of detecting disease transmission. Here, we integrate serological assays with environmental and spatial data to map priority areas for surveillance for multiple neglected tropical diseases in Northern Ghana using the two-stage cluster-based survey platform established for trachoma surveillance. The use of multiplex bead assays measuring exposure to multiple pathogens allows integrated surveillance of diseases of interest to the national control programme. We identify areas with high risks of transmission to selected diseases as well as areas with high uncertainty which are priorities for future control and surveillance efforts. Together, this highlights the utility of multiplex serological platforms as a tool for integrated surveillance and mapping of neglected tropical diseases. Neglected tropical diseases (NTDs), such as trachoma, schistosomiasis, onchocerciasis, lymphatic filariasis and soil-transmitted helminthiases, cause substantial public health burdens globally. With increasing investment in NTD control, elimination and eradication programmes, community-based surveys are used to monitor impacts of interventions, identify residual transmission and target high-risk populations ,2. TheseAs transmission of infectious diseases decrease, the probability of detecting infections becomes correspondingly low and requires prohibitively large sample sizes to identify infections. For many diseases, this also corresponds with more pronounced spatial heterogeneity, with transmission concentrated in specific geographic areas or sub-populations \u20139. SerolThe development of multiplex serological assays increases the operational feasibility of serological techniques by enabling measurement of a broad range of responses with high repeatability from limited blood samples. Multiplex bead assays (MBA) are a well-validated method to measure population-level serological responses to a wide panel of NTDs, malaria, vaccine preventable diseases and other infections . These aDespite increasing collection of serological data, challenges remain in translating these data into actionable programmatic information . SpatialHere, we adapt a commonly used Gaussian mixture model and binomial geostatistical models to describe the spatial distribution of antibody responses to multiple diseases in a population-based survey of children in Northern Ghana. Conducted as part of routine surveillance for trachoma elimination, this survey utilised a two-stage cluster-sampling population-based survey design and identified very low levels of the sign \u201ctrachomatous inflammation\u2014follicular\u201d, a finding supported by estimates of seroconversion rates \u201329. AlthThis study was approved by the Ghana Health Service Ethics Review Committee (GHS-ERC: 03/07/15) and the London School of Hygiene & Tropical Medicine (10285). Written informed consent was sought from parents or guardians of all participating children. Verbal assent was additionally obtained from children who were able to provide this. The CDC investigators were not considered to be engaged in human subjects research.www.getodk.org).This study was conducted in the Northern, North East, Savanna and Upper West regions of Ghana in a predominantly rural agricultural population . The cliChlamydia trachomatis), Wb123 lymphatic filariasis (Wucheria bancrofti), Ov16 onchocerciasis (Onchocerca volvulus), NIE strongyloidiasis , soluble egg antigen (SEA) schistosomiasis (Schistosoma mansoni), rp17 and TmpA yaws , VSP3 giardiasis (Giardia lamblia). Glutathione s-transferase (GST) was used as a negative control. MBA were conducted using standard methods )Within this setting, serological data support other estimates of NTD burdens and associated environmental risk factors within Northern Ghana. These results are consistent with previous findings of very low prevalence of trachoma and additionally demonstrate how serology may be employed to identify areas for post-elimination surveillance for potential recrudescence ,28. AddiO. volvulus transmission. However, lymphatic filariasis MDA ceased in 2014, and these serological data indicate an increase in onchocerciasis previously unknown to GHS and as a direct result of the integrated surveillance approach, GHS decided to start MDA specifically for onchocerciasis in this focus . While further work is required to confirm transmission and disease burdens may have changed since 2015, this identifies a priority area for surveillance.Geostatistical modelling of serological data representing exposure to multiple pathogens has important implications for survey design. The systematic and random population-based sampling strategy used for trachoma mapping enabled assessment of the distribution of other NTDs; this approach would not have been feasible with purposive sampling. For example, this study identified a focus of onchocerciasis with a significant prevalence of anti-Ov16 antibodies in children aged 1\u20139 years in Saboba-Cherepon. Previous mapping of onchocerciasis in this area through the Rapid Epidemiological Mapping of Onchocerciasis (REMO) in 2009 determined this to be an area of hypo-endemicity, not requiring onchocerciasis specific MDA at that time. Since then, the area has been treated for lymphatic filariasis, which includes the delivery of ivermectin  and the expectation had been this would also impact on For control and elimination programmes needing to make operational decisions quickly without access to technical expertise needed to develop geostatistical models, very simple metrics can be applied to identify locations at high risk of transmission. While the relationship between arithmetic mean MFI values and estimated seroprevalence is not linear, prioritising control activities at clusters with the highest mean MFI values would likely ensure that interventions are reaching communities with the highest seroprevalence. This agrees with previous studies showing high correlation between mean quantitative antibody levels and other infection-based metrics of NTD transmission ,24. As sDespite the value of this approach, this study had several important limitations. As this study does not include adults, further validation of these methods may be required in settings with very high historical transmission and exposure in older age groups. While serological surveys of children are likely to be a better marker of recent rather than historical exposure, the utility of this approach will vary for specific diseases and associated risk factors. For trachoma, young children under 9 are believed to be the primary source of infection. In contrast, children aged under 5 years have lower risks of onchocerciasis and schistosomiasis, which predominantly impact school-aged children and adults with high-risk occupational activities. This highlights a key methodological challenge of integrated surveys targeting multiple diseases with different risk groups and transmission mechanisms. Additionally, this analysis relied on a single dataset collected over one time point. These diseases may additionally have differing immune responses, antibody kinetics and infection periods and longitudinal data may be able to more accurately identify recent infections or characterise transmission . The uncDespite these limitations, this study demonstrates how integrated serological surveillance can characterise the spatial distribution of exposure to multiple pathogens. An adaptable framework is provided to understand the spatial and environmental factors driving transmission in elimination settings when infection data are rare. As countries approach elimination, this study additionally highlights the need for innovative surveillance approaches utilising population representative sampling to maximising efficiency by collecting data across multiple diseases. Applying these techniques can provide valuable information for control programmes needing to identify and target remaining foci of infection.S1 TextTable A. Priors used for proportions in three component mixture models. Table B. Spatial and environmental covariates. Fig A. Disease-specific antibody responses for all included children, i. Density plots of log-transformed MFI values, ii. Age distributed antibody responses. Fig B. Antibody densities by age categories. Fig C. Relationships between mean posterior estimates of seroprevalence and arithmetic mean MFI per cluster for: A) Trachoma; B) Filariasis; C) Onchocerciasis; D) Strongyloides; E) Schistosomiasis; F) Giardiasis.(DOCX)Click here for additional data file."}
+{"text": "Glutathione is an intracellular antioxidant that neutralizes reactive oxygen species and prevents tissue damage. Dietary supplementation with the glutathione precursors glycine and n-acetylcysteine supports the maintenance of normal glutathione levels in several age-related diseases, but the optimal doses and their efficacy in healthy elderly are not established. We report results from a randomized controlled clinical trial in 114 healthy volunteers (mean age = 65 years) receiving glycine and n-acetylcysteine (GlyNAC) at three different doses for two weeks . Older subjects showed increased oxidative damage and a lower reduced-to-oxidized glutathione ratio (GSH:GSSG) compared to young subjects, but unchanged total glutathione levels. GlyNAC did not increase levels of circulating glutathione compared to placebo treatment, the primary study endpoint. However, stratification analyses suggest that subjects with high oxidative stress and low glutathione status responded with glutathione generation. We find that unrelated to glutathione status, healthy aging was associated with lower levels of fasting glycine that can be increased towards those observed in young subjects with supplementation. Using preclinical models, we find that tissue glycine depletion is a common feature of healthy aging. Supplementation of old mice with glycine efficiently improved age-related decline of mitochondrial respiratory function in skeletal muscle and prevented a gene program associated with protein catabolism observed in control-treated animals. In conclusion, GlyNAC is safe and well-tolerated and may selectively increase glutathione levels in older subjects with oxidative stress and glutathione demand. Our data further suggest that glycine may support mitochondrial function independently of NAC."}
+{"text": "Suicide rates increase over the life-span, necessitating concern in older adults. Recent studies suggest that anxiety disorders are associated with suicidal thoughts and behavior. The present study examined the association between anxiety symptoms  and suicide risk (Suicide Behaviors Questionnaire-Revised), testing whether the association differs between younger and older adults. Depression symptoms  were controlled for in the analyses. In a sample of 944 participants (46% 60+ years), anxiety symptoms, depression symptoms, and suicide risk were lower among older adults (60+ years) than younger adults . Age moderated the significant association between anxiety symptoms and suicide risk . Results indicate that an increase in anxiety is associated with a smaller increase in suicide risk for older adults than younger adults. The need for suicide risk screening among individuals with elevated anxiety symptoms is critical, especially for younger adults."}
+{"text": "This session will provide updates on how the pandemic led to horrific situations in long-term care facilities and how the pandemic influenced major federal efforts to address elder abuse, neglect, and exploitation."}
+{"text": "Although numerous risk factors are reported in the literature, many are non-modifiable and management of the injury remains difficult. Lower leg muscle structure and function are modifiable characteristics that influence tibial loading during foot-ground contact. Therefore, this study aimed to determine whether long-distance runners with MTSS displayed differences in n\u2009=\u200920) and matched asymptomatic controls (n\u2009=\u200920). Means, standard deviations, 95\u2009% confidence intervals, mean differences and Cohen\u2019s d values were calculated for each variable for the MTSS symptomatic and control limbs.Lower leg structure was assessed using ultrasound and a measure of lower leg circumference to quantify muscle cross-sectional area, thickness and lean lower leg girth. Lower leg function was assessed using a hand-held dynamometer to quantify maximal voluntary isometric contraction strength and a single leg heel raise protocol was used to measure ankle plantar flexor endurance. Outcome variables were compared between the limbs of long-distance runners suffering MTSS (MTSS symptomatic limbs displayed a significantly smaller flexor hallucis longus cross-sectional area, a smaller soleus thickness but a larger lateral gastrocnemius thickness than the control limbs. However, there was no statistical difference in lean lower leg girth. Compared to the matched control limbs, MTSS symptomatic limbs displayed deficits in maximal voluntary isometric contraction strength of the flexor hallucis longus, soleus, tibialis anterior and peroneal muscles, and reduced ankle plantar flexor endurance capacity.Differences in lower leg muscle structure and function likely render MTSS symptomatic individuals less able to withstand the negative tibial bending moment generated during midstance, potentially contributing to the development of MTSS. The clinical implications of these findings suggest that rehabilitation protocols for MTSS symptomatic individuals should aim to improve strength of the flexor hallucis longus, soleus, tibialis anterior and peroneal muscles along with ankle plantar flexor endurance. However, the cross-sectional study design prevents us determining whether between group differences were a cause or effect of MTSS. Therefore, future prospective studies are required to substantiate the study findings. Medial tibial stress syndrome (MTSS), more commonly known as shin splints, is one of the most common forms of exercise induced lower leg pain . ResearcTwo risk factors for MTSS that could easily be modified is structure and function of the lower leg muscles that contribute to the changes in lower leg girth seen in individuals who develop MTSS. Authors have previously reported that compared to asymptomatic controls, MTSS symptomatic individuals displayed less lean lower leg girth , reducedin vivo lower leg muscle cross-sectional area (CSA) or thickness to determine whether reduced lean lower leg girth associated with MTSS is due to atrophy of specific lower leg muscles or a uniform reduction in lower leg muscle size. A better understanding of how lower leg muscle composition differs between MTSS symptomatic and asymptomatic controls will provide evidence to develop future intervention studies that target specific lower leg muscles to treat or prevent MTSS.Lean lower leg girth is a circumferential measure of lower leg muscle bulk measured while a participant is standing and then corrected for adipose tissue thickness. Lean lower leg girth, however, does not provide information regarding how individual lower leg muscle composition affects the overall circumference measurement. To date, no study could be located that has assessed in vivo structural composition measurements. Researchers have previously reported that when matched to asymptomatic controls, MTSS symptomatic individuals display less ankle plantar flexor endurance, increased flexor hallucis longus plantar flexion torque and a greater isokinetic evertor strength compared to invertor muscle strength  measured the lower leg muscle thickness and CSA, lean lower leg girth and lower leg MVIC strength of a convenience sample of two females and four males on two separate occasions. Intraclass correlation coefficients for lower leg muscle thickness all >\u20090.671) and CSA , lean lower leg girth (0.992) and lower leg MVIC strength  confirmed the measurements were moderate to highly reliable. The ankle plantar flexor endurance protocol has previously been shown to have excellent test-retest reliability [71 and CSp\u2009<\u20090.05) differences in the outcome variables between the 20 MTSS symptomatic and 20 matched control limbs. The effect size was calculated using Cohen\u2019s d where 0.2, 0.5 and 0.8 were considered small, moderate and large, respectively [Descriptive statistics  were calculated for each variable for the MTSS symptomatic and control limbs. Nine of the eleven MTSS symptomatic participants experienced bilateral symptoms. Therefore, a mixed-model linear regression design was used to determine whether there were any significant  at the middle and distal thirds of the medial margin of the tibia, which coincides with the site of MTSS pain. Given the findings of Naderi et al. [A thinner SOL and lower SOL MVIC strength, combined with a thicker GL, could be compensatory strategies by MTSS symptomatic participants to reduce SOL traction on the tibia. Naderi et al.  prospecti et al.  and thati et al. . FurtherMTSS symptomatic limbs in the current study also displayed a significant deficit in ankle plantar flexor endurance capacity compared to control limbs. This is unsurprising given the significantly lower ankle plantar flexor muscle strength, notably reduced SOL strength, considering its endurance capacity associated with postural tasks . These fThe FHL and TA help control medial longitudinal arch (MLA) height and attenuate ground reaction forces during the stance phase of gait. Naderi et al.  concludeAnother possible explanation for the lower strength of FHL, P, SOL and TA in MTSS symptomatic participants could be due to pain and associated neuromuscular adaptations. Although the mechanics are not entirely understood, individuals who experience pain (e.g. lower back pain) display altered muscle activation patterns and morphological muscle changes . FurtherIt is acknowledged that, as a cross-sectional study, we cannot determine whether the between group differences identified in this study were a cause or effect of MTSS development. Furthermore, the small sample size prevents definitive conclusions from being made. We were also not able to assess the structure of tibialis posterior due to constraints of our ultrasound probe. Tibialis posterior contributes to ankle plantar flexion and foot inversion and, therefore, assists in reducing the negative tibial bending moment during the stance phase of gait. Future research should be prospective in design and assess the structure and function of tibialis posterior to determine its role in resisting negative tibial bending moments.Compared to well-matched control participants, runners suffering MTSS symptoms displayed less FHL CSA and SOL thickness but greater GL thickness, as well as lower FHL, SOL, P and TA MVIC strength and ankle plantar flexor endurance capacity. These differences may contribute to the slow recovery time typically seen by MTSS patients because they might be less able to withstand the negative tibial bending moment generated during midstance, which can cause greater tibial strains. Furthermore, future investigation of asymptomatic runners using a prospective design is required to determine whether the between group differences identified in this study are consistent in runners who develop MTSS."}
+{"text": "ABSTRACT IMPACT: Access to intracranial recording in our epileptic sample provides a unique opportunity to characterize neurological activation patterns associated with attention and implicit learning; this foundational physiological understanding will serve to better guide cognitive rehabilitation techniques in TBI patients that aim to improve functioning across these cognitive domains. OBJECTIVES/GOALS: 1) Investigate the network level interactions of attention and learning during an attention network task (ANT) and an implicit learning contextual cueing (CC) task. 2) Assess the effect that attention rehabilitation strategies have on behavioral and neural responses pre/post-attentional intervention. METHODS/STUDY POPULATION: This study involves refractory epilepsy patients (rEP) with implanted intracranial electrodes and moderate-to-severe traumatic brain injury (m/sTBI) survivors. In rEP, we are identifying network level modulations of cortical regions via the ANT, which probes components of attention  and a CC task that probes implicit learning. We hypothesize that modulation of attention and learning can be seen at the neuronal level. In TBI we will assess improvement following two behavioral attention rehabilitation paradigms; and use our results from epileptic patients to guide measurement of treatment-related neuroplastic change via scalp electroencephalography. RESULTS/ANTICIPATED RESULTS: Preliminary behavioral results from the rEP cohort are in line with previous studies and the intracranial data is suggestive of region- and task-specific modulations in memory and attention related systems. Following completion of recruitment, we expect to more concretely identify regions and networks that exhibit modulatory effects associated with attention and implicit learning. Additionally, we anticipate that deficits in attention will be mitigated following training and hypothesize that implicit learning rate will improve in TBI patients as a result of both attentional rehabilitation paradigms. DISCUSSION/SIGNIFICANCE OF FINDINGS: Characterizing intracranial activity in epilepsy patients will give electrophysiology data unattainable in TBI patients. This intracranial perspective will enable us to propose mechanisms of action that may result from our interventions and enable critique of current rehabilitation treatments."}
+{"text": "Fifteen Veterans Administration Medical Centers (VAMCs) offer geriatric specialty care telehealth services through a hub and spoke model to patients at affiliated community-based outpatient clinics (CBOCs). These services are not used to the extent they could be. Through interviews with 50 staff and providers at rural CBOCs we identified several implementation facilitators and barriers. CBOC-level barriers included space constraints, low staffing, internet connection issues, and limited knowledge of services available and referral processes. Patient-level barriers included discomfort with technology, cognitive decline, and inability to travel to the CBOC. We found that champions within the CBOC and iterative, targeted outreach from the hub helped facilitate uptake of services. We entered the identified barriers into the CFIR-ERIC (Consolidated Framework for Implementation Research-Expert Recommendations for Implementing Change) Implementation Strategy Matching Tool to help generate targeted strategies that will be used to refine each hub\u2019s implementation approach."}
+{"text": "Relationship research has suggested that health among spouses is interdependent and should be considered jointly. Using data from the 2008/2010 and 2016/2018 waves of the Health and Retirement Study , we investigated the joint influence of married partners\u2019 individual and shared cumulative biological risk on future health outcomes. Two risk indicators were constructed to indicate biological health in different domains. Individual grip strength, walk speed, lung function, and cystatin-C were biomarkers selected to construct frailty risk whereas blood pressure, pulse, waist circumference, C-reactive protein, glycohemoglobin, high-density lipoprotein cholesterol, and total cholesterol were biomarkers used to construct cardiometabolic risk. Shared risk was calculated as the number of risks the partners shared. We employed multilevel Poisson regression models to nest partners within couples and examine the effects of individual and shared cumulative risks on future functional limitations. Heckman correction was performed to correct potential selection bias. Our unadjusted models showed individual  and shared  risks are associated with greater future functional limitations. Further, shared cardiometabolic risk moderated the effect of individual risk . In the adjusted models, the direct associations between shared risks and future functional limitations were explained by indicators of partner selection and shared experiences. In the fully adjusted model, the cross-level interaction for frailty risk became statistically significant. The unique set of dynamics shown in our study offered new insights into understanding how couples influence one another in the context of multisystem biological health."}
+{"text": "Most prior research on caregivers\u2019 mental health focused on individual or household factors, we know much less about the influence of neighborhood factors on mental health of spousal caregivers. The current study fills the gap in our knowledge by examining the association of neighborhood characteristics  and depressive symptoms among spousal caregivers. We used data from 2006 to 2016 waves of the Health and Retirement Study, which includes 2,362 spousal caregivers. Negative binomial regression models were estimated to examine the association of perceived neighborhood disorder and neighborhood social cohesion with depressive symptoms. A greater perceived neighborhood disorder was associated with higher CES-D scores, which indicates more depressive symptoms. On the other hand, a higher level of neighborhood social cohesion was associated with lower CES-D scores. When they were included in the same model, the association between neighborhood disorder and depression disappeared, while respondents who reported higher levels of neighborhood social cohesion continue to exhibit lower CES-D scores than those lived in less cohesive neighborhoods. This study highlights the importance of neighborhood contexts in understanding caregivers\u2019 well-being. Findings of this study suggest that neighborhood social cohesion may attenuate the negative effects of neighborhood disorder. Therefore, enhancing positive characteristics of the neighborhood may promote well-being of spousal caregivers."}
+{"text": "Research on professional burnout during the pandemic has focused on hospital-based health care workers. This study examined the psychological impact of the pandemic on home-based primary care (HBPC) providers. We interviewed 13 participants from six HBPC practices in the New York including medical/clinical directors, program managers, nurse practitioners, and social workers and analyzed the transcripts using inductive qualitative analysis approach. HBPC providers experienced emotional exhaustion and a sense of reduced personal accomplishment. They reported experiencing grief of losing many patients at once and pressure to adapt to changing circumstances quickly. They also reported feeling guilty for failing to protect their patients and reduced confidence in their professional expertise. Strategies to combat burnout included shorter on-call, regular condolence meetings to acknowledge patient deaths, and peer support calls. Our study identifies potential resources to improve the well-being and reduce the risk of burnout among HBPC providers."}
+{"text": "Despite successful defect coverage by means of complex skin or muscle flaps, particularly large and deep problematic wounds with exposed bradytrophic tissues after soft tissue loss are very susceptible to surgical revision.A dermal matrix, consisting of native collagen  supplemented by an elastin hydolyzate was first used for the treatment of burns, predominantly those that were full-thickness. Subsequently, its use was extended to defect coverage especially after soft tissue loss caused by degloving injuries.52 patients with exposed bradytrophic tissues caused by severe burn or degloving injuries were treated the same way.In all patients operative debridement showed soft tissue loss with free bone or free periostal structures, exposed tendons or joint capsules.In all patients after accurate wound bed preparation defect coverage was performed with collagen-elastin matrix and unmeshed split skin grafts in combination with negative pressure wound therapy for fixation of dermal matrix and split skin grafts.Two-years follow up of these collagen-elastin matrix procedures in defect coverage showed an excellent functional outcome:Up until now, no areas with unstable scars have occurred, no surgical scar revisions were required. The patients were still able to wear normal footwear, clinical gait analysis showed perfect functional outcome.The application of collagen-elastin matrix in patients with exposed bradytrophic tissues after severe burn or degloving injury treated so far represents an excellent reconstruction method, from initial coverage to scar development."}
+{"text": "Whether slowing disease progression or combatting the ills of advancing age, the extensive utility of exercise training has contributed to the outright declaration by the American College of Sports Medicine that \u2018exercise is medicine\u2019. Consistent with general framework of adaptation, the advantages of exercise training are indiscriminate\u2014benefitting even the most susceptible clinical populations. Still, the benefit of exercise training presupposes healthy adaptation wherein progressive overload matches sufficient recovery. Indeed, a difference exists between healthy adaptation and non-functional over-reaching \u2014a difference that may be blurred by cancer treatment and/or comorbidity. Recent advances in smartwatches make them ideally suited to non-invasively monitor the physiological stresses to exercise training. Resolving whether individuals are successfully adapting to exercise training via load monitoring bears clinical and practical relevance. While behaviour-change research aims to identify positive constructs of exercise adherence, further attention is needed to uncover how to optimise exercise prescription among cancer populations. Herein, we briefly discuss the constituents of exercise load monitoring, present examples of internal and external load and consider how such practices can be applied to cancer populations. The systemic benefits of exercise training are irrefutable.A difference exists between healthy adaptation and non-functional over-reaching \u2014a difference that may be blurred by cancer treatment and/or comorbidity.Smartwatches are ideally suited to non-invasively monitor the physiological stresses to exercise training.Resolving whether individuals are successfully adapting to exercise training via load monitoring bears clinical and practical relevance.The benefit of exercise training presupposes healthy adaptation wherein progressive overload matches sufficient recovery. However, one of the most challenging barriers of exercise prescription is knowing how and when to modulate frequency, intensity and duration for continued improvement .et al were some of the concerns surrounding exercise training in cancer patients assuaged.In the last 20 years, considerable momentum has been achieved within in the field of exercise oncology\u2014now recognised as subdiscipline of oncology research.10.1136/bmjsem-2021-001134.supp1Supplementary dataFrom a practical perspective, recent advances in smartwatches make them ideally suited to non-invasively monitor the physiological stresses to exercise training. Such an approach extends the reach beyond laboratory settings and the need for expensive instruments to evaluate progress. Given the current challenges attributed to the COVID-19 pandemic, having remote access to individual exercise training responses is an attractive option to strengthen home-based exercise. Resolving the nuances of healthy adaptation and recovery will assuredly influence exercise prescription with related effects on injury risk and exercise adherence as well. The exercise training dose\u2013response relationship is akin to a pharmacological investigation evaluating the efficacy of a medication. Indeed, a difference exists between healthy adaptation and non-functional over-reaching Though the absolute workload is appreciably higher among athletic populations, the same principles of training, recovery and adaptation apply to cancer populations. While the implementation of exercise load monitoring may vary, the importance of individualising such an approach cannot be overstated. Since age, cardiorespiratory fitness and non-exercise stressors all contribute to the rate of recovery, it is unsurprising to observe large within-person/between-person differences emerge regarding exercise tolerance and subsequent adaptations. Therefore, to promote further sophistication in the field of exercise oncology, the present viewpoint briefly discusses the constituents of exercise load monitoring, presents examples of internal and external load and considers how such practices can be applied to cancer populations.It is customary to delineate the quantification of exercise training load into internal and external constructs. Internal training load reflects physiological ) and psychological ) stressors, whereas external training load represents metrics of work performed such as distance travelled, steps per day or repetition counts. Consensus indicates a combined approach yields a clearer perspective about the inherent oscillations involving exercise adaptation and recovery.2) share a linear relationship at submaximal intensities. Given the combined effects of blood volume expansion, increased stroke volume and heightened parasympathetic outflow, one of the most prominent phenotypic attributes of exercise training is a lowered HR at rest and during exercise. Since HR fluctuates daily, a single measurement provides little useful interpretive information such that repeated measurements and consideration for adequate hydration are essential. Unlike the transient changes in HR over the course of a day, resting HR when measured under standardised conditions is thought to reflect global cardiovascular health. Thus, changes in resting HR over days may be indicative of physiologic or psychologic stressors, whereas alterations over weeks may represent increased (or decreased) cardiorespiratory fitness.7Wearable health monitoring technologies including smartwatches have become a familiar sight. Owing to the non-invasive capabilities of photoplethysmography, infrared light is used to measure the volumetric variations of blood circulation\u2014making it possible to measure and record HR in real time. At the onset of exercise, sympathetic activity rises to produce an intensity-dependent increase in HR. As such, HR and oxygen uptake  modification. This common shortcoming is thought to interfere with study reproducibility, interpretation and cross-study integrationAccess to wearables can expedite the collection of internal and external load data, however, having a system in place to make meaningful inferences about adaptive responses can be challenging. Numerous research publications have endeavoured to extract the most from exercise training in elite athletes\u2014yet such efforts are still gaining traction in cancer populations.Resolving whether individuals are successfully adapting to exercise training via load monitoring bears clinical and practical relevance. While behaviour-change research aims to identify positive constructs of exercise adherence, further attention is needed to uncover how to optimise exercise prescription among cancer populations. Consideration for measurement error notwithstanding, there is need to identify early signs of maladaptation, including the smallest worthwhile change,"}
+{"text": "While existing microbots display effective propulsion, their functionalities decrease dramatically upon decreasing the robot size. Accordingly, it is desired to customize microscale robots for their specific mission and body location. Selecting the microbot constituents with task-specific tailored functionalities will enhance their practicality in performing their primary mission. A myriad of synthetic microbots, based on various propulsion mechanisms and different designs and materials, have thus been developed7. New functionalities and capabilities have been added to these tiny machines, including fast motion in complex biological media, large cargo-towing force, collective behavior and excellent biocompatibility for use in living systems. These attractive capabilities have paved the way to sophisticated microscale robotic devices capable of performing complex tasks and have motivated researchers to explore exciting new important in vivo biomedical applications ranging from targeted drug delivery to precise surgery and intracellular biosensing10. While the scaling down of robotic platforms has tremendous potential for advancing the treatment and diagnosis of patients, it also brings fundamental engineering challenges such as power sourcing, motion control and tracking, integration of multifunctionality, safety and related recovery and degradation capabilities11. Unlike large robots, the tiny footprint of microbots greatly hampers the ability to integrate multiple functions (without compromising their dimensions). For example, important microbot operations, such as drug delivery and cleaning out clogged arteries, have completely different requirements and hence rely on largely incompatible functions, which are extremely challenging to combine with a single microscale robot.Over the past 15 years the field of microbots has exploded with many teams from around the globe contributing to major innovationsConsidering the major challenges of fabricating multifunctional microscale robots, a key question arises: is the future hold for general-purpose universal microbots capable of performing a wide range of tasks or to simple microbots tailored to meet the demands of specific applications and target locations Fig.\u00a0? Big rob2, but these fabrication methods also face critical miniaturization constraints, which limit their functional capabilities to few basic functions. Instead, future multifunctional microscale robots could rely on smart multi-responsive materials capable of imparting several mission-specific functions into a single portion of such a microbot for executing multiple tasks. Such bio-inspired responsive materials can enable programmable, reconfigurable mobile microscale robots and increase the adaptability of such microbots for complex operations without scaling up the robot\u2019s footprint12. For example, smart biomarker responsive materials can lead to theranostic microbots, performing \u201csense and release\u201d functions by detecting disease-specific marker to trigger autonomous release of their embedded therapeutic payload13. Such route can enable diabetes theranostic applications based on autonomous closed-loop glucose-responsive insulin-delivery gated acoustic vehicles14.In contrast, the preparation of multifunctional microscale robots requires a paradigm shift from the traditional mechanical assembly fabrication route used for preparing larger (millimeter) scale robots, e.g., ingestible capsules. While these larger robots commonly rely on different sections to obtain their different functions, microbots are too small to be prepared by such mechanical assembly fabrication route. Some efforts have been devoted to advanced rolled-up and template deposition techniques for fabricating microbots with several functional unitsAdvanced robotics fabrication and functionalization technologies are paving the way to new robotic capabilities which are attractive for a wide range of biomedical applications. However, despite of these tremendous technological advances, it is extremely challenging to design and efficiently manufacture multifunctional microbots capable of performing diverse tasks. Considering the tiny dimensions of microbots and the largely different operational requirements of different microbot applications and body locations, the design of small-scale multi-purpose robots faces distinct challenges. Typical strategies for preparing large multi-purpose robots cannot be adapted to the microscale.11. Despite the major progress towards developing such bio-inspired microbots there is still a long way for the performance of synthetic microbots to compete with the sophistication of nature\u2019s biomotors. A multidisciplinary collaboration in science, engineering and medicine and researchers trained with cross-disciplinary research skills are vital for addressing critical barriers for translating microbots into the clinical practice toward establishing a new era in the treatment of diseases.The efficiency of microbots to perform their main mission will be greatly improved by using simple robot design custom-made specifically to this mission. Designing the microscale robots with task-specific tailored materials and functionalities will allow customization of microbots for their primary biomedical mission and will enhance their practicality and efficiency in performing this mission. Incorporating additional features that are not essential for this specific biomedical operation can greatly compromise their effectiveness to perform their main task. Complex biomedical operations, requiring multiple tasks, will require multifunctional microbots based on new advanced fabrication techniques. In particular, bio-inspired responsive materials offer tremendous promise for designing theranostic microbots, integrating the sense and release functions. Alternately, it may be possible to combine different single-function microbots in swarms for performing different operational tasks"}
+{"text": "Growing evidence shows that the thalamus, beyond serving as an information relaying center, has key roles in motivated behaviors  contribute to both normal  and abnormal  salience processing.The hypothesis-and-theory by Qui\u00f1ones-Laracuente et al. examined the time-dependent recruitment of pre-limbic (PL) prefrontal inputs onto PVT following auditory fear learning. The authors showed that PL to PVT projections are activated by conditioned stimuli (CS) 7 d, but not 2 h, following learning. In contrast, the PL-amygdala circuit is preferentially recruited 2 h following learning. In addition, unit recordings of Layer VI PL neurons, the origin of projections to PVT, exhibit increased cue-induced inhibition at later, but not earlier, time points. Together, these results suggest that PL signaling of simple fear associations shifts with time toward inhibitory modulation of PVT, which may underlie disinhibition of PVT neurons  and subsequently enhanced central amygdala output.In our collection, five articles exclusively focus on PVT. The original research article by Matzeu and Martin-Fardon reported that posterior PVT injections of orexin-A peptide promotes reinstatement of extinguished cocaine seeking after intermediate (2\u20133 weeks), but not protracted (4\u20135 weeks), abstinence. Intermediate but not protracted abstinence is associated with an upregulation of orexin 2 receptor expression in PVT, while orexin cell numbers increase after both intermediate and protracted abstinence. This work extends previous work on the role of hypothalamic orexin (hypocretin) neurons in PVT in addiction-related behavior  but not reward value (incentive information). In contrast, activity of PVT neurons that fire immediately before reward delivery is correlated with reward value but not predictive information. Together, these data capture the heterogeneity of PVT responses to discrete processes involved in cue-induced motivated behaviors.Rowson and Pliel provide a timely review on the sex-dependent effects of acute vs. chronic stress on PVT, and outline the implications of this dimorphism for motivated behaviors. Consistent with the idea of PVT as a complex integrator of varied physiological signals, Petrovich elegantly discusses the role of PVT in controling feeding behavior. Petrovich describes a framework whereby PVT integrates homeostatic and hedonic needs to feed with physiological and environmental stress signals, ultimately guiding the balance between food seeking and consumption.PVT is also a regulator of stress  in action selection. Further discussion of afferents of each structure leads to the hypothesis that Pf and OFC together contribute to internal state representation during action selection either through direct Pf to OFC projections or convergence of their respective inputs onto striatal cholinergic interneurons.Two reviews focus on ILN, recently implicated in goal-direct behaviors  and individual central thalamic nuclei  in delayed conditional discrimination tasks through lesion studies in rodents. The authors review electrophysiological findings in MD and mPFC during adaptive goal-directed behaviors, which suggest that MD affects both action and outcome-related neuronal responses in mPFC.Finally, We appreciate these excellent contributions. These articles not only summarize the current findings on the role of individual thalamic nuclei mediating motivated behavior, but also raise intriguing questions about how thalamus exerts these effects. We hope that this issue gives impetus to ongoing work in the field to better characterize the role of thalamus in motivated behaviors and related disorders.XL and MJ took the lead in writing this editorial. GM contributed to its finalization. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Purpose: The purpose of this study was to assess whether there was an association between care-recipient relationship type and the QoL of older adults and their informal caregivers, and whether this association pertained to older adults\u2019 cognitive function. Methods: This was a secondary data analysis. Older adults (n=1230) and their informal caregivers (n=1871) were identified from participants in the National Health and Aging Trends Study (NHATS) Round 5 and the National Study of Caregiving (NSOC) II. A series of bivariate and multivariable regression models examined the associations among the care-recipient relationship type and QoL in older adults and their informal caregivers, adjusted for socio-demographic variables as well as cognitive functioning. Results: Both older adults and caregivers\u2019 QoL outcomes varied by the type of relationship. Recipients cared for by adult-child caregivers or multiple caregivers experienced higher functional limitation than those cared by spousal caregivers . \u201cOther\u201d caregivers, such as siblings, friends, etc., had lower odds of experiencing negative emotional burden than spousal caregivers . \"Other\" caregivers were also 51% less likely to experience social strain than spousal caregivers. Lower odds of experiencing negative emotional burdens were also found with multiple caregivers. The association between adult-child caregivers and social strain was explained by the recipients\u2019 cognitive function. Conclusions: Care-recipient relationship type impacts the QoL in both recipients and their informal caregivers. This association appears to be affected by care recipients' cognitive function level."}
+{"text": "Most clinical studies supporting procalcitonin (PCT)-guided management of lower respiratory tract infections have been performed in adults. There is a paucity of studies evaluating the clinical impact of PCT use in children and limited data informing age-appropriate PCT cut-offs; diagnostic accuracy in immunocompromised children; patient subgroups most likely to benefit from PCT testing; whether PCT adds value beyond available rapid molecular viral diagnostics; and optimal implementation strategies for PCT-guided treatment. At the present time there is little evidence to support routine use of PCT to aid management of paediatric pneumonia. Procalcitonin (PCT) is a biomarker that shows promise in identifying bacterial infection and is increasingly used in patients of all ages. Several PCT assays are approved by the US FDA for prediction of mortality and to guide antimicrobial management in sepsis and lower respiratory tract infection (LRTI). However, the vast majority of clinical studies supporting PCT-guided management have been done in adults. Few rigorous, interventional studies have evaluated the impact of PCT use in children, in whom its clinical utility is unclear. At the present time there is little evidence to support routine use of PCT to aid management of paediatric pneumonia.et al.P\u2009<\u20090.001). However, more recently, the ProACT trial enrolled 1656 adults with LRTIs from 14 US emergency departments and randomized them to management using a PCT testing and treatment algorithm versus usual care. The primary outcome was antibiotic days by 30\u2009days after enrolment.Despite extensive evaluation in adults, it is still not clear whether use of PCT provides benefit for management of adult LRTI. Schuetz P\u2009=\u20090.039). In another RCT, Esposito et al.P\u2009<\u20090.05), and fewer antibiotic days . Both the above trials enrolled subjects before 2010, prior to widespread use of molecular viral diagnostics; had a small sample size; did not include many subjects with severe CAP; and did not report compliance with the PCT algorithm, so the applicability of these studies to current practice is unclear.In contrast to the numerous published adult LRTI PCT trials, there are only two paediatric RCTs evaluating PCT use in paediatric pneumonia. The ProPAED trial enrolled 337 subjects <18\u2009years old with LRTIs in two emergency departments in Switzerland and randomized them to receive either PCT-guided antibiotic management or usual care.,et al.Several observational studies highlight the limitations of PCT as a diagnostic aid for management of paediatric pneumonia. Twenty years ago a study of 72 children hospitalized with CAP found greater positive and negative predictive values of PCT than other biomarkers, including C-reactive protein and WBC count, for differentiating bacterial and viral causes of pneumonia.Additional paediatric-specific evaluations of PCT in LRTI are clearly needed to address numerous questions about PCT, including determining appropriate age-based PCT cut-offs, diagnostic accuracy in immunocompromised children, and patient subgroups most likely to benefit from PCT testing. In some studies of paediatric sepsis and LRTI, low PCT values may reduce antibiotic use among patients with low acuity illness and low likelihood of having bacterial infection; thus, PCT may be most promising for ruling out rather than ruling in bacterial disease, but further studies are needed to confirm this.In conclusion, the clinical utility of PCT to guide diagnosis and antibiotic management of paediatric pneumonia is unproven due to a paucity of paediatric studies. Even in adult populations, where numerous evaluations of PCT have been conducted, results are conflicting regarding whether use of PCT provides clinical benefit. There are several questions around PCT implementation and impact in paediatrics that are promising areas for future research. The existing body of evidence is not convincing that PCT adds anything beyond what other, cheaper biomarkers (like C-reactive protein) or clinical assessment can provide for management of paediatric pneumonia.None to declare."}
+{"text": "The COVID-19 pandemic caused significant disruptions for people and institutions across healthcare settings. Clinical trials are an important research tool to test interventions in real-world healthcare settings and provide high quality evidence that supports older adults\u2019 longevity and wellness. Clinical trialists must consider how to account for unpredictable and ever-changing environmental contexts. The COVID-19 pandemic is a specific example of a changing context that impacted all stages of the clinical trials process from planning, to administration, and outcomes. Reflecting on ways clinical trialists navigated their studies during the COVID-19 pandemic may unlock opportunities to design flexible clinical trials that meet the needs of older adults in real-world environments. This symposium highlights five clinical trials for older adults that occurred during the COVID-19 pandemic. Dr. Carpenter will discuss lessons learned in implementing a palliative care intervention in nursing homes. Brianna Morgan will describe the pivots needed to complete a clinical trial testing an advance care planning website for nursing home residents with dementia. Dr. Nuckols will describe obstacles and opportunities to implementing a randomized controlled trial on hospital nursing units, including implications for medication safety. Dr. Pevnick will highlight barriers and facilitators to implementing a pharmacist-led intervention to reduce hospital readmissions. Dr. Stark will share novel procedures for conducting clinical trials in the community that reduce burden for older adult participants while maintaining fidelity. Presenters will address practice transformations that researchers can bring forward to design flexible clinical trials that meet the needs of older adults in different healthcare contexts."}
+{"text": "The medial prefrontal cortex (mPFC) has robust afferent and efferent connections with multiple nuclei clustered in the central thalamus. These nuclei are elements in large-scale networks linking mPFC with the hippocampus, basal ganglia, amygdala, other cortical areas, and visceral and arousal systems in the brainstem that give rise to adaptive goal-directed behavior. Lesions of the mediodorsal nucleus (MD), the main source of thalamic input to middle layers of PFC, have limited effects on delayed conditional discriminations, like DMTP and DNMTP, that depend on mPFC. Recent evidence suggests that MD sustains and amplifies neuronal responses in mPFC that represent salient task-related information and is important for detecting and encoding contingencies between actions and their consequences. Lesions of rostral intralaminar (rIL) and ventromedial (VM) nuclei produce delay-independent impairments of egocentric DMTP and DNMTP that resemble effects of mPFC lesions on response speed and accuracy: results consistent with projections of rIL to striatum and VM to motor cortices. The ventral midline and anterior thalamic nuclei affect allocentric spatial cognition and memory consistent with their connections to mPFC and hippocampus. The dorsal midline nuclei spare DMTP and DNMTP. They have been implicated in behavioral-state control and response to salient stimuli in associative learning. mPFC functions are served during DNMTP by discrete populations of neurons with responses related to motor preparation, movements, lever press responses, reinforcement anticipation, reinforcement delivery, and memory delay. Population analyses show that different responses are timed so that they effectively tile the temporal interval from when DNMTP trials are initiated until the end. Event-related responses of MD neurons during DNMTP are predominantly related to movement and reinforcement, information important for DNMTP choice. These responses closely mirror the activity of mPFC neurons with similar responses. Pharmacological inactivation of MD and adjacent rIL affects the expression of diverse action- and outcome-related responses of mPFC neurons. Lesions of MD before training are associated with a shift away from movement-related responses in mPFC important for DNMTP choice. These results suggest that MD has short-term effects on the expression of event-related activity in mPFC and long-term effects that tune mPFC neurons to respond to task-specific information. To survive in a dynamic environment organisms must be able to adapt efficiently to changes in conditions, responding in ways that optimize favorable consequences. Behavioral ecologists have demonstrated that foraging animals select among food patches of different quality in a way that maximizes food intake while reducing energy costs  plays a critical role in adaptive goal-directed behavior  has dense reciprocal connections with the agranular medial cortex and adjacent motor and cingulate areas. Afferent inputs to VM include branches of axons that also innervate MD and GABAergic projections from the basal ganglia. Thalamocortical neurons in VM have dense widespread projections to layer 1 in agranular medial and adjacent motor and cingulate cortices and less dense projections in parietal and occipital cortices that appear organized to control integrative motor responses Vertes, . The antAnatomical analyses indicate that rodent mPFC is homologous to primate anterior cingulate and premotor cortices and lacks an area homologous to primate dlPFC Preuss, . Here weEarly studies of delayed response deficits in monkeys  designed around the octagonal hub used for radial DNMTP tasks . In VSRTIt has been argued that mPFC is important for evaluating actions and outcomes along multiple dimensions  and rhomboid (Rh) nuclei in the ventral midline thalamus are important sources of thalamic input to the hippocampus and mPFC that appear organized to modulate mPFC\u2014hippocampal interactions , and hippocampal lesions had no significant effect on RT or accuracy  and others that were directionally specific and fired during movements from the base to the sample and from the base to the choice levers . Lever press-related responses included neurons firing during all four lever presses  and others that fired only during base lever presses .Of 1,335 isolated neurons recorded with moveable tetrode arrays, 458 (34.3%) exhibited criterion event-related activity of which 445 (33.3%) exhibited temporal patterns of activity related to actions or outcomes that were characterized as normalized population peri-event time histograms PETH; , 8. ThesN = 191) included reinforcement anticipation  that fired beginning 0.7 s before predictable times of reward and persisted for an average of 2.7 s throughout reward delivery; reinforcement excitation  that fired within 0.2 s after reward delivery and remained elevated for an average of 3.0 s; error responses  that fired within 0.2 s of when the expected reward was not delivered; delay (D) responses (n = 58) that started firing within 0.4 s of when sample rewards were delivered and continued until the delay lever press; and post-reinforcement (PR) responses (n = 16) that began after reward delivery ended when rats disengaged from drinking spouts where rewards were delivered.Outcome related responses  along with single examples for base lever press , reinforcement excitation , and reinforcement anticipation . Although the data were insufficient for vector or decoding analyses , lever presses (both LPE and BLP), and preparatory responses . VentralEach of the response types observed in rodent mPFC during dDNMTP represents task-specific aspects of goal-directed behavior that are consistent with mPFC functions identified by behavioral analyses of lesion effects. PFC relies on working memory to temporarily maintain information not available to the senses to support adaptive goal-directed responding. This is thought to be represented by persistent neuronal firing during delay intervals , day 2 , and day 3  aligned with reinforced sample  and correct choice  and unreinforced incorrect choice . Event-related responses observed on day 1 largely disappeared with thalamic inhibition on day 2 and recovered substantially on day 3. Averaged across all neurons studied, day 2 thalamic inhibition reduced normalized activity during critical response windows to 46.9% of the day 1 response and this recovered to an average of 79.5% during day 3 recovery. Mixed model ANOVAs revealed significant effects of inactivation on day 2 and significant recovery on day 3 based on normalized activity during critical response windows. These effects did not interact with response type, the effect of thalamic inhibition on average firing rate , location of neuron in dorsal vs. ventral mPFC, or muscimol dose. These results show that dDNMTP event-related responses are reduced nonspecifically in mPFC with behaviorally-significant inactivation of MD and IL.Francoeur et al.  examinedOptogenetic studies have provided evidence that MD amplifies and sustains behaviorally-relevant information in PFC  supports multiple functions required for adaptive goal-directed behavior: working memory, flexible trial-by-trial response selection, attending to task-relevant information, encoding relationships between actions and their consequences, and organizing and executing action sequences. mPFC lesions produce delay-independent impairments of egocentric (response-related) DMTP and DNMTP tasks that affect RT and accuracy of responding. They spare comparable allocentric tasks.2.During the dDNMTP task, mPFC functions are served by discrete populations of neurons with responses related to preparation to respond, movements between levers, lever press responses, reinforcement anticipation, delivery of or lack of expected reinforcement, and memory delay following reinforcement. Population analyses show that these different response types effectively tile the temporal interval from when dDNMTP trials are initiated until they end.3.No individual thalamic nucleus can fully account for the broad effects of mPFC lesions on adaptive goal-directed behavior. Lesions of specific nuclei have distinct effects on behavior consistent with their anatomical connections.(a)MD has very limited effects on egocentric DMTP or DNMTP tasks that depend on mPFC. While some reports find no significant effect of MD lesions on these tasks, others have described delay-dependent deficits that spare RT or impaired acquisition that disappears with training. The reports of delay-dependent deficits are consistent with evidence that MD sustains and amplifies neuronal responses that represent behaviorally-relevant information in mPFC. Impairments in the acquisition are consistent with evidence that MD interacts with PFC to detect and encode action-outcome contingencies that are the basis of goal-directed learning.(b)Rostral intralaminar and VM nuclei affect speed and accuracy of responding based on learned conditional rules, effects consistent with their prominent connections with striatum and motor cortices, respectively. Like mPFC lesions rostral intralaminar and VM lesions produce delay-independent impairments affecting response speed and accuracy for egocentric DMTP and DNMTP tasks while sparing allocentric DNMTP.(c)Anterior thalamic and ventral midline Re and Rh nuclei affect allocentric spatial function, consistent with their prominent connections with the hippocampal system. Anterior thalamic lesions spare egocentric DMTP and DNMTP tasks affected by mPFC lesions. ReRh lesions affect tasks that depend on both mPFC and hippocampus.(d)Dorsal midline nuclei integrate inputs from visceral-, arousal-, and emotion-related areas of the brain and influence cortical and subcortical circuits related to mPFC function. They are important for behavioral-state control of adaptive responding and response to salient stimuli in associative learning. Dorsal midline lesions spare DMTP and DNMTP tasks that depend on mPFC.4.During the dDNMTP task, most MD neurons with criterion event-related responses (237/254) exhibit temporal patterns of firing that closely match response types in mPFC. A preponderance of these are movement and reinforcement-related responses critical for dDNMTP choice. MD lesions made before initial training selectively decrease the number of movement-related responses in mPFC.5.Drug inactivation of MD and adjacent intralaminar nuclei broadly suppresses the expression of event-related activity in mPFC during the dDNMTP task. Optogenetic studies suggest that MD amplifies and sustains behaviorally-relevant information in the PFC, a process that might help tune mPFC neurons to respond to task-relevant information during goal-directed behavior or suppress the expression of event-related activity during more prolonged drug inactivation.RM was primarily responsible for writing the article. MF and BG contributed to writing and discussion of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The management of unruptured cerebral aneurysms in elderly patients remains controversial.Key challenges including frailty, cognitive dysfunction, reduced life expectancy, vasculopathy and poor prognosis with aneurysm rupture add complexity to endovascular and surgical decision making not encountered with younger demographics.A thorough understanding of available treatment options, likelihood of treatment success and associated risks weighed against the risk of aneurysm rupture informs patient discussion and management.Unruptured cerebral aneurysms are increasingly identified in elderly patients as the global life expectancy continues to rise and non-invasive vascular imaging becomes more prevalent. The optimal management of unruptured aneurysms in elderly patients remains controversial. Variability in life expectancy, comorbidities and rupture risk coupled with heterogenous endovascular and surgical treatments contribute to a paucity of clear guidelines, and current management is highly individualized. Elderly patients present unique considerations including frailty, cognitive dysfunction, vasculopathy, reduced life expectancy and overall worse prognosis in case of rupture which shape the risks and likelihood of success of endovascular and microsurgical treatment. In this review, we provide a comprehensive overview of unruptured cerebral aneurysms in the elderly, with a particular focus on the natural history, key challenges associated with advanced age, management and future innovations to further refine treatment. Life expectancy is increasing at unprecedented rates. By 2050, the proportion of individuals 65 years or older will more than double from 8.1% to 21% [Multiple guidelines regarding the management of unruptured cerebral aneurysms in the general population have been established by cornerstone neurosurgical trials . OptimalThe prevalence of unruptured cerebral aneurysms in the elderly and the association between age and aneurysm development remain controversial. Several autopsy reports describe an increased prevalence of unruptured cerebral aneurysms with advancing age. Inagawa et al. reviewed 10,259 autopsies performed in New York, NY and found the incidence of unruptured cerebral aneurysms highest in patients over 60 years, with a peak prevalence of 1.2% in the seventh decade of life . In the The incidence of aneurysm rupture and association with advanced age has been evaluated in multiple prospective studies. In the general population, the overall risk of rupture per patient-year at risk is 0.6\u20131.3% . The IntThe overall rupture rate in elderly patients appears similar to the general population. A pooled analysis evaluating 1896 patients 70 years and older with 2227 unruptured aneurysms reported an annual rupture rate of 1.6% . AdditioFrailty is defined as a decrease in homeostatic reserve and is closely associated with increasing age . FrailtyNumerous attempts have been made to quantify frailty based on phenotypic characteristics, functional deficits, social situations and medical comorbidities, with the modified frailty index (mFI) representing a well establish metric of physiologic reserve. Including five (mFI-5) or eleven (mFI-11) factors, based on the original 70-item Canada Study of Health and Ageing Frailty Index, the mFI predicts morbidity and mortality across all subspecialties . In neurBrain frailty resulting from intrinsic damage to small perforating arterioles, endothelial dysfunction, blood\u2013brain barrier breakdown and inflammation is an additional marker of poor cerebral reserve in elderly patients, and is readily evident on advanced imaging as white matter hyperintensities, microbleeds, prominent perivascular spaces, lacunar infarcts and cerebral atrophy. Baseline brain frailty scores on magnetic resonance imaging and computed tomography are associated with poor functional outcomes following lacunar and non-lacunar stroke . Brain fPreserved cognitive function is particularly relevant in elderly patients, as any neuropsychological decline either from the anxiety of harbouring an unruptured aneurysm or as a direct consequence of treatment may have dramatic consequences on quality of life, independence and overall life expectancy. Patients with unruptured cerebral aneurysms may harbour cognitive impairments at baseline, which can influence long-term outcomes. Fukunaga et al. evaluated 30 patients with unruptured cerebral aneurysms and described neuropsychological impairment in three . Haug etCurrent literature is inconclusive regarding cognitive outcomes following elective aneurysm treatment. ISUIA reported impaired cognitive function in 3.2\u20137.1% of patients who underwent either clipping or coiling at 1 year after treatment . Particuvs. after treatment of an unruptured aneurysm. Srivatsan et al. evaluated Montreal Cognitive Assessment scores following elective coiling of unruptured aneurysms in 33 patients and found no difference compared to baseline scores [Additional studies, however, report no difference in cognitive function before e scores . Similare scores . Few stue scores .Given the lack of definitive guidelines, conflicting outcomes regarding cognitive function following treatment, and few studies in the elderly, neurocognitive prognosis must be highly individualized. New evaluations in elderly patients should emphasize the anxiety of harbouring an unruptured aneurysm, which may improve with definitive aneurysm repair. Cerebrovascular cognitive reserve, baseline ischaemic white matter disease and evidence of vascular cognitive impairment are particularly important. Meticulous surgical dissection and endovascular technique may minimize parenchymal injury and preserve cognitive function post-operatively. Nevertheless, patients with extensive chronic ischaemic changes may be unfavourable candidates for treatment due to increased susceptibility to long-term neurocognitive changes, as seen in the landmark studies such as ISUIA .et al. performed a life expectancy analysis of patients with unruptured aneurysms with and without repair based on prospective data from ISUIA to identify circumstances under which aneurysm repair would be beneficial [The long-term risks of unruptured cerebral aneurysms in the elderly are challenging to determine based on the existing literature. As life expectancy declines, the likelihood of rupture combined with comorbidities that are more likely to cause death may call into question the benefit of aneurysm treatment. Vindlacheruvu neficial . They foPre-existing medical conditions and comorbidities, along with age, predict remaining life years following hospitalization. One year survival after first admission for heart failure or initiation of dialysis is 67% and 45.5%, respectively ,33. EldeChronic hypertension and atherosclerotic disease, common comorbidities that increase with advancing age, may accelerate vessel or aneurysm calcification, reduce arterial compliance, increase vessel tortuosity and narrow parent vessels, thereby complicating treatment. Atherosclerotic aneurysm calcification is more common in larger aneurysms and in older patients, and is associated with increased morbidity following clipping. In a study of 208 patients treated with clipping or coiling of unruptured aneurysms, the presence of calcification in an aneurysm was the sole marker of adverse outcome . In addiet al. found that arterial stenosis and tortuous anatomy limits the spread of microcatheter tension, may increase the risk of intra-procedural aneurysm rupture and plaque mobilization, decreases the rate of complete occlusion, and may necessitate the use of adjuvant stent or balloon assistance, which increases the risk of in-stent thrombosis and arterial dissection [Intracranial atherosclerotic disease adjacent to cerebral aneurysms also influences the efficacy and complication profile of endovascular treatment. Gao ssection . While essection .et al. analysed outcomes of elderly patients with aneurysmal subarachnoid haemorrhage stratified by age and clinical presentation [Advanced age is recognized as a poor prognostic indicator after subarachnoid haemorrhage, and the overall worse outcome in elderly patients following aneurysm rupture has important implications regarding patient counselling and management. Lanzino et al. evaluated the relationship between age and outcome in aneurysmal subarachnoid haemorrhage using data from the multicentre randomized trial of nicardipine in subarachnoid haemorrhage . They reentation . They reCoiling provides a minimally invasive alternative to open surgery for treatment of intracranial aneurysms. Coiling is generally the favoured treatment in elderly patients despite a lack of supportive randomized controlled trials. For ruptured aneurysms, the landmark International Subarachnoid Aneurysm Trial (ISAT) in 2002  and 2015Coiling of unruptured aneurysms in the elderly appears overall to be safe and effective. Hwang et al. coiled 122 saccular unruptured aneurysms in 96 consecutive patients 70 years or older; they successfully occluded the aneurysm with no adverse clinical events in 95.9% of cases . A meta-Elderly patients may be particularly prone to complications following coiling of unruptured aneurysms. Khosla et al. compared the complication profile associated with elective coiling of intracranial aneurysms between elderly and non-elderly patients, reporting major complications with and without neurologic disability more prevalent in patients 65 years and older . IschaemAdjuvant techniques for coil embolization, including balloon assistance and stent assistance, have been studied only modestly in the elderly, potentially due to their relatively infrequent usage. In a meta-analysis by Sturiale et al. evaluating 21 studies with 1511 elderly patients undergoing endovascular treatment of both ruptured and unruptured aneurysms, only 5% utilized balloon assistance and 3% utilized stent assistance . BalloonMicrosurgical clipping of unruptured aneurysms is a more invasive alternative to endovascular treatment, and elderly patients are less likely to tolerate clipping as compared to younger patients. Barker et al. compared age-dependent outcomes in 3498 patients who underwent clipping or coiling for unruptured aneurysms . When divia a supraorbital or pterional approach in 62 non-frail elderly and 198 non-elderly patients reported no increase in complication rates, hospital duration, aneurysm recurrence, morbidity or mortality with advanced age [via a supraorbital or pterional approach, sufficient drilling of the frontal skull base or sphenoid ridge, and wider subdural spaces in elderly patients improved aneurysm access and minimized excessive brain retraction, contributing to lower rates of neurological morbidity, mortality and cognitive dysfunction compared to standard clipping.Increased morbidity, mortality and institutionalization following discharge for microsurgical clipping of unruptured aneurysms in elderly patients suggests the need for less invasive surgical techniques focussed on minimal tissue disruption. The superciliary keyhole approach has been advocated as an alternative to pterional craniotomy for anterior circulation aneurysms, but validation in elderly patients has not been described . A retronced age . A minimFlow diverting stents are approved for the treatment of cerebral aneurysms of the internal carotid artery. Their reduced porosity creates a scaffolding for endothelialization across the cerebral aneurysm neck, reducing intra-luminal flow and allowing for slow obliteration. No recurrences have been reported once occlusion is achieved, and flow diversion has become a standard treatment for wide-necked saccular or fusiform internal carotid artery aneurysms for which traditional endovascular and surgical treatments are limited.Elderly patients have reduced but acceptable rates of aneurysm occlusion following flow diversion. Kuhn et al. evaluated the effects of age on aneurysm occlusion following flow diversion for treatment of unruptured cerebral aneurysms . At 12\u20131Older patients treated with flow diversion are more likely to harbour aneurysms of larger size, complex morphology and within the posterior circulation compared to younger counterparts which, along with increased frequency of comorbidities, atherosclerosis and arterial tortuosity, raises concern for increased morbidity and mortality. Brinjikji et al. reviewed age-related outcomes following pipeline reconstruction of unruptured aneurysms in 711 patients and found increasing age associated with higher neurological mortality . Patientvia inhibition of cyclooxygenase-2 (COX-2), supporting the inflammatory hypothesis of aneurysm formation and rupture [Aspirin lowers rates of aneurysm rupture in animal models  rupture . In a sm rupture .Preliminary prospective and retrospective studies suggest that aspirin is safe in patients with unruptured aneurysms and may lower the risk of aneurysmal subarachnoid haemorrhage. A prospective, multicentre observational study that followed patients with unruptured cerebral aneurysms and ischaemic cerebrovascular disease found that aspirin was safe in patients with concurrent small unruptured cerebral aneurysms and was associated with low rate of aneurysm rupture . Hasan eAspirin may also limit aneurysm growth. A prospective cohort study following 272 patients with unruptured aneurysms 7\u2009mm or smaller, 113 of which were on aspirin continuously, found that aspirin was associated with a low risk of aneurysm growth . An addiStatins have anti-inflammatory effects in various vascular diseases, but their protective effects on the formation and progression of cerebral aneurysms remain unclear. A multicentre case\u2013control study compared 117 patients with aneurysmal subarachnoid haemorrhage to 304 patients with incidental, unruptured cerebral aneurysms and found a lower rate of statin use in rupture cases, suggesting an inverse relationship between statin use and aneurysm rupture . AlternaFuture alternatives to stratify treatment decisions in high-risk elderly patients, evaluation of new endovascular devices and microsurgical innovation will continue to improve elderly patient outcomes. Wall enhancement on black-blood MRA, observed more frequently in unstable, growing and ruptured aneurysms ,73, may The optimum management of unruptured cerebral aneurysms in elderly patients remains undefined. The process of ageing presents unique considerations and challenges, and management is currently individualized, requiring precise knowledge of natural history and risk of rupture that must be weighed against an individual\u2019s comorbidities, life expectancy, treatment-related risks and likelihood of treatment success. This report provides a comprehensive review of unruptured cerebral aneurysms in the elderly, with a special focus on the key challenges that this age group presents, including frailty, cognitive dysfunction, reduced life expectancy, vasculopathy and poor prognosis in case of rupture. These challenges determine the risk, benefit and likelihood of success of both surgical and endovascular treatments, drive innovative surgical techniques, and contribute to the trend in endovascular treatment in patients of advanced age. While coiling with or without adjunctive techniques or flow diversion will continue to increase, robust preclinical studies regarding the role in neuroinflammation in aneurysm development, growth and rupture represent potential future targets that may be particularly relevant to the elderly population. We anticipate that this review will provide a clinical framework for managing unruptured aneurysms in this challenging cohort, which will only enlarge with time as the population ages."}
+{"text": "Many studies have reported that dietary fibers play a crucial role in promoting intestinal health of the host, since it strengthens functions of epithelial barrier and meanwhile maintains intestinal homeostasis of the host by modulating gut microbiota and short\u2010chain fatty acid (SCFA) production. Pig is a good animal model to study effects of dietary fiber on gut health and microbial community. This review has summarized the relevant knowledge available based on roles of various dietary fibers in gut health and energy metabolism of pigs and humans. Evidences summarized in our review indicated that modulating intestinal microbial composition and SCFA production by consuming specific dietary fibers properly could be conducive to health improvement and disease prevention of the host. However, types of dietary fiber from edible foods exert divergent impacts on gut health, energy metabolism, microbial composition, and SCFA production. Therefore, more attention should be focused on different responses of various dietary fibers intake on host metabolism and health. Modulating intestinal microbial composition and short\u2010chain fatty acid (SCFA) production by regulating specific dietary fibers intake properly could be conducive to host health improvement and disease prevention. Types of dietary fiber from edible foods exert divergent impacts on gut health, microbial composition, and SCFA production. More specifically, gut microbiota intensify integrity of the gut barrier comprised by intestinal epithelial cells, suppress colonization of enteric pathogens, and produce antibacterial peptides in the mucus layer of host intestine  to identify the specific mechanisms of SCFA produced from dietary fiber fermented by gut microbiota on functions of animal tissues and organs, (2) to clarify the relationship between host health and gut microbiota shaped by the dietary intervention with dietary fibers, (3) to further illustrate different responses of various dietary fibers derived from edible foods and their combinations on host health. Overall, we suggest that more attention should be focused on specific chemical constituents and physical characteristics of various dietary fibers when they take actions in regulating host metabolism and health.None of the authors had a financial or personal conflict of interest in relation to the present study.Pan Yang: Conceptualization (supporting); Data curation (supporting); Formal analysis (lead); Investigation (lead); Visualization (lead); Writing\u2010original draft (lead). Jinbiao Zhao: Conceptualization (lead); Data curation (lead); Formal analysis (supporting); Funding acquisition (lead); Project administration (lead); Writing\u2010review & editing (lead).Not applicable.All authors consent that raw data presented in this review are available after publication. Please contact author for data requests."}
+{"text": "Theories of age and emotional wellbeing posit that older age is associated with better affective well-being through avoidance or minimization of distressing experiences and prioritizing positive experiences and emotions. To test these theories, researchers have examined change in affect  associated with negative interpersonal experiences in daily diary studies, given the compromising effects these interpersonal stressors exert on daily affect. In contrast, age differences in the potential affect-enhancing effects of positive interpersonal experiences have been comparatively neglected. Using the second wave of the National Study of Daily Experiences, we evaluated age differences in the frequency of daily negative and positive interpersonal interactions, as well as the affective responses to these interpersonal interactions. Positive and negative affect, as well as negative and positive interpersonal interactions were assessed on eight consecutive evenings. Analyses included 818 participants  who experienced both negative and positive interpersonal interactions during the 8-day protocol. Preliminary results revealed increased frequency of negative interpersonal interactions and decreased frequency of positive interpersonal interactions with age (ps<.01). Further, negative interpersonal interactions were associated with increases in negative affect and decreases in positive affect (ps<.01), while positive interpersonal interactions were associated only with increased positive affect (p<.01). Finally, modest evidence of age-related reductions in the affective impact of negative, but not positive, interpersonal interactions emerged (p=.03). Discussion will focus on how studies of interpersonal interactions in daily life can inform theories of aging and promote emotional wellbeing throughout adulthood and later life."}
+{"text": "As the coronavirus disease 2019 (COVID-19) spread in the early days of the pandemic, governments neglected World Health Organization (WHO) guidance and imposed travel restrictions. These public health measures employed varied levels of restrictiveness at national borders, in some cases banning all travel between countries. Where these border control measures were undertaken for domestic political reasons, enacted without consideration of public health evidence, they divided the world when solidarity was needed most.With the emergence of the Omicron variant, national governments once again returned to international travel restrictions, posing challenges for the rule of law in global health governance. Future reforms of global health law must account for this continuing impulse to enact travel restrictions, ensuring that international legal obligations reflect evolving public health evidence.International Health Regulations, 2005 revision; IHR (2005) govern how countries address collective threats in global solidarity; yet international travel bans can drive countries apart through economic isolation, trade disruptions, discriminatory restrictions and rights violations.The In the early COVID-19 response, we remained concerned where national governments bypassed WHO\u2019s public health recommendations in a rush to impose travel bans that targeted specific countries in ways that exacerbated political divisions, blocked essential goods and deflected from established mitigation measures \u2013 including travel advisories, diagnostic testing and quarantine policies.We continue to be concerned, however, that many governments are still reflexively deploying discriminatory travel restrictions to meet domestic political imperatives, prioritizing government action without sufficient justification in public health evidence. The latest round of travel restrictions, enacted in response to the Omicron variant, reveal the often-pernicious effects of such decision-making on low- and middle-income countries. When South Africa transparently reported a new variant of concern, countries immediately limited travel to and from South Africa, in some cases expansively targeting additional Southern African countries, without consideration of WHO guidance and despite updated evidence of variant spread well beyond the targeted countries.The mixed public health success of travel restrictions during the pandemic calls into question IHR (2005) obligations in the context of evolving public health knowledge.,In reforming global health law to reflect evolving public health knowledge, IHR (2005) revisions and pandemic treaty negotiations must provide flexibility in implementing evidence-based travel restrictions while strengthening WHO guidance to reflect epidemiologic data, facilitate health equity and support international cooperation."}
+{"text": "The chemical diversity of natural products is established by an elegant network of biosynthetic machinery and controlled by a suite of intracellular and environmental cues. Advances in genomics, transcriptomics, and metabolomics have provided useful insight to understand how organisms respond to abiotic and biotic factors to adjust their chemical output; this has permitted researchers to begin asking bigger-picture questions regarding the ecological significance of these molecules to the producing organism and its community. Our lab is motivated by understanding how select microbes construct and manipulate bioactive molecules by utilizing vanadium-dependent haloperoxidase (VHPO) enzymology. This commentary will give perspective into our efforts to understand the unique VHPO-catalyzed conversions which modulate the activities within two ecologically relevant natural product families. Through enhancing our knowledge of microbial natural product biosynthesis, we can understand how and why these bioactive molecules are created. Natural products (NPs), also known as secondary or specialized metabolites, are composed of small organic molecules that have long been appreciated for their therapeutic potential . The marAs the tools of chemical ecology have matured, researchers have been able to ask more targeted questions about the factors that elicit NP production. With modern genomic, transcriptomic, and metabolomic profiling techniques, the field has started to reify links between secondary metabolite production and the specific internal state of a single organism while considering its surrounding community. The signal-molecule-based activation of silent NP BGCs has emphasized the role that the local microbiota plays in the elicitation of diverse community-modulating NPs , 10. OurStreptomyces and other bacteria site-specifically halogenate small molecules to elicit precise biosynthetic transformations (One of the many unique features of the marine biosphere is the relative abundance of vanadium and its subsequent utilization by microbial and macroalgal communities . In the rmations . We intermations .The most explored area of site-specific VHPO biosynthetic enzymology has involved the diverse naphthoquinone-based family of meroterpenoids. These mixed polyketide-terpene NPs are produced by marine and soil actinobacteria and exhibit a range of useful Gram-positive antibacterial, cytotoxic, and antifouling activities . DespiteStreptomyces NP biosynthesis but also within less established marine and terrestrial microbes.Of the THN-derived meroterpenoids, the napyradiomycins are uniquely well suited for hypothesizing \u201chow-and-why\u201d NPs are interconverted by VHPOs and other accessory enzymes in the marine biosphere. Over 50 unique napyradiomycins have been isolated, and new molecules continue to be discovered . Some ofPseudomonas species (Microbulbifer host species while increasing their toxicity toward other bacteria (Although less established than their roles in constructing endogenous NPs via biosynthetic routes, there is increasing evidence to suggest that VHPOs may modulate exogenous quorum sensing molecules. A macroalgal VHPO has been previously established to disrupt bacterial communication through homoserine lactone degradation and bromofuranone production to minimize surface fouling . The alk species . These m species . We are bacteria . This VHin vitro enzymology with ecologically relevant marine bacterial homologs. Pending the generalizability of this halogenation biochemistry, we aim to begin assessing the in vivo activities of these VHPOs in axenic cultures and within simulated communities alongside known AQ producers. Transcriptomic and metabolomic analyses using liquid coculturing experiments may provide insight into the role of VHPO-mediated AQ modification. Imaging mass spectrometry in combination with solid-phase coculturing conditions can additionally assess the spatial localization of quorum sensor production, interconversion, and microbial interactions. We envision that a rigorous understanding of AQ halogenation enzymology will enable us to target specific ecological questions regarding the significance of VHPOs in marine microbiology.We intend to initially investigate the impact of AQ-modulating VHPOs using In comparison to common terrestrial transition metals like iron, molybdenum, and zinc, the full extent of the biological and ecological roles that vanadium plays is less well understood , 12. Muc15\u2013"}
+{"text": "Numerous microbial diversity surveys conducted over the past decade have attempted to link specific ASD biomarkers to gastrointestinal tract disturbances, but results generated across cohorts and studies remain inconsistent. This commentary discusses multidirectional interactions between the host, the microbiome, and external factors germane to autism. Recent studies posit the heritability of the gut microbiome itself, confounding attempts to discern heritable from nonheritable effectors in neurodevelopmental disorders. Elucidating the ever-evolving gut microbiome\u2019s role in modulating the ASD phenotype will most certainly require new experimental methodologies and designs. In a recent paper published in  Elucidating the countless factors contributing to the etiology of autism is incredibly challenging. Upon entering this field \u201clate\u201d in my career, I was then, and remain today, awestruck at both how much and how little is known about this disorder. Over the past decade, even the very definitions of the core symptoms of autism spectrum disorder (ASD) have changed. Between 2010 and 2015, both the number of known cistrons associated with autism  whose unprecedented size would otherwise preclude meaningful study, and innovative techniques enabling the segregation of features of the host from those of its microbiome.Finally, the scientific community desperately needs to bolster the current understanding of the complex interplay between genetic-driven and heavily microbiome-influenced systems. Within this vein, we must explore whether exposure to detrimental environmental factors early in life coupled with innate genetic susceptibility might impair brain development. Addressing such questions will require novel experimental design frameworks, emerging analytical tools capable of leveraging data sets (both preexisting publicly available data sets and"}
+{"text": "This symposium brings together four papers that address racial health disparities by investigating stressful aspects of social relations at different points in the life course. Cleary and colleagues focus on racial disparities in psychological health by testing cross-sectional effects of intergenerational stress over time. In particular, they investigate effects of network composition on the relationship between mothers' stressors and their children's depressive symptoms at three time points over 23 years. Camacho and colleagues use longitudinal data from the National Social Life, Health and Aging Project to examine cognitive decline among U.S. African-American, Latino, and White adults aged 60 and above. Results indicate loneliness predicted greater global cognitive decline over time in all groups. However, race differences in this association were found across cognitive function domains. Turner and colleagues consider dementia caregiving challenges among non-Hispanic Blacks. Data from five focus groups were analyzed to reveal distinctive challenges to caregiver health during the COVID-19 pandemic including increased burden and barriers to service access. Finally, Sol and colleagues examined the bidirectional association between loneliness and self-rated health over time among a racially diverse sample. Findings illustrate racial patterns in how loneliness at midlife influences health in later life. Antonucci will discuss the role of stress from social relations as a means to fully understand racial disparities in health across the life course."}
+{"text": "Plant genebanks provide genetic resources for breeding and research programs worldwide. These programs benefit from having access to high-quality, standardized phenotypic and genotypic data. Technological advances have made it possible to collect phenomic and genomic data for genebank collections, which, with the appropriate analytical tools, can directly inform breeding programs. We discuss the importance of considering genebank accession homogeneity and heterogeneity in data collection and documentation. Citing specific examples, we describe how well-documented genomic and phenomic data have met or could meet the needs of plant genetic resource managers and users. We explore future opportunities that may emerge from improved documentation and data integration among plant genetic resource information systems. Genebanks offer a broad range of plant genetic diversity for use in research and breeding programs. For decades, crop researchers have collected phenotypic trait data on genebank accessions. New high-throughput technologies facilitate the collection of phenomic data . Similarly, smaller-scale DNA marker data have been eclipsed by more comprehensive genomic data for characterizing collection genetic diversity. With these large datasets, the challenges of digital information management are becoming as important as managing the physical collection of germplasm. Databases that integrate data types, promote standardized data collection and documentation methods, incorporate appropriate analytical tools and provide user-friendly access will help curators and users of plant genetic resources (PGR) to manage, locate and identify diversity of agronomic and horticultural importance . TanksleTriticum aestivum L.] variety \u2018Jagger\u2019 and maize [Zea mays L.] inbred line \u2018B73\u2032). An example of homozygous/heterogeneous accessions are landraces of self-pollinating crops that are comprised of an assortment of different genotypes. Heterozygous/homogeneous accessions include clonally maintained but originally outcrossing crops . Heterozygous/heterogeneous accessions are represented by wild species accessions and outcrossing landraces. As wild species accessions are regenerated, the extent of heterozygosity may decrease  [Cicer arietinum L.] [Genome-wide association analysis has enabled PGR to contribute more extensively to marker/gene discovery in most species. Diversity subsets from genebank collections are a readily available resource to perform GWAS using a range of markers from simple sequence repeats (SSRs) to SNPs from GBS or SNP arrays . Whole-gtiva L.] ; soybean) Merr.] ; chickpeinum L.] ) and perinum L.] . GWAS isPlant breeders and researchers require an understanding of the phenotypic/phenomic data that are available. This includes documentation about how the data were collected, such as the numbers of individuals sampled and experimental field designs (particularly for heterogeneous accessions), as well as the use of standardized descriptors and ontologies. Most of the traits important to breeders exhibit significant genotype \u00d7 environment interactions so the full environmental context under which phenotypic measurements were made is necessary ,48. HighPisum sativum L., and many fruits. However, pea and other new crop ontologies are under development. Other harmonious crop ontologies can be found on Planteome [Beginning in the 1990s, an evolution occurred from simple, formal phenotypic descriptors to the machine-readable ontologies available today, wherein the controlled vocabulary includes not only trait definitions but also relationship terms, so that complex phenotypic information can be processed by computer. Phenotypic descriptors for PGR have been published for over 100 crops under the auspices of the CGIAR centers IPGRI and Bioversity International . Bioversity used these to develop crop ontologies and the Crop Ontology Curation Tool . These olanteome  and Agrolanteome . The goalanteome . As geneHigh-quality genebank collections contain well-curated passport, phenotypic, and genotypic data. Acquiring these data is challenging due to resource limitations and the vast size of most genebank collections. Success depends upon partnerships between genebanks and user communities. As they become available, genomic and phenomic data can help guide collection management and improve the value of the collection. These data permit the identification of collection gaps, which can be filled with new acquisitions . They alGenomic and phenomic data can provide knowledge applicable to curation, such as whether accessions are correctly assigned to taxon, whether they are redundant, or whether they differ when they should not . They caLens species and Lens culinaris Medik. sub-species, are difficult for non-taxonomists to identify. Wong et al. [Availability of accession-level genomic data for genebank collections has facilitated taxonomic identification of unusual or hybrid species. Lentils, which include g et al.  used seqGenotyping the maize Ames Panel revealed several interesting findings related to curation . First, Hordeum vulgare subsp. spontaneum C. Koch.) collection\u201d [Solanum tuberosum L.) accessions with a 12K SNP array and identified putative misclassified accessions [Lactuca sativa L.) PGR in the USDA collection lack genetic diversity, hindering genetic advances in this important crop [Genomic data have provided useful information about genetic gaps in collections. Previously, geographic coverage was the primary criterion for targeting plant acquisitions and assembling core collections. Correlation of geographic gap-filling and genomic gap-filling has shown the advantage of using genomic data. The IPK genebank analyzed GBS data for 21,405 barley accessions to identify gaps in the collection. They found \u201ca pronounced under-representation of some regions of the world in IPK\u2019s wild barley  offer numerous visualizations and capabilities connected to genebank accessions. Maize SNP data were used to establish an IBS relationship matrix among 2800 inbred lines, and this matrix was used to populate a tool called \u201cTYPSimSelector\u201d ,97, wherLooking forward, data curation will likely involve the use of persistent identifiers (PIDs) such as Plant Introduction (PI) numbers or Digital Object Identifiers (DOI) for sample identification. Through the adoption of BrAPI, the GRIN-Global information management system can become interoperable with Breeding Insight and crop-specific databases. Several databases, including Bridge IPK  and GermCurrent and future genebank users, as well as curation teams, will increasingly require access to high-quality genomic and phenomic data. Access to genetic diversity information could help ensure phenotypic data are collected from an adequate number of individuals. Integration of genomic and phenomic data for heterogeneous accessions requires special attention to DNA polymorphism and elevated or complex patterns of phenotypic variance. Technological advances in information management systems have focused primarily on specific crops. Future efforts should consider the relative heterogeneity of genebank accessions and how it can be effectively managed when data are collected. Systems must be user-friendly and widely applicable to diverse customers. In addition, they must be adaptable and scalable, to support new genomic and phenomic technologies. Future research should focus on ensuring that tools are available to effectively use genomic and phenomic data for informed curation decisions.Sorghum bicolor (L.) Moench) demonstrated the power of this approach for selecting accessions for high biomass from a large PGR collection [Increasingly sophisticated artificial intelligence methods and sequence data lead to the question of whether every accession must be phenotyped to choose accessions for gene(s) or trait(s) of interest. Advances in statistical prediction may change how characterization data can select germplasm for further evaluation. FIGS (Focused Identification of Germplasm Strategy) applies machine learning (ML) algorithms and environmental data to identify candidate accessions associated with a trait of interest . In Barillection . Improvellection ,107."}
+{"text": "Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease. In peripheral arterial disease (PAD), atherosclerosis limits blood flow to the lower extremities and represents approximately 25% of the global burden of cardiovascular disease and 1.7% of the overall global burden of disease . The curThe endogenous revascularization after ischemic insult involves multiple biological processes including vasculogenesis, angiogenesis, and arteriogenesis. While vasculogenesis occurs mainly during embryonic life, experimental evidence has shown that vasculogenesis contributes to adult neovascularization at least to repair the damaged capillary networks. In vasculogenesis, blood vessels form de novo via the differentiation of progenitor vascular cells into discrete vascular cells such as endothelial cells ,11, smooNevertheless, most of our knowledge about the pathophysiology of arteriogenesis is based on experimental animal studies of arterial occlusion. The terms collateralization and arterialization are often confused with arteriogenesis and are poorly defined . This reWhen a primary arterial trunk is occluded, it leads to a pressure drop downstream of the arterial network subsequently creating a pressure gradient across pre-existing collateral circulation and forcing the diversion of blood flow through the collaterals. The altered blood flow generates hemodynamic forces in collateral arterioles and arteries triggering two vascular responses: short-term vasodilation and long-term expansive vascular remodeling . The shoSynthetic smooth muscle cells migrate from the media to the subendothelial space (intima) where they proliferate abundantly and produce ECM components including collagen, elastin, and proteoglycans to the subintimal space resulting in the formation of a new layer of SMC . At thisUpon successful arteriogenesis, the collaterals exhibit an extensive outward and hypertrophic remodeling, which is associated with the transformation of a small microvascular resistance vessel into a large conductance artery . The smoVascular smooth muscle cells in the adult vasculature are not terminally differentiated cells. They possess extensive plasticity such that it can be stimulated to undergo a structural and functional transition into proliferative/migratory/synthetic phenotype or undergo an extreme phenotypic change into osteochondrocyte-like cells , foam-liThe mature contractile phenotype of SMCs is morphologically characterized by low numbers of protein synthesis organelles, e.g., rough endoplasmic reticulum, Golgi apparatus, or free ribosomes . They deThe molecular basis of sustaining the SMC contractile state has been explained by maintaining CArG\u2013SRF\u2013Myocardin complex . Any heaSeveral pathways transduce signals from cell surface receptors or integrins in response to the surrounding environmental factors to maintain the contractile phenotype. The RhoA/ROCK signaling triggers actin polymerization increases post-translational modification of MRTFs and releases it to the nucleus to induce contractile gene expression . TGF\u03b2 enThe loss of the contractile phenotype occurs via growth factors such as Platelet-derived growth factor-BB (PDGF-BB), FGF, and EGF that activate MAPK cascade via the Ras/Raf/MEK/ERK pathway. The MAPK activation can phosphorylate and activate TCF proteins such as Elk-1 to displace MYOCD or induce SRF-dependent transcription of early response growth, dedifferentiation genes, and repression of smooth muscle contractile genes . ERK canUpon arterial occlusion, the increase of blood flow and intravascular pressure in the bypass collaterals can generate two primary forces: fluid shear stress and circumferential wall tension . The fluIn contrast, after arterial occlusion, early vasodilation of collaterals leads to a rapid decrease in the intra-luminal pressure. Thus, according to Laplace\u2019s formula, we expect that the circumferential wall stress would not change significantly in the early stage. In addition, the diminished blood pressure in downstream vessels is much lower than the proximal arterial pressure; thus, this pressure is unlikely to cause a significant stretch force on medial SMC at this phase. Indeed, the SMC in small arteries and arterioles generally react to the acute rise of intraluminal pressure by contraction (myogenic response) to regulate the tissue blood flow ,90. HoweThe increase in fluid shear stress force is transmitted to the SMC by diffusible molecules such as nitric oxide (NO) . NO is sMost collaterals tend to be tortuous small arteries . The steEndothelial surface glycocalyx and its components can act as a mechanoreceptor and can transmit mechanical stimuli to the cytoskeleton, which can then activate downstream signaling pathways such as PI3K/AKT/eNOS and NF\u03baB . The plaIn contrast, the alterations in the intraluminal pressure in the later stages of arteriogenesis can be extended to exert a mechanical force on the cellular components of VSMCs, which act as a mechanosensor to initiate subsequent signal transduction events . Medial Additionally, activation of integrin receptors, stretch-activated cation channels, and G proteins are also observed in SMC membranes of collateral vessels in response to stretch forces . These fCyclic stretching is a critical inducer of MCP-1 expression in SMC of remodeling collaterals . It goveThe arterial wall strain is chronically elevated in systemic hypertension conditions. The small arteries and arterioles remodel inwardly through a eutrophic process of rearrangement of the same SMC around a smaller lumen . ConversThe initial phase of collateral vasodilation is driven by fluid shear stress and occurs within the early stage of post-occlusion. However, this vessel enlargement accounts for a small proportion of final vessel expansion, and it slows following shear stress normalization . The appEndothelial cells in pre-existing collaterals are the first effectors to initialize an inflammatory process following arterial occlusion . In resphighCCR2highCX3 CR1low) and tissue repair (Ly6 ClowCCR2lowCX3 CR1high) in mouse [high) are detected mainly in the collaterals during the early phase of arteriogenesis whereas the anti-inflammatory monocytes (Ly6 Clow) predominate the collaterals during the growth and expansion phase of arteriogenesis [high monocytes are more likely to differentiate into M1 macrophages, which secrete various pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-12, and TNF\u03b1. They exhibit high proteolytic activity [low monocytes may differentiate into M2 macrophages, which secrete anti-inflammatory cytokines such as IL-10 and TGF\u03b21 and express growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thus promoting collateral remodeling and expansion [Medial SMCs also contributes to initiating or amplifying stretch-induced inflammation in collateral remodeling . They prin mouse . The infogenesis . Ly6 Chiactivity . In contxpansion . Many ofxpansion ,145,146.xpansion . Other fxpansion ,149.Monocytes and macrophages are an important source of metalloproteinases and other proteases such as cathepsins during vascular repair process . During Other inflammatory cell populations have been reported to infiltrate the collateral sites during arteriogenesis, e.g., neutrophils , mast ceArteriogenesis is a physiological remodeling response of the collateral arteries in the occlusive arterial diseases. Despite the dramatic outward remodeling of collaterals, blood flow is restored only up to 40\u201350% of the unblocked artery without intervention. One reason for the limited restoration of blood flow is the premature normalization of fluid shear stress (primary trigger of arteriogenesis). This natural compensatory capacity is diminished even further in subjects with co-morbid diseases such as diabetes . Using aVascular smooth muscle cells play a central role during arteriogenesis due to their plasticity. Phenotypic switching of the contractile VSMC to a synthetic state is a critical cellular event that sustains the growth and outward remodeling of collaterals. In contrast, VSMC re-differentiation back to their contractile state is important to regain vascular functions and prevent inappropriate hypertrophic remodeling of collaterals that could perturb the blood flow for distal ischemic tissues. The physiological normalization of fluid shear can lead to a premature switch of synthetic VSMC to a contractile quiescent phenotype; this switch eventually attenuates the collateral wall growth and remodeling. It has been shown that growth factor therapy can stimulate angiogenesis and also is able to stimulate arteriogenesis ,163. ManTargeting vascular smooth muscle cell phenotype switching has been suggested to be a therapeutic approach for tackling other vascular diseases such as atherosclerosis and hypertension. However, since the dynamics of VSMC phenotype switching are different in arteriogenesis, the timing of intervention would be challenging to achieve effective therapy. Another challenge of targeting VSMC in arteriogenesis is that several cellular events of atherosclerotic plaque development are also involved in arteriogenesis. For instance, extracellular matrix degradation, VSMC migration, and proliferation are activated in both arteriogenesis and atherogenesis. The stimulation of arteriogenesis through agents that promote VSMC proliferation or positive arterial remodeling could have side effects on the aggravation of atherosclerotic plaques in PAD patients who typically suffer from atherosclerosis. While many experimental studies have been conducted to investigate the molecular mechanisms of VSMC phenotype regulation in the context of atherosclerosis, the molecular mechanisms of VSMC phenotype switching that specifically control arteriogenesis in ischemic vascular disease remain largely unknown. Previous studies have been carried out to trace the VSMC phenotype dynamics in vascular repair and atherosclerosis models. Further studies are required for VSMC lineage tracing studies during arteriogenesis. These can help to identify novel specific molecular targets for therapeutic arteriogenesis of peripheral arterial disease patients."}
+{"text": "Heritability of cognitive ability changes across late adulthood, although whether genetic variance increases or decreases in importance is not understood well. We performed a systematic review of the heritability of cognitive ability derived from longitudinal twin studies of middle-aged and older adult twins. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, articles were identified in APA PsycINFO and Clarivate Web of Science electronic databases. Identified articles were screened by title and abstract; remaining full-text articles were then fully evaluated. Reference sections served as an additional method for identification of relevant articles. In total, 3,106 articles were identified and screened, 28 of which were included and were based on data from 10 longitudinal twin studies published from 1994-2021. There are large genetic influences on an initial level of cognitive performance across domains whereas there are small to moderate genetic influences on change in performance with age. Evidence was less definitive about whether the same or different genetic factors contribute to both level and change. Non-shared environmental influences appeared to drive individual changes in cognitive performance. Heritability tended to either be stable or decline after 65 years, possibly because of the increasing importance of non-shared environmental influences on cognitive ability. Recent studies report increases in heritability across specific subtests and domains. Shared environmental variance accounted for little variance in cognitive ability. Emerging research questions and future directions for understanding genetic and environment influences in the context of gene-environment interplay are highlighted in this review."}
+{"text": "Glutathione is an intracellular antioxidant that neutralizes reactive oxygen species and prevents tissue damage. Dietary supplementation with the glutathione precursors glycine and n-acetylcysteine supports the maintenance of normal glutathione levels in several age-related diseases, but the optimal doses and their efficacy in healthy elderly are not established. We report results from a randomized controlled clinical trial in 114 healthy volunteers (mean age = 65 years) receiving glycine and n-acetylcysteine (GlyNAC) at three different doses for two weeks . Older subjects showed increased oxidative damage and a lower reduced-to-oxidized glutathione ratio (GSH:GSSG) compared to young subjects, but unchanged total glutathione levels. GlyNAC did not increase levels of circulating glutathione compared to placebo treatment, the primary study endpoint. However, stratification analyses suggest that subjects with high oxidative stress and low glutathione status responded with glutathione generation. We find that unrelated to glutathione status, healthy aging was associated with lower levels of fasting glycine that can be increased towards those observed in young subjects with supplementation. Using preclinical models, we find that tissue glycine depletion is a common feature of healthy aging. Supplementation of old mice with glycine efficiently improved age-related decline of mitochondrial respiratory function in skeletal muscle and prevented a gene program associated with protein catabolism observed in control-treated animals. In conclusion, GlyNAC is safe and well-tolerated and may selectively increase glutathione levels in older subjects with oxidative stress and glutathione demand. Our data further suggest that glycine may support mitochondrial function independently of NAC."}
+{"text": "Practitioners frequently tailor programming to meet participant characteristics and logistic constraints, or to incorporate diverse participants, such as intergenerational programming. Adapted programming may be responsive but reduce impact on outcomes. With growing interest in and limited availability of intergenerational protocol, implementation science guides program tailoring to ensure that youth and older adults mutually benefit from adapted programming. We integrated guidelines for tailoring interventions (Framework for Reporting Adaptations and Modifications-Expanded: FRAME) and evidence-based intergenerational practice. We illustrate how program fidelity can be supported in intergenerational settings using examples from an adapted USDA-approved preschool nutrition curriculum delivered intergenerationally. Program acceptability, appropriateness, and feasibility were rated favorably by program stakeholders, and observational implementation data suggest fidelity can be maintained using evidence-based intergenerational strategies. Our findings support the potential for protocol developed for one age group to benefit youth and older adults when it is adapted using implementation and intergenerational guidelines."}
+{"text": "Are eusociality and extraordinary aging polyphenisms evolutionarily coupled? The remarkable disparity in longevity between social insect queens and sterile workers\u2014decades vs. months, respectively\u2014has long been recognized. In mammals, the lifespan of eusocial naked mole rats is extremely long\u2014roughly 10 times greater than that of mice. Is this robustness to senescence associated with social evolution and shared mechanisms of developmental timing, neuroprotection, antioxidant defenses, and neurophysiology? Focusing on brain senescence, we examine correlates and consequences of aging across two divergent eusocial clades and how they differ from solitary taxa. Chronological age and physiological indicators of neural deterioration, including DNA damage or cell death, appear to be decoupled in eusocial insects. In some species, brain cell death does not increase with worker age and DNA damage occurs at similar rates between queens and workers. In comparison, naked mole rats exhibit characteristics of neonatal mice such as protracted development that may offer protection from aging and environmental stressors. Antioxidant defenses appear to be regulated differently across taxa, suggesting independent adaptations to life history and environment. Eusocial insects and naked mole rats appear to have evolved different mechanisms that lead to similar senescence-resistant phenotypes. Careful selection of comparison taxa and further exploration of the role of metabolism in aging can reveal mechanisms that preserve brain functionality and physiological resilience in eusocial species. Eusocial animals, characterized by reproductive division of labor, cooperative brood care, and overlap of generations, can have extraordinary lifespans. Eusocial hymenopteran  queens may live 100 times longer than solitary insects. In some eusocial species there is a similar lifespan differential between queens and workers . Naked mHarpagnathos salatator, workers can facultatively become reproductive upon queen loss  declines with age (superoxide dismutase (SOD), lowers levels of protein carbonylation (a measure of oxidative damage) and extends lifespan  store sperm from a single insemination for life, allowing sperm counts to reliably estimate queen age . Queens Caste theory  can be aMost aging comparisons with NMRs involve studies of other taxa. Mutant dwarf mice with growth hormone mutations exhibit pedomorphic traits and have at least 50% longer lifespans than wild-type mice, and fewer aging-associated diseases . ExperimReticulitermes speratus reproduce in hypoxic, hypercapnic chambers, conditions that enhance their reproductive output (Harpegnathos saltator (Brain metabolism is little explored in eusocial and solitary species . Is enere output , althouge output . Future saltator  hint at saltator  will allEusocial insects and eusocial mammals share aging phenotypes despite phylogenetic divergence, but different mechanisms appear to have evolved to facilitate delayed aging in their nervous systems. The striking difference in worker and reproductive lifespan in eusocial insects is less pronounced in NMRs, further suggesting the evolution of multiple pathways to achieve long and healthy lifespans in eusocial taxa. To enable precise comparisons between vertebrate and invertebrate taxa, similar methodologies, such as quantifying levels of homologous biochemical markers of aging or comparisons among divergent taxa must be applied. Integration of theories of aging and development in eusocial and solitary species will enhance our understanding of how social organization shapes aging phenotypes and mechanisms that promote longevity.YG, MM, and JT wrote the manuscript. YG and JT provided the funding. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Lack of insurance or funds for dental services, lack of access to dental offices, fear of dentists, and avoidance of dental offices during COVID can lead to oral health problems in older adults. Brushing, flossing, and drinking fluoridated water can protect teeth when dentists are unavailable. Limiting intake frequency of carbohydrates and chewing sugarfree gum after eating add protection. A recent systematic review and meta-analysis confirmed the effectiveness of sugarfree gum in reducing caries, in children and adults who chewed sugarfree gum compared with those who did not chew. Chewing sugarfree gum significantly reduced caries increment, with a prevented fraction of 28 percent, roughly equivalent to the prevented fractions for fluoride toothpastes and supplements. A follow-up systematic review provides further evidence that chewing sugarfree gum reduces the numbers of Streptococcus mutans in the oral cavity. Finally, chewing sugarfree gum could alleviate symptoms of xerostomia and may reduce caries."}
+{"text": "Manis javanica) achieved notoriety during the Coronavirus disease pandemic because of flawed evidence suggesting that pangolins could be intermediate hosts . Native to Java (thus javanica), their habitat includes Southeast Asia, especially the Indomalayan archipelago and Sunda Islands. Humans hunt pangolins for their meat, consume their blood as an elixir, and use their scales and other body parts as ingredients for crafting leather products and nonefficacious medications. Linnaeus named the genus"}
+{"text": "The search for novel prostate cancer biomarkers is one of the major topics in recent urologic research. Given the still unsatisfactory performance of the available diagnostic biomarkers in the detection of significant prostate cancer cases and the lack of prognostic and predictive biomarkers with high specificity, there is still an urgent need for new biomarkers. This special issue presents nine original research papers and two reviews elucidating novel developments in prostate cancer biomarkers. Interestingly, two major topics were in focus, microRNAs (miRNAs) as biomarkers ,2,3,4 anThe fast-growing field of miRNA biomarkers in liquid biopsies reflects the high expectations raised in the implementation of miRNA diagnostics. Freds\u00f8e and colleagues analyzed 92 circulating miRNAs in plasma samples of 753 patients and found distinct regulation of miRNAs in patients with benign prostatic hyperplasia (BPH), localized prostate cancer, and advanced prostate cancer with large overlaps between the groups [Using urine and urinary cells, respectively, is the second major approach in minimally invasive liquid biopsies for PCa detection. Borkowetz and colleagues used urinary sediments to analyze a 12-miRNA panel by qPCR [Successful implementation in routine clinical use requires standardization of miRNA measurements. Konoshenko and coworkers evaluated the diagnostic potential of ratios constructed from a panel of 12 cell-free miRNAs, using urine extracellular vesicles, clarified urine, and plasma. Eight miRNAs combined into six ratios showed maximum stability and 97.5% accuracy in separating PCa patients from the control group  . In a seBlood and urine are also profitable sources of metabolites, which have recently been used in numerous disease states. Yang and colleagues conducted a study searching for urine metabolite biomarkers for the detection of PCa. They found twenty differentially expressed urine metabolites in a cohort of 50 prostate cancer patients compared to non-cancerous individuals . The comWhile liquid biopsies are an upcoming promising tool of non-invasive PCa diagnostics, verification of biomarkers in tissues is mandatory to prove PCa being the primary cause of the alterations in liquid biopsy biomarkers. Latosinska and colleagues present a proteomic study comparing the proteome of PCa tissue with benign prostatic hyperplasia (BPH), a common co-morbidity especially in aged patients . They dePatients with GS \u2264 6, i.e., at low risk, are eligible for active surveillance. Yu and colleagues asked whether multiparametric MRI (mpMRI) can be a substitute or supplement of traditional tools as PSA, digital rectal examination, and transrectal ultrasound-guided biopsy (TRUS) . They reTwo papers in this special issue elucidate oxidative stress related enzymes and peptides as potential biomarkers in PCa. As shown by Veljkovi\u0107 and colleagues, xanthine oxidase (XO) activity was significantly higher in tumor tissue compared to heathy controls and strongly correlated with serum PSA levels . The autFinally, two reviews provide updates on prognostic and predictive omics-derived biomarkers for therapy of advanced PCa and especially of serum biomarkers in metastatic disease ,11. In tSaxby and colleagues focused on serum biomarkers , which can be used in conjunction with PSA as prognostic or predictive biomarkers for metastatic PCa. Forty-three were analyzed and revealed numerous biomarkers with potential value for identifying patients with advanced PCa and of value for the development of targeted treatment strategies. However, while basic data are available, clinical validation in prospective trials is urgently needed to bring them to routine use in clinical practice.This special issue elucidates some important aspects of PCa biomarker development and their potential clinical benefit and highlights advanced techniques of biomarker discovery. The future of those biomarkers strongly depends on prospective multicenter clinical diagnostic studies, which hopefully will find the support of the major funding agencies."}
+{"text": "Daily oral pre-exposure prophylaxis (PrEP) is highly effective at preventing HIV when used as directed among men who have sex with men (MSM). However, challenges with uptake and adherence to daily oral PrEP have prompted the development of new modes of administration, including a long-acting, intramuscular injectable. We sought to explore the treatment characteristics that may influence the willingness and uptake of long-acting injectable PrEP as opposed to the daily pills among a racially diverse sample of MSM.Between January and May 2021, we actively recruited 28 HIV-negative MSM  who lived in Philadelphia, PA during the past 12 months using social networking sites  and a community listserv. Qualitative data collection used a hybrid approach in which 4 focus groups and 10 semi-structured interviews were conducted virtually. Focus groups were kept racially and ethnically homogenous to identify differences in emerging themes related to PrEP willingness and preferences for specific prevention modalities.Participants discussed differing levels of interest and willingness to use long-acting injectable PrEP as opposed to the daily pills. The main perceived facilitator for injectable PrEP included convenience of use such as having fewer concerns with adhering to daily pills. Perceived barriers to injectable PrEP included (1) a dislike of needles as well as (2) concerns of potential side effects and (3) lower treatment efficacy . While Black and Latinx MSM reported experiences of racism and discrimination within the healthcare system, they also reported greater willingness to consider intramuscular injectables if their healthcare providers would provide in-depth information about the risks and benefits of this new modality. Our findings provide important guidance for the development and promotion of future strategies to enhance the uptake of long-acting injectable PrEP to address the HIV epidemic among MSM. Primary care providers should play a key role in ameliorating concerns related to hesitancy towards injectable PrEP, including emphasizing ease of dosing, effectiveness, and safety of long-acting PrEP to prevent infection.All Authors: No reported disclosures"}
+{"text": "Supportive marital relationships may reduce partners\u2019 problematic health behaviors, whereas unhappy relationships may lack efficacious spousal monitoring of health and increase the likelihood of using maladaptive coping strategies, such as heavy alcohol use, to deal with relationship problems. We used pooled data from the 2014 and 2016 waves of the Health and Retirement Study to examine how both partners\u2019 perceptions of marital quality were associated with heavy drinking. Our analytic sample included married couples in which both spouses were over age 50, completed the leave-behind psychosocial questionnaire, and provided non-missing data on marital quality and alcohol use . Measures included both positive and negative dimensions of marital quality and controls for sociodemographic, economic, health, household and marital characteristics. Using Proc Glimmix, we estimated a dual-intercept Actor-Partner Interdependence Model (APIM), in which separate equations were computed simultaneously for husbands and wives. For husbands, higher negative marital quality was associated with an increase in the odds of their own heavy drinking (OR=1.27), but there was no significant association between wives\u2019 marital quality and husbands\u2019 heavy drinking behavior. For wives, marital quality was not significantly associated with their own heavy drinking, but husbands\u2019 higher ratings of both negative and positive marital quality increased the risk of wives\u2019 heavy drinking . Results suggest that marital quality is associated with heavy drinking in later life: self-ratings of marital quality matter for men, whereas spousal perceptions of marital quality are more important for women."}
+{"text": "Pre-pandemic, evidence existed that intergenerational service-learning programs support knowledge of aging and positive attitudes and perceptions . As spring 2020 COVID-19 lock downs and public health warnings urged physical distancing of community dwelling older adults, growing concern about the unintended consequences of increased social isolation on mental and physical health prompted the Secretary\u2019s Office of Pennsylvania Department of Aging to design a pilot project with university faculty for virtual intergenerational social interaction. The Department identified older adults at the highest risk for social isolation . The resulting pilot project is fully integrated as a high impact practice into eight sections of recreational therapy and gerontology courses with participation by 210 undergraduate students and 210 older adults for 9 weeks of both the fall and spring semesters. Students, who received extensive classroom instruction aimed at avoiding negative stereotypes of older adults as helpless and dependent, called their assigned partner several times a week for at least an hour of communication. Using the UCLA loneliness scale, community-dwelling older adults reported frustration with isolation due to the pandemic. Those with low and moderate loneliness reported positive feelings about program and looking forward to interactions with students. Students gained virtual communication skills that may contribute to telehealth competencies, intervention skills such as assessment, life review/reminiscence, mindfulness techniques, and leisure education. Moreover, an analysis of student reflections revealed positive changes in attitudes toward older adults and the ability to enjoy common interests despite age differences."}
+{"text": "OBJECTIVES/GOALS: Pancreatic cysts are comprised of both precancerous mucinous lesions and non-mucinous lesions with minimal malignant potential. Our goal is to improve our ability to classify the type of cyst using a combination of novel radiomic features and cyst fluid proteolytic activity. METHODS/STUDY POPULATION: Preoperative pancreatic protocol CT images from 30 patients with proteolytic assay characterization, followed by surgical resection with a pathologically confirmed pancreatic cyst diagnosis between 2016-2019 will be used in this study. We will contour images using the widely available software 3D Slicer, and extract radiomic features using IBEX software. We will analyze area under the ROC curves to identify the radiomic features that best differentiate mucinous from non-mucinous cysts, and identify features to be cross validated. The predictive ability of identified radiomic features combined with proteolytic assay will be determined by performing multiple logistic regression analysis and comparing AUROC analysis. We will determine sensitivity and specificity for individual, as well as combinations of, analytes to determine the optimal classifier. RESULTS/ANTICIPATED RESULTS: We anticipate that the predictive ability, sensitivity, and specificity of utilizing radiomic features combined with proteolytic assay data will exceed the performance of any individual test. DISCUSSION/SIGNIFICANCE OF IMPACT: This work is designed to provide a predictive radiomic model that will enable us to better identify mucinous cysts that require further evaluation, and potentially prevent unnecessary surgery in other patients. Ultimately, we would like to improve the accuracy of noninvasive radiographic evaluation using radiomic markers. CONFLICT OF INTEREST DESCRIPTION: Dr. Charles Craik is a co-founder of Alaunus Biosciences, Inc."}
+{"text": "Black adults and women are more likely to experience serious cognitive decline in older age than their white and male counterparts. Evidence suggests perceived discrimination is associated with poor cognition in older adults, though the mechanisms remain unclear. Perceived discrimination has been linked to elevated inflammatory markers, such as C-reactive protein (CRP), which increases risk for worse cognitive functioning. Yet, little research has investigated whether CRP is implicated in the association between discrimination and cognition among Black older adults or if this relationship differs by gender. Using 2006-2016 data from Black adults \u226565 years old(N=1343) in the nationally representative Health and Retirement Study, random effects linear regression models (1) tested the association between discrimination and cognitive functioning; (2) explored whether this relationship differed for women and men; and (3) assessed whether elevated CRP mediated the association between discrimination and cognitive functioning. More frequent discrimination was associated with worse cognitive functioning , though gender did not moderate this relationship. Elevated CRP was significantly associated with worse cognitive functioning . Discrimination remained statistically significant in this model, indicating no mediation by CRP. Of note, inclusion of depressive symptoms and cardiometabolic conditions accounted for the association between both discrimination and CRP with cognitive functioning. These findings demonstrate the need for more within-group research on older Black adults documenting the complex relationship between discrimination, inflammation, and cognitive health. This approach will provide greater understanding of the biopsychosocial mechanisms underlying disparities in cognitive functioning in Black adults."}
+{"text": "Between the years 1999-2008, a substantial increase in nursing home use occurred among Black and Latinx older adults, while white older adults\u2019 use of nursing homes decreased. These disparate trends suggested potential racial and ethnic disparities in options for preferred long-term services and supports (LTSS) settings. Over the last decade, several initiatives have been put in place to support LTSS needs in the community. However, it is unclear whether Black and Latinx older adults are continuing to use nursing home services at disproportionate rates. We used LTCfocus data for 2011-2017 to explore current trends in nursing home use and access among Black and Latinx older adults in light of these current initiatives. Our findings reveal a continued rise in Black and Latinx older adults\u2019 use of nursing homes while white older adults\u2019 use continues to decline. More notably, there has been a decline in nursing homes servicing these minority groups."}
+{"text": "ATP channels may provide analgesia and attenuate opioid tolerance and withdrawal OBJECTIVES/GOALS: Our long term goal is to develop therapeutics for the treatment of the overuse of opioids. The objective of this application is to test novel KATP channel-targeting prodrugs in rodent models of neuropathic and inflammatory pain in addition to opioid tolerance after chronic morphine administration. METHODS/STUDY POPULATION: In one study, two different measures for chronic pain were implemented in mice. Male and female mice (n=10) were subjected to spinal nerve ligation (SNL) or intraplantar injection of Complete Freund\u2019s Adjuvant (CFA) to induce neuropathic and inflammatory pain, respectively. Administration of KATP channel prodrugs  attenuated mechanical hypersensitivity after SNL or CFA compared to vehicle . In a separate study, changes in mechanical hypersensitivity were tested while mice undergo chronic morphine treatment  with administration of the prodrugs. Tolerance was measured as the loss of antinociception, and withdrawal is measured \u02dc24 hours after the final morphine injection. RESULTS/ANTICIPATED RESULTS: Intrathecal administration of either KATP channel prodrugs significantly attenuated mechanical hypersensitivity after SNL and significantly attenuated mechanical hypersensitivity after CFA in mice. We predict that intrathecal administration of these prodrugs will also attenuate morphine tolerance and withdrawal in mice. This hypothesis is based off our previous data indicating non-water soluble KATP channel agonists produce analgesia and attenuate morphine tolerance in mice. DISCUSSION/SIGNIFICANCE OF FINDINGS: Pharmaceutical strategies to utilize KATP channels for therapeutics have been hindered due to the low solubility and low ability to cross the neurovascular unit. Newly developed, water-soluble KATP channel openers could be useful pharmaceutical strategy to reduce chronic pain, opioid tolerance, and withdrawal in human populations.ABSTRACT IMPACT: Pharmacological activation of K"}
+{"text": "Standard of care for patients with glioblastoma (GBM) includes resection with concurrent temozolomide (TMZ) and radiotherapy, with inevitable disease recurrence. Upon recurrence, tumors are often resistant to first-line therapies and/or have infiltrated eloquent or deep brain regions, precluding repeat resection. There is currently no standard of care for recurrent GBM and patients succumb to their disease burden within 12- 15 months of their initial diagnosis of recurrence, exposing an unmet need to find novel therapies to treat recurrent disease. Bromodomain and extraterminal (BET) proteins are chromatin readers that affect transcription of genes. The oral BET inhibitor (BETi) OTX-015 has shown promise in a dose-escalation, phase I study in patients with acute leukemia and other BET inhibitors are currently in phase I studies for the treatment of primary brain tumors. We have recently shown that BET inhibition increases DNA damage and mitotic catastrophe in oncogenic cells by increasing transcription-replication conflicts and downregulating expression of key DNA damage checkpoint proteins, and have also shown its efficacy in decreasing tumor burden and improving survival when combined with TMZ in intracranial mouse models of glioma. We have also demonstrated that BETi's synergize with Olaparib by downregulating expression of the BRCA-driven DNA damage repair pathway and further leverages additive effects when triply combined with other DNA damaging agents such as Lomustine to decrease tumor burden and improve survival in patient-derived mouse models of GBM and medulloblastoma. We therefore hypothesize that the synergistic and additive effects of this triple combination seen in our preclinical studies will achieve therapeutic benefits in patients with recurrent GBM."}
+{"text": "Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues. We have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E-B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the aging CNS and improve cognition and memory in aging mice. These neuroprotective benefits are markedly reminiscent of those observed in the aging CNS post-exercise, suggesting enhancing muscle proteostasis may be sufficient to replicate the local and systemic effects of exercise. Identification of pathways regulating crosstalk between skeletal muscle and CNS may yield targets with high therapeutic potential for diseases of the aging CNS."}
+{"text": "Mature cystic teratoma (MCT) is a common benign ovarian germ cell tumor. It is more predominantly seen in premenopausal women and contains at least two or more well-differentiated germ cell layers. It is termed a dermoid cyst if the ectodermal tissue is the predominant component. The complications of a dermoid cyst include torsion, malignant degeneration, rupture, and infection. The incidence of a ruptured dermoid cyst is around 1%-2% resulting in chemical aseptic peritonitis from spillage of the cyst contents. Usual clinical presentation is with diffuse abdominal or pelvic pain and abdominal distension. Around 93-96% of dermoid cysts demonstrate fat in the cyst cavity however, minimal or no fat poses diagnostic challenges. In this case, we discuss a rare case of spontaneously ruptured lipid-poor and thyroid tissue-rich left ovarian dermoid presenting with chemical peritonitis. Special magnetic resonance (MR) Imaging sequences such as fat saturation imaging, chemical shift imaging, and gradient-echo imaging assist in detecting scant amounts of fat in the cyst cavity or cyst wall. Teratomas are the most common ovarian germ cell tumors which arise from primitive germ cells . ConstitA 33-year-old nulligravida presented to the emergency department with acute onset of non-radiating left lower quadrant abdominal pain. The patient reported worsening pain with movement, which gets relieved by lying still. She also reported a progressive increase in abdominal girth over the past several weeks. Denied new vaginal bleeding, discharge, or usage of contraception. Diagnostic imaging with ultrasonography (US), computerized tomography (CT), and magnetic resonance imaging (MRI) were performed in the emergency room and are described in Figures Discovering findings of a ruptured adnexal mass on imaging, the patient underwent exploratory laparotomy with left salpingo-oophorectomy. Intraoperative findings revealed a ruptured left ovarian cyst on the inferior aspect emanating serous fluid into the peritoneal cavity. The tumor was identified as mature lipid-poor cystic teratoma on the frozen section. The postoperative recovery was uneventful. The histopathology of the resected specimen is shown in Figures Ovarian germ cell tumors (OGCTs) are a group of tumors that include benign (mature cystic teratoma [MCT]) or malignant  neoplasms . TeratomUltrasonography (US) is the first line of imaging used in the evaluation of adnexal masses . DiffereIn combination with findings from US, the CT assists in additional fat detection with a sensitivity of 93%-98% . The HouT1-weighted and T2-weighted MRI in MCTs will show a hyper-intense signal representing sebaceous fluid. It can be differentiated from hemorrhagic cyst by fat suppression, chemical shift artifact, or gradient-echo imaging. The fat becomes hypointense on fat-saturated MR Figure , 6, wherThis case study emphasizes the importance of a multimodality approach to complex pelvic masses that present with pelvic pain. Advancement imaging modalities like Pelvic MRI can detect acute complications from these masses like torsion or rupture. Hence, aiding in more accurate diagnosis and pre-operative planning. Surgery is performed for definitive diagnosis and treatment. In the current case of the ruptured teratoma leading to peritonitis, the patient underwent exploratory laparotomy and salpingo-oophorectomy with peritoneal lavage. The ascitic fluid was serous without significant fat content. Histologically, the tissue demonstrated abundant colloidal material and minimal fat consistent with Struma ovarii.\u00a0The tumor is termed struma ovarii when the thyroid tissue is predominant and comprises >50% of the tumor .In the emergency room setting initial work up for pelvic pain in female patients starts with a good quality ultrasound examination. Upon discovery of a complex mass further evaluation should be done with a pelvic MRI with IV contrast. Pelvic MRI can help identify immediate complications and determine the correct surgical approach. Identifying components of MCTs across multiple imaging modalities assist in differentiating adnexal masses. The wide range of presence of fat in the dermoid cyst makes it easily detectable on CT and MR imaging. Although some cases demonstrate low fat, using special techniques such as fat suppression MRI plays a vital role in early detection and emergency management. Once rupture and peritonitis are suspected, patients should be managed by emergent laparotomy (lower spillage rate than laparoscopy) followed by cystectomy."}
+{"text": "Metastasis is an inefficient process in which the vast majority of cancer cells are fated to die, partly because they experience oxidative stress. Metastasizing cancer cells migrate through diverse environments that differ dramatically from their tumor of origin, leading to redox imbalances. The rare metastasizing cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We review the changes in redox regulation that cancer cells undergo during metastasis. By better understanding these mechanisms, it may be possible to develop pro-oxidant therapies that block disease progression by exacerbating oxidative stress in cancer cells.Oxidative stress often limits cancer cell survival during metastasis, raising the possibility of inhibiting cancer progression with pro-oxidant therapies. This is the opposite strategy of treating patients with antioxidants, an approach that worsened outcomes in large clinical trials. Metastasis is the leading cause of death in patients with cancer because disseminated disease is no longer curable by surgery and is often therapy-resistant . MetastaCancer cells must be plastic to survive metastasis . GeneticMultiple factors contribute to the death of cancer cells during metastasis, including immune-mediated destruction , growth + are important sources of reducing equivalents for oxidative stress resistance  is generally considered an antioxidant, but it exists in oxidized and reduced forms and when it is infused intravenously it selectively kills cancer cells by acting as a pro-oxidant . This isDietary interventions could also have pro-oxidant effects. Ketogenic diets may suppress metastasis partly by increasing oxidative stress in cancer cells . KetogenNew technical approaches to study metastasis, including whole-body imaging of metastasis patterns , improveIn at least some cancers, metastasizing cells appear to experience unusually high levels of oxidative stress, raising the possibility that these cells might be particularly sensitive to pro-oxidant therapies. It is an open question whether such therapies could prevent disease progression in patients with high-risk primary or regionally metastatic lesions. Nonetheless, this merits deeper study in preclinical models. Beyond this big-picture question, there are a number of pressing biological questions central to understanding redox regulation during metastasis: Does oxidative stress limit the survival of metastasizing cells from all cancers or only certain cancers?What causes the oxidative stress experienced by metastasizing cells?Are anabolic pathways downregulated in metastasizing cells to preserve reducing equivalents? Does this sometimes lead to dormancy in metastatic cells?How is mitochondrial function modulated in metastasizing cancer cells as compared with the primary tumors from which they arise?Do micrometastases continue to experience oxidative stress? For how long?To what extent do interactions with immune and stromal cells influence oxidative stress in cancer cells?Do differences in oxidative stress among distinct metastatic sites influence organotropism?"}
+{"text": "Candidalusitaniae, a previously unreported cause of candidal vaginitis .Increasing use of short-course antifungal therapies in patients with recurrent vulvovaginitis may enable theemergence of less-common, more resistant yeast strains as vaginal pathogens. We report the case of a patient withchronically symptomatic and repeatedly treated vaginal candidiasis whose infection was attributable to"}
+{"text": "The G-protein-coupled receptors (GPCRs) constitute one of the largest and most ancient superfamilies of membrane proteins. They play a central role in physiological processes affecting almost all aspects of the life cycle of an organism. Availability of the complete sets of putative members of a family from diverse species provides the basis for cross genome comparative studies.Tetraodon complement with the availability of complete sequence of the freshwater puffer fish Tetraodon nigroviridis. Almost all 466 Tetraodon GPCRs (Tnig-GPCRs) identified had a clear human homologue. 189 putative human and Tetraodon GPCR orthologous pairs could be identified. Tetraodon GPCRs are classified into five GRAFS families, by phylogenetic analysis, concurrent with human GPCR classification.We have defined the repertoire of GPCR superfamily of Tetraodon and human genomes displays a high level of orthology and supports large-scale gene duplications in Tetraodon. Examples of lineage specific gene expansions were also observed in opsin and odorant receptors. The human and Tetraodon GPCR sequences are analogous in terms of GPCR subfamilies but display disproportionate numbers of receptors at the subfamily level. The teleost genome with its expanded set of GPCRs provides additional and interesting comparators to study both evolution and function of these receptors.Direct comparison of GPCRs in  The G-protein-coupled receptors (GPCRs) constitute one of the largest and most ancient superfamilies of membrane proteins, accounting for 1\u20132% of the vertebrate genome. GPCRs are characterized by the presence of highly conserved molecular architecture encoding seven transmembrane (TM) hydrophobic regions linked by three extracellular loops that alternate with three intracellular loops [GPCRs have been aggressively pursued as drug targets due to their central role in physiological processes affecting almost all aspects of the life cycle of an organism . Almost Drosophila; additional species provide new comparators for GPCR studies. Teleost fish, Tetraodon nigroviridis is one of the smallest known vertebrate genomes. It has all the specialized functions of higher vertebrates and can be a good vertebrate model system to study [T. nigroviridis genome now allows for the identification and analysis of its full set of GPCRs. Here, we describe the genome wide survey of Tnig-GPCR repertoire and a detailed analysis of opsin, fish-odorant receptors (FOR) and taste receptors (T1R).The completion of several other vertebrate and invertebrate genome sequencing projects paves the way for \"functional genomics\". The quest for assigning function to putative gene products exploits the sequence and structural similarities to known genes and further could be elucidated using molecular biology techniques ,10. Suchto study ,15. The Tetraodon nigroviridis genome (>90% sequence coverage) has shown that it possesses one of the smallest known vertebrate genomes and revealed a set of 27,918 predicted genes, much similar to the number of predicted genes in human genome [Tetraodon genome, we developed a comprehensive strategy . For almost all Tnig-GPCRs, a putative human GPCR homologue could be identified. 189 putative human and Tetraodon GPCR orthologous pairs are identified , whereas about two fold as many GPCR sequences as in fugu and about three fourth of the zebrafish GPCRs [Tetraodon also has similar numbers of frizzled receptors as expected in mammals and fish genomes. Some of the gene families in Tetraodon like opsins and fish odorant receptors have shown species-specific expansions similar to trace amine receptors in zebrafish [Tetraodon like other known fish genomes [Rhodopsin family in sh GPCRs . Tetraodebrafish . However genomes .Tetraodon and humans show many GPCRs for which there are two copies in Tetraodon but one in the human genome. Chromosomal distribution of putative Tetraodon-human GPCR orthologous pairs and corresponding Tnig-GPCR paralogs show correspondence between two different chromosomal regions in Tetraodon genome to one region in the human genome , rhodopsin (R), adhesion (A), frizzled (F) and secretin (S) (GRAFS classification) ,23,24.Te 368 see ; A, 29; ebrafish ,25.Tetraodon. These OR genes are found in clusters of 3\u20134 members in the Tetraodon genome, located on different chromosomes. They display higher sequence identity within a cluster suggesting tandem duplication events might be responsible for OR gene family expansion in Tetraodon as observed in the genomes of every vertebrate organism investigated earlier, including zebrafish, mice and humans [Tetraodon ORs with fish odorant receptor subfamily members  grouped them into six clusters of orthologues with very high boot strap support  were identified in fish odorant receptor (FOR) subfamily of rhodopsins in d humans . Phyloget Figure . In teleh Figure . High diTetraodon genome  taste receptors in e Figure . They haTetraodon GPCRs and found high level of orthology with human counterparts. The human and Tetraodon GPCR sequences are analogous in terms of GPCR subfamilies, but display disproportionate number of receptors at the subfamily level. The teleost genome, with its expanded set of GPCRs, provides an additional and interesting model to study both evolution and function of these receptors. The availability of repertoire of Tetraodon GPCRs will facilitate further studies through \"functional genomics\" and \"reverse pharmacological\" strategies to match their cognate ligands and to elucidate biological functions. Systematic mutation of Tetraodon GPCRs will help to determine their neural, developmental and behavioral roles. They might also yield novel insights into the physiological functions and mutational pathologies of their human homologues in particular and other vertebrate homologues in general.We have identified and analyzed repertoire of Tetraodon nigroviridis are obtained from NCBI and Genoscope Tetraodon Genome Browser [12 [Tetraodon nigroviridis EST hits, as there were few or no Tetraodon nigroviridis EST sequences available in the database.Sequences of the  Browser . HumanGP Browser   Sequence alignment of the T1Rs of Tetraodon, human and rat are aligned with the rat mGluR1 metabotropic glutamate receptor (Accession no. P23385). Ligand binding residues of mGluR1 are highlighted in red. The C-terminus is not shown. Potential transmembrane segments are indicated using arrows.Click here for fileTransmembrane Helix (TMH) prediction of human GPCRs by different TMH prediction programs  A dataset of 327 annotated human GPCRs are predicted for Transmembrane Helices (TMH) by HMMTOP, SOSUI, TMHMM and MEMSAT. A range of 6\u20138 predicted TM helices acquired maximum coverage to predict 7TM domain region.Click here for file"}
+{"text": "Bacsi A, Choudhury BK, Dharajiya N, Sur S, Boldogh I. 2006. Subpollen particles: carriers of allergenic proteins and oxidases. J Allergy Clin Immunol 118:844\u2013850.During the flowering season, high humidity and moisture trigger the release of pollen grains from grasses, trees, and shrubs. Allergens contained in these pollen grains can cause reactions in the skin, eyes, and upper and lower respiratory tracts. Seasonal asthma also is associated with pollen exposure.How pollen allergens contribute to inflammation in the lower airways has puzzled researchers since few pollen grains reach the peripheral airways due to their size. In this report, NIEHS grantees Sanjiv Sur and Istvan Boldogh, with colleagues at the University of Texas Medical Branch in Galveston, present new findings suggesting that fragments of pollen grains, called sub-pollen particles (SPPs), are capable of reaching the lower airway regions and causing the clinical symptoms associated with seasonal asthma.Ambrosia artemisiifolia) and redroot pigweed (Amaranthus retroflexus) pollen grains. They also used an experimental mouse model of asthma to challenge sensitized mice with intranasally applied SPPs.This same research team recently reported that ragweed pollen grains contain intrinsic NAD(P)H oxidases, and that exposure to them generates oxidative stress in the airway epithelium within minutes of exposure. In the current study, the investigators analyzed bronchial epithelial cells after exposure to hydrated short ragweed H oxidase activity. Exposure of cultured cells to SPPs caused significant increases in the generation of reactive oxygen species and induced airway inflammation in laboratory mice. Pretreatment of the SPPs with NADH and NAD(P)H oxidase inhibitors reduced their ability to increase reactive oxygen species in the airway epithelial cells and reduced airway inflammation.This is the first report to demonstrate the presence of allergenic proteins and oxidase activity in SPPs of respirable size. The study provides insight into the potential role of SPPs in seasonal asthma and suggests that oxidase inhibitors may be useful therapeutic agents in reducing or preventing oxidative damage and inflammation."}
+{"text": "We examined the expression of pancreatic secretory trypsin inhibitor (PSTI) in colorectal cancer by immunohistochemical staining using an anti-PSTI antiserum, an in situ hybridisation technique utilising sulphonated PSTI cDNA probe, and a Northern blot hybridisation method, using a 32P-labelled PSTI cDNA probe. Immunohistochemically, PSTI was detected in 80 of 95 (84%) colorectal cancer cases. Analyses with in situ hybridisation as well as Northern blot hybridisation demonstrated PSTI mRNAs in immunohistochemically positive cases, showing PSTI could be produced in colorectal cancerous cells. Histologically well or moderately differentiated adenocarcinoma showed higher incidence of PSTI immunoreactivity than the other types. Furthermore, the intensity of the immunohistochemical staining for PSTI increased the more cases advanced, particularly in regard to depth of invasion and tumour size. Thus, PSTI expression is widespread in colorectal cancer, and occurs more commonly in advanced cases. Considering the suggestion that PSTI is a growth-stimulating factor as an well as inhibitor to proteolytic proteinase, the present findings may indicate that PSTI expressed in colorectal cancerous cells may play a role possibly closely associated with tumour development."}
+{"text": "Adjuvant psychological therapy (APT) is a newly developed cognitive behavioural treatment which has been designed specifically to improve the quality of life of cancer patients by alleviating emotional distress and inducing a fighting spirit. We report a phase I/II study which evaluates APT in routine clinical practice. A consecutive series of 44 outpatients with various cancers referred for psychiatric consultation and receiving APT at the Royal Marsden Hospital was studied. Standardised self-report questionnaires were used to measure anxiety, depression and four principal categories of mental adjustment to cancer, namely, fighting spirit, helplessness, anxious preoccupation and fatalism. Statistical comparisons between pre-therapy scores and scores after an average of five APT sessions revealed significant improvement in anxiety, depression, fighting spirit, anxious preoccupation and helplessness. Fatalism scores showed the same trend, but the changes were smaller. Patients with advanced disease showed as much improvement as those with local or locoregional disease. Present results indicate improvement in both psychiatric symptoms and mental adjustment to cancer associated with APT. Whether this association is causal remains to be determined by randomised controlled trials. Such a trial is in progress."}
+{"text": "Melospiza melodia) to quantify long-term effects of parental immune experience on offspring immune response. We experimentally vaccinated parents with a novel antigen and tested whether parental vaccination influenced the humoral antibody response mounted by fully grown offspring hatched the following year. Parental vaccination did not influence offspring baseline antibody titres. However, offspring of vaccinated mothers mounted substantially stronger antibody responses than offspring of unvaccinated mothers. Antibody responses did not differ between offspring of vaccinated and unvaccinated fathers. These data demonstrate substantial long-term effects of maternal immune experience on the humoral immune response of fully grown offspring in free-living birds.Knowledge of the causes of variation in host immunity to parasitic infection and the time-scales over which variation persists, is integral to predicting the evolutionary and epidemiological consequences of host\u2013parasite interactions. It is clear that offspring immunity can be influenced by parental immune experience, for example, reflecting transfer of antibodies from mothers to young offspring. However, it is less clear whether such parental effects persist or have functional consequences over longer time-scales, linking a parent's previous immune experience to future immune responsiveness in fully grown offspring. We used free-living song sparrows ( Variation in host immunity to parasitic infection is thought to underpin major evolutionary processes, including host\u2013parasite coevolution, inter-sexual selection and the evolution of sex, and to influence host and parasite population dynamics  to test whether parental exposure to a novel antigen influenced the future humoral immune response of fully grown offspring. During September 2004, we vaccinated a sample of song sparrows with tetanus toxoid. Twelve months later, we tested whether baseline tetanus antibody titre or primary antibody response differed between fully grown offspring of vaccinated and unvaccinated parents. Our use of a novel antigen to assess humoral immunity allows us to distinguish long-term effects of parental vaccination from effects of subsequent natural parasite exposure on offspring immune response  or released without vaccination (n=28). Approximately 40 further colour-ringed individuals were observed but not captured. Then, during September 2005, we measured baseline tetanus antibody titres and the primary antibody response to tetanus vaccination in adult song sparrows and their fully grown offspring that had hatched during 2005 . Briefly, sparrows were mist-netted, blood sampled, vaccinated with 70\u200a\u03bcl of tetanus toxoid and released. Individuals were recaptured and blood sampled ca 10 days later. Tetanus antibody titres in baseline and post-vaccination plasma samples were quantified by enzyme-linked immunosorbent assay. Tetanus response was estimated as the difference between post-vaccination and baseline antibody titres. Fieldwork was approved by the University of British Columbia Animal Care Committee.During September 2004, we mist-netted song sparrows on Mandarte as part of a wider study of individual variation in immune response. Captured individuals were vaccinated with 70\u200a\u03bcl of tetanus toxoid in the pectoral muscle and released (f), and the period between baseline and post-vaccination blood samples, since these variables influence tetanus response in song sparrows . Eleven mothers (of 21 offspring) and 10 fathers (of 19 offspring) had been vaccinated in 2004. Ten mothers (of 25 offspring) and 13 fathers (of 27 offspring) had not been vaccinated. Vaccinated and unvaccinated parents did not differ with respect to  in 2005 .Across all 46 offspring, baseline antibody titres averaged 7.2\u00b10.7 units and did not differ between offspring whose parents had and had not been vaccinated the previous year . TetanusFicedula hypoleuca) chicks.Previous studies have demonstrated increased antibody titres in eggs or young chicks of parents exposed to specific immune challenges . In songParus major) exposed to nest parasites during laying produced offspring that were more likely to recruit locally , these patterns are not an artefact of selective vaccination-induced mortality in poor quality parents.Maternal antibody transfer may particularly benefit young offspring whose own immune systems have not yet developed, but has also been suggested to permanently alter offspring immune function , but it Such long-term consequences of maternal vaccination may represent direct, permanent effects of maternal antibody transfer on offspring immunology (Although substantial, the increased tetanus response in offspring of vaccinated mothers was considerably lower than the average secondary antibody response measured in 2005 in seven parents that had also been vaccinated in 2004 (4488\u00b1664 units, see also"}
+{"text": "Three intraperitoneal human ovarian cancer xenografts  were used to assess the antitumour activity of intraperitoneal therapy with liposome encapsulated MTP-PE. MTP-PE led to significant prolongation of survival in all three xenograft models, but with varying efficacy. In one tumour model (OS), 80% of mice were cured of tumour by twice weekly therapy for 4 weeks, whereas in another xenograft model (LA), the median survival time was approximately doubled compared to PBS injected and placebo liposome injected controls . The antitumor efficacy of MTP-PE did not correlate with the extent of peritoneal neutrophil infiltration after intraperitoneal therapy. Combined therapy with liposome encapsulated MTP-PE and recombinant murine granulocyte-macrophage colony stimulating factor led to increased survival of mice bearing the LA and HU xenografts, compared to tumour bearing mice treated with either agent singly."}
+{"text": "When you're a single-celled organism at the bottom of the food chain, it pays to be resourceful. Diatoms, highly successful photosynthetic plankton responsible for 40% of the net primary production in the oceans, undergo seasonal population explosions called phytoplankton blooms that attract billions of krill, copepods, and other grazing predators. As a defense, wounded diatoms release aldehyde compounds that minimize future diatom casualties by compromising the hatching success of grazers. But these diatom-derived aldehydes can also kill diatoms.In a new study, Assaf Vardi, Chris Bowler, and their colleagues investigated the possibility that the contrasting effects of aldehydes reflect their role as \u201cinfochemicals\u201d that trigger different responses attuned to changing conditions in the diatoms' habitat. The authors found that different concentrations of aldehydes produce different diatom responses. At low doses, aldehydes induce resistance to the compound's toxic effects. High aldehyde concentrations, on the other hand, trigger cell death, which may lead to termination of a bloom. Thus, diatom-derived aldehydes regulate the population dynamics of both diatoms and their predators.Thalassiosira weissflogii is a ubiquitous, cosmopolitan species; Phaeodactylum tricornutum is a standard model for understanding diatom biology.To investigate aldehyde effects on diatom cell fate and population dynamics, the authors studied how two cultured diatom species responded to a highly reactive aldehyde called decadienal. Reactive compounds like decadienal are likely to generate a variety of potentially harmful molecules called reactive oxygen species (ROS). But the authors detected increased levels of just one ROS, nitric oxide, an unstable compound involved in a wide range of physiological processes. Monitoring nitric oxide levels with a nitric oxide\u2013sensitive fluorescent dye and time-lapse imaging revealed that both diatom species experienced similar bursts of nitric oxide production about five minutes after decadienal treatment.Treated cells succumbed to decadienal in a time- and dose-dependent manner, with significant increases in fatalities above a specific threshold. Below this threshold, cells survived, but underwent cell cycle arrest. To clarify nitric oxide's role in cell death, the authors stimulated nitric oxide production without using decadienal by using molecules called nitric oxide donors. Next, they pretreated cells with a nitric oxide inhibitor before exposing them to decadienal. The number of dying cells increased along with the levels of nitric oxide in the first experiments, and incidence of decadienal-related cell death decreased with the inhibitor. These results clearly implicate nitric oxide in cell death.P. tricornutum cells that express a calcium-sensitive bioluminescent protein, they tracked changes in intracellular calcium levels in response to aldehydes. As predicted, intracellular calcium levels spiked following decadienal exposure. None of the nitric oxide donors stimulated intracellular calcium production, suggesting that nitric oxide functions downstream of calcium. And, indeed, the nitric oxide synthase that produces nitric oxide was shown to be calcium-activated: after perceiving ambient aldehyde levels, the cell undergoes transient calcium increases that result in nitric oxide production.How does the cell stimulate nitric oxide production? Since plant and animal cells use calcium to perceive a wide range of environmental signals, Vardi et al. reasoned that diatoms might, too. Using Interestingly, nitric oxide production levels varied among the diatoms. Some cells showed rapid increases in nitric oxide production while their neighbors showed delayed responses, suggesting that the signal to produce nitric oxide was propagating through the diatom population. Healthy cells sensed the level of stressed cells in their midst by detecting the wounded cells' aldehyde-generated signal. Cells pretreated with a lower dose of decadienal before receiving a higher dose had far better survival and growth rates than cells treated with only a single high dose. These results suggest that lower decadienal doses may immunize cells, stimulating resistance to normally lethal aldehyde concentrations. This induced resistance may provide diatoms who escape grazing predators with a better chance of surviving the toxic aldehydes released by the dying diatoms.Altogether, these results suggest that decadienal-like aldehydes not only affect the reproductive capacity of grazers but also act as infochemicals that monitor stress levels in diatom populations. During phytoplankton blooms, this stress surveillance system can induce resistance or death. The authors propose that this differential response, regulated by the sophisticated use of intracellular calcium and nitric oxide signals, may determine the fitness and succession of phytoplankton communities.The finding that diatoms use chemical signaling for cell\u2013cell communication provides new insights into the cellular mechanisms mediating biotic interactions at the population level and challenges traditional concepts of phytoplankton bloom dynamics. With thousands of different diatom species potentially producing a diverse array of aldehydes, these reactive compounds may prove to be even more versatile than shown here\u2014and may be a key factor contributing to the ecological success of these organisms. Now researchers can begin to unravel the mechanisms that endow one group of molecules with the means to mediate such diverse responses."}
+{"text": "We are pleased to see that our Essay  has sparThere seems to be no disagreement with our main theses\u2014antidepressant advertisements do not accurately represent the evidence base from psychopharmacology, experimental psychiatry, and neuroscience; are not strictly based on the United States Food and Drug Administration (FDA)-approved prescribing label; and may mislead consumers.We believe many have bought into the serotonergic hypothesis of depression/generalized anxiety/social anxiety/obsessive-compulsive disorder/panic disorder/post-traumatic stress/bulimia/premenstrual dysphoric disorder largely because the serotonin reuptake inhibitor (SSRI) medications are licensed for these conditions. We reemphasize that pathophysiology cannot be established through clinical efficacy , yet thiAt the date of this letter, the advertising we presented in our Essay is still widespread, and quite visible on consumer advertising Web sites of SSRI manufacturers."}
+{"text": "Chinese hamster ovary (CHO) cells were exposed in vitro to combinations of bleomycin and misonidazole under hypoxic conditions. Only one drug was present at any given time and cells were washed before being exposed to the second drug. Both drugs induced potentially lethal damage (PLD). This damage was repaired under hypoxic conditions very rapidly, and bleomycin-induced PLD was repaired more rapidly than misonidazole-induced PLD. If, after the combined treatment, cells are kept in hypoxia, much of the damage can be repaired."}
+{"text": "Airway inflammation increases during acute exacerbations of COPD. Extrinsic factors, such as airway infections, increased air pollution, and intrinsic factors, such as increased oxidative stress and altered immunity may contribute to this increase. The evidence for this and the potential mechanisms by which various aetiological agents increase inflammation during COPD exacerbations is reviewed. The pathophysiologic consequences of increased airway inflammation during COPD exacerbations are also discussed. This review aims to establish a cause and effect relationship between etiological factors of increased airway inflammation and COPD exacerbations based on recently published data. Although it can be speculated that reducing inflammation may prevent and/or treat COPD exacerbations, the existing anti-inflammatory treatments are modestly effective. Exacerbations are a cardinal feature of the natural history of moderate and severe Chronic Obstructive Pulmonary Disease (COPD). PatientTreatment decisions for COPD patients are frequently made according to exacerbation rates. In the ATS/ERS guidelines it is stated that patients with frequent exacerbations should be initiated a trial of inhaled steroids. Systemiwhy inflammation is increased during COPD exacerbations. For practical purposes an attempt is made to categorize aetiological factors of increased inflammation into extrinsic or intrinsic, as it can be seen in table how increased inflammation is associated with the pathophysiology of COPD exacerbations.Although evidence for increased inflammation on COPD exacerbations has been reviewed previously, there has been little focus on why inflammation increases and which the consequences of this increase are,10. InveBacterial infections are generally considered to be the most common causes of COPD exacerbations. It is estimated that more than 40% of all exacerbations are of bacterial origin,11,12. AThe most common bacteria connected to COPD exacerbations are non-typable H. Influenzae, S. Pneumoniae, and M. Cattarhalis,11,12. TAirway bacteria initiate airway inflammation through several interconnecting mechanisms. The surface of bacteria allows the complement system to be activated through the alternative pathway, while specific surface molecules of the bacteria, called Pathogen-Associated Molecular Patterns (PAMPs), bind to pattern recognition receptors on a variety of leukocytes and initiate signalling pathways that lead to the activation of NF-\u03baB and production of proinflammatory cytokines. Once acA significant number of studies in stable COPD patients suggest that airway bacterial infections are associated with increased airway inflammation(18\u201321). Finding a relationship between bacteria and inflammation on stable COPD adds weight to the argument that bacteria may play a causative role in airway inflammation during COPD exacerbations.Soler et al used protected specimen brush and bronchoalveolar lavage sampling to determine inflammatory cell counts, levels of cytokines concentrations and microbial patterns in stable COPD patients and found that increased neutrophils and tumour necrosis factor-alpha  levels may be related to bronchial colonization. IncreasA large prospective longitudinal study by Sethi et al addressed the hypothesis that patients with bacterial-positive exacerbations show increased inflammation compared to bacterial-negative exacerbations. Among HConsistent with these observations, airway inflammation can be decreased with treatment of the infection. Early evidence came from a relatively small study, which showed that neutrophilic mediators' levels may decrease after treatment of bacterial exacerbations. GompertIn conclusion, three major findings support the hypothesis that bacterial infections are actively implicated in the mechanisms of increased airway inflammation during COPD exacerbations: 1) bacterial infections increase airway inflammation in colonized stable COPD patients 2) bacterial-positive exacerbations show increased inflammation (particularly of neutrophilic type) compared to bacterial-negative exacerbations and 3) eradication of bacteria after a bacterial exacerbation is accompanied by a significant decrease in airway inflammation. A summary of these findings is presented in table Respiratory viruses are important triggers of COPD exacerbations. Initial studies using serology and cell cultures for detecting viral infections suggested that 30% of COPD exacerbations are related to viral infections -30. LatePossible mechanisms of viral-induced inflammation have been described. The airway epithelial cell is the principal host cell for most respiratory viruses. Viral rThere is convincing data that viruses induce inflammation in asthma. In animFurther to these observations, two recent studies showed that viral airway infections during COPD exacerbations are related to airway eosinophilia,40. ThisAtypical pathogens with potential importance in acute exacerbations include M. Pneumoniae, C. Pneumoniae and Legionella spp. Considerable confusion exists in the literature regarding the significance of these potential pathogens in acute exacerbations of COPD. This isin vivo studies on the effect of PM exposure on airway inflammation in COPD patients. There is also lack of information on airway inflammation during PM exposure induced COPD exacerbations, which may be due to difficulties in defining such exacerbations.Epidemiologists have linked ambient particulate air pollution (PM) exposure with exacerbations of pre-existing pulmonary diseases, such as COPD. PM-mediAn imbalance between oxidants and antioxidants may be involved in the development of COPD exacerbations. Almost a decade ago Rahman et al showed that plasma Trolox equivalent antioxidant capacity is decreased in patients presenting with acute exacerbation of COPD. Recent Oxidant stimuli induce cellular expression of inducible nitric oxide synthase and heme-oxygenase-1(HO-1) and increase nitrotyrosine formation. We have shown that there is increased HO-1 expression and nitrotyrosine formation in the airways of COPD patients during severe exacerbations relatively to stable state and that this is accompanied by an increase in indices of neutrophilic inflammation, i.e. neutrophil numbers, MPO and IL-8 levels. EvidencOxidative stress induces the transcription of various inflammatory factors, such as nuclear factor-kappaB (NF-\u03baB) and activator protein-1 (AP-1). It has Activated neutrophils and other inflammatory cells can in turn release reactive oxygen species and increase airway oxidative stress. Because oxidative stress can induce inflammation and vice versa, it is not clear which of the two, oxidative stress or inflammation, is primarily involved in the mechanisms of COPD exacerbations-[the chicken and egg problem].Alterations in innate and adaptive immunity are implicated in COPD pathogenesis. EvidencAccording to our observations changes in lymphocyte subpopulations occur during severe COPD exacerbations. In specAlthough Saetta et al also found increased T cell numbers in endobronchial biopsies from chronic bronchitis patients on mild exacerbations, no difference was detected in CD4 or CD8+ve cell numbers. This diIt would be logical to assume that small increases in airway inflammation in patients with already increased baseline levels of inflammation can easily trigger a COPD exacerbation. This presumes the existence of an inflammatory threshold, above which exacerbation occurs. In relation to this hypothesis, Bhowmik et al showed that COPD patients with frequent exacerbations (\u2265 3 episodes/year) have increased baseline sputum IL-6 and IL-8 levels. HoweverOn the contrary, Gombertz et al did not detect any difference in neutrophilic mediators (including IL-8) between frequent (\u2265 3 episodes/year) and infrequent exacerbators. InteresIn conclusion, data relating baseline airway inflammation to exacerbation frequency are rather controversial. Part of the existing confusion may be due to significant heterogeneity among COPD patients and to the existence of several factors, like bacterial colonization and bronchiectasis that may increase airway inflammation. In particular, COPD patients with bronchiectasis may represent a distinct group characterized by higher rates of bacterial colonization, increased baseline levels of airway inflammation and longer symptom recovery times at exacerbation.Episodes of COPD exacerbations are characterized by an acute increase in a patient's baseline dyspnoea, cough and/or sputum production. Severe Increased airway inflammation induces many pathologic changes on the airways. Accumulation of inflammatory cells in the airway mucosa by itself causes airway wall thickening. Inflammatory cells can release potentially harmful mediators, such as proteases and reactive oxygen species. NeutropA brief summary of the pathophysiologic events that may link airway inflammation to the symptoms of COPD exacerbations and to respiratory failure is given in figure Increased airway inflammation would be also expected to increase lung tissue oxygen demand and oxygen consumption. In patients with acute lung injury no relation has been found between pulmonary oxygen consumption and lung inflammation, but there is no relevant data in COPD exacerbations.Despite the increasing recognition of the importance of airway inflammation in the development of COPD exacerbations, there is still confusion regarding the role of anti-inflammatory strategies in the prevention and treatment of COPD exacerbations,94. TherOther drugs with anti-inflammatory properties, like methylxanthines and mucolytic agents seem not to be effective on COPD exacerbations. B-agoniIt has been long postulated that airway inflammation may be increased during COPD exacerbations and this may be involved in the pathophysiology of exacerbations. There is now sufficient data to support such a hypothesis. Firstly, there are accumulating observations for increased inflammation during COPD exacerbations. Secondly, specific aetiological factors for this increase have been identified. Thirdly, possible mechanisms that may link airway inflammation with the pathophysiology of exacerbations have been unmasked. Despite significant advances in our understanding of the role of inflammation in COPD exacerbations, the existing anti-inflammatory treatments remain modest and there is little overall benefit for the patient. Further research is needed to target therapies to the appropriate patient populations and to develop new therapeutic strategies.The author(s) declare that they have no competing interests."}
+{"text": "Site of first recurrence, disease-free interval (DFI), female sex steroid receptors, ploidy measurements as well as histological grading have been analysed as potentially valuable predictive factors in 313 cases of recurrent breast cancer. Univariate and multivariate analyses show histological grading, site of recurrence and disease free interval to be useful prognostic variables when assessing prognosis once disease has recurred. High concentrations of oestrogen receptors (ER) were found in patients with bone metastases, whereas lower concentrations of ER were related to visceral recurrences. Ploidy measurements failed in this study to give any predictive information once disease recurred."}
+{"text": "Internationally there is a 4-fold variation in age-adjusted incidence rates for childhood leukaemia , with only slightly greater worldwide differences specifically for acute lymphocytic leukaemia (ALL) and for acute nonlymphocytic leukaemia (ANLL). Total leukaemia rates are highest among Hispanic populations in Costa Rica and Los Angeles , due primarily to elevated ALL incidence, while low rates occur among US blacks, Kuwaitis, Israeli non-Jews, and Bombay Indians. In most populations the patterns for ALL are similar to those for total leukaema, with peak incidence at ages 1-4 and a decline thereafter. Lower and more uniform rates are generally observed at all ages for ANLL. Age-adjusted rates for ANLL appear to vary substantially among some populations with uniform ALL incidence rates  and yet appear to be similar in other populations with variation in ALL rates . Possible variation among registries in completeness of childhood leukaemia ascertainment and accuracy of diagnosis by cell type should be assessed, while case-control investigations among populations with very high and very low rates may provide useful information about the cell-type specific determinants of childhood leukaemia."}
+{"text": "Giardia lamblia has been intensively studied. We have performed a sequence survey project resulting in 2341 expressed sequence tags (EST) corresponding to 853 unique clones, 5275 genome survey sequences (GSS), and eleven finished contigs from the diplomonad fish parasite Spironucleus salmonicida (previously described as S. barkhanus).Comparative genomic studies of the mitochondrion-lacking protist group Diplomonadida (diplomonads) has been lacking, although S. salmonicida from its human parasitic relative G. lamblia were identified such as nineteen putative lineage-specific gene acquisitions, distinct mutational biases and codon usage and distinct polyadenylation signals.The analyses revealed a compact genome with few, if any, introns and very short 3' untranslated regions. Strikingly different patterns of codon usage were observed in genes corresponding to frequently sampled ESTs versus genes poorly sampled, indicating that translational selection is influencing the codon usage of highly expressed genes. Rigorous phylogenomic analyses identified 84 genes \u2013 mostly encoding metabolic proteins \u2013 that have been acquired by diplomonads or their relatively close ancestors via lateral gene transfer (LGT). Although most acquisitions were from prokaryotes, more than a dozen represent likely transfers of genes between eukaryotic lineages. Many genes that provide novel insights into the genetic basis of the biology and pathogenicity of this parasitic protist were identified including 149 that putatively encode variant-surface cysteine-rich proteins which are candidate virulence factors. A number of genomic properties that distinguish Our results highlight the power of comparative genomic studies to yield insights into the biology of parasitic protists and the evolution of their genomes, and suggest that genetic exchange between distantly-related protist lineages may be occurring at an appreciable rate in eukaryote genome evolution. Giardia lamblia , which is a major cause of water-borne enteric disease in humans in both industrialised and developing countries .The sequences reported here were deposited in GenBank at the National Center for Biotechnology Information [Genbank:JOA co-constructed the second GSS library, finished the sequence of seven contigs, carried out the EST and GSS assemblies, all phylogenetic and most bioinformatic analyses, and drafted and coordinated the editing of the manuscript. \u00c5MS co-constructed the second GSS library, carried out the majority of the GSS sequencing, and performed initial bioinformatic analyses. DSH grew the organism, purified nucleic acids, constructed the EST library, and carried out some of the initial EST sequencing. CAM constructed the lambda and the initial GSS libraries, carried out the majority of the EST sequencing, the initial GSS sequencing and the sequencing and assembly of three lambda clones. PLD carried out some of the initial EST sequencing. SGS provided advice on the analyses of molecular biological aspects and drafted these parts of the manuscript. RPH performed part of the analyses of cysteine rich and putative mitosomal proteins. JML, MAR, RPH, and AJR co-initiated and supervised the project in their respective laboratories, provided advice on the analyses and edited the manuscript. All authors read and approved the final manuscript.A table showing the characteristics of the finished contigs.Click here for fileComplete list of gene annotations.Click here for fileA table showing the genes putatively involved in LGT events.Click here for filePhylogenetic trees 1\u201325 for genes putatively involved in LGT events and listed in Additional file 3.Click here for filePhylogenetic trees 26\u201350 for genes putatively involved in LGT events and listed in Additional file 3.Click here for filePhylogenetic trees 51\u201372 for genes putatively involved in LGT events and listed in Additional file 3.Click here for file"}
+{"text": "A world first pineapple EST sequencing program has been undertaken to investigate genes expressed during non-climacteric fruit ripening and the nematode-plant interaction during root infection. Very little is known of how non-climacteric fruit ripening is controlled or of the molecular basis of the nematode-plant interaction. PineappleDB was developed to provide the research community with access to a curated bioinformatics resource housing the fruit, root and nematode infected gall expressed sequences.Arabidopsis homologues, both MIPS based and Gene Ontology functional classifications, and clone distributions. The online resource can be searched by text or by BLAST sequence homology. The data outputs provide comprehensive sequence, bioinformatic and functional classification information.PineappleDB is an online, curated database providing integrated access to annotated expressed sequence tag (EST) data for cDNA clones isolated from pineapple fruit, root, and nematode infected root gall vascular cylinder tissues. The database currently houses over 5600 EST sequences, 3383 contig consensus sequences, and associated bioinformatic data including splice variants, The online pineapple bioinformatic resource provides the research community with access to pineapple fruit and root/gall sequence and bioinformatic data in a user-friendly format. The search tools enable efficient data mining and present a wide spectrum of bioinformatic and functional classification information. PineappleDB will be of broad appeal to researchers investigating pineapple genetics, non-climacteric fruit ripening, root-knot nematode infection, crassulacean acid metabolism and alternative RNA splicing in plants. Ananas comosus (L.) Merrill] is the third most important tropical fruit after banana and mango. Pineapple fruits are classified as non-climacteric, as there is no respiratory burst or spike in ethylene production during ripening and exogenous application of ethylene does not rapidly accelerate fruit ripening. Much has been learnt about the control of fruit ripening in climacteric fruit using tomato as a model system. In particular, manipulation of genes involved in the ethylene biosynthetic pathway and a MADS box transcription factor have led to altered ripening characteristics   . Those cContig consensus sequences containing a polyA tail were analyzed for open-reading frames using EditSeq sequence analysis software  and were BLASTX searched against the GenBank nr protein database . Contig Edited clone sequences generally assembled into contigs with 97\u2013100% homology. However, the contig assembly report occasionally revealed incidences where some clones clustered with between 90\u201397% homology or that some clones did not cluster into existing contigs due to homology somewhat below the 90% threshold. An inspection of these clone sequences and contigs revealed the presence of apparently unspliced intron sequence, and/or the absence of exon sequence in some of the clones. A comparative analysis to other clone sequences within the contig alignment and to homologous protein coding sequences in GenBank verified that 120 clones contain an apparent \"mis-splicing\" event. The putative splice variant clones containing un-spliced intron sequence and/or missing spliced exon sequence are listed in the pineapple bioinformatic resource. The presence or absence of a putative splice variant is also reported in contig/clone search outputs.Despite precautions to remove nematodes from root tissues prior to library construction, it was anticipated that there would be some contamination of the pineapple gall libraries with nematode derived sequences. All contig consensus sequences containing root and gall EST's were BLASTN searched against the GenBank dbEST and BLASTX searched against the GenBank nr database. Matches to known nematode sequences were manually inspected and 77 contigs identified as containing a putative nematode sequence. All contigs containing putative nematode sequence are listed within the online pineapple bioinformatic resource.Arabidopsis thaliana.The pineapple EST sequencing project was initiated as a first step toward identifying genes involved in and the molecular basis of non-climacteric fruit ripening and the nematode-plant interaction. The online pineapple bioinformatics resource was developed to house EST sequence information and associated bioinformatic data in a user-friendly format. PineappleDB can be freely accessed via the internet, and currently contains BLAST and text search tools to efficiently mine the dataset for clones and contigs of interest. The resulting search outputs contain comprehensive information on the clone and contigs including cloneID, contig number, number of clones in each contig, nearest BLASTX match, accession number of match, length of match, percent similarity, putative annotation, splice variants, MIPS based functional classifications, Gene Ontology classifications, and the distribution of clones from each library fig. . Links aPineappleDB houses the first reported collection of EST sequences isolated from pineapple. PineappleDB will grow as more EST sequence information becomes available. Furthermore, we have initiated a pineapple microarray project and it is anticipated that gene expression data will be incorporated into the online pineapple bioinformatics resource in the future. The EST database will periodically be upgraded as annotation, functional classification, and gene ontology information is updated.The PineappleDB resource can be accessed via j.botella@uq.edu.auContact: Dr. Jos\u00e9 R Botella at *The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint first authors. RM was responsible for data collection, the bioinformatic pipeline and manuscript preparation. MC developed the online database and undertook batch BLAST processes. JR-K contributed to the fruit EST editing and identification of full length coding sequences. DJF participated in the conception, design and co-ordination of the study and helped complete the manuscript. JRB designed, supervised and coordinated the project."}
+{"text": "Foetal acinar components associated with the development of the hamster pancreas have been previously defined with the aid of an antifoetal pancreas serum. In immunohistology this antiserum also stained malignant ductal cells in N-nitrobis (2-oxopropyl) amine (BOP)-induced pancreatic adenocarcinoma. It did not stain adult pancreas structures including acini, ducts and islets of Langerhans. In this study, re-expression of foetal acinar antigens was disclosed before formation of tumours. Adenocarcinomas were not detected by conventional histology before the 24th week following initiation of the chemical treatment. However, staining with the antiserum was observed from the 7th week appearing in the apex of some acini cells having an almost normal histological appearance. Later, foetal acinar expression was frequently associated with evident morphological alterations in acini like dyskaryosis, enlarged cytoplasm or lumina. Staining of ducts with marked atypical epithelium and  of neoplastic ducts was also observed. It was not detected in other pancreatic lesions viz. cystadenomas, mucoid glands and regular hyperplastic ducts. Acinar dedifferentiation as assessed by expression of foetal components preceded formation of tumours in all instances."}
+{"text": "The occurrence of different intercellular junctions in epithelial rat skin tumours induced by methylcholanthrene was investigated using thin sections and freeze-fracture replicas examined by electron microscopy. Tumours which appeared first were basal cell carcinomas. Later, different tumours of hair follicle and of sebaceous gland origin were formed. Finally, in the majority of tumours a squamous component evolved. Metastases developed from the squamous carcinomas exclusively. Desmosomes and gap junctions were detected in basal cell carcinomas whereas, in squamous carcinomas, tight junctions were also seen. While all three types of junction were found in the primary squamous tumours, the tumour metastases in lymph nodes and lungs contained only desmosomes."}
+{"text": "A monoclonal antibody, H317, has been used for the sensitive and specific detection of placental-type alkaline phosphatase (PLAP) in sera, solubilized tissue extracts and fixed tumour tissue sections from patients representing a variety of ovarian tumours. PLAP was detected in over 30% of these sera and in most solubilized tumour tissue extracts. There was no association between circulating PLAP levels and either tissue extract levels or immunohistological staining of ovarian tumour tissue sections with H317. Nevertheless, immunohistology demonstrated the heterogeneity of cellular localization of PLAP within different tumours, and can often be of value in localizing tumour tissue."}
+{"text": "Numbers of intestinal goblet cells containing specific acid mucins were determined in male Sprague-Dawley rats receiving azoxymethane  with or without jejunoileal bypass (JIB). Controls had injections of vehicle and sham bypass. Thirty weeks postoperatively colorectal length and crypt depth were increased by azoxymethane and further increased by JIB. JIB doubled the yield of intestinal tumours (P less than 0.01). Goblet cells containing sulphomucins normally predominated throughout the intestinal tract. Contents of sulphomucins and especially sialomucins were consistently higher in the small bowel and colon of rats receiving azoxymethane alone, but again the highest values were observed in animals with azoxymethane plus JIB. Both small-bowel bypass and azoxymethane stimulate adaptive growth of the colon and small bowel remaining in circuit. Goblet-cell hyperplasia is a feature of this response, and sialomucins are preferentially secreted by the adapting epithelium."}
+{"text": "It is suggested that most childhood acute lymphoblastic leukaemias and some other paediatric cancers are chemo-curable because they arise in stem cell populations that are functionally transient, chemosensitive and programmed for apoptosis. Most adult acute leukaemias are chemo-incurable at least in part because they originate in relatively drug resistant stem cells with extensive self-renewal capacity. The latter property in turn increases the probability of clones evolving with multi-drug resistance. Particular mutations may superimpose additional adverse features on leukaemic cells."}
+{"text": "In plants, tandem, segmental and whole-genome duplications are prevalent, resulting in large numbers of duplicate loci. Recent studies suggest that duplicate genes diverge predominantly through the partitioning of expression and that breadth of gene expression is related to the rate of gene duplication and protein sequence evolution.Arabidopsis, there are 53 MST genes that form seven distinct subfamilies. We created profile hidden Markov models of each subfamily and searched EST databases representing diverse land plant lineages to address the following questions: 1) Are homologs of each Arabidopsis subfamily present in the earliest land plants? 2) Do expression patterns among subfamilies and individual genes within subfamilies differ across lineages? 3) Has gene duplication within each lineage resulted in lineage-specific expansion patterns? We also looked for correlations between relative EST database representation in Arabidopsis and similarity to orthologs in early lineages.Here, we utilize expressed sequence tag (EST) data to study gene duplication and expression patterns in the monosaccharide transporter (MST) gene family across the land plants. In Arabidopsis, one or a few genes within most subfamilies have much higher EST database representation than others. Most highly represented (broadly expressed) genes in Arabidopsis have best match orthologs in early divergent lineages.Homologs of all seven MST subfamilies were present in land plants at least 400 million years ago. Subfamily expression levels vary across lineages with greater relative expression of the STP, ERD6-like, INT and PLT subfamilies in the vascular plants. In the large EST databases of the moss, gymnosperm, monocot and eudicot lineages, EST contig construction reveals that MST subfamilies have experienced lineage-specific expansions. Large subfamily expansions appear to be due to multiple gene duplications arising from single ancestral genes. In Arabidopsis MST gene family are ancient in land plants and show differential subfamily expression and lineage-specific subfamily expansions. Patterns of gene expression in Arabidopsis and correlation of highly represented genes with best match homologs in early lineages suggests that broadly expressed genes are often highly conserved, and that most genes have more limited expression.The seven subfamilies of the  Large proportions of genes within genomes are members of hierarchical gene families and superfamilies. Gene families appear to evolve through a combination of tandem, segmental and whole genome duplication (polyploidy) events. A number of researchers in the first half of the twentieth century observed relationships between chromosome duplications and morphological variation . In 1970More recent theoretical and empirical work suggests that gene duplicates are retained more frequently than the classical model permits and that new function or expression arises through the processes of neo- and subfunctionalization ,6. In suPlant genomes contain large fractions of duplicate loci due to the frequent occurrence of segmental duplications and polyploidy events. Following a polyploidy event, there is a rapid loss of duplicate loci in the transition to functional diploidy and the remaining duplicate loci undergo rapid functional divergence . Recent +-sugar symporters localized in the plasma membrane (see references below).In this study, we investigate the monosaccharide transporter (MST) gene family in land plants. MSTs are found in all three domains of life, have fundamental importance in carbohydrate flux and are highly conserved across lineages. All MST proteins are characterized by 12 hydrophobic membrane-spanning domains separated by interconnecting cytoplasmic and extracellular loops, with cytoplasmic N- and C-terminal domains . This hiArabidopsis thaliana genome reveals 53 MST genes that cluster into seven subfamilies on phylogenetic analysis  and whisk ferns (Psilotaceae) that form a monophyletic group which is sister to the seed plants . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for fileAlignment of MST subfamily profile HMM consensus sequences. Multiple sequence alignment of consensus sequences generated from profile HMMs for each of the seven MST subfamilies. Sequences were aligned using the ClustalW option in the AlignX component of the VectorNTI package. Amino acid residues highlighted in yellow indicate 100% identity across sequences.Click here for fileArabidopsis thaliana EST database.Summary of identified MST ESTs in Click here for fileMarchantia polymorpha, Selaginella lepidophylla, Ceratopteris richardii).Summary of identified MST ESTs in small databases (Click here for filePhyscometrella patens and Physcomitrella patens subsp. patens EST databases.Summary of identified MST ESTs in Click here for filePinus taeda EST database.Summary of identified MST ESTs in Click here for fileZea mays EST databaseSummary of identified MST ESTs in Click here for fileLycopersicon esculentum EST databaseSummary of identified MST ESTs in Click here for file"}
+{"text": "PCR-based microsatellite polymorphisms have proved their power in genetic linkage analysis and other identification methods, due to their high information content and even distribution over the chromosomes. In the present study we applied microsatellite polymorphisms to detect loss of heterozygosity in fresh (snap-frozen) and in archival ovarian tumour tissue. Clear allele losses were found in fresh and paraffin embedded tumour samples. Conventional Southern analysis of flanking markers on the same tumour DNA samples confirmed the observed losses detected by microsatellite polymorphisms. Titration experiments suggest that loss of heterozygosity remains detectable in tumour samples despite 60% contamination with normal DNA. This technique provides a fast and reproducible alternative to conventional Southern blotting in the detection of loss of heterozygosity, with the crucial additional advantages of minimal sample requirements, making archival material available for genetic investigation."}
+{"text": "Human colon adenocarcinoma cells (LoVo) resistant to the new antitumor agent FCE 24517 [benzoyl-mustard derivative of distamycin A] (LoVo/24517) are resistant to the selecting agent and related molecules as well as to vinblastine, with marginal or no resistance to other antitumour drugs. Treatment with verapamil, tamoxifen, nicergoline or cyclosporin A only partially restores the activity of FCE 24517 against LoVo/24517 cells. Such results suggest that resistance mechanisms possible specific for this class of compounds are operating."}
+{"text": "From 1,211 breast cancers, 15 oestrogen receptor (ER) negative-progesterone receptor (PgR) positive breast cancers by conventional dextran coated charcoal steroid binding assays in cytosol were reassessed using Elisa techniques with monoclonal antireceptors antibodies in the cytosolic and nuclear fractions, and immunocytochemistry on cryostat sections. Three categories of results were found in this series. Two tumours were false negative ER due to receptor sites occupancy by hormonal contraceptive treatment. A second group of ten tumours, with high PgR concentrations and immunoreactive ER, corresponds to non ER-binding forms of receptors. One PgR positive tumour was found to be devoid of PgR by using monoclonal antiPgR antibodies might contain a progesterone binding cyst protein. Only two tumours were found to be true ER negative-PgR positive by all methods. This rare phenotype deserves further study of the regulation of the PgR gene."}
+{"text": "The metastatic sites of infiltrating duct (IDC) and infiltrating lobular carcinoma (ILC) have been compared using both clinical and autopsy data. The following statistically significant differences were found: Lung parenchymal metastases were more common in IDC. Bone trephine biopsies were more likely to be positive in ILC. Carcinomatous meningitis was associated almost exclusively with ILC. Peritoneal/retroperitoneal metastases of distinctive pattern occurred in ILC. There was often associated linitis plastica-like involvement of the stomach wall and diffuse infiltration of the uterus. Hydronephrosis was a common secondary phenomenon."}
+{"text": "Mutagenicity and cytotoxicity are basic cellular effects of cigarette smoke which underlie the development of lung cancer and chronic obstructive airways disease. This study reports that, on a weight-for-weight basis, cigarette smoke condensates from low, middle and high tar cigarettes produce similar mutagenic effects detected by induced sister chromatid exchanges and similar cytotoxic effects detected by vital dye exclusion in human leucocytes. These findings, taken with the strong evidence that smokers extract more smoke from lower tar cigarettes to compensate for low nicotine yields, suggest that the health dangers associated with smoking these \"safer\" products are underestimated."}
+{"text": "Mexipyrgus churinceanus) and a molluscivorous cichlid (Herichthys minckleyi), we examined three components of this interaction: 1) spatial variation in two putative defensive traits, crushing resistance and shell pigmentation; 2) whether abiotic variables or frequency of molariform cichlids are associated with spatial patterns of crushing resistance and shell pigmentation and 3) whether variation in primary productivity accounted for small-scale variation in these defensive traits.Recent models suggest that escalating reciprocal selection among antagonistically interacting species is predicted to occur in areas of higher resource productivity. In a putatively coevolved interaction between a freshwater snail  and snail defensive traits. However, crushing resistance and frequency of pigmented shells were negatively correlated with molariform frequency. Crushing resistance and levels of pigmentation were significantly higher in habitats dominated by aquatic macrophytes, and both traits are phenotypically correlated.M. churinceanus exhibit striking variation at small spatial scales often associated with differences in primary productivity, substrate coloration and the frequency of molariform cichlids. These local geographic differences may result from among-habitat variation in how resource productivity interacts to promote escalation in prey defenses.Crushing resistance and pigmentation of  Mexipyrgus churinceanus.Spatial variation in defensive traits is common in many antagonistic interactions -3. The gMexipyrgus churinceanus as well as its polymorphic fish predator Herichthys minckleyi are endemic to the isolated Cuatro Ci\u00e9negas valley in the Mexican Chihuahuan desert . Increased resource availability probably allows greater investment in costly shell material, leading to the prediction that hotspots may occur in areas with greater food resources for snails.Alternatively, variation in shell strength might be primarily a response to biotic influences. We address whether spatial variation in snail defenses is associated with two biotic factors: molariform frequency and resource productivity. If molariform H. minckleyi, and this divergence occurs at very small spatial scales in a geographically mosaic fashion, we predict there will be no significant positive autocorrelation at small spatial and genetic distances. In the current study, we determine genetic distances between snail populations from a previously published study of mtDNA sequence variation in Mexipyrgus [A critical assumption of these population-based measures of phenotypic divergence is that they are statistically independent. This assumption may be violated because nearby snail populations may experience similar predation pressure because cichlids are more mobile than these brooding snails. To address this issue we assess whether the similarity of shell defensive traits among nearby populations can be attributed to either geographic proximity or genetic similarity -25. Genexipyrgus .Mexipyrgus. First, we examine spatial variation in two putative defensive traits, crushing resistance and shell pigmentation. Then, we tested whether abiotic or biotic variables account for spatial patterns of crushing resistance and shell pigmentation. Finally, we determine whether variation in primary productivity accounts for small-scale variation in these defensive traits.We address three questions concerning the evolution of defenses in 2 = 43.9%, p < 0.0001), whereas shell shape explained little variation in crushing resistance . We next used analysis of covariance to examine the effect of population on crushing resistance using size as a covariate. The interaction term (shell size by population) was not significant (p = 0.24), and there was a highly significant effect of population on size-adjusted crushing resistance . There was considerable spatial variation in size-adjusted crushing resistance, ranging from 42.3 Newtons in a Rio Mesquites population to 92.3 Newtons in a Tierra Blanca population , indicating the absence of autocorrelation among populations at any scale.Mean and standard errors of crushing resistance and shell size are presented in Table ion Fig. . The cor2 = 310.7, n = 19, p < 0.001). The correlograms of pigmentation frequency and all distance measures were not significant (see figure b distance classes), again indicating the absence of autocorrelation among populations at any scale.There was considerable variation in the frequency of pigmentation among populations Fig.  and therp = 0.19) or conductivity . Similarly, there was no significant correlation between pigmentation frequency and temperature  or conductivity . In contrast, there were significant negative correlations between molariform frequency and both size-adjusted crushing resistance .There was no significant correlation between size-adjusted crushing and temperature , crushing resistance was higher where Nymphaea was abundant . Similarly, RM1 had significantly higher crushing resistance than nearby RM3 . The Los Remojos populations did not differ significantly in size-adjusted crushing resistance . In the paired adjacent populations, the frequency of pigmented shells was significantly higher in darker versus lighter substrates in all 3 comparisons: Rio Mesquites 1 and 3 ; Los Remojos N and S ; and Tio Candido N and S .In the two of the three paired adjacent populations that differ in t Figure . For exaMexipyrgus churinceanus in Cuatro Ci\u00e9negas and the presence of the molariform cichlids are suggestive of coevolutionary selection [Pronounced geographic differences in prey defenses are probably common ,27. Whilelection ,15, the Mexipyrgus churinceanus requires an assessment of phenotypic variation and the spatial autocorrelation of these traits among populations at small genetic and geographic distances. There is significant spatial variation in M. churinceanus crushing resistance and pigmentation at small spatial scales suggesting that certain factors may cause this mosaic distribution of snail defensive traits. In paired populations separated by very small linear and genetic distances, elevated crushing resistance occurs in habitats containing extensive Nymphaea stands. Crushing resistance is dramatically lower in light colored substrates lacking Nymphaea. Because Tio Candido and Rio Mesquites populations represent distinct lineages based on mtDNA sequence differentiation [Mexipyrgus feeds extensively . Increased resource availability likely allows greater investment in costly shell material, and experiments that manipulate resource availability to test its effect on Mexipyrgus shell strength would provide a further test of this hypothesis.To address whether prey defenses have evolved independently across the geographic range of ntiation , it suggCamellia host plant indicate that escalation in armaments only occurred in southern latitudes [Mexipyrgus is the result of coevolutionary interactions between endemic snails and the molluscivorous morph of H. minckleyi [Nymphaea habitats, increased snail crushing resistance may reduce molariform fitness due to increased costs of crushing, while papilliform fitness is higher due to increased availability of plant material for shredding. We plan to experimentally test whether these alternative cichlid morphs have fitness trade-offs in different resource environments, and more quantitatively measure resources available to Mexipyrgus.Although there is considerable documentation of hotspots and coldspots in coevolved antagonistic interactions, how spatial processes and community composition promote coevolution and generate selection mosaics has received less attention. A recent study of herbivorous weevils and their atitudes . More noinckleyi . SurprisMexipyrgus shell pigmentation is also associated with different substrate coloration and there is no evidence of genetic or spatial autocorrelation among populations. In the three geographically-paired populations, snails with pigmented bands were significantly more common in Nymphaea habitats and unbanded snails were more common where the benthic substrate was light and marled- colored. Unbanded snails are probably more cryptic against lighter benthic substrates and banded snails are more cryptic against the darker substrates found in association with Nymphaea. This type of background matching by prey under selection from highly visual predators is common in many organisms [Microspatial variation in rganisms -30 and eNymphaea is absent, investment in crushing resistance may be constrained due to resource limitation, so that crypsis is the most effective defense against molariform predation. We suspect that investment in shell pigmentation is not as costly as having more robust shells, and that snails are capable of inexpensively modifying their pigmentation in Nymphaea habitats to increase crypsis. Whether correlational selection acts on pigmentation patterns and shell strength in these habitats requires a deeper understanding of the phenotypic plasticity in both traits. One hypothesis is that increased pigmentation in these environments does not increase background matching, and pigmentation only increases due to correlational selection on crushing resistance. This hypothesis could be easily refuted if predation success on banded shells is less in Nymphaea habitats. Given evidence for inducible defenses in snails [The positive relationship between the two snail traits across environments suggest that pigmentation and crushing resistance may represent phenotypically-correlated traits. In resource-poor environments where n snails -33, we aH. minckleyi undoubtedly use their jaws to crush snails, Cuatro Ci\u00e9negas may represent an ideal system for investigating mosaic predator-prey coevolution. In future studies, we plan to examine local adaptation of molariforms, escalation of molariform traits in resource rich environments, and heritability and phenotypic plasticity of both crushing resistance and pigmentation across resource gradients.Spatial variation in two prey defense traits, crushing resistance and shell pigmentation, exhibits striking variation at small spatial scales often associated with habitat differences in primary productivity and substrate coloration. These local geographic differences may result from among-habitat variation in how resource productivity interacts to promote escalation in prey defenses. Because molariform Mexipyrgus churinceanus from various drainages throughout the entire Cuatro Ci\u00e9negas basin , and whether these correlations change as a function of geographic and/or genetic distance. Under the spatial mosaic hypothesis, we predicted no positive autocorrelations of geographically-adjacent or genetically-similar populations. We estimated Moran's I using Passage . Moran'sariation  using a To assess the potential influence of abiotic factors on shell strength, we measured temperature and conductivity in the 19 populations . Conductivity measures were temperature compensated. Above ground flow connects a few of the populations examined here, but the abiotic factors of each are influenced by large discharge from separate isothermal springs . Therefoet al [To estimate the relationship between frequency of molariforms and both size-adjusted crushing resistance and frequency of pigmented shells, the frequency of molariforms in ten populations was obtained from two sources. The frequency in Mojarral Oeste, North Tio Candido, Tio Candido, Los Remojos Negro, and Los Remojos Blanco was estimated in 2001 by Kloeppel , and waset al . Fish weNymphaea is associated with variation in snail crushing resistance and pigmentation, we compared the crushing resistance  and frequency of banded snails (Log likelihood tests) in three pairs of adjacent populations in the Rio Mesquites, Los Remojos, and Tio Candido. These paired populations are in very close proximity to one another . In these paired populations, substrate coloration differed dramatically due to the presence or absence of Nymphaea beds. We also examined the phenotypic correlation between mean population estimates of the number of bands and crushing resistance. We conducted all statistical analyses in SPSS [To address whether the presence or absence of  in SPSS .All authors conceived the study and participated in its design and conducted field work. SGJ performed statistical analysis and drafted the manuscript. CDH and FJGL helped with revisions of the manuscript. All authors read and approved the final manuscript."}
+{"text": "As animal extinctions continue at the rate of one every 16 years, it's unclear how declining biodiversity will disturb ecosystem dynamics. Of special concern are the pollinators, essential players in the reproductive biology of plants, the earth's primary producers. Millions of years of evolutionary coadaptations lie behind the perfect pairing of pollinator proboscis anatomy with plant flower structure, as well as the mechanisms plants use to attract reproductive assistants to their food rewards. Agave plants emit musky aromas that attract lesser long-nosed bats to nectar stores within their flowers, for example. As the bats travel from flower to flower, pollen collects and then falls from their fur, facilitating cross-pollination.These mutually beneficial relationships are sometimes so specialized that the loss of one species threatens the existence of the other, raising troubling questions about the likely consequences of declining diversity in pollination networks. In a new study, Colin Fontaine et al. tackled this question by experimentally manipulating plant and pollinator interactions under natural conditions. The authors found strong functional relationships between different pollinators and plant communities, with the highest plant community sustainability associated with the most diverse group of pollinators. These findings suggest that loss of biodiversity in pollination networks may threaten the persistence of plant communities.For their study, the authors chose plants with easy and harder access to food rewards\u2014three open-flower and three tubular-flower species\u2014and insects with short and longer mouthparts\u2014three syrphid fly and three bumblebee species. In the spring of 2003, Fontaine et al. set up 36 plant communities in nylon-mesh enclosures in a meadow 80 kilometers (about 50 miles) southwest of Paris, after sterilizing the soil to destroy seeds and pathogens. They planted 30 adult plants in each plot at the same density, and then captured and released local pollinators into the cages during the flowering season . To test all the possible plant\u2013pollinator combinations, the authors set up three plant treatments , then applied three pollination treatments  to each plant treatment.A month after the first pollination treatments, the authors tallied all the fruit on each plant, then randomly selected five fruits per plant (excepting one plant species from each group that would have required harvesting the fruit) to estimate seed production per plant. During the seedling season, they totaled the plants and the seedlings to measure plant population and reproductive success. Pollinator identity determined fruit production, with bee-pollinated plants most productive, and the different plant groups responded differently to the two pollinator groups. As expected, short-mouthed syrphid flies pollinated only open flowers, while bees pollinated both plant types. As a result, tubular flowers produced far fewer fruits with syrphid pollinators while open-flower fruit production remained the same regardless of pollinator. Fruit production increased along with both plant and pollinator diversity. Seed production was a bit more complicated. Though bee-pollinated open flowers produced fewer seeds per plant than those pollinated by syrphids, higher fruit production compensated by producing more seedlings. Fruit production increased with pollinator diversity. As for long-term effects on plant reproductive capacity and success, tubular plant communities had fewer plants at the seedling stage than openflowered plants (and even fewer when pollinated by syrphids). The plant species number and total plant number increased when both pollinator groups were present, and were highest with maximum plant and pollinator diversity. Seedling production showed a similar pattern: mixed plant communities treated with both pollinators yielded the most seeds.What happened? Not surprisingly, the pollinators stuck to their preferred plant: syrphids visited mostly open flowers, and bees visited mostly tubular flowers. Bees can pollinate open flowers but prefer tubular flowers when they have the choice, suggesting that bees may not fill a void left by a different pollinator. The presence of both pollinators allowed more appropriate pairings between insects and flowers\u2014each performing a complementary role\u2014leading to increased pollination efficiency and plant reproductive success.Liza GrossWhile the study offers an admittedly pared down view of pollination networks, it demonstrates the value of studying the functional effects of pollination networks in the field. These results show that losing a species affects plant\u2013pollinator communities, and that such losses may ultimately trigger further reductions in biodiversity, possibly reverberating through the food chain. With as many as 70% of plant species dependent on animal pollinators and at least 82 mammalian pollinator species and 103 bird pollinator species considered threatened or extinct, this is sobering news. \u2014"}
+{"text": "James and Lange proposed that emotions are the perception of physiological reactions. Two-level theories of emotion extend this model to suggest that cognitive interpretations of physiological changes shape self-reported emotions. Correspondingly false physiological feedback of evoked or tonic bodily responses can alter emotional attributions. Moreover, anxiety states are proposed to arise from detection of mismatch between actual and anticipated states of physiological arousal. However, the neural underpinnings of these phenomena previously have not been examined.We undertook a functional brain imaging (fMRI) experiment to investigate how both primary and second-order levels of physiological (viscerosensory) representation impact on the processing of external emotional cues. 12 participants were scanned while judging face stimuli during both exercise and non-exercise conditions in the context of true and false auditory feedback of tonic heart rate. We observed that the perceived emotional intensity/salience of neutral faces was enhanced by false feedback of increased heart rate. Regional changes in neural activity corresponding to this behavioural interaction were observed within included right anterior insula, bilateral mid insula, and amygdala. In addition, right anterior insula activity was enhanced during by asynchronous relative to synchronous cardiac feedback even with no change in perceived or actual heart rate suggesting this region serves as a comparator to detect physiological mismatches. Finally, BOLD activity within right anterior insula and amygdala predicted the corresponding changes in perceived intensity ratings at both a group and an individual level.Our findings identify the neural substrates supporting behavioural effects of false physiological feedback, and highlight mechanisms that underlie subjective anxiety states, including the importance of the right anterior insula in guiding second-order \u201ccognitive\u201d representations of bodily arousal state. Recent theory distinguishes between two levels of emotional experience: phenomenology and awareness The importance of second-level appraisal mechanisms to emotional judgments is highlighted by false feedback experiments Recent studies of interoceptive awareness In the present study, we examined neural activity associated with effects of false feedback of arousal state (heart rate) on emotional evaluations. Our approach differed from that of Valens We first examined the influence of physiological feedback  on behavioural ratings of intensity of face stimuli  in a repeated measures ANOVA. We observed a significant multivariate interaction of expression type and feedback on attributed emotional intensity , in addition to a significant main effect of facial expression . Planned contrasts revealed a significant interaction between expression  and feedback  . Further, the emotional intensity of neutral faces was rated significantly higher during false relative to true feedback . Across all conditions, the emotional intensity of neutral expressions was rated significantly lower than either angry  or happy expressions  see We next examined the influence of isometric exercise in a repeated measures ANOVA, including the factors exercise (present absent) emotion  and feedback . Exercise did not alter behavioural ratings of emotional expressions, and did not differentially influence false feedback effects.2\u200a=\u200a0.751] diastolic  and mean arterial pressure , stroke volume  cardiac output  and heart rate  relative to the no-exercise condition  and exercise  isometric exercise was associated with significant increases in systolic . This interaction was observed in the right anterior insula cortex  and alsoWe next examined evidence for a cardiac synchronous/asynchronous comparator mismatch function for the anterior insula cortex during interoceptive demand. Predicated on the on the notion that interoceptive information has greater salience when processing ambiguous  stimuli, we hypothesised that this would enable us to test for a comparator function of insula cortex in responding to mismatches in cognitive and interoceptive representations of physiological state, even at conditions of low bodily arousal. Thus, we specifically tested for a greater difference between asynchronous and synchronous cardiac feedback during the processing of neutral expressions, relative to the same difference during the processing of either happy or angry expressions; i.e. [ > ]. Significant interactions were observed in three regions; bilateral anterior insula cortex and dorsal cerebellum .As detailed above, exercise did not alter behavioural ratings of facial expressions-and showed no interaction with false feedback when rating neutral expressions. As a consequence we did not focus our investigations on exploration of neural correlates of non-significant behavioural interactions. Nevertheless, mapping of changes in first level representation within consciously accessible interceptive cortices, notably right anterior insula, was of direct interest.In both exercise and rest conditions, the pattern of activity reflecting the influence of feedback veracity on rating of facial expressions was maintained, with significant interactions observed within right amygdala, bilateral posterior insula and right anterior insula. Within the right anterior insula cortex, the mean BOLD signal change in response to face stimuli portraying neutral expressions predicted individual differences in the magnitude of intensity ratings of these stimuli in the context of false feedback .Pursuing the relationship between cerebral activity and false feedback induced biasing of emotional judgements, we used parametric analyses to examine within each participant the relationship between trial-by\u2013trial behavioural ratings of neutral faces and regional BOLD activity. Again, within the right anterior insula cortex, we observed a significant association between BOLD activity and attributed intensity of neutral expressions during false feedback  . IncreasThe present study demonstrates the influence of false feedback of physiological arousal on emotional appraisal of facial expressions through engagement of a discrete set of brain regions implicated in social and motivational behaviour. This neuroanatomical matrix encompasses brain regions that have been implicated functionally in the encoding of external emotional cues , representation of internal visceral information (insula cortex) and the contextual synthesis of emotional information for declarative awareness (anterior insula/operculum).Our findings suggest a central integrative role for the anterior insula cortex. This region mapped differential influences of false feedback of arousal on differential processing of emotion, was sensitive to the timing of cardiac feedback  and predicted within and across participants the degree to which behavioural ratings were altered during false physiological feedback. Together these novel data reveal neural substrates supporting the second level appraisal of emotional information, arising from an integration of perceptual processing within the context of physiological feedback representations, and influencing subjective affective judgement. Previous studies report right anterior insula engagement during conscious processing of emotional stimuli and in response to evoked physiological arousal responses False feedback of increased cardiac rate during rest enhanced the perceived intensity of neutral facial expressions but not angry or happy facial expressions. This is consistent with previous findings within the false feedback literature that the influence of physiological feedback is greatest during ambiguous judgements Anatomically, Craig argues that the specialised contribution of right anterior insula in conscious interoception derives from a remapping of mid and posterior viscerosensory representations We anticipated a contribution from amygdala to the emotional appraisal task. Patients with selective amygdala lesions show impairments in general social behaviour that correlate with deficits in emotional judgments of face stimuli Behaviourally, false physiological feedback enhances attention to stimuli presumed to be physiologically arousing Overall, we report the modulation of intensity judgements of face stimuli, particularly neutral faces by false feedback of physiological arousal state. Our neuroimaging data indicates engagement and interaction of three systems governing; first, initial representation and homoeostatic control of bodily arousal (insula); second, \u2018automatic\u2019 encoding of emotionally salient events  and; third, visual and cognitive appraisal of stimuli . Further, our observations suggest a critical role for right anterior insula cortex in integrating information across these systems to support a second-level representation of emotionality that underpins subjective and behavioural experiences arising from false feedback. We did not observe any direct influence of first level physiological arousal on intensity judgements in the current study despite inducing significant increases in cardiovascular responses through isometric exercise. It is likely that misattribution of arousal is most probable where participants are unaware of the cause of their physiological arousal (i.e. excitation transfer effects). We did not observe misattributed arousal in the present study, presumably because first-level physiological arousal could be correctly attributed to isometric exercise.The present study represents the first investigation of neural responses during both false feedback and exercise induced arousal. We observed an interaction of emotion and feedback on subjective measures, and a parallel interaction within regions implicated in cognitive appraisal, emotional processing and interoception. Our findings suggest an integrative contribution of right anterior insula cortex in second level representations of emotion that, in turn, predict individual differences in emotional behaviour. In sum, our findings provide insight into emotional appraisal mechanisms proposed in two-level theoretical models of emotion and identify the functional neuroanatomical substrate for hierarchical emotional appraisals of the social brain.Twelve healthy right handed individuals  gave informed written consent to take part in this study which was approved by the joint ethics committee of the Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, UK. Participants were screened to exclude psychiatric or systemic medical disorders and current medication usage.Before scanning, each participant was familiarised with the task and procedures. Participants were informed that we were interested in the effects of different facial expressions on heart rate during exercise and rest. Individual heart beats were recorded via a pulse oximeter linked to the task computer and were audible as tones (pulses) through headphones. Participants were also informed that the tones  were essentially irrelevant, but were generated to allow us to measure heart responses. During questioning after the study, no participant said that this cover story raised suspicions.true feedback, tones were presented synchronous with individual heartbeats. During asynchronous feedback, tones were delayed by half the inter-beat interval. During false feedback, no-exercise tones were presented at a rate ten percent faster than the preceding exercise heart rate, whereas exercise tones were presented at a rate 10 percent slower than the preceding no-exercise heart rate. Afterwards, participants completed another three minutes of the emotional appraisal task in the alternative exercise condition (either exercise or no-exercise) and with all three feedback conditions. The order of feedback and exercise conditions was randomized. In sessions where a no-exercise condition followed an exercise condition, a 90-second pause followed the instruction to relax grip, to allow exercise associated arousal to decline. At debriefing, participants were asked about their perceptions of heartbeat feedback. All participants were unaware (i.e. did not declare on direct questioning) of the manipulations of the auditory feedback of their heart rate . Further, participants confirmed that they remained focused on the face rating task.During the experimental task , a compu3 T1-weighted structural scans were acquired from each participant.Functional echo-planar datasets sensitive to BOLD (Blood Oxygen Level Dependent) contrast were acquired at 1.5 Tesla (Siemens Sonata) The sequence, minimizing orbitofrontal signal dropout http://www.fil.ion.ucl.ac.uk/spm/), employing spatial realignment and sequential co-registration . Structural scans were segmented into CSF, grey and white matter images and iteratively normalized to standard space  using a single generative model Images were pre-processed using SPM5  of discrete contrasts within the general linear model. Subsequent second-level group random effects analyses were performed on the SPM contrast images of first level canonical HRF responses to permit formal inferences about population effects Peripheral physiological responses were also explored outside the scanner in an independent group of eight healthy right handed participants  because recording equipment was not compatible with the fMRI environment. Participants were given identical task instructions and completed the experimental task while a finger cuff recorded beat-to-beat blood pressure with a Finometer . This allowed a reconstruction of brachial artery pressure from cardiological measures were obtained, including arterial pressure at systole and diastole, stroke volume, cardiac output, left ventricular ejection time, total systemic peripheral resistance, and heart rate."}
+{"text": "I read the paper by Chi et al. with interest. The authors found a greater hypoxia response gene expression in carcinomas than stromal cells grown in vitro, but were not sure of the underlying explanation (see Discussion in ). The unThe differences in mitotic activity could also explain greater hypoxia-related gene expression in clear-cell carcinoma compared with chromophobe carcinoma, normal tissue, or oncocytoma, as clear-cell carcinomas are more active mitotically. Did the authors compare the hypoxia gene expression with mitotic activity in various tumors?"}
+{"text": "Many biological problems such as the detection of co-expressed genes, co-regulated genes, and transcription factor binding motifs rely heavily on the analyses of these image patterns. The increasing availability of ISH image data motivates the development of automated computational approaches to the analysis of gene expression patterns.Staining the We have developed algorithms and associated software that extracts a feature representation of a gene expression pattern from an ISH image, that clusters genes sharing the same spatio-temporal pattern of expression, that suggests transcription factor binding (TFB) site motifs for genes that appear to be co-regulated (based on the clustering), and that automatically identifies the anatomical regions that express a gene given a training set of annotations. In fact, we developed three different feature representations, based on Gaussian Mixture Models (GMM), Principal Component Analysis (PCA), and wavelet functions, each having different merits with respect to the tasks above. For clustering image patterns, we developed a minimum spanning tree method (MSTCUT), and for proposing TFB sites we used standard motif finders on clustered/co-expressed genes with the added twist of requiring conservation across the genomes of 8 related fly species. Lastly, we trained a suite of binary-classifiers, one for each anatomical annotation term in a controlled vocabulary or ontology that operate on the wavelet feature representation. We report the results of applying these methods to the Berkeley Drosophila Genome Project (BDGP) gene expression database.Our automatic image analysis methods recapitulate known co-regulated genes and give correct developmental-stage classifications with 99+% accuracy, despite variations in morphology, orientation, and focal plane suggesting that these techniques form a set of useful tools for the large-scale computational analysis of fly embryonic gene expression patterns. This technique localizes specific mRNA sequences in tissues/cells by hybridizing a labeled complimentary nucleotide probe to the sequence of interest in fixed tissues. Visualizing the probe by colorimetric or fluorescent microscopy allows for the production of high quality images recording the spatial location and intensity of gene expression.A large body of work analyzing DNA micro-array data from microorganisms has demonstrated the value of gene expression analysis in understanding gene function and dissecting gene regulation -3. Whilein situ databases, such as the Berkeley Drosophila Genome Project (BDGP) gene expression pattern database , sh, shin siIn Figure In regard to the automatic annotation of gene expression patterns, we also collected statistics of the use of the ontology annotation terms (results not shown). The percentage of genes corresponding a common annotation term ranges from less than 1% to about 20%. Given this small fraction, it is unlikely that our image-based gene clustering results in Figures Our image analysis methods can be applied to 3D gene expression patterns or other types of aligned image patterns in different contexts. For example, in  we definin situ hybridization brain images of 20,000 genes were aligned to a standard reference atlas. The effective clustering and recognition of these gene expression patterns, based on various image features , could in situ fly gene expression patterns. We have successfully extracted useful local and global image features, and used these to automatically cluster and annotate gene expression patterns with high reliability. Our techniques provide useful tools for the large-scale computational screening of fly embryonic gene expression patterns, as well as the aligned image patterns for similar problems in other model systems.We have developed a set of automatic image analysis methods for For the BDGP database, 2D embryonic images of gene expression patterns were acquired using a digital camera. In a typical image, a single embryo resides in the central part of the image and presents a lateral view. Only lateral views were used, but the embryo can otherwise have an arbitrary orientation. As the embryonic region has much richer texture information than the image background, the embryo can be segmented by thresholding the local variance of a small region (e.g. 3 \u00d7 3 pixels) around each pixel. The pixel is binarized to \"foreground\" if the variance is larger than a predefined threshold (e.g. 2), otherwise to \"background\". Binarization classifies most embryo pixels as \"foreground\" and most background pixels as \"background\", thus producing a mask image that essentially captures the embryonic region. For a segmented embryo, we computed the principal direction along which the variation of all embryonic pixel-coordinates is the greatest and considered this the anterior-posterior axis of the embryo. We then rotated the image to make this axis horizontal. Finally, the embryonic region was cropped and its size was standardized to 400 pixels wide and 200 pixels high.in situ gene expression images in the BDGP database for 1,700 fly genes. We found that about 67% of the images have only one embryo region in the center, and can be easily segmented based on thresholding the pixel variance. These 20,000 extracted image patterns were automatically rotated so that their longest axes are horizontal. We developed a web-based image pattern browser at [We processed about 30,000 owser at , which cowser at .In analyzing the data, we further ignored all images that were not of a lateral view of the embryo. While most images are lateral views, a significant fraction is taken from difference vantage points, such as along the dorsal/ventral axis or some tilted angle. From these viewpoints it is especially difficult to understand the 3D pattern as the embryo is clear and one is essentially seeing the 2D projection of the stain along the viewing axis. It remains an open problem how to effectively use such additional data.For the experimental results reported, we focused on a set of 456 genes. We separated the lateral and dorsal views manually and also adjusted the orientations of these images to assure these images are compared in the correct way, i.e. anterior is at the left and dorsal is up. If in a particular stage-range a gene has multiple images, our computer program merged these images and used their mean-image as the \"representative\" for this gene. In this way, the image clustering and annotation algorithms would not be biased by the image-numbers of genes. Due to the great variation of the quality of the BDGP 2D image patterns, these processing steps were necessary to produce meaningful results.Abbreviations of the anatomical annotations used throughout the paper:AM amnioserosaAAISN amnioserosa anlage in statu nascendiAISN anlage in statu nascendiAEA anterior endoderm anlageAEAISN anterior endoderm anlage in statu nascendiAEP anterior endoderm primordiumAMP anterior midgut primordiumCMP cardiac mesoderm primordiumCB cellular blastodermCLP clypeo-labral primordiumDEA dorsal ectoderm anlageDEAISN dorsal ectoderm anlage in statu nascendiDECP dorsal ectoderm primordiumDEDP dorsal epidermis primordiumDPMP dorsal pharyngeal muscle primordiumEAISN endoderm anlage in statu nascendiECBG embryonic central brain gliaECBN embryonic central brain neuronECNS embryonic central nervous systemEDE embryonic dorsal epidermisEH embryonic hindgutELDV embryonic/larval dorsal vesselELCS embryonic/larval circulatory systemELO embryonic/larval oenocyteEM embryonic midgutEOLP embryonic optic lobe primordiumEFP external foregut primordiumFA foregut anlageFAISN foregut anlage in statu nascendiFP foregut primordiumGC germ cellHMPP head mesoderm P2 primordiumHMA head mesoderm anlageHA hindgut anlageHPP hindgut proper primordiumIHP inclusive hindgut primordiumLC lateral cordLCG lateral cord glia.LCN lateral cord neuronLVMP longitudinal visceral mesoderm primordiumMA mesectoderm anlageMEP mesectoderm primordiumMIP midline primordiumMAISN mesoderm anlage in statu nascendiMLP midline primordiumMP mesectoderm primordiumNOVNS neuroblasts of ventral nervous systemOSA oenocyte specific anlagePC pole cellPTEA posterior endoderm anlagePTEP posterior endoderm primordiumPMP posterior midgut primordiumPCEA procephalic ectoderm anlagePCEAISN procephalic ectoderm anlage in statu nascendiPCEP procephalic ectoderm primordiumPCN procephalic neuroblastsPEA procephalic ectoderm anlagePEP procephalic ectoderm primordiumPCP protocerebrum primordiumPMP posterior midgut primordiumPP proventriculus primordiumPTEAISN posterior endoderm anlage in statu nascendiSDP salivary duct primordiumSGBSA salivary gland body specific anlageSGDSA salivary gland duct specific anlageSGBP salivary gland body primordiumSNSSA sensory nervous system specific anlageSMP somatic muscle primordiumS subsetTP tracheal primordiumSNSP sensory nervous system primordiumSNSSA sensory nervous system specific anlageTMA trunk mesoderm anlageTMAISN trunk mesoderm anlage in statu nascendiTMP trunk mesoderm primordiumVEA ventral ectoderm anlageVECP ventral ectoderm primordiumVEPP ventral epidermis primordiumVNCP ventral nerve cord primordiumVNA ventral neuroderm anlageVSCSA ventral sensory complex specific anlageVM ventral midlineVMP visceral muscle primordiumVNC ventral nerve cordVP visual primordiumThe authors declare that they have no competing interests."}
+{"text": "Adherent cells from carcinomatous pleural effusions of lung cancer patients were tested for their ability to suppress natural killer (NK) cell activity, and the mechanism involved in the suppression of NK cell activity was determined. Adherent effusion cells (AEC) were isolated from malignant pleural effusions of patients by centrifugation discontinuous Ficoll-Hypaque gradients and adherence to serum-coated plastic dishes, and large granular lymphocytes (LGL) were purified from the peripheral blood of normal individuals by centrifugation on discontinuous Percoll gradients and further depletion of high-affinity sheep erythrocyte rosette formation. LGL-mediated lysis of K562 cells was suppressed when LGL were cultured with AEC for 20 h, then washed and tested in a 4-h 51Cr release assay. More profound suppression of NK cell activity was observed when cytotoxicity was assayed in flat-bottomed wells rather than in round-bottomed wells. Cytotoxicity assays conducted at the single cell level in agarose revealed that the frequency of LGL binding to K562 cells and of dead conjugated target cells was reduced after overnight contact with AEC. In agarose microdroplet assays, functional LGL from normal donors exhibited definitive motility, expressing polarized shape. In contrast, a small number of LGL with non-polarized configuration migrated from the agarose droplet after overnight culture with AEC. These results indicate that functionally suppressed NK cells lose their motility, binding capacity and killing activity, which could be responsible for the suppression of NK cell activity by AEC."}
+{"text": "Arrhythmogenic right ventricular dysplasia/cardiomyopathy is a disorder characterized by frequent ventricular tachycardia originating from the right ventricle and fibro-fatty replacement of right ventricular myocardium. Though the disorder was originally described during surgical ablation of refractory ventricular tachycardia, catheter ablation of tachycardia is one of the options for patients not responding to anti arrhythmic agents. Direct current fulguration was used in the initial phase followed by radiofrequency catheter ablation. In the present day scenario, all patients with risk for sudden cardiac death should receive an implantable cardioverter defibrillator. Radiofrequency catheter ablation remarkably reduces the frequency of defibrillator therapies. Direct current fulguration can still be considered in cases when radiofrequency ablation fails, though it requires higher expertise, general anesthesia and carries a higher morbidity. Newer mapping techniques have helped in identification of the site of ablation. In general, the success rate of ablation in arrhythmogenic right ventricular dysplasia is less than in other forms of right ventricular tachycardias like right ventricular outflow tract tachycardia. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD) is a disorder characterized by fibro-fatty replacement of the right ventricular myocardium, frequent ventricular tachycardia originating from the right ventricle and right heart failure. It was originally described by Fontaine et al during surgical ablation of refractory ventricular tachycardia . The firThough historically the original description of ARVD was during surgical ablation, pharmacological therapy was the initial mode of treatment in most cases. Surgical ablation by right ventricular disconnection was resorted to in resistant cases . PeroperThe initial reports on catheter ablation in ARVD were using direct current fulguration -8. One oRadiofrequency catheter ablation for ARVD has been in use since early nineties . It has Entrainment mapping can be used to characterize reentry circuits in ARVD to guide ablation -15. The Endocardial mapping can detect abnormal fragmented electrograms with delayed potentials. Pacemapping confirms the ablation site by producing a QRS morphology identical to the clinical VT . RecentlThree dimensional Real-time Positioning Management System (RPM) has also been used for guiding ablation in ARVD . RPM useO'Donnell et al have highlighted the electrophysiological differences between patients with ARVD and right ventricular outflow tract tachycardia (RVOT VT) . Though Ablation of ventricular tachycardias in ARVD still remains a clinical challenge, though more and more cases are being reported in the literature -23."}
+{"text": "Glutathione S-transferase (GST) isoenzyme expression is altered in a variety of neoplasms and the enzymes are implicated in metabolism of carcinogens and resistance to drugs, including cisplatin. We have studied GST Alpha, Pi, Mu and microsomal isoenzyme expression by immunohistochemistry in normal and cryptorchid testes, intratubal germ cell neoplasia (ITGCN), seminoma and non-seminomatous germ cell tumours. In 16 stage II-IV malignant teratoma intermediate (MTI) both orchidectomy and post-treatment residual surgical masses were studied. All four isoenzymes were strongly expressed in Leydig and Sertoli cells. GST Pi was absent from normal spermatogonia but strongly expressed by the neoplastic germ cells of ITGCN and seminoma. GST Pi was strongly expressed in all elements of teratoma, irrespective of differentiation. There were no qualitative differences in expression between primary and post-chemotherapy metastases. GST Alpha expression in teratoma correlated with epithelial differentiation. GSTs may be important in normal spermatogenesis and protection of germ cells from teratogens and carcinogens. They may have a role in testicular tumour drug resistance but this role is not well defined. GST Pi is a new marker for ITGCN."}
+{"text": "Using an indirect immunohistochemical technique on paraffin sections, employing a polyclonal antibody to the acidic  form of glutathione-S-transferase (GST), we have evaluated cytoplasmic and nuclear staining in a series of 67 cervical biopsies including normal non neoplastic tissue, immature squamous metaplasia, all grades of cervical intraepithelial neoplasia (CIN) and invasive carcinomas of keratinising and non-keratinising types. No differences in cytoplasmic staining between the varied lesions studied were seen. However, there were marked differences in nuclear staining. While normal non-neoplastic stratified squamous epithelium showed weak staining of the lower one-third of the epithelium only, in immature squamous metaplasia and in all grades of CIN there was intense nuclear staining in all layers of the epithelium. Invasive carcinomas showed generally less intense nuclear staining than CIN lesions. Endocervical cell nuclei also showed intense nuclear staining. These findings indicate that GST is of limited use as a marker of transformation in the human cervix uteri."}
+{"text": "Agouti-related protein encodes a neuropeptide that stimulates food intake. Agrp expression in the brain is restricted to neurons in the arcuate nucleus of the hypothalamus and is elevated by states of negative energy balance. The molecular mechanisms underlying Agrp regulation, however, remain poorly defined. Using a combination of transgenic and comparative sequence analysis, we have previously identified a 760 bp conserved region upstream of Agrp which contains STAT binding elements that participate in Agrp transcriptional regulation. In this study, we attempt to improve the specificity for detecting conserved elements in this region by comparing genomic sequences from 10 mammalian species. Our analysis reveals a symmetrical organization of conserved sequences upstream of Agrp, which cluster into two inverted repeat elements. Conserved sequences within these elements suggest a role for homeodomain proteins in the regulation of Agrp and provide additional targets for functional evaluation. Agrp expression is restricted to a discrete population of neurons that sense the levels of peripheral energy stores, and is dramatically elevated by deficits in energy balance.AGRP is an orexigenic, hypothalamic peptide whose role in energy homeostasis has been conserved during vertebrate evolution. In a wide range of species, including mammals Agrp mRNA levels Agrp regulation, where STAT3 represses and FoxO1 stimulates Agrp transcription. However, conserved STAT binding sites in the Agrp promoter region do not function as simple repressor elements and, paradoxically, are required for fasting induced stimulation of Agrp transcription AGRP neurons directly receive information about energy stores from leptin, an adipocyte-derived hormone that circulates at levels proportional to fat mass. Diminished levels of circulating leptin correspond to increased Agrp expression. For example, AGRP neurons directly mediate the orexigenic effects of glucocorticoids Agrp mRNA levels Agrp expression Support for this also stems from the observation that peripheral energy signals other than leptin regulate Agrp expression in transgenic mice and that contain regions of high sequence conservation between mouse and human, including a 760 bp region located immediately upstream of AgrpCross-species comparative sequence analysis has facilitated the detection of functional elements that participate in transcriptional regulation Agrp expression in vertebrates suggests that sequence comparisons of disparate vertebrate species provide an appropriate evolutionary scope for identifying Agrp regulatory elements. However, Agrp genomic sequences from distantly related vertebrate species have diverged to the extent that regional conservation is no longer detectable using traditional alignment methodologies Agrp genomic region from ten mammalian species, representing several different orders and all three subclasses of mammalia. Our analysis reveals a symmetrical organization of conserved sequences upstream of Agrp, which cluster into two inverted repeat elements (IREs). The proximity of the elements to Agrp and the nearly perfect evolutionary conservation of their specific constituent sequences in all ten mammalian species and in chickens suggest a role in Agrp regulation. In addition, the resolution of the conserved elements provided by this approach allows general predictions concerning putative trans-regulatory factors.The inclusion of sequences from multiple, divergent species sharing a commonly derived phenotype improves the resolution of comparative sequence analysis. The conserved nature of Agrp locus for chimpanzee (Pan troglodytes), human (Homo sapiens), dog (Canis familiaris), mouse (Mus musculus), and rat (Rattus norvegicus) was obtained from publicly available genome assemblies  on the UCSC genome browser (http://genome.ucsc.edu). Genomic sequence for other species, including chicken , cat (Felis catus), cow (Bos taurus), tenrec (Echinops telfairi), platypus (Ornithorhynchus anatinus), and opossum (Monodelphis domestica), was obtained from the trace sequence archives at NCBI (http://www.ncbi.nlm.nih.gov) and assembled using SeqMan . Our assembly of chicken genomic sequence at the Agrp locus differed from the publicly available genome assembly (Chicken v1.0), since additional trace sequence was available. Notably, the chicken sequence corresponding to the STAT site and inverted repeat element is not present in the public assembly. Our assembly of the chicken Agrp locus is provided as supplementary material  Agrp regulatory sequences has been previously interrogated using mouse transgenic models Approximately 1.8 kb of genomic sequence from the Agrp exons, the STAT sites, and the IREs, we modified the concept of an RS score, such that the score for constraint represents the sum of constrained alignment columns in these regions while ignoring unconstrained alignment columns. In this way, the constraint score reflects the level of sequence conservation within a particular region without penalizing unconstrained positions  surrounding Agrp, each one flanking a conserved STAT binding element Agrp underwent a duplication that occurred prior to mammalian radiation, and portions of the duplicated region have been subjected to purifying selection such that specific sequences (those corresponding to the STAT elements and IREs) are maintained in two closely related copies.As shown in Agrp locus, we aligned 1.8 kb of Agrp genomic sequence from 10 mammalian species \u2013 human, chimpanzee, mouse, rat, cow, dog, cat, tenrec, opossum, and platypus - with multi-lagan. We then used GERP Agrp locus and compares the position of constrained sequences with annotated elements. Based on this approach, the level of evolutionary constraint for sequences overlapping the IREs and the STAT binding sites are extremely high relative to other genomic regions Agrp coding sequences in this alignment of species  transcription factors, which are generally involved in the regulation of development and cell fate but also function post-developmentally to modulate cell type specific gene expression. While HD transcription factors represent a large family of proteins with over 100 members, most display restricted expression patterns that are predictive of function. Several HD transcription factors are regionally expressed in the hypothalamus.PomcOrexinGonadotropin Releasing Hormone (GnRH) GnRH has been extensively studied, due in part to an immortalized cell line which has retained important characteristics of endogenous GnRH neurons. Multiple HD transcription factors cooperatively bind to the sequences upstream of GnRH, regulating not only cell type specific expression but also dynamic, physiologic responses by serving as scaffolds for additional cofactors Agrp regulation proposed by Kitamura and colleagues to integrate observations regarding input from other signals and the organization of conserved sequences identified in this analysis.HD transcription factors have been previously implicated in the regulation of neuropeptide gene expression, and conserved HD binding sites have been identified in the regulatory regions of other hypothalamic neuropeptide genes, including Agrp defined by mouse/human sequence conservation, the IREs and STAT binding sites comprise the majority of non-coding sequence conserved among mammals. Only two other non-coding sequences, which are both \u223c15 bp in length, meet the threshold for constraint set by GERP  FoxO1 is capable of recognizing non-canonical FoxO1 binding sites in some species, (2) FoxO1 regulates Agrp expression only in a subset of mammalian species, (3) or FoxO1 associates with Agrp upstream regions through a mechanism that does not involve a direct interaction with the putative FoxO1 binding sites. Notably, direct interactions between forkhead and HD transcription factors have been previously described and implicated as a general mechanism for post-developmental regulation of gene expression In contrast to the STAT binding sites, the putative FoxO1 binding sites identified by Kitamura and colleagues, which are located between to the IREs and STAT binding sites, are not well-conserved Click here for additional data file.Text S2A FASTA file containing the mammalian sequences used for GERP analysis.(0.02 MB TXT)Click here for additional data file."}
+{"text": "Despite its popularity and rapid advancements in the field, many obstacles for cancer therapy PG still need to be overcome. By borrowing scientific systems from other disciplines such as cancer diagnosis, and therapeutic information from the diversity of tumor origins, categories and stages, cancer therapy PG may hopefully be improved. Furthermore, to quickly acquire genetic and pathologic information and seek therapeutic interventions, possible breakthroughs may come from beyond \u2013 changing the cancer therapeutic landscapes. The next generations of PG protocols and hospital routines for searching deadly cancer pathogenic pathways versus drug-targeting predictions are of great clinical significance for the future. Yet, progress of cancer therapy PG is entering into a bottleneck stage owing to simple model of relevant techniques and routines. Promoting or even innovating present PG modular is very necessary. This perspective highlights this issue by introducing new initiatives and ideas. Cancer is a common disease that claims the lives of about 7\u201310 million people annually across the world. As a result, cancer remains a great medical challenge worldwide . Many efDespite the popularity of cancer therapy PG, human genetic information used for forecasting disease risk, therapeutic agent options, drug characteristics (doses/toxicities and responses to cancer) in individual humans have not been perfected yet. The similarities and differences of PG between cancer therapy and other disease therapies are important for future scientific investigations and therapeutic improvements. Possible future perfections are proposed herein.Drug ADME studies by polymorphism analysis of individual metabolic enzymes and approximately 300 human metabolic enzyme genes and molecules have been subjected to PG investigations and clinical applications . TechnicThe paramount task of greatest therapeutic significance is to find the biologic relationships between disease progression (tumor genetic mutations/invasive/remote metastasis) and therapeutic outcomes (relevant anticancer drugs selections and applications). Ninety percent of cancer deaths are caused by neoplasm metastasis  and cancNeoplasm metastasis treatment is different from primary tumor treatment ,12\u201316. AOne of the thorniest problems in clinical cancer trials is the occurrence of multidrug resistance (MDR) in tumor cells or tissues. Soon after cancer chemotherapy, a series of drug transporter or DNA repair molecules, such as ATP-binding cassette transporters (ABC transporters), p-glycoprotein , MDR-related proteins (MRPs) and so on, work together to dramatically offset therapeutic efficacies and decide the nature of drug resistances and therapeutic failure in individual cancer patients. Thus, detecting polymorphisms of these genes and relevant biological molecules helps to predict the occurrence of drug resistance in tested cancer patients .Predictions of drug responses against cancers and toxicity to the human body are indispensable parts of cancer therapy. The polymorphisms or epigenetic information of drug-targeted genes, tumor environmental molecules, drug metabolic enzymes, tumor suppressive genes, metastatic-related or cancer stem cell-related molecules can impact on the chemotherapeutic outcomes for cancer patients . Proper Anticancer PG and PG for other disease therapies generally share the same analytical routines and technical supporting systems (mostly single nucleotide polymorphisms [SNPs]) of drug-related or DME genes \u2013 the same as for other disease therapies. Since the DME genes for anticancer drugs are biologically identical in human bodies and regarded as parallel systems, no difference has been applied between anticancer therapy and other disease therapies in general hospital protocols and routines. Despite the homogeneity of human metabolic enzymes, etiologic and pathogenic processes between cancer and other diseases are diversified greatly. For example, the etiologies of most diseases initiate in a fixed string of genes and molecules \u2013 pathogens commonly come from outside infections. Moreover, drug targets for most disease categories are fixed and can be repeated again and again. Cancer drug responsiveness prediction is, nonetheless, different because cancer comprises different diseases with pathogenesis of unlimited growth and metastasis. The great diversity and unresolved mechanisms of action for cancer progression and proliferative or metastatic inhibitions make current cancer therapy PG at its initial stages. Much effort must be created and verified for cancer therapy PG improvements that can save the life of a great numbers.Anticancer drugs, especially cytotoxic anticancer drugs, are highly toxic. Most cytotoxic anticancer drugs are even carcinogenic and can cause secondary tumors after administrations of higher than tolerated drug dosages. Approximately 1\u201310% of normal humans are deficient in one or several wild-type human metabolizing enzymes from one or several genetic polymorphisms. These patients cannot transform anticancer prodrugs into active metabolites (low-active drug components and responses) or reduce active metabolite clearance rates that lead to higher active metabolite concentrations in human plasma and toxicity. Increasing active anticancer drug or metabolite concentrations in patients\u2019 plasma or normal tissues means significantly harmful impacts on cancer patient treatments, or even the cost of a patient's life ,8\u201310 Fi. Yet incDifferent from other types of diseases, cancer is caused by a wide diversity of oncogenic mutations and environmental matrix and factors (such as vasculature activators like EGF or VEGF etc.) that support the transformations of normal cells into malignant ones . More seTumor growth and metastasis are determined by different cancer genes or hallmarks. Neoplasm metastasis is caused by the interactions of cancer cells and human environments . TheoretAfter the advent of cancer therapy PG, we have never attempted any new initiatives outside the boundary of the PG norm and technical routines that are different from widely practiced PG protocol in cancer therapy PG. If we stay on this course and in these mindsets, we might never have the opportunity to overcome the drawbacks and pitfalls of current cancer therapy and make a difference to now. Creative ideas and novel PG techniques for improving in cancer therapy are welcomed.Human cancer is a unique type of disease that in which a great diversity backgrounds of gene mutations and malfunctioning biomolecular profiling are found. According to general PG mindsets and routines, beside ADME-related metabolizing enzymes (\u2248300), at least the same amount of oncogenic genes can be mutated. From our past experience, at least 5\u201310 oncogenic genes or biomolecules will normally be found in tumor tissues among advanced cancer patients. Since a huge amount of human genes are related to cancer growth, metastasis, drug toxicities/responses, an indispensable topic is to design a high efficient strategy that can solve this technical difficulty. Brand-new strategies relevant to human gene and therapeutic prediction, even outside of current available polymorphisms information, might help us realize our dreams of making a difference to PG systems. However, this interesting topic seems unlikely to be solved by conventional PG routines in utilities.Since cancer is a complicated disease, conventional cancer therapy needs more than one anticancer drug. As a result, anticancer drug therapy PG is different from other PG diseases. These differences for complex therapeutic recipes call for new ideas and PG routines. Obviously, the next generations of anticancer therapy PG systems must be capable of predicting complicated clinical circumstances and situations in clinical cancer trials. How can this goal be realized? It needs to build the technical capability of translating biological modular into therapeutic optimizing paradigms. Technical innovations and computational data analytical systems can guide us into new clinical horizon and predict complex formulae of cancer treatment recipes.Apart from genetics of metabolic enzymes, anticancer drug targeting genes and oncogenic- or metastatic-related genes are other parts of personalized cancer therapy ,27\u201336. ADespite great monetary support and quick technical improvements, cancers remain to be an unresolved enigma and of therapeutic significance. Development of drug resistance, drug-induced severe side effects, cancer stem cells and tumor metastasis contribute to the majority of therapeutic failures in clinical cancer trials. Due to the poor drug specificity of many cytotoxic drugs, normal tissues are also damaged by such cancer treatments. As a result, the highest tolerated drug dosages cannot kill all tumor populations of large tumor volumes. Induction of drug resistance after conventional trials, cancer stem cells (mystery characteristics of tumors) and neoplasm metastasis and so on are the real culprits for therapeutic failures. Those PG systems designed to analyze genetic status of tumor or human tissues should be omnipotent for predicting both toxicity and efficacy of drugs in individual cancer patients. The present anticancer therapy PG systems are proving too little and too incapable for advanced cancer patients.Since oncogenic- or metastatic-related genes or molecules are too diversified and disconnected, it is hard to find optimal drugs utilizing present PG systems and routines. Apart from PG systems, other personalized cancer therapy strategies such as drug sensitivity testing (DST)  or canceThe overall theme of PG is the right drug for the right patient, by analyzing human genetics variations that play roles on predicting drug toxicities or responses. However, current PG systems are more suitable for fixed small ranges of pathological processes and change slightly after its advent. New knowledge coming from clinical case reports, doctors\u2019 experience or hypothesis-driven systematic studies ought to provide a useful foundation for updating PG systems, especially cancer therapeutic PG systems and routines. After accumulating enough clinical data and large-scale human genome drafting, computation and validating, framing different genetic markers and pathogenic-related therapeutic efficacies are followed. Finally, we need to transform our knowledge and understanding from empirical into successful clinical paradigms . PossiblSince genetic variations between individuals and disease progressions are not negligible, relationships between individual genes and drug therapeutic outcome are the priority. Much supportive information on this issue can easily come from other cancer biological or therapeutic advancements. Also, technical innovations can be implemented after absorptions of new fruits of scientific discoveries. However, basic rules behind the scenes are not understood yet.An approximately 1\u20135% difference between different races or ethnic groups is present worldwide. Presently, PG studies are heavily reliant upon European descendants (Caucasian) ,39. ThesDetermining the toxicities, activities and blood concentrations of anticancer drugs by PG plays an important role in clinical cancer trials. In spite of these utilizations, PG is not very useful for choosing the most suitable anticancer drugs from the large anticancer drug arsenal (\u224884 anticancer agents or drugs licensed in the USA)  and 178 Two cancer therapy PG systems (drug-oriented PG and pathogenesis-oriented PG) have been categorized  & 4. OptMoreover, potential new PG systems need an ingenious design via integration of two systems and scientific investigations supporting improvement of PG routines.Presently, cancer therapy PG, however, is only superior for drug dosages or toxicity determinations by SNPs of drug ADME profiling.An imbalance between the rapid development of genotyping technology and the slow pace of genetic testing marketing is generally met. The great degree of uncertainty in interpreting drug responses to tumor progressions, stem cells or metastasis PG has not been the breakthrough in cancer therapy worldwide. Despite a lot of successful stories, presently cancer therapy PG does not develop into compulsory routines, even in developed countries. A shortage of large sample-sized retrospective or clinical cohort studies has been reported . MoreoveGWAS are always the priority for PG technical updating. Owing to the invention of next-generation sequencing (NGS) techniques, human genome sequencing can be a joint effort between biomedical students and mathematical or physics students or scholars in the future. For these undertakings, mathematics or physics students and scholars will prove to be more adept than biomedical students in the postgenomic study age. Since the tremendous speed-up  and low budget  of genotyping human genomes by NGS  comparedBioinformatics (omics technology) are more advantageous for quantifying specific gene or biological molecular changes than those used by current PG systems. At first, we need to detect the clinical data of both PG and bioinformatics. Then, ingeniously designing a new generation of PG techniques or systems that can provide genetic information of both quantity and quality, even omnipotent systems, are possible routes to renew PG techniques for cancer therapy predictions. Cooperating merits from NGS and GWAS or other new techniques may improve cancer therapy PG or even change the landscape of personalized cancer therapies worldwide. Then, improvements of predicting therapeutic efficacies, toxicity and outcomes may be realized by integrating growing bodies of diagnostic or pathological profile information.Anticancer drug responses in tumor tissues and human bodies, especially those of cytotoxic anticancer drugs, are often multigenetic and multifactorial ,45. PresNo central dogma or paradigms of cancer therapy PG are capable of being universally utilized. Borrowing ideas and lessons from other scientific disciplines, hypothesis-driven data collections and workable computations for revealing the relationship of cancers diversity and a variety of therapeutic options are important resources for inventions of new generations of PG systems. In future, cancer therapy PG might transform from a number of genetic testing modalities into omnipotent, science-guarded and high-throughput predictive systems. The summary table outlines the roadmap and avenues of future directions of cancer therapy PG past and in future.Briefly, PG in clinics might no longer be considered a hobby in the future. Increasing occurrences of mandatory PG trials might be required in most advanced countries, or even become indispensable worldwide.Since we speculate that key breakthroughs of anticancer PG may not come from simply increasing the sample-size of clinical PG data, it relies on injections of insights and breakthrough of other disciplines, biological/medical discoveries or developments of new generations of anticancer drugs  and rulePresent cancer therapy PG systems are imperfect for large populations of cancer deaths . Possible future cancer therapy PG advancements may come from ideas and outcomes of other researchers instead of keeping up present mindsets and hospital routines.Techniques and strategies for prediction of both toxicity and efficacy in individual cancer patients.Pharmacogenetics (PG) study, especially drug absorption, distribution, metabolism and excretion molecules, such as metabolic enzyme genes and dose-optimizing.Description of established PG protocols and routines, comparisons between cancer therapy and other disease therapies.Outlook of different categories of PG techniques, such as drug-targets and disease-based genetic systems.Discover and predict the relationship between cancer pathology and treatments by PG practice in individual cancer patients.Find ways of pinpointing the diversity of pathologic origin and different therapy of primary, stem or metastatic cells or tissues in each cancer patient and be able to maximize the efficacy of drugs or therapy.Lacking established relations between therapeutic outcomes and PG applications.Limitations and shortcomings of conventional PG techniques and systems.The importance of neoplasm metastasis, multidrug resistance and cancer stem cells in cancer therapeutic outcome improvements.Comparisons of therapeutic efficacies between primary tumors and metastatic nodules.Create some original, innovative systems or biomedical software for integrating diversified and combinative pathological, pharmacological and clinical information into utility paradigms.Invest more money into developments of effective antimetastatic drugs or cancer stem cell inhibitors.Construct usable anticancer drug combinative PG systems.Promote genome-wide association studies, especially among different ethnic groups, races and/or tumor types and stages."}
+{"text": "Fusobacterium nucleatum and Porphyromonas gingivalis were highly increased within tissues, comprising 15\u201340% of the total bacteria. Furthermore, biofilm formation within the tissue was observed by Alcian Blue staining and atomic force microscopy, where degradation of fibers was prominent. Taken together, bacteria formed complex biofilm communities within gingival tissues that may serve as a reservoir for persistent infection. This novel finding may instigate new research into therapeutic strategies to treat periodontitis.Periodontitis is caused by dysbiosis of subgingival plaque that results in increased bacterial invasion into gingival tissues. Although shifts in subgingival microbiota from healthy to periodontitis have been well characterized, the characteristics of bacterial communities located within gingival tissues have not been studied. To characterize microbiota within the tissues of periodontal lesions in comparison with plaque microbiota, gingival tissues and subgingival plaque were obtained from the same tooth of patients with periodontitis (n = 7). A pyrosequencing analysis of the 16S rRNA gene revealed that species richness and diversity were not significantly different between the two communities. However, inter-subject variation in intra-tissue communities was smaller than that in plaque communities. Intra-tissue communities were characterized by decreased Firmicutes and increased Fusobacteria, compared with the plaque communities. Particularly,"}
+{"text": "Apis mellifera) implicated in elevated colony mortality rates worldwide and facilitated through vector transmission by the ectoparasitic mite Varroa destructor. Clinical, symptomatic DWV infections are almost exclusively associated with high virus titres during pupal development, usually acquired through feeding by Varroa mites when reproducing on bee pupae. Control of the mite population, generally through acaricide treatment, is essential for breaking the DWV epidemic and minimizing colony losses. In this study, we evaluated the effectiveness of remedial mite control on clearing DWV from a colony. DWV titres in adult bees and pupae were monitored at 2 week intervals through summer and autumn in acaricide-treated and untreated colonies. The DWV titres in Apistan treated colonies was reduced 1000-fold relative to untreated colonies, which coincided with both the removal of mites and also a turnover of the bee population in the colony. This adult bee population turnover is probably more critical than previously realized for effective clearing of DWV infections. After this initial reduction, subclinical DWV titres persisted and even increased again gradually during autumn, demonstrating that alternative non-Varroa transmission routes can maintain the DWV titres at significant subclinical levels even after mite removal. The implications of these results for practical recommendations to mitigate deleterious subclinical DWV infections and improving honeybee health management are discussed.Deformed wing virus (DWV) is a lethal virus of honeybees ( Apis mellifera). At highly elevated titres, it causes wing deformities in developing pupae, resulting in flightless adults that die shortly after emerging , , . I. IVarroacaricide . However removed .Varroa mite removal treatment to evaluate the time necessary to clear a DWV infection from a honeybee colony after mites are removed. Such information would be valuable for improving honeybee health management and colony survival by optimizing the duration and the timing of acaricide treatments.The aim of this study was to quantify the DWV infection dynamics during and following a \u2122  according to manufacturer recommendations while the other colony received no mite-control treatment. Apistan\u2122 is a potent synthetic pyrethroid acaricide with up to 98\u2013100% efficacy against Varroa mite infestation , , . T. TVarroatic bees .7 virus particles/bee are usually sufficient for successful oral infection of larvae or adult bees . D. D7 viruult bees . As brooult bees , 42]. S. S7 viruult bees .Varroa control treatments are administered too late in the season, the overwintering bees will have already been reared under Varroa-infested conditions and may be too ill-affected by virus infections to survive the winter, even if the mite treatment itself was effective at removing the mites.Honeybee colony death most often occurs during the winter months in temporal climates during the sensitive overwintering phase of the annual colony cycle . The lonVarroa treatment regime is probably more critical than previously realized. Highly infected adult bees must be replaced with a new generation of adults reared in a Varroa\u2013free environment, so that new and progressively healthier bees will nurse and feed the larvae of the long-lived overwintering bees. By conducting our study over the summer months it was possible to observe the influence of the bee population dynamics in addition to mite removal on DWV infections. A previous study using Apistan treatment in the late summer showed high DWV titres in adult bees (> 1010 copies / bee) and pupae (> 109 copies / bee) over the entire 6-week study , [, [Varroae spring , causingS1 FileVarroa mite removal and a bee population turnover.Persistence of subclinical deformed wing virus infections in honeybees following (XLSX)Click here for additional data file.S1 TablePrimer sequences and performance indicators, including the melting temperature of PCR products, for the RT-qPCR assays for DWV and internal reference gene RP-49.(PDF)Click here for additional data file."}
+{"text": "Normal, youthful arteries generally maintain constant radius/wall thickness ratios, with the relationship being described by the Laplace Law. Whether this relationship is maintained during aging is unclear. This study first examines the Laplace relationships in postmortem coronary arteries using a novel method to correct measurements for postmortem artifacts, uses data from the literature to provide preliminary validation, and then describes histology associated with low circumferential stress. Measurements of radius and wall thickness, taken at sites free from atheromas, were used with national population estimates of age-, gender-, and race-specific blood pressure data to calculate average circumferential stress within demographic groups. The estimated circumferential stress at ages 55-74 years was about half that at ages 18-24 years because of a disproportionate increase of wall thickness relative to artery radius at older ages, violating the expected relationships described by the Laplace Law. Arteries with low circumferential stress (estimated at sites distant from atherosclerosis) had more necrotic atheromas than arteries with high stress. At sites with low stress and intimal thickening, smooth muscle cells (SMCs) were spread apart, thereby diminishing their density within both the intima and media. Thus, older arteries displayed both low circumferential stress and abundant matrix of low cellularity microscopically. Such changes might alter SMC-matrix interactions."}
+{"text": "Extracorporeal membrane oxygenation (ECMO) is a therapeutic option used increasingly in the treatment of severe acute respiratory distress syndrome (ARDS). Choosing an adequate cannula type and insertion site can be a challenge. The insertion of a bi-caval dual lumen  catheter in the superior vena cava instead of two venous single-lumen catheters facilitates mobilisation and physiotherapy of patients, and hence is being used more and more .A middle-aged patient was admitted to our hospital after severe multiple trauma. Before admission to our hospital, damage control surgery including bilateral diaphragmatic repair and ileotransversostomy was performed.The postoperative course was complicated by disseminated intravascular coagulation (DIC). Six days after the accident, the patient could be stabilized to be eligible for transportation to the hospital by an air rescue service. The patient was transferred directly to the Surgical ICU under controlled mechanical ventilation.Within the first 24\u00a0h after admission, the respiratory function deteriorated to ARDS. Advanced respiratory support, including veno-venous ECMO, was applied to sustain gas exchange in the hope it could improve survival. Because of the underlying complex abdominal trauma we tried to insert a bi-caval dual lumen catheter into the right jugular vein. Due to surgical reconstruction of the bilateral diaphragmatic rupture and consecutive anatomical changes, several attempts to place either the guide wire or the catheter tip into the inferior vena cava (IVC) under transthoracic and transoesophageal echocardiography visual guidance failed; both guide wire and dual lumen catheter could not bypass the right ventricle to the IVC..Therefore, we decided to insert two single lumen catheters into the right jugular and femoral vein, whereupon ECMO treatment could be performed without further technical problems. In a post-hoc reconstruction of the thoracic computed tomography (CT) scan we discovered an altered path of IVC transition into the right atrium following surgical repair of the bilateral diaphragmatic rupture Fig.\u00a0.Fig. 1PIn patients with right-sided diaphragmatic rupture and surgical reconstruction we recommend a three-dimensional reconstruction based on three-dimensional echocardiography or CT of the venous inflow to the right atrium before attempting to insert a bi-caval dual lumen catheter . Notwith"}
+{"text": "The immune system has evolved pairs of activating and inhibitory receptors that modulate the magnitude of immune responses, enabling the maintenance of immune homeostasis. Inhibitory signaling dampens the immune response, which prevents inflammatory damage to the host. It has now become increasingly clear that viruses have evolved means of exploiting the inhibitory signaling pathways of the immune system in order to blunt the responses that would otherwise abrogate infection. Recent evidence demonstrates how viruses exploit inhibitory receptors both for host cell entry and to down-regulate antiviral responses for enhanced viral pathogenesis. Both acute and chronic viral infections also induce expression of intermediates of inhibitory signaling for improved odds of survival within the intracellular environment. This review highlights and synthesizes from recent findings how medically important viruses exploit the inhibitory pathways that maintain immune homeostasis for successful human infection.The rapid initiation and timely termination of the immune response are coordinated by paired receptors expressed on immune cells. Paired receptors consisting of activating and inhibitory receptors recognize self and non-self ligands. They are essential for maintaining self-tolerance, mounting an immune response during infection, and modulating the intensity of the response to prevent autoimmunity and inflammatory damage to bystander cells . ActivatAlthough activating and inhibitory signals are integrated for immune homeostasis, they might not contribute proportionately to signaling output due to dominant inhibitory signaling, as exemplified by natural killer (NK) cell responses . NK cellThe complexity of signal integration is further underscored by how signaling outcome is tuned by viral manipulation of inhibitory signaling. Coevolution of viruses and their hosts has resulted in viruses acquiring strategies for attenuating immune responses to favor viral replication and disease in humans. Viruses are known to utilize inhibitory receptors for host cell entry, which also initiate inhibitory signaling to down-regulate antiviral responses for enhanced viral replication. The recent use of quantitative temporal viromics, which profiles proteomic changes in viral and host cell proteins over time, has demonstrated how viruses also dramatically alter the expression of cell surface proteins to counter the host cell\u2019s defenses . FinallyThe viral life cycle starts with host cell entry, which involves direct fusion with cell membrane or ligating an appropriate receptor to trigger endocytosis, pinocytosis, or macropinocytosis. Use of inhibitory receptors during host cell entry could thus simultaneously initiate inhibitory signaling to dampen the immune response for enhanced viral replication .CD300a is an inhibitory receptor that belongs to the CD300 family of transmembrane receptors. It binds cell surface phosphatidylserine and phosphatidylethanolamine (PE), which are exposed following increased levels of intracellular calcium during human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) infection . InteracDENV is also known to ligate leukocyte immunoglobulin-like receptor B1 (LILRB1) , an inhi+ T cells, and binding of HIV-1 to DCIR promotes infection of DCs and CD4+ T cells .,42.+ T cnfection . T cell feration ,45.+ T cells, rapidly inducing a transcriptional state synonymous with T cell exhaustion   or respihaustion . AntigenA substantial body of work has now refined our mechanistic understanding of how various medically important viruses manipulate inhibitory signaling for survival within the host cell. Given that members of a virus family share many conserved structural and non-structural proteins, it is plausible that viral strategies to manipulate inhibitory signaling could be relevant to a broader range of viruses than those discussed here. Understanding how viruses exploit inhibitory signaling could lead to rationally designed interventions that interrupt these critical virus\u2013host interactions. The potential of an anti-PD-L1 antibody in reducing viral reservoirs in HIV-1 patients was recently evaluated in a clinical trial (NCT02028403). We anticipate that a combination of therapies targeting critical steps of the viral life cycle and boosting different arms of the immune response could provide recourse for both acute and persistent viral infections."}
+{"text": "The discovery of RNA interference (RNAi) has been a major scientificbreakthrough. This RNA-guided RNA interference system plays a crucial role in awide range of regulatory and defense mechanisms in eukaryotes. The key enzyme ofthe RNAi system is Argonaute (Ago), an endo-ribonuclease that uses a small RNAguide molecule to specifically target a complementary RNA transcript. Twofunctional classes of eukaryotic Ago have been described: catalytically activeAgo that cleaves RNA targets complementary to its guide, and inactive Ago thatuses its guide to bind target RNA to down-regulate translation efficiency. Arecent comparative genomics study has revealed that Argonaute-like proteins arealso encoded by prokaryotic genomes. Interestingly, there is a lot of variationamong these prokaryotic Argonaute (pAgo) proteins with respect to domainarchitecture: some resemble the eukaryotic Ago (long pAgo) containing a completeor disrupted catalytic site, while others are truncated versions (short pAgo)that generally contain an incomplete catalytic site. Prokaryotic Agos with anincomplete catalytic site often co-occur with (predicted) nucleases. Based onthis diversity, and on the fact that homologs of other RNAi-related proteincomponents (such as Dicer nucleases) have never been identified in prokaryotes,it has been predicted that variations on the eukaryotic RNAi theme may occur inprokaryotes. TtAgo fromThermus thermophilus and RsAgo fromRhodobacter sphaeroides. Like eukaryotic Argonautes, bothTtAgo and RsAgo are long pAgos that areco-purified with oligonucleotide guides , themajority of which are complementary to plasmids. Together with the observation thatTtAgo  target DNA,this has led to the conclusion that both pAgos play a role in host defense .However, apart from these similarities there are important functional differencesbetween the two bacterial Argonaute proteins. The guides acquired byRsAgo are mRNA-derived RNA oligonucleotides that target the templatestrand of plasmid genes. As RsAgo lacks a catalytic site, it mostlikely requires a partner nuclease for target cleavage. In contrast,TtAgo acquires DNA guides that allow targeting of AT-rich sequences ofdouble-stranded plasmid DNA. Whereas the functional nuclease site ofTtAgo catalyzes nicking of a single targeted DNA strand, twoTtAgos loaded with overlapping complementary guides can generatedouble-stranded DNA breaks. Recent studies by us and the working group of Alexei Aravin have described molecularanalyses of two distinct bacterial Argonautes, These studies have revealed interesting variations on the eukaryotic RNAi theme. Severalbasic features of these two variant pAgos remain elusive, concerning mechanistic detailsof both guide acquisition and target interference. Moreover, apart from the twocharacterized prokaryotic Argonautes, many more pAgo variants exist, that may differ infunctionality with respect to (i) guide preference (RNA/DNA), (ii) target specificity(RNA/DNA), and (iii) catalytic mechanism (nuclease activity). Apart from providinginsights in the evolution of the prokaryotic Ago variants and their eukaryoticcounterparts, future research will aim at revealing the molecular basis for the distinctfunctionality of these different pAgo variants. Moreover, gained insights will result inan interesting set of novel nucleases that may allow for dedicated geneticengineering."}
+{"text": "Coral reefs are among the most biodiverse and productive ecosystems on Earth, and provide critical ecosystem services such as protein provisioning, coastal protection, and tourism revenue. Despite these benefits, coral reefs have been declining precipitously across the globe due to human impacts and climate change. Recent efforts to combat these declines are increasingly turning to restoration to help reseed corals and speed-up recovery processes. Coastal restoration theory and practice has historically favored transplanting designs that reduce potentially harmful negative species interactions, such as competition between transplants. However, recent research in salt marsh ecosystems has shown that shifting this theory to strategically incorporate positive interactions significantly enhances restoration yield with little additional cost or investment. Although some coral restoration efforts plant corals in protected areas in order to benefit from the facilitative effects of herbivores that reduce competitive macroalgae, little systematic effort has been made in coral restoration to identify the entire suite of positive interactions that could promote population enhancement efforts. Here, we highlight key positive species interactions that managers and restoration practitioners should utilize to facilitate the restoration of corals, including (i) trophic facilitation, (ii) mutualisms, (iii) long-distance facilitation, (iv) positive density-dependence, (v) positive legacy effects, and (vi) synergisms between biodiversity and ecosystem function. As live coral cover continues to decline and resources are limited to restore coral populations, innovative solutions that increase efficiency of restoration efforts will be critical to conserving and maintaining healthy coral reef ecosystems and the human communities that rely on them. Coral reefs are one of the most biodiverse and productive ecosystems on Earth, and provide critical services to at least 500 million people throughout the world . In addiFor many decades, the paradigm in coastal restoration has been to minimize negative interactions  between transplant neighbors . This paWith increased consideration of facilitation in ecological theory , recent Trophic facilitation occurs when one species is positively impacted through the feeding activities of another species. One example includes trophic cascades where predators, by suppressing densities of primary consumers, can increase densities of basal prey species such as plants  has been studied for decades. Results of comparative and experimental studies have shown that herbivorous fish and urchins are critical for the success of corals, and this positive interaction is general across almost all regions where corals occur . BecauseDrupella snails in the Western Indian Ocean , which provide substantial nutrition to corals and enhance skeletal deposition  is one of the most well-known reciprocal positive interactions that can encourage healthy coral reef functioning. While coral reefs provide habitat, CCA is critical for cementing and stabilizing reef structure and facilitating settlement of coral larvae . Reef-dwseastars . Similarseastars , predatiseastars , and verseastars . Many fiseastars .Despite these many examples of mutualisms that support coral success, few studies to date have examined or experimented with incorporating species-specific mutualisms into restoration. One recent study that seeded a reef with sponges prior to transplanting corals found significant increases in rubble consolidation that in turn enhanced coral survivorship in that environment . SimilarPositive interactions can also occur between species that are not in contact but separated by distances of tens or thousands of meters . Long-diDecades of research has shown that the health, productivity, and biodiversity of coral reefs is directly related to their proximity to tropical seagrass meadows and mangrove forests. For example, both habitats facilitate corals by reducing stressors such as sedimentation or nutrient pollution from coastal development and runoff that may smother corals or enhance algal overgrowth . SeagrasDiadema) that live within the interstitial matrices of larger corals  found increasing density significantly reduced coral growth within the first three months of transplantation, likely due to competition for space (Montipora digitata in high density (spaced 10-cm apart) and low density (spaced 20-cm apart) plots over 15 months. These studies suggest that studies examining the effects of density on coral transplants may have varied results depending on spacing between colonies. For endangered Caribbean acroporid corals, recent experimental research shows a unimodal relationship may exist, with positive density effects occurring at moderate levels  but negative density effects occurring at higher densities  and planting configuration of staghorn coral Acropora ensities . Howeverxcrement  While most of these studies examine colony-specific metrics, such as growth and survivorship of individual corals, the effects of density are likely affected by environmental stressors and temporal scales. Although ecological theory  suggests that positive density dependency may emerge under high stress conditions in coral reefs, no studies to date have examined how the impacts of density vary across a stress gradient. For instance, because of the tendency of branching corals to fuse, higher density plots may enhance structural resistance to wave energy such as intense storms , due to a history of restoration methods that take advantage of their high growth rates and ease of propagation through fragmentation (Orbicella spp.). In addition, Caribbean branching corals can be more susceptible to natural enemies such as predators and disease  relative to conspecifics, however this facilitation stopped when nutrient enrichment was introduced to plots. Diverse coral species facilitated A. cervicornis growth and survivorship by reducing the number of coral predators  that attacked plots of A. cervicornis  or in areas where stress is not an issue but recruitment limitation is impeding natural recovery . For newHarnessing naturally-occurring positive interactions in restoration designs has recently been suggested  and demo (1)Identifying specific trophic linkages or food webs that promote coral health and transplanting corals in areas with where these food webs are robust and protected. (2)Identifying mutualisms between corals and other reef- or coral-associated organisms that promote coral health and enhancing or protecting these mutualistic partners. (3)Locating sites for coral restoration close to healthy and well-functioning seagrass and mangrove habitats and protecting these habitats from extractive or destructive uses. (4)Identifying species-specific density effects for corals of restoration interest to take advantage of transplant densities that facilitate coral growth or survivorship. (5)Exploring the legacy of former reef-builders or occupiers, such as coral skeletons left behind, for use in coral transplantation. (6)Determining ways in which increased coral diversity facilitates the success of coral transplants as well as the long-term success of the restored coral reef community to environmental fluctuations and disturbances ."}
+{"text": "Drosophila imaginal disc cells exhibit preferred cell division orientations according to location within the disc. These orientations are altered if cell death occurs within the epithelium, such as is caused by cell competition or by genotypes affecting cell survival. Both normal cell division orientations, and their orientations after cell death, depend on the Fat-Dachsous pathway of planar cell polarity (PCP). The hypothesis that cell death initiates a planar polarity signal was investigated. When clones homozygous for the pineapple eye (pie) mutation were made to initiate cell death, neither Dachsous nor Fat was required in pie cells for the re-orientation of nearby cells, indicating a distinct signal for this PCP pathway. Dpp and Wg were also not needed for pie clones to re-orient cell division. Cell shapes were evaluated in wild type and mosaic wing discs to assess mechanical consequences of cell loss. Although proximal wing disc cells and cells close to the dorso-ventral boundary were elongated in their preferred cell division axes in wild type discs, cell shapes in much of the wing pouch were symmetrical on average and did not predict their preferred division axis. Cells in pie mutant clones were slightly larger than their normal counterparts, consistent with mechanical stretching following cell loss, but no bias in cell shape was detected in the surrounding cells. These findings indicate that an unidentified signal influences PCP-dependent cell division orientation in imaginal discs. Oriented cell division influences how animal tissues grow, especially in tissues where cells are not very motile\u20134. It isDrosophila is altered in the vicinity of apoptotic cells. The. The53].pie homozygous clones to those of pie heterozygous or wild type cells at comparable locations  pathway of tumor suppressors, 60\u201363. s mutants. Cell dict growth. Recent ct growth, 68. Thi"}
+{"text": "Direct comparisons revealed that EOs showed greater response to cannabis cues in the dorsal striatum than LOs . Within-group analyses revealed that EOs showed greater neural response to cannabis cues in the dorsal striatum, whereas LOs exhibited greater neural response to cannabis cues in the ventral striatum. Although cross-sectional, these findings are consistent with recent addiction theories suggesting a progressive shift from ventral to dorsal striatal control over drug-seeking behavior and highlight the importance of age of onset of cannabis use on the brain and cognition.Addiction theories posit that addiction is the result of a progressive transition from voluntary to habitual, compulsive drug use\u2014changes that have been linked, in animals, to a shift from ventral to dorsal striatal control over drug-seeking behavior. Thus, we hypothesized that early-onset (EOs) cannabis users versus late-onset (LOs) cannabis users might exhibit, respectively, greater dorsal versus ventral striatal response to drug cues. We used functional magnetic resonance imaging and an event-related blood oxygen level-dependent backward-masking task to evaluate striatal responses to backward-masked cannabis cues  in EOs (<16 years old,  These transitions include a shift from ventral to dorsal striatal control over behaviors  that contribute to habitual and progressively compulsive drug seeking.10\u201312 The majority of the research supporting this theory has been conducted in animal models; however, recent human studies on age of onset of cannabis use may provide additional support for such brain changes and impairments in prefrontal inhibitory control. Specifically, early (before age 16) onset of cannabis use (EO) has been associated with structural connectivity differences of the orbitofrontal cortex (OFC),13 decreased white matter integrity in fibers connecting the right and left dorsolateral prefrontal cortex,14 and increased functional connectivity between the OFC and prefrontal and motor regions.15 Furthermore, research indicates that EO cannabis users (EOs) perform worse than late-onset (age 16 or later) cannabis users (LOs) across a variety of neurocognitive domains, including measures of sustained attention, impulse control, and executive functioning.17 Together, these findings suggest that EO of cannabis use may contribute to morphological alterations in prefrontal brain regions that are associated with cognitive control deficits observed in EOs.Although cannabis use may lead to alterations in the brain and cognition, these changes occur over time. Indeed, addiction theories posit that substance use disorders are the result of \u201ca series of transitions from initial voluntary drug use to habitual, and ultimately compulsive drug use\u201d19 and investigated the associations between striatal activity and cannabis craving. Based on the research described above, we expected that EOs would show neural response to backward-masked cannabis cues  in the dorsal striatum, whereas LOs would show neural response to cannabis cues in the ventral striatum. Because research suggests that heightened motivational/emotional states  lead to heightened sensitivity to associated cues,20 we also hypothesized that cannabis craving would correlate with these cannabis cue-related activations and that different association patterns would emerge in EOs and LOs.While morphological and cognitive changes have been well characterized in EOs, it remains unknown whether age of cannabis use onset is differentially associated with ventral or dorsal striatal activity or control over cannabis use. Thus, the current study explored potential differences in striatal activity during cannabis cue exposure  among EOs and LOs who report similar patterns of cannabis use. We compared striatal responses to cannabis cues presented during a functional magnetic resonance imaging (fMRI) backward-masked cannabis cue paradigm19 Participants were 41 treatment-seeking individuals who met the DSM-IV21 criteria for cannabis dependence. Participants were medically stable, educated, and had no concomitant serious comorbid psychiatric or substance use disorders (except nicotine dependence). See All study procedures adhered to the Declaration of Helsinki and were approved by the University of Pennsylvania Institutional Review Board. Details of the recruitment process and selection criteria were reported previously.As part of a larger study, participants completed baseline questionnaires, interviews, and an MRI session. Participants were asked to abstain from alcohol and illicit substances for the 24\u2009h before the MRI session and completed a urine drug screen and alcohol breathalyzer. All participants were positive for cannabis use and negative for other substance use.22 and the Addiction Severity Index23 measured lifetime alcohol and substance use and age of onset of cannabis use. Based on the existing literature and that age 16 is when significant brain changes typically occur,24 participants were grouped as EO (<16 years old) or LO (\u226516 years old). Lifetime cannabis exposure was quantified using gram years.25 The Marijuana Craving Questionnaire-Short Form (MCQ-SF)26 measured self-reported baseline cannabis craving using a scale covering behavioral experiences associated with aversive and appetitive aspects of drug motivation. The magnitude of cannabis craving was assessed before the neuroimaging session and was determined by summing items of the MCQ-SF.Cannabis, alcohol, and other drug use during the preceding 30 days was assessed with the Timeline Follow-Back interview,19 Briefly, imaging data were analyzed using statistical parametric mapping . Imaging analyses were focused on regions of interest (ROIs) in the dorsal and ventral striatum. The ROIs were created using the Harvard\u2013Oxford probabilistic anatomical atlas provided with the FMRIB Software Library.27 To control for type 1 error, neural activity within the ROI mask of each voxel was considered significant at a nominal alpha level of p<0.01 and a cluster extent of 50 contiguous resampled voxels as determined via Monte Carlo simulations using 3dClustSim Analysis of Functional NeuroImages software28 (http://afni.nimh.nih.gov/).A detailed description of the backward-masking cannabis cue paradigm, imaging parameters, and analyses are provided in previous publications.2 =4.37, p=0.04); however, small sample size prevented the exploration of potential sex differences in the current analyses.As noted in p<0.01, k>50 voxels). Analyses among EOs revealed greater response to backward-masked cannabis cues in the dorsal striatum, whereas LOs showed greater response to backward-masked cannabis cues in the ventral striatum . There were no significant correlations among LOs.Correlation analyses between cannabis craving scores and As hypothesized, preliminary analyses revealed that EOs and LOs showed different patterns of neural response to backward-masked cannabis cues, with EOs showing greater response within the dorsal striatum compared to LOs. When examining groups separately, EOs exhibited neural response to backward-masked cannabis cues in the dorsal striatum, yet LOs exhibited neural response in the ventral striatum. It is important to note that the EO and LO groups reported similar patterns of recent cannabis use, and as such, findings are not due to differences in recent cannabis use. Furthermore, groups did not show significant differences in lifetime cannabis use, suggesting that striatal activation findings in EOs and LOs were specific to age of onset of cannabis use and not due to history of daily use or duration of use. Correlation analyses revealed that dorsal striatal activations in EOs correlated with cannabis craving. Although cross-sectional, these preliminary findings are the first of their kind and suggest that differential striatal activation between EOs and LOs may reflect cannabis-induced alterations in neuroplasticity during early adolescent maturation that strengthened reward-related associations in EOs and possibly accelerated the shift from voluntary occasional use to habitual compulsive use.13\u201315 provide evidence that EOs also exhibit striatal brain changes that may underlie habitual, compulsive cannabis use, whereas LOs exhibit a pattern of neural activity in the ventral striatum that is characteristic of voluntary cannabis use, which may be regulated by prefrontal control processes. Although compulsivity and impulsivity were not assessed in the current study, future research in a larger sample could explore these hypotheses more fully.Our findings, in conjunction with previous research demonstrating altered prefrontal structure and function,Limitations should be considered when interpreting the findings. First, sample size is moderate; thus, future studies should include a larger sample with greater diversity to validate these findings and ensure generalizability. Furthermore, we did not assess or control for the influence of menstrual cycle phase/gonadal hormones, cannabis withdrawal symptoms, or motivations for treatment, and as such, it remains unclear as to whether these factors influenced findings. Finally, this study used a cross-sectional design, so it is not possible to know whether EOs exhibited ventral striatal activation earlier in their addiction. Longitudinal studies will be helpful in parsing the effects of these factors on cannabis cue reactivity.In summary, EOs and LOs exhibited differential patterns of striatal response to backward-masked cannabis cues, with EOs demonstrating dorsal striatal response and LOs showing a ventral striatal response. This differential pattern of striatal response parallels recent hypotheses of drug addiction, through which a series of transitions from initial voluntary use to habitual, compulsive use involve transitions from ventral to dorsal striatal control. Although additional research is warranted, our findings are the first neuroimaging findings among cannabis users to demonstrate differential striatal responding to cannabis cues in EOs and LOs."}
+{"text": "The redox balance modulation is also highly dependent on the level of physical activity. For example, both high-intensity exercise and inactivity, representing the two ends of the physical activity spectrum, are known to promote oxidative stress. Numerous to-date studies indicate that hypoxia and exercise can exert additive influence upon redox balance alterations. However, recent evidence suggests that moderate physical activity can attenuate altitude/hypoxia-induced oxidative stress during long-term hypoxic exposure. The purpose of this review is to summarize recent findings on hypoxia-related oxidative stress modulation by different activity levels during prolonged hypoxic exposures and examine the potential mechanisms underlying the observed redox balance changes. The paper also explores the applicability of moderate activity as a strategy for attenuating hypoxia-related oxidative stress. Moreover, the potential of such moderate intensity activities used to counteract inactivity-related oxidative stress, often encountered in pathological, elderly and obese populations is also discussed. Finally, future research directions for investigating interactive effects of altitude/hypoxia and exercise on oxidative stress are proposed.Increased oxidative stress, defined as an imbalance between prooxidants and antioxidants, resulting in molecular damage and disruption of redox signaling, is associated with numerous pathophysiological processes and known to exacerbate chronic diseases. Prolonged systemic hypoxia, induced either by exposure to terrestrial altitude or a reduction in ambient O Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are constantly produced within the living cells  , exercise likely drives more oxidative stress than systemic hypoxia per se. This hypothesis is congruent with the findings of Sinha et al. ]. The following section recaps the up-to-date studies scrutinizing the influence of activity during prolonged hypoxic/altitude exposures.Besides increasing oxidative stress, acute hypoxic exercise may also, at least transiently, alter antioxidant capacity  performed upon acute exposure and following 13-day of acclimation did not increase oxidative stress. It is also important to note that the employed oral antioxidant supplementation was inefficient in reducing hypoxia-induced oxidative stress. Very informative data on the effects of chronic exercise training during prolonged hypoxic exposures on oxidative stress and antioxidant status have also been derived from investigations related to altitude training in (mostly) endurance athletes. The vast majority of these studies were performed using the Live-High Train-Low altitude training modality (LHTL) first introduced by Levine and Stray-Gundersen  performed twice daily throughout the 10-day hypoxic confinement period was shown to improve antioxidant capacity and thereby blunt hypoxia-related oxidative stress in untrained individuals , mostly underlined by augmented antioxidant capacity. On the other hand, performing exercise of higher-intensities seems to additively increase hypoxia-induced oxidative stress. This might compromise adaptations to hypoxic training in athletes and also prove detrimental for individuals who exhibit chronically elevated systemic oxidative stress levels. These observations need to be taken into account while providing expert-advice on altitude/hypoxic training, as well as guidelines for high altitude sojourns in vulnerable populations. Given that the exact mechanisms of the interactive effects of hypoxia and physical activity on redox balance are not entirely clear, future well-controlled investigations should scrutinize different dose-response effects of both in healthy as well as patient populations.TD, GM, and VP: Drafted the manuscript, revised the manuscript critically for important intellectual content, and approved the final version of the manuscript submitted.This study was supported by the Institut Universitaire de France.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "COPD is a common inflammatory disease of the airways, alveoli and microvasculature that is under-diagnosed in smokers at risk for the disease. The majority of COPD patients have mild airway obstruction. Symptomatic smokers with mild COPD are at higher risk for earlier mortality and poorer perceived quality of life than non-smokers. Moreover, dyspnoea and activity restriction are common among smokers with minor spirometric abnormalities. Tobacco-related inflammatory injury of the lungs manifests as heterogeneous physiological impairment with highly variable clinical expression. Thus, simple spirometry provides only a crude assessment of disease pathophysiology, especially in the early stages of the disease.1, plethysmographic lung volumes and resting inspiratory capacity being within the normal range.Several studies have shown consistent physiological abnormalities on oscillometry, together with abnormal configuration of the mid-volume maximal expiratory flow-volume loop and increased pulmonary gas trapping, which collectively point to the presence of extensive small airway dysfunction despite FEVE/VCO2 nadir) is common in mild COPD and mainly reflects high physiological dead space  and thus a preponderance of lung units with high ventilation-perfusion ratios. This presentation explores the clinical consequences of this heterogeneous physiological impairment in smokers with unremarkable spirometry.Recent exercise studies in symptomatic smokers with or without mild COPD have highlighted that exercise limitation is common and is multifactorial but that respiratory factors such as increased dynamic mechanical constraints are contributory. Lung microvascular inflammation, disruption of the alveolar-capillary interface and reduced pulmonary perfusion are increasingly identified in smokers with minor spirometric abnormalities. In this context reduced ventilatory efficiency during exercise (high V"}
+{"text": "Tumour microenvironment (TME) is a key determinant of tumour growth and metastasis. TME could be very different for each type and location of tumour and TME may change constantly during tumour growth. Multiple counterparts in surrounding microenvironment including mesenchymal-, hematopoietic-originated cells as well as non-cellular components affect TME. Thus, therapeutics that can disrupt the tumour-favouring microenvironment should be further explored for cancer therapy. Previous efforts in unravelling the dysregulated mechanisms of TME components has identified numerous protein tyrosine kinases, while its corresponding inhibitors have demonstrated potent modulatory effect on TME. Recent works have demonstrated that beyond the direct action on cancer cells, tyrosine kinase inhibitors (TKIs) have been implicated in inactivation or normalization of dysregulated TME components leading to cancer regression. Either through re-sensitizing the tumour cells or reversing the immunological tolerance microenvironment, the emergence of these TME modulatory mechanism of TKIs supports the combinatory use of TKIs with current chemotherapy or immunotherapy for cancer therapy. Therefore, an appropriate understanding on TME modulation by TKIs may offer another mode of action of TKIs for cancer treatment. This review highlights mode of kinase activation or paracrine ligand production from TME components and summarises the findings on the potential use of various TKIs on regulating TME components. At last, the combination use of current TKIs with immunotherapy in the perspectives of efficacy and safety are discussed. Protein phosphorylation, one of the most prevalent post-translational modification of protein, is tightly regulated by specific protein kinase that transfer phosphate group to the amino acid residue . To our The binding of ligand such as growth factors or cytokines to the extracellular domains of RTKs initiate the signalling cascade by changing its structure and kinase activation. Whereas the non-RTKs which lack of extracellular domains mainly serves as the downstream effector of RTKs . UnderstKinase inhibition in tumour cells by tyrosine kinase inhibitors offers promising clinical benefit to cancer patients, especially, who have tumour with mutated kinases . NonetheEndothelial cells are known to play pivotal role in tumour neovascularization. The role of TKIs in endothelial cells has been identified either through direct action on endothelial cells or through mediating the communication between endothelial cells and tumour cells. Earlier studies observed the PKI 166, epidermal growth factor receptor (EGFR) inhibitor attenuated EGFR activation in tumour associated endothelial cells and caused cell apoptosis. The action is deemed to be EGFR-specific as it was not observed on EGFR-negative mice . SubsequGiven that several target receptors act as endothelial cell regulators, multi-targeted tyrosine kinase inhibitors are also being evaluated for better therapeutic outcome. The dual tyrosine kinase inhibitor AEE788 is utilized to inhibit EGFR and VEGFR binding on endothelial cells and resulted in apoptosis in both tumour and endothelial cells . The intCancer associated stromal cell, comprised of approximately 40% of total tumour volume , plays aFibroblast/stromal cells highly expressed PDGF receptors; production of PDGF ligands by cancerous cells triggered the up-regulation of fibroblast growth factors (FGF) by fibroblast which favours of tumour angiogenesis and proliferation. Notably, bone marrow stromal cells highly express PDGFR\u03b2, while minimally detected in cancer cells. Therefore, there are emerging strategies targeting PDGFR or FGF on fibroblast in regressing tumour cell growth. For instances, inhibition of PDGFR by imatinib declined the secretion of FGF-2 and FGF-7 by cancer associated fibroblast resulted in reduced tumour progression ; combinaThe acquired resistance of tumour cells towards TKI has been frequently reported , 54. TheApart from endothelial cells and fibroblast, mesenchymal stem cells are also able to secrete EGF and express EGF receptor. Suppressing EGF receptor using AG1478 therefore suppressed mesenchymal stem cells mediated mammosphere formation . YoshidaEarly findings postulated that the osteoblast, bone marrow precursor cells in bone marrow microenvironment tend to produce substances for instance HGF which further promotes cancer cell proliferation and migratory activities. Intervention of NK4, HGF inhibitor or imatinib mesylate declined the cancer cells functions in the presence of osteoblast , 73. As The immunosuppressive environment, which primarily composed of myeloid-derived suppressor cells (MDSCs), regulatory T lymphocytes (Treg) and tumour associated macrophages, promoted escape of tumour cells from immune surveillance . AccumulMyeloid-derived suppressor cells MDSCs, the bone marrow derived heterogenous suppressor cells, has been shown to positively correlate to cancer progression. In advanced stage of cancer patients, tumour may induce expansion of MDSCs and in turn resulted in suppressive action of innate and adaptive immune response by high populations of MDSCs in tumour microenvironment . SunitinIn addition to VEGFR/c-KIT as therapeutic target of MDSCs, the use of AZD4547, the FGFR inhibitor has also been proposed as a target of MDSCs action. AZD4547 reduced breast cancer proliferation and migration through declining the MDSCs population while enhancing T populations . ConsistAccumulating studies have related the cross-talk between MDSCs and regulatory T subset, generally, MDSCs recruited and supported the activation of T regulatory populations . Thus, iDasatinib, a multikinase inhibitor, reduced T cellular proliferation, its associated cytokine production and cellular response , 103. ThOn the other hand, many small molecules inhibitors may acquire resistance upon disease progression whereby single treatment may not sufficient in altering the immunosuppressive tumour microenvironment. The VEGFR inhibitor, axitinib has been shown to increase CD4 (+) and CD8 (+) T population, while progressive patients showed increase regulatory T subset and PD-1 expression following axinitib treatment . LikewisMuch of the past and current efforts in eliminating the tumour associated macrophages (TAMs) have focussed on blocking TAMs survival or recruitment, inhibiting TAMs function and re-polarizing the TAMs phenotype that favour tumour regression. Typically, the c-fms kinase, or known as CSF1 receptor is a ligand-activated kinase that modulate monocytes and macrophage survival and proliferation . The potTherefore, apart from macrophage depletion, therapeutic strategies in re-programming TAMs immunosuppressive phenotype towards anti-tumour profile by TKIs intervention have also emerged as potent TAMs-targeted cancer therapy. For instances, sorafenib treatment stimulated IL12, IL18 and IL6 production in TAMs after LPS priming, which further supported natural killer cells function . Tie2 reAccumulating studies postulate the BTK was activated/phosphorylated upon Toll like receptors (TLR) stimulation , and actRecruitment of mast cells to tumour microenvironment has been shown to promote pancreatic cancer cell survival and inhibition of mast cell degranulation led to cancer cell death. Intervention of PCI-32765, the BTK inhibitor, declined mast cells degranulation and cancer cell growth . The samExtracellular matrix ECM components including fibronectin, laminin and collagen have been shown to determine the fate of cancer cells whether to remain dormant or proliferative . It was It has been proposed in various types of human cancers that immunotherapeutic regimen could offer favourable outcome, though large-scale randomized, placebo-controlled trials shall be carried out prior to its application. Given the accumulating reports on acquired resistance of TKIs, the use of TKIs alone as first-line treatment seems challenging in spite of its better prognosis. TKIs treatment often gain rapid but not durable tumour response, which result in early improvement of survival curve of cancer patients without clear beneficial effect on the overall survival. The effect of TKIs could be strategically complemented by immunotherapy, which induces a low percentage but highly durable tumour response . This noFurthermore, safety of the combination use is still contradicting and unclear. Some studies have reported the increased risk of adverse reaction after combination therapy, including higher incidence of grade 3/4 liver enzyme elevation (40\u201370%) and high incidence of interstitial lung disease (38%) . A lot oThe development of acquired resistance remain as the major clinical challenge to TKIs treatment, despite TKIs are still the first line therapeutic regimen for many malignancies. For instances, non-small cell lung cancer patients who initially well responded to EGFR inhibitors, erlotinib or gefitinib had host adaptive response and tumor growth within 6\u201312\u00a0months , 157. MaAlso, it is believed that cancer cells develop an immunosuppressive microenvironment for evasion from immune surveillance upon TKIs intervention. Although the detailed mechanisms of acquired immune evasion is not yet understood, previous studies suggested that the inducible expression of immune checkpoints PD-1/PD-L1 may be involved. Notably, the elevated expression of PD-L1 was observed in EGFR-resistant tumor biopsy compared to pre-treated tumor samples. This suggests the activation of immune checkpoint may hinder the treatment efficacy of TKIs to cancer patients . FurtherWith recognition of the actions of TKIs on TME, our previous studies have also suggested the beneficial role of complementing TKIs with immune-modulatory therapy. Complementary treatment using PHY906, a composite herbal formula that had potential to increase the therapeutic index of cancer treatments in multiple clinical trials, was recently identified to modulate TME in sorafenib-treated hepatocellular carcinoma (HCC). This immune-modulatory effect of PHY906 improved the anti-tumour TME signature and thereby enhanced the efficacy of sorafenib . An actiIn past decade, tyrosine kinase inhibitors targeting at tumour cells represent a promising therapeutic agent for cancer patients; yet, the use of TKIs in modulating tumour microenvironment is still in its infancy. The recent advances we summarized here emphasize the potential use of TKIs for re-educating or normalizing the dysregulated tumour microenvironment for cancer treatment. An understanding of the modulatory effect of TKIs on tumour microenvironment could expedite the maximal use of TKIs on cancer therapy as well as re-positions the existing TKIs as combination cancer treatment. Furthermore, phosphorylated status of target protein could also be determined by protein phosphatase, which belongs to another group of protein involved in microenvironment status of tumour cells, is worthy for further exploration. Much more efforts, either pre-clinically or clinically, is therefore anticipated in order to maximize the efficacy and safety for patients."}
+{"text": "Macropinocytosis has long been known as a primary method for cellular intake of fluid-phase and membrane-bound bulk cargo. This review seeks to re-examine the latest studies to emphasize how cancers exploit macropinocytosis to further their tumorigenesis, including details in how macropinocytosis can be adapted to serve diverse functions. Furthermore, this review will also cover the latest endeavors in targeting macropinocytosis as an avenue for novel therapeutics. Macropinocytosis is an endocytic pathway that leads to internalization of large patches of plasma membrane along with extracellular fluid through irregularly formed vesicles called macropinosomes. When compared to endosomes originating from coated vesicles, macropinosomes are significantly larger by a factor of up to a thousand-fold  and pancreatic cancer cells. When macropinocytosis is upregulated in GBM cells by a quinine-derivative chemical, Vacquinol-1, massive membrane ruffling and macropinocytosis lead to cell death through excessive vacuolization and deformations in the plasma membrane  family receptors, where exosomes shed by cancer cells can internalize into distant cancer cells in a paracrine fashion through binding with RTKs  via macropinocytosis in an H-Ras dependent manner to evade TNF-related apoptosis-inducing ligands (TRAILs) and subsequent apoptosis  of one particular PIP5K, I\u03b3i2, leads to decreased oncogenic growth of breast cancer cells (Thapa et al., Another therapeutic venture includes disrupting cancer cell metabolic activity through inhibition of macropinocytosis (Zeitouni et al., Lastly, other therapeutic ventures have shown that hyper-stimulating macropinocytosis in cancer cells can lead to non-apoptotic cell death known as methuosis (Li et al., As cancer cells frequently employ macropinocytosis to aid in receptor regulation and internalize essential metabolites, extensive efforts have been underway in utilizing macropinocytosis to deliver cytotoxic therapeutics specifically into cancer cells. Some anti-cancer agents innately undergo macropinocytosis, such as AS1411, which internalizes into various cancer cells through cell-surface nucleolin-dependent mechanisms that activate macropinocytosis only in malignant cells (Reyes-Reyes et al., Potent cancer therapeutics that exhibit excessive, systemic toxicities or unstable pharmacokinetics from hydrophobic profiles are excellent candidates for conjugation to yield chemical conjugates or nanoparticles. The resultant conjugates or nanoparticles can be engineered to yield greater specificity and enhanced pharmacokinetics. In many other examples, synthetic conjugates comprising any combination of small chemicals, lipids, proteins, genetic components, and chemical scaffolds can be developed to form nanoparticles that can then be internalized into target cells via macropinocytosis. Nanoparticles, which vary widely in composition, size, chemical charge, and shape, all contribute to distinct, cellular specificities and in endocytic mechanisms (Kettler et al., Another intriguing therapeutic front includes conjugating cytotoxic payloads onto albumin primarily for enhancing drug pharmacokinetics and because albumin has long been observed to accumulate within solid tumors through macropinocytosis Kratz, . An examAnother component commonly used for conjugation is the poly-arginine peptide. As poly-arginine peptides induce macropinocytosis and cancer cells generally have increased macropinocytosis, efforts have been underway in conjugating poly-arginine peptides with cytotoxic compounds. These conjugates can be employed to deliver a variety of materials into cells, including cytotoxic reagents against cancer cells (Biswas et al., in vitro, with therapeutic proteins either electroporated into exosomes or intracellularly incorporated through targeted overexpression of genes in the cell cultures (Munson and Shukla, As cancers routinely internalize exosomes, a logical maneuver includes formulating therapeutics that mimic exosomes. Exosomes can be derived from same-host cells to avoid inducing immune responses (Hall et al., Mycobacterium smegmatis (Baltierra-Uribe et al., Salmonella (Francis et al., Plasmodium sporozoites, or malaria, also infiltrate into host hepatocytes by inducing macropinocytosis through the EphA2 receptor (Kaushansky et al., If cancers commonly exploit macropinocytosis for efficient endocytosis of scarce nutrients and proteins, it is not surprising that various pathogens also infiltrate into host cells through this pathway. Pathogens such as viruses and bacteria commonly enter human cells by activating macropinocytosis through receptor-dependent means. Several examples include human cytolomegavirus (Hetzenecker et al., Macropinocytosis appears to play vital roles across a variety of neurodegenerative diseases as well, and this has been comprehensively reviewed (Zeineddine and Yerbury, Cancer cells, in addition to pathogens and neurodegenerative diseases, all exploit macropinocytosis for its efficiency in endocytosis. In particular, cancer cells seem to possess increased macropinocytic activity to fulfill diverse functions that include metastasis, metabolism, and signal transduction Figure . For thiKH wrote the manuscript, SB edited the manuscript, BL selected the review topic and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Eurosurveillance invites authors to submit papers in the categories, Research articles, Surveillance and Outbreak reports, Reviews and Perspectives for a special issue on advanced diagnostics to inform public health policy.Recent advances in laboratory technology, including the application of qualitative and quantitative molecular diagnostics, proteomics (e.g. MALDI-TOF MS) and genomics, particularly whole genome microbial sequencing (WGS) and metagenomics are transforming the field of clinical and public health microbiology. The use of advanced methods enables unprecedented capability and capacity for rapid and comprehensive pathogen detection, quantitation and characterisation, when applied to clinical and environmental samples. Advanced diagnostics may therefore impact public health policy during specific incidents or on a wider scale.Topics of interest may include, but are not limited to:\u2022 Focused reviews portraying pathogen- or disease-specific use of advanced diagnostics in public health microbiology or practical aspects of integrating new diagnostics in public health;\u2022 Advanced laboratory tools for generating data that inform risk assessment and risk management;\u2022 Possible role of rapid diagnostic testing in public health and cross-border health security;\u2022 Moving to culture-independent public health microbiology;\u2022 Policy and Regulatory aspects of harnessing new technologies for public health.eurosurveillance@ecdc.europa.eu.The submission deadline is 15 April 2018. If you would like to submit a paper or ask for more information, please see our instructions for authors regarding article formats or contact the editorial team at"}
+{"text": "Cerebrovascular disease (CVD) is often present in old age and may be associatedwith microstructural pathology of white matter (WM) and cognitive dysfunction.The current review investigated the relationship between CVD, cognitive statusand WM integrity as assessed by diffusion tensor imaging (DTI).DTI studies were searched on ISI and Pubmed databases from 2002 to 2012.Studies evidenced DTI changes in WM as associated with vascular disease andprovide increasing support for DTI as a valuable method for early detectionof CVD.DTI parameters can serve as important biomarkers in monitoring vasculardisease progression and treatment response and may represent a surrogatemarker of WM tract integrity. Depending on thesite, intensity, and severity, CVD may either cause or contribute to furthercognitive decline.2 Earlier reportsdescribe CVD pathology as a consequence of blood perfusion deficits generated byhypoxia, hypoperfusion and hemorrhage which in turn result in neuronal injury,necrosis, apoptosis and ischaemic penumbra.2 The presence and severity of CVD hinge on non-modifiablerisk factors such as ageing, gender and genetics but also on several other variablessuch as smoking, systemic arterial hypertension, diet and metabolic diseases.Structural studies have identified subcortical hyperintensities as macroscopic whitematter (WM) changes which have been cited by several reports as associated with CVD,mood disorders, executive dysfunction and higher conversion to dementia. Morerecently, the underlying pathology associated with normal-appearing WM as well asits clinical significance has become the main focus of investigation.3Cerebrovascular disease (CVD) occurs in one third of the populationin vivo.6 One of themost useful of these techniques is diffusion tensor imaging (DTI), which issensitized to the motion of water molecules as they interact within tissues, thusreflecting characteristics of their immediate structural surroundings.8 Earlier DTI studies used a region-of-interest (ROI) analysisapproach, with brain areas being delineated manually or with semi-automatedmethods.11 However the ROI approach has a number ofdrawbacks, such as difficulty precisely replicating and delineating anatomicalregions as well as the use of pre-selected brain areas rather than consideringdiffusion changes in the whole brain.12 To improve the objectivity and interpretability of DTI studies,Tract-Based Spatial Statistics (TBSS) was developed to enable DTI scans to becompared across subjects more robustly.13 TBSS is based on voxel-wise analysis, which approaches thewhole brain without any a priori selection of regions. Anotheradvantage of TBSS is that it minimizes the problem of misalignment.14 To date, the vast majority ofstudies have concentrated on the role of FA in cognitive disorders.17 However, a rangeof factors influence FA decreases, including myelination, axon density, axondiameter and intra-voxel coherence of fiber orientation.19Therefore, there is an increasing awareness of the limitations of single FAmeasurements, and of the need to investigate how other DTI indices  change over the course of bothvascular and neurodegenerative diseases.15In recent years, novel methods of neuroimaging have enabled WM microstructureintegrity to be investigated 2 the influence ofmilder vascular risk factors such as controlled hypertension, or high normal bloodpressure is largely unknown.2Another promising topic of DTI investigation is the common pathological routesbetween CVD and Alzheimer's Dementia (AD), especially the landscape involvingneurodegenerative and vascular changes. Cerebral atherosclerosis is associated witha higher risk of AD while cardiovascular risk factors are associated withclinically-diagnosed AD and vascular dementia (VaD).20 Thesimilarities in association between cardiovascular risk factors and dementiadiagnosed as AD or VaD underline the relevance of CVD for aging-related cognitivedecline in general and the flaws in simplistic diagnostic categories.20 Although vascular and degenerationprocesses often overlap, relatively few studies have focused on the interactionbetween these two pathologies. Conversely, no serum or plasma biomarker has beenestablished as a reliable biomarker of CVD compared to other types of dementia andnon-demented individuals.20There is an open field of investigation on DTI and CVD. To date, the majority ofstudies conducted have investigated only WM abnormalities in relation toneurodegeneration predominantly among AD patients but the pathological processes ofWM associated with vascular disease are not yet fully understood. In contrast to thedamaging effects of CVD and untreated hypertension on diffusion-based parameters ofWM,This review investigated the main results of DTI studies in patients with CVD. Weaimed to discuss these results and the integration of diffusion findings withstructural data and WM microscopic pathology and progression of cognitive impairmentin relation to vascular disease.A systematic review of DTI studies on CVD was performed by searching data from ISIand Pubmed web databases from the first DTI studies in 2002 (January) to 2012 (May).The search strategy included key words aimed at investigating a broader spectrum ofprimary vascular disorders affecting subcortical areas, particularly white-matterlesions: DTI, vascular dementia, subcortical disease, white-matter, neuroimaging,dementia, MCI, blood vessels.All abstracts were independently read by six authors and those studies which complied with the inclusion criteria were selected forfurther reading. A manual search was also performed to retrieve articles related tothis subject found among the references of the selected studies. The articles whichsatisfied all the following criteria were included for further reading and analysis.For inclusion, articles had to:[1] have at least one DTI parameter, such as FA;21[2] be cohort, cross-sectional, or case-control studies with at least onecriterion for vascular dementia  and mild cognitive impairment, vascular type as developed by theNINDS research group;4 and[3] provide data on cognitively impaired patients \u226560 years ofage, with or without clinical diagnosis of dementia;[4] include a comprehensive neuropsychological assessment.The Pubmed electronic search retrieved 156 articles. Only 12 remained eligible forfurther analysis. 22 The classical viewin which vascular disease was related to WM hyperintensity (WMH) burden has beenprogressively substituted by new insights on the pathological development of brainvascular disease and its dynamic interaction with neurodegeneration. DTI paperssupport previous evidence from genetics and biomarkers25 showingthat vascular disease plays an important role in the development and clinical courseof AD.26 The ensuing topics coveraspects of the pathology and clinical features of the studies.The majority of studies evidenced diffusion changes in WM as associated with vasculardisease and supported DTI as a valuable method for the early diagnosis ofCVD.The pathological basis of vascular changes. There is growing evidencefrom DTI studies demonstrating that macroscopic and microscopic changes in WM resultfrom distinct pathological processes which have been described by some authors as WMlesion formation and WM atrophy.27Both processes result from a complex combination of independent factors such as age,hypertension, metabolic and degeneration, but there is no established modelexplaining these underlying changes.2826 whereas temporal and occipital lobes weredescribed by another study.29 In athird study, periventricular areas were described as more susceptible to ischemicinjury.30The territorial pattern of progression of WM changes has been discussed in somepapers with equivocal findings. Parietal WM and the centrum semiovale were reportedas the regions most associated with the vascular pathology27 Additionally,one study showed that atrophy of the corpus callosum was significantly associatedwith changes in diffusion in deep WM hyperintensities. According to Schimidt etal.,31 such findings canfurther etiologic understanding of age-related WM damage because they argue againsta diffuse pathological process as the origin of WMH.Among the WM tracts most susceptible to damage due to atrophy of WM were thosecomponents of the limbic system (which comprise the anatomic substrate ofAlzheimer's disease) such as the fornix, the cingulum tracts and in the region ofthe hippocampus.Correlation of WM changes with clinical variables. Diabetes andhypertension32 have beencited as the most important clinical variables associated with CVD. Hypertension hasbeen associated with reduction in WM volume35 and increase in WMH burden.38 In a recentinvestigation,39 theeffects of Mean Blood Pressure were present both in subjects with mildcardiovascular risk and those with established hypertension. Hence, significanteffects of cognitive decline were present even in individuals outside thehypertensive range.39 Takentogether, these findings support that systemic vascular function is an importantvariable to be considered in the investigation of cognitive changes also in thecontext of patients without known vascular disease or overt brain vascularchanges.Use of overlapping DTI indices in the differential diagnosis between vasculardisease and neurodegeneration. Contrasting with earlier reports, recentevidence in vascular disease has attempted to investigate WM pathology through thecombination of FA and non FA indices15 thus following a general tendency seen in otherstudies, e.g. those with Alzheimer individuals.40 The overlap between axial and radial diffusionincreases was associated with atrophy of WM in different regions , while acuteaxonal injury results in a decrease in diffusion parallel to the fibers .27 Theseincreases suggest decreased packing within a voxel.43 An alternative explanation is that apparentincreases in axial diffusion may stem from a loss in fiber coherence among regionswith fiber crossing.44 Early reports characterize thevascular pathology of subcortical areas by extensive occlusion of arterioles andmicro-atherosclerosis. One study28showed statistically significant FA and MD differences in areas of WMH burden andthose with apparent normal WM. FA-MD and MD-DR overlaps may thus reflectdemyelination and axonal loss within the fibers and early vascular disease. However,as the interpretation of multiple indices is not clearly established, furtherstudies should comprehensively analyze the application of DTI indices to theunderstanding of complex interactions between vascular disease and degeneration. regions  and coulCorrelation between DTI and neuropsychological testing. One outpatientstudy20 analyzed theassociation of brain structural parameters and cognitive tasks and found a greatercoefficient of correlation with diffusion indices than with WM volume or WM burdenrated by the Fazekas scale.20 In alarge multicenter study conducted by the LADIS multicenter group,31 which included 340 patients withvarying degree of macroscopic WMH (leukoaraiosis), the correlation of microscopicchanges in normal-appearing brain tissue was more strongly related to executive andmemory impairment than WM volume and WMH burden. A similar conclusion was found bythe Rotterdam study (28 Findings from these three studies31 evidence agreater variability of WM microscopic pathology and support non-FA indices assensitive biomarkers for assessing the integrity of WM independently of otherstructural measurements such as atrophy of white and gray matter or WM burden.Future studies should evaluate the usefulness of multiple diffusion parameters asbiomarkers of cognitive decline in research and their applicability in monitoringresponses to therapeutic interventions and treatment success.am study  in whicham study .28 Findi39 DTI parameterscan serve as important biomarkers in monitoring vascular disease progression andtreatment response and may represent a surrogate marker of WM tract integrity.Therefore, the studies discussed in the current review encourage the use of multiplediffusion indices as important tools for the diagnosis of microscopic changes in WMassociated with early-onset vascular disease.This summary of findings demonstrates that loss of integrity in normal-appearing WMpoints to an independent process of WMH burden and may reflect a constellation ofpathophysiological interactions, including ageing, neurodegenerative mechanisms andalso vascular disease. Current evidence highlights the increasing importance ofvascular health as a major component of general neural aging as demonstrated byprevious studies."}
+{"text": "Inspired by natural photonic structures , researchers have demonstrated varying artificial color display devices using different designs. Photonic-crystal/plasmonic color filters have drawn increasing attention most recently. In this review article, we show the developing trend of artificial structural color pixels from photonic crystals to plasmonic nanostructures. Such devices normally utilize the distinctive optical features of photonic/plasmon resonance, resulting in high compatibility with current display and imaging technologies. Moreover, dynamical color filtering devices are highly desirable because tunable optical components are critical for developing new optical platforms which can be integrated or combined with other existing imaging and display techniques. Thus, extensive promising potential applications have been triggered and enabled including more abundant functionalities in integrated optics and nanophotonics. Rather than using colorant-based pigmentation, structural color filtering devices ,5,6,7,8 Furthermore, investigations on magnetophotonic composites and relevant devices ,71,72,73In general, the working principle of dyes or pigments is based on light-matter interaction which in fact is that they can absorb light of only certain wavelengths and reflect the remaining frequency bands of the spectrum, leading to resonance peaks in either transmission or reflection. People have long benefited from nature\u2019s capability of creating coloration. The famous Morpho butterfly wings  were onepn) on top of a glass substrate (refractive index = sn), which can function as a planar waveguide. Periodicity, width, and height are labeled as L, d and h, respectively. Generally speaking, these 2D nanogratings can work as filters under phase-matching conditions. Diffracted waves can be generated and the reflected energy can be dramatically strengthened within certain frequency ranges. These 2D color filters exhibit unique optical properties compared with 1D nanogratings which have strong angle dependency on incident light. Theoretically, one can avoid relying on grating coupling for resonance mode excitation to minimize angle sensitivity. Different from grating coupling, plasmon-assisted resonators and nano-antennae normally need a large density for effectively scattering light to either viewers\u2019 eyes or photodetectors in the visible range. The angle dependence for plasmonic crystals is directly related to the surface plasmon polariton excitation via grating coupling which limits the practical applications due to relatively low coupling efficiencies since it is inherently angle-dependent because of momentum matching conditions. Overcoming this angle-dependent spectrum response will allow these structural filters to be integrated into practical applications such as high resolution visual displays, miniature hyperspectral imaging, and high sensitivity sensing devices.Inspired by distinctive Morpho butterfly wings, reflective photonic crystal color filters consisting of nanogratings were proposed and experimentally fabricated . As showNote that these 2D photonic crystal filters utilized the coupling between the incident light and the resonant modes (guided-mode resonance) to generate individual colors. Such filters show high reflectance (>70%) and angular tolerance and they can suppress the incident-angle dependency and enhance the chromatic properties  compared with traditional 1D color filters, leading to useful applications for display techniques. The geometry can also be further optimized to make the optical effect close to being independent of the tilt angle and therefore enable wide use in ambient light conditions, paving the way to more practical applications in displays. The pioneering experiments on angle robust optical devices were performed by Wu and coworkers  who utilFurthermore, the reflectivity for s- and p-polarization is different. For s-polarization, it does not change greatly in the Brillouin zone, while for p-polarization it lessens through the range. Thanks to the fast development of nanotechnology, color filters can be fabricated by using electron-beam lithography (EBL) and nanoimprint lithography (NIL) followed by inductively coupled plasma reactive ion etching (ICP-RIE) to transfer patterns from resists to silicon substrates. However, one should note that the crystallinity of the fabricated silicon color filters may affect the device performance significantly. For instance, the maximum reflectance is reduced tremendously for amorphous silicon due to large internal absorption. Therefore, the reflectance spectrum may vary due to different silicon crystallinity properties and various refractive indices. Using NIL and multi-scan excimer laser annealing, 2D photonic crystal color filters were experimentally demonstrated by Cho and coworkers . This coPlasmon-assisted nanophotonic devices have drawn particular attention in recent years because of their tremendous latent capacity for new imaging and display technologies ,87,88 siUsing simple nanostructures, various color filters have been demonstrated, including nanoslit antennae , ultrathAs shown in The development of plasmon related/enhanced reflective filtering devices is mainly limited by efficiency since metals have significant absorption at visible frequencies. To receive acceptable reflected energy, normally, high aspect ratio structures  are needed, resulting in challenging fabrication processes. Normal lift-off processes are only effective for thin devices because resists can be hardly removed if they are covered by thick metal films. One feasible solution to overcome the difficulties mentioned above is to use a dry etching method to transfer patterns (top-down fabrication process). By using argon ion milling, large aspect ratio silver nanorods were fabricated  and reflTo experimentally demonstrate the reflection-mode color filtering devices, high aspect ratio nanorod arrays were fabricated in silver films by using EBL followed by argon ion milling. Inter-rod spacing of 20 nm smallest was achieved to reveal blue color as shown in Structural color pixels can outperform their chemical counterparts since they can bear long-time constant illumination with stronger light intensities. In addition, they can achieve high compactness and resolution beyond the diffraction limit with wide tunability and highly stable device performance. Moreover, structure color filtering devices can enable high efficiency and low power consumption with dramatically slimmed dimensions and enhanced resolution. However, the incident angle tolerance limits the practical applications of such optical components. To achieve more promising applications, thinner spectral response is desired for vivid colors with high angle tolerance. Researchers have made every effort to realize angle robust optical filters with narrow broad spectral response and high optical performance to yield a superior color contrast. To obtain angle-insensitivity, one has to avoid relying on grating coupling for plasmonic mode excitation. In contrast to grating coupling, plasmon assisted resonators and antennae have been experimentally demonstrated as candidates for structure colors which have advantageous features such as brilliancy and color vividness. Gratings in metal surfaces without involving diffraction effects can be used to control the light polarization so that it is possible to use an analyzing polarizer to manipulate the transmitted colors, which are largely independent of the angle of incidence. Significant work remains to develop a reflective display that can provide a bright and full-color image comparable to printed media with low power consumption as a new class of display element, which allows the full-color emission from a single pixel under a broad range of ambient lighting conditions. However, one can still obtain individual colors based on tuning the incident angle of white light illuminated onto nanostructures. Instead of adjusting geometry parameters, different color outputs can be achieved via incidence scanning with a fixed design. Using a single plasmonic chip, photon-plasmon coupling interactions can be triggered and further engineered to reach continuous color tuning effects across the whole visible range .2) can be realized by using interference lithography to define patterns and ion milling to transfer patterns. As demonstrated in A large functional area  devices are enabled which may pave the way for next generation display productions. However, researchers still need to further improve the optical performance of color filtering devices for more practical applications. Filters with both high transmission intensity and narrow passing band are critical to produce high throughput and low-cost optical components for new optical devices. Additionally, high speed actively tunable devices are extremely important for future development of multiple-functional assemblies. In practice, low-cost and high-throughput approaches are desired because they are more suitable for industrial applications."}
+{"text": "Since the seminal finding almost 50\u00a0years ago that exercise training increases mitochondrial content in skeletal muscle, a considerable amount of research has been dedicated to elucidate the mechanisms inducing mitochondrial biogenesis. The discovery of peroxisome proliferator-activated receptor \u03b3 co-activator 1\u03b1 as a major regulator of exercise-induced gene transcription was instrumental in beginning to understand the signals regulating this process. However, almost two decades after its discovery, our understanding of the signals inducing mitochondrial biogenesis remain poorly defined, limiting our insights into possible novel training modalities in elite athletes that can increase the oxidative potential of muscle. In particular, the role of mitochondrial reactive oxygen species has received very little attention; however, several lifestyle interventions associated with an increase in mitochondrial reactive oxygen species coincide with the induction of mitochondrial biogenesis. Furthermore, the diminishing returns of exercise training are associated with reductions in exercise-induced, mitochondrial-derived reactive oxygen species. Therefore, research focused on altering redox signaling in elite athletes may prove to be effective at inducing mitochondrial biogenesis and augmenting training regimes. In the context of exercise performance, the biological effect of increasing mitochondrial content is an attenuated rise in free cytosolic adenosine diphosphate (ADP), and subsequently decreased carbohydrate flux at a given power output. Recent evidence has shown that mitochondrial ADP sensitivity is a regulated process influenced by nutritional interventions, acute exercise, and exercise training. This knowledge raises the potential to improve mitochondrial bioenergetics in the absence of changes in mitochondrial content. Elucidating the mechanisms influencing the acute regulation of mitochondrial ADP sensitivity could have performance benefits in athletes, especially as these individuals display high levels of mitochondria, and therefore are subjects in whom it is notoriously difficult to further induce mitochondrial adaptations. In addition to changes in ADP sensitivity, an increase in mitochondrial coupling would have a similar bioenergetic response, namely a reduction in free cytosolic ADP. While classically the stoichiometry of the electron transport chain has been considered rigid, recent evidence suggests that sodium nitrate can improve the efficiency of this process, creating the potential for dietary sources of nitrate  to display similar improvements in exercise performance. The current review focuses on these processes, while also discussing the biological relevance in the context of exercise performance. Strenuous exercise can increase the energetic demands of skeletal muscle by 100-fold over resting requirements, placing an enormous challenge on bioenergetic pathways to maintain concentrations of adenosine triphosphate (ATP), the basic unit of energy within muscle. Skeletal muscle is equipped with an intricate series of enzymatic reactions that resynthesize ATP to ensure cellular survival during these conditions. The diverse reactions buffering ATP fluctuations within muscle display a continuum of speed  relative to the capacity for ATP production. For instance, the breakdown of phosphocreatine (PCr) can produce ATP extremely rapidly for a relatively short period of time, while in contrast, aerobic metabolism within mitochondria produces ATP at a lower maximal rate, but essentially has a limitless capacity. As a result, aerobic metabolism dominates ATP production during most continuous exercise situations, highlighting the importance of mitochondria to overall metabolic homeostasis. This simplistic view of metabolism is efficient for teaching purposes as it enables \u2018compartmentalization\u2019 of each system; however, in reality, there is considerable integration between each bioenergetic process. Historically, an increase in mitochondrial content represents a fundamental exercise training response , contribIt has been known for almost a century that elite athletes have a higher maximal rate of oxygen consumption, higher maximal mitochondrial enzymatic activities, and ultimately improved performance. While originally attributed to genetics, Holloszy\u2019s landmark research in 1967 demonstrated the remarkable plasticity of skeletal muscle to increase mitochondrial content and improve exercise capacity . This seIn 1984, Holloszy postulated that an increase in mitochondrial content would alter the sensitivity of oxidative metabolism to ADP , and, inSpecifically, ADP activates glycogen phosphorylase kinase to covalently modify phosphorylase, while AMP allosterically regulates phosphorylase by increasing the sensitivity of the enzyme to glycogen, promoting glycogen breakdown. In the context of phosphofructokinase, ADP and AMP decrease the sensitivity of the allosteric inhibitory binding site for ATP, essentially removing an inhibitor for enzymatic flux, while ADP also inhibits PDH kinase activity, maintaining PDH in an active state and promoting pyruvate flux towards aerobic respiration. As a result, a reduction in cytosolic ADP levels, and the subsequent production of AMP, as occurs following training , provideGiven that increasing mitochondrial content represents a key mechanism for the improvement in exercise performance following training, it is understandable that research has focused on elucidating the molecular events responsible for the initiation of mitochondrial biogenesis. The induction of mitochondrial biogenesis requires the transcription of proteins contained within both the nuclear and the mitochondrial DNA genomes. The mitochondrial proteome consists of ~1600 proteins, the vast majority of which are encoded within the nucleus, as the mitochondrial DNA only encodes for 13 subunits of the electron transport chain and proteins required for messenger RNA translation within this organelle . The inA large body of literature has been devoted to studying the role of energy turnover and activation of AMP activated protein kinase (AMPK) as a key signal to induce mitochondrial biogenesis. However, high-intensity interval training and \u2018classical\u2019 endurance training result in similar accumulations of mitochondrial proteins, suggesting this process is not directly influenced by the rate of ATP hydrolysis . In addi2+/calmodulin-dependent protein kinase (CaMKII)] and reactive oxygen species (ROS)-mediated processes. Activation of CaMKII has been shown to induce the nuclear translocation of PGC-1\u03b1 and the expression of mitochondrial genes [The other \u2018signals\u2019 implicated in the regulation of mitochondrial content include calcium [specifically Caal genes , while pal genes . While Ral genes . Howeveral genes , 25, a ral genes . Moreoveal genes . These dal genes  reportedal genes , potentiThe notion that mitochondrial ROS contributes to exercise-induced mitochondrial biogenesis may help explain the lack of mitochondrial biogenesis observed in humans consuming antioxidants while exercise training . In thisThe induction of mitochondrial biogenesis, and the subsequent improvement in mitochondrial ADP sensitivity, has become synonymous with exercise training adaptations. This classical working model is premised on the belief that mitochondrial \u2018function\u2019 remains unaltered following a chronic training intervention. However, evidence is starting to accumulate to suggest that mitochondrial ADP transport is a regulated process, raising the possibility that lifestyle interventions can influence mitochondrial ADP sensitivity in the absence of the induction in mitochondrial biogenesis.The phosphate shuttling mechanism for energy transfer between matrix and cytosolic compartments includes three major protein complexes see Fig.\u00a0: voltageTraditional dogma stipulates that mitochondrial function is not externally regulated beyond the provision of substrates required for oxidative phosphorylation. This belief extends from Holloszy\u2019s original observation that in vitro assessments of mitochondrial stoichiometry (P/O ratios: ADP consumed per oxygen atom) remain constant following chronic training . HoweverGiven the relative novelty of identifying mitochondrial ADP transport as a regulated process, very little evidence has been generated with respect to nutritional approaches to augment this process. However, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation has been shown to alter the lipid composition of mitochondrial membranes in association with an increase in mitochondrial ADP sensitivity . IntriguOne of the most characterized responses to exercise training is an improvement in ADP sensitivity, sparing muscle glycogen and improving exercise capacity. Historically, these responses were exclusively attributed to an increase in mitochondrial content. However, recent evidence has accumulated to show that mitochondrial ADP transport is a highly regulated process. A better understanding of the molecular signals influencing the proteins directly controlling mitochondrial ADP transport, namely miCK and ANT, is required, as this knowledge could result in novel training programs aimed at optimizing muscle performance. While beetroot juice appears to influence excitation\u2013contraction coupling, as opposed to mitochondrial bioenergetics, a key event in the observed improvement in exercise capacity may involve the increase in mitochondrial ROS. In addition, given the link between mitochondrial ROS and mitochondrial biogenesis, consumption of beetroot juice while training may induce mitochondrial biogenesis and indirectly improve ADP sensitivity. EPA/DHA supplementation similarly increases mitochondrial ROS emission rates, and because PUFAs are potent ligand activators of PPARs, incorporating PUFAs into a training program may augment chronic adaptations. This is particularly interesting, as EPA/DHA supplementation directly improves mitochondrial ADP sensitivity. Clearly, compelling evidence for a nutritional intervention that improves mitochondrial bioenergetics beyond the typical exercise-mediated responses does not exist. The recent advancement in our understanding of the regulation of mitochondrial ADP transport has elucidated gaps in our working models that need to be addressed. However, the awareness of these knowledge gaps creates the possibility for unique experimental approaches to be designed with the aim to improve exercise performance in the future."}
+{"text": "Prominent etiological conceptions of psychosis implicate abnormal cortico-striatal circuits. Dysfunction in these critical systems, responsible for filtering information and modulating higher-order function, may account for heterogeneous presentations of symptoms and characteristics of psychosis. Collectively, a body of work from our group and from other teams indicates that evaluating select motor behaviors and abnormalities, which directly reflect function of these circuits, may be a useful method for understanding and predicting the neural underpinnings of psychosis. In the context of the psychosis risk period, partitioning clinical high-risk (CHR) youth based on objective behavior may help guide early detection and intervention efforts, and provide a novel perspective on different etiological pathways or patient subtypes.Using an unsupervised machine learning approach, 69 CHR young adults were included in a K-means cluster analysis based on their performance on instrumental measures of psychomotor slowing, dyskinesia, and neurological soft signs (NSS)\u2014distinct motor domains affected across the psychosis spectrum. We also recruited a group of 70 matched healthy controls (HC) for comparison. All participants were also assessed with a resting-state functional connectivity analysis (rcfMRI). The resulting CHR group clusters and HCs were then compared on positive and negative symptoms, multiple cognitive domains, and cortical-striatal seed based resting state analysis.Results of a 3-cluster solution suggest that there are subtypes of CHR individuals who show psychomotor slowing, average motor performance, and impairment on measures of dyskinesia as well as NSS domains for motor coordination, sequencing and sensory integration. The cluster of individuals showing dyskinesia and abnormal NSS also have more severe negative symptoms and impairment on a number of cognitive domains. Furthermore, the clusters of CHR individuals who show psychomotor slowing and the cluster showing dyskinesia and abnormal NSS have different cortical-striatal connectivity compared to UHR who show average motor behavior and healthy controls.These results provide evidence for etiological theories highlighting altered cortico-striatal networks and the importance of examining motor behavior prior to the onset of psychosis. Taken together, this approach may reflect a novel strategy for promoting tailored risk assessment as well as future research developing individualized medicine."}
+{"text": "There are great concerns about the impacts of soil biodiversity loss on ecosystem functions and services such as nutrient cycling, food production, and carbon storage. A diverse community of soil organisms that together comprise a complex food web mediates such ecosystem functions and services. Recent advances have shed light on the key drivers of soil food web structure, but a conceptual integration is lacking. Here, we explore how human-induced changes in plant community composition influence soil food webs. We present a framework describing the mechanistic underpinnings of how shifts in plant litter and root traits and microclimatic variables impact on the diversity, structure, and function of the soil food web. We then illustrate our framework by discussing how shifts in plant communities resulting from land-use change, climatic change, and species invasions affect soil food web structure and functioning. We argue that unravelling the mechanistic links between plant community trait composition and soil food webs is essential to understanding the cascading effects of anthropogenic shifts in plant communities on ecosystem functions and services. As increasingly evidenced by empirical studies, soil food webs play a key role in the functioning of terrestrial ecosystems7. Soil food webs affect carbon (C) cycling (with consequences for C storage and hence mitigation of elevated atmospheric carbon dioxide concentrations) and nutrient cycling. On the one hand, soil food webs play an important role in controlling the supply of nitrogen (N) to plants by mineralizing organic N. However, N mineralized through the soil food web does not necessarily result in nutrients freely available for plants8. Soil food webs can promote retention of N in the soil system either directly through sequestration in their living or dead biomass or indirectly through changes to soil chemistry or structure, thereby preventing it from getting lost through leaching and denitrification. It has been shown how shifts in the composition, network structure, and connectivity of soil food webs can alter the rates of these important ecosystem processes10. The soil food web further plays an important role in disease suppression and plant protection against root pathogens12. Finally, the soil food web is critical to ecosystem resistance and resilience against environmental disturbances and climate change. For example, studies have shown that fungal-based soil food webs associated with extensively managed grasslands  were more resistant to experimental drought than bacterial-based food webs associated with intensively managed crop production13. Collectively, these recent advances indicate that changes in soil food web composition and connectivity have important consequences for ecosystem functioning14.The soil food web consists of a large diversity of organisms differing in size and function. This includes root-associated biota such as pathogens or mutualists, saprotrophs involved in breaking down dead organic matter, and a variety of invertebrate consumers and predators at higher trophic levels15, soil food webs are often simplistically described in terms of distinct trophic levels. Trophic levels are composed of organisms that occupy the same level in a food chain. In the soil food web, this would be primary consumers , secondary consumers , and higher-level consumers or predators  . These inputs form the basal resource pool for the soil food web18  . Each of web18 . Althoug24. This implies that anthropogenic shifts in plant community composition could have major impacts on soil web structure, as has been shown for urban green spaces, for example25. Here, we follow a simple framework describing three mechanistic pathways of how shifts in plant community composition drive soil food webs , and bacteria are more specialized to break down simple, labile organic compounds 33. However, this traditional view has recently been challenged, and evidence has emerged that fungi may use organic compounds that are more labile than previously expected34. Second, there has been increasing interest in exploring how live plant roots affect soil food webs 42. Although each of these three pathways has been studied for individual plant species, these plant-mediated mechanisms are less well understood for plant communities44. We argue that together these three pathways largely explain the responses of soil food web structure and functioning to changes in plant community productivity, diversity, and composition. Finally, we propose that using a trait-based approach to help understand the mechanisms behind these drivers could provide further guidance.In recent years, it has been shown that individual plant species differ in their effects on the soil communities they supportod webs . First, od webs . The cheod webs . Root ch46 provides new avenues for understanding how shifts in plant communities can influence soil food webs. In plant community ecology, aboveground plant functional traits such as specific leaf area, leaf nutrient content, and leaf dry matter content have been widely used in place of taxonomic diversity measures to explain ecosystem processes and function50. Recently, recognition of the importance of root traits has gained increasing attention53, and greater focus has been put on linking root traits such as root dry matter content, nutrient content, and root architecture to soil processes. For example, changes to root traits associated with exudation could shift C allocation in the rhizosphere and have implications for the soil organisms involved in decomposition and C cycling54. Furthermore, biotic root traits that aid in nutrient acquisition, such as arbuscular versus ectomycorrhizal colonization, impact on the nutritional quality and total quantity of shoot and root litter that enters the soil food web55. To further elucidate the functional linkages between plant communities and the soil food web, recent work has developed and applied a trait-based approach to soil microbes57 and soil fauna60. It has been proposed that investigating the relationship between \u2018effect traits\u2019  and \u2018response traits\u2019  across plant and soil communities could enable better predictions of ecosystem function61.The increased use of functional trait-based approaches in plant community ecology62. However, in affecting soil food web complexity and diversity, trait variability  is probably at least as important as community-weighted mean trait values. Therefore, to better understand how plant community trait composition affects the soil food web, we use the concept of trait packing and diversity. High trait packing in a plant community means a high diversity or variation in litter and root traits, leading to more complex, diverse, and stable soil food web structure and function  strongly control litter decomposition rates, which are determined in part by the substrate quality  available to the microbes63. Therefore, inputs of chemically and structurally highly diverse litter, due to high trait packing within the plant community, could foster the development of a trait-packed microbial community and a more diverse soil food web that could help maintain the delivery of multiple ecosystem functions related to nutrient and C cycling and plant productivity. Furthermore, changes to plant community trait composition that affect indirect interactions initiated by belowground predators  could change the productivity and defense strategy traits of soil organisms on lower trophic levels in ways that affect soil food web connectivity64, which is important because more tightly connected soil food webs are known to promote nutrient retention9.In trait-based ecology, there is often a strong focus on community-weighted mean traits unction . If a stBelow, we explore this framework of trait packing and diversity and, more generally, shifts in litter and root trait values. We focus on areas of research that illustrate how anthropogenic disturbances can affect plant community trait values, leading to shifts in soil food webs. Specifically, we focus on (1) land-use change and secondary succession, (2) climate change and species loss, and (3) plant invasions and range shifts because they are all topical areas of research that are heavily driven by anthropogenic disturbance. We show that under these different scenarios, changes to plant community traits can generate major shifts in the soil food web, leading to positive or negative effects on how soil ecosystems function.67. For example, root exudate chemical traits have been shown to slow down soil microbial processes, and cereal crops cause slower phosphorus mineralization compared with legumes and this is potentially because of differences in exudate chemical composition68. Crop species and varieties may also strongly vary in root nutrient acquisition strategy, root chemical composition, and root architectural traits 69. Although studies so far have focused mostly on coarse traits, such as C:N ratio and specific root length, such trait differences can impact upon microbial communities68 and higher trophic levels of the soil food web70. Crop species also vary in their attractiveness to soil pests and pathogens, such as host-specific nematodes, because of their distinct root chemistry traits71. Given these inter-specific differences in crop traits, moving from monoculture cropping to mixed cropping would add traits to the system, thereby increasing trait packing and leading to positive effects on soil food web diversity and functioning  increased fungi and bacteria and those nematode groups that fed upon them. Interestingly, these two litters were also most effective in suppression of plant-parasitic nematodes. Taken together, agricultural practices that promote plant trait packing and diversity will likely generate higher connectivity in the soil food web, which will lead to increased resistance and resilience to anthropogenic disturbances in cropping systems80.Plant trait shifts associated with agricultural practices strongly drive soil ecosystem functions. Crop residues  and crops with contrasting root traits can have major impacts on soil food web functioningtioning . Mixed cructure , Leslie81. Depending on the management and grazing intensity after abandonment, plant communities typically develop toward species-rich grassland or forest83. Successional changes in plant community composition result in important shifts in litter and root traits, and increases in plant diversity result in more trait packing 9. Furthermore, increased dominance of slow-growing, later-successional plant species, which more strongly depend on associations with mycorrhizal fungi than early species, could shift the fungal community from fast-growing and pathogenic species to slower-growing, beneficial species87. This could affect the rate of C flow through the soil food web8.A relatively large body of research has focused on how shifts in plant community composition after conversion of agricultural land to (semi)natural systems affect soil food webs and their functioningpacking . For exa89 and how climate-induced changes in plant community composition can cause major shifts in root and litter trait spectra 92. Warming affects plant physiology and phenology and ultimately can result in altered plant dominance and shifts in range distributions of plant species (see \u2018Plant invasions and range shifts\u2019 section below). However, changes in precipitation regime, such as longer and more intense droughts, could be expected to most dramatically affect plant community trait spectra, at least in short to moderate timescales93. For example, along an aridity gradient, root tissue density and specific root length may shift to more conservative values with increasing aridity, and the diversity of acquisition trait values may increase, facilitating a wider array of resource acquisition strategies under conditions of water stress94. In old-field communities, experimental drought shifted plant cover dominance from a woody, N-fixing sub-shrub to a C3 bunchgrass and had far-reaching consequences for soil food web structure. Moreover, microbial enzyme activities and nematode feeding group composition indicated higher soil food web complexity but slower rates of nutrient cycling in soils beneath the sub-shrub compared with the grass, most likely because of high concentrations of polyphenolics and lignin in organic residues from the sub-shrub43. In general, drought- and other climate-induced changes in plant trait spectra could greatly modify or counteract direct climate impacts on the soil food web96.Climatic changes driven in part by anthropogenic activities can strongly influence plant community composition. An increasing number of studies have shown how plant traits are related to climatic adaptation98. In turn, loss of species from the plant community will lower litter and root trait diversity and packing  litter inputs caused by deciduous shrub removal may have detrimentally impacted on the microbial and nematode communities because these two groups are highly dependent on such inputs as both direct and indirect food sources101. For randomly assembled plant communities, the effects of lower plant species and functional group richness on soil biota are mostly negative but weaker for soil biota occupying higher levels in the soil food web102. For nematodes, these effects of plant species and functional group diversity have been linked to changes in litter quality 103, but potential effects mediated through shifts in root nutrient acquisition, architectural, and chemical traits remain to be tested.Climate change not only may alter plant species composition but also can result in species losspacking . Althoug104, and debate concerning the consequences of plant invasions for ecosystem functioning continues105. Invasive plants generally have higher values for traits associated with growth rate, tissue nutrient content, and competitive ability  compared with natives107. Therefore, invasive plants can introduce novel traits into the existent plant community that could affect the soil food web. For example, allelopathic chemicals produced by the invasive treeAilanthus altissima can hinder soil microbial activity and thereby nutrient mineralization, while high litter production can increase earthworm abundance, potentially offsetting this negative effect108. Furthermore, invasion by the forbSolidago gigantea increased fungal biomass and had disproportionate cascade effects on certain fungal-feeding nematode taxa that were probably due to disparate feeding abilities among the nematodes109. In contrast, invasion by a grass resulted in less allocation of C to higher trophic levels of soil nematodes compared with a native grass species110. Taken collectively, traits associated with contrasting functional groups of invasive plants  could lead to reduced trait packing  but that native congeners tended to use top-down control through changes to the microbial community. This finding corroborates the novel weapons hypothesis113 and showcases the role that range-expanding plant traits can play in changing the soil food web. Range-expanding plants might also escape their enemies in the soil food web 114, and this, combined with favorable climatic conditions, could lead to successful establishment115. Furthermore, range-expanding plants might fail to find suitable decomposer organisms for their litter 116 because of mismatches in litter chemistry traits and soil organisms specialized in breaking down this litter. Finally, range-expanding plants may not establish mycorrhizal associations  has the potential to introduce new species with new traits into the community and have repercussions for the soil food web. The widening of niche envelopes  that leads to range expansionood web .95, which link more strongly to ecosystem processes and function. (5) Soil food webs often respond slowly and show remarkable resistance to environmental changes. Hence, the effects of shifts in plant community composition may become apparent only at larger timescales. This requires long-term studies and awareness of long-lasting soil legacies. (6) Many studies exploring the relationships between plant communities and soil food webs use observational approaches122. Although observations allow coverage of large spatial and temporal scales , these studies do not disentangle the mechanisms. We advocate for additional empirical studies explicitly manipulating litter and root trait spectra and diversity. Only through continued research will we be able to better understand how anthropogenically driven shifts in plant community composition will affect complex soil food web interactions and the ecosystem services that they provide.Anthropogenic shifts in plant community composition and diversity are likely to have major implications for the composition and function of soil food webs as well as the services they provide. Much recent progress has been made, and our trait-based conceptual model provides guidance for future studies to elucidate the underlying mechanisms of how shifts in plant community traits could lead to cascade effects belowground. The following areas in particular warrant future attention: (1) We know relatively well how functional differences among individual plant species affect soil food webs, but much less is known about the effects of complex plant communities where multiple species coexist and interact. Here, it would be of interest to separate the effects of community-weighted mean values from the diversity of traits represented in the community. (2) The majority of studies inferring changes in soil food web functioning focus exclusively on microbes or use soil nematode communities as indicators of soil food web structure. These approaches have yielded important insights, but to fully understand the role of soil food webs in how shifts in plant community composition affect soil ecosystem functioning, we need to look at whole soil food webs, including organisms at higher trophic levels. (3) Knowledge about the quality and quantity of substrate required by soil microbes and fauna is increasing, and ideas about interactions between different trophic levels are being revised. However, further studies are needed to understand the complex transferring of energy between the different organisms in the soil food web. Therefore, it is integral to investigate how energy transfer within the soil food web is driving key ecosystem processes and to focus particularly on the traits involved. (4) Plant trait-based research has seen a steep increase in activity in recent years, including new research explicitly focusing on root traits. However, the traits most commonly used in these studies are not always the most meaningful in terms of their importance for the functioning of soil communities. Instead of focusing on coarse traits, such as C:N ratios of shoots and roots, it would be more ecologically informative to look at the molecular construction of plant-derived C and N compounds, such as phenolics and their derivatives, which are known drivers of soil microbial activity and resource use efficiency"}
+{"text": "Heavy metals are naturally occurring in the earth\u2018s crust but anthropogenic and industrial activities have led to drastic environmental pollutions in distinct areas. Plants are able to colonize such sites due to several mechanisms of heavy metal tolerance. Understanding of these pathways enables different fruitful approaches like phytoremediation and biofortification.Therefore, this review addresses mechanisms of heavy metal tolerance and toxicity in plants possessing a sophisticated network for maintenance of metal homeostasis. Key elements of this are chelation and sequestration which result either in removal of toxic metal from sensitive sites or conduct essential metal to their specific cellular destination. This implies shared pathways which can result in toxic symptoms especially in an excess of metal. These overlaps go on with signal transduction pathways induced by heavy metals which include common elements of other signal cascades. Nevertheless, there are specific reactions some of them will be discussed with special focus on the cellular level.The online version of this article (doi:10.1186/1999-3110-55-35) contains supplementary material, which is available to authorized users. Basal heavy metal tolerance is presumably found in all plant species. Thereby, they run a complex system consisting of uptake/efflux, transport/sequestration and chelation Figure\u00a0. These kThis review will provide an overview about these tolerance mechanisms with focussing on the cellular level and signalling pathways induced by metals. The discussion of some examples will underline the multitude and complexity of signals and responses. It will trigger further work on responses towards heavy metals in plants especially in the way of low, environmentally relevant metal concentrations.The majority of plants can be classified as non-accumulator plants. Nevertheless, all have to cope with heavy metals for nutrition purposes and growing in metalliferous soils, respectively. Hence, they have to possess finely tuned mechanisms for living with even toxic heavy metals Hall 2006. Thea and b  transporter family  across biological membranes. Thereby, HMA2 and HMA4 drive metal efflux out of the cell in A. thaliana  protein family) is highly overexpressed in the aforementioned hyperaccumulating plants compared to their closed related non-accumulators  and organic acids like citrate  which will be discussed in the next chapter. Functionalities of GSH (thiol and carboxylic groups) make it suitable for complex formation with heavy metals  are sulfur containing proteins inherently being highly flexible in their structure. This flexibility allows different coordination geometries for binding of different metals. Nevertheless, each MT exhibits preferences for a special metal ion due to coordination residues other than cysteine and differences in folding and stability in dependence on the bound metal ,Redox-active metals can directly generate ROS via Fenton like reactions and the Haber-Weiss cycle , there was no significant change of GSH whereas the amount of GSSG increased upon exposure of moderate uranium concentrations (\u2264 10\u00a0\u03bcM) in cell suspensions of canola (Brassica napus)  is impaired by heavy metal accumulation. This can be one reason for conflicting results regarding the GSH content upon metal exposure. Furthermore, the different points of sampling time should be attended. Copper or cadmium amendment in This reductive activity eliminates ROS generated either directly or indirectly by metals. The detoxification of ROS is GSH dependent. Such GSH consuming processes and an excess of ROS induce GSH synthesis   exhibited decreased levels of SOD, GR and CAT towards cadmium contact whereas Avena strigosa (Cd tolerant accumulator) showed increased activities towards the same Cd concentrations , Nramps , the cation diffusion facilitator (CDF) family, the ZIP  family, ABC transporters (ATP-binding cassette), cation antiporters and other putative transition metal transporters. A more detailed overview is provided by reviews written by Guerinot , Hall anAs it was mentioned before, metal sequestration in distinct cellular compartments plays a pivotal role in metal tolerance and supplement with essential metals. For this purpose cells provide a coordinated set of transport systems in each cellular membrane. An important metal sink in metal tolerant plants is the vacuole. A prominent example is the transport of metal-phytochelatin complexes into the vacuole by an unknown ABC transporter or by cation/proton exchanger (CAX) . Proton fluxes can establish so-called \u201cpH-signatures\u201d in the cytoplasm . FER encodes bHLH which controls the expression of genes with key functions in iron acquisition such as the iron-regulated transporter (IRT) and the ferric oxidase reductase (FRO) orthologs in tomato  during iron starvation in plants. A detailed review concerning this was published recently  gene expression was detected As it was discussed in a previous chapter heavy metal exposure can cause imbalances in the cellular redox homeostasis either by being itself redox-active or by replacing other metal ions (sometimes even redox-active ions) in biomolecules. A recently discussed issue in animal cells is the zinc coordination with sulphur donors of cysteine resulting in a redox switch with reversible oxidoreduction of the sulfur donor linked to zinc association and dissociation Maret . This phArabidopsis. These cascades end up by phosphorylation of transcription factors  interacting with gene promoters and thus inducing gene expressions. It should be noted that there are differences between metal-sensitive and metal-tolerant plants: ROS-MAPK signals cause several cellular damages like interruption of hormonal signalling, programmed cell death in metal-sensitive plants. In contrast, metal-tolerant plants are able to accumulate repair proteins such as chitinases and heat shock proteins (HSP). A more detailed overview provides a recently published review by Lin and Aarts  which can activate mitogen-activated protein kinase (MAPK) cascades in a plant species and metal dependent manner (Gupta and Luan nd Aarts . HoweverOther important elements are the soluble redox couples like glutathione or NAD(H), NADP(H) which provide a buffering system in the cytoplasm Noctor . Local p2005aAlmost all plants exhibit a basal metal tolerance when facing heavy metals. Some species are even capable of hyperaccumulation running different tolerance reactions compared with nonaccumulating plants. However, general tolerance mechanisms are based on exclusion, chelation and sequestration processes Figure\u00a0.Attention should be paid on signal transduction pathways induced by metals because they use common signal elements which can be also elicited by other environmental stresses. The critical evaluation of triggered signals and their responses is mandatory for understanding metal homeostasis. The challenge in the future will be the investigation of multiple stress factors as it occurs under real environmental conditions.Predictions about health risk which is caused by metal accumulation in crop plants failing visible symptoms of phytotoxicity.Generation of genetically engineered plants having an enhanced accumulation of metals valuable for nutritional purposes (biofortification).Clean up of metal contaminated soils (phytoremediation) and mining of rare metals which are accumulated in plant tissues (phytomining).Special focus should put on low, environmentally relevant heavy metal concentrations. Therefore, the further development of sensitive detection methods and the combination of different approaches are necessary. These tools enable for instance new insights in the metalloproteome and its interactions . Further knowledge about metal tolerance in plants is mandatory for several purposes:"}
+{"text": "The varicella zoster virus affects the central or peripheral nervous systems upon reactivation, especially when cell-mediated immunity is impaired. Among varicella zoster virus-related neurological syndromes, meningoradiculitis is an ill-defined condition for which clear management guidelines are still lacking. Zoster paresis is usually considered to be a varicella zoster virus-peripheral nervous system complication and treated with oral antiviral therapy. Yet in the literature, the few reported cases of herpes zoster with mild cerebral spinal fluid inflammation were all considered meningoradiculitis and treated using intravenous antiviral drugs, despite absence of systemic signs of meningitis. Nevertheless, these two clinical pictures are very similar.We report the case of an alcohol-dependent elderly Caucasian man presenting with left lower limb zoster paresis and mild cerebral spinal fluid inflammation, with favorable outcome upon IV antiviral treatment. We discuss interpretation of liquor inflammation in the absence of clinical meningitis and implications for the antiviral treatment route.From this case report we suggest that varicella zoster virus-associated meningoradiculitis should necessarily include meningitis symptoms with the peripheral neurological deficits and cerebral spinal fluid inflammation, requiring intravenous antiviral treatment. In the absence of (cell-mediated) immunosuppression, isolated zoster paresis does not necessitate spinal tap or intravenous antiviral therapy. Varicella zoster virus (VZV) is an exclusively human virus primarily causing chickenpox . After aHere we report the case of an alcohol-dependent older man with zoster paresis in the context of a VZV-associated meningoradiculitis. This clinical entity is not precisely defined in the literature and clear management guidelines about oral versus IV antiviral therapy are scant . ClearlyA 74-year-old Caucasian man was admitted to the Emergency Room, addressed by his general practitioner for a 3-day history of progressive lower left limb weakness. He complained of a non-traumatic lumbar pain since 10\u00a0days. Shortly after, a skin rash appeared on his lower back and extended to the left lower limb. He did not have fever or other new neurological complaints (in particular there was no urine or bowel retention or incontinence). His medical history showed arterial hypertension ; alcohol dependence (with macrocytosis and lower limb polyneuropathy) and benign prostate hypertrophy managed using tamsulosin. Otherwise, he took Aspirin Cardio\u00ae and tramadol.In addition to lower limb peripheral length-dependent abnormalities , the initial neurological assessment revealed significant weakness in hip flexion (M3) and foot dorsiflexion (M2), absence of the left patellar reflex and disturbed position sense on the lower left limb. The Leri sign was positive on the left side. On general examination, clusters of small erythematous vesicular lesions were present on the anterior and internal sides of his left thigh and upper leg. A few similar lesions were also seen on the left part of the lower back. In summary, the clinical picture of the patient showed left L3\u2013L4 sensory-motor deficit associated with radicular zoster. A lumbar computerized tomography (CT)-scan excluded local compression (there was only degenerative lumbar discopathy) and the skin smear was positive for VZV DNA but negative for Herpes simplex virus 1 and 2. The lumbar puncture  and showed mainly motor improvement . A few days after admission he developed postherpetic neuralgia that improved with pregabaline and subsequent amitriptyline and a fentanyl patch. Unfortunately analgesic overtreatment led to acute encephalopathy  that was reversed with dose adjustment. The patient was then transferred to a stationary neurorehabilitation center before returning home.The patient described here had zoster paresis associated with mild inflammation and VZV activity in the CSF; leading to treatment mainly by IV acyclovir. The very few reported cases of VZV meningoradiculitis in the literature can be divided into two groups. The first corresponds to radiculitis without meningitis symptoms  \u201316. The peripheral nervous system complication [If meningoradiculitis comprises clinical meningitis with peripheral nerve root involvement, then it should be treated, as with any other VZV-CNS complication, using IV antiviral drugs after spinal tap and other necessary investigations , 6, 12. lication . Such palication . The VZVlication , 15 to tlication , 16? Morlication . Along tNone of the frequently reported immunosuppressive states  triggering VZV reactivation  were fouIn conclusion, the patient had VZV cutaneous infection with radiculitis coincident with mild CSF inflammation. Reactivation of VZV was most probably precipitated by age- and alcohol-induced cell-mediated immunosuppression. He was diagnosed with meningoradiculitis and treated with IV acyclovir, despite the absence of clinical meningitis. In available published cases, we did not find a consensual definition or management scheme for meningoradiculitis. The presence of CNS symptoms or abnormal CSF findings did not allow discrimination of severe from benign cases and these patients were generally IV treated. However, well-designed clinical trials are needed to review severity criteria for patients with VZV-associated (meningo)-radiculitis, to study the efficiency of oral versus IV antiviral treatment and establish clear guidelines for management. Mild elevation of inflammatory markers in the CSF is not specific or sensitive enough to establish a diagnosis of meningitis without evocative clinical symptoms. Therefore we suggest that until otherwise demonstrated, the term \u201cmeningoradiculitis\u201d should be used for and IV antiviral drugs prescribed to patients with clinical meningitis associated with neurological peripheral deficit in the context of VZV infection. Patients with isolated VZV radiculitis should be exempt from CSF investigations and be given oral antiviral treatment, unless they are subject to any condition or pathology decreasing immunity, in particular CMI, in which case CSF workup and IV antiviral therapy may be necessary."}
+{"text": "Immune therapy has shifted the paradigm of modern cancer treatment: Instead of targeting the tumor itself, it focuses on enhancing tumor recognition and destruction. Harnessing the immune system by using monoclonal antibodies, adoptive T cell transfer or checkpoint inhibitor (CPI) therapy increased progression free survival with less side effects compared to conventional therapy . CheckpoThree of the major questions that arise for caregivers and scientists are: 1) Should pre-therapeutic screening be implemented to assess risk for fatal cardiovascular events and adjust mono- vs. combination CPI therapy? Certain features of the immune system may predispose to immune related adverse events, such as specific HLA phenotypes or composition of their T cell subtypes. 2) Should patients undergoing CPI therapy receive regular surveillance tests for early signs of cardiovascular adverse events? Which non-invasive technologies should be used? 3) Would local therapy be beneficial if cardiotoxicity develops? During CPI therapy, troponin elevation, changes in ECG, arrhythmias, and inflammation or ischemia on cardiac MRI have been observed -clinical signs that will likely guide therapy in the future. In some reported cases that tested for the most common viruses known to cause myocarditis , viral serologies from peripheral blood were negative in all patients . For genIn the event of increasing troponin levels, Wang and colleagues recommend to hold immunotherapy until troponin levels and ECG abnormalities normalize Figure  6]. In . In 6]. While these conclusions and recommendations reflect our interpretation of findings from case reports and case series, no guidelines for the treatment of immune related myocarditis have been published as of today due to limited availability of clinical data.Assuming an immune antigen reaction similar to an allograft rejection or a rheumatic disease, similar pathomechanisms have to be explored to widen treatment options for this rare but often fatal complication. In one reported case of CPI related and steroid resistant myocarditis, treatment with equine anti-thymocyte globulin (ATGAM) led to regression of the disease . Similar"}
+{"text": "Streptococcus pyogenes infection at 5, 12, and 18 hours post infection and correlated this to parameters of infection. The platelet population in ex-vivo blood samples showed no increased integrin activation or surface presentation of CD62P, however platelet-neutrophil complex formation and plasma levels of CD62P were increased during bacterial dissemination and the progression of sepsis, indicating that platelet activation had occurred in vivo. Platelet-neutrophil complex formation was the most discriminatory marker of platelet activation. Platelet-neutrophil complexes were increased above baseline levels during early sepsis but decreased to significantly lower levels than baseline during late sepsis. The removal of these complexes from the circulation coincided with a significant increase in organ damage and the accumulation of platelets in the liver sinusoids, suggesting that platelet activation in the circulation precedes accumulation of platelets in damaged organs. The results demonstrate that monitoring platelet activation using complementary methods may provide prognostic information during the pathogenesis of invasive S. pyogenes infection.Platelets contribute to inflammation however, the role of platelet activation during the pathophysiological response to invasive bacterial infection and sepsis is not clear. Herein, we have investigated platelet activation in a mouse model of invasive  W. Win vitobserved . The aimS. pyogenes AP1 infection , . PN. PN25]. Among the few studies of PNC formation in sepsis patients, PNC formation has been detected although other parameters of platelet activation were not increased . PNC levIntravital microscopy of liver sinusoids directly treated with LPS has demonstrated platelet dependent stimulation of neutrophil extracellular trap formation  and locaS1 Fig(PDF)Click here for additional data file."}
+{"text": "Stem cells are undifferentiated and pluripotent cells that can differentiate into specialized cells with a more specific function. Stem cell therapies become preferred methods for the treatment of multiple diseases. Oral and maxillofacial defect is one kind of the diseases that could be most possibly cured by stem cell therapies. Here we discussed oral diseases, oral adult stem cells, iPS cells, and the progresses/challenges/perspectives of application of stem cells for oral disease treatment. Stem cells are undifferentiated and pluripotent cells that can produce more new stem cells  and differentiate into specialized cells with a more specific function such as skin cells, bone cells, and blood cells , PDLSCs (N = 4), OESCs (N = 12), DPSCs (N = 5), adipose derived stem cells , SHED (N = 1), nasal stem cells (N = 1), and HSCs (N = 1). As outlined in Table N = 3, with autologous SHED or DPSCs), dental diseases correlated with tooth extraction , graft vs. host diseases with oral complications , facial diseases , and Xerostomia/Sj\u00f6gren's Syndrome . Among them, three trials have reported results. The clinical trials with reported results will be discussed below.Stem cell therapy has become a promising alternative in dentistry and maxillofacial rehabilitation since it could provide better physiological structure and functions . Bio-Oss scaffolds were transplanted together with PDLS cell sheets for the chronic periodontitis therapy in a completed clinical trial (NCT01082822). Commercially available collagen scaffolds (collagen fleece) are used to hold autologous BM-MSCs enriched with autologous fibrin glue in clean room facilities for regeneration of periodontal tissues in periodontal infrabony defects in an ongoing clinical trial (NCT02449005). For adult periodontitis patients, the surgical implantation of autologous MSCs with a 3D woven-fabric composite scaffold and platelet-rich plasma showed no clinical safety problems but decreasing trend of mobility and significantly improved changes in clinical attachment level, pocket depth, and linear bone growth  uses a bioengineered product composed of mesenchymal stem cells and a patented cross-linked matrix of autologous plasma for bone maxillary cysts refilling. Platelet rich fibrin (PRF) and bone allograft  are used to load the buccal fat pad derived stem cells for the treatment of alveolar bone loss in maxillary sinus augmentation (NCT02745379) and in posterior mandible augmentation (NCT02745366). Tissue engineered construction based on a synthetic tricalcium phosphate and autologous MSCs obtained from oral mucosa is used for maxilla alveolar process reconstruction in patients with verified diagnosis partially edentulous maxilla and alveolar bone atrophy (NCT02209311). Similarly, MSCs obtained from bone marrow are mixed with bicalcium phosphate to augment the alveolar ridge (NCT02751125).Stem cells are applied without scaffolds in most clinical trials . Intravenously infused allogeneic MSCs suppressed autoimmunity by directing T cells toward Treg and Th2, while suppressing Th17 and Tfh responses, and restored salivary gland secretory function in both mouse models and Sj\u00f6gren's Syndrome patients who have been resistant to multiple standard treatments (NCT00953485). The study suggests that allogeneic MSC treatment may provide an effective therapy for Sj\u00f6gren's Syndrome patients . Allogeneic human DPSCs are injected in local infected periodontal tissue for the treatment of chronic periodontal disease (NCT02523651) and a clinical trial UMIN000002050 aims to establish human dental pulp stem cell bank for dental diseases that extraction of tooth is necessary for treatment. A clinical trial is ongoing to clarify the efficiency of autologous SHED to regenerate pulp and periodontal tissue in the patients with immature permanent teeth and pulp necrosis (NCT01814436).Human PDLSCs, as well as DPSCs, SHEDs, and bone marrow stem cells have been studied to regenerate periodontal tissues  were related to the aspect ratio-dependent cellular internalization, suggesting the promising use of CeNMs to protect stem cells from the ROS-insult environments and ultimately improve the stem cell potential for tissue engineering and regenerative medicine  into a confined space, where biological function and viability of biomaterials are preserved within the printed construct (Murphy and Atala, in vitro without stemness loss or function change; try to speed up self-renewal of the in situ stem cells and precisely control their differentiation. For allogeneic stem cells, the in vitro expand technology is also very important and the technology to lower down the immune rejection is urgently needed. Besides the immune suppression drugs, regulatory immune cells such as Treg and Breg (Sun et al., In summary, there are endogenous/autologous and exogenous/allogeneic adult stem cells and iPS cells for oral disease treatment. As compared in Table BY, YQ, and NZ summarized the literature, wrote the manuscript, and prepared figures. BC, HO, and JD provided critical comments and wrote part of the manuscript. JS supervised all the works and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer VD, VT and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review."}
+{"text": "Melatonin administration to high cholesterol-treated and high fat-treated rats has been shown to suppress body weight and visceral adiposity. In addition, in various animal models related to obesity, metabolic syndrome, and diabetes, melatonin has beneficial efficacy in ameliorating various metabolic symptoms, including attenuating weight gain, lowering blood pressure (BP), and improving insulin resistance. This systematic review aims to investigate whether melatonin or melatonin agonists significantly attenuate metabolic side effects among psychiatric populations treated with atypical antipsychotics.Four randomized controlled trials were identified through a comprehensive literature search using MEDLINE, EMBASE, and the Cochrane Library on 22 October 2015. These four trials (including three melatonin studies and one ramelteon study) included 138 patients, of whom 71 were treated with melatonin or ramelteon and 67 were treated with a placebo. Because of high heterogeneity, we did not carry out a meta analysis.Melatonin was beneficial in lowering blood pressure among bipolar disorder patients; this blood pressure-lowering effect was not prominent among schizophrenic patients. Melatonin appeared to improve lipid profiles and body composition and attenuated weight gain among both schizophrenic and bipolar disorder patients. Ramelteon showed a significant efficacy in lowering total cholesterol level.Despite the few studies included, this systematic review provided promising evidence of the potential benefits of melatonin and its agonists in attenuating one or more components of metabolic syndrome among psychiatric patients using atypical antipsychotics."}
+{"text": "Sarcopenia, or loss of skeletal muscle mass and quality, has been studied as part of aging and adverse health outcomes in elderly patients but has only recently been evaluated as a separate condition in cancer patients and important indicator of adverse outcomes. Currently, its definition and method of assessment are still being debated. Sarcopenia within an increasingly obese population has led to a subgroup with sarcopenic obesity, at even higher risk of adverse outcomes. Yet, sarcopenia often goes undiagnosed in these patients, hidden beneath higher body mass index. Identifying sarcopenic and sarcopenic obese subpopulations would allow for more effective treatment plans and potential avoidance of suboptimal outcomes, as well as the chance to intervene and combat these modifiable risk factors. This review will examine available literature on the definition and methods of evaluating sarcopenia and sarcopenic obesity, summarize the effectiveness of sarcopenia and sarcopenic obesity as predictors of outcomes after gastrointestinal cancer surgery, including colorectal cancer resection, liver resection, and pancreatic resection, and outline strategies to minimize the impact of sarcopenia. It is clear that untreated sarcopenia and sarcopenic obesity can be associated with suboptimal post-operative outcomes, especially infections and disease-free or overall survival. Sarcopenia, the loss of skeletal muscle mass and quality that occurs as part of natural aging, can be exacerbated by systemic illnesses. Within the last 10\u00a0years, this geriatric syndrome has received increasing attention as a possible predictor of adverse outcomes after surgery ) are at higher risk of adverse outcomes, including disability  oncologic surgery outcomes, including colorectal cancer resection, liver resection, and pancreatic resection, and promising methods by which these risk factors can be modified.Early definitions of sarcopenia rely upon measures of muscle mass and neglect a functional specification. Evidence suggests the relationship between low muscle mass and adverse outcomes is not linear or direct; rather, they are linked when low muscle mass is associated with muscle weakness  or time required to complete five chair stands were also useful standards. Muscle strength was assessed through unadjusted grip strength and muscle mass via body mass-adjusted appendicular lean mass  that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment,\u201d which encompasses varying levels of body fat and muscle loss , computerized tomography (CT)-derived total body fat (TBF), or dual x-ray energy absorptiometry (DXA)/bioelectric impedance analysis (BIA)-derived body fat  is an overlooked contributor  index (the sum of lean soft-tissue masses for the arms and legs adjusted by height)  Fig.\u00a0 (Baumgarht) Fig.\u00a0 and thosht) Fig.\u00a0, total pht) Fig.\u00a0, and psoht) Fig.\u00a0.Fig. 1CoMuscle mass has traditionally been measured using BIA or DXA  disability than lean sarcopenic, non-sarcopenic obese, or patients with normal body composition  and impaired short-term outcomes after surgery  noted that there is currently no objective, accessible, accurate measure of a patient\u2019s condition before undergoing hepatectomy -sarcopenia and short-term outcomes than with TPA-sarcopenia , a measure of psoas muscle density and fatty infiltration, along with TPA  (Joglekar et al. While sarcopenia assessment can help identify cancer surgery patients at risk of worse outcomes, it is important to note that sarcopenia and SO themselves are modifiable. The most effective interventions to date are physical exercise and adequate nutritional protein intake (Deutz et al. The impact of sarcopenia on post-operative oncologic outcomes and its usefulness as a predictor is still unclear and often conflicting, particularly in the case of hepatectomy for colorectal liver metastases and hepatectomy for hepatocellular carcinoma. However, sarcopenia is promising as a predictor of short-term outcomes following colorectal cancer surgery and long-term outcomes following hepatectomy for hepatocellular carcinoma. SO is promising as a predictor of long-term outcomes following hepatectomy for hepatocellular carcinoma and short-term outcomes following pancreatic resection. The other associations need additional clarification, as studies provided inconsistent results.There remains considerable variation in definition, cutoffs, and assessment methods for sarcopenia and SO, which makes translation to clinical practice complicated. Recent criteria incorporating both grip strength and appendicular skeletal muscle allow more clinically meaningful associations with long-term outcomes and are preferred to definitions excluding a functional component (Studenski et al. Sarcopenia and SO may predict short- and long-term outcomes, and effective identification of patients at risk of poorer outcomes from cancer surgery allows for tailored interventions. As clinicians become increasingly aware of this subtle form of malnutrition, addressing sarcopenia preoperatively can optimize outcomes for at-risk patients.Further research is needed to reach consensus regarding the ideal manner of assessing sarcopenia in order to predict outcomes after various cancer surgeries and across cancers in a broad clinical sense. The prevalence and impact of SO in various cancer surgeries requires further examination. Risk of mortality associated with SO for all types of patients should be further evaluated (Prado et al."}
+{"text": "The conventional view that neuroinflammatory lesions contain strictly pro- and anti-inflammatory cytokines is being challenged. Some proinflammatory products e.g. TNF-\u03b1 are crucial intermediates in axon regeneration, oligodendroglial renewal and remyelination. A more functional system of nomenclature classifies cytokines by their neuro \u2018protective\u2019 or \u2018suppressive\u2019 properties. Beyond the balance of these \u2018environmental\u2019 or \u2018extrinsic\u2019 signals, specific \u2018intrinsic\u2019 determinants of cytokine signalling appear to influence the outcome of axoglial regeneration. In this commentary, we examine the potential importance of cytokine-induced histone modification on oligodendrocyte differentiation. Neuroinflammation mediates the release of astrocytic leukaemia inhibitory factor (LIF) and erythropoietin (EPO) which potentiates oligodendrocyte differentiation and myelin production. Meanwhile, histone deacetylation strongly suppresses important inhibitors of oligodendrocyte differentiation. Given that LIF and EPO induce histone deacetylases in other systems, future studies should examine whether this mechanism significantly influences the outcome of cytokine-induced remyelination, and whether epigenetic drug targets could potentiate the effects of exogenous cytokine therapy. Amongst an array of important extracellular signals, astrocytes release leukaemia inhibitory factor (LIF) and erythropoietin (EPO) which are neuroprotective cytokines that promote the differentiation of OLs and preserve the integrity of the myelin sheath , or more directly, the DNA itself (DNA methylation). Previous studies have shown that the process of (re)myelination is dependent on a variety of epigenetic remodelling mechanisms including histone modification, DNA methylation and miRNAs  pathway. McCool et al. showed that withdrawal of LIF leads to a global increase in histone acetylation that mimicked the effect of trichostatin A, a histone deacetylase inhibitor myelination. Histone deacetylation is associated with the repression of important inhibitors of oligodendrocyte differentiation and neurotrophic cytokines such as LIF and EPO have demonstrated a potential to induce these HDACs in other systems. Future research should specifically examine the epigenetic processes that occur downstream of LIF and EPO in oligodendrocytes. This could lead to a novel therapeutic approach to demyelinating disease that incorporates epigenetic drug targets e.g. HDACs to bolster the efficacy of exogenous cytokine therapy."}
+{"text": "Climate change is driving the thinning and retreat of many glaciers globally. Reductions of ice-melt inputs to mountain rivers are changing their physicochemical characteristics and, in turn, aquatic communities. Glacier-fed rivers can serve as model systems for investigations of climate-change effects on ecosystems because of their strong atmospheric\u2013cryospheric links, high biodiversity of multiple taxonomic groups, and significant conservation interest concerning endemic species. From a synthesis of existing knowledge, we develop a new conceptual understanding of how reducing glacier cover affects organisms spanning multiple trophic groups. Although the response of macroinvertebrates to glacier retreat has been well described, we show that there remains a relative paucity of information for biofilm, microinvertebrate, and vertebrate taxa. Enhanced understanding of whole river food webs will improve the prediction of river-ecosystem responses to deglaciation while offering the potential to identify and protect a wider range of sensitive and threatened species. The sustained dependency of human society on hydrocarbons is predicted to increase global near-surface temperatures, particularly across the second half of the twenty-first century  respond to glacier retreat, predominantly with a Northern Hemisphere focus because this is where most of the relevant research has been undertaken. This knowledge is then integrated within a new conceptual framework that considers simultaneous responses of biota to shrinking glaciers as part of multitrophic river ecosystems. This new multitaxonomic response framework is used subsequently to explore the consequences for how whole-river food webs can be expected to respond to ongoing glacier retreat. Such an approach is required to inform alpine conservation strategies by providing a holistic food-web context for the multiple cold-environment endemic species that are found in glacier-fed rivers around the world  dominating biofilm formation  remains limited in comparison with that of macroinvertebrates  shelter within the riparian vegetation and rocky banks of glacier-fed rivers, across the Pyrenean Region  and the absence of predators, including American mink  mirrors the dependency of the Iberian desman for cold running waters, hunting insects, crustaceans, frogs, and fish below 2500 meters\u2019 altitude  inhabits slow-flowing rivers and lakes of forested alpine floodplains , which is more heavily dependent on diminishing ice-melt reaches  and Soricinae (water shrew) are found in localized populations figure . The IbeSalamandra salamandra) and alpine newt  favor zones of reduced glacier influence, including alpine woodland rivers below 2500 meters  requires fast-flowing, highly oxygenated, cobbled river reaches for larval development (figure Rana temporaria) persists within mountain woodlands and meadows below 2300 meters, using rivers and lakes for larval development and overwintering in open water to avoid freezing conditions  have also colonized low-velocity proximal glacial streams in Arctic Canada and Norway, particularly where they are warmed by upstream glacial lakes  and the Pyrenean brook newt (C. asper) preferentially occupy high-velocity mountain rivers in the Pyr\u00e9n\u00e9es, increasing their density and in turn biomass with reducing glacier influence  and meiofauna (rotifers and nematodes), the relationship between taxonomic richness and reducing glacier influence appears to be linear, resulting in increases in biomass with glacier retreat figure . HoweverBaetis alpinus, Lednia tumana, and Rhyacophila angelieri) but can be found at multiple trophic levels within diatoms , algae , and vertebrates  and both epilithic diatoms and detritus  released from the glacier was probably consumed by microbes and then assimilated by macroinvertebrates.In a detailed mountain-river food-web study, Clitherow and colleagues  used gutSalvelinus malma) and America dipper (Cinclus mexicanus), absent from the Austrian glacial food webs. In addition, Khamis and colleagues (Perla grandis) in spring-fed, in situ experimental mesocosm channels. Their results suggested that the future range expansion of this species  will increase trophic height (and therefore food-chain length) and body-size spectrums through invasion, intraguild predation, and interference competition  and that other taxonomic groups can serve as differential indicators of climate change in mountain-river systems. It also holds value beyond alpine rivers because the reorganization of communities within glaciated headwaters will intrinsically influence the species pools available to colonize downstream reaches, potentially reshaping their assembly processes (Brown and Milner"}
+{"text": "The patient had been taking appetite suppressant  for the last 7 days.Electrocardiography showed no abnormalities although both serum creatinine kinase-MB (3.59ng/mL) and troponin I  were elevated. Coronary angiography revealed extensive and abrupt lumen narrowing in the obtuse marginal with a subtle intraluminal defect within the distal part of the vessel . Optical The etiology and pathogenesis of spontaneous coronary artery dissection are not completely understood, but primary disruption with bleeding of vasa vasorum and intramedial hemorrhage have been proposed as the underlying mechanisms. Alternatively, an intimal tear may result in separation of coronary wall layers with the creation of a false lumen. Pressure-driven expansion of this lumen induces axial propagation of the dissection and true lumen compression, causing myocardial ischemia. Eventually, as occurred in the current case, angiography shows a long eccentric narrowing without the presence of a visible intimal flap.Spontaneous coronary artery dissection is an unusual, underdiagnosed disease, and its clinical presentation ranges from unstable angina to sudden cardiac death. This condition predominantly affects young women without classical cardiovascular risk factors, and it is increasingly diagnosed in those who are not in the peripartum period. specially in doubtful cases by angiography. Optimal treatment is still controversial and includes medical management for asymptomatic patients with normal coronary flow. Percutaneous coronary intervention with stenting or coronary artery bypass graft operation should be considered for patients with ongoing ischemia, clinically unstable or spontaneous coronary artery dissection involving the left main or multiple proximal coronary dissections. Favorable prognosis has been reported in patients managed conservatively since resolution and healing can occur over time. The present case is the first documenting spontaneous coronary artery dissection and healing by high resolution imaging OCT.Thus, an invasive imaging modality, such as OCT or intravascular ultrasound, should be the gold standard to diagnose spontaneous coronary artery dissection,"}
+{"text": "Cognitive decline is a frequent but undervalued aspect of multiple sclerosis (MS). Currently, it remains unclear what the strongest determinants of cognitive dysfunction are, with grey matter damage most directly related to cognitive impairment. Multi-parametric studies seem to indicate that individual factors of MS-pathology are highly interdependent causes of grey matter atrophy and permanent brain damage. They are associated with intermediate functional effects  representing a balance between disconnection and  adaptive connectivity changes. Therefore, a more comprehensive MRI approach is warranted, aiming to link structural changes with functional brain organization. To better understand the disconnection syndromes and cognitive decline in MS, this paper reviews the associations between MRI metrics and cognitive performance, by discussing the interactions between multiple facets of MS pathology as determinants of brain damage and how they affect network efficiency. Although about 40 to 70% of MS patients develop significant cognitive decline,-,in vivo characterization of GM pathology remains challenging. Detection of focal GM lesions, especially in the cortical GM, requires advanced magnetic resonance imaging (MRI) techniques, such as high-resolution 3D-T1 and 3D-FLAIR,,Although MS has been traditionally classified as a white matter (WM) disease, involvement of grey matter (GM) by demyelination and neurodegeneration has become evident in all stages of the disease.-,,It has been suggested that WM lesions and inflammatory processes have stronger influence as determinants of GM damage in early stages of MS,,,,,,,,,-,-,,,,,,MRI is the main modality used to assess pathological changes in MS and it has been used to quantify WM lesions,,,,-,,,The neurodegenerative process in MS is likely to precipitate changes in brain function. Conventional MRI data  has been compared to neuropsychological tests scores to relate MS pathology to cognitive performance.This paper reviews the associations between MRI metrics and cognitive performance in MS, by discussing the interactions between multiple facets of MS pathology as determinants of brain damage. We also present an overview of new imaging analysis techniques studying structural and functional brain networks towards accessing the interplay between structural damage, functional changes and cognitive outcome. ,Cognitive dysfunction in MS is heterogeneous and usually affects multiple cognitive domains. The more frequently affected domains are memory, attention, information processing speed and executive functions.,Risk factors of cognitive symptoms in MS are not completely understood, but studies have suggested that sex, age and genetic predisposition may play a role. For instance, several studies reported that cognitive symptoms are more severe and occur more often in male patients than in female patients.Neuropsychiatric factors are an important aspect to consider when assessing cognitive performance in patients with MS: studies have shown that cognitive fatigue might be partially responsible for decreases in performance of tasks that require sustained mental effort.,Not surprisingly, progressive MS phenotypes present worse cognitive performance than early relapsing remitting MS (RRMS) or CIS patients.,Although cognitive deficits can be found in early stages of the disease, they are usually a feature of advanced disease. Natural history studies suggest that the cognitive decline tends to progress with increased disease duration and, once it appears in MS patients, it is unlikely to remit.White matter (WM) lesions. Depicting WM lesions disseminated in the CNS is indispensible for the diagnosis and early clinical management of MS.,,,,,,,,,,,,,,,It has been suggested that lesion location might be a stronger determinant of neurological dysfunction in MS,,,Most studies evaluating associations between lesion load and cognition were performed in patients with relative short disease duration. Baseline T2-hyperintense and T1-hypointense lesion loads are significant short-term predictors of disability and cognitive decline in patients with clinical isolated syndromes (CIS)Gray matter (GM) lesions. Renewed interest in MS GM pathology has revealed that the prevalence of GM lesions is high,,,,Double inversion-recovery (DIR) is a relatively new MRI sequence that selectively nulls the signals from WM and cerebrospinal fluid (CSF), leaving only GM and lesions visiblein vivo visualization of the most prevalent subtype - subpial lesions.Although DIR has considerably improved GM lesion detection, a post-mortem evaluation uncovered that about 80% of cortical lesions remain undetected at 1.5T.Despite the fact that multiple studies have shown the clinical relevance of cortical lesions, there are still several limitations to the assessment of cortical lesions in routine clinical practice. First, specific MRI sequences to detect cortical lesions, such as DIR and PSIR, are not available on most clinical scanners. The availability of ultra-high field scanners for clinical practice is even more limited. Second, DIR imaging is prone to artifactsDiffuse MS pathology. Quantitative MRI techniques, such as magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI), enable quantification of the extent and severity of structural changes occurring in NABT outside focal lesions.,,,,,,,,Several studies have shown that correlations between cognitive deterioration in MS and markers of diffuse MS pathology are stronger than correlations observed between cognitive decline and WM lesion load.,,Evidence suggests that MTR and DTI can be used to probe neurodegeneration  and might have prognostic value. First, MTRHowever, most of the MRI parameters used to investigate NAWM and NAGM abnormalities  are pathologically unspecific, and might correspond to (combinations of) demyelination, inflammatory processes or neurodegeneration.Brain atrophy. Brain atrophy is considered to be an end-stage phenomenon, strongly correlated to permanent brain damage / neurodegeneration. Patterns of GM atrophy are being identified from early stages of MS onward,,,,,,Global cortical thinning is mild in early stages of MS such as CIS and increases with disease severity,,Despite these efforts, it is still not well understood which pathological factors determine GM atrophy in MS. Previous studies showed associations between GM atrophy with WM,,,,-Traditional models of brain function employ modular paradigms, in which brain areas are postulated to act as independent processors for specific neural functions.,,,Most DTI studies show signs of microscopic damage/disconnection in several WM pathways involved in cognition. The fiber bundles more frequently associated with neuropsychological performance are the cingulum,,,,,,,Some of the disrupted WM connections are anatomically related to the default mode network (DMN).These results are difficult to interpret. Increased connectivity in cognitively preserved patients could be a sign of beneficial functional reorganization or compensatory mechanisms to sustain normal function, delaying the cognitive decline. Alternatively, it could be a maladaptive response secondary to the disruption of inhibitory WM connections. In this context, one would expect positive correlations between signs of WM disconnection and increased functional connectivity. Louapre et al.,,Different studies found similar results in structuralCognitive decline is an important source of disability in MS patients and an undervalued aspect of disease progression. Even though cognitive impairment is partly related to macroscopic lesion load, focal damage might play an indirect role as a cause of further tissue damage. Reflective of permanent damage and tissue loss, atrophy markers show stronger correlations with cognitive tests, but regional damage in target structures provides limited information about their specific relevance for a given cognitive domain and the integration between brain areas and systems. A more holistic investigation of brain networks seems to better capture the mechanisms of brain damage and adaptation encountered in cognitive dysfunction. However, multimodal imaging techniques and network analyses are still in their infancy and, although it is possible to visualize the associative areas more frequently affected in cognitive impaired MS subjects, we still lack a more specific comprehension of the interplay between function and structure to better understand initial adaptation and subsequent collapse of brain networks."}
+{"text": "Oscillations in neuronal activity tie the pathophysiology of schizophrenia to alterations in local processing and large-scale coordination, and these alterations in turn can lead to the cognitive and perceptual disturbances observed in schizophrenia. Here, we focus on the dual role of fast-spiking, parvalbumin (PV+) networks in the generation of gamma oscillations and critical periods of brain plasticity.We generated a mouse model of reduced recurrent inhibition only within local PV+ cell networks by selective removal of GABAA receptor alpha1 subunits (PV-\u03b11 KO mice). Electroencephalography (EEG), PV+ immunohistochemistry, perineuronal net (PNN) labeling and redox balance were compared to cortical measures of brain plasticity  that are typically limited to a critical period early in life.PV-\u03b11 KO mice exhibit chronically enhanced gamma-oscillations and extended juvenile forms of cortical plasticity into adulthood. Acute pharmacological suppression of excitatory input restored E-I balance onto these disinhibited PV+ cells and returned baseline EEG power to normal levels, preventing the extended plasticity. Enhanced gamma oscillations were further found to compromise the integrity of perineuronal nets (PNNs) surrounding PV+ cells, elevating oxidative stress and the turnover of metallopeptidases and structural components of the PNN. All of these aspects were also reversed by pharmacological dampening of excitation onto PV+ cells.Cortical gamma oscillations are associated with plasticity and cognition. Our results provide a cellular explanation of how elevated gamma oscillations may promote ectopic brain plasticity by regulating the extracellular matrix which normally stabilizes cortical circuitry. These results carry broad implications for subjects at-risk for schizophrenia who exhibit heightened gamma oscillations prior to psychosis onset ."}
+{"text": "Delphinapterus leucas) populations occur between July-November. Our goal was to develop population-specific beluga habitat selection models that quantify relative use of sea ice and bathymetric features related to oceanographic processes, which can provide context to the importance of changing sea ice conditions. We established habitat selection models that incorporated daily sea ice measures  and bathymetric features  to establish quantitative estimates of habitat use for the Eastern Chukchi Sea (\u2018Chukchi\u2019) and Eastern Beaufort Sea (\u2018Beaufort\u2019) populations. We applied \u2018used v. available\u2019 resource selection functions to locations of 65 whales tagged from 1993\u20132012, revealing large variations in seasonal habitat selection that were distinct between sex and population groups. Chukchi whales of both sexes were predicted to use areas in close proximity to Barrow Canyon  as well as the continental slope in summer, although deeper water and denser ice were stronger predictors for males than females. Habitat selection differed more between sexes for Beaufort belugas. Beaufort males selected higher ice concentrations (\u226540%) than females (0\u201340%) in July-August. Proximity to shore (<200 km) strongly predicted summer habitat of Beaufort females, while distance to the ice edge was important for male habitat selection, especially during westward migration in September. Overall, our results indicate that sea ice variables were rarely the primary drivers of beluga summer-fall habitat selection. While diminished sea ice may indirectly affect belugas through changes in the ecosystem, associations with bathymetric features that affect prey availability seemed key to habitat selection during summer and fall. These results provide a benchmark by which to assess future changes in beluga habitat use of the Pacific Arctic.There has been extensive sea ice loss in the Chukchi and Beaufort seas where two beluga whale ( Ursus maritimus) and ice-associated pinnipeds such as seals and walruses use sea ice as a platform for foraging, reproduction, and resting . Seas. SeasUrsng  are ice-associated cetaceans that utilize a broad range of habitats from open water, loose annual pack ice, sea ice edge, and multi-year pack ice )Males likely segregate from females as they mature to exploit alternative prey resources and reduce competition with females and calves, as do other socially-structured cetaceans (e.g. ). We fouDue to reductions in sea ice over recent decades as well as projections for continued loss ,81, therAlthough mitigation of sea ice loss primarily requires global reduction of greenhouse gas emissions, habitat models can help inform management of anthropogenic activities and conservation planning efforts that will increasingly need to identify seasonally important areas for this critical species. Our results suggest that belugas select habitat based on a number of factors. Sea ice variables were rarely the most significant factors affecting beluga summer-fall habitat selection compared with bathymetric features. This suggests perhaps sea ice loss may not impact beluga habitat use. However there are other ways changing sea ice cover could affect belugas, and a recent study showed Chukchi belugas shifted fall migration timing as sea ice freeze-up occurred later in the 2000s . Other e"}
+{"text": "The understanding of mitochondria and their quality control in cancer genesis and progression is increasing exponentially. While the Warburg hypothesis depicts mitochondria as silent within a glycolytic tumorigenic environment, it is now known that in malignant cells mitochondria are constitutively active, priming malignant reprogramming and promoting survival. Thus, in cancer cells mitochondria supply energy, provide building blocks for new cells, control redox homeostasis and define oncogenic signals commanding programmed cell death . Two othm) which provides a putative target for anti-cancer therapy. Mitochondrial redox molecules conjugated to triphenylphosphonium (TPP) exploit such differences and accumulate within the mitochondria as a selective therapeutic approach.Intrinsic aspects of mitochondrial function in cancer cells allow for the selective targeting of tumorigenic cells, including differences in mitochondrial membrane potential (\u0394\u03c8Biel and Rao, describe how these TPP-conjugated antioxidants trigger a mitophagy-mediated resistance mechanism . The rolm reported in aggressive cancer cells leading to sustained mitophagy [The pharmacological control of mitophagy could in turn be tested as a way to improve the therapeutic efficacy of chemotherapy. Hitherto, few selective non-toxic inducers of mitophagy have been developed, i.e. Urolithin A  and the itophagy . The autitophagy . InteresThis work re-invigorates the field of mitophagy in the progression and management of tumours. Discovering whether mitophagy induction is a feature of less aggressive cancer cells could unveil the culling of non-abiding mitochondria as a mechanism to reprogram cells towards metastatic tendencies. Conclusively, this research brings into focus mitochondrial life-cycle modulation as a key effector in cancer cell divergence and reveals therapeutic implications for the pharmacological fine-tuning of mitophagy to overcome chemotherapy resistance ."}
+{"text": "Whilst associations between polygenic risk scores (PRSs) for schizophrenia and various phenotypic outcomes have been reported, an understanding of developmental pathways can only be gained by modelling comorbidity across psychopathology, something no studies have done to date. We examine how genetic risk for schizophrenia relates to a broad range of adolescent psychopathology using a latent modelling approach, and compare this to genetic risk for other psychiatric disorders, to gain a more comprehensive understanding of development pathways at this age.PRSs for schizophrenia, major depressive disorder, neuroticism and bipolar disorder were generated for individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Multivariate linear regression was used to examine relationships of these PRSs with psychopathology factors modelled within i) a correlated factors structure, and ii) a bifactor structure.The schizophrenia PRS was associated with an increase in factors describing psychotic experiences, negative dimension, depression, and anxiety, but once modelling a general psychopathology factor specific effects above this persisted only for the negative dimension. Similar factor relationships were observed for the neuroticism PRS, with a (weak) specific effect only for anxiety once modelling general psychopathology.Psychopathology during adolescence can be described by a general psychopathology construct that captures common variance as well as by specific constructs capturing remaining non-shared variance. Schizophrenia risk genetic variants identified through genome-wide association studies mainly index negative rather than positive symptom psychopathology during adolescence. This has potentially important implications both for research and risk prediction in high-risk samples."}
+{"text": "Drugs of abuse have the capacity to hijack the cellular and neurocircuit mechanisms mediating reward learning, forming non-adaptable, compulsive behaviors geared toward obtaining illicit substances. Here, we discuss current findings demonstrating how drugs of abuse alter intrinsic and synaptic LHb neuronal function. Additionally, we discuss evidence for how drug-induced LHb alterations may affect the ability to predict reward, potentially facilitating an addiction-like state. Altogether, we combine  The ability to accurately predict rewarding or aversive outcomes throughout life is a critical adaptive behavior that promotes survival and allows avoidance of threatening or unpleasant confrontations. This adaptive ability is attributed to an evolutionarily conserved hedonic neurocircuit which consists of an interwoven network linking forebrain, midbrain and hindbrain regions, that together systematically regulate the release of monoamines  and reward outcomes , a brain region that sends inhibitory input to dopamine neurons in the ventral tegmental area (VTA). During negative RPEs, LHb neurons are activated and send excitatory signals to RMTg inhibitory neurons which project to and inhibit dopamine neuron firing  to a tail pinch have decreases in firing rates during cocaine microiontophoresis application  are decreased shortly after cocaine administration (0\u201310 min post injection), but this transient inhibition progresses to increased firing activity (15\u201335 min post injection) in specific neuronal populations  cocaine self-administration causes increases in LHb neuron excitability as measured using AR-mediated inhibition is decreased at entopeduncular nucleus (EPN)-to-LHb neuronal synapses (measured in brain slices)  amplitude are observed along with increases in the ratio of currents mediated by AMPA- and NMDA-type glutamate receptors (AMPAR/NMDAR) onto LHb neurons that specifically project to the RMTg  increases spontaneous action potential firing and membrane excitability in LHb neurons measured using These results suggest that the increased LHb activity may serve as a neural mechanism to facilitate drug-induced negative affect. Therefore, inhibiting LHb neuronal output could potentially prevent drug-induced anhedonia. To this end, low dose (0.25 g/kg) ethanol-induced conditioned place aversion is reversed to conditioned place preference (CPP) following lidocaine-induced LHb inhibition , likely invoking negative RPE signaling in the LHb and subsequent LHb-induced dopamine neuron inhibition Figure . TherefoGiven that positive RPE is associated with the phasic firing of dopamine neurons, and that negative RPE is associated with LHb signaling, one would expect that the acquisition or maintenance phase of drug self-administration (a positive RPE paradigm) might be independent of LHb control. In agreement with this, it has been shown that LHb lesions do not alter heroin or cocaine self-administration administration during the acquisition or maintenance phases, as LHb lesioned animals seek and obtain similar amounts of drug compared to non-lesioned animals (Wang et al., The LHb regulates dopamine neuron firing during negative RPE signaling and provides instructive signals for reward-seeking behaviors (Matsumoto and Hikosaka, In addition to regulating negative RPE, the LHb is critically involved in learning and memory processes that are associated with avoidance behaviors (Stamatakis and Stuber, In conclusion, we reviewed evidence supporting the importance of the LHb in regulating reward learning and updating of reward-related information. In preclinical experiments, lesioning the LHb or inhibiting LHb function elicits similar impairments in reward prediction when compared to human patients suffering from drug abuse. However, more work is needed in animal models of drug abuse to understand whether and how drugs of abuse facilitate reward-related learning impairments mediated by LHb function.NG, PN and YD developed the focus of this review. NG and PN wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Orchids are known for both their floral diversity and ecological strategies. The versatility and specialization in orchid floral morphology, structure, and physiological properties have fascinated botanists for centuries. In floral studies, MADS-box genes contributing to the now famous ABCDE model of floral organ identity control have dominated conceptual thinking. The sophisticated orchid floral organization offers an opportunity to discover new variant genes and different levels of complexity to the ABCDE model. Recently, several remarkable research studies done on orchid MADS-box genes have revealed the important roles on orchid floral development. Knowledge about MADS-box genes' encoding ABCDE functions in orchids will give insights into the highly evolved floral morphogenetic networks of orchids."}
+{"text": "Emerging research indicates that exercise combined with cognitive training may improve cognitive function in older adults. Typically these programs have incorporated sequential training, where exercise and cognitive training are undertaken separately. However, simultaneous or dual-task training, where cognitive and/or motor training are performed simultaneously with exercise, may offer greater benefits. This review summary provides an overview of the effects of combined simultaneous vs. sequential training on cognitive function in older adults. Based on the available evidence, there are inconsistent findings with regard to the cognitive benefits of sequential training in comparison to cognitive or exercise training alone. In contrast, simultaneous training interventions, particularly multimodal exercise programs in combination with secondary tasks regulated by sensory cues, have significantly improved cognition in both healthy older and clinical populations. However, further research is needed to determine the optimal characteristics of a successful simultaneous training program for optimizing cognitive function in older people. Age-associated cognitive decline, which can progress to mild cognitive impairment and dementia, are growing public health concerns with no known cure. Regular exercise has been shown to provide some cognitive benefits in healthy and cognitively impaired older adults , and/or whether the cognitive training was conducted prior to or after exercise training. For instance, a 16-week RCT in older adults observed no cognitive benefits when exercise training was delivered after the cognitive training  and memory training, are associated with cognitive improvements in healthy older adults , P < 0.01), but there were no differences between the combined intervention and cognitive training alone. Secondary analysis also revealed that the effect size for sequential interventions was less than those for simultaneous interventions , but did not include exergaming or more recently published studies. Another review of 13 studies also reported that simultaneous dual-task training interventions including low-intensity activity  performed with a secondary cognitive or motor tasks, can benefit both physical function  and the cognitive abilities of older adults in dual-task situations  on cognitive function have been observed following a 12-week exergaming (Nintendo Wii) trial in one study involving 32 independent living older adults aged 65\u201378 years , exergaming typically includes cognitive challenges embedded within realistic physical activities, whilst providing virtual feedback. One of the first RCTs of exergaming for older adults revealed a promising differential cognitive benefit of exergaming  or motor tasks requiring divided attention , have improved multiple cognitive abilities in older adults  of simultaneous exercise and cognitive-motor training that promotes cognitive improvement in older adults. Based on the available data, interventions incorporating functional stepping exercises  of exposure, with a training frequency between 1 and 3 times per week Table , but notThe neurophysiological mechanisms underlying the cognitive improvements observed through combined cognitive and exercise training are yet to be identified; however cognitive and exercise training may stimulate similar neurobiological processes which produce a synergistic response. Exercise and cognitive training both increase cerebral blood flow  remain to be determined, studies incorporating moderate-intensity multimodal training in combination with secondary tasks involving a functional response to sensory cues have improved executive abilities and memory, which may prolong functional independence in older adults. However, further research is needed to determine if these improvements can be maintained, and even prevent or delay the onset of cognitive impairment and dementia. Finally, an understanding of the neurobiological mechanisms underpinning any cognitive improvements available from combined exercise-cognitive training in older adults also requires further investigation.JT and RMD wrote the manuscript and RLD, CM, and LM reviewed the draft versions. All authors have read and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BY and handling Editor declared their shared affiliation."}
+{"text": "Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has increasingly been performed for the diagnosis and staging of thoracic malignancies. Findings of a necrotic lymph node raise concern for infectious process and malignancy. A hypoechoic area on ultrasound/EBUS within a lymph node without blood flow is suggestive of pathologies like infections or malignancy. Inspection of the fluid could suggest a diagnosis; clear aspirates usually suggest bronchogenic or mediastinal cysts and purulent material suggests abscesses or necrotic lymph nodes. Growing tumor cells require a blood supply; if the vascular stroma is insufficient due to rapidly growing malignant tumors this could lead to large central areas of ischemic necrosis. Necrotic aspiration of lymph nodes is not always of infectious etiology. Aspiration of fluid in EBUS-TBNA is a rare occurrence, and malignancy should be considered when purulent fluid material is obtained. We present an elderly woman who underwent bronchoscopy with EBUS-TBNA for evaluation of upper lung nodule and mediastinal lymphadenopathy. Pus-like material was obtained on needle aspiration and endobronchial biopsy and mediastinal core biopsy revealed squamous cell carcinoma. Ultrasound imaging has become part of the armamentarium of the pulmonologist; EBUS-TBNA plays an important role in the evaluation and diagnosis of several diseases especially malignancy .EBUS-TBNA is well accepted and increasingly being used as a safe minimally invasive procedure for the diagnosis and staging of lung cancers; it carries an overall sensitivity of 89% and a negative predictive value of 91% . It is aA 71-year-old woman from Dominican Republic was admitted for dyspnea, fever, and nonproductive cough of one-day duration. Her medical history was significant for diabetes mellitus, systolic heart failure, gastric B-cell lymphoma treated with chemotherapy, and surgically treated basal cell carcinoma of forehead. She was a heavy smoker with 40 packs/year. She denied alcohol or illicit drug use. Family history was noncontributory. There were no sick contacts, recent traveling, or occupational exposures and no history of exposure to tuberculosis.Initial examination showed an elderly woman on respiratory distress. Chest auscultation revealed bibasilar crackles and diffuse expiratory wheezing. There were no palpable lymphadenopathy, organomegaly, or skin lesions. The rest of exam was unremarkable. Significant laboratory findings included elevated Pro-BNP; there was no leukocytosis and renal and liver function was normal. A right sided thoracentesis was performed with pleural fluid analysis revealing transudative effusion with pleural/serum LDH ratio of 0.12 and pleural/serum protein ratio of 0.19.Patient was treated for exacerbation of heart failure with diuretics and antibiotics were given for presumptive community acquired pneumonia with clinical improvement.Chest-roentgenogram (CXR) on admission showed bilateral pleural effusion and infiltrates which rapidly improved suggesting a diagnosis of heart failure rather than pneumonic process . A chestPatient underwent flexible fiberoptic bronchoscopy (FFB) that revealed a small endobronchial lesion at the right upper lobe before the takeoff of anterior segmental bronchus. Endobronchial biopsy (EB) of the EBL as well as transbronchial biopsy (TBBx) of right upper nodule and EBUS-TBNA of the right paratracheal and subcarinal lymph nodes was performed. A 19\u2032\u2032 gauge needle was used for the EBUS-TBNA with a total of four needle passes per lymph node. Twenty ml of purulent appearing fluid was aspirated from the right paratracheal lymph node . AspiratAspiration of liquid material in EBUS-TBNA is uncommon. A hypoechoic area on ultrasound/EBUS within lymph nodes without blood flow is suggestive of pathologies like infections or malignancy. Inspection of the fluid is suggestive of a diagnosis; clear aspirates suggest bronchogenic or mediastinal cysts and purulent material suggests infection or rarely necrotic lymph nodes. Growing tumor cells require a blood supply; if the vascular stroma is insufficient due to rapidly growing malignant tumors this could lead to large central areas of ischemic necrosis , 5. Othe Histoplasma capsulatum leading to mediastinal abscesses and necrotic mediastinal lymphadenopathies [ Streptococcus related mediastinitis and mediastinal abscesses have also been reported in the literature [Necrotic mediastinal lymphadenopathy has been described in a wide variety of pathologies which include infectious and noninfectious etiologies. Tuberculosis is one of the most common infectious causes, especially in areas with high prevalence of tuberculosis . Other iopathies , 10. Bacterature .Noninfectious causes include histiocytic necrotizing lymphadenitis which is a benign lymphadenitis, characterized by enlarged lymph nodes with histopathological findings of proliferation of lymphocytes and histiocytes, nuclear debris, and necrotic lesions affecting mainly young women ; systemiLymphomas also may present as necrotic mediastinal lymphadenopathy. Usually metastases present more frequently as parenchymal lung nodules, but these are closely followed by mediastinal lymphadenopathy and pleural effusions .The initial differential diagnoses in our patient were infectious etiologies versus malignancy due to the strong medical history of malignancies and imaging findings. Bronchoscopic findings were conflicting, inspection revealed an endobronchial lesion, and EBUS sampling revealed cyst-like structure and aspirated material looked purulent. It is also important to note our patient had no clinical signs to suggest a rheumatologic disorder. To our knowledge, 2 cases of EBUS-TBNA of mediastinal lymph node revealing purulent material with a final diagnosis of malignancy have been reported in the English literature , 5. In bThe increased use of EBUS-TBNA to assess mediastinal diseases will likely lead to an increase in the number of patients with malignancies presenting with purulent aspirate. We suggest neoplastic conditions, especially squamous cell carcinoma, to be included in the differential diagnosis in patients where the EBUS guided needle aspiration reveals purulent material. Specimens should be analyzed to evaluate for infections like tuberculosis, fungal, and bacterial infections as well as malignancy."}
+{"text": "Aortic mycotic aneurysms are a rare but life-threatening potential complication of infective endocarditis. Rapid deterioration of the vascular wall in highly focal areas makes these pseudoaneurysms particularly prone to rupture, resulting in uncontrolled aortic hemorrhage. While computed tomography angiography (CTA) is the imaging modality of choice for the evaluation of mycotic aneurysms, it is not routinely performed in patients with known or suspected infective endocarditis (IE). However, current valvular heart disease guidelines support the use of cardiac CTA in cases of IE and suspected perivalvular extension when there is inadequate or ambiguous visualization on echocardiography. Here, we describe a case of IE in which cardiac CTA was used for two purposes: to assess perivalvular complications and to define coronary anatomy in a patient with a suspected embolic myocardial infarction. Subsequent detection of an aortic root mycotic aneurysm not previously demonstrated on transthoracic or transesophageal echocardiography allowed for timely and uncomplicated surgical intervention, while avoiding invasive coronary angiography. Mycotic aneurysm (MA) is a rare, potential complication of infective endocarditis that carries significant mortality risk. The pathogenesis begins with bacterial infiltration into the vessel wall, which may occur directly through trauma, by local extension from an existing infection, or by seeding from a distant site via septic embolism or bacteremia. A robust inflammatory response ensues, resulting in rapid, focal wall degeneration . InfectiA 67-year-old male with a known bicuspid aortic valve was admitted with fevers and chest pain one month following a dental procedure. Upon initial presentation to an outside hospital, he was reportedly found to have an elevated troponin of 2.78\u2009ng/mL and minor ST-segment elevations on ECG. Blood cultures drawn on admission grew alpha-hemolytic streptococci sensitive to penicillin and ceftriaxone. Both transthoracic and transesophageal echocardiograms demonstrated a subcentimeter aortic valve vegetation , moderatDue to vegetation size and the absence of heart failure symptoms, the patient was initially treated medically. A peripherally inserted central catheter was placed, and he was discharged on appropriate antibiotic therapy following negative repeat blood cultures. He subsequently returned five days later with persistent fever and new, severe left flank pain. Abdominal computed tomography demonstrated a wedge-shaped area of hypoattenuation consistent with a renal infarct . Blood cCardiac computed tomography angiography (CTA) was then performed to better visualize potential perivalvular extension and provide concomitant assessment of coronary arterial disease. CTA was performed using a prospective ECG triggered acquisition using a 64-slice scanner  during the administration of a triphasic contrast injection protocol . CTA revealed an eight-millimeter mycotic aneurysm of the aortic annulus extending into the intervalvular fibrosa and no residual aortic valve vegetation . AdditioMycotic aneurysms have widely varying clinical presentations depending on their location, the duration of infection, and patient comorbidities. The most common presenting symptoms are largely nonspecific, ranging from isolated leukocytosis or elevated erythrocyte sedimentation rate to bacteremia and fulminant sepsis . This maDue to exceedingly low incidence, little is known about the natural progression of mycotic aneurysms. Thrombosis, rapid enlargement, and even spontaneous regression are possible, though there are no known imaging findings that can accurately predict the clinical course . The repCTA is the imaging modality of choice for the diagnosis of mycotic aneurysms . By contIn this particular case, CTA identified a small but clinically relevant mycotic aneurysm that had not been visualized on either transthoracic or transesophageal echocardiography. The detailed assessment of both the coronary anatomy and the infarcted area allowed for confirmation of the embolic nature of the patient's MI and ruled out any atherosclerotic coronary disease requiring intervention during surgery.Resting or first-pass perfusion deficits can often be detected in patients with acute or chronic infarction with any modern CT scanner (64-slice or more) equipped to do coronary CTA. Cardiac MRI performed 8\u201310 minutes following gadolinium contrast (delayed enhancement) is a well-validated technique to detect myocardial scar (fibrosis) from any etiology based on the known retention of contrast material in areas of fibrosis. Scar (areas of hyperenhancement on delayed imaging) in a coronary distribution, as seen in this case, is typical of a myocardial infarction from a coronary etiology. Similarly, an additional noncontrast cardiac CT scan performed 8\u201310 minutes following the initial cardiac CTA can also be done to assess for scar (hyperenhancement on CT), similar to cardiac MRI. In this case, a delayed CT scan was not performed due to the presence of the previously performed delayed enhancement MRI and to reduce patient radiation exposure.Finally, this case highlights the advantage of cardiac CTA for coronary artery examination in lieu of high-risk catheterizations and nicely portrays its supplementary roles in both preoperative planning and the assessment of perfusion defects. It additionally demonstrates the utility of cardiac CTA for precise perivalvular assessment in infective endocarditis, particularly in cases of clinical suspicion for perivalvular extension and inadequate visualization on echocardiography."}
+{"text": "An efficacious vaccine for HIV remains elusive. Numerous groups have isolated antibodies from HIV infected individuals that can bind and neutralise antigenically diverse HIV strains, so-called broadly neutralising antibodies (bNAbs) . HIV bNAEBioMedicine, In the current issue of The complex interplay between viral escape and Env conformation observed by Bradley et al. and others gives some pause to reductionist approaches focussing on recapitulating single bNAb specificities by immunisation. Favourable linkage interactions between different bNAb epitopes, shown here for the MPER and the CD4 binding site or V3 loop, suggests vaccines simultaneously targeted to multiple epitopes may be advantageous. While targeting the MPER by vaccination may be difficult due to described self-mimicry and frequent generation of autoantibodies , the resThe authors declare no conflicts of interest."}
+{"text": "Brain-machine interfaces (BMI) may support motor impaired patients during activities of daily living by controlling external devices such as prostheses (assistive BMI). Moreover, BMIs are applied in conjunction with robotic orthoses for rehabilitation of lost motor function via neurofeedback training (restorative BMI). Using assistive BMI in a rehabilitation context does not automatically turn them into restorative devices. This perspective article suggests key features of restorative BMI and provides the supporting evidence: In summary, BMI may be referred to as restorative tools when demonstrating subsequently (i) operant learning and progressive evolution of specific brain states/dynamics, (ii) correlated modulations of functional networks related to the therapeutic goal, (iii) subsequent improvement in a specific task, and (iv) an explicit correlation between the modulated brain dynamics and the achieved behavioral gains. Such findings would provide the rationale for translating BMI-based interventions into clinical settings for reinforcement learning and motor rehabilitation following stroke. Such supported movements facilitate the detection of motor intention even in the absence of actual movements  and motor evoked potentials (MEP)  operant learning and progressive evolution of specific brain states/dynamics, (ii) correlated modulations of functional networks related to the therapeutic goal, (iii) subsequent improvement in a specific task, and (iv) an explicit correlation between the modulated brain dynamics and the achieved behavioral gains. Such findings would provide the rationale for translating BMI-based interventions into clinical settings for reinforcement learning and motor rehabilitation following stroke.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Some rodents produce ultrasonic vocalizations (USVs) for social communication using an aerodynamic whistle, a unique vocal production mechanism not found in other animals. The functional anatomy and evolution of this sound production mechanism remains unclear. Using laryngeal airway reconstruction, we identified anatomical specializations critical for USV production. A robust laryngeal cartilaginous framework supports a narrow supraglottal airway. An intralaryngeal airsac-like cavity termed the ventral pouch was present in three muroid rodents (suborder Myomorpha), but was absent in a heteromyid rodent (suborder Castorimorpha) that produces a limited vocal repertoire and no documented USVs. Small lesions to the ventral pouch in laboratory rats caused dramatic changes in USV production, supporting the hypothesis that an interaction between a glottal exit jet and the alar edge generates ultrasonic signals in rodents. The resulting undulating airflow around the alar edge interacts with the resonance of the ventral pouch, which may function as a Helmholtz resonator. The proposed edge-tone mechanism requires control of intrinsic laryngeal muscles and sets the foundation for acoustic variation and diversification among rodents. Our work highlights the importance of anatomical innovations in the evolution of animal sound production mechanisms. Rats et al. )"}
+{"text": "There are approximately 1 billion people living with chronic lower limb disability, many of whom are wheelchair users.Review cardiometabolic and neuromuscular risk profiles of wheelchair users, benefits of regular exercise and the causes of neuromuscular upper limb and hip injuries that hinder regular adherence.Literature published between 2013 and 2017 was adopted according to the standard practices for systematic reviews (PRISMA) through Crossref Metadata and Google Scholar searches. Individual paper quality was evaluated using a modified Downs and Black Appraisal Scale.The literature search identified 16 600 papers which were excluded if they were non-English, non-peer-reviewed or published before 2013. Finally, 25 papers were accepted, indicating that sedentary wheelchair users have poor cardiometabolic risk profiles (PCMRP) because of a lack of physical activity, limiting their quality of life, characterised by low self-esteem, social isolation and depression. Their predominant mode of physical activity is through upper limb exercises, which not only improves their cardiometabolic risk profiles but also precipitates neuromuscular upper limb overuse injuries. The primary cause of upper limb injuries was attributed to poor wheelchair propulsion related to incorrect chair setup and poor cardiorespiratory fitness.Wheelchair users have a high body mass index, body fat percentage and serum lipid, cholesterol and blood glucose concentrations. Empirical investigations illustrate exercise improves their PCMRP and cardiorespiratory fitness levels. Although literature encourages regular exercise, none discusses the need to individualise chair setup in order to eliminate wheelchair pathomechanics and upper limb neuromuscular injuries. Wheelchair users must be encouraged to consult a biokineticist or physiotherapist to review their wheelchair setup so as to eliminate possible incorrect manual wheelchair propulsion biomechanics and consequent overuse injuries. Many wheelchair users suffered injuries to the spinal cord, spinal nerves and cauda equina, and also underwent lower limb amputation  vascular and circulatory diseases precipitated through type 2 diabetes mellitus or peripheral vascular diseases, (2) trauma, (3) surgical removal of tumours and (4) congenital deformities  review the cardiometabolic risk profile and cardiorespiratory fitness status of wheelchair users, (2) determine the benefits of regular exercise, (3) determine common neuromuscular injuries adversely influencing wheelchair users adhering to regular exercise therapy and (4) identify wheelchair propulsion pathomechanics as the primary culprit of upper limb overuse and hip injuries. Previous literature encourages wheelchair users to engage in physical activity and exercise but they do not describe the initial challenges (such as muscle and neuromuscular pain and injuries) that users experience. The novelty of this commentary lies in the review of common neuromuscular injuries sustained by wheelchair users when they begin an exercise programme and which may prevent them from continuing with the programme. The identification of the cause of these upper limb overuse injuries among spinal cord injured (SCI) wheelchair users is unique to this review. This is the first commentary to discuss the abnormal force-couple relationships of the shoulder and hip muscles because of poor wheelchair setup and propulsion pathomechanics.The authors followed the standard practices for systematic reviews (PRISMA). The definitions were guided by the PRISMA checklist for participants, interventions, comparisons, outcomes and study designs (PICOS). The participants in this study were wheelchair users; the intervention was not necessarily a therapeutic intervention but is interpreted as an exposure, namely, the effect of exercise therapy on the well-being of wheelchair users. The outcomes of interest were (1) exercise therapy interventions for wheelchair users, (2) the effects of exercise therapy on wheelchair users\u2019 health and (3) common overuse injuries of physically active wheelchair users. The exclusion criteria were (1) publications prior to 2013, (2) literature not related to the health and physical status of wheelchair users, (3) psychological therapeutic interventions, (4) non-English papers and (5) non-peer-reviewed papers.A literature search of peer-reviewed and professional journal publications was conducted in the following search engine: Crossref Metadata database, an academic meta-database which comprises the following search engines: PubMed, Medline, Science Direct, Ebscohost, CINAHL and Google Scholar . The keyThe hierarchy of evidence and quality of appraisal tool were adapted from Abdullah, McDonald and Jaberzadeh  Table 1Table 1. The quality of each paper was appraised using a modified Downs and Black Appraisal Scale, which examined the quality of randomised controlled trials and non-randomised papers  cardiometabolic risk profile, (2) benefits of regular exercise to wheelchair users and (3) common neuromuscular injuries from upper extremity exercises.Wheelchair users often lead sedentary lifestyles and consequently have poor cardiometabolic profiles   are living with chronic disability and spend a considerable amount of time in wheelchairs Kate . Most ofThe most common overuse injuries include shoulder impingement, rotator cuff tendinitis, biceps tendinitis, lateral epicondylitis, ulnar neuropathy, De Quervain\u2019s tenosynovitis and carpal tunnel syndrome (Apple, Cody & Allen Manual wheelchair propulsion is categorised by the contact and recovery phases. Contact phase occurs when mechanical power is delivered to the wheelchair through hand contact with the rim of the wheel (Slowik et al. Sprigle  and WillSagittal plane analysis identifies an anterior pelvic tilt with increased hip flexor tightness and lumbar lordosis Sprigle  Figure . An anteIn an attempt to reduce wheelchair propulsion pathomechanics, scientists and engineers have redesigned the appearance and functionality of wheelchairs. Sports wheelchairs have undergone drastic and revolutionary design modifications in order to enhance sports performance and improve adherence to physical activity programmes. These ergonomic modifications improve the biomechanics of the user, which in turn curtails the incidence of upper limb overuse injuries (Sindall et al. It is recommended that manual wheelchair users have their wheelchairs reviewed in order to ensure that the wheelchair setup is ergonomically designed to meet their individual needs. Treatment and rehabilitation of the aforementioned overuse injuries pose a significant challenge because these individuals are primarily reliant on the upper limbs for weight-bearing activities and for mobility. It is further recommended that before starting an exercise programme, all wheelchair users should first receive clinical clearance from their medical practitioner regarding their participatory readiness. They must thereafter consult a biokineticist or a physiotherapist who will conduct a critical review of their wheelchair propulsion biomechanics in an attempt to prevent injuries. The biokineticist or physiotherapist should also prescribe an individualised therapeutic exercise programme.Wheelchair users have poor cardiometabolic risk profiles, low self-esteem and are at risk for socially withdrawn lives. Those who regularly exercise enjoy improved cardiorespiratory fitness and reduced cardiometabolic risk as well as reduced levels of depression and a consequently enhanced quality of life. Unfortunately, many wheelchair users who wish to be physically active are further restricted by upper limb overuse injuries. The primary cause of these injuries is wheelchair propulsion pathomechanics as a result of incorrect chair setup and limited cardiorespiratory fitness. It is therefore recommended that wheelchair users consult a biokineticist or physiotherapist before engaging in an exercise regime, so as to alleviate poor wheelchair propulsion biomechanics which may predispose them to overuse injuries. Medical practitioners, as well as the family and friends of wheelchair users, must encourage them to adhere to regular aerobic, muscle strength, and flexibility exercises in order to improve their quality of life."}
+{"text": "Endotherms regulate their core body temperature by adjusting metabolic heat production and insulation. Endothermic body temperatures are therefore relatively stable compared to external temperatures. The thermal sensitivity of biochemical reaction rates is thought to have co-evolved with body temperature regulation so that optimal reaction rates occur at the regulated body temperature. However, recent data show that core body temperatures even of non-torpid endotherms fluctuate considerably. Additionally, peripheral temperatures can be considerably lower and more variable than core body temperatures. Here we discuss whether published data support the hypothesis that thermal performance curves of physiological reaction rates are plastic so that performance is maintained despite variable body temperatures within active (non-torpid) endotherms, and we explore mechanisms that confer plasticity. There is evidence that thermal performance curves in tissues that experience thermal fluctuations can be plastic, although this question remains relatively unexplored for endotherms. Mechanisms that alter thermal responses locally at the tissue level include transient potential receptor ion channels (TRPV and TRPM) and the AMP-activated protein kinase (AMPK) both of which can influence metabolism and energy expenditure. Additionally, the thermal sensitivity of processes that cause post-transcriptional RNA degradation can promote the relative expression of cold-responsive genes. Endotherms can respond to environmental fluctuations similarly to ectotherms, and thermal plasticity complements core body temperature regulation to increase whole-organism performance. Thermal plasticity is ancestral to endothermic thermoregulation, but it has not lost its selective advantage so that modern endotherms are a physiological composite of ancestral ectothermic and derived endothermic traits. The basic principles of thermodynamics dictate that the rates of physiological functions in both endotherms and ecotherms are sensitive to changes in temperature , for example, let their body temperature vary considerably with environmental temperature  and Przewalski's horse  lowered peripheral temperatures in winter, with concomitant decreases in heart rates during activity and rest , physiological reaction rates shifted with seasonal and altitudinal changes in climate. R. fuscipes from two populations living in cold high altitude climates had significantly lower body temperatures compared to those from two warm coastal populations . These data indicate that adaptation or developmental processes lower the mode of thermal performance curves in cold climates, which would be beneficial for rats experiencing lower body temperatures.In rats from warm climates, residuals of state 3 rates were lowest at 33\u00b0C and increased with temperature. In contrast, state 3 rates of cold-climate rats were highest at 33\u00b0C and decreased with increasing temperature  represent the best studied mechanism that allows cells to detect changes in their environment directly (Nilius and Voets, Cyprinus carpio; Gracey et al., Hyla japonica; Sugimoto and Jiang, Temperature can also have direct effects on post-transcriptional processes, such as mRNA degradation, splicing, and translation efficiency. For example, temperature-dependent expression patterns of cold-inducible proteins are determined by the thermal sensitivity of post-transcriptional mechanisms (Sonna et al., The cold-shock RNA-binding protein RBM3 binds mRNAs to maintain translational efficiency (Peretti et al., Peripheral cells and tissues may also mount autonomous responses to local changes in temperature by indirect thermosensory pathways, where temperature-induced imbalances in cellular metabolites trigger compensatory responses. In skeletal muscle, decreasing temperatures cause an energy deficit, resulting in an increase in the AMP:ATP ratio (Towler and Hardie, The concept that endotherms have high and stable body temperatures despite environmental temperature fluctuations (Scholander et al., The mechanisms that mediate thermal plasticity are highly conserved among animals, and their broad range of functions is likely to preclude negative selection. For example, thyroid hormone action is essential for a broad range of physiological responses in animals, and is highly conserved across taxa (Heyland and Moroz, FS and AL conceived the ideas, prepared the manuscript and figures, and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "When exposed to stress, the hypothalamic-pituitary-adrenal axis is hyperactivated, which can cause the enlargement of the pituitary gland. Hence, pituitary gland volume could be a biomarker of stress present in psychosis. However, it remains unclear if individuals with psychosis have larger pituitary gland than healthy people. Previous studies investigating this question used small samples and reported inconsistent results. In the current study, we used an automated multi-atlas segmentation method to investigate the differences between pituitary gland volumes in a large sample of individuals on the psychosis spectrum.Data collection was completed across six sites in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium with a total of 755 participants included in the study - 174 individuals with schizophrenia (SZ), 115 with schizoaffective disorder (SZA), 167 with psychotic bipolar disorder (PBD), and 299 healthy controls (HC). Structural magnetic resonance images were acquired and pituitary gland volumes were obtained using the automated MAGeT-Brain algorithm. General linear model and post-hoc independent t-tests were used to analysis the differences between subgroups of patients using clinical diagnosis and agnostic Biotype classification (Biotype 1 being the most cognitively impaired). We also explored potential effect of antipsychotic intake, symptoms severity and duration of illness. In all analyses, we used Bonferroni correction for multiple comparisons and entered confounds as covariates .Overall, the pituitary gland volumes were not significantly different between patients and HC. No significant main effect of diagnosis was observed, but SZ patients had trending larger pituitary volume compared to HC . We observed a significant main effect of Biotype (p=.003), with Biotype 1 having significantly larger pituitary gland than HC and Biotype 2 (p=.004 and p=.013). In the patients group, no significant relationship between the pituitary gland and the amount of antipsychotic intake was observed . Significant correlations with the pituitary gland volume were observed with symptoms severity , and with the duration of illness . Importantly, Biotypes did not significantly differ in terms of symptoms severity nor duration of illness.As a group, individuals with psychosis do not have abnormal pituitary gland volume, but larger pituitary gland is related to shorter duration of illness and greater symptoms severity. Therefore, larger pituitary gland volume could be a state-related biomarker of psychosis. Moreover, while we did not observe any significant subgroup differences using clinical diagnosis, our results suggest an increase in pituitary volume in biotype 1 patients compared to HC. These findings clarify previous inconsistent reports, and encourage further investigation of stress biomarkers in individual with psychosis with lower cognitive abilities. In the future, this could lead to the development of more targeted treatments for this specific subgroup of patients."}
+{"text": "BluePen Biomarkers provides a unique comprehensive multi-omics biomarker discovery and validation platform. We can quantify, integrate and analyze genomics, proteomics, metabolomics and lipidomics biomarkers, alongside clinical data, demographics and other phenotypic data. A unique bio-inspired signal processing analytic approach is used that has the proven ability to identify biomarkers in a wide variety of diseases. The resulting biomarkers can be used for diagnosis, prognosis, mechanistic studies and predicting treatment response, in contexts from core research through clinical trials. BluePen Biomarkers provides an additional groundbreaking research goal: identifying surrogate biomarkers from different modalities. This not only provides new biological insights, but enables least invasive, least-cost tests that meet or exceed the predictive quality of current tests. The company was founded by experts from the field of biomarker discovery and validation at the University of Pennsylvania, which complements the bioinformatics expertise provided by Emerald Logic from Aliso Viejo . A major goal of the company is to address the problem of poorly predictive biomarkers that was identified by George Poste in his provocative 2011 article in Nature [BluePen Biomarker's team of management and scientific advisors comprises leading biomedical scientists who provide a coordinated approach to fully integrated biomarker solutions;Genomics, proteomics, metabolomics and lipidomics research is conducted in BluePen Biomarkers\u2019 laboratories using state-of-the-art instrumentation;The products of multi-omics research are integrated using sophisticated bioinformatics based on combinatorial signal processing and analytic approaches developed by Emerald Logic to provide a fully integrated biomarker solution ;The fundamental conviction of the company's founders is that any intervention that has a biologic outcome will have a detectable predictive biomarker signature. The challenge is to detect that signature;The comprehensive multi-omics systems biology platform available at BluePen Biomarkers coupled with Emerald Logic's innovative signal processing approach provides a powerful solution to the biomarker needs of academia as well as pharmaceutical and biotech industries ;The substantial expertise available within the company provides a unique resource for assessing potential clinical biomarker needs;Biomarker discovery and validation can be tailored to the particular project under consideration;BluePen Biomarkers now provides a commercial multi-omics platform that can quickly yield highly predictive biomarkers.BluePen Biomarkers was established in April 2016 in Philadelphia PA through a collaboration between the University of Pennsylvania's Center for Innovation, Blueprint Bio and Emerald Logic from Aliso Viejo , which is sometimes known as whole transcriptome shotgun sequencing. RNA-Seq, which is conducted by next-generation sequencing (NGS) using an Illumina HiSeq 3000 instrument, has largely replaced microarray analysis for the quantification of mRNA transcripts in a biofluid sample at a given moment in time. This can provide biomarker signatures of particular disease states. RNA-Seq can also be used to assess alternative gene-spliced transcripts, post-transcriptional modifications, gene fusion, mutations/single-nucleotide polymorphisms, different populations of RNA, total RNA, micro-RNA and transfer-RNA;Proteomics analyses normally involve targeted quantification of the major proteins that are identified as being upregulated by the RNA-Seq data. Analyses are conducted using nanospray ionization coupled with two-dimensional ultraperformance liquid chromatography/high-resolution mass spectrometry (UPLC-HRMS/MS) coupled with parallel reaction monitoring (PRM). These studies are conducted on a Thermo Q Exactive HF Hybrid Quadrupole-Orbitrap mass spectrometer operating in a targeted mode. Validation of differentially regulated proteins is conducted using rigorous stable isotope dilution UPLC-HRMS. Stable isotope-labeled protein standards are generated using stable isotope labeling by amino acids in cell culture (SILAC) based methodology ;Metabolomics and lipidomics analyses are conducted on serum samples that have been extracted using Bligh and Dyer methodology ,7. For bwww.lipidmaps.org). This means that BluePen Biomarkers can potentially discover lipid biomarkers where no standards are available to confirm structures. In this case, total synthesis is conducted using the extensive synthetic expertise that is available within the company so that absolute structural confirmation can be conducted before embarking on extensive clinical studies;Stable isotope-labeled metabolite and lipid standards are generated using stable isotope labeling by essential nutrients in cell culture (SILEC) methodology . There aBioinformatics analyses are conducted by Emerald Logic using a proprietary analytic platform that they have developed. This will identify signals in mRNA, protein, metabolite and lipid expression between cases and controls. An optimal panel of biomarkers will then emerge with maximal clinical specificity and sensitivity for a particular indication.Whole blood is normally provided to BluePen Biomarkers for genomics analysis; whereas serum is normally supplied for proteomics, metabolomics and lipidomics analyses. However, buffy coat or peripheral blood monocytes (PBMCs) are sometimes provided for proteomics analyses and platelets are sometimes provided for metabolism studies or specific mitochondrial protein quantification . BluePenDeveloping clinically useful biomarkers in biofluids is a complex process that often results in failure . TherefoQuantitative biomarker studies generally require the most sensitive means of detection possible ,11. The An authentic stable isotope-labeled analog of a biomarker is identical to the endogenous molecule, except for its mass . The resThe search for small molecule biomarkers that are predictive of cardiovascular disease, neurodegenerative diseases and cancers has been particularly intense and frustrating . HoweverBluePen Biomarkers was established in April 2016 to provide a coordinated approach to fully integrated biomarker solutions;The products of multi-omics research are integrated using sophisticated bioinformatics based on combinatorial signal processing and analytic approaches developed by Emerald Logic to provide a fully integrated biomarker solution;BluePen Biomarkers believes that by linking biomarker discovery and validation with the sophisticated bioinformatics provided by Emerald Logic that it will be possible to rationally approach the development of biomarkers for specific diseases;RNA-Seq is used to assess the potential utility of transcript profiling for biomarker analysis and upregulation of relevant proteins is confirmed by targeted proteomics;BluePen Biomarkers uses methods based on UPLC-HRMS for proteomics, metabolomics and lipidomics methods on their Thermo Q-Exactive HF instruments;This provides the only commercial multi-omics platform currently available that can quickly yield highly predictive biomarkers;The fundamental conviction of the company's founders is that any intervention that has a biologic outcome will have a detectable predictive biomarker signature."}
+{"text": "Negative symptoms are core features of schizophrenia and can be grouped into two domains. These are apathy including anhedonia, avolition and asocialty as well as diminished expression including blunted affect and alogia. A large body of research found that ventral striatal hypoactivation is linked to negative symptoms. In particular, it has been shown that this neural correlate is specific for apathy but not diminished expression. Here, we investigated whether this dissociation can also be found in ventral striatum volume.We included brain structural T1 MRI data of 60 patients diagnosed with schizophrenia (SZ) and 58 healthy controls (HC). Negative symptoms in these groups have been assessed using the Brief Negative Symptom Scale (BNSS). We performed voxel-based morphometry (VBM) using the statistical parametric mapping package . We performed a region of interest (ROI) analysis of ventral and dorsal striatal volume between patients with schizophrenia and healthy controls. Furthermore, we analyzed the correlation of right and left ventral striatal volume with apathy and diminished expression in patients with schizophrenia. Moreover, we analyzed potential group differences in gray matter volume in an exploratory whole-brain analysis. Finally, we performed an exploratory whole-brain linear regression to identify potential correlations between the two negative symptom dimensions and gray matter volume. Patients with schizophrenia showed no differences in ventral striatal volume compared to healthy controls. Apathy or diminished expression did not correlate with ventral or dorsal striatal gray matter volume in patients with schizophrenia. In the exploratory whole-brain analysis we found significant less gray matter volume in the right insula of schizophrenia patients compared to healthy controls . Our exploratory whole-brain linear regression revealed no significant correlation between apathy or diminished expression and gray matter volume changes in patients with schizophrenia.Although a correlation of apathy and ventral striatal volume has been shown in a previous study with fewer subjects, we could not reproduce this finding in a larger group of 60 patients with schizophrenia . However, while these negative findings do not support the association between apathy and ventral striatal volume, there may be more subtle brain structural changes linked to the pathophysiology of apathy, which cannot be detected by voxel based morphometry. The gray matter reduction in the right insula in subjects with schizophrenia replicated findings from previous studies in schizophrenia ."}
+{"text": "Medical students matriculating in the coming years will be faced with treating an expansive increase in the population of older lesbian, gay, bisexual, and transgender (LGBT) patients. While these patients face healthcare concerns similar to their non-LGBT aging peers, the older LGBT community has distinct healthcare needs and faces well-documented healthcare disparities. In order to reduce these healthcare barriers, medical school curricula must prepare and educate future physicians to treat this population while providing high quality, culturally-competent care. This article addresses some of the unique healthcare needs of the aging LGBT population with an emphasis on social concerns and healthcare disparities. It provides additional curricular recommendations to aid in the progressive augmentation of medical school curricula.Abbreviations: Liaison Committee on Medical Education (LCME); LGBT: Lesbian, gay, bisexual, transgender In the year 2000, 1 to 2.8 million lesbian, gay, bisexual, or transgender (LGBT) adults aged 65 and older were living in the United States . As suchRecently, the Association of American Medical Colleges (AAMC) published a 300+ page resource for medical educators outlining the implementation of curricular and institutional climate changes to improve the healthcare of LGBT and gender nonconforming patients . The pusOlder LGBT adults experience significant health disparities related to aging . In a poAging LGBT individuals experience a wide array of physical and psychological healthcare concerns synonymous with their heterosexual, binary, or gender-conforming peers . HoweverWith these \u2018chosen families\u2019 comes significant differences in caregiving and social support networks in the older LGBT community. While studies of the general US population indicate that between 25\u201344% of caregivers are male, within the LGBT community there is an even percent of male and female LGBT caregivers . Thus suConsiderations regarding \u2018chosen families\u2019 and unique caregiving responsibilities impact decisions related to retirement and end-of-life care. Completion of a living will or durable power of attorney is approximately 29% for both LGBT adults and non-LGBT adults . HoweverIn accordance with LCME accreditation Standard 7.6 emphasizing culturally competent care and development of solutions for healthcare disparities , studentIn addition to addressing concerns related to health disparities, medical students must be advised about the unique support systems and potential stressors in order to provide improved, culturally competent care to their future patients. This can be accomplished by increasing exposure of students to older LGBT adults by utilizing a panel of local community members. This panel could be modeled from The Gay and Grey Program (GGP)\u2019s trainings given by older LGBT adult volunteers to students and professionals in Portland, Oregon . OverallIn addition, complex end-of-life care decisions and the legal experiences of LGBT patients with \u2018chosen families\u2019 could be addressed in medical school ethics courses by utilizing a Problem Based Learning (PBL) approach. Unlike traditional passive learning with professor-designed didactic lectures, PBL involves active learning with dynamic interactions between learners and teachers . StudentIn order to educate a new generation of physicians equipped to provide culturally competent care, specific gaps in knowledge must be assessed. There are well-documented gaps in the cultural competency of LGBT older adult patients among health and social service providers . Gaps inSocietal problems of perceived discrimination, coupled with a lack of adequate training for future physicians, may contribute to unmet healthcare needs of the older LGBT patient population. Increased cultural competency related to physician-patient relationships must be addressed through progressive augmentation of medical school curriculum. As current and future healthcare providers, we must see that the needs of older LGBT adults are adequately addressed in medical education in order to ensure well-rounded, culturally competent care."}
+{"text": "Gilles de la Tourette syndrome (GTS) is a sensorimotor disorder where the sensitivity to external and internal stimuli might be increased and unwanted responses to such stimuli cannot be sufficiently suppressed.Transcranial magnetic stimulation (TMS) studies indicate that, at rest, axonal excitability of cortico-spinal neurons and intra-cortical inter-neurons was consistently normal in GTS. However, synaptic excitability in cortico-spinal neurons and the SICI circuit may be lower than normal. In addition, an electrophysiological marker of sensory motor integration, SAI, was reduced in the baseline state consistent with reduced efficiency of synaptic inhibition. Given the possible influence of sensory inputs in triggering the release of tics reduced SAI may be a direct physiological reflection of increased access of sensory input to motor output in GTS. Experiments examining control of voluntary movements revealed that in GTS motor cortex excitability increases less than in controls when preparing a movement even though intra-cortical inhibition (i.e. SICI) normalises.In GTS the gain of many motor circuits may be reduced and hence less sensitive to small changes in input from other areas. These cortical changes may constitute an adaptive response to abnormal basal ganglia-motor cortex inputs."}
+{"text": "Implementation of interprofessional clinical guidelines for the prevention ofneuropathic diabetic foot ulceration has demonstrated positive effects regardingulceration and amputation rates. Current foot care recommendations are primarilybased on research regarding the prevention of ulcer recurrence and focused onreducing the magnitude of plantar stress (pressure overload). Yet, foot ulcerationremains to be a prevalent and debilitating consequence of Diabetes Mellitus. Thereis limited evidence targeting the prevention of first-time ulceration, and thereis a need to consider additional factors of plantar stress to supplement currentguidelines.The first purpose of this article is to discuss the biomechanical theoryunderpinning diabetic foot ulcerations and illustrate how plantar tissueunderloading may precede overloading and breakdown. The second purpose of thiscommentary is to discuss how advances in biomechanical foot modeling can informclinical practice in the prevention of first-time ulceration.Research demonstrates that progressive weight-bearing activity programs to addressthe frequency of plantar stress and avoid underloading do not increase ulcerationrisk. Multi-segment foot modeling studies indicate that dynamic foot function ofthe midfoot and forefoot is compromised in people with diabetes. Emerging researchdemonstrates that implementation of foot-specific exercises may positivelyinfluence dynamic foot function and improve plantar stress in people withdiabetes.Continued work is needed to determine how to best design and integrate activityrecommendations and foot-specific exercise programs into the currentinterprofessional paradigm for the prevention of first-time ulceration in peoplewith Diabetes Mellitus. Exercise is often overlooked in current ulcer prevention guidelines.Abnormal plantar loading and foot function may contribute to ulceration.Progressive weight-bearing programs can be considered for ulcer prevention.Foot-specific exercises may improve foot function and ulcer prevention.Continued study may endorse inclusion of exercise into current guidelines.,Approximately one out of eleven adults, equating to 415 million people worldwide, havediagnosed or undiagnosed Diabetes Mellitus (DM)--,Among the numerous multi-system health consequences of DM, foot ulceration is an all toocommon problem. Lifetime prevalence estimations of foot ulceration in people with DM areas high as 25%, with a yearly incidence rate of 2-4%,recurrence,first-time ulceration. Yet, the evidenceto guide preventative efforts of first-time ulceration is strikingly limitedClinical guidelines have been developed to direct treatment and prevention strategiesfor foot ulceration, and are regularly updated based on current evidence---Biomechanical research has been an integral component underlying our understanding oftissue breakdown and in the development of ulcer prevention guidelines. For example, theuse of specialized footwear and/or insoles to relieve zones of high plantar pressure isfounded on the biomechanical theory that plantar tissue overload creates tissuebreakdown. While off-loading footwear is vital to ulcer healing and important to theprevention of ulcer recurrence, it is less clear how and when to apply the tissueoverloading principle to the prevention of first-time ulceration. Recent evidencesuggests that too much off-loading, as measured by decreased weight-bearing activityfrequency, may be counterproductive in ulcer prevention effortsThe purposes of this article are to present the contemporary biomechanical theoryunderpinning diabetic foot ulcerations and to discuss how advances in research andbiomechanical foot modeling can inform and influence clinical practice in the preventionof first-time ulceration.-,-overloading via momentary high stress or the accumulation ofundetected and repeated low to moderate stress on an area of the plantar neuropathicfootrepetition ofmechanical loading is as important as the magnitude of loading and howrepeated exposure to episodes of stress lowers the threshold of tissueinjury,-Neuropathic foot ulceration begins with insufficient blood glucose control, and it is acombination of intrinsic and extrinsic elements that beset the foot of an individualwith DM. Peripheral neuropathy coupled with the external stress of weight bearing hasbeen recognized historically as the primary pathway to neuropathic ulcerationunderloading may precede mechanical overloading of plantartissue. People with DM and peripheral neuropathy (DMPN) have reduced or variableweight-bearing activity prior to ulceration,,Therefore, external mechanical stress is a composite value that includes direction ofload application, time , and magnitude (force/area),,-Current ulcer prevention guidelines advocate for an interprofessional approach thatincludes physicians, nurses, physical therapists, orthotists, caregivers, and patients.A comprehensive strategy, including regular glucose monitoring, patient education, dailyfoot inspection, regular foot screenings and care, and footwear modification, isrecommendedmagnitude of plantarloading (pressure) are commonly combined with reduced weight-bearing activity todecrease the repetition of loading. Evidence suggests footwearintervention should aim for a pressure relief target value of 30% to reduce andredistribute plantar pressure and thus mitigate the potential for tissue breakdownand the assessment of the pressure-relievingeffects of the prescribed custom footwear/insoles. Further, footwear intervention iscontingent on patient adherence, as adherence below 80% negatively affects the footwearefficacy,,Contemporary recommendations for footwear intervention primarily ascribe to theoverloading theory of ulceration and remain an important aspect of ulcer prevention.Footwear interventions aimed at reducing the re-ulceration rates. While thepositive effects of footwear intervention are clear, differences in study designs andfootwear/insole strategies (over-the-counter vs. custom) have created different resultsacross studies. Nevertheless, a recent randomized clinical trial (RCT) that followedbest practice guidelines demonstrated that people with DMPN had less ulcer recurrencewhen wearing custom footwear with monitored pressure relief (<200 kPA or 25%reduction at targeted forefoot/midfoot sites) versus a custom footwear only groupIn a systematic review, van Netten et al.,,Recommendations for prevention of first-time ulceration also rely on the overloadingparadigm previously described. Rizzo et al.While the need for more research regarding footwear intervention and foot screeningpractices remains important, additional factors that may also prevent first-time tissuebreakdown should be considered. These factors include the frequency of weight-bearingactivity and the quality of dynamic foot function. Weight-bearing activity frequency isan important consideration as it pertains to plantar tissue tolerance to stress. Ratherthan reducing weight-bearing activity prior to tissue damage in the at-risk patient,maintenance or progression of weight-bearing activity  may helpavoid tissue underloading. An understanding of dynamic foot function and how the footmay be internally stressed during each step of every day in a patient with DMPN isequally important. Abnormal stress secondary to altered dynamic foot function fromneuropathic tissue changes may expedite deformity and plantar tissue damage. Withcontinued research focused on weight-bearing activity and dynamic foot function,interventions to modify these factors may advance and warrant inclusion in clinicalguidelines.increase the risk for futureulceration,,While exercise (including weight-bearing activity) is recommended to improve glycemiccontrol, current guidelines are vague regarding how clinicians should dose andpromote exercise in people with DM who are at risk for ulceration. Further, activityincrease in people with DM is complicated by co-morbid medical conditions. Yet,equally important is the idea that plantar tissue may already be deconditioned priorto first-time ulceration. Research demonstrates that too much off-loading duringpreventative care may potentially ,Efforts to increase weight-bearing activity and promote plantar tissue resilience andglycemic control in people with DMPN are promising regarding tissue breakdown. TwoRCTs demonstrate that ulcer rates do not increase following an intervention toincrease weight-bearing activity,reduce ulceration risk has yet to be delineated. Apossible barrier to the development of such a protocol is the lack of an establishedbiomarker  toguide the assessment of plantar tissue integrity. The inability to definitivelyassess tissue integrity and adjust activity dosage in a patient-specific mannerlikely precludes inclusion of weight-bearing activity regimens in currentpreventative guidelines. For this reason, it is relevant to consider not only howoften the foot is stressed during weight-bearing activity, but alsohow it is stressed.At present, conscientious patient instruction should include a program of regulardaily weight-bearing activity in an attempt to improve glycemic control andpotentially maintain plantar tissue integrity-In-vivo assessment of dynamic foot function fosters hypotheses generation about howinternal structures are performing and consequently stressed during weight-bearingactivity. Additionally, dynamic foot function represents the behavior of the footduring the time period when the primary extrinsic stimulus of ulceration occurs. Dynamic foot function can be assessed using single- or multi-segmentmodeling approaches . Single--Single-segment modeling investigations of foot biomechanics in people with DMPN haveproduced mixed results regarding factors potentially linked to tissue breakdown.There have been variable findings regarding passive ankle joint mobility, anklemotion during walking, and forefoot plantar pressure,,,-,,st metatarsal and lateral forefoot sagittal plane ROM, duringwalking to elevated forefoot plantar pressures in people with DMPN. Changes in DMPNmulti-segment kinematics are also present during higher-level tasks. Hastings etal.Studies employing multi-segment foot modeling approaches have identified changes inkinematics during walking in people with DM and DMPN and in people with DMPN with ahistory of ulceration,,The use of multi-segment models in diabetic foot research demonstrates how morespecific modeling approaches can better link regions of foot dysfunction to regionsof diabetic foot pathology ; however, relationships between foot kinematics and plantarpressures are commonly generated from data collected during separate walking trials.Giacomozzi et al.,both ankle andmidfoot power may better reflect the degree of internal stresses, particularly at themidfoot, during functional tasks in people with DMPN. DiLiberto et al.and midfoot as factors of abnormal dynamic foot function inpeople with DMPN. Specifically, the reduced active mechanism support at the archraises questions regarding abnormal internal stresses on passive structures at bothregions of the foot. The cumulative effect of this kinetic pattern may contribute tothe development and/or progression of midfoot deformityApplication of single- and multi-segment modeling approaches has also advanced ourunderstanding of kinetic performance  in people with DMPN. Studiesusing single-segment foot models demonstrate a reduction in peak ankle plantarflexionpower during walking in people with DMPN, as compared to healthy controls,Changes in DMPN dynamic foot function have been attributed to neuropathic tissuechanges such as decreased tissue extensibility  and muscle atrophy/fatty infiltration. Recent research specifically supportsthe relationship between neuropathic muscle changes, multi-segment foot kinematics,and deformity in people with DMPN. Hastings et al.There is increasing focus on how to design intervention strategies to improve dynamicfoot function in people with DM who are at risk for ulceration,-Some studies have demonstrated promising biomechanical results by incorporatingfoot-specific exercises in people with DMPNPreservation of plantar tissue integrity and foot function for the prevention offirst-time neuropathic foot ulceration is a challenging endeavor for people with DMPNand their care providers. The effectiveness of preventative interventions is predicatedon blood glucose control, the advancement of the neuropathic process, and plantar tissueintegrity. It is imperative for clinicians to address the interplay between themagnitude (pressure), frequency (weight-bearing activity), and quality (dynamic footfunction) of foot stress. One of the most difficult challenges is to determine how tostrike an effective balance between too much (overloading) and too little (underloading)stress. When deciding between parameters of loading, the clinician is advised that thethreshold for tissue damage is contingent on both the current state of the foot tissueand how it will be stressed in the future.While there is room for improvement regarding foot-screening procedures to best evaluatetissue integrity and predict injury, recent research offers insight that may augmentcurrent clinical guidelines. In addition to the interprofessional approach and foot carepractices described previously, advising patients on interventions to address thefrequency and quality of stress should be considered. A progressive and well-monitoredweight-bearing activity regimen that includes walking, balance, and leg strengtheningcan positively influence patient health and function. Activity regimens not only promoteglycemic control, potentially slowing the effects of neuropathy, but also possiblydecrease the potential of plantar tissue underloading. Further, multi-segment modelinginvestigations suggest that addressing dynamic foot function is an additional supplementfor the prevention of first-time ulceration. Specifically, assessment of forefoot andmidfoot mobility, as well as assessment of intrinsic and extrinsic muscle strengthshould be part of routine foot screening examinations. Examination findings should guideclinical decisions for implementation of progressive exercise programs to improvedynamic foot function or direct patients to other appropriate interventions/careproviders . Continued work is needed to determine how to best design andintegrate activity recommendations and foot-specific exercise programs into the currentinterprofessional paradigm for the prevention of first-time ulceration in people withDiabetes Mellitus."}
+{"text": "Postpartum haemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide. Experimental and clinical studies indicate that prolonged oxytocin exposure in the first or second stage of labour may be associated with impaired uterine contractility and an increased risk of atonic PPH. Therefore, particularly labouring women requiring cesarean delivery constitute a subset of patients that may exhibit an unpredictable response to oxytocin. We mapped the evidence for comparative studies investigating the hypothesis whether the risk for PPH is increased in women requiring cesarean section after induction or augmentation of labour.clinicaltrials.gov and the WHO registry platform. We identified a total of 36 controlled trials investigating the exogenous use of oxytocin in cesarean section. Data were extracted for study key characteristics and the current literature literature was described narratively.We performed a systematic literature search for clinical trials in Medline, Embase, Web of Science, and the Cochrane Library (May 2016). Additionally we searched for ongoing or unpublished trials in Our evidence map shows that the majority of studies investigating the outcome PPH focused on prophylactic oxytocin use compared to other uterotonic agents in the third stage of labour. Only 2 dose-response studies investigated the required oxytocin dose to prevent uterine atony after cesarean delivery for labour arrest. These studies support the hypotheses that labouring women exposed to exogenous oxytocin require a higher oxytocin dose after delivery than non-labouring women to prevent uterine atony after cesarean section. However, the study findings are flawed by limitations of the study design as well as the outcome selection. No clinical trial was identified that directly compared exogenous oxytocin versus no oxytocin application before intrapartum cesarean delivery.Despite some evidence from dose-response studies that the use of oxytocin may increase the risk for PPH in intrapartum cesarean delivery, current research has not investigated the prepartal application of oxytocin in well controlled clinical trials. It was striking that most studies on exogenous oxytocin are focused on PPH prophylaxis in the third stage of labour without differing between the indications of cesarean section and hence the prepartal oxytocin status.The online version of this article (10.1186/s12884-017-1584-1) contains supplementary material, which is available to authorized users. Postpartum haemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide \u20134. ApproThe most widely used uterotonic drug for augmenting labour or to maintain uterine contractility during labour is oxytocin , 16. OxyConsidering that PPH rates are higher in cesarean section compared to spontaneous labour , particuWe adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) protocol for identifying, screening and eligibility of studies to conduct the present research work ). Furthermore, significantly more women in the labouring group compared to the non-labouring group required additional uterotonic agents . (ii) The other dose-response study from Balki et al. estimated the minimum effective intravenous dose of oxytocin required for adequate uterine contraction after cesarean delivery for labour arrest, however, without using an active control group [From 36 studies identified, 8 studies (1705 patients) included solely women requiring intrapartum cesarean delivery, mainly because of labour arrest \u201333. Howeturients . Thirty-ol group \u201332. WhetOur mapping also revealed that the majority of studies investigating PPH rates for different treatment groups are focused on prophylactic uterogenics and included women with different types of cesarean delivery (intrapartum and prelabour cesarean section). However, the PPH rates given in these studies were not stratified according to the indications for cesarean section. In addition, the prepartal oxytocin status was not considered as confounding factor by conducting subgroup analyses \u201363.ClinicalTrials.gov Identifier: NCT01869556 and NCT02794779). The estimated completion date for both studies is by the end of 2017. In addition, we identified HOLDS, a multicentre, double-blind randomised controlled trial to compare standard and high dose regimens of oxytocin for women with confirmed delay in the first stage of labour (http://www.isrctn.com/ISRCTN99841044). This trial randomises 1500 women and measure differences in rates and complications associated with cesarean section. If this study provides a subgroup analysis of PPH rates in those women requiring cesarean sections, important insights addressing the present research question will be given.The search for ongoing and unpublished studies identified 2 RCTs which may provide subgroup data estimating the blood loss and risk for PPH after cesarean section for labour arrest  Checklist. (DOC 60 kb)Additional file 2:Search Strategy in Medline (OvidSP). (DOCX 14 kb)"}
+{"text": "Evolving multicellularity is easy, especially in phototrophs and osmotrophs whose multicells feed like unicells. Evolving animals was much harder and unique; probably only one pathway via benthic \u2018zoophytes\u2019 with pelagic ciliated larvae allowed trophic continuity from phagocytic protozoa to gut-endowed animals. Choanoflagellate protozoa produced sponges. Converting sponge flask cells mediating larval settling to synaptically controlled nematocysts arguably made Cnidaria. I replace Haeckel's gastraea theory by a sponge/coelenterate/bilaterian pathway: Placozoa, hydrozoan diploblasty and ctenophores were secondary; stem anthozoan developmental mutations arguably independently generated coelomate bilateria and ctenophores. I emphasize animal origin's conceptual aspects  related to feeding modes, cell structure, phylogeny of related protozoa, sequence evidence, ecology and palaeontology. Epithelia and connective tissue could evolve only by compensating for dramatically lower feeding efficiency that differentiation into non-choanocytes entails. Consequentially, larger bodies enabled filtering more water for bacterial food and harbouring photosynthetic bacteria, together adding more food than cell differentiation sacrificed. A hypothetical presponge of sessile triploblastic sheets (connective tissue sandwiched between two choanocyte epithelia) evolved oogamy through selection for larger dispersive ciliated larvae to accelerate benthic trophic competence and overgrowing protozoan competitors. Extinct Vendozoa might be elaborations of this organismal grade with choanocyte-bearing epithelia, before poriferan water channels and cnidarian gut/nematocysts/synapses evolved.This article is part of the themed issue \u2018Evo-devo in the genomics era, and the origins of morphological diversity\u2019. Bacteria and protists greatly exceed vertebrates in different kinds of organism too. Lamarck thought unicells so evolutionarily recent that they had not yet had time to inexorably become multicellular. Not so; they existed billions of years longer than complex multicells and may outlive them. There are hordes of excellent unicellular niches; multicellularity is often selectively disadvantageous. Yeasts evolved multiply from multicellular filamentous ancestors; Myxozoa are parasitic unicells that evolved from animals with nervous systems (early-branching Cnidaria), losing epithelia, connective tissue, nerves and 70% of genes as useless, only their multicellular spores keeping nematocysts . So how Multicellularity evolves in two ways. Naked cells, as in animals and slime moulds, evolve glue to stick together. Walled cells modify wall biogenesis to inhibit the final split that normally makes separate unicells, so daughters remain joined. The ease of blocking that split allowed almost every group of bacteria, fungi and plants (and many chromists) to evolve multicellular walled filaments, more rarely two-dimensional sheets, most rarely three-dimensional tissues. Tissues require more geometric control of daughter wall orientation, as in embryophyte green plants and chromist brown algae; both can grow longer than blue whales. Evolving tissues is selectively harmful to many walled multicells whose filaments are best for reproductive success. Almost all multicells retain unicellular phases , so adhesion is temporally controlled and developmentally reversible\u2014except for purely clonal vegetatively propagating plants or \u2018colonial\u2019 invertebrates (evolutionarily transient) the only organisms that are never unicellular.2O, CO2 and minerals) just as does a single cell; so does a saprotrophic bacterial or fungal filament. However, a phagotrophic amoeba could not aggregate into a multicellular body and still locomote and feed the same way. Nor could most other protozoa. Many amoebae have become multicellular, but only temporarily for spore dispersal, not feeding. Aggregative multicellularity has produced multispore fruiting bodies numerous times in fundamentally different protist lineages  to switch from intracellular phagocytosis, as in amoebae or ciliates, to eating with a multicellular mouth and gut, whose cells have novel functions and structures absent in their unicellular ancestors. Animal feeding is effective only if novel cell types cooperate at a higher organizational level; most give up the ability to feed or reproduce, huge selective disadvantages not easily overcome.In 1866, James-Clark discovered choanoflagellate protozoa and their feeding on bacteria trapped by a collar surrounding their undulating cilium that generates the water current that draws them towards it. He noted that sponge collar cells (choanocytes) have the same structure and feeding method, correctly suggesting that sponges evolved from a choanoflagellate . Often sAmong extant animals, only sponges could have evolved directly from protozoa without changing feeding mode. The key problems in understanding animal origins are therefore how and why sponges evolved from a craspedid-like stem choanoflagellate and later generated all other animals. I attempt to explain both after briefly outlining enabling protozoan innovations. I shall emphasize simple conceptual aspects of the choanoflagellate/animal transition, often overlooked but more important than discovering extra protozoan genes suitable as precursors to animal functions. Such ancestral features exist in both choanoflagellates and more distant protozoan relatives of substantially different cell structures and feeding mode .In the light of site-heterogeneous trees using 187 protein sequences ,17, figuSulcozoan flagellates clearly could not have retained their characteristic locomotory or feeding modes had they evolved glue to stick together as a multicellular organism; such mutants would necessarily quickly starve to death. Nor could their immediate ancestors\u2014three successive groups of swimming, not gliding flagellates  collectively called excavates because their ventral groove looks more obviously scooped out ,17. The Knowing the structure and evolutionary potential of the closest relatives and ancestors of animals  and thatDictyostelium has a \u03b2-integrin-like adhesion protein [Integrins and associated molecules used for epithelial cell adhesion to extracellular matrix (ECM) were secondarily lost by choanoflagellates and fungi; without full genomes for the deepest branching Sulcozoa, the exact point of origin is unclear : though  protein  and its  protein  \u2014or even why\u2014but defining the selective forces that promoted the fundamental differentiation between sponge feeding cells (choanocytes) and non-feeding cells and between cells that stick together as epithelia and connective tissue cells embedded separately in a gelatinous mesohyl. Did epithelia evolve first or did epithelia and mesenchyme coevolve?Carchesium, Zoothamnion); some algal, e.g. chrysophyte Dinobryon. Mucilaginous multicellular branching structures are formed by Rhipidodendron (cercozoan chromists) or Phalansterium (uniciliate Amoebozoa). As no branching protists evolved a multicellular tissue, similar \u2018colonial\u2019 choanoflagellates are probably not directly relevant to animal origins. Nonetheless, they show that various linked flagellates can still feed in the same way as when unicellular, and their frequency suggests that branching stalks advantageously enable them to sweep prey from a much larger water volume than can one sessile cell. Filtering more water by a different sessile body form is, I argue, the selective advantage that made sponges.Four different ways of making multicellular choanoflagellates exist. Many become \u2018colonial\u2019 sessile organisms by evolving thin extracellular stalks that join cells together to form branched tree-like structures analogous to corals or plants ,10. OtheProterospongia choanojuncta, but I doubt this had a potential to yield a sponge. Sponge collars also join laterally often by a second mucus mesh to achieve 100% removal of suspended bacteria [More rarely, choanoflagellate multicells arise by linking adjacent cells by their collar microvilli as in bacteria , showingDiaphanoeca sphaerica, where cells often clump in hollow balls with cilia pointing inwards [Diaphanoeca, like other loricates (Acanthoecida), are tiny cells suspended within a much larger lorica of siliceous strips porous to water currents carrying prey. Aggregating porous loricas by connecting longitudinal strips allows colonial feeding despite cilia pointing inwards, as the collar outer surface that traps food still faces outwards. Water and bacteria can pass through the lorica mesh or wide interlorica spaces, so feeding mode is unchanged compared with unicells; cell bodies are not in contact so could not evolve into an epithelium to make a sponge. Acanthoecida are necessarily an evolutionary dead end.The loricate  inwards , exempli inwards  was mislSphaeroeca is a multicellular planktonic craspedid whose colonies are hollow balls with a surface cell monolayer, associated by cell bodies not collars, analogous to the alga Volvox that Hardy [Salpingoeca rosetta reversibly makes little multicellular balls, a capacity influenced by bacteria [Non-loricates (Craspedida) never aggregate with cilium facing inwards like sponges as that would suicidally stop collar-based feeding. at Hardy  invoked bacteria . Numerou4.Willmer emphasized the basic dichotomy between ciliated epithelial and non-ciliated, amoeboid, connective tissue cells as fundamental to animal development . Figure\u00a0Dictyostelium dead stalk cells.The primary dichotomy between uniciliate choanocyte and non-ciliate pinacocyte is also mirrored by that between sperm and egg. Therefore, part of the same gene switches needed for somatic differentiation could also be used to differentiate gametes. Once a three-layered structure with just two somatic cell types evolved, presponges could become quite large (compared with choanoflagellate unicells); selection for rapid establishment of a large embryo would strongly favour oogamy  by modifying choanocytes, presumably hermaphrodite. The animal bauplan was in place once a selective force for ever-larger filtering structures built from two dissimilar cell types existed: two germ line and two soma cell types. Accidental fragments could also reproduce vegetatively as choanocytes retained pluripotency . There wAnother selective advantage of evolving mesenchyme and massive tissues perhaps gave extra impetus to early animal evolution. Mucilage easily harbours bacterial symbionts potentially able to provide enough extra food to repay a presponge several times over the trophic and reproductive costs of non-feeding cells. Cultivating cyanobacteria in ECM mucilage would make the photophagotrophic consortium an extremely effective competitor with merely branched choanocyte-only colonial choanoflagellates. Lichen fungi can survive solely by cultivating cyanobacteria; a presponge could be even better off, being also a phagotroph able to grow far faster than a lichen in bacteria-rich water. Great Barrier Reef sponges 1\u20132 m high are often red through being packed with cyanobacteria whose biomass is greater than that of the sponge cells. Lake Baikal giant freshwater sponge tissues cultivate green algae. Both habitats are oligotrophic, making internal algae especially advantageous, but even in habitats rich in particulate food, the majority of sponge species are often photosynthetic . In orgaExtra cell types could be added relatively simply to help presponges to grow bigger and be less susceptible to environmental damage. An individual could grow basally across a rock and erect multiple laminae. Spatial controls evolved to prevent laminae from interfering with each other. Presumably, various morphologies and arrangements and ratios of the two basic cell types were experimented with, giving different compromises between maximizing feeding and mechanical stability. An early innovation necessary for large structures was to increase the ECM-synthesizing cells initially perhaps by evolving a third cell type\u2014the ancestral archaeocyte that left the epithelium, entering the mesohyl for secreting ECM in all directions, making a triploblastic tissue with mesenchyme sandwiched between two epithelia. Nowadays archaeocytes and choanocytes are the demosponge stem cells, expressing PIWI double-strand RNA-binding domain proteins whose short-RNA related functions are associated with germline and stem cell maintenance in higher animals  as well 5.Site-heterogeneous multigene trees  maximally support choanoflagellates being sisters to animals ,33; theySite-heterogeneous multigene trees equally strongly show sponges as a clade, disproving Nielsen's assumption that eumetazoa are more closely related to homoscleromorphs than others, and invalidating his twin assumptions that ancestral animals were lecithotrophic and eumetazoa secondarily lost lecithotrophy . His sug6.This presponge was not a sponge, for it lacked an aquiferous system (AS) with incurrent pores (ostia) and larger excurrent osculum or oscula. AS architecture has two advantages: (i) it increases food supply by pumping much larger water volumes past the choanoderm; (ii) compared with the essentially \u2018free-living gills\u2019 of the presponge, placing the choanoderm inside a globular or encrusting body protects choanocytes from damage by sand and other things swept against them by vigorous water currents and from damage by the currents themselves. Essential innovations making a sponge were (i) controlled formation of ostia of appropriate size, frequency and distribution; (ii) rearrangement of pinacocytes and choanocytes to internalize the latter, make a more compact less easily damaged body, and optimize water flow through internal choanoderm-lined channels. Ostia are intercellular in all Homoscleromorpha and most demosponges, but are formed by channels through specialized porocytes in Calcarea and not obviously homologous contractile porocytes in a few haplosclerid demosponges. I suspect they originated not by evolving a new cell type but by spatially controlling pinacocyte contacts and geometry; porocytes evolved later independently in Calcarea and haplosclerids. If so, ostia arose as part of the supracellular rearrangements that made an axially polarized water channel system. This major innovation almost certainly depended on prior evolution of morphogen gradients and homeobox and other spatially controlled switch genes that sponges share with Eumetazoa ,38. BeneChlamydomonas and could be a general property of eukaryote cilia that evolved during the origin of two structurally and behaviourally dissimilar cilia in the eukaryote cenancestor [Ephydatia, oscular sensory cilia lack the centre-pair microtubules as in eumetazoan sensory cilia [Making AS development and functioning more efficient probably entailed differentiating pinacocyte subtypes: specialization of some as myocytes to exert some control on oscular and ostial opening; and multiplication of non-epithelial mesohyl cell types. The branched mesohyl cells that synthesize a variety of neurotransmitters are obvious candidates for precursors of eumetazoan nerve cells, requiring only the origin of electrosensitve channels to cause action potentials and synapses to make a nerve net. The syncytial body form and calcium/potassium action potentials of hexactinellid glass sponges are secondary, not the ancestral condition for sponges, as hexactinellids are related to demosponges not the deepest lineage . They arancestor . In the ry cilia . Early sry cilia  with a hThe greater complexity of true sponges over presponges required planktonic ciliated larvae for dispersal to new fixed sites that grew big enough to transform immediately into a tiny triploblastic sponge with internal choanoderm able to feed at once. Abundant egg yolk enabled more rapid development than feeding by surface choanocytes, making sponge larvae lecithotrophic unlike planktotrophic presponge and ancestral eumetazoan ciliated larvae. Larvae evolved phototaxis using cryptochromes , not rhoThe phrase \u2018from amoeba to man\u2019 epitomizing Haeckel's early phylogenetic views doubly misleads. Amoebae are not primitive but arose from zooflagellate ancestors independently in each of the three ancestrally biciliate eukaryotic supergroups . Epithel7.Hydra [Trichoplax (unlike sponges) has numerous presynaptic protein precursors as well as gap junctions, chemical and electrical synapses probably both originated after the pre-cnidarian lineage diverged from placozoa yielding an anthozoan-like stem coelenterate. Thus, neither muscular [1The larger larvae of true sponges provided a novel, hitherto unexploited, food for predators. One stem sponge lineage, I suggest, evolved nematocysts to catch and digest them, thereby becoming the ancestor of coelenterates , a clade on the best multigene trees . NematocHydra ), and thHydra , and synHydra ; very feHydra . As Tricmuscular  nor cilimuscular  initiateKey to neurogenesis was a multicellular precursor with neurotransmitter-making cells and already adjacent receptor and effector cells linkable by evolving synapses under a strong selective advantage, exactly as this flask cell to nematocyte transition postulates without missing links or improbable events. Thus, improving the sessile zoophyte lifestyle by increasing survival (e.g. against waves tearing settling larvae from rocks) at the crucial, but uniquely vulnerable, pelagic\u2013larval/benthic\u2013adult transition was, I contend, the selective force for evolving synapses, ultimately leading to brains, culture and science. Synapses evolved to make ciliated larval settlement faster and more effective by neural coordination of concerted banks of nematocysts under the control of ciliated sensors that selected the best sites. Flask cell precursors concentrate at the aboral pole. Nematocysts remain there to mediate settlement but concentrated also around the osculum (making it a mouth) and along ancestral anthozoan protosepta to trap food.+ and K+ channels (both originating in bacteria) were modified to generate sodium/potassium action potentials in longer nerve cell branches for distant coordination of feeding responses, making eating more efficient\u2014a selective advantage an automatic corollary of this explanation of synaptic origin. Action potentials evolved many times, thus easily\u2014not only in hexactinellids, but also filamentous fungi, plants and ciliate protozoa [Adding synaptic junctions not only between sensory cells and nematocysts, but between sensory cells and branched pre-existing branched transmitter-making cells  and myocytes, would establish local neuromuscular control by a nerve net. This speeded oscular contraction making it an effective mouth, its reversible closure plus adhaerens junctions being key innovations for initial extracellular digestion of larger prey caught by oral and septal nematocysts. Having established neuromuscular synapses, pre-existing voltage-dependent Naprotozoa . Axons eper se does not make nerves.Before tentacles evolved, partially redirected ciliary currents (importing food and exporting waste through the mouth) likely made an asymmetric single-siphonoglyph protopharynx; and eight functionally complementary nematocyst-rich septa  and Ctenophora.Without giving reasons, Nielsen unjustifiably asserted \u2018it seems impossible to derive eumetazoans from an adult sponge\u2019 , p. 148.8.I have argued that the ancestral coelenterate was a bilateral octomerous stem anthozoan that lost choanocyte microvilli as neurally controlled nematocyst/tentacle feeding on larger prey improved, its mouth evolving from the osculum, and ostia closed  suppressing water channels, yielding a single body cavity, the coelenteron. Choanoderm and endoderm are homologous , as are Contrary to dogma, Anthozoa, Scyphozoa and Cubozoa are mostly triploblastic with true mesoderm \u201374. The Probably before Medusozoa originated, a stem coelenterate switched completely from benthic to planktonic life by evolving multiaxonemal macrocilia and comb plates  and losing nematocysts no longer required for settlement and accelerating oral and sexual development. This radical shift in adaptive zone and developmental fate of the ancestral planula larva entailed numerous unique innovations giving Ctenophora such a different body form from crown cnidarian adults, and unique embryology. In Cnidaria, the larval nervous system is concentrated largely aborally but degenerates during metamorphosis after settlement, being replaced by an oppositely polarized adult system with an oral focus . UnsurprPolypodium, a tentaculate triploblastic polypoid cnidarian (class Polypodiozoa) whose highly modified planula endoparasites sturgeon oocytes [Polypodium triploblasty supports treatment as a separate class outside diploblastic Hydrozoa [Polypodium clade might be sister to Hydrozoa, as some trees indicate [Ideas that the nervous system evolved twice or was lost by sponges \u201356 are u oocytes . PolypodHydrozoa , their aindicate . Myxozoaindicate  might haindicate , as expeBeroe [Others advocate one neural origin and invoke tree artefacts, giving more supporting details . Saying Beroe ). The beBeroe  with no Rapid divergence of Anthozoa (benthic nematocystous adults) and Ctenophora  neatly partitioned the Early Cambrian adaptive zone for predating larger prey. By not settling, ctenophores could evolve anal pores at the statocyst pole, enabling more efficient unidirectional ingestion and defecation currents independently of unianal bilateria, allowing secondary biradial gut symmetry by losing the siphonoglyph . Like ctenophores, early adult anthozoa probably relied on ciliary feeding (often helped by mucus secretion as in scleractinia). More complex barbed nematocysts  and toxins evolved divergently only after bilateria arose and became cnidarian prey.9.Renilla) or by apical invagination (Alcyonium); the stomodaeal cavity/invagination joins the coelenteron secondarily when the two separating epithelia at the stomodaeal base degenerate, making a novel opening [Renilla to fuse basally with the side of the developing coelenteron wall before the breakthrough, would immediately connect the pharyngeal cavity not with the coelenteron but through the body wall to the outside  develops separately from the coelenteron cavity by an apical inwardly projecting tissue mass that secondarily develops an inner cavity  almost without further modification, and separated its mechanical functions from those of a gut. The new through gut could retain digestive and absorptive functions, likely improved by modifying their positional control to regionally differentiate the former pharynx and be suppressed in the former coelenteron, now coelom. By focusing on burrowing and processing ingested sediment, nematocysts were lost and tentacles modified in function to simple mouthparts (or lost in some lineages). Such a radical change would necessarily dramatically affect embryology; unsurprisingly, thereupon two different ways immediately arose to stabilize mouth/anus formation in this protobilaterian: the proterostome/deuterostome bifurcation.Sequence phylogeny makes it virtually certain that the deuterostome ancestor was non-cephalized, whether a burrower like acorn worm or tentaculate like pterobranchs, possibly colonial like tunicate and salp. All these could readily have arisen from this tentaculate/burrowing intermediate. Lophotrochozoa also appear primitively to have had non-cephalized tentaculate or burrowing forms. The common ancestor of both groups can be argued to have been a tentaculate form, retaining pharyngeal ciliary currents that Anthozoa use in feeding, but a better burrower than burrowing sea anemones. This protobilaterian would be preadapted as ancestor of all major deuterostome and lophotrochozoan groups; acquiring ecdysis and very different mouthparts was more radical, yielding a priapulid-like ecdysozoan ancestor. Site-heterogeneous multigene analyses show that deuterostome acoels lost gut ,85 and pSarcophyton mitochondrial genome [Although lacking synapses, sponge tissues and embryology are as complex as in Cnidaria ,88\u201391; Hl genome  confirmel genome . Radial Drosophila eyes; these eyes evolved independently by modifying eukaryote cells (not strictly homologous with the bacteria that invented rhodopsin) and arranging them into contrasting supracellular structures. It is too often overlooked that structural homologies like those of tetrapod limb bones are at a higher level of organization than are transcription factors or building blocks such as collagen that they may share with morphologically non-homologous arthropod or annelid limbs and can often be recognized unambiguously entirely independently of gene sequences; there is almost certainly no \u2018pentadactyl-limb gene\u2019. Non-homologous structures  are often built partly of homologous components.Hyman's assertion  that non10.Haootia might be a muscular cnidarian impression [Acetabularia being superficial. Acetabularia is not syncytial; its form requiring cell walls is adapted for photosynthesis. Habitat proves that Vendozoa were not generally phototrophs [Codium are never quilted. Absorptive feeding by filamentous syncytial fungi like zygomycetes would cease if they evolved that body form. Large fungal fruiting bodies are non-trophic for spore dispersal. Syncytial sponges evolved secondarily from cellular ancestors. The largest protozoan syncytia (myxogastrid Mycetozoa) are naked phagotrophs with no architectural potential to evolve a vendozoan body form, unassignable to any protist group. Vendozoan complexity required extensive connective tissue to make quilt seams as struts supporting two outward facing trophic epithelia. Broken frondule internal structure [Rejecting the then prevalent idea that Ediacaran macrofossils antedating the Cambrian explosion included bilateria , I arguepression . Howeverpression , his anatotrophs . Syncytitructure  suggestsThat Vendozoa were osmoheterotrophs  is implaPhalansterium and spongomonads are possibilities that in principle might retain their feeding mechanism after evolving a multicellular differentiated tissue. But I strongly doubt any did, as evolving a multicellular phagotroph with tissues is difficult (see above) except via a flagellate/sponge pathway, and vendozoan timing just before sponges and eumetazoa can hardly be mere coincidence. Vendozoa flourished 580\u2013541 Ma, becoming extinct at the Cambrian explosion approximately 541 Ma. Their reduced disparity and diversity 5 Ma before the Cambrian explosion [It is theoretically possible that Vendozoa arose independently of sponges by evolving a connective tissue in another colonial flagellate group\u2014xplosion  I attribFunisia [Eocyathispongia [Several simpler, seemingly non-quilted, sessile Ediacaran fossils could also be presponges, e.g. the tubular Funisia . The 1 mispongia  is more ispongia . Crown sispongia . Unique Kimberella may belong here [Eocyathispongia) new subhylum Varisarca: Diagnosis: extinct macroscopic sessile multicells inferred to be ciliary filter feeding phagotrophs with epithelial/ECM organization; body form: variable arrangements of thin sheets, neither arranged in a quilted array , nor having ostia and internal water channels (unlike Porifera); non-mobile as adults. Etymology Vari variable sarco Gk flesh signifies variable body forms of epithelioid/ECM presponge fleshy organization.I regard Vendozoa as the oldest phylum of kingdom Animalia, distinct from Porifera, Placozoa and Eumetazoa. I divide it into subphylum Petalonamae  for petaong here ) and forTrichoplax be direct descendants of presponges.Vendozoa likely had Wnt/catenin axial patterning and ciliated planktonic larvae for dispersal, as without an AS they could not have easily brooded larvae as most sponges do (perhaps secondarily as protection after coelenterates evolved). If Placozoa are sisters of Eumetazoa as most multigene trees suggest, Placozoa were secondarily simplified by AS or coelenteron loss, evolving neotenously by prolonging the usual larval presettling benthic creeping phase by evolving extracellular digestion of benthic microbes and losing metamorphosis. Only if nested within Eumetazoa (Coelenterata plus bilateria) as some unconvincing trees suggest, need they have lost neurons also, like Myxozoa. Only if branching deeper than sponges and Eumetozoa, which multigene trees mostly exclude, could 11.The Cambrian explosion is the most striking animal example of ultrarapid origins of novel body forms: Simpson's quantum evolution, convincingly attributed to the invasion of previously unexploited major adaptive zones . Some leThere truly was an Early Cambrian explosion of animal (and protist) phyla, now ecologically and evolutionarily quite easy to understand. Such an explosion is expected for the very reasons that Darwin and Simpson convincingly explained. When a bilaterian with through gut and coelom arose, it created a new competitor-free adaptive zone and was bound to diversify rapidly into all body plans developmentally readily made by simple modifications and able to survive ecologically . It woulA widespread explanatorily empty speculation that many groups originated long before their objective fossil dates is fuelled by deep uniformitarian prejudices about evolutionary rates that palaeontology long ago refuted, and three other prejudices/biases that synergistically led to the notion of a \u2018slow burning fuse\u2019\u2014a journalistic slogan, not critical evolutionary thought, evaluation or synthesis. First is excessive confidence in the certainly false idea of a \u2018molecular clock\u2019 and in the reliability of current implementations of oxymoronic \u2018relaxed clock\u2019 computer programs . Second 12.The best way to understand megaevolutionary events is by a coherent synthesis unifying data of every kind using explicit reasoning and well-tested explanatory principles. Haeckel's idea that animals evolved from a protozoan ancestor directly via a gastraea with triploblastic body, mouth, gut and anus, and that the animal archetype was a flatworm-like bilateral mobile predator like us minus coelom and anus must be wrong. A gastraea is far too complicated to evolve in one step. Instead, a choanoflagellate became a triploblastic sponge (arguably in two separate stages), a sponge became an anthozoan cnidarian, stem anthozoa generated pelagic ctenophores and independently an ancestral sessile bryozoan-like bilaterian, whose headless zoophyte descendants independently evolved morphologically contrasting heads through inventing burrowing, crawling or swimming, in annelids, molluscs, arthropods and vertebrates; all acoelomate bilateria arose secondarily by coelom occlusion. Nematocyst-triggered origin of neurons and zoophyte origin of bilateria adumbrated here put sessile headless animals central to eumetazoan and bilateria origins, just as they are to the already widely accepted choanoflagellate-sponge transition . All three problems are more deeply illuminated by a unifying zoophyte perspective than by Haeckel's anthropomorphic, self-mobile adult bias. Sessile presponge headless zoophytes with dispersive ciliated larvae were the first animals; muscle-driven mobility is secondary. Heads followed rather than led basic animal innovations. Can a simpler path fit the facts?"}
+{"text": "Persea americana Miller (Lauraceae), is an important fruit crop cultivated by small-holder farmers along Afrotropical highlands of Taita Hills in South-eastern Kenya and Mount Kilimanjaro in Northern Tanzania. The small-holder farmers in these East African regions generate substantial food and cash from avocado fruits. However, the avocado crop is faced with challenges of infestation by insect pests such as the common blossom thrips (Frankliniella schultzei Trybom) which feeds on pollen and floral tissue thereby reducing productivity of the trees. Moreover, there is no information describing distribution patterns of Frankliniella schultzei and associated weather in East African avocado orchards despite the fact that small-scale farming is dependent on rainfall. This article was, therefore, initiated to provide dataset on abundance of Frankliniella schultzei from the avocado plants that relates with monthly rainfall and air temperatures at Taita Hills and Mount Kilimanjaro. Frankliniella schultzei was collected using white coloured beating tray and camel brush whereas air temperatures (\u00b0C) and rainfall (mm) was recorded daily using automatic data loggers and rain gauge, respectively. The survey at the two transects commenced during peak flowering season of avocado crop in August up to end of harvesting period in July of the following year. Temporal datasets were generated by Kruskal-Wallis Chi-square test. Current temporal datasets presents strong baseline information specifically for Kenya and Tanzania government agencies to develop further agricultural strategies aimed at improving avocado farming within Taita Hills and Mount Kilimanjaro agro-ecosystems.Avocado,  Specifications TableValue of the data\u2022Frankliniella schultzei presents baseline information specifically for Kenya and Tanzania government agencies, scientists and avocado farmers to enhance agricultural strategies.Abundance datasets of \u2022Weather datasets contributes to precise climate information of Taita Hills and Mount Kilimanjaro.\u2022The weather variables may be used to relate with avocado plant phenology  and also seasonal abundance of pest or beneficial insect species.1Frankliniella schultzei in avocado orchards at Taita Hills and Mount Kilimanjaro, respectively. Frankliniella schultzei, rainfall, maximum temperature (Tmax), and minimum temperature (Tmin) in avocado orchards at Taita Hills and Mount Kilimanjaro, respectively. Frankliniella schultzei Trybom) specimen and 2This study was carried out in small-scale avocado farmlands at Taita Hills in South-eastern Kenya and at the South-eastern slopes of Mount Kilimanjaro in Northern Tanzania as described by Frankliniella schultzei Trybom, was sampled monthly from avocado trees using a white coloured beating tray and camel brush for two years as described by Palmer Air temperature (\u00b0C) of avocado orchards was recorded daily along the study areas using data loggers. The data loggers were hang on the lower canopy of avocado trees at a height of 2\u00a0m. Rainfall records was obtained from rain gauge for two years between August 2012 and July 2014. Geographical coordinates and elevation of study areas was verified using Geographical position system (GPS) Garmin model eTrex 30. The common blossom thrips,"}
+{"text": "A 46-year-old woman had a delayed breast reconstruction using a free deep inferior epigastric perforator (DIEP) flap raised on a single medial row deep inferior epigastric perforator, complicated by intraoperative pedicle avulsion. Following a 1-cm excision of the intimally damaged vessel, the pedicle was repaired and the flap was salvaged using a supermicrosurgical technique.What is supermicrosurgery?What levels of pedicle injury can occur?What are the intraoperative strategies to salvage the free flap from pedicle avulsion?What scope is there for future advancements in free flap reconstruction using supermicrosurgery?Supermicrosurgery was first used in the 1980s, with successful replantation of distal fingertips.2Mishandling of the pedicle by the surgeon. This can result in intimal injury to an intact vessel.3Avulsion of the vascular pedicle by excessive traction. Single-vessel avulsion involves either arterial or venous supply to the flap.4Double-vessel avulsion of both arterial and venous supplies to the flap.5Diathermy injuries to the pedicle, from direct cautery or local thermal spread.6Anastomotic aneurysmal rupture, due to a pressure gradient created by mismatched donor and recipient vessels or a poorly constructed anastomosis.7A vascular pedicle injury is potentially disastrous in free flap surgery. Although uncommon, pedicle injury is an important surgical complication and understanding how it arises is essential to effective management. Different levels of pedicle injury are as follows:Before flap inset: If avulsion occurs while raising the flap, use an alternative perforator if available or repair the injured vessels if none available.During flap inset: If avulsion occurs during the flap transplant or microsurgical anastomosis with recipient vessels, reattempt a primary anastomosis. However, if the pedicle is now too short to reach the recipient vessel, use an interposition vein graft to lengthen the vascular pedicle and perform a tension-free anastomosis.3After flap inset: If avulsion occurs after the flap is inset, identify and perform an anastomosis with another shorter recipient vessel or repair and reanastomose the avulsed vessel.8Salvage of free flaps where smaller diameter vessel injury has occurred is now possible using supermicrosurgical techniques. Importantly, the surgeon must excise the zone of trauma prior to repair. Selecting the appropriate operative strategy to then repair the avulsed pedicle will depend on the nature of injury. We therefore propose an algorithm to support this selection:double-vessel avulsion, repairing the artery first allows the vein to fill and become more prominent for repair. In DIEP breast reconstruction specifically, repairing only the artery produces flap congestion and backpressure that expands the superficial inferior epigastric vein, which can then be used instead.For Free flap vascular pedicle injury remains uncommon but potentially devastating. However, free flap salvage is possible by use of innovative supermicrosurgical techniques and the operative strategies proposed. Supermicrosurgery has already brought a new frontier to free tissue transfer. Autologous transfer of tissue segments for congenital, oncological, and trauma-related defects is now possible. Perforator-to-perforator and free-style flaps, raised on anatomically variable vessels, have increased the diversity of reconstructive options, especially when smaller diameter vessels can be exploited using supermicrosurgical techniques. This will lead to spare-part surgery where disposable tissues with minimal donor morbidity can be used instead of locally destructive reconstructive options. Supermicrosurgical transfer of tissue and organ segments for facial allotransplantation and end-stage organ failure is being explored."}
+{"text": "An enduring theme in microbial ecology is the interdependence of microbial community members. Interactions between community members include provision of cofactors, establishment of redox gradients, and turnover of key nutrients to drive biogeochemical cycles. An enduring theme in microbial ecology is the interdependence of microbial community members. Interactions between community members include provision of cofactors, establishment of redox gradients, and turnover of key nutrients to drive biogeochemical cycles. Pathways canonically conducted by isolated organisms in laboratory cultures are instead collective products of diverse and interchangeable microbes in the environment. Current sequence-based methods provide unprecedented access to uncultivated microorganisms, allowing prediction of previously cryptic roles in biogeochemical cycles and interactions within communities. A renewed focus on cultivation-based methods is required to test predictions derived from environmental sequence data sets and to address the exponential increase in genes lacking predicted functions. Characterization of enriched microbial consortia to annotate hypothetical proteins and identify previously unknown microbial functions can fundamentally change our understanding of biogeochemical cycles. As we gain understanding of microbial processes and interactions, our capacity to harness microbial activities to address anthropogenic impacts increases. Microorganisms represent the majority of life on earth, both in cell numbers and in diversity. They conduct critical ecosystem services, including biogeochemical cycling and contaminant transformations. Interactions between microbial community members are essential for maintenance of these ecosystem services. In most cases, microorganisms live within complex communities containing diverse populations, with key biogeochemical cycle steps distributed between community members. With significant heterogeneity across environments, characterization of microbial interactions is an ongoing endeavor within microbial ecology. High-throughput sequencing approaches, including total community DNA sequencing, or metagenomics, have provided a torrent of information on microbial distribution, diversity, and metabolic potential. This perspective argues that sequencing and enrichment cultivation together represent a powerful combination of new and old tools for examining microbial interactions and for identifying currently uncharacterized microbial activities.High-throughput sequencing combined with reconstruction of high-quality draft metagenome-associated genomes (MAGs) provides detailed information on taxonomy, metabolic potential, and organism abundance. Where initial metagenome studies were able to reconstruct genomes for the most abundant organisms in low-diversity environments, such as acid mine drainage or the oligotrophic ocean, genome binning from metagenome sequencing now routinely results in tens to hundreds, and even thousands, of MAGs for organisms within environments as complex as sediments and soils \u20134. This \u20132 . The majority of organisms implicated in denitrification contained a single pathway reaction encoded on their genomes, with the complete pathway dispersed across the microbial community. These trends held true for sulfur cycling as well, with the complete pathway from sulfide to sulfate present in only 3% of genomes for the organisms with predicted roles in sulfur oxidation, with single pathway reactions more commonly identified (2 formation is dependent on a functionally diverse community in many environments (With hundreds or thousands of MAGs available from a single environment, organismal roles in nutrient cycling can now be examined from a whole-community perspective, within the framework of partial genomes for the majority of populations. Deep metagenomic sequencing of a terrestrial sediment system identified a striking number of broken pathways within the thousands of reconstructed microbial genomes . The vas2 12 of 30, 3.6%.ronments . From thronments , alongsiThe current biggest challenge in environmental microbiology is annotating the thousands of hypothetical proteins identified from each new genome and metagenome\u2014the known unknowns. Reconstructed genomes can have upward of 40 to 50% of their genes as predicted open reading frames with no known function . The datHow best to identify unknown functions within organisms whose obligate interactions with community members preclude isolate cultivation? Enrichment cultures, originally developed by pioneering environmental microbiologist Martinus Beijerinck at the turn of the 19th century, remain a relevant and powerful tool. Enrichment cultures streamline the environmental community to a subset tractable for experimentation. The enriched consortia are frequently more robust than isolate cultures, as beneficial microbial interactions are maintained (Nitrospira species capable of conducting complete nitrification used enrichment cultures to simplify an environmental community without the need for isolation. Metagenome sequencing of the enrichments to reconstruct complete or high-quality draft genomes proved cooccurrence of ammonia oxidation genes with the nitrite oxidoreductase for nitrite oxidation (Candidatus Methylomirabilis oxyfera,\u201d the first genome for the NC10 phylum (Ca. Methylomirabilis oxyfera,\u201d where oxygen is produced intracellularly by metabolizing nitrite via nitric oxide into oxygen and dinitrogen gas (Combinations of metagenome sequencing and enrichment cultivation have already dramatically impacted our understanding of biogeochemical cycles. A major revision to the nitrogen cycle came with the discovery of comammox , 11. Botxidation , 11. Simxidation . Metagen0 phylum . Stable ogen gas . While togen gas , furtherParcubacteria, a CPR lineage of otherwise-uncultivated phyla (Parcubacteria in culture will allow experimentation to optimize further cultivation attempts. Enrichment cultures containing Dehalococcoides mccartyi sp. have been developed as bioremediation tools for chlorinated solvents, recalcitrant and common groundwater contaminants. Metagenome sequencing of D.\u00a0mccartyi enrichment cultures identified functionally conserved nondechlorinating microbes responsible for maintenance of a reducing environment, provision of cofactors including cobalamin, and carbon turnover (D.\u00a0mccartyi. Notably, the organisms conducting these roles within different consortia varied, preventing prediction of interactions from taxonomic information alone (Beyond explorations of biogeochemical cycles, enrichment cultivation coupled with metagenomics can identify interactions present within microbial consortia that contribute to a population\u2019s survival or that support a microbial activity of interest. An enrichment culture developed to examine benzene degradation contains the only known cultivated member of the ed phyla . Having turnover , activiton alone . EnrichmStudies connecting in-depth metagenomic characterization of environments with cultivation experiments to confirm predicted functions are the future of environmental microbiology . Bolster"}
+{"text": "Radiation-induced alopecia after fluoroscopically guided procedures is becoming more common due to an increasing use of endovascular procedures. It is characterized by geometric shapes of nonscarring alopecia related to the area of radiation. We report a case of a 46-year-old man presenting with asymptomatic, sharply demarcated rectangular, nonscarring alopecic patch on the occipital scalp following cerebral angiography with fistula embolization under fluoroscopy. His presentations were compatible with radiation-induced alopecia. Herein, we also report a novel scalp dermoscopic finding of blue-grey dots in a target pattern around yellow dots and follicles, which we detected in the lesion of radiation-induced alopecia. Radiation-induced alopecia after fluoroscopically guided procedures, although infrequently reported in the dermatological literature, is possibly becoming more common due to an increasing use of endovascular procedures. It is characterized by geometric shapes of nonscarring alopecia confined to the area of radiation, usually asymptomatic without signs of scalp inflammation. We report a case of a 46-year-old man presenting with asymptomatic, sharply demarcated rectangular, nonscarring alopecic patch on the occipital scalp, 1 month after cerebral angiography with fistula embolization under fluoroscopy. His distinct clinical presentations together with a history of endovascular embolization under fluoroscopy were compatible with radiation-induced alopecia.A 46-year-old Thai man presented with asymptomatic sharply demarcated rectangular balding patch on the occipital scalp of 2 weeks' duration. Ten months earlier, he had a car accident and was diagnosed as having traumatic right carotid-cavernous fistula and optic neuropathy. Cerebral angiography revealed direct carotid-cavernous fistula from the C1 segment of cavernous part of the right internal carotid artery to the right cavernous sinus. Six months later, he was treated with transarterial balloon embolization without any complications. A month earlier, a follow-up magnetic resonance imaging and magnetic resonance angiography of the brain showed residual shunt. He underwent a cerebral angiogram with transvenous coil and glue embolization under fluoroscopy. The total procedure duration and the total radiation exposure time were 150 minutes and 67 minutes, respectively. The peak skin dose was 2.9\u2009Gy. Two weeks after the procedure, he presented at the outpatient clinic with asymptomatic balding patch on his occipital scalp. Dermatologic examination revealed a sharply demarcated rectangular nonscarring alopecic patch, measuring 10 \u00d7 12 centimeters in size, on the occipital scalp, without erythema or scaling Figures . A 4\u2009mm Fluoroscopically guided endovascular procedures are becoming more common in medical practice with an increasing use of minimally invasive techniques for various medical conditions. In general, radiation-induced alopecia is common and develops following radiation therapy of neoplasms. However, alopecia secondary to radiation exposure from fluoroscopically guided procedures is increasingly being reported due to an increasing use of endovascular procedures.Alopecia after fluoroscopically guided endovascular procedures is rarely reported in the dermatological literature, although this complication seems to be relatively common. Given that the procedures often require prolonged and repeated fluoroscopic imaging, doses above a deterministic threshold can potentially react with the skin and hair follicles , 2. The Pathogenesis of radiation-induced alopecia involves acute damage to actively dividing matrix cells of anagen follicles causing immediate loss of dystrophic anagen hairs (anagen effluvium) and premature entry of some anagen hair follicles into catagen and then into telogen phase, resulting in delayed onset of hair shedding (telogen effluvium) . RadiatiClinical presentation of radiation-induced alopecia includes geometric shapes of nonscarring alopecic patch confined to the area of radiation, usually asymptomatic without signs of scalp inflammation. Occipital, parietal, and temporal scalp are commonly affected. Occasionally, the alopecic area is clinically similar to other nonscarring alopecia cases such as alopecia areata. However, important clues to diagnosis are a history of fluoroscopically guided procedure and alopecic area which is confined to the radiation site. Hair loss mostly occurs within 1\u20133 weeks after radiation exposure with spontaneous regrowth of hair within 2\u20134 months \u201314. Cho Diagnosis of radiation-induced alopecia is primarily based on distinct clinical presentations and history of radiation exposure. Investigations including trichogram, dermoscopy, and histopathology are more likely to exclude other causes of nonscarring alopecia rather than confirming the diagnosis. Trichogram performed during an early phase usually shows dystrophic anagen hairs. However, in our patient, the presence of telogen hairs without dystrophic anagen in trichogram was a result of prolonged time from radiation exposure to the examination. All dystrophic anagen hairs shed off in the first few weeks after radiation exposure. A study of 10 patients with postangioembolization alopecia by Cho et al. reported that dermoscopic findings demonstrated both yellow dots and black dots (60%), short vellus hair (50%), peripilar sign (20%), broken hair (10%), coiled hair (10%), and white dots (10%), whereas histopathology showed increased numbers of catagen and telogen hairs without peribulbar inflammatory cell infiltrate, unlike alopecia areata, which usually shows peribulbar inflammation . AlthougOther possible mechanisms of alopecia after fluoroscopy-guided endovascular embolization including alopecia secondary to an impairment of the external carotid blood supply of the scalp and pressure-induced alopecia should be also considered. The impairment of the external carotid blood supply of the scalp may result from therapeutic embolization of blood vessels or radiation-induced luminal fibrosis . Owing tTreatment of radiation-induced alopecia is usually unnecessary due to its benign and self-limiting nature. Complete hair regrowth generally occurs within 2\u20134 months after irradiation \u201314. In aIn conclusion, we report the case of radiation-induced temporary alopecia after endovascular embolization under fluoroscopy. In addition to other nonscarring alopecia cases, physicians should be aware of and include this condition in the differential diagnosis when individuals presenting with nonscarring alopecia had a history of prolonged fluoroscopic endovascular procedures. Although the condition is benign and self-limiting, awareness, monitoring, and limitation of radiation exposure to the patient are the most important strategies to prevent hair loss."}
+{"text": "Intracellular bacterial pathogens replicate within eukaryotic cells and display unique adaptations that support key infection events including invasion, replication, immune evasion, and dissemination. From invasion to dissemination, all stages of the intracellular bacterial life cycle share the same three-dimensional cytosolic space containing the host cytoskeleton. For successful infection and replication, many pathogens hijack the cytoskeleton using effector proteins introduced into the host cytosol by specialized secretion systems. A subset of effectors contains eukaryotic-like motifs that mimic host proteins to exploit signaling and modify specific cytoskeletal components such as actin and microtubules. Cytoskeletal rearrangement promotes numerous events that are beneficial to the pathogen, including internalization of bacteria, structural support for bacteria-containing vacuoles, altered vesicular trafficking, actin-dependent bacterial movement, and pathogen dissemination. This review highlights a diverse group of obligate intracellular bacterial pathogens that manipulate the host cytoskeleton to thrive within eukaryotic cells and discusses underlying molecular mechanisms that promote these dynamic host-pathogen interactions. Obligate intracellular bacteria comprise a group of highly infectious human pathogens that cause a spectrum of life threatening diseases. These bacteria demonstrate remarkable adaptations that support intracellular lifestyles comprised of unique challenges and advantages. To support diverse infection events, intracellular pathogens have evolved numerous methods to subvert host molecular signaling machinery that controls essential cellular functions. Intracellular pathogens display tropism for specific eukaryotic cell types and attach to these cells to initiate internalization, allowing intracellular growth using energy rich host metabolic products. Successful immune evasion is essential for productive infection, and the intracellular environment provides temporary cover from detection by immune cells and antibody/compliment-mediated immunity. Following replication, these pathogens exit the infected cell and disseminate to additional sites of infection.in vitro. These human pathogens include Chlamydia , Rickettsia , Anaplasma (human granulocytic anaplasmosis), and Ehrlichia (human monocytic ehrlichiosis) species. We also include the Q fever agent Coxiella burnetii, which replicates exclusively within host cells during natural infection, but can be cultured in specialized axenic media in vitro. The interaction of these pathogens with the host cytoskeletal network has been studied for many years, but detailed molecular mechanisms are lacking due to difficulty in genetically manipulating these bacteria. However, recent genetic breakthroughs provide tractable systems by which bacteria-actin interactions can now be defined for this intriguing group of pathogens -actin that hydrolyzes ATP to provide energy for F-actin polymerization Reisler, . Actin nHost cell entry is the first step in the intracellular pathogen invasion process. Bacterial cell wall components facilitate attachment to specific host cells via distinct receptors. Pathogens use the rearranging abilities of actin to facilitate rapid entry into the host cell, with phagocytic and non-phagocytic cells internalizing bacteria by different mechanisms Figure . BacteriC. burnetii preferentially infects phagocytic human macrophages via binding to CR3 receptors, triggering reorganization of filamentous actin at the attachment site  is essential for invasion -anchored protein DNase X located on the cell surface. This interaction triggers cytoskeletal rearrangement and filopodia formation  domain that binds to actin monomers and WASP proteins. RickA ultimately activates the Arp2/3 complex, promoting actin polymerization and intracellular motility  in macrophages. F-actin assembles around the PV and is required for optimal vacuole formation  signaling using a type IV secretion system, and this process is essential for PV formation  observed in infected patients. Typhus group Rickettsia do not form actin tails (Heinzen et al., Spotted Fever group E. chaffeensis uses two different exit strategies during early and late stages of infection (Thomas et al., E. chaffeensis is transported into filopodia that extend into neighboring cells, providing a direct path for bacterial entry into nearby cells without immune detection. Actin rearrangement in infected cells is essential for filopodia formation and bacterial localization into filopodia. However, during late stages of infection, bacteria exit following host cell lysis (Thomas et al., Anaplasma, it has been suggested that A. phagocytophilum exits host granulocytes by exocytosis and host cell lysis. However, specific roles for cytoskeletal components during pathogen exit have not been characterized (Rikihisa, Chlamydia can exit host cells by host cell lysis or extrusion of the inclusion. Extrusion requires actin rearrangement and is considered an exocytosis-like process. Extrusion initiates with formation of inclusion-containing protrusions from infected cells. Extrusions are then pinched into separable compartments located at the cell periphery, allowing inclusion release without triggering cell death (Todd and Caldwell, Obligate intracellular bacteria include a unique group of human pathogens that have adapted to thrive within the host cell environment. These pathogens hijack host cell signaling by secreting bacterial effector proteins into the host cytosol to promote formation of a replication-permissive niche. Intracellular bacteria constantly encounter the dynamic host cytoskeletal network and have evolved methods to use actin and related proteins to facilitate infection. Intracellular pathogens rearrange the actin cytoskeleton during internalization by phagocytic and non-phagocytic host cells. Some intracellular bacteria replicate within a specialized membrane-bound vacuole, while others replicate free in the cytosol. Host cytoskeletal proteins often form a filamentous cage around bacteria-containing vacuoles, providing structural support and allowing vesicle fusion with the vacuole. Other intracellular bacteria stimulate actin polymerization and form actin tails that aid bacterial movement within the host cytosol and propulsion into neighboring cells. Intracellular bacteria further manipulate the actin cytoskeleton to exit host cells by lysis or vacuole extrusion. In conclusion, major events in bacterial lifecycles require host cytoskeletal components, and blocking these interactions negatively impacts bacterial replication. However, we clearly have more to learn about the molecular mechanisms controlling pathogen interaction with the host cytoskeleton. Targeting these interactions may provide novel approaches to develop antibacterial therapeutics targeting obligate intracellular bacterial pathogens.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Eutrophication and climate warming are profoundly affecting fish in many freshwater lakes. Understanding the specific effects of these stressors is critical for development of effective adaptation and remediation strategies for conserving fish populations in a changing environment. Ecological niche models that incorporated the individual effects of nutrient concentration and climate were developed for 25 species of fish sampled in standard gillnet surveys from 1,577 Minnesota lakes. Lake phosphorus concentrations and climates were hindcasted to a pre-disturbance period of 1896\u20131925 using existing land use models and historical temperature data. Then historical fish assemblages were reconstructed using the ecological niche models. Substantial changes were noted when reconstructed fish assemblages were compared to those from the contemporary period (1981\u20132010). Disentangling the sometimes opposing, sometimes compounding, effects of eutrophication and climate warming was critical for understanding changes in fish assemblages. Reconstructed abundances of eutrophication-tolerant, warmwater taxa increased in prairie lakes that experienced significant eutrophication and climate warming. Eutrophication-intolerant, warmwater taxa abundance increased in forest lakes where primarily climate warming was the stressor. Coolwater fish declined in abundance in both ecoregions. Large changes in modeled abundance occurred when the effects of both climate and eutrophication operated in the same direction for some species. Conversely, the effects of climate warming and eutrophication operated in opposing directions for other species and dampened net changes in abundance. Quantifying the specific effects of climate and eutrophication will allow water resource managers to better understand how lakes have changed and provide expectations for sustainable fish assemblages in the future. Climate change and eutrophication are potent environmental stressors that are altering the fundamental ecological processes that structure freshwater communities throughout the world ,2. SigniAs climate changes the thermal structure of lakes, fish are influenced through a number of pathways and processes ,9. EpiliEutrophication has substantially altered fish assemblages around the world  and can Eutrophication and climate warming have affected many lakes in Minnesota ,26. NatiEcological niche modeling that incorporates specific effects of individual stressors has proven useful for disentangling multiple-stressor impacts on biotic communities ,33. EachUnderstanding the specific effects of eutrophication and climate warming is of critical importance for water resource managers and policy makers. Minnesota\u2019s lake fish taxa differ in their thermal and eutrophication tolerances ,29 and rEmpirical ecological niche models were developed for 25 species of fish commonly captured in Minnesota Department of Natural Resources (MDNR) lake netting assessments . The MinTaxa-specific ecological niche models were developed using generalized additive models (GAMs). The effects of several environmental and ecological stressor variables on the relative abundance of each species were quantified with the models. GAMs are particularly useful for modeling the ecological niche of biological organisms because they directly incorporate nonlinear smoothing to describe the effects of predictors on the response variable  and are http://prism.oregonstate.edu, retrieved 3 Dec 2015). Air temperatures were estimated for the geographical center of each lake for the period from 1981\u20132010 using the geoknife package in R [Mean annual air temperature (MAT), which integrates a number of ecological effects across all seasons, was used as a proxy variable that captured the effects of climate on fish assemblages. Lake-specific air temperature data were developed from high resolution spatial interpolations of historic air temperatures available from the Oregon State University PRISM Climate Group .Phosphorus was selected as a proxy variable that captured the effects of eutrophication because it is the primary limiting nutrient in many lakes, including Minnesota ,30. Meanmgcv  and by z-scores (subtracting the species-specific mean and dividing by the species-specific standard deviation) to allow for standardized comparisons among species. Lake size (ha) and depth (m) were log transformed and total alkalinity was square root transformed to normalize their distributions. Response surfaces of relative abundances were estimated from joint smooths of MAT and TP. The joint smooths allowed for the visualization of how responses of each variable changed as a function of the other variable. Individual responses can be visualized as slices through the response surface at specific values of the other variable. These interaction of MAT and TP can also be visualized as the shape of the slices change as a function of the other variable. Environmental variables  were entered into the model as single variable smooth terms. A Gaussian family, with an identity link function, was used for each GAM and a dimension basis of k = 4, was used to limit the degrees of freedom for each smooth term [The  package  in the soth term .Pre-disturbance lake conditions were estimated for climate and eutrophication variables which provided inputs into species-specific ecological niche models. Pre-disturbance climate was calculated from historical air temperatures retrieved from the PRISM data set using identical methods as the contemporary climate data for comparison to present-day conditions. Annual lake-specific air temperatures from 1896\u20131925 (a thirty year period of the same duration as the contemporary period) were processed using the geoknife package in R , and meaTP = mean summer epilimnetic total phosphorus concentration (\u03bcg/l), depth = maximum lake depth (m), outwash = proportion of glacial outwash soils in watershed, disturbance = proportion of disturbed land uses  in watershed. Assuming depth and proportion of outwash soils remained constant over both periods, estimation of pre-disturbance lake productivity collapses to:TPp = pre-disturbance mean summer epilimnetic phosphorus concentration (\u03bcg/l), TPc = contemporary, observed mean summer epilimnetic phosphorus concentration (\u03bcg/l), and disturbance = proportion disturbed land uses  currently in watershed. Watershed delineations were available for 1,236 lakes in the analysis. Contemporary values of land uses were calculated with the 2001 National Land Cover Database [Pre-disturbance land use corresponded to the late 1800s when prairies were first converted to agriculture and urban areas started to develop in Minnesota. Pre-disturbance eutrophication status was estimated by hindcasting the lake phosphorus model developed by Cross and Jacobson  to undisDatabase . Level 1Pre-disturbance fish assemblages were estimated by using the derived historical conditions as inputs to taxa-specific ecological niche models. Lake-specific CPEs were calculated from the fitted GAM models for each species to explore changes in abundance from pre-disturbance to contemporary conditions. The effects of climate warming and eutrophication on the relative abundance of each taxa were examined independently by using pre-disturbance conditions for one stressor while holding the other at contemporary levels, and then collectively by using pre-disturbance levels for both stressors.Generalized additive models described between 1.2 and 57.6% of deviance in fish relative abundance for the 25 species . Joint fResponse shapes of the joint effects of climate and productivity varied considerably between species . Some haMean annual air temperatures increased from pre-disturbance (1896\u20131925) to contemporary (1981\u20132010) times, although the magnitude of increase varied substantially between lakes and ecoregions . TemperaHindcasted total phosphorus concentrations indicated that lakes in the transition and prairie ecoregions have become more productive . Those eTrajectories of individual lakes within a 2-dimensional climate and productivity niche space  illustraStressor-specific changes in modeled fish relative abundance varied considerably by species and ecoregion . The dirFor most taxa, hindcast changes in abundance were largest in prairie lakes, where both climate and productivity shifts were substantial. All nine eutrophication-tolerant warmwater species were estimated to have increased in abundance from increased phosphorus and temperature, while six intolerant species  declined over the period. Stressors operated in opposite directions for a total of eight species, several of which experienced little change in abundance. Eutrophication-tolerant coolwater yellow perch benefited from increased total phosphorus, but warmer temperatures were detrimental. Conversely, intolerant warmwater bluegill benefited from warming temperatures, but gains in abundance were overwhelmed by detrimental effects of increased phosphorus. In general, eutrophication produced larger effects on relative abundance than climate warming for most taxa in the prairie ecoregion.Fish assemblages in the transition ecoregion also experienced significant changes after disturbance. Taxa-specific responses were similar to the prairie ecoregion with eutrophication-tolerant warmwater species benefitting most from increased temperatures and phosphorus concentrations. Increased phosphorus concentrations were detrimental to a number of eutrophication-intolerant species and increased temperatures were beneficial to warmwater taxa. Tolerant coolwater yellow perch also benefited from increased lake productivities, but increased temperatures were detrimental. Intolerant warmwater bluegill gains in abundance from increased temperatures were completely offset by losses from increased phosphorus concentrations and resulted in no net change. A total of 12 species in the transition ecoregion were affected by stressors that operated in opposite directions.Fishes in the forested ecoregion experienced changes primarily driven by temperature increases in the past century. Warmwater fishes such as black crappie, bluegill, largemouth bass, pumpkinseed, and yellow bullhead increased in abundance. The greatest abundance declines were seen within coolwater species such as white sucker, walleye, yellow perch, and smallmouth bass. The number of species affected by stressors that operated in opposite directions was large (15), but the net effect of increased phosphorus was very small in all cases.Grouping of taxa by thermal preference and eutrophication tolerance summarized fish assemblage changes that have occurred in the past century . WarmwatA century of eutrophication and climate warming profoundly affected lakes in Minnesota and consequently, their fish assemblages. Conversions of native prairies and forests to agricultural and urban uses increased nutrient concentrations in the prairie and transition ecoregions of the state. In response, abundances of eutrophication-tolerant fish likely increased. Climate also warmed in the past century throughout the entire state and reconstructed warmwater fish abundances increased accordingly. Trajectories of lake-specific changes spanned an extraordinary range of the 2-dimensional niche space represented by these two stressors in Minnesota. Together, eutrophication and climate warming likely drove an expansion of tolerant warmwater fish abundance at the expense of intolerant coolwater taxa. Conversely, climate and productivity shifts produced opposing effects on abundance of several species. For example, tolerant coolwater yellow perch likely benefitted from lake productivity increases, but climate warming was detrimental. Intolerant warmwater bluegill benefitted from climate warming, but gains in abundance were overwhelmed by negative effects of eutrophication. Disentangling the sometimes opposing, sometimes compounding, effects of these two important ecological stressors was critical for understanding changes in fish assemblages. Taxa-specific ecological niche models and explicit identification of stressor-specific tolerance guilds  were valEutrophication drove changes in modeled lake fish assemblages in the prairie and transition ecoregions of Minnesota more than climate. Vegetated fish habitat in the many shallow lakes of the prairie was likely reduced by nutrient enrichment . Shifts Climate drove modeled fish assemblage change in forested ecoregion lakes more than eutrophication. Watersheds of these lakes remained largely undisturbed and forested  resultinAlthough sequence and timing of individual stressor effects was not determined in this study, evidence exists that eutrophication was most important during the first part of the century and climate became more significant in recent years. Increases in mean annual temperatures in the state have accelerated since 1980 . Many laThe effects of climate warming on fish are expected to continue in all three ecoregions. Lakes in the forested ecoregion are likely to maintain suitable thermal habitat for cool- and warmwater species even under extreme warming scenarios ,55. ThusAlthough ecological niche modeling was useful for disentangling the effects of climate and eutrophication, significant uncertainty remains for predicting fish assemblage responses. Model errors propagated through the phosphorus hindcasting model and fish assemblage reconstruction were likely present. Modeled niches were assumed to remain unchanged from historic to contemporary conditions . PredictUnderstanding the specific effects of climate and land use change on lakes and fish assemblages is critical for developing management and adaptation strategies for effective conservation ,69. For S1 TableP-values and percent deviance explained for generalized additive models of the relative abundance of 25 fish species predicted by mean annual temperature (MAT) and mean summer epilimnetic total phosphorus concentrations (TP), depth, area, and alkalinity sampled in 1,577 Minnesota lakes.(XLSX)Click here for additional data file.S2 TableLake specific data used for ecological niche models developed from 1,577 Minnesota lakes. Metadata describing each data field are described in the first portion of the Table.(XLSX)Click here for additional data file.S1 FigGeneralized additive model responses of mean annual temperature (MAT \u00b0C) and mean summer epilimnetic total phosphorus concentrations (TP \u03bcg/l), depth (m), area (ha), and alkalinity on the relative abundance of 25 fish species sampled in 1,577 Minnesota lakes. Species codes are defined in (PDF)Click here for additional data file."}
+{"text": "Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress. While advances in neonatal care have resulted in improved survival rates of premature infants, limited progress has been made in reducing rates of BPD. Lack of progress may in part be attributed to the limited therapeutic options available for prevention and treatment of BPD. Several lung-protective strategies have been shown to reduce risks, including use of non-invasive support, as well as early extubation and volume ventilation when intubation is required. These approaches, along with optimal nutrition and medical therapy, decrease risk of BPD; however, impacts on long-term outcomes are poorly defined. Characterization of late outcomes remain a challenge as rapid advances in medical management result in current adult BPD survivors representing outdated neonatal care. While pulmonary disease improves with growth, long-term follow-up studies raise concerns for persistent pulmonary dysfunction; asthma-like symptoms and exercise intolerance in young adults after BPD. Abnormal ventilatory responses and pulmonary hypertension can further complicate disease. These pulmonary morbidities, combined with environmental and infectious exposures, may result in significant long-term pulmonary sequalae and represent a growing burden on health systems. Additional longitudinal studies are needed to determine outcomes beyond the second decade, and define risk factors and optimal treatment for late sequalae of disease. Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress but can also occur in neonates that had a less severe respiratory course ,2,3. BPDThe incidence of BPD in surviving infants less than or equal to 28 weeks gestational age has been relatively stable at approximately 40% over the last few decades ,10,11,12Criteria to define BPD have historically lacked uniformity. The earliest clinical definition of BPD was limited to oxygen requirement at 28 days with consistent radiologic changes. These were originally modified to include continuing need for oxygen therapy at 36 weeks corrected gestational age (CGA). However, this definition inadequately addresses highly variable clinical practices as well as the wide range of disease, leading to further modification to include a severity assessment at 36 weeks gestational age . The defAt greatest risk of poor long-term outcome are the approximately 25% of infants with BPD who are identified to have elevated pulmonary pressures or BPD-associated pulmonary hypertension (PH), resulting in mortality rates as high as 14%\u201338% with one series noting only 25% survival at 2\u20133 years of age with severe BPD-associated PH ,22,23,24As the population of NICU survivors grow, long-term manifestations of chronic lung injury with BPD is likely to represent a greater burden to health systems. This paper seeks to review the pathophysiology of BPD, recent management strategies and what is currently known about long-term pulmonary outcomes in survivors.The phenotype seen with BPD is the end result of a complex multifactorial process in which various pre- and postnatal factors compromise normal development in the immature lung.  The specBPD occurs almost exclusively in preterm infants that have received positive pressure ventilation suggesting that mechanical lung over-distension and alveolar stretch play a critical role in the pathogenesis of BPD. Ineffective pulmonary mechanics results in need for ventilatory assistance at birth. Recent data suggests that 65% of preterm infants born at 22 to 28 weeks gestational age are intubated in the delivery room, which has decreased since 1993 when 80% of this population was intubated immediately following birth . The preStudies in numerous animal models have identified that exposure to supraphysiologic oxygen alone induces a phenotype comparable to that seen with BPD, including compromised alveolar development and pulmonary vascular remodeling . ClinicaAnimal models suggest that even brief exposures to high concentrations of oxygen can result in long-term morphologic and functional changes in the lung . In addiEscherichia Coli endotoxin to pregnant ewes resulted in amplified inflammation with ventilation of the exposed preterm lambs including evidence of cellular apoptosis and compromised alveolar development [Controversy exists regarding the contribution of chorioamnionitis and prenatal inflammation to the risk of developing BPD . Clinicaelopment ,45. Whilelopment . This paelopment . Controvelopment .Less controversy exists regarding the contribution of postnatal inflammation or nosocomial infection to the increased risk of developing BPD ,48. NoviPreterm infants that are small for gestational age (SGA) at birth or with intrauterine growth restriction (IUGR) are at increased risk for adverse pulmonary outcomes ,54. StudExtremely premature infants are at additional risk for postnatal growth restriction secondary to challenges of delivering optimal nutrition. Despite significant advances in the content and use of both enteral and parental nutritional support, 55% of infants born less than 27 weeks gestation demonstrate growth failure with weight less than 10th percentile at 36 weeks postmenstrual age ,26,53. PWhile BPD results from cumulative exposures to both the pre- and postnatal factors noted above, there is a growing interest in the heritable contributions to development of BPD. Twin studies provide insight into genetic predispositions as monozygotic twins share 100% of their genetic information while dizygotic twins are 50% concordant . A totalMore recently, several genome-wide association studies (GWAS) have been conducted to identify candidate single nucleotide polymorphisms associated with BPD. The largest evaluated over 1700 infants and failed to identify genomic loci or pathways that accounted for the previously described heritability for BPD . A seconManagement strategies are aimed at protecting against lung injury and the development of BPD. As the pathogenesis of disease is multifactorial, diverse approaches have been adopted including both ventilation and medical strategies. Interestingly, both antenatal steroids and surfactant reduce rates of RDS and improve survival; however, neither has been shown to reduce incidence of BPD .2 targets (>52 versus <48 mmHg) [Evidence of lung injury induced by volutrauma has led to efforts to promote \u201cgentle ventilation,\u201d in part through the use of permissive hypercapnia. However, the data to support this strategy has been inconsistent and long-term neurodevelopmental outcomes remain unknown ,69. None48 mmHg) ,71. Gent48 mmHg) ,73,74. R48 mmHg) ,76; howe48 mmHg) . As manySignificant efforts have been made to move away from use of invasive ventilation over the past two decades . Meta-anUse of alternative non-invasive modalities including non-invasive positive pressure ventilation (NIPPV), bilevel nasal CPAP (biPAP) and high-flow nasal cannula (HFNC) is also increasing with some evidence to suggest these modes may also be effective in managing neonatal respiratory disease ,82,83. SAdditional controversy exists surrounding the use of non-synchronized NIPPV. Synchronization can be achieved and has been described in premature infants using an abdominal pneumatic (or Graseby) capsule to detect diaphragmatic descent. This approach has the theoretical advantage of ensuring glottis patency before flow is triggered. While randomized trials using SNIPPV have not been performed, a retrospective study suggested comparable clinical outcomes, including rates of BPD, in infants managed with synchronized as compared to non-synchronized NIPPV . More reFinally, for those infants who do require intubation, an early trial of extubation is encouraged to potentially reduce risks of ventilator-induced lung injury. Studies have identified that an early attempt at extubation alone may decrease the risk of BPD, regardless of need for reintubation or duration of ventilation ,89. ThesExtensive efforts have been made to define optimal saturation targets for premature infants with ongoing concerns for the quality of evidence available . A meta-Specific to the outcome of BPD, the Surfactant, Positive Pressure and Oxygenation Randomization Trial (SUPPORT) conducted in the US found slightly lower rates of BPD (38% vs. 41.7%) in the low-saturation group without statistical significance . The CanPostnatal glucocorticoids are recognized to reduce rates of BPD via reduced inflammation as well as the induction of lung maturational changes. However, the potential benefits of systemic steroids are often outweighed by concerns for long-term neurodevelopmental sequelae including increased risk of cerebral palsy (CP) ,99. RateIn attempt to more reliably deliver corticosteroids directly to alveoli of infants at risk of early lung injury, co-administration of budesonide with surfactant has been considered. Yeh, et al. have reported significant decrease in the incidence of BPD or death in ventilated infants with severe RDS who received endotracheal budesonide . AdditioIn the recent randomized, multicenter Caffeine for Apnea of Prematurity (CAP) trial, early initiation of caffeine was found to result in lower incidence of BPD as well as a shorter course of respiratory support as compared to controls . The speVitamin A deficiency may predispose to chronic lung disease as it plays a critical role in maintaining the integrity of respiratory tract epithelium and is a key regulator of normal lung growth ,111. WhiInhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia deserves mention as it has been explored in numerous studies with inconsistent findings ,116. WhiLong-term outcomes of BPD remain difficult to characterize as adult populations currently available to study represent survivors of outdated care. While BPD tends to improve with ongoing lung development, data available from follow-up studies identify concerns for persistent pulmonary sequelae of disease. Notably, the impact on late pulmonary health as well as the consequences of additional infectious or environmental exposures remain poorly characterized.It is important to recognize the tremendous emotional, medical, and financial efforts invested into care of extremely premature infants. The mean length of hospitalization for those born under 1000 grams is approximately 60 days with high rates of need for additional medical support including rehospitalization after discharge . During Numerous studies have evaluated long-term pulmonary function after premature birth alone. A meta-analysis including 59 articles identified that percent of predicted forced expiratory volume in 1 second (FEV1) is decreased in preterm-born survivors, even in patients who did not have a history of BPD . EvaluatAdditional studies have raised concerns for the persistence of pulmonary disease in patients with BPD. Correlation between maximal flow at functional residual capacity in infancy and forced expiratory flow at 8 years raises concerns that limited recovery occurs during late stages of alveolarization . In addiExposure to environmental insults including respiratory infections, tobacco and pollution may complicate resolution of BPD and prolong risks of pulmonary morbidity ,142. PreBeyond environmental insults, pulmonary morbidity in ex-preterm infants can be complicated by chronic reflux and microaspiration with risk of aspiration pneumonia and/or chronic inflammation. While the evidence is variable, improvement of respiratory status has been reported after Nissen fundoplication of infants with severe chronic lung disease with some programs advocating for this intervention in severe cases ,147,148.Many survivors of BPD demonstrate a component of reactive airway disease. Long-term follow-up of infants born <26 weeks gestation identified that 25% had an asthma diagnosis at 11 years of age while over twice this percentage (56%) had evidence of abnormal spirometry . While c2 consistent with alveolar hypoventilation [Survivors of BPD may experience exacerbation of pulmonary morbidities with exercise or exposure to hypoxia. Significant risk of exercise-induced bronchoconstriction has been demonstrated in children with BPD consistent with concerns for reactive airway disease noted above . Howevertilation .Chemoreceptor function in preterm infants is dysmature, resulting in abnormal ventilatory responses to alterations of oxygen content in these patients. Specifically, normal responses of increased ventilation with hypoxia as well as decreased ventilation with hyperoxia may be altered. Persistent chemoreceptor dysfunction has been documented in survivors of BPD ,157. InaDysmorphic pulmonary vasculature and compromised angiogenesis with BPD results in risk of elevated pulmonary pressures or BPD-associated pulmonary hypertension (PH). Retrospective studies of infants with BPD suggested that 25%\u201337% of infants with BPD develop associated PH, but these data are limited by inconsistent definition and screening protocols ,22,23. EAs previously noted, patients with BPD and elevated pulmonary pressures are at high risk for PH crisis and early mortality. Those who survive may ultimately demonstrate resolution of disease with additional lung growth. However, recent data suggests that subclinical right ventricular dysfunction can be detected in children assumed to have recovered from BPD-associated PH . Longer-While severity of BPD does not predict likelihood of associated pulmonary hypertension, sicker infants with prolonged ventilator and oxygen requirements are at greatest risk ,161. AddHowever, the threshold for intervention and optimal treatment of BPD-associated PH remains elusive with limited evidence to guide care . While rSome guidance for treatment has been provided in the literature. However, none of these to date are evidence based ,167. KulWhile the past decade has been notable for increasing use of vasodilator therapy in the treatment of BPD-associated PH , randomiThe definition, pathophysiology, and management of bronchopulmonary dysplasia (BPD) has evolved significantly since first described by Northway almost 50 years ago. Advances in neonatal care have resulted in increased rates of survival of extremely premature infants leading to both a new set of management challenges as well as an emerging population of long-term survivors of BPD. Interdisciplinary care to address the complex pulmonary, nutritional and developmental needs of these patients is critical and may itself influence outcomes of severe BPD .Randomized therapeutic studies in addition to longitudinal evaluation of these patients remains essential to optimize care and further discern risk factors for morbidity. While these studies require significant resources, they are much in need as evidence for optimal treatment is lacking. In addition, little is known regarding pulmonary outcomes of BPD beyond the second decade of life. Of concern are data highlighting the potential for increased risk of subclinical right ventricular dysfunction, obstructive lung disease, exercise intolerance, and asthma-like symptoms in survivors. Abnormal response to hypoxia and central airway disease may further exacerbate illness with risks of sleep disordered breathing. These baseline morbidities, complicated by environmental and infectious exposures, may represent a significant challenge for the aging cohort of BPD survivors.As trends demonstrate increasing survival of extremely premature infants, nearly half of whom will be diagnosed with BPD, it is imperative that future studies investigate mechanisms and risk factors influencing long-term morbidity with an overall goal of reducing the burden of disease."}
+{"text": "We administered neuropsychological measures considered sensitive to prefrontal dysfunction  to obsessive-compulsive disorder (OCD) patients and control subjects. OCD subjects exhibited performance deficits, in comparison to community controls, on three measures sensitive to orbitofrontal neocortex dysfunction. Contrary to expectation, OCD patients also exhibited performance deficits on measures sensitive to dorsolateral prefrontal neocortex dysfunction. However, distinct neurocognitive profiles emerged when we examined the impact of comorbid schizotypal personality features on neuropsychological test performance. Primary OCD patients displayed impaired performance on measures sensitive to orbitofrontal dysfunction; however, they did not differ from control subjects on tests of dorsolateral function. OCD subjects presenting with schizotypal personality features performed poorly not only on tests sensitive to orbitofrontal dysfunction, but also on tests sensitive to dorsolateral dysfunction. Findings suggest that OCD can be subdivided into clinical subtypes, and distinct prefrontal subsystems may be differentially involved in these subtypes."}
+{"text": "Abnormalities in GABA signaling in the forebrain at all stages - prenatal, postnatal and adult have been implicated with a wide range of neuropsychiatric illnesses ,2. AdditA receptors and GABA function with defective behaviors have been vital for understanding the pathobiology of neuropsychiatric illnesses, but all of these models were systemic or region-specific knockouts that could not serve to establish a cause - effect relationship between neuronal versus endothelial cells. Our observation of expression of GABAA receptor subunits and GAD65/67 in forebrain endothelial cells signified that forebrain angiogenesis has its own intrinsic GABA signaling mechanisms. To discover the functional significance of this endothelial GABA signaling pathway in vivo, we designed strategies to specifically turn off GABA release from endothelial cells or render endothelial GABAA receptors dysfunctional using cre-lox technology during early embryonic development. Both approaches first affected forebrain angiogenesis and in turn impaired neuronal migration. As endothelial GABA\u2019s roles were delineated individually for angiogenesis, neurogenesis, long distance GABAergic neuronal migration and radial migration of projection neurons, so too was the realization that neuronal GABA could not serve to compensate these roles. The data laid the foundation for a novel positive feedback signaling pathway in endothelial cells that functions via GABAA receptor mediated GABA release [Though there have been reports of GAD immunoreactivities in endothelial cells of cerebral arteries  and GAD6A receptors, NKCC1-KCC2 expression, and chloride concentration in forebrain endothelial cells and alterations in disease scenarios. And most importantly, additional questions begin to emerge about the significance of this vascular GABA pathway and novel mechanisms specifically in the postnatal, adult and aging brain (As we now know that a common GABA pathway operates in both endothelial cells and GABAergic neurons of the embryonic telencephalon, it is essential to gain further mechanistic insights by segregating this pathway in individual cell types. It is important for future work to understand how the endothelial GABA signaling pathway specifically influences angiogenesis related genes and specific processes like tight junction formation, tip cell functions, vascular sprouting and migration. Also, it is important to see how components of the neuronal GABA pathway are affected in the absence of endothelial GABA signaling. For instance, how does endothelial GABA modulate interneuron migration - does it affect receptor-mediated signaling that transduces extracellular information or directly the transcription factors that provide interneurons with their intrinsic migratory ability or both? It also brings up several new questions with respect to roles of GABAng brain . New und"}
+{"text": "BRCA1 or BRCA2 is recognized for its strong familial risk .Genome Wide Association Studies (GWAS) serve as a powerful approach for discovering common risk variants underlying disease etiology. Often these variants reside within the non-coding region of the genome making the determination of functional mechanisms driving susceptibility a challenging task . Differecis-associations (cis-eQTL) were interrogated for association with breast cancer risk. Three SNPs, rs11099601, rs656040 and rs738200 were significantly associated  with an increased risk of breast cancer. The most significant association with increased risk for both ER-positive and ER-negative breast cancer was rs110099601  at 4q21, which constitutes a novel breast cancer susceptibility locus [In the study, Hamdi et al. evaluated 313 SNPs in 175 genes related to cancer for association with breast cancer risk in 46,451 breast cancer cancers and 42,599 controls of Caucasian ancestry participating in the Breast Cancer Association Consortium (BCAC) genotyped using the custom Illumina Infinium array iCOGS  with rs11099601 were functionally annotated using ENCODE chromatin features such as overlapping with Histone epigenetic marks associated with promoters and enhancers or DNAse I hypersensitive sites , which may be particularly effective for tumor types with limited sample sets.In summary, Hamdi et al. reported a novel association to breast cancer risk likely to be related to changes in expression of multiple genes. Importantly, although the approach used by Hamdi et al. may exclude the discovery of genes not previously implicated in cancer, it provides an example of an approach likely to identify variants undetectable under stringent GWAS multiple testing threshold (typically"}
+{"text": "Optical internal urethrotomy (OIU) is the most common procedure performed for short segment bulbar urethral stricture worldwide. This procedure most commonly performed using Sachse\u2019s cold knife. Various perioperative complications of internal urethrotomy have been described in literature including bleeding, urinary tract infection, extravasation of fluid, incontinence, impotence, and recurrence of stricture. Here we report a unique complication of breakage of Sachse knife blade intraoperatively and its endoscopic management. Optical internal urethrotomy (OIU) is the most common procedure performed for short segment bulbar urethral stricture worldwide . HoweverA 30 year-old male presented with complaint of lower urinary tract symptoms for the last six months. Uroflowmetry voiding pattern was suggestive of urethral stricture disease. Retrograde urethrography (RGU) revealed a short segment bulbar urethral stricture (<1.5cms). Optical internal urethrotomy was performed. Intraoperatively blade of Sachse\u2019s urethrotome accidently broken and fell proximal to the stricture which was confirmed on fluoroscopy . We compOptical internal urethrotomy became popularized after the work of Sachse in 1971  and now This complication should be kept in mind and instruments should be checked properly by the operative surgeon prior to start the procedure. Retained sharp objects like knife blade in urethra as a result of breakage of Sachse knife blade can be managed endoscopically."}
+{"text": "Many real-world networks contain highly connected nodes called hubs. Hubs are often crucial for network function and spreading dynamics. However, classical models of how hubs originate during network development unrealistically assume that new nodes attain information about the connectivity (for example the degree) of existing nodes. Here, we introduce hub formation through nonlinear growth where the number of nodes generated at each stage increases over time and new nodes form connections independent of target node features. Our model reproduces variation in number of connections, hub occurrence time, and rich-club organization of networks ranging from protein\u2013protein, neuronal and fibre tract brain networks to airline networks. Moreover, nonlinear growth gives a more generic representation of these networks compared with previous preferential attachment or duplication\u2013divergence models. Overall, hub creation through nonlinear network expansion can serve as a benchmark model for studying the development of many real-world networks."}
+{"text": "To present a method, alternative to penetrating keratoplasty, for the restoration of impaired corneal clarity with anterior stromal scarring following long-standing corneal graft failure.A 48-year old female who had previously underwent Descemet stripping automated endothelial keratoplasty (DSAEK) for the treatment of pseudophakic bullous keratopathy, presented with long-standing corneal oedema and anterior corneal scarring. A significant improvement in corrected distance visual acuity was demonstrated, as corneal clarity was restored following graft exchange and phototherapeutic keratectomy (PTK).The combination of corneal graft exchange and phototherapeutic keratectomy may represent an effective therapeutic option for long-standing corneal oedema with concomitant anterior corneal scarring after failure of a DSAEK graft. Descemet stripping automated endothelial keratoplasty (DSAEK) has become the modality of choice for the treatment of corneal oedema arising from corneal endothelial diseases including Fuchs endothelial dystrophy and pseudophakic bullous keratopathy .In cases of DSAEK graft failure or rejection, corneal graft exchange could be attempted. Nevertheless, when corneal oedema is left to ensue, the subsequent chronic corneal decompensation may result in anterior corneal fibrosis. The aforementioned complication limits the final visual outcome of a new DSAEK procedure and, thus, may alter the surgeon\u2019s plan in favour of penetrating keratoplasty (PK).A 48-year old female sought medical consultation due to decreased vision of the left eye. Her past medical history included no necessity for spectacle correction at a younger age and phacoemulsification surgery of the left eye 4\u00a0years ago. Following cataract surgery, no improvement of her visual acuity was noticed due to pseudophakic bullous keratopathy. Therefore, the patient underwent DSAEK procedure in the left eye six months post cataract extraction. Restoration of good visual acuity following DSAEK that lasted for the next year was noticed; upon the aforementioned period the patient reported gradual deterioration of vision. Gradual visual impairment was attributed to graft failure.The ophthalmic examination of the left eye revealed uncorrected distance visual acuity HM (hand movement) that could not be improved with spectacles. Slit-lamp biomicroscopy of the left eye showed corneal oedema accompanied by anterior corneal fibrosis.We proceeded with a second Descemet stripping endothelial keratoplasty  in order to replace the non-functional graft with a healthy one. The procedure resulted in complete resolution of corneal oedema within the first postoperative month Fig\u00a0. NeverthIn the first postoperative month, anterior corneal fibrosis resolved Fig\u00a0 and the Corneal decompensation arising from a non-functional graft or from endothelial diseases such as Fuchs endothelial dystrophy  and pseuIn our case, failure of DSAEK graft led to chronic corneal oedema with a central opacity that involved the anterior stroma. We decided against PK in an attempt to achieve not only satisfying post-keratoplasty visual acuity, as well as to obviate the increased morbidity of a full-thickness corneal graft. A two-step procedure that included DSAEK graft exchange and phototherapeutic keratectomy with adjunctive MMC was performed. To date, 6\u00a0months following PTK, no recurrence of the anterior corneal fibrosis has been observed.Manual debridement of the fibrosis would be an alternative in case of a superficial scar. However, in the case of scar extension into the anterior stroma, manual peeling may give rise to deep corneal defects that may, in turn, lead to uneven healing and an unpredictable visual outcome . In addiIn conclusion, DSAEK graft failure prompts consideration for timely restoration of subsequent corneal oedema, as chronic corneal decompensation can result in anterior corneal fibrosis. In the adverse event of graft failure with anterior corneal scarring, combined graft exchange and PTK should be considered in an effort to spare the patient from the increased morbidity of a PK graft and to achieve a greater visual outcome."}
+{"text": "The book combines fields which experience increasing interest in recent years: optofluidics, microfluidics and fighting multiple drug resistance (MDR) seen as part of infectious diseases domain. Ther eported results are of interest for life sciences, environment quality control and biomedical basic and applied research. Biomedical specialists, chemists, physicists, public health experts and even outer space researchers may be among target readers, as well as students engaged in these fields.The book shows a convincing and useful connection between optofluidics and MDR studies. It is distributed along 18 chapters written by 40 authors from 9 countries and 12 laboratories.A set of chapters informs readers about selected non-antibiotic medicines which are exposed to UV pulsed laser beams for generating photoproducts with enhanced properties in fighting MDR. Such parent compounds are phenothiazines, quinazolines and hydantoin derivatives which do not have normally significant effects on bacteria or tumour tissues, but after being exposed to laser radiation in water (chosen as a biocompatible liquid) solutions, generate photoproducts with individual or synergistic effects on biological targets.The book shows the most recent results in the action of exposed chlorpromazine and thioridazine on Gram-positive and Gram-negative bacteria and their enhanced antibacterial and antibiofilm activity.Complementary data about the effects of two cytostatics, methotrexate and 5-Fluorouracil, exposed to optical radiation on eye pseudotumours are synthesised; showing that mixtures of photoproducts generated from them have higher anti-inflammatory effects then their parent compounds.These data are correlated with reports about microfluidic properties for microdroplets serving as vehicles for the transport of medicines to targets."}
+{"text": "Mol. Biol. Cell. (2015)]we used the well-established yeast [PSI+]/Sup35 and[+PIN\u00ac]/Rnq1 prion models to show thatautophagy prevents sporadic prion formation. Importantly, we found thatspermidine, a polyamine that has been used to increase autophagic flux, acts asa protective agent which prevents spontaneous prion formation. Prions are self-perpetuating amyloid protein aggregates which underlie variousneurodegenerative diseases in mammals. The molecular basis underlying theirconversion from a normally soluble protein into the prion form remains largelyunknown. Studies aimed at uncovering these mechanism(s) are therefore essentialif we are to develop effective therapeutic strategies to counteract thesedisease-causing entities. Autophagy is a cellular degradation system which haspredominantly been considered as a non-selective bulk degradation process whichrecycles macromolecules in response to starvation conditions. We now know thatautophagy also serves as a protein quality control mechanism which selectivelydegrades protein aggregates and damaged organelles. These are commonlyaccumulated in various neurodegenerative disorders including prion diseases. Inour recent study [Speldewinde  Oxidativelydamaged Sup35 was found to accumulate in mutants lacking core components of theautophagy pathway, and this was found to correlate with an increased frequency ofde novo [PSI+] prion formation. Weshowed that growth under anaerobic conditions in the absence of molecular oxygenprevented the accumulation of oxidized Sup35 and abrogated the high frequency of[PSI+] formation in an autophagy mutant. This suggeststhat autophagy normally functions to clear oxidatively damaged proteins prior to theirconversion to the prion form. A protective role for autophagy in preventing denovo prion formation was further confirmed by showing that increasingautophagic flux by treatment with spermidine abrogates the formation of prions inmutants which normally show high rates of de novo prion formation. Thisimportant new finding strongly implicates autophagy as a defense system which protectsagainst oxidative damage of the non-prion form of a protein. This is an importanttrigger for the formation of the heritable prion conformation, an event that has alsobeen implicated in the formation of mammalian prions.The molecular basis by which prions arise spontaneously is poorly understood. Our dataindicate that oxidative protein damage to Sup35, which is a known trigger for Our study highlights the potential use for autophagy-inducing agents such as spermidinein the prevention of the very early stages of spontaneous prion formation i.e.effectively acting as a prion prevention agent . By improving the clearance ofdamaged/misfolded proteins, there is less possibility for these abnormal proteins toaccumulate and to act as nucleation sites catalyzing the aggregation of other damagedproteins. Polyamines such as spermidine are polycations which play multiple roles incell growth, proliferation and longevity. Their beneficial effects in prolonginglifespan are thought to be mediated by increasing autophagic flux. Spermidine inhibitshistone acetylases and the resulting alterations in the acetylproteome increases thetranscription of different autophagy-related genes . More work will be requiredto determine whether the abrogation of prion formation by spermidine solely depends onincreasing autophagic flux, or whether spermidine additionally promotes other stressprotective pathways. For example, spermidine supplementation has been linked withincreased stress tolerance including heat and oxidative stress, which is not onlymediated by increasing autophagic flux. Whether spermidine modulates the expression ofother stress responsive genes, such as heat shock and antioxidant genes which are knownto influence protein misfolding and prion formation, has not been fully established.Hence, spermidine may amelioarte prion fomation via multiple mechnisms including theinduction of autophagy and other stress-related pathways. PSI+]-versions ofwild-type and atg1 mutant strains. Following short-term induction ofthe Sup35NM-GFP fusion construct, fluorescent foci can be detected due to thecoalescence of newly made Sup35NM-GFP with pre-existing Sup35 aggregates. FluorescentSup35 aggregates are normally visible in approximately 70% of[PSI+] cells examined . We found that spermidinetreatment reduced this number such that visible Sup35 aggregates are only detected inapproximately 25% of cells. This did not occur in an atg1 mutantconfirming the requirement for an active autophagy pathway to clear aggregates inresponse to spermidine treatment . This experiment suggests that increasingautophagic flux via spermidine treatment, not only promotes the removal of smallermisfolded/oxidized Sup35 proteins, but can also promote the removal of larger molecularweight Sup35 aggregates which are already formed within cells. It should be emphasizedthat visible Sup35-GFP aggregates do not necessarily correspond to the number of trueheritable [PSI+] aggregates in cells and more work will berequired to examine whether spermidine treatment can really cure cells of the[PSI+] prion. This may be unlikely though, since thepresence of only a few low molecular weight Sup35 propagons will be inherited bydaughter cells resulting in [PSI+] prion transmission.However spermidine may well be beneficial in the treatment of other non-heritable andamorphous protein aggregate diseases. Recent data from our lab, which was not included in the original pulication, demonstratesthat spermidine treatment can also promote the clearance of Sup35 aggregates from cellsin an autophagy-dependent manner . We used a Sup35NM-GFP fusion construct tovisualize Sup35 aggregate formation in [Polyamines, such as spermidine, are present in millimolar quantities within alleukaryotic cells. They play essential roles in a multitude of cellular processes relatedto cell growth, proliferation and metabolism. Spermidine is a naturally occurringpolyamine and rich dietary sources include soy products, legumes, corn, and whole graincereals. The cellular levels of polyamines, such as spermidine, decline with age andhave been linked to lifespan and age-related disorders. Supplementation of spermidineinto dietary regimes may therefore have added benefits for cellular health and healthyageing. Relative to other established pharmacological inducers of autophagy, such asrapamycin and resveratrol, spermidine can be readily obtained from dietary sources anddoes not exhibit deleterious side effects. This places spermidine as a promisingtherapeutic agent for the prevention and amelioration of protein homeostasis and relatedaggregation diseases."}
+{"text": "Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. Based on our previous publications and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism.Using immunohistochemistry technique and confocal imaging analysis, we assessed the relationship between oxidative stress  and PVI and their perineuronal net (PNN) in twelve established animal models relevant to autism  and schizophrenia  KO, GRIN2A KO, Gclm KO) with or without additional insult , methylazoxymethanol acetate developmental rodent model (MAM) and poly:IC).When PVI deficits in the anterior cingulate cortex were found in these animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders, oxidative stress was always present. Specifically, oxidative stress was negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune, and antioxidant signaling. As convergent endpoint, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models . D-serine, an allosteric modulator of brain NMDA receptor also protected PVIs and PNN against oxidative stress in SR KO mice.In view of the fact that the established pathophysiological processes dopamine excess, immune dysregulation and NMDA receptor hypofunction could all induce oxidative stress and are potentiated by additional oxidative insults, this mechanism could be central to damage of the highly metabolically active PVIs and the PNN surrounding them. Antioxidant systems are therefore potential therapeutic targets, assuming that redox regulators could be applied early, during environmental impacts, long before the clinical emergence of the disease."}
+{"text": "Oral delivery is the most accepted and economical route for drug administration and leads to substantial reduction in dosing frequency. However, this route still remains a challenge for the pharmaceutical industry due to poorly soluble and permeable drugs leading to poor oral bioavailability. Incorporating bioactives into nanostructured lipid carriers (NLCs) has helped in boosting their therapeutic functionality and prolonged release from these carrier systems thus providing improved pharmacokinetic parameters. The present review provides an overview of noteworthy studies reporting impending benefits of NLCs in oral delivery and highlights recent advancements for developing engineered NLCs either by conjugating polymers over their surface or modifying their charge to overcome the mucosal barrier of GI tract for active transport across intestinal membrane. Lay abstract: Oral administration of drugs is considered to be a convenient route; however, various drugs that are insoluble in water or unable to permeate across GI tract membrane cannot be delivered by this route. To deliver them effectively, various lipid carriers have been widely explored by researchers. Lipid carriers encapsulate drug inside them and deliver them effectively via the oral route. Also, encapsulation of drug protects them from degradation inside GI tract and safely delivers them to the site of action. This review summarizes application of lipid carriers, in other words, nanostructured lipid carriers, in eradicating these problems, with suitable examples. It is also highly preferred for chronically administered agents, such as anti-tumor, antidiabetic and antihypertensive agents. Drug candidates, which are stable in gastric environment, possess adequate hydrophilic lipophilic balance to cross the intestinal epithelium membrane with the absence of the significant GI tract (GIT), irritation and toxicity signs are ideal candidates for oral delivery . Unfortu effects ,2. Thereet al. extensively worked on biocompatible and biodegradable solid lipids to develop solid lipid nanoparticles (SLNs) in early 1990 and thus resolved the stability and toxicity issues associated with the conventional lipid-based delivery systems [For bioavailability enhancement, the researchers have attempted various approaches to overcome the challenges associated with oral delivery, such as nanosizing of the drug molecules, salt formation, prodrug synthesis and encapsulation of drugs in nanosized carriers, such as polymeric micelles, nanoparticles, liposomes, emulsions, etc. ,3\u20134. Var systems . The dru systems . Modifie systems .NLCs possess unique characteristics and are formulated using a combination of solid and liquid lipids where less ordered structures are produced, which offer the firmer inclusion of the drug molecules within the matrix during the shelf life ,15. It hin vitro release patterns in both SLNs and NLCs were similar but NLCs displayed high-percent cumulative drug release in comparison to SLNs in 55 h. A lesser mobility of drug in SLNs  in comparison to NLCs (disordered arrangement) was responsible for the slower release of drug. Differential scanning calorimetric analysis showed decreased recrystallization index of NLCs in comparison to solid lipids and physical mixture of solid lipid and liquid lipid favoring the formation of disordered arrangement and reduced capacity of solid lipids to recrystallize suggesting their higher long-term stability. The results of in vivo studies also suggested NLCs to be superior as they exhibited 2.29-fold increase in oral bioavailability when administered to mice. Similar results were also noted with lovastatin-loaded NLCs. Study of partitioning behavior of lovastatin in pure solid lipid and mixtures of solid lipid and liquid lipid also depicted higher partitioning of drug in the lipid phase consisting of a mixture of solid lipid (Precirol\u00ae ATO 5) and liquid lipid  thus suggesting that higher solubility of drug was favored by the presence of liquid lipid [As mentioned previously NLCs overcome the disadvantages associated with SLNs, in other words, they provide higher drug loading, faster release rate and storage stability due to a use of blend of solid lipid and liquid lipid in their formulations. id lipid . Anotherid lipid  and dompid lipid  SLNs andNLCs are generally composed of solid lipid, liquid lipid, emulsifiers and water. They are fabricated using various methods, such as emulsification-sonication, solvent injection, high-pressure homogenization, microemulsion and solvent diffusion techniques that have been reviewed elsewhere ,13,22. Tet al. observed that small sized NLCs (200 nm) showed higher AUC values in comparison to higher sized NLCs (600 nm) when administered orally to rats, this was attributed to their higher mucoadhesion capability in the body [Literature reveals that composition and processing parameters employed for fabricating NLCs play a vital role in defining their particle size, percent entrapment efficiency and drug release profile and have been manipulated by various formulation scientists to obtain desired characteristics. Tailoring these properties can be advantageous for obtaining high therapeutic levels of drug in blood plasma. For instance, Muchow the body .et al. revealed that higher solubility of miconazole in lipid provided its better encapsulation in NLCs. In this study, the authors screened various solid lipids  and liquid lipids for formulating miconazole-loaded NLCs. Gelucire 43/01 was selected as solid lipid because it presented highest solubility for miconazole. Among two liquid lipids, in other words, Migilol\u00ae 812 and Capryol\u00ae PGMC, short listed on the basis of solubility study, capryol PGMC was employed for the fabrication of NLCs as it had higher compatibility with solid lipid selected [et al. carried out 1H NMR analysis to determine any interaction between lipid and bicalutamide as it contains functional groups capable of accepting and donating protons that may interact with the lipids during the preparation of NLCs leading to incompatibility [Solid lipid and liquid lipids, the major constituents of NLCs, ideally should be biocompatible, biodegradable, chemically stable and not possess any toxic effects. The selection of lipids for formulating NLCs is usually done on the basis of solubility of the drug in the lipids as it has a direct impact on drug entrapment and loading efficiency of NLCs . For insselected . Similarselected . Hydrophselected . Kumbhartibility . FTIR antibility .et al. [et al. also reported that the particle size of NLCs was significantly affected by the presence of liquid lipid. Pure solid lipids generated higher sized particles, whereas continuous increment in liquid lipid content led to decrease in particle size due to decrease in viscosity and higher molecular mobility [et al. wherein the continuous addition of Labrafil M 1944CS to Compritol 888 ATO led to the formation of small-sized NLCs. Better entrapment efficiency was also obtained with the addition of liquid lipid due to enhanced solubility of drug facilitated by addition of liquid lipid [Amount of liquid lipid is another parameter that plays a significant role in tailoring particle size and release rate as it leads to reduction in viscosity and surface tension of the system that provides smaller sized NLCs, which in turn provides high surface area, promoting higher percent cumulative drug release as demonstrated by Tiwari et al. . Chen etmobility . A similid lipid .Various lipids/oils obtained from plants are also gaining popularity in the pharmaceutical field for formulating lipid nanoparticles. For instance, tripterine was encapsulated in lipid derived from an edible plant, in other words, broccoli by solvent diffusion method and enhanced oral bioavailability was achieved in comparison to Precirol ATO 5-based lipid nanoparticles and drug suspension suggesting the applicability of plant-based lipids . Also, sAmount of total lipid matrix is also known to affect particle size and entrapment efficiency of NLCs, in other words, an enhancement in both characteristics was observed with increasing the lipid matrix. The higher viscosity of the system is held responsible for growth in particle size, whereas reduction in drug escaping tendency due to higher lipid content results in higher entrapment efficiency. Thus, selection of optimal lipid content is crucial while formulating NLCs with desired properties .in vitro release study. Improved characteristics of myversol system resulted in higher bioavailability of lovastatin-loaded NLCs in orally administered rats  to determine the in vivo fate and exact absorption mechanism employing water quenching fluorescent probes demonstrated no evidence of absorption of intact nanoparticles through the intestinal membrane after oral administration [in vivo studies on engineered NLCs are not satisfactory and there is necessity of detailed future studies to determine effects of composition, physiochemical properties and surface modification on the fate of lipid nanoparticles.During GIT passage, NLCs circumventing digestion process can be either conveyed to the portal blood via paracellular route bypassing metabolism due to enterocyte enzymes or can be captured by M cells of Payer's patches delivering NLCs to the lymphatic system . Extensistration . Howeverstration ,35. Alsostration . HoweverOwing to the poor bioavailability of most of the developed drugs, various research groups have worked on designing suitable oral delivery systems for such drugs. NLCs have gained high recognition as suggested by various research reports published so far for drugs, such as isoliquiritigenin, fenofibrate, baicalin, etc. ,43,47. VAppropriate solubility of drug at the absorption site is necessary for achieving acceptable oral bioavailability. However, more than 40% of new chemical entities coming out from combinatorial screening programs are poorly aqueous soluble, which is a subject of major concern to formulation scientists . NLCs haet al. developed NLCs of thymoquinone for oral delivery using high pressure homogenization technique as an aid to improve its gastroprotective activity. Rats pretreated with thymoquinone-loaded NLCs developed significantly reduced areas of ulcers in stomach in comparison to rats pretreated with plain NLCs against ethanol-induced ulcers via higher modulation of pH of gastric contents [Lercanidipine HCl is an antihypertensive agent that suffers from low solubility and presents poor oral bioavailability (10%). Lercanidipine HCl-loaded NLCs led to the enlargement in surface area, which resulted in an improved release rate to a receptor compartment (pH 7.4) across the rat stomach membrane in comparison to a drug suspension suggesting a higher dissolution rate of the drug. Moreover, drug-loaded NLCs showed superior antihypertensive activity for 24 h in comparison to drug suspension . Repaglicontents .50 values for drug-loaded NLCs were decreased up to five times in comparison to free drug due to the small size of NLCs that were highly absorbed by cells and released high concentration of drug within cells suggesting the applicability of this delivery vehicle for poorly soluble drugs.NLCs have also shown improvement in the pharmacokinetic profile of flavanoid drug; isoliquiritigenin having multiple health benefits, but presenting diminished therapeutic efficacy of its oral administration in suspension form due to its lipophillic nature. In this study, NLCs composed of glyceryl monostearate (solid lipid); Miglyol 812 (liquid lipid) and Tween 80 (surfactant) were developed. Higher diffusion of NLCs across the unstirred water layer of intestine epithelial cells facilitated by the presence of hydrophilic surfactant led to augmented values of AUC in comparison to drug solution. Moreover, the small size of NLCs facilitated bioadhesion to intestine membrane, which lead to higher absorption of NLCs . Also etAn orally ingested substance is exposed to varying conditions in different sections of GIT, which can adversely affect the stability of ingested bioactives. For instance, being a hydrophilic and acid labile compound, ifosfamide degrades at stomach pH and has a limited access to cancerous cells. Also, sintering of this compound on storage decreases its dissolution rate, which also presents problems in its delivery. More recently, ifosfamide was encapsulated inside NLCs having chitosan coating over their surface to provide sustained release of the drug. Formulated NLCs showed only 13% release at pH 1.2 for 6 h, suggesting suitability of NLCs in delivering ifosfamide effectively inside the body . PreviouIn vitro antioxidant study also suggested higher potential of lutein-loaded NLCs [The bioactives are susceptible to different environmental conditions and it is mandatory to protect them from such harsh conditions during storage to provide them better shelf life. For example, lipophillic nutraceuticals, such as luetin, \u03b2-carotene or quercetin are obligatory due to their multiple health benefits, but their low aqueous solubility and poor chemical stability during storage presents problems in their oral absorption. To trounce these difficulties, researchers have explored the capability of NLCs for accommodating great amounts of such poorly water soluble bioactives and prevent their premature decomposition . \u03b2-carotded NLCs . Thus, pet al. reported an increase in the plasma half life of biochanin A from 6 to 21 h after single oral administration in rats when encapsulated in NLCs [max (1.918-fold) and AUC values (3.2-fold) in comparison to a drug suspension after single administration in Wistar rats [Appropriately designed NLCs may act as a delivery vehicle capable of protecting drugs from premature degradation during their transport across GIT due to first pass metabolism. NLCs interact with bile salt in GIT to form mixed micelles, which undergo selective lymphatic uptake, thus bypassing the liver . Also, t in NLCs . In anot in NLCs . Flow cytar rats . In a sitar rats .1/2 (2 h), which restricts its clinical use due to need of frequent dosing. After encapsulation of simvastatin in NLCs, AUC values were improved up to 4.87-fold and t1/2 was almost doubled in comparison to a drug suspension [et al. combined two novel strategies in a single system, in other words, vinpocetine was incorporated in cyclodextrin complexes that were further incorporated in NLCs matrix and showed 39% higher in vitro release at pH 6.8 and 7.4 and superior bioavailability in male rabbits (92%) in comparison to conventional NLCs [Simvastatin is a drug of choice for treatment of hypercholesterolemia and is available as an immediate release formulation. It is poorly water soluble and highly metabolized in intestinal gut and liver and exhibits very short tspension . Furtherspension . In an anal NLCs .Ex vivo studies showed that formulation having 247-nm particle size (NLCs B) avoided P-gp efflux as it entered by both pathways, whereas other formulations entered only by caveolae pathway (NLCs A and NLCs C) as depicted in P-gp, is a 170 kDa protein belonging to the ATP-binding cassette family and is a well-studied protein, which mainly transports large, hydrophobic, cationic or electrically neutral molecules that can have remarkably dissimilar structures . P-gp isWhen a drug is administered orally, it enters the systemic circulation and gets distributed in different tissues of the body because of its physiochemical properties, which leads to decreased activity of drug than expected and in turn shows drug-associated toxicity. Therefore, it is a prerequisite for a delivery vehicle to deliver the drug at the site of action and at the same time be safe and should also minimize the adverse effects of drug for the effective treatment of any disease. NLCs have helped in improving treatment of various diseases via encapsulating drugs inside them and actively targeting disease area thus minimizing its potential toxicity. For example, tamoxifen is used to treat cancer and its use is accompanied by systemic and hepatic toxicity. Tamoxifen was integrated into NLCs composed of glyceryl monostearate of stearic acid and labrafil WL 2609 BS. On oral administration of 1.5-mg/kg dose of tamoxifen-loaded NLCs, the mice displayed slower clearance and did not show any increased levels of hepatotoxicity markers, whereas their levels were highly elevated with the same dose of tamoxifen suspension and its marketed formulation suggesting the potential of NLCs in circumventing its toxicity .et al. carried out in vitro cytotoxicity studies on Caco-2 cells for validating potential of NLCs in reducing toxicity of tripterine. Encapsulation of tripterine decreased cell killing with an IC50 value of 2.11 \u03bcg/ml, whereas cells treated with an equivalent concentration of drug solution exhibited higher cytotoxicity. Significant reduction in intestinal toxicity of the drug was also observed, this could be attributed to the controlled release of tripterine after its encapsulation in NLCs [Oral delivery of tripterine is also associated with adverse affects on GIT and kidneys. Chen  in NLCs . Triptol in NLCs .max, mean residence time and AUC values in comparison to drug solution and marketed oral granules demonstrating the high therapeutic potential of NLCs in addition to overcoming its side effects.Metabolites of few drugs also lead to adverse affects in the body, which necessitates the development of sustained release system for them. For instance, metabolites of montelukast are known to cause hepatotoxicity during its conventional oral therapy. It is documented that long-chain lipids assure lymphatic uptake of NLCs and high drug concentration in mesenteric lymph nodes from NLCs composed with long-chain lipid, in other words, glycerylmonostearate of stearin has been observed . TherefoNLCs have also been employed for effective delivery of drugs in the oral cavity, especially with increasing their residence time in oral mucosa. The mucoadhesive properties of positively charged NLCs have promoted their interaction with negatively charged oral mucosa, thus providing optimal residence in the oral cavity. These systems have been studied to be employed for treatment of various bacterial and fungal infections of the oral cavity. However, considering the lower viscosity of NLCs dispersion, these systems are needed to be incorporated in semisolid preparations, such as hydrogels, to permit their better application in oral mucosa. Recently, miconazole-loaded NLCs have been studied to provide local delivery and controlled release to oral mucosa, which otherwise presents difficulty due to its poor solubility. In this study, the antifungal activity of drug-loaded NLCs was found to be more pronounced in comparison to its marketed formulation having 17-fold higher dose in comparison to NLCs . SimilarIn vitro studies revealed that thiomer (cysteine) conjugation onto the surface of docetaxel-loaded NLCs using postinsertion technique led to higher mucoadhesion (81.6%) with mucin in comparison to unconjugated NLCs (51.9%) [in situ intestinal perfusion investigation. Better pharmacokinetic parameters of modified NLCs in Sprague Dawley rats were also in concordance with results of intestinal perfusion study suggesting beneficial effects of engineered NLCs.The tight epithelial cells of the GIT are covered with a hydrophilic and negatively charged protective layer of mucus that restricts the passage of foreign particles across GIT. However, researchers have exploited mucus as a beneficial tool to increase plasma concentration and therapeutic efficacy of drugs via formulating engineered nanoparticles having the capability to anchorage with mucus. Binding of nanoparticles to mucus increases their residence time in GIT, which allows passive transport of drugs leading to their increased absorption. Two different approaches employing physiochemical properties of mucus have been documented to provide mucoadhesion property to nanoparticles A & B. Fi (51.9%) . Also, sIn vitro drug permeability study across mucus secreting cells (Caco-2/HT 29 MTX) depicted that coating of dextran-protamine to the surface of NLCs could remarkably (twofold) enhance the drug delivery across the cell in comparison to uncoated NLCs [It has been documented that customary rejuvenation of mucus layer by a turnover process hampers bioadhesion process . Therefoted NLCs .et al. observed prolonged-plasma concentration (24 h) in case of docetaxel-loaded PEGylated NLCs in comparison to drug solution, which was very low within 12 h postoral administration to rats as PEGylation prevented opsonin binding to intact NLCs in systemic circulation thus avoiding their macrophage uptake [et al. also incorporated an anticancer drug biochanin A in PEG-NLCs with the aim of achieving improved oral bioavailability [in vitro cytotoxicity study carried out over MCF-7 cell lines highlighted the superior performance of biochanin A loaded PEG-NLCs in comparison to drug suspension. Further, oral bioavailability of etoposide-loaded DSPE-PEG-NLCs in rats was also significantly improved when compared with conventional NLCs and drug suspension, which was attributed to their higher uptake due to opening of tight junctions of intestinal membrane by DSPE-PEG and reduced RES uptake [Hydrophilic moieties, such as poly(ethylene glycol) (PEG), also have the capability to penetrate the aqueous mucus layer of the GIT D. PEG coe uptake . Wang etlability . ResultsS uptake . Thus, Pin vivo. Thus, engineered NLCs have been used as a delivery vehicle for targeting drugs to specific tissues along with improving its pharmacokinetic profile  encapsulating montelukast [\u03b6-potential is one of the fundamental parameters for assessing colloidal stability, in other words, values of \u03b6-potential above \u00b130 mV are the foremost requirement for the electrostatic stabilization due to repulsion between particles . In addi profile E. For ex . NLCs also showed concentration-dependent cytotoxic effects and hemolytic activity [Safety of nanomaterials employed for therapeutic or diagnostic purposes is one of the prime concerns in the modern arena. Numerous  systems . Reportee nature . Similare nature  or any ae nature . An oraldelivery . In a moactivity . In an iactivity . Thus, iex vivo potency, these candidates suffer from poor oral bioavailability and other issues, such as poor permeability, high first pass metabolism, toxicity concerns and instability in GIT. Increase in pubmed data since last decade indicated huge interest of researchers toward lipid-based nanoparticles. Successful NLCs based dermal products (Cutanova Nanorepair Q10 and FloraGlo\u00ae) introduced on the market have also directed formulation scientists to evaluate their potential in other routes. Researchers have explored the capability of these lipid nanoparticles for accommodating great amounts of bioactives, preventing their premature decomposition and enhancing their oral bioavailability. The various surfactants employed in NLCs formulations can overcome P-gp efflux and could also enhance permeability of drugs across the intestinal membrane by causing disruption in the membrane. Better pharmacokinetic parameters of drug-loaded NLCs obtained during different studies suggested that NLCs can serve as promising tool for enhancing therapeutic efficacy of drugs and also providing controlled release of encapsulated drugs. Different engineered NLCs investigated for further boosting their potential suggested that tuning of physical characteristics of NLCs via changing their composition/method of fabrication could provide fruitful results. Although the exact mechanism underlying behind enhanced absorption by NLCs needs to be addressed and solubility of drugs in different lipids needs to be determined as drugs show limited solubility in various lipids limiting their dose. Thus, further detailed in vivo studies are mandatory for taking them to clinics and considering the increased research on this system, it can be concluded that the NLCs based system intended for oral delivery will definitely reach clinical studies in near future.The poorly water soluble nature of drugs, resulting from drug discovery processes remains a major concern for pharmaceutical scientists despite their constant hard work. Besides their high Nanostructured lipid carriers (NLCs) are promising oral delivery vehicle due to their higher stability during storage and ease of scalability without any requirement of sterile conditions.These systems are capable in entraping both hydrophilic and lipophilic drugs.Biocompatible and biodegradable lipids employed in their fabrication minimize toxicity issues.Various studies have been reported based on NLCs for overcoming solubility, permeability, stability and toxicity issues of bioactives.Different engineered NLCs for generating mucus adhesive, mucus-penetrating particles or for better targeting have been explored.Peptidic ligands are also finding wider applicability in oral delivery as they facilitate active transport of the drugs loaded inside NLCs across the intestinal membrane.Better pharmacokinetic parameters of drug-loaded NLCs have been obtained during different studies.in vivo studies addressing their mechanism underlying enhanced oral bioavailability are needed for bringing these systems in clinics.Further, significant"}
+{"text": "This study characterized regions of DNA which remained unassembled by either PacBio and Illumina sequencing technologies for seven bacterial genomes. Two genomes were manually finished using bioinformatics and PCR/Sanger sequencing approaches and regions not assembled by automated software were analyzed. Gaps present within Illumina assemblies mostly correspond to repetitive DNA regions such as multiple rRNA operon sequences. PacBio gap sequences were evaluated for several properties such as GC content, read coverage, gap length, ability to form strong secondary structures, and corresponding annotations. Our hypothesis that strong secondary DNA structures blocked DNA polymerases and contributed to gap sequences was not accepted. PacBio assemblies had few limitations overall and gaps were explained as cumulative effect of lower than average sequence coverage and repetitive sequences at contig termini. An important aspect of the present study is the compilation of biological features that interfered with assembly and included active transposons, multiple plasmid sequences, phage DNA integration, and large sequence duplication. Our targeted genome finishing approach and systematic evaluation of the unassembled DNA will be useful for others looking to close, finish, and polish microbial genome sequences. Since the first Next-Generation Sequencing (NGS) platform was released by 454 Life science  is available  and algorithm developments have facilitated improved genome assemblies. Progress in next-generation sequencing platforms, metrics, and performances has been reviewed  PacBio sequence coverage  and PacBio RS-II platforms. Clostridium pasteurianum ATCC 6013   to remove bases having PHRED quality score <30 and any reads shorter than 20 bp. Adapter trimming and filtering of raw PacBio data was performed through SMRT analysis software to obtain \u201cfiltered subreads\u201d with default parameters  . Positional preference was determined using PerPlot and PerScan tools  and B. cellulosolvens DSM 2933 (48X). Post-trimming and filtering statistics for Illumina and PacBio data including the number of reads, average read lengths and genome coverage and total bases are summarized in Tables Illumina sequence coverage for each genome is >200X, sufficient to derive high-quality draft genome assemblies  values. Mfold analysis of PacBio gap sequences revealed the potential to form small stem-loop structures but large and/or strong secondary structural loops that might interfere with DNA polymerase and result in low sequence coverage were not identified. Significant differences were not observed between minimum free energies and secondary structures of PacBio gaps and 20 randomly selected regions from the AD2 and DSM 2933 genomes Table . In addiFor further characterization, we analyzed 1 kb DNA sequences flanking PacBio gaps  from three near-finished genomes in this study. A self-blast was performed using 1 kb regions as a query against the entire genome using Geneious software with default parameters. The grade score from Geneious software  for the top blast hits for gap termini regions are described in Table C. thermocellum LQRI (LQRI), and P. fermentans DSM 17108 genomes  of 16S rRNA  genome assemblies. Short reads from Illumina technology have limited power to resolve longer repetitive regions , but random errors in the PacBio platform can be corrected by using high (>100x) sequence coverage and/or Illumina data. However, uniform sequence coverage across the entire genome is not guaranteed and low coverage regions are prone to base-call errors. Assembly polishing is a crucial step to obtain accurate consensus sequence and facilitate downstream applications. Two assembly base-call correction algorithms applied in this study are Quiver (correction using PacBio reads) and Pilon (correction using Illumina reads) while iCORN . Therefore, for future projects, the application of circlator software followed by a careful inspection of the trimmed regions is recommended.Another important aspect of finished genome sequences is an accurate representation of a circular chromosome. Automatically finished assemblies generated through HGAP often have (duplicated) overlapping ends which need to be trimmed off for the final assembly. This could be achieved using the circulator (Hunt et al., de novo microbial genome assemblies. Our datasets and analyses will aid future efforts to better understand and overcome unassembled DNA from PacBio assemblies.In this study, we present an effective manual finishing approach targeted toward near-finished microbial genome assemblies. The importance of genome polishing steps is demonstrated through its positive influence on gene calling accuracy and improved protein coding potential, which will be useful to others looking to improve long-read assemblies. Assessment of Illumina gaps confirmed previous findings that repetitive rRNA operons are major contributors to fragmented short-read assemblies. For PacBio assemblies, our initial hypothesis that structural features of DNA might affect the PacBio sequence coverage leading to assembly gap was not accepted. However, we demonstrated that certain biological features such as presence of active transposons, plasmid sequences, and phage integration are possible reasons for assembly fragmentation. Additionally, DNA regions flanking the PacBio gap sequences showed high degrees of similarity with other loci and are likely contributors to incomplete PacBio assemblies in this dataset. The PacBio gap sequences in this study are attributed to a cumulative effect of various aspects of repetitive DNA content and biological features for specific genomes. Despite a few limitations, long reads from third-generation sequencing, in this case from the PacBio platform, are particularly advantageous for generating SU designed the study, performed, and contributed to all the experiments and analyses and wrote the manuscript draft; DK extracted genomic DNA, performed Illumina sequencing, and assisted with PCR and Sanger sequencing; RH contributed to study design and edited the manuscript; SB contributed to study design, assisted with draft writing, and editing. All authors reviewed and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In a policy forum, Daniel Schar and colleagues discuss the need for surveillance of antimicrobial consumption in animals in low- and middle-income countries and propose the establishment of antimicrobial consumption monitoring systems. Antimicrobial use in low- and middle-income country (LMIC) food animal production sectors is accelerating, commensurate with expanded intensive production to meet rapidly increasing demand for animal-source nutrition.However, antimicrobial consumption in animal production contexts of LMICs remains largely undocumented, limiting the ability to establish and monitor progress toward achieving consumption targets.We propose the establishment of antimicrobial consumption monitoring systems in a phased manner that will be responsive and adaptive to LMIC contexts, while directing a path toward incremental enhancement of monitoring structures.This phased approach enables implementation of systems yielding standardized, globally comparable antimicrobial consumption data, which could inform policies to optimize antimicrobial usage in food animal production.The approach should be complemented by efforts to strengthen animal production systems, eliminate medically important antimicrobial growth promoters, and reduce reliance upon prophylactic antimicrobial use.Global antimicrobial consumption in terrestrial and aquatic food animal production is accelerating, associated with expanded production to meet increasing demand for animal-source nutrition . In SoutEfforts to meet rising demand for animal-source nutrition in LMICs are driving a shift in animal production from small holder, mixed crop, and livestock operations to increasingly intensive, large-scale, and specialized commercialization ,3. IntenQuantitative volumes of AGP usage from LMICs are not available. However, studies from LMICs indicate substantial nontherapeutic use. In the Mekong Delta of Vietnam, 84% of poultry farms surveyed indicated that antimicrobials were used for prophylactic rather than therapeutic purposes, and nearly a third of overall usage involved antimicrobial classes on the WHO list of highest priority, critically important antimicrobials for human medicine . In the The discovery and commercialization of antimicrobials stands as a defining achievement of 20th century medicine. As usage patterns drive rising rates of antimicrobial resistance (AMR)-linked morbidity and mortality \u2014compoundAntimicrobial usage (AMU) in humans and animals exerts selection pressure potentiating AMR ,5\u20138; polFacilitates identification of trends and usage profiles,Permits establishment of time-bound consumption targets,Monitors progress toward achieving targets,Guides policy and targeted interventions optimizing antimicrobial use.Monitor consumption trends and benchmarking for optimization of antimicrobial consumption.Comparison of consumption data ultimately disaggregated by species and comparable across human and animal sectors,Antimicrobial consumption data become globally comparable,Contributes to international benchmarking,Creates a globally standardized monitoring architecture, upon which a future international agreement capping consumption could be developed.Comparison of antimicrobial consumption data across countries, species, farms, and with human consumption.Builds a platform for studying the association between antimicrobial consumption and AMR surveillance data.The measurement of AMU in human health and animal health and production settings is a central goal of the Global Action Plan on Antimicrobial Resistance  and the The ecosystem in which veterinary antimicrobials are produced, distributed, and utilized in LMICs is complex and variable. A majority of LMICs currently lack structures capable of quantifying consumption at sufficient resolution to provide usage data by antimicrobial class, animal species, production context, purpose of usage, and route of administration, which are necessary to facilitate effective interventions to optimize use . Of the Patterns of antimicrobial use differ widely across animal production value chains, as evidenced by macrolide, fluoroquinolone, and tetracycline residue detection in animal products marketed for human consumption , but speDespite calls for establishing usage thresholds and targets ,7,17, inOther challenges frequently shared by LMICs  are equaLow rates of AMR awareness and risk perception among farmers and veterinarians ,Inconsistent policies governing antimicrobial use in animal production,Absent AMU regulation and enforcement structures enabling wide accessibility to critically important antimicrobials without prescription,Where a legal veterinarian\u2013client\u2013patient relationship exists governing prescription use of antimicrobials in animals, the link between prescription and sales presents a sales volume profit incentive, andLack of systematic post-market quality surveillance that would enable recall of substandard and counterfeit veterinary antimicrobial products impacting therapeutic efficacy.Multiple methodologies for quantifying usage have been variously employed, hindering data comparability across countries and production sectors. The OIE terrestrial animal health code, the guiding framework for its 180 member nations, outlines the minimum standard as measuring gross usage by weight of active ingredient per year [Through the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) activity, European Union member states voluntarily report antimicrobial use by food animal\u2013producing species . The ESVvet) and defined course dose in animals (DCDvet) [vet and DCDvet\u2014proprietary ESVAC reporting nomenclature similar to animal defined daily dose (ADDD) and animal defined course dose (ADCD), respectively\u2014are not suited to contexts in which measurement must also capture continuous-use, subtherapeutic dosing, as in LMICs where policies governing AGP use vary significantly.Antimicrobial consumption in food animals can be crudely estimated by quantifying the total weight of the active ingredient adjusted for biomass eligible for treatment, usually expressed as mg/kg population correction unit (PCU), where PCU is defined as total live and slaughtered animal weight per year in a prescribed geographic area. While this measurement of total volume of active ingredient per biomass considers neither the concentration of administered product nor its pharmacokinetics in individual species, it is a readily calculated estimate of usage. ESVAC guidelines use the mg/PCU methodology and introduce both defined daily dose in animals (DDD(DCDvet) , serving(DCDvet) . HoweverAccurate accounting of antimicrobial consumption in food-producing animals of LMICs must capture both therapeutic and nontherapeutic use, including AGPs and mass administration of antimicrobials delivered in medicated, premixed feed. Antimicrobial consumption monitoring is particularly important in aquaculture, in which mass administration of antimicrobials in medicated feed for disease prevention and control is a standard practice .We propose a standardized, internationally-endorsed, phased approach that accounts for the context and currently available structures for collecting AMU data from food-producing animals\u2014both terrestrial and aquatic species\u2014in LMICs. The foundation is built upon the annual measurement of total sales of antimicrobials by class in mg/PCU, which can be derived from the total sales by class for member states reporting to the OIE divided by animal biomass data. Consistency in deriving the numerator\u2014active pharmaceutical ingredient (API)\u2014across multiple formulations of veterinary antimicrobials necessitates that products be managed through a standardized classification scheme, such as the Anatomical Therapeutic Chemical (ATCvet) system established for veterinary medical products . SimilarAs countries establish refined data collection structures , measureIn 2015, Thailand\u2019s International Health Policy Program and One Health partners established a human and animal national Surveillance for Antimicrobial Consumption (Thai SAC) system ,26. ThaiTechnical assistance could be housed within existing or newly established coordinating bodies and should prioritize intraregional LMIC exchanges and solutions relevant to unique regional capacities and contexts. An intergovernmental panel on AMR has been suggested , similarSalmonella enterica Serovar Heidelberg following elimination of third-generation cephalosporins from poultry hatcheries in Quebec, Canada [Documenting usage\u2014particularly for WHO-classified highest priority critically important antimicrobials\u2014permits trends monitoring and identification of animal production sectors in which targeted interventions hold promise of arresting drivers of resistance. Conceivably, a reversion to susceptibility is achievable, as noted in , Canada .Establishing antimicrobial consumption monitoring systems in animal production sectors should be a central, near-term goal of multisectoral national AMR action plans aligned with the WHO Global Action Plan and the focus of advocacy and support from the UN FAO, OIE, and WHO tripartite. Embedding this approach within national AMR action plans promotes monitoring capacities endorsed across ministries, including those vested with budget authority, and costed, resourced, and prioritized for implementation.In parallel, the WHO Joint External Evaluation (JEE) tool, which explicitly considers AMR and is increasingly being utilized by countries as an independent assessment of International Health Regulations (2005) capacity requirements , could dAntimicrobial consumption monitoring systems alone, however, will be insufficient to realize progress in directing prudent AMU in food-producing animals. Concurrently, support for strengthened farm and market chain biosecurity, enhanced livestock vaccination coverage, and improved uptake of good animal husbandry and nutrition practices will be necessary in achieving optimized usage, particularly in transitioning food animal production contexts of LMICs. New production facilities in LMICs should be designed to achieve high standards of husbandry and biosecurity, enabling more rapid phaseout of AGPs. Eliminating AGPs can be achieved at negligible cost to productivity, particularly in the context of such strengthened production systems .The framework presented here should provide LMIC policy makers with high-quality antimicrobial consumption data that can be used to establish usage targets, while building incrementally enhanced monitoring capacities. The analyses derived from this approach could steer targeted policies optimizing antimicrobial consumption and scale back selective pressures currently driving AMR in animal production, with benefits expected to extend broadly across animal and human health.The authors\u2019 views expressed in this publication do not necessarily reflect the views of the United States Agency for International Development or the United States Government."}
+{"text": "Solanum lycopersicum) have not been extensively explored. In this study, we characterized the 13 SlGRF genes. In silico analysis of protein motif organization, intron\u2013exon distribution, and phylogenetic classification confirmed the presence of GRF proteins in tomato. The tissue-specific expression analysis revealed that most of the SlGRF genes were preferentially expressed in young and growing tissues such as flower buds and meristems, suggesting that SlGRFs are important during growth and development of these tissues. Some of the SlGRF genes were preferentially expressed in fruits at distinct developmental stages suggesting their involvement in fruit development and the ripening process. The strong and differential expression of different SlGRFs under NaCl, drought, heat, cold, abscisic acid (ABA), and jasmonic acid (JA) treatment, predict possible functions for these genes in stress responses in addition to their growth regulatory functions. Further, differential expression of SlGRF genes upon gibberellic acid (GA3) treatment indicates their probable function in flower development and stress responses through a gibberellic acid (GA)-mediated pathway. The results of this study provide a basis for further functional analysis and characterization of this important gene family in tomato.Growth regulating factors (GRFs) are plant-specific transcription factors that are involved in diverse biological and physiological processes, such as growth, development and stress and hormone responses. However, the roles of GRFs in vegetative and reproductive growth, development and stress responses in tomato ( GRF gene was identified in rice (Oryza sativa) where it mediates gibberellic acid (GA)-induced regulation of stem growth in deepwater rice . EF. EFhttp:GCAG-3\u2019)  was usedeatments .Statistical significance of the differences in relative expression levels of each gene between treatments (control versus stress) and of the differences in expression levels between time points within a treatment was determined with one-way analysis of variance (ANOVA) using the MINITAB statistical software 17 . The mean separation of expression values was analyzed using Tukey\u2019s pairwise comparison test.SlGRF family genes using different bioinformatics approaches and transcript expression analysis. We analyzed their intron\u2013exon organizations, chromosomal distributions, gene structures, evolutionary relationships and expression profiles in different tissues and under different stress conditions to predict their possible biological functions. The SlGRF genes are variably expressed in different tissues and fruits at different developmental stages with particularly high expression in flower buds, and meristems. The increased expression of SlGRF genes in response to abiotic stress and phytohormone treatments implies their function in growth and development of tomato plants under different stress conditions. Together, our results obtained from gene structure, phylogenetic relationships and transcript expression profiles in different tissues and under different stresses facilitate the identification of tomato GRF genes that might play roles in specific developmental processes and/or environmental stress conditions.This study systematically characterized"}
+{"text": "Negative symptoms (NSs) are more severe in Treatment Resistant Schizophrenia (TRS) than Antipsychotic Responder Schizophrenia (ARS) patients. NSs are predictors of outcomes of neurological soft signs and functional capacity in TRS but not in ARS patients. The scope of this work is to clarify whether NSs effects are integral to or independent from the TRS diagnosis in our sample of patients.70 out of 206 eligible putative TRS and ARS patients were included (enrollment still ongoing). Patients were tested by the Neurological Evaluation Scale (NES); the CGI-S; the PANSS; the Heinrichs\u2019 Quality of Life Scale (QLS); the UCSD Performance-Based Skills Assessment (UPSA); the Personal and Social Performance (PSP) scale and Specific Level of Functioning (SLOF). Patients were subdivided in NSHigh (severe NSs) and NSLow (mild NSs) based on ROC curve-derived cut-off.At the Student\u2019s t test, NSHigh had significantly lower scores than NSLow patients on: Verbal Fluency; QLS score; PSP score; UPSA Financial, Communication, and Family Skills; UPSA total score; all SLOF areas (except Area4). NSHigh patients had significantly higher scores than NSLow patients on CGI-S; PANSS Positive and General Psychopathology Subscale scores; and NES score.Distribution of NS patients was significantly different between TRS/ARS diagnostic groups, as NSHigh patients were significantly more frequent in the TRS group . Notably, mean PANSS Negative Subscale scores were significantly higher in TRS compared to ARS patients .Since multiple variables found to be significantly different in NSHigh vs. NSLow patients were also significantly different between TRS and ARS patients, the question arises whether the significant differences found between diagnostic groups may depend on the higher percentage of patients with more severe NSs in the TRS group. Therefore, a two-way ANOVA was carried out with dichotomous NS and Diagnosis variables as the independent variables. Outcomes on multiple clinical variables were significantly different among groups. A NS*Diagnosis interaction effect was found for NES score , Passive Social Withdrawal (N4), and Difficulty in Abstract Thinking (N5).These data suggest that NSs are both independent determinants and moderators of TRS/ARS diagnosis effect on multiple psychopathology, cognitive, and psychosocial factors. More impaired functions attributed to non-response to antipsychotics may depend on more severe NSs. However, only a subset of NSs appears to exert this action, possibly related to the multidimensional construct of these symptoms."}
+{"text": "Malignant hypertension may be the first manifestation of systemic hypertension. We report a clinical case of a Caucasian 41-year-old man with no previous history of blood hypertension seen at casualty because of blurred vision. Fundus examination disclosed optic disk swelling, retinal hemorrhages and infarcts. The blood pressure was 220/130 mmHg. After the appropriate management of hypertension, optic disk and retinal edema resolved, leaving minor changes as mild optic disk pallor and hard exudates."}
+{"text": "Atherosclerotic stenosis of the brachiocephalic artery sometimes occurs in patients with coronary artery disease, and can cause stroke during the perioperative period of coronary artery bypass grafting.We describe the case of a 77-year old male with severe stenosis of the brachiocephalic artery and severe coronary artery disease. He successfully underwent aorto-right subclavian artery bypass that was performed concomitantly with off-pump coronary artery bypass.Concomitant aorto-subclavian artery bypass with off-pump coronary artery bypass grafting is a therapeutic option that minimizes the risk of perioperative stroke in patients with brachiocephalic artery stenosis and coronary artery disease. Atherosclerotic stenosis of the brachiocephalic artery can be associated with coronary artery disease . StenosiA 77-year old male was referred to our hospital for known coronary artery disease and a history of antero-septal myocardial infarction and syncope. Coronary angiography showed severe triple vessel disease. Computed tomography revealed severe diffuse calcification from the aortic arch to the abdominal aorta. In particular, just proximal brachiocephalic artery was shown to be circumferentially calcified and 90% stenosed Fig.\u00a0. ProximaA median sternotomy was performed, and the bilateral internal thoracic arteries were dissected. At the same time, a saphenous vein graft was dissected. A direct ultrasonographic examination revealed severe atheromatous plaques inside the brachiocephalic artery; hence, we chose the right subclavian artery as the distal anastomosis site for the prosthetic bypass conduit. An 8-mm polytetrafluoroethylene graft was anastomosed to the right subclavian artery, and then the proximal end of this graft was anastomosed to the aorta with a side-biting clamp. Off-pump CABG was then performed using a method described previously . The lefPostoperatively, no neurological deficit was observed. The blood pressures of the bilateral upper extremities were identical. Computed tomography demonstrated the patency of the coronary bypass grafts and the aorto-right subclavian artery bypass graft Fig.\u00a0. PostopeAtherosclerotic stenosis of the subclavian artery or brachiocephalic trunk is sometimes associated with coronary artery disease . Many paPreoperative computed tomography revealed severe calcification just proximal brachiocephalic artery, and carotid ultra sound examination revealed subclavian steal phenomenon at right vertebral artery. But computed tomography revealed no significant stenosis from end of the brachiocephalic trunk to origin of right carotid artery and subclavian artery, and so we expected that the aorto-subclavian bypass provided a physiological brain perfusion and reduced the risk of stroke.Takach et al.  reportedConcomitant aorto-subclavian artery bypass with off-pump CABG is a therapeutic option that minimizes the risk of perioperative stroke in patients with brachiocephalic artery stenosis and coronary artery disease."}
+{"text": "Cyclosporin-A (CsA) and tacrolimus (FK-506) are immunomodulating agents used to prevent rejection in organ transplantation. They are both associated with several side effects, including nephrotoxicity and severe hypertension due to vascular injury, which often appears as a microvascular occlusive disorder . We report the first case of a microvascular occlusive disorder with the features of TMA in the small bowel of an orthotopic liver transplant (OLT) patient after immunosuppressive therapy with CsA and FK506. The patient presented with severe recurrent abdominal colics and distal subocclusion, requiring aggressive surgical treatment. Histological and ultrastructural analysis of the resected specimen disclosed intestinal TMA. Although rare, such a complication should be considered in the differential diagnosis of abdominal colics in patients undergoing immunosuppressant therapy after OLT."}
+{"text": "Biotic and abiotic factors are increasingly acknowledged to synergistically shape broad-scale species distributions. However, the relative importance of biotic and abiotic factors in predicting species distributions is unclear. In particular, biotic factors, such as predation and vegetation, including those resulting from anthropogenic land-use change, are underrepresented in species distribution modeling, but could improve model predictions. Using generalized linear models and model selection techniques, we used 129 estimates of population density of wild pigs (Sus scrofa) from 5 continents to evaluate the relative importance, magnitude, and direction of biotic and abiotic factors in predicting population density of an invasive large mammal with a global distribution. Incorporating diverse biotic factors, including agriculture, vegetation cover, and large carnivore richness, into species distribution modeling substantially improved model fit and predictions. Abiotic factors, including precipitation and potential evapotranspiration, were also important predictors. The predictive map of population density revealed wide-ranging potential for an invasive large mammal to expand its distribution globally. This information can be used to proactively create conservation/management plans to control future invasions. Our study demonstrates that the ongoing paradigm shift, which recognizes that both biotic and abiotic factors shape species distributions across broad scales, can be advanced by incorporating diverse biotic factors. Predicting and mapping species distributions, including geographic range and variability in abundance, is fundamental to the conservation and management of biodiversity and landscapes23There is an ongoing paradigm shift in understanding how biotic and abiotic factors shape species distributions. Until recently, it was widely accepted that abiotic factors, such as temperature and precipitation, played the primary role in shaping distributions of species and biodiversity at broad scales  and that biotic factors were most important at fine scales 9101213141515197In addition to species interactions, biotic factors related to vegetation can influence species distributions and abundance at broad scales. In particular, anthropogenic land-use change is rarely considered when evaluating species distributions at broad scales; however, given the human footprint globally23252613Invasive species are a primary driver of widespread and severe negative impacts to ecosystems, agriculture, and humans across local to global scalesMus musculus) and brown rat (Rattus norvegicus), wild pigs  have one of the widest geographic distributions of any mammal; further, it exhibits the widest geographic range of any large mammal353940Few species exhibit a global distribution that extends across Europe, Asia, Africa, North and South America, Australia, and oceanic Islands. Besides naturalized animals, such as the house mouse  evaluate how biotic  and abiotic  factors  shape po2), which resulted in 129 estimates of density across their global distribution used in our analyses  had\u2009>\u20091,000 times more support as the best approximating model than the top model considering only abiotic factors   . The var\u00d7\u200910\u221217) . Density\u00d7\u200910\u221217) ; percentUsing the full model-averaged results of parameter estimates, we created a predictive map of global wild pig population density . Wild piPopulation density of an invasive large mammal was strongly influenced by both biotic and abiotic factors across its global distribution. Consistent with the prediction that abiotic factors drive broad-scale patterns of species distribution, potential evapotranspiration (PET) and precipitation variables were important predictors of population density on a global scale. In addition, contributing to growing evidence that biotic factors are also important determinants of broad-scale patterns of species distributions, both biotic interactions and vegetation played important roles in predicting the distribution of wild pig populations globally. Further, land-use change mediated by human activities strongly predicted the broad-scale distribution of an invasive large mammal. Consistent with previous studies evaluating how population density of ungulates varied across broad scales, both bottom-up (resource-related) and top-down (predation) factors influenced the distribution of wild pig populations1942Using both biotic and abiotic factors to evaluate broad-scale species distributions can create more realistic maps of range and density with better predictive ability16Abiotic factors, such as temperature and precipitation, are consistently found to be primary determinants of species distributions at broad scalesBiotic factors were among the most supported variables predicting population density across a global scale. Our results indicated that the presence of large carnivores can influence wild pig population density. Large carnivore richness was strongly supported in our models and exhibited a negative relationship with wild pig density; as the number of large carnivore species increased, wild pig density decreased, which is consistent with studies in Eurasia and Australia4247495052531718Although biotic interactions between animals are the primary biotic factors evaluated in species distribution models at broad scales, the role of plant communities has received less consideration. In particular, anthropogenic land-use change increasingly influences vegetation communities across continents and warrants a better understanding for how human activities are shaping broad-scale distributions of plant and animal populations22235758Forest is considered a key habitat type preferred by wild pigs59In some systems, abiotic factors can be stronger predictors of species distributions, than biotic factors, because of high correlations between these two factorsAdditional biotic factors that can influences species distributions on a broad scale, particularly invasive species, include the role of humans in distributing the founding individuals of new populations. For example, invasive wild pig populations have arisen across several continents recently through human activities. Illegal translocations by humans for hunting purposes can facilitate the long-distance expansion of wild pig populations into new areas646539676860Population density, compared to presence-absence occurrence, can provide more informative conclusions of species distributions in relation to biotic and abiotic factors77374Predicting species distributions provides critical information to the management and conservation of biodiversity, especially for controlling invasive species. Without intensive management actions, our study predicts that there is strong potential for wild pigs to expand their geographic range and further invade expansive areas of North America, South America, Africa, and Australia. Although wild pigs currently occupy broad regions of predicted habitat in their non-native range, many regions of predicted habitat are currently unoccupied and may be at high risk for future invasion. These areas might warrant increased surveillance by local, state, and federal agencies to counter the establishment of populations. Although attention in unoccupied areas that are predicted to support high densities of wild pigs might warrant priority for countering population introductions, wild pigs can persist in relatively low quality habitat  and these areas also warrant attention to halt invasions. Given the potential for wild pig populations to rapidly expand once establishedet al.76To evaluate the population density  of wild pigs throughout their global distribution, we compiled density estimates from the literature throughout its native and non-native ranges across each continent and island for which data were available . PreviouModels evaluating and predicting species distributions can be improved by including areas of absence  or zero density to sample the full range of available landscape conditions73We considered a suite of biotic and abiotic landscape variables, which were divided into vegetation, predation, and climate factors  that we The biotic factors that we evaluated included agriculture, broadleaf forest, enhanced vegetation index (EVI), forest canopy cover, difference in the proportion between forest and agriculture (to characterize landscape heterogeneity), normalized difference vegetation index (NDVI), large carnivore richness, and unvegetated area . We expeThe abiotic factors that we evaluated included two measures of ecological energy regimes, actual evapotranspiration  and potential evapotranspiration , and calculated variable importance values93942 resolution). This map displays the maximal potential density of wild pigs in relation to the biotic and abiotic factors used in our modeling and reflects predicted densities that would be achieved if wild pigs had access to all landscapes, their movements were unrestricted, and management activities did not suppress populations. We validated our model using mean squared prediction error (MSPE)We used multiple linear regression to evaluate how population density was influenced by our final suite of biotic and abiotic factors . The disHow to cite this article: Lewis, J. S. et al. Biotic and abiotic factors predicting the global distribution and population density of an invasive large mammal. Sci. Rep.7, 44152; doi: 10.1038/srep44152 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "In our recent updated studies, we found a significant association between periprocedural blood transfusion and acute kidney injury (AKI) following transcatheter aortic valve replacement (TAVR) with an overall 1.95-fold increased the risk of AKI. We also demonstrated that a transapical approach was significantly associated with increased AKI risk compared with a transfemoral approach. Nevertheless, the TAVR approach did not affect severe renal outcomes or long-term renal function. In addition, our meta-analysis demonstrated no significant association between contrast media volume and risk of AKI after TAVR. Thus, the dose of contrast media likely does not play a significant role in the pathogenesis of TAVR-related AKI. Growing knowledge of these risk factors of TAVR on kidney function will help improve preventive measures to improve patients\u2019 outcomes.We agree with Onuigbo and Agbasi that previous studies have attempted to identify effective interventions to prevent postoperative acute kidney injury (AKI) events including cardiac surgery-associated AKI and most of them failed to be successful ,2. In thAll authors have contributed equally to the preparation of the manuscript.The authors declare no conflict of interest.Ethical issues  have been completely observed by the authors.None."}
+{"text": "Oncorhynchus spp.) carcasses might yield suitable DNA quality for noninvasive monitoring of brown bears (Ursus arctos). We compared the efficiency of monitoring brown bear populations using both fecal DNA and salivary eDNA collected from partially-consumed salmon carcasses in Southeast Alaska. We swabbed a range of tissue types from 156 partially-consumed salmon carcasses from a midseason run of lakeshore-spawning sockeye (O. nerka) and a late season run of stream-spawning chum (O. keta) salmon in 2014. We also swabbed a total of 272 scats from the same locations. Saliva swabs collected from the braincases of salmon had the best amplification rate, followed by swabs taken from individual bite holes. Saliva collected from salmon carcasses identified unique individuals more quickly and required much less labor to locate than scat samples. Salmon carcass swabbing is a promising method to aid in efficient and affordable monitoring of bear populations, and suggests that the swabbing of food remains or consumed baits from other animals may be an additional cost-effective and valuable tool in the study of the ecology and population biology of many elusive and/or wide-ranging species.Noninvasive genetic sampling is an important tool in wildlife ecology and management, typically relying on hair snaring or scat sampling techniques, but hair snaring is labor and cost intensive, and scats yield relatively low quality DNA. New approaches utilizing environmental DNA (eDNA) may provide supplementary, cost-effective tools for noninvasive genetic sampling. We tested whether eDNA from residual saliva on partially-consumed Pacific salmon ( Environmental DNA, or eDNA, has proven to be a comprehensive, noninvasive means of monitoring biodiversity, providing rapid, cost-effective, and efficient insights on species\u2019 distribution and abundance ,2. As a et al. , marten [Martes americana], etc.), particularly if the microsatellites used are shared among species. For example, the sex marker we used, SRY, amplifies in multiple mammalian species. Where contamination is possible, researchers should consider utilizing species-specific markers. Studies utilizing markers that overlap among species should ensure that all PCR replicates give consistent results. These considerations aside, saliva is a promising new source for bear DNA in salmon ecosystems.Additionally, because of the nature of bear feeding behavior, it is possible for carcasses to become contaminated with DNA from a second individual bear if scavenging occurs following the initial consumption event. In populations with high allelic diversity and heterozygosity, however, mixed samples should be detectable . ContamiWe found residual saliva collected from partially-consumed salmon carcasses to be a successful, labor- and cost-effective way to sample brown bear populations. As far as we are aware, this study is the first to use noninvasively collected saliva to estimate the population density of any species of wildlife. As we focused primarily on the methodology of saliva sampling in this study, we recommend that researchers looking to implement this technique as a method to monitor bear populations take into account potential capture heterogeneity and violation of assumptions for mark-recapture models that may arise due to differing levels of fishing success or consumption behaviors among individual bears.Although salmon carcasses provide a readily available source of saliva to aid in the monitoring of bear populations, baited saliva sampling should be easily generalizable to systematic surveys of carnivores if appropriate baits can be identified and tested . As an eS1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 FigNumber of samples that successfully genotyped  versus number of unique individuals identified  across all samples collected, with trendlines.(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file."}
+{"text": "Wolbachia (Alphaproteobacteria) and Spiroplasma (Mollicutes), are discussed. Although several general patterns of genome reduction associated with the adoption of symbiotic relationships could be identified, extensive variation was found among these facultative symbionts. These findings are incorporated into the established conceptual frameworks to develop a more detailed evolutionary model for the discussion of possible trajectories. In summary, transitions from facultative to obligate symbiosis do not appear to be a universal one-way street; switches between hosts and lifestyles  occur frequently and could be facilitated by horizontal gene transfer.Symbiosis between organisms is an important driving force in evolution. Among the diverse relationships described, extensive progress has been made in insect\u2013bacteria symbiosis, which improved our understanding of the genome evolution in host-associated bacteria. Particularly, investigations on several obligate mutualists have pushed the limits of what we know about the minimal genomes for sustaining cellular life. To bridge the gap between those obligate symbionts with extremely reduced genomes and their non-host-restricted ancestors, this review focuses on the recent progress in genome characterization of facultative insect symbionts. Notable cases representing various types and stages of host associations, including those from multiple genera in the family Enterobacteriaceae (class Gammaproteobacteria),  This review synthesizes the recent progress in genome characterization of insect-symbiotic bacteria, the emphases include (i) patterns of genome organization, (ii) evolutionary models and trajectories, and (iii) comparisons between facultative and obligate symbionts. None declared."}
+{"text": "Morphological responses of nonmammalian herbivores to external ecological drivers havenot been quantified over extended timescales. Herbivorous nonavian dinosaurs are an idealgroup to test for such responses, because they dominated terrestrial ecosystems for morethan 155 Myr and included the largest herbivores that ever existed. The radiation ofdinosaurs was punctuated by several ecologically important events, including extinctionsat the Triassic/Jurassic (Tr/J) and Jurassic/Cretaceous (J/K) boundaries, the decline ofcycadophytes, and the origin of angiosperms, all of which may have had profoundconsequences for herbivore communities. Here we present the first analysis ofmorphological and biomechanical disparity for sauropodomorph and ornithischian dinosaursin order to investigate patterns of jaw shape and function through time. We find thatmorphological and biomechanical mandibular disparity are decoupled: mandibular shapedisparity follows taxonomic diversity, with a steady increase through the Mesozoic. Bycontrast, biomechanical disparity builds to a peak in the Late Jurassic that correspondsto increased functional variation among sauropods. The reduction in biomechanicaldisparity following this peak coincides with the J/K extinction, the associated loss ofsauropod and stegosaur diversity, and the decline of cycadophytes. We find no specificcorrespondence between biomechanical disparity and the proliferation of angiosperms.Continual ecological and functional replacement of pre-existing taxa accounts fordisparity patterns through much of the Cretaceous, with the exception of several uniquegroups, such as psittacosaurids that are never replaced in their biomechanical ormorphological profiles. Sauropodomorph and ornithischian dinosaurs were the foremost herbivorous terrestrialvertebrates of the Mesozoic Era in terms of species richness, abundance, and functionaldiversity  in herbivorous nonavian dinosaursthrough time. This approach complements previous attempts to examine these questions thoughspatiotemporal comparisons of species-richness patterns and provides the only rigorousbiomechanically and functionally based analysis of these issues attempted to date. Wehypothesize that ornithischians and sauropodomorphs will show distinct morphologies andbiomechanical profiles . Wealso hypothesize that the shift in plant community structure after the J/K boundary willtrigger a corresponding shift in dinosaurian jaw biomechanical profiles, due to thediffering physiognomies, digestibility, and mechanical properties of the varied potentialfood plant clades that were ecologically important at different times throughout theMesozoic Bakker . We use Data for 2D landmark and biomechanical trait analyses were compiled from 167 sauropodomorphand ornithischian dinosaur taxa . Herbivorousnonavian theropods were excluded from this data set, as complete mandibular material forthese animals is rare. A mandibular biomechanical profile represents a good proxy forcharacterizing the feeding system, as the mandible is primarily adapted for feeding, whereasthe cranium has multiple functional roles, some of which are unrelated to feeding, such ashousing the brain and sensory organs  in Past, Version 3 , with the exception of Stegosaurus (twospecies). Regions of overlap are occupied by a wide range of both basal and derivedsauropodomorphs; these include: Plateosaurus gracilis,Lamplughsaura, mamenchisaurids, brachiosaurids, and two SouthAmerican titanosaurids (Antarctosaurus andBonitasaura). Sauropodomorphs occupy morphospace exclusively in the\u2212PC1 region: this region is characterized by dorsoventrally narrow jaws and the lack ofa prominent coronoid process. Noneusauropod sauropodomorphs , for the most part,account for sauropodomorph occupation of morphospace in +PC2: this region is typified byvery narrow anterior jaws. Macronarian and diplodocoid taxa (includingDiplodocus and Tapuiasaurus) primarily occupy \u2212PC2regions of morphospace . Jaws in this region exhibit a greater gap betweenlandmarks 1 and 2 than in sauropodomorph morphospace (due to the presence of thepredentary in iguanodontians). Disparate groups of nonthyreophoran ornithischians expandmorphospace occupation into +PC1 and +PC2 (hadrosaurids) and \u2212PC2 regions(leptoceratopsids and psittacosaurids). +PC1 and +PC2 regions typically contain jawswith prominent coronoid processes and downwardly deflected predentaries; \u2212PC2 regionscontain robust, dorsoventrally broad jaws. Nonceratopsid marginocephalian jawmorphologies, such as those of psittacosaurids and leptoceratopsids, contribute stronglyto the expansion of ornithischian shape morphospace, predominantly into +PC1/\u2212PC2. Taxaare absent in a region of morphospace around +0.05 PC1/\u22120.075 PC2.Our results demonstrate that sauropodomorph and ornithischian jaws occupy significantlydifferent regions of morphological morphospace p<0.01; ; Table2phospace . The cenp<0.01; Pisanosaurus, heterodontosaurids) and basal members of Thyreophora, Marginocephalia (Yinlong),and Ornithopoda .Sauropodomorphs occupy regions of +PCo1. Noneusauropod sauropodomorphs  predominate in+PCo1/\u2212PCo2. This region is characterized by jaws with a high mechanical advantage and alarge adductor muscle attachment area. Diplodocids, nonneosauropods, andnontitanosaurian macronarians  stretch sauropodomorph occupation into +PCo2. Jaws inthis region also display high mechanical advantages, coupled with high aspect ratios.Many iguanodontian, ceratopsid, and psittacosaurid jaw profiles occupy similar regionsof +PCo2 biomechanical morphospace (Montanoceratops). This region of functional space is characterized bydeep jaws with short adductor muscle attachment and a high posterior mechanicaladvantage. Expansion into \u2212PCo2 is accounted for by deep-jawed ankylosaurs, with low tooth:jawdepth ratios and high relative dental length  share areas ofbiomechanical morphospace with iguanodontians but occupy very different regions of shapespace  that plots between nonhadrosaurid ornithopods andankylosaurians  extend biomechanical morphospace occupation into theregion of morphospace characterized by deep mandibles with short adductor muscleattachment and high posterior mechanical advantages . By contrast,biomechanical disparity undulates through the Mesozoic . Thereare no significant differences in disparity between successive time bins for eitherbiomechanical or morphological disparity curves (at p=0.05) and nomarginal-likelihood values exceed the threshold value of 8. There are a few instanceswhere disparity diverges markedly from sample size, suggesting that a trend, albeitnonsignificant, might be observed. For example, morphological disparity rises in theEarly Cretaceous, immediately after the J/K extinction, and in the early LateCretaceous, while sample size drops. Likewise, biomechanical disparity drops in theMiddle Jurassic while sample size rises slightly. Conversely, in the latest Cretaceous,sample size rises sharply while biomechanical disparity drops very slightly.Morphological (shape) and biomechanical disparity measures are decoupled through theMesozoic . MorpholMesozoic , a decoun=5). The lack of manydinosaur-bearing formations between the Berriasian and Albian may partially account forthe low species richness observed in this interval, although it could also be attributedto the J/K extinction event , despite the former existing around 10Myr earlier: this pattern supports theresults of another recent quantitative craniodental study . Perhapssurprisingly, we find minimal convergent occupation in biomechanical morphospace betweentitanosaurids  and diplodocids   and titanosaurids with longer snouts and pencil-liketeeth (such as Antarctosaurus), and diplodocids are outliers in thisbiomechanical morphospace. This pattern supports quantitative work on sauropodomorphcranial morphology related to feeding, with similar placement of the same taxa incranial  and Manidens(Heterodontosauridae) share occupation of Late Jurassic sauropodomorph biomechanicalmorphospace . This suggests that mandibles withsimilar gross morphology were biomechanically and functionally differentiated by thistime. In general, sauropodomorphs and heterodontosaurids occupy similar regions of bothshape-based and biomechanical morphospace and do not extend their occupation ofmorphospace beyond regions already occupied by the end of the Early Jurassic (Camptosaurus), which is also reflected in the morphological disparitycurve  occupy novel regions of morphological andbiomechanical morphospace: these taxa share regions of biomechanical morphospace withhadrosauroids until the disappearance of basal marginocephalians prior to the last 20Myr of the Mesozoic (Triceratops) and leptoceratopsids . The biomechanical profiles of ceratopsids show nooverlap with those of hadrosaurids. This supports the conclusions of Mallon and Anderson leads to an increase in biomechanical disparity levels fromthe early Late Cretaceous. Marginocephalian, ornithopod, and thyreophoran biomechanicalmorphospace occupation in the latest Cretaceous suggests that these groups, whilevarying from each other in mandibular shape, also share a variety of functional andbiomechanical traits relating to feeding. Late Cretaceous hadrosaurids and ankylosauridsfilled the biomechanical roles vacated by Early Cretaceous nonhadrosaurid iguanodontiansand nodosaurids, respectively. Individual occupation of morphospace by each taxon can beviewed in Supplementary Figures 2\u20136.Early Cretaceous marginocephalians  . The exclusion of the Morrisontaxa removes the Late Jurassic peak in biomechanical disparity .A similar jackknifing of the taxa from the Dashanpu Formation (including the \u201cUpper andLower Shaximiao\u201d formations) yielded a trough in disparity in the Middle Jurassic butretained a strong peak in the latest Jurassic . These resultssuggest that the data may be sensitive to the inclusion or exclusion of particularlyrich fossil-bearing sites. In addition, the lack of available jaw material from Northand South American titanosaurs seriously underrepresents sauropodomorph diversity in theCretaceous. The addition of titanosaurid taxa to the analysis may increase both thedisparity and overall morphospace occupation of sauropodomorphs, although the titanosaurjaws sampled in this study already account for a broad range of morphologies.When disparity tracks sample diversity closely, as it does in this study forshape-based disparity, sampling bias cannot be ruled out. Morphological disparity inthis study partly tracks jaw sample size, suggesting a potential bias in the data setfor some features of the disparity curve  when compared with mid-browsing taxa , and almost equal in disparity to very low-browsingsauropodomorphs . This pattern contrasts with sample diversity, with thelowest sample size found in the high-browsing feeding envelope (n=6). Unfortunately, low sample sizes within each feeding levelprevent any significant differences or definitive conclusions to be made. However, thispattern remains intriguing and the addition of more mandibular remains from high- andmid-browsing taxa to our sample (as and when they are discovered) would complement thisstudy. This is an avenue of study that requires more investigation in the future toenable deeper insights into niche partitioning between sauropod groups based on maximumbrowse height.Supplementary analyses of biomechanical and shape-based disparity withinsauropodomorphs in relation to maximum feeding height show higher levels of disparity inhigh-browsing sauropods .The dip in biomechanical disparity after the J/K recovered by our analyses may,therefore, be an artefact due to either geological biases or uneven collection effort,underrepresenting the true diversity of jaw biomechanical profiles at this time. Due tothe lack of complete mandibles from rebbachisaurids, dicraeosaurids, and other clades,it is possible that the latest Jurassic and earliest Cretaceous disparity levelsreported herein are currently undersampling the total diversity of mandible morphologyand potential function. Such exclusions cannot be corrected for by our analyses andrepresent a limitation of the fossil material currently available.Udanoceratops), a group that is also present in North America. LateCretaceous hadrosaurids and ankylosaurids filled the biomechanical roles vacated by EarlyCretaceous nonhadrosaurid iguanodontians and nodosaurids respectively. Our results implythat, after the establishment of peak overall biomechanical variation in the latestJurassic, only marginocephalians demonstrated widespread variation in biomechanical profilesover time, triggered by the isolated adaptive radiations of psittacosaurids andleptoceratopsians. The remainder of Cretaceous herbivorous dinosaurs underwent progressiveniche replacement, with successive replacement by related taxa with comparable biomechanicalprofiles.For the first time, we have quantified the morphological and biomechanical variation ofornithischian and sauropodomorph jaws throughout the Mesozoic and examined how diversityrelated to external extrinsic drivers such as extinction events and the rise of angiosperms.We find that herbivorous dinosaur clades have jaws that occupy different regions ofmorphospace throughout the Mesozoic. Furthermore, sauropodomorphs and ornithischians havejaws that also function in broadly different ways, yet there is some potentially convergentoverlap in biomechanical function between different ornithischian clades in the Cretaceous.Basal members of each clade tend to be more similar in form and function to each other,while derived taxa are more functionally and morphologically divergent. Herbivorous dinosaurjaws maintained a numerically steady diversity of biomechanical traits, with a peak observedin the Late Jurassic triggered by the diversification of high-browsing sauropods. This isconsistent with a rapid evolutionary radiation in biomechanical diversity among herbivorousdinosaurs followed by a plateau. The Tr/J extinction had no overall effect on biomechanicalvariation among herbivorous dinosaurs, despite fundamental changes in floral and faunalcomposition across the boundary. This consistency suggests that Early Jurassic dinosaursfilled the functional feeding niches vacated by the extinction of Late Triassic taxa.Similar successive replacement patterns are also seen in Devonian gnathostomes and Devonianto mid-Pennsylvanian tetrapodomorphs (Anderson et al."}
+{"text": "The prognosis for children with high-risk neuroblastoma is often poor and survivors can suffer from severe side effects. Predictive preclinical models and novel therapeutic strategies for high-risk disease are therefore a clinical imperative. However, conventional cancer cell line-derived xenografts can deviate substantially from patient tumors in terms of their molecular and phenotypic features. Patient-derived xenografts (PDXs) recapitulate many biologically and clinically relevant features of human cancers. Importantly, PDXs can closely parallel clinical features and outcome and serve as excellent models for biomarker and preclinical drug development. Here, we review progress in and applications of neuroblastoma PDX models. Neuroblastoma orthotopic PDXs share the molecular characteristics, neuroblastoma markers, invasive properties and tumor stroma of aggressive patient tumors and retain spontaneous metastatic capacity to distant organs including bone marrow. The recent identification of genomic changes in relapsed neuroblastomas opens up opportunities to target treatment-resistant tumors in well-characterized neuroblastoma PDXs. We highlight and discuss the features and various sources of neuroblastoma PDXs, methodological considerations when establishing neuroblastoma PDXs, in vitro 3D models, current limitations of PDX models and their application to preclinical drug testing. One of the main reasons for the high attrition rate in oncology drug development is a lack of preclinical models that recapitulate the genotype and phenotype of the patient\u2019s disease. Xenografts based on conventional cancer cell lines have been used for decades and while this model system can provide valuable data, cultured cell lines that have adapted to the in vitro microenvironment often differ from the original tumor found in patients. Specifically, the addition of fetal calf serum to the culture medium can lead to cellular differentiation and significant genetic aberrations  are generated from the subcutaneous or orthotopic implantation of intact patient tumor fragments directly into immunodeficient mice or rats, thereby avoiding in vitro adaptation. The concept of PDXs has been around for decades but interest in PDXs has recently increased due to greater insights into the limitations of classical xenografts and the development of personalized cancer medicines based on genomic profiling. Thus, PDXs have been established and characterized for various malignant tumor types including breast cancer, malignant melanoma, colorectal cancer, pancreatic adenocarcinoma, non-small cell lung cancer and more   implemented the Pediatric Preclinical Testing Program (PPTP), which generated hundreds of pediatric subcutaneous tumor xenografts including neuroblastomas. Importantly, many of these xenografts were established at relapse following multi-modal chemotherapy. Several anti-cancer agents have been tested in the PPTP using in vivo and in vitro models and the effects of some of these agents are consistent with their known clinical activity , neuroblastoma protein markers , cellular differentiation status and proliferative index of their corresponding patient tumors. In contrast to many conventional cell-derived xenografts, PDOXs invade the surrounding tissues. Importantly, PDOXs spontaneously metastasize to the liver, lungs and bone marrow  through implantation of either fresh or viably cryopreserved na\u00efve and relapsed high-risk neuroblastoma tumor fragments , the Targeting Of Resistance in PEDiatric Oncology program , the IMI2 ITCC-P4 program (http://cordis.europa.eu/project/rcn/210764_en.html) and the recently established NCI-funded Pediatric Preclinical Testing Consortium  are other programs that aim to establish and characterize pediatric PDXs. In addition, The EuroPDX consortium, although mainly focused on adult cancers, has started to include pediatric PDXs (http://www.europdx.eu/).The Childhood Solid Tumor Network (CSTN) at St Jude Children\u2019s Research Hospital has established and characterized a number of pediatric cancer PDXs including neuroblastoma PDOXs. These PDOXs have undergone comprehensive molecular characterization including genomic and epigenomic analyses as well as drug sensitivity testing using short-term cultured cells , or tumor stroma, is critical for cancer progression, metastasis and treatment resistance  tumor cells in serum-free medium requires more experience, patience and time compared to classical serum-cultured cell lines. However, in light of the aberrant changes seen in serum-cultured cells and the preservation of molecular features in cells cultured in 3D in serum-free medium, we believe that this is well worth the effort. Furthermore, 3D-cultured human tumor cells provide a means to implement the important principles of the 3Rs  to minimize animal experimentation.Despite the promise of PDX models, they also have their limitations: (1) an abnormal immune system in the host mice, (2) the murine tumor microenvironment and (3) tumor heterogeneity. First, athymic nude mice lack functional T cells, NOD-scid mice lack functional T and B cells, while the NOD-scid-gamma (NSG) strain lack functional T, B and NK cells. The immunosuppressed status of these mice precludes immunotherapy testing until methods have been established to reconstitute the human immune system in the animals. It is conceivable that other therapeutic strategies also affect immune cells, a parameter not included in xenograft studies. Attempts are being made to reconstitute the human immune system in mice by injection of human hematopoietic stem cells  contain various subclones with different genotypes resulting in intratumoral heterogeneity , MAPPYACTS , SMPaeds, iTHER and INFORM , the IMI2 ITCC-P4 program (http://cordis.europa.eu/project/rcn/210764_en.html) and the EU funded Targeting Of Resistance in PEDiatric Oncology program . Genomics analyses of relapsed neuroblastomas indicate that such treatments could include inhibition of ALK and the RAS-MAPK pathway, YAP inhibition and/or pathways involved in EMT  are stored in ice-cold medium and cryopreserved through stepwise cooling in cryopreservation medium. These cryopreserved and viable samples can be stored and/or shipped on dry ice to another laboratory for implantation. We have previously shown that it is feasible to establish PDOXs from cryopreserved high-risk neuroblastoma samples (Braekeveldt et al. Clearly, establishing additional neuroblastoma PDXs from relapsed or post-mortem tumors would be very useful for testing therapies against treatment-resistant disease. Collection and injection of circulating tumor cells can also add value to the PDX model system (Girotti et al. Non-dissociated tumor fragments are commonly utilized to establish and serially propagate PDXs. As discussed above, cell culturing can lead to molecular and phenotypic deviations from the original patient tumor (Baysan et al. There is a possibility of contamination of tumor cells. First, patient tumor cell cultures can easily be contaminated with EBV-infected B lymphoblasts from the same patient tumor sample. Unfortunately, proliferative EBV lymphoblasts can, after prolonged culturing or in vivo growth, completely overgrow the tumor cells (Bondarenko et al. The site of implantation/injection will affect the features of established tumors. In experiments comparing subcutaneous injection of neuroblastoma cells versus orthotopic injection into the adrenal gland, orthotopic tumors retained a more relevant biological phenotype and spontaneous metastases to distant organs (Khanna et al. Not all patient tumor samples engraft in mice. The tumor engraftment rate using orthotopic implantations is around 50% (Braekeveldt et al. A final issue relates to the choice of mouse strain. Traditionally, patient samples have been implanted into athymic nude mice or scid mice to establish patient xenografts. We and others utilized severely immunodeficient NSG mice lacking T, B and NK cells, based on the assumption that these mice are more permissive to tumor engraftment due to their immunosuppressed status. Indeed, injection of patient-derived malignant melanoma cells results in much higher engraftment in NSG mice compared to NOD-scid mice (Quintana et al. There are a number of methodological issues regarding the establishment and use of PDXs as preclinical neuroblastoma models. Here, we discuss eight important issues that researchers using or intending to use these models might wish to consider.Subcutaneous and orthotopic neuroblastoma PDXs have been established at various institutions internationally and these PDXs retain the molecular and phenotypic features of patient tumors. Furthermore, neuroblastoma PDOXs retain robust spontaneous metastatic capacity and are therefore excellent models for targeting neuroblastoma metastasis. PDXs from various tumor types can predict clinical outcome, making them extremely good models for biomarker and preclinical drug development. Neuroblastoma PDXs might thus play an important role for personalized and precision medicine strategies against treatment-resistant disease, especially given our recent understanding of the genomic changes associated with relapsed neuroblastomas. However, establishing and characterizing additional PDXs from high-risk and relapsed tumors is crucial to cover the different biological subsets of high-risk neuroblastoma. Furthermore, initiation of a global clinical academic collaboration to include and share all existing neuroblastoma PDXs would increase the utility of these promising models. Despite their limitations, neuroblastoma PDXs hold promise to improve the treatment of children with high-risk metastatic neuroblastoma."}
+{"text": "A 32-year-old female with a history of cholecystectomy three years prior, presented to the emergency department with epigastric pain. Liver function tests (LFTs) were abnormal , however ultrasound (US) imaging was negative for gallbladder pathology and the patient was discharged home with normal vital signs and instructed to follow up in two days if symptoms persisted. At her follow up visit, her LFTs worsened  and the patient underwent a magnetic resonance cholangiopancreatography (MRCP) which showed a dilated common bile duct (CBD) with filling defect suspicious of stone . The patApproximately 5% of patients who have undergone cholecystectomy continue to have symptoms of abdominal pain, vomiting, dyspepsia, loose stool, and are thought to suffer from postcholecystectomy syndrome (PCS).1CBD stones are a serious complication after cholecystectomy, therefore the diagnosis of PCS must always be considered in patients status post cholecystectomy with upper abdominal pain.What do we already know about this clinical entity?Magnetic resonance cholangiopancreatography (MRCP) identifies retained stones in patients with prior gallbladder surgery, however MRCP is not a tool readily available to emergency physicians.What is the major impact of the image(s)?Given the wealth of information provided, perhaps MRCP imaging can be incorporated as part of a routine postcholecystectomy syndrome (PCS) workup and help to limit unnecessary hospital admissions.How might this improve emergency medicine practice?MRCP imaging can help to improve diagnostic capabilities for patients suffering from PCS presenting to the emergency department."}
+{"text": "Autism spectrum disorder (ASD) is characterized by deficits in social functioning and language and communication, with restricted interests or stereotyped behaviors. Anatomical differences have been found in the parietal cortex in children with ASD, but parietal subregions and associations between Sylvian fissure (SF) and parietal anatomy have not been explored. In this study, SF length and anterior and posterior parietal volumes were measured on MRI in 30 right-handed boys with ASD and 30 right-handed typically developing boys (7\u201314 years), matched on age and non-verbal IQ. There was leftward SF and anterior parietal asymmetry, and rightward posterior parietal asymmetry, across groups. There were associations between SF and parietal asymmetries, with slight group differences. Typical SF asymmetry was associated with typical anterior and posterior parietal asymmetry, in both groups. In the atypical SF asymmetry group, controls had atypical parietal asymmetry, whereas in ASD there were more equal numbers of individuals with typical as atypical anterior parietal asymmetry. We did not find significant anatomical-behavioral associations. Our findings of more individuals in the ASD group having a dissociation between cortical asymmetries warrants further investigation of these subgroups and emphasizes the importance of investigating anatomical relationships in addition to group differences in individual regions."}
+{"text": "Sunitinib, a multityrosine kinase inhibitor, is currently the standard first-line therapy in metastatic renal cell carcinoma (mRCC) and is also used in treating patients with pancreatic neuroendocrine and imatinib-resistant gastrointestinal stromal tumors (GIST). Nevertheless, most patients eventually relapse secondary to intrinsic or acquired sunitinib resistance. Autophagy has been reported to contribute to both chemo-sensitivity and -resistance. However, over the last few years, controversial regulatory effects of sunitinib on autophagy have been reported. Since gaining insights into the underlying molecular insights and clinical implications is indispensible for achieving optimum therapeutic response, this minireview article sheds light on the role of a network of prosurvival signaling pathways recently identified as key mediators of sunitinib resistance with established and emerging functions as autophagy regulators. Furthermore, we underscore putative prognostic biomarkers of sunitinib responsiveness that could guide clinicians toward patient stratification and more individualized therapy. Importantly, innovative therapeutic strategies/approaches to overcome sunitinib resistance both evaluated in preclinical studies and perspective clinical trials are discussed which could ultimately be translated to better clinical outcome. Following the initial breakthrough success of imatinib, the first FDA-approved tyrosine kinase inhibitor(TKI), TKIs were deemed to revolutionize cancer therapy. Nevertheless, emergence of imatinib-resistance prompted development of novel structurally distinct TKIs  is a central player  has been linked to tumorigenesis  and Mcl-1 protein levels could serve as markers that predict sunitinib response. Additionally, elevated IncARSR levels in pre-treatment RCC patients significantly correlated with poor sunitinib response. In contrast, low IncARSR levels conferred improved progression-free survival and favorable prognosis following sunitinib therapy  Ideally, though not easily achievable in clinical practice, tailoring sunitinib dose per each patient based on their response should select patients that need escalation of sunitinib dose to reach cytotoxic effects at tolerable doses. Rovithi et al. showed that an alternating schedule of high sunitinib efficiently impaired tumor growth (ii) Alternatively, pharmacological targeting of Mcl-1 and mTOR presents a promising strategy in combating/reversing sunitinib resistance. It is worth mentioning that FDA has already approved sequential treatment of sunitinib-resistant mRCC patients with everolimus, mTOR inhibitor. In addition, a phase I clinical trial aiming at determining the highest tolerable dose of \u201csunitinib and temsirolimus (mTOR inhibitor)\u201d combination that could be administered to mRCC patients has lately been completed. There are also parallel clinical trials testing the efficacy of sorafenib in treating sunitinib-resistant mRCC and GIST patients. Yet, the clinical outcome of combining sunitinib and Mcl-1 and/or mTOR inhibitor in sunitinib-resistant patients remains to be investigated. Consistent with the emerging role of MET and AXL signaling in mediating sunitinib resistance, combining a small molecule inhibitior of both MET and AXL, BMS777607, with sunitinib both suppressed the growth of sunitinib-resistant RCC xenografts and prevented the emergence of sunitinib resistance  and lysosomal dysfunction (owing to sunitinib sequestration and hence inactivation). Both events acted as pro-survival adaptive responses that compromised the anticancer activity of sunitinib. Conversely, cytotoxic sunitinib levels destabilized Mcl-1, inhibited mTORC1 and activated autophagy. Hence, this may mechanistically resolve the previously described discrepancy in terms of \u201cON/OFF\u201d autophagy regulation by sunitinib. Gaining deeper mechanistic insights into sunitinib resistance would provide better prognostic biomarkers that could guide clinicians toward patient stratification and more individualized therapy. Importantly, this would offer more innovative therapeutic strategies/approaches to overcome sunitinib resistance which could ultimately be translated to a better clinical outcome.AKA conceived and wrote the manuscript. ABA, SS, SM, and ME revised the manuscript. SM and ME reviewed the outline and content of the manuscript. All authors have read and approved the submitted manuscript for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Reinforcement learning involves flexible adaptation towards a changing environment and is driven by dopaminergic reward prediction error  \u2013 expectation (Q)) signaling in the midbrain and projecting regions, such as the ventral striatum . Schizophrenia patients show heightened dopamine levels in the striatum  as well as deficits in reinforcement learning  which may be mediated by disrupted prediction error signaling . Using model-based fMRI, the present study aims to assess these neural signals during a reversal learning paradigm in unmedicated schizophrenia patients and healthy individuals.In the current study, 19 schizophrenia patients and 23 age- and gender-matched healthy controls completed a reversal learning paradigm  during fMRI scanning where subjects had to choose between two neutral stimuli to maximize their reward. A Rescorla Wagner learning model  was fitted against the individual choice data using a softmax function. Individual RPE trajectories from the fitted Rescorla Wager learning model were correlated with the BOLD response during feedback onset. Parameter estimates of ventral striaral RPE trajectories were correlated with psychopathology scores from the PANSS .In the reversal learning task, schizophrenia patients chose the correct stimulus less often compared to healthy individuals . Across all participants, the RPE trajectories correlated with BOLD response in the bilateral ventral striatum . Schizophrenia patients displayed decreased RPE coding in the right ventral striatum compared to healthy individuals . In patients, extracted parameter estimates from the right ventral striatum correlated negatively with the PANSS total symptoms score .We found that unmedicated schizophrenia patients performed worse in the reversal learning task and displayed decreased striatal prediction error signaling. This neural deficit was increased in patients with overall higher symptom severity. While RPE coding seems to be intact in patients receiving antipsychotic medication , our findings are in line with previous studies in unmedicated schizophrenia patients . Therefore, deficient neural coding of this core reinforcement learning mechanism may reflect a characteristic of the disorder of schizophrenia and does not result from antipsychotic medication."}
+{"text": "Following a stroke, the resulting lesion creates contralateral motor impairment and an interhemispheric imbalance involving hyperexcitability of the contralesional hemisphere. Neuronal reorganization may occur on both the ipsilesional and contralesional hemispheres during recovery to regain motor functionality and therefore bilateral activation for the hemiparetic side is often observed. Although ipsilesional hemispheric reorganization is traditionally thought to be most important for successful recovery, definitive conclusions into the role and importance of the contralesional motor cortex remain under debate. Through examining recent research in functional neuroimaging investigating motor cortex changes post-stroke, as well as brain-computer interface (BCI) and transcranial magnetic stimulation (TMS) therapies, this review attempts to clarify the contributions of each hemisphere toward recovery. Several functional magnetic resonance imaging studies suggest that continuation of contralesional hemisphere hyperexcitability correlates with lesser recovery, however a subset of well-recovered patients demonstrate contralesional motor activity and show decreased functional capability when the contralesional hemisphere is inhibited. BCI therapy may beneficially activate either the contralesional or ipsilesional hemisphere, depending on the study design, for chronic stroke patients who are otherwise at a functional plateau. Repetitive TMS used to excite the ipsilesional motor cortex or inhibit the contralesional hemisphere has shown promise in enhancing stroke patients' recovery. Stroke remains a leading cause of long-term disability  , Action Research Arm Test (ARAT), and Stroke Impact Scale (SIS) ], saw significant motor gains associated with increased ipsilesional M1 recruitment with their experimental group as compared to control (Ramos-Murguialday et al., Reasons for the differences found in the BCI studies probably relate to the BCI/BMI designs and the patient exclusion criteria. For instance, Young and Song recruited patients with a greater range of severity of motor impairments than Ramos (Ramos-Murguialday et al., Overall, multiple BCI studies have found improved motor function for the severely impaired stroke patient correlated with contralesional M1 recruitment (Song et al., TMS therapy can inhibit or excite targeted brain regions, and applications of this technique may encourage stroke rehabilitation Hallett,  without Another method to regain interhemispheric balance and improve recovery is to excite the ipsilesional side with TMS (Talelli et al., A few studies have compared inhibiting the contralesional hemisphere to exciting the ipsilesional side through rTMS although the results remain inconclusive. Khedr et al.  comparedMajor factors influencing unilateral recovery post-stroke appear to include chronicity, as well as lesion size and location. Increases in unilateral ipsilesional M1 activation for movement on the affected side appears to positively correlate with chronicity, especially for well-recovered patients (Ward et al., BCI training demonstrates potential in assisting with motor recovery for stroke sufferers who have reached a functional plateau following traditional rehabilitation. Evidence suggests that this therapy, even for chronic stroke sufferers, may induce neuromodulatory changes that enhance motor function. Both BCI designs that demonstrate development of the contralesional M1, as well as designs that increase ipsilesional M1 activity, appear to enhance motor recovery. It is currently unclear if either type of BCI design is superior to the other for all, or certain subsets of, patients.Meanwhile, TMS is an effective and safe tool for research into this field and offers promising potential to be utilized for rehabilitation. TMS studies confirm that increased contralesional M1 activity as compared to the ipsilesional M1 is associated with lesser clinical outcome. Some TMS research suggests that for some well-recovered stroke patients contralesional corticomotor excitability does not decrease, but rather only the ipsilesional corticomotor excitability increases with recovery (Stinear et al., Both inhibition of the contralesional side and excitation of the ipsilesional side appear effective for motor recovery post-stroke. A few studies suggest that contralesional inhibition may be slightly more effective than ipsilesional M1 excitation although this is not seen throughout the literature. Initial degree of motor impairment and chronicity (Rose et al., Current evidence favors ipsilesional M1 excitation and development to be the most important for stroke recovery over contralesional hemispheric recruitment. However, the contralesional side does appear to play a significant role for at least a subset of stroke patients and some research suggests that certain BCI paradigms targeting the contralesional hemisphere may be beneficial for motor recovery. It is important to note the numerous confounding variables that require more research to completely understand their effects including lesion location and size, and chronicity.KD wrote the manuscript, VN and VP reviewed and edited it, and provided key guidance.VP has a pending US patent on the closed-loop neurofeedback used for BCI-facilitated intervention, application number 12/715090. The patent was filed jointly by VP and J. Williams. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Prehistoric human activities have contributed to the dispersal of many culturally important plants. The study of these traditional interactions can alter the way we perceive the natural distribution and dynamics of species and communities. Comprehensive research on native crops combining evolutionary and anthropological data is revealing how ancient human populations influenced their distribution. Although traditional diets also included a suite of non-cultivated plants that in some cases necessitated the development of culturally important technical advances such as the treatment of toxic seed, empirical evidence for their deliberate dispersal by prehistoric peoples remains limited. Here we integrate historic and biocultural research involving Aboriginal people, with chloroplast and nuclear genomic data to demonstrate Aboriginal-mediated dispersal of a non-cultivated rainforest tree.Castanospermum australe (Fabaceae), a non-cultivated culturally important riparian tree that produces toxic but highly nutritious water-dispersed seed. We validated cultural evidence of recent human-mediated dispersal by revealing genomic homogeneity across extensively dissected habitat, multiple catchments and uneven topography in the southern range of this species. We excluded the potential contribution of other dispersal mechanisms based on the absence of suitable vectors and current distributional patterns at higher elevations and away from water courses, and by analyzing a comparative sample from northern Australia.We assembled new anthropological evidence of use and deliberate dispersal of Innovative studies integrating evolutionary and anthropological data will continue to reveal the unexpected impact that prehistoric people have had on current vegetation patterns. A better understanding of how traditional practices shaped species\u2019 distribution and assembly will directly inform cultural heritage management strategies, challenge \u201cnatural\u201d species distribution assumptions, and provide innovative baseline data for pro-active biodiversity management. Studies of prehistoric human influences on the Australian vegetation have primarily centered around broad-scale change associated with the practice and cessation of Aboriginal burning , 2] and and2] anLivistona mariae in central Australia ..C. austrCastanospermum australe (black bean) is distributed along coastal eastern Australia, from Cape York to subtropical northern New South Wales . ). Castanredation . These credation , as wellredation .Our sampling strategy within the context of local Aboriginal dispersal focused on sites representing the species\u2019 southern distributional margin in northern New South Wales  and was not intended to exhaustively represent all populations to explore continent-wide connectivity, or broader biogeographic questions. Sampling was undertaken under a Scientific Licence (#100569), Section 132c of the National Parks and Wildlife Services Act 1974 issued by the New South Wales Office of Environment and Heritage (sampling did not involve endangered or protected species). The objective was to ensure sufficient geographic representation across the main NNSW catchment areas in order to investigate genomic homogeneity vs. genomic heterogeneity hypotheses. Highly homogeneous maternally-inherited plastid genomes across the study area, would suggest rapid and recent dispersal from a small founder event, while plastid heterogeneity would suggest lengthier local persistence and / or multiple founder events. The focus on NNSW was influenced by the current paucity of local disperser fauna and absence of megafauna , and by Casuarius casuarius johsonii). This northern area also has an extended archaeological record of the use of C. australe\u2019s seeds  de de26] de the AWT , 21], [, [C. aus the AWT  includinRecent mitochondrial DNA studies revealed that Aboriginal people have inhabited Australia in consistent geographic arrangements for up to 50,000 years . ContinuC. australe in NNSW  seeds as he journeyed inland from the east coast to the western Ranges . Common inheritance from the MRCA results in Bandjalangic vocabulary being inherited with only few sound changes [C. australe is uniformly bugam. This is in contrast with the rest of the distribution of C. australe where the terms exhibit little homology, even within members of the same low-level clade such as the Djirbalic languages from the AWT  is likely to be close to 1,500 years old , catchments and regions. Analyses of sequence data across 96 individual trees from 12 distinct sites yielded 987 cpDNA SNPs  and 29 nrDNA SNPs . None of these 12 sites yielded within-site cpDNA variability, suggesting that all eight individuals sampled within each population originated from a single maternal lineage. The nrDNA sequences produced between four and 12 heterozygotic variants across 5,813bp, confirming a pattern of low within-population diversity  and 5,813bp of nuclear ribosomal DNA (nrDNA) were analysed and compared among iversity .C. australe [C. australe is unlikely to favor rapid water-mediated inland expansion  and topographically complex area , and a single founder lineage would have rapidly expanded to its current distribution as habitat became increasingly available. Environmental niche models representing the availability of climatic conditions suitable to C. australe during the LGM suggest that available habitat is likely to have increased in the current interglacial period, and that environmental suitability in the south remains marginal compared to the north  cannot be excluded. However oceanic currents, tidal processes, extreme weather events or river capture cannot explain the location of multiple sites inland and well above current and historical sea level . SecondaC. australe is therefore at odds with its large, toxic and reward-free seeds. Even within the AWT, where the highest diversity of frugivorous animals persists , the high genetic divergence measured between neighbouring catchments  in collaboration with Aboriginal knowledge custodians.The new, combined evidence presented supports the deliberate dispersal of Cosgrove  suggesteEvidence of prehistoric Australian Aboriginal people dispersing plant propagules for their direct need and benefit also significantly challenges assumptions of \u201cnatural\u201d plant distributions, requiring reassessment of distributional interpretations that omit the possible impact of prehistoric human intervention . CurrentC. australe, future studies can explore broader biogeographic questions including possible dispersal routes along eastern Australia and across the Pacific Islands. A scenario of long-distance dispersal by ancestors from the north was independently put forward by Aboriginal knowledge custodian Uncle Ron Heron Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S4 Appendix(DOCX)Click here for additional data file.S5 Appendix(DOCX)Click here for additional data file.S6 Appendix(MP4)Click here for additional data file."}
+{"text": "The whole-genome sequences of eight fungal strains that were selected for exposure to microgravity at the International Space Station are presented here. These baseline sequences will help to understand the observed production of novel bioactive compounds. In a screening project of natural products, fungal strains isolated from environments associated with the Chernobyl nuclear power plant (ChNPP) accident  have beeAspergillus niger, an industrially important filamentous fungus, contains a sequence resembling the fumonisin gene cluster, which suggests that the fungus has the genetic potential to produce carcinogenic fumonisins   . Data frThis whole-genome shotgun project has been deposited in DDBJ/ENA/GenBank under the accession numbers given in"}
+{"text": "Patients with intractable temporal lobe epilepsy (TLE) undergo surgical resection of the anterior temporal lobe. Preoperative assessment of TLE patients involves a multidisciplinary assessment and may involve the use of invasive electroencephalogram (EEG) recording for lateralization of seizure focus in ambiguous cases. Understanding the white matter fibre tracts affected in TLE may assist in preoperative lateralization and planning. We studied pre- and postoperative white matter fibre tract changes in six patients with TLE who underwent surgical resection. Our results indicate that changes in the corpus callosum are highly specific, with the ability to lateralize the epileptogenic side in 100% of our patients (six of six). Contralateral changes were found in all patients with variable involvement of white matter tracts. Postoperatively, most patients (five of six) exhibited further changes to the tracts on the\u00a0ipsilateral side, with three patients showing contralateral abnormalities. We provide a detailed assessment of pre- and postoperative white matter fibre tracts in patients with TLE\u00a0and confirm that abnormalities in the ipsilateral corpus callosum may aid in preoperative lateralization and obviate the need for invasive EEG monitoring. Approximately 20% of patients with temporal lobe epilepsy (TLE) are refractory, exhibiting no response to anti-epileptic drugs . A subseThis study was approved by our Human Resources Ethics Committee via Institutional Review Board. The study included six patients with a\u00a0history of epilepsy resistant to anti-seizure medication . Clinicopathological data are summarized in Table We performed whole-brain tractography using the BrightMatter\u2122 System  neurosurgical planning system, which performs automated processing of T1-weighted anatomical images and diffusion-weighted images to perform skull-stripping, co-registration, diffusion tensor fitting, and whole brain tractography. Specific bundles were assessed through 1) modulating the tract filtering slide bars, 2) displaying tracts in specific orthogonal planes, and 3) filtering tracts according to the intersection with a surgical trajectory.Qualitative assessment was performed by the study author (FS) assessing reconstructed tracts on superimposed three-dimensional (3D) T1-weighted images and the methodology was verified by a neuroradiologist (MS). The anatomic course of each fibre was verified in axial, coronal, and sagittal planes. The healthy side was compared to the contralateral epileptogenic side. The preoperative and postoperative images and tracts were also evaluated for differences. In the postoperative patients, thinning was documented if there was additional thinning compared to the preoperative images only. Tract thinning between hemispheres was assessed by first isolating the tract using appropriate coronal or axial slices, then sweeping the tract reduction (thresholding) sliders across their extents, while assessing whether any asymmetries exist.\u00a0Assessment parameters included macroscopic white matter tract dislocation or thinning. The abnormalities were documented in the ipsilateral and contralateral sides in the preoperative and postoperative images\u00a0and compared.All patients underwent surgical resection following planning by a multidisciplinary team of epilepsy neurologists and neurosurgeons. Mesial temporal resection included the amygdala and anterior part of the hippocampus. Postoperative pathology was concordant with preoperative MRI findings in four patients with mesial temporal sclerosis (MTS). Two patients demonstrated non-specific gliosis.The white matter tracts evaluated for this study are the corpus callosum (CC), fornix (F), cingulum (C), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), arcuate fasciculus (AF), uncinate fasciculus (UF), inferior fronto-orbital fasciculus (IFOF), optic radiations (OR), corona radiata (CR), and corticospinal tracts (CST). Abnormalities in preoperative studies included thinning of white matter tracts on the side ipsilateral to the epileptogenic side (six patients), the contralateral side (six patients), or bilateral abnormalities (six patients) were appreciated in some tracts as specified below. The details are recorded in Table All six patients exhibited thinning and disruption of the corpus callosum in the ipsilateral side\u00a0with no documented abnormalities in the contralateral side Figure . AdditioNew or further thinning and disruption of ipsilateral white matter tracts were present in four patients. Table Recent DTI studies have demonstrated abnormalities within several white matter tracts in patients with TLE . The curWe evaluated six patients with TLE who underwent resection of the mesial temporal lobe for drug-resistant epilepsy. Fiber tract thinning and asymmetry was found in both the ipsilateral and contralateral sides to the seizure focus. Assessment of pre- and post-surgical white matter fiber bundles by MR imaging tractography revealed abnormalities in all 11 tracts studied. Pre-surgically, all patients demonstrated asymmetry in the white matter tracts within their ipsilateral corpus callosum, with most patients (five of six) exhibiting ipsilateral changes in the fornix, cingulum, uncinate process, and the CSTs. The strong association of ipsilateral thinning of the corpus callosum fibers, mainly along with the described abnormalities, may provide further lateralizing information and aid in the\u00a0determination of the epileptogenic side. Tractography may serve as an additional tool in the\u00a0preoperative assessment of patients in whom the epileptogenic focus is indeterminate and may obviate the need for invasive EEG recording, including subdural and depth electrodes.Our findings are in keeping with previous studies that showed abnormalities in the cingulum, fornix, and corpus callosum to provide distinctive diffusion indices in patients with TLE with the ability to distinguish the pathological side . Nazem-ZPostoperative assessment of the white matter fiber tract showed the\u00a0progression of preoperative abnormalities or new fiber tract abnormalities, most prominently in the OR and CR, as expected. These fibers course through the temporal lobe\u00a0and surgical resection impacts the anatomy and function. Ipsilateral abnormalities in postoperative patients can be directly attributed to resection of the\u00a0surgical lesion. The abnormalities were not, however, limited to the ipsilateral temporal lobe, concordant with previous findings of widespread changes in TLE patients who undergo resection . DegradaInvestigators have found more widespread contralateral and bilateral abnormalities in patients with left TLE, with more ipsilateral abnormalities in patients with right TLE . We founThe corpus callosum is a major interhemispheric tract that is essential in cognitive functions, and previous DTI studies have reported a high specificity for asymmetrical interruption of ipsilateral corpus callosum for lateralization of epilepsy. In our series, only one patient demonstrated changes to the contralateral corpus callosum postoperatively. The connections that exist between the corpus callosum and the temporal lobe may contribute to these postoperative abnormalities. Fiber tracts that originate from hippocampal formation and amygdala, which are involved in epileptogenesis and connections to other ipsilateral and contralateral anatomical structures, play an essential role in spreading neuronal activity during seizures and are altered in patients with TLE. Recently, reorganization of language tracts in the contralateral non-dominant hemisphere following resection of the anterior temporal lobe has been demonstrated , in keepThis small case series suggests the potential for the specificity of corpus callosum thinning in the ipsilateral side to the epileptogenic focus in patients with TLE for lateralization. All patients exhibited ipsilateral thinning and disruption of the corpus callosum preoperatively compared to the contralateral side. Therefore, preoperative whole brain tractography may be considered as an additional tool to complement EEG and clinical assessment in cases with an ambiguous seizure side, potentially obviating the need for invasive EEG recordings. We also demonstrated bilateral changes in pre- and postoperative patients, in keeping with the diffuse connectivity network involved in temporal lobe epileptogenesis and propagation. Further studies are underway to include inter-rater reliability assessment and correlation with quantitative evaluation."}
+{"text": "The electrocardiogram (ECG) is an essential investigation in the evaluation of chest pain in the emergency room (ER). Correct interpretation of the ECG findings, determines the diagnosis and management strategy. This ECG spot diagnosis will improve the skills of the residents and physicians working in ER. A 46-year-old man, who was earlier in sinus rhythm, presented with anginal type of chest pain of three hours duration. The electrocardiogram recorded in emergency room (ER) is shown in The electrocardiogram shows ST segment elevation in inferior leads suggesting inferior wall myocardial infarction. The underlying rhythm is atrial fibrillation. The irregularly, irregular R-R interval coupled with the continuously varying morphology of the fibrillatory waves establishes the diagnosis of atrial fibrillation. Though the rhythm appears like atrial flutter, this is unlikely due to the above mentioned reasons. Atrial flutter is characterized by undulating sawtooth like monomorphic flutter waves and the R-R interval is regularly, irregular due to fixed heart block. The varying atrioventricular block results in long-short cycle sequences that are followed by QRS complexes with increased width 130 msec) (indicated by * in 30 msec (Atrial fibrillation complicating inferior wall myocardial infarction with intermittent ventricular premature beats.As the fast, irregular ventricular response aggravates myocardial ischemia, reverting to sinus rhythm is mandatory. Since it is a new onset atrial fibrillation, electrical cardioversion can be done safely. The patient also requires reperfusion of the infarct related coronary artery at the earliest. He underwent successful fibrinolysis and electrical cardioversion to sinus rhythm. Post cardioversion he was started on oral beta-blocker therapy. The further in hospital course was uneventful and he continued to be in sinus rhythm at 4 months of follow-up.Atrial fibrillation complicating acute myocardial infarction is associated with increased morbidity and mortality. The proposed mechanism of atrial fibrillation in acute myocardial infarction includes congestive heart failure, ischemia and infarction of the conduction system, atrial infarction or ischemia, and vagal reflexes or increased sympathetic activity . ElectriIn conclusion, electrocardiographic recognition of atrial arrhythmias is important to risk stratify acute coronary syndrome patients. Identification and prompt treatment of atrial arrhythmias improve outcomes."}
+{"text": "Arabidopsis, treating shoots with uniconazole can result in enhanced primary root elongation and bolting delay. Uniconazole spraying has become an important cultivation technique in controlling the flowering and improving the fruit-setting of litchi. However, the mechanism by which uniconazole regulates the complicated developmental processes in litchi remains unclear. This study aimed to determine which signal pathways and genes drive the responses of litchi inflorescences to uniconazole treatment. We monitored the transcriptional activity in inflorescences after uniconazole treatment by Illumina sequencing technology. The global expression profiles of uniconazole-treated litchi inflorescences were compared with those of the control, and 4051 differentially expressed genes were isolated. KEGG pathway enrichment analysis indicated that the plant hormone signal transduction pathway served key functions in the flower developmental stage under uniconazole treatment. Basing on the transcriptional analysis of genes involved in flower development, we hypothesized that uniconazole treatment increases the ratio of female flowers by activating the transcription of pistil-related genes. This phenomenon increases opportunities for pollination and fertilization, thereby enhancing the fruit-bearing rate. In addition, uniconazole treatment regulates the expression of unigenes involved in numerous transcription factor families, especially the bHLH and WRKY families. These findings suggest that the uniconazole-induced morphological changes in litchi inflorescences are related to the control of hormone signaling, the regulation of flowering genes, and the expression levels of various transcription factors. This study provides comprehensive inflorescence transcriptome data to elucidate the molecular mechanisms underlying the response of litchi flowers to uniconazole treatment and enumerates possible candidate genes that can be used to guide future research in controlling litchi flowering.In  Litchi is an important tropical fruit widely cultivated in more than 20 countries in tropical and subtropical regions worldwide , 2. In CArabidopsis, treating shoots with uniconazole can result in enhanced primary root elongation and bolting delay , and flowering time  ] .LUG, which is a critical regulator of gynoecium marginal tissue development [AGAMOUS expression in the first two whorls of the Arabidopsis flower [LUG genes were highly induced by uniconazole treatment  controlling the development of flower have been cloned in Arabidopsis thaliana. SPT and ALC may be relevant to pistil development [AMS and DYT1 are closely related to the morphogenesis of anthers [The bHLH family includes genes regulating diverse processes of flower development. Four bHLH transcription factors Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S1 File(DOC)Click here for additional data file.S2 File(DOCX)Click here for additional data file."}
+{"text": "We have described a myocardial infarct scar identified by a standard dual source CT coronary angiography (CTCA). We were able to detect the scar during the routine coronary assessment without contrast late enhancement and without additional radiation exposure. It is therefore feasible to assess chronic scar using a standard CTCA technique. CT coronary angiography (CTCA) has become a robust and accurate imaging modality for the non-invasive assessment of coronary vessels. It is now being widely used, particularly in the low to intermediate cardiovascular risk group for the diagnosis and assessment of coronary disease severity .It has been postulated that the data obtained from multi-detector CT (MDCT) during CTCA can also be used to quantify myocardial scar and viability but only by using delayed myocardial contrast enhancement, which involves a second, albeit low radiation dose , 3.Late gadolinium-enhanced cardiac magnetic resonance imaging (CMRI) is considered the gold standard for detection of myocardial scar and viability, and few pilot studies have reported favorable results when comparing CTCA with MRI , 3.Delayed enhancement studies usually offer more accurate information about the infarct size but at the cost of additional radiation exposure and more contrast. Cury et al demonstrated that patients with recent myocardial infarction (MI)  could be detected using a standard MDCT dataset based on the presence of a perfusion defect (hypo-attenuation) with a sensitivity and specificity of 94% and 97% [We report the case of a 63-year-old gentleman presenting with chest pain who had previously undergone multi-vessel PCI in 2005. He underwent a CTCA  in March 2013 for the evaluation of his coronary arteries as well assessment of his stents, which revealed an antero-apical, antero-lateral and infero-lateral myocardial scar and wall motion abnormalities in the same territories . The ste99mTc-sestamibi) was performed. SPECT slices and polar displays, illustrated on In view of proximal LAD lesion patient was referred for myocardial perfusion scan to assess ischemic burden. Stress (treadmill exercise + regadenoson) radionuclide myocardial perfusion imaging single photon emission CT (MPI SPECT) study with the 2 days protocol  studies. Also it may be of prognostic importance in patients with previous silent infarction and in patients presenting with atypical chest pain in whom infarct size could influence the future management. However, we need to develop a technique to improve the accuracy of scar detection on the standard CTCA dataset without the need for further contrast and radiation exposure."}
+{"text": "American Indians experience high rates of cardiovascular diseases (CVD). Environmental tobacco smoke (ETS) has been linked to CVD, possibly due to pro-inflammatory and oxidative stress pathways. We examined the relationship between self-reported exposure to ETS and fatal and nonfatal CVD incidence using Cox proportional hazards models among 1843 non-smoking American Indians participating in the Strong Heart Study. We also evaluated potential modifying effects of several dietary nutrients high in anti-inflammatory and anti-oxidant properties with ETS exposure on fatal and nonfatal CVD by creating interaction terms between ETS exposure and the dietary variable. Participants exposed to ETS had a higher hazard  for developing CVD compared to persons not exposed. Interaction analyses suggested stronger effects of ETS on CVD incidence among those consuming diets lower in vitamin E as compared to those consuming higher amounts, particularly on the additive scale. Additional research is recommended to clarify whether public health prevention strategies should simultaneously target reductions in ETS exposures and improvements in diets that may exceed the expected benefits of targeting these risk factors separately. Exposure to environmental tobacco smoke (ETS) is one of the most important and common sources of indoor air pollution worldwide . ETS incIn general, American Indian populations experience higher rates of cardiovascular disease (CVD) and CVD-related risk factors as compared to the U.S. population as a whole . Eichner2.5 (particulate matter less than 2.5 microns in diameter), one of the constituents of ETS, has been implicated in CVD development , a sensitive and specific marker of ETS exposure with a half-life of about 3 weeks, and cotinine, the primary metabolite of nicotine are recommended. Furthermore, evaluation of subclinical cardiovascular disease endpoints  could provide more detailed insight into mechanistic pathways. Finally, assessment of diet via a food-frequency questionnaire may allow for more accurate information on long-term nutrient intake patterns.These results are limited by the use of self-reported exposure to ETS, making it impossible to distinguish between secondhand and thirdhand smoke, as well as the use of a single 24-h recall to assess diet. ETS exposure may be confounded by socio economic factors that can also be related to CVD incidence rates. To determine ETS exposure more reliably, more accurate long-term measures such as NNAL [4-, as well as the widening ethnic/racial disparities in rates of both ETS exposure and CVD-related health outcomes, there is tremendous public health relevance in understanding how long-term exposure to ETS increases risk of developing CVD and whether or not certain subgroups of the population are more susceptible. Modifying factors, such as diets, may be important targets in future interventions to complement anti-smoking campaigns.The present analysis confirms the previously observed detrimental influence of ETS exposure on cardiovascular health. The Strong Heart Study population allows for the examination of a unique population with high smoking rates but typically low doses. Our results suggest that further research  may be warranted to investigate whether consumption of diets high in certain nutrients may reduce these damaging effects. Further research is needed to clarify whether public health prevention strategies should simultaneously target both reductions in ETS exposures and improvements in diets to exceed the expected benefits of targeting these risk factors separately."}
+{"text": "We investigated the evolution of the neurological and neuropsychological characteristics in a right-handed woman who was 53-years-old at the onset and who showed personality changes and behavioral disorders accompanied by progressive dysarthria. She had hypernasality and a slow rate of speech with distorted consonants and vowels, which progressed as motor disturbances affecting her speech apparatus increased; finally, she became mute two years post onset. Her dysarthria due to bilateral voluntary facio-velo-linguo-pharyngeal paralysis accompanied with automatic-voluntary dissociation fit the description of anterior opercular syndrome. She showed personality changes and behavioral abnormalities from the initial stage of the disease, as is generally observed in frontotemporal degeneration (FTD), and her magnetic resonance image showed progressive atrophy in the frontotemporal lobes; thus, she was clinically diagnosed with FTLD. This patient\u2019s symptoms suggest that FTLD, including bilateral anterior operculum degeneration, causes progressive pseudobulbar paretic dysarthria accompanied by clinical symptoms of FTD, which raises the possibility of a new clinical subtype in the FTLD spectrum."}
+{"text": "Diabetic kidney disease is the leading cause of end-stage renal failure worldwide, however current treatments remain suboptimal. Recently various plants have shown beneficial effects not only on kidney function in diabetes mellitus, but also on kidney toxicities induced by some drugs or toxins. The active substances recognized in these plants include polysaccharides, flavonoids, xanthones and peptides.Panax quinquefolium, Vitis vinifera and glycosides from Stelechocarpus cauliflorus have also been shown to protect renal damage  have been completely observed by the authors.None declared."}
+{"text": "Bone marrow (BM) aspiration showed erythrocyte phagocytosis by macrophages (18F-fluorodeoxyglucose positron emission tomography (FDG-PET) performed for the staging showed splenic and multiple abdominal lymph node lesions and diffuse accumulation within the bones such as the vertebrae and pelvis , peripheral blood cytopaenia  has become a standard tool for the initial staging and reassessment of Hodgkin lymphoma, which is generally characterised by contiguous lymph node involvement.Haemophagocytic lymphohistiocytosis, which is the uncontrolled activation of lymphocytes and macrophages caused by various diseases including malignant lymphoma, can induce diffuse hypermetabolism in the bone marrow reflecting a systemic cytokine storm.Recognition of false-positive findings on FDG-PET is necessary for the evaluation of bone marrow involvement in order to accurately determine the stage of Hodgkin lymphoma, which requires bone marrow examination.Patients with HLH with FDG-PET images indicating multiple lymphadenopathy and/or patchy multiple bone lesions may appear to be LA-HLH with BM involvement (BMI)."}
+{"text": "Transcranial electrical stimulation (tES) uses low intensity current to alter neuronal activity in superficial cortical regions, and has gained popularity as a tool for modulating several aspects of perception and cognition. This mini-review article provides an overview of tES and its potential for modulating spatial processes underlying successful navigation, including spatial attention, spatial perception, mental rotation and visualization. Also considered are recent advances in empirical research and computational modeling elucidating several stable cortical-subcortical networks with dynamic involvement in spatial processing and navigation. Leveraging these advances may prove valuable for using tES, particularly transcranial direct and alternating current stimulation (tDCS/tACS), to indirectly target subcortical brain regions by altering neuronal activity in distant yet functionally connected cortical areas. We propose future research directions to leverage these advances in human neuroscience. Decades of empirical research have demonstrated involvement of diverse lateral and medial brain regions in spatial processing and navigation, including parietal, prefrontal and medial temporal areas  using parietal object representations  and a range of areas including retrosplenial cortex (RSC) and PCC, and secondarily to the hippocampus and parahippocampus , Figure Behavioral outcomes related to parieto-medial temporal pathway might be dissociated with outcomes of targeting the parieto-prefrontal pathway. Specifically, targeting lateral and ventral intraparietal areas might be expected to impact visuospatial spatial working memory performance, whereas targeting the cIPL may not. These types of dissociations between stimulation locations, stimulation conditions , and behavioral outcomes can help elucidate behavioral influences of each pathway, and reveal methods for altering spatial performance. Furthermore, as research reveals the oscillatory dynamics of the parieto-medial temporal pathway, frequency-specific tACS might also prove valuable for modulating network resonance and behavioral outcomes (Ali et al., People differ dramatically in spatial abilities (Hegarty and Waller, TTB conceived the review and prepared the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Cannabis use has repeatedly been associated with psychotic symptoms, with persistent risks beyond the direct effects of exogenous cannabinoids. However, it remains unknown whether cannabis use during pregnancy is a causal risk factor for psychotic symptoms in the offspring, or whether this relationship is explained by shared etiological factors, such as genetic and environmental vulnerabilities. More innovative study designs are needed to address this question. Here, we examined the adverse effects of cannabis exposure during pregnancy on psychotic symptoms in pre-adolescent offspring. Such a method would help causal inference as comparisons can be made between the observed associations of maternal versus paternal cannabis use during pregnancy and the risk of psychotic symptoms in the offspring. If the association between cannabis use and psychotic symptoms is causal, early intra-uterine exposure to cannabis could potentially affect neurodevelopment and, hence, contribute to the pathogenesis of psychotic phenomena in children who have not yet used cannabis themselves.This study used data from the Generation R Study, a prospective population-based birth cohort from Rotterdam, the Netherlands. Participants were included if data on maternal cannabis use during pregnancy of offspring psychotic-like symptoms at age ten years were available (N = 3692). To determine cannabis exposure, we used prospective maternal self-reports during pregnancy and cannabis metabolite levels from urine. Paternal cannabis use during pregnancy was obtained through maternal report. At age ten years, children were queried regarding psychotic symptoms. Ordinal logistic regression was conducted to investigate whether maternal and paternal cannabis use were associated with offspring psychotic symptoms. In a secondary analysis, a distinction was made between maternal cannabis use exclusively before versus continued maternal cannabis use during pregnancy. All models were adjusted for covariates that were previously associated with cannabis use in this cohort.Maternal cannabis use was associated with an increased risk for psychotic symptoms in their offspring . Estimates were comparable for cannabis use exclusively before pregnancy versus continued cannabis during pregnancy . Paternal cannabis use was significantly associated with offspring psychotic symptoms .Using data from a large population-based birth cohort, we demonstrated that maternal and paternal cannabis use were each associated with offspring psychotic symptoms at age ten years, well before the risk period of adolescent cannabis use initiation. Notably, estimates were similar for maternal cannabis use exclusively before pregnancy versus continued cannabis use during pregnancy. Moreover, estimates were comparable for maternal versus paternal cannabis use during pregnancy. This suggests that common etiologies, rather than solely causal intra-uterine mechanisms, underlie the association between parental cannabis use and offspring psychotic symptoms, shedding potential new light on the debated causal path from cannabis use to psychosis. Our findings indicate that diagnostic screening and preventative measures need to be adapted for young people at risk for severe mental illness, and that these programs need to offer a family-focused approach."}
+{"text": "Mild cognitive impairment is considered as the first clinical manifestation ofAlzheimer's disease (AD), when the individual exhibits below performance onstandardized neuropsychological tests. However, some subjects before having alower performance on cognitive assessments already have a subjective memorycomplaint.  A review about subjective cognitive decline, the association with AD biomarkersand risk of conversion to dementia.  We performed a comprehensive non-systematic review on PubMed. The keywords usedin the search were terms related to subjective cognitive decline.  Subjective cognitive decline is characterized by self-experience of deteriorationin cognitive performance not detected objectively through formalneuropsychological testing. However, various terms and definitions have been usedin the literature and the lack of a widely accepted concept hampers comparison ofstudies. Epidemiological data have shown that individuals with subjectivecognitive decline are at increased risk of progression to AD dementia. Inaddition, there is evidence that this group has a higher prevalence of positivebiomarkers for amyloidosis and neurodegeneration. However, Alzheimer's disease isnot the only cause of subjective cognitive decline and various other conditionscan be associated with subjective memory complaints, such as psychiatric disordersor normal aging. The features suggestive of a neurodegenerative disorder are:onset of decline within the last five years, age at onset above 60 years,associated concerns about decline and confirmation by an informant.  These findings support the idea that subjective cognitive complaints may be anearly clinical marker that precedes mild cognitive impairment due to Alzheimer'sdisease.  From the development of biomarkers that allow the detection ofb-amyloid peptide, tau protein and neuronal injury, it is known that the AD pathologyprecedes the onset of dementia by many years.,,The working group of the National Institute on Aging-Alzheimer's Association (NIA-AA)has produced new recommendations for the diagnosis of dementia due to Alzheimer'sdisease and proposed the concept of AD stages based on the model of the \"amyloidcascade\".,,,,This subtle cognitive decline is characterized by a self-experience of deterioration incognitive performance not detected objectively through formal neuropsychologicaltesting.We performed a comprehensive literature non-systematic review on PubMed for referencespublished between January 1990 and July 2016. The keywords used in the search were termsand words related to subjective cognitive decline: \"subjective memory complaint\",\"self-reported memory complaint\", \"subjective cognitive impairment\", \"subjectivecognitive concerns\" , \"Alzheimer's disease\", \"Alzheimer's biomarker\". The search wasrestricted to articles written in English, Spanish and Portuguese language.-,,Subjective cognitive decline: what is it and what is the risk? Various terms anddefinitions have been used in the literature, such as \"subjective memory complaint\",\"self-reported memory complaint\", \"subjective cognitive impairment\" and \"subjectivecognitive concerns\".-Several epidemiological studies have shown an increased risk of progression to ADdementia among individuals with subjective cognitive decline.Reisberg et al. followed 213 individuals for about seven years and found that 54.2% ofthe group with subjective cognitive impairment declined to mild cognitive impairment ordementia, compared to 14.9% among normal controls (hazard ratio 4.5).,,Some authors question whether the complaint of the individual would itself be sufficientto increase the risk of progression to dementia. This questioning arises from twoobservations: memory complaints are very prevalent in the elderly (and therefore can benonspecific) and a high prevalence of lack of insight among patients with dementiaexists. Consequently, some studies analyzed whether confirmation of cognitive decline byan informant increases the specificity and risk for progression to dementia.,However, akin to individuals with mild cognitive impairment, many with subjectivecomplaints may remain stable or even show improvement in cognition. Alzheimer's diseaseis not the only cause of subjective cognitive decline and various other conditions canbe associated with subjective memory complaints, such as normal aging, personalitytraits, psychiatric disorders and use of psychiatric drugs.,Subjective cognitive decline: how can it be identified? Although several studies haveevaluated subjective cognitive decline and its risk of progression to dementia, there isno standard on how the evaluation should be carried out. Ideally, the assessment ofsubjective cognitive decline in any study must provide balance and not be too sensitive or very specific (and therefore too restrictive).Several questionnaires and scales have been developed and applied in clinical andepidemiological studies. The most frequent self-reported measures include: QuestionnaireAgeCoDe Study,,,,As previously mentioned, not all subjective memory complaint is due to pre-clinicalAlzheimer's disease. Of other causes, mental disorders are among the most oftenassociated and therefore the evaluation of patients with subjective memory complaintmust include a neuropsychiatric inventory. However, even excluding patients who meetcriteria for a major psychiatric disorder, symptoms of depression and anxiety or morbidpersonality traits are fairly frequently observed in epidemiological studies.-Although subjective cognitive decline is defined as a complaint without detectableimpairment by standardized neuropsychological tests, a new generation of episodic memorytests has shown utility for the diagnosis of Alzheimer's preclinical disease with a goodcorrelation with subjective complaint.-Subjective cognitive decline studies in the Brazilian population. Although anincreasingly discussed topic in Cognitive Neurology, there are few studies involving theBrazilian population.In a community-based study, seventy-one healthy older adults were asked if they hadmemory complaints, filled out the Memory Complaint Questionnaire (MAC-Q) and underwent aformal test of episodic memory . Spontaneouscomplaints were associated with poor performance on the RAVLT, but not on theMAC-Q.,On the other hand, some studies have shown no correlation between worse performance oncognitive tests and the presence of subjective decline.in vivo of pathologic findings (using biomarkers) withclinical manifestations of Alzheimer's disease.,,,,-,--Alzheimer's disease biomarkers in subjective cognitive decline. In recent years, severalstudies  have been investigating thecorrelation ,Perrotin et al. compared two groups of normal elderly, one with positive PiB PET-CT andanother with negative PiB PET-CT, for subjective cognition and performance on aneuropsychological evaluation.-,Evidence also points to a correlation between subjective cognitive decline and corticalatrophy on structural MRI, especially in commonly vulnerable regions for Alzheimerdisease.-Similarly to imaging methods, studies of b-amyloid peptide, total tau and phosphorylatedtau proteins in cerebrospinal fluid (CSF) are widely used in investigations ofsubjective cognitive decline.,In addition to the biomarkers, AD has many other risk factors, but none is betterestablished than the e4 allele of apolipoprotein E (APOE). There is ample evidence thatindividuals with subjective cognitive decline have a greater frequency of expression ofthe allele, especially among those with positive biomarkers.Several studies have shown that individuals with subjective cognitive decline are atincreased risk of progression to AD dementia. According to epidemiological data, thefeatures which increase the likelihood of conversion are: onset of decline within thelast five years, age at onset above 60 years, associated concerns about decline andconfirmation by an informant. In addition, there is evidence that this group has ahigher prevalence of positive biomarkers for amyloidosis and neurodegeneration.Consequently, these findings support the idea that subjective cognitive complaints maybe an early clinical marker of pathology and help further understanding on the naturalhistory of Alzheimer's disease from pre-dementia stages. However, due to lack ofconsensus on how to define and assess subjective cognitive decline, it is still unclearwhich characteristics of subjective cognitive decline suggest the preclinical ADstage."}
+{"text": "Meta-analysis suggest that processing speed deficit is the largest single cognitive impairment in schizophrenia. Processing speed predicts functional outcome and indicates a vulnerability marker for schizophrenia. Several authors have proposed that abnormalities in white matter is related to reduced processing speed in schizophrenia. The purpose of this research was to investigate the relationship between processing speed and structural properties of white matter pathways in schizophrenia and healthy controls.The data using this study were from the SchizConnect. Participants included 64 patients with schizophrenia and 71 healthy controls. Diffusion tensor imaging(DTI) method was used to measure fractional anisotropy along white matter tracts. Group differences in white matter integrity-inferred from fractional anisotropy (FA), processing speed, verbal memory were examined. Mediation analysis were applied to inspect the relationship between FA and cognitive performance.Participants with schizophrenia had significantly reduced processing speed, verbal memory deficits, and whole-brain fractional anisotropy deficit. There were significant group differences in white matter integrity of the left thalamus occipital, right extreme capsule, and right thalamus occipital. FA in left thalamus occipital and right extreme capsule mediated group differences in processing speed, but not other cognitive domains.Study findings indicate that mediation effect of processing speed is regional tract-specific. These finding suggest that the structural integrity of white matter tracts associated with left thalamus occipital, right extreme capsule is closely related to reduced processing speed in schizophrenia, but not verbal memory and verbal learning."}
+{"text": "Recently, Patrick Micke and colleagues from Uppsala University have contributed an outstanding publication on the limitations to predict prognosis in non-small cell lung cancer . For thThe authors discuss several possible reasons for the negative result, one of them that global gene expression profiles may have performed better. However, despite the availability of several non-small cell lung cancer cohorts with genome-wide data an improvement over clinicopathological parameters including performance status has not yet been demonstrated. A possible reason not discussed by the authors is that tumor tissue used for biomarker or genome-wide expression analysis was taken by surgery soon after diagnosis, while metastasis occurs usually years later. Eventually, biomarker expression undergoes changes during this period and the surgically obtained tumor tissue may no longer be sufficiently representative of the tumor that finally progresses and leads to death.Currently, numerous studies are performed in several tumor entities aimed to predict prognosis (Selinski et al., 2017; Hellwig"}
+{"text": "Most retroperitoneal tumors such as renal cell carcinoma have been associated with tumor thrombus extending into the renal vein, inferior vena cava (IVC), and heart. The retroperitoneal metastatic potential of testicular tumors is well known. We report here the first instance of a cardiac murmur prompting diagnosis of metastatic testicular neoplasia in an 18-year-old patient. Chemotherapy was delayed and after successful surgical resection of the ventricular mass, the patient recovered uneventfully. This case underscores the need to pursue abnormal cardiac exams in newly diagnosed testicular cancer patients."}
+{"text": "Phonologically similar items  are more difficult to remember than dissimilar items , likely because of mutual interference of the items in the phonological store. Low-frequency transcranial magnetic stimulation (TMS), guided by functional magnetic resonance imaging (fMRI) was used to disrupt this phonological confusion by stimulation of the left inferior parietal (LIP) lobule. Subjects received TMS or placebo stimulation while remembering sets of phonologically similar or dissimilar pseudo-words. Consistent with behavioral performance of patients with neurological damage, memory for phonologically similar, but not dissimilar, items was enhanced following TMS relative to placebo stimulation. Stimulation of a control region of the brain did not produce any changes in memory performance. These results provide new insights into how the brain processes verbal information by establishing the necessity of the inferior parietal region for optimal phonological storage. A mechanism is proposed for how TMS reduces phonological confusion and leads to facilitation of phonological memory."}
+{"text": "The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migratory capacity, which is available for metastatic cancer targeting. Prodrug activating enzyme or anticancer cytokine expressing stem cells successfully inhibited the proliferation of cancer cells. Preclinical models have clearly demonstrated anticancer activity of these two platforms against a number of different cancer types and metastatic cancer. Several systems using therapeutic stem cells or oncolytic virus have entered clinical trials, and promising results have led to late stage clinical development. Consequently, metastatic cancer therapies using stem cells and oncolytic viruses are extremely promising. The following review will focus on the metastatic cancer targeting mechanism of therapeutic stem cells and oncolytic viruses, and potential challenges ahead for advancing the field. Cancer metastasis, which is a multiple process in which malignant cells spread from the primary site to colonize distant organs, is one of the greatest challenges in cancer treatment. Although metastasis is responsible for more than 90% of cancer associated mortality, it is difficult to diagnose and treat . For manConventional strategies of cancer therapy, including surgical resection, chemotherapy, radiotherapy and immunotherapy, have made significant contributions to cancer treatment. However, many people suffer from side-effects such as insufficient anti-cancer effects that involve drug resistance and systemic adverse reactions due to off target effects . For exaA mechanistic understanding of the metastatic process is important to development of anti-metastatic therapies that could reduce patient mortality. The metastatic process is initially derived from gene mutations that correlate with proliferative ability. Cells in normal tissues only divide when they receive growth stimulatory signals from other cells and stop dividing when they receive growth inhibitory signals; however, gene mutations providing the ability to be split ignore these signaling factors . AdditioIn this review, we will discuss recent strategies for the treatment of metastatic cancer based on stem cells and oncolytic viruses. Many stem cells have intrinsic tumor tropic properties that originate from chemokine interactions with cancer cells. Using this property, we can make a specific delivery system of anticancer molecules. Stem cells can migrate towards tumor microenvironments and eliminate tumors, enabling site specific delivery. Furthermore, stem cells can be modified to stably express various anticancer agents including cytokines and prodrug activating enzymes for induction of cancer apoptosis and removal of specific tumors. In addition, oncolytic viruses are a therapeutically useful system that can be used to selectively infect and damage tumor tissues without off target effects on normal tissues. Each virus has a specific cellular tropism that determines which tissues are preferentially infected. Viruses then increase in the tumors and destroy them, after which they infects another tumor cell. Viral oncotherapy can also be modified to increase tumor selectivity and enhance oncolytic activity. For example, some viruses have been modified to express capsid proteins that bind with specific cancer types and conditionally express the genes involved with the activation of host immune system. These two strategies will be able to complement the drawbacks of conventional cancer therapy.via stem cell engineering. Other signaling pathways have been found, including urokinase type plasminogen activator (uPA) - uPA receptor (uPAR) and vascular endothelial growth factor receptor 2 (VEGFR2) [Stem cells can trace cancer cells and tumor regions, which makes them very useful for tracing metastatic cancer and carrying anti-metastatic molecules. Various chemokine-chemokine receptor interactions are important to recognition of tumor cells and tumor tropism of stem cells. Stromal cell derived factor 1 alpha (SDF-1\u03b1) and its receptor, CSC chemokine receptor 4 (CXCR4), have been identified as key molecules responsible for the tropism of stem cells in many cancers . Accordi(VEGFR2) , 18. Thevia activation of JNK/activation protein-1 and stimulated the secretion of both tumor necrosis factor alpha and interferon gamma, which ultimately activated the caspase 3/7 pathway [Stem cells have intrinsic antitumor effects that occur through various factors secreted by stem cells and physical interactions of stem cells with tumor cells , 20. How pathway , 26. Neu pathway . In addi pathway . Using c pathway . Interfe pathway , 31. Sec pathway  as shownvia the bystander effect. Cytosine deaminase (CD) and 5-fluorocytosine (5-FC) are well-known suicide gene systems. E. coli cytosine deaminase can convert a prodrug, 5-FC, into its active drug, 5-FU. The metabolite of 5-FU (fluorodeoxyuridine monophosphate) binds to the nucleotide binding site of the thymidylate synthase and dNTP in tumor cells becomes imbalanced, which can cause DNA damage and cell apoptosis [Stem cell mediated suicide gene therapy is another strategy for killing tumor cells. Stem cells are engineered to express an enzyme that converts a non-toxic prodrug into a cytotoxic drug that can efficiently kill tumor cells poptosis . In addipoptosis . The CD-poptosis , 36. In poptosis . Furtherpoptosis  , which is one of the fusogenic membrane glycoproteins (FMGs) in neural stem cells, is a notable strategy for targeting tumor microenvironments . VSV-G eCancer treatments using stem cells have made improvements in regards to specific targeting of tumors, but a few obstacles must still be overcome prior to clinical application. The main concern is tumorigenicity of the stem cell and cell fate after systemic administration. To prevent therapeutic stem cells from forming tumors or aberrantly differentiating in the host, the tumorigenicity or differentiation potential should be tested in preclinical models. In addition, immortalized stem cells with therapeutic gene inserts may solve the difficulty of mass culture of stem cells and enable their stability in tumors. Therefore, it is important to develop a new strategy for mass culture of stem cells to ensure the ability of a suicide gene to perfectly eliminate stem cells after therapy. Therapeutic modifications could adversely affect the safety of stem cells. Therapeutic stem cells or secreted proteins interrupt host tolerance to self-antigens, which provokes additional complications in the patient and immune responses that might impair therapy. Improvement of stem cell specificity through detailed investigations of tumor tropism could relieve possible side effects.The idea of oncolytic virotherapy originates from clinical reports of cancer regression caused by viral infection and is currently being developed by genetically modifying viruses for the selective infection and destruction of cancer cells .The specificity of oncolytic viruses for tumors is very important to clinical trials. Many viruses have a natural specific tissue tropism for cell surface proteins that are overexpressed by cancer cells. This characteristic is very useful for metastatic cancer tracing. For example, measles virus recognizes the surface receptor CD46 (complement regulatory protein) for cell infection. CD46 is a cofactor for inactivation of complement components that is often overexpressed in cancer cells . Herpes in vitro by at least ten-fold. These data suggest an improved safety of Ad 5/3 in the setting of malignant glioma [Oncolytic viruses can be engineered to directly bind to unique surface molecules of cancer cells. This modification could assign additional specificity for metastasized tumor cells by improving infection of tumor tissues and decreasing infection of healthy tissues. This specificity can be achieved by modifying or combination protein of virus that require for cancer cell recognition. For example, glioma cells overexpress CD16 and CD80/86, which bind with adenovirus serotype 3 , 48. Bast glioma . The adet glioma . Other et glioma .Another strategy is a tumor specific transcriptional targeting using tumor specific promoters and microRNA target sequences. This strategy can restrict virus replication in off-target tissues. For example, adenovirus replication is correlated with their ability to promote cell cycle entry into the G1 phase through the viral immediate early protein E1A. Therefore, tumor specificity is achieved by placing the E1A gene under transcriptional regulation of a tumor specific promoter , CXCR4 iAfter oncolytic virus infection, cancer cells are destroyed by lysis. However, various strategies have been studied to achieve the maximum therapeutic efficacy for tumor cells. The therapeutic efficacy of oncolytic viruses can be enhanced using strategies that enable immunostimulatory factors to induce innate and adaptive immune responses against tumors. One successful strategy is the expression of granulocyte macrophage colony stimulating factor (GM-CSF), which stimulates stem cells to produce granulocytes and monocytes and stimulates adaptive immunity against tumor associated antigens . T-VEC iTransfer of metastatic suppressor genes or targeting metastasis related molecules is an effective strategy of targeting metastatic cancer. One of the tumor suppressor proteins, KAI1, plays a key role in downregulation of epidermal growth factor receptor (EGFR) signaling, which is associated with increased receptor desensitization and endocytosis . An adenSeveral studies have also explored the possibility of combining oncolytic viruses with stem cells to improve delivery . The theThe development of oncolytic viruses as therapeutic agents for metastatic cancer requires careful attention to establish appropriate clinical trial designs, as well as dosing regimens to minimize possible side effects. The most important technical challenge to overcome is the need to enhance tumor selectivity to decrease off target effects after systemic delivery of the oncolytic virus. The other major obstacle to successful application of viral therapy is neutralization of the virus by the host antibody. Many species of viruses are used in oncolytic virotherapy, and most people have already been exposed to the virus through previous vaccination or infection. Therefore, circulating antibodies can inhibit the oncolytic virus before it reaches the tumor site. Immune suppression agents and the aforementioned stem cell transport strategy is currently being investigated to solve this problem.Metastasis of cancer is one of the main factors leading to patient death. The unique properties of metastatic cancer, including their small size, high multiplicity and spread to multiple organs make it difficult to treat. Although conventional cancer treatment strategies have shown a lot of progress, they have been limited in metastatic cancer by recurrence of cancer, induction of drug resistance and systemic side effects after treatment. Accordingly, new strategies are needed to treat metastatic cancer.Stem cell based and oncolytic virus strategies have many potential benefits. Stem cell based therapies are emerging as promising strategies to treat metastatic cancer. Multiple types of stem cells have been shown to exhibit natural tropism towards tumors. In addition, when engineered to express therapeutic agents including prodrug activation enzymes, cytokines and oncolytic viruses, these vehicles can deliver treatments to target sites of metastasized tumor lesions and effectively kill the cancer cell. Many metastatic cancer models have shown therapeutic stem cells to be safe and effective. In addition, clinical trials using promising therapeutic stem cells are under investigation and summarized in Table via oncolytic virus particle modification, serotype changes and use of tumor specific activated promoters. Application of improved oncolytic viral constructs that can be delivered systemically or intratumorally will lead to effective treatments for metastatic cancer patients. Table Oncolytic virotherapy has rapidly advanced in a relatively short period through virological studies. In the early stage, oncolytic viruses destroyed tumors by their oncolysis ability alone; however, transduction of therapeutic transgenes and combination with other anti-tumor agents has enhanced the potency of the oncolytic virus platform. In addition, tumor selectivity has progressed Despite these advances, additional research is needed to develop safer strategies and a lot of validation is required before preclinical models can be applied to humans. By understanding of metastatic processes and biological mechanisms that specifically drive each step of metastasis, we can develop more advanced therapeutic stem cells and strategies of oncolytic virotherapy, which are highly promising approaches to the treatment of metastatic cancer."}
+{"text": "Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment option for both malignant and some benign hematological diseases. During the last decade, many of the newer high-dose regimens in different intensity have been developed specifically for patients with hematologic malignancies and solid tumors. Today there are three main approaches used prior to allogeneic transplantation: Myeloablative (MA), Reduced Intensity Conditioning (RIC) and Non-MA (NMA) regimens. MA regimens cause irreversible cytopenia and there is a requirement for stem cell support. Patients who receive NMA regimen have minimal cytopenia and this type of regimen can be given without stem cell support. RIC regimens do not fit the criteria of MA and NMA: the cytopenia is reversible and the stem cell support is necessary. NMA/RIC for Allo-HSCT has opened a new era for treating elderly patients and those with comorbidities. The RIC conditioning was used for 40% of all Allo-HSCT and this trend continue to increase. In this paper, we will review these regimens in the setting of especially allogeneic HSCT and our aim is to describe the history, features and impact of these conditioning regimens on specific diseases. Treatment regimen used for hematopoietic stem cell transplantation (HSCT) must accomplish two goals depending on the patient\u2019s disease and the source of stem cells. Since the majority of allogeneic transplantations are performed for the treatment of malignant disease, the regimen must provide tumor cytoreduction and ideally disease eradication ,5,6,7,8.Several studies showing high doses of total body irridation (TBI) causes death from marrow failure and intravenous infusion of marrow or spleen cells after TBI prevents death in mice attracted many researchers to investigate human transplantations in mid-1950s (19). Early trials of human marrow grafting had been unsuccessful since patients failed to engraft or developed fatal graft-versus-host disease (GVHD) . In lateConventional ablative allo-HSCT depends on the tolerated doses of systemic chemo-radiotherapy in order to eradicate malignant tumor burden. This resulted with high regimen-related toxicities in elderly and patients with comorbidities. In considering that, most hematological diseases occur at ages from 65 to 70 , investiThe MA/NMA/RIC conditioning regimens currently in use summarized in It is well known that a complete donor T-cell chimerism is correlated with a low risk of relapse or progression. MA regimens leads to state of full chimerism rather earlier than RIC regimens. Mixed chimerism is detected initially after transplant in most RIC conditioning regimens and in fact graft rejection is more common in RIC Allo-HSCT patients compared to conventional regimens . MyeloabIn AML, several retrospective comparisons of RIC and MA conditioning regimens are difficult to evaluate due to different patient populations. Patients who received RIC regimens had more high risk features and comorbidities than those received MA conditioning but the survival rates were found to be similar between RIC and MA conditioning . SeveralIncreased NRM in elderly patients with comorbidities may worsen the outcome of MA allo-HSCT in acute lymphoblastic leukemia (ALL). Marks et al.  had not Recently, the results of phase III multi-center randomized study of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901 have been released. This study compared outcomes on the basis of conditioning intensity in patients with Myelodysplastic syndrome (MDS) and AML. The study concluded that RIC results in higher relapse rates and lower TRM compared to MAC with a statistically significant advantage in RFS for patients receiving MAC. It has to be noted that inclusion of heterogeneous regimens in both RIC and MAC arms and lack of longer follow-up establishes the main weaknesses of the BMT CTN 0901 study .There are some controversies regarding the impact of conditioning intensity on disease control in MDS. Warlick et al. (55) reported improved disease control with MA regimens. High risk MDS patients (n=43) were treated with MA and T cell depleted alloHSCT resulted in EFS at 1 and 3 years as 47% and 34%, respectively. The overall toxicity was detected to be similar compared to multiple recorded series using RIC regimens. Martino et al.  reportedMyeloproliferative neoplasms (MPNs) include a group of clonal and chronic hematologic disorders with similar features. Classical MPNs are chronic myeloid leukemia (CML), idiopathic/primary myelofibrosis (MF), polycythemia vera (PV), essential thrombocytopenia (ET), systemic mastocytosis, chronic neutrophilic leukemia and chronic eosinophilic leukemia . Today, In newly diagnosed severe acquired idiopatic aplastic anemia patients younger than 30-40 years, allo-HSCT is the first line treatment of choice . The staIn patients with Hodgkin\u2019s lymphoma (HL), allo-HSCT is generally performed in relapsed disease after autologous HSCT or refractory disease status but MAC followed by allo-HSCT with conventional preparative regimens had been associated with high toxicity rates and TRM in this group of patients. In the era of reduced intensity regimens, EBMT Lymhoma Working Party reported a lower NRM and improved OS with RIC allo-HSCT in patients with relapsed or refractory HL . In a reSeveral studies have evaluated the efficacy HSCT following RIC or NMA conditioning as a treatment option in relapse or refractory non-HL (NHL) after failure of autologous HSCT. The PFS rate at 3-year was 82% in 18 refractory mantle cell lymphoma (MCL) patients treated with NMA conditioning containing fludarabine, cyclophosphamide and rituximab . Maris eCLL has an indolent and prolonged clinical course and mostly patients are in older age group. Sorror et al.  reportedBased on the growing knowledge on the immune system and T cell biology, allogeneic HSCT also represents a promising approach in some solid tumors. Several EMBT phase I and II studies which were conducted by Solid Tumors Working Party documented the presence of a graft-versus solid tumor effect in patients with various solid tumors such as renal, ovarian, colon and soft tissue sarcomas [27-78]. Aglietta et al.  reportedIn conclusion, allogeneic stem cell transplantation is a curative approach in many diseases. The advantages of RIC regimens are lower toxicity profiles and lower NRM rates. RIC or NMA allo-HSCT can be a feasible option in geriatric patients and patients with comorbidities. Future studies are needed for a clear-cut understanding of the mechanisms of GVL and GVT effects of donor T cells and its subsets in order to optimize the efficacy of such treatment modalities as RIC or MAC in allo-HSCT ."}
+{"text": "Memory deficits are a hallmark of psychotic disorders such as schizophrenia. However, whether neural dysfunction underlying these deficits is present prior to onset of illness and potentially predicts conversion to psychosis are unclear. This study aimed to investigate: 1) baseline brain functional alterations during memory processing in subjects at clinical high risk (CHR); 2) whether alterations are more severe in converters compared with non-converters and are thus predictive of psychosis; and 3) associations of these alterations with task performance, baseline symptoms and memory ability.A sample of 155 individuals at CHR  and 137 subjects who did not convert ) and 108 healthy controls  were drawn from the second phase of the North American Prodrome Longitudinal Study (NAPLS-2) consortium. All participants underwent functional magnetic resonance imaging (fMRI) with a paired-associate memory paradigm, which consisted of one run for encoding and another run for retrieval. During encoding, participants were presented a series of semantically unrelated word pairs and were asked to remember the presented word pair. During retrieval, a pair of words was presented on the screen on each trial and subjects were asked to indicate whether the given word pair had been presented during the encoding session. Active baseline conditions were included in the task for both encoding and retrieval runs.Data processing was performed for each run, following the standard procedures using the Statistical Parametric Mapping software (SPM12). At individual level, preprocessed images were entered into a general linear model (GLM), generating individual contrast maps (task vs baseline). These contrast maps were further used for a group-level GLM analysis, modeling group, sex, age and site as regressors. Significance was determined using family-wise error (FWE) correction across all voxels in the brain.The observed activation alterations were further tested for potential associations with task performance, clinical symptoms and/or general memory ability. Task performance was measured using the percentage of correct responses and the mean reaction time during retrieval. Clinical symptoms were evaluated by the summed scores of each domain  in the Scale of Prodromal Symptoms (SOPS). Memory ability was quantified by the Brief Visuospatial Memory Test- Revised (BVMT-R) and the Hopkins Verbal Learning Test- Revised (HVLT-R) total recall scores.No significant group differences in activation were found during encoding. However, during retrieval, a significant group effect was observed in five brain regions: left dorsolateral prefrontal cortex , left ventrolateral prefrontal cortex , left inferior parietal lobule , left superior temporal gyrus , and right middle temporal gyrus . This effect was indicative of greater activation in converters than non-converters and controls and was particularly manifest in unmedicated subjects (P < 0.001). Baseline hyperactivation was correlated with retrieval reaction time during scan in converters , and with baseline positive, negative and disorganization symptoms  and memory scores  in the whole sample.These findings suggest that hyperactivation during memory retrieval may mark processes associated with conversion to psychosis; such measures have potential as biomarkers for psychosis prediction."}
+{"text": "Functional brain networks are known to be affected by focal brain lesions. However, the clinical relevance of these changes remains unclear. This study assesses resting-state functional connectivity (FC) with electroencephalography (EEG) and relates observed topography of FC to cognitive and motor deficits in patients three months after ischemic stroke. Twenty patients  and nineteen age-matched healthy participants  underwent a ten-minute EEG-resting state examination. The neural oscillations at each grey matter voxel were reconstructed using an adaptive spatial filter and imaginary component of coherence (IC) was calculated as an index of FC. Maps representing mean connectivity value at each voxel were correlated with the clinical data. Compared to healthy controls, alpha band IC of stroke patients was locally reduced in brain regions critical to observed behavioral deficits. A voxel-wise Pearson correlation of clinical performances with FC yielded maps of the neural structures implicated in motor, language, and executive function. This correlation was again specific to alpha band coherence. Ischemic lesions decrease the synchrony of alpha band oscillations between affected brain regions and the rest of the brain. This decrease is linearly related to cognitive and motor deficits observed in the patients."}
+{"text": "Malayopython reticulatus ssp.) are primarily harvested from the wild for their skins\u2014which are prized in the luxury leather goods industry. Trade dynamics of this CITES Appendix II listed species are complex and management approaches on the country or regional level appear obscure. Little is known about the actual geographic point-of-harvest of snakes, how genetic diversity is partitioned across the species range, how current harvest levels may affect the genetic viability of populations, and whether genetic structure could (or should) be accounted for when managing harvest quotas. As an initial survey, we use mitochondrial sequence data to define the broad-scale geographic structure of genetic diversity across a significant portion of the reticulated python\u2019s native range. Preliminary results reveal: (1) prominent phylogenetic structure across populations east and west of Huxley\u2019s modification of Wallace\u2019s line. Thirty-four haplotypes were apportioned across two geographically distinct groups, estimated to be moderately (5.2%); (2) Philippine, Bornean and Sulawesian populations appear to cluster distinctly; (3) individuals from Ambon Island suggest recent human introduction. Malayopython reticulatus is currently managed as a single taxonomic unit across Southeast Asia yet these initial results may justify special management considerations of the Philippine populations as a phylogenetically distinct unit, that warrants further examination. In Indonesia, genetic structure does not conform tightly to political boundaries and therefore we advocate the precautionary designation and use of Evolutionary Significant Units within Malayopython reticulatus, to inform and guide regional adaptive management plans.As an important economic natural resource in Southeast Asia, reticulated pythons ( Habitat loss and degradation as a result of unsustainable per capita consumption of natural resources and rising human population levels  are haviMalayopython reticulatus ssp., Python bivittatus ssp., P. curtus, P. brongersmai and P. breitensteini) being heavily exploited for this purpose. Among these the reticulated python (M. reticulatus ssp.) is the most economically important species , the Philippine governments banned the export of M. reticulatus in 1986, and Viet Nam banned wild harvest of M. reticulatus in 1998 )Malayopython reticulatus across the species contemporary range, they offer an encouraging conservation genetics baseline that justifies implementing a precautionary approach [Although the results presented here offer a very provisional insight to the genetic structure of approach  to populMalayopython reticulatus are to be continually exploited for the skin trade, management strategies should not solely be tailored to obtaining the maximum economic yield. Populations should instead be managed following an adaptive management scheme to ensure their long-term sustainability . Among ity , and maTo regulate trade dynamics, wild harvest rates and exploitation levels require regular monitoring of the status of resource population(s) to reduce uncertainties.Further fine scale genetic analysis is also warranted to delineate local genetic partitions, and the potential application of adaptive genetic markers to establish conservation units should be considered (see ).To encourage and foster scientific collaborative networks with the countries of origin to permit construction of comprehensive, reference sample databases on which to base the development of robust traceability protocols.S1 TableThe table contains information about samples included in this study along with the corresponding haplotypes inferred from sequence variation across a mitochondrial cytochrome b fragment.(PDF)Click here for additional data file."}
+{"text": "Background: Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder which develops in approximately 10% of trauma-exposed individuals. Currently, there are few early preventive interventions available for PTSD. Intranasal oxytocin administration early posttrauma may prevent PTSD symptom development, as oxytocin administration was previously found to beneficially impact neurobiological  and socio-emotional PTSD vulnerability factors.Objective: The overall aim of this dissertation was to investigate the potential of intranasal oxytocin administration as early preventive intervention for PTSD.Methods: We performed a functional magnetic resonance imaging (fMRI) study to assess the acute effects of a single administration of oxytocin on the functional fear neurocircuitry \u2013 consisting of the amygdala and (pre)frontal brain regions \u2013 in recently trauma-exposed emergency department patients (range n\u00a0=\u00a037\u201341). In addition, we performed a multicentre randomized double-blind placebo-controlled clinical trial (RCT) to assess the efficacy of repeated intranasal oxytocin administration early after trauma for preventing PTSD symptom development up to six\u00a0months posttrauma (n\u00a0=\u00a0107).Results: In our fMRI experiments we observed acutely increased amygdala reactivity to fearful faces and attenuated amygdala-ventromedial and ventrolateral prefrontal cortex functional connectivity after a single oxytocin administration in recently trauma-exposed individuals. However, in our RCT we found that repeated intranasal oxytocin administration early posttrauma reduced subsequent PTSD symptom development in recently trauma-exposed emergency department patients with high acute PTSD symptoms.Conclusions: These findings indicate that repeated intranasal oxytocin is a promising early preventive intervention for PTSD for individuals at increased risk for PTSD due to high acute symptom severity. Administration frequency dependent effects of oxytocin or the effects of oxytocin administration on salience processing may serve as explanatory frameworks for the contrasting oxytocin effects on anxiety-related measures in our clinical and neuroimaging studies. As trauma exposure constitutes an identifiable event of potential PTSD onset, the first hours to weeks posttrauma serve as a suitable time-period for the provision of early preventive interventions for PTSD, aimed to reduce subsequent PTSD symptom development. Previously, administration of benzodiazepines  study to assess the acute effects of a single administration of oxytocin on the functional fear neurocircuitry \u2013 consisting of the amygdala and (pre)frontal brain regions \u2013 in recently trauma-exposed emergency department patients. In addition, we performed a randomized controlled clinical trial to assess the efficacy of repeated intranasal oxytocin administration early after trauma for preventing PTSD symptom development.3. 3.1. In chapter 2 . We observed that the effects of oxytocin administration on amygdala reactivity to emotional faces depended on stimulus valence and on sex. In all participants, oxytocin administration increased amygdala reactivity to fearful faces. Additionally, in women only, oxytocin administration increased amygdala reactivity to neutral faces. Our exploratory analysis showed that acute PTSD symptom severity was not associated with differential intranasal oxytocin administration effects on amygdala reactivity. Given these results we argued that a single intranasal administration of oxytocin may increase neural fear processing, possibly as a result of oxytocin-induced enhanced salience processing.We assessed the acute effects of a single administration of intranasal oxytocin on the fear neurocircuitry in a randomized double-blind placebo-controlled functional magnetic resonance imaging (fMRI) study in trauma-exposed emergency department patients within 11\u00a0days posttrauma. In chapter 4 . For each participant two resting-state fMRI scans were acquired: one after listening to a personal neutral script, and the second after listening to a personal trauma script which was based on the recent traumatic event. We observed that oxytocin-treated participants had diminished amygdala-left ventrolateral prefrontal cortex (vlPFC) functional connectivity in response to the trauma script compared to the neutral script, whereas an increase in amygdala-left vlPFC functional connectivity was observed in placebo-treated participants. In addition, irrespective of script condition, oxytocin administration enhanced amygdala-left (posterior) insula functional connectivity and decreased amygdala-ventromedial prefrontal cortex (vmPFC) functional connectivity. These neural oxytocin administration effects were accompanied by lower levels of sleepiness and higher flashback intensity after the trauma script in oxytocin-treated participants. Taken together, these observations indicate that that a single intranasal oxytocin administration may acutely impede emotion regulation in recently trauma-exposed individuals.In chapter 5 . However, the effects of oxytocin administration were moderated by acute PTSD symptom severity assessed prior to the intervention. Oxytocin administration reduced PTSD symptoms up to six\u00a0months posttrauma in trauma-exposed individuals with high acute PTSD symptoms only. These findings suggest that an eight-day intranasal oxytocin treatment regimen is a promising preventive early intervention for PTSD, specifically for individuals with high acute PTSD symptoms.In chapter 7  the results of our clinical trial are presented. We demonstrated that there was no overall effect of repeated oxytocin administration on PTSD, depression and anxiety symptoms up to six\u00a0months posttrauma . An administration frequency dependent effect on anxiety is a well-known phenomenon for selective serotonin reuptake inhibitors (SSRIs). A single SSRI administration acutely increased fear learning in rodents and may potentiate anxiety in humans  socio-emotional functioning; there is no direct evidence that the salience theory also holds for repeated oxytocin administration effects. An alternative suggestion for previously observed differential effects of oxytocin administration between healthy individuals and patients with a psychiatric disorder is that oxytocin administration may only have beneficial effects in individuals who have something to gain with regard to social or emotional functioning  oxytocin administration effects on reducing PTSD symptom development, (perception of) context factors should be explicitly assessed and tested as moderators of oxytocin effects in future studies.4.2. Although we were the first to study intranasal oxytocin effects in recently trauma-exposed individuals, meanwhile conducting the largest clinical RCT with intranasal oxytocin to date, some limitations of our studies need to be addressed. First, the statistical power of our clinical study was limited. We halted our study halfway, as our pre-planned interim analysis indicated low conditional power to detect a significant overall effect of oxytocin administration on PTSD symptoms at our primary outcome (1.5\u00a0month posttrauma follow-up). As results from studies with low statistical power are at increased risk for Type I error, replication of our findings is clearly warranted. In addition, the sample size of our imaging studies was also modest, therefore it was not possible to reliably test whether the effects of oxytocin administration on amygdala function were moderated by interindividual differences as we observed in our clinical study. We did explore whether acute PTSD symptom severity was differently associated with amygdala reactivity to fearful faces and found no differential effect , functional fear neurocircuitry and/or other socio-emotional processes (e.g. related to reward functioning).Furthermore, considering the potential future use of intranasal oxytocin in routine clinical practice \u2013 for PTSD prevention but for also other psychiatric indications \u2013 it is highly desirable to better understand when beneficial, null or even potentially non-beneficial effects of oxytocin administration can be expected. Particularly, oxytocin effects on fear memory consolidation and fear extinction should be studied, as there are indications that oxytocin-mediated enhanced fear and extinction memory consolidation may have either anxiolytic or anxiogenic effects, depending on administration frequency and timing in relation to fear conditioning (Janezic et al., In addition, a better understanding of the pharmacodynamics of intranasally administered oxytocin is needed. Oxytocin has a half-life of 3\u201320\u00a0min in blood, and the peptide is immediately degraded upon oral ingestion. There is no clear consensus on if and how intranasally administered oxytocin reaches the brain. Although intranasal oxytocin administration increased salivary (van IJzendoorn, Bhandari, van der Veen, Grewen, & Bakermans-Kranenburg, If our findings are replicated, intranasal oxytocin may be a safe and cheap preventive intervention for PTSD (MacDonald et al., Finally, there is only limited evidence linking functioning of the oxytocin system directly to PTSD risk (Lucas-Thompson & Holman, 5. We observed that repeated intranasal oxytocin administration early posttrauma reduced subsequent PTSD symptom development in recently trauma-exposed emergency department patients with high acute PTSD symptoms. Although replication is necessary, these findings indicate that intranasal oxytocin is a promising novel preventive intervention for individuals at increased risk for PTSD due to high acute symptom severity. However, we also observed acutely increased neural fear processing and impeded neural emotion regulation after a single oxytocin administration in recently trauma-exposed individuals. It remains unknown whether the positive clinical effects after repeated oxytocin administration are mediated by oxytocin effects on amygdala function, or whether the beneficial effects in our clinical study are mediated by other neurobiological and/or socio-emotional processes. Administration frequency dependent effects of oxytocin may be related to these seemingly contrasting effects on anxiety-related measures in our clinical and neuroimaging studies. In addition, the salience processing theory of oxytocin effects may serve as an explanatory framework for these seemingly contrasting results between the two study paradigms. Clinically relevant contextual and interindividual moderators of oxytocin effects should be investigated in the future, as well as underlying neurobiological and socio-emotional mechanisms that mediate oxytocin effects on anxiety-related outcomes and the development of PTSD symptoms. In all, our findings encourage further research into the clinical efficacy and feasibility of repeated oxytocin administration as early preventive intervention for PTSD, in order to try and reduce the high individual and societal burden associated with trauma exposure and PTSD."}
+{"text": "Motor and vocal tics are the core symptom of Tourette syndrome (TS). Tic generation seems to develop throughout the known motor pathways. This review focuses on functional neuroimaging in order to check this assumption. Also it elucidates the alterations and interactions of motor networks in TS depending on different contexts and circumstances like resting state, spontaneous tic movements, suppression of tics and premonitory urges, voluntary goal-oriented movements as well as electrophysiological neuronal stimulation. In general, the primary tic generating motor network uses the basic motor pathways differently, interacts with secondary sensorimotor networks and neuronal systems of cognitive behavioural control in a merely hierarchical manner, changing during neurodevelopment."}
+{"text": "Unfavorable left ventricular (LV) remodelling is associated with adverse prognosis after tetralogy of Fallot (TOF) repair. The aim of this study was to measure the extracellular volume (ECV) as a marker of diffuse LV myocardial fibrosis in children after TOF repair, and to understand its etiology and clinical significance.In this prospective, cross-sectional study ECV as a quantitative marker of diffuse fibrosis was measured in the LV myocardium using a modified look-locker inversion recovery (MOLLI) sequence. ECV was related to bypass and cross-clamp times at the time of surgery, to ventricular and myocardial function as well as to exercise tolerance.There was no difference in ECV between 31 TOF patients  and 15 controls . ECV correlated with z-scores of LV end-diastolic volumes and of right ventricular (RV) end-diastolic and end-systolic volumes . LV ECV did not correlate with with LV or RV ejection fraction, indexed right and left ventricular enddiastolic volumes or pulmonary regurgitation fraction or regurgitant volumes. Female TOF patients had higher ECVs as compared to males . There were no gender differences in controls. Bypass-time during complete repair correlated with LV ECV . Patients who had undergone either a valve sparing repair or received a valved right ventricle to pulmonary artery conduit had a lower ECV than those after transannular patch repair .Maximum workload on exercise testing, as a percent of predicted based on reference populations, correlated inversely with ECV . There were no correlations between ECV and myocardial strain, strain rate or torsion.Although children after TOF repair did not present with higher ECV than controls in this pilot study the amount of diffuse myocardial fibrosis was associated with longer bypass-times at the time of initial repair. There is early evidence that increased fibrosis is associated with decreased exercise tolerance in young patients after TOF repair. Female patients appear to have more diffuse myocardial fibrosis than males consistent with their generally less favourable hemodynamics after TOF repair."}
+{"text": "Human respiratory syncytial virus (RSV) remains the most common cause of severe lower respiratory tract disease amongst infants, and continues to cause annual epidemics of respiratory disease every winter worldwide. Demonstrating placental transmission of viable RSV in human samples is a major paradigm shift in respiratory routes considered likely for RSV transmission.Droplet digital PCR (ddPCR) was used to identify RSV present in cord blood mononucleocytes (CBM). CBMs testing positive for RSV were treated with phytohemagglutinin (PHA), PHA and nitric oxide (NO) or PHA, NO and palivizumab, and co-cultured with HeLa cell monolayers. Subsequent immuno-staining for RSV was used to visualize infective viral plaques.RSV was detected in 26 of 45 samples (57.7%) by ddPCR. CBM\u2019s collected in winter were more likely to test positive for RSV  compared to non-winter months . RSV plaques were observed in non-treated and treated co-cultured HeLa monolayers.in utero transmission of infective virus to the fetus without causing overt disease. This is likely to have an important impact on immune development as well as future virus-host interactions, thereby warranting further investigation.Demonstrating active RSV in CBMs suggests  Despite more than 50 years of research, human respiratory syncytial virus (RSV) continues to cause annual epidemics of respiratory disease every winter worldwide . RSV remRSV invades the epithelial cells of the lower respiratory tract following exposure to inhaled infective aerosolized droplets, or self-inoculation of the eyes and/or nose by contaminated fingers , 3. The RSV has also been shown to infect myeloid cells such as macrophages, dendritic cells (DCs), and cord blood monocytes \u201310; howein utero transmission, and activation of live virus in these cells to suggest a cellular reservoir. Findings from this study could be used to explain the prevalence of RSV bronchiolitis observed in infants every winter and inform novel targets for effective treatment of RSV induced airway disease.Based on observations from studies which have shown RSV persistence and replication reactivation in cells of monocyte lineage \u20139, we hyCord blood samples collected from 45 term infants  from healthy mothers 18\u201345 years) recruited antenatally. Samples were collected from August 2002 until September 2003. Cord blood was collected immediately after delivery by means of venipuncture of placental vessels, as previously described [\u201345 yearsRNA purified from a pooled preparation of nasopharyngeal aspirates collected from patients diagnosed with RSV bronchiolitis were used as positive controls for RSVA and RSVB detection in cord blood samples by digital PCR analysis.De-identified cord and maternal blood samples used for this study were collected under institutional ethics approval with informed adult written consent  Human Research Ethics Committee) to investigate developmental immunology. De-identified nasopharyngeal aspirates collected from patients testing positive for RSV were obtained with agreement from PathWest Laboratory Medicine  to validate the presence of RSV by droplet digital PCR. According to the Human Tissue Acts of Australia, ethics approval was not required for use of these human samples as they were collected for therapeutic and/or diagnostic purposes and subsequently de-identified for pathology purposes, including assay validation . All resRSV gene expression was measured using a commercially available fluorescent probe real-time PCR kit designed to detect all species of RSV  on a droplet digital PCR platform . Droplet digital PCR (ddPCR) is a next generation digital PCR with greater analytical sensitivity compared to conventional real-time PCR due to an enhanced ability to read nucleic acid at a single molecule level . Viral RImmuno-probing using an anti-RSV antibody was used to detect RSV plaques in order to demonstrate infective RSV detected by ddPCR in monocyte precursor cells contained in cord blood samples. Briefly, cryopreserved cord blood mononucleocytes (CBM) were thawed and allowed to rest for 3hrs at 37\u00b0C/5% CO2 in specialised dendritic cell media, X-VIVO . Following this, cultures were treated with one of the following: phytohaemagglutinin ; PHA with a soluble nitric oxide donor ; or PHA with NO and palivizumab . All cultures were incubated for 24hrs and then added to HeLa monolayers (American Tissue Culture Collection) grown to 70% confluence in Dulbecco\u2019s minimum essential medium (DMEM) supplemented with fetal calf serum (10% v/v). After 48 hours culture supernatants were removed and the remaining HeLa cell monolayers washed with PBS, and fixed with methanol containing hydrogen peroxide (1% v/v). These fixed HeLa cultures were then probed for RSV expression using anti-RSV HRP conjugated monoclonal antibody  followed by incubation with Sigma-Fast Red  to detect the presence of RSV as described previously . StainedA total of 45 samples were assessed for RSV expression and a minimum of 11 samples were used to compare RSV plaque assay formation in each treatment group. All samples were run in duplicate and all experiments completed at least twice to ensure reproducibility. Odd\u2019s ratios and relative risk for RSV detected in cord samples were calculated using cross-tabulations with Fishers exact analysis. Due to an absence of data regarding the prevalence of RSV in CBMs, post-hoc power analysis was used to assess if the study interpretations were feasible based on the sample size available. The observed power was calculated at 82% based on the relative risks of RSV detection and sample size used. In order to mitigate concerns surrounding use of observed power and demonstrate the precision of these findings, confidence intervals are reported for the effect sizes calculated. Due to the small sample size and skewed distribution of the dataset, Mann Whitney-U analysis was used to compare RSV expression between birth seasons, and to assess differences in RSV plaque numbers between non-treated and treated co-cultured cells. Stata software by StataCorp  was used to complete graphs and statistical analysis for this study with significance taken as p = <0.05 for two-tailed tests. Graphs represent median values with interquartile ranges unless stated otherwise.in utero transmission of RSV to the human fetus. RSV could not be detected in a subset of 16 matched maternal bloods analysed by the same methods.Low level RSV expression was detected in human cord blood samples using droplet digital PCR , the amount of virus was not significantly different to those samples testing positive and collected in non-winter months.This is the first study to show evidence of low level RSV expression in human cord blood samples, suggesting We believe acute maternal respiratory infection acquired during annual RSV winter epidemics in late pregnancy may explain the greater number CBM samples testing positive for RSV in winter. RSV infections are common throughout adult life but generally cause mild symptoms in healthy adults, meaning presentations of RSV induced illness in healthy adults are unusual . TherefoOf the non-winter seasons RSV was most prevalent in spring. This may represent persistence following acquisition of RSV during winter months. DCs have been shown to harbor RSV  with spoin utero. RSV release was significantly enhanced when CBMs were matured with phytohaemagglutinin (PHA) and treated with nitric oxide (NO), used as an environmental trigger of RSV replication. This effect was attenuated by treatment with the therapeutic anti-RSV antibody palivizumab, confirming RSV release from these cells. Therefore, this data suggests RSV is able to transmit from and between cells of monocyte lineage without inducing inflammatory symptoms usually associated with infection.Low level spontaneous release of RSV observed in epithelial cells co-cultured with CBMs suggest the fetus is exposed to low levels of infective RSV in utero during fetal immune system development may cause RSV immune tolerance [in utero exposure and the impact of viral exposure during fetal development is warranted due to maturing antigen-presenting precursor cell populations over the course of gestation [Importantly, exposure to infective RSV olerance , 27 explolerance \u201330. Dimiolerance , 3, 30. olerance . In ligholerance . Howeverestation .As this study was conducted retrospectively it was not possible to explore the impact of RSV detection on infant lung structure and function. An association between viral respiratory illness in asthmatic mothers and increased lower respiratory tract symptoms amongst their infants during the first year of life has been shown previously . The autin utero infection on host immune responses will have an important role in developing effective RSV vaccines and treatment in the future.The novel data generated in this study indicates RSV can cross the placenta and infect the fetus without causing overt disease. Trans-placental transmission of RSV appeared to be most common during the winter epidemic but was not limited to this period. While the implications of these findings remain confined to understanding the dynamics of RSV transmission, it is likely the effects of"}
+{"text": "Control participants (n = 51) were recruited from the same region. Participants generated personal approach goals  and avoidance goals  and completed self-report measures of goal attainment likelihood and depressive symptoms. Participants also completed a measure of ease of disengagement from unattainable goals and re-engagement with new goals. Compared to controls, depressed participants reported fewer approach goals , rated their approach goal (rewarding) outcomes as less likely to happen and avoidance goal (threatening) outcomes as more likely to happen. Depressed participants also reported greater ease of disengagement from unattainable goals and more difficulty re-engaging with new goals than controls. Our findings extend current knowledge of the psychopathology of depression from a goal regulation perspective, suggesting that pessimism around goal pursuit accompanies fewer approach goal pursuits and a general tendency to disengage when difficulties are encountered.Despite the development of prominent theoretical models of goal motivation and its importance in daily life, research has rarely examined goal dysregulation processes in clinical depression. Here we aimed to investigate problematic aspects of goal regulation in clinically depressed adults, relative to controls. Depressed participants ( Prominent theories of motivation posit that dysfunctions in approach and avoidance systems underpin emotional susceptibility and affective disorders \u2013 2. Gray\u2018to run a marathon\u2019) whereas avoidance goals refer to representations of undesirable future outcomes  ,,greater attempts . HoweverWe found that depressed individuals also reported struggling to engage in alternative goals when they have to stop pursuing unattainable goals, mirroring the apparent difficulty depressed persons had in generating idiographic approach goals relative to controls. The relative inability to engage with new goals among depressed persons may also reflect a generalized pessimism around goal attainment. Reduced goal re-engagement is consistent with the view that individuals who have difficulty developing new plans would be at a greater risk of depression . The resIn terms of clinical implications, our results suggest that depressed persons struggle to articulate positive goals to strive for and find it more difficult to engage in alternative goals when existing goals become unattainable. These findings also suggest that depressed people have reduced expectancies for attaining goal outcomes. Although these results are cross-sectional and do not in themselves identify treatment targets, they indicate that there may be value in helping depressed people to identify approach goals to strive for and challenge pessimistic reasons why participants think that goals cannot be achieved. In this respect, the results are consistent with behavioural activation, which encourages depressed persons to engage behaviourally with goals in the world, and cognitive-behaviour therapy, which may be useful in tackling hopelessness around goal attainment. Interventions that specifically address goal pursuit have shown promise in reducing depressive symptoms in clinical and non-clinical populations. Building confidence and self-efficacy around goal pursuit may also be a useful strategy in preventing depressive onset, but further research is needed.Some methodological considerations deserve comment. Diagnosis was determined via self-report (PHQ-9), clinical assessment and a brief structured interview. In contrast to the brief interview schedule designed for this study, the use of a validated interview schedule such as the SCID would provide a more comprehensive assessment. There were two 16-year-old participants in the otherwise adult sample, but the pattern of significant results was identical when these two participants were excluded. Furthermore, the cross-sectional design means that it is unclear whether depression causes dysregulation of goal processes or whether dysregulated goal processes cause depression, or whether goal dysregulation is epiphenomenal to the depressive episode. Longitudinal studies could usefully clarify whether dysregulated goal pursuit precedes depressive episodes. Future research would benefit from supplementing self-report measures of goal flexibility with behavioural measures that capture goal-directed effort among alternative pursuits.In conclusion, our findings illustrate altered goal processes in depression, characterized by blunted approach goal motivation, pessimistic goal expectancies, and increased goal disengagement and reduced goal re-engagement in the face of goal difficulties. Notably, effect sizes for group differences were large . AlthougS1 File(SAV)Click here for additional data file."}
+{"text": "Haemophilus influenzae (NTHi)-associated ear and respiratory diseases (including pneumonia) represent a major health burden in many parts of the world. NTHi strains retrieved from the upper airways commonly reflect those found in the lower airways. Despite growing genomic and genotyping data on NTHi, there remains a limited understanding of global and regional NTHi population structures. The aim of this study was to determine whether nasopharyngeal carriage in four Australian paediatric groups at varying risk of NTHi colonisation was dominated by the same NTHi genotypes. Genotyping data generated by PCR-ribotyping were evaluated for 3070 NTHi isolates colonising the nasopharynges of Aboriginal and non-Aboriginal children enrolled in four longitudinal studies in three separate urban and remote regions of Australia. Several NTHi PCR-ribotypes dominated in nasopharyngeal carriage, irrespective of study setting. Principal coordinates analysis confirmed a cluster of common PCR-ribotypes among all cohorts. In conclusion, we identified dominant PCR-ribotypes common to geographically disparate Australian paediatric populations. Future genomic analyses will shed further light on the precise factors underlying the dominance of certain NTHi strains in nasopharyngeal carriage.Non-typeable  Haemophilus influenzae (NTHi) represent a major health burden worldwide  and chronic [e.g. bronchiectasis]) NTHi populations by whole genome sequencing or other genotyping means is necessary to determine the relevance of carriage versus disease genotype frequency, and may shed light on the factors supporting dominance of certain NTHi genotypes. Although the Australian experience may not necessarily apply elsewhere, whole genome sequence data from Australian and international NTHi isolates have (to date) demonstrated a level of core genome similarity between global and Australian NTHi populations . Thus, w"}
+{"text": "Left ventricular pseudoaneurysm is a rare complication of myocardial infarction that carries a high mortality rate. Although conventional wisdom suggests prompt surgical repair in order to mitigate risk of expansion and rupture, there are some data to support non-operative management in asymptomatic individuals with likely chronic pseudoaneurysms, particularly when surgical candidacy is poor. We present a case of a medically managed left ventricular pseudoaneurysm subsequent to inferior ST-segment elevation myocardial infarction with 6-month follow-up data. Left ventricular pseudoaneurysm is a rare complication of myocardial infarction (MI) associated with serious morbidity and mortality . Unlike A 68-year-old man with history of chronic obstructive pulmonary disease and asbestos-related pneumoconiosis presented with chest pain and diaphoresis after a motor vehicle accident. Electrocardiogram revealed ST elevations in the inferior leads. The patient was promptly taken to the cardiac catheterization lab where he was found to have complete occlusion of the distal right coronary artery. The patient underwent successful percutaneous coronary intervention of the right coronary artery with placement of a drug eluding stent. One day after the coronary intervention, he remained asymptomatic when echocardiogram revealed a left ventricular pseudoaneurysm in the distal inferolateral wall . Left veA rare complication of either transmural MI or cardiac surgery, acquired pseudoaneurysm of the left ventricle, poses a difficult management dilemma, particularly among hemodynamically stable patients who are asymptomatic yet poor surgical candidates. The risk of expansion and eventual rupture must be balanced against a high surgical mortality, but the rarity of the condition has made understanding its natural history and identifying the highest risk patients challenging.Risk factors for development of left ventricular pseudoaneurysm include female sex, first occurrence of either lateral or anterior wall MI, age greater than 60 years and severe single-vessel coronary artery disease, the latter two of which were features in our patient . TransthConservative management of left ventricular pseudoaneurysms has been described in several case series (Our patient\u2019s severe underlying pulmonary disease precluded aggressive surgical management. Although possible, it is unlikely that his pseudoaneurysm was chronic and diagnosed incidentally on a routine post-infarct echocardiogram, which was not obtained under a high pre-test suspicion for pseudoaneurysm. As such, his clinical profile - an asymptomatic, acute and moderately sized pseudoaneurysm - reflects a slightly different demographic than captured by the aforementioned series, and makes application of a robust evidence-based management decision challenging. Development of a centralized registry of cases may help to better elucidate the true natural history of this rare entity, and should be the focus of future studies especially as advances in non-invasive diagnostic modalities are made and diagnostic awareness increases."}
+{"text": "The creation of false memories within the Deese-Roediger-McDermott (DRM) paradigm has been shown to be sensitive to many factors such as task instructions, participant mood, or even presentation modality. However, do other simple perceptual differences also impact performance on the DRM and the creation of false memories? This study explores the potential impact of changes in perceptual disfluency on DRM performance. To test for a potential influence of disfluency on false memory creation, participants viewed lists under either perceptually disfluent conditions or not. Results indicated that disfluency did significantly impact performance in the DRM paradigm; more disfluent presentations significantly increased the recall and recognition of unpresented information, although they did not impact recall or recognition of presented information. Thus, although disfluency did impact performance, disfluency did not produce a positive benefit related to overall task performance. This finding instead suggests that more disfluent presentations can increase the likelihood that false memories are created, and provide little positive performance benefit. The creation of false memories within the Deese-Roediger-McDermott  paradigincrease task performance )."}
+{"text": "The left ventricular (LV) remodeling process associated with significant valvular heart disease (VHD) is characterized by an increase of myocardial interstitial space with deposition of collagen and loss of myofibers. These changes occur before LV systolic function deteriorates or the patient develops symptoms. Cardiovascular magnetic resonance (CMR) permits assessment of reactive fibrosis, with the use of T1 mapping techniques, and replacement fibrosis, with the use of late gadolinium contrast enhancement. In addition, functional consequences of these structural changes can be evaluated with myocardial tagging and feature tracking CMR, which assess the active deformation (strain) of the LV myocardium. Several studies have demonstrated that CMR techniques may be more sensitive than the conventional measures (LV ejection fraction or LV dimensions) to detect these structural and functional changes in patients with severe left-sided VHD and have shown that myocardial fibrosis may not be reversible after valve surgery. More important, the presence of myocardial fibrosis has been associated with lesser improvement in clinical symptoms and recovery of LV systolic function. Whether assessment of myocardial fibrosis may better select the patients with severe left-sided VHD who may benefit from surgery in terms of LV function and clinical symptoms improvement needs to be demonstrated in prospective studies. The present review article summarizes the current status of CMR techniques to assess myocardial fibrosis and appraises the current evidence on the use of these techniques for risk stratification of patients with severe aortic stenosis or regurgitation and mitral regurgitation. Valvular heart disease (VHD) is an important public-health problem with an increasing prevalence along with ageing of the population . ModeratChronic pressure and volume overload caused by severe left-sided VHD results in LV remodeling. Changes in the extracellular matrix with deposition of collagen I and loss of myofibers at a later stage result in myocardial fibrosis, the hallmark of LV remodeling , 6. CardLV remodeling in response to chronic pressure and volume overload caused by VHD is characterized by progressive increase of the interstitial space with increased collagen volume fraction (reactive fibrosis) and eventually apoptosis of myocardial cells which are replaced by firm fibrous tissue (replacement fibrosis or scar). T1 mapping and LGE CMR techniques are currently the most frequently used techniques to directly assess myocardial fibrosis . Although still not implemented in routine clinical practice, the measurement of myocardial ECV in patients with AS has important clinical implications [2) but without LGE (replacement fibrosis) showed significantly higher all-cause mortality and AS-related mortality rates (36 per 1000 patients-year for both) as compared to the patients with normal myocardium  , pressure and volume overload induce growth of cardiomyocytes with addition of new sarcomeres in series and interstitial fibrosis, characterized by increased fibronectin and non-collagen components . SeveralMitral regurgitation (MR) is a heterogeneous disease, broadly classified as organic (primary) or functional (secondary) based on the underlying mechanism. Organic MR is due to intrinsic valvular disease whereas functional MR is caused by regional and/or global LV remodeling without structural abnormalities of the mitral valve . DegenerThese structural changes of the LV myocardium may be associated with subtle functional abnormalities. In 15 patients with chronic moderate and severe MR and preserved LV ejection fraction who underwent CMR with tissue tagging, Maniar et al. demonstrated preserved global longitudinal and circumferential strain but abnormal regional strain values: the septal LV segments exhibited impaired strain whereas the lateral segments showed compensatory hyper-contractility . SimilarTissue characterization and strain imaging with CMR have provided new insights into the pathophysiology of VHD. Current guidelines recommend valve surgery in severe symptomatic VHD or when LV function decreases , 3. HoweThe early valve replacement guided by biomarkers of left ventricular decompensation in asymptomatic patients with advanced aortic stenosis (EVOLVED) is the first multicenter randomized controlled clinical trial that will investigate whether the early valve intervention in patients with asymptomatic severe AS and midwall fibrosis on CMR improves patients\u2019 clinical outcomes compared to the standard care (NCT03094143). The results of this study may have an impact on future guidelines and recommendations on treatment of VHD."}
+{"text": "However, most species used for epigenomic studies are annual herbaceous plants, and epigenome dynamics has been poorly investigated in perennial woody plants, including grapevine. In this context, we propose grape as an essential model for epigenetic and epigenomic studies in perennial woody plants of agricultural importance.Epigenetic marks include Histone Post-Translational Modifications and DNA methylation which are known to participate in the programming of gene expression in plants and animals. These epigenetic marks may be subjected to dynamic changes in response to endogenous and/or external stimuli and can have an impact on phenotypic plasticity. Studying how plant genomes can be epigenetically shaped under stressed conditions has become an essential issue in order to better understand the molecular mechanisms underlying plant stress responses and enabling epigenetic in addition to genetic factors to be considered when breeding crop plants. In this perspective, we discuss the contribution of epigenetic mechanisms to our understanding of plant responses to biotic and abiotic stresses. This regulation of gene expression in response to environment raises important biological questions for perennial species such as grapevine which is asexually propagated and grown worldwide in contrasting  Epigenetic mechanisms regulate chromatin structure, gene expression, transposon mobility and DNA recombination . They ge5C) is found in all sequence context, including the CG and CHG  symmetrical motives and the non-symmetrical CHH motif , the remodeling of chromatin organization and specific classes of small RNAs and long non-coding RNAs . BrieflyHistone PTMs are also essential epigenetic signals that can occur at the N-terminal tail of core histones  through acetylation, methylation, phosphorylation and ubiquitination . Histone1). So far, histone PTM analysis relies on Chromatin Immunoprecipitation (ChIP) using specific antibodies followed by hybridization to tilling arrays , and analyzed with tilling arrays (MeDip-ChIP) or by Next Generation Sequencing (Medip Seq). Both approaches were used for methylome analysis for example in Arabidopsis, or poplar  and HUB2  or non-CG methylation  were markedly resistant to bacterial colonization.The profiling of the DNA methylomes of plants exposed to bacterial pathogen, avirulent bacteria, or salicylic acid revealed numerous stress-induced differentially methylated regions (DMRs) often coupled to differential gene expression . Mutant Arabidopsis since a triple mutant rdd (ros1 dml2 dml3), presents down-regulation of stress response genes and increased susceptibility to a fungal pathogen. Furthermore, these authors showed that DNA demethylases target promoter transposable elements in stress responsive genes to positively regulate them.DNA demethylation likely primes transposable elements as well as defense gene induction through the concomitant activation of their transactivators and/or the interference with other chromatin marks . Some imFigure 1; Natural epigenomic variation occurs during species evolution  and togeArabidopsis by generating Epigenetic Recombinant Inbred Line (EpiRILs) populations derived from decrease in DNA methylation 1-2 (ddm1-2) or the met1 parents .Several studies have already emerged in crops, in particular, recent analyzes carried out in tomato fruits  constituripening  as reporripening . In thisChemical treatments that affect DNA methylation patterns could also be utilized to generate epimutations  though tFigure 1). DNA methylation may generate multiple epialleles with various expression levels, thereby leading to continuous quantitative variation of a trait .In line with these ideas, the recent analysis of the transcriptomic changes associated with grape infection with the necrotrophic pathogen  defense . Genes cV. vinifera. Comparing the epigenomes of wild and cultivated Vitis species with and without biotic and non-biotic stresses will bring insights on the epigenetic basis of grapevine resistance to adverse conditions with potential impact in breeding strategies. Moreover, epigenetic marks may participate in the priming mechanisms to better withstand biotic and abiotic stresses . Crop improvement via locus-specific epigenetic manipulation has become increasingly feasible with TALE- or CRISPR-based genome editing technologies (In a near future, epigenetic marker-assisted breeding strategies will be applied to select for agronomical desirable epigenetic quantitative traits (nologies . Such teAF and PG designed the perspective and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Neurorehabilitation plays an important role for neural plasticity and functional recovery following neurological disease. Neurorehabilitation is based on rehabilitation medicine, neuroscience, and neurophysiology. This special issue focused on the efficacy and mechanism by which neurorehabilitation can induce neural plasticity and functional recovery.Articles published in this special issue covered neurorehabilitation following stroke, spinal cord injury, and other neurological disorders.T. Fujiwara et al. reviewed the neurorehabilitation using electromyography- (EMG-) controlled neuromuscular electrical stimulation for upper extremity motor function following stroke. This review showed that application of wearable EMG-controlled NMES for 8 hours in daytime improved both arm and hand function and can induce plastic change in intracortical interneuron and spinal reciprocal interneuron.J. Fu et al. reviewed the functional recovery induced by the exercise after spinal cord injury. Therapeutic exercise can induce reshaping of the skeletal muscle, physiological change of spinal motor neuron, and remodeling of the motor cortex.Neurophysiology and neuroimaging are great tools for revealing neural plasticity induced by neurorehabilitation.Neuroimaging studies in this special issue revealed novel findings of cortical reorganization following spinal cord injury, facial nerve palsy, hearing loss, and aerobic exercise in older adults.Neurophysiological studies in this special issue revealed neural activity related to reduction of gait speed in Parkinson's disease and functional recovery of hemiplegia following stroke.Advanced neurophysiological and neuroimaging techniques provided new insight into the functional recovery in neurological disorders.We hope this special issue provides further knowledge of neurorehabilitation.Toshiyuki FujiwaraNam-Jong PaikThomas Platz"}
+{"text": "In patients with schizophrenia, distributed abnormalities are observed in grey matter volume. A recent hypothesis posits that these distributed changes are indicative of a plastic reorganization process occurring in response to a functional defect in neuronal information transmission. We investigated the structural covariance across various brain regions in early-stage schizophrenia to determine if indeed the observed patterns of volumetric loss conform to a coordinated pattern of structural reorganization.Structural MRI scans were obtained from 40 healthy adults and 41 age, gender and parental socioeconomic status matched patients with schizophrenia. Volumes of grey matter tissue was estimated at regional level across 90 atlas-based parcellations. Group level structural covariance was studied using a graph theoretical framework.Patients had distributed reduction in grey matter volume, with high degree of localized covariance (clustering) compared to controls. Patients with schizophrenia had reduced centrality of anterior cingulate and insula but increased centrality of the fusiform cortex, compared to controls. Simulating targeted removal of highly central nodes resulted in significant loss of the overall covariance patterns in patients compared to controls.Regional volumetric deficits in schizophrenia are not a result of random, mutually independent processes. Our observations support the occurrence of a spatially interconnected reorganization with systematic de-escalation of conventional \u2018hub\u2019 regions. The resulting morphological architecture may be primed for compensatory functions, albeit with a high risk of inefficiency."}
+{"text": "Prenatal diagnosis of congenital heart disease is important to ensure both informed parental counselling before birth, and effective planning of potentially life-saving interventions after birth. MRI offers a safe, radiation-free adjunct to conventional diagnostic modalities, particularly in mothers with high BMI or at later gestations where ultrasound may be limited. However, cardiovascular imaging in the fetus presents several challenges, not least due to the small size and constant motion of the fetal heart, the lack of external cardiac gating, and gross fetal and maternal motion. We present our initial experience of 20 fetal cardiac MRI cases, each referred following fetal echocardiographic assessment to resolve specific points of diagnostic uncertainty.Referrals were based on the judgements of the attending fetal cardiologists between June 2014 and May 2015. A paediatric cardiologist with expertise in cardiac MR was present at every scan. Following a three-plan localiser, diagnostic sequences were generally limited to half-Fourier acquisition single-shot turbo spin-echo (HASTE) and balanced steady state free precession (bSSFP) gradient echo sequences. A large field of view bSSFP cine  scan with low spatial resolution but higher temporal resolution (303 ms) was used following the localiser to demonstrate the degree of gross fetal movement. If needed, further shortened localiser sequences were also used, followed by bSSFP scans with higher spatial resolution for diagnostic purposes.Single-shot turbo spin-echo (HASTE) sequences produced T2 weighted images with black-blood like contrast which was particularly useful for assessing the extracardiac vascular anatomy. Balanced SSFP images gave good contrast between the blood pool and surrounding tissue and were useful for intracardiac structures; however these were more susceptible to motion artefacts. Real-time SSFP sequences allowed for dynamic imaging of the beating heart in assessing moving structures (e.g. cardiac masses and diverticulums); when used in combination with HASTE sequences, we were able to characterise rhabdomyomas in three patients.Our preliminary experience of fetal cardiac MRI suggests that it can provide safe, clinically useful complimentary imaging in the majority of selected cases within a tertiary fetal cardiac unit, particularly for extracardiac vascular anatomy and intracardiac masses. In the future, prenatal MRI may have a more prominent role in routine fetal cardiovascular assessment."}
+{"text": "Volumetric brain differences between persons meeting criteria for a clinical high-risk state for psychosis (CHR) and healthy controls (HC) have been previously reported, yet little is known about potential abnormalities in surface-based morphological measures. Gyrification  remains relatively stable across the lifespan and is minimally influenced by ubiquitous confounding factors . Recently, a multi-site analysis conducted in 104 CHR persons found global increases in cortical gyrification compared to HC . If replicated, gyrification abnormalities in CHR could potentially serve as early neuromarkers of elevated risk, and thus could eventually be used to identify objectively and efficiently the CHR state.www.pronia.eu), a large-scale international longitudinal study currently consisting of 10 European sites. Cortical surfaces were reconstructed from structural MRI images using a volume-based, newly introduced technique called the Projection-Based-Thickness (PBT) as available in the SPM-based-toolbox CAT12. Local gyrification was quantified automatically across the whole brain as absolute mean curvature for each vertex of the brain surface mesh consisting of thousands of individual measurement points. Vertex-wise differences of curvature values were calculated applying a General Linear Model, corrected for age, gender and site effects. Results were investigated at corrected and uncorrected levels.A total of 124 CHR and 264 HC subjects were recruited as part of the PRONIA consortium (We found no significant differences in vertex-wise gyrification between CHR and HC at either corrected or uncorrected levels (p>0.05). Further investigations of potential confounding site effects also did not reveal differences.Our preliminary findings suggest that CHR subjects do not show whole-brain gyrification abnormalities when compared with healthy subjects. These negative results agree with literature suggesting that cortical convolution might be more affected by neurodevelopmental or genetic factors, and thus deviations from normal patterns might not be detectable in heterogeneous samples of at-risk subjects wherein the etiology and ultimate prognosis is unknown. In order to better investigate differences in cortical folding and address the role of gyrification as neuroanatomical biomarker for psychosis, future investigations should focus on subgroups within CHR populations  in addition to specific analyses of individuals with higher neurodevelopmental  or genetic  loadings."}
+{"text": "Women with signs and symptoms of ischemia--but no obstructive coronary artery disease--often have coronary microvascular dysfunction (CMD), and are at increased risk of major cardiovascular events, including heart failure. Using cardiac magnetic resonance tissue tagging, we recently found subclinical diastolic dysfunction in these women, suggesting that ischemia-related diastolic dysfunction may be mechanistically linked to the development of heart failure. Tissue tagging involves specialized image acquisition and post processing, and thus is not typically suitable for large patient studies. We hypothesized that feature tracking of conventional  cardiac cine images would provide similar information. We therefore compared feature tracking with gold-standard tissue tagging, and then, used feature tracking to assess left ventricular function in women with suspected CMD.We first conducted a validation study comparing feature tracking (applied to standard cine images) to the gold-standard tissue tagging approach (applied to tagged cine images). To this end, in n = 59 individuals, we measured circumferential strain and diastolic circumferential strain rate (CSdR) by tissue tagging  and feature tracking . Following the validation study, we performed feature tracking on cine images from n = 116 women with suspected CMD (\"cases\") enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) Study, and n = 28 aged-matched healthy reference controls.In the validation study, feature tracking correlated with tissue tagging Fig. , providiFeature tracking applied to cine myocardial function images provides a convenient method to analyze wall motion in conventional CMR protocols. In this study, we used this technique to both confirm and extend previous observations in a cohort of women with suspected CMD, demonstrating subclinical diastolic and systolic dysfunction. Further analysis is warranted to better characterize the advantages and limitations of this approach in studies involving patients with suspected CMD and no obstructive disease."}
+{"text": "Superior Longitudinal Fasciculus (SLF) differences are consistently reported in psychotic disorders. The SLF is a complex large bundle of association white matter fibers that bidirectionally connect caudal, temporal cortex and inferior parietal cortex to locations in the frontal lobe. Advances in tractography methodologies detail four discrete subdivisions ). Greater specificity of the SLF subdivisions and associated cognitive networks may clarify the mechanisms of divergent tract developmental and functional aspects associated with psychotic experience symptomology in population based samples of adolescents within the extended psychosis continuumA case-control sample of 25 adolescents reporting psychotic experiences versus 25 controls (mean age 13.7 years). We employed High Angular Resolution Diffusion Imaging (HARDI) based data with constrained spherical deconvolution (CSD) based fibre tractography to delineate the discrete subdivisions of the SLF including the arcuate fasciculous. Following tract identification, standard diffusion metrics, , and Diffusivity measures MD, AD and RD), were assessed. A secondary supportive \u201calong-tract\u201d analysis to ascertain more subtle patterns of variation of tract integrity over the tract length was applied. White matter nodal analysis exploring the structural connectivity was applied to investigate additional functional networks recruited by and interconnected via the SFL. We investigate the ability of tractography of the SLF subdivisions and nodal analysis to identify possible differences between adolescents experiencing subclinical psychotic like experiences and those who don\u2019t.Our results agree with recent studies of the SLF I and AF  revealing a pattern of asymmetry of these tracts with more extensive tract bundles being consistently identified in the left hemisphere compared to the right. Along-tract analysis revealed subtle patterns of change in discrete subdivisions of the SLF while nodal analysis shows promise in its ability to define precise organisational networksDelineating the SLF subdivisions may clarify potential developmental trajectories between frontal and parieto-temporal speech-related areas contributing to the pathogenesis of psychotic like experiences. These results reveal the presence of aberrant structural connectivity in young adolescents with psychotic experiences."}
+{"text": "Fourteen patients underwent surgery for benign intra-thoracic goitre many presented with respiratory distress due to tracheal compression, and in some desperately ill patients inoperable cancer of the lung was diagnosed. The plain chest X-ray revealed the goitre and once the true diagnosis was suggested, prompt surgical intervention followed."}
+{"text": "A 76-year-old male presented for reverse total shoulder arthroplasty (TSA) in the beach chair position. A preoperative interscalene nerve catheter was placed under direct ultrasound-guidance utilizing a posterior in-plane approach. On POD 2, the catheter was removed. Three weeks postoperatively, the patient reported worsening dyspnea with a subsequent chest X-ray demonstrating an elevated right hemidiaphragm. Pulmonary function testing revealed worsening deficit from presurgical values consistent with phrenic nerve palsy. The patient decided to continue conservative management and declined further invasive testing or treatment. He was followed for one year postoperatively with moderate improvement of his exertional dyspnea over that period of time. The close proximity of the phrenic nerve to the brachial plexus in combination with its frequent anatomical variation can lead to unintentional mechanical trauma, intraneural injection, or chemical injury during performance of ISB. The only previously identified risk factor for PPNP is cervical degenerative disc disease. Although PPNP has been reported following TSA in the beach chair position without the presence of a nerve block, it is typically presumed as a complication of the interscalene block. Previously published case reports and case series of PPNP complicating ISBs all describe nerve blocks performed with either paresthesia technique or localization with nerve stimulation. We report a case of a patient experiencing PPNP following an ultrasound-guided placement of an interscalene nerve catheter. Interscalene blocks (ISB) are frequently used as an adjuvant therapy for shoulder surgery to optimize postoperative pain, decrease the length of hospitalization, and minimize the time in the postanesthesia care unit . Up to 1Prolonged phrenic nerve paresis (PPNP) resulting from interscalene catheters is rare. One previous investigation identified cervical degenerative disc disease as a potential risk factor for developing PPNP following ISB . OtherwiVerbal and written permission was obtained from the patient for the publication of this report. Written permission was obtained for the use of the patient's medical records.A 76-year-old male of average body habitus with history of hypertension, chronic obstructive pulmonary disease (COPD), coronary artery disease, and myocardial infarction status after three percutaneous coronary interventions presented for reverse TSA in the beach chair position under general anesthesia with an interscalene nerve catheter for postoperative pain management. After obtaining surgical and anesthetic consent, the patient was placed in a semirecumbent position with his head turned slightly toward the nonoperative shoulder with care to avoid neck discomfort. Intravenous midazolam and fentanyl were administered to achieve moderate sedation for the placement of an interscalene nerve catheter under direct ultrasound-guidance utilizing a lateral-to-medial in-plane approach as described by Antonakakis et al. . A 17-gaThree weeks postoperatively, the patient presented to his PCP with a complaint of worsening dyspnea. He was diagnosed with bronchitis and prescribed a course of antibiotics and inhalers. After completing his antibiotic regimen, the patient continued to experience dyspnea and was referred to a pulmonologist for consultation. Further investigation revealed that the patient had both orthopnea and worsened dyspnea on exertion. The physical exam revealed decreased breath sounds in the right lower lobe lung field and bilateral upper airway expiratory wheezing. A chest X-ray (CXR) demonstrated an elevated right hemidiaphragm with a small right-sided pleural effusion.A repeat CXR six weeks postoperatively continued to demonstrate an elevated right hemidiaphragm and right-sided pleural effusion, unchanged from his previous CXR . A diaphThe anatomical proximity of the brachial plexus and phrenic nerve leads to a nearly universal transient blockade of the phrenic nerve with large volume ISB; however, PPNP is a rare complication with a reported incidence to be 1 out of every 2069 single shot ISB or 0.048% . The cloAlthough decreasing the volume of local anesthetic utilized for interscalene blockade has been shown to decrease the incidence transient phrenic nerve palsy , total dProposed mechanisms for PPNP complicating an ISB include compression neuropathy from needle trauma, intraneural injection, chemical toxicity, or neuronal ischemia , 11. ShoPreviously published case reports and case series of PPNP complicating ISBs all describe nerve blocks performed with either paresthesia technique or localization with nerve stimulation (NS). Of note, this patient's interscalene catheter was performed with only US guidance and did not rely on NS or paresthesia techniques. Although the use of US guidance for regional anesthesia has not demonstrated a reduction in peripheral nerve injury, routine use of US guidance allows practitioners many practical advantages . A recenWe attempt to add to the body of literature describing the phenomenon of PPNP following ISB. The only previously identified risk factor for PPNP is cervical degenerative disc disease . Our pat"}
+{"text": "De novo synthesis of folates in plants is tightly regulated through feedback-regulation of certain pathway catalysts. Recently, we investigated the prospects of incessant production of folates in an evolutionary conjunction, through the overexpression of feedback targeted and evolutionarily conserved heterologous E.coli dihydroneopterin aldolase (EcDHNA) in tobacco.EcDHNA surface having critical amino-acid differences as Ile 64 (His_63), Val 70 (Phe_69), His 75 (Arg_78) and Arg 79 (Glu_72). These structural characteristics are indicative of evolutionary signatures of the catalytic feedback-regulation of folate manufacturing. We exploited the biotechnological potential of such allosterically diverged trans-DHNA for improved folate production in plants. Nonetheless, genetic manipulation of single enzymes modulating complex pathways such as folate biosynthesis is often inadequate to achieve desired phenotypes; therefore, multi-gene integration with explicit genic-combination for folate enrichment in plants has also been projected for future folate agri-biofortification schemes. Also, the overexpressed bacterial DHNA protein was significantly correlated with the intracellular folate production in E. coli cells, assuming its potential usage for crop biofortification. Here, we provide additional data on the evolutionary characterization and homologies based allosteric site prediction at the surface of DHNA protein of bacterial and plant origins for the designing of genome engineering strategies, and also highlight the need of gene pyramiding for future crop biofortification programs.Recently, we reported the enhanced production of folates in tobacco leaves by the constitutive overexpression of recombinant i.e. bacteria, cyanobacteria and plants, the amino acid sequences were aligned using \u201cA la Carte\u201d mode of Phylogeny.fr online tool. In result, an unrooted phylogram was constructed having distinct clades of plants (both monocots and dicots), bacteria and cyanobacteria. Among bacterial DHNA sequences, E. coli and Xanthomans shared maximum sequence similarity whereas nodulating bacteria Rhizobium sp. showed prominent evolutionary relatedness with cyanobacteria members. On the contrary, selective bacterial representatives exhibited relatively more proximity to plants or algal species than other bacteria  reported that ectopic overexpression of folA enzyme in folate biosynthetic pathway led to very high production of pterins in the cell, whereas little increase in the folate level was observed. Therefore, important enzymes such as DHNA and DHPS that are subjected to feedback regulation may be genetically manipulated in crop plants by the overexpression of heterologous proteins having divergent protein-regulation sites.The phylogenetic analysis of DHNA orthologs among bacterial, cyanobacterial and plants (monocot and dicot species) revealed certain degree of protein sequence conservation highlighting their functional conservation at evolutionary scale . As follEcDHNA protein in plants would lead to the independent and uninterrupted synthesis of tetrahydrofolate, in-silico predictions of allosteric regulatory sites at EcDHNA and AtDHNA surfaces were predicted using PARS, a server for the prediction of allosteric and regulatory sites on protein structures.EcDHNA and AtDHNA were extracted from the Protein Data Bank (PDB) with accession codes 2O90 and 1SQL, respectively. In silico prediction of allosteric sites in both EcDHNA and AtDHNA responsible for protein-regulation mechanism was performed. This prediction analysis has identified seven and eight surface allosteric regulatory cavities on EcDHNA and AtDHNA, respectively. One common cavity (CAV_5_Z) in both the proteins was identified as substrate binding site  gene cassette as plant selection marker.EcDHNA to the cellular folate production under crucial metabolic constraints in cellular folate biosynthesis mainly through tight feedback regulation of native aldolases. The use of bacterial DHNA gene has definitely persuaded the turnover of end product in folate biosynthetic pathway that may have incredible impact on crop nutrigenomics programs.Could the folate levels be increased by ectopic over-expression of candidate folate biosynthetic pathway genes in plants? Based on the significant correlation between heterologous overexpression of DHNA gene and folate over-production, we assumed that the bacterial folE gene enhanced pterins biosynthesis up to 1250-fold without necessarily allaying with folate production in transgenic Arabidopsis,folE enzyme with aminodeoxychorismate synthase (ADCS) in p-ABA branch resulted into inadequate variation of the folate concentration in plants.p-ABA branch enzymes may not suffice for the ultimate genic-combination of folate vitamin enhancement in plants. If so, what genic-combination(s) should be preferred for improved folate production in the cell?Low amounts of folates in crop plants may be largely attributed to the tight feedback regulation of certain folate biosynthetic enzymes. Up to now, various plant species have been genetically modified with individual folate biosynthetic pathway genes for folate enhancement,folB) responsible for the formation of 6-hydroxymethyl-dihydropterin in folate biosynthesis pathway and DHPS (folKP) responsible for the formation of dihydropteroate are subjected to feedback regulation (EcDHNA gene potentially regulates folate biofortification in tobacco.EcDHNA has evolved with divergent allosteric sites at its surface which may avoid folate feedback regulation, it's pyramiding with other candidate genes of folate biosynthetic pathway such as folE and ADCS would be a promising experimental combination of genes for future folate metabolic engineering. As performed in our study,i.e. DHNA and DHPS genes and investigate their discrete impact on the folate production. Also, pyramiding of these two transgenes in the field through cross-pollination and analyze their collaborative impact on the folate production in F1 generation would be of tremendous scientific interest providing evidences for the genetics of folate agri-biofortification.Evidently, an aldolase enzyme DHNA (gulation . Recentl"}
+{"text": "Wolbachia, Rickettsia and Spiroplasma) across 20 species of dance flies. We found evidence of widespread infection by all three symbionts and variation in sex-specific prevalence across the taxa sampled. However, there was no relationship between infection prevalence and adult sex ratio measures and no evidence that female ornaments are associated with high prevalences of sex-biased symbiont infections. We conclude that the current distribution of endosymbiont infections is unlikely to explain the diversity in mating systems among dance fly species.Maternally inherited bacterial endosymbionts are common in many arthropod species. Some endosymbionts cause female-biased sex ratio distortion in their hosts that can result in profound changes to a host\u2019s mating behaviour and reproductive biology. Dance flies (Diptera: Empidinae) are well known for their unusual reproductive biology, including species with female-specific ornamentation and female-biased lek-like swarming behaviour. The cause of the repeated evolution of female ornaments in these flies remains unknown, but is probably associated with female-biased sex ratios in individual species. In this study we assessed whether dance flies harbour sex ratio distorting endosymbionts that might have driven these mating system evolutionary changes. We measured the incidence and prevalence of infection by three endosymbionts that are known to cause female-biased sex ratios in other insect hosts ( Vertically transmitted symbiotic bacteria that are inherited from mother to offspring are common infections of arthropods \u20133. TheseA strong female bias in population sex ratio can profoundly alter the dynamics of sexual selection e.g. \u20138). When. When8])The dance flies (Diptera: Empididae: Empidinae) exhibit incredible interspecific mating system diversity . Dance fThe ultimate evolutionary causes of these interspecific mating system differences across the dance flies remain largely unknown. One possibility is that reproductive parasites have caused female-biased population primary sex ratios in some species. Such biases could conceivably lead to competition among females for access to males, which could in turn favour the evolution of elaborate female sexual ornaments. Such symbiont-induced skewed sex ratios may have altered mating behaviour (see ), triggeWolbachia )We tested for evidence that sex ratio distorting reproductive parasites have driven female-specific ornament evolution in the Empidinae. We found no evidence that reproductive parasites with strong impacts on host population sex ratio are common in this insect group. Furthermore, there was no association between the presence of putative sex ratio distorting endosymbionts and the presence of exaggerated female ornamentation. Further study with a focus on methods that allow for the primary or secondary sex ratio of the hosts to be measured would be helpful to more comprehensively measure sex ratio distortion in dance flies. In addition, research looking into spatial patterns of both the sex ratio of the dance fly hosts and the sex-specific prevalence of symbionts would be fruitful. While we cannot definitively rule out the possibility that historical infections by symbionts caused sex ratio distortion in ancestral populations, our data strongly suggest that female-biased OSRs and female-specific ornaments are being maintained in dance flies for some other reason than sex ratio distorting symbionts. Further research into sexual and natural selection within the mating swarms and reproductive behaviours of dance flies are important for fully understanding the diversity of reproductive phenotypes observed across this system."}
+{"text": "Tissue damage derived from tumors, traumatic events, inflammatory diseases, or just aging causes life quality impairment. Thus, tissue regeneration not only represents the main goal of regenerative therapy but also is certainly one of the greatest challenges of modern medicine.Mesenchymal stem cells (MSCs) can be isolated from different source tissues in the adult organism. MSCs can differentiate in mature cells of different lineages; thus, if opportunely targeted, they have the potential to regenerate and heal the injured tissue. The scientific contributions which are part of this special issue present and analyzed these items both in the form of research articles and reviews.The bone marrow is still the gold standard tissue for harvesting MSCs: different clonal cells were analyzed showing heterogeneity; alkaline phosphatase assay could indicate the precursor's lineage . Dental tissues also contain MSCs: in particular, the dental follicle  and dentA great challenge in regenerative therapy is the guidance of wound healing. MSCs promote wound healing, and human umbilical cord MSCs accelerate wound repair and hair follicle regeneration via Wnt overexpression . Interestingly, as shown by X. Liu et al., overexpression of semaphorin 3A in adipose-derived stem cells leads to a phenotype switch toward the osteoblastic lineage by upregulating the Wnt pathway as well. These studies on alternative sources of MSCs highlight the importance of molecular signals that might direct MSC fate and more specifically guide them to form mineralized tissue .\u03b2 signaling pathway and stimulating the expression of microRNA21 . Given that natural composition and structure of the extracellular environment has a profound impact on MSC osteogenic differentiation [To increase healing at bone fracture sites, several approaches that stimulate physically the differentiation of MSC have been developed. Pulsed electromagnetic fields promote bone marrow MSCs osteogenic differentiation by activating TGF-ntiation , a varieGiorgio MoriGiorgio MoriGiacomina BrunettiGiacomina BrunettiFiliberto MastrangeloFiliberto MastrangeloElisabetta A. Cavalcanti-AdamElisabetta A. Cavalcanti-Adam"}
+{"text": "Hepatocellular Carcinoma (HCC) commonly develops in chronically damaged liver tissues. The resulting regenerative and inflammatory processes create an adverse milieu that promotes tumor-initiation and progression. A better understanding of the hepatic tumor-microenvironment interaction might infer profound therapeutic implications.Integrative whole genome and transcriptome analyses of different tumor regions, the invasive tumor border and tumor-surrounding liver (SL) were performed to identify associated molecular alterations and integrated with our existing HCC database. Expression levels and localization of established CSC markers were assessed in pre-neoplastic lesions and confirmed in two independent patient cohorts using qRT-PCR, immunohistochemistry and immunofluorescence.Our results indicate that genomic and transcriptomic profiles between SL and different tumor regions are quite distinct. Progressive increase in genetic alterations and activation of pathways related to proliferation as well as apoptosis were observed in the tumor tissue, while activation of stemness markers was present in cirrhotic SL and continuously decreased from pre-neoplastic lesions to HCC. Interestingly, the invasive tumor border was characterized by inflammatory and EMT-related gene sets as well as activation of pro-survival signaling. Consistently, integration of gene expression signatures with two independent HCC databases containing 300 HCCs revealed that border signatures are predictive of HCC patient survival.Prognostic significance of the permissive liver microenvironment might be a consequence of a pro-oncogenic field effect that is caused by chronic regenerative processes. Activation of key oncogenic features and immune-response signaling indicates that the cross-talk between tumor and microenvironment might be a promising therapeutic and/or preventive target. Hepatocellular carcinoma (HCC) ranks among the most common cancers worldwide . In the It is well recognized that acquisition of pre-neoplastic (epi-)genetic alterations in the hepatic microenvironment induces a continuum of morphologic changes from chronic inflammatory cell death over cirrhosis to dysplastic lesions which promotes malignant transformation . IntenseSeveral immune response-related and pro-oncogenic molecules induce opposing effects when activated in diverse parenchymal and non-parenchymal cell types (e.g. immune cells versus hepatocytes) and during different states of the chronic liver disease  which underlines the critical importance of the interaction of signals from the microenvironment and the tumor cells for tumor initiation and progression , 12. OthThe importance of the chronic inflammatory liver diseases for HCC initiation and progression has been repeatedly demonstrated . To charWe next assessed the somatic genetic alterations present in the different regions by profiling the corresponding tissues using Illumina OmniExpress arrays followed by GISTIC 2.0 analyses. Overall, progression from SL to T showed a continuous increase in genetic alterations Figure . As expeOur molecular analyses indicated a predominant activation of proliferative signaling in the T region that might reflect tumor cell proliferation thereby potentially supporting tumor expansion. Extension of the GSEA for the T region confirmed this finding and demonstrated an enrichment of gene sets associated with deregulation of cellular genes particularly related to tumor cell proliferation in cervical cancer  as well Since our molecular analyses indicated an activation of stemness in the SL region, we next assessed the gene expression levels of specific HCC/differentiation markers  as well as the selected (cancer-) stemness markers  and pluripotency genes (NANOG). As expected, a strong activation in expression levels of AFP and GPC3 as well as a concomitant downregulation of albumin levels were observed from SL to T Figure . NotablyTo confirm that the diseased hepatic tumor microenvironment is the critical determinant of stemness activation, we next assessed expression levels of the stemness genes in livers containing metastasis from different primaries (n = 5). Importantly, we found that these markers were not induced in the non-diseased liver tissue (i.e. in the absence of chronic liver damage) Figure . HoweverTo confirm the activation of inflammatory gene sets and dissect the corresponding immune cells reflected by the molecular changes, we limited our GSEA query to gene sets with association to immune-related properties. We observed a significant enrichment of gene sets related to alternative M2 macrophage activation that might exert pro-tumorigenic function Figure . FurtherFinally, we tested the clinical significance of our identified SL, B and T signatures and integrated all three signatures with our previously published gene expression dataset of 53 human HCC.  SubsequeThe notion that HCC patients display two diseases that are inextricably linked to each other, i.e. a chronic liver disease and a malignant tumor, is increasingly recognized, whereby the diseased hepatic microenvironment significantly promotes cancer initiation and progression while concomitantly limiting aggressive therapeutic approaches . TherefoTo address the importance of distinct peritumoral and tumoral regions for hepatocarcinogenesis we analyzed the molecular profiles of tumor-surrounding liver tissue, the invasive tumor border and core tumor tissue by genome-wide approaches and at different molecular levels. The transcriptome analyses confirmed a distinct gene expression profile for each of the different regions Figure . As expeTissue from 28 patients with confirmed HCC undergoing resection at the Department of Surgery, University of Mainz, Germany were collected following patient informed consent and local ethics committee approval. Validation cohort of 20 patients was obtained from the Institute of Pathology, University of Basel, Switzerland. Clinicopatholigical details are provided in http://www.ncbi.nlm.nih.gov/geo, accession number: GSE84598). Details of the analyses are provided in the A total of 200 ng RNA was linearly amplified as recommended by the manufacturer  and analyses were performed as described before . The micDiagnosis of HCC was established by expert pathologists. Tissue was either fixed in 4% formaldehyde and embedded in paraffin or preserved for cryosections and cut in 3-5 \u03bcm sections. Antibodies and conditions for fluorescence and immunohistochemical staining are listed in Statistical analysis was performed using Student's t-test, Friedman- test for multiple group comparisons followed by Dunns posthoc test as indicated. P-values \u22640.05 were considered statistically significant. Results are presented as means \u00b1 SD or means \u00b1 SEM as indicated. Survival analyses were performed using log rank (Mantel-Cox) tests."}
+{"text": "The significant proportion of schizophrenia patients refractory to treatment targeting the dopamine system suggests that more than one mechanism may cause psychotic symptoms. Reinforcement learning tasks have frequently been employed in schizophrenia to assess dopaminergic functioning and reward processing, but studies have not directly compared groups of treatment-refractory and non-refractory patients.In the current functional magnetic resonance imaging study 21 patients with treatment resistant schizophrenia (TRS), 21 patients with non-treatment resistant schizophrenia (NTR), and 24 healthy controls (HC) performed a probabilistic reinforcement learning task, utilising emotionally valenced face stimuli which elicit a social bias toward happy faces. Behavior was characterized with a reinforcement learning model. Trial-wise reward prediction error (RPE) signaling and the differential impact of emotional bias on these reward signals were compared between groups.Patients showed impaired reinforcement learning relative to controls, while all groups demonstrated an emotional bias favouring selection of the happy faces. The pattern of RPE signaling was similar in HC and TRS groups, whereas NTR patients showed significant attenuation of RPE-related activation. The TRS patients differed from the NTR patients in the relationship between emotional bias and subcortical RPE signal during negative feedback.TRS can be dissociated from NTR on the basis of a different neural mechanism underlying their symptoms. The data support the hypothesis that a favourable response to antipsychotic treatment may be contingent on dopaminergic dysfunction, characterized by aberrant RPE signaling, whereas treatment resistance may be characterized by an abnormality in distinct cognitive mechanisms interacting with this response."}
+{"text": "Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) are often comorbid and share similarities across some cognitive phenotypes, including certain aspects of attention. However, no functional magnetic resonance imaging studies have compared the underlying neural mechanisms contributing to these shared phenotypes.n = 20), boys with OCD (n = 20), and healthy control boys (n = 20) performed a parametrically modulated psychomotor vigilance functional magnetic resonance imaging task. Brain activation and performance were compared among adolescents with OCD, adolescents with ASD, and control adolescents.Age- and IQ-matched boys (11\u201317 years old) with ASD (Whereas boys with ASD and OCD were not impaired on task performance, there was a significant group by attention load interaction in several brain regions. With increasing attention load, left inferior frontal cortex/insula and left inferior parietal lobe/pre/post-central gyrus were progressively less activated in boys with OCD relative to the other two groups. In addition, boys with OCD showed progressively increased activation with increasing attention load in rostromedial prefrontal/anterior cingulate cortex relative to boys with ASD and control boys. Shared neurofunctional abnormalities between boys with ASD and boys with OCD included increased activation with increasing attention load in cerebellum and occipital regions, possibly reflecting increased default mode network activation.This first functional magnetic resonance imaging study to compare boys with ASD and OCD showed shared abnormalities in posterior cerebellar\u2013occipital brain regions. However, boys with OCD showed a disorder-specific pattern of reduced activation in left inferior frontal and temporo-parietal regions but increased activation of medial frontal regions, which may potentially be related to neurobiological mechanisms underlying cognitive and clinical phenotypes of OCD. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication difficulties and stereotyped repetitive behaviors  with a pVigilance incorporates sustained attention, or the ability to maintain focus toward infrequently occurring stimuli , and focOn cognitive and symptom-based measures, ASD has been related to inattention. Thus, ASD can be characterized by short attention span, and impulsivity and inattention symptoms are common . FurtherClinical symptoms of inattention have been reported especially in pediatric patients with OCD , and patGiven diagnostic overlap and potential etiological links between ASD and OCD, it is critical to understand neurofunctional mechanisms that are shared or unique between these disorders. Work has begun to focus on delineating neural mechanisms between these disorders , but a cA total of 60 right-handed  boys This study has several limitations. While patients with psychiatric comorbidities were excluded, we cannot rule out the presence of subthreshold symptoms of other disorders such as ADHD. This is in line with the debate around comorbidity versus overlapping phenotypes and their respective contribution to behavior and clinical presentation, particularly in the context of ASD and ADHD . It woulFuture work could compare ASD individuals with and without comorbid OCD with noncomorbid OCD individuals, building on this novel comparison to elucidate the mechanisms underlying clinical overlap of ASD and OCD. Moreover, it would be interesting to compare these patient groups with attention-related disorders such as ADHD to provide further insight into shared and/or disorder-specific neurofunctional attention mechanisms.This study provides the first evidence suggesting that adolescents with OCD have disorder-specific abnormalities in sustained attention networks, including left inferior and medial PFC and temporo-parietal regions, relative to adolescents with ASD, who had no frontal abnormalities. Findings suggest lateral inferior/medial fronto-temporo-parietal abnormalities during sustained attention may be a distinct neural signature of OCD but not of ASD. Individuals with ASD and OCD, however, shared abnormally enhanced activation in cerebellum/occipital lobe relative to healthy control individuals. These results provide promising evidence for identification of biomarkers that may clarify underlying mechanisms driving sustained attention and respective symptom profiles in autism and OCD."}
+{"text": "Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis.  \u2022Loading-related changes in osteocyte sclerostin expression spatially predict subsequent osteogenic responses.\u2022Acute sclerostin down-regulation is not sufficient for maximal osteogenic responses to loading.\u2022Inability to suppress sclerostin precludes bone gain following loading. Lack of sclerostin prevents bone loss in disuse.\u2022Sclerostin influences the osteogenic context in which loading acts as its deletion enhances functional adaptation. Loading levels or distributions which engender strains beyond a habitual minimum effective strain (MES) trigger bone formation resulting in increased bone mass, improved bone architecture and thus re-establishment of habitual levels and distribution of strain Mechanical loading is the primary functional determinant of bone mass and architecture Sost/sclerostin is almost exclusively expressed by osteocytes in the adult skeleton e.g. apoptosing osteocytes around microcracks secrete Rankl via the expression of osteoprotogerin (Opg); mice lacking \u03b2-catenin in osteocytes have dramatically reduced bone mass due to reduced Opg levels Osteocytes are embedded in the mineralised matrix and were long thought to have little or no function, but are now known to play a particularly important role in coordinating local bone remodelling responses and have recently described as \u2018master-regulators\u2019 Given their location and morphology, with long interlinked dendritic processes forming a functional syncytium extending to the bone surfaces, osteocytes are ideally suited to sense load-associated strains, including shear strains across their membranes as fluid is displaced through their canalicular system. Osteocytes are now considered to be the primary mechanosensors which locally coordinate adaptive (re)modelling responses For many years after this, the mechanisms underlying the coordination of adaptive remodelling responses by osteocytes were largely unknown. Hypothesised mechanisms included direct cell-cell communication 2Sost RNA expression in the mouse tibia. However, protein level analysis of sclerostin expression by immunohistochemistry following tail suspension did not detect changes in the proportion of osteocytes stained positive for sclerostin around the level of the tibia/fibula junction The model presented in Sost despite having opposite effects on bone mass The lack of change in sclerostin expression around the mouse tibia/fibula junction during tail suspension is potentially consistent with the finding that this region appears to be the least affected by disuse, with the most significant bone loss occurring proximal and distal to this region Tg) were generated Sost expression in these mice. Further supporting evidence that sclerostin down-regulation is required for loading-induced bone formation, was the observation that loading induced significantly greater bone formation in wild type than SostTg mice. These independent studies specifically test the roles of sclerostin in bone's adaptation to loading and as such provide strong evidence that both loading-related bone gain and disuse-associated bone loss require changes in sclerostin expression, at least in young mice.Evidence that the spatial correlation between loading-related sclerostin regulation and changes in bone (re)modelling may be causal is provided by loading studies using different genetically modified mouse models. Sclerostin knockout mice do not show bone loss in response to disuse induced by hind limb unloading Sost down-regulation in bones' osteogenic response to loading also comes from studies utilising mice with genetic modifications in mechano-responsive pathways which result in altered Sost regulation following loading. For example, increased basal sclerostin expression, abrogation of sclerostin down-regulation with loading and reduced load-related bone formation is observed in periostin knockout (Postn\u2212/\u2212) mice Sost down-regulation and triggers a diminished osteogenic response to loading compared with wild type controls Evidence supporting the potential importance of 3in vivo studies describing altered basal sclerostin expression and changes in the load-related regulation of sclerostin in genetically modified mice, while informative, provide limited insight into the molecular mechanisms by which osteocytes regulate sclerostin expression. Instead in vitro studies using a variety of model systems have been required to address this. These studies have shown that the basal rate of sclerostin expression is under both transcriptional and broader epigenetic control  enzymes such as Sirt1 and HDAC5 Sost RNA stability is influenced by micro-RNAs such as miR-218 The above  control . Its resSost is down-regulated by PTH Sost regulation by strain have been hindered by the limited availability of cellular models. Primary osteoblasts do not express readily detectable levels of Sost until they form mineralised matrix, which precludes their use for in vitro strain studies. Mouse osteocytic MLO cell lines do not reliably produce readily detectable levels of SostSost after prolonged periods of differentiation Sost. However, rat UMR-106 osteosarcoma cells do respond to strain Sost in a manner akin to them having a constitutively active gene Sost RNA and sclerostin protein in vitro strain by four point bending increases their proliferation Sost over a time course which parallels that seen in rodent bones following in vivo mechanical loading SOST promoter activity is enhanced by Mef2 binding to a distal enhancer element and inhibition of this binding is one of the mechanisms by which Sost down-regulation by strain involves Cox2-initiated PGE2 signalling through an EP4/ERK pathway in vivoSost expression is further demonstrated by the recent report that Cox inhibition with carprofen prevents sclerostin down-regulation in the ulnae of mice subjected to axial loading Sost down-regulation in osteoblastic cells in vivo, produced higher levels of NO when subjected to fluid shear in vitroUsing the Saos-2 model we initially reported that Sost down-regulation by strain in Saos-2 cells, rather ER\u03b1 inhibition in vitro or global deletion in vivo reduces basal Sost levels Sost levels, but prevents strain-induced Sost down-regulation in Saos-2 cells in vitro models.AR, NO and PGE2 signalling pathways are all influenced by estrogen receptors (ERs), which also interact with canonical Wnt pathway components in mechanically strained osteoblastic cells Sost down-regulation following strain, although ER\u03b2 may also act down-stream of PGE2 signalling as PGE2 treatment increases estrogen response element activation in osteoblastic cells VV in the osteoblast lineage prevents Sost down-regulation in the ulnae of mice subjected to axial loading V directly interacts with and facilitates Igf1/Igf1R signalling Sost down-regulation V also facilitates opening of connexin (Cx)43 hemichannels and Cx43 facilitates the release of PGE2, which is involved in the rapid activation of \u03b2-catenin in osteoblastic cells subjected to mechanical stimulation in vitroV expression is not required for ERK activation in calvarial osteoblastic cells subjected to fluid shear Both these roles of ER\u03b2 are consistent with a down-stream Cox-2/PGE2/ERK pathway mediating in vivo studies have been published that have systematically investigated the roles of different mechano-responsive signalling pathways in sclerostin regulation following loading. The majority of available studies are based on in vitro observations in osteoblastic cell lines subjected to defined mechanical stimuli which cannot fully replicate the effects of in vivo loading on the heterogeneous cell populations residing in and on bone. Currently, only Cox2/prostaglandin signalling has been demonstrated to acutely regulate sclerostin expression in vitro, suggesting a direct effect, and to also facilitate sclerostin down-regulation following loading in vivo. Furthermore, the mechanisms by which unloading results in sclerostin up-regulation have not been investigated and cannot be assumed to be the same as those which result in its down-regulation following increased loading. Nonetheless, putting the available jigsaw pieces together it is possible to propose a linear pathway which links early strain-related signalling events to ultimate down-regulation of Sost expression  as well as resumption of proliferation of cortical long bone derived osteoblastic cells This latter interpretation is consistent with the recent report that Sost knockout mice do not lose bone due to unloading, but still show osteogenic responses to increased loading in vitro is clearly demonstrated by their ability to very rapidly enter into the cell cycle after strain exposure in the absence of sclerostin In vivo, an increase in the number of osteoblasts on the periosteal surface is seen within 24\u00a0h following loading in vitro and the increase in the number of periosteal osteoblasts following loading in vivo were impaired. These deficiencies in osteoblast function that occur with age may not only limit bone's adaptive responses to loading but also the beneficial effect of sclerostin neutralising therapies The ability of osteoblasts to sense and respond to strain Sost has recently been independently replicated by Holguin et al. Sost in 5-month-old as well as 12-month-old and 22-month-old mice, although the bone formation response was blunted with age. A possible explanation is that Sost RNA down-regulation is more transient in bones from 22-month-old than 5-month-old mice and others have shown changes in Wnt pathway-related gene transcripts and blunting of \u03b2-catenin activity in the old Sost in young mice, only the first bout of loading results in Sost down-regulation in the old. This suggests that old bone cells become refractory to repeated bouts of increased loading. However, we have recently reported that prior and concurrent disuse enhances the osteogenic response to repeated bouts of axial tibial loading in aged mice The finding that osteocytes in tibiae of old mice remain able to sense changes in mechanical loading and acutely respond by down-regulating 6Numerous studies have demonstrated that sclerostin plays a role in the effective working of the mechanisms associated with regulation of bone mass and architecture in relation to mechanical loading (the mechanostat). Sclerostin expression increases following unloading with the consequent inhibition of Wnt signalling and associated bone loss. Down-regulation of sclerostin is permissive for osteogenesis in response to loading, at least in part by relieving inhibition of canonical Wnt signalling. This is consistent with the potently osteogenic responses observed in humans treated with sclerostin-inhibiting antibodies now in advanced stages of clinical development"}
+{"text": "The glucocorticoid (GC) drugs are one of the most commonly prescribed and effective anti-inflammatory agents used for the treatment of many inflammatory disorders through their ability to attenuate phlogistic responses. The glucocorticoid receptor (GCR) primarily mediates GC actions via activation or repression of gene expression. GCs directly induce the expression of proteins displaying anti-inflammatory activities. However, the likely predominant effect of GCs is the repression of multiple inflammatory genes that invariably are overexpressed during nonresolving chronic inflammation. Although most GC actions are mediated through regulation of transcription, rapid nongenomic actions have also been reported. In addition, GCs modulate inflammatory cell survival, inducing apoptosis in immature thymocytes and eosinophils, while delaying constitutive neutrophil apoptosis. Importantly, GCs promote noninflammatory phagocytosis of apoptotic cell targets, a process important for the successful resolution of inflammation. Here, the effects and mechanisms of action of GC on inflammatory cell apoptosis and phagocytosis will be discussed."}
+{"text": "A 90-year-old female presented after sudden collapse with a Glasgow Coma Score of 3, and profound hypotension. Shortly after endotracheal intubation, the patient developed significant hematemesis, and massive transfusion protocol was subsequently instituted. Computed tomography angiogram of the chest revealed active bleeding from an aortoesophageal fistula . During The most common causes of aortoesophageal fistulas are thoracic aortic aneurysm, foreign body ingestion, postoperative complications, and esophageal malignancy. The classic presentation of mid-thoracic chest pain and sentinel arterial hemorrhage followed by exsanguination is known as Chiari\u2019s triad.CPC-EM CapsuleWhat do we already know about this clinical entity?Aortoesophageal fistula is a rare and typically fatal pathology that presents as massive upper gastrointestinal hemorrhage.What is the major impact of the image(s)?This is a rarely seen image, given the degree of extremis and high mortality of patients with aortoesophageal fistula at emergency department presentation.How might this improve emergency medicine practice?Emergency medicine providers must be familiar with the presentation, diagnostics, rapid interruption of diagnostics and treatment of aortoesophageal fistulas."}
+{"text": "Dear Editor,We appreciate Drs. Itkonen and Lamberg-Allardt\u2019s interest in our recent article \u201cDietary Sources of Phosphorus among Adults in the United States: Results from NHANES 2001\u20132014\u201d [Total bioavailable phosphorus intake is the sum of bioavailable phosphorus from each source. See Equation (1) , below. Note that total phosphorus intake from a specific source is the product of phosphorus content (mg/serving) and intake (servings/day).Identifying important dietary sources of total phosphorus intake is the first step in identifying important dietary sources of bioavailable phosphorus intake. Sources that contribute a small total amount of phosphorus (such as dark cola) necessarily contribute a small amount of bioavailable phosphorus, even if they have high bioavailability. Sources that contribute a large total amount of phosphorus (such as bread) may still contribute a large amount of bioavailable phosphorus with relatively low bioavailability. Our study highlights grain products as an increasingly important source of total dietary phosphorus intake.Drs. Itkonen and Lamberg-Allardt also note the importance of added phosphates to the diet. Many foods, including grain products, contain a combination of different types of phosphorus . Added phosphates are of special interest due to the potential for food manufactures to increase or decrease their use more readily than naturally-occurring phosphates. The Food and Nutrient Database for Dietary Studies (FNDDS) does not currently provide the phosphorus content of foods specifically from added phosphates . In the Research into dietary intake of bioavailable and added phosphorus will benefit from an increased focus on important dietary sources of total phosphorus intake, such as grain products, rather than dietary sources with the highest phosphorus bioavailability."}
+{"text": "Although numerous studies have investigated the relationship between saccadic eye movements and spatial attention, one fundamental issue remains controversial. Some studies have suggested that spatial attention facilitates saccades, whereas others have claimed that eye movements are actually inhibited when spatial attention is engaged. However, these discrepancies may be because previous research has neglected to separate and specify the effects of attention for two distinct types of saccades, namely reflexive (stimulus-directed) and voluntary (antisaccades). The present study explored the effects of voluntary spatial attention on both voluntary and reflexive saccades. Results indicate that voluntary spatial attention has different effects on the two types of saccades. Antisaccades were always greatly facilitated following the engagement of spatial attention by symbolic cues (arrows) informing the subject where the upcoming saccade should be directed. Reflexive saccades showed little or no cueing effects and exhibited significant facilitation only when these cues were randomly intermixed with uncued trials. In addition, the present study tested the effects of fixation condition  on attentional modulation. Cueing effects did not vary due to fixation condition. Thus, voluntary spatial attention consistently showed different effects on voluntary and reflexive saccades, and there was no evidence in these studies that voluntary cues inhibit reflexive saccades, even in a gap paradigm."}
+{"text": "The importance to develop effective alternatives to known antibiotics due to increased microbial resistance is gaining momentum inrecent years. Therefore, it is of interest to predict, design and computationally model Antimicrobial Peptides (AMPs). AMPs are oligopeptideswith varying size (from 5 to over100 residues) having key role in innate immunity. Thus, the potential exploitation of AMPsas novel therapeutic agents is evident. They act by causing cell death either by disrupting the microbial membrane by inhibitingextracellular polymer synthesis or by altering intra cellular polymer functions. AMPs have broad spectrum activity and act as first lineof defense against all types of microorganisms including viruses, bacteria, parasites, fungi and as well as cancer (uncontrolled celldivision)progression. Large-scale identification and extraction of AMPs is often non-trivial, expensive and time consuming. Hence,there is a need to develop models to predict AMPs as therapeutics. We document recent trends and advancement in the prediction ofAMP. Machine learning is considerably applied in different areas ofbiological knowledge discovery for improved healthcare.Supervised, unsupervised and reinforcement learning are thethree major learning methods. Identification of AMPs using acombination of supervised and unsupervised learning techniquesis available. A set of experimentally annotated positive AMPpeptides collected from the databases is used for supervisedlearning. The negative data of short peptides collected from aspectrum of available non-secretary peptides is often used fortraining. A high performance machine learning model is built toclassify the data into AMPs and non-AMPs with domain featuressuch as amino acid frequencies and composition extracted fromknown data using the most suitable performance measures likeaccuracy, Mathew Correlation Coefficient, ROC etc. SupportVector Machines (SVM), Random Forests (RF) and ArtificialNeural networks have been used profusely for the identificationof AMPs. SVM employs a linear hyper plane in a higherdimensional feature space for separation. Random forestsclassifier combines a forest of decision tree models and builds aconsensus model. Artificial Neural Networks (ANN) usesinterconnected network of neurons.Thomas et al. 2009) , employe009 , empAMP's were also predicted elsewhere  using muDatabases and prediction servers have a key role in the rationaldesign of novel AMPs as reviewed elsewhere . The wor"}
+{"text": "Recent advances in the development of immunosensors using polymeric nanomaterials and nanoparticles have enabled a wide range of new functions and applications in diagnostic and prognostic research. One fundamental challenge that all immunosensors must overcome is to provide the specificity of target molecular recognition by immobilizing antibodies, antibody fragments, and/or other peptides or oligonucleotide molecules that are capable of antigen recognition on a compact device surface. This review presents progress in the application of immobilization strategies including the classical adsorption process, affinity attachment, random cross-linking and specific covalent linking. The choice of immobilization methods and its impact on biosensor performance in terms of capture molecule loading, orientation, stability and capture efficiency are also discussed in this review. Antibody (Ab) and antibody fragment-based biosensors or immunosensors are compact tools capable of providing sensitive and rapid detection or capture of a range of pathogens or cells of interests for further analysis. The history of biosensors dates back to 1956 when Leland C. Clark described the first biosensor which was developed to detect glucose levels in serum samples using a membrane bound biologically sensitive element [The fundamental basis of all immunosensors is to efficiently create stable linkages between desired capture molecules and the nanomaterial. Abs are the most extensively used antigen binding molecules due to their exquisite specificity and affinity. A vast selection of monoclonal Abs (mAbs) have been developed using hybridoma technology to provide excellent tools to detect, perturb, or enhance key components in biological systems. Recent efforts have been made to shrink Ab-based tools through the dissociation of full size Abs into smaller antigen binding fragments . InitialAbs or immunoglobulins (Igs) are highly soluble serum glycoproteins which can be divided into five main isotypes  based on their heavy chain constant region sequences . PolycloE. coli expression. VHH binders with desired properties can be recombinantly expressed with tag sequences, protein fusion partners, or artificial amino acids through covalent modification [Although full-size Abs generated through immunization have been widely used for immunosensors since the beginning of biosensor development, recently developed recombinant molecules generated in vitro have many advantages over conventional Abs. The advantages of these alternative scaffolds include their compact sizes, excellent thermal and chemical stabilities, as well as low production costs ,15. For fication . Similarfication .Supporting materials of an immunosenor can be selected based on analytic needs . OpticalThe performance of an immnosensor depends upon three key factors: (1) the binding affinity and specificity of antigen binding molecules; (2) the accessibility and proportion of binding sites intact after immobilization; and (3) the density of binding molecules coated on the surface of immunosensor. Different strategies for immobilization may result in different outcomes and efficiencies . ImmobilPhysical adsorption of Abs onto hydrophobic surfaces such as polystyrene offers the simplest attachment. However, the process is uncontrollable in terms of orientation and stability, and often results in denaturation and detachment of protein on surface . ProteinVHHs, also known as nanobodies, are recombinant, antigen-specific, single-domain, variable fragments of camelid heavy chain-only antibodies. Compared to full size IgGs, VHHs can be expressed in high yield in bacterial systems. The small size (~14 kD) provides significant advantages in medical diagnostic and therapeutic applications . HoweverH) and light chains (VL) of Abs connected via a short peptide linker. Shen et al. optimized a 15-mer peptide linker (RGRGRGRGRSRGGGS) to increase the adsorption efficiency on anionic charged biosensor surface [E. coli which can display anti-cancer ScFvs and gold binding peptide on the surface of bacteria at the same time  and highly soluble in aqueous solution. Deyev and others reported that DARPins can bind tightly to gold nanoparticles (GNPs) via adsorption . Aptamers are single-stranded DNA or RNA (ssDNA or ssRNA) oligonucleotides or peptides engineered through repeated in vitro selection or equivalent methods. However, aptamers have distinct limitations, especially for those composed of DNA or RNA. The rapid degradation of aptamers by nucleases in biological media is a serious problem. Such degradation causes instability which is unacceptable for biosensor application. Despite such limitations, many successful attempts have been made to create aptamer-based biosensors in relatively nuclease free systems. One approach employed terminally functionalized thiol group for gold surface binding . Other fThe performance of immunosensors is closely associated to the antigen binding molecules and immobilization approach. While Abs have been increasingly used as detection elements in immunosensors, recent development in antibody derivatives and other alternative binding molecules raise new opportunities and possibilities to create highly stable, efficient, and economically feasible diagnostic device. In this review, a wide range of immobilization strategies are presented for Ab and Ab alternatives and their applications on various nanomaterial surfaces are discussed. Pros and cons of each method are presented. The uniform orientation conferred by site-specific immobilization is essential for small Ab alternatives to retain their binding efficiency."}
+{"text": "We report the sequential changes of retinal vessels observed by optical coherence tomography angiography (OCTA) in a case of nonischemic central retinal vein occlusion (CRVO) that converted to ischemic CRVO. An 81-year-old woman visited our Retina Clinic because of visual acuity loss in the left eye. Funduscopic examination showed venous tortuosity and intraretinal hemorrhage in all four quadrants of the fundus. OCT showed macular edema. Fluorescein angiography (FA) and OCTA showed loss of small capillaries. Nonischemic CRVO was diagnosed. Antivascular endothelial growth factor (VEGF) treatment resolved the edema and improved visual acuity. However, during follow-up, capillary dropout was observed on OCTA, which gradually enlarged. Eventually, FA confirmed the conversion to ischemic CRVO. In this case, sequential observations using OCTA showed that nonischemic CRVO did not convert to ischemic CRVO abruptly but occurred stepwise. Additionally, vascular changes began around the veins and blood flow changes were observed more clearly in deep capillary plexus than in superficial capillary plexus. Central retinal vein occlusion (CRVO) is a significant cause of acquired vision loss . CRVO waAn 81-year-old woman was referred to our Retina Clinic because of loss of visual acuity (VA) in the left eye 3 months ago. She had a history of uncontrolled hypertension, hyperlipidemia, and diabetes mellitus. Her best-corrected visual acuity (BCVA) was 20/20 in the right eye and 20/30 in the left eye. Funduscopic examination of the left eye showed typical features of nonischemic CRVO, including venous tortuosity and intraretinal hemorrhage in all four quadrants of the fundus. Fluorescein angiography (FA) and OCTA showed loss of small capillaries but nonperfusion areas were not observed, confirming a diagnosis of nonischemic CRVO. Optical coherence tomography (OCT) showed retinal thickening in the fovea with associated inner retinal cysts.  drug aflibercept was initiated. One month later, visual acuity was improved to 20/25 along with gradual normalization of fundus findings associated with CRVO and macular cysts. After one more month OCTA revealed enlargement of the foveal avascular zone and broken foveal capillary ring in the superficial capillary plexus (SCP) and deep capillary plexus (DCP). Color fundus photograph demonstrated cotton wool spots located near the macula ; OCTA reWe performed sequential OCTA observations on a case initially presented with nonischemic CRVO which subsequently converted to ischemic CRVO. OCTA demonstrated capillary dropout occurring preferentially around the vein and these areas gradually enlarged forming avascular lesions. Moreover, OCTA revealed more extensive avascular zones in the DCP than in the SCP. Previous study has also reported that retinal vascular abnormalities in diseases of retinal veins develop more frequently in the DCP than in the SCP . GradualIn conclusion, the present case suggests that conversion to ischemic CRVO starts in the areas around the vein and progresses stepwise rather than abruptly. Moreover, in OCTA study, avascular zones are more readily recognized in the DCP than in the SCP. This is the first report of sequential observations of conversion from nonischemic CRVO to ischemic CRVO using OCTA. Further study of more cases may contribute to elucidation of the mechanism of conversion to ischemic CRVO."}
+{"text": "Altered cellular metabolism is considered a hallmark of cancer and is fast becoming an avenue for therapeutic intervention. Mitochondria have recently been viewed as an important cellular compartment that fuels the metabolic demands of cancer cells. Mitochondria are the major source of ATP and metabolites necessary to fulfill the bioenergetics and biosynthetic demands of cancer cells. Furthermore, mitochondria are central to cell death and the main source for generation of reactive oxygen species (ROS). Overall, the growing evidence now suggests that mitochondrial bioenergetics, biogenesis, ROS production, and adaptation to intrinsic oxidative stress are elevated in chronic lymphocytic leukemia (CLL). Hence, recent studies have shown that mitochondrial metabolism could be targeted for cancer therapy. This review focuses the recent advancements in targeting mitochondrial metabolism for the treatment of CLL. A sactivity . CLL cel induce nonclassical cell death that is mitochondrial ROS dependent and facilitated by TCL1 oncogene overexpression [in vitro to therapeutic agents generally used in the treatment of CLL. This also enables a suitable model for mitochondrial targeting in CLL.Increased oxidative stress and altered mitochondrial metabolism in CLL cells are associated with the lymphoid oncogene TCL-1 (T cell leukemia 1). Prinz et al. demonstrated that organometallic nucleosides pression . MCNA inpression . These aDNA crosslinking agents are activated aromatic nitrogen mustards, the ability to crosslink DNA. DNA inter-strand crosslinks are identified as one of principle mechanisms for the cytotoxic effect of many antitumor drugs. These compounds exhibit very powerful crosslinking abilities in the presence of H2O2 and provide a novel strategy for tumor-specific damage. Primary CLL samples were more sensitive (40\u201380% apoptosis) than non-CLL lymphocytes from healthy donors [ROS inducible y donors . They fuMitochondrial metabolism has only now become of interest in the realm of cancer therapy. CLL is a disease that has many mitochondrial metabolic dependencies. However, the nature of metabolic networks that enable abhorrent cell proliferation, cell-cell communication, evasion of apoptosis, and drug resistance remains poorly understood. The list of therapeutic compounds described in this review implements a strong suggestion that targeting mitochondrial bioenergetics and metabolic alterations may provide a mechanistic explanation for the growth advantage and apoptotic resistance of tumor cells. In CLL patients, standard chemi-immunotherapy and novel targeted agents continue to lead to treatment failures. In order to best target this cancer, a multipronged treatment strategy such as combinations with mitochondrial targeting agents and currently approved treatments may enable a chance at cure for a currently incurable cancer."}
+{"text": "Consciousness is often disrupted in epilepsy. This may involve altered responsiveness or changes in awareness of self and subjective experiences. Subcortical arousal systems and paralimbic fronto-parietal association cortices are thought to underpin current concepts of consciousness. The Network Inhibition Hypothesis proposes a common neuroanatomical substrate for impaired consciousness during absence, complex partial and tonic-clonic seizures.Neurostimulation in epilepsy remains in its infancy with vagal nerve stimulation (VNS) as the only firmly established techniqueand a series of other methods under investigation including deep brain stimulation (DBS), intracranial cortical stimulation andrepetitive transcranial magnetic stimulation (rTMS). Many of these systems impact on the neural systems thought to be involvedin consciousness as a continuous duty cycle although some adaptive (seizure triggered) techniques have been developed.Theoretically, fixed duty cycle neurostimulation could have profound effects on responsiveness, awareness of self and subjectiveexperience. Animal studies suggest vagal nerve stimulation positively influences hippocampal long term potentiation. In humans,a chronic effect of increased alertness in VNS implanted subjects and acute effect on memory consolidation have been reportedbut convincing data on either improvements or deterioration in attention and memory is lacking. Thalamic deep brain stimulation(DBS) is perhaps the most interesting neurostimulation technique in the context of consciousness. Neither bilateral anterioror centromedian thalamic nucleus DBS seem to affect cognition. Unilateral globus pallidus internus DBS caused transientwakefulness in an anaesthetised individual.As intracranial neurostimulation, particularly thalamic DBS, becomes more established as a clinical intervention, the effects onconsciousness and cognition with variations in stimulus parameters will need to be studied to understand whether these secondaryeffects of neurostimulation make a significant positive (or adverse) contribution to quality of life."}
+{"text": "Since the Korean language has two distinct writing systems, phonogram (Hangul) and ideogram (Hanja: Chinese characters), alexia can present with dissociative disturbances in reading between the two systems. A 74-year-old right-handed man presented with a prominent reading impairment in Hangul with agraphia of both Hangul and Hanja after a left posterior occipital- parietal lesion. He could not recognize single syllable words and nonwords in Hangul, and visual errors were predominant in both Hanja reading and the Korean Boston Naming Test. In addition, he had difficulties in visuoperceptual tests including Judgment of Line Orientation, Hierarchical Navon figures, and complex picture scanning. These findings are consistent with the hypothesis that Hangul reading impairment results from a general visual perceptual deficit. However, this assumption cannot explain why performance on visually complex Hanja was better than performance on visually simple Hanja in our patient. In addition, the patient did not demonstrate higher accuracy on Hanja characters with fewer strokes than on words with more strokes. Thus, we speculate that the left posterior occipital area may be specialized for Hangul letter identification in this patient. This case demonstrates that Hangul-Hanja reading dissociation impairment can occur after occipital-parietal lesions."}
+{"text": "Pulmonary vein stenosis is a well-established possible complication following an atrial fibrillation ablation of pulmonary veins. Symptoms of pulmonary vein stenosis range from asymptomatic to severe exertional dyspnea. The number of asymptomatic patients with pulmonary vein stenosis is greater than originally estimated; moreover, only about 22% of severe pulmonary vein stenosis requires intervention. We present a patient with severe postatrial fibrillation (AF) ablation pulmonary vein (PV) stenosis, which was seen on multiple imaging modalities including cardiac computed tomography (CT) angiogram, lung perfusion scan, and pulmonary angiogram. This patient did not have any pulmonary symptoms. Hemodynamic changes within a stenosed pulmonary vein might not reflect the clinical severity of the obstruction if redistribution of pulmonary artery flow occurs. Our patient had an abnormal lung perfusion and ventilation (V/Q) scan, suggesting pulmonary artery blood flow redistribution. The patient ultimately underwent safe repeat atrial fibrillation ablation with successful elimination of arrhythmia. Pulmonary vein stenosis, which occurs in 1% to 3% of cases, is a well-recognized potential complication after radiofrequency (RF) ablation of pulmonary veins. The clinical manifestations of pulmonary vein stenosis vary widely from asymptomatic to severe exertional dyspnea. While these symptoms are primarily affected by the severity and number of affected veins, pulmonary blood flow redistribution is thought to be one of the factors contributing to blunting clinical symptoms after RF ablation of atrial fibrillation (AF) [A 56-year-old male with history of AF, status after ablation, eight years ago at an outside hospital, presented with recurrent AF. Five years after his initial ablation, the patient developed symptomatic palpitations due to atrial fibrillation and he was prescribed flecainide and metoprolol. Despite antiarrhythmic therapy, the patient continued to have symptomatic atrial fibrillation with palpitations but no shortness of breath. The patient was taken for AF ablation. The preablation echocardiogram demonstrated normal ventricular function and pulmonary pressures. The preprocedural computed tomography (CT) scan along with the three-dimensional (3D) reconstruction was done on the procedural table prior to the transeptal puncture but did not pick up the pulmonary vein stenosis. Pulmonary vein potential mapping noted that there was a potential at the ostium of the left superior pulmonary vein. There was also difficulty advancing the catheter into the left superior pulmonary vein due to a possible obstruction. Direct angiography of the left superior pulmonary vein (LSPV) confirmed complete PV stenosis. The procedure was aborted in lieu of further diagnostic work up. A higher resolution cardiac CT angiogram  and leftThe frequency of PV stenosis, a well-established possible complication following an AF ablation of pulmonary veins, has been declining due to the improvement of technique. However, depending on the technique and diagnostic modalities used, PV stenosis occurs as often as 40% of patients who underwent AF ablation . PV stenUltimately, the patient underwent successful repeat atrial fibrillation ablation employing a wide antral circumferential ablation technique with successful resolution of the left superior pulmonary vein. The patient's pacemaker was interrogated six months after ablation and demonstrated successful elimination of atrial fibrillation .We present a patient with severe post-AF ablation PV stenosis without pulmonary symptoms.Our patient's perfusion scan, which demonstrated no perfusion of the affected lung, is suggestive of pulmonary artery blood flow redistribution via pulmonary artery to systemic collaterals. The patient ultimately underwent safe repeat atrial fibrillation ablation with successful elimination of arrhythmia."}
+{"text": "Comephorus spp.) represent a highly apomorphic taxon with unique skeletal morphology, soft anatomy, and reproductive ecology. Selection for novel behavior and life history may be evident in genes responsible for organismal energy balance, including those encoding subunits of the electron transport chain. Complete mitochondrial genomes were sequenced for the Big Baikal Oilfish  and Little Baikal Oilfish (Comephorus dybowskii). Mitochondrial genomes encode genes essential for electron transport, and data provided here will complement ongoing investigations of genome-to-phenome maps for teleost respiration and metabolism. Phylogenetic analyses including oilfish mitogenomes and all publicly available cottoid representative sequences are largely concordant with previous studies.Sculpins are predominantly benthic sit-and-wait predators that inhabit marine and freshwaters of the Northern Hemisphere. In striking contrast to riverine relatives, sculpins endemic to Lake Baikal have diversified in both form and function, with multiple taxa having adaptations for pelagic and bathyal niches within the world\u2019s deepest lake. Baikal Oilfishes ( Comephorus baicalensis; Pallas Comephorus dybowskii; Korotneff Comephorus baicalensis is distinguished from C. dybowskii by having greater total length, greater proportional orbit length, shorter proportional pectoral fins, and smaller cephalic pore chambers  was used as a reference sequence. A multiple alignment was conducted with MAFFT version 7 (Katoh and Standley Whole genomic DNA was isolated from fin clips collected from two specimens for each species, and voucher material was retained at the Sandel Laboratory of Aquatic Evolution at UWA. Mitochondrial genomes were generated using traditional Sanger sequencing at the Limnological Institute of the Russian Academy of Sciences and sequencing-by-synthesis on illumina HiSeq at the UAB Heflin Center for Genomic Sciences. Sanger reads were trimmed and aligned with Bioedit 7.0.0 Hall , and HiSCottus mitochondrial genomes (Balakirev et\u00a0al. MEGA 6 was used to select the optimum nucleotide substitution model and conduct a maximum-likelihood phylogenetic analysis (Tamura et\u00a0al."}
+{"text": "The main goal of this analysis was prioritization of co-expressed genes and miRNAs that are thought to have important influences in the pathogenesis of colon and lung cancers.MicroRNAs (miRNAs) as small and endogenous noncoding RNAs which regulate gene expression by repressing mRNA translation or decreasing stability of mRNAs; they have proven pivotal roles in different types of cancers. Accumulating evidence indicates the role of miRNAs in a wide range of biological processes from oncogenesis and tumor suppressors to contribution to tumor progression. Colon and lung cancers are frequently encountered challenging types of cancers; therefore, exploring trade-off among underlying biological units such as miRNA with mRNAs will probably lead to identification of promising biomarkers involved in these malignancies. Colon cancer and lung cancer expression data were downloaded from Firehose and TCGA databases and varied genes extracted by DCGL software were subjected to build two gene regulatory networks by parmigene R package. Afterwards, a network-driven integrative analysis was performed to explore prognosticates genes, miRNAs and underlying pathways. A total of 192 differentially expressed miRNAs and their target genes within gene regulatory networks were derived by ARACNE algorithm. BTF3, TP53, MYC, CALR, NEM2, miR-29b-3p and miR-145 were identified as bottleneck nodes and enriched via biological gene ontology (GO) terms and pathways chiefly in biosynthesis and signaling pathways by further screening.  Our study uncovered correlated alterations in gene expression that may relate with colon and lung cancers and highlighted the potent common biomarker candidates for the two diseases. The complex molecular interactions underlying cancers warrant identification of biological entities like miRNAs as well as the crosstalk between different cancers. Colon cancer is a fatal malignancy with estimated 1.4 million cases yearly  that canData acquisition and pre-processing In the present article, colon cancer gene expression dataset generated by Illuminaga_RNASeqV2 containing 192 normal and cancer samples and 20532 genes was chosen from Firehose (https://confluence.broadinstitute.org/display/GDAC/Home). For the miRNA expression profiling data, lung cancer Illumina HiSeq included 231 normal and cancer samples and 1045 genes were retrieved from TCGA (https://www.synapse.org/#!Synapse:syn300013/wiki/27406). The expression values of miRNAs and mRNAs were subjected to expression Based filter and variance Based filter functions implemented in DCGL v2.0 R package  to filteIn silico analysis and networking Predicted gene-miRNA interactions were collected from miRWalk 2.0 server  based on miRBase database. Regarding the mRNAs, only the miRNAs target genes were retrieved by miRWalk from colon cancer transcripts. Afterwards, two independent gene regulatory networks were built using unique miRNAs and their target genes using arcana function with eps=0.05 implemented in parmigene R package . Next, gGene Ontology analysis and visualization To find the significantly over-represented biological GO terms and functions of gene products within regulatory network mRNAs, functional classification was performed using BINGO Cytoscape plugin  running In order to study the functional roles of miRNA and their targets in biological pathways, pathway analysis was performed using PANTHER  and mirPath v.3 (http://snf-515788.vm.okeanos.grnet.gr/), respectively. Building miRNA-mRNA interaction networksThe 192 most variable miRNAs and target transcripts extracted from lung and colon cancer data were subjected to build two independent interaction networks by ARACNE algorithm implemented in parmigene software (setting epsilon to 0.05). Information-theoretic approaches like ARACNE  have beeAs shown in Exploring miRNA\u2013TF\u2013mRNA network The 192 miRNA variable transcripts of lung cancer data targeted 13711 validated genes based on miRWalk server. We then intersected between these 13711 targets and the most variable mRNAs in colon cancer data extracted from DCGL R package. As the parmigene method demands orthogonal matrices for inferring co-expression network, we then processed further with two matrices of miRNAs and mRNAs both including 192 samples and genes. Degree distribution and following motif discovery  and receThe crossroads among the screened miRNAs, genes and TFs was illustrated in GO and pathway functional enrichment analysisAs shown in By representing the molecular interactions underlying biological processes, network biology paves the path to drug discovery, better understanding of diseases mechanism and cancer therapeutics -37. miRNWe aimed to explore biomarkers underlying both colon and lung cancers ;therefore, in the frame of network mining methods and topology feature analysis, a small number of putative genes, miRNAs and transcription factors were explored whose interplays are probably related to colon and lung cancers. An expected outcome of such a work would possibly identify crosstalk of miRNAs and genes in tumorigenesis in different tissues and more evidence for cancer diagnosis and treatment. In the present study, NGS data was chosen over microarray because: I) this technique provides more sensitive detection of transcripts, which is likely to be the reason for the ability of NGS data to detect low expressed genes while microarrays fail to differentiate between very low expressed and non-expressed genes ; II) accHowever, this analysis is challenged by some limitations. Firstly, despite well-demonstrated roles of miRNAs in regulating multiples target genes involved in different oncogenic pathways in cancers, we should be cautious about the fact that each miRNA could potentially target hundreds of genes. Therefore, we need a deeper understanding of miRNA biology and undeniable role of experimental practices to improve fidelity of bioinformatics results. Next, evidently from ontology analysis, target genes could barely provide a clear biological finding; therefore, research works addressing validating miRNA sites within mRNAs will decrease the ambiguity in defining regulatory interactions among miRNAs-targets. Furthermore, we inferred information-theoretic based undirected networks while connectivity between nodes does not mean the causal relationships; we then should be cautious about dynamic nature of cancers via strict analysis of statics networks. Additionally, it is essential to remove overestimated regulation dependencies by employing more sophisticated gene regulatory inference algorithms. Finally, network analysis at transcriptome level could be more intensified through merging studies with protein networks to draw more practical conclusions.It is concluded that utilizing dual information of miRNAs and mRNAs in cancers trade-off can help to discover important findings to identify underlying mechanisms and enlighten more molecular underpinnings of different cancers. We observed that the identified miRNAs-mRNA covered a wide range of known functions, mainly signaling pathways and biosynthesis implicated in colon and lung cancers.To summarize, conserved miRNAs and TFs like miR-195, miR-145, BTF3, Myc and TP53 with their targets could be considered as hallmark genes for future diagnosis and therapeutic researches where their rules could be confirmed by experiments.Utilizing dual information of miRNAs and mRNAs in cancers trade-off can help to discover important findings to identify underlying mechanisms and enlighten more molecular underpinnings of different cancers. We observed that the identified miRNAs-mRNA covered a wide range of known functions, mainly signaling pathways and biosynthesis implicated in colon and lung cancers.To summarize, conserved miRNAs and TFs like miR-195, miR-145, BTF3, Myc and TP53 with their targets could be considered as hallmark genes for future diagnosis and therapeutic researches where their rules could be confirmed by experiments."}
+{"text": "Human learning and memory evaluation in real-life situations remains difficult due to uncontrolled variables. Buenos Aires waiters, who memorize all the orders without written support, were evaluated in situ. Waiters received either eight different orders and customers remained seated in their original locations (OL), or changed locations (CL). Match between orders, subjects and location was decreased only in CL. Waiters\u2019 feature/location strategy links client with position at the table and beverage later. The hypothesis we raise is that memory-schemas link working memory to long-term memory networks through rapid encoding, making the information resistant to interference and enabling its fast retrieval if necessary cues are present."}
+{"text": "Lower extremity trauma during earthquakes accounts for the largest burden of geophysical disaster-related injuries. Insufficient pain management is common in disaster settings, and regional anesthesia (RA) has the potential to reduce pain in injured patients beyond current standards. To date, no prospective research has evaluated the use of RA in a disaster setting. This cross-sectional study assesses knowledge translation and skill acquisition outcomes for lower extremity RA performed with and without ultrasound guidance among a cohort of M\u00e9decins Sans Fronti\u00e8res (MSF) volunteers who will function as proceduralists in a planned randomized controlled trial evaluating the efficacy of RA for pain management in an earthquake setting.Background:Generalist humanitarian healthcare responders, including both physicians and nurses, were trained in ultrasound guided femoral nerve block (USGFNB) and landmark guided fascia iliaca compartment block (LGFICB) techniques using didactic sessions and interactive simulations during a one-day focused course. Outcome measures evaluated interval knowledge attainment and technical proficiency in performing the RA procedures. Knowledge attainment was assessed via pre- and post-test evaluations and procedural proficiency was evaluated through monitored simulations, with performance of critical actions graded by two independent observers.Methods:Twelve humanitarian response providers were enrolled and completed the trainings and assessments. Knowledge scores significantly increased from a mean pre-test score of 79% to post-test score of 88% (p<0.001). In practical evaluation of the LGFICB, participants correctly performed a median of 15.0 (Interquartile Range (IQR) 14.0-16.0) out of 16 critical actions. For the USGFNB, the median score was also 15.0 (IQR 14.0-16.0) out of 16 critical actions. Inter-rater reliability for completion of critical actions was excellent, with inter-rater agreement of 83.3% and 91.7% for the LGFICB and USGFNB evaluations, respectively.Results:Prior to conducting a trial of RA in a disaster setting, providers need to gain understanding and skills necessary to perform the interventions. This evaluation demonstrated attainment of high knowledge and technical skill scores in both physicians and nurses after a brief training in regional anesthesia techniques. This study demonstrates the feasibility of rapidly training generalist humanitarian responders to provide both LGFICB and USGFNB during humanitarian emergencies.Discussion: Among geophysical disasters, earthquakes result in high mortality rates and account for the largest burden of injuries,,,,,,,,Prior studies have demonstrated that regional anesthesia (RA) is a rapid and safe method for reducing pain caused by lower extremity trauma, and as such may have a role in improving pain management during the acute response phase of a major earthquake,,,,,The Regional Anesthesia for Painful Injuries after Disasters (RAPID) study is randomized controlled trial (RCT) that will be carried out in the immediate aftermath of a major earthquake to determine whether RA provided by generalist humanitarian medical responders, either with or without ultrasound-guidance, can improve pain treatment for lower limb injuries, above current standards of careEthicsThe RAPID study has received ethical approval from the M\u00e9decins Sans Fronti\u00e8res Ethical Review Board (Reference number: 1524) and has been preregistered at ClinicalTrials.gov (number: NCT02698228)Study Design Setting and PopulationThis cross-sectional study was designed to evaluate the efficacy of a focused training in regional anesthesia for lower extremity injuries provided to MSF volunteers who will serve as research proceduralists in a future RCT of RA for pain management in earthquake victimsThe study population was comprised of physician and nurse responders who had previously been deployed to humanitarian emergencies and were members of the MSF-USA association. Participants were made aware of the RAPID study and training prior to the meeting via digital correspondence with study investigators and were solicited to volunteer for participation.Participant Training and AssessmentTraining activities were designed to provide understanding of RA principles and competence in performing landmark guided fascia iliaca compartment blocks (LGFICB) and ultrasound-guided femoral nerve blocks (USGFNB). Study throughput is outlined in Following the initial assessment, participants took part in a three-hour interactive didactic session lead by study investigators using a semi-structured discussion platform that allowed for open-form content exchange between all participants. The educational information focused on RA principles and specific methodologies in performing LGFICB and USGFNBAfter completion of training activities, each participant was assessed through two observed simulation exams for performance of the LGFICB and the USGFNB. In each exam, participants were asked to perform the RA techniques using standard clinical equipment and a femoral regional anesthesia ultrasound model . During the simulation exams, two independent reviewers assessed each participant\u2019s technical competency using a preformed critical actions checklist with an objective scoring system. Assessed parameters evaluated appropriate positioning; identification of anatomic and ultrasonographic landmarks; use of sterile technique; provision of local superficial anesthetic; needle delivery; anesthetic injection; and proper procedural monitoring for possible adverse events.A post-training, fifteen question multiple-choice exam was performed to assess interval knowledge attainment. In the post-training assessment, participants were crossed-over to complete the alternative exam to the one they took at baseline .Data Collection Outcome MeasuresBaseline data on participants was collected using a structured questionnaire. Information on demographics, healthcare training, humanitarian response activities, ultrasound and RA experience was gathered. Knowledge assessment exams were scored with a single best answer for each question and participants were assigned a percent correct for both the pre-test and post-test. During observed simulation exams for the RA techniques, each rater provided a critical action completion score ranging from zero to sixteen based on eight assessment parameters. Accrued data was de-identified and entered into a password-protected database that was accessible only by study personnel.The primary outcome measures were the change in knowledge attainment based on mean pre- and post-test scores on the standardized exams and demonstration of technical competency in performing the LGFICB and USGFNB RA techniques. Technical competency was assessed based on adequate performance of critical actions during simulation assessments. Secondary outcome measures included the inter-rater reliability for the standardized critical action checklist and separate subgroup analyses of physician and nurses.Statistical AnalysisStatistical analyses were performed using STATA 13.0 . Characteristics of the cohort were evaluated using descriptive methods. Categorical variables were explored using frequencies with percentages, and continuous variables were analyzed using medians with corresponding interquartile ranges (IQR) or means with associated 95% confidence intervals (95% CI). Given the small sample size knowledge attainment data was analyzed using Shapiro-Wilks tests and frequency distributions to evaluate for normality. The results were found to satisfy criteria for normality and as such, one sample paired t-tests were used for the primary outcome of change in mean knowledge scores. A p value less than 0.05 was considered significant in primary outcome assessments.,Median scores with IQR for each rater were calculated for the LGFICB and USGFNB simulation assessments. Inter-rater reliability (IRR) was evaluated across all critical assessment variables based on rater agreement derived using Cohen\u2019s kappa calculation. Kappa values were interpreted according to previously utilized criteria with agreement classified as greater than 0.80 as representing excellent IRRTwelve MSF association members were enrolled and all participants completed the full study training and assessment procedures. The median age of the cohort was 41 years and the majority of participants were female. Half of participants reported their primary healthcare training as nurse and half as physician. The median years of healthcare practice and humanitarian response experience were eleven and five years respectively. Half of the cohort had prior experience with ultrasound use, though only a minority reported previous clinical application of RA techniques  .The primary study outcomes are summarized in This study assessed knowledge translation and skill acquisition outcomes for simulated lower extremity RA performed both with and without ultrasound guidance among a small cohort of MSF volunteers who will function as proceduralists in a planned randomized controlled trial that will assess the efficacy of RA for pain management in the acute phase of a major earthquake,,,,,,,,,In the acute response phase to a natural disaster, where resources are often constrained, oligoanalgesia is common,,,Standardized assessment and training in research procedures is important in reducing error and deriving valid trial results,,,Although prior studies have assessed the performance of femoral never blockades after brief trainings in emergency department settings among physician and nurse trainees this study is the first to evaluate formal training of generalist humanitarian response providers in RA methodsThis work must be interpreted in the context of certain limitations. The presented results illustrate short-term acquisition of knowledge and skills among the MSF volunteers trained, but do not allow for assessment of application in actual disaster situations, nor for evaluation of skill retention over time. It is likely that similar to most technical skill sets, the study proceduralists will require refresher training prior to execution of the RAPID study, which has been built into the trial design. Although the population of humanitarian responders was drawn from a large pool of MSF volunteer personnel, the cohort was relatively small and not randomly selected, and as such the generalizability of these outcomes to the greater population of disaster healthcare personnel is not certain. During completion of the RAPID study this will be partially addressed, as there will be further onsite training for locally recruited healthcare providers, who will also serve as proceduralists during the later study phases. These later phase providers will be trained and assessed onsite using the same methods as described in this report.Prior to conducting a trial of RA in a disaster setting, providers need to gain the knowledge and skills necessary to perform the interventions. This study demonstrated high knowledge and technical skills scores with excellent inter-rater agreement between independent evaluators, illustrating the success of the focused training for generalist humanitarian response providers in the selected RA techniques. This work, in conjunction with the planned RAPID study, will contribute to the development of an enhanced evidence base to guide future care and improve health outcomes among high-risk patients injured in the settings of humanitarian emergencies.The data used for this analysis can be accessed via: https://figshare.com/s/1825267cbf21863b6cf4.All authors declare that they have no competing interests to disclose.Adam R. Aluisio, MD, MScWarren Alpert School of Medicine, Brown University, Department of Emergency Medicine55 Claverick Street, Room 274Providence, Rhode Island 02912, USAEmail: adam.aluisio@gmail.comCRED: Centre for Research on the Epidemiology of DisastersFICB: Fascia iliaca compartment blockFNB: Femoral nerve blockIQR: Interquartile RangeIRR: Inter-rater reliabilityLG: Landmark guidedLGFICB: Landmark guided fascia iliaca compartment blockLMIC: low- and middle-income countriesMoH: Ministry of HealthMSF: M\u00e9decins Sans Fronti\u00e8resRA: Regional anesthesiaRCT: Randomized Controlled TrialSAE: Serious Adverse EventsSD: Standard DeviationUS: UltrasoundUSG: Ultrasound guidedUSGFNB: Ultrasound guided femoral nerve blockWHO: World Health Organization"}
+{"text": "The circadian clock underpins most physiological conditions and provides a temporal dimension to our understanding of body and tissue homeostasis. Disruptions of circadian rhythms have been associated with many diseases, including metabolic disorders and cancer. Recent literature highlights a role for the circadian clock to regulate innate and adaptive immune functions that may prime the host response to infectious organisms. Viruses are obligate parasites that rely on host cell synthesis machinery for their own replication, survival and dissemination. Here, we review key findings on how circadian rhythms impact viral infection and how viruses modulate molecular clocks to facilitate their own replication. This emerging area of viral-clock biology research provides a fertile ground for discovering novel anti-viral targets and optimizing immune-based therapies. Circadian rhythms are autonomous, self-sustaining, 24-h oscillations that synchronise physiological processes, such as sleep\u2013wake cycles, hormone release, cell regeneration, fluctuations in body temperature and metabolism, to external environmental cues. These rhythmic processes are controlled by the circadian timekeeping system that consists of a central circadian clock located in the suprachiasmatic nucleus (SCN) that links to a network of peripheral clocks located in every tissue Fig.\u00a0. The mamBMAL1 is a key component of the circadian clock ; mice deMany aspects of the innate and adaptive immune systems are under circadian control , 10. To Inflammatory lung diseases frequently show time-of-day variation in their severity, and a recent study from Gibbs and colleagues  showed t. To assess the functional consequences of this observation, the authors immunised mice with ovalbumin and TLR9 ligand (CpG ODNs) adjuvant at various times of day. Vaccination at the time of increased TLR9 expression (ZT19) resulted in a greater immune response to ovalbumin, and this phenotype was lost in PER2 deficient mice. These observations are consistent with emerging evidence showing a role for the circadian clock to regulate host defences against bacterial pathogens [In addition to regulating host immunity to viral infections, the efficacy of viral vaccination has been reported to be under circadian control in rodents and humans. Silver et al. reported that expression of pattern recognition receptor Toll-like receptor 9 (TLR9) that recognises bacterial and viral DNA is circadian regulated . To asseathogens  and suggPhillips et al. showed that patients immunised in the morning developed greater antibody responses to both hepatitis A and influenza vaccines . More reThe liver is one of the most circadian-regulated organs with 20% of genes showing circadian patterns of expression . Benegiabmal1-/- mice. Importantly, both studies confirmed an anti-viral role for BMAL1 using in vitro viral replication models that lack systemic circadian cues or host defenses, supporting a model where BMAL1 regulates cellular factors that are essential for viral replication. A comprehensive proteomic analysis of wild type and bmal1-/- primary cells revealed an enrichment of proteins involved in protein biosynthesis, endoplasmic reticulum function and intracellular vesicle trafficking [Bmal1 shows seasonal variation in human blood samples with the lowest levels observed during the winter months [Two recent studies report increased replication of herpes, influenza , respirafficking ; all patr months  coincidir months .Herpes simplex virus (HSV) is a DNA virus whose gene expression is limited by histone deacetylation. CLOCK can function as a histone acetyltransferase, and Kalamkovi et al. reported that HSV hijacks this clock repressor to facilitate transcription of viral genes, where depletion or silencing CLOCK reduced viral protein expression , 31. TheGlucocorticoids (GCs) regulate carbohydrate, lipid and protein metabolism and are widely used as anti-inflammatory agents. GCs are secreted from the adrenal gland in a rhythmic circadian fashion, and their peak expression coincides with the onset of the active phase, suggesting a role in synchronizing signals between the SCN and peripheral tissues. GCs regulate gene transcription by activating the glucocorticoid receptor that binds GC response elements (GRE) in target gene promoters . Of noteWhile individual molecular circadian components have been reported to modulate viral infection, melatonin, a potent regulator of the circadian rhythm secreted by the pineal gland  exhibitsA growing awareness of \u2018circadian disruption\u2019-associated pathologies, such as a high risk of cancer in shift workers, highlights the potential for this pathway to be deregulated in viral-associated cancers \u201344. Yang+ T-lymphocytes between the morning and evening coinciding with changes in the circadian pattern of serum cortisol levels [Human Immunodeficiency Virus (HIV) infection has been associated with the disruption of circadian-regulated physiological processes, including a blunting of systolic blood pressure decline from day to night . Malone l levels . To undel levels . Furtherl levels , 54.Studies with Simian Immunodeficiency Virus (SIV) reported perturbation of several circadian parameters of body temperature and activity parameters, where the amplitude of temperature and locomotor activity was significantly reduced . The autOther viral infections have been reported to influence circadian rhythms. Coxsackievirus A16 (CVA16) is one of the major causes of hand, foot and mouth disease, and transcriptomic analysis of infected human embryonic kidney cells identified differentially expressed miRNA target genes involved in circadian rhythm pathways, providing some insights into CAV16 induced pathogenesis . Human TAedes aegypti mosquito acts as a carrier for many viral infections such as dengue fever and Zika virus. Lima-Camara et al. reported that dengue virus infection increased the amplitude of rhythmic locomotor activity in the mosquito and speculated this would increase the vector\u2019s capacity to transmit virus [Culicoides biting midges that are vectors for African horse sickness and Bluetongue virus [A. aegypti, circadian regulators may provide new therapeutic targets [Circadian rhythms are likely to impact viral transmission especially if one considers zoonoses where multiple species can act as viral reservoirs Fig. . For patit virus . This ciue virus . Conside targets .Given the interplay between virus and the host circadian mechanism, host susceptibility to infection or disease is not only dependent on the infectivity of the viral inoculum, transmission route and length of exposure, but on the time of day when the pathogen is encountered. Understanding how viruses interact with host circadian rhythms has the potential to influence the treatment and clinical management of viral infections. In terms of circadian modulating therapies for treating or preventing viral infections, this could involve both pharmacotherapy and chronotherapy. Thus, it is possible that the efficacy of current anti-viral therapies could be improved by altering the time of drug administration. Recent advances in T cell engineering therapies show promising results using T cell receptor (TCR) or chimeric antigen receptor engineered T cells targeted against human viral antigens \u201367. InteHow do viruses engage with the molecular clockwork and modulate timekeeping? The discovery that the transcriptional clock mechanism is universal and exists in essentially every cell of the body highlights the potential of these TFs to regulate host susceptibility to viral infection directly via binding viral DNA genomes or indirectly via controlling host gene expression Fig. . The rep"}
+{"text": "These data show that cigarette smoke exposure decreases in vivo MSC and HSC number and also increases pro-proliferative gene expression by cigarette smoke-exposed MSCs, which may stimulate HSPC expansion. These results of this investigation are clinically relevant to both bone marrow donors with a history of smoking and bone marrow transplant (BMT) recipients with a history of smoking.Effects of tobacco smoke on hematologic derangements have received little attention. This study employed a mouse model of cigarette smoke exposure to explore the effects on bone marrow niche function. While lung cancer is the most widely studied consequence of tobacco smoke exposure, other malignancies, including leukemia, are associated with tobacco smoke exposure. Animals received cigarette smoke exposure for 6 h/day, 5 days/week for 9 months. Results reveal that the hematopoietic stem and progenitor cell (HSPC) pool size is reduced by cigarette smoke exposure. We next examined the effect of cigarette smoke exposure on one supporting cell type of the niche, the mesenchymal stromal cells (MSCs). Smoke exposure decreased the number of MSCs. Transplantation of na\u00efve HSPCs into irradiated mice with cigarette smoke exposure yielded fewer numbers of engrafted HSPCs. This result suggests that smoke-exposed mice possess dysfunctional niches, resulting in abnormal hematopoiesis. Co-culture experiments using MSCs isolated from control or cigarette smoke-exposed mice with na\u00efve HSPCs  While pulmonary disorders are the most obvious manifestation of cigarette smoke-induced disease, there is a growing appreciation that smoking and chronic lung disease are associated with significant systemic consequences and comorbidities. Distal organ and tissue injury, linked to systemic inflammation and oxidative stress, commonly result in skeletal myopathy, cardiovascular disease, osteoporosis, depression and metabolic derangement.Stem and progenitor cells play a pivotal role in tissue maintenance and repair in response to injury, and it has been proposed that resident and/or hematopoietic progenitor cell perturbations may be pathogenic in smoking-related emphysema . Further+ cytotoxic T cell lymphocytosis and neutrophilia. BrdU labeling studies show decreased transit time through the post-mitotic pool of the bone marrow, consistent with chronic stimulation of hematopoiesis .,33.18,33These data support our hypothesis that hematologic changes in cigarette smokers are caused by damage to niche cells, specifically MSCs and their progeny. We have shown that smoke exposure decreased HSPC pool size and concomitantly deceased MSC number. The decreased number of MSCs corresponded to a decrease in na\u00efve HSPC engraftment after bone marrow transplantation in smoke-exposed animals. In spite of this decrease in engraftment and number of HSPCs and MSCs, smoke exposure also altered MSC gene expression of pro-proliferative signaling proteins. Our data thus suggest that smoke exposure leads to dysregulation of hematopoiesis through disruption of MSC signaling pathways in addition to decreasing MSC number. This may serve as one mechanism by which smoke exposure promotes greater peripheral leukocyte production in cigarette smokers. These data also offer potential targets of therapeutic intervention with regards to both bone marrow donor and transplant recipient with a history of cigarette smoke exposure."}
+{"text": "Aortic valve replacement is the second most common cardiothoracic procedure in the UK. With an ageing population, there are an increasing number of patients with prosthetic valves that require follow-up. Imaging of prosthetic valves is challenging with conventional echocardiographic techniques making early detection of valve dysfunction or complications difficult. CT has recently emerged as a complementary approach offering excellent spatial resolution and the ability to identify a range of aortic valve replacement complications including structural valve dysfunction, thrombus development, pannus formation and prosthetic valve infective endocarditis. This review discusses each and how CT might be incorporated into a multimodal cardiovascular imaging pathway for the assessment of aortic valve replacements and in guiding clinical management. The utility of cardiac CT for the assessment of possible aortic valve replacement dysfunction has risen rapidly over the past 10\u2005years following a similar, albeit delayed, trajectory to CT coronary imaging. It can be used to assess mechanical and bioprosthetic valves inserted surgically as well valves inserted using transcutaneous aortic valve implantation (TAVI). Clinicians familiar with both cardiac CT and valvular heart disease have identified a number of specific situations where CT can help in the assessment of possible aortic valve replacement dysfunction by providing complementary diagnostic information to transthoracic echocardiography, transoesophageal echocardiography and cardiac MR. These include the identification of pannus formation, thrombus, premature bioprosthetic leaflet degeneration, assessment of bileaflet mechanical valve leaflet motion and aortic root abscess formation. While the role of cardiac CT is relatively new in this setting, its use is steadily expanding across the world, with many experienced centres now using it routinely. This article evaluates the evidence in support of cardiac CT imaging for the detection of possible aortic valve replacement dysfunction and aims to prompt clinicians to consider it in specific clinical scenarios.Selecting the appropriate prosthetic heart valve has traditionally been a difficult decision for many patients undergoing surgical aortic valve replacement. However, recent advances in bioprosthetic valve design, coupled with an ageing population, have witnessed increasing use of these valves in preference to metallic valves. With the recent addition of TAVI, the number of patients with functioning bioprostheses is only set to expand further. Surveillance of bioprosthesis function, looking for evidence of valve degeneration, forms an integral part of the long-term management of patients with these valves and a substantial healthcare burden.Structural valve dysfunction can have catastrophic consequences, yet its underlying pathophysiology remains incompletely understood. The term structural valve dysfunction encompasses intrinsic functional changes to the valve leaflets including retraction or tearing, progressive stenosis and disruption of the annular housing or sewing ring. The principal pathological driver behind this degeneration and eventual failure appears to be leaflet calcification. This most commonly results in valvular regurgitation due to tearing of the leaflets but may also cause increasing valve stiffness, restenosis and peripheral embolism.The mechanisms driving prosthetic valve calcification are incompletely understood with several different processes having been implicated.While large-scale clinical trials are currently lacking, the requirement for improved assessment of bioprosthetic valve calcification was recently illustrated in the case of severe bioprosthetic valve obstruction in a 13-year-old girl who died suddenly just 23\u2005months after implantation of a bovine pericardial aortic bioprosthesis.et alOne of the major advantages biological prosthetic heart valves have over mechanical alternatives is the lack of a requirement for long-term anticoagulant use. During bioprosthesis endothelialisation, in the first 3\u2005months after implantation, thrombus formation can occur in 0.8\u20134.0% of cases.et alLeetmaa In light of the asymptomatic presentation of cusp thrombosis that occurs in spite of dual-antiplatelet therapy, important questions have been raised regarding the clinical relevance of hypoattenuated thickening and whether CT may more appropriately stratify antithrombotic therapy following transcatheter valve implantation. Importantly, the clinical significance of HALT has not been validated beyond these observational studies and the recent publication of low 30-day stroke rates following TAVI suggests that the presence of this finding does not always translate into significant thromboembolic events.Imaging of mechanical prosthetic valves has traditionally been performed using transthoracic echocardiography, transoesophageal echocardiography and fluoroscopy.Acquired mechanical prosthetic valve obstruction (PVO) is an uncommon but serious and potentially fatal complication of valve replacement.30Cardiac CT in suspected acquired mechanical PVO enables evaluation of leaflet opening and closing angles, dynamic leaflet motion and the composition of perivalvular masses valve helping to differentiate between valve thrombosis and pannus formation.33Prosthetic valve infective endocarditis carries a very high in-hospital mortality rate of 20\u201340%.37While the temporal resolution of echocardiography often means that highly mobile vegetations are better visualised on echocardiography, large prosthetic valve vegetations can be readily seen on CT as microlobulated, hypoattenuating lesions attached to the leaflets or sewing ring.35et alIn 2014, Ghersin 2.40Multiple factors can affect image quality when assessing mechanical aortic valve prostheses using CT, in particular the presence of cardiac arrhythmia and older prosthetic valve types.Based on current practice in experienced valve centres, we suggest that CT should be performed as an anatomical assessment following transthoracic echocardiography in patients with suspected prosthetic aortic valve dysfunction  and 5. TThe diagnosis and management of aortic valve replacement dysfunction remains a significant clinical challenge. Cardiac CT provides complementary assessments of these valves allowing detection of structural dysfunction, leaflet calcification, thickening, thrombus and pannus formation. This can help to stratify downstream management and clinical decision-making as part of multimodality imaging approach."}
+{"text": "In utero exposure to infections is associated with adverse neurocognitive outcomes in the offspring. Elevated maternal prenatal serum inflammatory markers, such as C-reactive protein (CRP), have been associated with increased risks of neurodevelopmental disorders, including schizophrenia, later in life. The objective of this study is to investigate the associations between elevated serum concentrations of CRP in early gestation, prospectively assayed in maternal sera, and adolescent psychotic experiences and academic performance. We hypothesised that elevated maternal CRP is associated with adolescent psychotic experiences and poorer academic performance.Using data from the Northern Finland Birth Cohort 1986 (NFBC1986), a prospective birth cohort including data since before birth, we examined the association between maternal CRP levels in early gestation  and adolescent psychotic experiences  and poorer academic performance , controlling for sex and maternal education level using multivariable regression analysis. Prior to analyses we determined there was sufficient power to detect small associations (OR>1.68) for these variables.After controlling for sex and maternal education, those in the highest tertile of prenatal maternal CRP had increased odds of auditory hallucinations (on the PROD-screen) at age 16 years , and poorer school academic performance .Maternal prenatal immune activation is associated with neurodevelopmental outcomes in adolescent offspring. This work extends previous findings regarding prenatal/childhood immune activation and clinical psychiatric diagnoses in adult offspring."}
+{"text": "Salmonella enterica subsp. enterica serovar Poona strain ATCC BAA-1673. We employed in silico bioinformatics tools to subtract the strain-specific paralogous and host-specific homologous sequences from the bacterial proteome. The sorted proteome was further refined to identify the essential genes in the pathogenic bacterium using the database of essential genes (DEG). We carried out metabolic pathway and subcellular location analysis of the essential proteins of the pathogen to elucidate the involvement of these proteins in important cellular processes. We found 52 unique essential proteins in the target proteome that could be utilized as novel targets to design newer drugs. Further, we investigated these proteins in the DrugBank databases and 11 of the unique essential proteins showed druggability according to the FDA approved drug bank databases with diverse broad-spectrum property. Molecular docking analyses of the novel druggable targets with the drugs were carried out by AutoDock Vina option based on scoring functions. The results showed promising candidates for novel drugs against Salmonella infections. The emergence of novel pathogenic strains with increased antibacterial resistance patterns poses a significant threat to the management of infectious diseases. In this study, we aimed at utilizing the subtractive genomic approach to identify novel drug targets against Salmonella enterica subsp. enterica serovar Poona str. ATCC BAA-1673 using the subtractive genomics approach.Recent progress in the field of computational biology and bioinformatics has generated various in silico analysis and drug designing approaches, eliminating the time and cost involved in the trial and error experimentations that go into drug development . These mSalmonella enterica subsp. enterica serovar Poona str. ATCC BAA-1673 is a potent food-borne pathogen in humans  N-acetyl-glucosamine-deacetylase and 3-deoxy-manno-octulosonate cytidylyltransferase (CMP-KDO synthetase) are associated with lipopolysaccharide biosynthesis pathway. Phosphate regulon response regulator OmpR, nitrogen regulation sensor histidine kinase GlnL, and response regulator CheB are associated with two-component system pathway. LPS is composed of a conserved core oligosaccharide, lipid A, linked to a variable O-antigen in the cell membrane of the Gram-negative bacteria, thus providing outer membrane stability [ Salmonella Poona have developed pathways that attribute resistance to CAMP [The proteins in tability . Drug th to CAMP , 20. Met to CAMP , 18. ThuThe current study was further reinforced by performing comparative docking studies of the novel druggable proteins with the ligands. Binding affinities from docking were compared between our target proteins and intended targets from other species against the corresponding drug. The shortlisted potential drug targets showed a pattern of similar binding characteristics, similar residues involved in the active site, and lower free energy \u20137. Thus, Salmonella Poona system. Among these, 11 proteins were already highly identical with the FDA approved drug targets. 6 proteins were proposed as novel drug targets to combat against Salmonella Poona which showed moderate similarity (65\u201330%) with the targets of FDA approved drugs that were used against other organisms. Furthermore, docking studies were used to predict the binding of existing FDA approved drugs to the novel targets within the proteome of the pathogen and also with the drug-specific FDA approved database target to compare the binding pattern between them.The vast array of information regarding the proteomes and genomes of various prokaryotic organisms and knowledge obtained from the human genome project can be manipulated to accelerate drug designing and gain further knowledge of pharmacogenomics in the treatment of bacterial infections. Subtractive genomics can aid in the identification of proteins targeted by existing FDA approved targets. A total of 52 potential targets were found within the"}
+{"text": "Dear SirAlimentary tract duplications are epithelial-lined cystic or tubular structures attached to bowel wall and supplied by mesenteric vessels. Association between intestinal malrotation and duplication cyst, especially of jejunal location is rarely mentioned in literature[1-5]. We are reporting a rare coexistence of isolated jejunal duplication cyst and malrotation in a neonate with intestinal obstruction.A 15-day-old male neonate was brought to emergency for multiple episodes of bilious vomiting. The baby was born full-term by spontaneous vaginal delivery at home and antenatal ultrasonography(USG) was not done. At presentation, he was 2500 gm, moderately dehydrated, pulse 160/min and respiratory rate was 46/min. Resuscitation was started immediately and the nasogastric tube inserted. Abdomen was soft, non-tender and a mobile mass was palpable in left upper abdomen. Plain X-ray abdomen showed distended stomach and duodenum. Rest of the abdomen was gasless, but there was presence of rectal gas in pelvis . USG revealed a well defined thick walled cystic lesion in left mid abdomen measuring 42\u044537mm suggestive of duplication cyst . Doppler imaging showed \"Whirlpool sign\" in epigastric region with superior mesenteric vein (SMV) curving from right to left of superior mesenteric artery (SMA) suggesting midgut malrotation . At surgery, a non-communicating jejunal duplication cyst, intimately adherent to jejunal wall and compressing the intestinal lumen was found . Malrotation was also present which was corrected. Duplication cyst was excised along with a portion of adjoining jejunum. End-to-end jejunal anastomosis was done. Postoperative period was uneventful. Combination of enteric duplication and intestinal malrotation is a rare entity and may present as an acute surgical emergency [1-5]. Gastric and duodenal distension on plain X-ray of abdomen is suggestive of duodenal obstruction. The presence of rectal gas in addition to dilated stomach and duodenum will commonly point towards partial duodenal obstruction. This can occur in malrotation due to compression of distal duodenum by Ladd's bands [3]. Similarly our preoperative suspicion was malrotation on plain X-ray abdomen. Color Doppler imaging showing Whirlpool flow pattern of SMV around SMA is suggestive of midgut malrotation. Ultrasonography is very reliable in diagnosing duplication cysts.It will show an inner hyperechoic rim of mucosa-submucosa and an outer hypoechoic rim of muscular layer [2]. Duplication cysts are thick walled because it is composed of smooth muscle and mucosa as opposed to other types of cysts such as mesenteric and omental cysts. Our preoperative diagnosis coincided with operative findings.Surgical removal of duplication cyst preserving normal bowel is possible in some cases, but is extremely difficult [1]. Resection of duplication with the native bowel is the usual procedure due to common blood supply . This case represents a rare coexistence of two congenital malformations of GIT. Ultrasonography is very helpful in detecting both duplication cyst and malrotation.Source of Support: NilConflict of Interest: None"}
+{"text": "Neurodegenerative disorders, such as Alzheimer\u2019s disease (AD), are associated with characteristic patterns of neuropathological spread in the brain. Disease progression is usually accompanied by regional atrophy that can be detected noninvasively using structural magnetic resonance imaging (MRI). A wealth of data has demonstrated the value of quantitative measurements of regional atrophy in AD, suggesting that volumetric MRI (vMRI) may be a useful clinical tool. vMRI provides biological evidence of neurodegenerative disease in patients with cognitive impairment. However, several hurdles impede implementation of vMRI in clinical practice. These include a lack of standardized MRI acquisition protocols, spatial distortions in MRI data, labor-intensive vMRI methods susceptible to interoperator variability, a lack of normative ranges for volume measures, and difficulty integrating vMRI in clinical workflow. Advances in vMRI have resulted from multi-institutional studies of brain imaging, such as the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI), and help address these challenges. New, fully-automated measures of brain structure volumes coupled with large, multi-center studies using standardized MRI protocols now allow the development of age-adjusted normative ranges for vMRI. Such advances are critical for providing physicians a framework for assessing the pattern and degree of regional atrophy in a patient's brain and applying vMRI in clinical practice."}
+{"text": "Impairments in self-assessment are commonly found in people with schizophrenia and impairments in introspective accuracy (IA) predict impaired functional outcome. previous studies have suggested mis-estimation of cognitive and functional skills predict impairment in everyday functioning at least as much as ability scores. In this study, we examined self-assessment of social cognitive ability and related these self-assessments to assessments of social cognition from informants, to performance on tests of social cognitive ability, and to everyday outcomes. The difference between self-reported social cognitive abilities and informant ratings was our measure of IA.People with schizophrenia (n=135) performed 8 tests of social cognitive abilities. They also rated their social cognitive abilities on the Observable Social Cognition Rating Scale (OSCARs). High contact informants also rated social cognitive ability and everyday outcomes, while unaware of the patients\u2019 other scores. Social competence was also measured with a performance-based assessment and clinical ratings of negative symptoms were also performed.Patient reports of their social cognitive abilities were uncorrelated with performance on social cognitive tests and with three of the four domains of everyday functional outcomes. IA, in specific overestimation of performance compared to informant ratings, predicted impaired everyday functioning across all four functional domains. IA scores predicted functional outcomes even when the influences of social cognitive performance, social competence, and negative symptoms were considered in regression models. Thus, self-assessment of social cognition had a relatively specific impact social outcomes.Mis-estimation of social cognitive ability was a more important predictor of social and nonsocial outcomes in schizophrenia than performance on social cognitive tests. These results suggest that consideration of IA is critical when attempting to assess causes of everyday disability and when implementing interventions aimed at disability reduction."}
+{"text": "Until now, no consensus is reached for the standardized assessment and quantification of extent and severity of myocardial ischemia and necrosis by cardiac magnetic resonance imaging (CMR). However, there is a good evidence base suggesting that these parameters might ameliorate established risk prediction models and thus might lead to an improved management of patients with stable coronary artery disease (CAD). Objective of this study therefore is to elaborate an easy-to-use algorithm for the quantification of ischemia and necrosis and to validate the obtained data in a large cohort of CAD patients.Patients with known or suspected CAD referred for adenosine-perfusion CMR were consecutively and prospectively enrolled. Examinations were conducted on a 1.5 Tesla whole-body scanner  using a 5-element phased array surface receiver coil. All patients underwent standard first-pass perfusion imaging  under adenosine infusion for the detection of myocardial ischemia and late gadolinium enhancement (LGE) imaging  for the assessment of myocardial necrosis. Based on these sequences, ischemia and necrosis were quantified using a novel algorithm.Primary endpoint was defined as combination of cardiac death, non-fatal myocardial infarction and stroke. Several risk prediction models containing clinical and CMR parameters were built and analyzed with regard to correct risk stratification and endpoint prediction.The study cohort consisted of 845 patients. Median follow-up was 3.66  years. During this time, 61 primary endpoints occurred. Cutoff values for myocardial ischemia and LGE could be defined . A risk prediction model containing this information proved to be superior in comparison to models based on conventional CMR features .Myocardial ischemia and necrosis above the defined cutoff values are strongly associated with major clinical endpoints. Quantification of these parameters provides additive information and leads to improved risk stratification."}
+{"text": "Cognitive impairments are a core feature in schizophrenia patients and are also observed in first-degree relatives of the schizophrenia patients. However, substantial variability in the impairments exists within and among schizophrenia patients, first-degree relatives and healthy controls. A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories.Here, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery  among 81 schizophrenia patients, 20 unaffected first-degree relatives and 25 healthy controls. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses , cognitive clustering was performed using a k-means clustering analysis approach, and differences in the BACS subscales  among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined.As expected, there were significant differences in the five BACS subscales among the diagnostic groups . The cluster-analytic approach generated three meaningful subgroups: (i) neuropsychologically normal , (ii) intermediate impaired  and (iii) widespread impaired . The cognitive subgroups were mainly affected by the clinical diagnosis , and significant differences in all BACS subscales among clusters were found . The effects of the diagnosis (SCZ<FR<HC) and cognitive clusters (Clusters 3<2<1) on brain volumes overlapped in the frontal, temporal and limbic regions. Frontal and temporal volumes were mainly affected by the diagnosis, whereas the anterior cingulate cortex volumes were affected by the additive effects of diagnosis and cognition .We investigated the cognitive heterogeneity and cognitive continuum among schizophrenia patients, first-degree relatives and healthy controls. The cognitive clustering approach without using clinical diagnoses successfully produced more homogeneous cognitive clusters: a neuropsychologically normal, an intermediately impaired and a globally impaired cognitive cluster. Clinical diagnoses  were not evenly distributed into the three clusters; i.e., these clusters were mainly affected by clinical diagnoses. Both diagnoses and cognitive clusters were associated with decreased anterior cingulate cortex volumes. Our findings demonstrate a cognitive continuum among schizophrenia patients, first-degree relatives and healthy controls and support the hypothesis that cognitive impairments and the related anterior cingulate cortex volumes would be useful intermediate phenotypes in the pathophysiology of schizophrenia."}
+{"text": "Christopher et al. (see pages 5159\u20135172) used multi-temporal, Normalised Difference Vegetative Index (NDVI) measurements with crop simulation modelling to demonstrate the value of various stay-green phenotype parameters for improving grain yield across different environment types.Improved genotypic performance in water-limited environments relies on traits, like \u2018stay-green\u2019, that are robust and repeatable, correlate well across a broader range of target environments and are genetically more tractable than assessment of yield Plant breeding is a slow and costly process. The potential release of a new, improved crop variety is limited by many factors, including the extent of genetic variation in key traits that contribute to yield, the confidence a breeder has in the selected phenotype and its association with underlying genotype, and the genotypic association of selected traits with extrapolation to performance across environments. Yield is phenotypically complex, reflecting an underlying genetic complexity and often unpredictable gene\u2013environment interactions, and hence selection for less complex surrogates is desirable.per se.Selection for greater yield in water-limited and hot environments is particularly challenging owing to reduced heritability that reduces the breeders\u2019 ability to identify elite families or lines. Frameworks reflecting underlying biological understanding of adaptation have been hypothesized and numerous traits suggested specifically targeting adaptation to target environments  cover and NDVI scores are also given for each assessment date.LiDAR incorporating a red laser captured the bi-weekly change in vertical distribution of the green vegetation profile . The useAssembling all bi-weekly LiDAR images together generates a temporal point-cloud detailing changes in canopy development for any genotype in a population. Box 3 compares canopy development throughout the season for two wheat NILs contrasting in leaf erectness. Differences in plant stature and canopy erectness are clearly demonstrated with maintained spacing between rows of plants for the erect NIL C676\u2013, whereas canopy closure occurred early for the planophile leaf NIL C676+.\u00ae thermo-imaging sensors .Cooler canopies infer greater stomatal conductance and potentially photosynthetic rates (The work of"}
+{"text": "Background: Antipsychotic-induced weight gain (AIWG) and other adverse metabolic effects represent serious side effects faced by many patients with psychosis that can lead to numerous comorbidities and which reduce the lifespan. While the pathophysiology of AIWG remains poorly understood, numerous studies have reported a positive association between AIWG and the therapeutic benefit of antipsychotic medications.Objectives: To review the literature to (1) determine if AIWG is consistently associated with therapeutic benefit and (2) investigate which variables may mediate such an association.Data Sources: MEDLINE, Google Scholar, Cochrane Database and PsycINFO databases were searched for articles containing all the following exploded MESH terms: schizophrenia [AND] antipsychotic agents/neuroleptics [AND] (weight gain [OR] lipids [OR] insulin [OR] leptin) [AND] treatment outcome. Results were limited to full-text, English journal articles.Results: Our literature search uncovered 31 independent studies which investigated an AIWG-therapeutic benefit association with a total of 6063 enrolled individuals diagnosed with schizophrenia or another serious mental illness receiving antipsychotic medications. Twenty-two studies found a positive association while, 10 studies found no association and one study reported a negative association. Study variables including medication compliance, sex, ethnicity, or prior antipsychotic exposure did not appear to consistently affect the AIWG-therapeutic benefit relationship. In contrast, there was some evidence that controlling for baseline BMI/psychopathology, duration of treatment and specific agent studied  strengthened the relationship between AIWG and therapeutic benefit.Limitations: There were limitations of the reviewed studies in that many had small sample sizes, and/or were retrospective. The heterogeneity of the studies also made comparisons difficult and publication bias was not controlled for.Conclusions: An AIWG-therapeutic benefit association may exist and is most likely to be observed in OLZ and CLZ-treated patients. The clinical meaningfulness of this association remains unclear and weight gain and other metabolic comorbidities should be identified and treated to the same targets as the general population. Further research should continue to explore the links between therapeutic benefit and metabolic health with emphasis on both pre-clinical work and well-designed prospective clinical trials examining metabolic parameters associated, but also occurring independently to AIWG. Second generation antipsychotics  are the cornerstone of schizophrenia treatment. They effectively reduce psychotic symptoms while demonstrating a reduction in extrapyramidal side effects as compared to their typical, or first generation counterparts. However, SGAs are not without their own set of common side effects. Numerous studies have linked SGAs to metabolic changes which place patients at risk for cardiovascular complications, including antipsychotic-induced weight gain (AIWG), dyslipidemia, insulin resistance and type-2 diabetes , and olanzapine (OLZ), representing the two SGAs with the most adverse metabolic profile. Despite differences among agents, even the SGAs considered to be most metabolically neutral, , are associated with significant weight gain in antipsychotic antipsychotic-na\u00efve individuals Correll, . MoreoveDespite the associated cardio-metabolic morbidity, the underlying causes of AIWG and other metabolic changes remain largely elusive. Increased food intake appears to be a component  and 5-HT2c receptor (HTR2C) genes have been substantially investigated. Although DRD2 variants have been associated with improvement of psychopathology  and glucagon-like peptide-1 (GLP-1) were reported to be associated with AIWG. Leptin plays a role in regulating circulating insulin  is a gastric hormone which stimulates the secretion of insulin. Previous associations have been reported between AIWG and GCG rs13429709 in OLZ- or CLZ- treated patients, as well as, the SULT4A1-1 haplotype in OLZ-treated patients from the CATIE trial for which patients had greater clinical response but gained significantly less weight        include MC4R). MC4R has been implicated in appetitive behavior, as well as, metabolic and weight regulation  has been associated with SGA-related AIWG in at least three independent samples  might be associated with AIWG, with each of them contributing limited risk, as expected in complex phenotypes. While there might be genetic variants which contribute to AIWG and therapeutic benefit simultaneously, there is a paucity of studies addressing this relationship and questions remain if AIWG and therapeutic benefit operate independently, i.e., where AWIG would be a pure side effect without therapeutic benefit.In this review, we set out to evaluate whether an association between AIWG and/or other antipsychotic-related metabolic effects  exists in relation to the therapeutic benefit of antipsychotics, across illness stage , ethnicities and study designs. We also discuss evidence whether such an association could be spurious vs. a true phenomenon with clinical implications. If indeed a true association exists between antipsychotic-induced metabolic dysregulation and treatment response, this would carry important clinical implications, such as the ability to safely target metabolic side-effects without compromise of treatment response, and the development of metabolically neutral yet effective drugs.To answer our research questions, we conducted a systematic review of studies investigating the association between therapeutic benefit and AIWG. We searched for relevant systematic review databases, including PROSPERO and the Cochrane Database, and found no similar reviews on this topic. We also followed the PRISMA guidelines and completed a PRISMA checklist (see Supplementary Table schizophrenia [AND] antipsychotic agents/neuroleptics [AND] (weight gain [OR] lipids [OR] insulin [OR] leptin) [AND] treatment outcome. Results were limited to full-text, English journal articles that studied humans up to a publication date of November 2016. The resulting abstracts were reviewed by ATR and MKH and those articles of relevance were assembled. Each of these articles was then hand-searched by ATR and MKH and only those that investigated the association between AIWG or antipsychotic-induced metabolic changes  and therapeutic benefit either by correlation or comparison were included in further analysis. The bibliographies of the remaining articles were then hand-searched by ATR for further relevant articles and any of these additional articles which investigated for an AIWG/metabolic changes and therapeutic benefit link were included in our analysis. Finally, articles that did not perform a statistical analysis were excluded from our analysis.We searched MEDLINE, Google Scholar and PsycINFO databases for articles containing all the following exploded MESH terms combine in the following way: p < 0.05) correlation between AIWG and therapeutic benefit or a statistically significant (p < 0.05) difference in measures of therapeutic benefit relative to weight gain/metabolic changes. In addition, we performed an exploratory analysis to investigate clinical and demographic factors which might impact the association between AIWG and therapeutic benefit to identify potential mechanisms and mitigating factors.Our primary outcome of interest was the examination of a correlation between AIWG metabolic changes and therapeutic benefit. A study population was considered to provide evidence for an AIWG/metabolic changes and therapeutic benefit association when patients treated with an antipsychotic showed a statistically significant   . Study length ranged from 4 to 384 weeks. Weight change was the most commonly reported metabolic effect; 22 of the 31 studies examining AIWG demonstrated evidence for an association between weight gain and symptom improvement. Eight studies found no significant association and only 1 study showed evidence for the reverse relationship . Examining the studies according to study design, DBRCTs and prospective trials demonstrated roughly the same proportion of studies which found an association (67%), while post-hoc analysis of the CATIE trial, Hermes et al. , OLZ (19 studies), risperidone (14 studies) and haloperidol (8 studies) were the most commonly used antipsychotics in our examined studies . Several studies examined specific domains of psychopathology in relation to metabolically-related changes during treatment. Improvement in both positive and negative symptoms appeared to be similarly correlated with AIWG  as compared to those with clinical deterioration  which have rapid weight gain trajectories showed an AIWG-therapeutic benefit association more consistently earlier-on in treatment than lower metabolic liability antipsychotics which have a slower weight gain trajectory. Finally, and notably, the individual antipsychotic examined appeared to influence the AIWG-therapeutic benefit association: those published studies looking at highest metabolic liability antipsychotics, specifically OLZ and CLZ, appeared more likely to show an association between weight gain and improvements in psychopathology, whereas those employing risperidone or haloperidol reported an association less frequently.If indeed there is a correlation between AIWG and therapeutic efficacy, an important question becomes: what is the causal nature of this relationship? There are three potentially overlapping explanations for this association: (1) weight gain directly causes clinical improvement; 2) clinical improvement directly causes weight gain; (3) antipsychotic activity of the drugs causes both AIWG and therapeutic benefit by a) common/interdependent or b) independent/mutually exclusive pathways  and therapeutic response in schizophrenia would have important clinical implications. If a degree of metabolic dysregulation is necessary for therapeutic effects in a subset of patients, this may mean that as clinicians we may have to accept that a certain trade-off between cardiovascular health and mental health is inevitable. By the same token, an early and rapid onset of metabolic changes could potentially be used as a marker of good clinical response. Identification of specific metabolic pathways with overlap to treatment response may be exploited to develop more efficacious treatments.Despite these potential implications, the available literature examining the association between antipsychotic-induced metabolic dysregulation and therapeutic benefit does not allow us to draw firm conclusions as to the clinical significance of what appears to suggest a \u201cstatistical,\u201d and somewhat variable association noted mainly between AIWG and treatment response. Thus, given our current state of knowledge, the following observations should be emphasized: (1) AIWG, insulin resistance, and dyslipidemia are considered modifiable, and treatable cardiovascular risk factors; (2) these should be screened for and treated at minimum according to current guidelines , we chose not to undertake a meta-analytical approach. We also did not control for a publication bias in our sample of studies which may have skewed our results in favor of a positive result .In conclusion, this review supports an association between AIWG and therapeutic benefit in patients with schizophrenia, but evidence in terms of clinical significance remains sparse. Additionally, this link was weighted toward patients treated with OLZ and CLZ suggesting these medications possess a shared unique mechanism of action that may relate to their metabolic liability. In this regard, we speculate that the unique effects of CLZ and OLZ on insulin dysregulation could possibly indirectly explain the link between AIWG and therapeutic benefit in a subset of patients. Further research should continue to explore the links between therapeutic benefit and metabolic health with emphasis on both pre-clinical work , and well-designed prospective clinical trials examining metabolic parameters associated, but also occurring independently to AIWG. Evidence from genetic studies examining genes implicated in energy homoeostasis or appetite/satiety regulation and also overlapping with clinical improvement may also provide clues as to shared pathways. More recent results have also pointed to a role of the gut microbiome in the etiology of schizophrenia and in antipsychotic treatment outcomes, which warrants further investigation (Kanji et al., AR and VM summarized studies and drafted the manuscript. AC and IG contributed to drafting and revising the manuscript and enhanced succinctness and clarity. DM and MH contributed clinical and basic expertise in AIWG and therapeutic benefit, overseeing the synthesis of extracted information and manuscript drafting and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The ideal balance between viral oncolysis and immune stimulation is unknown yet very consequential. Cytolysis from virus replication exposes previously unexposed cancer antigens to immune effector cells which are attracted to the area by the virus in the context of a danger response and can attack the tumor; however the immune cells can also remove the virus, and thereby limit viral oncolysis.Oncolytic herpes simplex virus (oHSV) therapy offers great promise at targeting difficult-to-treat solid tumors as evidenced by the first FDA approval of an oncolytic virus, modified HSV-1 talimogene laherparepvec  to treat advanced melanoma [Researchers have explored combination approaches with oHSVs including various chemotherapeutics and low-dose radiation to maximize both viral oncolysis and the effect of the added therapy. In most combination studies with chemotherapy drugs, apoptosis was increased but viral replication was not enhanced -4. Interin vivo thereby prolonging oncolysis possibly by preventing the influx of virus-mediated NK cells that may limit virus replication. 3) Alisertib prevented the increase of monocyte myeloid derived suppressor cells (MDSCs) induced by HSV1716. MDSCs have been shown to be pro-tumorigenic. Taken together, these exciting results demonstrate how a combination strategy may be used to not only improve the effectiveness of oncolytic virotherapy but also increase the efficacy of the combined drug. Further studies are needed to determine if there is one principal mechanism resulting in the increased antitumor effect or if each of these findings (and perhaps others not yet described) combined are responsible for the outcomes. Additionally, the generalizability of these findings to other models will be interesting to investigate.In a recent issue of Oncotarget, Currier et al. describe the synergistic effects of combining Aurora A Kinase inhibitor alisertib (MLB8237) with HSV1716, a first-generation oHSV currently in phase I clinical trial in children with non-central nervous system solid tumors (NCT00931931), in neuroblastoma and malignant peripheral nerve sheath cell lines [In addition to maximizing virus replication and the effect of an added agent, a critical challenge remains exploiting the immune system to create a sustained anti-tumor response. The combination of HSV1716 and alisertib removed unfavorable MDSCs which are known to promote pro-tumorigenic M2 macrophages. Additional opportunities exist with adjuvant immunotherapies such as natural killer (NK) cell therapy and checkpoint molecule inhibitors. Recently, researchers demonstrated synergy between bortezomib, a proteasome inhibitor, and oHSV in causing inflammatory necroptotic tumor cell death ["}
+{"text": "Despite an increasing research and clinical focus on trans-diagnostic approaches to mental health, it remains unclear whether different diagnostic categories share a common neuronatomical basis. The current investigation sought to investigate whether a shared (trans-diagnostic) set of structural alterations characterized schizophrenia, depression, post-traumatic stress disorder and obsessive-compulsive disorder, and determine whether any such alterations reflected markers of psychiatric illness or pre-existing familial vulnerability.A total of 404 patients with a psychiatric diagnosis were recruited  alongside 201 healthy controls and 20 unaffected first-degree relatives. We collected structural Magnetic Resonance Imaging scans from each participant using the same 3.0 Tesla scanner and acquisition sequence, and tested for trans-diagnostic alterations using Voxel-Based Morphometry.We report that the four psychiatric groups were all characterized by significantly greater gray matter volume in the bilateral putamen relative to healthy controls . Furthermore, the volume of this region was positively correlated with severity of symptoms across groups, so that a higher gray matter volume in the putamen was associated with higher severity of symptoms . Bilateral putamen enlargement was also evident in unaffected relatives compared to healthy controls .These findings indicate that increased putamen volume may reflect a trans-diagnostic marker of underlying familial vulnerability to psychopathology. This raises the prospect that this region could be used to assess degree of familiar vulnerability to psychopathology above and beyond traditional diagnostic boundaries. Our investigation provides support to emerging conceptualisations of psychiatric illness, in which each disorder is best understood as a combination of diagnosis-specific features and a trans-diagnostic factor reflecting general psychopathology."}
+{"text": "Therefore, whether mossy fiber sprouting is a potential therapeutic target for epilepsy remains under debate. Moreover, the axon guidance mechanisms of mossy fiber sprouting have attracted the interest of neuroscientists. Sprouting of mossy fibers exhibits several uncommon axonal growth features in the basically non-plastic adult brain. For example, robust branching of axonal collaterals arises from pre-existing primary mossy fiber axons. Understanding the branching mechanisms in adulthood may contribute to axonal regeneration therapies in neuroregenerative medicine in which robust axonal re-growth is essential. Additionally, because granule cells are produced throughout life in the neurogenic dentate gyrus, it is interesting to examine whether the mossy fibers of newly generated granule cells follow the pre-existing trajectories of sprouted mossy fibers in the epileptic brain. Understanding these axon guidance mechanisms may contribute to neuron transplantation therapies, for which the incorporation of transplanted neurons into pre-existing neural circuits is essential. Thus, clarifying the axon guidance mechanisms of mossy fiber sprouting could lead to an understanding of central nervous system (CNS) network reorganization and plasticity. Here, we review the molecular and cellular mechanisms of axon guidance in mossy fiber sprouting by discussing mainly  These mThe basically unidirectional projection of mossy fibers is ensured by several axon guidance cues Figure . Studiesin vivo and epileptiform seizures in vitro have replicated this mossy fiber sprouting  has received the most attention . The expd slices , and intd slices . Additiod slices . Taken td slices  nor BDNFd slices  resultedThe BDNF-induced signaling pathway that is involved in mossy fiber sprouting has not been fully identified. The axonal branching induced by neurotrophins, including BDNF, is partly mediated by 3\u2032,5\u2032-cyclic adenosine monophosphate (cAMP) . An optoO-acetylated gangliosides, whose expression has been shown to correlate with axonal growth in several brain regions, did not contribute to mossy fiber sprouting in adult epileptic rats , whose expression was high in the granule cell layer, blocked activity-dependent mossy fiber sprouting in hippocampal slice cultures by preventing the sprouted collaterals from invading the inner molecular layer . Shetty pocampus \u201368 in a After the reverse-traveling mossy fibers enter the molecular layer, they are tightly confined in the inner molecular layer and usually do not invade the middle or outer molecular layers [but see the study from Babb and colleagues , which sWhen the pioneer mossy fibers complete their extension to the molecular layer, it is possible that the following mossy fibers fasciculate with them in a manner guided by contact-dependent axon guidance cues, such as PSA-NCAM, which is expressed on mossy fibers. Based on an organotypic coculture system, it has been suggested that PSA-NCAM serves as a contact cue for the following mossy fibers when diffusible chemoattractants from CA3 are no longer available in the late developmental stage .Adult neurogenesis in the dentate gyrus could also account for additional fasciculation to the sprouted mossy fibers, as it has been suggested that adult-born granule cells are the main source of sprouted mossy fibers after status epilepticus (SE) . DentateThe misguidance of mossy fibers to the inner molecular layer has been demonstrated to be regulated by several molecules Figure . It shouRK and YI discussed and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Within each sensory modality, age-related deficits in temporal perception contribute to the difficulties older adults experience when performing everyday tasks. Since perceptual experience is inherently multisensory, older adults also face the added challenge of appropriately integrating or segregating the auditory and visual cues present in our dynamic environment into coherent representations of distinct objects. As such, many studies have investigated how older adults perform when integrating temporal information across audition and vision. This review covers both direct judgments about temporal information  and judgments regarding stimuli containing temporal information . Although an age-related increase in integration has been demonstrated on a variety of tasks, research specifically investigating the ability of older adults to integrate temporal auditory and visual cues has produced disparate results. In this short review, we explore what factors could underlie these divergent findings. We conclude that both task-specific differences and age-related sensory loss play a role in the reported disparity in age-related effects on the integration of auditory and visual temporal information. The normal aging process degrades both auditory and visual temporal perception, contributing to the difficulties older adults encounter with everyday tasks. For example, age-related impairments in speech comprehension and driving performance are associated with temporal processing deficits within audition  and visiIntegration binds auditory and visual stimuli into a unified percept, altering their perception relative to how they are perceived in isolation . CorrectPhysiological aging affects the auditory and visual pathways from the sensory periphery to the cortex, resulting in a decline in many aspects of temporal perception. Within audition, older age reduces sensitivity to temporal fine structure , amplituWithin vision, many age-related temporal processing deficits have been documented, including reduced flicker sensitivity , reducedFurthermore, sensory decline is typically uneven across vision and audition, though the more adversely affected sensory modality varies between tasks . For exaStudies have investigated age-related changes to various measures of audiovisual temporal perception presumed to reflect multisensory integration, with disparate results for transient stimuli like flashes and beeps. Older adults are more susceptible to the sound-induced flash illusion . In thisAge-related effects on the integration of temporally modulated stimuli depend on audiovisual congruency. Partial integration of non-identical auditory and visual temporal rates distorts perceived rate such that the auditory or visual rate subjectively equivalent to a reference is non-veridical . This efResearch on audiovisual speech perception in aging is also relevant to this review, since the temporal relationships between auditory and visual speech cues facilitatIn the McGurk effect, integration of incongruent auditory and visual speech results in a fused percept that matches neither cue . Most stAltogether, research indicates an age-related increase in the integration of temporally offset auditory and visual events. Older adults perceive the sound-induced flash illusion at larger temporal offsets between auditory and visual stimuli than younger adults . When juTables 1, 2). This suggests that age-related effects on integration may be task-specific, as discussed in the next section.In summary, integration of temporal auditory and visual information may be increased, decreased or unchanged by physiological aging  also influences audiovisual interactions . In contUnfortunately, studies of audiovisual integration in older adults have not employed a consistent definition of what constitutes normal hearing and vision, and may not screen both sensory modalities for age-abnormal changes. Even so, screening measures commonly used in older adults such as audiometric thresholds and visual acuity are poor indicators of other aspects of auditory e.g.,  or visuaAudiovisual integration may not necessarily provide older adults with an effective compensatory mechanism for age-related unisensory decline in temporal information. While older adults often benefit from the provision of complimentary auditory and visual cues, it can be to a reduced extent compared to younger adults. Older adults sometimes demonstrate an increased tendency to synthesize conflicting temporal auditory and visual cues into a unified percept but this is not a universal finding. Further research elucidating how closely integration is linked across different audiovisual tasks is needed to clarify this pattern of results. Currently, it remains unclear to what extent age-related changes in audiovisual temporal perception reflect true changes in integration rather than sequential effects of age-related sensory loss. Future research should account for individual differences in unisensory reliability to distinguish age-related sensory loss from age-related effects on integration.CB: conception and planning of review and wrote the manuscript. YC: planning of review and contributed to the writing of Section \u201cAge-Related Changes in Audiovisual Temporal Perception.\u201d AM and AA: conception of review and revision of the manuscript. All authors approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Psammoma bodies (PBs) are observed most commonly in papillary thyroid carcinoma, meningioma, and papillary serous cystadenocarcinoma of the ovary. We report one case of peritoneal malignant mesothelioma (PMM) with massive deposition of PBs. A 72-years-old man presented with abdominal swelling and marked weight loss. Contrast enhanced computed tomography showed fluid diffuse in peritoneal recesses, thick septa with micronodules in the greater omentum and adjacent enhancement of the thickened peritoneum. The explorative laparoscopy showed diffuse minute parietal peritoneal nodules. The peritoneal biopsy revealed a superficial papillary growth of malignant epithelial-like cells with diffuse involvement of submesothelial tissues. Massive deposition of PBs was observed. Nuclear and cytoplasmic calretinin immunoreactivity was present in neoplastic cells along with membranous D2-40 and membranous/cytoplasmic cytokeratin 5 staining. The patient was treated with chemotherapy . PBs may represent an active biologic process ultimately leading to degeneration/death of tumor cells and retardation of growth of the neoplasm. It may also serve as a barrier against the spread of tumor. Psammomatous malignant mesothelioma may simulate serous psammocarcinoma of the peritoneum. The behavior of serous psammocarcinoma is more closely similar to borderline serous tumor than to serous carcinoma. Further studies are necessary to establish if massive deposition of PBs may define a new variant of psammomatous malignant mesothelioma with a favorable impact to the prognosis of usual psammomatous malignant mesothelioma, as well as in serous psammocarcinoma of the peritoneum. Psammoma bodies (PBs) are concentrically laminated calcific spherules that occasionally appear cracked (psammos [\u201csand\u201d] + oma [\u201ctumor\u201d]). PBs are observed most commonly in papillary thyroid carcinoma, meningioma, and papillary serous cystadenocarcinoma of the ovary . PBs havA 72-year-old man presented with abdominal swelling and marked weight loss. No history of exposure to asbestos was found. Abdominal ultrasound revealed abundant perihepatic, perisplenic and pelvic fluid. Contrast enhanced computed tomography showed fluid diffuse in peritoneal recesses, thick septa with micronodules in the greater omentum and adjacent enhancement of the thickened peritoneum . MalignaPMM is universally regarded as a fatal disease (median survival 6-12 months; mean symptoms-to survival time 345 days [Attanoos and Gibbs reported that PBs may be seen in approximately 5% to 10% cases of PMMs . But the"}
+{"text": "Sparus aurata). Cultured sea breams were fed three isonitrogenous diets. The organically produced feed contained sustainable certified fish meal (45%), fish oil (14%), and organic certified wheat; the laboratory feed contained fish meal (45%), fish oil (14%), wheat meal, and soya meal; and the commercial feed included fish meal (46%), fish oil (17%), soya meal, wheat meal, and corn gluten meal. The organic diet had higher amounts of vitamins A, C, and E; specific amino acids; and minerals that enhanced the biosynthesis of collagen. This study shows that fish fed the organic feed had significantly bigger collagen fibril diameters than the fish fed the conventional feed. Furthermore, the organically fed fish had similarly sized collagen fibril diameters as wild fish. More research is needed to understand the long-term effects and the mechanism and function of fish collagen peptide intake on lipid absorption and metabolism; and to identify dietary regimes that are able to improve whole body lipid profiles and suppress the transient increase of plasma triglycerides.This study aims to measure liver collagen fibril diameter in cultured and wild sea breams ("}
+{"text": "A 52-year-old man with prostatic hyperplasia presented to the emergency department with complaints of lower abdominal pain worsening over three days and inability to urinate. Abdominal examination revealed a protuberant, distended bladder . A FoleyUrinary outlet obstruction is commonly treated by insertion of a Foley catheter, allowing drainage of the distended bladder. Previous recommendations have suggested gradual drainage of an obstructed bladder, for instance by intermittent catheter clamping, to avoid complications of hematuria, hypotension, and post-obstructive diuresis, although the value of this practice is debatable.A systematic literature review of related studies published from 1920 to 1997 found no cases of hematuria severe enough to necessitate further invasive therapy, such as bladder irrigation or blood transfusion.2What do we already know about this clinical entity?Traditional warnings against rapid bladder decompression may prolong definitive care in the ED and result in use of additional resources.What is the major impact of the image(s)?Hematuria is demonstrated after bladder decompression, although the patient suffered no adverse complications.How might this improve emergency medicine practice?Despite the possibility of hematuria, ED patients with bladder outlet obstruction can be rapidly decompressed with low risk of serious sequelae."}
+{"text": "Bladder cancer treatment remains a challenge despite significant improvements in preventing disease progression and improving survival. Intravesical therapy has been used in the management of superficial transitional cell carcinoma (TCC) of the urinary bladder  with specific objectives which include treating existing or residual tumor, preventing recurrence of tumor, preventing disease progression, and prolonging survival. The initial clinical stage and grade remain the main determinant factors in survival regardless of the treatment. Prostatic urethral mucosal involvement with bladder cancer can be effectively treated with Bacillus Calmette-Guerin (BCG) intravesical immunotherapy. Intravesical chemotherapy reduces short-term tumor recurrence by about 20%, and long-term recurrence by about 7%, but has not reduced progression or mortality. Presently, BCG immunotherapy remains the most effective treatment and prophylaxis for TCC  and reduces tumor recurrence, disease progression, and mortality. Interferons, Keyhole-limpet hemocyanin (KLH), bropirimine and Photofrin-Photodynamic Therapy (PDT) are under investigation in the management of TCC and early results are encouraging. This review highlights and summarizes the recent advances in therapy for superficial TCC."}
+{"text": "We report on a 69-year-old male who presented with an indwelling urinary catheter due to obstructive prostatic disease. The patient also complained of impotence. With repetitive prostatic massage combined with antimicrobial therapy the urinary obstruction was released, the patient's urinary symptoms resolved, and sexual function improved."}
+{"text": "Optical coherence tomography angiography (OCTA) is a new, noninvasive technology that enables detailed evaluation of flow in the retinal and choroidal vasculature. The authors believe this to be the first report to describe the optical coherence tomography angiography findings associated with combined central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO). Combined central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO) is a rare vasoocclusive entity that has been associated with multiple etiologies that can cause devastating vision loss \u20138. In thOptical coherence tomography angiography (OCTA) is a new, fast, noninvasive imaging modality that allows detection of blood flow through the retinal and choroidal plexuses without intravenous dye injection . The depThe authors believe this report to be the first to describe the optical coherence tomography angiography findings associated with combined central retinal artery occlusion and central retinal vein occlusion. The commercially available Cirrus 5000 with AngioPlex  was used, without any subsequent image modification or processing.A healthy 69-year-old female presented to the Emergency Department with sudden, painless, visual loss that started immediately following cataract surgery with retrobulbar anesthesia in the left eye (OS) nine days prior to presentation. The patient denied jaw claudication, temporal headache, scalp tenderness, or visual loss in the right eye (OD). Immediately following the event, the patient underwent a work-up which included a transthoracic echocardiogram (TTE), electrocardiogram (EKG), carotid ultrasound, erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP), computed tomography (CT), and magnetic resonance imaging (MRI) of head. All tests were within normal limits.A complete ophthalmologic exam was performed. Best corrected visual acuity was 20/40 OD and hand motion OS. Intraocular pressure measured by Tono-Pen XL (Reichert Technologies) was 18\u2009mmHg OD and 19\u2009mmHg OS. Full ductions were present without pain. Pupils were equally round with an afferent pupillary defect OS. Anterior segment examination in the right eye was significant for a nuclear sclerotic cataract and examination of the left eye revealed corneal edema, trace cell, +1 flare, and a well-centered intraocular lens.Fundus examination by indirect ophthalmoscopy was unremarkable OD. Funduscopic exam OS demonstrated mild disc edema, macular edema, whitening of the macula, subtle tortuosity of vessels, and flame-shaped hemorrhages and cotton wool spots in all quadrants .Spectral domain optical coherence tomography (SD-OCT) was performed on OS and showed increased hyperreflectivity and edema of the inner retina with disruption of the ellipsoid zone (EZ) .OCTA revealed an absence of flow in the foveal and perifoveal area in the superficial and deep retinal capillary plexuses Figures . In contA combined CRAO and CRVO is a rare entity, and the etiology is incompletely understood. Although cardiovascular diseases, hypercoagulopathy, and inflammatory diseases are potential risk factors, our patient presented with a combined occlusion without any history of systemic diseases following cataract surgery with retrobulbar anesthesia \u20134. SeverThe exact mechanism of combined CRAO and CRVO has not been elucidated, but there are multiple mechanisms proposed to explain the association with retrobulbar injection. Combined occlusion could result from optic nerve sheath hematoma secondary to needle penetration or direct injection into the optic nerve sheath , 21. AnoCombined CRAO and CRVO is an ophthalmological emergency that should be recognized as a serious postsurgical complication due to its poor outcome. Without timely intervention, combined occlusion can lead to rubeosis iridis, neovascular glaucoma, retinal necrosis, periphlebitis of the central vein, and eventually permanent vision loss , 22. VarIn the current report, OCTA showed that the vascular flow of the superficial and deep retinal plexuses were both interrupted OS Figures . In contThis case demonstrates clinical features of combined CRAO and CRVO imaged with OCTA following retrobulbar anesthesia associated with cataract surgery. OCTA technology can facilitate diagnosis and extent of combined CRAO and CRVO as it enables discrimination between superficial and deep retinal vasculature. Additional advantages of OCTA compared to FA include faster image acquisition and no potential allergic systemic effects , 23, 24.In conclusion, OCTA is a new, fast, noninvasive imaging technology that has enabled improved understanding of the pathophysiology of many retinal vascular diseases including combined CRAO and CRVO. To the best of our knowledge, this is the first reported case that describes the OCTA findings associated with combined CRAO and CRVO. Future studies with OCTA will hopefully illuminate additional features of combined CRAO and CRVO and provide a better understanding of this complex disease."}
+{"text": "Erectile dysfunction (ED) following treatment for clinically localized prostate cancer, particularly radical prostatectomy (RP), is a major quality of life issue that remains unsatisfactorily addressed. With the introduction and use of cavernous nerve\u2013sparing procedures over the past 25 years, many men recover erections postoperatively that enable sexual intercourse unlike in the prior surgical era, when permanent ED postoperatively was certain. Despite this advance, 26\u2013100% of these patients may never recover normal erectile function (EF). Recent advances in the understanding of ED after RP have stimulated great attention to develop penile rehabilitation programs and neuromodulation. The purpose of penile rehabilitation is to prevent adverse corpus cavernosal tissue structural alterations and thereby maximize the chances of recovering functional erections. Rehabilitation programs are common in clinical practice, but there is no definitive evidence to support their efficacy. Neuromodulation represents another strategy for promoting erection recovery postoperatively. This therapy involves the application of neuroprotective interventions, conceivably targeting biological elements involved in the erection response that are affected by neuropathic injury. Well-conducted, controlled trials with adequate follow-up are required in order to determine the erection preservative benefits of these therapeutic strategies. The purpose of this essay is to describe the mechanisms related to post-RP ED, assess the need for penile rehabilitation and neuromodulation following surgery, and analyze the basic science and clinical trial evidence associated with these applications for preserving EF following prostate cancer treatment."}
+{"text": "The human brain possesses a superior capacity to reorganize and profound plasticity after focal lesions following brain injury such as trauma, ischemia, and degenerative disorders. The concept of plasticity describes the mechanisms that rearrange cerebral organization following a brain injury. The development of sophisticated noninvasive neuroimaging techniques over the past decade provides a unique opportunity to examine brain plasticity in humans and invaluable insights into the mechanisms underlying neuroplasticity. Unifying pathogenesis of brain injury by neuroimaging techniques can be beneficial to develop therapeutic strategies with broad applicability for disease prevention and an opportunity to decrease morbidity and mortality from these disorders in human beings.In this special issue on imaging neural plasticity following brain injury, we compiled a series of articles that represent novel primary research and explore brain plasticity following brain injury. T. Wang et al.  investigate the brain impairments following asymptomatic carotid stenosis by utilizing an integrated MRI including pulsed Arterial Spin Labeling (pASL) 22 MRI, Proton MR Spectroscopy (MRS) and resting-state functional MRI (R-fMRI). They found that hypoperfusion in the left frontal lobe, lower NAA/Cr ratio in the left hippocampus, and decreased connectivity to the posterior cingulate cortex in the anterior part of the default mode network might partly contribute to the cognition impairment in these patients.X. Fan et al.  explore the distinctive brain structural and effective connectivity changes within the semantic cognition network by comparing left and right mesial temporal lobe epilepsy (mTLE) patients and these patients to matched healthy controls. Since seizure attacks were rather targeted than random for patients with hippocampal sclerosis (HS), gray matter atrophy of left mTLE was more serve than that of right mTLE across the whole brain and especially within the contralateral semantic cognition network. This study suggested that left HS patients had a higher vulnerability to seizure attacks, reflecting the compensation strategy. The altered effective connectivity between subregions of the ATL may be the possible reason to explain the more severe name-finding impairment but good comprehension ability.H. Yan et al. (\u201cAltered Effective Connectivity of Hippocampus-Dependent Episodic Memory Network in mTBI Survivors\u201d) examined the altered effective interaction in mild traumatic brain injury (TBI) survivors' episodic memory network. Results presented that mild TBI induced increased bilateral and decreased ipsilateral effective connectivity in the episodic memory network compared with normal controls. This study provided some evidence to note the overrecruitment of the right anterior PFC caused dysfunction of the strategic component of episodic memory, which caused deteriorating episodic memory in mTBI survivors.Z. Guo et al.  aimed to evaluate the effects of high frequency repetitive transcranial magnetic stimulation (HF-rTMS) on stroke patients with motor dysfunction and to investigate the underlying neural mechanism. Fifteen stroke patients were assigned to the rTMS treatment (RT) group and conventional treatment (CT) group. RT group showed better improvement in motor scale and enhanced diffusion metrics in the posterior limb internal capsule, which was associated with motor functions.S. Zhang et al.  explored the cortical thickness and white matter integrity following mild-to-moderate hydrocephalic in children. They found that decreased cortical thickness in the left middle temporal and left rostral middle frontal gyrus in these children compared with normal controls, and diffusion metrics were also decreased in the right body part of the corpus callosum. This study provides the evidence that structural brain changes can be used to monitor long-term outcomes and follow-up in the mild-to-moderate hydrocephalic of children.Finally, N. Ilves et al.  investigate the dysfunctions in the large-scale resting-state functional networks following perinatal stroke in children and its association with congenital hemiparesis and neurocognitive deficits. Results indicated that there were no differences in severity of hemiparesis between the periventricular venous infarction (PVI) and arterial ischemic stroke (AIS) groups. A significant increase in default mode network connectivity (FDR 0.1) and lower cognitive functions were found in children with AIS compared to the controls and the PVI group. The children with PVI had no significant differences in the resting-state networks compared to the controls and their cognitive functions were normal. They further inferred that changes in the resting-state networks found in children with AIS could possibly serve as the underlying derangements of cognitive brain functions in these children.Great progress has been made and demonstrated the role of functional connectivity and structural abnormalities underlying brain injury , while there is also unclarity about whether these brain changes can provide a clue (as a biomarker) to establish prognostic models, develop focused treatments, and stratify patients for interventional trials. U. Horn et al. (\u201cMRI-Biomarkers for Hand-Motor Outcome Prediction and Therapy-Monitoring following Stroke\u201d) conducted a comprehensive review about MRI-biomarkers on the evaluation of corticospinal integrity and functional recruitment of motor resources. Compared with the functional connectivity parameters, corticospinal integrity evaluation using structural imaging showed robust and high predictive power for patients with different levels of impairment. They further suggested a combination of different measures in an algorithm to classify fine-graded subgroups of patients, because the best therapy approaches will become feasible as the subgroup become more specified.This special issue provides promising evidence to elucidating neural plasticity associated with a wide range of brain injuries. These articles may enhance further research into examining whether the neuroprognosis of imaging biomarker is beneficial to treatment selection and effectiveness evaluation following brain injury.Lijun BaiLin AiKevin K. W. Wang"}
+{"text": "Dissociative experiences, including depersonalization and derealisation, represent perturbations of consciousness and selfhood, and are commonly reported by patients during early stages of a psychotic illness. The continuity and integrity of a conscious sense of self is proposed to be grounded upon the control of internal physiological state and its predictive representation through interoception, i.e. the sensing of internal bodily changes. We tested the hypothesized relationship between dissociation and interoceptive deficits in patients with first episode psychosis (FEP), combining behavioural testing with functional neuroimaging.Individuals with first episode psychosis (N=41) and matched community control participants (N=21) performed an interoceptive task (heart-tone synchrony judgments) during functional magnetic resonance imaging (fMRI). Trial-by-trial confidence ratings indexed subjective performance, and measures of metacognitive interoceptive awareness (insight) were derived from confidence-accuracy correspondence. We tested for regional brain activity relating to dissociative symptom scores and objective, subjective and metacognitive aspects of interoception.In patients with FEP, metacognitive impairments in interoception predicted magnitude of dissociative symptoms, accompanied by hypoactivation of right insula cortex. Other dimensions of interoception, and accuracy, confidence and metacognitive insight on an exteroceptive task were unrelated to dissociative symptoms and there were no group differences between FEP patient and control groups.Our findings suggest that symptoms of disturbed conscious integrity and selfhood in early psychosis arise through selective disruption of higher-order metacognitive representations of interoceptive signals. Brain systems supporting the conscious integration of bodily feelings may represent a target for interventions to enhance functioning and, speculatively, mitigate illness progression in psychosis."}
+{"text": "Lung cancer is the most common cause of cancer-related death worldwide, less than 7% of patients survive 10\u00a0years following diagnosis across all stages of lung cancer. Late stage of diagnosis and lack of effective and personalized medicine reflect the need for a better understanding of the mechanisms that underlie lung cancer progression. Quantitative proteomics provides the relative different protein abundance in normal and cancer patients which offers the information for molecular interactions, signaling pathways, and biomarker identification. Here we introduce both theoretical and practical applications in the use of quantitative proteomics approaches, with principles of current technologies and methodologies including gel-based, label free, stable isotope labeling as well as targeted proteomics. Predictive markers of drug resistance, candidate biomarkers for diagnosis, and prognostic markers in lung cancer have also been discovered and analyzed by quantitative proteomic analysis. Moreover, construction of protein networks enables to provide an opportunity to interpret disease pathway and improve our understanding in cancer therapeutic strategies, allowing the discovery of molecular markers and new therapeutic targets for lung cancer. Lung cancer is the most common cancer-related mortality worldwide, with approximately 27% of all cancer deaths per year . Lung caProteins are involved in all biological processes which can be regarded as the final stage of biological information from genome. Proteomics is extremely dynamic and complex due to the continuous response to the change of environment, drug treatment, and post-translational modification . Large-sProteomics is an analysis of dynamic systems in biology which consists a range of diversity that are insufficient to analyze with any single method. Quantitative proteomics not only provides a list of identified proteins, it also quantifies the changes between normal and disease sample profiles in order to generate classification models. Here, we review quantitative proteomics into four major approaches: gel-based, stable isotope labeling, label free, and targeted proteomics for lung cancer studies Fig.\u00a0.Fig. 1ThMr) and isoelectric point (pI)-based separation. DIGE has been developed as a multicolor detection for comparing protein abundance of samples within a single gel, where each protein sample is prelabeled with spectrally distinct fluorescent dye [The first and most important step in quantitative proteomic analysis is the separation of a complex protein mixture . Gel-bascent dye . To reducent dye . Gel-frecent dye . Both gecent dye .15N spirulina with a protein-free chow to overcome the limitation of SILAC to cell culture [For quantitative analysis, stable isotope labeling coupled with mass spectrometry (MS)-based techniques is often performed in cancer research . Mass sp culture .Table 1CTo characterize the post-transcriptional modifications in proteomics, several isobaric reagents were developed for selective labeling such as carbonylated residues and cysteine residues which might expand our knowledge of dynamic system in cancer progression \u201326. MoreLabel-free quantification is an alternative method for samples that cannot directly label, and enables the comparison of protein expression across different samples or treatment regardless the number of samples . Label-fSelected reaction monitoring (SRM), multiple reaction monitoring (MRM), and data-independent acquisition (DIA) are widely used MS-based proteomics which have been considered as true quantification techniques for targeted quantification of protein , 33, 34.Quantitative proteomics allows the discovery of molecular markers and new therapeutic targets for lung cancer. Predictive markers of drug resistance, lung cancer diagnosis, and prognostic markers in lung cancer have also been discovered by quantitative proteomics analysis .Biomarker is a measurable biological indicator found in tissue, cells, blood or other body fluids that may be used for detection, diagnosis treatment and monitoring in cancer research . The chaThe survival rate of lung cancer patients is highly correlated to the stage of lung cancer; therefore, improve the diagnostic strategies for early lung cancer detection may increase patient survival. Hsu et al. identified 133 protein candidates from paired adenocarcinoma (ADC) tissues with different extents of lymph node involvement by iTRAQ-labeling technology coupled with 2D-LC-MS/MS . They fuLabel-free quantitative proteomic analysis was performed and a significant higher protein levels of hepatocyte growth factor (MET), dipeptidyl peptidase IV (DDP4) and Receptor-type tyrosine-protein phosphatase F (PTPRF) in malignant pleural effusion (PE) samples were found comparing to benign and paramalignant PE samples . ProteomA recent study applied highly multiplexed liquid chromatography-selected reaction monitoring (LC-SRM) assay to verify the biomarker candidates in plasma samples for lung cancer. A total of 17 proteins were verified as potent tumor markers, especially, a novel plasma-based biomarker, zyxin (ZYX) was identified as a potential early diagnostic marker for NSCLC . OverallThe major challenge for lung cancer therapy is chemoradioresistance, where protein markers might serve as the potential molecular predictors of drug resistance and overcome this shortage. Recent study of a SILAC-based quantitative proteomic approach has been utilized to evaluate the cellular protein abundance changes upon paclitaxel (PTX) treatment. Tumor suppressor programmed cell death 4 (PDCD4) in lung cancer tissues were positively correlated with the longer overall survival of lung cancer patients with PTX treatment, suggesting that PDCD4 may be used as a predictive marker of resistance to PTX in lung cancer patients . FurtherDuring the stages of drug development, proteomics can also take place in a high-throughput analysis for the identification and optimization of suitable lead compounds. Several tyrosine kinase inhibitors (TKIs) have been approved from the US Food and Drug Administration (FDA) for use in advanced lung cancer. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are the two common biological targets for lung cancer drug development , 50. AppEGFR has become an important biological target for lung cancer. Inhibitors that target EGFR and block the signaling pathway have been developed and are clinically active . Three EChromosomal rearrangements of ALK have been found to be associated with lung cancer and its inhibitors ceritinib are superior for patients with chemotherapy . CeritinOur recent study demonstrated ectopic ATP synthase that presents on the plasma membrane of lung cancer cells is a potential biological target for drug development , 63. CitModern high-throughput technologies generate a huge amount of data, however, proper data mining tools is the key for discovery of cancer-related proteins and networks. Fully understanding of the biological significance of differential protein networks from normal to disease cells depends on the information generated from proteomic datasets. Exploration of proteomic datasets using bioinformatic analysis enables us to elucidate new molecular interactions, protein functional annotation, protein motif and complex interaction and disease pathway.With the advent of high-throughput omics data, bioinformatics has become a viable tool to improve our knowledge of health and disease individuals and it also provides a systems-level approach to interpret organisms and functional activities of their components by studying underneath interactions. Bioinformatics can be defined as a combination of mathematical and computational strategies for interpreting biological processes from the existing raw data. Data curation, tool development, and practical applications are the three major aims for bioinformatics . To dateMathematical and statistical approaches have become essential components for bioinformatics tool development. For example, developing a tool for protein structure requires serious consideration of the primary protein sequence, differential geometry and topology of the protein folding regardless of its biological functions. It is painstaking task for experimental biologists to interpret their dataset without bioinformatics tools, therefore, bioinformatics tool development takes an important part of proteomic and biological researches.Protein-protein interaction (PPI) networks provide an overall picture for the understanding of biological processes in cancer research. Proteins are not functioning solely, they have interactions with other proteins or molecules that mediate signaling pathways and biological processes. Hub proteins are highly connected to other proteins in a network, whereas some others have few interactions . The dysA dynamic PPI network of lung cancer associated with smoking was constructed by bioinformatic analysis using Human Protein Reference Database and Gene Expression Omnibus Database. Yu et al. used the support vector machine (SVM) model and found 520 dynamic proteins and 2754 static proteins and further predicted 7 dynamic PPI subnetworks for lung cancer patients with smoking history .Mathematical modeling is a time and cost-effective method that provides insight into underlying molecular reactions and biological processes as alternatives to conventional laboratory experiments . MathemaChmielecki et al. developed isogenic TKI-sensitive and TKI-resistant pairs of cell line that mimic the behavior of NSCLC with evolutionary cancer modeling . They coSince lung cancer is a heterogeneous disease, a comprehensive and in-depth discovery of lung cancer proteomic profiling is needed for precise target treatment. The microenvironment interface of the tumor cells and host cells directly impacts the tumor-host communication system by affecting signaling and growth factors, therefore cancer processing . To unde"}
+{"text": "Using next generation sequencing we have systematically analyzed a large cohort of 489 patients with bone marrow failure (BMF), including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), aplastic anemia (AA), and related conditions for the presence of germline (GL) alterations in Fanconi Anemia (FA) and telomerase genes. We have detected an increased frequency of heterozygous FA gene mutations in MDS and to lesser degree in AML suggesting that the presence of one normal allele may not be completely protective and indeed heterozygous FA lesions may have a long latency period before hematologic manifestation. In contrast, GL telomerase gene mutations were not associated with increased disease risk. When compared to large control cohorts, we have not detected an increased frequency of damaging variants among telomerase complex genes, including those previously believed to be involved in the pathogenesis of AA. Our results may suggest that while low penetrance and delayed disease onset can confound identification of genetic predisposition factors, GL FA alterations can be also associated with MDS. RUNX1 mutations are associated with thrombocytopenia and subsequent clonal evolution . All the variants from tested genes were extracted for further functional annotation and processing. Sequencing results were annotated using ANNOVAR, http://annovar.openbioinfromatics.org. Mutations that were predicted to be damaging/probably damaging by 4/5 algorithms  were prioritized for further analysis (tier1). This functional pre-processing analysis was also carried out on control population variants that were extracted from ExAC database. Ethnically matched population and the variants extracted that we analyzed were derived from ExAC database consisting 33370 normal, White/Caucassian individuals. For the purpose of this analysis, the candidate alterations were sub-classified to prioritize known disease-prone sequence alterations/mutations (OMIM/Rockefeller Fanconi mutation database)We used Exome Aggregation Consortium (ExAC), Cambridge, MA , according to the manufacturer's protocols. The captured targets were subjected to massive sequencing using Illumina HiSeq 2000 . Generation of .bam files with its preprocessing and detection of somatic point mutations/insertions and deletions was according with GATK best practices.Whole exome capture using SureSelect Human All Exon 50 Mb kit was used for targeted, exome capture according to the manufacture's protocol (SureSelectTargeted sequencing was completed using TruSeq Enrichment library (Illumina). Two panels were created, one for somatic mutations and one for GL variants. Somatic variants were reported previously . List oft-test  and Fisher's Exact test (for discrete data). Reported p-values here are not adjusted for multiple comparisons. Odds ratio were calculated as follows: number of patients with damaging variant multiplied by a number of normal individuals without damaging variants and divided by number of normal individuals with damaging variant multiplied by number of patients without damaging variants.For comparison between groups, with and without FA mutations, statistical analysis was performed using standard, unpaired, two sample"}
+{"text": "Major renal injuries follow ischemia reperfusion take place in two steps: one, ischemia (hypoxia) that induce ATP depletion and leads to epithelial tubular cells or endothelial cells injuries; and second, reperfusion that leads to oxidative stress, nitrosative stress and inflammation.Renal I/R (ischemia reperfusion) occurs in kidney surgeries such as partial nephrectomy or transplantation because of renal vessels ligation during the procedures. Ischemia (tissue hypoxia) leads to renal damages especially proximal convoluted tubules (PCT) injuries -3. SerioIschemia decreases ATP production and finally leads to tissue ATP depletion. ATP depletion leads to Rho GTPase inactivation that makes activation of ADF (Actin depolymerizing factor) or cofilin in the apical brush border of proximal tubules -6. ActivATP depletion also dissociates the actin-stabilizing proteins such as tropomyosin and ezrin , permittPCT cell death occurs from at least two cell death mechanisms, necrosis and apoptosis. Activation of cofilin after ATP depletion also can induce apoptosis by activating intrinsic pathway  and alsoChallenges for the future clinical use of apoptosis inhibition in acute kidney injury (AKI) include determining the best timing of therapy, optimizing the specificity of inhibitor, minimizing the extra renal adverse effects, and tubule-specific targeting of the apoptosis modulatory maneuvers . In my oInterruption of the apical cytoskeleton by ATP depletion also results in loss of tight junctions and adherents junctions between tubular cells and leads to tubular cells disconnection .Ischemia leads to disruption of at least two proteins, Na, K-ATPase and integrins. Deterioration of basolateral Na, K-ATPase in PCT is cause of increasing in excretion of sodium in tubular lumen . IntegriSome PCT cells maybe remain viable after I/R and undergo recovery. These cells show the appearance of dedifferentiated epithelial cells, and then the cells up regulate genes that encode some growth factors and undergo proliferation and undergo re-differentiation until the normal epithelium is restored .Cofilin also degrades actin cytoskeleton and junctional complexes in endothelial cells in experimental AKI  and leadAfter ischemia and restoration of blood flow, production of reactive oxygen species (ROS), such as superoxide, hydroxyl, H2O2 and activation of leukocytes and endothelial cells contribute to reperfusion injury .Decrease of innate antioxidant enzymes, increase of intracellular sodium and calcium, stimulation of NO synthetize, endonucleases and phospholipases also occur during reperfusion . Nitric Ischemic proximal tubule cells also generate mediators such as proinflammatory cytokines  and chemotactic cytokines such as monocyte chemo attractant protein-1 (MCP-1) and IL-8 .There are many studies that administration of antioxidant agent attenuated renal I/R injury -4,20. InAlthough many experimental studies show a decreased injury and preserved renal function after ROS inhibition by antioxidant agents, efficient treatments are still limited ,25. CurrIn summary major renal injuries follow I/R take place in two steps: one, ischemia (hypoxia) that induces ATP depletion and leads to epithelial tubular cells or endothelial cells injuries; and second, reperfusion that leads to oxidative stress, nitrosative stress and inflammation.With respect to above background may be said that the major trigger of pathogenesis in renal I/R are ATP depletion (Hypoxia), ROS and in follow activation of other pathogenetic pathways. By these insights the new suggestions introduce to investigate in animals and especially clinical trial in combat with renal I/R injuries.- Compensation of ATP depletion via pretreatment with ATP and AMP injection.- Inhibition of hypoxia through normobaric or hyperbaric hyperoxia pretreatment.- Administration of cofilin inhibitor or agents that inhibit actin\u2013cofilin interaction before ischemia.- Use of powerful antioxidant agents that can increase activation of innate antioxidant enzymes and inhibit complement and inflammation.- Pretreatment with creatine or creatine phosphate.- Combination of mentioned suggestions.The author wants to thank from Bardia Tavafi and Rezvan Bagheri.Majid Tavafi is the single author of the manuscript.The author declare no competing interests.Ethical issues  have been completely observed by the author.None."}
+{"text": "Overall Abstract: Dopamine plays a central role in shaping circuitry within the brain, thus affecting learning and behavior. It also plays a central role in schizophrenia and addiction. This panel will examine the impact of dopaminergic signaling on specific circuits that may create special vulnerability for the emergence of comorbidity between schizophrenia and addiction. The talks will include two presentations in clinical samples using molecular and functional imaging and two presentations in animal models.Jared Van Snellenberg will discuss connectivity of striatal substructures to the rest of the brain in drug free patients with schizophrenia and their relationship to abnormal cortical D2 signaling and psychotic symptoms. He will present recent unpublished work, motivated by pre-clinical studies with a D2 receptor over-expressing mouse model, using simultaneous multi-slice (multiband) functional MR imaging in these patients. These results suggest that unmedicated patients have altered connectivity between specific basal ganglia subnuclei, consistent with the animal model.Nora Volkow will focus on the role of bidirectional interactions between dopamine reward system and prefrontal regions in the addicted brain with emphasis on the role of D2 receptor signaling in the striatum. She will discuss the functional impact of these interactions on reward/motivation and executive-function networks and will discuss the variables that influence D2 receptor function including genes, sleep and social stressors and how they interact with drug exposures to provide resilience or vulnerability to substance use disorders or schizophrenia. Finally, she will discuss how this knowledge can be used to tailor interventions to remediate or buffer neurocircuity dysfunction triggered by drugs and for prevention.Bita Moghaddam will present an animal model of behaviorally induced dysfunction in the mesocortical circuit by using a task where actions are consistently rewarded but probabilistically punished. Spike activity and local field potentials are recorded during this task simultaneously from VTA and mPFC, two reciprocally connected mesocortical regions. Under no risk of punishment, a synchronous interaction at multiple time scales between PFC and VTA dopamine neurons is observed. This synchrony collapsed as a function of punishment contingency during reward-seeking actions, with risk of punishment diminishing VTA-driven neural synchrony between the two regions. These data reveal a dynamic coding scheme in VTA-mPFC neural circuits in representing aversion-based modulation of rewarded actions. These data suggest that driving VTA dopamine neurons by drugs of abuse may reverse the diminished synchrony and serve as self-medication in comorbid conditions.Finally, Aurelio Galli will discuss the structural, functional, and behavioral insights into the dopamine dysfunction of comorbid conditions as modeled by a deletion of the SLC6A3 affecting the function of the human dopamine transporter (hDAT). Genetic variants in hDAT have been associated with neuropsychiatric disorders. An in-frame deletion in hDAT at N336 (\u2206N336) leads to abnormal DA homeostasis. He demonstrated these dysfunctions in brains of Drosophila melanogaster expressing hDAT \u2206N336. Furthermore, these flies are hyperactive and display fear and impaired social interactions, traits associated with impaired DA neurotransmission. Insights from X-ray crystallography, electron paramagnetic resonance, molecular dynamic simulations, electrophysiology and behaviors describe how a genetic variation causes DA dysfunction resulting in combined behavioral alterations and psychostimulant use."}
+{"text": "The degree of inhospitable terrain encountered by migrating birds can dramatically affect migration strategies and their evolution as well as influence the way we develop our contemporary flyway conservation responses to protect them. We used telemetry data from 44 tagged individuals of four large-bodied, Arctic breeding waterbird species  to show for the first time that these birds fly non-stop over the Far East taiga forest, despite their differing ecologies and migration routes. This implies a lack of suitable taiga refuelling habitats for these long-distance migrants. These results underline the extreme importance of northeast China spring staging habitats and of Arctic areas prior to departure in autumn to enable birds to clear this inhospitable biome, confirming the need for adequate site safeguard to protect these populations throughout their annual cycle. WhateveThe 44 tagged individuals of four large-bodied, Arctic breeding waterbird species  flew non-stop over the Far East taiga forest, despite their differing ecologies and migration routes. These results underline the extreme importance of northeast China spring staging habitats and of Arctic areas prior to departure in autumn to enable birds to clear this inhospitable biome, confirming the need for adequate site management to protect these populations throughout their annual cycle.10.7717/peerj.4353/supp-1Supplemental Information 1Appendix A. Details of tracked birds and loggers.Appendix B. Detailed methods used to identify waterbird stopovers and flight segments.Appendix C. Relief map showing the relative elevated height above sea level of the taiga zone of Far Eastern Asia compared to that of Western Eurasia.Click here for additional data file."}
+{"text": "Hereditary hemorrhagic telangiectasia is a rare autosomal dominant inherited disease that is usually complicated by visceral vascular malformations. Patients harboring such malformations are at increased risk of brain abscess formation, which despite advances in diagnostic and surgical methods remains a life threatening medical emergency with high mortality and morbidity rates. In the present report we describe a case of cerebral abscess due to silent pulmonary arteriovenous malformation (AVM) in a young patient previously undiagnosed for hereditary hemorrhagic telangiectasia syndrome (HHT). Hereditary hemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu syndrome is a rare systemic angiodysplasia inherited as an autosomal dominant disorder. Approximately 1% of patients with HHT are expected to develop a brain abscess . HoweverA 24-year-old male presented to the Emergency Department of Evangelismos Hospital, due to generalized tonic clonic seizures accompanied by fever, increasing right hemiparesis and motor dysphasia. Brain CT and MRI scans , revealeHereditary hemorrhagic telangiectasia (HHT) also known as Osler-Weber-Rendu syndrome is a rare systemic angiodysplasia inherited as an autosomal dominant disorder. Four diagnostic criteria for HHT have been proposed i) epistaxis ii) telangiectasia on face, fingertips and nasal/oral mucosa iii) familial history of HHT and iv) visceral vascular anomalies including hepatic, pulmonary, spinal and cerebral arteriovenous malformations . DiagnosOur case illustrates that a brain abscess may be the first clinical manifestation of a nearly asymptomatic HHT patient. Furthermore patients with a history suggestive of HHT should be screened for the presence of visceral vascular malformations as they are at increased risk of brain abscess formation. In conclusion, it should be clearly pointed out not only to neurologists and neurosurgeons but to clinicians in general, that patients with signs suggestive of HHT and new onset of neurological symptoms, should be deemed to harbor a brain abscess until proven otherwise. This aggressive approach is mandated by the high prevalence and mortality associated with a brain abscess in this group of patients."}
+{"text": "Background: Restless legs syndrome (RLS) is a relatively common neurological disorder affecting sleep and health-related quality of life. Neuroimaging studies, autopsy investigations and experimental studies using animal models have been conducted to investigate the potential causes of RLS, resulting in the generation of multiple pathophysiological hypotheses.Methods: This paper reviews the neurobiology and pharmacotherapy of RLS, with a critical analysis of the heterogeneity and methodological limitations of the existing scientific literature.Results: Although several neurotransmitter systems dysfunction and neuroanatomical abnormalities have been implicated in RLS pathogenesis, dopamine dysfunction within basal ganglia pathways, iron deficiency and opioid system abnormalities have consistently been found to be involved. Their involvement is further strengthened by the therapeutic effectiveness of dopaminergic agents, iron supplementation and opioid medications.Discussion: Converging evidence from neuroimaging, autoptic and animal studies points towards dopamine dysregulation and iron metabolism alterations as the main contributors to RLS pathophysiology. The possible interactions between different neurotransmitter systems should guide further neuropharmacological research in order to improve therapeutic efficacy for this disabling condition."}
+{"text": "P. falciparum. We synthesized an artemisinin analogue withan alkyne tag, which can be coupled with biotin through click chemistry. Thisenabled selective purification and identification of 124 protein targets ofartemisinin. Many of these targets are critical for the parasite survival.In vitro assays confirmed the specific artemisinin bindingand inhibition of selected targets. We thus postulated that artemisinin killsthe parasite through disrupting its biochemical landscape. In addition, weshowed that artemisinin activation requires heme, rather than free ferrous iron,by monitoring the extent of protein binding using a fluorescent dye coupled withthe alkyne-tagged artemisinin. The extremely high level of heme released fromthe hemoglobin digestion by the parasite makes artemisinin exceptionally potentagainst late-stage parasites (trophozoite and schizont stages) compared toparasites at early ring stage, which have low level of heme, mainly derived fromendogenous synthesis. Such a unique activation mechanism also confersartemisinin with extremely high specificity against the parasites, while thehealthy red blood cells are unaffected. Our results provide a sound explanationof the MOA of artemisinin and its specificity against malaria parasites, whichmay benefit the optimization of treatment strategies and the battle against theemerging drug resistance.Artemisinin and its analogues are currently the most effective anti-malarialdrugs. The activation of artemisinin requires the cleavage of the endoperoxidebridge in the presence of iron sources. Once activated, artemisinins attackmacromolecules through alkylation and propagate a series of damages, leading toparasite death. Even though several parasite proteins have been reported asartemisinin targets, the exact mechanism of action (MOA) of artemisinin is stillcontroversial and its high potency and specificity against the malaria parasitecould not be fully accounted for. Recently, we have developed an unbiasedchemical proteomics approach to directly probe the MOA of artemisinin in Plasmodium falciparum, isresponsible for more than half-a-million deaths per year. Currently, artemisinin-basedcombination therapy is heavily relied to treat malaria. The artemisinin derivativesshare a unique endoperoxide bridge which has been suggested to be cleaved insideP. falciparum by iron sources (either heme or ferrous iron) torelease highly reactive carbon centered radicals. These radicals can modify and inhibitvarious parasite molecules, resulting in parasite death. Yet the precise MOA ofartemisinin has remained obscure. Recently, our group has developed an activity-basedartemisinin probe and revealed a broad spectrum of artemisinin targets that arepreviously unidentified. We have also provided multiple lines of evidences todemonstrate that heme, rather than free ferrous iron, is the predominant iron source forartemisinin activation. Notably, the parasite\u2019s propagation largely relies on hemoglobindigestion, which releases high concentration of heme. Thus, such process makesartemisinin an extremely selective and potent anti-malarial drug. Once activated, thepromiscuous targeting of artemisinin disrupts the essential biological processes of theparasite, leading to its death. Furthermore, we have shown that the endogenouslysynthesized heme might play a key role in activating artemisinin at the parasite\u2019s earlyring stage. These findings significantly enhance our understanding of artemisinin\u2019s MOA,which may help to improve our treatment strategies against malaria, one of the mostdeadly diseases. The systematic identification of artemisinin targets providesinvaluable information for future anti-malarial drug development. Enhancing theartemisinin activation level at the early ring stage through modulation of theparasite\u2019s heme synthesis pathway may pave a feasible way to curb the emergingartemisinin resistance in Southeast Asia due to K13 mutations, which result in aprolonged early ring stage that diminishes the drug\u2019s killing effect. Another possibleapproach to overcome the artemisinin resistance might be to extend the length of drugtreatment. We anticipate that the thorough understanding of artemisinin\u2019s MOA would helpto develop better strategies to treat malaria with better treatment schemes and betterdrugs or drug combinations. Our list of identified artemisinin targets also provides newavenues for studying, tracking and coping with the emerging resistance of this drug.The most pathogenic human malaria parasite,"}
+{"text": "Receptor tyrosine kinase (RTK) pathways serve as frequent oncogene drivers in solid cancers and small molecule and antibody-based inhibitors have been developed as targeted therapeutics for many of these oncogenic RTKs. In general, these drugs, when delivered as single agents in a manner consistent with the principles of precision medicine, induce tumor shrinkage but rarely complete tumor elimination. Moreover, acquired resistance of treated tumors is nearly invariant such that monotherapy strategies with targeted RTK drugs fail to provide long-term control or cures. The mechanisms mediating acquired resistance in tumors at progression treated with RTK inhibitors are relatively well defined compared to the molecular and cellular understanding of the cancer cells that persist early on therapy. We and others propose that these persisting cancer cells, termed \u201cresidual disease\u201d, provide the reservoir from which acquired resistance eventually emerges. Herein, we will review the literature that describes rapid reprogramming induced upon inhibition of oncogenic RTKs in cancer cells as a mechanism by which cancer cells persist to yield residual disease and consider strategies for disrupting these intrinsic responses for future therapeutic gain. Receptor tyrosine kinases (RTKs) function as oncogene drivers in solid tumors through diverse mechanisms including mutation, amplification and autocrine/paracrine activation. As an example, lung adenocarcinomas (LUADs) harbor diverse oncogenic RTKs and many, such as EGFR, ALK, and ROS1 have approved tyrosine kinase inhibitors (TKIs) that induce dramatic tumor responses . AdditioOver the past decade, mechanisms mediating acquired resistance to RTK inhibitors have been investigated through analysis of tumor samples obtained at disease progression and represents a thoroughly reviewed topic \u201320. SeleA common feature of treatment failure with monotherapy, whether antimicrobial or anticancer, is the incomplete elimination of the bacterial or tumor cell targets , 23. TheAn extensive literature demonstrates the dynamic nature of the kinome, the subset of the genome encoding protein kinases , in respKlezcko et al.  analyzedThe literature reveals that altered gene transcription is not required for all rapid, TKI-induced reprogramming. Zhang et al.  used phoF1174L-positive human neuroblastoma cells [In addition to mechanisms involving rapidly induced bypass signaling, RTK inhibitor-induced epithelial to mesenchymal transition (EMT) has emerged as a mechanism of resistance, especially in response to EGFR inhibitors. EMT (reviewed in ) is an ima cells .Fig. 2PhBecause of the chronic method by which TKI-resistant cell lines exhibiting mesenchymal differentiation were selected, it is unclear if TKI-induced EMT represents a rapid reprogramming event. Anecdotally, cell morphology changes occur within weeks of TKI treatment . Also, oClinically, emergence of TKI-resistant EGFR mutant LUADs that exhibit small cell lung cancer (SCLC) lineage markers and heralded by RB1 and TP53 loss Fig.  has beenOverall, these studies indicate that, with sufficient foresight of specific bypass signaling pathways induced in response to TKI-stimulated cellular reprogramming, effective drug combinations could be designed and deployed to bring about greater tumor inhibition. However, in many cases, there appears to be significant diversity and/or redundancy in bypass pathway utilization in different cancer cell lines. For full implementation, the degree of variability in the reprogramming response across an oncogene-defined set of cancers will need to be fully understood. In this regard, a general caveat of the preclinical studies showing TKI-induced reprogramming is that the conclusions are frequently derived from a limited number of cell lines. As further developed below, it will be critical to interrogate the reprogrammed state in primary cancers under treatment to fully appreciate the heterogeneity of response. Moreover, if multiple mechanisms emerge in oncogene-defined cancer subsets, consideration must be given to biomarkers in pretreatment biopsies that may predict a specific reprogramming response.An alternative approach to combinations of RTK inhibitors with specific bypass pathway inhibitors is to target the driving RTK oncogene in combination with agents that block the reprogramming response at the transcriptional level. As an example, Stuhlmiller et al. demonstrated rapid lapatinib-induced reprogramming in a panel of ERBB2+ breast cancer cell lines . The adaStudies investigating reprogramming responses to RTK inhibitors in cancer cells addicted to specific oncogenic RTKs have tended to largely interpret the results from a cancer cell autonomous viewpoint. It is clear that RTK inhibitor-induced reprogramming induces secretion of myriad factors, some of which may signal in a paracrine fashion to the TME Fig.\u00a0. In the A well-defined side effect of small molecule and antibody-based inhibitors of EGFR is an acneiform rash . The litFunctional genomics screens have been deployed to provide an unbiased approach to interrogating vulnerabilities in oncogene-driven cancer cells. To identify targets that could be inhibited in combination with EGFR-specific TKIs to yield deeper growth inhibition in EGFR mutant lung cancer cell lines, Casas-Selves et al.  used a gIn addition to oncogenic EGFR and distinct RTKs activated through gene-rearrangements, increased expression of the non-mutated RTK, FGFR1, is observed in lung cancers of all histologies \u201386, mesoA study by Harbinski et al.  used a cNumerous studies have examined mechanisms of acquired resistance presenting at tumor progression which likely reflect outgrowth of dominant evolutionarily-selected clones. By contrast, much less is known about signaling and transcriptional mechanisms in the setting of early residual disease following oncogene inhibition, in part because patient biopsies are rarely performed early during response to therapy . ObviousEarly Rebiopsy to Identify Biomarkers of Tumor Cell Survival Following EGFR TKI Therapy (NCT03042221)\u201d will molecularly analyze paired baseline biopsy specimens from advanced stage EGFR mutant lung cancers and biopsies obtained following 2 weeks of EGFR TKI-targeted treatment with the intention to identify early adaptive mechanisms of cell survival in the setting of oncogene-targeted therapy. Preliminary RNAseq analysis of two sets of paired biopsies reveals evidence of both tumor cell autonomous and non-autonomous transcriptional responses [clinicaltrials.gov indicates other similar neoadjuvant trials based on oncogene-targeted agents have either been completed or are open and active (Surgery for Early Lung Cancer With Preoperative Erlotinib (Tarceva): A Clinical Phase II Trial (SELECT), NCT00462995 ; Study of TARCEVA (Erlotinib) as Adjuvant Treatment for Locally Advanced Head and Neck Squamous Cell Carcinoma, NCT01515137 ). These clinical protocols with specific intention to collect samples of tumors early during targeted therapy are anticipated to provide a clearer molecular understanding of residual cancer that will prompt informative laboratory studies.Similar \u201cwindow of opportunity\u201d trials are being launched to study remnant lung tumor samples after oncogene targeted therapies. McCoach and colleagues  are implesponses . AnalysiThe aforementioned clinical protocols will provide rich insight into the biology of residual disease and potentially drive reverse translational research  to exploThe clinical experience with TKI monotherapy in cancers bearing oncogenic RTKs highlights the importance of defining next-generation strategies that will reduce or eliminate acquired resistance. While serial deployment of 2nd and 3rd generation TKIs may increase the duration of response, resistance still eventually emerges due to residual disease. Based on the studies reviewed in this article, approaches whereby novel and rational \u201cupfront\u201d combinations of TKIs and drugs targeting signal pathways that prevent rapid tumor cell reprogramming must be identified and prioritized for preclinical testing. Evidence that blocking oncogenic pathways within cancer cells unleashes paracrine signaling between cancer cells and the TME, including the innate and adaptive immune systems, supports the continued development of transplantable murine cancer cell lines that faithfully represent oncogene-driven human cancers for subsequent analysis of the impact of TME-cancer cell crosstalk on TKI efficacy in fully immune competent hosts. This latter approach will permit rational evaluation of combinations of TKIs with drugs targeting TME pathways as well as approved and emerging immunotherapeutics. Finally, these studies must be accompanied by deep evaluation of molecular responses in primary human tumors early during TKI treatment to determine the kinetics of the processes as well as the degree of variation across tumor subtypes. Combined, these strategies may yield novel combination therapies that maximize the initial tumor shrinkage response, thereby leading to stable disease or perhaps cures."}
+{"text": "The central nervous system (CNS) requires sophisticated regulation of neuronal activity. This modulation is partly accomplished by non-neuronal cells, characterized by the presence of transmembrane gap junctions (GJs) and hemichannels (HCs). This allows small molecule diffusion to guarantee neuronal synaptic activity and plasticity. Astrocytes are metabolically and functionally coupled to neurons by the uptake, binding and recycling of neurotransmitters. In addition, astrocytes release metabolites, such as glutamate, glutamine, D-serine, adenosine triphosphate (ATP) and lactate, regulating synaptic activity and plasticity by pre- and postsynaptic mechanisms. Uncoupling neuroglial communication leads to alterations in synaptic transmission that can be detrimental to neuronal circuit function and behavior. Therefore, understanding the pathways and mechanisms involved in this intercellular communication is fundamental for the search of new targets that can be used for several neurological disease treatments. This review will focus on molecular mechanisms mediating physiological and pathological coupling between astrocytes and neurons through GJs and HCs. Classical studies carried out by the end of 19th and during the 20th century classified astrocytes mainly based on their differences in morphology and localization into two different populations, protoplasmic and fibrous  to neurons, participate in the turnover of neurotransmitters such as glutamate and gamma-aminobutyric acid , adenosine triphosphate (ATP), glutamate, lactate and D-serine that diffuse through GJs to impact back on neuronal function . This specialized intercellular communication gives rise to a complex syncytial network that allows diffusion of several essential molecules for signaling and information processing  directly to the extracellular space. HCs also dock with other HCs or connexons of adjacent cell membranes to establish GJs  that spread from cell to cell. Presence of astrocytic calcium ions mobilizations suggests that glial cells may have some excitability and neuromodulator activities  that stratum radiatum astrocytes respond with an increase in [Ca2+]i when activated by ligands. Among the many receptors expressed in astroglial cells are purinergic  and metabotropic glutamate receptor (mGLURs) activation , inhibition of Cx43 HCs by mimetic peptide Gap26 reduces the amplitude of postsynaptic excitatory currents mediated by NMDA receptors and impairs long-term potentiation (LTP) induced by high-frequency stimulation , neurotransmitter release and uptake (Glutamate and GABA), and receptor stability (homeostatic plasticity).Astrocytes like neurons have complex morphologies characterized by the presence of processes that protrude into synapses. For synapses to work efficiently, astrocytes and neurons should have developed mechanisms controlling astrocytic processes extension into synapses, limiting astrocyte territories in the synaptic cleft, which is essential to re-uptake neurotransmitters without affecting synaptic transmission. Cx30 knockout mice show a decreased excitatory neurotransmission and impaired synaptic plasticity  and diacylglycerol , and non-dependent vesicular release. Astrocytes express Synaptotagmin IV (a Ca2+ sensor expressed in synaptic vesicles) and SNARE type proteins. Synaptotagmin IV knockdown experiments have revealed this Ca2+ sensor is involved in glutamate release from astrocytes  in astrocytes starts a cascade of events that stimulate membrane phospholipid hydrolysis to inositol triphosphate  has critical neuromodulator functions  that regulates blood vessel tone or by increasing glucose uptake from blood , requiring Na+/K+ ATPase activity. Furthermore, in astrocytes, this coupling demands glucose utilization and oxidation  transport , are responsible for maintaining extracellular glutamate concentrations within a range that permits normal excitatory neurotransmission , and nitric oxide (NO). These toxic molecular species can be released through HCs and propagated from damaged cells to healthy cells through GJs  and intracellular neurofibrillary tangles of hyperphosphorylated Tau protein, loss of synaptic connections, and oxidative stress increase leading to neuronal death  activation , Cx43 expression increased, and pre-treatment with Gap26 and Gap27 peptides powerfully decreased cerebral infarct volume and improved muscle strength, motor coordination and spatial memory skills. Furthermore, Gap26 treatment reduced Cx43 expression and astrocytosis after HI insult, suggesting Cx43 could be considered a therapeutic target ischemic or hypoxic disease treatment , Ca2+, and metabolic changes that stimulate the probability of pore opening (Retamal et al., During neural activity interglial communication regulates neurotransmitter and KLCM and AVR wrote the article and drew the figures. J-JS wrote the article and SLA conceptualized and wrote the article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "In tumor samples, our analysis detected major conserved mitogenic and survival signaling pathways strongly associated with HNSCC, suggesting that some of the pathways identified by our algorithm, but not yet validated as HNSCC related, may be attractive targets for future research. While pathways activation landscape in the majority of leukoplakias was different from that seen in OSCC, a subset of pre-neoplastic lesions has demonstrated some degree of similarity to the signaling profile seen in tumors, including dysregulation of the cancer-driving pathways related to survival and apoptosis. These results suggest that dysregulation of these signaling networks may be the driving force behind the early stages of OSCC tumorigenesis. While future studies with larger leukoplakia data sets are warranted to further estimate the values of this approach for capturing signaling features that characterize relevant lesions that actually progress to cancers, our platform proposes a promising new approach for detecting cancer-promoting pathways and tailoring the right therapy to prevent tumorigenesis.A subset of patients with oral squamous cell carcinoma (OSCC), the most common subtype of head and neck squamous cell carcinoma (HNSCC), harbor dysplastic lesions  prior to cancer diagnosis. Although evidence suggest that leukoplakia represents an initial step in the progression to cancer, signaling networks driving this progression are poorly understood. Here, we applied  Despite improvements in molecular diagnosis, oral squamous cell carcinoma (OSCC), the most common subtype of HNSCC, has a poor prognosis with a 5-year overall survival of ~50%, and no targeted curative treatments for late-stage OSCC are currently available. As such, there is a significant unmet clinical need for development of novel targeted approaches against OSCC.Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, As some of these lesions evolve to malignant neoplasms, they represent intermediate steps in OSCC progression. It has been postulated, that this multistep process from normal epithelium to early pre-malignant change to fully invasive OSCC, involves the accumulation of molecular and cellular changes. Indeed, several signaling pathways have been shown to be dysregulated in OSCC through genetic and epigenetic alterations such as those involving TP53, PIK3CA, NOTCH1, SMAD4, CDKN2A, CCND1, FBXW7, HRAS, NRAS and FAT1. Although these signaling axes have been implicated in tumorigenesis, and are correlated with poor patients prognosis, relatively few molecular changes critical to the progression of oral leukoplakia to OSCC are currently recognized, and our understanding of the complex signaling networks that both promote OSCC pathogenesis and can be targeted therapeutically is still limited.Nearly 20% of patients with OSCC harbor multiple pre-malignant lesions showing signs of dysplasia, often visually identified as leukoplakia. analyses that rely solely on gene enrichment statistics fail to capture subtle differences between samples that arise from dynamic interactions between genes at the level of signaling networks. The major advantage of pathway-based methods is their capability to perform biologically relevant dimensionality reduction as a result of the analysis. However, despite the significant advancements in large-scale analytical methodologies that infer complex transcriptomic changes into the network of biologically relevant signaling axes, a systematic comprehensive analysis of the signaling pathways activation in OSCC and oral pre-neoplastic lesions has never been done.The Gene Expression Omnibus (GEO), the largest public repository for high-throughput gene expression data, provides unprecedented opportunities to reveal molecular mechanisms of cancer. Although multiple efforts taken to identify differentially expressed genes between OSCC and normal samples have led to the identification of prospective genetic biomarkers and expression signature patterns,in silico Pathway Activation Network Decomposition Analysis (iPANDA) as a scalable robust method for quantitative and qualitative large-scale transcriptomic data analysis. The iPANDA method combines pre-calculated gene co-expression data with gene importance factors based on the degree of differential gene expression and pathway topology decomposition for obtaining pathway activation scores. It has been demonstrated that iPANDA provides significant noise reduction in transcriptomic data and identifies highly robust sets of biologically relevant pathway signatures. In this study, we applied iPANDA on the transcriptomic data from hundreds of OSCC and leukoplakia samples to identify the differentially dysregulated signaling pathways between these neoplasms and normal oral mucosa tissues. Our work further contributes to the current understanding of the complex signaling networks underlying HNSCC, and may aid in the development of novel means of prevention, diagnosis and treatment.We have recently introduced the in silico pathway activation analysis of 359 OSCC samples obtained from the publicly available data sets deposited at NCBI GEO database   , and used for the computational algorithm as described previously. Using the normal samples cohort as a reference, we determined a quantitative measure of the signaling pathway activation scores  for each one of the signaling axes analyzed. The iPANDA values represent the signed scores showing the intensity and direction of the pathway activation . A total of 248 of 374 pathways analyzed (including the 64 main pathways) were significantly dysregulated (P<0.05) in OSCC tumors when these samples were compared with non-tumorous oral mucosa  . All theata set) . A collel mucosa . Focusinl mucosa . Upregulcontrols . Our pat\u03b2 expression and spontaneous HNSCC formation. Whereas activation of PI3K/AKT via loss of PTEN or copy-number gain/activating mutations in PIK3CA also occurs in 40\u201360% of HNSCCs, leading to increased IL-6 production, STAT3 activation and tumor-promoting inflammation in HNSCC stroma. In concordance with this evidence, PTEN and SMAD signaling, as well as pathways associated with apoptosis were significantly downregulated in the cohort of 359 OSCC tumors analyzed  in leukoplakia samples compared to healthy controls (P<0.0005) in both OSCC (red bars) and leukoplakia (blue bars) samples  . Given tcontrols . The hea samples . Unlike l cohort . Since il cohort . Notably and potentially unravel the most critical branches associated with cancer progression. A list of pathway branches predicted to be significantly dysregulated (P<0.0005) in both OSCC and leukoplakia samples is shown in Many well-established cancer-driving genes simultaneously modulate activation or repression of multifunctional signaling networks that control cell growth, differentiation and migration. Since \u2018main\u2019 pathways aggregate branches that may be inversely activated, analysis of the pathway branches (which represent linearized fragments of the main pathway networks with multiple downstream targets) may help to scale down the complexity of common non-linear topology To adjust for the possible batch effect and other variations that may arise during the microarray processing, we have employed cross-platform normalization and filtering procedures as previously described . While most of the leukoplakia samples clustered together according to their pathway activation landscape, a subset of 20 pre-neoplastic lesions has clustered toward the center of the heatmap, demonstrating some degree of similarity to the pathway activation profile seen in OSCC , indicating that predisposition for leukoplakia progression may not have significant manifestation on the functional (pathway) level. One possible explanation is that the most differentially expressed genes in a given signature may not be part of the pathways that actually drive tumor behavior. Alternatively, expression of some genes within the cancer-driving pathways is not always predictive of the overall pathway activation. While iPANDA may be a useful tool when used as input for machine learning algorithms to make better prediction models, we were unable to use modern machine learning methods, since currently available data to system dimensionality ratio precludes the development of a strong classifier at the pathway level. As comprehensive analysis of the tumor pathway activation profile may provide broader clinical utility than raw gene expression evaluation, it would be of paramount importance to reanalyze the data upon accumulation of additional leukoplakia data sets, and further estimate the values of this approach for capturing signaling features that characterize relevant lesions that actually progress to cancers.Using the transcriptomic data from the same 86 leukoplakia samples and multiple independent OSCC data sets, Mao and colleagues proposed a 29-trancript prediction model of oral cancer progression (with 8% predicting error rate), indicating that gene expression levels can be effectively used for phenotype prediction. often fail to provide stable pathway signatures of a specific phenotype. iPANDA, a recently reported method for biologically relevant dimensionality reduction in transcriptomic data, demonstrates better performance for the noise reduction test in comparison to other pathway analysis approaches, and produces highly consistent sets of biologically relevant pathway perturbation signatures on multiple transcriptomic data sets. Here, we applied this novel bioinformatics prediction algorithm on transcriptomic data from 359 OSCC and 86 oral pre-neoplastic samples.An understanding of the protein signaling dynamics during the HNSCC progression is of critical importance for the development of new therapeutic approaches and identification of novel prognostic biomarkers. Signaling pathway activation analysis is a powerful tool for extracting biologically relevant features from large-scale transcriptomic data. While systematic application of such approach may contribute to better understanding of complex signaling networks in various types of cancer, many popular pathway-based methods\u03b2-catenin and TGF\u03b2/SMAD signaling) in almost every OSCC tumor analyzed. Confirming the emerging view that while the specific molecules altered in each individual tumor may be distinct, they all participate in a handful of dysregulated molecular pathways that are likely shared among most HNSCC lesions. Although the association of the above signaling pathways with HNSCC is not novel, the ability of the gene aggregation algorithm to identify highly robust sets of pathway signatures relevant to the HNSCC tumorigenesis, suggests that our platform provides a rational biomathematical framework for studying signaling alterations driving the tumorigenic processes, and further supports the credibility of the pathway activation analysis as a promising analytical approach. It also suggests that some of the most dysregulated pathway branches identified by our algorithm but not yet wet-lab validated as HNSCC related, may provide an attractive target for future research.By utilizing our approach, we were able to detect dysregulation of the major molecular processes involved in HNSCC tumorigenesis  relies solely on gene enrichment statistics, treating pathways as unstructured sets of genes. Whereas our method estimates the topological coefficients for each gene module as a whole, rather than for individual genes inside the module, and therefore outperforms ssGSEA in respect to ranking of the putatively relevant pathways (described in details here).Interestingly, while gene set enrichment (GSEA) analysis of the same microarray data set with GSEA algorithm detected that gene sets related with proteasome machinery, MYC upregulation and ribosomes components were associated with a high risk of oral cancer development,Although this study focused on fundamental signaling processes involved in the development of OSCC, branched axes radiating from these main tumor-driving pathways may provide safer and more efficient targets for therapeutic intervention than a pan-pathway blockade. Since most of the existing pathways collections are being developed and cataloged within individual research groups, both in industry and in academia, inconsistency in pathway names annotations and number of pathway components (branches) poses a major challenge associated with prediction modeling of subnetworks within a large cancer driver superpathway. Therefore, systematic standardization and optimization of existing signaling pathways databases  will eventually contribute to better resolution of the signaling landscape, and enhance the development of novel prognostic biomarkers for risk assessment and treatment interventions at various stages of cancer progression.In conclusion, our work poses pathway-based expression data analysis as a promising hypothesis-generating approach for detecting cancer-promoting pathways at different stages of tumorigenesis. However, due to the limited number of currently available leukoplakia data sets, we could not dissect the molecular pathways predictive of progression from pre-neoplasia to carcinoma. As more data sets will become available, transcriptomic analysis of longitudinally collected leukoplakias and tumors that developed in the same patient over time may allow better detection of early drivers of OSCC carcinogenesis on the pathway level.For this study, we utilized microarray gene expression data obtained from NCBI GEO database. OSCC samples and tissue-specific normal controls used as a reference are listed in www.bioconductor.org). Microarray raw data were background-adjusted and quantile-normalized using the corresponding R packages . Obtained gene expression values were averaged across all replicates. Heatmap generation and hierarchical clustering were performed using R package gplots. Statistical tests and correlation analysis were done with the MS Excel software .OSCC and leukoplakia data with corresponding normal samples were processed using AFFY (version 1.46.1) and FRMA (version 1.20.0) algorithms from Bioconductor ) contains a set of 374 signaling pathways that cover a total of 2294 unique genes. Main pathways represent complex signaling networks with multiple downstream targets. Whereas branching axes represent dissected linear signal transduction units of a large multifunctional pathway. Each pathway contains an explicitly defined topology represented as a directed graph. Each node corresponds to a gene or a set of genes, while edges describe biochemical interactions between genes in nodes and/or their products. All interactions are classified as activation or inhibition of downstream nodes. The pathway size ranges from about 20 to over 600 genes in a single pathway. The algorithm accounts for the gene grouping into modules based on the precalculated gene co-expression data (using information from COEXPRESSdb database). Each gene module represents a set of genes that experience significant coordination in their expression levels and/or are regulated by the same expression factors. As described, it enables calculation of the iPANDA pathway activation scores, a value that serves as a quantitative measure of differential pathway activation between the two states. Pathway scoring is based on the expression level and the role of a particular gene in proprietary maps of 300 of signaling pathways. For estimation of pathway activation, we apply the following rule pathways with positive iPANDA values that are considered upregulated, while negative iPANDA values correspond to downregulated pathways.Pre-processed gene expression data were loaded into pathway analysis software, a proprietary suite developed by Insilico Medicine, Inc. that represents an implementation of the iPANDA algorithm,45 .To perform cross-platform normalization between Affymetrix U133 Plus 2.0 Array and Affymetrix 1.0 ST Array, we utilized XPN algorithm"}
+{"text": "The \u201cinterhemispheric competition\u201d model posits that the contralateral hemisphere suppresses activity of the ipsilateral hemisphere to reduce putative interference of ipsilateral descending pathways thought to degrade motor performance. Non-invasive brain stimulation paradigms are well positioned to test models of motor control. For instance, transcranial direct current stimulation (tDCS) applied to the human motor cortex (M1), can induce polarity-dependent changes in corticospinal excitability that outlast the period of stimulation. Therefore, facilitatory anodal tDCS of the contralateral hemisphere and/or inhibitory cathodal tDCS of the ipsilateral hemisphere should enhance motor learning. While the interhemispheric competition model has guided therapeutic application of tDCS in neurorehabilitation (Di Pino et al., Therapy to facilitate motor learning requires Recently, Waters et al.  investigWhile the conclusions of Waters et al.  were supNevertheless, both conventional and reverse-polarity bihemispheric tDCS induce similar improvements in motor learning. To explain this observation, Waters et al.  propose A and GABAB receptor mediated inhibition can be tested using paradigms known as short-latency intracortical inhibition and long-latency intracortical inhibition. Since GABA plays an important role in synaptic plasticity and motor learning (Stagg et al., To further examine the proposed interhemispheric cooperation model, we suggest additional TMS experimental approaches. First, paired-pulse TMS paradigms can be employed to investigate inhibitory synaptic activity Figure . Both GAThe recent study from Waters et al.  providesBH and MG all made substantial intellectual contributions to the manuscript and approved the final version for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Telomerase elongates telomeres and is crucial for maintaining genomic stability. While stem cells and cancer cells display high telomerase activity, normal somatic cells lack telomerase activity primarily due to transcriptional repression of telomerase reverse transcriptase (TERT), the catalytic component of telomerase. Transcription factor binding, chromatin status as well as epigenetic modifications at the TERT promoter regulates TERT transcription. Myc is an important transcriptional regulator of TERT that directly controls its expression by promoter binding and associating with other transcription factors. In this review, we discuss the current understanding of the molecular mechanisms behind regulation of TERT transcription by Myc. We also discuss future perspectives in investigating the regulation of Myc at TERT promoter during cancer development. Terc and accessory proteins   and associated histone acetyl transferases (HATs). It can also recruit P-TEFb, which is a kinase that phosphorylates the C-Terminus of RNA polymerase II, thereby helping in promoter clearance. However, the mechanism employed by Myc to activate the TERT promoter is not known  at positions \u2212165 and +44 nucleotide position relative to the transcription start site (TSS)  mutations commonly occur in low-grade gliomas  domain  ligands inhibit TERT mRNA expression in colon cancer cells via modulation of the Myc/Max/Mad network (Toaldo et al., Alterations in Myc expression are commonly observed during cancer initiation and progression. They occur via chromosomal translocations, amplifications and gene mutations Dang, . TelomerMyc expression is usually measured at the protein level using immunohistochemistry. For measurement of TERT expression, some studies use mRNA expression, while others measure telomerase enzyme activity since TERT mRNA levels positively correlate with telomerase activity (Armstrong et al., Myc and TERT play crucial roles during normal development as well as in carcinogenesis. Therefore, understanding their interplay in both these processes is important. Myc can activate TERT transcription directly or by cooperating with other transcription factors like SP1, ER and ETS. The factors that discriminate Myc-dependent TERT regulation during normal development from cancer are not known and need further investigation. Mutations in the TERT promoter represent the most common non-coding somatic mutations in cancer and it would be interesting to investigate the role of Myc in regulating the mutant TERT promoter. The existing correlation studies between Myc and TERT are not very conclusive and need further analysis.EK conceived, designed and wrote the manuscript. EK and VT revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Echinococcus granulosus, development of jaundice in a patient with liver cyst is initially suspected to have hydatid cyst.Rupture into the biliary ducts is the most frequent complication of hydatid liver disease. In endemic areas of A 48 year-old woman with history of asymptomatic hydatid liver cysts was admitted to the emergency department with right upper quadrant abdominal pain, increased levels of liver enzymes, bilirubin and alkaline phosphatase and the initial clinical diagnosis was the hydatid cyst rupture into the bile ducts. Surgery was planned but radiological evaluation (MRI) revealed non-dilated intra-extra biliary ducts. High suspicion of hydatid rupture required diagnostic ERCP that was normal and surgery was cancelled then. A possible diagnosis of coexistent hepatitis was suspected. Liver function tests normalized gradually and no cyst rupture was determined during surgery. These findings suggest considering the possible development of cryptogenic hepatitis in patients with preexisting hydatid cyst. Echinococcus granulosus and it is still a serious health problem in endemic areas. Hydatid cysts can originate from all visceral organs but most often is located in the liver. Rupture of cysts into the biliary tract is the most frequent complication  1386 U/L, aspartate aminotransferase (AST) 1071 U/L, alkaline phosphatase (ALP) 307 U/l and gamma glutamyl transpeptidase (GGT) 156 U/L. Abdominal ultrasound showed a 68 mm in diameter exophytic and multivesicular hydatid cyst located at segment II and III of the liver.Gallbladder, biliary tract and pancreas were normal. Abdominal magnetic resonance imaging confirmed sonographic findings without dilation of intrahepatic and extrahepatic biliary ducts . Viral hepatitis and tumor markers were negative. She denied using any drugs or toxic products. The initial diagnosis of the patient was hydatid liver cyst ruptured into the biliary tract, hence an endoscopic retrograde cholangiopancreatography (ERCP) was performed with normal findings. The possibility of hepatitis with unknown origin (cryptogenic hepatitis) caused to postpone surgery until three weeks later when the levels of serum bilirubin, ALP and GGT decreased to normal values, but ALT and AST values \u200b\u200bremained high at 464 U/L and 372 U/L, respectively. The patient underwent an exploratory surgery which found no cyto-biliary rupture. A liver biopsy was performed and the patient was discharged on postoperative day 5. At this time, the ALT and AST values were 175 U/L and 58 U/L, respectively. Histopathology of the hydatid cyst was confirmed. The patient was well in the last follow-up performed 6 years after discharge with normal liver function tests and normal findings in computed tomography scanning .(i) an existing hydatid liver cyst, (ii) elevated bilirubin levels (direct bilirubin increase was dominant) and (iii) negative laboratory results for viral hepatitis and tumor markers. Retrospectively, we examined the diagnostic errors and found a clue against the presence of hydatid jaundice. The following findings may be helpful in ruling out hydatid jaundice; (i) normal color stool, (ii) greater increase in the serum levels of AST-ALT as compared to ALP-GGT and (iii) unremarkable dilatation in the bile ducts. Rupture into bile ducts is the most common and serious complication of hydatid liver disease. The predisposing factors for cysto-biliary communications are; preoperative increased levels of liver enzymes and large size cysts or multiple cysts . The symHepatocellular jaundice is the injury of hepatocytes without biliary obstruction. The most frequent causes of acute hepatocellular damage are viruses, natural and chemical toxic agents and drugs. Although performing laparotomy is necessary in patients with hydatid cyst rupture, anesthesia and trauma of surgery may cause hepatocellular jaundice to deteriorate, perhaps fatally . In the In the countries where hydatid disease is rare, the differential diagnosis of hydatid jaundice can be difficult as well . It may"}
+{"text": "Auditory mismatch negativity (MMN) and its magnetic counterpart (MMNm) are event-related potentials/fields elicited by violations of previously established auditory regularities . Reduced MMN amplitude is a robust finding in both medicated and unmedicated schizophrenia (ScZ) patients , potentially indicating impaired predictive processes . Furthermore, several studies have examined MMN responses in individuals at clinical high risk for psychosis (CHR) and have found MMN deficits to be present already in this population, indicating that MMN is compromised before psychosis onset and could represent a marker of risk for psychosis development. However, not all studies have reported significant differences in MMN amplitude between clinical high risk and healthy individuals and there is evidence to suggest that MMN deficits are primarily observed in CHR individuals who transition to psychosis .The purpose of the present study is to investigate MEG recorded MMNm amplitude responses to both duration deviants and sound omissions in n = 90 CHR-individuals who were screened with the Schizophrenia Proneness Instrument and the Comprehensive Assessment of At Risk Mental States. N = 50 healthy controls served as a comparison group. We employed an auditory oddball paradigm in which three different sequences of auditory stimuli were presented binaurally at ~ 70 dB . The standard sequence contained five identical tones (80 ms) and the deviant sequence contained four identical tones and one duration deviant tone (40 ms). In addition, an omission sequence which contained only four identical tones was included to examine auditory predictions. Participants were instructed to focus their attention away from the sounds and to perform a simple visual detection task. We analyzed MMNm responses to unpredictable deviant and omitted sounds in bsensor and source space. The linearly constrained minimum variance (LCMV) beamformer was used to identify the generators of the MMNm responses and to compute artefact-free source-level time-courses.Consistent with previous studies revealing MMN sources in auditory cortical areas, bilateral MMNm sources were localized in auditory cortices for both duration deviants and sound omissions. Our data show attenuated MMNm responses elicited by duration deviant sounds in CHR individuals compared to healthy controls.Taken together, the study findings suggest that reduced MMNm amplitude is present before psychosis onset and reflects aberrant predictive processing rather than deficient stimulus-specific adaptation. Clinical follow-up measurements will be obtained to determine whether MMNm amplitudes are a potential biomarker for predicting onset of psychosis."}
+{"text": "Assessment of pyrazinamide susceptibility may be prudent before using it in regimens for drug-resistant tuberculosis.Although pyrazinamide is commonly used for tuberculosis treatment, drug-susceptibility testing is not routinely available. We found polymorphisms in the  We calculated the frequency of each pncA polymorphism and classified mutations as synonymous or nonsynonymous. We compared polymorphisms with those reported in the literature to identify any that are known to be associated with phenotypic susceptibility and to determine the proportion that are likely to confer phenotypic resistance  . CulturepncA mutations, we also compared IS6110-based restriction fragment-length polymorphism (RFLP) patterns with pncA mutations for the isolates from South Africa . The distribution of RFLP patterns among isolates with identical pncA mutations was examined to determine if the pncA mutation arose de novo or may have been transmitted.To determine the effect of clonal expansion of MDR and XDR TB on the diversity of pncA gene sequencing for 554 unique patient-isolates [1 isolate/patient], 167 MDR TB and 387 XDR TB; of these, 99 (59%) of MDR TB and 215 (56%) of XDR TB patients had previously received treatment for TB. A pncA polymorphism was found in 117 (70%) MDR TB and 370 (96%) XDR TB isolates .We completed targeted isolates , 2. The pncA polymorphisms were identified  have previously been associated with phenotypic pyrazinamide susceptibility  were present in >1 patient . We founmutation . MoreovepncA polymorphisms. Given the high likelihood of frameshift mutations resulting in resistance and the high specificity (94%\u201398%) of pncA SNPs for pyrazinamide resistance  (pncA sequence, but its diagnostic accuracy has not yet been adequately tested (A diversity of \u2013A limitation of our study is that phenotypic pyrazinamide susceptibility testing was not performed on the sequenced isolates. Nonetheless, correlation with phenotypic testing has been previously reported in the literature for most polymorphisms, enabling us to estimate the proportion likely to be pyrazinamide resistant (pncA polymorphisms from geographically disparate countries suggests that guidelines to empirically use pyrazinamide in drug-resistant TB regimens, including shorter MDR TB regimens (The high prevalence of pncA gene mutations associated with pyrazinamide resistance in drug-resistant tuberculosis, South Africa and Georgia.Supplemental methods for study of"}
+{"text": "The initiation and progression of malignant tumors is driven by distinct subsets of tumor-initiating or cancer stem-like cells (CSCs) which develop therapy/apoptosis resistance and self-renewal capacity. In order to be able to eradicate these CSCs with novel classes of anti-cancer therapeutics, a better understanding of their biology and clinically-relevant traits is mandatory.Several requirements and functions of a CSC niche physiology are combined with current concepts for CSC generation such as development in a hierarchical tumor model, by stochastic processes, or via a retrodifferentiation program. Moreover, progressive adaptation of endothelial cells and recruited immune and stromal cells to the tumor site substantially contribute to generate a tumor growth-permissive environment resembling a CSC niche. Particular emphasis is put on the pivotal role of multipotent mesenchymal stroma/stem cells (MSCs) in supporting CSC development by various kinds of interaction and cell fusion to form hybrid tumor cells.A better knowledge of CSC niche physiology may increase the chances that cancer stemness-depleting interventions ultimately result in arrest of tumor growth and metastasis. Various models are available for the generation of tumor initiating cells which subsequently give rise to neoplasias and malignant cancers including a hierarchical , 2 and aTumor initiation of the hierarchical model starts within a normal stem cell niche (SCN) which regulates proliferation, apoptosis resistance and maintains stemness whereby a normal stem cell evades regulation resulting in an aberrant/tumorigenic stem-like cell, also known as cancer stem-like cell (CSC) , 12. BesExamples of the hierarchical model have been shown in solid tumors such as breast cancer and in non-solid tumors such as acute myeloid leukemia , 2. For The stochastic model represents a second feasibility to circumstantiate tumor initiation. In comparison to the hierarchical model, every tumor cell within the stochastic model is biologically homogenous with an equal probability to initiate, maintain and promote tumor growth whereby functionalities depend on both, extrinsic factors originating from the tumor microenvironment and intrinsic factors such as signaling pathways and levels of transcription factors , 27. TumExamples of the stochastic model can also be found in solid and non-solid tumors such as colorectal cancer, lung adenocarcinoma and lymphoblastic leukemias \u201332.Whereas the stochastic model primarily addresses genetic heterogeneity without consideration of potential phenotypic variations within the genetically homogenous tumor cell population , the hieConsequently, both models of tumor initiation result in aberrant/tumorigenic stem-like cells which further promote tumor development and progression. However, little is known about the mechanism and the existence of a cancer stem cell niche (CSCN) for CSC generation and maintenance of tumor growth.Whereas tumor tissue harbors a variety of different cell populations including tumor cells in different states of development, one possibility of CSC development includes the hypothesis to be derived from neoplastic transformation during development or self-renewal of normal tissue-specific stem cells and to be primarily associated with solid tumors . AlternaMoreover, in a human myeloid leukemia model, phorbol ester-induced differentiation of U937 leukemia cells resulted in acquired adherence of cell cycle-arrested and differentiated monocyte/macrophage-like cells for several weeks. A decreasing threshold of phorbol ester or interference with the downstream signaling cascade of phorbol ester-activated protein kinase C interrupted transactivating processes via AP-1 (predominantly Jun/Fos) and NF\u03baB and induced retrodifferentiation , 42. ThiTogether, these findings suggest that certain stimuli which may include damage products and DAMPs within a tumor cell population can establish a CSCN and contribute to a retrodifferentiation process to rejuvenate tumor cells to a more stem-like phenotype with enhanced self-renewal capacity Fig.\u00a0. MoreoveA sensitive balance of timely available internal and external stimuli within a CSCN may also enable other modes of CSC development such as MSC-tumor cell fusion or entosis. Both types of interaction involve MSC as a potential cellular partner resulting in distinct functional hybrids. Although generally considered rare events, formation of hybrid cells via entosis or via fusion follow completely different mechanisms . EntosisThe normal SCN harbors stem cells and is responsible for regulating stem cell maintenance, in particular the balance between self-renewal and differentiation. Moreover, the normal SCN represents a dynamic and complex compartment whereby additional components including endothelial, immune and stromal cells, extracellular matrix, cell adhesion molecules, soluble factors and microvesicles/exosomes contribute to an environment necessary for enabling both, self-renewal and the capability to differentiate . Based oPrevious work described that stem cells reside in fixed compartments together with other cells determining stem cell behavior and regulating stem cell maintenance . Thus, tOne major prerequisite for tumor growth is the supply with nutrients and oxygen via blood vessels indicating the necessity of a CSCN localizing in the vicinity of vascular structures. Indeed, brain tumor stem cells have been reported to reside at perivascular regions . In variBesides neo-vascularization within the tumor microenvironment, the extracellular matrix (ECM) provides an important structural scaffold comprising fibrous proteins such as collagens, elastin, laminins, and fibronectin, globular proteins including the IgG superfamily integrins and cellular proteases, for instance MMPs, cathepsins and kallikreins for ECM remodeling . During When viewing a CSCN as a coordinated network of locally interacting cells  cells, adipocytes, immune cells  cells, dendritic cells (DC), macrophages) and mesenchymal cells ) together with dynamic thresholds and gradients of soluble factors  in a specific ECM environment , then interference with this balanced homeostasis is predicted to alter CSC development Fig.\u00a0. Thus, EHuman tissue kallikreins also belong to the family of serine proteinases that are involved in degradation of ECM components such as fibronectin, laminin and collagen , 80. In Apart from distinct ECM components and appropriate restructure by distinct proteases that are required for a CSCN to promote CSC development, self-renewal and migration, adjacent cell types are also associated with a CSCN establishment via direct and indirect communication processes with tumor-derived cells to enable CSC development.An important cell population during tumorigenesis is represented by MSC. These multipotent stromal cells are located predominantly at perivascular niches of nearly all human tissues and organs and display a plethora of functions including tissue repair, immunomodulation and stem cell homeostasis \u201389. SubpRegulation of CSC generation also involves a diverse range of soluble factors including cytokines, chemokines, growth factors, hormones, metabolites and further trophic molecules. Breast cancer stem-like cells which are characterized by low levels of CD24, high levels of CD44, and aldehyde dehydrogenase expression , 103 havProduction and release of CCL5 by MSC has been suggested to activate corresponding receptors such as CCR5 on adjacent breast cancer cells thereby promoting altered breast cancer development and metastasis . MoreoveAccording to their recruitment to tumor sites associated with direct interactions of MSC with tumor cells, multipotent MSC may represent a major cellular component of a CSCN since various studies reported mutual acquisition of properties between both interaction partners which alter the original cell fate , 52.2+, small molecules such as microRNAs or second messenger are transported and exchanged via gap junctions allowing regulation of cell proliferation, differentiation and homeostasis maintenance [Gap junctions enable the direct interaction between two neighboring cells, also known as gap junctional intercellular communication (GJIC). Thereby, each cell contributes equally to gap junction formation. Gap junction channels consist of hemichannels/connexons which in turn are composed of six connexin protein subunits that form a pore through the plasma membrane , 112. Inntenance , 113. Duntenance . Furtherntenance . Moreoventenance . Dormancntenance  Whereas GJIC proceeds between two tightly adjacent cells, nanotubes are characterized by thin, F-actin rich structures which link interacting cells over longer distances. These dynamic cytoplasmic protrusions facilitate communication via exchange of various biological cargo including small molecules and organelles . NotablyThe Notch signaling pathway plays a crucial role in cellular processes including tissue repair, stem cell maintenance and regulation of immune cell functions . There iTrogocytosis has been initially observed between immune cells as an active mechanism whereby lymphocytes extract surface molecules from antigen-presenting cells . More reDirect interaction and communication between MSC and tumor cells including GIJC, nanotube formation, Notch signaling, and trogocytosis may contribute to the generation of CSCs together with mutual exchange of distinct factors which alter properties of the involved cell populations. For example, cancer cell\u2013derived interleukin1 can stimulate prostaglandin E2 secretion by MSC operating in an autocrine manner to further induce expression of cytokines by the MSC which in turn activate \u03b2-catenin signaling in the cancer cells in a paracrine fashion and formation of CSCs .Together, these different types of direct interactions emphasize the importance and requirements of tumor-associated cells such as MSC within a CSCN to relay cellular properties that alter the original phenotype of tumor cells towards CSCs.In addition to direct interactions altering CSC phenotype and function, indirect communication plays a pivotal role within CSCN. It involves both the release of soluble molecules such as metabolites and hormones and the exchange of microvesicles and exosomes .In CSCN, metabolites including lactate, glutamine and keton bodies mutually reprogram metabolism of stromal stem cells and cancer cells favoring adaption of tumor cells to dynamic fluctuation of CSCN. Activation of CSCN homing CAFs by tumor cells leads to metabolic reprogramming of CAFs to a glycolytic phenotype meaning elevation of glucose uptake and elevation of lactate secretion serving as nutrient for adjacent cancer cells , 130. OnFurthermore, hormones as soluble agents have been demonstrated to influence CSCs. For instance, progesterone induced the expansion of breast cancer stem-like cells .Exosomes are characterized as homogeneous, 40 to 100\u00a0nm small endocytosed membrane particles which can be mutually exchanged by tumor cells and adjacent cell populations in the tumor microenvironment, particularly macrophages and MSC. These small particles contain a variety of proteins, lipids, functional RNAs and regulatory miRs , 136. AlAlthough knowledge about CSCs originating from a CSCN is limited, the tumor microenvironment in which CSCs reside, provides a structural scaffold with various resident cancer-associated aberrant cell types which contribute to tumor growth and exchange soluble factors by mutual intercellular communications. Due to progressively increasing tumor cell growth and impaired vascularization, some tumor cells within the center of a solid tumor have limited access to nutrients. An impaired nutrient availability during expansion of the tumor size leads to hypoxic and more acidic conditions with starvation of the inner tumor cells eventually resulting in autophagy and necrosis/necroptosis  , a process required for metastasis, through activation of EMT transcription factors resulting in e.g. loss of E-cadherin , 157. InFollowing hypoxia and EMT, cancer cells can escape the primary tumor niche and migrate and disseminate to distant organs , 165.Besides the contribution of hypoxic conditions to metastasis, low pH/acidic conditions as a result of lactate release from increased anaerobic glycolysis of tumor cells may favor metastasis as well. Acidic conditions are proposed to activate proteases such as cathepsins which in turn degrade ECM for tumor invasion \u2013168. Alslow/CD44high breast cancer stem-like cells [Hypoxic and more acidic conditions in the inner part of a tumor are often accompanied by starvation and reduced tumor cell viability, Enhanced cell death of centrally located tumor cells by progressive nutrient deficiency, starvation and low oxygen levels can involve three main mechanisms: apoptosis, autophagy and necrosis/necroptosis. Apoptosis is a highly regulated cell death program that can be triggered by both extrinsic and intrinsic stimuli after induction in consequence of inevitable cell stress , 171. Hoke cells . Converske cells  further Necrosis depicts another process of cell death characterized as random, accidental and unregulated . NonetheThe release of DAMPs initiates an innate and adaptive immune response attracting immune cells such as DC, NK cells, macrophages and regulatory T cells (Tregs)  Fig.\u00a01)1). AlthoReduced immune response to tumor cells can also be mediated by MSC which are recruited to tumor sites due to the inflammatory microenvironment Fig.\u00a0. OverallMacrophages (M1) contribute to tumor destruction via IFN\u03b3 activation followed by production of type 1 cytokines and chemokines. Conversely, activation of M2 macrophages via MSC promotes tumorigenesis by production of type 2 cytokines and chemokines strengthening the dual role of macrophages depending on the phenotype and activation status. During progressive adaption to the tumor microenvironment, TAMs represent a further macrophage phenotype that triggers tumor development through support of angiogenesis and ECM remodeling . ConsequTogether, the cascade of hypoxic conditions and low nutrient supply accompanied by limited apoptosis, autophagy and necrosis/necroptosis followed by release of DAMPs evokes an inflammatory microenvironment which is modulated by interacting MSC. These mechanisms which are also influenced by protease activities and subsequent ECM modulation interfere with the dynamic and sensitive equilibrium of the CSCN which can critically alter the amount of CSCs affecting clinical outcomes and patient prognoses .The presence of a CSC population as part of a heterogeneous tumor entity  is suggeAccording to metabolic alterations and functional interference with the requirements of a carefully balanced factor homeostasis for CSC generation, the sensitive maintenance of a CSCN is likely subject to changes. Such CSCN structures can be disabled at certain sites of the tumor and newly established at more favorable places within the tumor suggesting multiple and simultaneous possibilities for CSCNs with appropriate turnover. A potential CSCN turnover may depend on the stability of the environment. For example, CSCNs of tumor metastases in the bone marrow are more protected and stabilized in the spongy bone cavities as compared to CSCNs in more metabolically-exposed tissues such as primary organ-associated tumor tissues or lymph node metastases. Nevertheless, the dynamic generation and changes of CSCs within the plasticity of tumor tissues and the continuously functional alterations/adaptations of developing and metastasizing tumor cells by loss of distinct functions and/or acquisition of new properties represent the real challenge of a successful tumor therapy."}
+{"text": "Our study aimed to present the distinctive correlates of formal thought disorder in patients with schizophrenia, using the Clinical Language Disorder Rating Scale (CLANG).We compared the formal thought disorder and other clinical characteristics between schizophrenia patients with (n = 82) and without (n = 80) formal thought disorder. Psychometric scales including the CLANG, Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Calgery Depression Scale for Schizophrenia (CDSS) and Word Fluency Test (WFT) were used.After adjusting the effects of age, sex and total scores on the BPRS, YMRS and WFT, the subjects with disorganized speech presented significantly higher score on the poverty of contents of abnormal syntax , lack of semantic association , disclosure failure , pragmatics disorder , dysarthria , and paraphasic error  items than those without formal thought disorder. With defining the mentioned item scores as covariates, binary logistic regression model predicted that disclosure failure  and pragmatics disorder  were distinctive correlates of formal thought disorder in patients with schizophrenia.Disclosure failure and pragmatics disorder might be used as the distinctive indexes for formal thought disorder in patients with schizophrenia."}
+{"text": "Deficits in social cognition and on social perception tasks are well studied and widely found in populations with schizophrenia. In addition, our work consistently replicates findings that individuals with schizophrenia report severe loneliness, significantly higher than healthy matches. Loneliness is a chronic, gnawing condition that induces distress and impedes life satisfaction and function across the spectrum of mental health. We also find social isolation impedes interpretation of social information and may lead to socio-perceptual deficits.The present study examines the effectiveness of a novel, adaptive virtual reality simulated social exposure training intervention  in both decreasing feelings of loneliness and improving social cognitive function in individuals with schizophrenia. We investigate baseline relationships between social isolation, loneliness and social cognition abilities, as well as pre to post intervention changes in function and subjective social well-being.Fifteen medicated SZ outpatients completed 10 virtual reality social skills training sessions over the course of 5 weeks. Training sessions depicted three naturalistic social scenarios in which participants were instructed to complete 12 total social \u201cmissions\u201d to obtain information from VR avatar characters. Prior to training and following the final training session, participants were assessed using the CogState Brief Schizophrenia Battery Social Emotional cognition task and rated loneliness using the UCLA Loneliness Scale. Independent raters conducted pre- and post-training clinical interviews to assess changes in participants\u2019 levels of positive, negative, and overall psychiatric symptomsGreater overall psychiatric symptoms were significantly correlated with higher levels of experienced loneliness, consistent with previous findings. There was a significant improvement in social emotional cognition accuracy, and a trend-level reduction in loneliness from pre-training to post-testing following social VR training.Previous research indicates that individuals higher on the psychosis spectrum perform worse at social cognition and social perception tasks. Our own research indicates that individuals higher on the psychosis spectrum also endorse higher levels of social distress via social isolation and loneliness. The present study attempts to enhance social cognitive and interpersonal abilities of individuals with schizophrenia while decreasing loneliness by strengthening social bonds and skills using a virtual reality training game. We find that following 10 sessions of VR social training, accuracy on measures of social cognition is improved significantly, however loneliness is reduced non-significantly. These initial results demonstrate potential feasibility of a novel VR social skills training game for improving social experience for patients with schizophrenia."}
+{"text": "Chromatin is a very long DNA\u2013protein complex that controls the expression and inheritance of the genetic information. Chromatin is stored within the nucleus in interphase and further compacted into chromosomes during mitosis. This process, known as chromosome condensation, is essential for faithful segregation of genomic DNA into daughter cells. Condensin and cohesin, members of the structural maintenance of chromosomes (SMC) family, are fundamental for chromosome architecture, both for establishment of chromatin structure in the interphase nucleus and for the formation of condensed chromosomes in mitosis. These ring-shaped SMC complexes are thought to regulate the interactions between DNA strands by topologically entrapping DNA. How this activity shapes chromosomes is not yet understood. Recent high throughput chromosome conformation capture studies revealed how chromatin is reorganized during the cell cycle and have started to explore the role of SMC complexes in mitotic chromatin architecture. Here, we summarize these findings and discuss the conserved nature of chromosome condensation in eukaryotes. We highlight the unexpected finding that condensin-dependent intra-chromosomal interactions in mitosis increase within a distinctive distance range that is characteristic for an organism, while longer and shorter-range interactions are suppressed. This reveals important molecular insight into chromosome architecture. How chromatin is spatially organized within the cell nucleus and within chromosomes is a fundamental question in cell biology. Centimeter-long DNA molecules change their spatial chromatin organization within micrometer-sized cells during cell cycle progression. In interphase, chromatin is distributed throughout the nucleus to express the genetic information. When cells enter mitosis, chromatin becomes compacted to form mitotic chromosomes. Chromosome condensation, the gross morphological change of spatial chromatin organization in mitosis, is indispensable for the faithful inheritance of genetic information. Structural maintenance of chromosomes (SMC) complexes are large proteinaceous rings that control spatial chromatin organization at various stages during cell growth and differentiation. By topologically entrapping more than one DNA strand within its ring, SMC complexes are thought to mediate interactions between DNA strands for the establishment of chromatin architecture Uhlmann . Two memChromosome conformation capture is a powerful technique to investigate spatial chromatin organization (Dekker et al. Recent Hi-C results have illustrated the dramatic alteration of chromatin organization during cell cycle progression in several species (Gibcus et al. A notable feature of mitotic chromosomes is a steep drop of contact probabilities at very large genomic distances, over 10\u00a0Mb in human cells (Naumova et al. The mitotic reduction of local chromatin contacts comes as a surprise, as one would expect that all DNA sequences come closer together in a condensed chromosome. However, new interactions at longer distances will restrict the freedom of movement of the chromatin chain, thereby reducing the probability of local interactions. Consistently, local chromatin motility becomes constrained in mitosis (Kakui et al. All the above described changes of chromatin contacts in fission yeast mitosis are dependent on condensin Fig.\u00a0 Kakui e. FurtherThe recent Hi-C experiments unveiled that SMC complexes drive a dramatic reorganization of chromatin contacts as cells enter mitosis. They did not elucidate the mechanism of how SMC complexes mediate chromatin interactions. Two proposed models how SMC rings modulate chromatin contacts are the stabilization of stochastic pairwise interactions and loop extrusion, two models that need not be mutually exclusive (Cheng et al."}
+{"text": "Motivational deficits are prevalent feature of schizophrenia, which have been tightly linked to real-world outcomes. Abnormalities in effort cost computations have been proposed as a candidate mechanism underlying these deficits. In the present study, we sought to employ behavioural economic analyses to further understand cost-benefit decision making abnormalities in schizophrenia.58 young adults with schizophrenia and 58 matched controls participated in this study. Participants completed an effort-based decision-making task in which they made decisions to expend physical effort in exchange for monetary rewards. From participants choice behaviour, we computed indifference values  for each individual participant. Other computational parameters were also computed such as choice consistency and subjective reward valuation.Patents and controls did not differ in their subjective valuation of reward. On the decision-making task, patients made more inconsistent choices relative to controls. In both univariate and multivariate analyses controlling for potential confounders, patients had higher indifference values meaning that patients required more money in the exchange of their effort. Among patients, higher indifference values were associated with more severe clinical motivational deficits.Patients had multiple abnormalities related to their decisions to expend effort for reward. Choices were more chaotic and reward value was discounted by effort at a steeper rate in patients. These results point toward an abnormality in the computation of effort costs or in the integration of these costs with value signals."}
+{"text": "Intra-aortic balloon pump (IABP) counterpulsation is a catheter-based treatment for coronary artery disease and decompensated heart failure to increase coronary blood flow and improve cardiac output. IABP is generally well tolerated, and complications are usually related to peripheral vasculature or red blood cell and platelet consumption. The usual insertion site via femoral artery renders the patient bedbound. Recently, axillary artery has been used in patients with atherosclerotic peripheral vascular disease and documented small arteries or in those awaiting transplant to ensure ambulation and prevent deconditioning. We present a patient with ischemic cardiomyopathy and severe left ventricular dysfunction, awaiting Orthotropic Heart Transplant. His worsening intractable angina and dyspnea necessitated IABP placement via left axillary artery, significantly improving his condition. He subsequently experienced migraine-type persistent unilateral headache refractory to standard pain management. Multiple strategies were utilized to treat his pain, but the patient insisted that his pain commenced after IABP placement. Ultimately, the removal of the pump led to complete resolution with no recurrence. The authors hypothesize that the unilaterally directed blood flow and direct increase in cerebral perfusion from the intra-aortic balloon pump may have caused vasodilation of the extracranial arteries, leading to a persistent and debilitating headache in this susceptible patient. Intra-aortic balloon pump (IABP) is a cylindrical polyethylene device inserted into the descending thoracic aorta, which increases myocardial oxygen delivery and cardiac output . Its \u201ccoA 63-year-old male with ischemic cardiomyopathy and severe left ventricular dysfunction was admitted with chest pain and dyspnea at rest. He was on maximal medical therapy and had received multiple prior percutaneous coronary interventions and two previous coronary artery bypass surgeries. Recent coronary angiography revealed no possibility of further revascularization. He was evaluated for Orthotropic Heart Transplant (OHT) and listed as Status 1A-e (urgent need). His worsening intractable angina and dyspnea necessitated IABP placement via left axillary artery, which significantly improved his condition. Axillary artery was the chosen site of insertion  in order to enable ambulation and prevent deconditioning, as the patient was awaiting transplant . The IABExamination revealed tender and bulging left temporal artery suspicious of temporal arteritis (TA); however, his normal erythrocyte sedimentation rate minimized TA as a likely diagnosis. Nonetheless, he was offered prophylactic prednisone, which he refused. Pain management service was consulted and multimodal treatment including acetaminophen, oxycodone, citalopram, and tizanidine was initiated, while nitrates were withheld . The patIn accordance with patient's wishes, the IABP was weaned and removed, and nitrates were initiated for angina prophylaxis. On postremoval assessment, the patient's headache had completely resolved with no future recurrence. He subsequently received OHT and was discharged with normal EF and no further headaches.Intra-aortic balloon pump (IABP) is a widely used circulatory assist device to improve coronary perfusion in acute coronary syndromes and improve cardiac output in acute decompensated heart failure. Coronary perfusion has often been compared to cerebral perfusion, drawing similarities in the pathophysiology and pharmacology of myocardial infarction and acute stroke , 8. AugmOne study showed that IABP augmentation causes a significantly higher increase in transcranial Doppler CBF velocity change in the middle cerebral artery with enhanced CBF especially in patients with preexisting left ventricular dysfunction . Data inFurther case reports suggest that IABP placement can increase proximal pressures and carotid blood flow above the IABP and decrease distal pressures and perfusion below it, leading to distal perfusion injuries (ischemia) , 18. The"}
+{"text": "Swift and adequate fluid loading is a cornerstone of septic shock therapy. Yet, careful assessment of volume responsiveness and volume amount during the resuscitation process is a prerequisite. Both overzealous initial fluid administration and late fluid overload are harmful and may be associated with increased mortality.Static  pressure readings are erroneous for monitoring fluid resuscitation and should be abandoned. Dynamic measurements  better predict fluid responsiveness than static filling pressures but the conditions necessary for these parameters to correctly evaluate preload dependency are frequently not met. The passive leg raising maneuver as a means to alter biventricular preload in combination with real-time measurement of cardiac output changes is an easy-to-use, fast, relatively unbiased, and accurate bedside test to guide fluid management and to avoid fluid overload during early septic shock treatment. Moreover, PLR may also be particularly useful to assist various treatments that trigger fluid removal during the \u201cde-resuscitation\u201d phase of septic shock.The passive leg raising maneuver in combination with real-time measurement of cardiac output changes is an easy-to-use, fast, relatively unbiased, and accurate bedside test to guide fluid management during septic shock. The recently published Surviving Sepsis Campaign guidelines strongly recommend ample volume resuscitation during the first day of septic shock treatment . Such agJournal of Intensive Care, Krige et al. prospectively investigated the use of a novel generation Vigileo FloTrac\u2122 system during a PLR maneuver in medico-surgical patients with vasopressor-dependent circulatory shock [At the beginning of this millennium, several authors proposed to use physiologic heart-lung interactions during positive pressure ventilation as more reliable predictors of fluid responsiveness in septic shock . Variatiry shock . The stuThrough the years, awareness has risen that after initial aggressive fluid resuscitation the focus should shift towards obtaining a net and even negative fluid balance . Late liIn conclusion, PLR testing in combination with more sophisticated real-time hemodynamic monitoring actually seems to be the most appropriate method to guide a bedside \u201cdo not harm\u201d volume resuscitation strategy in septic shock. Future studies should assess the PLR maneuver using calibrated intermittent  or continuous  monitoring and evaluate whether this test could become pivotal in managing fluid removal during the \u201cde-resuscitation\u201d phase of septic shock."}
+{"text": "Our understanding of the neurobiology of psychiatric disorders remains limited, and biomarker-based clinical management is yet to be developed. Induced pluripotent stem cell (iPSC) technology has revolutionized our capacity to generate patient-derived neurons to model psychiatric disorders. Here, we highlight advantages and caveats of iPSC disease modeling and outline strategies for addressing current challenges. Even as neuropsychiatric research has boomed, psychiatric disorders have remained a leading cause of global morbidity and disease burden . CurrentAs a result, definitive diagnoses and treatment strategies based on objective biomarkers continue to evade us. The development of human iPSC technology offers one approach to allow researchers to address the genetic complexity issue in psychiatric disorder research. Somatic cells such as skin fibroblasts from adult patients can be dedifferentiated to a pluripotent state by transient overexpression of the reprogramming transcription factors. Theoretically, iPSC clones can then be differentiated to any other cell type by exposure to an appropriate combination of patterning molecules. Parallel in vitro disease modeling efforts for studying the neural correlates of disease-associated genotypes may provide novel insights into the neurological underpinnings of psychiatric disorders . iPSCs aDISC1) gene altered synaptic activity and downstream signaling in iPSC-derived neurons, establishing a causal relationship between patient genetics and cellular phenotypes [A central goal of biological psychiatry is to understand how healthy and aberrant brain function may arise from the interaction of neural circuits. Crucial to this effort is generating relevant neural cell types from iPSCs, because studying the basic units of neural circuits in isolation enables the construction of in vitro model systems. Given the diversity of cell types in the mammalian brain, the field continues to develop protocols for generating relatively homogeneous populations of neuronal and glial subtypes, as well as genetic reporters to help label and identify specific cell types in mixed populations . This apenotypes . Furtherenotypes .While recent studies provide evidence for mechanisms that may contribute to disease pathology, excitement must be tempered by experimental knowledge addressing the caveats of in vitro disease modeling Fig.\u00a0. A downsAnother issue is that of variability between cell lines and across experimental batches, possibly due to somatic mosaicism in donor cells prior to reprogramming, accumulation of de novo mutations with selective advantages, stochastic events during differentiation, and heterogeneous patient genetics . HoweverOne such approach is the stratification of large patient cohorts based on factors such as genetic risk, pharmacological response profiles, distinctive and quantitative endophenotypes, or comorbidities with other diseases. Modeling genetic risk includes rare variants conferring large genetic risk, such as copy number variation, or higher frequency common variants, such as single nucleotide polymorphisms, conferring relatively lower risk . CellulaAnother strategy is to study iPSC-derived neurons from a subset of well-characterized patients from a larger cohort. Here, in vitro phenotypes can be correlated with multiple continuous variables such as clinical severity, behavioral/biological measures, brain activity, and blood metabolites. Obtaining such multidimensional data from even small patient cohorts could inform the predictive value of individual variables and lead to the discovery of biomarkers. The explosion of rich neuropsychiatric disease sequence databases coincides with the emergence of powerful and accessible predictive machine learning tools. In conjunction with large-scale genetic data, deep-learning models may enjoy improved performance by using intermediate cellular phenotypes from patient-derived cells to bridge the gap between molecular and circuit or clinical features .In addition to careful study design, picking appropriate in vitro models will be critical for discovering clinically relevant in vitro phenotypes. Three-dimensional iPSC-derived organoids may be able to recapitulate maturation-related signatures in developing circuits, as has been successfully done with autism spectrum disorder . SimilarIt is increasingly clear that gaining fresh insights into the biology of psychiatric disorders demands a multipronged approach, including but not limited to patient iPSC-based diseased modeling. Furthermore, concerted efforts across laboratories for tackling the inherent variability of in vitro systems may pave the way for establishing standardized in vitro parameters, which would be immensely helpful for moving toward high-throughput profiling and screening in the future . Despite"}
+{"text": "Despite numerous medical advances in the care of at-risk preterm neonates, oral feeding still represents one of the first and most advanced neurological challenges facing this delicate population. Objective, quantitative, and noninvasive assessment tools, as well as neurotherapeutic strategies, are greatly needed in order to improve feeding and developmental outcomes. Pulsed pneumatic orocutaneous stimulation has been shown to improve nonnutritive sucking (NNS) skills in preterm infants who exhibit delayed or disordered nipple feeding behaviors. Separately, the study of the salivary transcriptome in neonates has helped identify biomarkers directly linked to successful neonatal oral feeding behavior. The combination of noninvasive treatment strategies and transcriptomic analysis represents an integrative approach to oral feeding in which rapid technological advances and personalized transcriptomics can safely and noninvasively be brought to the bedside to inform medical care decisions and improve care and outcomes.The study aimed to conduct a multicenter randomized control trial (RCT) to combine molecular and behavioral methods in an experimental conceptualization approach to map the effects of PULSED somatosensory stimulation on salivary gene expression in the context of the acquisition of oral feeding habits in high-risk human neonates. The aims of this study represent the first attempt to combine noninvasive treatment strategies and transcriptomic assessments of high-risk extremely preterm infants (EPI) to (1) improve oral feeding behavior and skills, (2) further our understanding of the gene ontology of biologically diverse pathways related to oral feeding, (3) use gene expression data to personalize neonatal care and individualize treatment strategies and timing interventions, and (4) improve long-term developmental outcomes.A total of 180 extremely preterm infants from three neonatal intensive care units (NICUs) will be randomized to receive either PULSED or SHAM (non-pulsing) orocutaneous intervention simultaneous with tube feedings 3 times per day for 4 weeks, beginning at 30 weeks postconceptional age. Infants will also be assessed 3 times per week for NNS performance, and multiple saliva samples will be obtained each week for transcriptomic analysis, until infants have achieved full oral feeding status. At 18 months corrected age (CA), infants will undergo neurodevelopmental follow-up testing, the results of which will be correlated with feeding outcomes in the neo-and post-natal period and with gene expression data and intervention status.The ongoing National Institutes of Health funded randomized controlled trial R01HD086088 is actively recruiting participants. The expected completion date of the study is 2021.Differential salivary gene expression profiles in response to orosensory entrainment intervention are expected to lead to the development of individualized interventions for the diagnosis and management of oral feeding in preterm infants.ClinicalTrials.gov NCT02696343; https://clinicaltrials.gov/ct2/show/NCT02696343 (Archived by WebCite at\u00a0http://www.webcitation.org/6r5NbJ9Ym) The biological complexities of oral feeding have made it the most advanced neurological milestone of the newborn and a predictor of both short- and long-term developmental outcomes in the at-risk premature neonatal population ,2. SucceThere is currently no objective and quantitative tool to assess oral feeding maturity in premature infants. The current standard of care to determine oral feeding readiness in the EPI population is to use largely subjective, qualitative, and unvalidated cue-based assessment tools -22. CareA new translational application, approved by the FDA in 2008, has been shown to promote ororhythmic motor patterning (nonnutritive suck) in preterm infants who exhibit delayed or disordered nipple feeding behaviors. This approach is based on mechanosensory entrainment of the suck central pattern generator using servo-controlled pulsed pneumatic stimuli to drive peri- and intra-oral afferents, which in turn modulate local reflex activity and produce nonnutritive suck rhythms -31. Sinc\u03bc L of saliva , and (3) Santa Clara Valley Medical Center . The research protocol has been approved by each site\u2019s Institutional Review Board (IRB). Participant recruitment began in July 2016, and NTrainer intervention is expected to be completed by 2020. Neurodevelopmental follow-up testing will begin in 2018.The primary outcome variables include salivary gene expression of a panel of genes previously identified as playing a role in oral feeding of preterm infants, time to transition to full oral feeding, and oromotor NNS pattern formation. Secondary outcome variables include: NICHD NRN 18-month Feeding-Growth-Nutrition Questionnaire, and Bayley III scores of cognitive, motor, and language skills at 18 months\u2019 corrected age (CA).Oral feeding is a complex neurological milestone that can pose a significant challenge for many preterm infants, particularly for those born extremely prematurely , as well as those with a compromised respiratory status. Persistent feeding difficulties can result in numerous short- and long-term medical complications, as well as place infants at risk for developmental disabilities. Currently, there is no objective method for treating delayed or disordered feeding skills, or for assessing oral feeding maturity. Therefore, there is a strong need for objective assessment tools and novel therapeutic interventions to identify the underlying mechanisms that delay and disrupt oral feeding success and provide evidence-based intervention strategies to help ameliorate outcomes. The current study aims to combine safe, noninvasive treatment strategies and salivary diagnostics in EPIs to improve oral feeding skills as well as long-term neurodevelopmental outcomes and to further our understanding of the gene ontology of biological pathways related to oral feeding, which may ultimately individualize the type and timing of interventions and personalize neonatal care."}
+{"text": "To date, the oral cavity has yielded a diverse menagerie of adult stem cells that includes dental pulp stem cells (DPSCs), dental follicle stem cells (DFSCs), stem cells from apical papilla (SCAP), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), and gingival mesenchymal stem cells (GMSCs). These stem cells have various useful applications in clinical dentistry that is dental pulp regeneration after root canal treatment, osseous integration of titanium implants, and maxillofacial and periodontal regeneration. Stem cells-based approaches in clinical dentistry are reviewed by D. Hughes and B. Song, as well as S. Miran et al. within this special issue. in vitro culture, these dental and oral-derived adult stem cell populations exhibit much divergent characteristics  and express variable cell surface markers and transcription factors. In this special issue, C.-M. Kang et al. compared the transcriptional profile of human DPSCs and umbilical cord stem cells (UCSCs) with microarray and qRT-PCR techniques and found similar expression levels of the various canonical mesenchymal stem cell markers. However, gene ontology analyses revealed significant differences in the expression of genes related to cell proliferation, angiogenesis, immune responses, growth factor activities, and signal transduction, between DPSCs and UCSCs, which could indicate divergent propensity to differentiate into various lineages.Despite their common embryonic origin from the cranial neural crest and their similar fibroblastic morphology within in vitro culture. Subsequently, L. Liu et al. demonstrated that transgenic expression of the human xeroderma pigmentosum group C (XPC) gene through a lentiviral vector could mitigate this age-related decline in pluripotency markers expression by DPSCs.Dental and oral-derived stem cells have a number of advantages over other more commonly utilized sources of adult stem cells. Compared to the invasive surgical procedure required for obtaining mesenchymal stem cells from bone marrow, these adult stem cells are readily isolated from biological waste produced during routine dental treatment . Several studies have reported that dental and oral stem cells such as SHED possess much more extensive multidifferentiation potential and proliferative capacity compared to other adult stem cells. This is extensively discussed in a review on SHED by V. Rosa et al. within this special issue. Even more surprising are reports of the expression of pluripotency markers such as OCT4, MYC, and SOX2 by some dental and oral-derived stem cells, which are not usually expressed in most other adult stem cell types. Expression of these markers might be indicative of the more extensive plasticity and multilineage differentiation potential of dental and oral-derived stem cells when compared to other sources of stem cells. In this special issue, the study of L. Liu et al. reported that these pluripotency markers were strongly expressed in DPSCs at early passage numbers but were gradually downregulated with extendedIt is possible that the relatively high baseline expression of pluripotency markers by dental and oral-derived stem cells such as DPSCs could render these adult stem cells more amenable to reprogramming into induced pluripotent stem cells (iPSCs). This is critically examined and discussed in a review by J.-H. Lee and S.-J. Seo within this special issue. The study of H. Okawa et al. utilized iPSCs derived from GMSCs to fabricate scaffold-free osteoinductive cellular constructs. Besides the derivation of iPSCs from dental and oral-derived stem cells, it may also be worthwhile to explore the reverse approach, which is the derivation of dental and oral adult stem cell-like lineages from pluripotent stem cells. This may allow us to recapitulate the developmental pathway of the various differentiated somatic lineages of the oral cavity, thus providing us with an extremely useful tool for studying the underlying genetic and developmental basis of various oral and maxillofacial disorders. In this special issue, Q. Zhu et al. reviewed the potential applications of pluripotent stem cell-derived neural crest stem cells, which resemble the various adult stem cell niches of the oral cavity. The study of G. Sriram et al. demonstrated that human embryonic stem cell-derived fibroblasts could be utilized as an alternative to GMSCs for studying the innate immune response to pathogens related to periodontitis (periodontopathogens).In view of the various promising biomedical applications of dental and oral-derived stem cells, we have organized this special issue as a platform to highlight some of the recent developments and cutting-edge research in this field. It is hoped that the comprehensive reviews and research articles presented in this special issue would stimulate greater interest amongst the scientific community to pursue this field of research, as well as facilitating the translation of research data into clinical therapy.Boon Chin HengBoon Chin HengChengfei ZhangChengfei ZhangXuliang DengXuliang DengYin XiaoYin XiaoAlessandra PisciottaAlessandra PisciottaFahad KidwaiFahad KidwaiThimios A. MitsiadisThimios A. Mitsiadis"}
+{"text": "We describe a patient with right hemisphere damage affected by mild left visuo-spatial neglect and constructional apraxia. During the rehabilitation, he failed to draw a draught-board using horizontal and vertical trajectories, but he performed it successfully using oblique trajectories. These observations suggested an impairment of vertical/horizontal spatial coordinates system. In copying tasks including figure elements in different orientations he drew more accurately components in oblique orientation, whereas failed to reproduce components in horizontal orientation. The patient performed visuospatial perceptual and perceptual-imaginative tasks successfully. From these findings, it is possible to suggest that the oblique coordinate system of reference operates independently of vertical and horizontal coordinate systems in building a complex figure and that, therefore, cardinal orientation do not constitute a reference norm to define oblique orientation, as previously suggested."}
+{"text": "To accurately predict atherosclerotic plaque progression, a detailed phenotype of the lesion at the molecular level is required. Here, we assess the respective merits and limitations of molecular imaging tools. Clinical imaging includes contrast-enhanced ultrasound, an inexpensive and non-toxic technique but with poor sensitivity. CT benefits from high spatial resolution but poor sensitivity coupled with an increasing radiation burden that limits multiplexing. Despite high sensitivity, positron emission tomography and single-photon emission tomography have disadvantages when applied to multiplex molecular imaging due to poor spatial resolution, signal cross talk and increasing radiation dose. In contrast, MRI is non-toxic, displays good spatial resolution but poor sensitivity. Preclinical techniques include near-infrared fluorescence (NIRF), which provides good spatial resolution and sensitivity; however, multiplexing with NIRF is limited, due to photobleaching and spectral overlap. Fourier transform infrared spectroscopy and Raman spectroscopy are label-free techniques that detect molecules based on the vibrations of chemical bonds. Both techniques offer fast acquisition times with Raman showing superior spatial resolution. Raman signals are inherently weak; however, leading to the development of surface-enhanced Raman spectroscopy (SERS) that offers greatly increased sensitivity due to using metallic nanoparticles that can be functionalised with biomolecules targeted against plaque ligands while offering high multiplexing potential. This asset combined with high spatial resolution makes SERS an exciting prospect as a diagnostic tool. The ongoing refinements of SERS technologies such as deep tissue imaging and portable systems making SERS a realistic prospect for translation to the clinic. Atherosclerosis is a complex multifactorial pathology that progresses over many decades. Immune-inflammatory responses play key roles in all phases of the pathology and inflammation contributes to plaque rupture resulting in clinical manifestations such as myocardial infarction (MI) and stroke.Multiple imaging techniques are available for both invasive and non-invasive imaging of the vasculature. These include contrast-enhanced ultrasound (CEUS), CT, MRI, positron emission tomography (PET), single-photon emission tomography (SPECT), near-infrared fluorescence (NIRF) microscopy and vibrational spectroscopy. MRI, CT and PET/SPECT are already in clinical use for diagnosing and monitoring atherosclerosis and can provide structural information such as quantifying stenosis and plaque size/location. In some instances, invasive imaging using intra-arterial probes employing one of the above modalities can reveal basic morphological information on plaque composition, yet there remains an urgent unmet requirement for non-invasive imaging tools that can provide information beyond the anatomic and functional level that are able to interrogate the cellular and molecular pathways driving local inflammatory responses that promote plaque vulnerability.Molecular imaging moves beyond anatomic and morphological detail to the level of cellular and molecular events. Activated endothelium offers a number of potential imaging targets, including adhesion molecules promoting leucocyte binding and transmigration into subendothelial locations. The complex inflammatory environment of a developing atherosclerotic plaque offers additional targets such as scavenger receptors present on macrophages/foam cells, and plaque destabilising proteases and peroxidases. True molecular imaging requires a targeting ligand , peptides, aptamers) to specific molecules/cells which are conjugated to a detection agent compatible with the imaging tool of choice, eg, microbubbles (CEUS), iodinated compounds (CT), radionucleotides (PET/SPECT), magnetic/superparamagnetic compounds (MRI) or fluorochromes (fluorescence imaging). Vibrational spectroscopy, such as Raman spectroscopy, offers the advantage of not requiring external imaging tracers owing to direct detection of endogenous biological molecules; however, Raman spectroscopy employing exogenous targeted nanoparticles\u00a0(NPs) (surface-enhanced Raman spectroscopy (SERS)) results in an imaging capability with remarkably increased sensitivity and ability to simultaneously detect multiple analytes (multiplexing), which may improve diagnostic specificity. Advantages and limitations of the described techniques are summarised in In this review, we will highlight recent advances in molecular imaging and their application in identifying vascular inflammation, with a particular focus on the potentialities of Raman and SERS.et alUltrasound-based molecular imaging relies on CEUS, which employs the use of microbubbles as a vascular wall targeting agent. Signals are generated through vibration/oscillation or release of free gas when the microbubbles are exposed to sonic energy. Kaufmann CT possesses relatively good temporal and spatial resolution which can further be improved on by multidetector spiral computed tomography and the concomitant use of iodinated contrast agents. This approach allowed the non-invasive identification of plaque location and sizeAs the current technology stands, clinical use of CT for cellular and molecular imaging of atherosclerosis may be restricted to the narrow use of identifying plaque mineral composition and cellular density. As with anatomic CT imaging, use in this area will be subject to careful review of the radioactive burden associated with CT X-ray exposure, especially in the context of repeated scans. To date, the low sensitivity of CT contrast agents combined with spatial resolution inadequate to detect vulnerable plaque componentsPET and SPECT are widespread imaging tools that rely on the administration of radionucleotides and subsequent detection of \u03b3-rays to construct three-dimensional images of biological tissue forming the cornerstone of nuclear imaging. PET/SPECT are attractive options for molecular imaging owing to their non-invasive nature and high sensitivity. Furthermore, the high sensitivity of nuclear imaging is frequently combined with CT or MRI, tools with superior spatial resolution to form hybrid imaging systems such as PET/CT, SPECT/CT and PET/MRI.18F]-Fluorodeoxyglucose (FDG) is a glucose analogue radiotracer commonly used in PET and uptake by tissues correlates with metabolic activity. Combined PET/CT imaging has shown that FDG accumulates more in symptomatic lesions than asymptomatic sites of stenosis, particularly in macrophage-rich regions.F-FluorodMRI is perhaps the most studied tool to date for molecular imaging in atherosclerosis, owing to excellent spatial and temporal resolution without requiring the administration of ionising radioactive nucleotides.-/- mice offering the potential for early intervention and monitoring.To overcome the major weakness of MRI (poor sensitivity), the use of paramagnetic agents such as gadolinium (Gd) chelates and superparamagnetic (iron oxide microparticles and nanoparticles) contrast agents have been employed to non-invasively image arterial diseases. MRI molecular imaging of atherosclerosis primarily employs ultrasmall paramagnetic iron oxide particles . The properties of USPIOs allow extravasation into vascular tissues enabling potential analysis of atherosclerotic lesions. This approach has been used as a tool for measuring plaque macrophage burden through MRI signal loss following phagocytic uptake of USPIOs in rabbits-/- mice.The use of microparticles of iron oxide (MPIO) offers several advantages over USPIOs. Their larger size (0.9\u20138\u2009\u00b5m) confines their location to endothelial surfaces, preventing cellular uptake and potential consequences of cellular toxicity and loss of molecular specificity. Furthermore, the greater iron payload carried by MIOPs improves signal detection. These attributes coupled with rapid clearance from the circulation can allow early imaging of vascular inflammation with a high degree of specificity.-/- mice.Fluorescence imaging is an optical imaging technique that detects the emission spectra from fluorescent probes excited by a light source. As with other imaging modalities, probes are either passively or actively targeted to a biological molecule or tissue of interest or can act as \u2018smart probes\u2019 that are activated at the target site, for example, enzymatic conversion from a non-fluorescent substrate to a fluorescent product allowing functional read outs of local enzyme activity.The wide optical imaging window available for NIRF imaging allows the use of multiple probes to be assessed in a single system owing to fluorochromes emitting in distinct spectral regions; however, the difficulty in resolving such spectra often requires multiple excitation wavelengths for optimal signal discrimination.Vibrational spectroscopy mainly encompasses two techniques: infrared (IR) and Raman spectroscopies, which create molecularly specific spectra based on the vibrational energies of chemical bonds.FTIR, the most refined modern form of IR spectroscopy gains information from the vibration of molecular bonds caused by absorbance of light; requiring no external labelling method. The ability to detect chemically specific IR spectra over a wide wavelength window allows FTIR to detect multiple classes of biological molecules. FTIR is especially useful for differentiating lipids and proteins and these have been the main focus of FTIR research in cardiovascular studies to date.FTIR has been employed to map the distribution of collagen I, collagen III and elastin in the fibrous cap region of human atheroma samples postmortemLike FTIR, Raman spectroscopy has been used to map the detailed composition of atherosclerotic plaques but improves on FTIR in terms of both spatial and spectral resolution.Raman spectroscopy is a particularly attractive molecular imaging tool for interrogation of atherosclerotic plaques and potential diagnostic agent due to its ability to non-destructively acquire biochemical data on the processes that drive plaque development. Although the non-invasive nature of Raman is an important advantage of the technique, the main disadvantage pertains to its low sensitivity due to the weakness of the Raman scattering effect leading to long imaging times and an inability to discriminate low-level target molecules from background \u2018noise\u2019. Furthermore, many biological molecules are spectrally similar requiring complex chemometric analysis to separate signals of interest.The shortcomings associated with Raman spectroscopy have led to the development of SERS, a highly sensitive advancement of conventional Raman spectroscopy. The enhancement of Raman signal is achieved when a molecule is adsorbed onto or in close proximity to a metal surface and is dependent on the nature of metal surface, the excitation frequency used, the attachment of the molecule to the surface and also the nature of the molecule itself.-/- mice with a superior signal-to-noise ratio compared with immunofluorescence.We have previously shown that intercellular adhesion molecule 1 (ICAM-1)-targeted NPs could detect ICAM-1 expression on aortic sinus tissue sections derived from apoEThe use of metallic NPs offers potential therapeutic applications to atherosclerosis, specifically through photothermal therapy in addition to acting as enhancers of Raman scattering. The photothermal effect arises when the plasmonic resonance wavelength of the NP matches the excitation wavelength of the laser and light is absorbed and converted to heat. If NPs are attached to or internalised by cells, the energy produced can be dissipated to the surrounding biological medium causing thermal destruction of the cell. Gold nanorods and single-walled carbon nanotubes are internalised by carotid artery resident macrophages in vivo following carotid ligation in mice and subsequent exposure of excised ligated vessels to NIR excitation-induced photothermal apoptosis of the macrophage population.https://clinicaltrials.gov/ct2/show/NCT01270139). This multicentre trial involved 180 patients aged 45\u201365 years\u00a0diagnosed as having coronary artery disease with flow-limiting lesions. The two treatment groups received either a surgical implanted \u2018on-artery\u2019 patch capable of transferring silica-gold NPs to the plaque (Nano group) or an intracoronary infusion of silica-gold iron-bearing NPs with CD68 targeted microbubbles and stem cells via a magnetic navigation system (Ferro group). A control group received a stent implantation void of any NP. Following \u2018detonation\u2019 of the NPs via intravascular or transcutaneous NIR laser excitation, no adverse events related to the procedure such as site-related thrombosis were recorded throughout the 1-year follow-up. Both treatments were associated with a reduction in total atheroma volume and the nano group displayed increased survival relative to control during follow-up.The first human trial using plasmonic phototherapy, as a technique for regressing atherosclerosis, was the Plasmonic Nanophotothermal Therapy of Atherosclerosis (NANOM-FIM: Despite risks associated with induced apoptosis in the atheroma, this approach highlights the range of options coupled with SERS/NP usage. Gold NPs are also amenable as carriers for drug delivery to the vessel wall owing to their low toxicity, versatile surface chemistry conjugation and efficient uptake by vascular endothelial cells.Looking forward, this review has summarised activities in the common molecular imaging approaches in atherosclerosis, focusing on Raman and SERS. Images showing typical findings with each modality are shown in"}
+{"text": "Ectopic cardiac fatty images are not rarely detected incidentally by computed tomography and cardiac magnetic resonance, or by exams focused on the heart as in general thoracic imaging evaluations. A correct interpretation of these findings is essential in order to recognize their normal or pathological meaning, focusing on the eventually associated clinical implications. The development of techniques such as computed tomography and cardiac magnetic resonance allowed a detailed detection and evaluation of adipose tissue within the heart. This pictorial review illustrates the most common characteristics of cardiac fatty images by computed tomography and cardiac magnetic resonance, in a spectrum of normal and pathological conditions ranging from physiological adipose images to diseases presenting with cardiac fatty foci. Physiologic intramyocardial adipose tissue may normally be present in healthy adults, being not related to cardiac affections and without any clinical consequence. However cardiac fatty images may also be the expression of various diseases, comprehending arrhythmogenic right ventricular dysplasia, postmyocardial infarction lipomatous metaplasia, dilated cardiomyopathy, and lipomatous hypertrophy of the interatrial septum. Fatty neoplasms of the heart as lipoma and liposarcoma are also described. Ectopic intracardiac fatty images are not uncommon findings in thoracic imaging in both healthy and diseased patients. Development of diagnostic techniques with high spatial and contrast resolution as computed tomography (CT) and cardiac magnetic resonance (CMR) enabled detailed fat visualization within the heart. An incidental frequency of cardiac adipose images in about 11% of the patients performing cardiovascular CT examinations has been estimated .Physiologic ectopic cardiac adipose tissue may normally be present in healthy adults not affected by any cardiac disease, without clinical consequences . In factArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by structural and functional abnormalities that may lead to arrhythmias and sudden cardiac death . PatholoPostmyocardial infarction lipomatous metaplasia (PILM) is a tissue transformation process that may take place within the scar region after a healed myocardial infarction (MI). The prevalence of PILM at histology in the LV reached values of 68\u201384% of excised heart transplanted for ischemic heart disease . In imagIdiopathic or \u201cprimary\u201d dilated cardiomyopathy (DCM) is characterized by left or biventricular dilatation and impaired systolic function without significant coronary artery lesions, excluding other possible etiologic causes . PrimaryRegarding the differential diagnoses of this disease, left-dominant ARVC with fibrofatty replacement of the LV represents an affection hardly distinguishable from idiopathic DCM at CMR imaging: in this case a careful evaluation of the adipose tissue and of the LGE location is crucial, being both in ARVC predominantly represented in the subepicardium and not in the middle layer of the myocardium as in primary DCM.Besides the evidence of fatty intramyocardial tissue at imaging sparing the subendocardial layer and having no relationship with a coronary artery perfusion territory allows excluding a DCM secondary to a PILM.Finally fatty myocardial metaplasia phenomena in secondary DCM have also been described after an inflammatory process as chronic myocarditis  28]. In. In28]. Lipomatous hypertrophy of the interatrial septum (LHIAS) is an uncommon benign disorder with fatty accumulation into the interatrial septum that usually measures a transverse diameter > 2\u2009cm in this condition . LHIAS iTuberous sclerosis complex (TSC) represents a genetic multisystemic disorder with cardiac tumor-like manifestations such as rhabdomyomas that regress during childhood and intramyocardial fat-containing lesions in adults [n adults . Fatty in adults . A previn adults . Althougn adults . A possin adults . Notwithn adults . Howevern adults .Muscular dystrophies (MD) are X-linked recessive diseases characterized by cardiac involvement with replacement of the myocardium by connective and adipose tissue [e tissue . Particue tissue . Typicale tissue .Hypertrophic cardiomyopathy (HCM) has also been described to be related to the presence of intramyocardial fatty foci, with adipose tissue placed within the thickened myocardial segments involved by this disease [ disease . The rea disease .Although the presence of ectopic adipose tissue within the myocardium is often detectable in CT and CMR images, the \u201ccardiac steatosis\u201d defined as cardiomyocytes accumulation of lipids is not easily appreciable with these imaging techniques. Cardiomyopathies secondary to lipid metabolism disorders may have a heterogeneous clinical expression, mimic dilated or hypertrophic cardiomyopathy, and led to progressive heart failure.Fabry disease is a rare X-linked genetic lysosomal storage disease, resulting from dysfunctional metabolism of sphingolipids [golipids .Intramyocardial triglyceride deposition is linked to various pathological hereditary and acquired conditions .Triglyceride deposit cardiomyovasculopathy is a genetic disorder with accumulation of triglyceride in cardiomyocytes and smooth muscle cells due to abnormal intracellular deposit of triglyceride and its substrates [bstrates , 44.Usually in these conditions myocardial signal is not altered in the conventional T1- and T2-weighed sequences, whereas T1 mapping technique has emerged as a sensitive and specific CMR biomarker of tissue lipid accumulation irrespective of ventricular morphology and function .Moreover a case has been reported where the excessive production of fatty acids in subjects with high alcohol consumption caused an alcohol-related cardiomyopathy associated with left ventricular fatty infiltration .LP represent the second most common benign cardiac tumor after myxomas, accounting for about 10% of primary cardiac neoplasms . They arPrimary cardiac liposarcomas (LS) are extremely rare neoplasms, mostly originating from the right chambers of the heart, particularly from the right atrium . CardiacCardiac metastases from a primary LS located in other anatomical districts have also been reported, although rare . In factTypical features in CT imaging of cardiac primary LS or its metastatic lesions consist of large unencapsulated hypoattenuating inhomogeneous masses, mostly rounded shaped with thick septa and mild contrast enhancement, infiltrating the surrounding cardiac structures and the pericardium . Notably"}
+{"text": "Transcranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation technique which uses a weak electric current from electrodes across the scalp to modulate targeted brain areas. It has been suggested that tDCS may be useful in reducing psychotic symptoms such as auditory hallucination. The aim of this study was to find alteration of key neurotransmitters in schizophrenia in temporo-parietal area (TPA) after tDCS intervention, using magnetic resonance spectroscopy (MRS) technique.Ten schizophrenia patients with auditory hallucination were recruited from the outpatient clinic of Seoul National University Hospital (SNUH). The anode was placed over the left dorsolateral prefrontal cortex (DLPFC), and the cathode was placed over the left TPA. Patients underwent MRS scan with the very short echo time phase rotation STEAM sequence before and after the tDCS sessions, respectively.Seven of the participants completed MRS scans before and after the tDCS sessions. Positive and Negative Symptom Scale (PANSS) total and general psychophathology scale showed a significant improvement after tDCS. There was no significant difference between glutamate/creatinine (Cr) level before and after tDCS sessions. However, a significant positive correlation between the pre-tDCS glutamate/Cr value in left TPA and the improvement in auditory hallucination measured by Auditory Hallucination Rating Scale (AHRS) after tDCS was found.The results of this investigation show that the schizophrenia patients whose auditory hallucination benefits the most from tDCS treatment had lower glutamate/Cr level in left TPA. Previous studies regarding the relationship between glutamatergic system and treatment response mostly have only focused on the frontal area and striatum. However, this study suggests a potential role of glutamatergic system in TPA in predicting treatment response of auditory hallucination."}
+{"text": "Edema bullae typically forms at the site of skin swelling during acute states of volume overload, most commonly during renal or cardiac failure. Herpes zoster is a reactivation of latent varicella zoster virus that typically presents as painful vesicles in a dermatomal distribution. In immunocompromised individuals, disseminated herpes zoster skin manifestations\u00a0may occur with several lesions in multiple dermatomes or widespread individual lesions or both, even visceral organs can be involved. Additionally, many conditions are known to mimic the lesions and distribution of herpes zoster. A 53-year-old immunosuppressed male with a history of renal transplant presented with dermatomal and non-dermatomal, disseminated herpes zoster that was confirmed by polymerase chain reaction testing. After one week of intravenous antiviral therapy during which his virus infection-associated lesions were resolved, new blisters developed near the insertion site of a peripheral venous line located on a previously uninvolved yet swollen upper extremity. The varicella zoster virus disease was initially suspected, but lab studies and skin biopsy of a blister excluded progressive or persistent viral infection and established a diagnosis of acute edema bullae. The blisters resolved following removal of the peripheral catheter. Acute edema bullae should be added to the list of mimickers of\u00a0disseminated varicella zoster virus infection. Edema bullae are the blisters that occur following\u00a0the swelling at an affected site, most commonly in the lower extremities of the patients with acute exacerbation of fluid overload or chronic leg swelling . Herpes A 53-year-old immunosuppressed male with the history of the kidney transplant presented with two weeks of painful vesicles on his left forearm, left leg, and the abdomen. His past medical history was significant for kidney transplant four years prior and disseminated herpes zoster two years prior. His daily medications included 7.5 milligrams of prednisone, 6 milligrams of Tacrolimus, and 720 milligrams of mycophenolate sodium.The cutaneous examination showed individual and grouped, erythematous-based vesicles located in a dermatomal distribution on the left side of his abdomen, and more than 20 individual lesions in a diffuse, nondermatomal distribution on his body. Initial polymerase chain reaction testing of a lesional swab was positive for varicella zoster virus and negative for herpes simplex virus. He was started on 10 mg/kg of intravenous acyclovir three times per day for disseminated herpes zoster involving multiple dermatomes but without organ or central nervous system involvement.After seven days of intravenous antiviral therapy, his VZV-associated lesions had nearly resolved Figure . HoweverThe polymerase chain reaction testing of the new lesions was negative for varicella zoster virus and herpes simplex virus. Microscopic examination of a biopsy taken from the edge of a blister showed a paucicellular subepidermal vesicle with epithelial necrosis, focal ischemic alteration of the eccrine apparatus, and pronounced dermal edema Figure .Correlation of the laboratory studies and microscopic examination of the skin biopsy of the new, painless, polymerase chain reaction VZV-negative bullae in a patient with resolving disseminated herpes zoster following one week of antiviral therapy established a diagnosis of acute edema blister. These blisters were likely secondary to lymphedema from intravenous catheter-associated pressure or trauma since the new blisters were located in a limb previously uninvolved with VZV but associated with intravenous catheter access. The peripheral intravenous catheter was relocated to the left limb and lesions resolved.Edema bullae are the blisters that occur most commonly in the elderly and immobile during acute increases in interstitial fluid pressure . They prWhen capillary filtration develops too rapidly for compensatory lymphatic drainage, dermal edema may occur, leading to blister formation . This ocThe treatment of acute edema blisters is directed towards reducing fluid overload. The elevation of the dependent extremity may promote lymphatic drainage and lesions typically resolve once the fluid imbalance is corrected ,6. In ouThe herpes zoster classically manifests as grouped, painful vesicles in a dermatomal distribution. However, disseminated herpes zoster may present with skin lesions simultaneously involving multiple dermatomes (on one or both sides of the body) or with a widespread distribution of more than 20 lesions either alone or be accompanying lesions that are located in one or more dermatomes. The diagnosis is typically established clinically, but confirmation with polymerase chain reaction testing for VZV deoxyribonucleic acid (DNA) or direct fluorescent antibody testing can be performed . Ninety The treatment of uncomplicated herpes zoster involves oral antiviral therapy for seven to 10 days, while disseminated disease or visceral involvement warrants intravenous therapy. Immunosuppressed patients with uncomplicated herpes zoster may also be treated orally, although intravenous acyclovir is recommended in the severely immunocompromised in order to prevent disseminated disease . This poResolved areas of prior VZV infection may become \u201cimmunocompromised districts\u201d, areas of skin with increased susceptibility to other skin disorders, including malignancy (such as cutaneous metastases), opportunistic infections, and granulomatous disorders (such as granuloma annulare and sarcoidosis) . The preMany dermatological conditions are known to mimic VZV infection, including cellulitis, contact dermatitis, dermatitis herpetiformis, drug eruptions, herpes simplex infection, and tinea infection . Rarely,Edema bullae present as the medium to large-sized vesicles and typically manifest during states of volume overload causing acute swelling in the\u00a0affected site. Our patient\u2019s lesions occurred in the setting immediately following disseminated herpes zoster infection, and were initially misinterpreted as progressive disease. However, the viral studies were negative for VZV and herpes simplex virus, while a lesion biopsy showed a non-inflammatory subepidermal blister; correlation of these studies and the clinical history of recent intravenous therapy near the involved site established the correct diagnosis of acute edema bullae. In conclusion, the acute edema bullae may result from prolonged pressure or trauma from a peripheral venous line; in addition, acute edema bullae can be added to the list of dermatological conditions that may mimic varicella zoster virus infection."}
+{"text": "We evaluated the impact of man-made conflict events and climate change impact in guiding evidence-based community \u201cOne Health\u201d epidemiology and emergency response practice against re-/emerging epidemics. Increasing evidence of emerging and re-emerging zoonotic diseases including recent Lassa fever outbreaks in almost 20 states in Nigeria led to 101 deaths and 175 suspected and confirmed cases since August 2015. Of the 75 laboratory confirmed cases, 90 deaths occurred representing 120% laboratory-confirmed case fatality. The outbreak has been imported into neighbouring country such as Benin, where 23 deaths out of 68 cases has also been reported. This study assesses the current trends in re-emerging Lassa fever outbreak in understanding spatio-geographical reservoir(s), risk factors pattern and Lassa virus incidence mapping, inherent gaps and raising challenges in health systems. It is shown that Lassa fever peak endemicity incidence and prevalence overlap the dry season (within January to March) and reduced during the wet season (of May to November) annually in Sierra Leone, Senegal to Eastern Nigeria. We documented a scarcity of consistent data on rodent (reservoirs)-linked Lassa fever outbreak, weak culturally and socio-behavioural effective prevention and control measures integration, weak or limited community knowledge and awareness to inadequate preparedness capacity and access to affordable case management in affected countries. Hence, robust sub/regional leadership commitment and investment in Lassa fever is urgently needed in building integrated and effective community \u201cOne Health\u201d surveillance and rapid response approach practice coupled with pest management and phytosanitation measures against Lassa fever epidemic. This offers new opportunities in understanding human-animal interactions in strengthening Lassa fever outbreak early detection and surveillance, warning alerts and rapid response implementation in vulnerable settings. Leveraging on Africa CDC centre, advances in cloud-sourcing and social media tools and solutions is core in developing and integrating evidence-based and timely risk communication, and reporting systems in improving contextual community-based immunization and control decision making policy to effectively defeat Lassa fever outbreak and other emerging pandemics public health emergencies in Africa and worldwide.The online version of this article (10.1186/s40249-018-0421-8) contains supplementary material, which is available to authorized users. Please see Additional file The increasing evidence of climate change and other man-made conflict events impacts on emerging and re-emerging zoonotic or vector-borne diseases such as Lassa fever outbreak direct risk-effect occurrence and burden worldwide and particularly in developing countries. Acute Haemorrhagic Fever Syndrome is a general term broadly attributable to diverse mild to severe group of animal and human illnesses that encompass: Lassa fever (arenaviridae), Rift Valley fever (RVF), Crimean-Congo haemorrhagic fever (CCHF) (bunyaviridae), yellow fever (flaviviridae), Ebola and Marburg viral diseases (filoviridae), dengue (dengue haemorrhagic fever (DHF) and other viral diseases such as rickettsial or bacterial diseases with ability to result in epidemics , 2.Mastomys natalensis is the rodent reservoir of the Arena spp. the virus responsible [Lassa fever a known endemic infectious disease of poverty has emerged as a severe outbreak of public health threat and burden in Nigeria in the recent past . Nigeriaponsible . Followiponsible , 3. Spatponsible , 2.nd week, 9.53% of suspected cases were confirmed by laboratory tests. However, of the 75 laboratory confirmed cases 90 deaths occurred i.e. 120% laboratory case fatality. That means 20% of observed Lassa fever related deaths were not confirmed as cases by laboratory tests hinting to a systems gap in the disease detection and surveillance. However, by 2017, this observed health systems gap in infectious disease and outbreak detection and surveillance was not appropriately addressed [Nigeria is no doubt now endemic for Lassa fever, there was an observed 21.3% seropositive prevalence in a countrywide study . A briefddressed . Of the The paper assesses the current trends in re-emerging Lassa fever geo-spatial distribution, inherent gaps and raising health system challenges towards improving interlinkage of laboratory and epidemiology surveillance to evidence for community towards one health approach and practice.M. natalensis and not M. erythroleucus correlates geographically with observed Lassa fever seropositivity prevalence in humans [Since the Lassa fever virus is transmitted to humans via contact with food or household items contaminated by rodent hosts, sexually or direct/indirect contact with body fluids such as the blood, urine, and saliva of an infected person , 5, an in humans . A studyn humans , similarn humans . Peak inn humans . Howevern humans . The endn humans , 14, 15.Hence, in absence of preventive medication or vaccine against Lassa fever, increasing community awareness and health education to avoid contact with reservoir sources mainly rats, prevention of food infestation rodent\u2019s and food safety practice to appropriate waste management coupled with improved water, sanitation and hygiene (WASH) program implementation is crucial. Since, sexual transmission of Lassa virus has also been reported, improved access to sexual and reproductive preventive measures is also important in line with WHO recommendations as well as shared traveller information support.Importantly, there is an urgent need to linking disease ecology with enhanced surveillance data garnered from 1969 across Sub-Saharan Africa , 16.Strengthening local and regional robust and sustainable integrated disease surveillance and response (ISDR) implementation into routine laboratory diagnostic and epidemiologic surveillance services, and surge resource capabilities is imperative. Scaling up adequate community social mobilization, nationwide enlightenment and health education outreach coverage using various social media and mass media outlets by various stakeholders is needed to prevent and respond promptly to potential epidemic events at each identified community health system level . LeveragLeveraging on digital, cloud-sourcing and social media in developing and integrating timely risk communication and reporting systems can be seen to start from the lowest administrative level at the community up to Central or Federal level while a feedback process flows from the development partners and Federal government back to the communities. Fostering key operational coordination, epidemiology and surveillance capacity building programs should ensure effective and concurrent trans-disciplinary outbreak response actions and Lassa fever clinical case management guidelines. Hence, strengthening community health centres and laboratory capacity, data sharing access and operational logistics for evidence operational research priorities and decision making policies, supply chain and timely risk communication and share livelihoods .st and 22nd of August, 2017, with the whole essence of building and strengthening robust and effective health system to achieve increasing access to universal health coverage (UHC) and sustainable development goals(SDGs). Noteworthy, was the technical support from the WHO Africa Regional Office (AFRO) and the National Lassa fever Steering Committee at the forum. The Nigeria Centre for Disease Control (NCDC) in partnership with the aforementioned as well as other supporting partners  participants from State governments affected by Lassa fever endemicity and epidemics.The Federal Government of Nigeria has embarked on integrated infectious diseases prevention and control; however integration in primary healthcare is still seldom and unstructured at all levels nationwide. Integrating community-based \u201cOne Health\u201d surveillance and emergency response practice is crucial in addressing the persistent scourge of poverty-related Lassa fever outbreak and other emerging zoonotic disease pandemic threats amongst vulnerable populations across the region. In reviewing the 2016/2017 Lassa fever year, stakeholders hosted an interdisciplinary action review meeting in Abuja between 21Scaling up contextually diagnostic and care access at the point of need no matter the location and time without any encumbrances is critical to improving vulnerable population quality of life, productivity, reduction financial impoverishment and poverty alleviation , 19. TheContemporary increasing in consumer/provider-generated mhealth technology and application, social media penetration and acceptance, online disease data and information literacy and communication to emergency response or recovery to immunization scale coverage and effectiveness should exploited to optimize health benefits, wellbeing impacts and return of investment as coupled with traditional mass media  in reachIn controlling the scourge of Lassa fever an early warning system and rapid response is important. Once one case of Lassa fever is suspected an alert should be made and once this is confirmed in the laboratory then the situation must be treated as an epidemic , 2. ThisBuilding early warning indicators and rapid response to adequately prevent or respond to Lassa fever medical care needs at the hospitals, scaling up access to medical supplies and vaccines stockpile are needed in preparedness and during potential epidemics. The following are usually supplied to Local Government Areas (LGAs) at risk in Nigeria , 17. MedIt is important to note that in effectively tackling this scourge, test kits and laboratory analysis to confirm suspected cases as soon as possible need to be readily accessible. Lassa virus and other emerging viral diseases detection and confirmation requires Biosafety level 4 (BSL-4) laboratories across the world, but very few exist in Africa . Some AfIt is alarming that the true incidence of Lassa fever is unknown as quoted incidences are extrapolations from 1980s studies. Thus the Lassa fever research field is in dire need of more accurate and recent studies on disease incidence, geographic distribution and virus seroprevalence , 30. RivAccelerating health systems strengthening and rebuilding transformations in affected West Ebola outbreak countries is important through improving ISDR system and scaling up access to routine immunization programs; while leveraging on community-based and vulnerable populations\u2019 empowerment and resilience activities in endemic regions to traveller medical information , 35. LikLassa fever virus outbreak, a poverty-related infectious diseases outbreak remains a public health threat and burden on vulnerable populations in West Africa and Nigeria in particular. Robust and sustainable leadership commitment and investment of all stakeholders and affected communities in Lassa fever outbreaks prevention and containment is crucial and requires strengthening integrated Lassa fever outbreak surveillance quality data gathering to support evidence data sharing, contextual local and regional outbreak early warning alert, preparedness and response systems. Collaborative \u2018One Health\u2019 approach operational research is needed in understanding spatio-geographical risk factors patterns, reservoir(s) mapping and phylogenetic in guiding evidence-based, appropriately tailored and timely integrated programs and strategic interventions implementation against the zoonotic disease epidemics and pandemics threats in Nigeria and the sub-Saharan Africa foci terrain. Furthermore, fast-tracking R&D for more sensitive diagnostic tools, safer and effective drugs and vaccine development is imperative in improving contextual community-based immunization decision making policy to effectively outwit Lassa fever outbreak and other emerging pandemics public health emergencies. Moreover, fostering local community to regional re-merging and emerging epidemics and pandemics data sharing and coordinated invasive pathogens epidemiology surveillance and early warning indicators metrics capacity building, monitoring and evaluation is crucial for timely and quality risk communication and operational research. Integrating community \u201cOne Health\u201d surveillance and rapid response approach practice against Lassa fever epidemic and other emerging pandemic threats offers new opportunities in understanding human-animal and environment interface and expanding zoonotic diseases public awareness and resilience strategies and mitigation measures in attaining national and global health security.Additional file 1:Multilingual abstracts in the five official working languages of the United Nations. (PDF 423 kb)"}
+{"text": "This review focuses on the cognitive neuroscience of Attention Deficit Hyperactivity Disorder (ADHD) based on functional magnetic resonance imaging (fMRI) studies and on recent clinically relevant applications such as fMRI-based diagnostic classification or neuromodulation therapies targeting fMRI deficits with neurofeedback (NF) or brain stimulation. Meta-analyses of fMRI studies of executive functions (EFs) show that ADHD patients have cognitive-domain dissociated complex multisystem impairments in several right and left hemispheric dorsal, ventral and medial fronto-cingulo-striato-thalamic and fronto-parieto-cerebellar networks that mediate cognitive control, attention, timing and working memory (WM). There is furthermore emerging evidence for abnormalities in orbital and ventromedial prefrontal and limbic areas that mediate motivation and emotion control. In addition, poor deactivation of the default mode network (DMN) suggests an abnormal interrelationship between hypo-engaged task-positive and poorly \u201cswitched off\u201d hyper-engaged task-negative networks, both of which are related to impaired cognition. Translational cognitive neuroscience in ADHD is still in its infancy. Pattern recognition analyses have attempted to provide diagnostic classification of ADHD using fMRI data with respectable classification accuracies of over 80%. Necessary replication studies, however, are still outstanding. Brain stimulation has been tested in heterogeneously designed, small numbered proof of concept studies targeting key frontal functional impairments in ADHD. Transcranial direct current stimulation (tDCS) appears to be promising to improve ADHD symptoms and cognitive functions based on some studies, but larger clinical trials of repeated stimulation with and without cognitive training are needed to test clinical efficacy and potential costs on non-targeted functions. Only three studies have piloted NF of fMRI-based frontal dysfunctions in ADHD using fMRI or near-infrared spectroscopy, with the two larger ones finding some improvements in cognition and symptoms, which, however, were not superior to the active control conditions, suggesting potential placebo effects. Neurotherapeutics seems attractive for ADHD due to their safety and potential longer-term neuroplastic effects, which drugs cannot offer. However, they need to be thoroughly tested for short- and longer-term clinical and cognitive efficacy and their potential for individualized treatment. Attention Deficit Hyperactivity Disorder (ADHD) is characterized by symptoms of age-inappropriate inattention, hyperactivity and impulsivity , that are mediated by late developing fronto-striato-parietal and fronto-cerebellar networks Rubia, . The mosSince the advent of fMRI, several hundreds of fMRI studies have been published in ADHD children and adults over the last two decades, the majority of them targeting cognitive functions. The first fMRI studies conducted in very small numbers of ADHD patients found reduced inferior fronto-striatal activation in ADHD children relative to age-matched healthy controls during motor inhibition /anterior insula, the supplementary motor area (SMA), anterior cingulate cortex (ACC), left striatum and right thalamus . Thus, ADHD patients showed enhanced activation in typical regions of the DMN such as in rostromedial prefrontal cortex during interference inhibition  or orbitofrontal cortex (OFC) and striato-limbic regions during tasks that tap into \u201chot\u201d EF such as reward-related decision making or temporal discounting tasks. One of the most consistent findings is reduced ventral striatum activation during reward anticipation, as shown in a recent meta-analysis of eight fMRI studies of a monetary reward anticipation task using region of interest analysis in 340 ADHD patients and healthy controls , which are hypothesis-driven and measure changes in interactions across brain activations. In children and adults with ADHD, reduced functional connectivity has been observed between task-relevant regions during cool EF tasks, suggesting dysfunction of entire networks and not just regions.In ADHD children, during motor response inhibition and WM tasks reduced functional connectivity has been reported relative to healthy controls between the right IFC and basal ganglia, parietal lobes and cerebellum, and between cerebellum, parietal and striatal brain regions during sustained attention  and transcranial direct current stimulation (tDCS) have found successful applications in other psychiatric disorders. Pioneering applications of these techniques to ADHD over the past decade targeting IFC or DLPFC have been mixed, but revealed some promising findings of improving cognition and clinical behavior. The following sections will review these clinical applications of neuroimaging in ADHD.Despite the fact that ADHD is a neurodevelopmental disorder with consistent evidence for brain structure and function deficits, currently ADHD is diagnosed solely on the basis of subjective clinical and self-rating measures, which are often unreliable, leading to diagnostic variability between clinicians, cultures and countries  and can make predictions  for individual subjects as opposed to group-level inferences. These methods have been shown to provide sensitive and specific diagnostic indicators for individual patients with other pathologies in particular for neurological disorders such as Alzheimer\u2019s disease but also for autism and depression  diagnosis or prognosis of individual patients and build the path for brain function (or brain structure)-based patient stratification and personalized medicine. Multimodal multivariate approaches including several imaging modalities, including functional and structural imaging data as well as non-imaging data such as cognitive and genetic measures are likely to achieve superior classification accuracy than univariate approaches  rTMS promotes cortical excitability, while low frequency (1 Hz) rTMS inhibits cortical excitability  or sham dTMS (N = 13). dTMS is a modification of standard TMS that enables deeper non-invasive cortical stimulation at an effective depth of approximately 3 cm depending on the coil\u2019s design and the stimulation intensity. Stimulation was applied over bilateral prefrontal cortex in 20 daily sessions over 4 weeks, each session consisting of 55 trains of pulses at 18 Hz . The study found an improvement in ADHD symptoms in both groups suggesting a placebo effect and no cognitive improvements in either group  or decreasing  the excitability of neurons via the generation of subthreshold (stimulation-polarity dependent) alterations of membrane potentials that modify spontaneous discharge rates, thus increasing/decreasing cortical function and synaptic strength  relative to sham stimulation (N = 8); furthermore, all symptom improvements were still significant 2 weeks after stimulation, suggesting longer-term effects \u2014that has been shown to interact with physiological slow oscillatory activity, which is typically abnormal in ADHD\u2014over lateral prefrontal cortex during deep sleep in 12/14 ADHD adolescents compared to sham stimulation in a double-blind within patients design with 1 week break in between conditions. The outcome measures were slow oscillatory power during deep sleep in the non-stimulation periods and cognitive function improvements relative to sham tDCS in the next morning. Slow oscillatory power during deep sleep was increased, indicating an enhancement of endogenous oscillatory activity with the intervention. Cognitive improvements were in declarative memory  had to learn to upregulate the rIFC, while the control group (N = 13) had to upregulate a control region, the left parahippocampal gyrus (lPHG). Both groups were tested before and after treatment in clinical and cognitive measures as well as in an fMRI Stop task and were followed up a mean of 11 months later in the main ADHD clinical outcome measure. Participants were trained to enhance activation of the target/control regions in 11 sessions of 8.5 min of rtfMRI-NF over four scan hours over 2 weeks. They were trained on a computer game where a rocket moved towards the sky, passing through clouds, and ultimately reaching some planets every time they managed to increase the activation of the target/control region. The fMRI data showed significantly enhanced activation as well as enhanced linear activation increase in two regions of the rIFC across all 11 sessions in the active relative to the control group and enhanced linear activation increase in three regions of the lPHG in the control relative to the active group  and electromyography-NF (N = 9). Only NIRS-NF resulted in significant improvements in clinical ADHD symptoms and in cognitive inhibition and attention functions after 11 h sessions over 4 weeks, which was, however, not superior to EEG-NF or electromyography-NF  of the left DLPFC in nine ADHD children, compared to EEG-NF  neurobiological basis of different ADHD subtypes such as inattention without hyperactivity, or ADHD with emotional dysregulation. Furthermore, more understanding is needed on comorbid cases with other disorders such as autism, anxiety and affective disorders as well as on females with ADHD and gender differences. Future studies therefore ideally should be longitudinal, multimodal and tied to epidemiological samples.Clinical translation of neuroimaging is still in its infancy in the field of ADHD. Pattern recognition analyses applied to functional  imaging data to make individual predictions on diagnostic status are promising, but more so for homogenous subtypes that likely share the same \u201cbiotype\u201d rather than heterogenous large groups of ADHD patients with different comorbidities or medication status. They will need to show replicability and clinical utility which will be the challenge over the next decades.Several brain stimulation studies with heterogeneous study designs have been conducted in small groups of ADHD children and adults, most of them using tDCS in either single or five sessions targeting mostly DLPFC or IFC based on the fMRI studies conducted in ADHD over the last two decades. The findings show some improvements on clinical symptoms or selective cognitive functions, with, however, also negative findings. Larger sham-controlled studies are needed to further test the efficacy of tDCS and potential costs on non-targeted cognitive or behavioral functions. In addition, far more knowledge is needed on the optimal stimulation protocols for different age and patient subpopulations . It is likely that brain stimulation combined with cognitive training has a larger potential to enhance brain plasticity in ADHD than brain stimulation alone. This will also require the development of good cognitive training tasks that target ADHD-relevant functions to be used in combination with brain stimulation techniques. Given minimal side effects, tDCS is a promising tool for the treatment of childhood onset psychiatric disorders, since it provides the opportunity to positively influence atypical brain development early and persistently , potential costs that may accompany the benefits, and their potential for individualized treatment (which ADHD subtype responds to which neurotherapy and why). It is likely that different subgroups of ADHD patients will benefit from either NF, brain stimulation or medication and establishing this knowledge will be crucial to the benefit of individual patients.The author confirms being the sole contributor of this work and approved it for publication.The author has received grants from Lilly and Shire and speaker\u2019s honoraria from Shire, Lilly and Medice."}
+{"text": "Retinal artery occlusion is extremely rare in the pediatric population and most patients have risk factors. We report a case of a healthy child with segmental optic atrophy, complicated by incidental branch retinal artery occlusion (BRAO).A 10-year-old boy who had a history of his mother\u2019s gestational diabetes presented with an inferonasal visual field defect in the left eye. His best-corrected visual acuities were 20/20 in both eyes (OU). Fundoscopic examination revealed segmental pallor of the left optic disc, thinning of the superotemporal rim, a relative superior entrance of the central retinal artery and superior peripapillary scleral halo. Fluorescein angiography showed patchy filling delays in the corresponding disc area without retinal vascular abnormalities. Spectral domain optical coherence tomography (SD OCT) via automated segmentation analysis demonstrated sectoral absence of the ganglion cell layer and retinal nerve fiber layer with thinning of the inner plexiform layer, inner nuclear layer and outer plexiform layer in the corresponding retina. OCT angiography (OCTA) showed focal attenuation of superficial and intermediate/deep capillary plexuses in the corresponding areas. Systemic evaluation was unremarkable. The patient was diagnosed with segmental optic atrophy caused by incidental BRAO.Retinal vascular occlusions are rare in childhood, and may present as segmental optic atrophy mimicking congenital anomalies. OCTA allows the detection of previous microvascular abnormalities in the chronic phase. To the best of our knowledge, this is the first report of a child with segmental optic atrophy presumably caused by BRAO, which was documented by SD OCT and OCTA in detail. When segmental atrophy of the optic disc is found in children, benign conditions such as isolated superior segmental optic hypoplasia (SSOH) are mostly considered, particularly in healthy children of an insulin dependent diabetic mother . Rarely,A visually asymptomatic 10-year-old boy presented with an inferonasal visual field defect in the left eye Fig.\u00a0. He had Optic nerve atrophy is the secondary pathogenic endpoint of numerous diseases that cause intrinsic or extrinsic insult to the visual pathway. Although, partial optic atrophy with homonymous visual field defect is characteristic for cortical visual impairment, various congenital lesions involving the retina, optic nerve, chiasm, optic tract, or retrogeniculate pathways as well as acquired conditions such as periventricular leukomalacia also show segmental optic nerve changes , 7. HoweRetinal artery occlusion is an extremely rare condition in the pediatric population and most patients have some detectable risk factors . Surpris"}
+{"text": "There are now several immunotherapy trials for ovarian cancer although the clinical benefits have been limited to a subset of patients . We receBRCA mutation (gBRCAm) associated platinum-sensitive recurrent disease [gBRCAm-associated platinum-sensitive recurrent ovarian cancer (NCT02734004) to examine how clinical benefits by immune checkpoint inhibitors are added to PARPi\u2019s activity in the background of gBRCAm. Interestingly, in our study, none of the women receiving durvalumab+olaparib >= 9 months  had germline or somatic mutations in BRCA or other DNA repair genes [PARP inhibitors (PARPi) are intriguing combination therapy partners with other pathway inhibitors such as immune checkpoint blockade . The com disease . A phasegBRCAm, in which the role of neoantigen expression and changes in immune microenvironment induced by PARPi will be further examined. The optimal selection of patients for treatment with PARPi and immune checkpoint inhibitor in non-BRCA mutated settings and better understanding of the mechanisms of action will require further characterization and analysis.PARPi blocks DNA repair, resulting in DNA breaks . FragmenImmunotherapy manifests differently from traditional chemotherapy, eliciting delayed response kinetics . It has The overexpression of PD-L1 is an important and widely explored biomarker for response to immune checkpoint inhibitors. However, PD-L1 expression by immunohistochemistry fails to accurately select all patients suitable for PD-1/PD-L1 inhibitors . The preThe advent of immunotherapy combination therapy presents us with new approaches in ovarian cancer treatment with promising outcomes, preliminarily. Multiple clinical trials are currently being conducted to better define the role of PARPi and immunotherapy combinations, and further investigation is warranted to develop and identify predictive biomarkers. Assessing how immunotherapies should be incorporated with current standard-of-care treatments, such as PARPi is essential to make progress in the treatment of ovarian cancer."}
+{"text": "The development of cardiac complications during or after endoscopic procedures is rare. However, mortality from myocardial ischemia, particularly in the elderly population, is elevated. We illustrate the rare case of a 79-year-old man with multiple cardiovascular risk factors who developed a non-ST elevation myocardial infarction (NSTEMI) after endoscopic removal of a foreign body. This case report summarizes a rare complication of a low-risk procedure and highlights the importance of considering this potential adverse event, particularly in patients with significant cardiovascular risk factors, to promote early diagnosis and proper treatment. Incidence of Acute Coronary Syndromes (ACS) following endoscopic procedures is low <1%), and usually these interventions do not require further preoperative testing [%, and usCardiac complications are 2\u20135 times more likely to occur during emergency procedures than with elective interventions , which cA 79-year-old man, former smoker and with type 2 diabetes, hypertension, and hyperlipidemia, presented to the hospital after swallowing a piece of denture while eating carrots. On arrival physical exam and laboratory tests were unremarkable. Computed tomography (CT) scan showed esophageal distention compatible with ingested foreign body, as well as aortic and coronary atherosclerosis. A flexible esophagogastroduodenoscopy was done attempting foreign body removal; however it was unsuccessful and during the procedure ST-segment elevation was noted on the cardiac monitor. An emergent rigid esophagoscopy was performed and the foreign object was removed. Electrocardiogram (ECG) showed a left bundle branch block (LBBB) that did not meet Sgarbossa criteria; however there was no prior ECG to compare with ; vital sRepeat ECG  showed sCoronary angiography was attempted once but patient became very agitated during the procedure; the Interventional Cardiology team increased the sedation to try to finish the study but patient remained restless and kept moving all his extremities, so continuing the procedure under these circumstances would have been extremely dangerous.Transthoracic echocardiogram (TTE) revealed anteroseptum, apex, and distal-anterior wall akinesis; left ventricular ejection fraction was 30% . Troponin T peaked at 9.37\u2009ng/mL and then trended down. Before being discharged, the medical team discussed extensively the importance of having a coronary arteriogram done to evaluate the presence of obstructive lesions in the coronary vasculature. Despite the insistence of the team and the broad discussion with the patient regarding different methods of anesthesia, patient refused to undergo this procedure given his prior experience. He remained hemodynamically stable and was discharged in stable condition.This is, to the best of our knowledge, the first case report of NSTEMI associated with esophageal microperforation after endoscopy in the setting of foreign body ingestion. A few reports do exist; however, of myocardial ischemia following gastroscopy , suggestMyocardial ischemia results from imbalance between oxygen demand and supply. During endoscopy, catecholamine-induced tachycardia can trigger it in patients with high atheromatous burden and fixed coronary stenosis or with development of hypoxia during a difficult procedure. In our patient, the ACS could have been induced by stress of aspirated dentures and the intervention triggering any of these mechanisms; however we were unable to exclude other etiologies such as Takotsubo cardiomyopathy.Adverse cardiopulmonary events attributable to endoscopic procedures are rare \u20139 and raCurrent guidelines for preoperative cardiovascular evaluation do not recommend a preoperative 12-lead ECG or any other form of preprocedural cardiac assessment in asymptomatic patients undergoing low-risk interventions , and endECG is an inexpensive and very useful tool that could benefit some asymptomatic patients with multiple cardiovascular risk factors undergoing low-risk procedures and could be a cost-effective test to promote early diagnosis and treatment of cardiac complications. This case report summarizes an example of these adverse events aiming to increase awareness of this potentially fatal complication and highlight the relevance of prompt intervention and judicious use of preprocedural testing  despite guideline statements to the contrary. This underscores that guidelines are just that and are not rigid, unbreakable rules with proper documented justification."}
+{"text": "The Accreditation Council for Graduate Medical Education (ACGME) implemented revisions to resident duty hour requirements (DHRs) in 2011 to improve patient safety and resident well-being. Perceptions of DHRs have been reported to vary by training stage and specialty among internal medicine and general surgery residents. The authors explored perceptions of DHRs among all residents at a large academic medical center.medical and pediatric, surgery, or other.The authors administered an anonymous cross-sectional survey about DHRs to residents enrolled in all ACGME-accredited core residency programs at their institution. Residents were categorized as In total, 736 residents representing 24 core specialty residency programs were surveyed. The authors received responses from 495 residents (67%). A majority reported satisfaction (78%) with DHRs and believed DHRs positively affect their training (73%). Residents in surgical specialties and in advanced stages of training were significantly less likely to view DHRs favorably. Most respondents believed fatigue contributes to errors (89%) and DHRs reduce both fatigue (80%) and performance of clinical duties while fatigued (74%). A minority of respondents (37%) believed that DHRs decrease medical errors. This finding may reflect beliefs that handovers contribute more to errors than fatigue (41%). Negative perceived effects included diminished patient familiarity and continuity of care (62%) and diminished clinical educational experiences for residents (41%).A majority of residents reported satisfaction with the 2011 DHRs, although satisfaction was significantly less among residents in surgical specialties and those in advanced stages of training. TDespite the differences we observed between the surgical versus nonsurgical disciplines and senior versus junior residents, it is worth stating that a majority of these subgroups did ultimately report overall satisfaction with the DHRs. Most respondents also indicated that the DHRs were respected and enforced by their institution. While most indicated that situations do exist where violation of DHRs is justified, few reported more than sporadic violations within the past year.Although a majority of respondents believed the DHRs mitigate resident fatigue, only 37% believed that the requirements decreased medical errors. More than one-half of respondents believed that DHRs did not impact (44%) or increased (19%) medical errors. Our findings are congruent with a study using a grounded-theory analysis of resident comments, that found residents did not associate patient safety with DHR compliance , 25. ThiOnly 26% of residents perceived the DHRs to have a positive impact on their clinical educational experience. Prior studies have demonstrated findings of perceived reductions in bedside teaching, clinical educational experiences , and surStrengths of our study are the large sample size and high resident response rate. In addition, we surveyed residents currently enrolled in all ACGME-accredited core residency programs at a large academic institution, and included residents at all levels of training within those programs. We also endeavored to conduct a thorough evaluation of the survey instrument by piloting our survey among experienced medical educators prior to its implementation.Limitations of our study include a cross-sectional study design, single-institution sampling, and a subjective assessment by the study subject relating to Level 1 outcomes . BecauseIn this cross-sectional survey study of residents enrolled in all ACGME-accredited core residency programs at a large academic medical center, a majority of respondents were satisfied with the current ACGME DHRs and believed they affected their training in an overall positive manner. Residents in surgical specialties and those in advanced stages of training were significantly less likely to view DHRs favorably, although in these subgroups as well, a majority of the respondents did report overall satisfaction with the DHRs."}
+{"text": "Epigenetic mechanisms have emerged as key players in cancer development which affect cellular states at multiple stages of the disease. During carcinogenesis, alterations in chromatin and DNA methylation resulting from genetic lesions unleash cellular plasticity and favor oncogenic cellular reprogramming. At later stages, during cancer growth and progression, additional epigenetic changes triggered by interaction with the microenvironment modulate cancer cell phenotypes and properties, and shape tumor architecture. We review here recent advances highlighting the interplay between epigenetics, genetics, and cell-to-cell signaling in cancer, with particular emphasis on mechanisms relevant for cancer stem cell formation (CSC) and function. Epigenetic regulators are one of the most commonly mutated classes of genes in cancer. During cancer initiation, mutated epigenetic regulators lead to oncogenic cellular reprogramming and promote the acquisition of uncontrolled self-renewal. The emergence of CSCs requires elaborate reorganization of the epigenome.During cancer growth, epigenetic mechanisms integrate the effect of cell-intrinsic  and cell-extrinsic  changes and establish intratumoral heterogeneity, either promoting or inhibiting the CSC state.\u2018Loose\u2019 epigenetic constraints in cancer cells enhance cellular plasticity and allow reversible transitions between different phenotypic states. Enhanced cellular plasticity favors cancer cell adaptability and resistance to therapy.Modulation of epigenetic processes allows targeting of the most downstream determinants of the CSC state. The molecular makeup of a cancer is the result of multiple changes occurring progressively during its lifetime. Early in the disease, alterations in key genes disrupt normal cell function and endow cells with the ability to initiate a tumor or a hematological malignancy. Subsequently, as a cancer grows, additional changes superimpose onto the initiating events and affect the biological properties of cells, either enhancing or inhibiting their malignant properties. As a result of this constant modulation of cell function, tumors comprise a remarkable collection of distinct cellular phenotypes which differentially contribute to disease progression.Intratumoral functional heterogeneity  and cell-extrinsic  mechanisms modulate the epigenome of cancer cells, and their combined effect determines which cells preserve the self-renewal capacity acquired during tumorigenesis. These cells, referred to as cancer stem cells (CSCs) or leukemic stem cells (LSCs), are those responsible for driving long-term cancer growth and disease progression cellular plasticity at various stages of the disease.Similarly, The recent identification of driver mutations affecting a wide range of epigenetic regulators in hierarchically organized cancers provides direct evidence for the importance of epigenetic dysregulation in the formation of CSCs. These mutations are typically clonal and promote the acquisition of uncontrolled self-renewal.KMT2A/MLL gene. KMT2A/MLL encodes a histone methyltransferase that orchestrates several essential cellular processes through modification of chromatin, mainly regulating accessibility to enhancer regions de novo self-renewal capacity Leukemias represent a paradigm of hierarchical cancers maintained by LSCs. Numerous studies have identified mutated epigenetic regulators that favor the acquisition of uncontrolled self-renewal ability and initiate the disease. A prominent example is offered by mixed lineage leukemia (MLL)-associated leukemia, which is characterized by chromosomal rearrangements involving the H3F3A, and a K27M substitution is the most common alteration Probably the most compelling evidence supporting a key role of chromatin in the acquisition of uncontrolled self-renewal comes from studies in glioblastoma (GBM), a highly aggressive form of brain cancer characterized by an undifferentiated phenotype and a high frequency of CSCs. Recent sequencing efforts have identified gain-of-function mutations in genes encoding histone H3 in about one third of pediatric GBMs. The gene mainly affected is Proteins involved in the establishment and maintenance of DNA methylation have also been identified as drivers of CSC formation. The methylation status of CpG dinucleotides depends on the action of DNA methyltransferases , which apply the methyl-group to cytosines, and methylcytosine dioxygenases (TET1 and TET2), which convert 5-methylcytosine to 5-hydroxymethylcytosine and initiate a demethylation process. DNMT3A is the DNMT most commonly affected by DNA lesions, being mutated in \u223c25% of AML patients de novo self-renewal capacity. In both cases, epigenetic constraints imposed during development to keep cellular plasticity under control are disrupted, and cells transform, losing their normal cellular identity  in many cancers has been the basic observation supporting the hierarchical model of cancer development over the past two decades. Recent single-cell transcriptomic studies have extended our understanding of the gene expression programs that shape tumor architecture and have confirmed that aberrant differentiation programs establish cellular hierarchies within individual cancers. In a pioneering study, colon cancers were shown to contain multiple cell types with transcriptional profiles resembling those of the cellular lineages making up the normal epithelium. Importantly, single cancer cells could recapitulate the lineage diversity of the primary tumors in transplantation assays, demonstrating that multilineage differentiation represents a key source of intratumoral transcriptional heterogeneity The observation that IDH-induced oligodendrogliomas contain differentiated, non-self-renewing cells underscores the diverse, and at times antithetic, role of epigenetic mechanisms in cancer development. During tumorigenesis, mutations in IDH proteins drive CSC emergence partly through alteration of DNA methylation profiles and epigenetic reprogramming of committed oligodendrocytes. However, during tumor growth, additional epigenetic changes occur and establish developmental hierarchies that restrict the proliferative potential of some cells, counteracting the effect of the initiating mutations .Figure 2in vitroWhat are the mechanisms that generate distinct epigenetic states within tumors and confer distinct functional properties to CSCs and differentiated cells? Epigenetic regulators belonging to two distinct groups have so far been identified: those that inhibit cancer cell self-renewal and establish differentiation hierarchies, and those that are hijacked by CSCs to avoid differentiation and sustain their phenotype . Within Although many cancer cells succumb to differentiation during tumor growth, CSCs evade this process and preserve their self-renewal capacity acquired during transformation. Not surprisingly, considering the importance of epigenetic regulators in normal stem cell maintenance, many chromatin-related proteins and DNA-methylating enzymes are essential to maintaining the CSC state. Remarkably, most of the proteins implicated in CSC maintenance are typically not mutated but are co-opted in their wild-type state by CSCs to avoid differentiation and sustain their malignant properties. Prominent examples of hijacked proteins are Polycomb complex proteins. The PRC2 catalytic subunit EZH2 has a tumor-promoting role in many malignancies, and inhibition of its activity or genetically induced loss of the protein strongly impairs tumor growth A key feature of epigenetic mechanisms is their inherent reversibility. Thus, the dependence of CSCs on epigenetic regulators offers an opportunity to target their self-renewal capacity. The chromatin \u2018reader\u2019 BRD4 best illustrates this concept As with any therapeutic strategy, epigenetic modulation of CSCs faces challenges. Early concerns regarding targeting wild-type proteins that exert pleiotropic functions in normal cells have been mitigated by the observation that many tested inhibitors are not associated with major toxicity, suggesting that cancer cells exhibit a specific epigenetic vulnerability HOX oncogenes methylated in their promoter regions in particular AML cells and not in others A key question related to epigenetic regulation of the CSC state is: what determines epigenetic heterogeneity within tumors? For example, why do some cells express high levels of histone H1.0 and consequently differentiate, and others instead maintain low H1.0 levels and thus self-renewal capacity Variations in oxygen and nutrient concentrations are a likely source of phenotypic variation within tumors, and histone modifiers have been reported to act as sensors of hypoxia lo cells to CD44hi CSCs. Importantly, this cellular plasticity appears to be dependent on the chromatin status of the ZEB1 promoter because a poised, bivalent configuration allows reversion to CD44hi CSCs upon stimulation, while the presence of repressive marks renders CD44lo cells insensitive to TGF-\u03b2 et al. identified a subpopulation of cells that is required for continuous tumor growth and is marked by the expression of the histone demethylase JARID1B. However, instead of being a stable subpopulation, JARID1B+ cells are a dynamic subset whose composition changes over time as cells gain and lose JARID1B expression, and transiently acquire stemness properties depending on the tumor context A major difference between normal cellular hierarchies and cancer is that, although cell fate decisions triggered by environmental cues are generally stable and heritable in normal cells, cancer cells maintain an intrinsic plasticity that allows them to easily change their phenotype in response to new signals and possibly switch between cellular states. Evidence exists in some cancers that differentiated cells can reacquire self-renewal ability and revert to a CSC state . This ocet al. who reported the existence of a reversible drug-tolerant state in non-small cell lung cancer (NSCLC)-derived cell lines, and which can survive exposure to lethal concentrations of EGFR tyrosine kinase inhibitors. This drug-tolerant state does not involve drug efflux and is instead associated with an altered chromatin state and requires the histone demethylase KDM5A/JARID1A and IGF-1R signaling NOTCH1-driven T cell ALL, clinical trials using \u03b3-secretase inhibitors (GSI) have shown limited efficacy owing to the presence of a reversible subpopulation of GSI-tolerant cells characterized by BRD4-dependent transcriptional programs. Notably, combined treatment of patient-derived xenografts with NOTCH and BRD4 inhibitors showed greater efficacy than individual treatments Despite significant progress in the development of effective therapies against numerous cancer types, therapeutic resistance is still relatively common. CSCs are the likely source of resistant cells responsible for disease relapse because cells deprived of self-renewing potential are unable to reconstitute the cancer even if they survive treatment. While drug resistance primarily has a genetic basis, chromatin-related mechanisms have emerged as additional players in this context that are exploited by cancer cells to enhance their plasticity and adaptability . A paradEpigenetic alterations affecting chromatin and DNA methylation patterns are universal features of cancer. Historically, it has been difficult to distinguish whether these changes play a functional role in the disease or are a bystander phenomenon that merely reflects alterations in cell behavior. However, studies over the past 5\u201310 years have crystallized the importance of epigenetic mechanisms at various stages of cancer development and have uncovered unprecedented therapeutic opportunities . The reain vivo. The presence of cellular hierarchies in cancer clearly indicates that mechanisms inhibiting cell self-renewal ability exist, and can efficiently deprive cells of their malignant properties. Differentiation therapies that \u2018exaggerate\u2019 such mechanisms and restrict cellular plasticity may prove useful to exhaust CSCs and thus halt tumor maintenance, and also to impair cancer cell adaptability  cells is established? Can cancer cell plasticity be modulated to reduce resistance to treatment? How prevalent are epigenetic mechanisms in the development of therapeutic resistance?Why do cancer cells, including CSCs, show specific sensitivity to epigenetic drugs that target wild-type proteins expressed in normal cells as well? Could epigenetic drugs be generally useful as agents to be administered in combination therapies?Considering the diverse role of epigenetics in cancer, and the possible interference with normal homeostasis, epigenetic modulation of CSCs clearly still faces many challenges, but at the same time offers unprecedented opportunities to hit the beating heart of the disease."}
+{"text": "A 79-year-old female with no relevant past medical history was admitted in our emergencydepartment for dyspnea on minimal exertion and chest discomfort over 2 weeks. Blood gasanalysis showed severe hypoxemia and hypocapnia. Troponin was slightly positive. Despitea negative D-dimer assay, contrast-enhanced chest CT was performed to exclude pulmonaryembolism. It showed a large filling defect centered in the pulmonary valve plane (PanelsA and B). Bedside transthoracic echocardiogram showed a large echodense mass, apparentlymobile, extending across the right ventricle outflow tract, pulmonary valve, and themain pulmonary artery, with dilatation of the right sided chambers and transtricuspidpeak gradient of 70 mmHg (Panels C and D). Lower-limb venous compression ultrasound wasnegative for deep vein thrombosis. The patient remained stable, but required high oxygeninspiration fraction to maintain saturation above 90%. As pulmonary embolism was deemedunlikely given the clinical findings, the patient underwent cardiac surgery. Surgeryrevealed a pearly mass in the main pulmonary artery obliterating almost the entire lumenand with upstream extension to the pulmonary valve and right ventricle outflow tract(Panel E). The tumor was excised as much as possible and the pulmonary valve wasreplaced by a homograft. Pathological examination was compatible with angiosarcoma.Pulmonary artery angiosarcoma is exceedingly rare and carries a very poor prognosis. Itcan be clinical and radiologically indistinguishable from acute or chronic pulmonaryartery thromboembolism. Our clinical suspicion was heightened by a negative D-dimerassay and venous ultrasound and the apparent infiltration of pulmonary arterial walls onCT."}
+{"text": "Analyses of covariance employed to partial out the influences of language and perceptual impairments, which frequently co-occur in these patients, provided evidence of different underlying cognitive mechanisms. These analyses revealed that language impairments explained the original poor scores obtained by the SD patients on the Ekman 60 and Emotion Selection tasks, which involve verbal labels. Perceptual deficits contributed to Emotion Matching performance in the bvFTD and AD patients. Importantly, all groups remained impaired on one task or more following these analyses, denoting a primary emotion processing disturbance in these dementia syndromes. These findings highlight the multifactorial nature of emotion processing deficits in patients with dementia. Patients with frontotemporal dementia  as well as those with Alzheimer's disease (AD) show deficits on tests of face emotion processing, yet the mechanisms underlying these deficits have rarely been explored. We compared groups of patients with bvFTD ("}
+{"text": "Fetal or prenatal programming, i.e. the process in which environmental events during pregnancy are shaping and determining the development of the embryo, can be embedded by epigenetic changes including DNA methylation. Apart from environment, also the genome plays an important role and a variety of studies which identified meQTLs  have been published.Focusing on variably methylated regions (VMRs), we investigated if genotype (G), prenatal environment (E) or the combination of both  best explain cordblood DNA methylation in sample of 817 Finnish neonates. Furthermore, we used an epigenetic clock predictor to evaluate if accelerated or decelerated epigenetic age was associated with prenatal environment or with childhood psychiatric problems at age 3.We found that SNP genotype alone best explained methylation status in 44%, SNP x environment in 32% and SNP and prenatal environment in 24% of all VMRs. While functionally relevant meQTLs were located in close proximity to the specific CpG-site, functionally relevant SNPs involved in interaction models showed much broader peaks.Concerning the epigenetic clock, lower gestational age was associated with maternal depression diagnosis and greater depressive symptoms throughout pregnancy. Epigenetic age deceleration was associated with pre-eclampsia. Furthermore, lower epigenetic gestational age was significantly associated with greater total and internalizing problems in boys.Not only environment but also genotype should be considered in epigenetic studies. Furthermore, our results suggest that long-distance effects are present in GxE interactions. The epigenetic clock which mirrors prenatal environment is partially predictive for future development of the child. Lower epigenetic gestational age seems to be developmentally disadvantageous for boys, who in early childhood show greater psychiatric problems."}
+{"text": "A case of a renal artery stenosis and ipsilateral renal cell carcinoma with long term results is reported. A 65-year-old man with renovascular hypertension, renal insufficiency, and nephrotic range proteinuria presented with an incidental renal cell carcinoma. Concomitant in situ left partial nephrectomy and splenorenal arterial bypass was achieved. The patient is doing well without evidence of malignancy, stable renal function, markedly improved proteinuria and stable blood pressure more than three years later. The techniques of this procedure are detailed and underscore the possibility of successful removal of a renal cell carcinoma with preservation of renal function despite renal artery stenosis."}
+{"text": "Based on the responses of 5,557 Chinese secondary students in Hong Kong, the relationships between perceived family functioning (systemic correlate), parent-adolescent communication (dyadic correlate), and suicidal ideation were examined in this study. Results showed that suicidal ideation was negatively related to global family functioning and parent-adolescent communication. Regression analyses indicated that the dyadic and systemic factors had similar importance in predicting suicidal ideation. Theoretical and practical implications of the findings are discussed."}
+{"text": "Social cognition impairments are found in schizophrenia patients and hamper their ability to form social relationships. The biological underpinnings of this social cognition impairment are poorly investigated. We hypothesize that structural disconnectivity, which is replicated in schizophrenia, might has a relevant role in social cognition.The study we present here is under development. We have assessed social cognition using the Mayer, Salovey and Caruso emotional intelligence test (MSCEIT) in 30 patients with schizophrenia and 20 healthy controls. Structural connectivity is assessed with anatomical and Diffusion weighted (DWI) images acquired in a 3 Tesla MRI system. Anatomical and DWI images are processed to obtain fractional anisotropy (FA) values in the tracts connecting prefrontal cortex with anterior cingulate, superior temporal gyrus, insula and superior parietal cortex. The following statistics are assessed i) the differences in MSCEIT scores between patients and controls, ii) the differences in FA values between groups, iii) the relation between MSCEIT punctuation and FA values.In our preliminary analyses, patients show significantly lower MSCEIT scores. Furthermore, MSCEIT scores are directly related to FA values in the tracts connecting prefrontal cortex to anterior cingulate and superior temporal gyrus in the patients.Social cognition impairments seem to be associated with altered structural connectivity in the patients."}
+{"text": "Arabidopsis have revealed the involvement of genes and proteins in the glycolytic and other metabolic pathways, particularly processes involved in dehydration tolerance, osmoprotection, and membrane transport. Furthermore, successful recovery appears to be dependent upon the presence of antioxidant protection from reactive oxygen species. Characterization of specific genes and proteins will lead to significant advances in plant cryobiology research.Plant cryobiology has primarily emerged from the classical fields of cryobiology and plant stress physiology. Cryopreservation tools are now available to geneticists for germplasm preservation and the field itself is advancing significantly through the use of molecular techniques. Long-term preservation of vegetatively propagated tissues can minimize the risks of long-term maintenance under tissue culture or field conditions. Cells can be successfully cryopreserved when the adverse affects of ice crystal formation are mitigated by the removal of water or procedures to limit ice formation and crystal growth. The addition of cryoprotectant solutions to hydrated cells may improve the survival of microdissected shoot tips or embryonic axes. Recent discoveries in the genetic pathways leading to cold acclimation and freezing tolerance suggest the involvement of key cold-regulated genes in the acquisition of cold tolerance in plant tissues. Model systems of banana and  The field of plant cryobiology seeks to understand the physiological and molecular processes that allow plants to survive low temperatures. The focus of cryobiology is predominantly cryopreservation: the process and methods that permit long term survival of organisms at liquid nitrogen temperatures.Once cryopreserved, materials remain safe and available for a low annual cost. Novel, mutant, or transformed cell lines that can no longer be maintained in laboratory settings can be cryopreserved to prevent their loss . Clonal Successful cryogenic storage is dependent upon having a reliable source of coolant as well as a good documentation system. Once achieved, propagules often have extended storage longevity compared to conventional storage regimes (refrigerator or freezer conditions). Genetic drift and mutations are minimized compared to when materials are maintained in an actively growing state for extended intervals .Long term storage reduces the frequency of regenerations of accessions in genebanks and facilitates the use of specific individuals in breeding programs. Availability and transportability of cryopreserved pollen allows breeders to have access to materials that might otherwise be unavailable. Cryopreservation of embryo cultures lets breeding programs prolong the availability of juvenile materials while waiting for characterization of mature tree selections . CryothePlant cryobiology is a research discipline that is beginning to enter into the genomics arena. Traditionally, the discipline has been considered an extension of the cold hardiness and drought tolerance fields, centered primarily on long term preservation of seeds, shoot tips, dormant buds, pollen, embryos, cell lines, and other propagule types. A greater application of genomics techniques can increase our understanding of plant cryobiology. By combining physiological and genomic approaches, an array of methods are available to understand how cells are protected from freezing stress.One of the key issues in plant cryobiology is understanding why some genotypes are less tolerant of preservation stresses than other genotypes. Widescale adoption of cryopreservation technologies will likely depend on identifying universal cryoprotection protocols for each propagule type. A characterization of the genetic response to diverse cryoprotectants will determine if methods that rely on rapid cellular desiccation, permeable cryoprotectants, freeze desiccation, or air desiccation all result in similar cellular responses. Do cells sense and respond to the stresses differentially? Alternatively, do cells ultimately respond to either desiccation and/or temperature extremes? Careful analyses of gene expression responses will reveal which stress is perceived by cellular machinery and the pathways that are activated.Seeds and dormant buds can acquire an endogenous tolerance to desiccation and cryogenic temperature stresses. Dormant buds from temperate species collected mid-winter are more amenable to cryopreservation than those collected prior to acquiring cold tolerance or those which lose their cold-hardiness in the springtime . This acThe process of propagule recovery is poorly understood. Do cells acquire adequate protection from undesirable chemical effects  that are generated during recovery? Is it possible to minimize production of free radicals while promoting cellular repair? Comparison of gene expression patterns will provide key information as to the timing and nature of the recovery pathways in systems that survive or fail to survive cryopreservation.Molecular marker technologies have already been applied to cryopreserved plant materials to ascertain if recovered explants are true-to-type. Generally, there is consensus that plant genotypes remain stable after cryopreservation when a single genotype is the conservation target -13. Key Both dehydration and low temperature affect water relations within the cell. Lethal ice forms when hydrated cells are cooled below their freezing point. Thus, for successful cryopreservation, cells must be desiccated to prevent ice propagation. Cells must also have intact membranes and stable proteins to tolerate the desiccation and cold stresses. The rich literatures of cold and desiccation tolerance have revealed that extraordinarily similar response pathways are triggered by these different stresses.It is not surprising that the regulatory mechanisms for desiccation and cold tolerance partially overlap. These stresses invoke second messengers such as calcium, reactive oxygen species, and inositol phosphates within minutes of stress signal perception . The casArabidopsis [Microarray chip methods have identified 299 drought inducible, 54 cold inducible, and 245 abscisic acid (ABA) inducible genes in bidopsis , 20. Of bidopsis . In thisCold treatments cause abrupt changes in the structure of cellular lipids and cytoplasm. Ice forms in hydrated cells and the plasma membrane undergoes an undesirable phase change that is induced by low temperatures. Formation of extracellular ice removes freezable cellular water, but also invokes a desiccation stress.Cold acclimation treatments can increase the levels of unsaturated fatty acids, alter lipid and protein composition, change the lipid/protein ratio, and increase the proportion of phospholipids to stabilize membranes and prevent phase changes , 23. LipoC [Genomic evaluations of cold acclimated and exposed plants have revealed complex response pathways. The DREB1 proteins are transcriptional activators of over 300 genes in the CBF cold response pathway . TranscroC . The coloC . The CBFoC .Desiccation tolerant seeds and pollen undergo extreme dehydration as part of the developmental maturation process. Orthodox seeds can lose most of their moisture during maturation, resulting in moisture contents of around 8%. At low moisture content, the cytoplasm enters a glassy state where molecular movement is minimal . GlassesVegetative cells can also tolerate desiccation. Tonoplast and plasma membrane specific aquaporins, water channels across membranes, may play critical roles in water movement during both desiccation and rehydration. Desiccation stresses may cause the plasma membrane to lose surface area. Sugars and other polyhydric solutes are believed to protect protein and membrane structures during desiccation, though the mode of action remains poorly understood , 32.LEA proteins accumulate in seeds when desiccation tolerance is acquired during seed maturation. LEA proteins are hydrophilic and remain soluble at boiling temperatures (e.g. ). They mA.The genetic response to drought or desiccation has been identified in several model systems. ABA independent pathways ultimately affect the pathways that regulate osmotic equilibrium and detoxification . The DRE/CRT cis-acting element associates with the desiccation-specific DREB2 transcription factor, found in the ABA independent pathway response to drought stress , 38. ERDB.Arabidopsis, several hundred genes were induced by exogenous ABA treatment [Exogenous ABA induces genes that are also activated by dehydration. In reatment . An exogreatment -46. Endogenous ABA is essential for some drought stress-responses , includiMAP kinases also play a role in the regulation of stress responses by affecting protein phosphorylation and dephosphorylation states . MAP kinAn alternative ABA dependent pathway involves the MYC and MYB transcription factors that bind to MYB and MYC recognition sequences and activate the drought inducible RD22 gene .Survival after desiccation is dependent upon cellular protection from the stress of water loss as well as the availability of functional repair mechanisms after rehydration. Desiccation tolerant seeds and pollen generally survive rehydration; whereas it is much more challenging to successfully regenerate less tolerant propagule types. Recovery is dependent upon having enough cells survive for successful propagule regeneration. In shoot tip systems, many of the larger cells in regions surrounding the meristem become extremely plasmolyzed and do not survive cryopreservation .Ribes accessions exhibited higher hydroxyl radical activity, antioxidant status, phenolic accumulation and anthocyanin pigments than Ribes accessions that were cryo-sensitive [The presence of reactive oxygen species within cells after stress can damage cells and generate lipid peroxides, aldehydic products and protein carbonyls , 51. Higensitive . The reaensitive . Reactivensitive . The cytensitive .Arabidopsis T87 suspension cells to facilitate conservation of transgenic lines. Arabidopsis can also be a good model to identify the gene expression responses to cryogenic stress [Arabidopsis shoot tips are easy to produce and readily survive diverse cryo-exposure protocols [et al. published methods for the cryopreservation of Arabidopsis shoot tips using three of the more common shoot tip cryoprotection protocols. Cryoprotectants serve to both dehydrate and promote the glassy state within cells [Arabidopsis methods employed the cryoprotectants Plant Vitrification Solution 2  or in solution-filled cryovials. In contrast, PGD-treated shoot tips are slowly cooled within cryovials to -30 or -35oC prior to LN exposure.Many plant cryobiologists have focused on finding methods to conserve horticultural species that are vegetatively propagated since seed storage does not maintain the genotype of interest. Recently, a cryopreservation protocol has been published for c stress . Arabidorotocols . In 2006in cells . Publishsucrose; ), Plant sucrose; ) and PGDArabidopsis system. Comparisons of gene expression patterns during cryoprotectant treatment, liquid nitrogen exposure, and recovery of Arabidopsis shoot tips using cDNA microarrays have revealed suites of genes up- and down-regulated in shoot tips that survive cryopreservation .Cryoprotectants vary in their toxicity as well as their protective mechanisms , 61, thuMusa shoot tips from multiple species are amenable to vitrification methods [Musa, proteomics approaches have proved advantageous [Musa proteomics efforts (http://www.pdata.ua.ac.be/musa/ modules/listview/?table=spot). These high sucrose treatments serve to decrease Musa meristem water content and increase the intracellular sucrose concentration [             methods , 64. Sinntageous -67. Merintageous . A websintration .Progress in genomic research in other kingdoms may reveal fundamental stress responses of cells to extreme conditions. Insects and microbes have adapted to polar environments . ReptileCryoptopygus antarcticus) from Antarctic regions upregulate structural and cuticle proteins. Furthermore, expression of genes involved in moulting supports a role of moulting in cold tolerance [Onychiurus arcticus) have also served as model to study desiccation and cold tolerance in insects [O. arcticus in various states of desiccation identified clones representing genes that fall into classes of aquaporins, dehydrins, heat shock proteins and those relating to antioxidant production  that were upregulated [Desiccation and cold response pathways are interrelated in insects. Cold acclimated microarthopods (olerance . Arctic  insects . As in p insects . Sequencegulated . Subtracegulated .The Storey laboratory at Carleton University has made remarkable progress identifying genomic responses in cold-tolerant vertebrates. Frogs and reptiles overwinter in a frozen state and use ice nucleators to initiate the freezing process extracellularly and use antifreeze proteins to inhibit recrystallization during freezing. High osmolyte contents limit cell volume reduction, membrane stabilizers such as trehalose and proline prevent lipid biolayer compression, and physiological adaptations regulate the cessation and reactivation of breathing and the heart . Novel gSuccessful cryoprotection in both animals and plants is dependent upon minimizing freezeable water within cells and the maintenance of sufficient cell volumes , 77. ColIt is clear that similar mechanisms have evolved in diverse kingdoms that enable organisms to tolerate extreme temperatures and desiccation. Cells have reduced biochemical reaction rates, increased cellular viscosities, alterations in membrane lipids and changes in protein conformation in response to extremely cold conditions . By miniPrevention of cellular ice formation and maintenance of intact membranes are critical for successful plant cryopreservation. Identification of the genomic responses to cold and desiccation stresses during the cryopreservation process will reveal how propagules respond to diverse cryoprotectants, extreme temperatures, and recover. Understanding plant acclimation is key to determining endogenous responses and more information about the recovery process is needed. Comparing the genetic responses to tolerance and longevity within and among plant species and propagules will guide conservation scientists in their quest to design improved preservation strategies."}
+{"text": "Investigations were carried out on two lines of human melanomas  xenografted in nude mice. The tumours were characterised by a similar vascular supply but showed a pronounced difference in the rate of volume growth and in the radiobiologically hypoxic fraction. The distribution of ATP, glucose and lactate in the tumours was investigated using quantitative bioluminescence and single photon imaging. Concentrations of the metabolites were obtained as global values for the entire tumour mass, in regions with densely packed, structurally intact tumour cells ('viable zones'), in areas with necrosis, stromal cells and fibrous material ('necrotic zones') and in adjacent normal tissue. In all melanomas investigated glucose concentrations were significantly lower and lactate concentrations were significantly higher than in normal tissue. In contrast, no significant differences for ATP were detected. ATP and glucose concentrations were significantly less in necrotic than in viable tumour zones, whereas lactate concentrations were nearly equal in these tumour parts. Corresponding results were obtained in central versus peripheral tumour zones. There was no dependency of global or regional metabolite concentrations on tumour size within the volume range 110-1470 mm3. Based on this lack of dependency, metabolic concentrations were averaged over the whole tumour size range. Metabolite concentrations were not significantly different either globally or regionally between the two tumour entities investigated, a finding which held true for all three metabolites registered. Thus, metabolite distributions apparently mirror the similarity in vascularity of MF and EE melanomas rather than reflecting intrinsic properties with regard to tumour growth rates or susceptibility to radiation."}
+{"text": "Septic shock is a life-threatening clinical syndrome that, despite its rare occurrence in obstetrics,remains a leading cause of maternal mortality. Its pathophysiology is explained by a profoundsystemic response to a complex variety of host cellular and humoral mediators elaborated afterexposure to microbial toxins. Early recognition, prompt diagnostic workup, and immediate initiationof therapy improve outcomes. Therefore, recent publications have popularized the concept of the\u201csepsis syndrome,\u201d a preshock list of clinical criteria associated with progressive sepsis. Neededdiagnostic studies should never be withheld because of \u201cpregnancy concerns.\u201d With critically illpatients, the risk-to-benefit ratio supports the use of these diagnostic studies in almost all circumstances.Standard therapy is directed principally at restoring tissue perfusion by intravascularvolume expansion and in some instances vasoactive pharmacological intervention. Simultaneously,identification of the source of infection and commencement of appropriate empiric antibiotic treatmentare critical. In some cases, surgical abscess drainage or debridement of infected necrotic tissuewill need to be considered. Novel approaches to treatment that attempt to reduce the systemicresponse to microbial toxins are promising and under active investigation. Pregnancy-specific considerationsinclude the following: 1) initial signs or symptoms of septic shock may be masked bynormal physiologic alterations of pregnancy; 2) a mixed polymicrobial group of organisms, consistentwith lower genital tract flora, should be anticipated; and 3) initial therapy should be directedat maternal concerns since adverse fetal effects are most likely the result of maternal decompensation."}
+{"text": "The prognosis of colorectal cancer has not significantly changed during the last 30 years. While evaluation of tumour cell proliferation may provide prognostic information, results obtained so far have been contradictory Heterogeneity in tumour cell proliferation may explain these contradictions. With in vivo injection of iododeoxyuridine (IdUrd), estimation of labelling index (LI), S-phase transit time (Ts) and potential doubling time (Tpot) may be performed from a single sample. A total of 109 colorectal cancers were studied after in vivo injection of IdUrd before surgical removal. From each cancer, four to eight samples were processed for both flow cytometrical (FCM) and immunohistochemical (IHC) visualization of IdUrd incorporation. LI/IHC was morphometrically quantified at both the luminal border and the invasive margin of these tumours. LI was significantly higher at the luminal border compared with the invasive margin, although they were correlated with each other. Using combined IHC and FCM methods, rapidly growing colorectal cancers (high LI and/or low Tpot) showed an increased survival  in the entire unselected material and for radically removed Dukes' B tumours. FCM data alone did not discriminate for survival, with the exception of Ts in diploid and radically removed Dukes' B tumours."}
+{"text": "The question of whether initial prognostic factors in small-cell lung cancer patients have a predictive value for patients' quality of life (QL) during chemotherapy is addressed in the context of a randomised clinical trial comparing early and late alternating chemotherapy (SAKK protocol 15/84). The relative impact of initial tumour stage and performance status, previous weight loss, sex and age on patient-rated QL was analysed over six chemotherapy cycles in 124-130 patients (according to available QL data) with more than 400 questionnaires. Fatigue/malaise, personal functioning, emotional and general well-being were prospectively selected as QL indicators. Predefined summary measures  were analysed separately by scale in various patient groups. General linear models adjusted for treatment arm and response were used to confirm the univariate findings. Within the overall sample, the average QL scores over six cycles were predicted by initial prognostic factors. Patients with poor prognostic factors reported worse QL. Within a limited sample (with baseline QL), patients with poor prognostic factors reported worse QL at baseline and greater improvement under treatment. Graphical comparison of QL patterns over cycles showed permanent discrimination by levels of prognostic factors. The impact of initial prognostic factors was consistently confirmed in the three analyses. Levels of performance status and weight loss best discriminated QL. Initial tumour stage, performance status and previous weight loss can predict QL in small-cell lung cancer during chemotherapy, even after controlling for response to treatment. Our results may contribute to clinical decision-making with regard to the intensity of chemotherapy and QL outcome, especially in patients with extensive disease."}
+{"text": "Among these chemicals is bisphenol A (BPA), a pervasive endocrine-disrupting compound used to make polycarbonate plastic and epoxy resins. Now researchers report evidence that exposure to environmentally relevant doses of BPA during pregnancy may alter insulin sensitivity and glucose homeostasis in mice, with potential disease-related consequences for both the mother and her male offspring The study evaluated the effects of two different doses of BPA (10 or 100 \u03bcg/kg/d) administered to pregnant mice during days 9\u201316 of gestation. Glucose metabolism experiments were performed on the mice during pregnancy and subsequently on their offspring.BPA exposure aggravated the insulin resistance that occurs during pregnancy, and four months postpartum, BPA-treated mice weighed more and had more severe insulin resistance than untreated females. The BPA-treated mice also showed elevated plasma levels of insulin, leptin, triglycerides, and glycerol (a breakdown product of triglycerides), as well as molecular changes indicating reduced insulin sensitivity in skeletal muscle and liver.Given that levels of the hormone leptin are normally increased during pregnancy, the authors propose that future research should seek to determine whether BPA directly regulates leptin release from fatty tissue or whether the observed hyperleptinemia is a consequence of the altered metabolic state of these animals.in utero had reduced glucose tolerance, increased insulin resistance, and altered blood parameters compared with offspring of untreated mothers. Moreover, studies of the male offspring\u2019s pancreases showed altered calcium signaling and insulin secretion.Previously the same research team had shown a relationship between BPA exposure and glucose intolerance and insulin resistance in adult male mice. In the present study, they further observed that, at 6 months of age, male offspring exposed to BPA The authors conclude that BPA exposure during pregnancy can alter the mother\u2019s glucose metabolism during pregnancy and later in life, and may contribute to metabolic disorders relevant to glucose homeostasis in the male offspring. The findings also suggest that BPA exposure should be further examined as a risk factor for diabetes."}
+{"text": "Intrahepatic stones are difficult to manage, especially when they are associated with bile duct stricture,cholangitis and destruction of liver parenchyma. Suggested modes of treatment include surgical bile ductexploration, endoscopic procedures, transhepatic cholangiolithotomy and liver resection. This paper reports2 patients in whom liver resection was performed because of intrahepatic ductal stones, bile duct stricturesand repeated episodes of cholangitis. Liver resection was uncomplicated and long-term results were satisfactory.Our results support the view that liver resection is indicated in rare instances of intrahepatic bile ductstones associated with bile duct strictures."}
+{"text": "The mechanism by which phagocytosed mast cell granules (MCGs) inhibit macrophage superoxide production has not been defined. In this study, rat peritoneal macrophages were co-incubated with either isolated intact MCGs or MCG-sonicate, and their respiratory burst capacity and morphology were studied. Co-incubation of macrophages with either intact MCGs or MCG-sonicate resulted in a dose-dependent inhibition of superoxide- mediated cytochrome c reduction. This inhibitory effect was evident within 5 min of incubation and with MCG-sonicate was completely reversed when macrophages were washed prior to activation with PMA. In the case of intact MCGs, the inhibitory effect was only partially reversed by washing after a prolonged co-incubation time. Electron microscopic analyses revealed that MCGs were rapidly phagocytosed by macrophages and were subsequently disintegrated within the phagolysosomes. Assay of MCGs for superoxide dismutase (SOD) revealed the presence of significant activity of this enzyme. A comparison of normal macrophages and those containing phagocytosed MCGs did not reveal a significant difference in total SOD activity. It is speculated that, although there was no significant increase in total SOD activity in macrophages containing phagocytosed MCGs, the phagocytosed MCGs might cause a transient increase in SOD activity within the phagolysosomes. This transient rise in SOD results in scavenging of the newly generated superoxide. Alternatively, MCG inhibition of NADPH oxidase would explain the reported observations."}
+{"text": "A 26-year-old woman born with Tetralogy of Fallot initially underwent a left Blalock-Taussig shunt followed by a complete repair with a transannular patch at 2 years of age. She complained of non-sustained short episodes of palpitations. Her Holter monitor showed episodes of six beat run of non-sustained ventricular tachycardia. She was scheduled to undergo surgical pulmonary valve replacement. In view of her symptoms and Holter results she underwent an electrophysiology study to map any substrate of ventricular tachycardia for intra-operative ablation. Her baseline electrocardiogram demonstrated complete right bundle branch block pattern (RBBB) with QRS duration of 174 msec secondary to surgical interruption of the right bundle branch. During the electrophysiology study she was noted to have intermittent narrow QRS complexes .The QRS On initial assessment of the intracardiac tracings as well as the 12 lead electrocardiogram, there is evidence of baseline RBBB  with intermittent appearance of normally conducted sinus activations with normal AH and slightly shortened HV. However on further analysis there seems to be a premature ventricular complex from the right ventricular apex that occurs immediately after the His deflection causing the apparent narrowing of the QRS complexes.Intermittent transition from wide to narrow QRS complex has been described with multiple mechanisms. These include change in heart rate, 'peel-back' refractoriness, rate dependent progressive shortening of bundle branch refractoriness, gap phenomena, supernormality, loss of pre-excitation, premature ventricular complex (PVC) ipsilateral to the bundle branch block and equal conduction delay in both the bundle branches . PresencThis physiological mechanism may have potential clinical applications for optimizing the timing of pacing intervals to obtain narrow QRS complexes as well to obtain interventricular synchrony."}
+{"text": "Experiments conducted in vitro are described which indicate that a family of specifically substituted phosphoramides may share the carcinogenic properties displayed by the structurally novel carcinogen, hexamethylphosphoramide (HMPA). Most of the analogues tested only gave a positive response in vitro when using a substantially modified liver homogenate activation system (S-9 mix). The analogy drawn in our earlier paper between this new class of potential carcinogens and the nitrosamine carcinogens, has been strengthened. The following compounds gave a positive response in the cell transformation assay of Styles: hexamethylphosphoramide (HMPA), hexamethylphosphorous triamide, hexamethylphosphorothioic triamide, tripiperidinophosphine oxide, phosphorothioic trimorpholide and diethoxymorpholinophosphine oxide (DEMPA)."}
+{"text": "Luminol-enhanced chemiluminescence was measured in fresh whole human blood, or human neutrophils isolated from heparinized blood, human alveolar macrophages and rat alveolar macrophages stimulated with bacterial endotoxin (LPS). Tetraacetate esters of rooperol, a dicatechol showing anticytokine activity, added to cells simultaneously with LPS inhibited the respiratory burst. The effective concentrations of rooperol were in the range of 1-10 \u03bcM depending on cell type and corresponded well with inhibition of nitric oxide production by rat alveolar macrophages. Thus rooperol may reduce some effects of excessive phagocytic activity and inflammatory reaction but by quenching free radicals production may also diminish the resistance to bacterial infections."}
+{"text": "Endolaryngeal microscopic laryngosurgery (microlaryngosurgery) using a direct laryngoscopeis the preferred surgical method for treating laryngeal lesions under general anesthesia.However, this method does not provide a wide-angle view of the larynx and does not allowdetailed observations of the ventricle and subglottis of the laryngeal cavity, resulting in blindareas. Video-assisted endoscopic laryngosurgery using a direct laryngoscope and a longtransurethral rigid endoscope was therefore utilized to allow clear observations and completeresection of laryngeal lesions in these blind areas. This endoscopic surgical technique isintroduced, and clinical cases are presented."}
+{"text": "Begomovirus (family Geminiviridae), with potential recombination hot- and cold-spots also having been identified. Nevertheless, because very little is understood about either the biochemical predispositions of different genomic regions to recombine or what makes some recombinants more viable than others, the sources of the evolutionary and biochemical forces shaping distinctive recombination patterns observed in nature remain obscure. Here we present a detailed analysis of unique recombination events detectable in the DNA-A and DNA-A-like genome components of bipartite and monopartite begomoviruses. We demonstrate both that recombination breakpoint hot- and cold-spots are conserved between the two groups of viruses, and that patterns of sequence exchange amongst the genomes are obviously non-random. Using a computational technique designed to predict structural perturbations in chimaeric proteins, we demonstrate that observed recombination events tend to be less disruptive than sets of simulated ones. Purifying selection acting against natural recombinants expressing improperly folded chimaeric proteins is therefore a major determinant of natural recombination patterns in begomoviruses.With the development of reliable recombination detection tools and an increasing number of available genome sequences, many studies have reported evidence of recombination in a wide range of virus genera. Recombination is apparently a major mechanism in virus evolution, allowing viruses to evolve more quickly by providing immediate direct access to many more areas of a sequence space than are accessible by mutation alone. Recombination has been widely described amongst the insect-transmitted plant viruses in the genus  The exchange of genetic material between different virus species, called inter-species recombination, has the potential to generate, within a single genome replication cycle, an almost unimaginable number of genetically distinct virus strains, including many that might cause deadly new human, animal, or plant diseases. Many fear that inter-species recombination could provide viruses with quick access to evolutionary innovations such as broader host ranges, altered tissue tropisms, or increased severities. However, mounting evidence suggests that recombination is not an unconstrained process and that most inter-species recombinants that occur in nature are probably defective. It is suspected that networks of coevolved interactions between different parts of virus genomes and their encoded proteins must be kept intact for newly formed inter-species recombinants to have any chance of out-competing their parents. One category of coevolved interaction is that between contacting amino acids within the 3-D structures of folded proteins. Here we examine the distributions of recombination events across the genomes of a group of rampantly recombining plant viruses and find very good evidence that this class of interaction tends to be preserved amongst recombinant sequences sampled from nature. This indicates that selection against misfolded proteins strongly influences the survival of natural recombinants. Besides its vital cellular role in maintaining and repairing broken DNA molecules ,2, recomIn virology, two recombinational processes can be distinguished: genome reassortment and true recombination. Genome reassortment, also called pseudo-recombination, involves the exchange of intact genome components between viruses with multipartite genomes to yield viruses whose genomes are comprised of new combinations of components. True recombination, on the other hand, involves the exchange of genetic material between individual genomic molecules. The rearrangement of genetic information mediated by both true recombination and pseudo-recombination must yield fully functional and reasonably fit genomes for these processes to be easily detectable in nature. However, analysis of the functionality of recombinant genes ,9 and thWhile full accounts of experimentally verified intra-genome interactions are currently unavailable for any virus species, potential amino acid interactions within folded proteins can be inferred with reasonable accuracy given high resolution protein structural data. In the past five years, protein engineers have made substantial progress in the development of computational methods capable of accurately inferring degrees of recombination-induced fold disruption in experimentally generated chimaeras of proteins with known structures ,14,15. Arep) gene encoding a protein for which a high resolution crystal structure is available. In this paper we describe an expanded analysis of recombination amongst begomoviruses. We identify sets of unambiguously unique recombination events detectable in publicly available monopartite begomovirus DNA-A-like sequences and bipartite begomovirus DNA-A sequences. We then determine the distribution of recombination breakpoints across the analysed sequences and confirm the recombination hot- and cold-spots identified previously. We use a method called SCHEMA  (AY795983), ToLCYTV-[Dem] (AJ865341), and TYLCSV (X61153). The Protein Data Bank (http://www.pdb.org/) ID number for TYLCSV N-terminal region structure is 1L2M.The National Center for Biotechnology Information ("}
+{"text": "The principles and design of a Hadamard transform UV absorbance detector for liquid chromatography are outlined, and some spectra of aromatic compounds passing through its flow cell are presented. This approach could be valuable in providing alow-cost multi-wavelength detection method for liquid chromatography."}
+{"text": "The occurrence of biliary stricutures in allografts following liver transplantation correlateswith the duration of preservation time. The correlation between preservation timeand biliary strictures suggests that anoxic or reperfusion injury of the bile duct epitheliumcauses stricture formation. However, the relative susceptibility of bile duct cells to anoxicor reoxygenation injury is unknown. Our aims were to determine the vulnerability of ratliver bile duct cells to anoxic and reoxygenation injury and to compare the results withhepatocytes. During anoxia, bile duct epithelial cells were significantly more resistant tocell killing than hepatocytes. Rates of cellular proteolysis were also 2.5-fold lower in bileduct cells than in hepatocytes during anoxia. In contrast to anoxia, reoxygenation ofanoxic cells increased cell killing of bile duct cells but improved viability of hepatocytes.The rate of toxic oxygen species formation by bile duct cells was 5-fold greater than inhepatocytes during reoxygenation. In addition, basal levels of glutathione are lower in bileduct cells than in hepatocytes. These data suggests that bile duct cells are more susceptibleto reoxygenation injury than to anoxia. These studies support the hypothesis thatreoxygenation injury during liver preservation leads to bile duct injury during livertransplantation."}
+{"text": "Long term complications of laparoscopic cholecystectomy are uncommon. However, as experience with this procedure accumulates, sporadic reports of non-biliary complication have been published. We report a case of abdominal wall sinus formation secondary to gallbladder perforation and stone spillage occurring during laparoscopic cholecystectomy."}
+{"text": "Ichthyosis uteri is a rare condition in which the entire surface of the endometrium is replaced by stratified squamous epithelium. Though the condition often is considered as benign, anaplastic and dysplastic changes have been reported. We describe herein a rare case of low-grade squamous cell carcinoma of endometrium associated with extensive ichthyosis uteri with dysplasia. The cervix showed moderate to severe dysplastic changes while the right fallopian tube showed extensive squamous metaplasia with dysplastic changes. We conclude that squamous cell carcinoma could develop into pre-existing ichthyosis uteri. A 65-year-old multi-gravida presented with complaints of abdominal pain and postmenopausal bleeding per vagina for seven months. Her past medical history was insignificant with no history of tuberculosis, inflammatory conditions of the uterus or iatrogenically introduced substances in uterus. She had attained menopause about 15 years back.Gynecological examination revealed atrophic ectocervix flushed with vagina. The vagina appeared normal. Uterus was bulky of around 12 weeks and adnexae were unremarkable. Colposcopy showed schiller's unstained areas on anterior lip of cervix. Ultrasound abdomen showed endometrial thickness of 2.6 cms. and fluid in the endometrial cavity. Ectocervical biopsy showed strips of moderate to severe dysplastic stratified squamous epithelium. Endometrial curetting revealed strips of stratified squamous epithelium showing moderate dysplastic changes. No normal endometrium was seen. The pyometra was drained, following which the patient underwent type-II radical hysterectomy. The procedure was well tolerated and the postoperative period was uneventful.The hysterectomy specimen revealed thickened and widened endometrial cavity with gray white nodule in the sub-adjacent myometrium. The cervix showed no obvious growth. The cut-section of the right fallopian tube showed thickened mucosa. Both the ovaries did not show any gross abnormality.The sections revealed entire endometrium replaced by stratified squamous epithelium showing areas of heavy keratinization, koilocytic changes, nuclear hyperchromasia and moderate increase in nuclear-cytoplasmic ratio indicating low grade dysplastic changes in underlying ichthyosis uteri Fig . ExtensiZeller coined the term \"ichthyosis uteri\" in the year 1885 to describe a condition of extensive squamous metaplasia of the surface endometrium following iatrogenically introduced caustic substances such as formalin or iodine [Ichthyosis is considered as benign condition. However, anaplastic and dysplastic changes have been reported by some authors -3. TheseBesides the dysplastic or anaplastic changes, a case of malignant degeneration has also been reported in ichthyosis uteri . This caIn summary, we describe a case of low-grade squamous cell carcinoma of endometrium developing in pre-existing extensive ichthyosis uteri with dysplasia. Though considered as benign condition, based on the present case report and that of Heckeroth et al , the posThe author(s) declare that they have no competing interests.KM, UM, VS drafted the manuscript. TR revised the draft critically for intellectual content. All authors read and approved the final manuscript."}
+{"text": "This was performed under fresh (resting) conditions and after incubation for 6 h without (unstimulated) and with (stimulated) Escherichia coli endotoxin. The malignant groups showed higher mTF levels than each of the three controls for resting  unstimulated  and stimulated cells . Similarly, the benign inflammatory groups had higher mTF levels than controls for resting , unstimulated  and stimulated cells . There was no significant difference between malignant and benign inflammatory groups in each organ. mTF levels showed an increase corresponding to that of histological tumour progression and were higher in non-surviving patients. In conclusion, mTF levels are raised in malignant and inflammatory disease compared to controls and patients with non-inflammatory conditions. Stimulated cells give better discrimination between the groups and may be of value in identifying high risk individuals. mTF levels showed an association with tumour grade or stage and the patients' survival time. \u00a9 1999 Cancer Research CampaignMonocytes express tissue factor (mTF) in several conditions including cancer where levels may be valuable in assessing tumour presence and progression. Using a two-stage kinetic chromogenic assay (KCA), mTF levels were measured in controls [normal subjects ("}
+{"text": "Brassica genome structure and systematically relate it to the Arabidopsismodel. Hitherto, our view of the co-linearities between these closely related genomeshad been largely inferred from comparative RFLP data, necessitating substantialinterpolation and expert interpretation. Sequencing of the Brassica rapa genomeby the Multinational Brassica Genome Project will, however, enable an entirelycomputational approach to this problem. Meanwhile we have been developingdatabases and bioinformatics tools to support our work in Brassica comparativegenomics, including a recently completed draft physical map of B. rapa integratedwith anchor probes derived from the Arabidopsis genome sequence. We are alsoexploring new ways to display the emerging Brassica\u2013Arabidopsis sequence homologydata. We have mapped all publicly available Brassica sequences in silico to theArabidopsis TIGR v5 genome sequence and published this in the ATIDB databasethat uses Generic Genome Browser (GBrowse). This in silico approach potentiallyidentifies all paralogous sequences and so we colour-code the significance of themappings and offer an integrated, real-time multiple alignment tool to partition theminto paralogous groups. The MySQL database driving GBrowse can also be directlyinterrogated, using the powerful API offered by the Perl Bio\u2237DB\u2237GFF methods,facilitating a wide range of data-mining possibilities.Recent advances, such as the availability of extensive genome survey sequence (GSS)data and draft physical maps, are radically transforming the means by which wecan dissect"}
+{"text": "A case report is presented of intra-mural gallbladder carcinoma discovered incidentally after laparoscopic cholecystectomy who subsequently developed abdominal wall recurrence at the epigastric exit port, and axillary lymph node metastases. Possible preventative steps for tumour dissemination and a management plan if incidental carcinoma is diagnosed is discussed. The use of a non-porous retrieval bag, early recognition of the carcinoma and excision of the exit wound are advocated."}
+{"text": "Novel antiangiogenic agents currently being developed may ultimately be more effective against solid tumours and less toxic than cytotoxic chemotherapy. As a result of the early clinical trials of angiogenesis inhibitors, investigators are beginning to appreciate the complexity of targeting angiogenesis and the realisation that developing clinically useful antiangiogenic therapy will be more challenging than originally thought. It is now apparent that new methods and surrogate markers to assess these agents' biological activity are crucial for their successful development. This review summarises the currently available clinical data on the development of surrogate markers of angiogenesis inhibitors. Many anPreclinical studies suggested that angiogenesis inhibitors are cytostatic (growth-delaying) rather than cytotoxic. Traditionally, the maximum tolerated dose of a cytotoxic agent (determined by its dose-limiting toxicity) provided an estimation of the active dose range for subsequent clinical studies  that are recruited from the bone marrow during tumour neovascularisation  after initiation of treatment might provide an early indication of antiangiogenic activity before clinically demonstrable reductions in tumour size. Elevated levels of angiogenic growth factors, proteases, and endothelial adhesion molecules have been detected in sera of patients with malignant disease  and the basement membrane during angiogenesis include the family of matrix metalloproteinases (MMPs) . Proteolvs those with stable disease  of action of the angiogenesis inhibitor or the disease under study. In a Phase I study of tetrathiomolybdate  can provide early proof of whether the biologic agent has successfully reached its hypothesised target. Some of the most compelling studies involved quantitative analysis by laser scanning cytometry (LSC) . In contrast, preclinical studies suggested that these small molecules had great potential, as they induced significant levels of apoptosis in endothelial cells, consequently inhibiting tumour growth  . In addition, LSC-mediated analysis of additional surrogate markers hypothesised to be effected by endostatin including nuclear hypoxia-inducible factor-1\u03b1 and endothelial cell Bcl-2 levels peaked at similar doses of endostatin but failed to reach statistical significance. Importantly, two patients treated at intermediate doses of endostatin had minor antitumour responses  and tumour metabolism [18F](FDG-fluorodeoxyglucose) 28 and 56 days after endostatin therapy . Importantly, the 95% confidence interval identified for blood flow overlapped the OBD (250\u2009mgm2d) determined from the tumour biopsy studies. Thus, integration of surrogate marker data along with imaging studies was crucial for assessing the OBD of recombinant human endostatin.Routine radiographic imaging techniques  are useful for conventional measurement of disease and evaluating the effect of a biologic agent on tumour size  after initiation of therapy may provide an assessment of optimal antivascular activity. Indeed, LSC-mediated analysis of apoptosis in tumour cells 48\u2009h after initiation of treatment has proven useful for predicting clinical response to cytotoxic therapies in breast cancer ("}
+{"text": "Epidemiologic evidence has recently identified an association between an endemic outbreak of pleural and peritoneal mesothelioma in the Urgup region of Turkey and exposure to zeolite fibres. This malignancy is usually associated with exposure to asbestos dusts whose mineralogical characteristics differ from those of zeolites. The present study further defines the in vitro biologic activity of erionite, a common zeolite fibre found in the Urgup region of Turkey. Both erionite and crocidolite asbestos fibres were clastogenic in synchronous Chinese hamster ovary (CHO) fibroblasts. Both fibres also altered CHO ploidy. Erionite, unlike crocidolite or Min-U-Sil quartz, caused a slight increase in sister chromatid exchanges in synchronous CHO cells. Neither erionite nor crocidolite was mutagenic in a human lymphoblastoid cell line. Erionite fibres thus produced in vitro cytogenic changes similar to those caused by asbestiform mineral dusts and, like asbestos fibres, did not induce mutations in human lymphoblastoid cells."}
+{"text": "We have addressed the question whether the epithelial stroma in the thymus is derivedfrom a common stem cell or whether cortical and medullary epithelial cells are derived fromdifferent embryonic stem cells emerging, for example, from endoderm and ectoderm. By theuse of rapidly expanding cultures of thymic epithelial cells (TEC) from 14 to 16 day-oldmurine fetuses and by specific antibodies against cortical and medullary epithelium,respectively, we were able to demonstrate a small subpopulation of double-labeled TEC inthe cultures. These cells were not present in TEC cultures initiated from thymuses ofneonatal mice. Double-labeled TEC were also found in tissue sections from fetal thymuses.These findings may indicate that TEC populations of the cortex and the medulla are derivedfrom a common stem cell, with potential for differentiation toward both cortical andmedullary TEC."}
+{"text": "The heterogeneity evident among home care clients highlights the need for greater understanding of the clinical and social determinants of multi-dimensional health-related quality of life (HRQL) indices and of potential sex-differences in these determinants. We examined the relative contribution of social and clinical factors to HRQL among older home care clients and explored whether any of the observed associations varied by sex.The Canadian-US sample included 514 clients. Self-reported HRQL was measured during in-home interviews (2002-04) using the Health Utilities Index Mark 2 (HUI2). Data on clients' sociodemographic, health and clinical characteristics were obtained with the Minimum Data Set for Home Care. The relative associations between clients' characteristics and HUI2 scores were examined using multivariable linear regression models.Women had a significantly lower mean HUI2 score than men . Clients with distressed caregivers and poor self-rated health exhibited significantly lower HRQL scores after adjustment for a comprehensive list of clinical conditions. Several other factors remained statistically significant  or clinically important  correlates of lower HUI2 scores in adjusted analyses. These associations generally did not vary significantly by sex.For females and males, HRQL scores were negatively associated with conditions predictive or indicative of disability and with markers of psychosocial stress. Despite sex differences in the prevalence of social and clinical factors likely to affect HRQL, few varied significantly by sex in their relative impact on HUI2 scores. Further exploration of differences in the relative importance of clinical and psychosocial well-being  to HRQL among female and male clients may help guide the development of sex-specific strategies for risk screening and care management. Health-related quality of life (HRQL) represents an important construct in understanding the health status and outcomes of older home care clients  and ultiarthritis, heart failure, stroke, chronic obstructive pulmonary disease (COPD), urinary incontinence and mental health disorders. Despite some suggestion of sex differences in the strength of the associations between selected chronic diseases and HRQL indices ), cognitive and emotional status from MDS-HC items, we chose not to present the adjusted models including these scales because of interpretation difficulties due to collinearity between these measures (and other correlates of interest) and the single attributes comprising the HUI2 [As illustrated by the multivariable linear regression results, the strongest associations with overall HUI2 scores were observed for high caregiver stress and poor self-rated health. Several other factors remained statistically significant  or clinically important  correlates of lower HUI2 scores in the adjusted analyses  displayed clinically important lower HUI2 scores. Some caution is warranted in the interpretation of the sex-differences observed for pressure ulcers and urinary tract infections given the relative low occurrence of these conditions and missing data (for pressure ulcers). A clinically important difference in HUI2 scores was observed for male  clients reporting feelings of loneliness. None of the two-way interaction terms with sex were found to be statistically significant at p < 0.05 in the full model.and social factors to multi-dimensional HRQL indices such as the HUI2. Even less consideration has been paid to potential sex-differences in the relative importance of selected associations. In addition to highlighting the relative importance of the above disability-related conditions we found statistically significant and clinically important decrements in clients\u2019 HRQL associated with poor selfrated health, urinary infections and caregiver distress . Clients\u2019 HUI2 scores varied little with age, marital status, or the presence of several common disease diagnoses. HUI2 scores were clinically reduced for those with self-reported loneliness, congestive heart failure and pressure ulcers. Generally, the observed associations were not significantly modified by sex; however, the magnitude of score differences associated with selected factors  did vary between females and males. Older home care clients often show considerable variability in physical, cognitive and social indices of vulnerability. The relative frailty of our client sample is reflected by their significantly lower overall mean HUI2 scores  compared with published age-specific HUI2 norms  . The lowThe relatively weak associations between individual disease diagnoses and clients' HRQL have also been reported by others ,7,37 andIn interpreting the relatively strong impact of poor self-rated health and caregiver distress on the HRQL of female and male clients it is important to acknowledge that these factors may serve as proxy measures for poorer clinical and functional status. Yet, both remained significantly associated with lower HUI2 scores after adjusting for clients' clinical and functional status including additional MDS-HC measures of ADL and cognitive impairment. Consequently, a broader interpretation might suggest that both factors provide unique information about clients' psychosocial well-being  relevant to their overall HRQL ,39. AddiWidowhood and reported loneliness, although significantly more common among women, were not significantly associated with lower HRQL. Self-reported loneliness did, however, show a clinically important association with lower HUI2 scores among male clients. Others have reported weak to no associations between both marital status and living arrangements  and HRQL in older populations ,21,22. AOur cross-sectional study precludes any clear discussion of the causal nature of selected observed associations . The absence of longitudinal data also limits our ability to detect and comment on relevant changes in clients' HRQL precipitated by expected fluctuations in their clinical and health conditions . ConsistWith our relatively select and small sample, some caution is warranted in generalizing our findings to other older populations and care settings including those in rural areas, in long-term care institutions and with moderate to severe cognitive impairment. Our relatively small number of male clients may also explain the relative absence of significant sex differences. As with other commonly used HRQL measures the HUI2 is particularly sensitive to physical impairment . Also, iAs expected, we observed important decrements in clients' HRQL for common health conditions predictive or indicative of disability, including arthritis, mental health disorders and incontinence. For both females and males, HUI2 scores varied little with the presence of several other prevalent clinical diagnoses. Most of the observed variation in clients' HRQL scores was accounted for by two factors, poor self-rated health and caregiver distress. Although the direction of these associations are unclear, both factors may serve as important markers of psychosocial frailty and increased risk for poor client outcomes including future declines in HRQL. Despite sex differences in the prevalence of social and clinical factors likely to affect HRQL, most did not vary significantly by sex in their relative impact on HUI2 scores. However, our findings highlight several areas worthy of further investigation with larger samples, including possible sex differences in the relative importance of arthritis, incontinence, mental health and self-reported loneliness. Further demonstration of a differential impact of these factors among female and male clients may assist in the identification of appropriate sex-specific strategies for risk screening and care management of vulnerable seniors in community care settings.DHF has a proprietary interest in Health Utilities Incorporated, Dundas, Ontario, Canada. HUInc. distributes copyrighted Health Utilities Index (HUI) materials and provides methodological advice on the use of HUI. All other authors declare that they have no competing interests.CJM developed the initial study, supervised data collection, directed data analyses and wrote and edited the manuscript. JK conducted the primary analyses. JW assisted with study design and implementation, data preparation and analyses. JZ assisted with data preparation and analyses. DBH assisted with study development and implementation. DHF assisted with study design and implementation. WW co-led the development of the initial study, supervised data collection and assisted with data analyses. All authors made meaningful contributions during the editing of the manuscript and approved the final version."}
+{"text": "Ralstonia  metallidurans (Rme) is better able to withstandhigh concentrations of heavy metals than any other well-studied organism. This factrenders it a potential agent of bioremediation as well as an ideal model organism forunderstanding metal resistance phenotypes. We have analysed the genome of Rmefor genes encoding homologues of established and putative transport proteins; 13%of all genes in Rme encode such homologues. Nearly one-third of the transportersidentified (32%) appear to function in inorganic ion transport with three-quartersof these acting on cations. Transporters specific for amino acids outnumber sugartransporters nearly 3 : 1, and this fact plus the large number of uptake systems fororganic acids indicates the heterotrophic preferences of these bacteria. Putative drugefflux pumps comprise 10% of the encoded transporters, but numerous efflux pumpsfor heavy metals, metabolites and macromolecules were also identified. The resultspresented should facilitate genetic manipulation and mechanistic studies of transportin this remarkable bacterium."}
+{"text": "Occurrence of bioprosthetic valve thrombosis less than a year after replacement is very uncommon. Here, we describe a case of a 57 year old male, who presented 10 months after receiving a bioprosthetic mitral valve replacement with a two week history of dyspnea on exertion, worsening orthopnea and decreased exercise tolerance. Echocardiography revealed severe mitral regurgitation (MR), thrombosis of the posterior mitral leaflet, left atrial (LA) mural thrombus and a depressed left ventricular ejection fraction of twenty-five percent. Given severe clot burden and decompensated heart failure (New York Heart Association - NYHA class III) repeat sternotomy was done to replace the bioprosthetic mitral valve and remove LA mural thrombus. MR was resolved postoperatively. This brief report further reviews promoting factors, established guidelines and management strategies of bioprosthetic valve thrombosis. Bioprosthetic mitral valves are advantageous over mechanical valves as their incidence of thrombosis, pannus formation and embolic events are significantly lower. This disparity in thromboembolic events as compared to mechanical valves avoids a need for chronic anticoagulation in many patients receiving bioprosthetic valve replacement . HoweverA 57 year old male with a past medical history of chronic atrial fibrillation, a depressed ejection fraction of 25%, and severe MR underwent mitral valve replacement with a bioprosthetic Mosaic valve  and a complete left and right sided MAZE procedure. Post operative transthoracic echocardiogram (TTE) showed a competent mitral valve tissue prosthesis and the patient was discharged on warfarin. Anticoagulation was discontinued three months after valve replacement and the patient remained in sinus rhythm on electrocardiography.Ten months following mitral valve replacement, the patient presented with a two week history of progressive dyspnea on exertion, orthopnea and weight gain. TTE revealed severe mitral valve stenosis and mitral regurgitation, with a mean gradient of 8.5 mmhg (max. gradient -- 25.5 mmhg) across the mitral valve, and restricted motion of mitral leaflets. On transesophageal echocardiogram (TEE), a mitral mass was observed on the posterior leaflet along with mural thrombus in a dilated left atrium measuring 4.90 cm in diameter figure . EjectioIntraoperatively, mural clot was debrided from the free and posterior left atrial walls. The mitral bioprosthesis was incompetent with pannus growing on the posterior leaflet. This valve was excised and replaced with a 25 mm On-X mechanical valve  that functioned without leakage after placement. Postoperatively, the patient had improved exercise tolerance and was discharged on indefinite warfarin therapy.Clinically significant bioprosthetic valve thrombosis is considered uncommon, however, its incidence on routine echocardiographic surveillance is reported as high as six percent . Specifi2 score is greater or equal to 2 [Although freedom from long term anticoagulation is a feature of bioprosthetic valve replacement, this case calls for a brief review of current anticoagulation guidelines following bioprosthetic valve replacement and a radioablative MAZE procedure. The 2008 American Heart Association (AHA) and American College of Cardiology (ACC) guidelines state that high risk patients with any of the following risk factors including atrial fibrillation, LV dysfunction with EF < 30%, recurrent thromboembolic events or a hypercoagulable condition meet a class I indication for indefinite anticoagulation . To reduual to 2 . These gThis case also calls for frequent post operative echocardiographic monitoring in non- anticoagulated patients with risk factors promoting valve thrombosis. The 2007 European Society of Cardiology (ESC) guidelines  recommenAccording to the 2007 ESC guidelines , once vaManagement of non-obstructive prosthetic valve thrombosis depends on the occurrence of thromboembolism (TE) and thrombus size . InitialIn the present case, obstructive valve thrombosis, large clot burden and critical illness made surgical replacement a reasonable and successful treatment option.Bioprosthetic mitral valve thrombosis is an under recognized complication in high risk patients that leads to rapid valve incompetence. Post-operatively, patients must be stratified in high or low risk categories, and anticoagulation should be maintained indefinitely for high risk patients. If anticoagulation is not maintained for individualized reasons then a semi-annual TTE within the first year and annually thereafter may detect subclinical bioprosthetic valve thrombosis in asymptomatic patients.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-n-Chief of this journal.OML discloses that he has served as a consultant and received research grants from Medtronic Corporation and On-X Life Technologies. The rest of the authors declare that they do not have any competing interests.OS: Resident physician, provided pre-operative care and primary author.BRW: Cardiologist, provided pre-operative care and advice during the manuscript writing process.MK: Assisted in writing and preparing manuscript.OL: Cardiothoracic Surgeon, performed the bioprosthetic valve repair and provided advice during the manuscript writing process.All authors have read and approve the final manuscript."}
+{"text": "Hemangiomas and venous lymphatic malformations are the two most common orbital vascular lesions seen in pediatric patients. Orbital venous-lymphatic malformations (OVLMs) (previously referred to as \u2032lymphangiomas\u2032) are uncommon, benign cystic type I vascular malformations.OVLMs may remain clinically unapparent or might manifest in childhood with slowly progressive proptosis, periorbital swelling and displacement of globe. These malformations usually enlarge slowly. Spontaneous intraorbital hemorrhage or venous thrombosis may cause sudden acute proptosis, severe pain, compressive optic neuropathy or loss of vision, when intervention is indicated . Orbital2A 20-year-old girl presented with left-sided progressive painless orbital proptosis since birth . On examSystemic corticosteroids have been used as an adjuvant treatment to surgery, although their role is controversial. The diffuse form of orbital lymphangioma is well known for its difficult surgical treatment and frequent recurrences. Small, repeated excisions may be required. Surgical debulking with carbon dioxide laser through a lateral orbitotomy combined with three-wall orbital decompression is a preferred surgical technique and may be a useful alternative treatment in patients with severe proptosis.Ultrasonography of OVLMs show high amplitude echoes with a very wide separation due to large encapsulated fluid lakes. On CT scan, these are poorly defined slightly enhancing lesions that cross anatomic boundaries, such as the conal fascia and orbital septum. Areas of hemorrhage cause cyst-like masses with rim enhancement. In the last decade, role of MRI has been emphasized in the literature as it has the capability to precisely delineate and characterize these lesions. It is reWe conclude that imaging plays a crucial role in diagnosis of OVLMs and intracranial associations. However, atypical characteristics may be seen in a few pediatric patients and excision biopsy may be indicated to facilitate diagnosis."}
+{"text": "Heterotransplantation of a human colonic neoplasm with classical morphologic characteristics of a carcinoid was sucessful in the cheek pouches of unconditioned, adult golden hamsters after a short sojourn in cell-impermeable chambers in rats. Although no mucin-secreting cells were detected in the donor carcinoid, the cheek pouch transplants exclusively exhibited mucinsecreting tumour cells of signet-ring type consistent with adenocarcinoma. This transplantable tumour, designated GW-77, has retained this appearance as well as expansive growth characteristics in xenogeneic hosts for a period of 4 years.These findings represent strong biological evidence consonant with views, based upon morphological findings, advocating a histogenetic relationship between colonic carcinoid and adenocarcinoma. It is believed that colonic adenocarcinoma has a selective advantage over carcinoid for serial propagation in an alien environment, indicating the less differentiated nature of its cellular components. Since the donor carcinoid cells failed to exhibit argentaffin reactions, these conclusions may be limited only to the nonreactive forms of carcinoid."}
+{"text": "Several pathogens of humans and domestic animals depend on hematophagous arthropods to transmit them from one vertebrate reservoir host to another and maintain them in an environment. These pathogens use antigenic variation to prolong their circulation in the blood and thus increase the likelihood of transmission. By convergent evolution, bacterial and protozoal vector-borne pathogens have acquired similar genetic mechanisms for successful antigenic variation. Borrelia spp. and Anaplasma marginale (among bacteria) and African trypanosomes, Plasmodium falciparum, and Babesia bovis (among parasites) are examples of pathogens using these mechanisms. Antigenic variation poses a challenge in the development of vaccines against vector-borne pathogens."}
+{"text": "Effects of neonatal androgenization or neonatal ovariectomy in female rats on endocrine functions and mammary tumourigenesis are examined. Pituitary gonadotrophin contents (both LH and FSH) are significantly lower in neonatally androgenized rats (TT) and significantly increased in neonatally ovariectomized rats (NO) when compared with controls of the same age. Plasma and pituitary prolactin levels are higher in TT rats than in the control rats of the same age, but the difference is not significant. Mammary tumours developing in TT rats after DMBA treatment are predominantly fibroadenomata, and lactogenesis in TT rats occurs almost entirely in those receiving DMBA treatment. Neonatal ovariectomy in female rats protects against subsequent induction of mammary cnacer by DMBA. The relationship between neonatal modification of endocrine functions and mammary tumourigenesis is discussed."}
+{"text": "Myopotential oversensing in implantable defibrillators causing inhibition of pacing and inappropriate therapies is well described. Current literature is dominated by reports of diaphragmatic muscle as the source of such far-field oversensing. Those reporting pectoral muscle sources were invariably due to unipolar sensing circuits, incorrect DF-1 connections or inappropriate programming. We report an interesting case of pectoral muscle myopotential oversensing causing inhibition of bradycardia pacing leading to presyncope and syncope. Oversensing of skeletal muscle myopotentials is well described -3 and isA 60 year old female with hypertrophic cardiomyopathy had originally presented with syncope and documented ventricular tachycardia. A dual chamber cardioverter-defibrillator (Guidant VENTAK 1861) was implanted in June 2003 and an integrated bipolar right ventricular defibrillator lead was used (Guidant SN 0158). Electrogram amplitudes, pacing and defibrillation thresholds at the time of implantation were normal.After the procedure, the patient was without symptoms for two years. Device interrogation during routine follow-up demonstrated low levels of noise on ventricular electrograms. There were no appropriate or inappropriate therapies although three therapies were diverted.In Feb 2006 the patient developed persistent atrial fibrillation. Pharmacological attempts to maintain sinus rhythm were unsuccessful, she declined a left atrial ablation procedure and in May 2007 the patient underwent atrio-ventricular (AV) node ablation for ventricular rate control and was rendered pacemaker dependant. One month after AV node ablation the patient attended the cardiac device clinic complaining of recurrent episodes of dizziness and syncope during certain physical activities such as showering or washing dishes. At this time pacing thresholds, electrogram amplitudes and impedances were normal. A chest X-ray showed no radiographic evidence of loss of lead integrity.Device interrogation revealed 16 diverted therapies in the VF zone. One such episode is shown in At interrogation, these potentials were not reproducible with the usual provocative manoeuvres such as rapid, deep respiration and generator agitation, but were reproducible with isometric upper limb exercise  and resulted in pacing inhibition and dizziness.Our immediate management was to reduce the sensitivity to the minimum programmable setting. This was deemed safe as a short term measure as VF detection at minimal sensitivity was confirmed at defibrillation threshold testing at implantation. We advised the patient to avoid driving and provocative manoeuvres. The patient was admitted electively for re-operation. At procedure the existing lead connections to the generator were found to be secure and appropriate. Invasive lead tests were satisfactory. We elected to leave the integrated lead in situ and implant a new dedicated bipolar pacing lead (Medtronic 5076) for ventricular sensing and pacing. The new pace/sense lead was connected to the ventricular IS-1 socket on the existing device and the old integrated defibrillator lead remained connected via the DF-1 sockets. The defibrillator lead IS-1 terminal was capped and secured within the prepectoral pocket.  Subsequently, the patient's symptoms resolved and no further myopotentials were recordable.The case highlights a problem specific to integrated bipolar lead technology, that is, far-field myopotential oversensing due to distance between the lead tip and distal defibrillator coil.This patient only became symptomatic when rendered pacing dependant after AV node ablation when upper body muscular movement caused pacing inhibition through myopotential oversensing. Fortunately, this consistently caused dizziness or syncope which stopped physical activity thus terminating myopotential oversensing. As a result, therapies were always diverted and pacing resumed. It is therefore curious that no inappropriate therapies were delivered prior to AV node ablation. This may simply be explained by a dynamic ventricular sensing threshold facility available in most defibrillators, in this case, automatic gain control see . FollowiAtrial and T-wave oversensing, which have also been reported with integrated bipolar leads are usually easily overcome with re-programming. True myopotential oversensing however, invariably requires re-operation. Our solution in this case was to introduce a separate dedicated bipolar pace/sense lead and retain the integrated lead for defibrillation. An alternative solution would have been to replace the lead with a dedicated bipolar defibrillator lead and either extract the integrated lead or leave it redundant  .The alternative to re-operation is to reduce ventricular lead sensitivity to exclude unwanted potentials. This particular device had three sensitivity settings - \"nominal\", \"less\" and \"least\". Although implant testing is done at \"least\" sensitivity, VF re-induction at \"least\" sensitivity to confirm VF sensing would have been a reasonable approach (though not without risk) as changes in sensing may have occurred with lead maturation. In this case, we employed this strategy only as an interim, particularly as \"least\" sensitivity would not have guaranteed a resolution to myopotential oversensing, because it could not be confidently reproduced in the setting of the device clinic as myopotential interference may change with patient position and activity.With dedicated bipolar (quadripolar) defibrillator leads available, the use of integrated leads may be questioned. Quadripolar leads are, however, not without problems. Increased pacing thresholds and sensing latency causing ventricular pseudofusion and unnecessary ventricular pacing are not uncommon . More prProgress in lead technology has not paralleled the rapid advances in generator design and technology. Newer quadripolar constructions with active fixation are gaining merit but longevity data is still anticipated. Hence, to date lead choice remains at the discretion of the implanter rather than guided by evidence."}
+{"text": "Leucocyte interactions with the cremaster muscle microcirculation in vivo were investigated in response to culture medium conditioned with different cell types in 25 adult male Swiss mice. Animals were divided into five groups. Three groups received ex vivo fluorescently labelled lymphokine activated killer (LAK) cells systemically and had either tumour (murine melanoma K1735)-conditioned medium (TCM), fibroblast (murine 3T3)-conditioned medium (FCM) or fresh culture medium administered topically to the cremaster muscle. In the two remaining groups, the host leucocytes were labelled fluorescently by systemic administration of acridine red, and either TCM or FCM was applied topically to the cremaster muscle. There was an immediate but transient increase in the frequency of rolling and adherent LAK cells, and a subsequent (90-120 min later) increase in rolling and adherent host leucocytes, demonstrating temporal differences in the response to topical administration of TCM. These increases in contact with the vascular endothelium occurred in all vessel types, venules, arterioles and capillaries, with the greatest response observed in the venules. The FCM and normal culture medium did not affect the distribution and localization of either LAK cells or host leucocytes. These data suggest that there are one or more soluble tumour-specific chemoattractants for leucocytes present in the conditioned medium. The mouse cremaster muscle microcirculation is therefore a useful model to investigate the mechanism of leucocyte-endothelium interactions in tumour biology."}
+{"text": "The patient had exertional chest pain and dyspnea prompting referral for cardiac evaluation. These symptoms were reproduced during intravenous adenosine infusion, and simultaneous first-pass perfusion imaging showed a significant subendocardial defect; both symptoms and perfusion deficit were absent at rest. Epicardial coronaries were free of disease by invasive angiography; together, these findings support the notion of impaired myocardial perfusion reserve in FA.We present the first  This report describes myocardial perfusion reserve abnormality in Freidreich's ataxia (FA), a heritable disorder whose major manifestations are neurological and myocardial disease. In more than 90% of cases, this autosomal recessive condition results from excess of DNA triplet repeats (GAA) in the first intron at the end of exon 1 leading to suppression of FRDA (frataxin) gene expression. Around 5% of patients have a point mutation in the frataxin gene; both forms result in a deficiency of the protein frataxin that is located in the inner mitochondrial membrane, neitherA 26 year-old nonsmoking Middle Eastern woman presented for evaluation of exertional chest pain and shortness of breath. The past medical history was notable for genotype-proven Friedreich's ataxia (FA) diagnosed at age 19 that had produced ambulatory limitation with frequent falls due to her ataxia. Genotyping showed 846GAA repeats  consistent with FA. Family history revealed extensive affected members and carriers  with a 12-channel phased array coil. Resting steady-state free precession cine imaging showed normal left ventricular (LV) size and systolic function, with LV end-systolic volume 21 cc/mBased on the reproduction of chest pain with adenosine stress and accompanying perfusion abnormality, she was referred for invasive coronary angiography. This showed angiographically normal epicardial coronary arteries Figure  and normIn summary, we identified impaired microcirculatory reserve in FA using CMR that occurred in the absence of epicardial coronary artery disease. Friedreich's ataxia is a neurodegenerative condition frequently accompanied by cardiomyopathy due to a mutation in the gene frataxin, resulting in intra-mitochondrial accumulation of iron. The predilection for neuromuscular and myocardial involvement in FA reflects the high energy demands of both systems.et al. using positron emission tomography; their work suggested that compensation for impaired energetics in FA occurs by increasing myocardial oxygen consumption rather than myocardial blood flow, though this study was conducted under resting conditions only[Prior magnetic resonance-based evaluation of FA cardiomyopathy has focused on cardiac magnetic resonance spectroscopy  or quantions only.The detection of subendocardial perfusion abnormality afforded by adenosine CMR is similar to that described in other conditions such as syndrome X and coarctation of the aorta,7, thougThe author(s) declare that they have no competing interests."}
+{"text": "Whole-blood caeruloplasmin measured by electron spin resonance was studied in 41 patients with chronic lymphocytic leukaemia. The levels were above normal at all stages of the disease, rose with increasing clinical involvement, and were higher in progressive than inactive disease. Whole-blood iron transferrin levels were more variable, and were significantly raised only in patients with marrow failure."}
+{"text": "Patients with advanced idiopathic pulmonary artery hypertension have often a chronic pericardial effusion. It is the result of increased transudation and impaired re-absorption due to elevated venous pressure. These patients have pre-existent symptoms and signs of chronic right heart failure. High degree of suspicion is required to detect of development of an atypical form of tamponade with isolated compression of left heart chambers as shown in present case report. Transthoracic echocardiography provides a rapid access to the correct diagnosis, a prompt relief of symptoms following the ultrasound guided pericardiocentesis and important diagnostic tool for regular follow up of patients thereafter as shown in our case report. Circumferential pericardial effusion typically results in biventricular tamponade and equalization of intracardiac and pericardial pressure during diastole. In classic subacute tamponade the rising of pericardial pressure causes a progressive collapse of right atrium and ventricle preventing venous return to the right atrium. Symptoms and signs referable to increased filling pressure and diminished cardiac output ensue. Patients presents with dyspnea, orthopnea, peripheral edema, fatigability, hepatic engorgement. The three principal features: jugular venous distention, soft or absent heart sounds and hypotension (Beck's triad), tachycardia and pulsus paradoxus are present. However, tamponade may involve the right or left heart. While isolated left ventricular tamponade can occur as a postoperative complication form localized posterior pericardial effusions or hematoma, circumferential pericardial effusions leading to left heart tamponade are rare .We present a clinical course and echocardiographic examination in a patient with idiopathic pulmonary artery hypertension (IPAH) and chronic pericardial effusion who developed a subacute isolated left heart tamponade.A 57-year-old patient with IPAH and a previously known chronic pericardial effusion presented in an outpatient clinic with symptoms of dyspnea on exertion, in the last days even at rest, ortopnea and leg edema. During the past few months he was in good physical condition. He was on therapy with sildenafil, amlodipine, acenocoumarol and had a combination inhaler containing fluticasone propionate and salmeterol xinafoate. The clinical examination showed distended jugular veins, leg edema and an accentuated second heart sound. A chest radiogram showed an enlarged heart shadow. The echocardiographic examination showed a dilated right atrium and ventricle Figure  with redAfter the normalisation of the haemosthasis with fresh frozen plasma echocardiographicly guided pericardiocentesis using a parsternal approach was performed. Immediately after removal of 250 ml of yellow fluid the patient became normopnoic. There was still 1.5 cm large pericardial effusion behind the left ventricular posterior wall without left heart collapse  were negative. Rheumatic markers , angiotensin-convertyng enzyme and tumor markers  were all in normal range. The function of the thyroid gland was normal.Patients with cor pulmonale and circumferential pericardial effusion develop an atypical form of cadiac tamponade with isolated left heart compression. Pre-existing pulmonary arterial hypertension can modify the classic presentation. Symptoms and signs of right heart failure could already be present, so a high index of suspicion for tamponade is required in every worsening of right heart failure symptoms. When the pericardial pressure starts to increase in a patent with cor pulmonale, elevated pressure in right heart chambers prevent right atrial and ventricular compression, but while the pericardial pressure rises to the point to exceed left chambers pressure, this results first in diastolic collapse of left atrium and later on in left ventricle collapse due to a transient reversal of the transmural pressure ,3. SignsThe most probable mechanism of accumulation of pericardial fluid in patients with IPAH is transudation and impaired re-absorption of pericardial fluid due to elevated venous hydrostatic pressure in the setting of cor pulmonale.In the setting of pulmonary arterial hypertension large hemodynamically significant pericardial effusions might be treated surgically and/or conservative and it is known that prognosis of patients with this complication is poor ,5. HowevThe right ventricle-to-right atrial pressure gradient may be difficult to estimate in the setting of severe tricuspid regurgitation, when there is a large color flow regurgitant jet. In this case, the peak velocity may not reflect the true pressure gradient.In conclusion, patients with advanced IPAH have often a chronic pericardial effusion. It is the result of increased transudation and impaired re-absorption due to elevated venous pressure. These patients have pre-existent symptoms and signs of chronic right heart failure. High degree of suspicion is required to detect of development of an atypical form of tamponade with isolated compression of left heart chambers. Transthoracic echocardiography provides a rapid access to the correct diagnosis, a prompt relief of symptoms following the ultrasound guided pericardiocentesis and important diagnostic tool for regular follow up of patients thereafter.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.TM: carried out interpretation and drafted the manuscriptHM: carried out interpretation and drafted the manuscriptBS: treated the patient, carried out interpretation and drafted the manuscriptMP: treated the patient, made acquisition of data, carried out interpretation and drafted the manuscriptAll authors read and approved the final manuscript.Transthoracic echocardiography from apical four chamber view shows enlarged right ventricle (RV) and right atrium (RA). There is pericardial effusion (PE) compressing left ventricle (LV) and left atrium (LA).Click here for fileTransthoracic echocardiography from short-axis plane at the papillary muscle level shows enlarged right ventricle (RV) with paradoxical movement of intraventricular septum. Left ventricle is compressed by RV and pericardial effusion (PE).Click here for fileTransthoracic echocardiography from apical four chamber view shows enlarged right ventricle (RV) and tricuspid regurgitation (TR).Click here for fileTransthoracic echocardiography from apical four chamber view after pericardiocentesis. Right ventricle (RV), right atrium (RA), left ventricle (LV), left atrium (LA).Click here for file"}
+{"text": "Dear Sir,Communicable and nutritional eye diseases are declining in Oman while age-related and chronic eye diseases are on the rise. All stak2At present, there are three private hospitals with surgical eye care facilities in Oman. In addition, there are twelve private eye clinics with ophthalmologists, nearly 30 qualified contact lens practitioners, and 150 optical shops.[The private sector could assist national eye care services and contribute in policy making efforts within VISION 2020 initiative of Oman, in the following key areas:Refractive surgery and contact lens practice.Corneal transplant and collagen cross-linkage for keratoconus.Photo therapy and intravitreal management modalities for retinal diseases such as age-related macular degeneration and advanced cases of diabetic retinopathy.Individualized case management of rare eye conditions where multisystem care is needed.Low vision care to the adult population.Eye screening procedures in private schools for amblyopia and refractive error as per the recommendations of the National policies.Offering eye screening for driving licensing, insurance, and preemployment medical checkups.Provision of eye care through insurance and payment system to citizen of Oman, thereby reducing the workload of MOH institutions.Training Omani mid-level eye care people through collaboration with institutions of international standards.Keeping the ophthalmic fraternity knowledgeable through periodic meetings, where internationally renowned guest speakers could be invited."}
+{"text": "Habitat use may lead to variation in diversity among evolutionary lineages because habitats differ in the variety of ways they allow for species to make a living. Here, we show that structural habitats contribute to differential diversification of limb and body form in dragon lizards (Agamidae). Based on phylogenetic analysis and ancestral state reconstructions for 90 species, we find that multiple lineages have independently adopted each of four habitat use types: rock-dwelling, terrestriality, semi-arboreality and arboreality. Given these reconstructions, we fit models of evolution to species\u2019 morphological trait values and find that rock-dwelling and arboreality limit diversification relative to terrestriality and semi-arboreality. Models preferred by Akaike information criterion infer slower rates of size and shape evolution in lineages inferred to occupy rocks and trees, and model-averaged rate estimates are slowest for these habitat types. These results suggest that ground-dwelling facilitates ecomorphological differentiation and that use of trees or rocks impedes diversification. Anolis lizards , Diporiphora [size]; see In addition, our sampling of agamid species likely influenced the pattern of evolutionary rate variation we document. Our data set represents approximately one-quarter of recognized agamid species diversity, though this proportion is not uniform across the major clades. The under-sampling of species from the southwest Asian/African clade may be the most problematic with respect to our conclusions because at least two primarily terrestrial genera, Our results provide compelling evidence that habitat use shapes diversification of limb and body form in Agamidae. The pattern of variation in rates of morphological evolution suggests that terrestrial habitats promote ecological differentiation whereas diversification is slower in rocky and arboreal habitats; however, the precise mechanism by which these habitats contribute differently to diversification remains speculative. We recommend that future research investigate the extent to which functional constraints, habitat complexity or biotic interactions within habitats influence the pattern we document. For example, locomotor performance tests could be applied across a range of agamid forms to determine whether arboreal and rocky surfaces impose more stringent functional demands than terrestrial surfaces. Also, comparisons of the number of co-occurring agamid species within each habitat type could assess whether these habitats present different numbers and types of species interactions. Application of such studies to Agamidae or other animal taxa has the potential to provide further insights into how habitat contributes to differential diversification among evolutionary lineages."}
+{"text": "Biliary tract abnormalities occur in about one of every three people, usually being minor and of noclinical significance.Major abnormalities, however, may present in an unusual manner and provide amajor hazard to the unsuspecting surgeon.A patient presenting with cholangitis without jaundice or abnormal liver function tests is reported.Endoscopic retrograde cholangiography failed to demonstrate any bile ducts in the right postero-lateralsegments of the liver, the \u201cnaked segment sign\u201d. A percutaneous transhepatic cholangiogram demonstrateda stricture obstructing the right posterior segmental hepatic duct with hepatolithiasis above thestricture. At operation an anomalous vessel was found at the site of the stricture.This case highlights the unusual way in which biliary tract anomalies may present and the importanceof adequate pre-operative investigation."}
+{"text": "Biliary tact carcinoids are extremely rare: only ten cases have been reported up to now. TheAuthors describe a successfully treated carcinoid tumour ofthe proximal bile duct and review theliterature about these rare malignancies.Despite extensive preoperative work-up, including ultrasound, CT scan and ERCP, a definitediagnosis is hardly possible prior to histologic examination of the operative or necropsyspecimen.Due to the slow-growing nature and the non-aggressive behaviour of these malignancies,surgical resection followed by biliodigestive anastomosis should be the treatment of choice."}
+{"text": "Clinicopathologic correlation offive cases ofcystadenomas of the liver are reported. All patientswere female and radical surgical procedure, total excision or resection was performed four times,and partial excision once. In all patients the postoperative course was uneventful and they are allalive and well. Examined by conventional histological and special immuno-histochemical stainsthe tumors fulfilled diagnostic criteria for these rare cystic growths. The cyst wall was composedof three, histologically distinct layers. From the viewpoint of histogenesis and differentialdiagnosis immunohistochemical properties were analysed. CEA and EMA were demonstratedin epithelial cells and Vimentin in stromal cells."}
+{"text": "We read with great interest the article by Xynos et al. reporting 2 cases of leishmaniasis in patients treated with biologic drugs  infections occur more frequently than clinically apparent VL cases. An estimated 10%\u201320% of persons with asymptomatic infections develop clinically overt VL  role in detecting Leishmania infection in this vulnerable patient population. Screening for leishmaniasis has been hampered by the lack of a standard test. Currently available serologic methods have variable sensitivities, specificities, and cross-reactivities, depending on the species being tested and the region where tests are performed. Many experts believe that serologic tests may complement other existing diagnostic tools, raising cost-efficiency concerns, especially in financially deprived countries  result indicates exposure to Variations in specificities and sensitivities limit the diagnostic potential of available diagnostic tools. The context of immunosuppression further contributes to the diagnostic complications and increases the need for additional research in leishmaniasis diagnostics."}
+{"text": "Prion diseases are fatal neurodegenerative disorders caused by accumulation of abnormalprion protein . PrPres accumulation is also detected in lymphoidorgans after peripheral infection. Several studies suggest that follicular dendritic cells(FDC) could be the site of PrPres retention and amplification.            in situ and in vitro. When tonsillar cryosections were treated with anti-PrPantibody, the label was found on some very delicate cell extensions inside the lymphoid follicles,especially in the germinal centres. These extensions react with DRC1 antibody, used frequentlyto label FDC. Other structures labelled with anti-PrP antibody were the keratinocytes.Here we show that human follicular dendritic cells can express normal cellular prion protein(PrPc) both             To confirm the ability of FDC to synthesise PrPc, we isolated FDC by a non-enzymaticprocedure and cultured them. By cytochemistry and flow cytometry it was clearly shown thatFDC do produce PrPc."}
+{"text": "Stroke caused by brain ischemia is the third leading cause of adult disability. Active prevention and early treatment of stroke targeting the causes and risk factors may decrease its incidence, mortality and subsequent disability. Pien Tze Huang (PZH), a Chinese medicine formula, was found to have anti-edema, anti-inflammatory and anti-thrombotic effects that can prevent brain damage. This study aims to investigate the potential mechanisms of the preventive effects of Pien Tze Huang on brain damage caused by chronic ischemia and hypertensive stroke in rats.The effects of Pien Tze Huang on brain protein expression in spontaneously hypertensive rat (SHR) and stroke prone SHR (SHRsp) were studied with 2-D gel electrophoresis and mass spectrometric analysis with a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF)/TOF tandem mass spectrometer and on brain cell death with enzyme link immunosorbent assay (ELISA) and immunostaining.2 in the electron transfer chain of mitochondria preventing reactive oxygen species (ROS) damage and possibly subsequent cell death (caspase 3 assay) as caused by chronic ischemia or hypertensive stroke to hippocampus and cerebellum.Pien Tze Huang decreased cell death in hippocampus and cerebellum caused by chronic ischemia and hypertensive stroke. Immunostaining of caspase-3 results indicated that Pien Tze Huang prevents brain cells from apoptosis caused by ischemia. Brain protein expression results suggested that Pien Tze Huang downregulated QCRPien Tze Huang showed preventive effects on limiting the damage or injury caused by chronic ischemia and hypertensive stroke in rats. The effect of Pien Tze Huang was possibly related to prevention of cell death from apoptosis or ROS/oxidative damage in mitochondria. Cerebral ischemia and stroke are the major causes of mortality and morbidity worldwide -4. In thHypertension is the most important risk factor for ischemic stroke ,2,11 whicirca 1555 AD) in China, contains musk, Calculus Bovis , Shedan  and Panax notoginseng (Tianqi or Sanqi) and is used to treat liver diseases, cancer and inflammation Click here for fileDirected acyclic graph of proteins. Expressed proteins in cerebellum. [Note: This graph should be read from top to bottom.]Click here for fileFunctional annotation by protein information resources (RIP). 3 most frequent gene ontology in hippocampus and cerebellum.Click here for file"}
+{"text": "Myocardial MIBG scintigraphy is established in the diagnosis and differential diagnosis of Parkinson's disease (PD). Numerous studies address the pathophysiological impact of myocardial MIBG scintigraphy: the myocardial MIBG uptake correlates with the clinical phenotype of PD; the background of this phenomenon is unclear. Furthermore MIBG scintigraphy enables to study the extracranial Lewy body type-degeneration. In combination with cerebral dopamine transporter imaging, MIBG scintigraphy allows to correlate cerebral and extracranial Lewy body type-degeneration in PD. The accumulation of MIBG is visualized and measured by planar whole-body scintigraphy. In clinical practice, the MIBG scintigraphy is mainly used to detect (and sometimes to treat) neuroendocrine tumours, primarily pheochromocytomas and neuroblastomas /[counts per pixel in the upper mediastium] [The myocardial MIBG scintigraphy measures the postganglionic sympathetic cardiac innervation . In the iastium] , 18. PD iastium] \u201313. For iastium] , age, diiastium] \u201324.Coronary heart disease represents an exclusion criterion for myocardial MIBG scintigraphy, since a myocardial hypoperfusion due to coronary heart disease may influence myocardial MIBG scintigraphy. 99mTc-Metoxy-Isopropyl-Isonitril (MIBI) scintigraphy can detect a local myocardial hypoperfusion . TherefoPD is diagnosed clinically. The UK Brain Bank criteria  represenPD and Lewy body dementia (LBD) share a common pathology with a Lewy body type-degeneration of the nervous system. The anatomical distribution of this Lewy body type-degeneration\u2014in PD primarily in the basal ganglia, in LBD primarily in cortical areas\u2014decides whether the patient shows clinical symptoms of PD or LBD. Both diseases, PD and LBD, are characterized by a remarkable Lewy body type-degeneration of postganglionic myocardial sympathetic neurons. Therefore MIBG scintigraphy discloses a pathologically reduced myocardial MIBG uptake in both PD and LBD patients , 39. MyoThere exist only small data to MIBG scintigraphy in hereditary Parkinsonism (HP): Quattrone et al.  reportedIn multiple system atrophy (MSA), the autonomic nervous system is mainly affected in its preganglionic structures, whereas postganglionic involvement of the autonomic nervous system predominates in PD . FollowiOrimo et al.  reportedSmall case series disclosed contradictory findings: Nagayama et al.  observedPatients with essential tremor (ET) reveal a normal myocardial MIBG uptake, as reported by Lee et al.  in 22 ETSince myocardial MIBG scintigraphy measures the sympathetic myocardial function, it is of interest whether myocardial MIBG uptake correlates with other autonomous functions. The autonomous nervous system can be investigated by means of several clinical tests such as orthostatic reaction, deep breathing, or Valsalva manoeuvre. During these clinical tests, the blood pressure (regulated mainly by the sympathetic nervous system), the heart rate, and variability of heart rate (regulated mainly by the parasympathetic nervous system) are measured . There aMyocardial MIBG uptake correlates with motor symptoms in PD; patients with tremor dominant PD reveal a significantly higher MIBG uptake  than patPD is characterized by a cerebral as well as extracranial Lewy body type-degeneration. The cerebral\u2014predominantly nigrostriatal dopaminergic\u2014Lewy body degenerations is usually visualized by cerebral SPECT of the presynaptic dopamine transporters (DAT). As mentioned above, MIBG scintigraphy quantifies exactly the extent of extracranial myocardial sympathetic Lewy body degeneration. It is unclear whether cerebral nigrostriatal dopaminergic and extracranial sympathetic Lewy body degeneration occur independently from each other or not. \u201cExtreme\u201d cases might be possible in whom only the cerebral nigrostriatal system but not the extracranial sympathetic system degenerates or vice versa. The intraindividual comparison between cerebral nigrostriatal DAT SPECT and myocardial MIBG scintigraphy may clarify this aspect: Spiegel et al.  and SpieMyocardial MIBG scintigraphy helps to differentiate between PD and other parkinsonian syndromes in clinically difficult cases. Furthermore, the myocardial MIBG scintigraphy allows insights into the pathophysiology of PD; myocardial MIBG uptake correlates significantly with the motor phenotype and with the nigrostriatal function (measured by DAT SPECT). These facts suggest that cerebral nigrostriatal dopaminergic degeneration and myocardial sympathetic degeneration are closely coupled in PD."}
+{"text": "Prediction of optimal cytoreduction in patients with advanced epithelial ovarian caner preoperatively.Patients with advanced epithelial ovarian cancer who underwent surgery for the first time from Jan. to June 2008 at gynecologic oncology ward of TUMS  were eligible for this study. The possibility of predicting primary optimal cytoreduction considering multiple variables was evaluated. Variables were peritoneal carcinomatosis, serum CA125, ascites, pleural effusion, physical status and imaging findings.Univariate comparisons of patients underwent suboptimal cytoreduction carried out using Fisher's exact test for each of the potential predictors. The wilcoxon rank sum test was used to compare variables between patients with optimal versus suboptimal cytoreduction.41 patients met study inclusion criteria. Statistically significant association was noted between peritoneal carcinomatosis and suboptimal cytoreduction. There were no statistically significant differences between physical status, pleural effusion, imaging findings, serum CA125 and ascites of individuals with optimal cytoreduction compared to those with suboptimal cytoreduction.Because of small populations in our study the results are not reproducible in alternate populations. Only the patient who is most unlikely to undergo optimal cytoreduction should be offered neoadjuvant chemotherapy, unless her medical condition renders her unsuitable for primary surgery. Ovarian cancer is the leading cause of morbidity and mortality among the gynecologic cancers . EpithelIt is not possible to do primary optimal debulking for all patients, in these cases primary surgery not only dose not have any benefit but also causes morbidity . The 30-Primary debulking in patients with advanced epithelial ovarian cancer has been compared with chemotherapy and interval debulking in different studies. Equal survival has been reported in patients undergoing primary surgery compared to patients undergoing debulking surgery after taking chemotherapy by Onnes et al. . They haIn 1999, Shwartz et al. demonstrated that women who underwent cytoreductive surgery after induction chemotherapy had statistically improved overall survival compared to women who did not undergo surgery.One randRegarding that residual tumor is more than 1 cm in many patients underwent primary surgiery, considering another method in this group of patients seems necessary. Although neoadjuvant chemotherapy and interval cytoreduction sounds to be good management but its indications have not yet determined.A critical point in order to define indications of neoadjuvant chemotherapy for advanced ovarian cancer is determination of uniform selection criteria that can consistently identify patients with surgically unresectable disease without depriving others from potential advantage associated with an optimal primary resection. Several studies have been done for determining markers which can reliably predict optimal resectability -18. CT-SApproval to conduct this study was obtained from research organization of gynecologic oncology department of Tehran University of Medical Sciences(TUMS). Patients with stage 3 and stage 4 epithelial ovarian cancer underwent primary surgery between Jan. to June 2008 at gynecologic oncology ward of Vali-e-Asr hospital of TUMS were eligible for entering the study.The possibility of predicting primary optimal cytoreduction considering multiple variables was assessed in this group. Variables were peritoneal carcinomatosis, serum CA125 level, ascites, pleural effusion, physical status and imaging findings.All surgeries were performed by gynecologic oncologists of TUMS. Optimal cytoreduction was defined as \u2264 1 cm residual disease. All imagings were reported by the professors of radiology of TUMS. Considered imaging parameters included: omental extention, liver involvement, peritoneal involvement and suprarenal adenopathy. Blood samples for measuring serum CA125 levels were taken at the morning.Physical statusesof patients were defined according to physical status classification of the American society of anesthesiology. In addition we considered optimal and suboptimal cytoreduction. Residual tumor less than 1 cm after surgery was considered as optimal cytoreduction.Univariate comparisons of the percentage of patients who underwent suboptimal cytoreduction carried out using Fisher's exact test for each of the potential predictors. The wilcoxon rank sum test was used to compare variables between patients with optimal versus suboptimal cytoreduction.Forty one patients from patients who were admitted at Vali-e-Asr hospital of TUMS from Jan. to June 2008 met study inclusion criteria. Demographic and clinical data are described in table Peritoneal carcinomatosis and suboptimal cytoreduction had statistically significant assosciation. There were no statistically significant differences between physical status, pleural effusion, imaging findings, CA125 serum levels and ascites in patients with optimal cytoreduction compared to those who underwent suboptimal debulking.Table Our current study identifies intraperitoneal carcinomatosis as being the only statistically significant predictor of suboptimal cytoreduction. Table There is no statistically significant difference between pleural effusions in individuals underwent optimal cytoreduction compared to those with suboptimal cytoreduction. It seems that low number of patients caused this result because the number of patients who were suboptimally cytoreduced is in confidence interval range of those who were optimally cytoreduced.The number of patients in our study is only 41. Considering small sample size of the study, proofing these results demands larger randomized study. We used imaging findings as predictive predictors of suboptimal debulking according to previous studies which had mentioned these factors have predictive value.To date, the predictive performance of clinical parameters, serum CA-125 threshold values, and radiographic imaging criteria have not demonstrated sufficient accuracy to achieve widespread applicability ,21-24.The most common criteria cited as justification for abandoning an up-front attempt at surgical cytoreduction are ascites volume greater than 1000 ml, peritoneal carcinomatosis, parenchymal liver disease, splenic metastasis or omental extension to the spleen, porta hepatitis disease, and bulky disease involving the diaphragm one of tOne of the principle difficulties in development of any reliable predictive model of surgical outcome for patients with advanced ovarian cancer is the challenge of factors in the significant impact of each institute surgeons' philosophy, effort and ability to utilize advanced surgical techniques to achieve maximal cytoreduction, in order to omit this factor, in this study all surgeries were performed by gynecologic oncology professors of TUMS.In summary, identification of risk factors for suboptimal cytoreduction in small populations such as ours is not reproducible in alternate populations. Until prospective randomized trials have demonstrated that neoadjuvant chemotherapy followed by interval cytoreduction is equivalent in terms of survival outcomes to primary optimal cytoreduction followed by chemotherapy, extreme caution should be used when applying preoperative predictors to decide between primary surgical exploration and neoadjuvant chemotherapy in the medically fit patient. Only the patient who is most unlikely to undergo optimal cytoreduction should be offered neoadjuvant chemotherapy, unless her medical condition renders her unsuitable for primary surgery.The authors declare that they have no competing interests.AM: supervised research project, carried out operations, supervised statistics. MMM: participated in operation as first aid, collect data, drafted the manuscript, and acted as corresponding author and did the revisions. MMG: carried out operations, she was head of the department. FG: carried out operations. NB: carried out operations. SA: participated in operation as first aid."}
+{"text": "Immature teeth with necrotic pulp and large periapical lesion are difficult to treat via conventional endodontic therapy. The role of materials such as calcium hydroxide and mineral trioxide aggregate in apexification is indispensable. This case report presents the successful healing and apexification with combined use of white mineral trioxide aggregate and demineralized freeze-dried bone allograft. Complete asepsis and three-dimensional obturation of the root canal system are essential for long-term endodontic success. In certain cases such as immature teeth, the absence of natural apical constriction creates a challenge. Therefore, one of the aims of endodontic treatment is to produce an apical barrier or stop, against which one can place a root canal filling material avoiding overextrusion. This technique is termed apexification.Clinicians have tried several materials to form apical barrier in the past. These include: calcium hydroxide paste, calcium hydroxide powder; mixed with different vehicles,\u20133 tricalMineral trioxide aggregate (MTA) was developed at Loma Linda University for use as a root-end filling material. MTA has 13Bio-resorbable demineralized bone matrix (DMBM) is the protein component of bone and is widely used in various clinical conditions such as periodontal defects and oral and maxillofacial bone defects. Periodontal defects grafted with demineralized bone matrix allograft showed histologic evidence of regeneration of new bone and periodontium. ConsiderThe apical matrix of some resorbable and biocompatible material is essential to control extrusion of MTA. \u201cModified matrix concept\u201d for repair of perforation utilized resorbable collagen as a matrix followed by condensation of MTA. ConsiderTherefore, present case report highlights the nonsurgical management of symptomatic tooth with blunderbuss canal and large periapical radiolucency using bio-resorbable demineralized bone matrix and MTA.A 16-year-old male patient of south Indian origin reported to the department of conservative dentistry and endodontics, PMNM Dental College and Hospital, Bagalkot, Karnataka, India, with the complain of pain in right mandibular posterior teeth since 3 weeks. Careful intraoral examination revealed sinus opening in relation to the right lower second premolar. Hard tissue examination revealed the presence of \u201cdens evaginatus\u201d and a deep pit in right mandibular second premolar . ConcernDespite the higher success rate of apical barrier formation using calcium hydroxide, long-term follow-up is essential. Problems such as failure to control infection, recurrence of infection, and cervical root fracture may occur.18 ApexifMTA has superior biocompatibility and sealing ability and is less cytotoxic than other materials currently used in pulpal therapy. The 5-mmApexification using MTA lessens the treatment time between the patient\u2019s first appointment and the final restoration. The importance of this approach lies in the expedient cleaning and shaping of the root canal, followed by apical seal with a material that favors regeneration. In addition, there is reduced potential for fracture of immature teeth with thin roots, because of immediate placement of bonded core within the root canal.In the present case, combination of calcium hydroxide and iodoform was used as intracanal medicament for 15 days to make the canal dry and free from infection. Use of calcium hydroxide for such a short term does not adversely affect the fracture resistance of the tooth.The demineralized bone matrix acts as an osteoconductive and possibly as an osteoinductive material.26 Hence,Decalcified freeze-dried bone allograft material has been extensively used in the management of extensive periodontal defects. Its use results in significant probing depth reduction, clinical attachment gain, and bone fill. Definite evidence exists that sites grafted with DFDBA heal with regeneration of periodontium.28 Follow\u2018Dens evaginatus\u2019 or \u2018evaginated odontoma\u2019 is a developmental anomaly that occurs more often in mandibular premolars; however,This case report presents a novel approach to achieve single visit apexification of the cases with open apex and large periapical lesion. Present case also stresses the early detection and treatment of \u2018dens evaginatus\u2019 which if undetected can cause undue damage."}
+{"text": "C. elegans and Drosophila), have contributed enormously to defining homology. The characteristics of specificity and memory and whether the antigen is pathogenic or nonpathogenic reveal considerable information on homology, thus deconstructing the more fundamentalist view. Senescence, cancer, and immunosuppression often associated with mammals that possess both innate and adaptive immunity also exist in invertebrates that only possess innate immunity. Strict definitions become blurred casting skepticism on the utility of creating rigid definitions of what innate and adaptive immunity are without considering overlaps.Adaptive immunity has often been considered the penultimate of immune capacities. That system is now being deconstructed to encompass less stringent rules that govern its initiation, actual effector activity, and ambivalent results. Expanding the repertoire of innate immunity found in all invertebrates has greatly facilitated the relaxation of convictions concerning what actually constitutes innate and adaptive immunity. Two animal models, incidentally not on the line of chordate evolution ( All multicellular animals (invertebrates and vertebrates) manage to keep self-integrity. Any attempt to answer questions concerning immune recognition must consider the universality of receptor-mediated responses. These may designate two forms: 1) rearranging clonally distributed antigen-specific receptors that distinguish between self and nonself according to classical Burnet hypothesis; and/or 2) pattern recognition receptors introduced by Janeway [ rearrang pattern With this in mind, we felt compelledto clarify and extend what seems to be the blurring or masking of certainimmunological characteristics of invertebrates and vertebrates \u20138. TodoAncient innate immunity-related functions like phagocytosis and cytokine production  were already developed 700 million years ago in sponges and higher aquatic invertebrates . These fundamental functions remained unaltered during phylogenesis. A major evolutionary step happened 500 million years ago when fish developed jaws accompanied by evolution of the gut associated immune system. This system was fundamental to providing the genetic material required for recombination and mutation to produce variability and diversity of proteins . This system also enabled the occurrence of a wide spectrum of antigen-presenting proteins like the major histocompatibility complex (MHC). These MHC molecules developed from a primordial molecule over 300 million years ago .A genetically colorful background is generally considered to be advantageous for species in their constant adaptation to the neighboring environment. On the other hand, for a suddenly emerging costly macroscopic function like adaptive immunity, working with clonally distributed receptors, intraspecies genetic backcrosses can make survival difficult. Therefore, in such cases, interspecies borders may help the genetic solidification of evolutionarily novel characteristics. However, drawing interspecies borders is not always easy as often seen in cases of hybridogenesis with certain invertebrate arthropods or even with vertebrate fish and amphibian species \u201312.In the case of invertebrate organisms, species survival is maintained at the population level,which is risky for individuals. Whenever a new pathogen takes its toll, theremaining individuals are spared because they are more resistant than others.Such differences are genetically encoded . HoweverEcological immunology is a young but increasing science that examines causes and consequences of changes in immune function in the context of evolution and of ecology. Millions of invertebrate species depend exclusively on using innate immunity, in contrast to the only 45 000 vertebrate species that employ an additional acquired immune system. Regardless of this major distinction, most studies of ecological immunology discuss only vertebrates. Nevertheless, insect immunity might be more specific and similar to vertebrate immunity than previously thought \u201317.An explanation to why an anticipatory immune system employing clonally distributed receptors has not developed in invertebrates may be provided by immunological ecology. Highly developed organisms tend to be large in size. Since the size of individual cells does not show significant interspecies variances, being larger means having more cells. Adaptive immunity works with a huge number of recognition molecules distributed in a clonal pattern. Therefore, only highly developed organisms can afford to run such a costly immune system; otherwise costs would always outweigh benefits. It seems that having huge and complex communities of cells not only demands a highly effective adaptive immune system, but actually provides its basic framework in order to exist , 19.Senescence and age-related research isa promising approach that discovers revolutionary data. Immunological senescence of vertebrate adaptive immunity is a process widely accepted by most immunologists. This is, however, less evident when thinking in terms of invertebrate innate immunity. However, this will likely change in the near future as there is accumulating evidence of senescence and more specifically immunological senescence in invertebrate species.Morphological features of the aging process (senescence) have been recognized for many years in invertebrates. For example, when earthworms are maintained for long periods in the laboratory, a progressive decrease in size reminiscent of degeneration and a kind of wasting syndrome occur . Congo rDrosophila melanogaster expresses increasing levels of numerous antimicrobial peptides if exposed to septic bacterial infections, but not in response to bacterial extracts [Caenorhabditis elegans ortholog of the above MRG15) in the aging process has also been demonstrated [Caenorhabditis elegans and this function seems to be evolutionarily conserved: the DAF pathway also affects aging in Drosophila melanogaster and rodents [Caenorhabditis elegans are also regulated by the TGF\u03b2-like and the p38 MAPK pathways. The requirement of the DAF-2 cascade in regulating senescence and immunity raises molecular-level linkage of these processes [During senescence, extracts . Mortalinstrated . The DAF rodents . Innate ocesses .Cancer development has often been addressed in vertebrate species especially its relation with adaptive immunity. However, invertebrates also develop tumors in response to environmental carcinogens. Studying cancer development in species possessing innate immunity alone is a very promising field of research and may highlight adaptivelike functions present in invertebrates.Mytilus edulis homologue of vertebrate ras and p53 demonstrates extreme evolutionary conservatism in active domains, including four mutational hot spots [Mya arenaria have also been reported [Mussels are vulnerable to several environmental toxicants and carcinogens. DNA sequence alignment of the ot spots . Cases oreported \u201330.Drosophila offers a unique platform for the rapid identification and characterization of tumor suppressor genes, many of which have mammalian homologues. Genomewide microarray analysis of Drosophila brain tumor caused by the disfunction of the Brat tumor suppressor gene has identified over three hundred associated genes. Sixty of these sequences show homology to existing mammalian genes involved in tumor development [wts) sequence. The wts sequence was identified by the massive overgrowth of clones homozygous for wts deletion [elopment . As in deletion , 33. Sideletion .Cotesia congregata is a wasp thatinjects its eggs into the host caterpillar Manduca sexta. However, inthis particular host-parasite relation, the presence of a third partner isnecessary for successful parasitism: a bracovirus. The C. congregata bracovirus (CcBV) is injected simultaneously with the wasp eggs. Expression ofviral genes hijacks the caterpillar's immune defense responses, which favorsthe survival and development of adult parasitoid wasps [blurring of immunological functions [For those who believein the orthodox split between innate and adaptive immunities in terms of characteristics,it is perhaps difficult to accept the existence of viruses that specifically suppressthe cellular components of innate immunity. Nevertheless, as proved by experimentaldata, innate immunity-specific immunosuppressive viruses exist. id wasps , 64. Thid wasps . In inveunctions .C. elegans and Drosophila. In contrast, the lophotrochozoan systems share some distinct differences; mollusks may havemanaged immunological defense in a special manner similar to the annelidsincluding earthworms [Numerous examples have been presented of animal immune responses that may developfollowing challenge by pathogenic organisms or nonpathogenic stimuli . Here, rthworms   [Sea urchins and seastars exhibit immune responses against grafted tissues similar to those foundin vertebrates , 50. Thed Fu/HC) , 75\u201378.Ciona intestinalis has been sequenced, it allows for the rapid identification ofearly evolutionary roots of adaptive immunity. In the hemocytes of C. intestinalis, certain adaptive-immunity homologous ESTs have been identified including vWF-like (von Willebrandfactor-like), distant homologues of type I interferon (IFN) receptors, and C6-like(complement 6-like) elements [Since the complete genome of the urochordate elements , 80. Moelements .The emergence of adaptive immunity was not a sudden event; its far-reaching evolutionary roots are currently under investigation by modern molecular biological methods. Genomewide sequence analysis of invertebrates has focused on the genes of innate immunity including complement components, Toll-like receptors, and those involved in intracellular signal transduction of immune responses. Assessment of extracellular C-type lectins, immunoglobulin domains, intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and immunoreceptor tyrosine-based activation motifs (ITAMs)  suggests that activating and inhibitory receptors have an early evolutionary origin .\u03b1\u22121, and GM-CSF. Malagoli et al.have identified a putative helical cytokine in Drosophila melanogaster by elaborate bioinformatics transcriptomeanalysis. It is very promising that transcription from this homologue isupregulated in parallel with the known antimicobial factors defensin andcecropin A1 following Gram\u2212 or Gram+ challenge [Pacifastacus leniusculus by mass spectrometry and PCR using degenerate primers. An astakine homologue has also been identified in the shrimp Penaeus monodon. In vertebrates, PK domains direct angiogenic growth. It has been demonstratedthat injections of recombinant astakine actively influencedifferentiation and growth of hemopoietic stem cells in vivo [After decades of anticipation, the ancestors of some cytokines\u2014soluble intercellular signaling moleculesthat form a complex network for the regulation of immunity\u2014have recently beenidentified. In vertebrates, helical cytokines inlude IL2, IL6, INF hallenge , 84. Si in vivo .14 unique VLR receptors [It is a notable observation that even our most distant vertebrate relatives, jawless fish, have an adaptivelike immune system. It operates by means ofclonally distributed leucine-rich repeat (LRR) receptors (similar to Toll-likereceptors) using a novel mechanism of gene rearrangement other than RAG. TheseLRR modules constitute the variable lymphocyte receptors (VLRs). Computer-assistedprediction suggests a repertoire of approximately 10ceptors \u201389. In rceptors . Recent ceptors .blurring and the strict distinction between innate and adaptive immunitiesmight need revision  . Consequrevision ."}
+{"text": "Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Klebsiella pneumonae. The activity data show the metal complexes to be more active than the parent freeligands against one or more bacterial species.Biologically active complexes of Co(II), Ni(II), Cu(II) and Zn(II) with novel ONO, NNO andSNO donor pyrazinoylhydrazine-derived compounds have been prepared and characterized on the basis ofanalytical data and various physicochemical studies. Distorted octahedral structures for all the complexeshave been proposed. The synthesized ligands and their complexes have been screened for their antibacterialactivity against bacterial species"}
+{"text": "Members of the small multidrug resistance (SMR) protein family are integral membrane proteins characterized by four \u03b1-helical transmembrane strands that confer resistance to a broad range of antiseptics and lipophilic quaternary ammonium compounds (QAC) in bacteria. Due to their short length and broad substrate profile, SMR proteins are suggested to be the progenitors for larger \u03b1-helical transporters such as the major facilitator superfamily (MFS) and drug/metabolite transporter (DMT) superfamily. To explore their evolutionary association with larger multidrug transporters, an extensive bioinformatics analysis of SMR sequences (> 300 Bacteria taxa) was performed to expand upon previous evolutionary studies of the SMR protein family and its origins.groEL mutations (SUG), and paired small multidrug resistance (PSMR) using protein alignments and phylogenetic analysis. Examination of SMR subclass distribution within Bacteria and Archaea taxa identified specific Bacterial classes that uniquely encode for particular SMR subclass members. The extent of selective pressure acting upon each SMR subclass was determined by calculating the rate of synonymous to non-synonymous nucleotide substitutions using Syn-SCAN analysis. SUG and SMP subclasses are maintained under moderate selection pressure in comparison to integron and plasmid encoded SMR homologues. Conversely, PSMR sequences are maintained under lower levels of selection pressure, where one of the two PSMR pairs diverges in sequence more rapidly than the other. SMR genomic loci surveys identified potential SMR efflux substrates based on its gene association to putative operons that encode for genes regulating amino acid biogenesis and QAC-like metabolites. SMR subclass protein transmembrane domain alignments to Bacterial/Archaeal transporters (BAT), DMT, and MFS sequences supports SMR participation in multidrug transport evolution by identifying common TM domains.A thorough annotation of unidentified/putative SMR sequences was performed placing sequences into each of the three SMR protein subclass designations, namely small multidrug proteins (SMP), suppressor of Based on this study, PSMR sequences originated recently within both SUG and SMP clades through gene duplication events and it appears that SMR members may be evolving towards specific metabolite transport. Anthropogenic drug overuse combined with the rapid horizontal distribution of multidrug efflux genes encoded on mobile genetic elements has facilitated drug resistance in distant or unrelated microorganisms -3. One sgroEL mutations (SUG), and paired small multidrug resistance (PSMR) subclasses  proteins from Archaea and Firmicutes, ethidium multidrug resistance protein E (EmrE) from Proteobacteria, and plasmid and/or integron encoded Qac proteins such as QacE, QacF and QacH (as reviewed by [Escherichia coli EmrE (Eco-EmrE) serve as the paradigm for all SMR members.The SMR protein family can be subdivided into three subclasses namely, small multidrug proteins (SMP), suppressor of iewed by ,12). Theiewed by ). ProteigroEL mutation phenotypes [qacC' [smr-2 [E. coli SugE (Eco-SugE) and Citrobacter freundii (Cfr-SugE) [SUG subclass members were initially identified based on their ability to suppress enotypes  and thesenotypes ,12). Memenotypes ,15. To denotypes ,17 that s [qacC'  and smr-' [smr-2 . Membersfr-SugE) ,15,20.B. subtilis YvdR/YvdS and YvaD only of the YvaD/YvaE pair [Members of the PSMR subclass are distinct from both SMP or SUG subclasses since they require co-expression of two SMR homologues to confer host resistance to QAC and toxic metabolites ,11,21-25vaE pair  which suEach SMR subclass is thought to have a similar structural architecture based on hydropathy plot analysis and predicts that all SMR homologues adopt four TM strands connected by short loops of varying hydrophilicity ,28. One The short length and limited number of TM strands that comprise the SMR protein family have led to the proposal that they are the evolutionary building blocks of larger \u03b1-helical multidrug efflux proteins -31. AlthThe objective of this work is to explore the evolutionary origins of the SMR protein family by examining SMR diversity among Archaeal and Bacterial genomes. The specific goal is to gain insight into the evolutionary constraints exerted upon SMR subclass members to validate the notion that SMR proteins acted or are acting as the evolutionary starting points for larger transporters. We began these studies by surveying SMR sequences within Archaea and Bacteria from diverse taxonomic backgrounds using current genomic and plasmid sequence databases (as of March 2008). This effort identified 685 SMR amino acid sequences which were aligned to putatively classify SMR sequences into the three SMR protein subclasses. The evolutionary relatedness of assigned SMR protein sequences was refined by using phylogenetic analysis and assisted with SMR homologue classification. The degree of amino acid conservation and the selective pressures exerted upon selected taxonomic SMR representatives was determined by their rate of synonymous to non-synonymous nucleotide substitutions. Finally, the genomic loci of SMR homologues were surveyed within the currently sequenced Archaeal and Bacterial genomes to explore their functional association to metabolite transport and their affiliation with transposon and integron mediated inheritance among diverse microorganisms. The results from this bioinformatics exploration support the current models that SMR protein sequences act as genetic building blocks for much larger multidrug efflux proteins based on their diversity and rapid evolution.subtilis and E. coli as seed sequences. In total, 685 putative SMR protein sequences were retrieved from Archaea and Bacteria and a summary of their subclass distribution is presented in Table To understand and explore the extent of SMR subclass distribution and diversity, we surveyed the NCBI sequence database for chromosomally encoded SMR sequences among Archaea and Bacteria using characterised SMR homologues from B. -3). All three Crenarchaeal SMR sequences  served as outgroups for subsequent phylogenetic analysis and will not be discussed further.The results from Archaeal genome surveys identified that SMR sequences are present within Euryarchaeal sub-phylum genomes Table . The lacB. subtilis YvaE (Bsu-YvaE). The presence of Methanomicrobia yvaE homologues could suggest that YvaE potentially represents a PSMR progenitor. This observation is supported upon closer examination of their genomic loci, where all of the Euryarchaeal yvaE homologues lacked the presence of yvaD a poorly conserved SMR that is commonly located in the same putative operon among Bacillus species [Overall, SMR homologues we identified from surveyed Euryarchaeal genomes belonged to SUG, SMP, and the PSMR (only YvaE) subclasses only Table . All Eur species .As expected from the wealth of bacterial genomic sequences available, SMR diversity among bacterial species far outnumbered Archaea Table . SurveysThe SUG subclass prevailed over all other subclasses in Bacteria since SUG homologues were found in nearly every class we examined Table . The preXanthomonas [Vibrio [SMP subclass sequences were identified within the genomes of particular Bacterial classes namely, Cyanobacteria, Chloroflexi, as well as \u03b1-, \u03b2- and \u03b3-proteobacteria Table . Unlike thomonas  or Vibri [Vibrio -36 that yvaD in Bacilli and Lactobacilli only suggests that yvaD may be a rapidly diverging yvaE gene duplication product within Bacilli and Lactobacilli.PSMR subclass members have the most specific sequence distribution among the sequenced Bacterial genomes we surveyed strongly suggesting they are maintained under selective pressures different from either the SUG or SMP subclasses Table . ParticuTaken together, the unique distribution pattern of SUG, SMP and PSMR subclass members strongly supports SMR diversification that is tailored to particular genera.To explore the evolutionary relationships of SMR protein family members further, we analyzed a taxonomically diverse set of 338 SMR protein sequences. Previous phylogenetic analyses of SMR amino acid sequences using smaller taxonomic data sets ,12,26,37Our phylogenetic analysis demonstrated a division of SMR members into two major clades Figure , namely Since the greatest number of SMR homologues we identified are from Actinobacteria, Bacilli, and various Proteobacteria, it is not surprising that the phylogenetic groupings of SMR homologues within our dendrogram are strongly dominated by these Bacterial classes Figure . PreviouSimilar to the observations made from SMR sequence surveys Table , a trendPSMR subclass homologues grouped in distinct branches to either the SUG or SMP clades Figure . YvaD hoE. coli and B. subtilis, were selected for pairwise comparison to their respective putative homologues from Bacterial and Euryarchaeal class in our survey. Integron and plasmid encoded SMR homologues were included in this analysis to determine the extent of nucleotide changes within chromosomally encoded SMR sequences compared to the rate of divergence from their horizontally transferred counterparts. This comparison also served as a method to gauge differences that arise from the codon bias within the various host genomes.Since SMR subclass distribution is enriched within particular Bacteria, we wanted to compare the frequency of synonymous to non-synonymous changes occurring within SMR sequences at the nucleotide level. Examining the degree of nucleotide changes throughout the whole SMR sequence relative to the rate of change at each codon can identify regions of the protein that are actively evolving. Experimentally examined SMR sequences, specifically SMR homologues from The rate of synonymous to non-synonymous changes (dS/dN) in nucleotide sequences of SMP subclass homologues selected from various Euryarchaeal and Bacterial genera resulted in a mean value of 3.6 Table .Individual dS/dN values from pairwise SMP sequence comparisons indicated that the rate of synonymous and non-synonymous changes range from 1\u20136 among examined chromosomal SMP sequences Table . These vHalorubrum lacusprofundi sugE (Hla-sugE) sequence relative to the values of Eco-sugE  compared to other PSMR members, reflecting its frequent diverse distribution in the genomes of both Archaea and Bacteria. Although the rate of synonymous to non-synonymous changes among comparisons of Bsu-yvaE to other yvaE homologues are in many cases indeterminable due to pS values exceeding the Jukes-Cantor threshold limits, those that could be calculated resulted in high overall dS/dN values  suggesting that it is maintained under the least amount of selective pressure among all the PSMR members we examined.Members of the PSMR subclass appear to have very different selective constraints placed upon their sequences as reflected by the variable mean dS/dN values for each PSMR homologue in comparison to either SMP or SUG subclasses Table . B. subt to date ,22,25,26dN value .16 compaebrA/ebrB have a slightly lower mean dS/dN value (2.84) than the mean dS/dN values of yvaE, SMP, and SUG homologues , but not when compared to integron encoded Qac homologues   than its counterpart ydgF (0.3\u20130.6) indicating that only ydgE is actively maintained. This trend is in good agreement with observations made by three dimensional cryo-electron microscopic structural studies of Eco-EmrE protein that support an asymmetrical arrangement of each protein monomer [E. coli has revealed its involvement in spermidine excretion and confirmed that only YdgE (MdtI) was essential for transport activity based on site-directed mutagenesis experiments of each active site Glu14 residue in the pair [ydgF and ydgE homologues to plasmid and integron encoded SMR homologues indicated that only ydgE members were maintained at similarly high levels.YdgE/YdgF homologues demonstrated a much lower mean dS/dN value (1.84) suggesting that these homologues are under far less selective pressure than the SMP or SUG members surveyed  and yvdR/yvdS (2.0), revealed that each pair is maintained under moderately high selective pressures in comparison to all other PSMR members  selective pressures on both pairs. Active maintenance of both homologues in the pair may reflect functional interdependency. More importantly, only ykkC demonstrated high dS/dN values when compared to plasmid/integron encoded SUG homologues suggesting that ykkC has closer association to horizontally transferred SUG counterparts. This contrasts our phylogenetic analysis of these sequences which suggest YkkD has greater evolutionary relationships to plasmid and integron encoded SUG homologues  values were also calculated at each codon position in the SMR nucleotide alignment using Syn-SCAN analysis to determine the selective pressures exerted on each residue of the protein. Sd values were determined from pairwise comparisons of selected members (10\u201320 species/SMR subclass) and then averaged to generate the mean Sd at each codon. A summary of both analyses are shown in Figures Both SUG and SMP subclasses demonstrated a unique amino acid consensus in addition to the core SMR motif previously reported  Figures and 3A. A striking feature within each panel of Figures Periodic \u03b1-helix conservation is also maintained in many PSMR subclass consensus maps but distinctly varies from TM strand to TM strand, where the least TM conservation is observed in the last strand TM4) Figures , and 4.  Figures Amino acid sequence alignments for the PSMR subclass members EbrA and EbrB were difficult to distinguish from each other since they both had similar residue conservation patterns, especially when Actinobacterial EbrA and EbrB homologues were examined. The inability to reliably separate EbrA/EbrB homologues from each other forced an initial comparison of these PSMR members altogether. High amino acid conservation is observed for EbrA/EbrB homologues within the loop and C-terminus regions of the protein Figure . ConservDespite having a distinct amino acid consensus motif from SMP and SUG, YvaE demonstrated a similarly strong periodic amino acid conservation pattern, particularly within predicted loop and turn regions. As expected, YvaD homologues show low overall amino acid conservation throughout the entire protein with the exception of the three to four moderately conserved residues at the ends of the last two TM strands towards the C-terminus. This clearly indicates that YvaD has diverged dramatically from other PSMR members. An important feature of YvaD homologues to consider is loss of the highly conserved residue E14 (according to Eco-EmrE); yet conserved residues within the C-terminal residues are only partially maintained. These infrequently conserved residues are shared with both YvaE and SMP subclass members strongly supporting the idea that YvaD likely originated from YvaE but is maintained under very little selective pressure within the hosts.Examination of mean Sd values at each codon position within all SMR nucleotides demonstrated strong agreement to its corresponding amino acid consensus value within predicted loop and TM regions Figures , and 4. The mean Sd values observed for both SUG and SMP subclass sequences show a similar \u03b1-helical periodicity pattern to conserved amino acid residue positions strongly validating the observation that specific TM \u03b1-helix faces are highly conserved. However, it should be noted that there are also occasional amino acid positions in each SMR subclass consensus where codons corresponding to loop or TM strand regions have high mean Sd values but very low amino acid consensus value and vice versa. For example, numerous positions in TM4 of the SUG consensus map have high mean Sd values but low values for its conserved amino acid at the same position Figure . ConversA. nicotinovorans plasmid pAO1 encoding NepA and NepB have specifically demonstrated efflux of potentially toxic metabolites such as spermidine and nicotine intermediates, respectively [Experiments implicating SMR protein involvement in toxic metabolite transport suggest broader roles for this family of proteins during host metabolite regulation. Although members of the SMR protein family are known for conferring multidrug resistance to its host organism, very little is known about potential 'natural' substrates. PSMR members Eco-YdgE and Eco-YdgF and ectively ,11. In aectively ,14,48 anAfter completing our SMR genomic loci survey, many trends in SMR genomic arrangement were noted. The first common characteristic identified from these surveys was detection of horizontal gene transfer genes that encoded for integrases, transposons, insertion sequences (IS), plasmid maintenance genes, and bacteriophage replication and coat proteins downstream or upstream from the SMR sequence (within our 10 ORF radius cut-off), strengthening our arguments for horizontal SMR inheritance as shown in the phylogram Table . Mobile The second characteristic we observed upon examining SMR genomic loci was frequency of SMR subclass co-occurrence to various metabolite biosynthetic genes Table . In geneydgE/ydgF and ykkC/ykkD, were shown to frequently overlap (95%\u201398% surveyed respectively) in all proteobacterial genomic loci we surveyed. This contrasted the PSMR homologues ebrA/ebrB that did not frequently overlap and were often separated by other ORFs within their putative operons. In our survey EbrA/EbrB homologues were also found to correspond to a single gene only within species from Actinobacteria (32%), Clostridia (14%), Cyanophyceae (13%), Chloroflexi (25%) and Planctomycetacia (33%). This observation is similar to the situation we described for yvaE and yvaD pairing suggesting that some isogenic ebrA/ebrB homologues may possess functional activity alone or frequently undergo losses of either pair.The last final characteristic observed from the surveys of genomic loci showed that PSMR homologues had characteristic arrangements in gene pair at the locus. This observation may reflect their potential to act as predecessors of much larger transporters. To clarify this statement, the PSMR gene pairs, It is important to mention again that these surveys in no way prove the functional activities of the various SMR subclasses, but identify potential substrates or activities that could and should be examined experimentally. It also reaffirms that the distribution of particular SMR subclasses are focusing in on specific Archaeal and Bacterial groups, in addition to their shared proximity with other organisms enabling SMR mobile genetic element exchange.et al. 2001 was shown from alignments of SMR TM domains to portions of DME and BAT family proteins in either the N- or C-terminus region of the protein. According to these alignments SMR proteins shared the greatest amount of sequence identity to the C-terminus regions of BAT or DME families [SMR proteins are one of the 14 families that encompass the DMT superfamily  and inclfamilies . Hence, E. coli and B. subtilis homologues) in both heterogeneous (e.g. Eco-EmrE to Eco-SugE) and homogenous (Eco-EmrE to Eco-EmrE) protein combinations to serve as seed sequences for phi-BLAST analyses of genomic databases. These searches identified numerous TM domain regions within SMR fusions that had similarity to various DMT superfamily members in addition to members of MFS  but not E. coli YdgE-YdgF (10%) alignment to DMT superfamily member RarD  and Escherichia coli  [-4 and served as the cut-off value for positive SMR identification. The 685 putative SMR protein sequences were aligned using ClustalW [SMR sequences used for this study were obtained from NCBI genomic blast surveys (tBLASTn and BLASTp) using SMR sequences functionally characterized for transport activity ,22,26,58_416117) . As a reClustalW ,61 and TClustalW  . SMR suSMR proteins alignments to BAT, DMT and MFS transporters were performed using ClustalW and manual alignment using the editing program GeneDoc (v 2.5.010 ). BAT, DemrE codon 3 (W3) to codon 107 (L107). The distribution of point mutations from SMR sequences was examined spanning a 300 bp region which included nucleotides that encoded each of the four predicted transmembrane strands as well as loop/turn regions and truncated poorly conserved codons from the encoded N- and C-termini. For yvdR/yvdS and ebrA/ebrB sequences, poor alignment of three codons within the region encoding the first putative loop1 had to be removed. The rate of synonymous to non-synonymous changes (dS/dN) was determined using the online Syn-SCAN program website [SMR nucleotide sequences used for Syn-SCAN analysis  were sel website -69 and t-3 and each sequence produced highly similar tree arrangements and bootstrap values (data not shown). Therefore, Archaeoglobus fulgidus QacE sequence was selected arbitrarily as the outgroup for the final tree. The results of these analyses are presented in Figure To examine the evolutionary relatedness of the all SMR subclass members assigned from the original 685 SMR protein alignment, a smaller alignment of 338 SMR protein sequences was prepared to adequately represent the taxonomic diversity of sequence origin ; TM: (transmembrane); QAC: (quaternary ammonium compounds).The following abbreviations used in the manuscript are listed here in alphabetical order: BAT: ; DME: (drug metabolite exporter); DMT: (drug metabolite transporter); dS/dN: (rate of synonymous to non-synonymous mutations); MFS: (Major facilitator superfamily); PSMR: ; Sd: (number of synonymous nucleotide substitutions); SMP: ; SMR: ; SUG:  are listed beside their respective nodes above 59%. Plasmid and integron encoded SMR proteins are underlined. SMR sequence accession numbers are indicated adjacent to its genus and species name.Click here for fileSummary of synonymous to non-synonymous nucleotide substitution patterns within PSMR subclass members.Click here for fileAn alignment of 338 SMR protein sequences identified from BLAST surveys of completed Archaeal and Bacterial genomes. The 338 SMR protein sequence alignment was truncated from a larger alignment of 685 SMR sequences that was generated using a manually edited ClustalW alignment. It is important to note that this alignment may contain truncated versions of some SMR sequences.Click here for file"}
+{"text": "A case of 49-year-old woman with a retroperitoneal undifferentiated foregut cyst attachedto the right adrenal gland is reported. The bronchogenic cyst is a type of foregut cyst witha cartilage component, but in this case the multicystic tumor lacked both cartilage andgland. It is quite rare among retroperitoneal tumors and has not been reported so far tohave malignant potential. The preoperative diagnosis was an adrenal benign incidentaloma, and the patient successfully underwent laparoscopic resection of the cystic tumor togetherwith the right adrenal gland by lateral transabdominal approach. Laparoscopic surgery for a retroperitoneal tumor is problematic, however, since benignancy cannot be predicted. In laparoscopic adrenalectomy for non-functioning adrenal tumor, therefore, a differential diagnosis from retroperitoneal tumor should be given serious consideration."}
+{"text": "Aiming to discern the mechanisms by which circulatingglycated albumin alters the glomerular filtration propertiesthat lead to glomerular dysfunction in diabetes, the authorsstudied the distribution and densities of anionic chargesthrough the rat glomerular wall upon intravascular infusionof Amadori products, as well as in various conditions ofincreased glomerular permselectivity. Polylysine-gold wasused as the probe to reveal the anionic charges. The studywas carried on renal tissue sections of bovine serum albumin(BSA)- and glycated BSA\u2013injected, normoglycemicanimals. Results were generated through morphometricalevaluations of the gold labeling. Changes in glomerular anionicdistribution were corroborated on renal tissue sectionsof short- and long-term diabetic rats and of normal newbornrats, situations known for abnormal glomerular filtration.Altered renal function in these conditions was clearlyassociated with changes in glomerular anionic charges. Onthe other hand, the infusion of glycated albumin in the circulationof normal rats, though altering glomerular filtrationproperties, did not modify the distribution and density ofthe polylysine-gold labeling through the glomerular basementmembrane. Thus, anionic charges seem not to be thefactor involved in the early changes of glomerular permeabilityinduced by circulating glycated albumin."}
+{"text": "More optimistic perceptions of cardiovascular disease risk are associated with substantively lower rates of cardiovascular death among men. It remains unknown whether this association represents causality (i.e. perception leads to actions/conditions that influence cardiovascular disease occurrence) or residual confounding by unmeasured factors that associate with risk perceptions and with physiological processes that promote cardiovascular disease .To evaluate whether previously unmeasured biological markers of inflammation or endothelial dysregulation confound the observed association between cardiovascular disease risk perceptions and cardiovascular disease outcomes;We conducted a nested case-cohort study among community-dwelling men from Southeastern New England (USA) who were interviewed between 1989 and 1990 as part of the Pawtucket Heart Health Program. We measured C-reactive protein (CRP) and Vascular Endothelial Growth Factor (VEGF) levels from stored sera for a random sample of the parent cohort  and all cases of cardiovascular death observed through 2005 . We evaluated potential confounding using stratified analyses and logistic regression modeling.Optimistic ratings of risk associated with lower odds of dying from cardiovascular causes among men . Neither CRP nor VEGF confounded these findings.The strong cardio-protective association between optimistic ratings of cardiovascular disease risk and lower rates of cardiovascular mortality among men is not confounded by baseline biomarkers of systemic inflammation or endothelial dysfunction. Risk perceptions are plausibly influenced by psychological conditions  that influence inflammatory status and endothelial reactivity. Since biomarkers of systemic inflammation (C-reactive protein) and endothelial dysregulation  also predict CVD events [Considering plausible causal mechanisms D events -16, thesD events .We conducted a case-cohort study nested within a community-based sample of men from southeastern New England (USA). A case-cohort study is an efficient epidemiologic design similar to a case-control study, except that the control group is chosen without regard to the outcome (i.e. a random sample of the base population), thus allowing comparison to multiple \"case\" groups . This strategy averts the time and financial cost of analyzing frozen sera from a full cohort.All participants completed household interviews between 1990 and 1993. Serum samples were obtained during household interviews and frozen per standard protocol. Death record information was obtained from the National Death Index through December 2005 to identify cases. In depth description of this nested case-cohort study  and the All participants were enrolled during the post-intervention period of the Pawtucket Heart Health Program (PHHP), a controlled community intervention designed to lower prevalence of CVD risk factors . One thoParticipants were asked at the beginning of the household interview, \"Compared with persons of your own age and sex, how would you rate your risk of having a heart attack or stroke within the next 5 years?\" Participants rated their CVD risk as \"high\", \"average\", \"low\", or \"don't know\". Endorsing one's risk to be lower than average we refer to as an optimistic rating.We obtained the date of death and underlying cause of death by linking personal identifiers  for each participant to the Center for Disease Control National Death Index (NDI) for the years 1990-2005. Linkage and cause of death were established using NDI-standardized protocols. Cases were those participants whose primary or contributing cause of death was due to cardiovascular disease, as defined by International Classification of Disease (ICD) codes for coronary heart disease or stroke .Using thawed sera, the concentrations of CRP and VEGF were measured using immunoturbidimetric and ELISA assays, respectively. Prior epidemiologic research has verified the validity of these samples and measurement procedures .st degree family history of early-onset coronary heart disease, current use of lipid or blood pressure lowering medications, current aspirin use, physical inactivity, alcohol, and psychotropic medications.We considered the following as potential confounders or effect measure modifiers of the association between comparably optimistic self-rated CVD risk and CVD mortality: CRP, VEGF, age, race/ethnicity, income, education, foreign birth, city, Framingham Risk Score, total/HDL cholesterol ratio, hypertension, smoking status, body mass index, 1We evaluated the frequency and distribution of key study variables. For univariate comparisons shown in Table Since more elaborate adjustment for potential social, biologic and behavioral confounders  for all statistical analyses. Where p-values are reported, we used a statistical significance threshold of 0.05.The institutional research review boards at Memorial Hospital of Rhode Island and the University of Rochester School of Medicine and Dentistry approved this study.i.e. optimistic ratings). Forty-four participants died of cardiovascular causes during the 15-year surveillance period. Higher levels of CRP and VEGF were associated with higher risk of CVD mortality  and CRP  for comparative optimists compared to others were small and statistically insignificant.Thirty one percent of the participants endorsed their risk of having a cardiovascular event in the next five years as lower than average for their age and sex . Adjusting for CRP alone, VEGF alone, or in combination with age, income and Framingham Risk Score did not substantially change these findings [see Table i.e. inflammation and endothelial dysregulation) would confound these provocative observations. We observed that controlling for baseline CRP and VEGF did not weaken the protective association between optimistic ratings of CVD risk and CVD mortality.Following previous findings of an independent association between optimistic perceptions of CVD risk and substantially lower rates of CVD mortality among men, we evaluated whether biomarkers of stress  that will shape our society's understanding of cardiovascular risk.CRP: C-reactive protein; VEGF: vascular endothelial growth factor; ICD: International Classification of Disease; NDI: National Death IndexThe authors declare that they have no competing interests.All authors participated in the interpretation of these findings, contributed substantively to the writing of this manuscript and approved this submission. RG, MR, and CB participated in data collection and initial analyses. WK, LZ, and KH participated in subsequent revised analyses."}
+{"text": "The present study set out to evaluate perceptions of risk, psychological morbidity and health behaviours in women with a family history of breast cancer who have attended genetic counselling and determine how these differ from general population risk women. Data were collected from 62 genetic counselees (cases) attending the Royal Marsden and Mayday University Hospital genetic counselling services and 62 matched GP attenders (controls). Levels of general psychological morbidity were found to be similar between cases and controls; however, cases reported significantly higher breast cancer-specific distress despite clinic attendance . Although cases perceived themselves to be more susceptible to breast cancer, many women failed correctly to recall risk figures provided by the clinic; 66% could not accurately recall their own lifetime chance. Clinics appeared to have a positive impact on preventive behaviours and cases tended to engage more regularly in breast self-examination , although few differences were found between groups in terms of health beliefs. We conclude that counselees and GP controls showed considerable similarities on many of the outcome measures, and risk of breast cancer was not predictive of greater psychological morbidity; although cases were more vulnerable to cancer-specific distress. Despite genetic counselling, many cases continued to perceive their risk of breast cancer inaccurately."}
+{"text": "Previous investigators have noted that certain ovarian cancer cell lines secrete and respond to transforming growth factor-alpha , suggesting that endogenous activation of the epidermal growth factor (EGF) receptor through autocrine or paracrine mechanisms might contribute to the proliferative response. In order to determine whether autocrine stimulation was partly responsible for the proliferative response in ovarian cancer, we investigated whether the EGF receptor expressed by ovarian cancer cell lines was constitutively activated as assessed by the presence of tyrosine phosphorylation. A specific anti-phosphotyrosine antibody was used in conjunction with an immunoblotting technique in order to detect EGF receptor phosphorylation in ovarian cancer cell lines in the absence and presence of exogenous EGF. The effects of neutralising anti-EGF receptor antibody on the proliferation of ovarian cancer cell lines was also examined. We found no evidence for constitutive tyrosine phosphorylation of the p170 EGF receptor in eight epithelial ovarian cancer cell lines tested, although each line demonstrated inducible phosphorylation in response to exogenous EGF. The absence of constitutive EGF receptor activation was also noted when cells were grown under high density conditions, thus excluding a role for membrane-bound EGF or TGF-alpha in this process. Media conditioned by five ovarian cancer cell lines, as well as malignant ascites obtained from 12 different ovarian cancer patients, were not capable of stimulating EGF receptor phosphorylation. Finally, the proliferation of ovarian cancer cell lines was not significantly inhibited in the presence of neutralising anti-EGF receptor antibody. These data suggest that EGF receptor activation through autocrine pathways is not a major mechanism for the growth of many ovarian cancer cell lines. Other pathways of signal transduction which bypass the requirement for EGF receptor activation may be important in the proliferation for ovarian cancer cells. Such EGF receptor-independent pathways may limit the effectiveness of strategies designed to inhibit ovarian cancer cell growth through disruption of EGF receptor function."}
+{"text": "Tubularized incised plate repair is based on an old principle of urethral plate tubularization, also known as the Thiersch-Duplay procedure. Although a good concept, its main drawback was the limitation imposed by the width of the urethral plate. Snodgrass popularized the concept of urethral plate incision with subsequent tubularization and secondary dorsal healing for primary hypospadias repair. This relatively simple yet elegant and effective procedure has gained widespread acceptance, currently being recognized as the surgical technique of choice for distal and other types of hypospadias repair.\u20103 In theDecision making in hypospadias repair is no longer determined by meatal location, as in the past, but by severity of penile curvature and appearance of the incised urethral plate. Severe curvature, requiring plate transection or an \"unhealthy\" incised plate are uncommonly encountered.A treatment Algorithm must consider the following:Differentiation between functionally necessary and aesthetically feasible operative proceduresEstablishing therapeutic objectivesPre-operative hormonal treatmentAge at surgeryPenile curvaturePreservation of the well-vascularised urethral plateRe-do hypospadias repairsUrethral reconstructionUrine drainage and wound dressingAdolescent satisfaction with penis sizeRate of fistula formationThe second thing is the rate of fistulae. Although it is comparable to the literature, they do not favour use of a two-layer coverage and deny that Snodgrass has recommended two-layer neourethra closure to decrease fistula formation in all types of hypospadias defects. Several factors may influence fistula formation, such as surgical technique, delicate tissue handling, patient age, type of hypospadias defect, surgeon's experience, water-proof urethroplasty coverage and concomitant foreskin reconstruction.The meatal stenosis rate varies from 0 to 17%, and Snodgrass has reported meatal stenosis rates below 1%. This has been a controversial topic and considered to be possibly related to the surgical technique. In the present study, meatal stenosis was high (8.8%), with no explanation for this high rate."}
+{"text": "The presence or absence of venousinvasion did not influence lymph node metastasis. Laparoscopic surgery involving lymph nodedissection should be indicated for sm1 carcinoma lesions with unfavorable histological factors.In lesions diagnosed as sm2 or sm3 prior to resection, intestinal resection involving lymph nodedissection by laparoscopic surgery should be directly performed without endoscopic resection.We investigated the relationship between histological factors and lymph node metastasis in77 lesions with submucosally invasive colorectal carcinomas to establish useful criteria forlesions in which endoscopic treatment alone results in cure of malignancy. There were positivecorrelations between histological factors, including the level of invasion, the histologic grade,presence or absence of lymphatic invasion, presence or absence of budding, and lymph nodemetastasis  or II (moderately-differentiated), andthe absence of lymphatic invasion and budding, endoscopic treatment alone is sufficient."}
+{"text": "Major heart diseases such as ischemia and hypertrophic myocardiopathy are accompanied with significant changes in the passive mechanical properties and active contractility of myocardium. Identification of these changes helps diagnose heart diseases, monitor therapy, and design surgery. A dynamic cardiac elastography (DCE) framework is developed to assess the anisotropic viscoelastic passive properties and active contractility of myocardial tissues, based on the chamber pressure and dynamic displacement measured with cardiac imaging techniques. A dynamic adjoint method is derived to enhance the numerical efficiency and stability of DCE. Model-based simulations are conducted using a numerical left ventricle (LV) phantom with an ischemic region. The passive material parameters of normal and ischemic tissues are identified during LV rapid/reduced filling and artery contraction, and those of active contractility are quantified during isovolumetric contraction and rapid/reduced ejection. It is found that quasistatic simplification in the previous cardiac elastography studies may yield inaccurate material parameters."}
+{"text": "Experiments were conducted to determine whether the histological pattern of tumour growth of hormone-responsive MCF-7 human mammary adenocarcinoma varied in different tissues of athymic mice. Tumours in the uterus following intrauterine injection were rapidly proliferating and highly invasive. Tumours injected intracerebrally were also highly invasive. In contrast, s.c. tumours and those which arose in the lung following intrapleural injection, grew as small localized nodules without evidence of aggressive invasion of surrounding tissues. These findings indicate that selective implantation of human tumours in athymic mice can be used to develop different models of tumour growth and aggressiveness."}
+{"text": "Borna disease virus, a newly classified nonsegmented negative-strand RNA virus with international distribution, infects a broad range of warm-blooded animals from birds to primates. Infection causes movement and behavioral disturbances reminiscent of some neuropsychiatric syndromes. The virus has not been clearly linked to any human disease; however, an association between infection with the virus and selected neuropsychiatric disorders has been suggested. We reviewed recent advances in Borna disease virus research, focusing on evidence of infection in humans."}
+{"text": "DNA fingerprinting has demonstrated predominance of the Beijing genotype among Mycobacterium tuberculosis strains isolated in Southeast Asia. We prospectively examined the occurrence of Beijing genotype strains in tuberculosis patients in Indonesia. Early in treatment, patients infected with Beijing genotype strains more often had fever unrelated to disease severity, toxicity, or drug resistance, indicating that Beijing genotype strains may have specific pathogenic properties."}
+{"text": "Metabolite ratios (phosphocreatine (PCr)/beta nucleoside triphosphate (beta NTP), PCr/Pi, beta NTP/Pi) calculated from the NMR spectra were compared with ratios obtained from acid extracts of tumours of similar size. Measurements of creatine and ADP were also made. Three of the tumours showed positive correlations between increasing tumour size and decreasing metabolite ratios measured both by NMR and in extracts, whereas the Walker carcinosarcoma showed no correlation between size and any parameters measured. Phosphorus metabolite ratios, measured in extracts of skin overlying the tumours, indicated a fall in high energy phosphate when there was histological evidence of skin invasion by the tumour. Surface coil 31P-NMR spectra of subcutaneously grown or induced tumours in the rat represent a slowly changing steady state as the tumour increases in size. We conclude that increasing numbers of hypoxic tumour cells, rather than large areas of necrotic tissue, contribute largely to the NMR spectrum."}
+{"text": "Twelve mongrel dogs were randomly allocated into two groups using matched paired-design. Catheterswere inserted into the hepatic artery, hepatic vein and the femoral vein, respectively. In the first group,gelfoam supplemented with mitomycin C (MMC) was injected into the hepatic artery, whereas thesecond group received a hepatic arterial injection of MMC solution alone. Simultaneous blood samplingfrom the hepatic and femoral veins at regular intervals was performed. MMC concentrations in plasmawas determined using high performance liquid chromatography (HPLC) and the pharmacokinetics ofMMC were determined.MMC concentrations in hepatic and femoral veins did not differ and no significant difference inpharmacokinetics was found when comparing MMC administration into the hepatic artery with orwithout gelfoam supplementation. Thus, our results revealed that gelfoam could not delay the clearanceof MMC from the liver."}
+{"text": "It was demonstrated previously that mice undergoing an inflammatory reaction induced by subcutaneous (SC) implantation of copper rods, produce humoral factors that initially enhance, but subsequently inhibit, diffusion chamber (DC) granulopoiesis. This provided evidence that granulopoiesis is under the control of both humoral stimulators and inhibitors. In order to test the granulopoietic regulatory mechanism in leukaemic mice, we investigated the regulatory role of granulopoietic humoral inhibitors during in vivo granulopoiesis. We noticed that mice suffering from acute myeloid leukaemia (AML) are unable to augment the production of these humoral inhibitory factors when acute inflammation is induced, since no change in DC cell content was observed with or without prior inflammation. Moreover, unlike healthy mice, the serum of leukaemic mice withdrawn during the inhibition phase of acute inflammation did not show any inhibitory activity toward granulocyte\u2014monocyte (GM) colony growth in vitro. Our results also show that increased levels of normal humoral inhibitors do not influence the proliferation and/or differentiation of leukaemic cells implanted in diffusion chamber cultures."}
+{"text": "The major histocompatibility complex (MHC) class II is involved both in thymocyte maturationand peptide presentation and might thus play a key role in the pathogenesis of paraneoplasticmyasthenia gravis (MG) in thymomas. To further investigate this issue, we analyzedand scored the expression of epithelial class II expression in 35 thymomas  and correlatedit with the histological tumor subtype, prevalence of MG and thymocyte maturation, whichwas analyzed by flow cytometry and RT-PCR. Our results show that both MHC class IIexpression and thymocyte maturation are highly dependent on the histological tumor subtype.CT / WDTC retain features of the normal outer thymic cortex, namely substantial MHC classII expression together with normal early thymocyte maturation until late phases of positiveselection, but disturbed terminal thymopoiesis. By contrast, MDT and MXT retain features ofthe normal inner cortex and the medulla with low to absent class II expression and highlyabnormal early thymocyte maturation including impaired positive selection, while terminal Tcell maturation in MXT appeared undisturbed. There was no correlation between MHC classII expression and MG status for a given tumor subtype. In conclusion, our results provide evidencefor a different histogenesis of cortical thymomas and well differentiated carcinomas onthe one hand and mixed and medullary thymomas on the other.Decreased expression levels of MHC class II, although of crucial importance for abnormalintratumorous maturation, are not sufficient to explain the emergence of paraneoplastic MG."}
+{"text": "The total N-acetyl neuraminic acid (NANA) content of lymphocytes, erythrocytes and plasma obtained from normal and lymphatic leukaemic patients was measured by the Warren thiobarbiturate technique. Lymphocytes from patients with chronic lymphatic leukaemia and lymphoblasts from patients with acute leukaemia had decreased levels."}
+{"text": "Miniature spectrometers incorporating array detectors are becoming a viable, low-cost option for field and process deployments. The performance characteristics of one such instrument are reported and compared with those of a conventional benchtop instrument. The parameters investigated were wavelength repeatability, photometric linearity, instrumental noise (photometric precision) and instrumental drift."}
+{"text": "Background: Resection of hepatocellular carcinoma is associated with high rates of morbidity and mortality. Since intensive nutritional support can reduce the catabolic response and improve protein synthesis and liver regeneration, we performed a prospective study to investigate whether perioperative nutritional support could improve outcome in patients undergoing hepatectomy for hepatocellular carcinoma.            Methods: We studied 124 patients undergoing resection of hepatocellular carcinoma. Sixty-four patients  were randomly assigned to receive perioperative intravenous nutritional support in addition to their oral diet, and 60 patients  were randomly assigned to a control group. The perioperative nutritional therapy consisted of a solution enriched with 35 percent branched chain amino acids, dextrose, and lipid emulsion (50 percent medium-chain trigylcerides) given intravenously for 14 days perioperatively).            Results: There was a reduction in the overall postoperative morbidity rate in the perioperative-nutrition group as compared with the control group , predominantly because of fewer septic complications . There were also a reduction in the requirement for diuretic agents to control ascites , less weight loss after hepatectomy , and less deterioration of liver function as measured by the change in the rate of clearance of indocyanine green . These benefits were seen predominantly in the patients with underlying cirrhosis who underwent major hepatechtomy. There were five deaths during hospitalization in the perioperativenutrition group, and nine in the control group (P not significant).            Conclusions: Perioperative nutritional support can reduce complications after major hepatectomy for hepatocellular carcinoma associated with cirrhosis."}
+{"text": "Two proprietary semi-permanent hair dyes were tested for carcinogenicity in A and DBAf mice by repeated topical applications in aqueous acetone. Mice of both strains developed lymphoid tumours but experimental differences were marked only in DBAf mice. A number of tumours of the ovary and uterus, and some skin papillomas near the penis, occured in dye-treated but not in control DBAf mice. As many hair-dye constituents are known mutagens, adequate carcinogenicity testing of these substances, and epidemiological study of exposed human populations, are needed for evaluating possible health hazard from hair dyeing."}
+{"text": "Streptococcus pneumoniae is a major cause of acute otitis media, pneumonia, bacteremia, and meningitis. Because in recent years antibiotic-resistant pneumococcal strains have been emerging throughout the world, vaccination against pneumococcal infections has become more urgent. The capsular polysaccharide vaccine that has been available is neither immunogenic nor protective in young children and other immunocompromised patients. Several pneumococcal proteins have been proposed as candidate vaccines, but no human studies associated with them have been reported. Clinical trials of first-generation pneumococcal conjugate vaccines have shown that covalent coupling of pneumococcal capsular polysaccharides to protein carriers improves the immunogenicity of the polysaccharides. The protective efficacy of the conjugate vaccines against carriage, acute otitis media, and invasive infections is being studied."}
+{"text": "In patient tumour samples the activity in vitro of Taxol corresponded fairly well to the known clinical activity and Taxol showed low cross-resistance to standard cytotoxic drugs. However, the Taxol solvent Cremophor EL--ethanol was considerably active alone, whereas paclitaxel formulated in ethanol was less active. Taxol thus seems to contain two components active against patient tumour cells in vitro."}
+{"text": "In accordance with the suggested adenoma\u2013carcinoma sequence of the colon, four patients reflected the progressive accumulation of genetic defects in synchronously appearing tumours during carcinogenesis. However, two patients with non-hereditary malignomas presented different genetic instabilities in different but synchronously appearing tumours suggesting non-clonal growth under almost identical conditions of the environment. Thus, sporadically manifesting multiple lesions of the colon were not necessarily driven by similar genetic mechanisms. Premalignant lesions may transform into malignant tumours starting from different types of genetic instability, which indicates independent and simultaneous tumorigenesis within the same organ. \u00a9 2000 Cancer Research CampaignThe colorectal adenoma\u2013carcinoma sequence represents a well-known paradigm for the sequential development of cancer driven by the accumulation of genomic defects. Although the colorectal adenoma\u2013carcinoma sequence is well investigated, studies about tumours of different dignity co-existent in the same patient are seldom. In order to address the distribution of genetic alterations in different lesions of the same patient, we coincidently investigated carcinomas, adenomas and aberrant crypt foci in patients with sporadic colon cancer. By utilizing polymerase chain reaction, single-strand conformation polymorphism, heteroduplex-analysis, restriction fragment length polymorphism, protein truncation test and sequencing techniques we looked for mutations and microsatellite instability of APC, H-"}
+{"text": "Human ovarian carcinoma cells obtained from ascites were tested for susceptibility to lysis by peripheral blood NK cells, alpha-interferon-activated NK cells, and interleukin 2-activated killer cells. Cryopreserved tumour cell preparations were used to allow repeated testing of the same target, and the tumour cells were fractionated using albumin density gradients to determine if fractions containing clonogenic (stem) cells were killed. Four tumour cell donors were studied and each showed a different pattern of susceptibility of unfractionated tumour to lysis by different effector cells. Using fractionated tumour cells, we found that NK and interferon-activated NK cells did not always lyse cells in the clonogenic fractions and that interferon activation could in some cases shift killing away from the clonogenic fractions and towards the peak of proliferating (but not self-renewing) colony forming cells. Interleukin 2-activated killer cells (LAK) however, killed the fractions containing clonogenic cells in all 4 cases. The magnitude of killing seen when fractions of the original tumour were tested were often striking when compared to lysis of the unfractionated cells. Apparent heterogeneity between patients and stem cell susceptibility to effector cells may be important determinants of the efficacy of treatment of patients with biologic response modifiers such as interferon and interleukin 2."}
+{"text": "Damage of laryngeal mask airway and other supraglottic airway devices has always been a matter of concern. Although manufacturer recommends maximum 40 uses of LMA (and its congeners) but damage before 40 uses needs to be evaluated. We hereby, describe a novel method of repair of supraglottic devices when damage occurs at mask inflation line or pilot balloon valve assembly. Various supraglottic airway devices like laryngeal mask airway (LMA), Proseal LMA, laryngeal tube etc. are novel innovative devices for upper airway management.Laryngeal mask airway and its variants are most often used in elective surgical procedures, emergency difficult airway management and in fields or camp surgeries. The currently manufactured model is made of silicone rubber and needs special care for its longitivity . The devBiting of airway tube or LMA damage often occurs at cuff portion or airway tube shaft. The junction where airway tube is attached to the cuff may break while inserting laryngeal cuff in oral cavity and this may cause an irreparable loss of the equipment. The mask inflation line or valve assembly of supraglottic airway devices like LMA (and its congeners ) etc. can also damage while handling, washing or cleaning of expensive equipment. We hereby, recommend novel indigenous method of securing various supraglottic airways when damaged at mask inflation line or valve assembly.LMA and its variants contain mainly 4 parts- cuff, connector, airway tube and mask inflation line  to the mask inflation line.The steps of repairing the supraglottic devices (LMA or its congeners) are as follows:1. Expose and clear the damaged part of pilot balloon assembly Fig. 2. Attach mask inflation line  to 'Threeway Stopcock and closed leur access split septum port' assembly by inserting inflation line (teared end) inside End A of Threeway stopcock)Fig. .3. End B of Threeway stopcock is attached to closed leur access split septum port4. Completely repaired LMA assembly is ready  in 1981, it has been successfully used as a ventilatory device in both predicted and unpredicted difficult airway. In certain situations, such as cardiac arrest, there is no time to predict and/or act on the prediction of a difficult airway and supraglottic airway devices act as rescue airway management devices . The othDuring training period of residents, the probability of tearing of mask inflation line of any supraglottic devices is very high and consequently it leads to irrepairable loss of equipment. Further, the mask inflation line may get damaged during extubation phase and this can occur most often in patients with surgeries in psychiatric patients. In situations like cardiac arrest or unanticipated difficult airway if SAD is damaged from inflation line or valve assembly then it may create panic in anaesthesiologist's mind.The present supraglottic equipment repairing technique is a novel indigenous method and can be useful for anaesthesiologists working in developing countries and working in fields/camps. This repairing can also be utilized in cases of patients with trauma and in emergency airway management when LMA or such expansive equipments may damage. This indigenous method can be applicable to expansive equipments like LMA proseal, LMA C-trach, Laryngeal Tube, Laryngeal Tube Suction, ILMA, ETT of ILMA etc. and the cost-effectiveness of equipment can be maintained by this simple, cheap and easier repair technique."}
+{"text": "Multiple sclerosis (MS) is a central nervous system disease in which activated            autoreactive T-cells invade the blood brain barrier and initiate an inflammatory            response that leads to myelin destruction and axonal loss. The etiology of MS, as            well as the mechanisms associated with its unexpected onset, the unpredictable            clinical course spanning decades, and the different rates of progression leading            to disability over time, remains an enigma. We have applied gene expression            microarrays technology in peripheral blood mononuclear cells (PBMC) to better            understand MS pathogenesis and better target treatment approaches. A signature            of 535 genes were found to distinguish immunomodulatory treatment effects            between 13 treated and 13 untreated MS patients. In addition, the expression             pattern of 1109 gene transcripts that were previously reported to significantly             differentiate between MS patients and healthy subjects were further analyzed to              study the effect of cytokine-related pathways on disease pathogenesis. When              relative gene expression for 26 MS patients was compared to 18 healthy controls,              30 genes related to various cytokine-associated pathways were identified. These              genes belong to a variety of families such as interleukins, small inducible cytokine              subfamily and tumor necrosis factor ligand and receptor. Further analysis disclosed              seven cytokine-associated genes within the immunomodulatory treatment              signature, and two cytokine-associated genes SCYA4               and FCAR  that were common to both the MS gene              expression signature and the immunomodulatory treatment gene expression              signature. Our results indicate that cytokine-associated genes are involved in various            pathogenic pathways in MS and also related to immunomodulatory treatment effects."}
+{"text": "Most lumbar artificial discs are still composed of stainless steel alloys, which prevents adequate postoperative diagnostic imaging of the operated region when using magnetic resonance imaging (MRI). Thus patients with postoperative radicular symptoms or claudication after stainless steel implants often require alternative diagnostic procedures.Possible complications of lumbar total disc replacement (TDR) are reviewed from the available literature and imaging recommendations given with regard to implant type. Two illustrative cases are presented in figures.Access-related complications, infections, implant wear, loosening or fracture, polyethylene inlay dislodgement, facet joint hypertrophy, central stenosis, and ankylosis of the operated segment can be visualised both in titanium and stainless steel implants, but require different imaging modalities due to magnetic artifacts in MRI.Alternative radiographic procedures should be considered when evaluating patients following TDR. Postoperative complications following lumbar TDR including spinal stenosis causing radiculopathy and implant loosening can be visualised by myelography and radionucleotide techniques as an adjunct to plain film radiographs. Even in the presence of massive stainless steel TDR implants lumbar radicular stenosis and implant loosening can be visualised if myelography and radionuclide techniques are applied. Total disc replacement (TDR) is an evolving surgical option for patients with degenerative disc disease ,2. The aIt is widely accepted that lumbar disc arthroplasty is associated with several access- and implant-associated complications. Unfortunately imaging modalities after TDR cannot simply be transferred from fusion patients. In this review the complications following total disc replacement are discussed and guidelines for imaging following lumbar disc arthroplasty are provided.All commercially available lumbar artifical discs are composed of a stainless steel core with titanium surfacing Table . This haMyelography alone and later combined with CT has for many years been the primary diagnostic means in suspected lumbar spinal stenosis. Myelographic findings in central canal stenosis include complete or partial block to the contrast column, appearing as an hour-glass constriction on the AP view. There appears to be poor correlation between clinical symptoms and findings at myelography, with myelography commonly showing more abnormalities than would be expected ,7, althoScintigraphy with 99mTc radionuclide tagged white blood cells can be a helpful means in diagnosing suspicious infections . 99mTc-HPostoperative low-grade-infection or implant loosening can be hard to visualise. As in hip or knee arthroplasty radionuclide scintigraphy has some value with regard to sensitivity, but has lower specificity with regard to loosening or low-grade infection. Gallium 67 scans have a sensitivity and specificity of 89% and 85% .In the last years the increased availability of positron emission tomography (PET) enabled postoperative diagnostics with greater specificity for infection. Gratz et al  found flDespite the biomechanically appealing concept of motion preservation, lumbar disc arthroplasty is associated with access-related and implant-specific complications. Access and implant related complications can be due to technical errors or may be due to abnormal anatomy . ImplantAll commercially available FDA-approved lumbar total disc replacements require an anterior access for the implantation of artificial discs. Lumbar discs can be implanted via a transperitoneal or a retroperitoneal approach, of which the latter is favoured by most surgeons. Complications with regard to these accesses are well known and differ not from those of anterior fusion, even though TDR-implantation requires a wider exposure of the disc, which often requires more traction and pressure of retractors on the surrounding tissue . EspeciaMost access-related complications can be visualised by sonography and abdominal CT with intravenous contrast. In few cases an angiography or an uretherography may be necessary.There is no specific data on the occurrence of infection of artificial discs, but early and mid-term infections may occur as likely as in anterior fusion with 0 and 12% in lumbar instrumented fusion . NeverthPostoperative infections of the spine can optimally be visualised by MR with contrast. A sensitivity and specificity of 93% and 97% makes the MRI superior to all other radiological imaging modalities . If MRI-Daly et al presented a case series of five anterior dislocations of the Charit\u00e9 (Link) or the AcroDisc (DePuy) disc prosthesis causing compression and erosion of vascular structures. In figure Mobile polyethylene cores can dislocate, too, and can cause compression to anterior abdominal or pelvic structures. This is especially true in non-constrained PE inlays (i.e. Charit\u00e9 TDR) Mathew et al  presenteImplant dislocation can easily be diagnosed with plain radiographs figure . This isThe long-term investigation of the first implanted lumbar discs  by Putzier et al  includedImplant fractures are mostly visible on plain radiographs.Since implant wear has for decades been a major issue in hip and knee-arthroplasty it is not surprising that other weight-bearing implants with articulating surfaces \u2013 as in lumbar disc prostheses \u2013 will have to deal with implant wear and loosening, too. Punt et al  retrieveMetal-metal articulations are known to cause metallosis with chronic inflammation leading to implant loosening . Fran\u00e7oiDiagnostics of implant loosening range from standard plain radiographs \u2013 revealing radiolucencies around the implant \u2013 to scintigraphy and PET, showing increased metabolism in the bone-implant interface.The case in figure MR diagnostics are the gold-standard for investigation of spinal canal pathologies. In cases where this is not possible \u2013 i.e. stainless steel TDR \u2013 other modalities as CT and myelography have to be considered.Bendo et al  found thTo control implant positioning plain radiographs are usually sufficient.Long-term investigations failed to present preservation of motion of the operated segment. Putzier et al  found thTo diagnose fusion either a CT-scan showing ankylosis or dynamic radiographs excluding remaining segmental mobility are required.In osteoporosis or poor bone quality, years after the original implantation, the artificial disc can subside into the endplates, causing secondary implant dislocation and increasing pain. To avoid this complication the choice of the largest possible implant and a placement close to the rim of the endplates is recommended .To visualise implant subsidence plain radiographs are sufficient. If an osteoporotic vertebral endplate fracture is suspected, radionuclide scans may show increased uptake of the fractured vertebra.Postoperative imaging of lumbar total disc replacement requires alternative imaging techniques to conventional MRI-diagnostics. All currently available lumbar artificial discs contain stainless steel alloys, and, therefore, generate major artefacts on MRI. Alternative imaging modalities include plain film radiographs, myelography and radionucleotide imaging. These imaging modalities should be utilised in cases with suspected postoperative complications after lumbar TDR.The appearance of artificial discs on the implant market meant a drawback in postoperative radiological transparency with regard to MR-diagnostics, since all lumbar disc prostheses are still based on stainless steel alloys, thus causing major artefacts. Other imaging modalities are available and are in the first line of choice in cases with suspected postoperative complications after lumbar TDR. Until lumbar titanium artificial discs are available postoperative imaging of the operated segment requires altered radiological strategies.The authors have no competing interests with regard to the publication of this manuscript.YR wrote the manuscript and BS critically revised it. Both authors read and approved the final version of the manuscript"}
+{"text": "Serum bone alkaline phosphatase (BALP), serum carboxy-terminal propeptide of type I procollagen (PICP) and serum bone gla protein (BGP) as markers of bone formation, serum carboxy-terminal telopeptide of type I collagen (ICTP) as a marker of collagen resorption and fasting molar ratio of urinary calcium to creatinine (CaCr) and serum parathyroid hormone (PTH) were determined in two groups of cancer patients: 48 with advanced or metastatic disease with negative bone scan and 174 with bone metastases categorised as having lytic, mixed or blastic lesions and with more or fewer than or equal to three sites involved. In patients without apparent bone involvement, bone formation markers were rarely elevated. Conversely, serum ICTP was frequently found to be supranormal, showing it to be a non-specific marker for early detection of bone metastases. As expected, values of bone formation markers progressively increased in patients with lytic, mixed and blastic lesions, but ICTP levels did not show any differences according to the types of bone appearances, confirming previous reports of elevated osteoclast activity also in patients with apparent blastic lesions. Serum PTH increased significantly in patients with lytic compared with patients with mixed and blastic appearances, paralleling the bone formation markers, but CaCr showed the opposite pattern. These data are compatible with calcium entrapment in the bone in patients with increased osteoblast activity. This so called 'bone hunger syndrome' is further confirmed by the finding that in the subgroup of blastic appearances CaCr diminished whereas both ICTP and PTH increased according to the extent of tumour load in the bone."}
+{"text": "Epidemiologic and pathologic features of prostate cancer have given rise to an interestin focal treatment for carefully selected patients. Prostate cancer remains highlyprevalent, particularly in the U.S. and Europe. As screening programs have become moreaggressive and widespread, a substantial proportion of men diagnosed with localizedprostate cancer have disease characteristics associated with a low risk of progression. Treatments such as radical prostatectomy and radiation therapy can lead to durable recurrence-free survival in most patients, but carry variable risks of bowel, urinary, andsexual side effects. Few men and few urologists are comfortable leaving a potentiallycurable prostate cancer untreated. Focal therapy offers an attractive alternative for thepatient faced with a choice between aggressive local intervention (radiation or surgery)and watchful waiting. Contemporary diagnostic biopsy strategies and imaging tools, andthe development of predictive statistical models (nomograms), have led to improvementsin tumor characterization and risk stratification, making focal therapy a viable treatmentoption for specific men. This article reviews the rationale and indications for focaltherapy and highlights vascular-targeted photodynamic therapy (PDT) as one of manypromising focal therapy techniques."}
+{"text": "Accurate amino acid insertion during peptide elongation requires tRNAs loaded by cognate amino acids and that anticodons match codons. However, tRNA misloading does not necessarily cause misinsertions: misinsertion is avoided when anticodons mismatch codons coding for misloaded amino acids.Occasional compensation of misacylation by codon-anticodon mismatch necessarily occurs. Putatively, occasional error compensation may be enhanced beyond the random combination of independent errors in tRNA loading and codon-anticodon interactions: tRNA misacylation might alter potentials for codon-anticodon mismatches, perhaps specifically increasing potentials for mismatching those codons coding for the misacylated non-cognate amino acid. This hypothetical phenomenon is called 'error coordination', in distinction from 'error compensation' that assumes independence between misacylation and mismatch.Eventually, the hypothesis should be tested for each combination of amino acid misacylation and codon-anticodon mismatch, by comparing stabilities or frequencies of mismatched codon-anticodon duplexes formed by tRNAs loaded by their cognate amino acid with stabilities formed by that tRNA when misloaded with the amino acid coded by the mismatched codon. Competitive mismatching experiments between misloaded and correctly loaded tRNAs could also be useful, yet more sophisticated experiments.Detecting error coordination implies estimating error compensation, which also promotes protein synthesis accuracy. Hence even in the absence of evidence for error coordination, experiments would yield very useful insights into misacylation and mismatch processes. In case experiments consider post-transcriptional RNA modifications , results on codon-anticodon mismatches would enable significant improvements and sophistications of secondary structure prediction softwares. Positive results would show that protein translation enhances accuracies of products, not of single steps in the production. Ancient translational machineries putatively optimized error coordination, especially before tRNA editing by tRNA synthetases evolved: few primitive, but functionally versatile tRNA species perhaps executed low accuracy translation. Systems artificially designed/selected for low complexity and high efficiency could make use of this property for anticodons with high levels of error compensation and coordination. The two major groups of tRNA synthetases, class I and II, seem to minimize impacts of misinserted amino acids in protein sequences by tRNAs that were misloaded by these tRNA synthetases ,2. AccurDespite editing, misinsertion sometimes occurs. However, misinsertion is avoided if the misloaded tRNA's anticodon mismatches a codon coding for the misloaded amino acid, a phenomenon potentially meaningful for organisms. If mismatch is unaffected by misacylation, combinatorial probabilities predict their joint occurrence. This phenomenon is called here error compensation. The hypothesis suggested here is that misacylation affects mismatch potentials and hence joint occurrences of misacylations and mismatches do not match combinatorial probabilities, called error coordination. Error compensation is an unavoidable phenomenon whose potential effects are explored elsewhere. Here I focus on error coordination, which is a more readily testable phenomenon because it can be compared to a null hypothesis, that defined by error compensation, hence its detection implies estimating error compensation.The tRNA's acceptor stem and the anticodon are not adjacent. Hence properties of amino acids may have little impact on anticodon potentials for interactions with codons. It is nevertheless plausible that such effects exist, even if subtle. These may be larger when the tRNA molecule has relatively low molecular weight , and/or is relatively small. Sometimes, small tRNA-like molecules might transfer amino acids, as suggested by the observation of aminoacylated RNA corresponding to the mitochondrial light strand replication origin  and hypoAnother amino acid property potentially affecting error coordination is its charge. Charge differences between cognate and misloaded amino acid could affect the tRNA's electro-magnetic properties, including of its anticodon. Codon-anticodon interactions depend on electro-magnetic properties of the interacting atoms . Misacylations altering amino acid charges could affect codon-anticodon interactions: positive charges  might enhance positive partial dipole moments, decrease negative ones; the opposite would occur for negative charges (aspartic and glutamic acids). These effects would alter codon-anticodon duplex stabilities, including for mismatches. Such effects on anticodons are difficult to predict, because tRNA acceptor stems are not adjacent to anticodons. Charge effects on anticodon interactions may be buffered as well as enhanced by particular RNA sequences connecting amino acid and anticodon. Perhaps RNA rich in pyrimidines (which have high dipole moments) functions as conductor of effects of amino acid charge on anticodons. Softwares predicting dipole moments of proteins exist ,18, hencEscherichia coli and Homo sapiens).Other amino acid properties might also affect codon-anticodon interactions. This suggests that experimental observations on effects of misacylations on mismatches should be made for all combinations of misacylations and codon-anticodon mismatches, because effects of swapping one amino acid with another may be unpredictable, as different amino acid properties may be relevant. As noted above, specific tRNA sequences may also influence. If this is the case, models predicting these influences would be particularly important for predicting error coordination, because tRNA sequences frequently vary between species and individuals, and it is unrealistic that experimental data will be produced for more than a few model species , so as to test for associations between that quantity and its assumed effects on protein metabolism and related phenomena at higher organismic levels . Error compensation is a case where a null hypothesis is in itself biologically interesting, similar to the neutral theory of evolution. Error coordination is more adequate in relation to designing classical manipulative experimental tests. It expects that misacylated tRNAs form more stable (or more frequently) mismatched codon-anticodon duplexes with codons coding for the misloaded amino acid than the same tRNA when it is correctly aminoacylated. This can be tested by comparing results from different, independent experiments. Experiments designed to estimate 'competition' between molecules can also be designed. For example, matching and mismatching codons are put in presence of either correctly or incorrectly loaded tRNAs, and duplex stabilities/frequencies of correctly matched and mismatched anticodons are compared (one way competition between codons). Mixing correctly and incorrectly loaded tRNAs with either matching or mismatching codons would estimate one way competition between correctly and incorrectly loaded tRNAs. Two-way competition  could also be considered. Ideally, such experiments should be done for all combinations of codons, anticodons and amino acids.Recent observations suggest that ribosomes select against misacylated tRNAs . Error cPrecisely estimating error coordination would imply producing data that include effects of posttranscriptional tRNA modifications -22, in pError compensation and coordination suggest that accurate translation has probabilistic properties. Design of artificial translational systems might take advantage of error compensation and coordination. Primordial systems at the origins of life perhaps used few versatile, yet accurate tRNAs (or tRNA-like molecules), thanks to high error compensation and coordination. Various editing mechanisms ,26 existThe author declares that he has no competing interests.HS is the sole author of this publication."}
+{"text": "The lengthof time the recipient remained euglycemic was used to measurethe ability of the transgenes to protect the graft fromautoimmune destruction. Although the results of these cotransfectionsgave little evidence of a synergistic relationship,they were useful to show that gene combinations can be used to more efficiently protect islet grafts from diabetogenicT cells.Islet transplantation therapy would be applicable to awider range of diabetic patients if donor islet acceptanceand protection were possible without systemic immunosuppressionof the recipient. To this aim, gene transferto isolated donor islets ex vivo is one method that hasshown promise. This study examines the combined effect ofselected immunomodulatory and anti-inflammatory genesknown to extend the functional viability of pancreatic isletgrafts in an autoimmune system. These genes, indoleamine2,3-dioxygenase (IDO), manganese superoxide dismutase(MnSOD), and interleukin (IL)-1 receptor antagonist protein(IRAP), were transferred to isolated NOD donor isletsex vivo then transplanted to NOD"}
+{"text": "Xenopus thymustumor-derived lymphoid cell lines undergoing apoptosis and also in apoptotic, nontransformedsplenocytes. Cultured Xenopus tumor lymphoid cells induced to undergo, apoptosis by serumdeprivation or treatment with the calcium ionophore, ionomycin, displayed altered morphologytypical of apoptotic cells, as judged by flow cytometric light-scatter characteristics and byfluorescence microscopy of acridine-orange-stained cells. Flow cytometry of permeabilized cellsand fluorescence microscopy of acetone-fixed cytospins revealed that apoptotic Xenopus tumorcells, especially those displaying loss or condensation of DNA, displayed increased expressionof epitopes recognized by a rabbit polyclonal antibody against ASP. Flow cytometry confirmedthat ASP is also expressed in splenocytes induced to apoptose by culture in ionomycin orfollowing concanavalin A stimulation. No increased expression of ASP was seen when lymphoidtumor cells or splenocytes were induced into necrosis by overdose with the antifungal agentamphotericin B. Western blotting with antibody against ASP identified the emergence of severalprotein bands in cell lysates from apoptotic, but not necrotic, Xenopus tumor cells. The new andsimple methodology for identifying apoptotic cells described here is likely to be of value to thosestudying immune system development and associated programmed cell death in Xenopus.A novel apoptosis-specific protein (ASP) has recently been identified in the cytoplasm ofapoptotic mammalian cells. This paper investigates whether ASP is found in"}
+{"text": "Despite previous advances on miRNA regulation of gene expression, little has been investigated from a genome scale.To gain new insight into miRNA regulation in humans, we used large scale data and carried out a series of studies to compare various features of miRNA target genes to that of non-miRNA target genes. We observed significant differences between miRNA and non-miRNA target genes for a number of characteristics, including higher and broader mRNA expression, faster mRNA decay rate, longer protein half-life, and longer gene structures. Based on these features and by analyzing their relationships we found that miRNA target genes, other than having miRNA repression, were most likely under more complex regulation than non-miRNA target genes, which was evidenced by their higher and broader gene expression but longer gene structures. Our results of higher and broader gene expression but fast mRNA decay rates also provide evidence that miRNA dampening of the output of preexisting transcripts facilitates a more rapid and robust transition to new expression programs. This could be achieved by enhancing mRNA degradation through an additive effect from multiple miRNA targeting.Genome-scale analysis on the nature of miRNA target genes has revealed a general mechanism for miRNA regulation of human gene expression. The results of this study also indicate that miRNA target genes, other than having miRNA repression, are under more complex gene regulation than non-miRNA target genes. These findings provide novel insight into miRNA regulation of human gene expression. Caenorhabditis elegans as post-transcriptional regulators of genes involved in developmental timing ,  were then subjected to the prediction of miRNA binding sites through the RNA22 web server Supplemental Figure 1. Shows the expression differences between non-miRNA and miRNA target genes predicted from TargetScanS and RNA22.Click here for fileSupplemental Figure 2. Shows the expression breadth differences between non-miRNA and miRNA target genes predicted from TargetScanS and RNA22.Click here for fileSupplemental figure 3. Shows the correlation between mRNA expression and decay rate for miRNA target genes predicted from TargetScanS.Click here for fileShows the correlation between mRNA expression and decay rate for miRNA target genes predicted from RNA22.Click here for fileShows the correlation between gene expression and protein stability for miRNA target genes predicted from TargetScanS.Click here for fileShows the correlation between gene expression and protein stability for miRNA target genes predicted from RNA22.Click here for file"}
+{"text": "Specialized cells found near the dermal-epidermal junction, characterized by numerous membrane-bound granules with dense cores. The cells were named after German anatomy professor Friedrich Sigmund Merkel, who experimented with osmium tetroxide staining and described these cells in 1875. First identified in the skin of a mole, they were later found in human skin. The cells are responsible for the highly malignant skin tumor known as Merkel cell carcinoma. An infectious cause for Merkel cell carcinoma has been proposed."}
+{"text": "A middle aged chronic alcoholic presented with deep jaundice, markedly enlarged and tender spleen with leukoerythroblasticblood picture and bone marrow biopsy showing mild fibrosis. He was tested negative for HIV, hepatitis B and C viruses.Besides very high serum bilirubin, alkaline phosphatase was raised four times the normal value. Contrast enhanced CTshowed enlarged spleen and liver with multiple heterogenous lesions in spleen and tiny hypo-dense lesions in liver. Inhospital, he developed haemolytic uraemic syndrome and succumed to his illness. At autopsy spleen weighed 5200 gms andvariegated in appearance due to large areas of necrosis and whitish tumour nodules. Histology revealed morphology of anangiosarcoma. Liver was also infiltrated by the tumour mainly in and around portal tract areas."}
+{"text": "To assess regional systolic function and global contractile function in patients with WPW Syndrome.pRS) or range (difference between maximum and minimum peak RS i.e. RangepRS). Spectral Doppler (continuous wave) measurements were acquired through the left ventricular outflow tract to determine Pre Ejection Period (PEP), Left Ventricular Ejection Time (LVET) and measures of left ventricular systolic performance.Eleven cases with manifest Wolff-Parkinson-White (WPW) syndrome in sinus rhythm were compared to 11 age matched controls. 2D strain analysis was performed and peak segmental radial strain (pRS) values obtained from basal ventricular parasternal short-axis images (70 \u00b1 5 frames/sec) using a dedicated software package. Heterogeneity of radial strain pattern in six circumferential basal left ventricular segments was measured in terms of standard deviations of peak RS  and corrected PEP  were significantly longer in WPW patients compared to controls. The PEP/LVET ratio was also significantly greater in WPW cohort  suggesting global systolic dysfunction.LV segmental radial strain was profoundly heterogeneous in WPW cases in contrast to fairly homogenous strain pattern in normal subjects. Wide SDPatients with manifest preexcitation (predominantly those with right-sided pathways) have regional and global contractile dysfunction resulting from aberrant impulse propagation inherent to the preexcited state. Abnormal electrical activation of the accessory pathway results in characteristic electrocardiographic abnormalities and clinical symptoms manifesting as WPW syndrome .  Data oTraditionally, regional left ventricular function has been evaluated using visual wall-motion analysis as well as by other quantitative methods such as integrated backscatter, automatic border detection and tissue Doppler imaging (TDI) -9. HowevIt has recently become evident that chronic right ventricular apical  pacing induced dyssynchrony leads to  deleterious effects on left ventricular systolic function  ,13.  AccTo the best of our knowledge, no data on the prevalence of left ventricular dysfunction in patients with accessory pathway conduction exists in the literature. We sought to characterize regional left ventricular function in patients with manifest WPW syndrome by examining radial myocardial strain patterns. We also attempted to investigate the presence of global dysfunction using systolic time intervals.The study included 11 cases with manifest pre-excitation on surface ECG and an equal number of age-matched controls .  None oAll accessory pathways were localized using the algorithm proposed by Milstein and colleagues  on a staContinuous wave Doppler measurements were acquired through the left ventricular outflow tract. PEP was defined as the time from the beginning of the QRS complex to the onset of ventricular ejection (opening click). LVET was measured from the onset of ventricular ejection (opening click) to the closure of the aortic valve (closure click) . CorrectAll patients and controls were in sinus rhythm and image acquisition was performed in the resting state in the left lateral position. Standard short axis views at the level of mitral valve were obtained from the left ventricle (LV) at a frame rate of 70 \u00b1 5 frames/second during end-expiratory apnea and stored in cine-loop format for subsequent offline analysis . The endocardial border was then traced using the built-in software at end-systole by a 'point-and-click' approach with care taken to adjust tracking of all endocardial segments. Upon defining this endocardial circle, a larger concentric circle was automatically generated outlining the epicardium with a default width of 11 mm and perimeter adjusted manually as needed to track the myocardium. Strain tracings were then generated using a dedicated software package  from a  six segment  LV model . Radial strain values at peak systolic period  were obtained for each individual LV segments using online calipers .pRS): One standard deviation of six  pRS   in each case. Range of pRS (RangepRS): Arithmetic difference between maximum and minimum of six pRS values in each case.For descriptive purpose, following parameters were calculated: Global LV Peak radial strain = Arithmetic mean of pRS of six individual segments for each case as a surrogate marker of overall LV peak systolic radial strain. To measure heterogeneity, following dispersion indices were calculated ): Standard Deviation of pRS . Data are presented as mean \u00b1 SD unless stated otherwise. Non-parametric Wilcoxon's signed rank and the Mann-Whitney U test were used to compare the continuous variables in WPW patients and controls. All measurements were done by two independent observers with a minimal degree of variability. Intraclass correlation coefficients (ICC), commonly used as a measure of reliability, with a value of 1 representing a perfect correlation was used to quantify the intraexaminer and interexaminer variation. The ICC was calculated  from mean values according to Portney ,19.  TwoThe study cohort consisted of eleven cases  and age-matched eleven controls . Baseline characteristics of the study population and accessory pathway location are shown in pRS as well as RangepRS) were profoundly greater for WPW cases compared to healthy controls (p<0.001)  . This siAs shown in pRS and RangeSDpRS although the average global LV radial strain was similar to the healthy subjects (mean of pRS)}. Moreover, global systolic contractile function appeared to be depressed as well, as evident from systolic time interval analysis.Our findings suggest that patients with manifest WPW have evidence of regional contractile dysfunction. This is evidenced from a wide dispersion of pRS {higher SDEjection fraction (EF), the most frequently used index to assess global cardiac function is the LV stroke volume expressed as a percentage of the end-diastolic volume. This measure has gained popularity largely because it is widely available, easily obtainable and also because no other alternative optimal measures of myocardial contractility have emerged despite extensive investigation. Nevertheless, accurate EF calculation using the recommended Simpsons biplane method requires precise measurement of LV end-diastolic and end-systolic volumes in multiple views with special attention to avoid foreshortening of the LV cavity. Averaged values from both 4-chamber and 2-chamber views, preferably from 2 or 3 beats are recommended for more reliable estimation of ventricular volumes and EF. However, this technique is predicated on geometric assumptions  and although it is fairly accurate in ventricles with symmetric contractility, it is less reliable in ventricles with overt/subtle regional wall motion abnormalities or geometrically deformed ventricles such as ventricular aneurysms. This limitation of the Simpsons method to reflect regional asymmetry of LV function is the reason why EF was not selected as the preferred metric to assess global systolic function in the present study.Systolic and diastolic 'wall motion' abnormalities have been well described  in patients with WPW Syndrome -3,5,20. In our study, WPW cases exhibited a wide dispersion in pRS values of LV segments during systole suggesting markedly heterogenous strain pattern and contractility. It has to be emphasized that wall motion abnormalities are not necessarily always associated with altered contractility. Toyoda et al studied interventricular septal (IVS) contractile patterns in patients post coronary artery bypass surgery (CABG) and reported that peak tissue Doppler velocities in the IVS were attenuated . HoweverRadial strain data obtained in our patients extends the well-recognized observations of pre-excitation on wall motion and unequivocally demonstrates its detrimental effects on regional left ventricular function.The transmural arrangement of myocardial fibers is not uniform across the wall of the LV. Subendocardial and subepicardial muscle bundles are aligned longitudinally (long axis contraction), with a slight spiral arrangement, and midwall fibers are aligned circumferentially . Although the precise mechanism for abnormal contractile function in the pre-excited state remains speculative, we believe that accessory pathway conduction leads to ventricular depolarization via myocyte-myocyte conduction as opposed to the normal orderly propagation of the impulse via the His-Purkinje system. Depending on the degree of pre-excitation, ventricular insertion site of bypass tract and/or layer of muscle fibers/bundles being recruited, further heterogeneity of depolarization may ensue. As observed with dependent right ventricular apical pacing  it is plSystolic time intervals have been reported as reliable surrogate parameters of left ventricular systolic function. Electromechanical systole comprises the PEP and LVET. LVET is the effective contraction phase during electromechanical systole. Weissler and co-workers -18 have During the cardiac cycle, regional deformation of the myocardium occurs in three major directions: longitudinally, circumferentially and radially, all of which can be quantified using 2-dimensional strain techniques providing real-time automatic assessment of regional cardiac function. This technique analyzes myocardial motion objectively by tracking natural acoustic markers in grey scale ultrasonic images in two dimensions (speckle tracking) and is a validated Doppler-independent method of quantifying regional cardiac deformation ,11,27. TWe found the dispersion indices like standard deviation or range segmental radial strain to be superior estimate of heterogeneity of regional contractility compared to mean radial strain. Interestingly, we also observed hypercontractility in segments diametrically opposite to those with impaired radial strain probably accounting for the lack of difference in mean radial strain values and ejection fraction between groups.Abnormal motion does not always imply contractile dysfunction. With 2D strain imaging, an angle-independent quantification of regional cardiac deformation, relatively independent of wall motion is possible. Our data suggests that the preexcited state is associated with an impairment of regional and global left ventricular contractility. In some respects, the mechanism by which RV apical pacing or left  bundle branch block adversely influence LV contractility in the setting of congestive heart failure appear to be similar to those responsible for impaired contractility in the pre-excited state; both essentially mediated by  electromechanical delay. The extent, progression and reversibility of left ventricular dysfunction in the setting of  chronic  preexcitation  however, is unknown but  certainly merits further study.The number of patients enrolled was limited and they predominantly appeared to have right-sided pathways, even though we enrolled consecutive patients; whether or not patients with left sided pathways have disordered contractility is uncertain. The accuracy of pathway localization using the surface ECG has inherent drawbacks; clearly localization of pathways by electrophysiological studies would be desirable. Speckle Tracking Imaging is very image quality dependent and short axis images cannot eliminate longitudinal motion entirely. We found frame rates in the range of 65 Hz  to be most suitable for speckle-tracking analysis and the algorithm performed poorly with frame-rates of > 100 Hz.We used a modified method for systolic time interval assessment using Doppler-based data but had a control group for comparison; however, direct comparison of normative values with established techniques would have to be done with caution. Controversy exists regarding 'rate' correction for systolic time intervals; it is also not clear whether the prolonged PEP intervals ought to be corrected in the setting of LV conduction blocks. No specific recommendations relating to PEP adjustments in patients with pre-excitation could be found in the literature.Our observations indicate that patients with manifest WPW (predominantly right-sided pathways) have impairment of regional contractility as ascertained by radial strain dispersion parameters, resulting from the abnormal temporal sequence of activation in the pre-excited state.  Differences in surrogate measures of global contractility such as PEP/LVET seem to indicate global LV dysfunction in this cohort of patients. Our findings will need to be validated in a larger group of patients that includes left-sided pathways."}
+{"text": "Patients with head and neck cancer were treated with synchronous radiotherapy and chemotherapy . Before treatment, mucositis was absent and low amounts of prostaglandin-like material were extracted from peripheral plasma. As treatment proceeded mucositis occurred, and its degree correlated with the amount of prostaglandin-like material extracted from the plasma. Some patients were given moderate doses of drugs which inhibit prostaglandin synthesis, but mucositis still occurred."}
+{"text": "Steven Opal reviews the phenomenon of bacterial communities and discusses the role played by bacterial communication and cooperation in host-pathogen interactions, particularly in urinary tract infection. PLoS Medicine, Rosen and colleagues [Escherichia coli commonly exist and are likely of to be of clinical significance in uncomplicated bacterial cystitis. This novel finding is remarkable in many respects, not the least of which is the circuitous route by which our understanding about bacterial communities has evolved in the pathogenesis of infectious diseases.In this issue of lleagues  present Since the inception of the germ theory of disease over 150 years ago, it has generally been assumed that potential pathogens invade the host essentially as solitary microorganisms (\u201clone soldiers\u201d). Successful pathogens must find a susceptible host and then gain access to host tissues through a defect in epithelial barriers. The pathogen must replicate rapidly, and either overwhelms the host's innate and adaptive immune system, or successfully evades antimicrobial defenses by avoiding host recognition and clearance mechanisms .Vibrio fischeri, which forms an unusual symbiotic relationship with the Hawaiian bobtail squid (Euprymna scolopes). The bioluminescent V. fischeri is taken up by light organs along the body of the squid and, when high concentrations of bacteria are attained, the bacterium induces its luciferase genes to generate visible light.This traditional view of microbial pathogenesis was turned on its head about 30 years ago when three microbiologists, Nealson, Platt, and Hastings [PLoS Medicine:This Research in Translation article discusses the following new study published in 10.1371/journal.pmed.0040329Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ (2007) Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med 4(12): e329. doi:Analyzing urine specimens from women with bladder infections, David Rosen and colleagues find evidence for intracellular bacterial communities, which have been associated with recurrent urinary tract infections in mice.V. fischeri.The bacteria benefit from this mutualistic relationship, as the squid provides a source of nutrients for the bacteria. Meanwhile, the squid benefits from the microbial light source, which provides a unique form of camouflage for the squid during nighttime mating rituals. The adult squid populations congregate in large numbers along the water's surface for mating. On moonlit nights, the squid's body is silhouetted against a starlit sky and is thus readily detectable from below by predatory fish. Light organs on the underside of the squid provide a \u201cstarry sky camouflage\u201d by their association with the light-generating clusters of Vibrio species is only activated with high bacterial densities. But how do individual bacterial cells know their relative concentration within the light organ of the squid? The answer was discovered when V. fischeri was found to produce a soluble \u201cquorum sensing\u201d molecule that co-activates the operon for luciferase production in neighboring bacteria when the organisms are in high concentration [The bioluminescent potential of this ntration .E. coli, use quorum sensing genes to regulate critically important virulence genes during microbial invasion.This observation was initially viewed as a mere curiosity unique to marine microbiology until genome searches revealed homologous quorum sensing genes among many clinically relevant microbial pathogens . RemarkaV. fischeri and uses acyl homoserine lactone (acyl HSL) molecules for signaling. This system is widely used by medically important gram-negative bacterial pathogens. The second system, found in gram-positive bacteria, is a functionally homologous version of quorum sensing that uses a series of short cyclic peptides and a two-component receptor\u2013kinase signaling pathway. A third hybrid system, found in both gram-positive and gram-negative bacterial species, uses some elements similar to the acyl HSL system of gram-negative bacteria and the receptor\u2013kinase system of gram-positive bacteria [At least three separate systems of quorum sensing and auto-induction molecules exist in bacteria. The first is highly homologous to the system found in bacteria ,6.What is now clear is that bacterial communication and cooperation is a ubiquitous phenomenon and that these communications systems are control elements in host\u2013pathogen interactions . The entPseudomonas aeruginosa can sense human gamma interferon, alerting the bacterial pathogen to physiologic stress within the infected host [Recent evidence now reveals that these communication pathways can cross kingdom boundaries . Bacterited host .Quorum sensing is essential to the production of healthy and fully developed biofilms. These palisade-like complex multicellular structures are relatively stable communities of bacterial populations living in a sessile, protected environment . Their sBiofilm communities develop rapidly on catheter surfaces and on mucous membranes along epithelial surfaces. Bacterial communities residing on urinary catheter surfaces are relatively refractory to the lytic action of many antibiotics. This resistance undermines the capacity of antimicrobial agents to eradicate infections on biofilmladen foreign bodies within the genitourinary system .Qazi et al., 2006 [S. aureus; this pathway could favor the quorum sensing gram-negative pathogens over S. aureus when in competition for limited resources during microbial invasion of the host.l., 2006  The sameShiner et al., 2005 [l., 2005  This manWu et al., 2005 [P. aeruginosa uses its quorum sensing apparatus to detect and signal transcriptional programs for virulence expression in response to human interferon gamma. This interferon marker signals an inflammatory stress in the host during microbial invasion by the microbial pathogen.l., 2005  P. aerugNovick et al., 2003 [l., 2003  An excelSmith et al., 2003 [P. aeruginosa and their respective roles in biofilm formation and bacterial pathogenesis.l., 2003  This papE. coli cystitis. Up to 41% of urine specimens in women with cystitis have evidence of filamentous bacterial forms, a morphologic hallmark of recent residence among sessile bacterial communities. Similar findings have previously been reported in the murine model of cystitis [Rosen and colleagues  now go ocystitis . CytologAcyl homoserine lactone: a highly soluble, cyclic homoserine moiety covalently linked to short fatty acids that functions as a quorum sensing signal molecule for many gram-negative bacteriaAuto-induction molecule: diffusible low-molecular weight signal molecule recognized by the microorganism that produced the molecule and capable of inducing changes in the transcription of specific genesHalophilic: capable of living in a salty environmentOpen reading frames: Sequences of DNA that include the start codon AUG and appropriate translation sequences that generate a functional protein productOperon: a series of adjacent open reading frames transcribed from a single promoter site that generates gene products working on the same metabolic pathwayQuorum sensing: ability to detect the density of a bacterial population and alter genetic programs in response to that population densityReceptor\u2013kinase signaling pathway: two-component system consisting of a membrane receptor to detect extracellular ligands, linked to an intracellular phosphorylating enzyme, which alters the transcriptional programs of the bacterial cellToll-like receptor: Pattern recognition receptor used by the innate immune system to detect and respond to highly conserved microbial mediators such as bacterial lipopolysaccharide or bacterial flagellinE. coli have the capacity to invade epithelial lining cells, where they find sanctuary from immune surveillance and urinary clearance mechanisms [Uropathogenic chanisms ,16. The There are numerous implications of these findings for the pathogenesis of urinary tract infections, and for the possible treatment options available to prevent recurrent infection in UTI-prone women. These sessile bacterial communities might easily provide a sequestered site from antimicrobial defenses, allowing for repopulation of the urinary tract after a seemingly appropriate course of antimicrobial agents for bacterial cystitis. The formation of IBCs is a Toll-like receptor (TLR4)-dependent process in the murine system  and is lE. coli? Staphylococcus aureus regulates many of its virulome invasion genes through its auto-inducing peptides and quorum sensing system [S. aureus or other gram-positive bacterial pathogens use communal intracellular invasion strategies.The current study was performed in young, sexually active women. Many women had a history of recurrent bacterial cystitis. What is the prevalence of IBCs in children, the elderly, or men or women experiencing their first episode of UTI? Does the presence of IBCs in first episodes of UTI indicate a greater propensity for treatment failure or relapsing urinary tract infection? What is the prevalence of IBCs in patients with upper urinary tract infections or complicated urinary tract infections associated with urinary obstruction or foreign bodies? Are similar IBCs identifiable with pathogens other than g system ,5. It woThe findings of Rosen et al.  raise th"}
+{"text": "Earlier studies on the kinetics, glucosedependenceand sensitivity to metabolic inhibitorsof the interaction between NAT and KATP channelssuggested a distinct signaling pathways with NATcompared to REP, glyburide (GLY) or glimepiride(GLI). To obtain further evidence for this concept,the present study compared the insulin secretion invitro from rat islets stimulated acutely by NAT, GLY,GLI or REP at equipotent concentrations during 1-hrstatic incubation following overnight treatmentwith GLY or tolbutamide (TOL). The islets fullyretained the responsiveness to NAT stimulationafter prolonged pretreatment with both SUs, whiletheir acute response to REP, GLY, and GLI wasmarkedly attenuated, confirming the desensitizationof islets. The insulinotropic efficacy of NAT in isletsdesensitized to SUs may result from a distinctreceptor/effector mechanism, which contributes tothe unique pharmacological profile of NAT.Chronic exposure of pancreatic islets to sulfonylureas(SUs) is known to impair the ability of isletsto respond to subsequent acute stimulation bySUs or glucose. Nateglinide (NAT) is a novelinsulinotropic agent with a primarily site of actionat"}
+{"text": "Here we report the unusual case of a patient who suffered from acute optic neuropathy following hemispherical subdural hematoma. Although confirmed up to now only through necropsy studies, our case strongly suggests a local, microcirculatory deficit identified through magnetic resonance imaging A 70-year-old Caucasian German who developed a massive left hemispheric subdural hematoma under oral anticoagulation presented with acute, severe visual impairment on his left eye, which was noticed after surgical decompression. Neurologic and ophthalmologic examinations indicated sinistral optic neuropathy with visual acuity reduced nearly to amaurosis. Ocular pathology such as vitreous body hemorrhage, papilledema, and central retinal artery occlusion were excluded. An orbital lesion was ruled out by means of orbital magnetic resonance imaging. However, cerebral diffusion-weighted imaging and T2 maps of magnetic resonance imaging revealed a circumscribed ischemic lesion within the edematous, slightly herniated temporomesial lobe within the immediate vicinity of the affected optic nerve. Thus, the clinical course and morphologic magnetic resonance imaging findings suggest the occurrence of pressure-induced posterior ischemic optic neuropathy due to microcirculatory compromise.in vivo magnetic resonance imaging diagnostics which may remain unconsidered by computed tomography.Although lesions of the second cranial nerve following subdural hematoma have been reported individually, their pathogenesis was preferentially proposed from autopsy studies. Here we discuss a dual, pressure-induced and secondarily ischemic pathomechanism on the base of  In these studies, microcirculatory compromise of the optic nerve was proven as a pathogenic mechanism . In thisA 70-year-old Caucasian man of German nationality receiving warfarin therapy for the primary prevention of chronic atrial fibrillation was admitted to our hospital due to symptoms of a coronary syndrome. An initial international normalized ratio (INR) of 1.7 was elevated to therapeutic ranges (INR = 2.5). Three days later, the patient was found comatose after a first-ever generalized seizure. Cerebral computed tomography (CT) revealed a subdural hematoma measuring 16 mm at its maximum thickness and covering almost the entire left convexity which caused a massive midline shift Figure . Rapid cTwo days after extubation and recovery from anaesthesia, the patient complained of severe sinistral visual loss. Neurologic and ophthalmologic examinations confirmed a severely reduced visual acuity on his left eye with concomitant afferent pupillary defect. A normal vascular fundoscopy and the lack of papilledema led to the working diagnosis of posterior ON. Four days after the surgery, a follow-up DWI of the cerebral MRI Figure  showed aThe corresponding hyperintensity of T2-weighted images indicated focal brain edema in line with regional hypoperfusion and the preceding uncal shift Figure . Thus, pin vivo findings do not at all elucidate its aetiology. Generally, reports do not present the existence of papilledema or of radiologic in vivo evidence of optic nerve compression by mass effects [To date, only a few cases of ON following subdural hematoma are presented, and their pathomorphologic  effects . In cont effects .The pathophysiology of ON has been discussed in the context of diverse aetiological events, and adequate diagnostic approaches have already been proposed. Table At present, only a few cases refer to the diagnostic value of MRI in ON. By means of MRI, unilateral  and simuin vivo. Radiological signs of herniation were discrete, although highly sensitive MRI revealed a mechanic, pressure-induced brain lesion of the mesiobasal temporal lobe in proximity to the affected optic nerve. However, focal ischemic injury was missed in detecting basal brain shift by CT. Since MRI pathologies fulfilled the criteria of ischemic compromise, we suggest that the local increase in intracranial pressure (ICP) exceeded the perfusion pressure of both structures, namely the formation of the uncus and the nearby passing optic nerve. Consistent with this notion of a microcirculatory deficit, the lesion did not follow the characteristic extent of a vascular territory.Using the MRI technique, we now provide a pathophysiologic insight on ON following space occupying subdural hematoma early We suggest that rare cases of acute ON following subdural hematoma are due to local pressure-induced optic nerve infarction. This pathomechanism may remain neglected when massive brain shift is lacking or when CT is the only diagnostic means. The use of serial MRI may help balance the discrepancy between the paucity of clinical reports and frequent neuropathological findings of anterior visual pathway damage in space-occupying brain injury .ADC: apparent diffusion coefficient; AION: anterior ischemic optic neuropathy; CT: computed tomography; DWI: diffusion-weighted imaging; FLAIR: fluid attenuated inverse recovery; ICP: intracranial pressure; INR: international normalized ratio; MRI: magnetic resonance imaging; ON: optic neuropathy; PION: posterior ischemic optic neuropathy.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.AK and CP interpreted the patient data and clinical course regarding the neurological disease. HF, OW and CT were major contributors in conceiving and writing the manuscript. All authors read and approved the final manuscript."}
+{"text": "Helix pomatia (HPA), is associated with metastatic competence and poor patient prognosis in a range of human adenocarcinomas. These glycoproteins remain poorly characterised, and their functional role has yet to be elucidated. This study describes characterisation of a range of human breast/breast cancer cell lines for the expression of the N-acetylgalactosaminylated glycoproteins of interest, and their comparison with normal breast epithelium and a range of clinical breast carcinoma samples. Confocal and light microscopy studies revealed cytochemical HPA-binding patterns consistent with a fundamental disruption in normal glycobiosynthetic pathways attending increasing metastatic potential. We report the most complete comparative analysis of HPA-binding ligands from cultured breast cells, clinical breast carcinoma samples and normal breast epithelium to date. Lectin blotting identified 11 major HPA-binding glycoprotein bands common to both clinical tumour samples and breast cell lines and 6 of these bands were also expressed by samples of normal breast epithelium, albeit at much lower levels. Moreover, very marked quantitative but not qualitative differences in levels of expression consistent with metastatic capability were noted. \u00a9 2001 Cancer Research Campaignhttp://www.bjcancer.comOver-expression of N-acetylgalactosamine glycoproteins as detected by binding of the lectin from"}
+{"text": "We have previously documented the development and subsequent disappearance of cytolytic activity mediated by lymphocytes from lymph nodes draining Moloney sarcomas destined either to regress or grow progressively. We now report that these tumour-draining lymphnode cells (LNC) that were no longer cytotoxic, spontaneously regenerated peak levels of killing after culture in vitro for 4 days in the absence of exogenous tumour antigen. Cytolytic activity, which was antigenically specific, was mediated by T lymphocytes. Resurgence of cytolytic activity in vitro was accompanied by proliferative changes  which peaked on the 3rd day of culture. Although normal, nonimmune LNC underwent quantitatively similar proliferative changes in culture, the killing that developed was weak and antigenically nonspecific. Transfer of cultured, tumour-draining LNC to immunologically compromised, syngeneic mice conferred complete protection from Moloney sarcoma progression. Adoptive transfer could be delayed for 6 days after tumour induction without loss of protection. These results suggest that there exists in Moloney sarcoma-bearing mice a mechanism that limits the differentiation of pre-killer cells into cytolytically active T lymphocytes, and that such inhibition is eliminated when LNC are explanted into culture."}
+{"text": "This report presents histopathological evidence of mycotic infection of the gingival epithelium followed by inverted verrucous giant cell epitheliomata of the gingiva. Sections from biopsy tissue revealed intercellular spaces of the parabasal squamous epithelium parasitized by Periodic Acid Schiff stain positive branching septate hyphae and conidia of morphological appearance of Trichophyton. Epithelial cells presented epitheliomatous proliferation with formation of giant cells showing phagocytosed fragments of mold. Some fungi are known for carcinogenic metabolites and signaling. Dermatop13, differential leucocyte count - P68L29E2M1, fasting blood sugar 95 mg/dL, serum urea 29 mg/dL and serum creatinine 1.1 mg/dL. Screening tests for human immunodeficiency virus, hepatitis and syphilis were negative.A 52-year-old goldsmith's ash washerman with a history of extraction of aching right upper second molar tooth 2 years back followed by painful on-and-off swelling, managed by the patient by frequenting dentists' prescriptions and consumption of countryside liquor a bottle a day, was referred to this hospital. Gingival biopsy with clinical diagnosis of leukoplakia/squamous carcinoma was submitted for histopathological diagnosis. The patient had no history of fungal infection of the skin or nails. The total leucocyte count was 8,000 cells/mmSections from the biopsy tissue revealed surface dyskeratosis with underlying keratinocytic hyperplasia of the gingival epithelium. Basal and parabasal layers presented with epitheliomatous proliferation of cells with formation of giant cells. Retepegs were broadened and elongated with keratinocytes in a pearl arrangement forming the core and hyperplastic cells dotted by giant cells at the periphery . At placPeriodic Acid Schiff (PAS) stained sections revealed septate branching fungal hyphae of mold parasitizing intercellular clefts in basal and parabasal squamous layers, with the cells around undergoing immunoactive and giant cell transformations . Some ofLow-mitotic basal\u2013parabasal epitheliomatous proliferation with dyskeratotic\u2013acanthocytic hyperplasia, pearl formation and papillary clubbing and elongation of retepegs are the features diagnostic of epitheliomatous-inverted papilloma or verrucous\u2013hyperplastic leukoplakia, which di4th century. Oral mycosis, particularly periodontal infection caused by dermatophytosis, and host-defensive activity of human cells in response to trichophyton have also been reported,[Histopathological evidence in the present case was diagnostic of mycotic giant cell epitheliomatous inverted papilloma of the gingiva. Oropharyngeal proliferative verrucous leukoplakia and its related lesions, like invreported,7 besidesreported,2 TrichopDermatophytes are known for cutaneous infections and for invading and parasitizing superficial keratinocytic layers, while keratin is believed to be the source of nourishment for the mold. In the pDermatophytes are rarely known to infect the wet epithelium of the gum, except through periodontal mycosis leading to gingival hyperplasia. History Trichophyton mold can infest and parasitize the basal and parabasal layers of the gingival squamous epithelium. The portal of entry may be periodontal.Acanthocytes around the hyphae of the mold may respond by giant cell epitheliomatous response and verrucous keratinocytosis.Intercellularly parasitizing PAS-positive hyphae, phagocytosed segments of hyphae and conidia may be demonstrable in the giant cell epitheliomatous areas.No fungal hyphae or identifiable fragments of mold may be visible in areas of the gingival epithelium undergoing advanced keratinocytic change.Giant cells in the epithelioma call for detailed meticulous histopathological examination for the pathogenic organism."}
+{"text": "Current Neuropharmacology devoted to the theme of AED conversions and related issues. In this series of articles, we reviewed the role of AED monotherapy in newly diagnosed epilepsy, the practice of transitional polytherapy during AED monotherapy conversions in patients experiencing breakthrough seizures or adverse effects, chronic maintenance polytherapy for refractory epilepsy, and the related topics of strategies for minimizing adverse effects, appropriate blood level monitoring, and patient-related factors in AED conversions. Successful conversion between AED monotherapies and polytherapy drug sequencing requires that practitioners possess and apply a thorough knowledge of epilepsy, AED pharmacology, and clinical reasoning, while being sensitive and reactive to patient reported adverse effects of treatment.The process of conversion between AED monotherapies is frequently necessary in epilepsy care, yet little practical guidance is available to practitioners. This article introduces an issue of  That which grows fast, withers as rapidly. That which grows slowly, endures.\u201dDr. Josiah Gilbert Holland, Founder of Scribner\u2019s Monthly\u201cWhen the music changes, so does the dance.\u201dAfrican ProverbThe first antiepileptic drug (AED) monotherapy utilized successfully manages nearly half of epilepsy patients; however, conversion to a second monotherapy is necessary for those who fail to become seizure-free or who do not tolerate an initially chosen AED, and chronic polytherapy is necessary in many patients who develop refractory epilepsy . Over thMonotherapy is widely favored over polytherapy by neurologists in the treatment of newly diagnosed epilepsy, limited evidence for this \u201cmonotherapy maxim\u201d notwithstanding. Abundant evidence is available when initiating adjunctive AED therapy in refractory epilepsy, on practical grounds an important setting for use of newer AEDs since when a new AED becomes available, it is generally first limited to use in refractory patients having the greatest need for improved seizure control, until its safety and tolerability profile and expanded evidence for use in other settings is well established. While it is probable that all AEDs proven effective in adjunctive polytherapy settings are also efficacious for use as monotherapy, available evidence guiding AED monotherapy remains somewhat limited, leading to relatively narrow FDA indications in United States practice. Several newer AEDs have randomized controlled trial evidence for monotherapy application, while clinical experience and lesser evidence lead to FDA \u201cgrandfathering\u201d of older AEDs for monotherapy indication in newly diagnosed epilepsy. However, relatively little evidence is available to guide clinicians as they implement changes between monotherapy or polytherapy AED regimens for patients with epilepsy. A panel of epilepsy neurologists and clinical pharmacologists was recently convened to address this important topic. The goal of the SPECTRA panel (Study by a Panel of Experts: Considerations for Therapy Replacement in Antiepileptics) was to develop consensus regarding practical issues in AED monotherapy conversions. This panel developed consensus on a key overriding treatment principle: to fully titrate an adjunctive drug prior to tapering a baseline drug when possible. The panel also developed drug-specific consensus recommendations that expand and complement available prescribing information that is useful in planning AED monotherapy conversions as well as AED sequencing in chronic polytherapy regimens .Current Neuropharmacology focuses on the topic of AED conversions in epilepsy care. This series of articles begins with a practical review of AED monotherapy in newly diagnosed epilepsy, next examines factors involved in monotherapy conversions during the process of transitional polytherapy, then outlines important considerations in ensuring successful chronic polytherapy. A discussion of the rationale and strategies for minimizing adverse effects in epilepsy care is then followed by a review of principles for appropriate blood level monitoring. Finally, this issue considers important patient-related factors in AED conversions. The above-referenced motivational sentiment of 19th century physician, author, and poet Josiah Holland well anticipated the approach to epilepsy treatment favored herein: initiate AED treatment as monotherapy, sequence medications as needed to achieve seizure control or improve a patient\u2019s acceptance and tolerability of therapy, and titrate most medications slowly and carefully to ensure maximal success. However, as the ensuing proverb reminds us, conversion between different AEDs may require specific modifications to ensure treatment success. The SPECTRA data summarized herein provides clinicians with a helpful new approach to guide conversions between AED therapies, and the accompanying review articles offer further relevant guidance for clinicians implementing AED conversions in epilepsy care.This issue of"}
+{"text": "Respiratory papilloma is a rare lesion that arises in the larynx, trachea and bronchus.We describe a patient with laryngeal papilloma that spread to the trachea and whichwas effectively treated by Nd-YAG laser. Two years after the initial treatments of thelaryngeal and tracheal papillomas, a recurrent lesion (solitary papilloma) was observedon the membranous portion of the trachea. We examined the recurrent lesion by bronchoscopyincluding bronchoscopic ultrasound (US), helical computed tomography (CT)and tracheal biopsies. Respiratory papillomatosis sometimes shows either malignanttransformation or invasion to tracheal wall without displaying cytohistological atypia.Therefore, we concluded that bronchoscopic US and helical CT were useful for decidingon therapeutic strategy in cases of recurrence of tracheal papilloma."}
+{"text": "Circumscribed choroidal hemangiomas are vascular tumors associated with secondary changes in the overlying retinal pigment epithelium and neuro-sensory retina. Spectral-domain optical coherence tomography, a recent advancement in fundus imaging techniques provides high resolution images of the retina. We describe spectral domain Optical coherence tomography findings in a case of circumscribed choroidal hemangioma which was successfully treated with photodynamic therapy.A 41-year-old white male presented with decreased vision in his right eye. Fundus evaluation showed findings consistent with circumscribed choroidal hemangioma. Spectral-domain optical coherence tomography revealed a large serous retinal detachment overlying the tumor with an intact photoreceptor layer. The patient underwent photodynamic therapy and a repeat tomography scan confirmed the resolution of serous detachment with return of normal foveal contour.Spectral domain optical coherence tomography is an emerging modality in imaging of the retina and reveals ultrastructural changes occurring in various retina pathologies. In this case report we illustrate the use of spectral domain optical coherence tomography for the first time to document retinal changes overlying a choroidal hemangioma and its role as a non-invasive tool in planning the treatment and prognosticating the final visual outcome following treatment for circumscribed subfoveal choroidal hemangiomas. Choroidal hemangiomas are vascular hamartomas of the choroid and can cause visual loss due to subfoveal location, associated exudative retinal detachment, cystoid macular edema or subretinal fibrosis ,2. A numSpectral domain OCT, in recent times, has been an important advancement in OCT technology, having enhanced speed and sensitivity in acquiring retinal images. It acquires upto 40000 scans in a short period of time and renders a 3-dimensional image with cross-sectional sections providing detailed ultrastructural changes within the retina . PDT. PDT8]. In conclusion, SD OCT is an emerging tool in the imaging of retina and provides high definition ultrastructural changes associated with vitreo-retinal disorders. In this case report we illustrate the use of SD OCT for the first time to document retinal changes overlying a choroidal hemangioma and its role as a non-invasive tool in planning the treatment and prognosticating the final visual outcome following treatment for circumscribed subfoveal choroidal hemangiomas.CCH: circumscribed choroidal hemagioma; ICG: indocyanine green; PDT: photodynamic therapy; RPE: retinal pigment epithelium; SD OCT: spectral domain optical coherence tomography.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.KC and SG identified the case and directly participated in management. They also revised the manuscript and verified its intellectual content. VB and RM worked in collaboration to collect data, acquire clinical photographs, and draft, revise, and reference the manuscript."}
+{"text": "In these patients, the number of apoptotic lymphocytes was significantly increased within tumour and peripheral blood. Furthermore, sFasL was present in the corresponding supernatants and induced apoptosis of Jurkat cells in a dose-dependent manner. These findings suggest that mFasL-positive colon cancer cells release sFasL, and thus may induce apoptosis of host lymphocytes as a potential mechanism for immune evasion. \u00a9 2001 Cancer Research Campaignhttp://www.bjcancer.comExpression of membrane-bound Fas ligand (mFasL) on colon cancer cells serves as a potential mechanism to inhibit host immune function by inducing apoptosis of host lymphocytes. Membrane-bound FasL can be cleaved and released as a soluble mediator (sFasL), which may spread the apoptosis induction effect. Our study examined whether colon adenocarcinoma cells release sFasL, and induce apoptosis of host lymphocytes without direct cell\u2013cell contact. In 12 consecutive patients with colon adenocarcinoma mFasL was identified in the tumours, sFasL was measured in the sera and apoptosis identified in tumour-infiltrating and peripheral blood lymphocytes. To analyse the function of sFasL, colon cancer cells were primarily cultured; sFasL was isolated from supernatants, measured, incubated with Fas-bearing Jurkat cells, and the resulting apoptosis was analysed. Serum levels of sFasL were significantly elevated in all colon cancer patients with mFasL expression in tumour tissues ("}
+{"text": "Five species of sigmodontine rodents have been identified in Argentina as the putative reservoirs of six circulating hantavirus genotypes. Two species of Oligoryzomys are associated with the genotypes causing hantavirus pulmonary syndrome, Oligoryzomys flavescens for Lechiguanas and O. longicaudatus for Andes and Oran genotypes. Reports of human cases of hantavirus pulmonary syndrome prompted rodent trapping  at potential exposure sites in three disease-endemic areas. Antibody reactive to Sin Nombre virus was found in six species, including the known hantavirus reservoir species. Risk for peridomestic exposure to host species that carry recognized human pathogens was high in all three major disease-endemic areas."}
+{"text": "We present a case of a man admitted to our Hospital for right acute scrotum that six months before had undergone a right hernioplasty with mesh implantation. Clinical history and testicular color Doppler sonography (CDS) patterns suggested an orchiepididymitis following acute prostatitis. After 48h the clinical picture worsened and testicular CDS showed a decreased telediastolic velocity that suggested testicular ischemia. The patient underwent surgical exploration: spermatic cord appeared stretched by an inflammatory tissue in absence of torsion and releasing of spermatic cord was performed.In patients with genitourinary infection who previously underwent inguinal mesh implantation, testicular CDS follow-up is mandatory. The acute scrotum constitutes the most common urological emergency and color Doppler sonography (CDS), along with the physical exam, represents the imaging modality more frequently employed in the clinical assessment of acute scrotum.The two most important entities that must be ruled out in every case of acute scrotal pain are torsion of spermatic cord and orchiepididymitis, while other causes occur more rarely. In case of inguinal hernia repair using mesh techniques the spermatic cord is potentially affected by chronic inflammatory tissue remodeling that may impair testicular perfusion inducing acute scrotum.A rare case of testicular ischemia following mesh hernia repair and acute prostatitis that presented as acute scrotum is reported herein.A 23-year-old man was admitted for right orchialgia arising 24h before admission; although he referred urinary symptoms  and fever of five days\u2019 duration, no therapy was previously administered. Six months before, the patient underwent a mesh implantation to treat a recurrent right inguinal hernia. At admission, history, genitourinary exam, blood and urine test and transrectal CDS suggested an acute prostatitis; testicular CDS revealed normal signal in correspondence of the testis and epididymis. The patient was hospitalized and submitted to antibiotic therapy. After 48h the clinical picture worsened: testicular pain and fever increased, CDS showed a decreased TDV (telediastolic velocity) on intratesticular artery  and a hiSpermatic cord torsion, orchiepididymitis and trauma constitute the main causes of acute scrotum, although the differential diagnosis refers essentially to the torsion of spermatic cord vs. inflammatory lesions. A careful physical exam and anamnesis combined with CDS parameters often address toward the diagnosis of testicular ischemia that, more rarely, can be secondary to severe epididymitis, inguinal hernia repair, spontaneet al. performed an experimental study in 15 adult male pigs that underwent transinguinal preperitoneal implantation of polypropylene mesh and shouldice repair on the contralateral side. The authors reported that mesh repair led to a decrease of arterial perfusion, testicular temperature and seminiferous tubules.[et al.[et al.[The use of mesh during hernia repair is associated with a relative reduction in the risk of hernia recurrence of around 30-50%; however, there is no apparent difference in recurrence between laparoscopic and open mesh methods of hernia repair. Experime tubules. Dilek ets.[et al. reportedl.[et al. showed tl.[et al. reportedIn our case report testicular ischemia was secondary to spermatic cord compression by an inflammatory and scar tissue in absence of torsion and only after releasing of spermatic cord the patient became asymptomatic.In conclusion, in patients with genitourinary infection who previously had an inguinal mesh implantation, clinical observation and CDS follow-up is mandatory to treat in time this unusual complication."}
+{"text": "An assay system is described in which effector cells added along with suitable target cells inhibit, in a quantitative fashion, the subsequent uptake of 3H-thymidine by those target cells. Effector cells active in this assay, using embryonic fibroblast cells as targets, develop spontaneously in cultures of mouse lymphoid cells, but are apparently different from those described earlier by investigators of activity in cytotoxic assays. Further evidence is presented to show the development of spleen-derived effector cells with cytostatic activity (for embryonic fibroblast target cells) in mice during the course of normal pregnancy, or growth of spontaneously appearing mammary adenocarcinomas. Indeed, such effector cells can also be found within the growing solid mass itself. Different populations of tumour cells isolated from a solid tumour apparently differ in their susceptibility to growth inhibition by tumour-bearer-derived cytostatic effector cells, a phenomenon which may be related to metastatic spread of tumour cells."}
+{"text": "Symptomatic prostatic cyst presenting as obstructive lower urinary tract symptoms (LUTS) is an infrequent diagnosis in males. Midline cysts are much more likely to obstruct the bladder outlet. We report our experience with four such cases in the last one year, along with a short review of the literature. Two of these cases had additional presenting symptoms besides LUTS - febrile Urinary tract infection (UTI) with perinephric abscess and primary infertility. One case had an anterior midline prostatic cyst which is an extremely rare entity. The remaining three had midline posterior cysts. All cases were treated with transurethral marsupialization, had good relief of symptoms and no adverse effects. Prostatic cysts, an erstwhile infrequent diagnosis in males, are usually asymptomatic and mostly detected incidentally during abdominal or trans-rectal ultrasonography (TRUS). Etiological factors include chronic prostatitis as a predominant cause of lateral prostatic cysts and congenital causes for midline cysts. Existent literature on midline prostatic cysts is mostly in the form of isolated case reports, which highlights their uncommon occurrence and even lower propensity for causing symptoms. We report our experience with managing symptomatic benign midline prostatic cysts, including a rare variant of an anterior midline prostatic cyst for which only three cases have been reported so far.Four young males  presented to us with lower urinary tract symptoms (LUTS) and/or other associated symptoms . ObstrucInitial evaluation included a urine microscopic analysis and culture, uroflowmetry and a screening abdominal ultrasonography which documented the presence of a prostatic cyst . AdditioAll patients underwent cystoscopy and transurethral incision of the prostatic cyst ; Case 4 The widespread use of TRUS for evaluating bladder outlet obstruction, infertility, UTI, hemospermia, ejaculatory pain, chronic pelvic pain, prostatic carcinoma or guiding prostatic biopsy has resulted in more frequent identification of prostatic cysts. Most proSymptomatic prostatic cysts are reported to be associated with prostatic abscess, chronic/recurrent prostatitis; as a cause of chronic pelvic pain, upper or lower UTI, infertility, hemospermia and rarely malignancy.4Lower urinary tract symptoms surprisingly are uncommon presenting symptoms, though midline cysts more frequently present with LUTS than laterally placed cysts. The large intraprostatic cyst may compress the prostatic urethral lumen, cause ejaculatory duct obstruction or stretch the prostatic capsule causing pelvic pain.Etiologically, prostatic cysts include the utricle, mullerian duct cyst, hemorrhagic prostatic cyst, hydatid cyst and cysts associated with prostatitis. Midline cysts, located posteriorly at the prostatic floor, are mostly developmental in origin and arise from remnants of fetal tissue \u2013 utricle or m\u00fcllerian duct. Utricular cysts are endodermal in origin, contain no spermatozoa and are located near the verumontanum, whereas m\u00fcllerian cysts are mesodermal in origin, contain spermatozoa and are located more posterior and nearer the prostate base. Some cysts are primarily prostatic glandular in origin and are acquired later in life. Most lateral prostatic cysts are related to chronic prostatitis, where they may play a causative role or may be consequent to it. Anterior midline cysts of prostatic origin are extremely rare with only three cases reported in the literature so far.\u20137 Case 1In some cases it may be fairly easy to directly relate the presence of the prostatic cyst as the etiology behind the patient's clinical symptoms. Though the diagnosis of a midline prostatic cyst can be made on TRUS examination, the functional implication of the midline prostatic cyst cannot be determined by TRUS alone. Thus, inet al., reported durable, recurrence-free results in a series of patients with medial prostatic cyst treated with transurethral incision.[et al., reported excellent outcome with transurethral resection of midline prostatic cyst projecting into the prostatic urethra and presenting as obstructive LUTS.[Various therapeutic options for managing midline prostatic cysts described include transrectal aspiration with or without sclerotherapy, transurethral marsupialization and open surgery. Dik et aincision. Similarlive LUTS."}
+{"text": "Mycobacterium ulcerans is an infection of the subcutaneous tissue leading to chronic necrotising skin ulcers. The pathogenesis is associated with the cytocidal and immunosuppressive activities of a macrolide toxin. Histopathological hallmark of progressing disease is a poor inflammatory response despite of clusters of extracellular bacilli. While traditionally wide excision of the infected tissue was the standard treatment, provisional WHO guidelines now recommend an eight week pre-treatment with streptomycin and rifampicin.Buruli ulcer caused by We conducted a detailed immunohistochemical analysis of tissue samples from Buruli patients who received antibiotic treatment. Cellular immune response along with bacterial load and distribution were monitored. We demonstrate that this treatment leads to the development of highly organized cellular infiltration surrounding areas of coagulative necrosis. Diffuse infiltrates, granulomas and dense lymphocyte aggregation close to vessels were observed. Mycobacterial material was primarily located inside mononuclear phagocytes and microcolonies consisting of extracellular rod-shaped mycobacteria were no longer found. In observational studies some patients showed no clinical response to antibiotic treatment. Corresponding to that, one of five lesions analysed presented with huge clusters of rod-shaped bacilli but no signs of infiltration.M. ulcerans, lacking patient compliance or poor drug quality are responsible for the absent clinical responses in some patients. In future, analysis of local immune responses could serve as a suitable surrogate marker for the efficacy of alternative treatment strategies.Results signify that eight weeks of antibiotic treatment reverses local immunosuppression and leads to an active inflammatory process in different compartments of the skin. Structured leukocyte infiltrates with unique signatures indicative for healing processes developed at the margins of the lesions. It remains to be analysed whether antibiotic resistance of certain strains of  Buruli ulcer (BU) is a debilitating disease of the skin presenting with extensive tissue destruction and suppression of local host defence mechanisms. Surgical removal of the affected area has been the standard therapy until in 2004 WHO recommended eight weeks' treatment with the anti-mycobacterial drugs rifampicin and streptomycin. We performed a detailed histological analysis of the local immune response in biopsies from five children medicated according to WHO provisional guidelines. One patient still revealed all histopathological signatures of an active BU lesion with huge bacterial clusters in areas of fatty tissue necrosis. Different factors can contribute to treatment failure, such as poor patient compliance and resistant bacterial strains. In four patients, different compartments of the skin presented active immune processes with only limited residues of bacterial material persisting. We demonstrated that antibiotic treatment not only directly controls the infectious agent but is also associated with fulminant host immune responses. Characterization of the healing process in BU due to therapy is highly relevant to increase our knowledge of the impact of treatment strategies to fight the disease. Mycobacterium ulcerans is a chronic necrotizing skin disease mainly affecting subcutaneous and adipose tissue M. ulcerans bacteria Buruli ulcer (BU) caused by BU is considered to be the third most common mycobacterial infection after tuberculosis and leprosy. Clinical lesions usually start as painless subcutaneous nodules that may develop into plaques or oedema. If left untreated, extensive ulcerations with typical undermined edges of the dermis develop. Spontaneous healing can occur, often leaving the patient behind with extensive scarring, retractions and deformities Until recently, surgery has been the only WHO recommended treatment for BU M. ulcerans strains indicate that infiltrating cells are killed due to the cytotoxic and apoptosis inducing activity of mycolactone M. ulcerans may be captured by phagocytes during different stages of infection, it appears to persist only transiently inside these host cells Histopathological hallmarks of progressing BU are a poor inflammatory response and growing regions of necrosis of the dermal and adipose tissue eventually leading to the collapse of the overlying epidermis . ClusterMycobacterium ulcerans disease, WHO, 2001), IS2404 PCR, microscopic detection of acid-fast bacilli and observation of characteristic histopathological changes. After receiving informed consent the immunologically non responding patient was tested for HIV positivity. Ethical approval for analysing patient specimens was obtained from the ethical review board of the Noguchi Memorial Institute for Medical Research and the National Ethics Committee of Cameroon.Surgical specimens from five patients aged between six and 11 years with ulcerative lesions were obtained from the Amasaman Health Centre in Ghana and the Ayos district hospital in Cameroon . Lesions3 were collected from different areas of the excised lesions to characterize the gradient of histopathological changes from necrotic areas to healthy appearing tissue at the excision margins  and Haematoxylin/Eosin (HE) was performed on all collected tissue specimen. Staining for acid-fast bacteria was performed according to WHO standard protocol (WHO Diagnostic booklet). In brief, sections were deparaffinized and rehydrated followed by incubation with ZN carbolfuchsin for 30 min at RT. Subsequently slides were washed in cool tap water for 5\u201310 min and individually differentiated with acid-alcohol. Counterstain was completed with haematoxylin and slides were mounted with Eukitt mounting medium.Pictures taken with a Nikon optiphot-2 microscope were saved using analySIS soft imaging system and processed with Adobe Photoshop CS.M. leprae and highly cross-reactive with other mycobacteria, was used to stain M. ulcerans for confirmation of ZN staining results. Staining of common mycobacterial antigens with polyclonal anti-leprae antibody (pAbLep) antiserum and haematoxylin counterstain revealed an accumulation of mycobacteria  highly organized epithelioid granulomas of different size and state of differentiation, primarily located in deeper dermal tissue ; (ii) leHistopathological characteristics of BU were still found in all four patients. These included psoriasiform and pseudoepitheliomatous epidermal hyperplasia and depigmentation  with excThe distribution of mycobacterial material was assessed by ZN staining  and immu+ T lymphocytes  (+ B cells appeared at the outer margins of the T lymphocyte layer (+ antigen-presenting cells (APCs) in particular Langhans' giant cells (+ phenotype (+ (proliferating) cells (+ polymorphonuclear neutrophilic leucocytes (PMNL) nor CD56+ natural killer (NK) cells could be detected in granuloma formations.A panel of antibodies specific for leukocyte markers  were usephocytes  with CD4 T cells  always o T cells . These ls (dDCs) . Occasiote layer . Cytoplant cells insert ant cells . Staininnt cells , arrow. henotype . Variablg) cells  presenteg) cells insert. + PMNL (+ NK cells showed a similar distribution with even lower cell counts (not shown). Foci of PMNL and NK cells with signs of apoptosis were located within necrotic tissue . Small clusters of CD20+ B lymphocytes were scattered within infiltrates Click here for additional data file.Table S1Main data of enrolled patients(0.03 MB DOC)Click here for additional data file."}
+{"text": "Patients with pre-existing neurological disease present a unique challenge to the anaesthesiologist. The cause of postoperative neurological deficits is difficult to evaluate, because neural injury may occur as a result of surgical trauma, tourniquet pressure, prolonged labour, or improper patient positioning or anaesthetic technique. Progressive neurological diseases such as multiple sclerosis may coincidentally worsen perioperatively, independently of the anaesthetic method. The most conservative legal approach is to avoid regional anaesthesia in these patients. However, high-risk patients, including those with significant cardiopulmonary disease, may benefit medically from regional anaesthesia and analgesia. The decision to proceed with regional anaesthesia in these patients should be made on a case-by-case basis. Meticulous regional anaesthetic technique should be observed to minimise further neurological injury.Neurological injury directly related to regional anaesthesia may be caused by trauma, neurotoxicity and ischaemia. Direct needle- or catheter-induced trauma rarely results in permanent neurological injury. The overall incidence of persistent paraesthesias has been estimated at 0.08% after spinal anaesthesia and at 2% after brachial plexus block1The needle-bevel configuration may influence the frequency and severity of peripheral nerve damage during regional anaesthesia. In an in vitro study, Selander et alNeurological deficits after regional anaesthesia may be a direct result of local anaesthetic toxicity. Clinical and laboratory findings indicate that anaesthetic solutions are potentially neurotoxicNeural ischaemia may occur as a result of systemic or local vascular insufficiency. Systemic hypotension with or without a spinal anaesthetic may produce spinal cord ischaemia in the watershed areas between radicular vessels, resulting in flaccid paralysis of the lower extremities . The use of local anaesthetic solutions containing epinephrine or phenylephrine may theoretically result in local ischaemia, especially in patients with microvascular disease, but clinical data are lacking8Previous spinal surgery has been considered to represent a relative contraindication to the use of regional anaesthesia. Many of these patients experience chronic back pain and are reluctant to undergo epidural or spinal anaesthesia, fearing exacerbation of their pre-existing back complaints. Several postoperative anatomical changes make needle or catheter placement more difficult and complicated after major spinal surgery. In a study 105 of 48 patients with chronic low back pain after spinal fusion, 8 showed significant spinal stenosis on computed tomographic scans and requited surgical decompressionThe guidelines for epidural anaesthesia after spinal surgery are unclear. Daley et alCrosby and HalpernHubbertThus, historically it was concluded that epidural anaesthesia may be successfully performed in patients who have had previous spinal surgery, but successful catheter placement may be possible on the first attempt in only 50% of patients, even by an experienced anaesthesiologist. Although adequate epidural anaesthesia is eventually produced in 40-95% of patients, there appears to be a higher incidence of traumatic needle placement, unintentional dural puncture and unsuccessful epidural needle or catheter placement, especially if spinal fusion extends to between L-5 and S-1.A more recent investigation examined the overall success and neurological complication rates among 937 patients with spinal stenosis or lumbar disc disease undergoing neuraxial block between 1988 and 2000Success rates did not differ between patients who had previous surgery and those who had undergone a spinal procedure. Ten  patients experienced new or progressive neurological deficits compared with preoperative findings. Although the majority of the deficits were related to surgical trauma or tourniquet ischaemia, the neuraxial block was the primary aetiology in 4 patients.The preliminary nature of these data warrants care in their interpretation. However, overall, patients with spinal stenosis or lumbar disc disease may undergo successful neuraxial block without a significant increase in neurological complications. Importantly, this includes patients who have undergone prior (minor) spinal surgery.Progressive neurological disease is considered by some to be a relative contraindication to regional anaesthesia, because of the difficulty in determining the cause of new neurological deficits that appear perioperatively. There are no controlled clinical studies identifying regional anaesthesia as a significant factor in increased risk of neurological injury, only anecdotal reports are available. The medicolegal issue, however, remains, and if regional anaesthesia is indicated for other pre-existing medical conditions or by patient request, the patient should be informed of the risk of neurological complications, including coincidental progression of preoperative deficits, associated with anaesthesia and surgery. This discussion, along with preoperative neurological status, should be fully documented in the patient's record.Patients with preoperative neurological deficits may undergo further nerve damage more readily from needle or catheter placement, local anaesthetic systemic toxicity, and vasopressor-induced neural ischaemia. Although the use of paraesthesia techniques is not contraindicated, care should be taken to minimize needle trauma and intraneuronal injection. Dilute local anaesthetic solutions should be used whenever feasible to decrease the risk of local anaesthetic systemic toxicity.The use of epinephrine-containing solutions is controversial. The potential risk of vasopressor-induced nerve ischaemia must be weighed against the advantages of predicting local anaesthetic intravascular injections, improved quality of block, and decreased blood levels of local anaesthetics. Because epinephrine also prolongs and block and therefore neural exposure to local anaesthetics, the appropriate concentration and dose of local anaesthetic solutions must be considered. Patients with microvascular disease in combination with an underlying peripheral neuropathy, such as those with diabetes, may be most sensitive to the vasoconstrictive effects of epinephrine.Efforts should also be made to decrease neural injury in the operating room through careful patient positioning. Postoperatively, these patients must be followed closely to detect potentially treatable sources of neurological injury, including constrictive dressings, improperly applied casts and increased pressure on neurologically vulnerable sites. New neurological deficits should be evaluated promptly by a neurologist for formal documentation of the patient's evolving neurological status and the arrangement of further testing and long-term follow-up."}
+{"text": "In brain mapping studies of sensory, cognitive, and motor operations, specific waveforms of dynamic neural activity are predicted based on theoretical models of human information processing. For example in event-related functional MRI (fMRI), the general linear model (GLM) is employed in mass-univariate analyses to identify the regions whose dynamic activity closely matches the expected waveforms. By comparison multivariate analyses based on PCA or ICA provide greater flexibility in detecting spatiotemporal properties of experimental data that may strongly support alternative neuroscientific explanations. We investigated conjoint multivariate and mass-univariate analyses that combine the capabilities to (1) verify activation of neural machinery we already understand and (2) discover reliable signatures of new neural machinery. We examined combinations of GLM and PCA that recover latent neural signals (waveforms and footprints) with greater accuracy than either method alone. Comparative results are illustrated with analyses of real fMRI data, adding to Monte Carlo simulation support."}
+{"text": "Avery and Avery, who find comparing conventional Japanese and organic Swedish beef production misleading, propose relying on \u201ccomprehensive life cycle analyses\u201d (LCAs) to quantify emissions from conventional U.S. beef production. However, neither study they cite  appears These results indicate that the intensification of beef production systems may be counterproductive because net emissions of carbon dioxide as well as nitrogen and other pollutants would increase.For a more comprehensive analysis, additional production aspects must be considered. A better comparison of conventional versus organic beef production may be an LCA of greenhouse gas (GHG) emissions from three Irish systems reported by In contrast to conventional production, organic farming can reduce nitrous oxide emissions by avoiding excessive amounts of manure, as stocking densities are limited to land available for manure application. Organic agriculture typically also uses less fossil-fuel energy, in part because thousands of feed transport miles may be reduced .2O in pasture soil organic matter , the Intergovernmental Panel on Climate Change  concludeMost of the observed increase in global average temperatures since the mid-20th century is very likely due to the observed increase in anthropogenic GHG concentrations.The link between GHG mitigation and organic or extensive animal agriculture systems is well established, as are the other environmental and public health benefits of less-intensive production systems. Understanding the efficacy of less technology-dependent mitigation strategies is critical as the effects of global warming become more evident."}
+{"text": "Studies on the zebrafish model have contributed to our understanding of severalimportant developmental processes, especially those that can be easily studied in theembryo. However, our knowledge on late events such as gonad differentiation in thezebrafish is still limited. Here we provide an analysis on the gene sets expressed inthe adult zebrafish testis and ovary in an attempt to identify genes with potentialrole in (zebra)fish gonad development and function. We produced 10 533 expressedsequence tags (ESTs) from zebrafish testis or ovary and downloaded an additional23 642 gonad-derived sequences from the zebrafish EST database. We clustered thesesequences together with over 13 000 kidney-derived zebrafish ESTs to study partialtranscriptomes for these three organs. We searched for genes with gonad-specificexpression by screening macroarrays containing at least 2600 unique cDNA insertswith testis-, ovary- and kidney-derived cDNA probes. Clones hybridizing to only oneof the two gonad probes were selected, and subsequently screened with computationaltools to identify 72 genes with potentially testis-specific and 97 genes with potentiallyovary-specific expression, respectively. PCR-amplification confirmed gonad-specificityfor 21 of the 45 clones tested . Our study, which involvesover 47 000 EST sequences and specialized cDNA arrays, is the first analysis of adultorgan transcriptomes of zebrafish at such a scale. The study of genes expressed inadult zebrafish testis and ovary will provide useful information on regulation of geneexpression in teleost gonads and might also contribute to our understanding of thedevelopment and differentiation of reproductive organs in vertebrates."}
+{"text": "Cardiac surgery is associated with excessive bleeding as compared to non-cardiovascular surgery. In many situations excessive bleeding is expected but unexpected bleeding may pose problem during and, or after surgery. Studies have found certain predictors for bleeding like, increased age, emergency surgery, low body surface area, prolonged cardiopulmonary bypass (CPB) time > 150 minutes, combined intracardiac and bypass surgery, number of bypass grafts (> 4), reoperative surgery and preoperative antiplatelets agent. Between 3% to 14% of patients with significant bleeding require re-exploration.3Liberal use of red blood cells transfusion is associated with increased nosocomial infection and mortality in critically ill patients.5Current blood conservation practice guidelines suggest that institutions strategy should start with preoperative evaluation to identify high risk patients and appropriate management of antiplatelet therapy. In all planned surgery thienopyridines (clopidogrel) should be stopped 5 to 7 days prior to surgery except in patients with drug eluting stents, in whom sudden withdrawal of antiplatelets can result in sudden stent thrombosis. Aspirin should only be discontinued in purely elective cases without acute coronary syndrome. The addition of clopidogrel to aspirin increases postoperative haemorrhage. Yende and Wunderink demonstrated that aspirin and clopidogrel increase postoperative bleeding sevenfold.Evidence for transfusion trigger recommends use of haemoglobin level and platelets count for red cells and platelets transfusion respectively. More advanced measurements such as whole body oxygen-carrying capacity, oxygen consumption, oxygen extraction ratios, and oxygen delivery provide more accurate means to estimate the need for red blood cell transfusions.9Intraoperative techniques in blood conservation cannot be underemphasized. Meticulous haemostasis and operative technique can play an important role in reducing blood loss. Acute normovolaemic haemodilution (ANH) has not only been shown to be more cost effective than preoperative autologous donation but also is not limited by time restraints preoperatively. The strategy behind ANH is to lower the red blood cell mass loss during surgery while preserving clotting factors. However, the efficacy of ANH is controversial. Segal et at showed that ANH was only moderately effective in reducing transfusions by 10% or 1 to 2 units less than the control group.11To limit blood transfusions, The Society of Thoracic Surgeons(STS) and The Society of Cardiovascular Anesthesiologists(SCA) guidelines recommend use of aprotinin and lysine analogues epsilon am inocaproic acid (EACA) and tranexamic acid (Cyclokapron) in high risk patients. Aprotinin (Trasylol) and the lysine analogues have very different modes and scope of action but ultimately inhibit fibrinolysis by limiting the action of plasmin. A metaanalysis on aprotinin concluded significant reduction in blood transfusion in patients undergoing CABG, redo CABG and valve replacement.13Factor VIIa is recommended for intractable bleeding, unresponsive to usual hemostatics and non surgical means.Some intervention and modification during CPB are useful in blood conservation. Open reservoir membrane oxygenator system during CPB may reduce blood utilization and improve safety. Similarly activated clotting time (ACT) guided heparin dosing during prolonged CPB not only reduce blood transfusion but also haemostatic system activation, and platelets and proteins consumption as compare to fixed dose heparin supplements. Retrograde autologous priming of the CPB circuit, intraoperative autotransfusion, either with blood directly from cardiotomy suction or recycled using a cell-saving device, shortly after the completion of CPB, salvage of pump blood, either administered without washing or after washing with a cell-saving device should be used for blood conservation.8Lastly, one cannot ignore importance ofa multimodality approach involving multiple stakeholders, institutional support and enforceable transfusion algorithms supplemented with point-of-care testing to prevent blood loss and blood transfusion.8This becomes particularly important in a developing country like India with limited resources, variable quality of blood banking and surgical expertise with exponential growth of cardiac surgical centres. The role of anaesthesiologist is vital for implementing evidence based transfusion practices in cardiac surgery."}
+{"text": "Mucobilia is a rare condition characterized by theaccumulation of abundant mucus within the intra- orextrahepatic biliary tree. A variety of hepatobiliaryand pancreatic neoplasms are mucin producingand have been associated with the development ofmucobilia including biliary mucinosis, biliary papillomatosis,mucin-producing cholangiocarcinoma(MPCC), or cystic neoplasms of the pancreas orbiliary tree (cystadenoma or cystadenocarcinoma).We report the case of 46 year-old male with a biliarycystadenocarcinoma of the caudate lobe which resultedin chronic biliary obstruction and relapsingcholangitis. A review of the literature for both mucobiliaand biliary cystadenocarcinoma is providedalong with a discussion addressing the clinical presentation,diagnosis, treatment, and prognosis forthis rare entity."}
+{"text": "Vascular abnormalities are uncommon causes of uterine bleeding. Laparoscopic surgeries, however, require expertise and improper techniques can lead to major vascular complications. We report an unusual case of utero-adenexal arterio- venous fistula with arterio - venous malformation due to pelvic trauma caused during laparoscopic sterilisation procedure, which was treated by percutaneous embolisation technique. To the best of our knowledge, this is the first documentation of such a complex vascular injury caused by laparoscopic sterilisation and its endovascular management. Vascular abnormalities are rare but potentially life-threatening causes of uterine bleeding in women of reproductive age, especialA 35-year-old female presented with profuse, irregular, intermittent vaginal bleeding for the past six months. One month prior to onset of the symptoms she underwent a laparoscopic tubal ligation at a peripheral centre. Her past obstetric history was non-contributory. General, systemic and gynaecological examinations were unremarkable except for the presence of significant pallor. Abdominal and transvaginal sonography showed presence of multiple vascular channels in the parametrium and myometrium with a bulky uterus and fluid in the endometrial cavity. Color Doppler imaging, suggested presence of arterio-venous shunting. Pelvic magnetic resonance imaging (MRI)  revealedDurreil and Loubat first described uterine AVM in 1926 and clasUltrasound with Color Doppler remains the primary imaging modality, which shows many hypoechoic or anechoic spaces, with evidence of flow on colour Doppler. Angiography is the gold standard for diagnosing these lesions and is essential to landmark the pattern of blood supply to the lesion pre-operatively. In addition, percutaneous endovascular embolisation preceding surgery can help contain the per-operative blood loss. Angiographic features consist of a complex tangle of vessels supplied by enlarged feeders from the uterine arteries. Early venous drainage indicated an associated AVF as was sAlthough laparoscopy is a relatively safe procedure occasionally serious complications such as major vascular injury (0.1 per 1000) arise. Such casEndovascular embolotherapy may serve as a viable option for management of vascular complications secondary to surgical trauma. The present report highlights a rare vascular complication due to a minimally invasive technique which was managed by another minimally invasive endovascular approach."}
+{"text": "Bacterial pathogens have evolved extraordinary mechanisms to efficiently infect host organisms. A majority of these pathogens do so by delivering virulence factors into host cells, which act to dampen host defenses or utilize the host as a niche for replication. Although regulation of virulence factor expression by bacterial pathogens is a well known pathogenic mechanism Yersinia spp., Shigella flexneri, Helicobacter pylori, and diarrheagenic Escherichia coli are well known for their ability to kill host cells. For Yersinia, death of infected macrophages dampens cytokine release and enables the pathogen to propagate with minimal challenges from the immune system Yersinia species is tightly regulated. Yersinia pestis, the etiologic agent of plague, and gastroenteritis-inducing Yersinia pseudotuberculosis and Yersinia enterocolitica all encode a cytotoxic virulence factor called YopJ/P (YopJ in the two former species and YopP in the latter), which are translocated into infected cells via a type III secretion system (T3SS) Y. pseudotuberculosis affects its virulence. Decreased secretion of YopJ was shown to enhance Y. pseudotuberculosis pathogenesis in vivo Y. pestis, enhanced cytotoxicity results in decreased incidence of pneumonic plague in vivo Yersinia is an efficient virulence strategy. Increased apoptosis of infected immune cells decreases production of proinflammatory cytokines; however, some inflammation at the early stages of infection is thought to facilitate tissue damage necessary for movement of bacteria and infected cells to other sites of replication within the host Escherichia coli, enterohaemorrhagic E. coli , and Citrobacter rodentium are attaching and effacing (A/E) pathogens that cause severe diarrheagenic disease espZ mutant (\u0394espZ) caused enhanced cytotoxicity in host cells when compared to the wild-type strain espZ strain is severely attenuated for virulence in vivo Enteropathogenic H. pylori causes apoptosis of infected gastric epithelial cells H. pylori has been linked to a secreted toxin called VacA, which induces cytochrome c release from mitochondria  by which S. flexneri enhances NF\u03baB-mediated pro-survival signals are unknown.All of the above pathogens have evolved strategies to attenuate their own host-damaging virulence factors. In many of these scenarios, removal of host-protective mediators actually reduces pathogenicity of the bacteria. The observation that EPEC encodes a host-protective virulence factor that is essential for its pathogenesis suggests that protecting host cells may be a key to the pathogenic strategies of other bacterial pathogens. The concept of host-protective virulence factors is only just emerging, and we believe host-protective virulence factors will become more apparent in other pathogenic strategies and may become interesting targets to combat bacterial disease. Importantly, virulence phenotypes that appear counterintuitive should not be ignored. Future studies into pathogenic mechanisms of virulent bacteria will likely reveal important roles for effectors or regulatory mechanisms that help the host cell and promote bacterial pathogenesis."}
+{"text": "Background: Disseminated herpetic infections during pregnancy have             been reported in the literature.            Case: This case presentation describes a pregnant patient who             presented with fever, elevated liver enzymes, and upper abdominal tenderness and             succumbed from fulminant herpetic hepatitis.            Conclusion: Early diagnosis and treatment are essential because of the             high mortality rate."}
+{"text": "The authors have determined that epineurial arteriolesof the sciatic nerve are innervated by nonadrenergic,noncholinergic nerves that contribute to the regulation ofvasodilation. Using immunohistochemistry, the authorsdetermined that nerves innervating epineurial arteriolescontain the neuropeptide calcitonin gene\u2013related peptide(CGRP). Using streptozotocin-induced diabetic rats, the authorsdemonstrated that CGRP content in sensory nervesinnervating epineurial arterioles and vasodilation in responseto exogenous CGRP was decreased. In summary,epineurial arterioles of the sciatic nerve are innervated bysensory nerves containing the neuropeptide CGRP. Thediabetes-like condition induced by streptozotocin reducesthe content of CGRP in these nerves and exogenous CGRPmediatedvasodilation. CGRP is likely an important regulatorof vascular tone and compromising its function couldcontribute to nerve ischemia and diabetic neuropathy."}
+{"text": "This prompted us to examine the 3D vascular network of normal colon mucosa, adenomas and invasive carcinomas by means of quantitative microvascular corrosion casting. Fresh hemicolectomy specimens from 20 patients undergoing cancer or polyposis coli surgery were used for corrosion casting, factor VIII and VEGF immunostaining. In addition, immunostaining was done on colorectal tissue from 33 patients with metastatic and non-metastatic carcinomas, polyposis coli and adenomas. This first quantitative analysis of intervessel and interbranching distances, branching angles and vessel diameters in human cancer specimens revealed distinct patterns of the microvascular unit in the tumour centre and periphery. Irrespective of the tumour localization and grading all individual tumours displayed qualitatively and quantitatively the same vascular architecture. This gives further evidence for the existence of a tumour type-specific vascular architecture as recently demonstrated for experimental tumours. Metastatic tumours displayed different vascular architectures only within hot spots, in terms of smaller intervascular distances than in non-metastatic tumours. Pre-cancerous lesions have in part virtually the same vascular architecture like invasive carcinomas. Comparison of VEGF immunostaining also suggests that angiogenesis sets in long before the progress towards invasive phenotypes and that the so-called angiogenic switch is more likely a sequence of events. \u00a9 2001 Cancer Research Campaign"}
+{"text": "Previously we have demonstrated that diabetescauses impairment in vascular function ofepineurial vessels, which precedes the slowingof motor nerve conduction velocity. Treatmentof diabetic rats with aldose reductaseinhibitors, aminoguanidine or myo-inositolsupplementation have been shown to improvemotor nerve conduction velocity and/ordecreased endoneurial blood flow. However,the effect these treatments have on vascularreactivity of epineurial vessels of the sciaticnerve is unknown. In these studies we examinedthe effect of treating streptozotocininducedrats with sorbinil, aminoguanidine ormyo-inositol on motor nerve conduction velocity,endoneurial blood flow and endothelium dependentvascular relaxation of arterioles thatprovide circulation to the region of the sciaticnerve. Treating diabetic rats with sorbinil,aminoguanidine or myo-inositol improved thereduction of endoneurial blood flow and motornerve conduction velocity. However, onlysorbinil treatment significantly improved thediabetes-induced impairment of acetylcholinemediatedvasodilation of epineurial vessels ofthe sciatic nerve. All three treatments were efficaciousin preventing the appropriate metabolicderangements associated with either activationof the polyol pathway or increased nonenzymaticglycation. In addition, sorbinil wasshown to prevent the diabetes-induced decreasein lens glutathione level. However, other markers of oxidative stress were not vividlyimproved by these treatments. These studiessuggest that sorbinil treatment may be moreeffective in preventing neural dysfunction indiabetes than either aminoguanidine or myoinositol."}
+{"text": "Photofrin accumulation in malignant and host cell populations of various tumours was studied by flow cytometry analysis of cells dissociated from the tumour tissue. The transplantable mouse tumour models included in this analysis were sarcomas EMT6, RIF, KHT and FsaN, Lewis lung carcinoma, SCCVII squamous cell carcinoma (SCC) and slowly growing moderately differentiated AT17 SCC. An example of spontaneous mouse adenocarcinoma was also examined. Staining with specific monoclonal antibodies was used to identify the various cell populations present in these tumours. The main characteristic of Photofrin cellular accumulation was a very high photosensitiser content found exclusively in a subpopulation of tumour-associated macrophages (TAMs). Photosensitiser levels similar to or lower than in malignant cells were observed in the remaining TAMs and other tumour-infiltrating host cells. Photofrin accumulation in malignant cells was not equal in all tumour models, but may have been affected by tumour blood perfusion/vascularisation. Results consistent with the above findings were obtained with SCC of buccal mucosa induced by 9,10-dimethyl-1,2-benzanthracene in Syrian hamsters. The TAM subpopulation that accumulates by far the highest cellular Photofrin levels in tumours is suggested to be responsible for the tumour-localised photosensitiser fluorescence."}
+{"text": "Research on the evolution of reproductive isolation in African cichlid fishes has largely focussed on the role of male colours and female mate choice. Here, we tested predictions from the hypothesis that allopatric divergence in male colour is associated with corresponding divergence in preference.Pseudotropheus zebra complex. We predicted that more distantly-related populations that independently evolved similar colours would interbreed freely while more closely-related populations with different colours mate assortatively. We used microsatellite genotypes or mesh false-floors to assign paternity. Fisher's exact tests as well as Binomial and Wilcoxon tests were used to detect if mating departed from random expectations.We studied four populations of the Lake Malawi P. emmiltos observed under control conditions. By contrast, assortative mating broke down when direct contact between female and male was prevented.Surprisingly, laboratory mate choice experiments revealed significant assortative mating not only between population pairs with differently coloured males, but between population pairs with similarly-coloured males too. This suggested that assortative mating could be based on non-visual cues, so we further examined the sensory basis of assortative mating between two populations with different male colour. Conducting trials under monochromatic (orange) light, intended to mask the distinctive male dorsal fin hues (blue v orange) of these populations, did not significantly affect the assortative mating by female We suggest that non-visual cues, such as olfactory signals, may play an important role in mate choice and behavioural isolation in these and perhaps other African cichlid fish. Future speciation models aimed at explaining African cichlid radiations may therefore consider incorporating such mating cues in mate choice scenarios. Drosophila . Theosophila , the breosophila , and theosophila  providedCichlid fishes specialised to live on rocky shores are known to be philopatric and poor dispersers, with significant genetic structure among populations isolated by habitat discontinuities ,18. It hGasterosteus spp.) in North American lakes that have adapted to different ecological conditions  and  and P. eklebacks ,54,55. THaplochromine cichlids are usually strongly sexually dimorphic in colour. We do not yet know whether olfactory signals involved in mate choice are expressed by both sexes. If so, it would greatly increase the likelihood that mate preferences may be learned by imprinting on the mother during mouthbrooding, a situation that may enhance the probability of speciation . Sexual The three principal implications of the findings presented here are that: (i) behavioural mating preferences in cichlid fish depend, in some populations, not on colour, but on other forms of sensory communication, which in some cases is not visual; (ii) between-population divergence in male colour does not necessarily imply divergent female preferences, so parallel evolution of male colour is not necessarily coupled with parallel evolution of female mating preference; (iii) sensory cues involved in behavioural isolation among haplochromine cichlids may vary among species and lakes and so speciation models based on one particular mate choice scenario may not apply to whole or all radiations of cichlids. This last point is worth bearing in mind because the type of trait involved in species isolation might provide important clues about which evolutionary force has driven population divergence and speciation.JB performed microsatellite genotyping, statistical analyses, and drafted the manuscript. MP performed behavioural experiments. CR provided critical review and discussion of draft versions. MIT performed microsatellite genotyping and contributed to preparation of the final manuscript. OS provided critical review and discussion of draft versions and supervised the data collection for experiment 1. CVO contributed with critical discussion of draft versions. GFT coordinated the study and was involved throughout the design, analysis, interpretation and writing of the work. All authors have read and approved the final manuscript.Pseudotropheus zebra and related species populations.Results of mate choice trials involving  The data presented are statistical analyses of the full data set, including female multiple spawnings and male multiple sirings, in mate choice trials involving either geographically and phylogenetically distant or proximal Pseudotropheus zebra and related species populations.Click here for file"}
+{"text": "The concept of endotoxin-mediated rather than direct liver injury in biliary obsruction wasinvestigated using the experimental rat model of bile duct ligation (BDL) and small bowelbacterial overgrowth (SBBO). Small identical doses of intravenous endotoxin caused a significantly more severe liver injury in rats with BDL, compared with sham-operatedrats, suggesting the possible contribution of LPS in this type of liver damage. BDL was thencombined with surgically created jejunal self-filling blind loops, which resulted in SBBO. PlasmaLPS level increased significantly, and once again a more severe liver injury, determined by liverhistology and serum gamma-glutamyl transpeptidase levels, was observed compared with thecontrol group of rats with BDL+self-emptying blind loops. The data presented suggest thatsmall amounts of exogenous LPS and/or the ordinarily innocous amounts of LPS constantlyabsorbed from the intestinal tract may be critical in the hepatic damage caused by obstructionof the biliary tract."}
+{"text": "Immunofluorescence studies of sera from mice with induced enhancement of tumour growth demonstrated that these sera contained factors (\"interfering factors\") which in an apparently competitive manner interfered with the subsequent binding of specific antibodies to antigenic sites on the tumour-cell membrane. The factors were tumour-specific but lacked some of the immunoglobulin determinants. They could not be detected by polyvalent FITC-antimouse gamma-globulin. Interfering factors did not seem to be related to IgA or IgE. They were demonstrable in sera from tumour-free animals without growing tumours, thus differing from the tumour-specific \"blocking factors\"."}
+{"text": "The value of neuron specific enolase (NSE) immunoreactivity as a marker for small cell lung cancer (SLC) has been assessed using a monoclonal antibody (MCAB) against NSE, MCAB specificity was confirmed using purified enolase isoenzymes, sections of human brain, a panel of lung tumours, neuroendocrine and non-neuroendocrine tumours and normal tissues. Using this MCAB in radioimmunoassay and immunohistochemistry, NSE immunoreactivity was detected in all SCLC material examined. However, considerable reactivity was also observed in a number of non-small cell lung cancer cell lines and tumour biopsy specimens. Furthermore, intratumoral heterogeneity with respect to NSE immunostaining was observed in several cases. Factors which may underlie such intratumoral phenotypic diversity were assessed using flow cytometry together with MCABs directed against both NSE and non-neuronal enolase. Such studies revealed that enolase expression in cells which were no longer actively proliferating differed markedly from that of cells in exponential growth. Furthermore, cells grown under conditions of increasing hypoxia exhibited increased enolase expression relative to those grown under oxygenated conditions. It is concluded from these studies that NSE immunoreactivity per se is an unreliable marker for the SCLC phenotype."}
+{"text": "ELISAs for pesticides and herbicides in environmental andagricultural samples are becoming very important in screeningapplications [1-3]. Traditional chromatographic methods areexpensive and results need long turnaround times, making themincompatible with rapid on-site decision making. ELISA methodshave been shown to meet or exceed the performance of gaschromatography\u2014they offer rapid low-cost analysis, therebyincreasing the frequency of sampling and enhancing data quality.Automated ELISA workstations allow the full benefit of these kitsto be realized. Sample preparation, reagent pipetting, incubation,and photometric evaluation can be performed without userintervention. Reliability is increased through the elimination ofoperator error, better accuracy and precision, and often higher speed.Much larger batch sizes are possible and these systems can providesample tracking with report generation for documentationrequirements. In this paper the manual procedures and ELISAmethods are compared and some critical aspects of automating theseELISA kits are discussed."}
+{"text": "A 41-year-old female patient was admitted with streptococcal meningitis on a background of 5-month history of CSF rhinorrhoea. Imaging revealed an extensive skull base lesion involving the sphenoid and ethmoid sinuses, the pituitary fossa with suprasellar extension and bony destruction. Histological examination of an endonasal transethmoidal biopsy suggested a diagnosis of olfactory neuroblastoma. A profuse CSF leak occurred and the patient developed coliform meningitis. A second endonasal endoscopic biopsy was undertaken which demonstrated the tumour to be a prolactinoma. Following endonasal repair of the CSF leak and lumbar drainage, she developed profound pneumocephalus. The patient underwent three further unsuccessful CSF leak repairs. Definitive control of the CSF leak was finally achieved through a transcranial approach with prolonged lumbar drainage. This case illustrates some of the potentially devastating complications which can occur as a consequence of complex skull base lesions. A multidisciplinary approach may be required to successfully manage such cases. Traditionally, complex paranasal and anterior skull base lesions have been managed with either transcranial or transphenoidal microsurgical approaches. The application of endoscopy to neurological surgery and advances in neuronavigation have provided further options to skull base surgeons. One of the commonest complications of skull base lesions and their management is the occurrence of CSF leakage, which can result in the potentially fatal consequences of pneumocephalus and meningitis. Despite advances in microsurgical and endoscopic technology and expertise, definitive management of complex lesions and their resultant complications may require multidisciplinary team management and open transcranial neurosurgery. A 41-year-old female patient was referred to the ENT outpatient clinic with 5-month history of clear fluid discharging from the nose. Fluid samples were sent for tau protein analysis and outpatient imaging was requested. Prior to completion of skull base imaging, the patient was admitted in an acute confusional state, with a nonblanching rash, pyrexia, and signs of meningism. A diagnosis of streptococcal meningitis was made following lumbar puncture and she was commenced on appropriate antibiotics. Magnetic resonance imaging demonstrated an extensive skull base lesion involving the sphenoid and ethmoid sinuses, pituitary fossa, and suprasellar region . ComputeAn endonasal transethmoidal biopsy was undertaken, following which there was profuse CSF rhinorrhoea. Subsequently, the patient developed clinical signs of meningism with pyrexia, neck stiffness, photophobia, and deterioration in neurological status. CSF analysis revealed gram-negative coliforms and antibiotic treatment was commenced.The patient was transferred to the regional neuroscience centre for joint neurosurgical and ENT management. On recovery from the second episode of meningitis, she underwent an endoscopic endonasal biopsy and repair of the anterior pituitary fossa and planum sphenoidale using layered fat graft and artificial dural substitute sealed with Tisseel fibrin sealant . Histological analysis of this biopsy specimen confirmed the tumour to be a prolactinoma. Although her initial serum prolactin level was only 451\u2009miu/mL , it did rise to 953\u2009miu/mL in the immediate postbiopsy period. Following endocrine review, she was commenced on cabergoline.Despite satisfactory intraoperative appearances, CSF rhinorrhoea recurred. A CT cisternogram was undertaken to further characterise the site of CSF leakage . ThroughBoth attempts were unsuccessful and lumbar CSF drainage resulted in profound pneumocephalus . The patOnce sufficient neurological recovery had occurred, a second CT cisternogram  was undeFollowing the fourth unsuccessful attempt, the patient underwent a transcranial repair of the CSF leak through a right-sided pterional craniotomy. Intraoperatively, no dural defect was visible; however, bony defects in the anterior pituitary fossa floor were palpable and therefore sealed with layers of temporalis fascia and muscle grafts secured with Tisseel sealant. A prolonged post-operative period of lumbar CSF drainage (7 days) was also undertaken which resulted in a successful control of CSF rhinorrhoea. The initial and subsequent biopsies were reviewed and showed an identical tumour consisting of sheets of cells with mildly pleomorphic round to oval nuclei and moderate amounts of eosinophilic cytoplasm . MitoticThe difficulties encountered in definitive occlusion of the bony defects resulting in CSF rhinorrhoea in this case are likely to have resulted from a number of causes. Whilst bony destruction is a recognised feature of aggressive prolactinomas, the extensive infrasellar growth pattern seen in this case is unusual . Once thThe potential pitfalls in differentiating olfactory neuroblastoma from prolactinoma and other paranasal tumours on histological examination have previously been described . The hisComplex paranasal and skull base lesions can result in bony defects and problematic CSF leaks. Although dopamine receptor agonists are the treatment of choice for prolactinomas, tumour shrinkage can take several weeks and residual tumour may contribute to recurrence of CSF leakage. Consequently, tumour debulking might be considered in patients with recurrent CSF rhinorrhoea in whom a histological diagnosis of prolactinoma has been confirmed. This case illustrates some of the potentially devastating complications of untreated CSF rhinorrhoea including recurrent meningitis and consequent raised CSF pressure, and pneumocephalus resulting in seizures and reduced conscious level. Management of these lesions requires a multidisciplinary approach involving ENT surgeons, neurosurgeons, neuroradiologists, and endocrinologists. The time at which endoscopic or transphenoidal approaches are abandoned in favour of transcranial surgery will depend on the surgical experience of the team and the anatomy of the site of CSF leakage. Despite advances in neuro-navigation and endoscopic surgery, transcranial repair maybe the only successful solution."}
+{"text": "New computational tools were used to find a robust set of DNA oligomers that can distinguish artificial vector sequences from all available background viral and bacterial genomes. Using newly designed computational tools we show that, despite substantial shared sequences between natural plasmids and artificial vector sequences, a robust set of DNA oligomers can be identified that can differentiate artificial vector sequences from all available background viral and bacterial genomes and natural plasmids. We predict that these tools can achieve very high sensitivity and specificity rates for detecting new unsequenced vectors in microarray-based bioassays. Such DNA signatures could be important in detecting genetically engineered bacteria in environmental samples. Synthetic vector sequences are of fundamental importance in molecular biology. Cloning and expression vectors are among a multitude of synthetic sequence types commonly used as part of a basic tool set for DNA amplification and protein production . As the Large-scale computational pipelines have advanced bio-defense by efficiently finding polymerase chain reaction (PCR) assay-based primers that are able to accurately identify dangerous bacterial and viral pathogens -10. The A computational analysis was performed on the available synthetic vector sequences, which form an important basis for current tools in genetic engineering . One of k-mer matching (a k-mer is a nucleic acid sequence of length k). This alignment-free comparative sequence approach  and [GenBank:4323404].The vector sequences with the greatest number of he graph  with theCDS, coding sequence; MCS, multiple cloning site; PCR, polymerase chain reaction, RAM, random access memory.JEA, SNG and TRS conceived and designed experiments. JEA implemented experiments and drafted the manuscript. All authors read and approved the final manuscript.The following additional data are available with the online version of this paper. Additional data file The list of artificial vector identifiers.Click here for additional data fileThe list of natural plasmid identifiersClick here for additional data fileThe complete set of 30-mer signatures used in the cross-validation setClick here for additional data fileThe complete set of 60-mer signatures used in the cross-validation setClick here for additional data file"}
+{"text": "Metering liquid reagents into reaction mixtures in a controlled andreproducible manner has often been a problem in syntheticchemistry. Carrying out the real simultaneous addition of two ormore liquid reagents (concurrent additions) is even more inconvenient.Difficulties increase when addition volumes become small,when addition times become long, or when the reagents are corrosiveor air-sensitive. We have constructed and tested an inexpensive,automated device for the slow, precise delivery of liquid reagentsinto laboratory-scale reaction mixtures. Controlled by a standardpersonal computer, this slow adder can accommodate liquidvolumes from hundreds of microlitres to litres and addition timesfrom minutes to days. Its glass and Teflon construction makes ituseful for nearly all reagents. By using multiple slow adders, trueconcurrent addition of several liquids can be easily achieved."}
+{"text": "Cryostat sections and established in vitro cultures of dimethylnitrosamine(DMN)-induced renal mesenchymal tumours and monolayer cultures of transformed kidney cells derived from rats treated with a carcinogenic dose of DMN were examined by indirect immunofluorescence with human serum containing smooth muscle antibody. Eight mesenchymal tumours examined showed filamentous cytoplasmic staining of spindle cells infiltrating between renal tubules, whilst in normal kidneys interstitial cells were only weakly positive. In established in vitro cultures from 6 mesenchymal tumours, different patterns of staining were observed in morphologically different cell forms, ranging from fine filamentous staining in giant cells to diffuse cytoplasmic fluorescence in small bipolar cells, and cell outline staining in polygonal cells. In addition filamentous staining of microvillous projections and nucleolar staining were observed in some tumour cells. Monolayer cultures of transformed kidney cells showed strong staining of coarse, randomly-orientated cytoplasmic filaments, whilst fibroblasts cultured from normal rat kidney demonstrated an ordered array of fine, parallel filaments. Specificity of the immunofluorescent staining reaction was established by failure to obtain staining with normal serum, with smooth muscle antibody serum neutralized by homogenates of smooth muscle or extracts containing actin derived from smooth muscle. These results indicate that there is an apparent increase of actin-like contractile microfilaments in transformed cells and in renal mesenchymal tumours. The cytoplasmic contracile microfilaments in these cells may play a role in tumour cell mobility and invasion."}
+{"text": "Plasmodium falciparum can induce immunity in patients from which further inhibits fertilization of gametes, and consequently oocyst production in the mosquito midgut [P. falciparum-infected blood fed to female Anopheles mosquitoes showed no oocyst production. Twenty-six percent of these oocyst inhibitory plasma distorted morphology and hampered maturity of the gametocytes (Fig.Gametocyte antigens of o midgut . Here, wytes Fig.. A possiAnti-gametocyte antibodies were elicited during natural malaria infection. The oocyst inhibitory antibodies diffused to and interacted with developing intraerythrocytic gametocytes and reduced number of stage II to V gametocytes, and hampered their maturation. Therefore the alternative development of transmission blocking vaccine in the high transmission area should focus on the identification of the gametocyte antigens inducing inhibitory antibodies to reduce gametocytemia."}
+{"text": "A series of intensive, longitudinal, mark-recapture studies of hantavirus infection dynamics in reservoir populations in the southwestern United States indicates consistent patterns as well as important differences among sites and host-virus associations. All studies found a higher prevalence of infection in older  mice; one study associated wounds with seropositivity. These findings are consistent with horizontal transmission and transmission through fighting between adult male rodents. Despite very low rodent densities at some sites, low-level hantavirus infection continued, perhaps because of persistent infection in a few long-lived rodents or periodic reintroduction of virus from neighboring populations. Prevalence of hantavirus antibody showed seasonal and multiyear patterns that suggested a delayed density-dependent relationship between prevalence and population density. Clear differences in population dynamics and patterns of infection among sites, sampling periods, and host species underscore the importance of replication and continuity of long-term reservoir studies. Nevertheless, the measurable associations between environmental variables, reservoir population density, rates of virus transmission, and prevalence of infection in host populations may improve our capacity to model processes influencing infection and predict increased risk for hantavirus transmission to humans."}
+{"text": "Although basic mechanisms of bronchial hyper-responsiveness (BHR)are still incompletely understood, inflammation of airways is likelyto play a fundamental role in modulating BHR in patients withasthma. The involvement of several inflammatory cells  andof bioactive mediators secreted by these cells in the pathogenesisof asthma is well documented. Sodium cromoglycate and nedocromilsodium are two pharmacological agents which have anti-allergic andanti-inflammatory properties. Their clinical effectiveness in mildto moderate asthma, and the capacity to reduce BHR under differentnatural and experimental conditions, make them valuable drugs formaintenance therapy in patients with asthma."}
+{"text": "Beyond the classic Normal Pressure Hydrocephalus (NPH) triad of gait disturbance, incontinence, and dementia are characteristic signs of motor dysfunction in NPH patients. We used highly sensitive and objective methods to characterize upper limb extrapyramidal signs in a series of NPH subjects compared with controls. Concentrated evaluation of these profound, yet underappreciated movement disorders of NPH before and after techniques of therapeutic intervention may lead to improved diagnosis, insight into pathophysiology, and targeted treatment.Twenty-two (22) consecutive NPH patients and 17 controls performed an upper limb motor task battery where highly sensitive and objective measures of akinesia/bradykinesia, tone, and tremor were conducted. NPH subjects performed this test battery before and more than 36 h after continuous CSF drainage via a spinal catheter over 72 h and, in those subjects undergoing permanent ventriculo-peritoneal shunt placement, at least 12 weeks later. Control subjects performed the task battery at the same dates as the NPH subjects. Statistical analyses were applied to group populations of NPH and control subjects and repeated measures for within subject performance.Twenty (20) NPH subjects remained in the study following CSF drainage as did 14 controls. NPH subjects demonstrated akinesia/bradykinesia (prolonged reaction and movement times) and increased resting tone compared with controls. Furthermore, the NPH group demonstrated increased difficulty with self-initiated tasks compared with stimulus-initiated tasks. Following CSF drainage, some NPH subjects demonstrated reduced movement times with greater improvement in self- versus stimulus-initiated tasks. Group reaction time was unchanged. Resting tremor present in one NPH subject resolved following shunt placement. Tone measures were consistent for all subjects throughout the study.Clinical motor signs of NPH subjects extend beyond gait deficits and include extrapyramidal manifestations of bradykinesia, akinesia, rigidity, and propensity to perform more poorly when external cues to move are absent. Objective improvement of some but not all of these features was seen following temporary or permanent CSF diversion. The classic clinical triad of Normal Pressure Hydrocephalus (NPH) includes gait disturbance, incontinence, and dementia though most patients exhibit less than three of these signs early in the progressive clinical course ,2. In adThat ventriculo-peritoneal shunting reverses each of the classic signs in some NPH patients suggests a causative role in CSF dynamics, but the mechanisms underlying the neuronal and glial pathophysiology of NPH remain obscure. During the course of NPH, periods of elevated intracranial CSF pressure are hypothesized to result in dysfunction of white and gray matter of the brain  . These hFew investigations of NPH patients have included objective and sensitive analysis of extrapyramidal motor signs, and examination of these signs outside of gait dysfunction are rarer still ,10-12. WThis study, together with patient recruitment, was approved by the Johns Hopkins University Institutional Review Board. Signed, informed consent was obtained from each subject. Twenty-two (22) consecutive subjects above the age of 50  referred for evaluation of possible NPH were recruited from the Johns Hopkins University Outpatient Center, with no enrollment restrictions based on race or ethnic origin. Requirements for inclusion were radiographic evidence of ventriculomegaly by CT scan or conventional MRI, and clinical signs of NPH that included gait impairment, urinary incontinence, or cognitive impairment. Subjects were excluded if they had undergone prior shunt or intracranial surgery, were unable to undergo lumbar puncture for CSF drainage or had other active neurologic disease . Controls (n = 17) were partners of eligible NPH subjects  and were required to be free from clinical signs of NPH.NPH subjects were tested with the entire battery of tasks at 1) baseline, 2) within 36 h following removal of approximately 10 ml CSF/h for 72 h via a temporary spinal catheter and 3) approximately 12 weeks following ventriculo-peritoneal shunt insertion (Medtronic). Control subjects were tested with the entire battery of tasks on the same days of testing as NPH subjects. Two NPH subjects demonstrated signs of infection following CSF drainage via spinal catheter and were excluded from further testing and analysis. One subject withdrew consent to participate in the study after baseline testing such that subsequent data were not collected.Subjects performed ballistic movements using their dominant hand by moving a manipulandum that constrained two-dimensional movement about the wrist. Targets, 10\u00b0 wide and unbounded , were separated by 50\u00b0. Practice trials were performed for this simple task to avoid any potential learning curve barriers. Subjects reacted and moved in response to an auditory \"GO\" signal (stimulus-initiated tasks) or performed the identical movement task in the absence of a \"GO\" signal (self-initiated tasks). All subjects were informed ahead of time if they were to perform stimulus- or self-initiated tasks, and in both cases received preparatory auditory cues of \"ready\" and \"set\" in the initial stages of the task. In stimulus-initiated tasks, these preparatory cues preceded randomly delivered \"GO\" signals, and in self-initiated tasks, where no \"GO\" signal was delivered, a minimum time of 2 s of hold time was required after the \"set\" cue before initiating movement. Errors were recorded and the task discarded if movement occurred prior to 150 ms more than \"GO\" signal, more than 1 s after the \"GO\" signal, or if final target was overshot. An electronic goniometer continuously recorded manipulandum position during the task and was fed into an online recording computerized system  along with auditory cues and electromyographic recordings of agonist and antagonist wrist muscles performing the task. Forty-five correctly performed trials were performed by each of the subjects. Reaction time (RT) was measured as time between \"GO\" signal and first significant change of the agonist electromyographic record (EMG) over baseline (RT/EMG) and between \"GO\" signal and movement onset (MO) (RT/MO). Electromechanical delay (EMD) was determined as the time between first agonist EMG and movement onset. Movement time (MT) was defined as the time between movement onset (MO) and achieving final target.k = the slope of force over displacement), or active EMG activity in primary agonists or antagonists about the elbow [Muscle tone was measured by an apparatus that quantifies tone about the elbow. Subjects rested their dominant forearm in a molded and padded cradle mounted on a metal beam. The cradle rotated on low-friction ball bearings and an electronic goniometer measured angular displacement. A load cell  located at the side of the metal beam measured the torque applied by the examiner. The torque plotted against the angle (degrees) represented muscle stiffness, and post-hoc least squares fit analysis was then performed to determine the slope of the contour representing tone about the elbow . The tonhe elbow . Three dhe elbow .Tremor was analyzed using triaxial solid-state accelerometers  that detect frequency (Hz) and amplitude  in \u03bcm. Triaxial accelerometers were placed on the distal hand while the subjects' hands were at repose for a period of 120 s. Subjects were then asked to hold their arms outstretched, and tremor analysis was repeated during the next 60 s. All data were fed online to a Pentium based computer and analyzed using Fast Fourier Transforms. Mean tremor amplitude and dominant frequency were recorded while at rest and with outstretched arms.Group statistical analyses for parametric measures were compared using ANOVA tests with Fisher's Least Square Difference Post-Hoc analysis when F scores were significant or Kruskal-Wallis comparisons for non-parametric measures of reaction time. Analyses within individuals were compared using Repeated-measures ANOVA with Fisher's Least Square Difference or Friedman's analysis with Mann-Whitney Post-Hoc analysis.p < 0.01), or as RT/MO  when compared with the control group  . Mean movement times for stimulus-initiated and self-initiated tasks are plotted for each NPH subject at baseline in Figure As a group, NPH subjects demonstrated prolonged MT versus controls Table . At baseThose NPH subjects with fastest movement times (least bradykinetic) were least apt to exhibit discrepancies between self- and stimulus-initiated movements. Furthermore, those NPH subjects with fastest movement times were least apt to exhibit wide intertrial movement time variability as reflected by size of error bars Figure .p < 0.05), but this did not hold true for the group analysis comparing NPH subjects before and after continuous CSF drainage . Those subjects demonstrating significant differences of movement times from baseline following CSF drainage maintained this difference following shunt placement. Furthermore, selective improvement of self- versus stimulus-initiated movement times persisted with shunt placement Figure . Controlp < 0.02, Table p < 0.02, R2 = 0.79). Following CSF drainage and following shunt placement, there were also no significant changes in slope (representing rigidity at the elbow) for the NPH subjects. However, there were qualitative differences in tone hysteresis loops following CSF drainage in NPH subjects including greater incidence in EMG activity and sudden tone perturbations in the NPH group not seen in control subjects.Tone measures at baseline demonstrate increased passive tone about the elbow in NPH subjects compared with control cohorts . Although some subjects improved in both gait and upper extremity measures, this was not uniformly so \u2013 such that substantial improvement in gait measures did not always coincide with improvement in ballistic measures. Since none of the subjects improved in measures of tone, improvement in gait did not correlate with this measure. Interestingly, some of those subjects that demonstrated increased upper extremity bradykinesia following CSF drainage also demonstrated worsening bradykinesia in gait testing.In a parallel study, these same subjects underwent formal gait analysis  in NPH subjects. This implies that different pathophysiological substrates underlie each of these motor signs in NPH, and/or that these signs emerge independently. Of these extrapyramidal signs, not all respond equally to CSF drainage. Why would only some symptoms respond to CSF drainage? It is plausible that some structures revert to normal function with reduction of direct shearing forces, while others  are irreversible or require time for tissue recovery or compensatory pathways to develop. In addition, there is always a potential for multiple etiologies to confound the presentation and responsiveness of clinical signs related to NPH, but our selection criteria sought to minimize these factors.It is an interesting finding that some NPH patients demonstrated the classic Parkinsonian motor characteristic of improved movement execution in the presence of external cues. Others have seen a less dramatic benefit of external cues when studying NPH patients during gait analysis ,18. Our NPH subjects demonstrate increased tone compared with controls. This tone is unrelated to spasticity and independent of movement speed. Our measures of tone are highly sensitive, and even a significant increase in tone compared with controls may be subclinical. From what is known of NPH, one would expect a supraspinal mechanism underlying increased tone. Such mechanisms have been proposed for the increased tone seen in Parkinsonism . There wThe underlying motor pathophysiology of NPH signs extends beyond gait and bladder dysfunction with prevalence of extrapyramidal signs. These include even complex Parkinsonian signs of reliance upon external cues for improved motor performance. That NPH subjects demonstrated improvement of some signs in short order following CSF drainage suggests reversible pathophysiologic mechanisms that can improve activities of daily living. However, sensitive and objective motor measures in this sample suggest other motor dysfunction is resistant to immediate correction by CSF drainage and may be recalcitrant or require chronic treatment to see improvement.Dr. Michael A. Williams and Dr. Daniele Rigamonti have received honoraria in the past from Medtronic, Inc. Dr. George Thomas worked at the Adult Hydrocephalus Center at Johns Hopkins when this study was conducted. His salary was supported by a grant from Medtronic, Inc.ASM provided study design, oversight of data acquisition, data analysis, and drafting the manuscript. JH tested each subject, performed data collection and first stage data analysis. GT provided subject recruitment, scheduling and evaluation. REM participated in critical review of the manuscript and in evaluation of study design. TOC participated in provided testing environment and critical analysis on data collection and interpretation. MAW contributed in patient evaluation and categorization and critical manuscript review. DR contributed to study design, patient evaluation and critical manuscript review. All authors have read and approved the final manuscript."}
+{"text": "Recent advances in genomics provide genetic information from humans and othermammals  traditionally used as models as wellas new candidates (pigs and cattle). In addition, linked enabling technologies,such as transgenesis and animal cloning, provide innovative ways to design andperform experiments to dissect complex biological systems. Exploitation of genomicinformation overcomes the traditional need to choose naturally occurring models.Thus, investigators can utilize emerging genomic knowledge and tools to createrelevant animal models. This approach is referred to as reverse genetics. In contrastto \u2018forward genetics\u2019, in which gene(s) responsible for a particular phenotypeare identified by positional cloning (phenotype to genotype), the \u2018reverse genetics\u2019approach determines the function of a gene and predicts the phenotype of acell, tissue, or organism (genotype to phenotype). The convergence of classicaland reverse genetics, along with genomics, provides a working definition of a\u2018genetic model\u2019 organism (3). The recent construction of phenotypic maps definingquantitative trait loci (QTL) in various domesticated species provides insights intohow allelic variations contribute to phenotypic diversity. Targeted chromosomalregions are characterized by the construction of bacterial artificial chromosome(BAC) contigs to isolate and characterize genes contributing towards phenotypicvariation. Recombineering provides a powerful methodology to harvest geneticinformation responsible for phenotype. Linking recombineering with gene-targetedhomologous recombination, coupled with nuclear transfer (NT) technology canprovide \u2018clones\u2019 of genetically modified animals."}
+{"text": "Repeated treatment with streptozotocin selected toxin resistant subpopulation of insulin producing tumor RINmS cells, characterized increased level of insulin content and secretion. In the present study RINmS cells were found to have higher glucose sensitivity and insulin response compared with parental RINm cells. In addition, compounds known to induce elevated level of cAMP beta-cells, such as isobutyl methyl xanthine, and forskolin, potentiated glucose-induced insulin secretion of RINmS, but had no effect on the naive parental RINm cells. These experiments suggest that differentiation therapy can be utilized for engineering insulin producing cells with improved defense and secretory mechanisms.Differentiation therapy has been proposed as a new approach to selectively engage the process of tumor cell differentiation during chemotherapy of cancer. Our recent"}
+{"text": "Molecular epidemiologic studies of infectious diseases rely on pathogen genotype comparisons, which usually yield patterns comprising sets of DNA fragments (DNA fingerprints). We use a highly developed genotyping system, IS6110-based restriction fragment length polymorphism analysis of Mycobacterium tuberculosis, to develop a computational method that automates comparison of large numbers of fingerprints. Because error in fragment length measurements is proportional to fragment length and is positively correlated for fragments within a lane, an align-and-count method that compensates for relative scaling of lanes reliably counts matching fragments between lanes. Results of a two-step method we developed to cluster identical fingerprints agree closely with 5 years of computer-assisted visual matching among 1,335 M. tuberculosis fingerprints. Fully documented and validated methods of automated comparison and clustering will greatly expand the scope of molecular epidemiology."}
+{"text": "Tissue sections of frozen biopsy specimens obtained from normal and hyperplastic human lymphoid tissues, 33 cases of non-Hodgkin lymphomas as well as various forms of immunoregulatory disorders (angioimmunoblastic and dermatopathic lymphadenopathy) were analysed in immunofluorescence tests (using red TRITC and green FITC double-labelling). A panel of antisera including well-characterized conventional reagents to immunoglobulin classes, T lymphoid and Ia-like antigens, and monoclonal antibodies was used. In selected cases the results were compared with the observations of membrane-marker staining on viable cells in suspension. the findings show that the immunological methods can give a very accurate analysis of the normal and malignant lymphoid cells, and can provide complementary information to conventional histology. The investigator can choose the reagent combinations which give answers to various specific questions: e.g. antisera to light chains establish the monoclonality of lymphomas, whilst staining combinations for human T and Ia-like antigens are particularly useful in various immunoregulatory disorders. Monoclonal antibodies will be particularly useful in various immunoregulatory disorders. Monoclonal antibodies will be particularly useful reagents for analysing the tissue distribution of lymphoid subpopulations and ancillary cells in tissue biopsy specimens."}
+{"text": "Mycobacterium ulcerans infection, all of whom received rifampicin-based oral antibiotic therapy followed by surgical resection (three patients) or oral antibiotics alone (one patient). Following oral antibiotics for between 4 and 8 weeks, viable M. ulcerans was not detectable by culture in three of the patients, or by histology in a fourth patient from whom no specimen for culture was obtained. All cases spent time in a BU-endemic area in coastal Victoria, Australia. Baseline characteristics, diagnosis, treatment received, and histopathology of resected specimens are detailed in Buruli ulcer (BU) was treated primarily with wide surgical excision until recent studies confirmed the efficacy of oral rifampicin combined with intramuscular streptomycin. Whether all-oral antibiotic regimens will be equally effective is unknown. This report describes four patients with M. ulcerans was confirmed by positive polymerase chain reaction (PCR) and isolation of M. ulcerans by culture from swabs obtained prior to treatment. Three patients had ulcerative lesions  suggest that shorter periods may be effective as suggested for the combination of rifampicin and streptomycin In the four patients we have described here, combination oral antibiotic therapy prior to excision led to the inability to recover Treatment of patients with limited BU prior to surgery using rifampicin-based oral antibiotics resulted in culture-negative resection specimens.Clinical healing is slow despite the microbiological activity of oral antibiotics.Apparent relapses that occur during or after treatment may be due to immunologically driven paradoxical reactions rather than primary treatment failure.M. ulcerans infection followed by delayed surgery appears to simplify management by allowing excision and closure in one step without relapse.Rifampicin-based oral antibiotic therapy for the treatment of"}
+{"text": "Iodised oil (lipiodol) administered via the hepatic artery localises selectively in primary liver cell cancers (hepatocellular carcinomas or HCCs) for prolonged periods and has been used as a vehicle for cytotoxic agents. Despite clinical use, the mechanism of lipiodol retention by tumours has remained unclear, embolisation of oil droplets in the tumour vasculature being the prevailing hypothesis. We have investigated the role of tumour and endothelial cells in lipiodol retention. Human liver tumour (Hep G2) cells and human umbilical vein endothelial cells in culture were exposed to lipiodol. Light microscopy using selective silver impregnation stains and transmission electron microscopy revealed lipiodol incorporation by both cell types, probably by pinocytosis. This was not associated with cellular injury in terms of cell lysis, cell replication or radio-labelled leucine uptake. Histological analysis of 24 HCCs either surgically resected or discovered incidentally at liver transplantation  revealed vesicles of lipiodol in the cytoplasm of tumour cells and endothelial cells lining tumour vessels. Thus, lipiodol is likely to deliver cytotoxic agents directly into tumour cells and endothelial cells, both in vitro and in vivo. This may also apply to other lipids and to other human tumours. These findings have significant therapeutic implications."}
+{"text": "Progressive night blindness and constriction of the visual fields are features of Bietti crystalline corneoretinal dystrophy, but here we report a case with the most probable diagnosis of Bietti crystalline dystrophy and good central visual acuity and severely decreased electroretinogram.The patient was a 28-year-old woman with complaint of decreased vision without night blindness. Her both eyes visual acuity were 20/25 with plano refraction. Fundus examination showed intraretinal crystals distributed in the posterior pole and also midperiphery. Fullfield electroretinogram showed decreased scotopic a and b-wave amplitudes.In our patient central foveal region was relatively intact; and this can explain subnormal visual acuity. Although visual acuity was nearly spared, electroretinogram was extremely affected. Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive disorder of retinal degeneration characterized by numerous tiny sparkling yellow-white spots at the posterior pole of the fundus. The small glistering crystals can also occur in the corneal limbus and circulating lymphocytes ,2. CliniA 28-year-old Iranian Caucasian woman referred to our clinic with complaints of decreased vision without night blindness and visual acuity of both eyes was 20/25 with plano refraction. Her slit lamp examination revealed clear cornea and clear lens, and 1+ pigment in vitreous. Intraocular pressure was 18 mmHg for right eye and 17 mmHg for left eye. She did not have any history of associated other medical conditions or drug usage.Fundus examination showed intraretinal crystals distributed in the posterior pole and also midperiphery. There was midperipheral RPE and choriocapillaris atrophy, peripheral pigment clumping and retinal scarring . FlouresFullfield ERG showed severely decreased scotopic a and b-wave amplitudes. Moreover, the photopic a and b wave amplitudes were both severely attenuated . Visual Bietti first reported cases of tapetoretinal degeneration characterized by yellow glistering retinal crystals, choroidal sclerosis, and marginal crystalline dystrophy of the cornea. Similar cases with no limbal crystalline deposits have been reported and called Bietti crystalline fundus dystrophy or crystalline retinopathy -8. The pAffected patients presented with visual symptoms from the third decade onward. The most common presenting symptom is a decrease in visual acuity, often accompanied by nyctalopia. In the presented patient, visual acuity was good and central vision had not been affected. This sparing of the central vision until late in the disease is also recently described in European patients with BCD .Patient with RPE atrophy and intraretinal crystals confined to the posterior pole tend to show lesser disturbances in the full-field electroretinogram (ERG) . This isHistologically, BCD shows evidence of advanced panchorioretinal atrophy characterized by generalized loss and sclerosis of the choriocapillaris with crystals and complex lipid inclusions within the choroidal fibroblasts. The abnormal inclusions are similar to those found in circulating lymphocytes, keratocytes, and conjunctival and skin fibroblasts ,2. AccorBietti initially noted similarities with retinitis punctata albescens and fundus albipunctatus. These conditions are considered flecked retina syndromes and do not have the distinctive crystalline deposits in patients with Bietti\u2019s crystalline dystrophy. Several advanced cases of Bietti\u2019s crystalline dystrophy have been misdiagnosed as retinitis pigmentosa, since advanced cases may have severe visual loss, extensive chorioretinal atrophy, pigment deposition, minimal crystals, and nonrecordable ERG. The diagnosis of BCD is based on clinical findings; biomicroscopic and ophthalmoscopic appearance are usually sufficient to make diagnosis . We can"}
+{"text": "The regulation of cholesterol esterification during cell proliferation was studied. The serum free cholesterol, cholesterol esters and lecithin: cholesterol acyltransferase (LCAT) activity of nude mice with and without pancreatic acinar cell tumours and rats with proliferating tissues were determined. In addition, the apparent activity of acyl-CoA: cholesterol acyltransferase (ACAT) in homogenates of nude mouse tumours and proliferating rat tissues were determined and compared with those of normal nude mouse and rat tissues. Serum cholesterol ester levels were significantly lower in host nude mice with tumours and in rats with regenerating liver, and increased significantly in pregnant rats when compared with respective controls. Circulating LCAT activity levels decreased in host nude mice, in pregnant rats, and in rats with regenerating pancreas and regenerating liver. Apparent ACAT activity levels increased significantly in nude mouse tumours and in foetal and postnatal rat pancreata and also in postnatal liver. At the same time, apparent ACAT activity levels decreased in foetal and regenerating rat livers when compared with respective control tissues. These results suggest that serum cholesterol esters, circulating LCAT and cellular ACAT levels are modulated during cell proliferation."}
+{"text": "We describe a novel, testable theory of autoimmunity, outline novel predictions made by the theory, and illustrate its application to unravelling the possible causes of idiopathic thrombocytopenia purpura (ITP). Pairs of stereochemically complementary antigens induce complementary immune responses (antibody or T-cell) that create loss of regulation and civil war within the immune system itself. Antibodies attack antibodies creating circulating immune complexes; T-cells attack T-cells creating perivascular cuffing. This immunological civil war abrogates the self-nonself distinction. If at least one of the complementary antigens mimics a self antigen, then this unregulated immune response will target host tissues as well. Data demonstrating that complementary antigens are found in some animal models of autoimmunity and may be present in various human diseases, especially ITP, are reviewed. Specific mechanisms for preventing autoimmunity or suppressing existing autoimmunity are derived from the theory, and critical tests proposed. Finally, we argue that Koch's postulates are inadequate for establishing disease causation for multiple-antigen diseases and discuss the possibility that current research has failed to elucidate the causes of human autoimmune diseases because we are using the wrong criteria."}
+{"text": "High-throughput custom designed genotyping arrays are a valuable resource for biologically focused research studies and increasingly for validation of variation predicted by next-generation sequencing (NGS) technologies. We investigate the Illumina GoldenGate chemistry using custom designed VeraCode and sentrix array matrix (SAM) assays for each of these applications, respectively. We highlight applications for interpretation of Illumina generated genotype cluster plots to maximise data inclusion and reduce genotyping errors.We illustrate the dramatic effect of outliers in genotype calling and data interpretation, as well as suggest simple means to avoid genotyping errors. Furthermore we present this platform as a successful method for two-cluster rare or non-autosomal variant calling. The success of high-throughput technologies to accurately call rare variants will become an essential feature for future association studies. Finally, we highlight additional advantages of the Illumina GoldenGate chemistry in generating unusually segregated cluster plots that identify potential NGS generated sequencing error resulting from minimal coverage.We demonstrate the importance of visually inspecting genotype cluster plots generated by the Illumina software and issue warnings regarding commonly accepted quality control parameters. In addition to suggesting applications to minimise data exclusion, we propose that the Illumina cluster plots may be helpful in identifying potential in-put sequence errors, particularly important for studies to validate NGS generated variation. The generation of next-generation sequencing (NGS) quencies ,2. For cThe Illumina platform  has proven reliable and efficient for a number of high-throughput genotyping applications using DNA extracted from several sources, -9. VeraCIn this study, we assess genotype information generated on custom-designed Illumina 96-SNP VeraCode and BeadArray Sentrix Array Matrix (SAM) assays, for optimal generation of accurate genotyping and NGS generated variant validation. Application of strict analysis parameters may lead to valuable genetic information being lost. Alternatively, limited QC may result in the addition of incorrect genotype calls confounding data analysis. The SNP assays described in this study have the potential of being disregarded or falsely included during analysis based on the current QC selection criteria. We discuss the importance of visually inspecting each cluster plot, particularly for custom designed genotype arrays, and suggest strategies for interpreting data in plots that would normally be discarded during the QC process.Sarcophilus harrisii). DNA was genotyped as part of a validation of sequence variation determined from minimal coverage (0.3\u00d7 versus 0.5\u00d7) of NGS de novo sequencing data of two animals using the Roche/454 Titanium chemistry (unpublished data). Genotype analysis was performed using a custom 96-plex SAM array for 96 samples. For both studies, the GoldenGate genotyping procedure was performed as outlined by Illumina [Two sample data sets were used to assess and interpret Illumina-generated genotype cluster plots. The first was part of a gene/pathway targeted human prostate cancer association study. In brief, DNA was extracted from dried blood spots (Guthrie card) and genotyped using a custom 96-plex VeraCode SNP array for 768 samples (unpublished data). In the second study, DNA was extracted from ear clippings of Tasmanian devils , the eight VeraCode runs were assessed individually. The genotype cluster plots generated by each VeraCode and SAM assays were visually inspected for quality of calls. Plots that appeared to be \"unusually\" clustered ) were further investigated by selecting samples to assess by direct Sanger sequencing for genotype confirmation. Samples were sequenced using Big Dye Terminator v3.1  chemistry according to manufacturer's guidelines and sequenced on an AB 3730 genetic analyzer (AB).Using the VeraCode technology we observed several consistent examples of SNP cluster plots that appeared to be incorrectly genotyped due to a combination of a short \u03b8 and the presence of outlier DNA samples. In the two examples discussed in this study Figure , the previce versa for the X-linked variants , genotyping technologies must accurately perform two-cluster calling. In this study successful two-cluster calling was observed for both rare autosomal , direct Sanger sequencing revealed a single nucleotide error in the NGS generated data surrounding the putative SNP. In the examples highlighted in this study  Large-scale custom-designed genotyping studies have been made feasible by the development of high-throughput technologies and improvements of automated genotype calling software. In this study we demonstrate how simple applications for interpreting automatically generated Illumina cluster plots can be used to avoid spurious genetic associations as well as optimising data inclusion and interpretation, particularly for custom designed target arrays.Variation in quality and quantity of DNA input, is largely unavoidable in large-scale studies. In order to limit the effect potential outlier DNA samples may have on genotype calls, it is important to visually inspect the genotype plots and exclude outliers as demonstrated in this study Figure . In addiInvestigating the disease-causing potential of rare variants , can prde novo generated NGS data, we observed several examples of individual clusters being partially segregated within the one genotype group  which lead to the identification of NGS-generated sequencing error. We therefore suggest that visual inspection and closer investigation of unusually clustered scatter plots, may provide information that exceeds the initial goal of SNP validation and is a complimentary tool for NGS data validation.A growing number of laboratories are employing the use of NGS technology to sequence as yet unclassified genomes, as well as resequencing of human and human disease-associated genomes. From the predicted sequence variants generated by these projects, custom-designed arrays are being employed for validation and frequency determination. Although the optimal coverage required to distinguish true sequence variation is highly debatable, and dependent on the type of NGS platform used, high-throughput genotyping platforms allow for rapid, cost-effective validation at even minimal coverage. The SAM array discussed in this study was developed from long-read NGS information generated from minimal coverage of two samples of an as yet unsequenced species (unpublished data). In both the VeraCode assay, custom designed to genotype 96 confirmed human variants, and the SAM array, designed to verify newly identified variants from p Figure  and 4. Ap Figure , the unuWe demonstrate in this study, applications to optimise and improve the efficiency of data analysis generated using the Illumina GoldenGate chemistry using logical interpretation of both rare and common genotyping data. We also present this platform as a successful tool for NGS variant validation, which is applicable to even limited sequence coverage.The authors declare that they have no competing interests.WM and SCS provided analysis of NGS data, EAT, DCP and SN performed genotyping and Sanger sequencing analysis; EAT, DCP, SN and VMH were involved in data analysis; and EAT and VMH participated in study design and manuscript drafting. All authors read and approved the final manuscript."}
+{"text": "Many growth factors are implicated in the pathogenesisof proliferative diabetic retinopathy. Alteration of growthfactors and their receptors in diabetes has been shown inboth experimental and clinical studies. Sustained hyperglycemiaresulting from long-standing diabetes leads to severalbiochemical abnormalities that consequently result inretinal hypoxia. Retinal oxygenation state regulates variousgrowth factors that promote angiogenesis in order to meetthe oxygen demands of the tissue. However, unregulated expressionof these growth factors and induction of complexcascades leading to augmentation of other proangiogenicfactors, which may not be regulated by tissue oxygenation,leads to uncontrolled retinal neovascularization and blindnessin diabetic patients."}
+{"text": "Complete mitochondrial genome sequences have become important tools for the study of genome architecture, phylogeny, and molecular evolution. Despite the rapid increase in available mitogenomes, the taxonomic sampling often poorly reflects phylogenetic diversity and is often also biased to represent deeper (family-level) evolutionary relationships.Solenopsis, which represent various evolutionary depths. Overall, ant mitogenomes appear to be typical of hymenopteran mitogenomes, displaying a general A+T-bias. The Solenopsis mitogenomes are slightly more compact than other hymentoperan mitogenomes (~15.5 kb), retaining all protein coding genes, ribosomal, and transfer RNAs. We also present evidence of recombination between the mitogenomes of the two conspecific Solenopsis mitogenomes. Finally, we discuss potential ways to improve the estimation of phylogenies using complete mitochondrial genome sequences.We present the first fully sequenced ant (Hymenoptera: Formicidae) mitochondrial genomes. We sampled four mitogenomes from three species of fire ants, genus The ant mitogenome presents an important addition to the continued efforts in studying hymenopteran mitogenome architecture, evolution, and phylogenetics. We provide further evidence that the sampling across many taxonomic levels (including conspecifics and congeners) is useful and important to gain detailed insights into mitogenome evolution. We also discuss ways that may help improve the use of mitogenomes in phylogenetic analyses by accounting for non-stationary and non-homogeneous evolution among branches. There has been a rapid proliferation of whole mitochondrial genomes (mitogenomes) sequenced in recent years, no doubt driven in part by the increasing speed and decreasing cost of sequencing technologies. Whole mitogenomes are increasingly used in phylogenetic studies -6 and inHowever, the utility of these datasets for these purposes greatly depends on taxon sampling. Currently, 237 insect mitogenomes have been fully sequenced , yet the taxa utilized for these sequencing studies often do not reflect the distribution of species diversity. For example, Hymenoptera is one of the most species-rich insect orders , yet onNasonia  and Drosophila yakuba [GenBank: NC001322]. We subsequently designed additional primers spanning other regions with no or low coverage using sequence data generated for fire ants. All primers developed and used for this study are presented in Additional file Complete mitochondrial genomes were generated for four individuals from three closely related  Brazil) . We sequ Brazil)  as well Several lines of evidence suggest that our sequences generated specifically represent mitochondrial genomic DNA rather than nuclear mitochondrial-like sequences (numts), which appear to be common and are generally short and highly fragmented in ants and other Hymenoptera -83: The HQ215537, HQ215538, HQ215539, HQ215540].All PCR amplicons were sequenced in both directions and each strand was assembled into single contigs with overlapping ends, indicating that our mitogenome sequences contained no gaps. Leading and lagging strand for each mitogenome were then aligned and manually checked for indels or ambiguous base calls. Mitogenomes were deposited in the NCBI GenBank database , 3 beetles , and 3 moths ). jModeltest  and sub-tree pruning and regrafting [SPR]) on five random starting trees. In addition to running one hundred bootstrap replicates to estimate levels of branch support, we also implemented the SH-like aLRT, which assesses the likelihood gain of the presence of that branch [Maximum likelihood analyses were implemented on the PhyML 3.0 webserver http://wwt branch . To accot branch  using deThe evolution of tRNA-N was studied using phylogenetic analyses as suggested by Saks et al.  and DowtJC and DDS carried out all aspects of the molecular lab work. DG and DDS performed all analyses of the data and wrote the manuscript. All authors read and approved the final manuscript.Primers used for PCR amplification and sequencing of fire ant genomes. Primers names and sequences used in this study. J and N within primer names refer to heavy and light strands, respectively, and indicate the orientation of the primers. Primer names beginning with \"Gem\" were designed specifically to amplify the mitogenome of S. geminata.Click here for file"}
+{"text": "Lindbergh.Pacemakers have evolved over a period of time trying to mimic the normal response rates, conduction and activation characteristics, though are still far from what nature has bestowed upon us. Better understanding of cardiac physiology and hemodynamics has led to current available pacing technology and we do recognize now that to achieve physiological pacing we should have an appropriate heart rate response, ventriculo-ventricular (VV) synchronization and atrio-ventricular (AV) synchronization.Patients receiving rate responsive pacemakers for sinus node dysfunction, in spite of using various sensors and rate response algorithms -5, stillRight ventricular (RV) pacing represents a non-physiological activation of the heart causing wide QRS (left bundle branch block) with electrical and mechanical VV dyssynchrony . Higher Optimal AV interval at rest ranges from 100 to 150 milliseconds. In normal individuals the AV interval shortens with increased heart rate during exercise in a predictable and linear fashion. Most pacemakers have a programmable shortening of AV delay at higher rates, the hemodynamic benefits of which have not yet been shown . Device An electrocardiogram based method to determine optimal AV interval is described by Sorajja et al  in this Based on echocardiographic parameters and natriuretic peptide levels, AV delay optimization is found to be beneficial in patients with normal LV function in short term small studies -25. TherAdopt the pace of nature:  her secret is patience  - Ralph Waldo EmersonLook deep into nature, and then you will understand everything better  - Albert Einstein"}
+{"text": "Tibialis posterior has a vital role during gait as the primary dynamic stabiliser of the medial longitudinal arch; however, the muscle and tendon are prone to dysfunction with several conditions. We present an overview of tibialis posterior muscle and tendon anatomy with images from cadaveric work on fresh frozen limbs and a review of current evidence that define normal and abnormal tibialis posterior muscle activation during gait. A video is available that demonstrates ultrasound guided intra-muscular insertion techniques for tibialis posterior electromyography.Current electromyography literature indicates tibialis posterior intensity and timing during walking is variable in healthy adults and has a disease-specific activation profile among different pathologies. Flat-arched foot posture and tibialis posterior tendon dysfunction are associated with greater tibialis posterior muscle activity during stance phase, compared to normal or healthy participants, respectively. Cerebral palsy is associated with four potentially abnormal profiles during the entire gait cycle; however it is unclear how these profiles are defined as these studies lack control groups that characterise electromyographic activity from developmentally normal children. Intervention studies show antipronation taping to significantly decrease tibialis posterior muscle activation during walking compared to barefoot, although this research is based on only four participants. However, other interventions such as foot orthoses and footwear do not appear to systematically effect muscle activation during walking or running, respectively. This review highlights deficits in current evidence and provides suggestions for the future research agenda. The tibialis posterior (TP) muscle has a vital role during gait; via multiple insertion points into the tarsal bones it acts as the primary dynamic stabiliser of the rearfoot and medial longitudinal arch (MLA) ,2. The sThe TP muscle is contained within the deep posterior compartment of the lower limb, arising from the adjacent posterior surfaces of the tibia, fibula and interosseus membrane Figure . The tenThe TP tendon has multiple insertions within the foot, dividing into three main components: (i) anterior; (ii) middle; and (iii) posterior -23. The The most common modality used to quantify TP muscle activation is via EMG recorded with intramuscular electrodes. The advantage of using EMG over other modalities (such as MRI and ultrasound) is the ability to investigate muscle activation simultaneously with dynamic weightbearing tasks such as walking. However, due to the deep location of the muscle within the posterior compartment of the leg, surface electrodes cannot record TP EMG activity without signal cross-talk from various superficial muscles Figure . Therefo(i) the posterior-medial; and (ii) the anterior insertion. A video demonstration of both approaches can be viewed via downloadable supplements  with the use of ultrasound guidance. All five electrodes were correctly located in the muscle belly of TP; figure Experience gained (GSM) in performing more than 150 intramuscular EMG electrode insertions into TP has led to some important practical insights. Participants usually describe low to mild discomfort during the insertion procedure with approximately 1 in 20 describing severe pain, although this has not been quantified using a validated pain scale. When participants experience severe pain, the wires are removed and a second attempt at relocating new wire electrodes is undertaken; rarely is a third attempt required. During walking, participants usually describe 'mild' pain for the first couple of minutes, which frequently subsides to 'no' or 'low' pain after this period. Mild calf pain is often experienced for 24 hours following the insertion procedure. There were no reported cases of serious complications such as infection. The use of wire electrodes is generally a safe and effective method of investigating tibialis posterior EMG during walking.Current literature has characterised TP EMG during gait among normal and pathological populations and with various interventions including antipronation taping, foot orthoses and athletic footwear. Figure Normative EMG for TP during walking is based on studies with typically small sample sizes (ranging from 5 to 12) and with participants' age ranging from 18 to 76 years ,12,27-29TP EMG activity during running was characterised by Reber and colleagues  when theOverall, the availability of normative EMG for TP during walking is based on relatively small sample sizes and is limited to only adult and older adult participants. Despite the absence of normative data, other studies have investigated TP EMG activation with pathological conditions including rheumatological and neurogenic diseases. With the high variability seen in healthy people, it is difficult to conclude whether the findings from studies investigating abnormal muscle activity are meaningful.Tibialis posterior tendon dysfunction (TPTD) has been reported as the most common cause of adult acquired flatfoot ,22,31,32It has been suggested that certain rheumatological conditions may predispose to TPTD including rheumatoid arthritis (RA) ,39 and sDespite the uncertainty regarding the pathogenesis of pes plano valgus, gait analysis has been shown to improve our understanding of this condition in RA ,45. Yet TP muscle dysfunction is likely to occur with many neurogenic conditions, however little is known about how many of these conditions affect TP muscle activity during walking. Cerebral palsy is one neurogenic condition where TP muscle activation has been investigated as part of several laboratory-based clinical assessments -53. CereIntramuscular electrodes have been utilised to assess TP muscle activation among infants, children and young adult patients (age range: 4\u201324 years) \u2013 often as part of a surgical planning procedure Figure  46-50].-50.46-50A further study by Michlitsch and colleagues  involvedWhile there is consensus among these investigations that both TP and tibialis anterior contribute to varus or equinovarus foot deformity with cerebral palsy, one major shortcoming is that none of these investigations have directly compared TP EMG profiles to age matched control groups within the same study. This may account for the different and potentially invalid classifications among these studies of TP dysfunction with cerebral palsy. Further normative EMG from TP is required to inform studies investigating pathological sub-types of TP muscle dysfunction in children with cerebral palsy.Only one study has investigated the effect of foot orthoses on TP activation during walking  despite These findings contrast another investigation on the effect of anti-pronation taping on TP EMG during walking in four young- to middle-aged adults with flat-arched feet . FranettA number of studies investigating TP EMG activation in health and disease have been undertaken with small sample sizes providing preliminary evidence of either abnormal function or response to intervention. Accordingly, further EMG studies, recruiting larger sample sizes and representation from the younger and older populations, are required to investigate both the effect of interventions on TP muscle activity and to establish a reference database. Whilst it has been recognised that TP plays a vital role during gait, further work is required to more fully understand the role of TP in the development of pathology and in disease-specific populations including RA, cerebral palsy and TPTD.In summary, TP EMG remains a specialist investigation undertaken in relatively few centres internationally; however, this technique has multiple applications both in research and in planning interventions and evaluating outcomes. Recent advances in technology, including imaging, represent an opportunity to employ this technique more frequently and advance our understanding in a variety of areas.The authors declare that they have no competing interests.DET and JW conceived the idea for the review, RS and GSM drafted the manuscript and the figures, GSM prepared the video supplement, JW and DET critically revised the manuscript. All authors read and approved the final manuscript.Posterior approach. A video demonstration of the posterior approach of intramuscular electrode insertion. Additional files 1 and 2 can only be viewed using the latest version of QuickTime Player which can be downloaded via the following link: http://www.apple.com/downloads/Click here for fileAnterior approach. A video demonstration of the anterior approach of intramuscular electrode insertion.Click here for file"}
+{"text": "We report a case of a rapid renal deterioration due to ureteropelvic junction obstruction (UPJO) in an asymptomatic woman with prior normal diuretic renography. This case illustrates \u201csilent\u201d renal obstruction and the inability of diuretic renography in detecting significant renal obstruction. This case may favor close surveillance of any adult patient with potential UPJO, especially those with underlying renal disease or solitary kidney. Ureteropelvic junction obstruction (UPJO) is an uncommon condition in adults. UPJO is most commonly diagnosed during childhood with treatment required for any patient demonstrating renal deterioration, stone formation, infection, or pain. Not all patients with hydronephrosis require intervention, although the natural history of untreated UPJO is better understood in children than adults. We describe a woman who rapidly developed renal deterioration due to UPJO despite lacking symptoms and previous normal evaluation by diuretic renography.A 62-year-old woman was referred for a brief episode of left flank pain and imaging demonstrating fullness of the left renal pelvis . She hadAt the request of her primary care physician, the patient underwent repeat computed tomography (CT) imaging 12 months later despite being asymptomatic. Repeat imaging demonstrated severe left-sided hydronephrosis . Repeat The natural history of UPJO in adulthood is poorly understood but believed to be related to intrinsic narrowing of the upper ureter or extrinsic pressure on the ureter caused by aberrant vessels or fibrous bands. As prenaAlthough there is evidence that not all pediatric patients demonstrating hydronephrosis require intervention, the natural history of untreated UPJO in adults is less well documented. Most studies document preservation or improvement of renal function following treatment for adult UPJO.\u20135 A smalThe case presented documents rapid renal deterioration from UPJO in an asymptomatic adult patient with prior normal evaluation for presence of obstruction. Although undoubtedly rare, this case illustrates that diuretic renography may not detect significant renal obstruction, and that renal deterioration may occur in an otherwise asymptomatic patient. The sensitivities of current standards for the diagnosis of UPJO, namely diuretic renography and CT scanning, are imperfect. There remains room for improvement in the diagnosis, perhaps at a functional imaging level or at a molecular level, of UPJO.Nonetheless, serial imaging in all asymptomatic patients who have a normal evaluation for the presence of UPJO cannot be recommended, however repeat imaging (ultrasound or CT scanning) may be prudent in patients at risk for renal compromise . Patients and physicians need be aware of silent renal obstruction and the potential for diuretic renography and CT scanning to, at least transiently, miss the diagnosis."}
+{"text": "The streptococcal preparation OK432 was studied for its effects on natural killer (NK) activity of peripheral blood lymphocytes (PBL) from normal donors and from ovarian cancer patients, and of tumour-associated lymphocytes (TAL) from peritoneal effusions. OK432 augmented NK activity against the susceptible K562 line and induced killing of the relatively resistant Raji line. Freshly isolated ovarian carcinoma cells were relatively resistant to killing by unstimulated PBL and TAL. OK432 induced significant, though low, levels of cytotoxicity against 51Cr-labelled ovarian carcinoma cells. Augmentation of killing of fresh tumour cells by OK432 was best observed in a 20 h assay and both autologous and allogeneic targets were lysed. PBL were separated on discontinuous Percoll gradients. Unstimulated and OK432-boosted activity were enriched in the lower density fractions where large granular lymphocytes (LGL) and activity against K562 were found. Thus, OK432 augments NK activity of PBL and TAL in human ovarian carcinomas and induces low, but significant, levels of killing of fresh tumour cells. Effector cells involved in killing of fresh ovarian tumours copurify with LGL on discontinuous gradients of Percoll."}
+{"text": "A new imaging modality framework, calledelasto-mammography, is proposed to generate the elastograms ofbreast tissues based on conventional X-ray mammography. Thedisplacement information is extracted from mammography projectionsbefore and after breast compression. Incorporating thedisplacement measurement, an elastography reconstruction algorithmis specifically developed to estimate the elastic moduli ofheterogeneous breast tissues. Case studies with numerical breastphantoms are conducted to demonstrate the capability of theproposed elasto-mammography. Effects of noise with measurement,geometric mismatch, and elastic contrast ratio are evaluated inthe numerical simulations. It is shown that the proposedmethodology is stable and robust for characterization of theelastic moduli of breast tissues from the projective displacementmeasurement."}
+{"text": "Recent preclinical work investigating the role of progenitor cell therapies for central nervous system (CNS) injuries has shown potential neuroprotection in the setting of traumatic brain injury (TBI), spinal cord injury (SCI), and ischemic stroke. Mechanisms currently under investigation include engraftment and transdifferentiation, modulation of the locoregional inflammatory milieu, and modulation of the systemic immunologic/inflammatory response. While the exact mechanism of action remains controversial, the growing amount of preclinical data demonstrating the potential benefit associated with progenitor cell therapy for neurological injury warrants the development of well-controlled clinical trials to investigate therapeutic safety and efficacy. In this paper, we review the currently active or recently completed clinical trials investigating the safety and potential efficacy of bone marrow-derived progenitor cell therapies for the treatment of TBI, SCI, and ischemic stroke. Our review of the literature shows that while the preliminary clinical trials reviewed in this paper offer novel data supporting the potential efficacy of stem/progenitor cell therapies for CNS injury, a great deal of additional work is needed to ensure the safety, efficacy, and mechanisms of progenitor cell therapy prior to widespread clinical trials. Central nervous system (CNS) insults including ischemic stroke, traumatic brain injury (TBI), and traumatic spinal cord injury (SCI) represent a major burden to the healthcare system worldwide. Approximately 5 million people are burdened by the long-term physical, cognitive, and psychosocial deficits associated with TBI in the United States with 40% of patients reporting unmet needs 1 year post injury . OverallPreliminary research is currently underway to evaluate the potential efficacy of adult tissue progenitor (stem) cell therapies for the treatment of CNS injury. Adult tissue progenitor cells are located in select microenvironments (niches) which protect against overproliferation and depletion as well as regulate progenitor cell involvement in resident tissue repair and regeneration . By defiRecent preclinical work investigating bone marrow derived-progenitor cell therapies for CNS injury has shown potential neuroprotection after TBI , ischemiin vitro with subsequent implantation into rodent cortex after focal ischemic injury. The implanted progenitor cells were found to display neural cell markers and engraft up to 100 days after injury with associated behavioral recovery ..46].Geron Corporation  has started a United States Food and Drug Administration (FDA) approved trial using embryonically derived oligodendroglial precursor cells  to replace myelin-forming cells within injured spinal cords. The cell preparations are injected directly into the spinal cords at the lesion site. The treatment population is restricted to adults with complete thoracic (T3\u2013T9) level SCI. Patients must undergo treatment within 7 to14 days following injury. Preclinical data showing that SCI animals treated with Geron's cell line developed cysts at the level of treatment caused the FDA to put a hold on the clinical trial. Geron and the FDA have reached an agreement to allow the trail to move forward if subsequent preclinical studies provide satisfactory outcome.in vivo cell tracking need to be completed to ensure the safety of potential trials while affording them the best possible chance at success. Additional preclinical work to more clearly delineate the progenitor cell mechanism of action would also aid in the planning of quality-controlled clinical studies. Overall, while the very preliminary clinical trials reviewed in this paper offer novel data supporting the potential efficacy of cell therapeutics for CNS injury, a great deal of additional work is needed to ensure the safety and efficacy of progenitor cell therapy prior to widespread clinical trials.Prior to large, multicenter clinical trials investigating the potential efficacy of progenitor cell therapies for CNS insults, a number of issues need to be addressed. Further research into optimal cell dosing, cell delivery method, and techniques for"}
+{"text": "Fungal diseases are increasing among patients infected with human immunodeficiency virus (HIV) type 1. Infections due to Candida and Cryptococcus are the most common. Although mucocutaneous candidiasis can be treated with oral antifungal agents, increasing evidence suggests that prolonged use of these drugs results in both clinical and microbiologic resistance. The optimal therapy for cryptococcal meningitis remains unresolved, although initial treatment with amphotericin B, followed by life-long maintenance therapy with fluconazole, appears promising. Most cases of histoplasmosis, coccidioidomycosis, and blastomycosis occur in regions where their causative organisms are endemic, and increasing data suggest that a significant proportion of disease is due to recent infection. Aspergillosis is increasing dramatically as an opportunistic infection in HIV-infected patients, in part because of the increased incidence of neutropenia and corticosteroid use in these patients. Infection due to Penicillium marneffei is a rapidly growing problem among HIV-infected patients living in Southeast Asia. Although the advent of oral azole antifungal drugs has made primary prophylaxis against fungal diseases in HIV-infected patients feasible, many questions remain to be answered before the preventive use of antifungal drugs can be advocated."}
+{"text": "A(PDPK FA) was overexpressed in various cancerous tissues relative to normal controls. However, the functional role of overexpressed PDPK FAin cancer remains to be established. In this report, we explore the potential role of PDPK FAin leukaemia cell growth by investigating the effects of partial inhibition of this kinase on the malignant phenotype of human chronic myeloid leukaemia cells (K562). Cloning of PDPK FAcDNA and its recombinant antisense expression vector and PDPK FA-specific antibody were successfully developed. Two stable antisense clones of K562 cells were subcloned which expressed 70% and 45% of PDPK FArespectively, compared with control-transfected clone in both immunoprecipitate activity assay and immunoblot analysis. In sharp contrast, these two antisense clones expressed no significant suppression of any other related PDPK family members, indicating the specificity of these two antisense clones. Moreover, these antisense clones proportionally and potentially exhibited cell growth retardation, poor clonogenic growth in soft agar and loss of serum independence. The results demonstrate that specific antisense suppression of PDPK FAis sufficient to interfere with the growth of K562 cells, indicating that PDPK FAis essential for human chronic myeloid leukaemia cell growth. \u00a9 2000 Cancer Research CampaignInitial studies revealed that proline-directed protein kinase F"}
+{"text": "The importance of the applications of lanthanides, as an excellent diagnosticand prognostic probe in clinical diagnostics, and an anticancer material, is remarkably increasing. Lanthanidecomplexes based X-ray contrast imaging and lanthanide chelates based contrast enhancing agents formagnetic resonance imaging (MRI) are being excessively used in radiological analysis in our body systems.The most important property of the chelating agents, in lanthanide chelate complex, is its ability to alter thebehaviour of lanthanide ion with which it binds in biological systems, and the chelation markedly modifiesthe biodistribution and excretion profile of the lanthanide ions. The chelating agents, especially aminopolycarboxylic acids, being hydrophilic, increase the proportion of their complex excreted from complexedlanthanide ion form biological systems. Lanthanide polyamino carboxylate-chelate complexes are used ascontrast enhancing agents for Magnetic Resonance Imaging. Conjugation of antibodies and other tissuespecific molecules to lanthanide chelates has led to a new type of specific MRI contrast agents and theirconjugated MRI contrast agents with improved relaxivity, functioning in the body similar to drugs. Manyspecific features of contrast agent assisted MRI make it particularly effective for musculoskeletal andcerebrospinal imaging. Lanthanide-chelate contrast agents are effectively used in clinical diagnosticinvestigations involving cerebrospinal diseases and in evaluation of central nervous system. Chelatedlanthanide complexes shift reagent aided"}
+{"text": "Peripheral-blood monocytes from normal individuals and from patients with malignant melanoma reduce nitroblue tetrazolium (NBT). A quantitative assay for dye reduction was applied to 25 healthy donors and 31 patients with malignant melanoma. NBT reduction expressed as dye reduction per monocyte was significantly impaired in patients with disseminated disease, and they responded poorly to a phagocytic stimulus. Monocytes from patients with micrometastatic disease, however, showed normal resting NBT reduction but, following exposure to a suspension of latex-polystyrene, showed significantly greater NBT reduction than those from normal individuals. Since NBT reduction is an indirect measure of intracellular hexose-monophosphate-shunt activity we conclude that the monocytes from patients with minimal disease are in some way activated."}
+{"text": "The STAR-VA training program in Veterans Health Administration Community Living Centers (CLCs) has been helping interdisciplinary care teams understand and manage dementia-related behaviors in the nursing home setting, with promising clinical outcomes. However, sustaining a new care approach in a health care system poses multiple challenges. This presentation will discuss facilitators and barriers to STAR-VA sustainability based on CLC team and nurse leader feedback. Findings are informing development of a new site coaching program and a sustainability toolkit. Feedback to date suggests that critical STAR-VA implementation and sustainability strategies include: regularly scheduled team meetings to discuss behavioral assessment and care plans; ongoing staff training ; communicating care plans across shifts and in the health record; multiple nurse/shift champions; impromptu huddles; acknowledging staff successes; leadership engagement. The coaching program engages teams in setting and tracking site sustainability goals. Lessons learned will be discussed."}
+{"text": "Persons with dementia frequently demonstrate behavior symptoms of dementia (BSD), associated with poorer outcomes. A measure of BSD was created for routine use in VA Community Living Centers (CLCs). Reliability and validity of Minimum Data Set (MDS 3.0) behavior items was established using exploratory factor analysis and a multitrait, multimethod correlation matrix. 385 CLC residents with BSD were assessed using validated measures of BSD, depression, and anxiety, and team ratings of the frequency and severity of target behaviors identified for intervention. Factor analysis on MDS items closest to baseline resulted in two stable factors. MDS behavior factors related to validated clinical measures in predicted ways at baseline and post-intervention. MDS distress behavior factor sensitivity to change was evaluated by using change score correlations with validated clinical measures. The MDS distress behavior factor can be used routinely, evaluate the impact of intervention effectiveness, and provide quality improvement feedback."}
+{"text": "Primary immunodeficiencies (PID) are a heterogeneous group of disorders with a variable clinical spectrum of manifestations. The central nervous system may be involved in PID with symptoms which may present initially or develop at later stages. The purpose of this study was to review the neurological manifestations of different PID syndromes.We focused on 104 selected studies on PID with certain neurological abnormalities which may accompany these disorders or may later signify a PID in their course.Diverse neurological deficits accompanying certain PIDs may be mild or they may greatly influence the course of the disease with major impacts on the quality of life of these patients.Early recognition and treatment is important to prevent or reduce future irreversible neurological sequelae. Therefore physicians should be aware of the neurological features accompanying PID. Primary immunodeficiencies (PID) are a heterogeneous group of 354 distinct disorders with 344 different gene defects  with a vPIDs have been classified practically according to the affected immune function to the following groups: immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies with associated or syndromic features, antibody deficiencies, diseases of immune dysregulation, congenital defects of phagocytes, defects in intrinsic and innate immunity, autoinflammatory disorders, complement deficiencies and phenocopies of PIDs . The cenNeurological manifestations will be discussed in detail according to the specific classification of primary immunodeficiencies to assist the treating physicians\u2019 timely diagnosis and prompt treatment in order to avoid irreversible neurologic sequelae. The categorization of the inborn errors of immunity is based on the International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity ADA is a ubiquitous enzyme in purine salvage pathway which is also expressed in both the peripheral and central nervous systems . ADA defDNA Ligase IV deficiencyThis autosomal recessive form of SCID is caused by an impairment of the DNA damage repair process with a pronounced radiosensitivity . DNA douCernunnos deficiencyThis is another rare autosomal recessive form of SCID with severe T and B lymphopenia and dysgammaglobulinemia in addition to radiosensitivity caused by mutations in the CERNUNNOS or XRCC4-like factor (XLF). Microcephaly and developmental delay are the prominent neurological features . CID with associated or syndromic featuresAtaxia-TelengiectasiaThis autosomal recessive complex disorder with substantial severity in affected individuals  is charaThere are also Ataxia Telengiectasia-Like Disorders (ATLD) which are clinically similar to ataxia telengiectasia although without telangiectasia and a slower progression of neurologic manifestations. These patients remain ambulatory until their third decades of lives , 20.Nijmegan Breakage SyndromeThis is a rare autosomal recessive, multisystemic disease of chromosomal instability presenting at birth with microcephaly but no additional neurologic manifestation . The mutImmunodeficiency, Centromeric Region Instability and Facial Anomalies SyndromeThis genetic disease is due to a mutation in DNA methylteransferase gene  which caRiddle SyndromeThis syndrome is characterized by a defect in DNA damage response causing immunodeficiency and increased radiosensitivity accompanied by neurologic symptoms and growth delay due to an increased apoptosis and reduced proliferative capacity during brain development presenting as mild motor control and learning difficulties . DiGeorge SyndromeIn addition to the characterizing triad of cardiac defects, hypocalcemia and cellular immune deficiency, there may be neurological manifestations which present with developmental delay in motor, language and speech areas, neuropsychiatric problems and epilepsy . Most paHyper-immunoglobulin E syndromeThese syndromes are characterized by recurrent skin and pulmonary infections in the presence of elevated IgE concentrations and usually eosinophilia. The hyper-IgE syndromes have four distinct genetic causes including mutations in signal transducer and activator of transcription 3 (STAT3), dedicator of cytokinesis 8 (DOCK8), tyrosine kinase2 (TYK2) and phosphoglucomutase 3 (PGM3) , 34. VasSchimke Immuno-osseous DysplasiaThis autosomal recessive disorder is caused by mutation in the SMARCAL1 gene which encodes a chromatin remodeling protein. Defective cellular immunity causes recurrent bacterial, fungal and viral infections which in association with short stature and progressive renal insufficiency characterizes the disorder . NeuroloHoyeraal-Hreidarsson syndromeThis is an X-linked recessive disorder of telomere dysfunction which represents a severe form of dyskeratosis congenita characterized by a classic triad of reticular skin pigmentation, dysplastic nails and oral leukoplakia . PancytoPurine Nucleoside Phosphorylase DeficiencyThis rare autosomal recessive metabolic disorder, similar to ADA deficiency, results from impaired purine salvage pathway which causes combined immunodeficiency in association with prominent neurological abnormalities . \u201cMutatiHepatic Veno-Occlusive Disease with ImmunodeficiencyThis is caused by homozygous mutation in the autosomal SP110 gene. The onset of clinical features usually occurs before the age of six months with hepatic sinusoidal obstruction. Serum Ig levels are low. T cell subsets and B-cell numbers are reduced. Neurological abnormalities include leukodystrophy and extensive cerebral necrosis on postmortem examination are found in one third of the patients .VICI Syndrome This rare autosomal recessive disorder is caused by mutation in the EPG5 gene which results in defective autophagy . ClinicaPredominantly Antibody deficiencyCommon variable immunodeficiencies and agammaglobulinemia  are the most frequent forms of presentations of antibody deficiency. Symptoms mainly consist of respiratory or gastrointestinal involvement. However, neurologic manifestations may also occur. Common Variable ImmunodeficiencyNeurologic manifestations are a complex of diverse and rare complications of CVID including brain or spinal cord infections (meningitis as the most common neurologic manifestation), autoimmune involvements  , transveAgammaglobulinemiaIn patients with agammaglobulinemia symptoms mainly consist of recurrent respiratory or gastrointestinal infections. Serum immunoglobulins are severely decreased and usually undetectable . CNS comDisorders of Immune RegulationChediac Higashi SyndromePatients with this autosomal recessive lethal disorder present with recurrent respiratory and bacterial skin infections due to severe immunodeficiency, partial oculocutaneous albinism, bleeding tendency and progressive neurological features . This syHermansky-Pudlak syndrome type 2Among Hermansky Pudlak syndromes, this type is characterized by an immunodeficiency due to neutropenia and T lymphocyte dysfunction which differentiates it from other types of this syndrome . These pFamilial Hemophagocytic LymphohistiocytosisFHL comprises a group of autosomal recessive life-threatening disorders characterized by uncontrolled proliferation of activated lymphocytes and macrophages associated with massive secretion of cytokines infiltrating into organs including lymph nodes, bone marrow, liver, spleen and central nervous system , 71. CNSCongenital defects of phagocytic number or functionChronic Granulomatous DiseaseChronic granulomatous disease is the most common inherited disorder of phagocytic cells. It results from an inability of phagocytes to produce bactericidal superoxide anions due to defects of the NADPH oxidase system and it leads to the defect in killing of a specific spectrum of bacteria and fungi resulting in concomitant hyper-inflammation and tissue granuloma formation . NeuroloSevere Congenital NeutropeniaThis term is used for a heterogeneous group of primary immunodeficiencies including sporadic autosomal recessive, autosomal dominant and x-linked types  of whichSchwachman-Diamond SyndromeThis is a multisystem disorder characterized by bone marrow failure, exocrine pancreatic insufficiency and metaphyseal chondrodysplasia. These features are attributed to mutation in SBDS gene . HoweverLeukocyte Adhesion Deficiency type 2LAD syndromes consist of rare autosomal recessive disorders among which only LAD type 2 presents with neurologic abnormalities. These patients are characterized by recurrent bacterial infections without pus formation in the first years of life and severe mental retardation later . Other n\u03b2-Actin deficiencyThis autosomal dominant immunodeficiency disorder caused by a non-lethal mutation, characterized by defects in neutrophil migration, mental retardation, short stature, thrombocytopenia and photosensitivity . The halAutoinflammatory DisordersMevalonate Kinase Deficiency (MKD)This is a term used for a wide clinical spectrum of autosomal recessive disorders due to a congenital error in cholesterol biosynthesis, with hyperimmunoglobulinemia D syndrome as the benign variant of the disorder and Mevalonic aciduria as the more severe form of MKD . MevalonNeonatal Onset Multisystem Inflammatory DisorderThe disease results from mutations in the CIAS-1 gene which encodes cryopyrin . CryopyrBlau syndrometh nerve palsy, cerebral vasculitis and cerebral infarction (This rare autosomal dominant syndrome clinically resembles early onset sarcoidosis characterized by granulomatous inflammation mostly involving joints, eyes and skin -97 and ifarction , 101.Aicardi-Goutieres syndromeThis is a genetically determined encephalopathy caused by mutations in TREX1 genes encoding RNAs involved in removing RNA, leading to the accumulation of endogenous RNA, triggering Toll-like receptor-dependent interferon-\u03b1 production in the brain with the resultant activation of neurotoxic lymphocytes and immune system in addition to the inhibition of angiogenesis , 103. NeIn conclusion, neurological manifestations of primary immunodeficiencies are common with diverse pathologic mechanisms. Neurological deficits may be mild or they may greatly influence the course of the disease with major impacts on the quality of life of the patients. Some of these complications may even cause death. Neurological manifestations may have an early onset, beginning at birth or they may appear later which in both situations may lead to misdiagnosis and delayed therapy. Therefore a high suspicion of an underlying primary immunodeficiency is important in any type of neurological problems occurring with recurrent infections. All three authors were involved in data collection, and writing the article.The authors declare that there is no Conflict of Interest."}
+{"text": "Previous studies highlighted the destructive effects of neurotoxin  on integrity of nigral dopamine system, accompanying series of changes in motor regulating network relate to striatal pathways. The fact that L-Dopa or deep brain stimulation (DBS) improves motor gaits in Parkinson's disease (PD) further strengthened the potential importance of subcortical circuits in motor ability control. A recent study highlighted the contribution of cortical inhibition in the process, and therefore might imply the cortical targeting strategy in motor disorder management , which might contribute to the decreased ability of motor learning. This rapid turnover correlates to enhanced apical dendrite Ca2+ spike generation, which is dependent on local NMDA receptors, the major source of calcium permeable glutamate receptors.Somatostatin (SST) interneuron provides important sources to dendritic inhibition, while Parvalbumin (PV) preferably targets somatic region of cortical pyramidal neurons . Indeed, several studies reported aberrant neuronal activity at cortex and GABA deficits in PD patients or animal models of PD. In addition, L-dopa administration enhanced GABA efflux at primary motor cortex, which might be relate to partly the motor improvement, and sometimes the dyskinesia as well . TMS pulses evoke cortical oscillation changes and dis-inhibit cortical dendrites by modulation cortical inhibition (Murphy et al., Taken together, many lines of evidences co-suggest the importance of motor cortical inhibition in motor learning ability, and potentially other aspects of motor functioning. Targeting cortical inhibition with drugs, exercise, and TMS stimulation are feasible approaches for motor rehabilitation.All authors designed the study together and wrote the manuscript together.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The goal of cancer eradication has been overshadowed despite the continuous improvement in research and generation of novel cancer therapeutic drugs. One of the undeniable existing problems is drug resistance due to which the paradigm of killing all cancer cells is ineffective. Tumor microenvironment plays a crucial role in inducing drug resistance besides cancer development and progression. Recently, many efforts have been devoted to understand the role of tumor microenvironment in cancer drug resistance as it provides the shelter, nutrition, and paracrine niche for cancer cells. Cancer-associated fibroblasts (CAFs), one major component of tumor microenvironment, reside in symbiotic relationship with cancer cells, supporting them to survive from cancer drugs. The present review summarizes the recent understandings in the role of CAFs in drug resistance in various tumors. Acknowledging the fact that drug resistance depends not only upon cancer cells but also upon the microenvironment niche could guide us to formulate novel cancer drugs and provide the optimal cancer treatment. Various studies have already identified that the nature of tumor does depend not only upon the malignant cancerous cells themselves but also to their microenvironment components Kalluri . The conCAFs constitute major proportion of non-neoplastic stromal compartment in various human tumors. Various researches have suggested that they are capable of modulating tumor cells by forming the communication network with cancer cells or with other elements and hence susceptible to cancer drug resistance  inhibitor in genetically engineered pancreatic ductal adenocarcinoma (PDAC) and chemically induced bladder cancer mice model showed reduction in stromal contents consequently promoting tumor growth and malignancy, which indicated stromal cells function as tumor suppression  and myofibroblast (myCAFs), where they observed that myCAFs lack tumor-promoting chemokines and cytokines , which is regulated by NF-\u03ba\u03b2 after DNA damage, activates the canonical Wnt program in tumor cells and induces cytotoxic chemotherapy resistance in prostate cancer  breast cancers. A research performed in ER+ MCF-7 cells showed that CAF was the source of tamoxifen and fulvestrant resistance and also protected cancer cells from doxorubicin and PARP inhibitor  was decreased in breast CAFs and promoted cancer invasion by overexpression of thrombospondin type 1  , poor prognostic marker in pancreatic cancer cells, did not inhibit tumor growth and they verified two subtypes: saa3-competent and saa3-null CAFs, which showed pro-tumorigenic and anti-tumorigenic effect, respectively  was blocked by CXCL12 receptor inhibitor  unable to identify its specific origin  (Fujiwara et al. One previous study showed that despite the heterogeneity of CAFs, they are genetically more stable than cancer cells. Therefore, targeting CAFs in cancer treatment would have smaller possibilities to develop drug resistance Kerbel ]. RecentIn conclusions, CAFs, the building block of microenvironment, have a crucial role in modulating cancer drug sensitivity and understanding in detail could minimize the existing challenge of drug resistance and direct the future innovation of cancer drug by avoiding or overcoming the drug resistance."}
+{"text": "The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter. Ever since the discovery of naturally occurring neural stem cells (NSCs) residing in discrete niches of the adult mammalian central nervous system (CNS) ,2,3,4,5,While screening the publicly available literature, it became evident that there is a large degree of heterogeneity when it comes to the NSC transplantation procedure itself, related for example to age and species of donor- as well as host tissues, the question whether sorted/enriched cell populations versus mixed cell grafts were applied or concerning time-points at which host tissue and grafted cells were analyzed. Likewise, the localization and type of an injury prior to engraftment of stem cells, as well as their positioning within lesion zones additionally influence cellular integration and differentiation. It would therefore be important to define rate limiting and dominating parameters to ensure a larger degree of comparability across different investigations and to promote the development of protocols that will eventually lead to a successful clinical translation.Clinical research depends on animal models, which mimic human disease or injury. For neuropathological studies of the CNS various animal models such as acute and chronic spinal cord injury (SCI); traumatic brain injury (TBI); inflammatory-, genetically-, or chemically induced demyelination/neurodegeneration have been used to assess the impact of NSC transplantation on either lesion amelioration or tissue regeneration. The outcome of these studies shows a surprising degree of variability in terms of cell fate acquisition, migration within the host tissue as well as the implanted cell\u2019s potential to fully mature 5 or P75 old mice for transplantation into the striatum, motor cortex, and lateral posterior thalamic nucleus, Seidenfaden and colleagues showed that transplanted cell survival is independent of the donor animal age\u2014at least when comparing immature postnatal- to young adult brains . FurtherA related transplantation study used rats instead of mice for both donor cells as well as host animals . HoweverFurther support for the assumption that exogenous factors influence the fate of transplanted NSCs  resultedFor a successful treatment of neurological conditions such as multiple sclerosis (MS) or adrenoleukodystrophies transplanted NSCs would have to distribute well within diseased brains in order to access multiple and irregularly dispersed lesions. Active migration within the brain parenchyma appears indeed to be a rare feature of implanted NSCs as for example transplantation of SVZ-derived NSCs into neighboring SVZ regions of adult healthy mice did not result in any observable migration activities . TransplSupporting evidence that brain region specific cues act across different species arose from a subsequent study in which embryonic human NSCs (huNSCs) were applied to injury-free models . Here, dThe astonishing impact especially the RMS exerts on transplanted NSCs was corroborated by yet another study . This inComparing outcomes of NSC transplantation in different neuropathological or injury inflicted models is important in order to understand the adaptability NSCs are capable of and also for the development of CNS repair strategies. Nevertheless, due to the high degree of variation and heterogeneity across the different model systems this section will focus on selected models representing both common and rare as well as global and focal pathologies. Working out the details between different injury models, and taking into account heterogenic responses of different brain regions depends on comparable starting conditions. This includes information on donor age, on the particular donor stem cell niche, on isolated cell types and whether they were propagated in culture or whether genetic manipulation was applied prior to transplantation. Moreover, variations deriving from different model systems will also be considered.Treatment of hereditary white matter disorders characterized by abnormal or complete absence of myelin due to mutations in genes encoding for myelin proteins (such as in Pelizaeus-Merzbacher disease) will most likely depend on engraftment of healthy cells giving rise to functionally unimpaired myelin forming oligodendrocytes. In shiverer mice (shi) homozygous mutations in the myelin basic protein (MBP) gene lead to the absence of MBP expression and consequently to low levels of compact and functional myelin ,21 and ishi/shi) were used as host animals, which in terms of methodology makes these studies highly comparable. Therefore, the reason for such differential fate outcome remains obscure.However, intracerebroventricular transplantation of the same NSC cell line (C17.2) into shi mice of comparable age (P1-P3) resulted in mainly neuronal differentiation . While tStudies in which transplantation experiments were performed using different  stem cell types but exclusively applying a single neuropathological model are of special value since methodological differences can be ruled out. When adult forebrain SVZ neural precursor cells (aNPCs) were grafted into the dysmyelinated spinal cord of shiverer rats, the majority differentiated into oligodendroglial cells and even into mature myelinating OLs . In contTraumatic brain injury (TBI) results from forced impact to the skull and brain, which leads to a primary- (direct negative influence on tissue architecture and homeostasis) as well as a secondary  injury . Due to The study by Koutsoudaki and colleagues elegantly demonstrated the non-necessity of NSC modulation prior to transplantation into injured adult mouse brains. Upon TBI to the hippocampus by stabbing multiple times 2 mm deep through the cortex, corpus callosum, and hippocampus, non-modified (reporter-gene expression only) and insulin like growth factor 1 (IGF1) overexpressing NSCs  were transplanted close to the lesion site. Considering fate outcome as well as functional improvement , no differences between IGF1 producing and reporter gene only expressing NSCs were observed. Both cell populations ameliorated injury-induced spatial learning deficits and in both cases transplanted NSCs mainly differentiated into oligodendroglial cells . As in sIn contrast to the TBI wound induced by a blunt-end needle, which also disrupts WM structures , the modIn a comparable experimental set up (modified Feeney method) neonatal mouse hippocampus-derived NSCs were transplanted 24 h after injury into the pericontusional region . SimilarTemporal lobe epilepsy (TLE) is a common form seen in about 30% of epileptic patients. By injecting kainic acid (KA) into the rodent hippocampus or the SVZ, neurodegeneration is induced and neuronal cell death and functional impairments similar to TLE patients can be mimicked. While NSC transplantation has also been investigated in terms of trophic support these NSCs can confer to the damaged environment, this section will focus on the aspect of NSC mediated cell replacement and fate choice.Since kainate induced hippocampal degeneration represents a focal CNS injury, transplantation of P5 mouse SVZ-derived NSCs into the hippocampus close to the injection site resulted in only minor migration towards the lesion area . Stem ceWhile transplantation of NSCs into the kainate-induced neurodegenerative hippocampus resulted in mostly neuronal differentiation and ameliorated cognitive function , anotherA further TLE study also reported primarily astroglial fate choices although NSCs were transplanted into an acute TLE model . A changAnother interesting finding is that SVZ-derived NSCs transplanted into healthy non-injured hippocampi were also located close to the SVZ several weeks after transplantation \u2014a distriSly disease is a rare hereditary lysosomal storage disorder, characterized by the deficiency in \u03b2-glucuronidase (GUSB) and subsequent accumulation of glycosaminglycans in many organs including the brain leading to mental retardation. Applying NSCs as early as technically feasible might provide a potential therapeutic approach in order to restore global dysfunction of the developing brain. The mucopolysaccharidosis VII (MPS VII) mouse strain mimics human sly disease pathological features. Upon transplantation of GUSB-expressing C17.2 NSCs into lateral ventricles of neonatal MPS VII mice, cells distributed and integrated in the whole brain and no tumorigenesis was observed . WidesprThe lack of oxygen supply in the brain results in ischemic stroke, leading to irreversible neuronal damage . IschemiTransplantation of neurosphere-derived cells from neonatal mice hence containing NSCs, various progenitors and more differentiated cells  into theRegarding differences in the microenvironment of ischemic brain regions over time, Darsalia and colleagues compared the differential outcome of intrastriatally transplanted human fetal striatal NSCs 48 h and six weeks after stroke. Transplantation after 48 h following stroke resulted in a higher NSC survival rate as compared to transplantation at the later time-point. However, different time-points did not affect the extent of migration, differentiation and proliferation. Interestingly, analysis of neuronal fate acquisition revealed no change in the percentage of Dcx-positive neuroblasts but for both transplantation time-points the percentage was lower as compared to injury-free animals . Such ob35\u201355) peptide induced EAE, which leads to a T-cell mediated autoimmune response towards oligodendrocytes with the first symptoms appearing ten days after initial immunization.Multiple sclerosis (MS) is an autoimmune disease characterized by oligodendrocyte and myelin loss, which ultimately leads to axonal degeneration and subsequent sensory, motor, and cognitive dysfunction . The mosIntracerebroventricular transplantation of human embryonic stem cell-derived early multipotent neural precursor cells (hESC-NPCs) demonstrated robust migration into the host WM, which led to significantly reduced clinical sings of EAE in host mice . The benFurther evidence for a high migratory activity of implanted cells in the EAE brain derived from a report on human induced pluripotent stem cell-derived NSCs (iPSC-NSCs) having migrated into the dentate gyrus one month following intraventricular transplantation in EAE mice . Co-locaMinor regeneration promoting effects using allogenic NSCs were also reported for a chronic EAE model, into which transplantation was performed 40 days post-immunization. Here, treatment with non-modified bone marrow-derived (BM) NSCs (derived from six- to eight-week-old mice)  blocked While the two previous studies report minor regeneration promoting effects using allogenic or na\u00efve NSCs in EAE mice, Einstein and colleagues could show that intraventricularly transplanted striatal newborn rat multipotential NSCs migrated into inflamed WM tracts and subsequently differentiated into glial cells in EAE rats. This transplantation strategy resulted in a reduced inflammation of the host brain and ameliorated the disease course. Whether beneficial effects were due to additional processes attributed to particularly the rat system remains open.Intraventricular transplantation of both, glial-derived neurotrophic factor (GDNF) overexpressing- (GDNF-NSCs) or na\u00efve newborn rat cerebrum-derived NSCs ten days following EAE induction led to a delayed disease onset and significant reduction of clinical EAE signs . More spwww.alzforum.org) [Neurodegeneration in Alzheimer\u00b4s disease (AD) results in learning deficits and dementia. In a murine AD model (APP/PS1 mice), neuron-specific Thy1 promotor driving the co-expression of KM670/671NL mutated amyloid precursor protein (APP) and of L166P mutated presenilin-1 (PS1) leads to human amyloid depositions and local neuronal loss in the dentate gyrus ,50. The rum.org) ,53,54,55rum.org) ,60,61,62rum.org) ,57,61,62rum.org) . Using arum.org) . The obsInterestingly, most of the compiled studies report that transplanted NSCs showed high migratory behavior leaving injection sites ,63,64,65Using a chemical model to mimic AD related neuropathological features by okadaic acid injection into the lateral ventricles  only traHuntington\u00b4s disease (HD) is an inherited neurodegenerative disease caused by the progressive loss of GABAergic medium spiny neurons (MSNs) in the striatum. Injection of 3-nitropropionic acid (3-NP) into the striatum serves as an animal model to mimic HD symptoms and related neurodegenerative aspects. Transplantation of human NSCs  into the injured striatum one week prior to the injury resulted in decreased loss of striatal neurons as well as the appearance of calbindin-expressing  donor cell-derived neurons . Upon imSpinal cord injury (SCI) is a devastating neurological condition, which is caused by a traumatic impact to the spinal cord. It results in permanent impairment of motor- and sensory functions due to the interruption of descending and ascending nerve fiber tracts. Local cell loss at sites of injury is followed by glial scar formation and accompanied by inflammation which prevent regeneration of transected axons and exert an additional negative impact on functionality and survival of remote neurons ,75. StemIn this regard, we compared data on fate acquisition of transplanted NSCs from two methodologically different SCI models. Compression or contusion used to induce broader and probably medically more relevant spinal cord lesions is compared to more defined injuries resulting from spinal cord hemisection or complete transection. Both models affect spinal cord integrity and lead to motor and sensory dysfunction while differing in terms of lesion volume and extent of secondary damage. Transplantation of various NSCs indeed led to the generation of different cell fates correlating with the type of evoked injury.Interestingly, rodent and human NSCs transplanted into a compression or a contusion lesion preferentially differentiated into oligodendrocytes ,89,90,91While most NSC transplantation based SCI studies focused on rodent models, Iwanami and colleagues used a primate contusion model. Upon cervical contusion in marmosets and subsequent transplantation of human NSCs, assessment of fate acquisition of the engrafted NSCs showed the following distribution: 46% GFAP-positive astrocytes, 25% nestin-positive stem cells, 21% \u03b2-III-Tub-positive neurons, and 5% Olig2-positive oligodendroglial cells . Since iMigration of transplanted NSCs towards an injury site, into lesion zones or close to demyelinated axonal fibers is key for a potential beneficial role of transplanted NSCs in terms of local neurotrophic factor secretion or remyelination. Considering the migratory potential of transplanted NSCs, it was found that migration exclusively occurs in spinal cords with a contusion or compression injury ,99,103. Despite the well described self-renewing potential of  stem cells in vitro as well as in their discrete niches in vivo, transplanted stem cells showed little or no proliferation activities within host tissues in all SCI studies considered here ,91,95,98The aforementioned studies revealing differences and similarities in different SCI models all used subacute or acute application conditions, in that NSC transplantation was performed immediately or shortly after injury. However, this does not necessarily reflect a patient\u2019s situation who will first receive emergency surgery in order to stabilize general conditions and to avoid secondary damage preceding possible regeneration directed therapies. Moreover, for autologous stem cell transplantation a timely application of appropriate cell numbers is not feasible. Investigating chronic SCI models in which cells are transplanted several weeks after SCI might therefore be more relevant in terms of clinical translation and feasibility. In this regard, not only the type of induced injury (pressure or cut) appears to be important but also the disease process seems to account for the NSC fate. This particular question was addressed by several groups comparing chronic  to a subacute (days after injury) transplantation approaches. In two studies, a lower survival rate of NSCs transplanted after four and eight weeks into contusion lesions compared to a subacute transplantation process was observed ,86. WhilOf note, given that at least for transplanted OPCs heterogenic responses in gray vs. white matter have been described , a systeThe high complexity of adult mammalian central nervous systems and the low degree of intrinsic repair capacity results in devastating functional impairments and persisting disabilities in most neuropathologies. The discovery of neural stem cells and their potential to give rise to all cell lineages of the CNS has revived the field in terms of functional cell replacement. Initial concerns related to exogenously applied NSCs and possible adverse effects were refuted as the majority of NSC transplantation studies revealed no tumor formation. Interestingly, studies investigating the outcome of NSC transplantations into healthy CNS tissue revealed dominant region-specific cues instructing the grafts. Despite a great heterogeneity among different CNS lesion models, transplanted NSC migration towards lesion sites and subsequent differentiation into to be replenished cell types are common observations in the majority of neuropathological models. These observations raise hope for the development of NSC-mediated CNS regeneration therapies as most neural stem cell types seem to be sensible to injury environments and their requirements and since even delayed NSC applications can confer functional benefits."}
+{"text": "Angina with no obstructive coronary artery disease (ANOCA) is a common syndrome with unmet clinical needs. Microvascular and vasospastic angina are relevant but may not be diagnosed without measuring coronary vascular function. The relationship between cardiovascular magnetic resonance (CMR)-derived myocardial blood flow (MBF) and reference invasive coronary function tests is uncertain. We hypothesise that multiparametric CMR assessment will be clinically useful in the ANOCA diagnostic pathway.The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) trial is a prospective, blinded, randomised, sham-controlled study comparing two management approaches in patients with ANOCA. We aim to recruit consecutive patients with stable angina undergoing elective invasive coronary angiography. Eligible patients with ANOCA (n=150) will be randomised to invasive coronary artery function-guided diagnosis and treatment (intervention group) or not (control group). Based on these test results, patients will be stratified into disease endotypes: microvascular angina, vasospastic angina, mixed microvascular/vasospastic angina, obstructive epicardial coronary artery disease and non-cardiac chest pain. After randomisation in CorMicA, subjects will be invited to participate in the Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) substudy. Patients will undergo multiparametric CMR and have assessments of MBF (using a novel pixel-wise fully quantitative method), left ventricular function and mass, and tissue characterisation (T1 mapping and late gadolinium enhancement imaging). Abnormalities of myocardial perfusion and associations between MBF and invasive coronary artery function tests will be assessed. The CorCMR substudy represents the largest cohort of ANOCA patients with paired multiparametric CMR and comprehensive invasive coronary vascular function tests.The CorMicA trial and CorCMR substudy have UK REC approval (ref.16/WS/0192).NCT03193294. Angina with no obstructive coronary artery disease (ANOCA) is a common syndrome with unmet clinical needs.A significant proportion of these patients may suffer from microvascular and vasospastic angina.Diagnosis in this patients may be challending, are there are uncertain associations between the results of reference invasive diagnostic tests and the non-invasive ischaemia test results.Novel CMR methods for measuring myocardial blood flow have not been validated in patients with ANOCA and underlying microvascular and vasospastic angina.The CorCMR substudy represents the largest cohort of ANOCA patients with paired multiparametric CMR and comprehensive invasive coronary vascular function tests. CorCMR will provide information on the diagnostic value of quantitative pixel-wise mapping of myocardial perfusion in patients with ANOCA.In contrast to the reference standard invasive tests of coronary artery function, non-invasive imaging is safer and more acceptable to patients.The CorCMR sub-study presents a unique opportunity to assess and validate the diagnostic accuracy of fully-quantitative stress perfusion CMR in patients with ANOCA and comprehensive invasive coronary artery function testing.Ischaemic heart disease is the leading cause of mortality standardised by age and sex.Patients with angina and no obstructive coronary artery disease (ANOCA) present a diagnostic conundrum.The underlying pathogenesis in patients with ANOCA is unclear, as specific disease endotypes are not routinely tested for. CMD may result from coronary structural abnormalities, whereby decreased capillary luminal size and number result in increased microvascular resistance to myocardial blood flow (MBF) and reduced vasodilatory capacity.Abnormalities of coronary vascular function portend a worse prognosis in patients with both obstructive epicardial CAD and ANOCA.Diagnosis of coronary microvascular and vasomotor dysfunction is challenging due to the heterogeneity of underlying disease mechanisms, the potentially patchy distribution of disease throughout the myocardium, and limited spatial resolution of existing diagnostic tests.There is no accepted guideline-directed diagnostic algorithm for coronary vascular dysfunction in routine clinical practice.The available non-invasive ischaemia tests were all validated for the detection of obstructive epicardial CAD. There has been a low yield of inducible myocardial ischaemia in ANOCA patients with traditional non-invasive ischaemia tests .Coronary microvascular disease may be revealed by a deficit in MBF during stress CMR. The spatial distribution of this abnormality typically involves the subendocardium, which is the location of the microvascular plexus.There are uncertain associations between the results of invasive diagnostic tests and the non-invasive ischaemia test results in patients with ANOCA. There is no accepted objective diagnostic threshold for the diagnosis of coronary vascular dysfunction , with either PET or perfusion CMR. Recent studies have investigated the relationships between invasive tests of coronary artery function and semiquantitative perfusion CMR analysis.The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) clinical trial is a proof-of-concept, prospective, blinded, randomised, sham-controlled study comparing two management approaches to the clinical problem of patients with ANOCA.The IDP consists of coronary artery function testing using a dual pressure-sensitive and temperature-sensitive guidewire and adenosine followed by intracoronary acetylcholine provocation testing. Assessment of microvascular resistance (IMR), microvascular vasodilatory capacity (resistance reserve ratio (RRR)), epicardial and microvascular vasodilatory capacity (CFR), endothelial function (acetylcholine provocation testing) and epicardial CAD ) will be performed. Following these invasive tests of coronary artery function, patients will be classified into the following ANOCA disease endotypes : (1) micPatients in the control group will receive standard care based on the interpretation of the invasive coronary angiogram alone. Patients in the intervention group will have care based on the disease endotypes disclosed by invasive tests of artery function, and pharmacotherapy linked to the underlying disease endotype will be commenced.Novel CMR methods for measuring MBF have not been validated in patients with ANOCA and underlying microvascular and vasospastic angina. The CorCMR substudy of the CorMicA clinical trial presents a unique opportunity to assess and validate the diagnostic accuracy of fully quantitative stress perfusion CMR in patients with ANOCA and comprehensive invasive coronary artery function testing.We hypothesise that abnormal myocardial perfusion, as revealed by a novel fully quantitative pixel-wise CMR perfusion sequence, will be prevalent in a contemporary UK cohort of patients presenting with ANOCA and that multiparametric CMR imaging will be clinically useful in the diagnostic pathway of patients with ANOCA.We aim to assess the diagnostic validity of quantitative stress perfusion CMR in patients with ANOCA and specific disease endotypes of coronary vascular dysfunction. Our specific aims are to assess:The proportion of ANOCA patients with abnormal myocardial perfusion. There is no accepted threshold for abnormal MPR. Thresholds for reduced CFR of 1.5\u20132.6 have been described, however <2.0 is commonly used.The diagnostic accuracy of the perfusion CMR metrics for abnormal invasive tests of coronary artery function  and the associations between specific disease endotypes and myocardial perfusion in patients with ANOCA. We also aim to assess the correlation between abnormal CMR-derived perfusion and invasive tests of coronary artery function, of qualitative versus quantitative perfusion methods.The proportion of patients with ANOCA and abnormal myocardial tissue characterisation derived from CMR  imaging) and its association with abnormal myocardial perfusion.The associations between baseline patient characteristics and abnormal myocardial perfusion.The proportion of patients with a change in diagnosis based on quantitative CMR findings, as compared with the initial diagnosis by the attending cardiologist based on the coronary angiogram.Prespecified substudy of the CorMicA stratified medical therapy clinical trial.Patients referred from 14 acute hospitals to two large regional UK hospitals  providing invasive care to all patients in the West of Scotland (population 2.5 million). All CMR studies will be performed at the Golden Jubilee National Hospital.Consecutive outpatients undergoing clinically indicated elective diagnostic angiography for investigation of suspected angina will be screened and invited to participate in the CorMicA trial. Informed consent is obtained before the invasive coronary angiogram. A minimum of 400 consecutive patients undergoing elective invasive coronary angiography is expected to be screened to enrol 150 subjects with ANOCA within 24 months. Consenting patients who are not randomised  will enter a registry. Only patients randomised in the CorMicA trial (both in the intervention and control groups) are eligible to participate in the CorCMR substudy.Age \u226518 years, a clinically indicated plan for invasive coronary angiography and symptoms of angina (according to the Rose angina questionnaire).A non-coronary indication for invasive angiography , obstructive epicardial CAD disease evident in a main coronary artery (diameter >2.5 mm) (defined as diameter stenosis >50% or FFR \u22640.80) and contraindication to contrast-enhanced CMR .Patients will undergo perfusion CMR within 42 days of the CorMicA trial invasive coronary artery function testing. CMR studies will be performed at 1.5 Tesla , and patients will undergo a standardised CMR protocol. All patients will be asked to abstain from caffeine-containing beverages or foodstuffs for 24 hours and vasoactive medications for 48 hours prior to the CMR examination. All scan acquisitions will be spatially coregistered. All CMR analyses will be performed by analysts blinded to the invasive coronary artery function test results. The standardised CMR protocol is demonstrated in Stress and rest first-pass perfusion imaging will be performed using an echo planar imaging dual-sequence investigational perfusion method, which consists of a low resolution arterial input function image, followed by three short axis  myocardial images during each R\u2013R interval.The raw stress and rest perfusion images will be qualitatively assessed for inducible or fixed perfusion defects. Perfusion defects will be reported on a segmental basis according to the American Heart Association 16-segment model.Pixel-wise perfusion maps will be generated and analysed to derive fully quantitative MBF estimates on a pixel-wise basis in mL/g/min of myocardium. The pixel-wise perfusion method uses a series of automated postprocessing steps on the raw Digital Imaging and Communications in Medicine images to generate fully quantitative pixel maps.2] and percentage coefficient of variation of time to maximum signal intensity upslope and time to peak myocardial signal intensity enhancement.The myocardial perfusion dyssynchrony index is a novel perfusion metric that assesses temporal differences in the distribution of gadolinium-based contrast media myocardial wash-in. This index has the potential to increase the diagnostic sensitivity and specificity of perfusion CMR for abnormalities of myocardial perfusion in patients with ANOCA.Fast gradient echo images in the axial, coronal and sagittal planes will be qualitatively assessed for extra cardiac anatomy and pathology and clinically relevant incidental findings.Steady-state free procession \u2018cine\u2019 imaging using a trueFISP sequence (multislice single-shot breath-hold true fast imaging) will be performed in the three long-axis and short-axis planes for assessment of LV volumes, function and mass.Native T1 mapping will be performed using a modified look-locker inversion recovery investigational prototype sequence. Images will be obtained in three short-axis images . T1 mapping will be performed pre- and post-gadolinium contrast to assess the myocardial native T1 relaxation time and estimate the myocardial extracellular volume (ECV) in both the mid-septum and globally.LGE imaging will be performed using a segmented phase-sensitive inversion recovery turbo fast low-angle shot imaging sequence.Abnormal myocardial perfusion reserve .A summary of the secondary outcomes is shown in Box 2.LV EFLVEDVLV EDV indexLV ESVLV ESV indexLV massLV mass indexLV COLV CO index2)Left atrial area (cmLeft atria dilated (Y/N)2)Right atrial area (cmRight atria dilated (Y/N)Abnormal perfusion (Y/N)Number of abnormal segments (n)Transmurality of perfusion defects (%)Pattern Global MPR <2.0 (Y/N)Segmental/AHA MPRGlobal stress and rest MBFSegmental/AHA territory stress and rest MBFGlobal stress endocardial:epicardial MPR ratioSegmental/AHA territory endocardial:epicardial MPR ratioMyocardial perfusion dyssynchrony index Splenic switch-off (Y/N)HR and BPchangeRate-pressure product at rest and stressAbnormal LGE (Y/N).Number of affected AHA segments (n)Pattern of abnormal LGE (ischaemic and non-ischaemic)Myocardial infarct scar burden Native T1 ECV Feature-tracking and DENSE (two methods)Longitudinal strain Circumferential strain Radial strain Present (Y/N)Clinically significant (Y/N)Sex, age and traditional CAD risk factorsCAD risk scores (JBS3 and ASSIGN)Gensini score of epicardial plaque burdenAssociation of myocardial perfusion with IMR, CFR, RRR and endothelial function testing (continuous and binary)Subset of patients with multivessel invasive coronary artery function measurementsAssociation with clinical diagnosis (ANOCA disease endotype)LV volumes and massMyocardial strainNative T1 relaxation time and ECVPresence of LGEDiagnostic accuracy of quantitative perfusion CMR to detect abnormal IMR, CFR, RRR and endothelial dysfunctionAHA, American Heart Association; ANOCA, angina with no obstructive coronary artery disease; BP, blood pressure; CFR, coronary flow reserve; CAD, coronary artery disease; CO, cardiac output; CorCMR, Coronary Microvascular Angina Cardiac MRI; EF, ejection fraction; EDV, end-diastolic volume; ESV, end-systolic volume; ECV, extracellular volume; HR, heart rate; IMR, index of microcirculatory resistance; LV, left ventricular; LGE, late gadolinium enhancement; MBF, myocardial blood flow; MPR, myocardial perfusion reserve; RRR, relative resistance ratio,The CorMicA trial has a comprehensive statistical analysis plan that governs all statistical aspects of the study authored by the trial statistician. The statistical analysis plan includes the prespecified CorCMR substudy that is designed to assess for associations between CMR measures and invasive measures and endotypes (reference dataset). Continuous outcomes will be analysed using linear regression with adjustment for baseline levels where available. Where continuous data are clearly not normally distributed, standard transformations will be applied to achieve approximate normality prior to analysis. Appropriate alternative regression methods will be applied to other types of data .The primary outcome is the proportion of patients with an MPR<2.0. The proportion of patients with microvascular angina defined by invasive endotyping will be assessed. We will further assess the MPR ratio with the highest AUC for microvascular angina classified invasively.Considering the correlation between CFR measured invasively and MPR measured non-invasively within the common territory of a major epicardial coronary artery, then a sample size of 110 subjects would enable a minimum clinically significant correlation of 0.3 to be detected with 90% power at a 5% significance level. If only 60 subjects have available data, then 80% power would be available to detect a correlation of 0.37 at the 5% level.The British Heart Foundation CorMicA trial will assess a routine stratified medicine strategy in a large cohort of prospectively enrolled patients with ANOCA. The prespecified CorCMR substudy will involve comprehensive invasive tests of coronary artery function paired with multiparametric perfusion CMR studies. The analysis will provide information on the diagnostic value of quantitative pixel-wise mapping of myocardial perfusion in this population.Contemporary guidelines recommend functional testing, including with CMR, to assess for myocardial ischaemia in patients in whom multidetector CT coronary angiography has shown CAD of uncertain functional significance or is non-diagnostic.The CorCMR substudy will be performed on a 1.5 Tesla MRI scanner. In comparison, 3.0 Tesla imaging permits improved signal-to-noise ratio and provides higher in-plane spatial resolution perfusion imaging.et alet alPatients with confirmed microvascular or vasospastic angina have a precise diagnosis of the underlying disease endotype, and pharmacotherapy may be commenced as appropriate. Conversely, patients with normal invasive coronary artery function tests may have antianginal therapy appropriately discontinued, and alternative causes of chest pain investigated. In comparison with invasive tests of coronary artery function, non-invasive CMR imaging may be more attractive to patients, but at present, the role of CMR in the diagnostic work-up of patients is uncertain. CorCMR will provide data on the role of CMR in the diagnosis of patients with ANOCA. Traditional non-invasive ischaemia testing in patients with ANOCA has provided mixed results. Panza et al compared semiquantitative perfusion CMR against IMR measurement in 50 patients with ANOCA and 20 age-matched healthy control subjects.et alCorCMR will inform the nascent evidence on the presence and magnitude of associations between invasive and non-invasive assessments of coronary vascular function. Liu et alCMR permits the reference-standard non-invasive assessment of myocardial tissue characterisation. CorCMR will provide data on diffuse interstitial fibrosis, ECV and myocardial scar. The role of T1 mapping and ECV analysis in patients with ANOCA is uncertain. In a substudy of the iPOWER natural history study, 54 women with ANOCA underwent native T1 mapping and ECV analysis, PET-derived MBF measurement, and transthoracic Doppler echocardiography CFR assessment.http://www.equator-network.org/reporting-guidelines/stard/) and Consolidated Standards of Reporting Trials (http://www.consort-statement.org/) guidelines.Progress in the trial will be monitored by the trial anager (KB) and sponsor. The study will be subject to internal and external audit that is routinely coordinated by the sponsor. An annual report will be submitted to the Research Ethics Committee on a 12-month basis. The flow diagram illustrates conservative estimates of patient enrolment and activity on a single site. The study will follow Standards for Reporting of Diagnostic Accuracy (STARD) (The CorCMR data will be presented at conferences and/or published in peer-reviewed journals."}
+{"text": "Coarctation of aorta (CoA) is a discrete narrowing in aorta causing obstruction to the flow of blood. It accounts for 6\u20138% of all congenital heart diseases. With advances in fetal echocardiography rate of prenatal diagnosis of coarctation of aorta has improved but it still remains a challenging diagnosis to make prenatally. Transthoracic echocardiography is mainstay of making initial diagnosis and routine follow-up. Cardiac magnetic resonance imaging (MRI) and computed tomography (CT) are great advanced imaging tools for two-dimensional and three-dimensional imaging of aortic arch in complex cases. Based on type of coarctation, size of patient, severity of lesion, and associated abnormalities various management options like surgical treatment, transcatheter balloon angioplasty and transcatheter stent implantation are available. There is significant improvement in long-term survival from pre-surgical era to post-surgical era. But, among the postsurgical era patients, the long-term survival has not significantly changed between older and contemporary cohort. Patients with coarctation of aorta need lifelong follow-up event after successful initial intervention. Coarctation of aorta (CoA) can be simply defined as cardiac abnormality resulting in obstruction to the blood flow in the aorta. CoA can occur at any region in the thoracic and abdominal aorta. Most common location for CoA is just distal to the left subclavian artery at the point where ductus arteriosus connects to the aorta. Typically there is presence of medial thickening with \u201cshelf like\u201d tissue protruding in the lumen of aorta from the posterior aortic wall , 2. CoA EpidemiologyCongenital heart disease (CHD) accounts for nearly 28% of all major congenital anomalies . The birPathogenesisDuring embryonic period aorta develops from pharyngeal arches and its arterial system. Development of aortic arch starts in third week of gestation and the primordial pharyngeal arch arterial pattern is transformed into the final fetal arterial arrangement during eighth week of gestation. Ventral primitive aorta forms the aortic sac and dorsal primitive aorta forms the descending aorta. Developing pharyngeal arch arterial system connects these two portions. There are six sets of pharyngeal arches that contribute towards development of aortic arch and its branches. It should be noted that all the arches are not present at the same time during fetal period. Primary portion of the aortic arch develops from fourth pharyngeal arch and other arches contribute to development of branch pulmonary arteries, ductus arteriosus and aortic arch branches , 13. AnyThere are three leading developmental theories regarding formation of CoA. First, during development of aortic arch the tissue from ductus arteriosus may get incorporated in the aortic wall where it connects to the descending aorta. As the ductus arteriosus constricts after birth, this tissue in isthmus area constricts causing development of CoA , 14. SecClinical presentationThe clinical presentation and exam findings are variable based on patient\u2019s age. Typically earlier presentation corresponds to severe disease.Younger ChildrenNewborns and neonates are usually asymptomatic right after birth as patent ductus arteriosus (PDA) helps perfuse lower body irrespective of severity of CoA. Neonates with severe/critical CoA develop\u00a0signs and symptoms of cardiogenic shock as the ductus arteriosus closes after birth. Clinically, babies may show absent/feeble femoral pulse, delayed capillary refill, feeding problems, decreased responsiveness, metabolic acidosis, mesenteric ischemia, myocardial depression, etc. It is empirical to keep ductus arteriosus open with prostaglandin E1 infusion as soon as the diagnosis of severe/critical CoA is made and further definitive intervention can be performed. Beyond the neonatal period, cardiogenic shock is an unusual presentation but still a possibility during early infancy. Older pediatric patients are usually diagnosed due to weak femoral pulse, upper extremity hypertension, a systolic murmur over upper sternal border with radiation to the back, and upper-lower extremity systolic blood pressure gradient. Newborn pulse oximetry screening is a great tool in detecting cases of critical congenital heart disease in newborns. Although, its utility is limited in patients with pure CoA without presence of PDA (due to lack of mixing/shunting). Newborns with severe/critical coarctation with presence of PDA may have positive results on pulse oximetry screening due to right to left shunting at PDA .Adolescent and AdultsAlmost always these patients are diagnosed with CoA during workup of systemic hypertension or heart murmur. Clinical signs may include upper extremity hypertension, weak femoral pulse, arm-leg blood pressure gradient (>20 mmHg is significant), a systolic murmur on the back from flow through the coarctation segment or a continuous murmur from the collateral flow around the coarctation site. Patients may also complain of frequent headaches resulting from systemic hypertension and lower limb claudication from chronic hypoperfusion. If the collateral circulation around the coarctation site is significant then distal pulses may be adequate and arm-leg blood pressure gradient may not be significant.HypertensionSystolic hypertension improves and need for antihypertensive medications decreases in almost all patients after successful intervention, but chronic hypertension remains a significant issue in large proportion of patients with CoA. Prevalence of hypertension is lower in patients who are treated during neonatal period and infancy. Overall prevalence of long-term hypertension is noted at 25\u201368% .\u00a0PreoperDiagnostic imagingTransthoracic echocardiography (TTE) is the preferred diagnostic modality for diagnosis and follow-up of CoA. Fetal echocardiography (FE) has advanced significantly over past couple of decades to allow us to make prenatal diagnosis of CoA and avoid cardiovascular catastrophe after birth. Cardiac MRI (cMRI) and cardiac computed tomography (CT) have emerged as a sophisticated second line of advanced imaging that provides excellent image resolution and anatomical details. Prior to advances in echocardiography, cardiac catheterization was the mainstay for making the diagnosis of CoA. In current era, it is primarily used for interventional purpose.Fetal EchocardiographyPrenatal diagnosis of CoA helps with parental counselling, delivery planning, avoids postnatal cardiac emergencies, and guides timely management . PrenataTransthoracic EchocardiographyTTE remains the mainstay of postnatal diagnosis and follow-up for aortic arch anomalies. Goal of TTE is to identify arch anatomy, site of coarctation, determine severity, and assess for associated intracardiac abnormalities , 25. SupTransesophageal EchocardiographyTransesophageal echocardiography is seldom used for primary diagnosis of CoA due to its invasive nature and limited views for arch imaging . It is uComputed TomographyCT angiography uses intravenous contrast and ionizing radiation to obtain intracardiac and extracardiac structural data with very high spatial resolution . CT alloMagnetic Resonance ImagingcMRI is a preferred non-invasive advanced imaging for patients with CoA . cMRI doElectrocardiogramElectrocardiogram is a typical initial screening test for heart rhythm evaluation and to assess for possible cardiac chamber enlargement. This can be normal or show evidence of left ventricular hypertrophy in patients with CoA. Newborns may show presence of right ventricular hypertrophy on electrocardiogram.Chest X-RayChest X-ray is helpful at looking for aortic arch sidedness on most patients. Classic \u201cfigure of three\u201d sign can be seen on some patients with CoA. This is formed by patent pre-stenotic aortic nob, indentation from stenotic segment, and post-stenotic dilated segment. Patients with long standing unrepaired coarctation develop extensive collateral circulation through dilatation of intercostal arteries. These arteries run on the inferior aspect of the ribs. These patients can show inferior rib notching bilaterally from third to eighth ribs on chest X-ray .TreatmentSurgical repair, transcatheter balloon angioplasty and transcatheter stent implantation are treatment modalities available for management of CoA . Preferr- Non-invasive systolic blood pressure gradient of >20 mmHg between upper and lower limbs- Peak-to-peak transcatheter gradient of >/= 20 mmHg across the coarctation site- Peak-to-peak transcatheter gradient of <20 mmHg in the setting of extensive collateral circulation around the coarctation site- Significant left ventricular hypertrophy- Left ventricular systolic dysfunction- Uncontrolled systemic hypertension in the setting of coarctation of aorta- Abnormal blood pressure response during exercise stress testSurgerySince the first surgical repair of CoA in early 1940s by Dr. Crafoord, surgery remains a major treatment option for patients of all age group with CoA . In neonTranscatheter Balloon AngioplastyTranscatheter balloon angioplasty for native CoA was first introduced in the early 1980s . During Transcatheter Stent ImplantationTranscatheter stent implantation was introduced in the late 1980s and was widely accepted as a therapeutic measure for patients with CoA in the early 1990s . This isForbes et al. compared safety and efficacy of surgical and transcatheter treatment options for native coarctation at acute interval and at follow-up for patients between the years 2002 and 2009 from 36 institutions . They noCoA remains most common aortic arch abnormality in children. Key to optimum management of these patients is early detection and timely intervention. Various surgical and transcatheter options are available for management of CoA. Treatment option should be individualized for each patient based on associated factors. Lifelong follow-up is mandatory for these patients to monitor for any late complications."}
+{"text": "Pseudomonas aeruginosa is known to tolerate antibiotic therapy during infection. This prevents clearance of infection and negatively impacts patient outcomes. Pseudomonas aeruginosa is known to tolerate antibiotic therapy during infection. This prevents clearance of infection and negatively impacts patient outcomes. Here, we report the transcriptome sequence of antibiotic-treated and untreated P. aeruginosa cultures and the differential gene expression observed when treated cells are compared to untreated cells. Pseudomonas aeruginosa is a Gram-negative bacterium which causes various human infections using a suite of virulence factors  reached 0.5, at which point the cells were collected and preserved in RNAprotect. Biofilms were formed in LB broth on borosilicate glass discs as described previously and preserved in RNAprotect (NC_002516) using Bowtie, allowing 2 mismatches in a default seed length of 28 nucleotides to prevent the mapping of low-quality reads  may be involved in antibiotic tolerance, these data will provide a starting point for investigating the mechanisms of tolerance in GSE120602.The RNA-seq reads and the DESeq results have been deposited in the NCBI Gene Expression Omnibus (GEO)  and are"}
+{"text": "Life on earth is sustained by oxygenic photosynthesis, a process that converts solar energy, carbon dioxide, and water into chemical energy and biomass. Sunlight is essential for growth and productivity of photosynthetic organisms. However, exposure to an excessive amount of light adversely affects fitness due to photooxidative damage to the photosynthetic machinery, primarily to the reaction center of the oxygen-evolving photosystem II (PSII). Photosynthetic organisms have evolved diverse photoprotective and adaptive strategies to avoid, alleviate, and repair PSII damage caused by high-irradiance or fluctuating light. Rapid and harmless dissipation of excess absorbed light within antenna as heat, which is measured by chlorophyll fluorescence as non-photochemical quenching (NPQ), constitutes one of the most efficient protective strategies. In parallel, an elaborate repair system represents another efficient strategy to maintain PSII reaction centers in active states. This article reviews both the reaction center-based strategy for robust repair of photodamaged PSII and the antenna-based strategy for swift control of PSII light-harvesting (NPQ). We discuss evolutionarily and mechanistically diverse strategies used by photosynthetic organisms to maintain PSII function for growth and productivity under static high-irradiance light or fluctuating light environments. Knowledge of mechanisms underlying PSII maintenance would facilitate bioengineering photosynthesis to enhance agricultural productivity and sustainability to feed a growing world population amidst climate change. Cyanobacteria, algae, and plants convert sunlight into chemical energy through photosynthesis to provide oxygen and food building blocks that are essential for most life forms on earth. Photosynthesis starts with capture of light by light-harvesting antenna, which drives photosynthetic electron flow through photosynthetic machinery comprising several large protein complexes embedded in the thylakoid membranes of prokaryotic cyanobacteria and eukaryotic chloroplasts. Oxygen-evolving photosystem II (PSII) is a highly conserved multi-subunit pigment-containing membrane complex that functions as a light-driven water:plastoquinone oxidoreductase during photosynthetic electron transport  LQY1 (LOW QUANTUM YIELD OF PHOTOSYSTEM II 1) protein\u2014interacting with HHL1\u2014regulates repair of damaged core complexes to sustain high PSII efficiency upon exposure to excessive light  and diatom Phaeodactylum tricornutum both need the LHCSR (LHC STRESS-RELATED PROTEIN) family protein for NPQ formation. Synthesis of the Chlamydomonas LHCSR protein is dramatically induced by high light, and it is responsible for the majority of flexible NPQ  protein in higher plants plays a similar role to the algal type LHCSR. It senses the pH of the chloroplast thylakoid lumen when there is excess light and induces flexible NPQ . Short-lin, LCNP . Intriguin, LCNP . These din, LCNP . The impin, LCNP .The wide distribution of NPQ across photosynthetic prokaryotes and eukaryotes highlights its crucial role in PSII photoprotection. Notably, different NPQ systems have evolved in these diverse photosynthetic organisms. Flexible NPQ (qE), the major and also best-studied component of photoprotective excess energy dissipation, constitutes three systems, which are classified based on their associations with the diversification of the light-harvesting equipment in photosynthetic organisms: the OCP (ORANGE CAROTENOID PROTEIN)-dependent system in cyanobacteria, the LHCSR-dependent system in algae and mosses, and the PsbS-dependent system in mosses and vascular plants . Therefolhcsr mutant  . Althougvia an ancient endosymbiotic event  protein is reported to have a crucial role in adjusting Arabidopsis photosynthesis to fluctuating light  and MET1 (MESOPHYLL-ENRICHED THYLAKOID PROTEIN 1) caused stunted phenotypes when exposed to fluctuating light intensities   is that NPQ relaxation lags behind fluctuations in sunlight during sudden transitions from high to low light. This happens when passing clouds or movement of neighboring leaves/plant species shade sunlit leaves. The slow NPQ response could cost up to 30% of carbon gain , suggestnditions . Much moIn oxygenic photosynthesis, it is important to (1) safely handle excess absorbed light energy that would otherwise cause massive ROS production and damage the photosynthetic machinery and (2) efficiently convert solar energy into chemical bond energy. Tight regulation of these two aspects may contribute to an increase in productivity in agriculture and natural ecosystems. Understanding the elaborate NPQ mechanisms and the robust PSII repair systems may help identify targets to optimize photosynthetic efficiency. This would facilitate translational work toward exploring yield potential to sustainably meet the global rising demands for food, fuel, and fiber in the future climate change. Prior to accomplishing these grand goals, multiple outstanding questions await to be addressed:Do antenna-based photoprotection and reaction center-based repair operate in concert or in parallel to regulate PSII efficiency and photosynthetic capacity under photoinhibitory light and other environmental stresses? How does evolution of NPQ in the oxygenic organisms contribute to that of repair and vice versa?How do ROS regulate PSII activity under fluctuating light environments or field conditions?Are the molecular mechanisms of PSII repair under changing light different or similar to those under high-light irradiance? Can photosynthetic species discern PSII damage caused by these two types of light conditions and initiate distinct repair strategies?JL and RL conceived the project. JL, YL, WH, and RL wrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Alcohol-related problems affect increasing numbers of older adults. Recent studies have begun to investigate problem drinking among older adults based on a conceptual model proposing correlations between personal characteristics, life context , treatment, and drinking-related outcomes. In a community sample of older problem and nonproblem drinkers, alcohol consumption, life stressors, social resources, and coping responses differed between the two groups, although these factors did not directly and uniformly affect late-life drinking behavior. Furthermore, drinking behavior did not always have the expected effects on older drinkers\u2019 life contexts. Findings from a sample of treated alcohol and other drug-abusing older patients demonstrated the importance of providing mental health aftercare for this group. Historically, most efforts to understand and treat problem drinkingThis heightened interest in the alcohol-related problems of older adults has inspired studies yielding considerable information about the scope and correlates of alcohol consumption and problem drinking in late adulthood. The current prevalence of alcohol abuse and dependence in the general population of older adults is between 2 and 4 percent; it is considerably higher\u20145 to 30 percent\u2014in clinical populations . Most stRecent research highlights the importance of distinguishing between two groups of older problem drinkers: late onset and early onset. Late onset problem drinkers, of whom a significant proportion are women, first develop drinking problems later in life . Early onset problem drinkers, in contrast, develop drinking problems earlier during adolescence or adulthood and maintain them into late life. Compared with early onset problem drinkers, late onset problem drinkers generally are in better health , have better social relations , and are less likely to have been treated for alcohol and other drug (AOD) abuse , preventing inferences about the direction of causality between variables . Moreover, most studies have focused on correlations between personal characteristics  and late-life drinking behavior; few have considered the influence of the drinkers\u2019 environmental contexts . Finally, little is known about either the factors that prompt older adults to seek help for their alcohol-related problems or the treatment efficacy for this group. This article presents a model for conceptualizing late-life drinking behavior. Based on this research model, the article also describes the findings of two long-term  research studies aimed at elucidating predictors of alcohol consumption, drinking problems, treatment seeking, and treatment outcome in older adults.The conceptual framework presented in The late-life drinking behavior model posits several relationships between these four domains :Both personal characteristics and life context affect treatment seeking as well as drinking behavior and outcomes.Drinking behavior, in turn, influences a person\u2019s life context and certain personal characteristics.Some personal characteristics moderate the relationship between life context and outcomes.Treatment, including specific aspects of treatment programs, influences drinking-related outcomes.The validity of these assumptions was tested using a sample of older community residents as well as a sample of treated older AOD-abuse patients. The findings obtained with these two samples are described in the following sections.To examine the relationships between personal characteristics, life context, treatment seeking, and late-life drinking behavior, Brennan, Moos, and colleagues  studied Focusing on the latter two groups, the investigators addressed four questions: (1) Do the personal characteristics, life contexts, and coping responses of older problem drinkers differ from those of older nonproblem drinkers? (2) Do personal and life context factors at the beginning of the study predict drinking behavior 1 and 4 years later? (3) How does initial alcohol use in older problem drinkers affect their subsequent life context and psychological well-being? (4) What factors prompt older community residents to seek treatment for alcohol-related problems?Older problem and nonproblem drinkers differed with respect to several personal characteristics . As expeProblem drinkers also had more stressful life contexts than did nonproblem drinkers . Thus, tFinally, problem drinkers and nonproblem drinkers differed in their coping responses to stressful situations. Two broad categories of coping responses are approach coping and avoidance coping. Approach coping involves attempts to master or resolve a stressful situation; avoidance coping consists of efforts to avoid thinking about a stressor and its implications and includes the expression of stress-related emotions without attempting a resolution. A comparison of older problem and nonproblem drinkers showed that although both groups used comparable levels of approach-coping strategies to manage stressors, problem drinkers were more likely to use avoidance-coping strategies  Moos et.Consistent with earlier research  several Overall, these results implied that experiencing more stressors, having fewer social resources, and relying more heavily on avoidance coping could lead to late-life drinking problems. The results also suggested that drinking problems might harm the life contexts and psychological well-being of older adults. To learn more about these causal relationships, the participants were reassessed over extended periods of time.reduced alcohol consumption over intervals ranging from 1 to 10 years  tends to determine how social resources influence drinking behavior . Thus, iThe study\u2019s findings also illustrate the influence of an older person\u2019s drinking history on the relationship between life context and drinking behavior: The more alcohol the older drinkers consumed at the beginning of the study, the more likely were certain stressful life events, such as a relative\u2019s sickness or injury, to cause an increase or a smaller-than-expected decrease in alcohol consumption at followup . SimilarThe use of certain coping responses also appears to moderate the effects of life context on late-life drinking behavior. For instance, more non-health-related negative life events predicted elevated drinking problems among older drinkers who relied heavily on avoidance coping. In contrast, among drinkers who used fewer avoidance-coping strategies, negative life events prompted a decline in drinking problems . SimilarTaken together, these observations belie the idea that life context directly and uniformly affects drinking behavior in later life. Whether and how stressors and social resources influence late-life drinking appear to depend on several factors, including (1) the specific type of stressors , (2) the type of drinking behavior being assessed , and (3) personal risk factors .Although several studies have analyzed the effects of life context on late-life drinking, few have considered the effects of older adults\u2019 drinking behavior on their subsequent life contexts and personal well-being. Contrary to intuitive expectations, these studies indicate that ongoing drinking problems generally do not adversely affect the life contexts of older drinkers. For example, at the 1-year followup in the community study of older adults, problem-drinking women experienced a decline in spouse stressors, and problem-drinking men reported a reduction in conflicts with friends . MoreoveSimilarly, older adults\u2019 drinking behavior affected their psychological well-being in unexpected ways. For example, heavier initial alcohol consumption among women predicted fewer subsequent depressive symptoms; among men, more initial drinking problems predicted reduced depression .Finally, one would expect remission from drinking problems to improve the life contexts of older men and women. However, remission had little influence on the life contexts of male problem drinkers. Moreover, women who remitted experienced a loss of support from extended family members and reported more family stressors at followup than did remitted men . Thus, fLonger term followups are needed to determine the permanence of these effects as well as their consequences. For example, do ongoing drinking problems eventually lead to increased interpersonal stressors? And do adverse family contexts or self-medication with alcohol to avoid depression pose relapse risks for older, remitted women? The answers to these questions might have treatment implications; older women in early remission, for example, may need enhanced support to cope with family conflict and depressive symptoms.Older adults rarely seek formal treatment . ConsistSeveral factors predicted whether these community residents sought treatment. The most important predictors were prior treatment seeking and a greater number of health problems compared with the rest of the group. Frequently using avoidance-coping responses, experiencing more negative life events, and having fewer friends who approved of drinking also predicted more treatment seeking . FinallyThese findings suggest that older adults in the community are reluctant to identify themselves as having drinking problems and therefore delay treatment until their health problems and stressful life contexts require it. This result highlights the importance of identifying and treating older adults\u2019 drinking problems early. In addition, more information is needed about the personal characteristics, life contexts, and treatment features that deter older adults from seeking help for alcohol-related problems.Despite their reluctance to seek treatment, older adults constitute at least 20 percent of the AOD-abuse population in inpatient settings . Yet litBased on this information, the researchers addressed two broad sets of questions: (1) What are the extent and the predictors of health service use by older AOD-abuse patients? (2) To what extent is AOD-abuse treatment effective for older patients, and which specific treatment program characteristics predict better outcome?The VA AOD-abuse patients used health care services heavily. They received more than 920,000 days of care for AOD abuse or psychiatric disorders in the 4 years before their index episodes of care as well as 1.2 million days of care in the 4 years afterwards b. MoreovOlder and younger AOD-abuse patients received different types of treatment. Compared with younger patients, older patients received care focused more on their medical needs  than on their AOD-abuse and psychiatric treatment needs . MoreoveThe readmission rates of older patients depended in part on their AOD-abuse histories. First-time AOD-abuse patients had lower readmission rates than the total sample b. This fCo-occurring psychiatric disorders also affected the frequency of health service use and complicated the treatment of older AOD abusers. At the index episode of care, almost 30 percent of the patients suffered from concomitant psychiatric disorders, most commonly depressive disorders, personality disorders, and schizophrenia . These dIn addition to AOD-abuse history and the presence of psychiatric disorders, the study identified several other predictors of higher readmission rates for older AOD-abuse patients at both the 1- and 4-year followups. These predictors included being unmarried, more prior service use, more severe and complex psychiatric diagnoses, disrupted or shorter length of treatment, and insufficient mental health aftercare b, 1995.The question of treatment effectiveness among older AOD-abuse patients usually is framed as a comparison: Do older patients respond as well to AOD-abuse treatment as younger patients do? No definitive answer exists for this question (for reviews, see Some recent investigations have begun to clarify this issue by examining the match between age and specific treatment modalities. For example, Although the studies reviewed here have contributed new data about late-life drinking behavior, many questions remain. For example, further information is needed on the relationships between life context and drinking behavior in later life. Moreover, longitudinal studies should investigate the predictors of late onset problem drinking and its remission. Researchers must identify factors that deter older adults from seeking assistance for their alcohol-related problems and devise new screening and referral methods that facilitate earlier recognition and treatment of late-life drinking problems.The study of VA patients has demonstrated that older, treated AOD-abuse patients\u2014especially those with long histories of alcohol abuse and psychiatric comorbidity\u2014place a heavy burden on the health care system. Consequently, researchers and other professionals must work to evaluate and improve the treatment effectiveness in this patient population. Factors such as continuity of care and followup mental health care appear to promote better outcomes among older patients and may be especially important for patients who have fewer informal social resources from which to draw. Accordingly, researchers must determine how much and what kind of mental health aftercare is optimal for maintaining successful treatment outcomes among older patients.Future research also should address the match between the treatment needs of older AOD-abuse patients and particular treatment program characteristics. Currently, the data more clearly indicate which treatment approaches do not work well for older patients than which ones do. More broadly, a need exists for further theory development in the study of late-life drinking behavior and for more longitudinal investigations of older adults\u2019 drinking behavior, especially among understudied populations, such as older women and older adults in racial minority groups. Such work should enhance our understanding of the course and predictors of late-life drinking behavior and assist clinicians in treating older adults\u2019 alcohol-related problems."}
+{"text": "Background: Given findings that generally support the benefits of information and communication technology (ICT) for older adults\u2019 psychosocial adjustment, one might surmise that lonely older adults, who have a stronger need for psychological support, would reap more psychosocial benefits from ICT use. However, scant research has examined this view, much less the likelihood that ICT use might worsen the psychological well-being of lonely older adults, as has been shown to be the case in younger adults. Objective: To examine whether the association between ICT use and psychological adjustment  among older adults depends on their loneliness levels. Methods: A representative sample of 738 Hong Kong SAR Chinese older adults aged 60 years or older  was interviewed in 2017 on loneliness, frequency of ICT use , psychological distress , and SOC. Results: Regression analyses showed that loneliness significantly moderated the relationship between ICT use frequency and psychological adjustment ; more frequent ICT use was associated with more psychological distress and less SOC, with higher levels of loneliness. Conclusion: These findings suggest that ICT use may be a mixed blessing for older adults, i.e., using more ICT might predict worse psychological adjustment among lonelier older adults. Efforts that promote ICT use among older adults should take their loneliness levels into account."}
+{"text": "Early recognition of VATS-related complications is crucial for early interventions, treatments and better outcomesPatient presented with post-obstructive pneumonia like symptoms 1 week after VATS pulmonary resection.CT scan chest showed evidence of complete consolidation of the lobe where the pulmonary segmentectomy resection took place.Diagnostic bronchoscopy confirmed the erroneous transection of the Superior Segment (SS) of Right Lower Lobe (RLL). Patient was then taken back for completion lobectomy and found with necrotic SS of RLL. This finding potentially could have caused significant complication if not recognized and treated earlyPatient recovered well after completion lobectomy and was discharged home several days laterErroneous bronchial transection should be suspected early in patients presenting with post-obstructive pneumonia after VATS pulmonary resection. CT scan chest and diagnostic bronchoscopy are the 2 main diagnostic tests This minimally invasive approach is currently employed for diagnostic and therapeutic lung surgery, as well as other procedures involving the mediastinum, chest wall, pericardium, esophagus and diaphragm. In general, VATS procedures are well tolerated and the prevalence of major intraoperative complications is around 1.5%.2We present a 65 year old woman, with a history of prior left upper lobectomy for early stage non-small cell lung cancer, who underwent elective VATS for a highly suspicious right lower lobe lung nodule Fig. . The nod3In this case, diagnostic bronchoscopy led to an early recognition of erroneous bronchial transection which ultimately was treated with completion lobectomy and saved this patient significant morbidity. Had the bronchoscopy not been performed, her clinical and radiographic findings would have been blamed on severe pneumonia and broad-spectrum antibiotics would have been administered hoping for clinical improvement.\u20135 In all cases, the fissure-last technique has been identified as a potential cause of this complication. In this technique, the surgeon dissects and transects the hilar structure first then proceeds to complete the fissure with a stapling device last.,7 The fissure-last lobectomy requires advanced expertise and recognition of anatomical structures prior to attempting transection of the hilar structures. A ventilation test after clamping the targeted bronchus could also be helpful. The fissure-last technique could be challenging especially in right-lower lobectomy and when a ventilation test is neglected or not performed.,7The erroneous bronchial transection has been reported as a major complication of VATS pulmonary resection ranging from 0.9 to 1.8%.Just like in this case, the evaluation of pneumonia early after VATS lung surgery should include a CT scan of the chest. Careful review of the operative report, identification and visualization of ipsilateral remaining proximal airways, and localization of surgical clips on imaging are crucial in diagnosing an erroneous bronchial transection of remaining neighboring lobes or segments to the resected part of the lung. If the CT scan shows an unexplained complete consolidation of any lobe or segment and bronchus cut-off sign with presence of proximal surgical clips, a diagnostic bronchoscopy is warranted with careful examination of the airways looking for erroneous transection. Discussion with the surgical team and aggressive surgical resection of the affected segment or lobe are the mainstay of treatment approach.In summary, in patients presenting early after VATS pulmonary resection with signs and symptoms of pneumonia, CT scan chest with careful focus on airway patency is an important diagnostic test. Suspicious findings should be futher investigated with a diagnostic bronchoscopy to rule out an erroneous bronchial transection followed with surgical intervention if applicablePatient has provided informed consent for publication of the case and accompanying imagesWriting \u2013 original draft: Amit Borah, Steven Cocciardi, Ziad Boujaoude, Wissam Abouzgheib.Writing \u2013 review & editing: Amit Borah, Steven Cocciardi, Ziad Boujaoude, Wissam Abouzgheib."}
+{"text": "This study examined the trajectories of pain, insomnia, and depression during a four-year period in community-dwelling participants aged 65 or older  from the National Health and Aging Trends Study. Self-reported pain, insomnia, and depressive symptoms were collected at each wave. Dementia status was determined using a modified previously validated algorithm. We analyzed retrospective trajectories of each symptom using mix-effect models and a backward timescale. We also tested for differences in each symptom trajectory between those with and without dementia. Results showed that the trajectory of depression significantly differed by dementia status . Participants with dementia had persistently higher depression level than those without dementia, particularly during the year before dementia onset. Trajectories of pain and insomnia did not differ before dementia onset. Depression increases risks of dementia and studies with longer length of follow-up are needed to detect significant trajectories of pain and insomnia before dementia onset."}
+{"text": "Retroviruses have invaded vertebrate hosts for millions of years and left an extensive endogenous retrovirus (ERV) record in the host genomes, which provides a remarkable source for an evolutionary perspective on retrovirus-host associations. Here we identified ERV variation across whole-genomes from two chicken lines, derived from a common founder population subjected to 50 years of bi-directional selection on body weight, and a distantly related domestic chicken line as a comparison outgroup. Candidate ERV loci, where at least one of the chicken lines indicated distinct differences, were analyzed for adjacent host genomic landscapes, selective sweeps, and compared by sequence associations to reference assembly ERVs in phylogenetic analyses. Current data does not support selection acting on specific ERV loci in the domestic chicken lines, as determined by presence inside selective sweeps or composition of adjacent host genes. The varying ERV records among the domestic chicken lines associated broadly across the assembly ERV phylogeny, indicating that the observed insertion differences result from pre-existing and segregating ERV loci in the host populations. Thus, data suggest that the observed differences between the host lineages are best explained by substantial standing ERV variation within host populations, and indicates that even truncated, presumably old, ERVs have not yet become fixed in the host population. Retroviruses have infiltrated vertebrate germline for millions of years by integrating as proviruses in host DNA, which have then passed down to the offspring through generations as inherited endogenous retroviruses (ERVs). The genomic ERV record represents retroviruses that were replicating at the time of integration and constitutes large fractions of contemporary vertebrate genomes, for example about 7\u20138% of human DNA ,2 and abgag, pol, and env genes [Diverse sets of ERVs can be identified across all studied vertebrate genome assemblies  by screenv genes . Over tinv genes . ERV connv genes , modificnv genes ,7. On thnv genes ,8,9. ERVnv genes ,11,12,13It is desirable to identify orthologous ERV loci across the compared host lineages in order to evaluate potential effects of retroviruses and ERVs on host biology because it allows for connecting ERV integrations to host phenotypic differences and evolutionary history. ERV studies have benefited from recent advancements in sequencing technology and a growing catalogue of reference host genome assemblies, where much focus has been placed on comparing ERV records across related host species reference genome assemblies, an approach that suffers from undersampling of the diversity within vertebrate species, and thus presents challenges for reaching a better understanding of potential factors that contribute to the long-term retrovirus-host associations . More reIn an attempt to further explore ERV-host associations in a hitherto un-examined system, we make use of an artificial selection system where selection lines of domestic chicken that have been undergoing strong bi-directional selection on body weight at eight weeks of age for more than 50 years . This seDomestic animals provide rare possibilities, currently not feasible in human biomedicine, to study connections between genes, phenotypes, and biological function . CrossbrThe rationale for utilizing chicken as a model dates back more than 100 years to pioneering studies of retroviruses and ERVs, reviewed in ,20, and Here, we identify ERV insertion differences across available re-sequenced genomes derived from the two bi-directionally growth-selected chicken lines and compare candidate ERV loci with a commercial layer chicken outgroup. We map insertions and deletions to establish their positions relative to the adjacent host genomic landscape and compare candidate loci associated by sequence similarity to ERVs identified in the Red junglefowl reference assembly  along with reference retroviral sequences within a phylogenetic framework.http://genome.ucsc.edu) by Rubin et al. [Whole-genome re-sequenced DNA from domestic chicken selection lines was analyzed for differences in ERV makeups as potential markers for effects of ERVs on host genome function and evolution, see n et al. .Briefly, to allow identification of reference as well as non-reference assembly ERVs using mate-pair short reads sequencing technology, we applied a strategy where reads were mapped to an independent ERV library and then located along host chromosomes by anchoring their mate-pair reads to positions in the flanking host DNA. The RetroTector software  was usedp < 4 \u00d7 10\u22126) after Bonferroni correction for multiple testing.Candidate ERV loci were tested for read mapping differences across the re-sequenced chicken lines  using Fisher\u2019s exact test if the minimum observed read counts at the locus were fewer than 15 and otherwise by comparison to the Chi distribution. Loci where short reads were missing in one or two of the three chicken lines were kept for further analyses if p-values for ERV-associated read counts passed the conservative threshold (http://genome.ucsc.edu) and intersected with positions for candidate ERV loci in order to explore biological significance of genes located adjacent to ERVs and their potential associations with the chicken selection line phenotypes. Associations among chromosomal genes and ERVs, intragenic as well as intergenic positions covering 150 kb up- and downstream of reference gene transcription start sites were analyzed. Candidate ERV loci were intersected with sweep regions previously determined for the H and L chicken selection lines [https://david.ncifcrf.gov/) to explore biological impact of differences in ERV integrations across the H and L chicken selection lines.The Red junglefowl  reference gene dataset was downloaded from the UCSC genome browser , and visualized using FigTree v1.4.2 (http://tree.bio.ed.ac.uk/software/figtree/).Phylogenetic analyses of ERVs identified in the reference assembly  together with reference retrovirus sequences were performed as previously described ,25,26. BastTree2 . The resWhole-genomes from domestic High-Growth (H), Low-Growth (L), and White Leghorn (W) chicken selection lines were previously sequenced using high throughput SOLiD technology and mapped to the chicken reference assembly  by Rubin et al. , see TabGallus gallus, which was separated from the investigated chicken lines about 8000 years ago when chicken was first domesticated, see The bi-directionally growth-selected chicken lines (H and L) diverged from a single broiler founder population about 60 years ago and were separated more than 100 years ago from the branch leading to the comparison outgroup represented here by the commercial White Leghorn (layer) chicken. For reference, the compared chicken lines share a relatively recent common ancestry, compared to the reference genome assembly, generated from the Red junglefowl, http://genome.ucsc.edu) and previously determined selective sweeps for the H and L chicken selection lines [p = 0.1, binomial test), given the size of the sweep areas and the number of detected ERV insertions elsewhere in the host genomes. In addition, gene ontology searches were inconclusive and could not establish links between ERVs and adjacent host genes that could help explain the distinct phenotypes. We, therefore, analyzed candidate ERV insertion orientations and distances relative to host genes. Candidate ERV loci within host gene transcripts show a clear bias in antisense orientation relative to the host gene transcript, which could be explained by purifying selection due to potential splice interference from canonical splice signals as previously discussed [To explore potential connections between the observed divergent ERV loci across the domestic chicken lines, we intersected chromosomal positions with the reference assembly host genes , divergent ERV loci in the domestic H, L, and W chicken lines located across the phylogenetic tree that was rooted on a distant outgroup, rather than being found inside any specific retroviral clade, which is what could be expected if variation was due to retroviral expansion after the last common ancestor. Instead, the result indicates that the observed candidate ERV insertion differences do not result from recent retrovirus replication and integrations as ERVs in one or two of the chicken lineages, but rather it is consistent with standing variation of segregating ERV loci present at the onset of the bi-directional selection experiment as well as during breed formation since the domestication of chicken. Multiple radiations involving candidate ERV loci associated with assembly ERVs showing short terminal branch lengths indicate relatively recent expansions occurring within several retroviral genera across the phylogeny. It seems plausible that these radiations have generated a substantial number of segregating ERV insertions in the domestic chicken lines, thus providing the standing variation that explains the observed differences in ERV makeups, and that the number of divergent ERV loci is largely a product of the accelerated genomic divergence caused by the strong selection imposed on the H and L lines specifically, as well as directed selection of host features during domestication, which has affected all three studied  chicken lines.The known breeding history and well-studied phenotypic traits among domestic animals make them first-rate model organisms to identify potential ERV contributions to biological functions and dynamics of complex genetic traits. Rare genomic changes resulting in host phenotypes that would require thousands of years to establish, or become lost, in wild host populations may be selected for in domestic settings during fewer generations ,21,29. THere, we utilized whole-genome sequences from two bi-directionally growth-selected domestic broiler chicken lines and a distantly related domestic layer chicken line  for idenAs high-throughput parallel sequencing technologies generate short reads and limited coverage into the ERV loci depending on mate-pair insert sizes for reliable chromosomal anchoring, we utilized ERVs identified in the Red junglefowl reference assembly to generate an independent ERV search library and anchored loci to chromosomal positions by ERV-associated short reads mate-pair mapping. Despite limited ERV sequence coverage, it is thus possible to associate the best fit for candidate ERV loci reads with assembly ERV sequences, which could be used to construct phylogenetic frameworks and to determine associations between ERV loci and host genomic landscapes.The whole-genome sequences were generated from pooled individual DNA, see However, although gene ontology searches for genes adjacent to divergent candidate ERV loci could not explain host phenotypic variation, which could be due to the known highly polygenic nature of the trait under selection ,29, inteSimilar observations have also recently been made in other vertebrate host populations , demonstWhile it can be informative to study ERV variation from host species assemblies covering multiple species over long evolutionary time scales ,25, analIn summary, it appears increasingly important to employ careful experimental design to control the occurrence of artifacts and incorrect inferences due to unbalanced sampling in analyses aimed at evaluating host species ERV makeups. In order to obtain valid comparisons from population and distantly related genomes, it is valuable to focus on well-known pedigrees like those offered by domestic animal selection lines, where the prior knowledge makes it possible to compare observed patterns with expectations that are based on the evolutionary context of the specific case with higher precision than is generally achievable in natural populations. Sequencing and analyses of domestic animal populations and single genomes from known selection pedigrees facilitated by improved sequencing technologies that provide depth and coverage over long insertion sizes together with newly developed and fine-tuned analysis methods will facilitate mapping of ERVs previously not feasible and thereby generate new knowledge about contributions from retroviruses and ERVs to host genome function and evolution."}
+{"text": "The literature is mixed with respect to how stress reactivity changes with age. Previous studies have overlooked contexts, ignoring whether stressors occurred in the laboratory or in daily life. The Health and Daily Experiences (HEADE) study includes 126 younger and older adults who completed both laboratory stressors and ecological momentary assessments (EMA) of affect and stressor experiences in daily life. We found that the laboratory stressor elicited the greatest levels of negative affect reactivity  and positive affect reactivity  compared to the two types of daily life stressors. Interpersonal stressors were associated with greater negative and positive affect reactivity compared to non-interpersonal stressors in daily life. Younger adults exhibited greater stress reactivity than older adults. Together, these findings support age-related reductions in stress reactivity. Implications for understanding stressor-health links are discussed."}
+{"text": "Background Serum tumor markers are ubiquitously used in the clinic for cancer screening. However, the mechanisms accounting for the elevated levels of the serum tumor markers remain to be explored.Methods We performed a pan-cancer analysis of serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA). The relation between concentration of serum tumor markers and the expression of their coding genes was assessed. Then the expression of AFP and its genomic background in hepatocellular carcinoma (liver cancer) was studied.Results High expression of AFP mRNA was found mainly in liver cancer. In gastric cancer, breast cancer and lung cancer, high AFP mRNA expression was also discovered occasionally. In liver cancer patients, serum AFP levels correlated significantly with AFP mRNA expression in cancer tissues . Whole transcriptome analysis revealed that serum AFP levels clearly separated liver cancer into two classes with distinct expression profiles according to PCA analysis. Gene co-expression analysis revealed that AFP expression was connected to a module enriched with genes accounting for cell cycle and cell proliferation regulation. In addition, high AFP expression was associated with the molecular classification of liver cancer, including iCluster . Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, which was significantly related to AFP mRNA expression. Survival analysis indicated high serum AFP levels was prognostic of poorer survival of the liver cancer patients (Log-rank test: p = 0.046). This was confirmed by an independent dataset in which liver cancer patients with high serum AFP also had poorer survival (Log-rank test: p = 0.024).Conclusion High expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. De-methylation of cytosine from CpG di-nucleotides in AFP promoter may be the cause of AFP re-expression in adult human liver cancer tissue. Serum tumor markers are essential noninvasive tools for the screening and diagnosis of various cancer types. Many serum tumor markers have been studied and approved for use in the clinic. For example, alpha-fetoprotein (AFP) is widely used for the diagnosis of hepatocellular carcinoma (liver cancer). In addition, positive AFP could also be encountered in other cancer typesAFP is the main component of mammalian fetal serum. It is synthesized by visceral endoderm of the yolk sac and by fetal liver. After birth AFP level decreases dramatically in blood. However, AFP synthesis can be reactivated in liver tumors and germinogeneous teratoblastomas. As a result, serum AFP is an important marker for liver tumors and is widely used in clinical practice Carcinoembryonic antigen (CEA) is a glycoprotein of about 200,000 Daltons in molecular weight. It is expressed in significant amounts during embryonic life, especially by the large intestine, and postnatally by carcinomas arising from this site. Many tumors of epithelial origin at other sites may also express CEA and are associated with elevated CEA levels in blood circulation PSA is most frequently detected in prostate cancer. Positive correlation has been confirmed between the PSA level and tumor stage and volumeAlthough serum tumor markers like AFP, CEA and PSA have been extensively studied and used in the clinic, questions regarding the mechanisms leading to their expression in cancer have not been well answered. This is exemplified by AFP, for which the molecular mechanisms leading to re-expression of AFP in adult human liver cancer and other tumor types is still unclearIn this study, we tried to address the questions mentioned above using genomic data from large cohort of cancer patients. We compared the expression of the coding genes of AFP, CEA and PSA, and found that only AFP expression correlated with its serum levels in liver cancer patients. Further analysis revealed aberrant AFP re-expression actually represented a shift of cell transcriptome that involved many genes, especially those related to cell proliferation regulation. We then identified de-methylation of a CpG locus located at the promoter of AFP that may be accountable for the AFP re-activation.Totally 4,666 tumor samples were included in the pan-cancer gene expression analysis of tumor markers. There were 421 liver cancer samples, 326 colon cancer samples and 549 prostate cancer samples. The details of patient and sample information could be found in the publications associated with each studyFor hepatocellular carcinoma dataset from TCGA (The Cancer Genome Atlas) study, all patients received surgical resection of their tumors. No other treatment, for example ablation, chemotherapy, or radiotherapy had been given to the patients before surgery. Surgical specimens of primary hepatocellular carcinoma and matched blood samples were collected for each patient. Totally 371 patients with full genomic data were included in this study. For clinical data analysis, patient information from the TCGA hepatocellular carcinoma publication was used, which contained 196 samplesGenomics data from TCGA project were downloaded using RTCGA package in R. The most recent version of RTCGA dataset was used (2016-01-28). For mRNA sequencing analysis, the RNASeq v2 data was used. For methylation analysis of TCGA data, the beta values of each CpG locus derived from Human Methylation 450 array platform was used. For survival analysis, a recently updated follow-up data processed by Liu J et.al. was usedGene co-expression network analyses was performed using Co-Expression Modules identification Tool (CEMiTool), an R package that can identify and analyze co-expression modules in a fully automated manner. CEMiTool is featured by unsupervised gene filtering, automated parameter selection for identifying modules, enrichment and module functional analyses, as well as integration with interactome data to generate molecular interactionsThe whole genome methylation analysis was performed using Human Methylation 450 array platform. There are 4 probes targeting AFP gene, including one probe mapped onto the promoter region (cg10778295), two probes mapped onto around -5,000 from the transcription start site , and another probe mapped onto the interior of the gene (cg02387745). However, the probe inside AFP has no readings. Pearson correlation analysis was performed to assess relationship between methylation status of each probe with AFP expression.Statistical analysis was performed using R software. Human genome assembly hg19 was used as the reference genome. Liver cancer patients were separated into three groups based on serum AFP levels: high (>= 300 ng/ml), middle , low (< 6 ng/ml). Survival plot was estimated using Kaplan-Meier method and groups were compared with log-rank test. For correlation analysis between the levels of markers in serum and tumor, serum marker levels were added by 1 and then log2 transformed. Pearson correlation analysis was then performed. For comparison of means of gene expression or methylation between two groups, t test was used.To unveil the roots of serum tumor markers, we selected AFP, CEA (encoded by CEACAM5)Next, we asked whether the presence of tumor markers in the bloodstream was resulted from high expression of these markers by tumors. We compared the expression of CEA, AFP and PSA in tumor tissue with their serum levels. In liver cancer, a strong correlation between AFP gene expression and serum levels was observed   . In addiPrincipal component analysis (PCA) was performed to assess the inner structure of liver cancer expression data. The distribution of liver cancer samples was plotted using the top three principal components and patients are colored by their serum AFP levels. A clear separation between high and low serum AFP patients could be seen Figure A. This dTo identify key genomic modules co-regulated with AFP, we performed gene co-expression analysis using mRNA sequencing data of liver cancer. Five gene modules were revealed for liver cancer and AFP belonged to M4 module. M4 and M5 module were significantly related to AFP high expressing liver cancer   Figure . To furtRecent high throughput genomic studies classified liver cancer into several molecularly distinct subtypes. We thus asked whether AFP activation is related to the molecular classification of liver cancer. Higher serum AFP level was significantly associated with iCluster  of liver cancer. The iCluster clustering of liver cancer was derived by integrating multiple whole genome platforms, which is supposed to be the most comprehensive and unbiased classification of cancer Aiming at identifying the molecular mechanisms underlying the elevated levels of the serum tumor markers, we performed a pan-cancer analysis of AFP, CEA and PSA to assess the relationship between concentration of serum tumor markers and the expression of their coding genes. Only AFP expression in tumor tissue correlated with its serum levels. In addition, high expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, and was significantly related to AFP mRNA expression.Previous studies suggested that serum AFP levels are mainly controlled at transcriptional level in fetal liver. For example, in normal development of mouse liver, a parallel accumulation of both AFP and albumin mRNAs before birth, followed by a selective nonreciprocal decrease in AFP mRNA after birth, was observedLiver cancer is a heterogeneous disease. Many molecular subtypes have been proposed for liver cancer Most previous studies investigated AFP alone. What we found in this study suggested aberrant activation of AFP was not an isolated event. It was actually part of the systematic diversion of the transcriptome in the liver cancer cells. More importantly, this diversion in transcription also has clinical significance. The most obvious features of AFP high tumors is its poorer prognosis compared with serum AFP normal tumors. Actually, the inferior prognosis in serum AFP positive tumors has been reported by many other studies alreadyIn vivo experimental using mouse models revealed that a 7 kb regulatory region upstream of AFP gene was related to the regulation of AFP expression Although the transcriptional control of AFP expression is evident, it's unclear how liver cell cease expressing AFP after birth, and how AFP expression is re-activated in liver cancer. 2+ influx, prompting DNA synthesis and enhancing tumor cell proliferation Evidence suggests that AFP may not only be a biomarker for cancer diagnosis, but also play functional roles in tumorigenesis. AFP can promote cancer cell proliferation through binding AFP receptor (AFPR), activating PI3K/AKT and many other cancer related genes In conclusion, this study indicates that AFP re-activation is a result of the systematic transcriptome change, which collectively define a molecular subtype of liver cancer. More importantly, high AFP expression is associated with over activation of cell growth or cell cycle control genes. In addition, high AFP expression is related to poor survival in the patients. These data highlights AFP as a biomarker for both liver cancer classification and prognosis.Supplementary figures and tables.Click here for additional data file."}
+{"text": "Empirical evidence supports positive associations between social support, interpersonal connections, and health as people age. This symposium addresses how human-animal interaction may facilitate connection throughout later life. Each talk presents unique ways pets: fit into social networks; expand interpersonal connections; and thereby, impact health and wellbeing. The first talk presents longitudinal associations of a history of pet ownership and marital status on health, in particular cognitive functioning, over time. The second talk presents qualitative evidence for how pets fit into older adults\u2019 social network and quantitative evidence for the impact of animal and interpersonal companionship on overall and functional health. The third talk builds upon the literature linking dog walking with older adults\u2019 physical health, by providing evidence for the positive impact of dog walking improving interpersonal connections with neighbors. The fourth talk discusses the influence of a unique intergenerational human-animal interaction service-learning course on university students\u2019 attitudes towards older adults and those with disabilities. Enrolled students provide pet care  to low-income pet owners ages 60 and older and disabled adults. Students reported decreased biases towards older adults and those with disabilities after completing the course. The final talk is the first study to focus on the influence of pets in LGBTQ older adults living in rural southern Appalachia. Identifying as a LGBTQ person and living in a rural environment can present unique challenges and these qualitative results provide insight into pets\u2019 influence on aging in this understudied population."}
+{"text": "For older adults living with dementia, social network quality influences health outcomes. However, current social network measurement methods are time consuming and mentally draining for people living with dementia. This study aimed to accurately measure social networks using sensor technology. Bluetooth and radio-frequency identification (RFID) sensors were used to collect social network data in a simulation of a falling nursing home resident living with dementia. Participants wore sensors on their clothing, and video recordings were compared to sensor data. Bluetooth data reflected general direction of movement and instances of idling but were neither precise or accurate. RFID data was accurate after applying data filters. Both systems detected multiple sensors simultaneously. The Bluetooth system is not feasible for clinical use, but the RFID system shows potential for clinical application and accurate measurement of social network factors as interaction frequency and duration."}
+{"text": "Following stroke, the leading cause of disability in the United States, muscle alterations commonly occur. These alterations include gross atrophy and shift in fiber type, particularly in the paretic limb, which have lasting implications on gait ability. We will discuss the current evidence supporting a mechanism for these changes  and how these factors differ between the paretic and non-paretic limbs. Further, we will discuss how various therapeutic exercise modalities can be used to modify or reverse skeletal muscle abnormalities and alter physical functioning post-stroke."}
+{"text": "Mycobacterium tuberculosis - a global threat, the recent breakout in MDR-TB and XDR-TB has challenged researchers in diagnosis to provideeffective treatment. The main objective to combat drug resistance is to provide rapid, reliable and sensitive diagnostic methods in healthcare centres. This study focuses on development of an effective pipeline to identify drug resistance mutations in whole genome data ofMycobacterium tuberculosis utilizing the Next Generation Sequencing approach and classification of drug resistance strains based on geneticmarkers obtained from TGS-TB, tbvar and TBDReamDB. 74 isolates are characterized into 20 DR-TB, 16 MDR-TB, 16 XDR-TB and 6 nonresistantstrains based on known drug resistance genetic markers. Results provide mutation pattern for each of the classified strains andprofiling of drug resistance to the group of anti-TB drugs. The presence of specific mutation causing resistance to a drug will help set thedosage levels which play an important role in the treatment. Findings on amino acid changes and its respective codon positions incandidate genes will provide insights in drug sensitivity and a way for discovery of potent drugs. The implementation of these approachesin clinical setting provides rapid and sensitive diagnostics to combat the emerging drug resistance. Mycobacteriumtuberculosis and has plagued humans since antiquity. The discoveryof antibiotics brought a revolution in Tuberculosis Chemotherapy,which started, in 1943with Streptomycin, followed by advent ofmany potent anti-TB drugs. The implementation of these drugs intuberculosis therapy immediately resulted in a drastic reduction ofTB incidence all over the world. TB was considered to be no longera public health concern in many developed countries until theoutbreaks of multidrug resistant strains in 1980s Tuberculosis (TB) is an infectious disease caused by M. tuberculosis has evolved to emerge as drug resistant strain thathas resulted in the restriction of TB chemotherapy which pose anurgent public health problem and requires rapid intervention. Thestrains were initially resistant to single drugs, have now evolvedwith sequential accumulation of resistance mutations which hasled to the emergence of Multi-Drug Resistance strain (MDR-TB),Extensively Drug Resistance (XDR-TB) and most recently, totallydrug resistant (TDR) strains. First-line drugs, which are commonlyused for treating tuberculosis such as Rifampicin, Isoniazid,Pyrazinamide and Ethambutol, are becoming ineffective due tomutations in certain genes. These genetic markers are essential forthe identification and classification of drug-resistant strains andmost importantly give scientists an opportunity to design drugs,which counteract the effects of these mutations. MDR-TB showsresistance to at least one of the two most potent drugs: isoniazid(INH) and rifampicin (RIF). The emergence of XDR-TB resistanceis due to having developed resistance to both rifampicin andisoniazid, as well as to fluoroquinolones and at least one of thesecond-line drugs The NGS whole genome sequencing paired-end data ofMycobacterium tuberculosis was procured from NCBI-SRA database.The data isfreely accessible, and the datasets accession numbers arelisted in the supplementary data. The reference genome sequenceH37Rv was retrieved from Genbank database.NGS data may encompass sequence artefacts which include poorquality reads, read errors, duplication and adapter/primercontamination which will have an impact on downstream analysis.Therefore, the quality of the data is crucial in distinguishing thetrue mutations from the sequencing errors otherwise they may leadto wrong conclusions. Pre-Processing of the data was executedusing FastQC tool kit to assess the read quality  For mapping of raw reads versus Mycobacterium tuberculosis h37rvcomplete genome, BWA-MEM algorithm was used The variants were identified using Genome Analysis Toolkitvariant calling best practice workflow including indel realignmentand base recalibration The annotated VCF files generated from SNPeff were combinedusing VCFcombine tool from Galaxy web-based platform, whichcombines all the VCF, files positionally when sites and alleles areidentical  Out of screening 480 entries in the SRA database search formycobacterium whole genome data, 74 isolates were selected basedon quality control and genome coverage. These samples werefurther processed for variant calling and the generated VCF fileswere combined to obtain the union list of mutations positionally.This resulted in identification of 11,130 variants of which 8554(76.85%) were SNPs, 776 (6.97%) were insertions and 1024 (9.2%)were deletions. These mutations were mapped to the known drugresistant mutations obtained from various databases includingTGS-TB, tbvar and TBDReamDB to generate the resistance profilingof each isolate. Further annotation was performed using SNPefftopredict the effects of variants, gene annotation, codon change andits impact for all the variants called. The number of SNPs annotatedfrom various databases arelisted in the Antimicrobial resistance pattern was determined based onmutations conferring drug resistance to anti-TB drugs. Thedetermined resistance pattern for XDR, MDR and DR strains areillustrated in The annotated SNPs of the predicted resistant types were combinedto obtain the list of mutations specific to each resistant type. Pythonscript was written to read the annotated VCF files and to count thefrequency of synonymous and missense mutation across thegenome to derive the mutation pattern which is represented inIdentification of amino acid changes is crucial to understand theassociation of resistance with drugs. Python script was written togenerate the pattern of codon variations in 25 candidate drugresistant genes The present study explains the classification of drug resistant strains basedon the known drug resistance mutations obtained from various TB mutationdatabases. The mutation pattern generated for the classified strains helps tounderstand the distribution of the SNPs in certain genomic regions resultingfrom the drug selection pressures, thus providing the information onevolutionary targets of drug resistance mechanism. Profiling resistance tovarious TB drugs is important to decide the drug regimen. Otherwise, afaulty diagnosis leading to the ineffective regimen will further increase thedevelopment of Antimicrobial Resistance. The schematic representation ofcodon variations gives overall picture of resistance regions in the candidategenes. The hot spot regions will serve as diagnostic tool for screeningresistance and non-drug resistant regions can be alternative drug targets tocombat resistance. Rapid and accurate prediction of drug resistance throughmolecular diagnostics promise to improve patient's treatment outcome. Infuture directions, implementation of molecular based diagnosis in theclinical setting will help in timely diagnosis and efficient treatment of TBpatients will reduce the development of AMR.Authors declare no conflict of interest."}
+{"text": "Until recently, consumers have had limited resources to assess quality of hospices agencies, contributing to growing numbers of consumers turning to online review sites, such as Yelp. Yet little is known about the content of hospice Yelp reviews and how these relate to recently available Center for Medicare and Medicaid Services\u2019 Hospice Compare site data. No study has examined Yelp hospice reviews and compared the themes identified in Yelp reviews to the topics addressed by CMS\u2019s HC measures. To better understand how consumers perceive hospice care, we drew a purposeful sample of 67 hospices in California. Researchers used grounded theory to identify themes and categories within the hospice reviews. Each of two teams of two researchers independently coded the reviews and then met to compare coding and reconcile discrepancies until 100% consensus was reached. We coded a total of 692 consumer Yelp reviews, identifying 15 themes and grouping them under five overarching thematic categories: patient/caregiver-provider relationship; clinical care; agency competency; staff professionalism; and medical equipment and supplies. We found that overall Yelp comments were positive. The most frequently mentioned Yelp themes in hospice reviews were compassionate, caring staff; patient/family gratitude; and staff responsiveness. There was considerable overlap between the themes captured in HC caregivers survey items and Yelp. However, Yelp reviews cover a greater number and more diverse themes than those measures reported on the CMS Hospice Compare site. We recommend that consumers consider both HC and online review sites such as Yelp when evaluating a hospice."}
+{"text": "Globally, neonatal mortality rates remain relatively stagnant despite overall progress in reducing under-5 mortality . In regiSignificant gaps exist in infection prevention and control (IPC) practices in maternal-neonatal care settings, resulting in increased risk of health care-associated infections (HAI) for both mother and baby . HealthcAcinetobacter species (spp) and Klebsiella spp [In many resource-limited settings, neonatal sepsis is predominantly caused by Gram-negative organisms, with high prevalence of antimicrobial resistance ,5. A recella spp .As contributors to HAI risk are variable and IPC resources are limited, standardized assessments linked to improvement strategies are essential to guide health care facilities in LMIC to prioritize high-impact strategies to reduce neonatal HAI and death. The WHO has designed several tools to assess hospital-wide IPC practices, including the Hand Hygiene Self-Assessment Framework and the Infection Prevention and Control Assessment Framework at the Facility Level (IPCAF) ,8. StrenThe United States Agency for International Development (USAID) sponsored Infection Control Assessment Tool (ICAT) is a more comprehensive tool designed to assess IPC practices across acute care hospitals. It includes 22 modules as well as checklists for direct observation of several key practices . StrengtThese findings suggest that an assessment tool targeting facility-based maternal and neonatal IPC practices is needed and should address several key factors. First, an assessment tool must cover the wide spectrum of care provided for mothers and neonates in LMICs. Fundamental elements of IPC practice, such as hand hygiene, must be incorporated, but advanced care content, such as IPC related to the use of invasive devices and prolonged supportive care in neonates, should also be included for use by sites where these interventions are provided. Components of the tool focusing on antibiotic administration should also embrace antimicrobial stewardship principals targeting areas with high endemic rates of antimicrobial resistance. While self-assessment would facilitate broad uptake in LMICs, direct observation of key IPC practices by a trained assessor, whether internal or external, would ensure observations made had a high probability of guiding true gaps in IPC practice. An assessment tool should highlight strengths and opportunities for improvement, guiding facilities to plan and implement interventions with the ultimate aim of creating a sustained improvement in IPC practices. Linkage to educational materials and implementation tools would strengthen such a tool, providing key recommendations to health care facilities seeking to improve IPC in maternal and neonatal care. Ultimately, a comprehensive assessment tool designed specifically for maternal and neonatal care will allow facilities to most effectively reduce morbidity and mortality due to HAI in this vulnerable population."}
+{"text": "Antibody-based therapy has revitalized the world of cancer therapeutics since rituximab was first approved for the treatment of Non-Hodgkin\u2019s Lymphoma. Monoclonal antibodies against cancer antigens have been successful strategies for only a handful of cancer types due to many reasons including lack of antibody specificity and complex nature of tumor milieu which interfere with antibody efficacy. Polyspecific antibodies are promising class of anti-cancer agents which can be directed at multiple tumor antigens to eradicate tumor cells more precisely and effectively. They may overcome some of these limitations and have already changed treatment landscape for some malignancies such as B cell acute lymphoblastic leukemia. Pre-clinical studies and early phase clinical trials have demonstrated that this approach may be an effective strategy even for solid tumors. This review focuses on the development of bispecific and trispecific antibody therapy for the treatment of solid tumor malignancies and highlights the potential they hold for future therapies to come. Cancer remains the second leading cause of death in the United States, with lung cancer being the leading cause of cancer deaths, followed by breast cancer in women and prostate cancer in men Siegel . Over th. Although some of these primitive formats showed appreciable activity against certain malignancies, the vast majority had a dismal therapeutic-risk index. With rapid advances in genetic engineering, the past two decades have seen a dramatic increase in the production of polyspecific antibodies with more than 120 described formats now in clinical use or undergoing evaluation in clinical trials  are genetically engineered proteins that can simultaneously engage two or more different types of epitopes Figs.\u00a0 and 2 F. They shBispecific antibodies with ability to engage two different antigens are the most commonly used PsMabs. Since the initial experiments to produce BsMabs , tandem single chain variable fragments (taFvs), diabodies (Dbs), single chain diabodies (scDbs), and triplebodies. Due to their small size, these scFV based antibody fragments have high tumor specificity and tumor penetration. However, their small size also limits serum half-lives which could potentially limit efficacy and increase cost by requiring repetitive dosing  into the proximity of the tumor cell to enhance antitumor effect Fig.\u00a0. This fu. DART bispecific antibodies, created by engineering two Fv fragments with the variable heavy chain portion exchanged with one another, are larger than BITEs and show better serum stability  antibodies, tandem diabodies appear to potently eliminate targets expressing their tumor associated antigen (TAA) in the absence of costimulatory models or IL-2 pre-activated T cells . Blinatumomab is a novel bi-specific T cell engager which binds sites for both CD19  and CD3 T cell receptor complex, leading to T cell proliferation and activation resulting in target cell (lymphoblast) apoptosis. Unlike catumaxomab, which uses large IgG-like bi-specific antibodies with Fc regions, blinatumomab was created by the fusion of two single chain variable fragments (scFv) connected in a flexible manner through a peptide linker , which first allows tumor specific antibodies to distribute to the tumor antigen site followed by the administration of a small radioactive agent with high affinity for the tumor antibody, limits the accumulation of radiation in non-target sites  and histamine- succinyl-glycine (HSG), when used with lutetium-177 labeled peptide for PRIT in prostate cancer demonstrated effective targeting and permeability in mice pre-clinical studies  and radioimmunotherapy (RIT) use the antibody specificity of tumor-based antigens in conjunction with emitted radiation from suitable radioisotopes to image malignancies (RIS) for diagnostic and treatment purposes. The radioantibody is injected intravenously and distributes to the antigen binding site on tumor cells where the radionuclide delivers the tumoricidal dose to the tumor mass  for detection of colonic liver lesions in an orthotopic murine model , breast cancer, uterine, and bladder cancers [NCT02324257], [NCT01284231]  and met gene amplification has been shown to be a major mechanism in which cancers develop resistance to EGFR inhibitors , and also found in breast and lung carcinoma, was recently found to be expressed in glioma stem cell lines , which binds CD3 and targets EpCAM, increased the sensitivity of tumor cells to cytotoxic T cell death in multiple EpCAM positive ovarian and endometrial cancer cell lines including ovarian carcinosarcoma and primary uterine serous papillary carcinoma  or programmed death-1 (PD-1) or its ligand (PD-L1) and transforming growth factor-\u03b2 (TGF-\u03b2), which mediates immune tolerance using a bifunctional antibody-ligand trap was recently reported  and tri-specific killer cell engagers (TriKEs). BiKEs are created by the fusion of a single chain variable fragment (Fv) against CD 16  and a single-chain Fv against a tumor associated antigen  and targets the death receptor 5 , can selectively and potently kill melanoma cells. This approach may prove beneficial in those patients resistant to monoclonal antibody therapy  directed against HER1, HER3, c-MET and IGF1R with enhanced antitumor effects in a preclinical model , there are many new molecules with three or four binding sites. For example, Castoldi et al.Another example of how novel approaches may simplify treatment is a recent preclinical study demonstrating elimination of large tumors by in-vivo production of bispecific antibodies induced by parenterally administered engineered mRNA (Holzinger et al. Advances in antibody directed therapy have simultaneously fostered the development of another form of immunotherapy, CAR-T cell therapy. While an in-depth discussion on this exciting topic is out of scope for this review article which is focused on polyspecific antibodies, we present a brief review on the topic here and compare the two forms of immunotherapy. CAR-T cell therapy consists on removing T cells from patients and modifying ex vivo using gene transfer to enable expression of specific receptors targeting tumor cells through an antibody-derived binding domain. Once the T cells are genetically modified to express the chimeric antigen receptor, they are infused back into the patients to directly kill the cancer cells Fig.\u00a0 Caruana. CurrentWhile both monoclonal antibody therapy and CAR T-cells are antigen specific immunotherapies, CAR T cells, at present, have to be individually manufactured for each patient resulting in high cost of production. Despite this, CAR T-cells exhibit several qualities that could make them more advantageous than antibody directed tumor therapy. The genetically engineered receptors allow CAR T-cells to recognize tumor cells with low antigen expression and cause direct lysis of tumor cells whereas classical monoclonal antibodies need a high density of tumor antigens to trigger the ADCC or complement cascade (Caruana et al. Antibody-based cancer directed therapy is an exciting and rapidly advancing field. The introduction of monoclonal antibodies such as rituximab revolutionized cancer therapy and have given way to the creation of bi-specific and tri-specific antibodies which work with more precision and efficacy than their predecessors. The one currently approved bi-specific antibody therapy, blinatumomab and catumaxomab, have shown improved survival rates and quality of life for subsets of cancer patients. Multiple agents are currently being evaluated in clinical trials while optimal structures and treatment algorithms are being defined to maximize benefit-risk ratio. Newer approaches concurrently targeting checkpoint molecules and cancer-specific antigens seem promising in preclinical models and may change the landscape of cancer therapeutics (Junttila et al. Several biological parameters are still missing in the understanding of the tumor biology and its complex microenvironment. Engineered polyspecific antibodies will likely play a major role in oncotherapeutics as cancer research continues to climb to new heights."}
+{"text": "Dual-plating of the distal femur is required in some cases to achieve stable fixation. The indications of a medial plate in addition to the lateral plate are medial supracondylar bone loss, low trans-condylar bicondylar fractures, medial Hoffa fracture, peri-prosthetic distal femur fractures, non-union after failed fixation with single lateral plate, poor bone quality and comminuted distal femur fractures (AO type C3). We recommend orthogonal plate configuration with locked plates by a single incision or dual incision approach as per surgeon choice. Supracondylar femur fractures are commonly associated with severe comminution and significant soft tissue injury. Distal femoral fractures are mostly caused by high-energy injuries, such as falling injury and traffic accidents, and fractures are often severely comminuted. Despite the recent advances in techniques and implants, the treatment of intra-articular multi-fragmentary distal femoral fractures remains a challenge. Long-term disability can occur in patients with extensive articular cartilage damage and marked comminution. Distal femur fractures in the elderly are complicated by poor bone quality (severe osteoporosis), a distal segment that is too short for adequate fixation, blood loss, malunion and non-union, and increased mortality -4.Locked plating is one of the best and modern options for treating supracondylar femur fractures with relatively low failure rates. Single lateral plating of distal femur fractures was often found to have a relatively higher failure rate .A medial plate in addition to lateral plating reduces the chances of failure of fixation . This arPre-operative planningDecision making before surgical stabilization is important. The treating surgeon should examine the injured limb to check for the soft tissue status and any distal neurovascular deficit. Also, other injuries should be ruled out. Good quality radiographs in two planes are necessary. Computed tomography of the distal femur with coronal and sagittal reformations helps in delineating fracture patterns. Proper pre-operative planning will guide towards the need for dual plating of distal femur fractures .Indications for dual platingSupracondylar femur fractures were previously treated with condylar buttress plates . SubsequMedial Supracondylar Bone LossIn distal femur fractures with extensive metaphyseal comminution, osteopenic bone and in high-energy or open fractures, there is functional loss of medial cortical buttress. In these situations, there is less chance of healing of the medial column. The addition of a medial plate helps in giving additional stability and reduces the chances of implant failure ,14. RajaLow Trans-condylar Bicondylar FracturesHigh energy injuries sometimes lead to a low horizontal trans-condylar fracture pattern which is associated with an intercondylar split. In this fracture pattern, fixation with a single lateral plate may not achieve stable fixation as sufficient screw purchase will not be possible because of the intercondylar notch. A medial buttress plate in addition to the lateral plate is helpful in this situation ,16.Medial Hoffa FractureAnatomical restoration of the articular surface is necessary for comminuted distal femur fractures. In fractures with a large medial Hoffa fragment, the application of a medial neutralization plate is necessary to achieve stable fixation. This fixation provides stability in addition to interfragmentary lag screws .Peri-prosthetic Distal Femur FracturesIn peri-prosthetic fractures of the distal femur, dual plating offers stable fixation, especially in osteoporotic bone. This allows for early mobilization and rehabilitation. Stable fixation of peri-prosthetic fractures is necessary to avoid failures of fixation. Cicek et al. advocated dual locked plate fixation of peri-prosthetic distal femur fractures with osteoporotic bones .Non-union after Failed Fixation with Single Lateral PlateThere is an increased risk of non-union in patients with comminuted distal femur fractures treated with single lateral locking plate . In thesPoor Bone QualityIn patients with distal femur fracture with osteoporotic bone, there is a high incidence of failure of fixation with a single lateral plate due to poor purchase of screw in osteoporotic bone. Metwaly and\u00a0Zakaria demonstrated that dual plating in osteoporotic distal femur fractures by a single incision offers the stability of fixation with resultant early mobility and accelerated rehabilitation . In the Comminuted Distal Femur Fractures (AO type C3)In patients with AO type C3 distal femoral fractures, dual plating offers a more stable construct. Imam et al. demonstrated that dual plating fixation using anterior approach for type C3 distal femoral fractures is an efficient and safe method of management. It has several advantages such as precise exposure, easy manipulation, anatomical reduction, and stable fixation . SteinbeSurgical techniquePositionThe patient is positioned supine on a radiolucent operating table with the knee flexed at 30 degrees. Tourniquet use depends on the surgeon and may be used in very distal fractures. The use of a lateral femoral distractor with pins placed in the femoral diaphysis and proximal tibia metaphysis facilitates fracture alignment and disimpacts intra-articular fragments. Intra-operative use of C-arm is necessary for proper plate placement and fracture reduction and alignment .ApproachThe choice of approach depends on the surgeon. There are two approaches, the dual incision approach\u00a0and the single incision approach. The dual incision approach involves placing a medial and lateral incision for exposure of fracture and articular surface . The sinPrecautionsSoft tissue attachments to bone fragments should be preserved to prevent any devascularisation of bone fragments. Soft tissue retractors should be used with care .Choice of ImplantDual 4.5 anatomically contoured locking plates are generally used. The T-buttress plate can also be used for medial condyle fixation. Cancellous screws of 6.5 mm are preferred for intercondylar fragment fixation .Plate ConfigurationOrthogonal dual plate configuration provides more stable fixation and is biomechanically superior to dual adjacent plating for constructs fixed with either standard compression or locking plates .Post-operative careEarly mobilization in a protected hinged knee brace should be done. Weight-bearing is to be allowed according to radiographic and clinical examination findings at the subsequent follow-up visits. Radiographic healing is established by the union of three cortices of the bone on the anteroposterior (AP) and lateral radiographic views of the bone. Clinical healing is confirmed by the absence of pain either with weight-bearing or with the application of stress over the injured area on examination. Malrotation is detected clinically by comparing the injured side to the normal side. Follow-up is to be continued until fracture healing and full weight-bearing .Dual plating of distal femur fractures offers a reliable stable fixation in cases with medial supracondylar bone loss, low trans-condylar bicondylar fractures, medial Hoffa fracture, peri-prosthetic distal femur fractures, non-union after failed fixation with single lateral plate, poor bone quality and comminuted distal femur fractures (AO type C3). Single-incision or dual incision approach may be used. Orthogonal plate configuration with locked plates provides stable fixation and allows for early rehabilitation. Early mobilization is necessary to prevent joint stiffness."}
+{"text": "However, recent studies demonstrate the existence of a novel, centrally-derived peripheral glial population called motor exit point (MEP) glia, which myelinate spinal motor root axons in the periphery. Until recently, the boundaries that exist between the CNS and PNS, and the cells permitted to cross them, were mostly described based on fixed histological collections and static lineage tracing. Recent work in zebrafish using  Myelin is a unique plasma membrane extension produced by specialized glial cells that is wrapped around axons and facilitates rapid transmission of electrical impulses over long distances. Although myelin appeared 430 million years ago in the vertebrate lineage  consists of the brain and the spinal cord, while the peripheral nervous system (PNS) consists of neural tissue outside of the CNS, including motor and sensory axons and sensory neurons clustered in ganglia. While many neurons establish circuits within the CNS, some of these cells send their axons  freely across specialized CNS boundaries known as transition zones (TZs) and travel long distances throughout the organism and ultimately make synapses on peripheral tissues, including muscle. By associating tightly with axons to ultimately ensheath and insulate them with fatty membranes called myelin, myelinating cells increase nerve impulse conduction speed and strengthen the function and efficiency of the whole nervous system.In the CNS, oligodendrocytes (OLs), which are derived from neural tube precursors, make myelin in the brain and spinal cord, while Schwann cells (SCs), which originate from the neural crest (NC), myelinate axons of the PNS  and OL lineage cells. After exiting the CNS, MEP glia reside just outside of the ventral spinal cord along spinal motor nerve root axons, occupying axonal territory between SCs in the periphery and OLs in the spinal cord. The pMN domain constitutes the major site of expression of the basic helix-loop-helix (bHLH) transcription factor Olig2. In zebrafish, olig2  mutants, which harbor a mutation in sox10 and lack SCs, have peripheral OPCs that differentiate and myelinate spinal motor nerves, suggesting that sox10 may be required for MEP glial function or survival  transgenic line that faithfully mimics the endogenous expression of foxd3 , a transcription factor expressed by boundary cap (BC) cells that is also required for SC myelination  and MEP TZs, where axons enter and exit the spinal cord, respectively  that are not found all together in any other myelinating glial cell type  and both mbp and transcript and MBP protein can be detected along motor nerve root axons as early as 4 dpf  mutants, where SCs are arrested at the pro-myelinating stage and fail to myelinate peripheral axons, Monk et al. (gpr126 mutants are, in fact, MEP glial myelin sheaths (Figures gpr126 to initiate myelination. And as previously mentioned, these glial cells also do not express Krox20. Therefore, they are a CNS-derived, peripheral glial cell that myelinates peripheral axons, but uses a distinct molecular mechanism to initiate myelination.Fascinatingly, in k et al.  describe Figures . These d+Krox20 BC cells project membrane processes across the MEP TZ into the ventral spinal cord (Radomska and Topilko, + cells residing within the mouse spinal cord give rise to SCs, which are usually NC-derived (Zawadzka et al., Drosophila, zebrafish and mouse (Sepp et al., For years, mammalian BC cells were thought to constrain MN cell bodies to the spinal cord by repulsion from outside the spinal cord (Bron et al., MEP glial development and function raise many new questions. What are the signals mediating OPC-MEP glial interactions across the MEP TZ? Do MEP glia also interact with SCs and via which molecular mechanisms? Does this novel, centrally-derived glial cell population adopt a central-like myelination pattern, involving the extension of multiple membrane processes to wrap more than one axonal segment? Or does it behave more like a Schwann cell, ensheathing a single axonal segment in a truly peripheral-like fashion? Or alternatively, is MEP glial myelin a kind of hybrid myelin featuring both central and peripheral characteristics? How do MEP glia myelinate if they do not require Krox20 or Gpr126? Electron microscopy of the MEP TZ will be needed to examine MEP glial development at the ultrastructural level to characterize their myelin sheaths that connect the CNS and PNS. RNA-sequencing coupled to genome editing tools such as CRISPR/Cas9 will shed light on the molecular mechanisms that drive MEP glial development, their gating function and differentiation into peripheral myelinating glia. Recent studies in zebrafish have uncovered the existence of novel centrally-derived myelinating glia that function in the PNS and are required for nervous system TZ integrity, and future work may change our way of thinking about mammalian myelinating glia as well.LF wrote the manuscript with input from SK.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Although a number of new systemic therapeutic options in patients with advanced solid cancers have emerged due to the improved knowledge of molecular dysregulation in cancers, the durable, long-term, objective responses infrequently occur. This editorial article highlights the major limitation of current systemic therapy due to an inefficient drug delivery. While several mechanisms contributing to cancer drug resistance have been described, the common key barrier among solid cancers is the unique tumor microenvironment that causes the high interstitial fluid pressure (IFP). We discussed the mechanism causing an elevated IFP and how it interferes with drug delivery. To target the high IFP, we demonstrated the novel approach using gold nanoparticle carrying recombinant human tumor necrosis factor (TNF), a vascular disrupting agent, that preferentially and specifically targets tumors while the systemic toxicity is markedly reduced. The addition of cytotoxic agent by either directly conjugating to the gold nanoparticle or by systemic administration following gold nanoparticle carrying TNF resulted in significantly reduced tumor burden and increased survival in multiple mouse models with primary and metastatic endocrine cancer and pancreatic ductal carcinoma. A clinical trial in patients with advanced solid cancers is warranted based on the promising results in preclinical studies. In the era of \u201cprecision medicine\u201d for cancer, efforts have been made to identify agents that preferentially target expressed molecular pathways specific to the cancer cells. Despite the potential of these new targeted therapies, durable long-term responses rarely occur. A major limitation of current systemically delivered cancer therapies is the failure of these drugs to effectively reach their target, the cancer cells. Because of inefficient systemic drug delivery, high doses of systemically-administered cancer drugs are usually given, which inevitably cause off-target toxicity, to achieve anti-tumor efficacy. Several factors contribute to the failure of systemic cancer treatments to effectively kill cancer cells. These include the ATP-binding cassette (ABC) transporters that can actively pump cytotoxic drugs out of cancer cells  and the Normally, water and molecules transported through convection flow out of capillaries, flow through the interstitial space, and into the lymphatic system and/or the venous drainage system. This transcapillary flow, created by the gradients of hydrostatic and colloid osmotic pressures in capillaries and in the interstitium, is typically outward (capillaries to lymphatic and/or venous system) because of the slightly negative pressure gradients in the normal interstitium . The eleTumor necrosis factor alpha (TNF) is a cytokine involved in systemic inflammatory response. This cytokine also has a potent effect on vascular endothelium, causing vascular leakage. Because of the severe systemic toxicity, the EU-approved clinical role for TNF in cancer treatment is currently limited to a cumbersome but effective surgical procedure that regionally delivers the combination of TNF and a high dose cytotoxic agent to the affected limb for locally advanced melanoma (isolated limb perfusion). To mitigate the systemic toxicity associated with TNF, our group demonstrated in a phase I clinical trial in patients with advanced solid cancers that CYT-6091, a PEGylated colloidal gold nanoparticle carrying recombinant human TNF, preferentially targets tumor tissue and had no dose-limiting toxicity at a dose 3-times higher than previous clinical trials in cancer patients treated with systemically administered recombinant human TNF. Although CYT-6091 was safe, the anti-tumor activity was minimal as only one patient of 27 achieved a partial response . Thus, Cand a paclitaxel prodrug. We studied the effect of CYT-21625 and CYT-6091 in 3 mouse models of thyroid cancer and neuroendocrine tumors. In this recent publication, we performed CT scan, FDG-PET, and histologic analyses showing that CYT-6091 and CYT-21625 specifically and preferentially target tumor tissue without histologic or clinical evidence of toxicity to normal organs. In addition, both nanomedicines caused intratumoral vascular damage and leakage only in tumor tissue. CYT-21625 treatment resulted in statistically significant lower tumor burden in mice with metastatic anaplastic thyroid cancer, poorly differentiated thyroid cancer (PDTC) and in genetically engineered mice that naturally develop pancreatic neuroendocrine tumors. The survival benefit was observed in mice with metastatic PDTC. Histologic analysis showed that CYT-21625 treated xenografts had lower tumor cell proliferation and increased caspase-dependent apoptosis [all mice that received CYT-6091 pretreatment followed by protein-bound paclitaxel survived. None of the mice receiving vehicle control survived at day 42  support this approach as the treatments induced tumor vascular leakage, increased cytotoxic drug accumulation, and improved animal survival. Because tumor vascular architecture in these mice resembles that seen in patients, such promising responses in preclinical studies of nanomedicine targeting tumor microenvironment need to be expanded to patients with advanced solid cancers in clinical trials."}
+{"text": "Physical examination revealed a back abrasion, stupor, and spasmodic laughter  is rare.What do we already know about this clinical entity?Malignant catatonia (MC) often leads to fatal consequences. Administration of low-dose lorazepam typically leads to rapid resolution of symptoms; thus, definite diagnosis is crucial.What is the major impact of the image?Because MC resembles tetanus, diagnosis is often difficult and delayed.How might this improve emergency medicine practice?Administration of low-dose benzodiazepines may be warranted when patients presenting with MC symptoms have a history of psychological disorders and normal blood, urine, cerebrospinal fluid testing and imaging.Documented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report."}
+{"text": "Post-traumatic Stress Disorder (PTSD) is a stress related syndrome. Chronic PTSD has increasingly been associated with poor health outcomes, neurodegeneration and risk for cognitive impairment (CI). However, the biological mechanisms underlying the development and maintenance of symptoms and potential associations in accelerating aging are not well understood. The aim of this study was to evaluate whether specific biomarkers influence functional limitations and cognitive impairment in rescue and recovery workers (i.e. responders) from the attacks on the World Trade Center (WTC) in New York. Plasma biomarkers were collected during annual health and wellness visits at the WTC responder clinic between 2012 and 2014. Short Physical Performance Battery (SPPB) and clinical data were examined with prospective PTSD symptom scores collected during participant\u2019s initial enrollment into the parent study as early as 2002. We examined the relationship between cardiovascular , metabolic  and inflammation markers  with Post-traumatic Stress Disorder (PTSD), cognitive functioning  and frailty  in responders from the World Trade Center (WTC). We first examined correlations between biomarkers, PTSD symptom severity, PTSD dimensions, cognitive functioning and frailty. We then conducted multivariate regression analyses. In models adjusted for potential confounders, among N=1,045 responders, elevated PTSD was strongly associated with increased frailty, cardiovascular dysregulation and mild cognitive impairment. Current work is ongoing to identify trajectories of change in cognition with frailty and biological factors."}
+{"text": "We sought to extend recent research that explored model-based approaches for combining clinical and gait measures to determine the most sensitive grouping for retrospectively classifying fallers from non-fallers which resulted in a model with 92% sensitivity and 66% specificity and an overall model of 83%. In the present study, the clinical assessment battery was augmented by incorporating more challenging balance items while removing clinical measures characterized by ceiling effects and restricted range. Thirty-two community-dwelling older adults  completed a battery comprising 76 measures of more challenging clinical measures of mobility and balance, and retained gait (GaitRITE), postural sway and physiological measures. Within each domain, highly collinear and theoretically-redundant measures were removed. Next, a Principal Component Analysis (PCA) identified those clinical and gait variables that accounted for the most unique variance. Finally, a backward stepwise logistic regression was performed on the reduced set of variables from the PCA to develop predictive equations. The current analysis yielded improved specificity of 75%, but slightly lower sensitivity 81%. Interestingly, when the results for the PCA from the previous study were used with the current data, the model classified fallers with 87% sensitivity and 86% specificity and an overall model of 86%. Notably, in all analyses, gait variables were central in identifying fall risk, with single- vs. dual-task difference scores of particular predictive importance. The differences observed between the best-fitting models across the two cohorts implies that modelling methods should accommodate and harness individual differences ."}
+{"text": "Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. Activating mutations in KIT or PDGFRA receptor tyrosine kinases (RTKs) are central to GIST biology and drive GIST growth and progression . This onKIT exon 14 T670I gatekeeper mutation was also suppressed by regorafenib, but not KIT exon 13 V654A resistance mutation, the most common secondary mutation present at the onset of imatinib failure. These results were further corroborated in biopsies from GIST patients treated with regorafenib in the phase II trial, underscoring V654A mutation as the main vulnerability for regorafenib treatment. Remarkably, we found that all TKIs, either approved or investigated in clinical trials, had activity profiles targeting only a subset of KIT secondary mutations  and growth. Together, we established the rationale for a phase I clinical trial that tested, for the first time in cancer, a rapid alternation treatment-schedule using agents with complementary activity against resistant subclones (NCT02164240).In the absence of approved drugs with pan-KIT inhibitory activity, novel therapeutic strategies are urgently needed in order to overcome the inter- and intra-tumor heterogeneity of subclones harboring different KIT secondary mutations. Interestingly, several TKIs had complementary profiles against secondary resistant mutations, including second- and third-line approved agents for advanced GIST, sunitinib and regorafenib, respectively. Combination of these two drugs widens the spectrum of secondary-resistant clones effectively targeted and may augment the magnitude and/or duration of clinical response. However, dose reduction due to overlapping effects might preclude activity in patients. We first established co-cultures of barcoded GIST cell lines containing clinically relevant KIT primary and secondary mutations, thus representing the polyclonal imatinib-resistance heterogeneity observed in many GIST patients. We subsequently modeled preclinically a rapid alternation treatment schedule of sunitinib and regorafenib, to maintain selective pressure against polyclonal secondary-resistance GIST cells, thereby impeding the regrowth of targeted subclones when the relevant drug for those subclones is withheld. Alternation of three days of sunitinib followed by four days of regorafenib was more effective than either drug alone inhibiting cell proliferation of these polyclonal populations and preventing emergence of a single dominant clone. The intrinsic heterogeneity of resistant subpopulations challenges standard management of cancer patients based on the sequential use of single-agent therapies that are discontinued upon progression or unbearable toxicities. Further, although combinations of kinase inhibitors have a biologic rationale highly needed, clinical development has encountered difficulties due to enhanced and/or overlapping toxicities . In this"}
+{"text": "The discovery of a fossil survival strategy in modern corals explains unexpected recoveries after warming-induced mortalities. Climate change is affecting reef-building corals worldwide, with little hope for recovery. However, coral fossils hint at the existence of environmental stress\u2013triggered survival strategies unreported in extant colonial corals. We document the living evidence and long-term ecological role of such a survival strategy in which isolated polyps from coral colonies affected by warming adopt a transitory resistance phase, in turn expressing a high recovery capacity in dead colony areas. Such processes have been described in fossil corals as rejuvenescence but were previously unknown in extant reef-builder corals. Our results based on 16 years of monitoring show the significance of this process for unexpected recoveries of coral colonies severely affected by warming. These findings provide a link between rejuvenescence in fossil and extant corals and reveal that beyond adaptation and acclimatization processes, modern scleractinian corals show yet undiscovered and highly effective survival strategies that help them withstand and recover from rapid environmental changes. Corals are subjected to climate change\u2013related impacts worldwide, with overwhelming evidence of mass mortalities affecting vast geographical areas in tropical  Mediterranean Sea, Spain]  Red List . Near-full recoveries  are located 30 nautical miles off the nearest coast . A marine reserve encircles the archipelago, covering an area of 5500 hectares. Illa Grossa , the largest of the islets in the Columbretes, is a C-shaped, drowned, Quaternary volcanic caldera. The monitored C. caespitosa colonies was annually monitored in the Columbretes Islands from 2002 to 2017. Each colony was examined after the summer, when mortality-triggering thermal anomalies occur, and the extent of the necrosed surface was recorded with photographs and sketches  recovered from the last major mortality event suffered by each colony to the last annual monitoring.n = 21) from the Columbretes Islands, previously cleared of organic matter, and a corallite sample from a Holocene fossil reef in Menorca  (Samples of rejuvenated corallites ("}
+{"text": "Despite research documenting gender differences in numerous outcomes in later life, we know little about gender differences in quality of life (QoL) for older adults who receive institutional long-term care. To address this gap, this study examines the relationship between gender and nursing home (NH) residents\u2019 QoL, including possible reasons for differences observed. We used a mixed methods design including surveys with a random sample of Minnesota NH residents using a multidimensional measure of QoL , resident clinical data, facility-level characteristics, and qualitative interviews with NH residents (n=64). We used mixed models and thematic analysis of resident interviews to examine possible differences in resident QoL based on gender. After controlling for individual and facility characteristics, women reported higher overall QoL than men, with men reporting significantly lower QoL in 4 of 8 QoL domains. In interviews, men noted being especially dissatisfied with facility activities, whereas women more frequently described having friends in the facility and relying on family for support. Some women viewed the NH as a place of respite and described wanting to stay long-term, even though their families asked them to return home. In contrast, men more often described the NH as necessary due to physical needs, but undesirable for long-term living. Our findings provide preliminary evidence that men and women experience QoL differently, with men reporting lower QoL in several domains. Tailoring more activities for men and finding ways to strengthen relationships for men within the facility may help reduce the gender disparities in QoL we observed."}
+{"text": "Iatrogenic aortocoronary arteriovenous fistula is a very rare complication of coronary artery bypass grafting in which one of the arterial grafts inadvertently forms a fistulous tract with a cardiac vein, shunting blood from the anastomosed coronary artery. We report a patient with an iatrogenic left internal mammary artery graft to cardiac vein fistula presenting with recurrent angina three years after a three-vessel coronary artery bypass grafting. This case of iatrogenic aortocoronary arteriovenous fistula (ACAVF) is interesting because it is a rare but important complication of coronary artery bypass grafting (CABG) which can result in significant clinical consequences like heart failure, tamponade, and death. To the best of our knowledge, only 38 similar cases of ACAVF have been reported in the literature. We have included a brief review of the literature on this rare complication and the various available treatment options.A 61-year-old woman with diabetes mellitus, hypertension, and hyperlipidemia initially presented with unstable angina; a regadenoson stress nuclear myocardial perfusion imaging (MPI) revealed anterolateral wall ischemia. Subsequent coronary angiography demonstrated severe stenoses of the left anterior descending (LAD) artery, left circumflex artery, and right coronary artery. She underwent CABG with a left internal mammary artery (LIMA) graft to the LAD artery and saphenous venous grafts (SVG) to the right posterior descending (RPDA) and obtuse marginal 4 (OM4) arteries. After CABG, the patient was doing well on guideline-directed medical therapy. Three years later, she presented with acute onset of chest pain suggestive of unstable angina. On admission, her heart rate was 80/min, blood pressure was 140/86\u2009mmHg, and her physical exam was unremarkable.Electrocardiogram showed normal sinus rhythm without any evidence of ischemia. Serially monitored cardiac enzymes were within normal limits, and transthoracic echocardiography revealed normal ejection fraction with no distinct regional wall motion abnormalities. Regadenoson stress nuclear MPI showed anterolateral ischemia, a territory which should have been supplied by the LIMA to LAD graft. Diagnostic coronary angiography revealed known severe native, three-vessel coronary artery disease. The native LAD vessel was very small. Proximal LAD was medium sized. Mid LAD had 100% stenosis at the origin of diagonal branch. Distal LAD was not visualized . Graft aThe case was discussed with the cardiac surgical team as well as in a multicenter interventional conference to explore both surgical and percutaneous options. A percutaneous approach of coiling of the fistula is anatomically complex; a surgical approach which would involve ligation of ACAVF and redo CABG, would put the patient at higher risk of perioperative cardiac morbidity and mortality. Because of the coronary arterio-venous fistula with steal, it was unclear whether revascularization of the native LAD would be of any significant benefit to the patient. After full discussion about the risks versus benefits of treatment options with the heart team, the patient elected for medical management and intervention only if she has escalating symptoms. The patient's anti-anginal therapy was optimized with Metoprolol 50\u2009mg daily, which she tolerated well with gradual improvement in her exercise tolerance and resolution of her anginal symptoms. The patient is currently asymptomatic at 1 year follow-up. Repeat cardiac stress testing may be pursued if she has recurrent symptoms. The tentative plan is to offer her interventional coil closure or surgical closure of the ACAVF if she has recurrent angina or heart failure symptoms.Iatrogenic ACAVF is a rare complication of CABG causing significant morbidity. To the best of our knowledge, only 38 cases have been reported . ACAVF c"}
+{"text": "Gametocyte density and sex ratio can predict the proportion of mosquitoes that will become infected after feeding on blood of patients receiving nongametocytocidal drugs. Because primaquine and methylene blue sterilize gametocytes before affecting their density and sex ratio, mosquito feeding experiments are required to demonstrate their early transmission-blocking effects. Anopheles mosquitoes must ingest at least 1 male and 1 female gametocyte to become infected. The formation of Plasmodium oocysts on the mosquito midgut wall is commonly used as evidence for successful transmission. These oocysts enlarge over time to rupture and release sporozoites that render mosquitoes infectious. In the absence of treatment, infectivity of malaria-infected individuals can be reasonably well predicted by the density of male and female gametocytes in their peripheral blood  = 1.08 ;  density  or sex r density . Infecti density . There wWe found that measures of mRNA gametocyte density do not correlate with infectivity shortly after treatment with gametocytocidal drugs. The major implication of this finding is that studies that examine transmission-blocking effects of drugs and potentially vaccines require mosquito-feeding assays to measure infectivity. Gametocytocidal drugs rapidly clear gametocytes, distort the gametocyte sex ratio , 11, andHere, we present evidence that gametocyte density and sex ratio are unaffected in the first 48 hours after initiation of treatment, despite a near complete prevention of onward transmission to mosquitoes. Nongametocytocidal drugs did not alter the shape of the associations between gametocyte density, sex ratio, and mosquito infection prevalence; gametocytes appeared equally infectious before and after treatment. In contrast, gametocyte density and sex ratio no longer explained transmission after treatment with DP-MB or SP/AQ-PQ; gametocytes persisted with sex ratios similar to those before treatment, but mosquito infections were nearly completely prevented.The mechanism that underlies the early sterilizing effect despite continued presence of gametocyte mRNA transcripts is unclear. While mRNA is unlikely to survive in free-floating form and, also by microscopy, gametocyte densities remain unaffected shortly after treatment , it is pThe molecular mechanisms that underlie the apparent male-biased clearance of gametocytes after MB treatment and female-biased clearance after PQ treatment are currently unclear; however, they likely reflect the sexual dimorphism of gametocyte proteomes. Our findings thus provide evidence for an early sterilizing effect of MB and PQ. Molecular tools to quantify male and female gametocytes cannot replace mosquito-feeding experiments to assess transmission-blocking properties of antimalarials."}
+{"text": "Mobility impairments are prevalent in older adults. Whereas walking had traditionally been viewed as an autonomous process, evidence over the last decade has shown that cognitive processes such as attention and executive function have a significant impact on gait function in older adults. However, the exact neural mechanisms underlying difficulties in the control of mobility in older adults remains an open question. We examine the changes in the executive control of mobility in older adults with mobility impairments using functional near-infrared spectroscopy, as operationalized by performance in the community balance and mobility scale (CB&M). We hypothesized that prefrontal cortical (PFC) activity increases would be higher in older adults with mobility impairments, compared with older adults without mobility impairment, as dual-task walking difficulty increased. Older adults with  and without mobility impairment  were recruited from the local community. Dual-task walking was performed at a comfortable pace, while the difficulty of the concurrent cognitive task was increased using the modified Stroop test. PFC activity was measured using measures of oxygenated hemoglobin across the PFC. Older adults with mobility impairments demonstrated disproportionate increases in PFC activity, in comparison to those without mobility impairments, as the difficulty of the concurrent cognitive task increased (P<.001), even after controlling for age. In conclusion, these data suggest that older adults with mobility impairments may require greater attentional resources than those without mobility impairments when concurrently performing thinking and walking tasks."}
+{"text": "The effect was not dependent on the method of immortalization as it was seen in both SV40 and E6 KO cell lines. sAC activity was not directly proportional to expression suggesting that additional regulatory pathways exist. Interestingly, targeted delivery of sAC to the mitochondria was not as effective in rescuing glucose sensitivity as untargeted delivery of sAC into all possible microdomains. Therefore, even though mitochondrial sAC is known to influence metabolism, our data suggests that the nonmitochondrial isoform is most important for cancer cell metabolism. Although metabolomics analysis suggested that serine synthetic pathways are activated in sAC null cells, there is no evidence to suggest that serine is required for sAC null cell growth. Neither inhibition of serine synthesis nor serine starvation differentially affected the growth of sAC null cells compared with WT sAC. DISCUSSION/SIGNIFICANCE OF IMPACT: These data suggest that the Warburg metabolic phenotype in sAC null cells is regulated by specific sAC microdomains. By targeting sAC to specific microdomains, we can further distinguish the role of sAC localization in cellular metabolism. Cancer cells have been shown to exhibit altered metabolic circuitry of pathways like glycolysis, which allow them to adapt to increased metabolic demands of cellular proliferation and waning environmental resources. Beyond helping us improve the use of sAC immunolocalization as a cancer diagnostic, a better understanding of sAC microdomains in transformed cells will help us understand how this signaling pathway is important in cancer. Pharmacologic manipulation of sAC signaling may represent a new cancer therapeutic strategy.OBJECTIVES/SPECIFIC AIMS: The soluble adenylyl cyclase (sAC) is a noncanonical source of cAMP in mammalian cells. sAC is an ATP/bicarbonate ion sensor, whose activity responds to intracellular signals such as pH changes and metabolism. Unlike the more traditionally studied transmembrane adenylyl cyclase, sAC is not tethered to the cell membrane and instead is found in subcellular microdomains like the mitochondria and nucleus. In particular, sAC localization in the mitochondria has been implicated in oxidative phosphorylation and mitochondrial metabolism. Specific changes in sAC microdomain localization have diagnostic utility in a wide variety of cancers, namely melanoma. We have recently found that loss of sAC leads to tumorigenesis and a Warburg/cancer-like metabolic phenotype, consisting of an activated flux through glycolysis, increased lactate production, and dependence on glucose metabolism. In addition, computational analysis of the metabolomics profile of sAC null cells suggests an increased flux through serine synthetic pathways. We hypothesized that specific sAC microdomains are responsible for this cancer-like metabolic state. METHODS/STUDY POPULATION: We have established oncogenic SV40 large T antigen and HPV16-E6 expressing mouse embryonic fibroblasts lacking sAC expression . Using these parental lines, we reintroduced sAC by targeting the protein to specific microdomains. sAC was either driven into the mitochondria (mito-sAC) or was driven into all possible microdomains (WT sAC). Single clones were generated and sAC expression was confirmed by Western analysis. Stable cell lines were evaluated for mitochondrial metabolism, glucose sensitivity, and serine sensitivity. RESULTS/ANTICIPATED RESULTS: We found that reintroduction of WT sAC into sAC null cells rescued sensitivity to glycolytic inhibition compared with control cells ("}
+{"text": "The comorbidity between alcoholism and eating disorders, especially in young women, is well documented. Alcohol and other drug (AOD)-use disorders are particularly common in women with bulimia nervosa. Although the mechanisms underlying the coexistence of these disorders remain unknown, recent family epidemiology studies suggest that bulimia nervosa and AOD dependence are transmitted independently in families. Furthermore, bulimia nervosa generally develops before the onset of AOD dependence. Thus, factors other than addictive behavior may contribute to the development of bulimia nervosa in a substantial proportion of women. The comorbidity of AOD-use disorders with eating disorders has implications for the treatment of the affected patients. Clinicians working with either alcoholic patients or patients with eating disorders have observed that both types of disorders frequently co-occur. Only recently, however, have researchers begun to investigate the reasons for this comorbidity. This article describes some characteristics of the most common eating disorders and reviews studies examining their comorbidity with alcoholism and other drug-use disorders.The two most common eating disorders are bulimia nervosa and anorexia nervosa. Both disorders primarily affect young women, with the usual ages of onset being between early and late adolescence for anorexia nervosa and between adolescence and early adulthood for bulimia nervosa. Only approximately 10 percent of all eating disorder cases occur in men. Because of this gender distribution, the vast majority of studies have investigated eating disorders only in women. Therefore, this review also focuses mainly on studies of women with eating disorders. Clinically diagnosable eating disorders are relatively rare in the general population. The lifetime prevalence rates are 1 to 3 percent for bulimia nervosa and 0.1 to 1 percent for anorexia nervosa .Bulimia nervosa is characterized by lack of control over food intake, leading to the recurrent consumption of large amounts of food in short periods of time . These binge-eating episodes are interspersed with recurrent compensatory purging behavior(s), such as vomiting or laxative abuse, to prevent weight gain. In addition, the patients\u2019 self-evaluations are unduly influenced by their body shape and weight .Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM\u2013IV), two types of anorexia nervosa exist: a restricting type and a binge-eating/purging type. Patients with restricting anorexia nervosa lose weight primarily by extremely restricting their food intake. Patients with binge-eating/purging anorexia nervosa achieve or maintain a subnormal weight by regularly engaging in binge-eating and purging behavior in addition to restricting their food intake. Thus, binge-eating/ purging anorexia nervosa differs from bulimia nervosa in that the anorexic is severely underweight and amenorrheic, whereas the bulimic typically is of normal weight. These distinctions are important, because the rates of alcohol-use disorders vary among women with different eating disorders.Anorexia nervosa is characterized by the relentless pursuit of thinness, intense fears of becoming fat, and a distorted body image. People with anorexia nervosa experience substantial weight loss. In female patients, the resulting changes in the hormonal system also lead to the absence of menstruation  . AccordiAnother eating disorder described provisionally in the DSM\u2013IV is binge-eating disorder . Like buThe causes and mechanisms  underlying eating disorders remain unknown but most likely include genetic and environmental factors. Twin studies suggest that for bulimia nervosa, approximately 50 percent of the risk is attributable to genetic factors and 50 percent is attributable to the environment . MoreoveNumerous studies have investigated the prevalence of AOD-use disorders among women with eating disorders. A recent review of 51 studies  suggestsA recent survey of AOD-use disorders among women in the general population showed rates of 12 percent for alcohol abuse or dependence and 10 percent for other drug abuse or dependence . TherefoWomen with different eating disorders also differ in their rates of regular alcohol use : These rates were substantially higher among bulimics and binge-eating/purging anorexics (45 percent) than among restricting anorexics (11 percent) . These vThe frequency of eating disorders among alcoholic women has been studied less extensively than the frequency of alcohol-use disorders among eating-disordered women. Several studies have found, however, that the lifetime rates of any comorbid eating disorder among AOD-abusing women are significantly higher than in the general population, ranging from 15 to 32 percent . With reOne study of eating disorders among female and male Japanese alcoholics  in inpatient treatment found that 11 percent of the female alcoholics and 0.2 percent of the male alcoholics had lifetime histories of eating disorders . The verA striking finding emerged when the researchers analyzed different age groups of female alcoholics: Seventy-two percent of all the female alcoholics under the age of 30 had lifetime histories of comorbid eating disorders, compared with 11 percent in the entire sample. Again, the majority of these patients (89 percent) suffered from either bulimia nervosa or binge-eating/ purging anorexia nervosa. Thus, the association between eating disorders with bulimic features and alcohol-use disorders appears to be particularly strong among young women. The reasons for this concentration of eating disorders among young women are unclear. Although bulimia nervosa has been defined only relatively recently , its ratAnother study that examined the rates of eating disorders among female alcohol-dependent inpatients found that 30 percent of these women had lifetime histories of eating disorders . One-thiIn summary, the literature on both eating disorders and AOD-use disorders supports clinical observations of the frequent co-occurrence of both types of disorders. Furthermore, bulimia nervosa and the bulimic  subtype of anorexia nervosa are much more commonly associated with alcohol-use disorders than restricting anorexia nervosa. These findings are consistent with past research that determined behavioral and personality trait differences among patients with different eating disorders. For example, binge-eating/purging anorexics and bulimics share certain traits characteristic of impulsive behavior and mood swings, whereas restricting anorexics consistently have been described as behaviorally restrained and compulsive . Based oAlthough studies have confirmed that eating disorders and AOD-use disorders frequently coexist, the mechanisms underlying this comorbidity have not been elucidated. At least four potential explanations exist for the high rates of co-morbidity :Both disorders are different manifestations of a shared underlying etiology.The two disorders have different causes, but the presence of one disorder may increase a person\u2019s chances of developing the other.An independent disorder causes both disorders.The two disorders have some risk factors in common, whereas other risk factors are specific to each disorder.The first hypothesis of a common etiology has been studied most extensively. Supporters of this hypothesis believe that both eating disorders and AOD-use disorders may be manifestations of an underlying predisposition toward impulsivity or may result from a common mechanism involving endogenous opioids . EndogenVery few studies have investigated the possible roles of transmissible genetic or environmental familial factors in the comorbidity of eating disorders and alcohol-use disorders. In a recent family study, Accordingly, the researchers divided the bulimic subjects into two groups: those with and those without lifetime histories of comorbid AOD dependence. When the rates of AOD dependence were examined in the first-degree relatives of both groups, the prevalence was elevated only among the relatives of bulimics with comorbid AOD dependence but not among the relatives of non-AOD-dependent bulimics. The analyses produced similar, though less robust, results when the rates of not only AOD dependence but also AOD abuse and dependence were evaluated. These findings refute the hypothesis that eating disorders and AOD-use disorders are different manifestations of a shared underlying etiology and indicate instead that both disorders are attributable to independent transmissible factors.not exhibit familial vulnerability to AOD-use problems, factors other than addictions may contribute to the development of bulimia nervosa in a substantial proportion of women. These findings raise the possibility that two bulimic subtypes exist. The first type would represent a \u201cmulti-impulsive\u201d subtype, with a familial and personal history of AOD-use problems. The second type may best be described as an \u201canorexic-like\u201d subtype, with personality and behavioral traits similar to restricting anorexics . Similar to restricting anorexics, these bulimics have no extensive personal or family histories of AOD-use problems.If many bulimic women do Other recently published studies also suggest that alcoholism and bulimia nervosa do not share a common etiology. For example, Genetic analyses of six major psychiatric disorders in women, including bulimia nervosa and alcoholism, supported the existence of separate genetic liabilities for eating disorders and alcoholism . The stuThus, the three epidemiological studies described here suggest that although bulimia nervosa and alcoholism frequently coexist, they apparently do not share an underlying familial or genetic liability. Instead, the two disorders are likely to result from independent causal factors.The other three potential explanations for the high rates of comorbidity between alcoholism and eating disorders have been examined less thoroughly. Most studies investigating the hypothesis that the presence of one disorder may increase the chances of developing the other disorder found that the onset of bulimia nervosa generally preceded the onset of alcohol dependence see . AlthougThe theory that an independent disorder can cause both eating disorders and alcoholism also has not been well studied. One potentially fruitful line of research would be to examine the relationship among anxiety disorders, bulimia nervosa, and alcoholism, because anxiety disorders frequently co-occur with both of the other disorders .The most likely\u2014although also not well-investigated\u2014explanation of the frequent comorbidity of eating disorders, particularly bulimia nervosa, and AOD-use disorders may be that people with both types of disorders share some underlying traits, such as periodic behavior disinhibition and difficulty modulating feelings or emotions . In addition to these shared traits, other etiologic factors likely exist that are specific to each disorder. Clearly, more research is needed to further evaluate this hypothesis.Over the past decade, several researchers have hypothesized that bulimia nervosa, like alcoholism, is a type of addictive disorder . Both alThe addiction model of eating disorders  has contIn contrast, other therapies, such as cognitive-behavioral therapy (CBT) and antidepressant medication, have proven useful in treating eating disorders . CBT focThe most effective treatment approaches for alcoholism and eating disorders also will likely differ, because different behaviors must be addressed for both types of disorders. The primary focus in alcoholism treatment is to avoid consuming the substance, whereas the focus in bulimia nervosa treatment is to change the manner in which the substance  is consumed. Many bulimics and binge-eating/purging anorexics have difficulty modulating food intake and often alternate between periods of imposed food restriction and overconsumption combined with purging behaviors. Treatment must take into consideration both these consumption patterns as well as a disturbed body image. Accordingly, cognitive-behavioral approaches addressing all these issues differ greatly from the 12-step programs commonly used to treat alcoholics.Few empirical data exist to help identify and treat patients with coexisting eating disorders and AOD-use disorders. Still, the frequent comorbidity of these disorders underscores the necessity of determining whether eating disorders are present, especially among young, AOD-abusing women entering treatment. Adequate assessment is even more important, because alcoholic, eating-disordered patients also are likely to engage in other behaviors common among \u201cmulti-impulsive bulimics,\u201d such as shoplifting, suicide attempts, or self-mutilating behavior . These cAOD-abusing patients with coexisting eating disorders should receive thorough medical assessments and nutritional consultations. The management of these patients should include monitoring their weight, food intake, and purging behavior as well as assessing their cardiac, fluid, and mineral  statuses. The patients should be observed during and after each meal, with supervised bathroom use to minimize purging opportunities. Although monitoring eating-disordered patients in an AOD-abuse treatment facility may be challenging and labor intensive, it is necessary for treatment.Patients with comorbid AOD-use and eating disorders can pose a particular challenge for the individual clinician or the staff of a treatment facility. These patients may represent a group distinct from patients who only have an AOD-use disorder or an eating disorder. They may require different, more varied, and more intensive assessment and treatment approaches. Researchers and clinicians still have not identified the most beneficial treatment approaches for these patients, and future treatment outcome studies must address this difficult patient population."}
+{"text": "Chronic sterile inflammation is a pathological feature of Alzheimer\u2019s disease (AD) and other neurodegenerative diseases. The mechanisms that drive neuroinflammation and its impact on AD progression are still incompletely understood. The accumulation of molecular damage in somatic cells can trigger cellular senescence, an irreversible state of cell cycle arrest accompanied by the expression of proinflammatory mediators known collectively as the \u201csenescence-associated secretory phenotype\u201d (SASP). Misfolded tau forms pathogenic soluble aggregates that are released extracellularly and are transmitted trans-neuronally, promoting native tau phosphorylation and aggregation in target cells. We recently showed that, in addition to neurons, pathogenic soluble extracellular tau aggregates propagate to brain microvascular endothelial cells, where microtubule destabilization triggers senescence/SASP. Because astrocytes have a critical role in the regulation of both synaptic function and cerebral blood flow and are directly exposed to tau at its site of release at the tripartite synapse, we conducted studies to define whether soluble aggregated tau propagates to astrocytes, inducing astrocyte senescence/SASP and neuronal dysfunction/damage. Our studies indicate that tau can be propagated transcellularly to astrocytes, triggering cellular senescence/SASP. Our studies suggest that astrocyte senescence is detrimental to dendritic and synaptic structure and density, suggesting that pathogenic soluble tau-induced astrocyte senescence may contribute to synaptic dysfunction and loss in AD. Drugs that eliminate senescent cells are FDA-approved and antibody-based approaches to remove tau from brain are already in clinical trials. Our studies suggest that these interventions could be effective in the treatment of AD and other tauopathies."}
+{"text": "Nationally, there is a shortage of geriatric trained healthcare providers caring for older adults. As the population of older adults grows, health care systems and primary care providers struggle to provide high quality, cost effective care for older adults. Time for training is also limited in busy community health centers. The CATCH-ON Learning Communities (LCs) are telehealth educational interventions based on the ECHO model, modified to be less time intensive, thus decreasing cost to participating clinics. In the LC, geriatric specialists provide evidence-based, best practice training utilizing case discussions to illustrate pertinent learning points via monthly one hour video conferences. Practical, specific behavioral recommendations are offered for immediate implementation in each session. LCs are provided to interprofessional primary care teams. The first LC with a federally-qualified health center (FQHC) yielded consistently high satisfaction from participants, along with a 17% decrease in high risk medication prescriptions and 22% increase in falls screenings. Training the primary care workforce in evidence based geriatric interventions can improve the care of all older adults within each health system, improving healthcare access to help mitigate healthcare inequalities, slow adoption of best practices and rising costs of caring for complex older adults. The CATCH-ON Learning Community is an effective, low cost model of training the primary care work force without geographical or financial constraints that frequently limit access to specialized care."}
+{"text": "Financial exploitation (FE) in older adults is a significant public health problem linked to outcomes including depression, financial ruin and early mortality. This study applied exploratory data science techniques to a multi-year statewide protective services dataset of over 8,000 elder abuse cases. The goal was to derive data-driven psychosocial profiles of abuse with an emphasis on determining which factors, commonly shared across abuse cases, were most important for determining when elder FE was occurring and whether it was occurring alone or in conjunction with other types of abuse. We found that pronounced psychological distress  was most important for indicating when abuse had occurred and predicted non-FE related abuse. Drug paraphernalia in the home and perpetrator drug/alcohol use were important predictors of FE-related abuse. When differentiating pure FE from hybrid FE, factors indicative of long-term FE occurrence and substantial financial loss were most important . The findings parallel some existing work characterizing pure and hybrid FE, but also highlight new profile factors that may help determine when FE is occurring and when it is less likely. Applying data science approaches to other large protective service datasets and national datasets such as the National Adult Maltreatment Registry could help improve characterization of abuse types such as pure and hybrid FE resulting in better detection, response and prevention."}
+{"text": "Hepatitis C virus (HCV)-induced cirrhosis is a major cause of hepatocellular carcinoma (HCC) worldwide. HCC is an aggressive malignancy in which tumor thrombus can invade portal vein, hepatic veins and inferior vena cava (IVC) in the later stages. Our case brings to attention, HCV patient population who might need long-term follow-up to ensure HCV clearance. Physicians should ensure appropriate follow-up after treatment of HCV and should emphasize on the ongoing screening for HCC in patients with cirrhosis or advanced fibrosis, regardless of antiviral treatment outcome. Hepatocellular carcinoma (HCC) is the fourth most common cancer and the third leading cause of cancer-related deaths in the world . HCC is A 58-year-old male presented to the\u00a0hospital with chief complaints of dyspnea on exertion associated with pleuritic chest pain and fatigue for two weeks prior to presentation. Medical history was significant for hypertension and hepatitis C genotype 1 treated with ledipasvir/sofosbuvir four years ago. HCV was successfully treated with achievement of sustained virologic response four years ago. The patient did not follow-up after treatment completion. On physical examination, mildly distended, non-tender abdomen was noted. Computed tomography (CT) angiogram of chest was done due to an elevated D-Dimer of 1878 ng/ml and the patient was found to have a segmental pulmonary embolism in the right lower lobe of the lung Figure . Tumor tHCV-induced cirrhosis is a major cause of HCC worldwide. The redetection of HCV RNA in our patient can either be explained by ledipasvir-sofosbuvir treatment failure with HCV reactivation, HCV relapse or HCV reinfection. The preferred antiviral regimen for the vast majority of patients with chronic HCV infection was ledipasvir-sofosbuvir when our patient was treated . HCV NS5The diagnosis of HCC is typically made by radiological liver imaging in combination with serum AFP without the need for biopsy especially in patients with cirrhosis . TherefoExtension of IVC thrombus into right atrium (RA) can present as RA mass . Primary.Definitive therapy of pulmonary tumor emboli is directed at treating the primary tumor . SurgicaThe prognosis of HCC patients with tumor thrombi is extremely poor, with median survival of about three months from diagnosis without treatment . The oneIn conclusion, our case is unique as advanced HCC presented as pulmonary tumor embolism after successful treatment of HCV. In patients with HCC, who present with respiratory distress and chest pain, clinicians should have a high index of suspicion for pulmonary tumor embolism. Our case emphasizes the importance of HCC screening in patients treated for hepatitis C and have advanced fibrosis or cirrhosis for early detection and management of hepatocellular carcinoma."}
+{"text": "Plasmodium falciparum genetic diversity typing and resistance monitoring and proposes how the different tools could be employed in resource-poor settings. Advanced approaches enabling targeted deep sequencing is valued as a sensitive method for assessing drug resistance and parasite diversity but remains out of the reach of most laboratories in sSA due to the high cost of development and maintenance. It is, however, feasible to equip a limited number of laboratories as Centres of Excellence in Africa (CEA), which will receive and process samples from a network of peripheral laboratories in the continent. Cheaper, sensitive and portable real-time PCR methods can be used in peripheral laboratories to pre-screen and select samples for targeted deep sequence or genome wide analyses at these CEAs.The intensification of malaria control interventions has resulted in its global decline, but it remains a significant public health burden especially in sub-Saharan Africa (sSA). Knowledge on the parasite diversity, its transmission dynamics, mechanisms of adaptation to environmental and interventional pressures could help refine or develop new control and elimination strategies. Critical to this is the accurate assessment of the parasite\u2019s genetic diversity and monitoring of genetic markers of anti-malarial resistance across all susceptible populations. Such wide molecular surveillance will require selected tools and approaches from a variety of ever evolving advancements in technology and the changing epidemiology of malaria. The choice of an effective approach for specific endemic settings remains challenging, particularly for countries in sSA with limited access to advanced technologies. This article examines the current strategies and tools for  Malaria continues to cause significant morbidity and mortality across Africa, despite the intensification of control interventions . A worldPlasmodium falciparum as a parasite has been attributed partly to its enormous genetic diversity n, [T]n, and [TAA]n repeats [P. falciparum drug-resistance markers and flanking microsatellite loci can be employed to assess the genetic diversity and evolution of selective signatures around drug resistance genes [Microsatellites are tandem repeats of one to six base pairs (bp) that are highly polymorphic. They are abundant in the  repeats . Anderso repeats . These t repeats \u201379. Alsoce genes .msp/glurp typing, microsatellite typing depends on accurate DNA fragment amplification by PCR, which can result in artefacts. Accurate allele sizing requires expensive capillary electrophoresis equipment that are largely unavailable. Moreover, there are no methods for phase resolution of parasite haplotypes in mixed infections. However, thousands of P. falciparum genome sequences are now available for mining new microsatellite loci which can be developed into new assays for population diversity analyses. Low cost thermocyclers combined with HRM for determining sizes of DNA fragments can improve the availability of microsatellite typing to less specialized laboratories [Similar to ratories .P. falciparum isolates [I.A 96 genome-wide SNP panel used to assess the impact of decreased transmission on parasite diversity in Senegal and at the Thai-Burma border , 86. TheII.A 384-SNP custom GoldenGate Illumina Mass array that clearly resolved global patterns of genetic diversity and the structure of geographically distinct populations across global endemic populations .III.P. falciparum containing five mitochondrial and 18 SNPs of the apicoplast genomes thought to offer a higher resolution between isolates from different endemic blocs [P. falciparum isolates. This can identify imported cases of P. falciparum into elimination settings.23-SNP panel for ic blocs . The facIV.A recent malaria Taqman Array with 87 loci that enable both species classification and typing of markers across drug resistance and neutral loci . DeploymV.https://www.malariagen.net/projects/spotmalaria).The Spot malaria project currently provides a large panel of loci including targets for drug resistance and neutral sites for population diversity analysis. This has been constituted into a \u2018Genetic Report Card\u2019 (GenRE). This will become increasingly useful as the genotyping methods applied are sensitive enough to detect parasites genomes and alleles in very low-density infections  and the Human Hereditary and disease in Africa (H3Africa) Pan-African Genetic Epidemiology Network (PAMGEN). These programmes will expand access and application of WGS/GVA approaches to malaria elimination research in sSA. Effective deployment and translation could be further facilitated by sample pooling and employing cheaper but sensitive Real time PCR genotyping methods to pre-screen and select samples in peripheral laboratories prior to genome wide analyses at CEAs. Pre-screening could prioritize loci for diversity, drug or vaccine resistance most relevant to the local control and intervention strategies.Unlike the analysis of individual loci, which may be the target of strong natural selection, inferences from genome-wide diversity are less subject to target biases and, therefore, more accurately reflect overall patterns of Genetic epidemiology of malaria can improve understanding of parasite origins, flow rates between populations , drug resistance and potential susceptibility to candidate anti-malarial drugs and vaccines , 95, 96.Targeted deep and whole genome sequencing are sensitive and specific for detecting patterns of malaria parasite diversity and critical for \u2018drug resistant intelligence\u2019. Though they required significant investment in equipment and trained personnel, it is feasible to equip genomic Centres of Excellence in Africa, which will receive and process samples from a network of smaller laboratories with PCR capabilities. These centres will be hubs for developing field deployable genotyping assays for PCR and portable next-Generation sequencing technologies such as the Nanopore to boost genomic surveillance for malaria elimination in Africa. Centres of excellence and molecular surveillance nodes will need computational infrastructure to combine novel approaches for ancestry, relatedness, transmission models and machine learning to resolve spatial\u2013temporal parasite flow, population structure and drug resistance , 99. Thu"}
+{"text": "With the rise in global older adult populations, university programs need to produce an effective, gerontology-trained workforce . Career decision-making involves interactive learning , as adults explore career options, engage in career learning, and understand curriculum integration within professional settings . Gerontology faculty can utilize career planning models that integrate intergenerational engagement within the curriculum to aid student career decisions . This paper provides an overview of a career planning model and highlights the ways intergenerational programs can be intentionally staged in research, service, and extracurricular domains to promote career planning and success in post-graduate employment. Data from our recent gerontology alumni survey including graduates since the program inception will be outlined to support the importance and success of developing strong applied intergenerational career programs in gerontology."}
+{"text": "Two transport pathways  have long been proposed for entry of nanoparticles from the blood circulation into solid tumors. We examine and discuss available evidence supporting interendothelial and transendothelial transport processes and suggest new avenues for re-evaluating these pathways. Understanding of integrative mechanisms controlling nanoparticle extravasation into tumors is important for improving engineering and performance of anti-cancer nanopharmaceuticals. The enhanced permeability and retention effect (EPR) has become an equivocal concept in the targeting and development of anti-cancer nanomedicines. This concept has been recently scrutinized due to disappointing therapeutic efficacy and limited clinical success with anti-cancer nanomedicines compared with excellent results in small animal xenograft models  as well as many pathophysiological factors such as size heterogeneity seen in tumor vessel fenestrae (100\u20131200\u00a0nm), pore frequency/density, other architectural abnormalities, and stochastic intratumoral pressure  has contributed to ambiguity in transport pathways across tumor endothelium. Furthermore, the interaction between nanoparticles and vessel walls (and subsequent extravasation processes) might be controlled by the perfusing concentration of nanoparticles  as well as capillary architecture, and integrated mechanical and fluid dynamic factors that modulate local blood cell  stretching. Here, nanoparticle physicochemical properties such as size, shape, deformability, and surface characteristics all play important roles in establishing nanoparticle impaction with blood cells, contact with endothelium, and rolling on vessel walls. Recent developments in nanoparticle engineering include precision control of particle shape, mechanical stiffness, and surface properties (Moghimi et al."}
+{"text": "Participation in risky health behaviors can increase the potential for cognitive decline. Smoking, alcohol consumption, and minimal physical activity are modifiable risk factors associated with worse performance on cognitive assessments; however, the relationship between subjective cognitive decline (SCD) and risky practices has not been assessed. As a potential early indicator of cognitive impairment, SCD may serve as a screening measure for dementia. The Behavioral Risk Factor Surveillance System is an annual, self-reported telephone survey of Americans that includes fifteen core and twenty-five optional sections. The present study included Behavioral Risk Factor Surveillance System participants age 45 or older who completed the core and cognitive decline modules in 2015 . Roughly 11% of participants endorsed worsening memory in the previous year. Logistic regression examined the impact of smoking, drinking, and inactivity on self-reported cognitive decline. Current or former smokers had greater odds of endorsing cognitive decline compared to those who never smoked . Individuals who consumed at least one alcoholic beverage in the previous month had lower SCD odds compared to non-drinkers . Respondents who engaged in little to no physical activity had greater odds of endorsing cognitive decline compared to active respondents . Individuals who endorsed cognitive decline engaged in unhealthy habits such as smoking or inactive lifestyles; however, low to moderate alcohol consumption may be beneficial for cognitive functioning."}
+{"text": "Birds are a diverse and agile lineage of vertebrates that all use bipedal locomotion for at least part of their life. Thus birds provide a valuable opportunity to investigate how biomechanics and sensorimotor control are integrated for agile bipedal locomotion. This review summarizes recent work using terrain perturbations to reveal neuromechanical control strategies used by ground birds to achieve robust, stable, and agile running. Early experiments in running guinea fowl aimed to reveal the immediate intrinsic mechanical response to an unexpected drop (\u201cpothole\u201d) in terrain. When navigating the pothole, guinea fowl experience large changes in leg posture in the perturbed step, which correlates strongly with leg loading and perturbation recovery. Analysis of simple theoretical models of running has further confirmed the crucial role of swing-leg trajectory control for regulating foot contact timing and leg loading in uneven terrain. Coupling between body and leg dynamics results in an inherent trade-off in swing leg retraction rate for fall avoidance versus injury avoidance. Fast leg retraction minimizes injury risk, but slow leg retraction minimizes fall risk. Subsequent experiments have investigated how birds optimize their control strategies depending on the type of perturbation , visibility of terrain, and with ample practice negotiating terrain features. Birds use several control strategies consistently across terrain contexts: (1) independent control of leg angular cycling and leg length actuation, which facilitates dynamic stability through simple control mechanisms, (2) feedforward regulation of leg cycling rate, which tunes foot-contact timing to maintain consistent leg loading in uneven terrain , (3) load-dependent muscle actuation, which rapidly adjusts stance push-off and stabilizes body mechanical energy, and (4) multi-step recovery strategies that allow body dynamics to transiently vary while tightly regulating leg loading to minimize risks of fall and injury. In future work, it will be interesting to investigate the learning and adaptation processes that allow animals to adjust neuromechanical control mechanisms over short and long timescales. Birds are diverse and agile vertebrates capable of many combinations of aerial, terrestrial, and aquatic locomotion. Living birds vary in size from hummingbirds to ostriches, and exhibit diversity in the length and mass proportions of the wings and legs, reflecting adaptation for different locomotor ecologies . While wLegged locomotion is complex and dynamic, involving abrupt foot-contact transitions and uncertainty due to variable terrain and sensorimotor errors. Animals must precisely control limb dynamics to move effectively over varied and uncertain terrain while avoiding falls, collisions, and injury . It remaAvoiding slip, fall, and injury requires precise regulation of foot-contact timing and leg-substrate interaction forces . Yet, inOne inherent challenge of animal systems is sensorimotor delay that limits feedback response times ; 2013. SNerve transmission delays increase with the anatomical distances of neural pathways. This physical constraint creates a direct link between neuroanatomy and temporal scaling of control processes . ConsideThe phrase \u201cpassive-dynamics\u201d has often been used to refer to the intrinsic mechanical response of the locomotor system. However, this phrase can be somewhat misleading, because the intrinsic mechanical response is actively tuned by the selection of a specific muscle activation pattern from the possible solutions that could meet the mechanical requirements of the task . Each muTerrain perturbations are ubiquitous in nature and disrupt the predictability and timing of foot\u2013substrate interactions, requiring transient locomotor responses to recover from disturbances. Understanding transient locomotor dynamics is important for revealing natural locomotor behaviors, and for understanding the specific mechanical demands and constraints that have shaped animal locomotor control.in vivo muscle force\u2013length dynamics, body dynamics, leg\u2013substrate interaction forces, and joint mechanics during locomotion , and with ample practice negotiating visible terrain features. In comparing locomotor control strategies between hidden and visible potholes, guinea fowl slow down in anticipation of visible potholes when they encounter them for the first time, and actually stumble more when negotiating the visible drop . AlthougBlum and colleagues (2014) explored how animals manage the trade-off between terrain robustness and injury avoidance in leg angular control when given ample practice negotiating a visible drop in terrain. Under these conditions, guinea fowl converge upon a strategy similar to the hidden pothole strategy\u2014they maintain high speeds and allow intrinsic leg mechanics to mediate the perturbation response . The autBlum et\u00a0al. 2011In another series of experiments, Birn-Jeffery and colleagues investigated control strategies used by ground birds when negotiating visible obstacles, to investigate potential trade-offs in stance leg function . SimilarRegulation of leg cycling rate can be viewed as a combined feedforward plus \u2018preflexive\u2019 control strategy that minimizes the need for reactive adjustments by exploiting the intrinsic mechanical coupling between leg contact angle and leg loading. Experimental evidence from both humans and birds running over a range of terrain perturbations are consistent with leg angular trajectory as a key target of neural control . Humans Whereas leg angular trajectory appears insensitive to perturbations and adjusted over longer timescales, leg-length actuation shows high stride-to-stride variance, suggesting both predictive (feedforward) and reactive (feedback) adjustment in uneven terrain . Leg lenWhile modular control of leg angular trajectory and leg-length actuation have emerged as consistent control strategies for robustly stable running, it remains less clear whether, and under what circumstances, leg stiffness serves as a direct target of control. Research on humans running over soft and hard surfaces suggests that humans regulate leg stiffness to maintain steady body trajectory . HoweverDifferences between birds and humans in stiffness regulation could also relate to leg morphology. Birds have a more crouched leg posture with four segments, in contrast to the vertically oriented three-segment leg configuration of humans. The limb morphology of birds may allow more flexible adjustment of leg posture to accommodate terrain variation, minimizing the need for active regulation of leg stiffness. This idea is supported by evidence from a study that directly compared control strategies in humans and birds from a model-based perspective . Birds eIn vivo recordings of muscle force, length, and activation dynamics during perturbed locomotion can help reveal the relative contributions of intrinsic mechanical, feedback, and feedforward control mechanisms. These studies also help reveal how neuromechanics of locomotion are integrated across levels of organization, from individual muscle\u2013tendon dynamics to joint, whole limb, and body dynamics. The relationship between muscle activation and mechanical output is known to be nonlinear and dynamically variable, depending on instantaneous fascicle length, velocity and recent strain history  during stance decreases by 81% during perturbed steps compared to steady strides, despite maintaining the same electromyography (EMG) activation levels  investigated context dependent shifts in sensorimotor control by comparing muscle activation patterns during obstacle negotiation at low and high speeds, and with low and high-contrast obstacles. In slower speed obstacle negotiation, anticipatory increases in muscle activity are apparent in the steps preceding obstacles. At higher running speeds, the neuromuscular response is largely reactive, occurring after foot contact with the obstacle . AnticipWhile neuromechanical control of locomotion involves a complex interplay of mechanical and sensorimotor mechanisms, studies of running birds have revealed several strategies for robust, stable, and agile bipedal locomotion that are consistent across terrain contexts: (1) independent control of leg angular cycling and leg length actuation, which facilitates dynamic stability through simple control mechanisms, (2) feedforward regulation of leg cycling rate to maintain consistent leg loading in uneven terrain, (3) load-dependent muscle actuation to stabilize body mechanical energy in response to disturbances, and (4) multi-step recovery strategies that allow body dynamics to transiently vary while tightly regulating leg loading to minimize risks of fall and injury. Muscle proprioceptive feedback arising from non-steady force\u2013length dynamics likely plays important roles in effective tuning of perturbation responses over time, as well as maintaining accurate state estimates for internal models, path planning, and navigation in higher brain centers. However, it remains unclear how sensory feedback is integrated with spinal neural circuits and higher brain centers to adjust locomotor control over short and long time-scales. In future work, it will be interesting to investigate the learning and adaptation of neuromechanical control mechanisms through repeated exposure to perturbations in controlled conditions."}
+{"text": "Most older adults prefer to \u201cage in place\u201d and maintain independent regarding activities of daily living (ADL). Dependency in ADL might be caused by frailty. This study explored the relationship between multidimensional frailty and ADL dependency, and if protective factors, derived from a systematic literature review, moderate this relationship. A longitudinal study with a 24-month follow-up was performed among 1,027 community-dwelling older adults. Multidimensional frailty was assessed with the Tilburg Frailty Indicator, and ADL dependency with the Groningen Activity Restriction Scale. Other measures included socio-demographic characteristics and seven protective factors against ADL dependency, such as physical activity and non-smoking. Logistic regression analyses showed that frail older people had a twofold risk of developing ADL dependency in comparison to non-frail older people after 24 months . Analyses with interaction terms indicated that the selected protective factors against ADL dependency did not signi\ufb01cantly moderate this relationship. Nonetheless, higher levels of physical activity and having su\ufb03cient \ufb01nancial resources decreased the risk of becoming ADL dependent in the overall sample . In conclusion, multidimensional frail older people are at higher risk of developing ADL dependency and the studied factors against ADL dependency did not signi\ufb01cantly moderate this relationship. To develop prevention strategies for ADL dependency and facilitate aging in place, future studies might explore the relationship between each specific frailty domain and ADL dependency, and the role of (other) moderating factors."}
+{"text": "O-glycans serve as attachment sites and metabolic substrates to the gut commensal bacteria, which have adapted to the mucosal environment. Technology progress has advanced our understanding of mucin biosynthesis, glycosylation and organization. However, the molecular mechanisms underpinning gut bacteria-mucin glycan interactions remain poorly defined. The mucus layer covering the gastrointestinal tract plays a critical role in maintaining a homeostatic relationship with our gut microbiota. The large intestine, which is home to most microbial species constituting the gut microbiota, is lined by a bi-layer of mucus. The outer layer provides a habitat for bacteria, whereas the inner layer maintains them at a safe distance from the epithelial surface. The terminal mucin Lactobacillus acidophilus [Helicobacter pylori [Akkermansia muciniphila, revealing its occurrence in other anatomical regions of the gastrointestinal tract although its optimal ecological niche remains the mucus layer in the colon [This issue gathers eight articles covering various mechanistic aspects of gut bacteria-mucus interactions and impact on health and disease. These include comprehensive overviews of the role of mucus in the interaction with the gut microbiota in humans  or in hodophilus  or pathor pylori  highlighr pylori . This adr pylori . Two artr pylori , food adr pylori  influenche colon . It is c"}
+{"text": "Post-surgical complications are most common in older adults. While a number of factors contribute, one key determinant is malnutrition. Malnutrition is seen in up to 86% of older adults at hospital admission. Malnutrition and post-surgical complications are linked through two critical observations: 1) malnutrition dramatically reduces the ability of older adults to overcome postsurgical health stressors, and 2) nutritional status is likely to deteriorate further during hospitalization and after discharge. Despite convincing evidence that perioperative nutrition intervention can improve surgical outcomes, nutrition screening and assessment in the preoperative period is not required or standardized. We will review issues surrounding screening and assessment of malnutrition in older adults preparing for elective surgery and present data on screening (NRS-2002) and assessment tools  used in this high-risk population. Finally, we will discuss best practices for identifying and intervening with malnourished older adults in the preoperative setting."}
+{"text": "Lung cancer is among the most prevalent cancers and a leading cause of malignancy-related death . For a lThis morphological ITH goes along with multiple molecular alterations within primary and metastatic lesions of the same individual: Whole-exome sequencing of spatially separated tumor regions demonstrated extensive genetic and genomic ITH Figure  3]. App. App3]. EGFR and KRAS alterations with tumor cell content and the predominant morphological growth pattern, we recently analyzed central sections of 19 ADCs subdivided into 467 5\u00d75 mm segments. We demonstrated that EGFR and KRAS driver mutations were present in all malignant segments, suggesting a clonal origin. Despite high levels of inter-and intratumor heterogeneity, we found a significant correlation between variant allele frequencies (VAFs) and morphological growth patterns, but not with tumor sizes [Despite this considerable ITH, only few studies performed an integrative analysis of molecular and morphological markers in NSCLC. To comprehensively compare the spatial distribution of In addition to genomic ITH we addressed somatic mutations of the mitochondrial genome (mtDNA), which were either ubiquitously distributed throughout a tumor section or restricted to specific regions . SpatialTo analyze tumor heterogeneity on the epigenomic level, we recently used a similar segmentation approach  and deteTo infer the phylogenetic relationships between the segments, we calculated distance matrices based on DNA methylation and CNVs. In line with a previous publication , methylaIncreasing evidence suggests a crucial role of ITH as a driver of tumor progression and therapy failure. Hence, ITH poses a major challenge for the treatment and prognosis of patients. However, only little is known about epigenomic ITH to date. Our results suggest that extensive inter-as well as intra-tumor variation shape the molecular and phenotypic heterogeneity of ADCs. The challenge of future research will be to understand the interplay between these multiple genomic and epigenomic layers Figure . While aTo overcome the limitations of single tissue biopsies and to avoid repeated multiregional tissue sampling, novel approaches are required. To this end, tumor DNA circulating in the blood might depict tumor heterogeneity and clonal evolution under therapy more comprehensively , 10. How"}
+{"text": "The gut microbiota is a central regulator of host metabolism. The composition and function of the gut microbiota is dynamic and affected by diet properties such as the amount and composition of lipids. Hence, dietary lipids may influence host physiology through interaction with the gut microbiota. Lipids affect the gut microbiota both as substrates for bacterial metabolic processes, and by inhibiting bacterial growth by toxic influence. The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans. Furthermore, diseases linked to dyslipidemia, such as non-alcoholic liver disease and atherosclerosis, are associated with changes in gut microbiota profile. The influence of the gut microbiota on host lipid metabolism may be mediated through metabolites produced by the gut microbiota such as short-chain fatty acids, secondary bile acids and trimethylamine and by pro-inflammatory bacterially derived factors such as lipopolysaccharide. Here we will review the association between gut microbiota, dietary lipids and lipid metabolism The gut microbiota regulates many metabolic processes in the host including energy homeostasis, glucose metabolism and lipid metabolism . MicrobiLipid metabolism includes the biosynthesis and degradation of lipids such as fatty acids, triglycerides and cholesterol. Specialized lipoproteins facilitate the transport of lipids from the gut to the liver (the site of most lipid transformations) and between the liver and peripheral tissues. Obesity is linked to dysregulation of lipid metabolism, which may result in abnormal levels of blood lipids, ectopic lipid deposition and associated metabolic diseases such as non-alcoholic liver disease (NAFLD)  and atheThe gut microbiota has the capacity to perform many processes that cannot be carried out by the host. These processes can give rise to microbially produced or modulated metabolites that function as metabolic substrates and signaling molecules in the host, with major implications for host metabolism and health. Dietary composition is central to the metabolic output of the gut microbiota because: (1) the gut microbiota processes dietary nutrients into metabolites and (2) the diet affects the gut microbiota composition and thereby its metabolic potential and impact on the host. In particular, the importance of dietary fibers for gut microbiota composition and function has been extensively studied. In addition, several studies have reported an important role for dietary lipids.In this review, we will discuss interactions between lipids, the gut microbiota and the host. We will describe the current knowledge on how dietary lipids affect the gut microbiota, how interactions between dietary lipids and the gut microbiota influence host physiology and health, and how the gut microbiota affects host lipid metabolism.n-6 PUFA or n-3 PUFA) showed that diets with saturated fat or n-6 PUFA induced weight gain, but only saturated fat increased insulin resistance, colonic permeability, and mesenteric fat inflammation [n-3 PUFA diet differed from the other groups, whereas the gut microbiota of mice fed a saturated fat diet and a n-6 PUFA diet were similar. In another study where mice fed a high-fat diet containing lard, rich in saturated fat, were compared to mice fed a isocaloric high-fat diet containing fish oil, rich in n-3 PUFA, it was found that phylogenetic diversity and abundance of the beneficial bacteria Akkermansia muciniphila, Lactobacillus and Bifidobacterium were lower in mice on a lard diet [The gut microbiota has been shown to differ between mice fed diets that are high or low in fat and between diets that contain equal amounts of fat but from different sources \u201313  but not in GF mice when compared to palm oil [Not only fat sources with major differences in lipid composition, such as lard and fish oil, but also fat sources that are more similar, may give rise to different gut microbiota composition and function. Devkota et al showed that a diet with milk fat, but not diets with lard or safflower oil, increased expansion of  in mice . Milk fapalm oil . The larThe mechanisms by which dietary fatty acids affect gut microbiota are not well defined. Although most of the fatty acids consumed are absorbed in the small intestine, a minority will pass through the gastrointestinal tract and may therefore directly modulate colonic microbiota composition. Fatty acids have a broad spectrum of antibacterial activity including lysis and solubilization of bacterial cell membranes , 15 and Intestinal bacteria can also react with fatty acid double bonds to produce metabolites that cannot be synthesized by mammalian hosts. Bacterial processing of linoleic acid, for example, has been shown to produce metabolites that may influence host physiology and health. Conjugated linoleic acid (CLA) can be produced by several gut bacteria including Lactobacillus, Butyrivibrio, and Megasphaera , 20. DifBacterial production of CLAs is a multistep process involving several metabolic intermediates. These metabolites include several hydroxy fatty acids that affect processes related to host health. 10-hydroxy-cis-12-octadecenoic acid (HYA) enhances intestinal barrier function and suppresses the development of colitis in mice in a free fatty acids 1 (FFR1/GPR40)-dependent manner . AnotherStudies in gnotobiotic mice have shown that the gut microbiota affects host lipid metabolism. Importantly, GF mice are protected against diet-induced obesity through a combination of several mechanisms including increased fatty acid oxidation and decreased deposition of triglycerides in adipocytes compared to CONV-R mice . FurtherThe gut microbiota affects host lipid metabolism and lipid composition through interaction with the diet. In a recent study by Just et al, CONV-R and GF mice were fed palm oil or lard diet (both rich in saturated lipids) supplemented with bile acids . They foLactobacillus curvatus alone or together with Lactobacillus plantarum reduced cholesterol in plasma and liver and the two strains had a synergistic effect on hepatic triglycerides [Studies in mice treated with probiotics provide further evidence for a role of the gut microbiota in regulation of host lipid homeostasis. In mice fed a high-fat high-cholesterol diet, ycerides . Similarycerides .Overall, studies in mouse models show that the gut microbiota, in concert with the diet, regulates host lipid metabolism and lipid levels in serum and tissues.The fecal microbiota has also been linked to lipid metabolism in humans. Taxonomy and functional profiles of the bacteria differ between obese and lean subjects, but results from different studies are inconsistent, in part because of the complex nature of obesity but also because different methods have been used to analyze the microbiota . A numbeChanges in fecal microbiota composition are also present in individuals with pathophysiological conditions associated with dyslipidemia and ectopic fat deposition such as atherosclerosis and fatty liver. By analyzing the microbial composition of atherosclerotic plaques, fecal samples and the oral cavity in patients with symptomatic carotid artery stenosis , Koren eBacteroidetes in patients with fibrosis or NASH is the most consistent finding in these studies.Several studies have shown that the fecal microbiota composition in subjects with NAFLD differs from that of healthy controls and obese patients without fatty liver disease \u201345. HoylShort-chain fatty acids (SCFAs) such as acetate, propionate and butyrate are bacterial metabolites derived from fermentation of fibers in the colon Fig. . Both buGpr41 knockout mice are leaner and weigh less than their wild-type littermates, while these differences are not found in GF mice. Furthermore, the microbiota increases peptide YY (PYY) production through GPR41 [In addition to being metabolic substrates, SCFAs act as signaling molecules, notably through the G-protein coupled receptors GPR43/FFAR2 and GPR41/FFAR3. GPR43 protects against diet-induced-obesity in mice \u201355. Actigh GPR41 . Butyratgh GPR41 , and SCFgh GPR41 , reducedgh GPR41 .Overall, SCFAs have been shown to have a positive impact on metabolic health . Supplemde novo synthesis from cholesterol [Primary bile acids are synthesized from cholesterol and conjugated to taurine or glycine in the liver. The bile acids are stored in the gallbladder and excreted into the duodenum after food ingestion to aid emulsification of dietary lipids. Most of the bile acids are reabsorbed and recirculated to the liver, but bacterially mediated deconjugation of the glycine or taurine group reduces reabsorption. Deconjugated bile acids can be further metabolized to secondary bile acids through dehydrogenation, dehydroxylation and epimerization by colonic bacteria . Microbilesterol .In addition to their role in lipid digestion, bile acids can act as signaling molecules that regulate host metabolism by binding to the nuclear receptor farnesoid X receptor (FXR) and the Takeda G-protein coupled bile acid receptor TGR5. Microbial processing of bile acids increases the diversity of the bile acid pool and the different bile acids vary in their affinity to the receptors and can act as agonists or antagonists. Both of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) and the secondary bile acids lithocholic acid (LCA) and deoxycholic acid (DCA) are FXR agonists, but with different affinities . In humaFxr knockout mice with or without bacteria a high-fat diet, Pars\u00e9us et al showed that microbiota-induced weight gain, steatosis and inflammation were dependent on FXR signaling [Fxr knockout donor mice, demonstrating that FXR may contribute to increased adiposity by altering the microbiota composition. Comparison of whole body and tissue-specific Fxr knockout mice have revealed that activation of the liver and intestinal FXR result in distinct metabolic outcomes in obesity models [FXR is involved in the regulation of lipid metabolism, especially triglyceride trafficking, synthesis and utilization . Microbiignaling . FXR alsy models \u201377. Sevey models , 77 but Bile acids have also been shown to influence host lipid metabolism through TGR5. TGR5 activation in skeletal muscle and brown adipose tissue promotes energy expenditure . In addiBile acids have been implicated in the pathogenesis of fatty liver disease. Patients with NASH have been shown to have altered fecal bile acid composition . In addiLipopolysaccharides (LPS), also known as endotoxins, are structural compounds in the outer membrane of Gram-negative bacteria. LPS induces inflammation through activation of TLR4, which is expressed on immune cells such as macrophages as well as on many other cell types including hepatocytes and adipocytes. The intestinal epithelium works as a barrier to prevent translocation of bacterially derived factors. However, weight gain, high-fat diet  and incrLPS interacts with blood lipids in various ways. First, it increases the concentration of blood triglycerides by multiple mechanisms. In rats, low-dose LPS increases hepatic synthesis of VLDL, whereas high-dose LPS decreases lipoprotein catabolism . Mice laLPS has been shown to promote atherosclerosis and cardiovascular disease. LPS-treated hypercholesterolemic rabbits have increased atherosclerosis compared with controls  and miceMouse studies have shown that hepatic steatosis is induced by a high-fat diet and associated with dysbiosis and increased intestinal permeability . MoreoveApoe knockout mice show that increased microbial capacity for TMA production increases aortic lesions[The gut microbiota metabolizes methylamine-containing nutrients such as choline, lecithin and L-carnitine to generate trimethylamine (TMA), which is further processed to trimethylamine N-oxide (TMAO) by flavin monooxygenases (FMO) in the liver. TMAO levels have been correlated with risk of cardiovascular events and prevc lesions.Fmo3 results in reduced atherosclerotic lesion areas, altered lipid and cholesterol metabolism, and decreased TMAO plasma levels [FMO3 is the primary enzyme converting TMA into TMAO. Knockdown of a levels , 120. FMa levels . Gut micThe mechanisms by which TMAO contributes to atherosclerosis appears to be complex and not fully understood. Antibiotic treatment reduces production of TMA and has been shown to suppress foam cell formation. TMAO can also contribute to atherosclerosis by inhibiting reverse cholesterol transport  and by iApoe knockout mice fed diets with or without choline supplementation found no effect of choline enrichment on aortic root atherosclerosis in mice[Although many studies have reported associations between plasma levels of choline, TMAO, and cardiovascular disease , 125 thes in mice. TMAO prs in mice. Similars in mice, 127.The gut microbiota has been targeted for treatment of diseases related to dyslipidemia. Strategies include supplementing the diet with fibers to enhance the growth or activity of beneficial bacteria (prebiotics), live bacteria (probiotics) or a combination of pre- and probiotics (symbiotics).A meta-analysis of 11 minor clinical trials using fermented milk and probiotics show beneficial effects on serum lipid profiles. AnotherStatins lower cholesterol levels by inhibiting HMG-CoA reductase, but may also exert a lipid-lowering effect through interaction with the gut microbiota. Liu et al demonstrated that the cholesterol-lowering effect of rosuvastatin was reflected in microbial alpha diversity measured after eight weeks of treatment . StudiesThe studies performed on microbiota-targeted therapy against dyslipidemia and NAFLD are heterogeneous, the cohorts small and the intervention periods short. Therefore, long-term benefits remain uncertain. Prevention of atherosclerosis by modulation of the gut microbiota has not been studied in humans and data in mice are conflicting\u2013137.An intricate crosstalk links the gut microbiota, dietary lipids and host lipid metabolism. The microbiota processes lipids and other nutrient factors to produce metabolites with impacts on host lipid homeostasis and putative effects on pathophysiological processes. Studies in gnotobiotic and genetic mouse models have identified mechanisms behind these interactions, and studies in humans have found associations between microbial composition, lipid profiles and prevalence of metabolic diseases. However, although it is evident that fat from different sources has different effects on the gut microbiota, the role of specific fatty acids is not known. It also remains to be investigated how the combination of lipids with other nutrients - such as dietary fibers \u2013 affects the gut microbiota. Even though efforts have been made to understand how dietary pattern affect the gut microbiota, 139, th"}
+{"text": "Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism and would have impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose starvation as measured on a Seahorse XFp system. Additionally, aged monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged monocytes maintain effector and metabolic functions during glucose starvation, at least in an ex vivo context."}
+{"text": "Leaves are initiated as lateral outgrowths from shoot apical meristems throughout the vegetative life of the plant. To achieve proper developmental patterning, cell-type specification and growth must occur in an organized fashion along the proximodistal (base-to-tip), mediolateral , and adaxial\u2013abaxial (top-bottom) axes of the developing leaf. Early studies of mutants with defects in patterning along multiple leaf axes suggested that patterning must be coordinated across developmental axes. Decades later, we now recognize that a highly complex and interconnected transcriptional network of patterning genes and hormones underlies leaf development. Here, we review the molecular genetic mechanisms by which leaf development is coordinated across leaf axes. Such coordination likely plays an important role in ensuring the reproducible phenotypic outcomes of leaf morphogenesis. Arabidopsis, the leaf is subdivided into the proximal petiole and distal lamina. Leaf development also involves specialization of the upper and lower leaf surfaces, defining an adaxial\u2013abaxial (top-bottom) axis of asymmetry. At its inception, the leaf primordium possesses inherent asymmetry along this axis due to the proximity of the adaxial leaf surface to the SAM relative to the abaxial leaf surface ) and barley (NARROW LEAF DWARF1 [NLD1]), and yield comparable phenotypes when disrupted, although defects in margin patterning extend well into the leaf blade in these species ), petunia (MAEWEST [MAW]), and Medicago (STENEFOLIA [STF]) and have conserved roles in promoting the mediolateral outgrowth of the leaf blade . . miR319 YAB genes were linked to the control of abaxial cell identity in the leaf . . BOP gened light C 140]. . BOP genactivity ,142,143.KNOX genes by factors regulating development along all three axes. Clearly, KNOX repression is an essential and tightly regulated developmental program of the leaf. Additionally, coordinating factors frequently cross-regulate multiple patterning modules, as well as interact with a host of co-regulatory proteins to carry out their functions. Looking forward, advances in live imaging methods will allow for enhanced analysis of leaf development and its associated spatiotemporal gene expression patterns in real time. This, coupled with rapdily advancing genomics technologies, will provide a major boon to understanding the complex and interwoven leaf axial patterning pathways. Through such work, we will come closer to understanding the remarkable consistency of leaf patterning in three dimensions.Plants are capable of producing consistently patterned leaves throughout their lifespan, a feat that requires highly robust control of underlying genetic patterning factors. One way that such robustness may be achieved is through the close coordination of factors patterning the three growth axes of leaves, a prediction realized by the work of Waites and Hudson almost twenty five years ago. Here, we have described several genetic and hormonal factors that simultaneously regulate developmental patterning along multiple leaf axes simultaneously. Such control mechanisms likely ensure that growth along these axes proceeds in a synchronized and organized fashion. Perhaps most striking is the highly redundant repression of Class I"}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Brown adipose tissue (BAT) increases energy expenditure by dissipating chemical energy as heat. The combustion of glucose and lipids produces beneficial metabolic effects and renders BAT an attractive target to battle obesity and associated diseases. The majority of adults do not display active BAT on positron emission tomography (PET) without prior cold exposure. Interestingly, a fraction of individuals with BAT positive PET scans exhibits excessive BAT (eBAT) activity, indicating a possible underlying genetic contributor. We aim to identify genetic determinants of BAT activity by studying individuals with eBAT activity using next-generation sequencing. A cellular model will be used to validate variants and perform in-depth pathway analysis. METHODS/STUDY POPULATION: We performed a retrospective review of PET scans over a period of 12 months in patients presenting with suspected or diagnosed cancer . The distribution of BAT positive individuals (n=1251) was used to implement a threshold to define eBAT activity. Samples from prospectively recruited individuals with BAT activity above the threshold will undergo whole exome sequencing. Variants associated with eBAT activity will be engineered into an immortalized BAT cell line using CRISPR to validate results and perform in-depth pathway analysis. RESULTS/ANTICIPATED RESULTS: We expect to identify genetic variants associated with eBAT. Studying the effects of these variants on thermogenesis followed by in-depth pathway analysis in genetically engineered cellular and mouse models may enable us to find new regulators of BAT activity. These findings may eventually contribute to the development of new drugs targeting obesity and its sequelae. DISCUSSION/SIGNIFICANCE OF IMPACT: The contribution of genetic factors to individual BAT activity is currently unknown. Identifying individuals with eBAT on PET scans and studying the underlying genetic determinants may provide the foundation for the discovery of new pathways for BAT activation."}
+{"text": "Background: Both hearing loss and mobility decline are well-known risk factors of cognitive impairment among older adults. However, the effects of the accumulation of these functional impairments are still unclear. Thus, the present study examined whether the interactive effects of hearing loss and poor gait performance contribute to cognitive impairments. Methods: Hearing loss and gait performance were assessed in 716 community-dwelling older adults at baseline. Pure-tone audiometry was conducted to determine hearing loss at 1  and 4 kHz . Poor gait performance was defined as the lowest quartile (fourth quartile) of age- and sex-appropriate mean gait velocity. Participants were then classified into four groups according to the presence of hearing loss and poor gait performance. Cognitive function was assessed using MMSE and MoCA at baseline and four years later. Results: Older adults who had either hearing loss (low or high tone) or poor gait performance showed lower MMSE and MoCA scores at baseline. Multiple regression models showed that hearing loss and poor gait performance at baseline were significantly associated with decreased cognitive function at follow-up. Among older adults with low tone hearing loss, absence of slow gait was not associated with decreased cognitive function. Conclusions: Our results indicate the possibility that hearing loss and slow gait synergistically increase the risk of cognitive impairment. The results also suggest that the effect of slow gait on cognition exceeds the effects of hearing loss, indicating the importance of maintaining mobility in late life."}
+{"text": "Vector-borne disease control relies on efficient vector surveillance, mostly carried out using traps whose number and locations are often determined by expert opinion rather than a rigorous quantitative sampling design. In this work we propose a framework for ecological sampling design which in its preliminary stages can take into account environmental conditions obtained from open data  not necessarily designed for ecological analysis. These environmental data are used to delimit the area into ecologically homogeneous strata. By employing Bayesian statistics within a model-based sampling design, the traps are deployed among the strata using a mixture of random and grid locations which allows balancing predictions and model-fitting accuracies. Sample sizes and the effect of ecological strata on sample sizes are estimated from previous mosquito sampling campaigns open data. Notably, we found that a configuration of 30 locations with four households each (120 samples) will have a similar accuracy in the predictions of mosquito abundance as 200 random samples. In addition, we show that random sampling independently from ecological strata, produces biased estimates of the mosquito abundance. Finally, we propose standardizing reporting of sampling designs to allow transparency and repetition/re-use in subsequent sampling campaigns. SamplinGenomic technologies are radically transforming our understanding of vector-borne disease transmission dynamics  due to tAnopheles, Culex and Aedes) a priori Finally, our framework can be applied to other ecological studies. For example, Wang and colleagues  includedIn conclusion, big and open data and research outputs could enhance the power of ecological and genomic studies , facilit"}
+{"text": "In most patients, epilepsy arises due to various initial precipitating injuries during the developmental stages. A major challenge in the neuroscience and neuroclinical fields is understanding how this precipitating injury produces a persistent reorganization of the brain's neural network, thereby transforming the normal brain into epileptogenesis. Identifying the pathological basis of epileptic seizure may lay the foundation for the development of new anti-epileptic drugs, benefiting 60 million people with epilepsy worldwide. This is why our editors chose the theme \u201cThe Developmental Seizure-Induced Hippocampal Mossy Fiber Sprouting: Target for Epilepsy Therapies?\u201dCavarsan et al.]. The development of mossy fiber sprouting may be associated with epilepsy comorbidities rather than with seizure incidence. For example, people with mesial temporal lobe epilepsy (mTLE) and depression show more sprouting than those with only mTLE . A 4-week zinc-deficient diet exacerbated MFS caused by developmental seizures, accompanied by cognitive deficits and reduced seizure thresholds. In contrast, zinc supplementation for 4 weeks significantly reduced MFS and improved the above-mentioned damage-related changes. Mitophagy-mediated zinc homeostasis via mitochondrial activation may be a potential mechanism [ and three reviews. With respect to the demographics of this Research Topic collection, the corresponding authors are from Japan, the United States, Canada, Brazil, South Korea, and China. We hope that the information gathered from this topic will help promote post-epilepsy MFS study and help promote clinical translational medical research to better prevent and treat these injuries in the near future.This Research Topic collects seven articles: four animal studies (including one HN wrote the draft. TK, BN, and CH reviewed the manuscript.BN was employed by the company Expesicor Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Heart failure (HF) with either reduced or preserved ejection fraction is an increasingly prevalent condition. Cardiac imaging plays a central role in trying to identify the underlying cause of the underlying systolic and diastolic dysfunction, as the imaging findings have implications for patient\u2019s management and individualised treatment. The imaging modalities used more frequently in patients with heart failure in clinical routine are echocardiography and cardiac magnetic resonance. Both techniques keep some strengths and weakness due to their spatial and temporal resolution. Notably, several features in the diagnostic algorithm of heart failure with preserved systolic function (HFpEF) may be improved by an integrated approach. This review focuses on the role of each modality in characterising cardiac anatomy, systolic and diastolic function as well as myocardial tissue characterisation in the most common phenotypes of dilated and hypertrophied hearts. Cardiac imaging plays a central role in trying to phenotype the underlying cause of heart failure (HF) which has implications for patient\u2019s management and individualised treatment. Heart failure has recently been classified as heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) ; althougTwo-dimensional transthoracic echocardiography is the first line imaging tool providing information on function, cavity size, relative wall thickness (RWT) and myocardial mass which are used for classification of typical geometric phenotypes\u2014concentric or eccentric hypertrophy and remodelling , 5. MoreCardiac magnetic resonance (CMR) is the gold standard for cardiac anatomical and functional quantification, with unique capabilities of non-invasive tissue characterisation \u20139, complNovel CMR tissue characterisation techniques are called CMR relaxometry (T1 and T2 mapping and extracellular volume fraction (ECV)) which allow a more detailed and quantitative approach to tissue characterisation and 4D-Flow which provides quantitative information on intracavitary flows. Current applications appear particularly useful for diastolic dysfunction detection although they deserve a specific comparison with traditional Doppler and Tissue Doppler analysis in order to confirm the applicability in clinical practice.The most common cardiomyopathic processes underpinning HFpEF (hypertrophied phenotypes) and HFrEF (dilated phenotypes) are discussed below.Left ventricular (LV) hypertrophy (LVH) is a consequence of an underlying genetic or acquired condition and it is accompanied by alterations in cardiac function and haemodynamics. The differential diagnosis between LVH due to physiological adaptation or underlying pathology can be challenging.Non-physiological left ventricular hypertrophy (LVH) regardless to the underlying cause leads to important cardiovascular complications such as atrial fibrillation, diastolic and systolic heart failure , and it Systemic blood pressure elevation is the most common cause of the increment in ventricular mass with a high RWT, which results in concentric or eccentric hypertrophy and concentric remodelling . These sGlobal longitudinal strain (GLS) is an emerging parameter currently available with both methods. GLS is typically reduced in advanced stages of HHD, and it is strongly associated with diastolic dysfunction, it is less dependent on afterload changes and degree of LVH compared with EF, and it has a role in differentiating HHD from other hypertrophic phenotypes , 22. CMRe\u2032 velocity associated with increased E/e\u2032 ratio. Myocardial deformation parameters or patterns of regional strain values such as relative apical sparing or septal apical-base longitudinal strain gradient may have a better differentiating capacity in detecting and differentiating cardiac amyloidosis from other hypertrophic substrates, including HCM, hypertrophy in aortic stenosis or metabolic cardiomyopathies [Infiltrative myocardial disease particularly cardiac amyloidosis can present with very heterogenous hypertrophic phenotypes with wide ranges of wall thicknesses including normal . Granulaopathies . Using dopathies . Howeveropathies . These nopathies .Dilated phenotypes are a heterogenous group characterised by large LV cavities with eccentric remodelling or hypertrophy and impaired contractility. Such phenotypes can be a response to abnormal loading conditions typically in valvular disease or hypertension, severe coronary or congenital disease  or predoReflecting perfusion contraction matching and mismatching, ischaemic heart failure (IHF) consists of a spectrum of pathophysiological states, from early remodelling characterised by wall thinning and dilatation to irreversible late remodelling resulting from myocardial fibrosis and scar . EchocarMutations in over 50 genes have been associated with dilated cardiomyopathy . MultiplThe longitudinal trajectories of LV ejection fraction vary between the two conditions in a very sensitive way. When adequate follow-up is available, repeat echocardiograms in HFpEF can detect a maximum of 2\u20135% fell in EF over 5 years, with a larger fall in the presence of coexisting coronary artery disease , 62. A sMore similarities, than discrepancies, instead, can be detected when looking at diastolic dysfunction in HFpEF vs. HFrEF patients. Diastolic dysfunction contributes to exercise intolerance, both in systolic and primary diastolic dysfunction. In both conditions, in fact, diastolic impairment limits exercise tolerance before resulting in symptoms at rest .E/e\u2032 ratio have been debated. In theory, the occurrence of the above-mentioned picture is typical of a restrictive pattern and along with increased LA volume and increased pulmonary pressure, reflects high filling pressure in either HFrEF and HFpEF [E/e\u2032 ratio in relation to wedge pressure, but a complete measurement of left chambers pressure is lacking [E/e\u2032 ratio and LVEDP in a recent metanalysis appears modest and patients with atrial fibrillation (AF) were excluded [In the absence of mitral stenosis, the two major factors that determine the early diastolic mitral valve pressure gradient and the rate of LV filling are the rate of LV relaxation and the LA pressure at the time of mitral valve opening . With exnd HFpEF . However lacking , 72. Theexcluded . All theexcluded . We thinexcluded . Thus, fDiastolic dysfunction is a dominant feature in many HF patients. LV diastolic dysfunction causes LA dilatation, which can lead to AF . DespiteRecently, in characterising the governing role of the four-chamber (near) constant-volume pump physiology, wherein the atrial and ventricular volumes simultaneously reciprocate throughout the cardiac cycle, CMR has elucidated and characterised LA and LV phasic function, thereby quantifying the conduit contribution to ventricular filling as the integral of net, diastolic, instantaneous difference between synchronised atrial and ventricular volume curves . BecauseUsing single-beat simultaneous left atrial and ventricular full-volume 3D dataset, it was demonstrated that the atrial conduit contribution to ventricular filling has a direct relationship with the degree of underlying ventricular diastolic impairment in HF patients . More reIn addition to LA and LV volume curves, CMR can provide further information on myocardial tissue characteristics. Myocardial fibrosis have been implicated in the pathophysiology of HFpEF by promoting adverse ventricular remodelling, increasing myocardial stiffness, and in turn, causing diastolic dysfunction . DiffuseHeart failure is disease with large phenotypic variations in morphology, function and natural history. Such a heterogeneity in presentation is perhaps a reason why despite different clustering approaches, many interventions in clinical trials have not shown efficacy. Cardiac imaging provides diverse insights, but the ability to distinguish between overlapping phenotypes remains a challenging proposition. The evaluation of diastolic function by echocardiography and CMR with their traditional and novel techniques deserves specific analysis and a comparison with haemodynamic measurement before to be universally accepted. Diastolic function parameters derived by CMR may be applied in routine clinical care and matched with more feasible echo analysis in order to increase our awareness in the HFpEF mechanisms and reduces the current diagnostic gap. New parameters studying both radial and circumferential relaxation together with identification of extracellular collagen volume could facilitate the diagnosis and will play a central role in the identification of underlying pathophysiological mechanisms. Comparative imaging trials should be encouraged in order to discern which technique(s) alone, or in combination, could provide additional prognostic value."}
+{"text": "Imaging plays a central role in evaluating responses to therapy in neuro-oncology patients. The advancing clinical use of immunotherapies has demonstrated that treatment-related inflammatory responses mimic tumor growth via conventional imaging, thus spurring the development of new imaging approaches to adequately distinguish between pseudoprogression and progressive disease. To this end, an increasing number of advanced imaging techniques are being evaluated in preclinical and clinical studies. These novel molecular imaging approaches will serve to complement conventional response assessments during immunotherapy. The goal of these techniques is to provide definitive metrics of tumor response at earlier time points to inform treatment decisions, which has the potential to improve patient outcomes. This review summarizes the available immunotherapy regimens, clinical response criteria, current state-of-the-art imaging approaches, and groundbreaking strategies for future implementation to evaluate the anti-tumor and immune responses to immunotherapy in neuro-oncology applications. Central nervous system (CNS) malignancies are associated with significant morbidity and mortality. In adults, the extremely aggressive glioblastoma (GBM) has the highest incidence of all gliomas and causes more deaths than all other primary CNS malignancies combined. GBM is associated with a median overall survival of less than two years despite surgery and chemo-radiotherapy Cancer immunotherapy strategies aim to stimulate innate or adaptive immune responses against malignant cells. During the last decade, immunotherapy regimens have made remarkable clinical progress in cancer patients, particularly those with recalcitrant solid tumors, by overcoming immune-suppressive signals present in the tumor microenvironment Non-invasive, longitudinal imaging is central to measuring the progression of disease and the efficacy of treatment in neuro-oncology. Historically, response criteria based on conventional imaging through computed tomography (CT) or magnetic resonance imaging (MRI) techniques were used to monitor changes in tumor morphology and responses to tumoricidal chemo-radiotherapy regimens, where shrinkage corresponded with malignant cell death and therapeutic response, while enlargement or appearance of new foci corresponded to therapeutic failure and progressive disease. Studies over the last two decades with emerging biologic or immunotherapy regimens, which are predominantly tumoristatic, have shown the failure of traditional morphologic response criteria and conventional imaging techniques to predict therapeutic outcomes. Inflammatory responses and related effects from immunotherapy are often indistinguishable from progressive disease during conventional imaging, particularly at early stages of treatment An expanding effort is being mounted to address these challenges through modified response criteria and advanced imaging techniques in research and clinical settings Non-invasive imaging in neuro-oncology aims to define widely applicable clinical response criteria for evaluating disease progression and comparing response outcomes across studies. However, distinguishing between tumor response, pseudoprogression, and progressive disease is a significant challenge in neuro-oncology patients treated with immunotherapy. Pseudoresponse is an alternative imaging pattern where the malignancy falsely appears to have responded to a particular therapy regimen The Macdonald criteria, proposed in 1990 The response assessment in neuro-oncology (RANO) criteria were introduced in 2010 There are currently hundreds of concurrent clinical trials investigating various immunotherapy strategies in neuro-oncology. These studies have shown ongoing challenges to monitor therapeutic efficacy due to variations in response patterns observed during immunotherapy as opposed to traditional chemo-radiotherapy. The immunotherapy RANO (iRANO) criteria were published in 2015 to guide response assessment specifically in neuro-oncology patients treated with immunotherapy The RANO and iRANO criteria were developed primarily for patients with GBM, with the understanding that separate criteria would be required to most effectively define responses to therapy in patients with low grade glioma or with metastases from non-CNS malignancies. RANO characterizes low grade glioma tumor burden by FLAIR signal area rather than by contrast enhancing area, but is otherwise homologous to high grade glioma criteria 18F]fluoro-D-glucose [FDG] or radiolabeled amino acids) in clinical care and in trials that monitor outcomes to therapy, with the expectation that PET parameters could be incorporated into future response criteria in neuro-oncology Non-invasive imaging techniques for neuro-oncology can be grouped into the following categories: 1) structural imaging through conventional CT or MRI, 2) physiological imaging through advanced MRI, positron emission tomography (PET), or single photon emission computed tomography (SPECT) and 3) molecular imaging through advanced MRI, PET, or SPECT  based on the expression of biomarkers that correspond to the therapeutic regimen. While biopsy or surgical tissue samples can provide information for tumor progression or biomarker expression, tissue sample analyses are subject to sampling error, may not be representative of spatial-temporal tumor heterogeneity, and are not always available from essential CNS regions or serial time points. Conversely, non-invasive advanced imaging strategies allow global, serial assessment to predict response to treatment or identify biomarker expression 1T MRI and/or extent of 2T hyperintense areas observed on FLAIR MRI sequences are currently standard parameters used to monitor tumor progression in neuro-oncology. However, enlargement of MRI contrast enhancing components and/or enlargement of FLAIR hyperintense areas can be seen both in tumor progression and in inflammatory responses associated with immunotherapy  metric is used in clinical practice and in clinical trials to evaluate response. This parameter is an indication of water diffusivity, which is inversely proportional to cellularity + cell densities at the interface between the brain and secondary brain metastases in a cohort of 26 patients, suggesting that DTI could be a surrogate marker for immune cell response + cells, suggesting that immune cell localization can be detected by low fractional anisotropy values in peritumoral regions. While the effects of immunotherapy were not investigated, these findings support future studies to determine if similar fractional anisotropy patterns occur during immunotherapy in patients with brain metastases or with GBM.i. Diffusion tensor imaging (DTI) MRI adds directionality to DWI and has been used as an anatomic tool to map white matter tracts . DTI is also useful in functional MRI assessment ii. Diffusion kurtosis imaging (DKI) MRI enables quantification of non-random diffusion of water due to structural features present in tissues. This metric is more sensitive to structural abnormalities in gray matter compared to DTI q-space imaging MRI uses Fourier transformation of water diffusivity at high b values to quantify non-Gaussian mean water displacement, thus providing structural information about tissues. Theoretical calculations indicate q-space imaging MRI can detect tissue-restricted water diffusion in white matter with high sensitivity, although the sequences require relatively long acquisition times compared to alternative DWI methods q-space imaging MRI in patients with low-grade glioma iii. iv. Neurite orientation dispersion and density index MRI differentiates water diffusion within linear cell structures (axons), free fluid , and constricted water flow in cells or extracellular spaces PWI MRI monitors time-intensity parameters of fluid flow through tissues of interest to assess vascularity in the tissues. Various PWI parameters have also been used to monitor response in several immunotherapy trials in neuro-oncology patients. Through these imaging techniques, progressive disease is identified by increased fluid flow due to neovascularization to support tumor growth. Early stages of immunotherapy may also show increased fluid movement due to inflammatory responses, subsequent stabilization of vascularity and permeability during continued response to therapy is anticipated to show lower perfusion values relative to progressive disease.i. Dynamic susceptibility-weighted contrast-enhanced (DSC) MRI is the most common PWI technique in clinical practice. DSC MRI monitors contrast agent dynamics during the first pass of the contrast material through the brain to determine relative cerebral blood volume as a surrogate for microvessel density, relative cerebral blood flow, mean transit time of the contrast agent, and time to peak for contrast agent accumulation at a location of interest, which are all useful parameters for tumor grading and assessing response to chemo-radiotherapy. Confounders include artifacts from disruption of the BBB (accumulation of contrast agent) or from signal susceptibility at bone interfaces 1T-weighted sequence acquired before, during, and after the injection of a Gd-based contrast agent and then fit to a two-compartment model to assess the rate of transfer from plasma to extravascular extracellular space (Ktrans), the extravascular extracellular volume (ev), the volume plasma (pv), and the \u201cwash-out\u201d, or the transfer from the extravascular extracellular space to the plasma (*epk) ii. Dynamic contrast-enhanced (DCE) MRI is a iii. Arterial spin label MRI utilizes endogenous signaling of water molecules within moving blood (compared to static parenchyma) before entering the brain to provide contrast for perfusion analyses. Compared to other techniques, arterial spin label MRI provides poor signal due to relaxation and to the low amount of \u201clabeled\u201d blood relative to \u201cunlabeled\u201d blood in the region of interest during the scan. This technique has not yet been widely explored in neuro-oncology patients treated with immunotherapy 18F]-fluoromisonidazole for imaging hypoxia, have favorable properties for imaging because they can access all CNS tissues and are selectively retained in hypoxic malignant regions Advanced imaging of hypoxic or acidic tumor microenvironments, which are commonly observed in GBM, is an alternative strategy for physiological imaging in neuro-oncology. BBB-permeable small compounds, such as the PET agent methionine -L-tyrosine ([18F]FET), and 3,4,-dihydroxy-6-[18F]fluoro-l-phenylalanine ([18F]FDOPA). System L amino acid transporters are overexpressed in malignant glioma and CNS metastases relative to normal cells Amino acid PET imaging is increasingly being recognized for its potential clinical utility in neuro-oncology Antibodies or antibody derivatives that bind to prognostic or therapeutically relevant proteins or receptors overexpressed on tumor cells  or immune cells  are gaining use in oncology applications. Attaching a PET radionuclide or MRI contrast agent to these macromolecules provides a diagnostic companion for \u201cantibody-based\u201d molecular imaging of the target cells or tissues 18F]fluorothymidine, [18F]FLT) have been used in clinical neuro-oncology studies. As normal astrocytes are not significantly proliferative, proliferation PET imaging has shown encouraging results in monitoring GBM progression in pilot human studies PET compounds that indirectly monitor cell proliferation  spectra are the most commonly used MRS parameters, although other nuclei, including 31P or metal ions, have also been measured by MRS and have demonstrated potential utility to monitor malignant growth during pilot studies in neuro-oncology patients 1H MRS, myoinositol, choline, creatine, amino acids, N-acetylaspartate, and lipid/lactate picks are captured. The choline peak is a marker of cell membrane turnover, the creatine peak indicates cellular energy reserves, and N-acetylaspartate is for normal neurons. High tissue concentration of lipid/ lactate or specific amino acids can be measured using MRS. Classically, gliomas show a reverse of the normal ratio of choline to N-acetylaspartate or creatine  by MRS analyses when compared to normal brain parenchyma  due to loss of normal neurons and high cell membrane turnover associated with tumor cell proliferation. The myoinositol peak is a marker of tissue inflammation N-acetylaspartate would remain high due to continued malignant cell proliferation.MRS techniques evaluate characteristic signals in the magnetic spectrum of a tissue to determine the relative amounts of specific molecules within the tissue. Similar to the boom in immunotherapy trials for non-CNS malignancies, a growing number of pilot studies and phase I, II, or III clinical trials have tested the efficacy of various types of immunotherapy to impact patient survival in neuro-oncology. The majority of these studies are beyond the scope of this review and will not be discussed. The following sections briefly discuss four main classes of immunotherapy regimens that are under investigation in neuro-oncology and how advanced physiological or molecular imaging techniques have contributed to assessing or predicting patient responses to these treatment regimens in human patients: 1) vaccine immunotherapy, 2) cell-based immunotherapy, 3) checkpoint inhibitor immunotherapy, and 4) virus immunotherapy  T-cells (and their variants), lymphokine-activated killer cells, T-cell receptor-transduced T-cells, and activated tumor infiltrating lymphocytes, among others In cell-based immunotherapy strategies Figure B, precurAdvanced imaging has also been used to monitor tumor responses during cell-based immunotherapy Checkpoint inhibitor immunotherapies Figure C were deA study of 10 patients with recurrent GBM treated with anti-PD-1 and/or anti-CTLA-4 checkpoint inhibitor immunotherapy used intermediate ADC DWI volume changes within FLAIR regions of relatively high cellularity to correlate imaging parameters with response to immunotherapy Figure  105. The18F]FET  at initial assessment. Only one of the five patients had both pre- and post-immunotherapy assessment by [18F]FLT, so no definitive conclusions could be made regarding changes in PET signal and therapeutic outcome. This patient was evaluated by PET with [18F]FLT upon entrance to the study and one month after treatment with nivolumab and ipilimumab. The second PET/MRI scan showed a mixed partial response in the five evaluable CNS lesions, where three lesions decreased in size and showed lower uptake of [18F]FLT relative to the baseline image. New, small lesions (less than 1 cm diameter) were also observed on the post-immunotherapy MRI scan, although these lesions did not show appreciable accumulation of [18F]FLT. The patient was switched to an alternative therapy and not further evaluated by PET in the reported study. The results from this study warrant future work to determine correlations between [18F]FLT signals in the tumor and outcomes to immunotherapy in neuro-oncology patients.A pilot study used fluoro-3-(hydroxymethyl)butyl]guanine. A recent publication demonstrated the results of this strategy in six additional patients with recurrent GBM butyl]guanine increased in all brain lesions after injection of the transformed CAR cells relative to the pre-treatment PET scan with the tracer. The pattern of the increase in the PET signal intensity and volume of distribution varied among patients, thus precluding the definitive assessment of CAR cell trafficking to the tumors in the small cohort of patients. These studies highlight the importance of distinguishing between non-specific pooling of PET imaging agents and specific immune cell trafficking within GBM tumors to assess immunotherapeutic efficacy through transgene PET imaging.b. Transgene/reporter gene studies with immune cells. Imaging of transgene expression through a PET reporter has been used in clinical research to monitor immune cell trafficking and response to therapy. An initial case report published in 2009 18F]fluoro-9-\u03b2-D-arabinofuranosyl-adenine and imaged by PET prior to and following treatment with a dendritic cell vaccine in combination with pembrolizumab or bevacizumab  correlate with clinical outcomes during therapy. Future trials incorporating larger cohorts of patients and their long-term outcomes to therapy will be needed to discern the most reliable metrics for monitoring responses to immunotherapy regimens.Besides the approaches discussed above, additional imaging agents and analytical techniques are being developed to define prognostic parameters for immunotherapy responses Expansions in advanced imaging have catalyzed the emergence of research and clinical strategies defining patterns of response to immunotherapy for neuro-oncology patients. However, significant obstacles must be overcome prior to routine clinical adoption of experimental imaging strategies. As the incidence of GBM is low and patients with secondary CNS metastases often have confounding clinical factors , a main hurdle has been implementing prospective clinical trials with sufficient numbers of neuro-oncology patients to demonstrate statistically reliable correlates between imaging parameters and therapeutic outcomes during immunotherapy. Most patients in these trials have received multiple, varying courses of therapy before enrollment in immunotherapy trials, further complicating the assignment of defined imaging response patterns to a specific therapeutic regimen. An additional challenge is in implementing standardized terminology and response criteria across neuro-oncology studies, as a recent report found that 63% of neuro-oncology publications after 2010 did not use the RANO criteria 18F]-FDG are available from the European Organization for Research and Treatment of Cancer (EORTC) for glioma and brain metastases, and from PET Response Criteria in Solid Tumors (PERCIST) guidelines for brain metastases. While recommended guidelines to compare multi-modality imaging parameters have not yet been established, integrating imaging parameters from various modalities has been shown in previous studies to increase diagnostic specificity and sensitivity relative to separate, single-modality imaging in neuro-oncology patients Most advanced imaging approaches to evaluate response to immunotherapy are still in initial, exploratory stages in neuro-oncology research. For the field to make rapid, meaningful advancement, it will be important to reach consensus across studies and institutions regarding acquisition parameters and reported findings for a particular imaging technique Imaging scientists should work closely with referring physicians, neuro-oncologists, and the clinical research team to best integrate advanced imaging into trial design and patient care. Considering the limited patient population and the poor prognosis associated with primary or metastatic CNS malignancies, simultaneously enrolling the same patients into both immunotherapy and imaging trials would enable streamlined evaluation of non-invasive imaging methods and responses to immunotherapy. Incorporating advanced imaging sessions into large cohorts of patients in phase II or III immunotherapy trials would aid accumulation of sufficient patient data to yield statistically meaningful results for both therapeutic outcome and matched imaging parameters.As addressed above, distinguishing tumor progression from inflammation and other treatment-related effects is a significant clinical challenge in neuro-oncology. Utilizing multi-modality imaging to differentiate between these separate biological processes is an attractive strategy to address this challenge. One way to potentially identify responses to immunotherapy regimens is to specifically monitor trafficking and activity of effector immune cells  across serial imaging time points, and to correlate these changes to a biological outcome  While much progress has been made in the fields of advanced molecular imaging and immunotherapy during the last decade, further developments are needed to determine how they can best be merged to improve the outcomes for neuro-oncology patients. No single agent or imaging technique has yet been clinically validated as a satisfactory prognostic indicator for response to immunotherapy regimens. The clinical and imaging communities eagerly await emerging results from ongoing neuro-oncology clinical trials that utilize investigational immunotherapy regimens, novel imaging strategies, and improved response criteria. As these forthcoming data become available, it is anticipated that prognostic patterns will be realized and incorporated into future practice to improve the outcomes of neuro-oncology patients."}
+{"text": "Objective. To report a rare presentation of solitary retinal capillary hemangioma manifesting with combined retinal detachment as initial presentation and its successful management.Methods. A 35-year-old healthy Indian male presented with combined retinal detachment associated with solitary retinal capillary hemangioma as initial presentation; a clinical entity still not reported in literature. Patient was managed with pars plana vitrectomy combined with retinectomy, endolaser, & silicon oil tamponade with good visual & anatomical recovery.Results. Patient had good clinical outcome with final best-corrected visual acuity (BCVA) of 6/ 24 and well attached retina at last follow-up.Conclusion. Solitary retinal capillary hemangiomas can rarely present with advanced vitreo-retinal complications like combined retinal detachment as initial manifestation that can be effectively managed with skilled & appropriate surgical intervention.  Retinal hemangiomas are mainly asymptomatic but can present with vision loss that occurs due to exudation at the macular region or secondary tractional retinal detachment, which occurs due to development of gliotic tissue involving the macula [4]. Different treatment modalities undertaken for treatment of retinal hemangiomas include laser photocoagulation, cryotherapy, photodynamic therapy (PDT), anti-VEGF, and vitreo-retinal surgery depending on clinical presentation with variable outcome in these patients [5-9]. Retinal capillary hemangiomas are benign vascular tumors of the retina either occurring as isolated tumors or in association with tumors in other systems, especially central nervous system hemangioblastomas and renal cell carcinomas as part of von Hippel-Lindau (VHL) disease [We report a case of solitary retinal hemangioma that manifested with combined retinal detachment, a rare presenting feature of retinal hemangioma, and its successful management. To the best of our knowledge, this rare presentation has not been reported in published literature until now.Fig. 1) and examination of the left eye fundus was normal. We initially considered the differential diagnosis of retinal hemangioma and vasoproliferative tumors of the retina (VPRT). Fundus fluorescein angiography confirmed the diagnosis of retinal capillary hemangioma, showing typical feeder vessel with early hyperfluorescence of vascular mass and draining vein  in the right eye, with no evidence of hemangioma in the left eye.A 35-year-old, serving military soldier presented with diminution of vision in his right eye for the past 3 months, which has rapidly worsened over the last month. His systemic parameters were within normal limits. Ocular examination revealed a best-corrected visual acuity (BCVA) of hand movement close to face (HMCF) with accurate projection of rays in the right eye and 6/ 6 in the left eye. Examination of the anterior segment was normal in both eyes. Fundus examination in the right eye revealed total retinal detachment with about 6 Disc Diameter (DD) size reddish orange mass with two large stretch breaks stretching in the inferotemporal quadrant with surrounding fibrous tractions , thus showing a successful outcome in unusual presentation. Since the patient had already reached a stage in which the treatment modalities like laser photocoagulation, cryotherapy, photodynamic therapy (PDT), anti-VEGF, did not have any role due to total retinal detachment, he underwent combined surgery with sclera band buckle (240 size) with pars plana vitrectomy and endoresection of tumor with high viscosity silicon oil tamponade. There were no intra-operative complications with stable course post surgery and attached retina. Silicon oil was removed 5 months after the initial surgery, as soon as the emulsification was noted. At 9 months post surgery, BCVA in right eye had improved to 6/ 24 with attached retina, no evidence of remnant of tumor/ reproliferation and healthy well laser retinectomy site in temporal periphery  with pars plana vitrectomy, endoresection of tumor with high viscosity silicon oil tamponade. Patient had stable post-operative period with good visual recovery. He underwent silicon oil removal 5 months post initial surgery with good anatomical and visual outcome and no evidence of tumor proliferation/ redetachment at last follow-up, which was 9 months post vitrectomy.Thus, combined retinal detachment can be an unusual or atypical presentation of rare etiology like retinal capillary hemangiomas but appropriate and skilled vitreo-retinal surgical intervention can lead to successful visual and anatomical outcomes in these patients. Availability of Data & materialFreely available on request.Competing InterestNil.Conflict of InterestNo conflict of interest was declared by the authors.Financial DisclosureThe authors declared that this study received no financial support.AcknowledgementNil."}
+{"text": "Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p = 0.002) but not in the squamous carcinoma subtype (p = 0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis  in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 73 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival ( The World Health Organization (WHO) currently estimates that 1.69 million deaths per year worldwide are due to lung cancer, far more than any other cancer type. Non-small cell lung cancer (NSCLC), which includes the two major subtypes of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), accounts for about 85% of lung cancers. In terms of the biology of lung cancer, significant advances have been made ) contains correlation analyses based on mRNA expression levels with respect to clinical outcome for 17 major cancer types and almost 8000 cancer patients [Kaplan-Meier survival curves (mRNA expression): Overall survival (OS) was derived both from TCGA array data of lung cancer and from pan-cancer RNA-seq data. All analyses were performed online  analysis tool [http://maplab.imppc.org/wanderer/) [Methylation analysis: We used an online (sis tool  to gain nderer/)  to analyIn conclusion we have found that major changes in some specific connexin mRNAs often occur in lung tumours but in general this do not correlate well in relation to changes in promoter methylation. Connexin mRNA expression can however correlate with both good and poor prognosis, which depends on the connexin isoform analysed and the histological subtype (LUAD versus LUSC). In addition to changes in mRNA expression, it is clear that protein location and functionality is critical. In this study, we identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival. The prognostic value was highly significant in LUAD, and larger cohorts will be needed to definitively assess the correlation in LUSC. This study highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. It also proposes that modulation of Cx43 trafficking may be a useful therapeutic strategy."}
+{"text": "Epidemiology & Infection while also discussing advances in emerging infectious diseases.This invited editorial introduces a special issue of  World Health Organization (WHO) recently enumerated 10 threats to global health for 2019, notably emphasising Ebola and other high-threat emerging pathogens as growing priorities [annualised financial impact of a global pandemic has been estimated to be as high as US$80 billion, severely burdening already constrained national budgets and healthcare systems [The  systems . Outbrea systems . These fEpidemiology & Infection highlights new insights into many of the emerging infectious diseases mentioned in the WHO report, as well as re-emerging diseases that are gaining global prominence. They address a variety of diagnostic, therapeutic and epidemiological advances in outbreak preparedness. Several papers review data on priority pathogens with a focus on resource-limited settings. For example, Sikkema et al. present a systematic review on Middle East Respiratory Syndrome Coronavirus with the aim of characterising the distribution and spread of infection in dromedary camels [et al. review the recent Nipah virus outbreaks in Bangladesh and India, shedding light on transmission patterns of this emerging pathogen while also highlighting the importance of ongoing surveillance [et al. discusses genetic variations among avian influenza viruses circulating in Bangladesh and the impact of accumulating mutations noted in poultry. Lessons learned from the WHO response to the recent 2017 pneumonic plague outbreak in Madagascar are presented by Heitzinger et al., who highlight specifically the challenges of implementing rapid infection prevention and control measures in epidemic settings [This edition of y camels . Aditi eeillance . A reviesettings . These, Outbreaks of re-emerging infectious diseases in high-income countries are also discussed, often implicating products imported across borders as well as trans-national spread due to as yet unknown causes. Other papers discuss zoonotic and vector-borne disease epidemiology and present opportunities for predictive modelling. Several diagnostic advances are also mentioned, elucidating changing epidemiological trends in recently recognised re-emerging pathogens.Epidemiology & Infection represents a diverse overview of current concerns surrounding emerging infectious diseases globally. All highlight the importance of supporting ongoing surveillance efforts as the cornerstone of disease prevention. Early recognition of an outbreak allows control measures to be initiated in a timely way that can shift the epidemic curve, reducing its impact and possibly its geographic spread. Enhanced surveillance measures with an emphasis on innovation, transparency and incorporation of the One Health model are critical to epidemic preparedness measures in the future. It is also crucial to encourage research during outbreaks through rapid data sharing to facilitate rapid response efforts, as is promoted through organisations such as the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) [This issue of (ISARIC) . Vaccina(ISARIC) . These e(ISARIC) . Emergin"}
+{"text": "Writing and publication in an academic setting is vital for advancing careers and knowledge. Attempting to increase scholarly productivity, our division created a physician-writing group, led by a prolific humanities expert to hone our writing skills. An unexpected outcome was realized. Using a mix of reflective, intent-driven, impromptu writing exercises and group sharing we discovered new opportunities for personal and professional growth through empathy. During these 1-hour sessions, several organic themes emerged. These included gaining greater inner-personal insight and recognizing inter-personal similarities in career paths and provider benevolence as motivation to continue when experiencing emotional fatigue and burnout. Ultimately, while honing our professional writing skills we also stimulated compassion to ourselves and our colleagues, opening new sources of resilience. We plan to continue these sessions exploring the potential multifaceted impacts on professional/academic growth these sorts of writing groups can have for geriatric and palliative medicine professionals and other healthcare providers."}
+{"text": "Mesothelioma is an incurable cancer caused by exposure to asbestos. Several countries have witnessed a growth in incidence of epidemic proportions over the last two decades, and approved treatment is limited to front-line chemotherapy . The recCOMMAND was negative, despite hopes of recapitulating preclinically observed synthetic lethality in the context of NF2 mutation , as wellSince the initiation of the COMMAND trial, comprehensive genomic studies have revealed extensive genetic disruption of hippo signaling in mesothelioma involving multiple components of this tumor suppressor pathway , 8. In tA phase II window of opportunity trial involving defactinib monotherapy in patients prior to surgical resection demonstrated a promising 80% disease control and 13% response rate . InteresAfter the initiation of the COMMAND trial, another important insight into FAK biology came to light. FAK plays a crucial role in regulating the tumour microenvironment via augmentation of Treg abundance . Inhibithippo defective biomarkers, or directly antagonizing YAP/TEAD transcription may provide next-generation approaches to phenocopying this important tumor suppressor pathway in mesothelioma.In summary, targeting the Hippo pathway remains a potentially promising strategy for controlling mesothelioma. Widening the net to capture more hippo deficient phenotypes through the use of comprehensive"}
+{"text": "We recently identified pathogenic soluble aggregated tau (tau oligomers) in the cerebral microvasculature of human patients with tauopathies, including Alzheimer\u2019s disease (AD). The functional consequences of cerebrovascular tau accumulation are not yet understood. The aim of the present study was to determine whether pathogenic tau accumulation leads to cerebrovascular dysfunction. To this end, we measured neurovascular coupling (NVC), a highly regulated process that synchronizes cerebral blood flow to neuronal activation, using the PS19(P301S) mouse model of tauopathy. The change in cerebral blood flow evoked by whisker stimulation was measured using Laser Doppler flowmetry in PS19 and wildtype control mice and the functional contribution of neuronal and endothelial nitric oxide synthase  was calculated. Vascular reactivity was assessed using topical acetylcholine to evoke endothelium-dependent vasodilation. To assess the direct impact of pathogenic tau on cell-specific NOS function, we treated N2a neuroblastoma cells or mouse brain vascular endothelial cells with soluble tau aggregates and measured activity of nNOS and eNOS. Our data indicate isolated overexpression of mutant tau impairs NVC responses, and this deficit is mediated by a reduction in nNOS activity in vivo. Further, our studies suggest tauopathy also impairs endothelium-dependent vasoreactivity in the cortex. Additionally, soluble tau aggregates inhibit the phosphorylation of NOS in primary cultured cells. Therefore, inhibition of NOS phosphorylation by pathogenic soluble tau aggregates may underlie cerebrovascular dysfunction in tauopathies. Thus, therapeutic modulation of pathogenic tau may mitigate brain microvascular deficits, which occur prior to clinical onset in Alzheimer\u2019s disease and potentially other tauopathies."}
+{"text": "Patient portals are popular health care tools. Few portals target caregiving families and few use predictive modeling to assist caregiving families make decisions about elder care options. Our goal is to incorporate the algorithms being developed for predicting tipping points in elder care to assist caregiving families visualize changes in older adults\u2019 activity patterns, understand possible implications for continued in-home safety, and access educational information and consultation. While many patients use portals, use is restricted among persons in racial and ethnic minorities, with lower educational levels and poorer health literacy, and with fewer economic resources. The following strategies help us address these issues. Our portal archives data from affordable, wearable technology. Portal access uses similarly technology. Our educational materials use techniques known to be appealing and effective with older individuals in unique groups, e.g., results displays; fotonovelas. Input from community members/users helps maintain sensitivity to cultural appropriateness and health literacy."}
+{"text": "Culture change represents an organizational transformational process to become person-centered, through staff and resident empowerment. Culture change initiatives have been associated with fewer health-related deficiency citations and better psychosocial outcomes. Knowledge management, defined as the process of creating or locating knowledge, and managing the dissemination of knowledge within and between organizations, has been shown to be associated with the adoption of innovations such as culture change initiatives. This study examines the relationship between knowledge management activities of high Medicaid census (70% or higher) nursing homes (NHs) and the adoption of culture change initiatives. This study used facility survey data from approximately 324 nursing home administrators (30% response rate) from 2017- 2018, merged with data from LTCFocus, Area Health Resource File, and Medicare Cost Reports. Binary logistic regression models revealed that the probability of adopting a culture change initiative was 0.12 higher for facilities reporting a one-unit higher level of knowledge management activities. Additional interaction analysis revealed that knowledge management activities were associated with a greater likelihood of adopting a culture change initiative for NHs where the director had been in his/her position fewer years. Similarly, higher levels of overall knowledge management activities were significantly associated with greater adoption of culture change initiatives at intermediate levels of nurse retention. Results suggest that knowledge management activities may help high Medicaid NHs acquire and mobilize informational resources in ways that can support the adoption of patient-centered initiatives. These activities may be particularly effective in nursing homes with leadership and nursing staff instability."}
+{"text": "Circulating microRNAs offer attractive potential as epigenetic disease biomarkers by virtue of their biological stability and ready accessibility in liquid biopsies. Numerous clinical cohort studies have revealed unique microRNA profiles in different disease settings, suggesting utility as markers with diagnostic and prognostic applications. Given the complex network of microRNA functions in modulating gene expression and post-transcriptional modifications, the circulating microRNA landscape in disease may reflect pathophysiological status, providing valuable information for delineating distinct subtypes and/or stages of complex diseases. Heart failure (HF) is an increasingly significant global health challenge, imposing major economic liability and health care burden due to high hospitalization, morbidity, and mortality rates. Although HF is defined as a syndrome characterized by symptoms and findings on physical examination, it may be further differentiated based on left ventricular ejection fraction (LVEF) and categorized as HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The presenting clinical syndromes in HFpEF and HFrEF are similar but mortality differs, being somewhat lower in HFpEF than in HFrEF. However, while HFrEF is responsive to an array of therapies, none has been shown to improve survival in HFpEF. Herein, we review recent HF cohort studies focusing on the distinct microRNA profiles associated with HF subtypes to reveal new insights to underlying mechanisms and explore the possibility of exploiting these differences for diagnostic/prognostic applications.  Heart failure (HF) is a complex clinical syndrome arising from deficient cardiac output that is unable to meet the metabolic needs of the organs and tissues in the body. HF evolves from systolic and/or diastolic contractile dysfunction caused by progressive structural and functional alterations of the heart . MultiplThe overall prevalence of HF is about 1\u20132% worldwide with an estimated 37.7 million people affected globally ,8. In thSymptoms of HF include breathlessness, cough, interrupted sleep, exercise intolerance, edema, and fatigue. However, the nonspecificity of these symptoms can confound the diagnosis of HF as they also occur in noncardiac conditions including renal impairment and chronic obstructive pulmonary disease. More specific signs of HF include elevated jugular venous pressure and the displacement of the apical cardiac impulse. However, these signs may be hard to detect and difficult to interpret in patients with comorbidities such as obesity or airway diseases . Thus, tLeft ventricular ejection fraction (LVEF) is a widely adopted phenotypic parameter to define HF. HF with reduced ejection fraction  and HF with preserved ejection fraction  are two major HF subtypes that differ in terms of pathophysiology and etiology, as well as treatment responses . The twoThe poor prognosis in HF, despite advances in treatment, mandates efforts to enhance management and improve patient outcomes. HF is underpinned by multiple risk factors, comorbidities, and pre-existing conditions which have an adverse impact on cardiac structure and function. The first line of HF drugs were directed towards improving quality of life by attenuating symptoms and slowing down disease progression, as well as reducing morbidity and mortality in HFrEF. However, to date, no HF therapeutics have consistently and permanently halted progression of structural and functional cardiac deterioration. Drugs targeting the renin-angiotensin-aldosterone system (RAAS) including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), \u03b2-adrenergic receptor blockers, and mineralocorticoid receptor antagonists (MRAs) have been shown to ameliorate the symptoms of HF and improve outcomes including HF re-admissions and mortality ,35. ReceTo facilitate the development of next generation HF therapeutics, key knowledge gaps in the underlying mechanisms and pathophysiology of HF must be addressed. The current lack of circulating biomarkers that could provide definitive diagnosis, prognosis, risk stratification, and subtype categorization of HF remains an ongoing challenge. The detailed molecular mechanisms underlying HF pathogenesis and how pathological pathways differ between subtypes and their translation to phenotype-specific therapeutic strategies remain elusive. Unravelling the relationship between biomarkers and HF pathogenesis may shed the light for developing precision medicine for HF in the near future. MicroRNAs comprise a cluster of noncoding RNA species that are known to play important roles in modulating the expression of most protein coding genes at the post-transcriptional level . MicroRNWith increasing understanding of the characteristic differences between HFrEF and HFpEF, there has been active interest in finding signature microRNA profiles to facilitate HF subtype categorization. Ellis et al. pioneered early work on HFrEF and HFpEF microRNA profiling and reported a set of differentially expressed microRNAs in a dyspnea cohort comprising 16 HFrEF and 16 HFpEF with high NT-proBNP plasma concentrations . HoweverIt is noteworthy that each study reported a unique set of differentially dysregulated microRNAs and no overlap of microRNAs was observed across all four cohort studies. This discrepancy is not totally unexpected and may be attributed to the heterogenous comorbidities of HF and sample size of cohorts, as well as the different criteria used for patient enrollment. Profiling reported in the five studies highlighted in http://www.microrna.gr/miRPathv3), an online pathway analysis software [In addition to potential diagnostic applications, the discovery of microRNA clusters that are differentially expressed in HFrEF and HFpEF patients provides an approach to delineate the different pathobiological pathways underlying HFrEF and HFrEF. software . Based osoftware . The sigChanges in plasma concentrations of free fatty acids across three different HF subtypes have been reported previously . ResultsInterestingly, predicted targets analysis (microT-CDs) revealed that transforming growth factor beta (TGF-\u03b2) signaling and Forkhead box O (FoxO) transcription factors signaling are among the top pathways predicted to be affected by the eight HF signature microRNAs. TGF-\u03b2 signaling is known to play pivotal roles in the pathogenesis of cardiac remodeling and fibrosis. The putative roles of microRNAs in TGF-\u03b2 signaling have been reported and tested in various diseased models. For instances, miR-101a was shown to target the TGF-\u03b21 receptor, subsequently attenuating fibrogenesis and improving cardiac function in a rodent transverse aortic constriction (TAC) model . FoxOs aThe discovery of microRNAs and their roles in post-transcriptional modification have led to further advances in understanding the complexity of gene regulation. However, translating findings of distinct circulating microRNA compositions and their pathophysiological implications in different disease states to decipher underlying mechanisms with a view towards therapeutic exploitation remains challenging. MicroRNA-3\u2019UTR interactions do not require perfect Watson\u2013Crick pairing and this significantly increases the functional flexibility of microRNA. It is now known that one microRNA can have multiple 3\u2019UTR targets, and one 3\u2019UTR can be recognized by more than one microRNA so that biological homeostasis could be tightly controlled in the normal state while dynamic biochemical responses could also be triggered upon stimulation. Although it has been established that microRNAs play important roles in post-transcriptional modification, scientists have yet to fully understand the operating rhythm of microRNAs. The traditional approach of deciphering the regulatory effect of one microRNA on one gene is manifestly inadequate in bringing together the influence of the microRNA landscape on gene expression regulatory networks. Dysregulated microRNAs can be viewed as functional clusters that variously contribute to HF pathogenesis. This concept was supported by our previous study where data from microRNA/3\u2019UTR binding and gain-of-function assays demonstrated putative regulatory effects of HF-related microRNAs upon key molecules involved in neurohormonal signaling . Given the potential application of signature microRNAs in HF diagnosis, further independent verification of our findings by other reputable investigators is needed. Furthermore, the diagnostic performance of microRNAs may require further refinement according to comorbidities and clinical background. Further studies to clarify the association between HF-related microRNAs and pathogenesis will be essential to translate these epigenetic alterations into therapeutic applications. It is conceivable that linear algorithms will not be adequate to describe the interaction networks between transactivation and post-transcriptional regulation of microRNAs with their target genes. Hence, large scale international multi-disciplinary collaborative research integrating expertise in biomedicine, clinical practice, bioinformatics, artificial intelligence, and machine learning will be pivotal to advancing progress in HF research."}
+{"text": "The human hair follicle is a neuroendocrine mini-organ that can be used to study aging processes in vitro. Neurotrophins maintain homeostasis in hair biology via the Trk-family of receptors. TrkA, the high affinity receptor for nerve growth factor (NGF), is expressed in hair follicle melanocytes and keratinocytes, where it regulates proliferation, differentiation and apoptosis and may thereby play a role in hair pigmentation and growth. We investigated TrkA expression during the human hair cycle and the effects of a selective high affinity TrkA agonist, Gambogic Amide, on hair pigmentation and hair growth in human hair follicles in vitro. In human scalp skin, TrkA expression was strongest in proliferating melanocytes re-establishing the pigmentary unit in the hair bulb during the early hair growth phase, anagen. During high anagen and in the de-composing pigmentary-unit of the regression phase, catagen, bulb-melanocytes lost TrkA expression and only undifferentiated outer root sheath melanocytes maintained it. In cultured human anagen hair follicles, Gambogic Amide was able to prevent gradual pigment loss, while it stimulated hair shaft elongation. This was achieved by increased melanocyte activation, migration and dendricity, highlighted by distinct c-KIT-expression in melanocyte sub-populations. Our results suggest that Gambogic Amide can maintain hair follicle pigmentation by acting on undifferentiated melanocytes residing in the outer root sheath and making them migrate to establish the pigmentary-unit. This suggests that the selective TrkA agonist Gambogic Amide acts as an anti-hair greying and hair growth promoting molecule in vitro. In today\u2019s society healthy aging is crucial for well-being. One of the clinically visible signs of aging is greying hair . This isHair follicle pigmentation involves exact temporal and spatial regulation of the cells that produce the pigment, the melanocytes. Melanocyte turnover within the hair follicle, meaning renewal , maturation (differentiation) and removal (senescence and apoptosis) is highly regulated to prevent melanoma development and spontaneously occurring primary hair follicle melanoma is in fact rarely reported . To prevTo identify safe intervention strategies, it is therefore necessary to monitor melanocyte dynamics during hair growth. Hair shaft pigmentation, also called follicular melanogenesis, in both mice and humans is tightly linked to the growth phase (anagen) of the hair cycle \u20138, whichIdeally, the mechanisms allowing hair pigmentation to be reestablished with each hair cycle are in a state of homeostasis. This homeostasis works optimally for the first 10\u201315 hair follicle growth cycles (until about 40 years of age). Thereafter, the mechanisms that maintain pigmentation seem to exhaust and the regeneration potential of the pigmentary-unit diminishes, leading to grey or white hair .An agent stimulating hair follicle pigmentation should improve homeostasis but not interfere with it. One of the main routes studied to improve hair pigmentation focusses on melanin synthesis in hair follicle melanocytes and the gradual loss of factors maintaining it, such as alpha-melanocytes stimulating hormone  . In addiSkin has documented neuroendocrine properties , 21, andGarcinia hanburryi tree in South-eastern Asia [The question therefor arises, if expression and manipulation of TrkA plays a role in hair follicle pigmentation homeostasis . Gambogiern Asia , was ideern Asia . In addiern Asia . Based oTissue collection was essentially done as previously described . In brieAnagen VI HF were cultured for seven days in supplemented Williams\u2019 E medium  as published before , 37. On 8-\u03bcm-thick longitudinal cryosections through full thickness human scalp skin and cultured HF were processed and analyzed using a digital image analysis system  as previously described . For NKIStatistical analysis was performed as previously described . Means wNative human scalp skin was investigated for TrkA expression of distinct sub-populations of hair follicle melanocytes during the hair cycle and showed a staining of keratinocytes in the outer root sheath throughout. In addition, in early anagen hair follicles round undifferentiated melanocytes in the re-establishing pigmentary-unit strongly expressed TrkA . In highNext the capacity of the TrkA agonist nerve growth factor (NGF) to modulate pigmentation in cultured human hair follicles was tested. 5 ng/ml NGF maintained pigmentation in cultured human anagen hair follicles  over theBased on the findings in Figs To analyze target melanocyte subpopulations of Gambogic Amide we investigated c-KIT-expression of hair follicle melanocytes in response to Gambogic Amide in various compartments of the hair bulb after 7 days of culture . While cFurthermore, we observed a slight increase in melanocyte dendricity in response to Gambogic Amide (50\u20131000 nM) . No signTo control, if these effects occurred within the anagen phase or were associated with premature catagen development in cultured anagen hair follicles, hair follicles exposed to Gambogic Amide were subjected to hair cycle progression analysis. By histomorphometry, Gambogic Amide at all tested concentrations did not significantly alter hair cycle progression compared to control samples . In factConcerning melanocyte turnover and cellular homeostasis, we found here an increased p16 expression at all tested concentrations with a peak at 500 nM of Gambogic Amide in melanocytes of all follicular compartments . HoweverFinally, growth of hair follicles exposed to Gambogic Amide was analyzed and revealed that in addition to hair pigmentation maintenance, Gambogic Amide was able to increase hair shaft elongation at all concentrations tested . This fuIn this study we investigated the expression of TrkA in human hair follicles and studied the effects of a selective, plant derived TrkA agonist Gambogic Amide on the pigmentation of hair follicles in vitro to investigate its potential as an anti-aging ointment. We found TrkA expression during the human hair cycle in distinct melanocyte subpopulations suggestive of its expression primarily in undifferentiated melanocytes and potentially melanoblasts Figs  and 2. AIn the human scalp skin, we found that TrkA was strongly expressed in hair follicle melanocytes in the outer root sheath and in the developing pigmentary-unit at the beginning of anagen as well as in the outer root sheath of fully developed anagen hair follicles. This is in line with previous findings showing that TrkA is mainly expressed in melanocytes and keratinocytes in anagen hair follicles . HoweverIn addition, TrkA-positive melanocytes were round-shaped and expressed the melanocyte migration marker c-KIT. In mice, c-KIT was previously shown to be predominantly expressed in migrating melanoblasts in the developing hair follicle  and it iIn line with c-KIT being also a melanocyte differentiation marker, the melanocytes in hair follicle treated with Gambogic Amide also displayed slightly enhanced dendricity. Since melanocytes are derived from the neural crest it resembled the capability of Gambogic Amide to induce neurite outgrowth in various neuronal cell lines , 34. In Looking at hair follicle pigmentation we found that Gambogic Amide showed a similar activity as nerve growth factor NGF, which is the natural high affinity agonist of TrkA. In contrast to NGF however, we found that Gambogic Amide showed pro-pigmenting activity dose-dependently at higher concentrations, whereas NGF showed a maximum at 5 ng/ml. High concentrations of NGF like 50 ng/ml decreased hair follicle pigmentation in vitro . NotablyWe used here the Philpott model of hair follicles which are truncated below the bulge region. This means Gambogic Amide acted on undifferentiated melanoblasts released from the bulge already, and as such was able to sustain pigmentation in vitro more efficiently  without In summary, we provide evidence that it is possible to halt the hair aging process represented by hair greying in vitro with Gambogic amide. An important mechanism how Gambogic Amide stimulates pigmentation in hair follicle melanocytes is via induction of c-KIT expression . GambogiThe potential of Gambogic Amide or other molecules activating TrkA signaling in human hair follicle as a remedy to reverse signs of aging hair like greying is further corroborated by the finding that Gambogic Amide is able to induce hair follicle growth in vitro . In addiThe notion that Gambogic Amide recruits melanocytes of the outer root sheath while the hair continues or even improves its growth activity is evidenced by the maintenance of anagen morphology and increased hair shaft elongation. This is intriguing, as it was shown previously that without treatment, in vitro pigmentation correlated negatively with hair shaft elongation in cultured human anagen hair follicles and vice-versa and that this links with up-regulated gene-expression of keratins involved in active hair growth , 51. OurIn conclusion, we provide evidence that the TrkA agonist Gambogic Amide is a promising molecule able to protect hair follicle pigmentation in vitro by mobilizing TrkA and c-KIT-positive hair follicle melanocytes. Furthermore, Gambogic Amide has a growth promoting activity on hair follicles in vitro, further highlighting its potential as a hair health or hair anti-aging active."}
+{"text": "Pulmonary arteriovenous malformations (PAVM) are rare pulmonary vascular anomalies and hemothorax as a presenting feature of PAVM is a very rare occurrence.A 45-year old woman presented with chest pain and breathlessness. A chest x-ray showed left-sided pleural effusion. An emergency MSCT scan with contrast showed no signs of pulmonary embolism but instead a probable AV malformation was shown. Diagnostic thoracocentesis revealed hemorrhagic exudate with negative cytology and microbiology findings. Thoracic drainage was performed resulting with complete regression of hemothorax. Three months later, patient was treated with transcatheter embolization of PAVM with good clinical outcome.We have shown that management of PAVM related hemothorax initially by thoracic drainage followed by later on performed catheter embolization of the PAVM could lead to a successful outcome. Pulmonary arteriovenous malformations (PAVMs) are abnormal direct communications between pulmonary arteries and veins . They arA non-smoker 45-year old woman presented with left-sided chest pain and breathlessness over 7-day duration, with no history of chest trauma. She had no signs of hemodynamic instability and did not appear to be in significant respiratory distress with only mild partial respiratory insufficiency.Laboratory findings were within normal limits apart from mild normocytic anemia (Hgb 106 g/L) and elevated D dimers (2.06 mg/L). Accordant to clinical examination of the chest, chest x-ray confirmed left-sided pleural effusion. An emergency MSCT scan with contrast showed no signs of pulmonary embolism but instead a probable AV malformation 17 mm in diameter was shown in anterior segment of left upper lobe . DiagnosMSCT scan with contrast performed three months later then confirmed a simple PAVM in the peripheral lingular area supplied from superior left pulmonary artery, and with a drainage vein entering the pulmonary veins and left atrium . The fee During further treatment, the patient participated in pulmonary rehabilitation program because of persistent dyspnea on exertion and since then has been attending regular follow-ups with normal radiological and pulmonary function test findings without recurrence of pleural effusion .Pulmonary arteriovenous malformations (PAVMs) are rare abnormal communications between the branches of pulmonary arteries and veins , 3. TheyThe clinical manifestations and complications of idiopathic PAVMs are also similar to those associated with HHT . More thPotentially life-threatening complications that occur in less than 10-20 percent of patients with PAVMs are hemothorax and hemoptysis . HemothoWhile hemoptysis is likely due to rupture of either parenchymal PAVM or an endobronchial teleangiectasia, hemothorax results from rupture of a subpleural PAVM. As seen in our patient, probable rupture of PAVM in peripheral area led to this rare complication. Massive hemoptysis and massive hemothorax from rupture of PAVM into the pleural space have been reported, with fatal outcomes , but hem Contrast-enhanced pulmonary angiography remains the gold standard for defining the anatomy of PAVMs that are considered potentially suitable for embolotherapy, which has largely replaced surgical intervention. PAVMs were historically treated with surgical resection. As endovascular techniques developed, embolization became the mainstay of treatment. Initial management with therapeutic embolization may well be appropriate in most patients who present with symptomatic PAVM. In patients who are hemodynamically unstable or in whom embolization has failed, open surgical resection of the PAVM has been successful . Treatme Transcatheter embolotherapy has proven to be a safe and effective treatment for sporadic PAVMs providing excellent functional and radiological improvement , 4, as sIn reviewed cases, which included mostly acute onset of PAVM associated with hemothorax, primary treatment was surgical or urgent embolization interventions, or combination of both , 12, 13.In conclusion PAVMs are relatively rare disorders with very common presentations and they are an important part of the differential diagnosis of pulmonary problems like hemoptysis, pulmonary nodule and hypoxemia. Although rarely seen, a PAVM as underlying cause of a spontaneous hemothorax should also be considered. \u00a0Contrast-enhanced computed tomography is a valuable and widely available diagnostic tool for patients with abnormal chest radiography suspicious of PAVM. There is little data on idiopathic PAVMs in the literature, especially presenting with hemothorax, and hopefully this case could benefit treatment of some of PAVM patients, which is why we consider our case worthy of reporting.We have shown that management of PAVM-related hemothorax initially by thoracic drainage followed by later on performed catheter embolization of the PAVM in a low risk patient could lead to a successful outcome."}
+{"text": "Cancer cells accelerate glycolysis to maintain ATP and other metabolites which are necessary to maintain their survival and chemoresistance. Glutathione (GSH) is the major antioxidant in living organisms and has multiple functions including maintenance of intracellular redox homeostasis. Cancer cells produce reactive oxygen species (ROS) that results from mitochondrial dysfunction, aberrant metabolism, and frequent genetic mutations. Such circumstances cause accumulation of large amounts of oxidized molecules including proteins, DNA and lipids. Therefore, cancer cells require active synthesis and recycling of GSH under regulating the balance of glucose utilization between glycolysis and pentose phosphate pathway which is necessary to synthesize NADPH and nucleic acid precursors . Excess Ferroptosis has recently been identified as a novel type of regulated cell death caused by severe oxidative stress and subsequent lipid peroxidation against which GSH-dependent antioxidant system protects. Inhibition of xCT cystine transporter or the GSH-dependent enzyme glutathione peroxidase 4 has been shown to induce ferroptosis in cancer cells . Since mOncotarget, Okazaki et al. performed a synthetic lethal screen of a drug library to identify agents that sensitize the GSH deficiency-resistant cancer cells to the xCT inhibitor sulfasalazine and identified the oral anesthetic dyclonine. Dyclonine possesses a unique structure responsible for covalent inhibition of aldehyde dehydrogenase enzymes (ALDHs) [In this issue of  (ALDHs) . Treatme (ALDHs) . They al (ALDHs) . Further (ALDHs) .In this context, of importance is that an engineered human enzyme cyst(e)inase which can degrade cystine/cysteine systemically has been developed . The cli"}
+{"text": "Due to an editorial error, the Data Availability Statement containing the raw sequences was erroneously omitted from the article. The publisher apologizes for the mistake.MG242652-MG243345.Raw sequences have been deposited in Sequence Read Archive  SRR6187016 and BioProject PRJNA414535; the 694 OTUs (representative sequences) under GenBank accession #"}
+{"text": "Simultaneous cerebral and myocardial infarction is called cardiocerebral infarction (CCI), and is rarely encountered. Because of the narrow time window and complex pathophysiology, CCI is challenging to immediately diagnose and treat.A 73-year-old woman suddenly developed right hemiplegia and severe aphasia. Twelve-lead electrocardiography showed tachycardic atrial fibrillation without any significant ST-T change. Magnetic resonance imaging revealed a proximal middle cerebral artery occlusion. She was immediately treated with alteplase at the dosage approved for ischemic stroke followed by mechanical thrombectomy as bridging therapy, and complete recanalization was achieved. Aphasia improved and she began to complain of chest pain, and reported that she had experienced chest discomfort just prior to right limb weakness. Coronary angiography showed a partial filling defect in the right coronary artery with rapid and adequate distal flow, for which percutaneous coronary intervention was not required. Alteplase was suggested to have effectively resolved the coronary emboli. The occlusions of the cerebral and coronary arteries were assumed to have occurred nearly simultaneously and cardiogenic embolism due to atrial fibrillation was considered as the most likely etiology.As seen in the present case, CCI may benefit from immediate treatment with intravenous tissue plasminogen activator (IV-tPA). Although which of percutaneous coronary intervention or cerebral thrombectomy should be performed first remains unclear, we must decide whether to rescue the brain or heart first in each patient within a limited window of time. This dilemma has recently become evident in this era with mechanical thrombectomy strongly established as an effective intervention for acute ischemic stroke. Close cooperation between stroke physicians and cardiologists is becoming more important. Simultaneous cerebral and myocardial infarction is called cardiocerebral infarction (CCI), and is rarely encountered . Because4/\u03bcL. No abnormalities were evident on chest roentgenogram.A 73-year-old woman suddenly developed right hemiplegia and severe aphasia and was transported to our emergency service 47\u2009min after onset. Her medical history included hypertension and paroxysmal atrial fibrillation. Anticoagulants have been discontinued because of a few episodes of falls although she had previously received oral anticoagulation. Blood pressure was 105/75\u2009mmHg without any significant difference between right and left limbs. No cardiac murmurs were audible. Twelve-lead electrocardiography (ECG) showed tachycardic atrial fibrillation with a heart rate of 150 beats/min but no significant ST-T changes, although the baseline was undulating due to patient movement  and mechanical thrombectomy, followed by coronary angiography, which did not suggest any requirement for PCI. Coronary angiography suggested that alteplase at the dosage approved for ischemic stroke had resolved the coronary emboli. Because IV-tPA is effective for both cerebral and myocardial infarction, CCI is likely to benefit from immediate treatment with IV-tPA prior to endovascular therapy. Although the recommended dosages of IV-tPA differ between cerebral and myocardial ischemia, in 6 previously reported cases of CCI treated with IV-tPA therapy, the dosage of IV-tPA applied was that used for acute ischemic stroke , 10, 11 A dilemma exists regarding endovascular therapy: although the occluded cerebral and coronary arteries have to be recanalized as soon as possible in the case of CCI, prioritizing one therapy leads to delays in the other. In previous studies, four patients were treated with both PCI and cerebral thrombectomy , 14, witIn conclusion, simultaneous cerebral and coronary embolism is rare and its prompt and appropriate management is difficult. Coexistence of coronary embolization should be considered when planning the treatment strategy for acute cerebral embolism. Further cases need to be studied to resolve the dilemma inherent in the recanalization strategy for CCI."}
+{"text": "Intrauterine growth restriction (IUGR) continues to be a global epidemic that is associated with high early-life mortality rates and greater risk for developing metabolic disorders that lower length and quality of life in affected individuals.Fetal programming of muscle growth and metabolic function associated with IUGR is often comparable among nonlitter bearing mammalian species, which allows much of the information learned in domestic animal models to be applicable to humans .Recent studies in sheep models of IUGR have begun to uncover the molecular mechanisms linking adaptive fetal programming and metabolic dysfunction.Targets of adaptive fetal programming indicated by sheep studies include adrenergic and inflammatory pathways that regulate skeletal muscle growth and glucose metabolism. Adaptive changes in these pathways represent potential focus areas for prenatal interventions or postnatal treatments to improve outcomes in IUGR-born offspring.Low birthweight due to intrauterine growth restriction (IUGR) encumbers United States and global livestock production by increasing neonatal mortality, reducing growth efficiency, and diminishing carcass yield and quality. Low birthweight food animals that survive typically exhibit impaired muscle growth and metabolic dysfunction that leads to poor feed conversion, lighter carcasses, and reduced carcass merit  . The endThe above models create placental stunting indirectly by imposing maternal conditions that disrupt uteroplacental blood flow during placental development. However, techniques described in this section impair placental function by directly diminishing structural components of the placenta. In one model, 150-\u03bcm microspheres are embedded into placental capillaries by infusing them into the surgically catheterized descending aorta of the fetus . This teFetal growth restriction can be achieved through restriction of maternal nutrients, although it is unclear whether it is mediated by placental insufficiency . The resAG- , and y+   . A collerginine)  as the frginine) .fetal adrenal gland  and primary skeletal muscle (ex vivo) was substantially reduced in MI-IUGR fetal sheep  myoblasts and a ~10% reduction in late differentiating (desmin+) myoblasts after 72 hr in differentiation media . The fact that both proliferation and differentiation capacities were reduced in PI-IUGR fetal myoblasts (The \u03b22 adrenergic receptor is the predominant isoform in skeletal muscle, although \u03b21 and \u03b23 receptors are also present. However, we found that skeletal muscle and myoblasts from PI-IUGR fetal sheep as well as skeletal muscle from PI-IUGR neonatal lambs express less mRNA for the \u03b22 adrenergic receptor than controls . Conversyoblasts  shows thyoblasts .enhanced by muscle adaptations in MI-IUGR fetal sheep (Like the \u03b22 adrenergic signaling pathway, inflammatory cytokine pathways appear to be altered in muscle and myoblasts of PI-IUGR and MI-IUGR fetal sheep . Unlike al sheep . In addial sheep . Sustainal sheep . Moreoveal sheep . We specIntrauterine growth restriction is a leading cause of perinatal mortality worldwide and leaves individuals at 18-fold greater risk for metabolic disorders that reduce length and quality of life. Unlike other major maternofetal pathologies, the prevalence of IUGR in the United States has not fallen over the last two decades. The fetal conditions and postnatal outcomes of IUGR are consistent among most mammalian species, which makes observations in animal models translatable to humans. A number of models developed in pregnant sheep have drastically improved our knowledge of IUGR fetal programming, which provides the fundamental basis for improving health outcomes in IUGR-born individuals."}
+{"text": "Although bioturbation is commonly recognized in contourites, only a few studies have analyzed the ichnological content of these deposits in detail. These studies have mainly focused on meso-scale bigradational sequence (a coarsening upward followed by a fining-upward sequence resulting from variations in current velocity). Here we present data from gravitational cores collected along the NW Iberian Margin showing systematic variation in ichnological content across proximal to distal depocenters within a large-scale elongated contourite drift. Data demonstrate that tracemakers\u2019 behavior varies depending on the distance relative to the bottom current core. Trace fossils are already known to be a useful tool for studying of contouritic deposits and are even used as criterion for differentiating associated facies , though not without controversy. We propose a mechanism by which the distance to the bottom current core exerts tangible influence on specific macro-benthic tracemaker communities in contourite deposits. This parameter itself reflects other bottom current features, such as hydrodynamic energy, grain size, nutrient transport, etc. Ichnological analysis can thus resolve cryptic features of contourite drift depositional settings. Due to their implications for reconstruction of depositional conditions, contourite deposits have become a critical topic of investigation within the sub-disciplines of paleoceanography, slope-stability, and petroleum exploration. Due to their relative inaccessibility, however, contourites remain somewhat enigmatic. Only few studies have managed to investigate bioturbation and ichnofabrics in contour current settings6. Despite ongoing controversies8, trace fossil content is considered both a criterion for characterizing contouritic deposits and also a proxy for paleoenvironmental conditions7. These records are typically overprinted by bottom current activity9. In recent years, detailed ichnological studies conducted on contourite deposits in outcrops and core material have provided new insights into depositional processes, environmental conditions and the influence of bottom currents on tracemakers11. Due to lack of detailed records, the ichnological paradigm for contourites remains somewhat tentative. Here we describe unequivocal trace fossils in contouritic deposits from deep-sea gravity cores. Comparison of features reveals distinctive lateral variation with relative to bottom current cores.The role of bottom currents in shaping deep-sea deposits  is currently a matter of debate in the scientific community12 during the ForSaGal 09 research cruise around the Galicia Interior Basin  exhibit a clear pattern with contouritic intervals dominated by Thalassinoides and Planolites   experienced relatively low sedimentation rate and low organic matter flux. Organic matter at the sediment surface may be rapidly oxidized, preventing the development of shallow/middle tier structures. Under these conditions, only deep tier structures are produced, by organisms able to store organic matter deeper in the sediment as in the case of the Zoophycos tracemaker. Sediments from site FSG09-07  indicate higher sedimentation rate and organic matter flux. Under these conditions, organic matter burial prevents oxidation and allows the development of shallow/middle tier dwelling structures, e.g. Palaeophycus . In distal settings, sedimentation rate and organic matter availability is lower. Organic matter is rapidly oxidized at the surface, favoring development of middle and deep tier tracemakers, which transport organic matter to deeper layers of the sediment . Systematic lateral variation in ichnological content of contourite drifts demonstrates an impactful role for ichnological analysis in contourite research. Trace fossils not only could differentiate contourites from turbidites and associated deposits, they also record proximal to distal deposition within a contourite drift relative to core bottom current features.Sedimentation rate, oxygen conditions, and organic matter availability influence the macrobenthic tracemaker communities and resulting trace fossil assemblage in actively forming contourite drifts. This report provides novel evidence of systematic proximal, to core bottom current, versus distal variation in ichnological features from muddy contourites. Varying depositional conditions are interpreted to reflect distance from the bottom current core. Sedimentation rate and organic matter availability are higher in proximal areas where organic matter is rapidly buried. This prevents oxidation and makes organic matter available for shallow tier tracemakers  were previously characterized based on grain size, composition, sedimentary features and Computed Tomography (CT) scanning17. Contourite deposits, concretely muddy contourites, were identified in three cores. Only cores FSG09-07  and FSG09-17   along the NW Iberian margin36, then calculated according to the Bioturbation Index scale38. These values reflect the spatial extent of discrete trace fossils identified over a common mottled background.Ichnological analysis identified ichnotaxa based on ichnotaxabases , tiering , crosscutting relations, and degree of bioturbation. The degree of bioturbation was determined by calculating the percentage of bioturbated surface using a quantification method based on high resolution digital images14C ages for the cores material analyzed12.Age was calculated using the age model based on XRF data and AMS-"}
+{"text": "Therefore, this microbial ecosystem is intertwined with host physiology at multiple levels. While it is evident that microbes that reach the blood stream can trigger thrombus formation, it remains poorly explored if the wealth of microbes that colonize the body surfaces of the mammalian host can be regarded as a modifier of cardiovascular disease (CVD) development. To experimentally address the microbiota's role in the development of atherosclerotic lesions and arterial thrombosis, we generated a germ-free (GF) low-density lipoprotein receptor-deficient ( From a perspective of cultural evolution, during the past decades Western societies have faced an enormous shift from traditional fibre-rich nutrition to the consumption of industrial foods that severely affects the diversity and function of the gut microbiota. To a large extent, the mutualistic nature of this microbial ecosystem with its host relies on intact barriers that are typically are formed by the mucus layer, the integrity of epithelial cell layers and by a tightly regulated and multifaceted immune vigilance but is also determined by nutritional factors shaping the diversity of the commensal microbiota. These efficient barriers are disrupted by infectious pathogens and in case of injury. Related to infection, the concept of immunothrombosis views blood clotting as an intravascular effector pathway of innate immunity, constituting a physiologic response that prevents the invasion and dissemination of microbes but becoming detrimental to the host if exceeding, e.g. in sepsis. These microorganisms produce foreign products that, dependent on dietary habits, constitute a continuous stimulus of low-grade inflammation and at the same time possess an enormous metabolic capacity interfering with host metabolism. This is particularly relevant, as, in addition to the nutrition-dependent formation of microbiota-derived metabolites that can cross the intestinal barrier (e.g. the choline metabolite trimethylamine), cholesterol metabolism, a major pathway that drives atherogenesis, is strongly influenced by the gut microbiota. In recent years, numerous studies have identified the gut microbiota as a relevant source of microbial-associated molecular patterns in plasma. These microbial signatures retain their biologic activity and promote chronic low-grade inflammation, influencing for instance steady-state myelopoiesis and turn-over of myeloid cells but also acting on host metabolic pathways that influence atherogenesis.\u2212/\u2212Ldlr) atherosclerosis mouse model, we tested the microbiota's role in the development of atherosclerotic lesions and arterial thrombosis. Given the complexity of the gut microbial ecosystem, it is evident that such gnotobiotic approaches are invaluable to causally pinpoint the influence of the gut microbiota on plasma cholesterol levels and the size and cellular composition of atherosclerotic lesions at defined diets and standardized feeding regimes. Hence, we fed GF \u2212/\u2212Ldlr mice with Western diet and compared them to conventionally raised (CONV-R) \u2212/\u2212Ldlr control mice, which were colonized by a microbiota from birth. Furthermore, these gnotobiotic mouse models are especially interesting to experimentally address whether the absence of microbiota impacts on arterial thrombus growth, the lethal complication arising from the rupture of atherosclerotic lesions.Using a germ-free (GF) low-density lipoprotein receptor-deficient , could in principle result in an extended phenotype of the gut microbial ecosystem that enhances cardiovascular risk.. Due to the non-absorbable properties of coprostanol in the small intestine, an inverse relationship exists between serum cholesterol levels and the coprostanol/cholesterol ratio in feces. It is known for many years that the conversion of cholesterol to coprostanol via biohydrogenation is mediated by cholesterol-reducing enzymatic activities of Eubacterium, Bifidobacterium, Lactobacillus and Peptostreptococcus strains, promoting cholesterol excretion. Furthermore, in the small intestine, the bile salt hydrolases from different gut bacterial genera deconjugate bile salts and reduce their solubility and reabsorption . By studying GF \u2212/\u2212Ldlr mice relative to their CONV-R \u2212/\u2212Ldlr counterparts, our study confirmed increased plasma cholesterol levels and elevated very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels in this GF \u2212/\u2212Ldlr hyperlipidemia model when mice were kept on chow diet. However, this difference was abolished when the \u2212/\u2212Ldlr mice were fed a 0.2% cholesterol-rich diet for 16 weeks. This result was in line with earlier studies on GF apolipoprotein E-deficient (\u2212/\u2212Apoe) mice that also showed increased plasma cholesterol levels at chow diet conditions, but not at Western diet feeding, when compared to CONV-R controls, demonstrating unequivocally the cholesterol lowering impact of the gut microbiota. Hence, the targeted modulation of gut microbial communities towards communities with enhanced cholesterol biohydrogenation capacity and bile salt hydrolase activity could in the future hold promise for new cholesterol-lowering therapies.Atherogenesis is primarily driven by elevated plasma cholesterol levels and an altered lipoprotein profile. Cholesterol absorption takes place in the upper small intestine. Various experimental and analytical approaches have comprehensively shown that the conversion of cholesterol to the more hydrophilic coprostanol essentially depends on established gut microbial communities \u2212/\u2212Ldlr mouse model addressed whether the presence of gut microbiota affects the development of carotid artery lesions. Although we found myeloid blood cell counts significantly reduced in hyperlipidemic GF \u2212/\u2212Ldlr mice and lower counts of adherent leukocytes to the vessel wall of carotid artery plaques, relative carotid artery plaque areas did not differ between late atherosclerotic GF \u2212/\u2212Ldlr mice and their CONV-R \u2212/\u2212Ldlr counterparts. This could be explained by the relatively late time point of our atherothrombosis study (16 weeks of Western diet). Alternatively, the unchanged plasma cholesterol levels and lipoprotein profile of late atherosclerotic GF and CONV-R \u2212/\u2212Ldlr mice might be due to the relatively high cholesterol content (0.2%) of the Western diet. Future studies should therefore test standardized diets with lower cholesterol content and analyze whether the absence of the gut microbiota affects the time course of atherogenesis in the \u2212/\u2212Ldlr mouse model. Based on our results, further in-depth analyses of gnotobiotic mouse models on atherosclerotic lesion size and plaque composition are required to pinpoint whether the cholesterol-lowering impact of the gut microbiota or the pro-inflammatory roles of gut-resident commensals can influence the onset and time course of atherogenesis.As elevated plasma cholesterol levels are a critical determinant for the progression of atherosclerotic lesions, our study on the GF \u2212/\u2212Ldlr mice relative to CONV-R \u2212/\u2212Ldlr mice in standardized flow chamber experiments with anticoagulated whole blood . Interestingly, we observed a diminished exposure of the platelet activation marker phosphatidylserine on the outer leaflet of the platelet membrane of GF \u2212/\u2212Ldlr mice in this standardized flow chamber model. Thus, our data indicate that at Western diet feeding conditions, the presence of gut microbiota promotes adhesion-dependent platelet activation. This observation is largely coherent with recent studies from other laboratories that have linked the gut microbiota with diet-dependent platelet hyperreactivity and demonstrated that fecal microbiota transplantation potentially can influence procoagulant function.As atherosclerotic lesions in the carotid arteries are a frequent cause of stroke, our study put focus on atherothrombosis, the lethal complication of atherosclerosis. In our previous work, we have shown that the gut microbiota promotes carotid artery thrombosis even at chow diet conditions. In addition to the carotid artery ligation model that has revealed reduced platelet deposition to exposed subendothelial matrix in GF relative to CONV-R C57BL/6J mice at chow diet conditions, our recent study demonstrated that GF C57BL/6J mice kept on chow diet also show significantly reduced occlusion times in the ferric chloride injury model of carotid artery thrombosis. At chow diet conditions, pattern recognition of microbiota-derived ligands by hepatic endothelial cells influenced arterial thrombus growth through modulation of hepatic endothelial von Willebrand factor (VWF) synthesis and VWF plasma levels. In contrast, at Western diet conditions, the adhesion-dependent platelet deposition to type III collagen, a major constituent of atherosclerotic lesions, was significantly reduced in GF \u2212/\u2212Ldlr mice and results in a platelet phenotype of increased phosphatidylserine exposure . A number of recent studies have linked the microbiota with metabolic functions that promote platelet reactivity and arterial thrombosis, e.g. by the microbiota's positive impact on the host serotonin biosynthesis pathway or the conversion of choline to trimethylamine. Our study provides an alternative role of the gut microbiota in the modulation of platelet function, as we could show in a standardized flow chamber model that the extent of phosphatidylserine exposure in the platelets of hyperlipidemic \u2212/\u2212Ldlr mice was dependent on the presence of the commensal microbiota. Since at low cholesterol nutrition the gut microbiota protects the host from high blood cholesterol levels, mechanistic insights on how the metabolic capacity of specific community members affects arterial thrombosis might in the future turn out instrumental to develop new therapeutic interventions based on nutrition, prebiotics or the selective inhibition of metabolic functions of gut microbes to prevent cardiovascular risk.Collectively, our study argues for a prothrombotic role of the microbiota under hyperlipidemic Western diet conditions that is due to enhanced adhesion-dependent platelet activation on type III collagen in colonized"}
+{"text": "Home-delivered meals (HDMs) provided through the Older Americans Act (OAA) are intended to reduce hunger, promote socialization, and maximize wellness. However, HDM recipients are at increased likelihood of being hospitalized due to their complex health needs and risk for social isolation and depression. Drawing data from the OAA-HDM National Survey, we evaluated the predictors of hospitalization among HDM recipients in 2017. From our sample (n = 578), we conducted random forest classification analyses to identify the most important risk factors related to HDM recipient hospitalization. Our random forest model yielded an accuracy rate of 66.3% with risk factors most indicative of hospitalization being attributed to number of co-morbidities, depressive symptoms, and feelings of social isolation. These findings indicate that although HDMs may help alleviate hunger among older adults, innovate strategies are warranted to address the unmet mental health needs of HDM recipients."}
+{"text": "Senescent cells drive aging. Preclinical studies suggest that targeted elimination of senescent cells offers a unique therapeutic approach to counter numerous chronic diseases and geriatric syndromes. To foster the translation of basic science discoveries to clinical application, we have sought to identify circulating biomarkers that reflect systemic senescent cell burden. We first analyzed the secretome of multiple senescent human cell-types and developed a candidate panel of proteins that could be reliably measured in human blood. Multiple proteins demonstrated significant associations with chronological age in a community-based cohort of adults aged 20-to-90 years. Impressively, in two distinct surgical cohorts (severe aortic stenosis and ovarian cancer), candidate protein concentrations were associated with biological age indices, including frailty and adverse outcomes. Our data suggest senescence biomarkers may have utility for clinical practice as indicators of risk, and for clinical research as surrogate endpoints in trials of interventions targeting senescent cells."}
+{"text": "Throughout a marriage, couples will share countless ordinary moments together, such as laughing together or engaging in leisure activities. Although these moments may seem trivial in isolation, research suggests that accumulating small positive moments together helps couples build emotional capital, which serves as an essential resource for protecting marriages from the harmful consequences of relationship challenges. This study explored whether emotional capital may buffer couples not only from the negative effects of relational stressors, but also from the negative effects of life stressors encountered outside the relationship in a sample of younger (age 30-45) and older (age 60+) married couples. Drawing from theories of socioemotional expertise, we also examined whether the buffering effects of emotional capital may be stronger for older adults. One hundred forty-five couples completed a 21-day daily diary task assessing shared positive experiences with the partner, negative partner behaviors, marital satisfaction, life stress, and mood. Spouses who generally accrued more shared positive moments with their partner across the diary days maintained greater marital satisfaction on days of greater partner negativity compared to spouses who accrued fewer positive moments. Moreover, spouses who generally accrued more shared positive moments with their partner across the diary days also reported lower levels of negative mood on days in which they experienced more life stress compared to spouses who accrued fewer shared positive moments; in both cases, the buffering role of emotional capital was significantly stronger for older adults. All results held when adjusting for relationship length and general marital happiness."}
+{"text": "Prediction of transcription factor (TF) binding from epigenetics data and integrative analysis thereof are challenging. Here, we present TEPIC 2 a framework allowing for fast, accurate and versatile prediction, and analysis of TF binding from epigenetics data: it supports 30 species with binding motifs, computes TF gene and scores up to two orders of magnitude faster than before due to improved implementation, and offers easy-to-use machine learning pipelines for integrated analysis of TF binding predictions with gene expression data allowing the identification of important TFs.https://github.com/SchulzLab/TEPIC and can be used on Linux based systems.TEPIC is implemented in C++, R, and Python. It is freely available at Bioinformatics online. TEPIC 2 builds upon and extends the functionality of existing TFBS prediction tools. Among other features, TEPIC 2 allows the direct aggregation of TFBS predictions on the gene level and uses these scores to gain novel insights on cell type specific functions of TFs via several machine learning analysis. This is a unique feature not supported by competitive TFBS prediction approaches  are key players of transcriptional regulation. Prediction of TF binding is essential to gain a deeper understanding of their function. While experimental identification of TF binding is possible through laborious and expensive ChIP-seq assays, several computational approaches have been proposed to identify TF binding sites (TFBSs) . DYNAMITE has been successfully applied to discover regulators of CD4+ T cell differentiation (EPIC-DREM), which was used to analyze mesenchymal stem-cell differentiation of osteoblasts and adipocytes   . DetailsTEPIC 2 is a fast and easy-to-use tool for TFBS prediction combined with integrative analysis capabilities for gene expression and epigenomic data. TFBS prediction and downstream machine learning pipelines for various analysis settings allow a deep, seamless exploration of epigenomic datasets supporting data driven hypothesis generation about the role of individual TFs in complex regulatory landscapes.Supplementary MaterialClick here for additional data file."}
+{"text": "Transcranial magnetic stimulation (TMS) is among a growing family of noninvasive brain stimulation techniques being developed to treat multiple neurocognitive disorders, including Alzheimer\u2019s disease (AD). Although small clinical trials in AD have reported positive effects on cognitive outcome measures, significant knowledge gaps remain, and little attention has been directed at examining the potential influence of TMS on AD pathogenesis. Transcranial magnetic stimulation (TMS) is among a growing family of noninvasive brain stimulation techniques being developed to treat multiple neurocognitive disorders, including Alzheimer\u2019s disease (AD). Although small clinical trials in AD have reported positive effects on cognitive outcome measures, significant knowledge gaps remain, and little attention has been directed at examining the potential influence of TMS on AD pathogenesis. Our review briefly outlines some of the proposed neurobiological mechanisms of TMS benefits in AD, with particular emphasis on the modulatory effects on excitatory/inhibitory balance. On the basis of converging evidence from multiple fields, we caution that TMS therapeutic protocols established in young adults may have unexpected detrimental effects in older individuals or in the brain compromised by AD pathology. Our review surveys clinical studies of TMS in AD alongside basic research as a guide for moving this important area of work forward toward effective treatment development. There is an urgent need for the development of new, effective strategies in the battle against Alzheimer\u2019s disease (AD). Transcranial magnetic stimulation (TMS) has emerged as a promising possibility, but evidence regarding long-term efficacy and mechanism of action is limited. Among the major unresolved issues, findings linking the effects of TMS on excitatory/inhibitory balance with mechanisms of AD pathogenesis merit careful consideration. Our survey of clinical TMS studies in AD alongside basic research aims to move the area forward toward effective treatment development using noninvasive brain stimulation.Alzheimer\u2019s disease (AD), the most common form of dementia, is characterized by progressive memory impairment and associated decline in multiple cognitive domains, ultimately leaving patients incapacitated. Inexorably eroding the lifetime of memories that defines us, AD robs patients of their unique identity. The neuropathological hallmarks of AD prominently include microscopic foci of degenerating neurites and extracellular amyloid \u03b2-protein (A\u03b2) deposition, together with intracellular aggregates of hyperphosphorylated tau protein that disrupt microtubule organization . The sinCurrently approved pharmacological treatments for AD offer limited symptomatic relief for some patients, and none alter the underlying progression of disease. While the search for new drugs with improved clinical efficacy is ongoing, increasing attention is focused on disease-modifying strategies aimed at bending the trajectory of aging toward healthy neurocognitive outcomes. Ideally, intervention would be initiated in at-risk individuals before the clinical expression of disease, during the decades-long prodromal phase thought to precede AD diagnosis. Noninvasive brain stimulation (NIBS) has generated considerable interest in this context. Prominently including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, this family of related technologies shares a generally well tolerated safety profile in healthy young adults and is currently under investigation for treating a growing list of potential indications .Among the various types of NIBS, TMS has received the greatest attention in clinical research on neuropsychiatric disorders. The mechanistic basis of TMS benefits is poorly understood, but there is general agreement that cortical excitability can be persistently modified by the repetitive delivery of a high-intensity magnetic field, generated by passing electrical current through an inductive coil. Repetitive TMS (rTMS), delivered in daily hour-long sessions over the course of several weeks was approved by the US Food and Drug Administration (FDA) for the treatment of pharmacologically refractory depression in 2008. In general, trials of rTMS treatment versus sham showed significant improvement in depression scores and lower rates of remission with rTMS , benefitDeveloping NIBS as a potential intervention for any clinical indication critically involves the choice of an appropriate stimulation protocol. Generally, rTMS protocols are operationally classified as \u201clow frequency\u201d or \u201chigh frequency,\u201d and \u201cconventional\u201d or \u201cpatterned.\u201d Low-frequency typically refers to stimulation rates \u22641 Hz, whereas rates \u22653 Hz are considered high frequency . In conventional protocols, single TMS pulses are applied in a regular rhythm; in patterned rTMS, short, high-frequency bursts are interleaved with brief periods of no stimulation. Some examples of patterned rTMS include stimulation mimicking theta activity, wherein short bursts of high-frequency pulses repeated at 5 Hz [theta burst stimulation (TBS)] are delivered as continuous TBS or intermittent TBS (iTBS) pulses. Perhaps most important with respect to the clinical effects of stimulation, low-frequency rTMS protocols are understood to result in cortical suppression and inhibition, whereas high-frequency stimulation increases cortical facilitation and excitability . Beyond Initial studies of rTMS effects in AD focused on high-frequency protocols almost exclusively , 2008. OStudies directly comparing cognitive outcomes following high-frequency versus low-frequency stimulation in patients with AD were first reported in 2012. In one investigation, 20 or 1 Hz rTMS was delivered bilaterally over the dlPFC in participants with mild or severe dementia . High-frEncouraged by this background, together with the much larger literature of experimental studies in normal participants , stimulaComplementing these findings, rTMS-COG in a group of probable AD case patients reportedly produced statistically significant or numerical improvement relative to baseline, as assessed by a variety of standard measures , either immediately or 6 weeks after the intervention protocol . Effectswww.fda.gov, March 21, 2019, Neurological Devices Panel of the Medical Devices Advisory Committee: De Novo DEN160053). The following sections briefly consider some of the experimental design challenges in this area of research, and then turn to evidence concerning the neurobiological mechanisms that might mediate the effects of TMS. A comprehensive mechanistic review is available elsewhere  were not considered. Studies examining rTMS-COG protocols have generally lacked groups receiving either rTMS alone or cognitive assessment without stimulation . However, the available evidence regarding clinical efficacy and mechanism of action is limited. The view developed here is that defining the neurobiological substrates responsible for the effects of TMS and other NIBS modalities will be critical for maximizing their efficacy and safety. We encourage a constructive, dispassionate evaluation of the evidence, aimed at establishing an informed platform for moving TMS and related strategies forward toward clinical application in AD.The possibility that a safe, noninvasive, and relatively low-cost treatment such as TMS might prove effective in the battle against AD has generated understandable excitement (The evidence summarized in this review highlights at least three conceptually distinct targets for TMS intervention in AD. in vivo imaging in patients receiving TMS are also needed. Efficacy in appropriately controlled, well powered trials remains to be confirmed, and longer-term cognitive outcomes established. At what stage in the progression of AD pathology will TMS be most effective? If TMS is used to target excitatory/inhibitory balance, at what frequency and in which brain regions, recognizing that such effects may be brain region specific (The need for effective strategies in the battle against AD grows ever more urgent. The disappointing outcome of recent clinical trials encourages the consideration of fresh perspectives, and in this context, NIBS has emerged as a novel alternative to pharmacological therapeutics and other interventions. The exciting potential of this approach, however, should not overshadow the important questions that remain unanswered. Among them, the safety profile established for other indications merits reconsideration in the context of neurobiological changes associated with AD, including hyperexcitability and epileptic activity, consistent with current safety guidelines . Studiesspecific ? Indeed,specific . The cha"}
+{"text": "Hypomesus transpacificus) and Chinook Salmon (Oncorhynchus tshawytscha). Since many tidal wetland restoration projects are planned or have recently been constructed in the Delta, understanding the diversity and variability of wetland invertebrates that are fish prey items is of increasing importance. During this study, two different invertebrate sampling techniques were tested (leaf packs and sweep nets) in four habitat types within three different wetland areas to evaluate which sampling technique provided the most reliable metric of invertebrate abundance and community composition. Sweep nets provided a better measure of fish food availability than leaf packs and were better able to differentiate between habitat types. Generalized linear models showed submerged and floating vegetation had higher abundance and taxa richness than channel habitats or emergent vegetation. Permutational multivariate analysis of variance showed significantly different communities of invertebrates in different habitat types and in different wetlands, and point-biserial correlation coefficients found a greater number of mobile taxa associated with sweep nets. There were more taxa associated with vegetated habitats than channel habitats, and one area had more taxa associated with it than the other two areas. These results suggest that restoration sites that contain multiple habitat types may enhance fish invertebrate prey diversity and resilience. However, the effect of habitat diversity must be monitored as restoration sites develop to assess actual benefits to at-risk fish species.Restored tidal wetlands may provide important food web support for at-risk fish species in the Sacramento-San Joaquin Delta (Delta) of California, including Delta Smelt ( Tidal wetlands provide an important source of productivity to many estuaries worldwide, subsidizing the surrounding open-water areas with vascular plant detritus, phytoplankton, zooplankton, and nekton biomass \u20135. ProduOncorhynchus tshawytscha) and Delta Smelt (Hypomesus transpacificus) . Thi. Thi73].We found significant differences in macroinvertebrate communities that may be traced to habitat heterogeneity. This implies that constructing a diverse range of habitats, including emergent vegetation, floating vegetation, submerged vegetation, and open water, during tidal wetland restoration may increase the variety of invertebrates produced on the site. The difference in invertebrates between habitats is not surprising, as research in this and other systems have found large differences between habitats , 30, 71,A wider range of invertebrate prey may increase resiliency of at-risk fishes and the ecosystem as a whole. There are multiple ways a diverse ecosystem may respond to changes in taxon composition , but theSurprisingly, we found no significant differences in invertebrate catch between the two time periods (March versus May). This suggests that invertebrate abundance may remain somewhat constant throughout the spring, however further sample points are required before any conclusions can be drawn. Due to strong seasonal patterns in invertebrate communities found by other studies , 40, 85,Invertebrate community composition was highly variable within and between Delta wetlands. Sweep nets provided a simple, efficient way to sample the invertebrate community, and demonstrated that different areas and habitat types supported different groups of organisms. Measuring invertebrate abundance across all habitat types within a wetland will allow managers to evaluate the effectiveness of their restoration projects in providing food for at-risk fishes. Wetland restoration can benefit from incorporating multiple habitat types in each project to develop a diverse community of invertebrates. Furthermore, restoration projects in different areas may have different benefits, and a variety of restoration projects may provide greatest resilience for the aquatic food web and the at-risk fishes it supports.S1 Data(CSV)Click here for additional data file."}
+{"text": "In the accompanying article, Horiuchi et al. (Biosci. Rep. (2019) 39(4), BSR20190213) evaluate the availability of apolipoprotein B-depleted serum for CEC assays. Using their recently developed immobilized liposome-bound gel beads (ILG) method, Horiuchi et al. demonstrate that apolipoprotein B-depleted serum obtained with poly ethylene glycol precipitation enables CEC assays to be easily and accurately introduced into laboratory medicine.Cholesterol efflux capacity (CEC), an important functional step in reverse cholesterol transport, is the main anti-atherosclerotic function of high-density lipoprotein (HDL). Assays that improve the determination of CEC  Lack of symptoms for the risk prediction is one of the leading causes of death by cardio vascular disease (CVD). Serum HDL cholesterol (HDL-C) levels have long been shown to be a biomarker of CVD risk and is a powerful inverse predictor of CVD. Regular blood work estimating the HDL levels in addition to lipid metabolic profile is a guideline by American Heart Association and the National Cholesterol Education Program before administering drug therapies for coronary heart disease in United States. However, recent studies suggest that despite elevated HDL-C levels being consistent with atheroprotection, the causal relation between HDL levels and cardiovascular disease is not clear . Two cliin vitro measure of an individual\u2019s ability to efflux cholesterol [., macrophages in an ex vivo system that involves apolipoprotein B-depleted serum from the study participants, the assay acts as a good predictor of cardiovascular risk [Cholesterol efflux capacity is an lesterol . When aplar risk . CEC is lar risk ,7. This lar risk . The varviz., macrophages. The ex vivo system in a clinical set-up is not ideal as some clinical laboratories, especially in developing countries might lack cell culture, radioisotope handling or ultracentrifugation equipment and facilities. To address this dependency on infrastructure, authors developed a variation of CEC assay using immobilized liposome-bound gel beads  whole serum/plasma; (ii) Apo B depleted serum (BDS); and (iii) pure HDL. Isolation of serum HDL by ultracentrifugation is the most prevalent method. However, the method demands special equipment and is time consuming. In addition, HDL fraction concentrated by ultracentrifugation may not always reflect the concentration of HDL in the serum . The conTo circumvent the ultracentrifugation step for preparation of apolipoprotein B (ApoB)-100 depleted serum, as the cholesterol acceptor, assay developed by Horiuchi et al., use polyethylene glycol (PEG) precipitation. HDL fraction obtained from PEG method (BDS) is indeed an effective alternative instead of using laborious ultracentrifugation method in a clinical setting. Human plasma lipoproteins are routinely fractionated using PEG-6000 ,13 and wTypically, CEC assay requires cells loaded with excess of radiolabeled cholesterol and a cholesterol acceptor (HDL). Instead of radioisotope labeling the assay developed by Horiuchi et al., employs fluorescently labeled cholesterol using boron-dipyrromethene (BODIPY) dye. Fluorescent intensity is measured by using microplate reader, which is routinely available in a clinical setting, to measure the CEC. Use of fluorescently labeled cholesterol instead of radiolabeled one can be a great choice for working in safe laboratory environment. However, testing the effect of BODIPY-cholesterol concentrations during ILG preparation methodology would be a good option.One of the limitations of the Horiuchi et al.  study isBy changing three steps of CEC assay viz., (i) ILGs for cultured cells; (ii) fluorescently labeled cholesterol; (iii) PEG precipitated HDL, authors demonstrate that it sufficient to estimate CEC with a significant correlation with a conventional assay using foam cells derived from THP-1 macrophages. Here is a holistic approach in which an observation arising from using HDL fraction obtained from the simple PEG method as a cholesterol acceptor in CEC assay. Although there is change in cholesterol safe labeling and the quick method of isolation of HDL fraction, the cultured cells are the only choice for CEC assay until recently. Having artificial cells that is liposome containing fluorescent BODIPY-labeled cholesterol as a substitute for the cultured cells is an effective method in clinical laboratories."}
+{"text": "Very few studies have compared oral health status between the US-born and foreign-born immigrant older adults. Using data collected among 430 Chinese older adults age 55+ residing in Hawai\u2019i, we examined the association between immigrant status and oral health related quality of life (OHQoL) and the moderating role of resilience in linking the association. Controlling for some key covariates, our study results show that US-born Chinese immigrant older adults had better OHQoL than their foreign born counterparts. Factors such as higher level of education (graduate degree or higher), better self-reported health status and no significant tooth loss were related to better OHQoL. The association between immigrant status and OHQoL was moderated by resilience. Specially, resilience was positively and significantly associated with OHQoL among U.S.-born older adults but not among the foreign-born ones. Our findings indicate the importance of immigration and resilience in shaping oral health outcomes among older Chinese Americans."}
+{"text": "Chronic subdural hematoma (CSDH) is one of the most common neurological diseases, which mainly occurs among elderly people and usually develop after minor head injuries. Over the years, a simple burr hole evacuation of the hematoma has been accepted as the widespread method for most cases of CSDH, but acute parenchymal hemorrhage is a rare and deadly complication after surgery. We report three elderly cases of post-operative parenchymal hemorrhage and analyse the underlying factors and formulate relevant strategies in this article. Three advanced age patients had been admitted to our department with gradually increasing headache and limb activity disorder urgently and underwent an emergency operation of burr hole drainage of CSDH in frontal-temporal region after preoperative evaluations and examinations. Unfortunately, acute post-operative parenchymal hemorrhage occurred in three advanced age patients. Ultimately, the patients achieved satisfying outcome with no significant neurological deficit through conservative treatment. The exact mechanism of such uncommon complications are difficult to explain and remain poorly understood. Advanced age, hypertension, amyloidosis, high perfusion triggered by rapid hematoma release, cerebrospinal fluid (CSF) loss, oral anticoagulant, primary disease aggravation were the main mechanisms which were speculated in our report. Simultaneously, positive measures could be adopt to prevent this rare complication. Chronic subdural haematoma (CSDH) is one of the most common neurosurgical conditions and is especially prevalent among elderly individuals . BehavioCase 1: An 71-year-old male patient had been admitted to our department with two-week history of gradually increasing headache and slight limb activity disorder and a 2-month history of minor head trauma as a result of fall to the ground. Cranial CT revealed bilateral CSDH. There was hypertension and multiple lacunar infarction were the systemic diseases which were under normal control  and asthma. Neurological assessment confirmed mental confusion and gait imbalance without focal deficits. The CT scan revealed a sizeable right chronic subdural hematoma which caused midline left shift  loss, oral anticoagulant, primary disease aggravation. Although CSDH drainage is considered as a minimally invasive surgical approach, neurosurgeons must be aware of this rare and deadly event. Correction of coagulation function, control of blood pressure and treatment of primary diseases are essential in order to prevent such complications before operation. Careful and gentle evacuation of the subdural hematoma without excessive head rotation is suggested to avoid rapid shift of intracranial contents and local hyper transfusion during operation. Continuous electrocardiograph monitoring, repeated evaluation of neurologic conditions, prompt radiological assessment, positive therapy of primary disease, volume of drainage control strictly and the height of drainage tube adjustment are mandatory after operation. Above all, when the uncommon complication occurs, conservative treatment is recommended intensively unless enormous intracranial hematoma make the patients unconsciousness, even brain hernia. Unfortunately, evacuation of hematoma and decompressing craniotomy were only adopted to save lives accompanied by poor prognosis.The authors declare no competing interests."}
+{"text": "Following publication of the original article , the autEnzyme adsorption comparison on lignin materials derived from acid and alkali pre-treated corn stover.To further understand the role of lignin materials in enzyme adsorption, we enzymatically hydrolyzed dilute acid pre-treated and dilute alkali pre-treated corn stover excessively to remove all the carbohydrates that are hydrolyzable by the enzyme cocktail applied. The obtained cellulolytic enzyme lignin (CEL) materials were used to investigate their enzyme adsorption kinetics Fig. , and theFurther to this, the authors reported an error in Fig. The corrected Fig."}
+{"text": "Gaucher disease is an inherited metabolic disorder resulting in deficiency of lysosomal enzyme \u03b2-glucocerebrosidase causing the accumulation of abnormal macrophages (\u201cGaucher cells\u201d) within multiple organs, most conspicuously affecting the liver, spleen, and bone marrow. As the most common glycolipid metabolism disorder, it is important for radiologists encountering these patients to be familiar with advances in imaging of organ and bone marrow involvement and understand the role of imaging in clinical decision-making. The recent advent of commercially available, reliable, and reproducible quantitative MRI acquisitions to measure fat fractions prompts revisiting the role of quantitative assessment of bone marrow involvement. This manuscript reviews the diverse imaging manifestations of Gaucher disease and discusses more optimal quantitative approaches to ascertain solid organ and bone marrow involvement with an emphasis on future applications of other quantitative methods including elastography. Non-neuronopathic Gaucher disease most conspicuously involves bone marrow, liver, and spleen.Organ volumes are commonly used for disease severity and treatment response.Anatomic imaging is relatively insensitive to marrow infiltration in Gaucher disease.Quantitative marrow fat-fractions indicate musculoskeletal severity and show early treatment response.Elastography may aid in assessing fibrosis in Gaucher disease.GBA) gene identified to-date , 6522, 6Marrow infiltration manifests with low signal on T1-weighted imaging Fig.\u00a0. Early qNumerous semi-quantitative scoring methods have been developed to report overall extent of bone marrow involvement based on signal intensity alterations on MRI, each with specific objectives and limitations summarized in Table\u00a0Multiple quantitative factors have been proposed to objectively assess marrow involvement in Gaucher disease and are supported by histopathologic evidence of an inverse relationship between marrow glucocerebroside and triglyceride concentrations . Some ofCurrently, quantitative MRI-based fat fraction measurements have been applied to objectively assess marrow involvement in Gaucher disease. Quantitative chemical-shift imaging (QCSI) using Dixon-based techniques and MRS are both capable of reliably measuring bone marrow fat fraction \u201390. WorkThe importance of understanding developmental increases in marrow fat over the lifespan beginning first in the peripheral skeleton as well as normal variation in bone marrow fat fractions cannot be understated. Patient age, sex, and body mass index should be considered in the interpretation of these values, ideally in the context of normative data relevant to the measurement method , 96\u201398. DWI may also hold promise with some evidence of decreased vertebral marrow ADC reflecting increased cellularity corresponding with disease status . Last, iNuclear medicine studies are not routinely used for routine follow-up assessment of Gaucher disease at most institutions, although 99\u2009m-Tc-Sestamibi scintigraphy has been studied as an alternative means of quantifying bone marrow involvement with good agreement with MRI-based semi-quantitative scoring , 102. TrOne of the earliest skeletal manifestations of Gaucher disease type 1 in children is osteopenia . The devProgressive osseous involvement in type 1 Gaucher disease may begin with painful bone crises that may eventually result in osteonecrosis  in about half of patients that may be attributed to packing of the marrow with Gaucher cells leading to thrombosis in situ within the marrow , 110. OsRadiographic detection of early osseous complications such as osteonecrosis and bone infarct may be difficult, often being occult on initial imaging with subsequent development periosteal reaction that may be confused with osteomyelitis (\u201cpseudo-osteomyelitis\u201d) , 67. FocGiven these limitations, assessment of acute osseous complications is best performed with initial radiographs followed by prompt MRI assessment . Bone crBone-related malignancies may be slightly more common in Gaucher disease, perhaps related to osteonecrosis as a predisposing factor. MRI may often be warranted for evaluation of discrete lytic lesions given the incidence of malignant bone lesions such as multiple myeloma, osseous lymphoma, sarcomas, and malignant epithelioid hemangioendothelioma \u2013120. ParAs with the liver, spleen, and bone marrow, Gaucher cells can infiltrate in the lungs, typically depositing within interstitial spaces. Such lung involvement is quite rare, more common in the neuronopathic type, nd not likely to occur as an initial manifestation of this disease . ReticulThere are multiple proposed etiologies for pulmonary hypertension in Gaucher patients. Pulmonary hypertension is attributable to perivascular infiltration of Gaucher cells or secondary to hepatic disease . An earlThe extent of cardiac involvement in Gaucher disease is uncertain with small numbers of mitral valve prolapse and valvular calcifications reported in a few patients with homozygous D409H mutations . Given tThere is a clear need for an objective and reproducible scoring system capable of assessing disease severity to standardize patient monitoring. While clinical scoring methods (PGS3 and GD-DS3) are useful tools for estimating disease severity, these scoring methods do not assess diffuse hepatic disease such as fibrosis, iron accumulation, fat infiltration, and portal hypertension, nor do they assess the full extent of asymptomatic marrow involvement with inclusion of only subjective imaging assessment of marrow involvement.While ultrasound is affordable and may be sufficient for the assessment of organ volumes and liver lesion screening, there is increasing use of MRI in Gaucher disease with most authorities considering MRI the standard of care , 45. As Diagnostic imaging of hepatic and splenic involvement should consist of sequences tailored for volumetric organ measurement and screening for focal lesions. In conjunction with these conventional acquisitions, MR elastography should be considered, when available, to provide non-invasive assessment of liver and splenic stiffness. While the role of elastography in the clinical management of hepatic fibrosis in Gaucher disease is not yet established, acquisition of organ stiffness measurements may afford insights into disease and treatment effects in the future with wider clinical adoption. It is important to note that elastography results should be interpreted in the context of known limitations including inaccuracy of gradient recalled echo(GRE)-based elastography in patients with iron deposition and massive ascites ; as suchNewer proton density fat fraction (PDFF) sequences allow for single breath-hold acquisition of the entire liver to provide triglyceride fat fractions, R2* mapping, and some also provide automated liver volumes  \u2013128. TheSingle-voxel MRS for fat fraction measurement may also be considered as a supplement or alternative if PDFF sequences are not available. DWI is included in our protocol as it may also be provide indirect assessment of organ cellularity with ADC as a possible quantitative marker of disease severity .If suspicious focal lesions are noted on this surveillance evaluation, dedicated lesion work-up with dynamic hepatocyte-specific contrast-enhanced MRI, multiphase contrast-enhanced CT, or contrast-enhanced ultrasound should be recommended, depending on institutional resources , 130.Qualitative imaging of both the axial (lumbar spine) and appendicular skeleton  is important for assessment of global marrow involvement, as these sites may respond differently to treatment . While aDiscrete parameters for the frequency of follow-up of Gaucher disease patients with imaging are informed by consensus recommendations and institution-specific practices , 133. CoAs part of clinical severity scoring and recommended care for patients, bone mineral density measurement is recommended beginning at 6\u00a0years of age with follow-up obtained every 1 to 2\u00a0years , 18, 31.Regional radiographic assessment of acute bone pain should be the first-line examination to assess for the presence of pathologic fracture . HoweverDecisions regarding routine imaging assessment of cardiac abnormalities with echocardiography and cardiac MRI are beyond the scope of this review with some authors recommending baseline echocardiographic screening in all ages at diagnosis and follow-up evaluation in adults on treatment , 122. ThConventional imaging of non-neuronopathic Gaucher disease underestimates multisystem organ involvement in Gaucher disease, and recent clinical and experimental evidence shows a significant role of multifaceted processes of inflammation, chemotaxis, iron deposition, and fibrosis, even in treated patients. Quantitative bone marrow fat fraction measurements have been touted as a reliable marker of skeletal involvement for treatment response assessment but have been relegated to selected academic medical centers previously. Newer commercially available quantitative MRI methods enable efficient quantification of liver, spleen, and bone marrow fat fraction values and a comprehensive imaging protocol is introduced in this article to take advantage of this opportunity to better characterize this complex disease and guide personalized therapy."}
+{"text": "Social and behavior change approaches have shown promise for addressing the demand- and supply-side challenges in postabortion care. As implementers seek to improve the quality of postabortion care, systematically integrating long-standing models and emerging approaches, including behavioral economics, human-centered design, and attribute-based models of behavior change, can promote positive health outcomes. Social and behavior change approaches have shown promise for addressing the demand- and supply-side challenges in postabortion care. As implementers seek to improve the quality of postabortion care, systematically integrating long-standing models and emerging approaches, including behavioral economics, human-centered design, and attribute-based models of behavior change, can promote positive health outcomes. Unsafe abortion is the fifth leading direct cause of maternal deaths globally and in developing countries.Programmatic experience suggests that key behavior-related challenges in the delivery of high-quality PAC services arise before the PAC client reaches a facility, during her visit to a facility, and after she leaves a facility. These challenges include the followingBefore:Ensuring timely care seeking by women and their partnersDuring:Promoting respectful treatment of PAC clients by providers and addressing the stigma that specific client groups may experience in interactions with providersEnsuring that during counseling, providers address client needs for clear information about return to fertility and family planning options and acknowledge barriers to postabortion family planningEnsuring providers offer a full range of voluntary family planning methods prior to discharging the client, including long-acting reversible contraceptives and permanent methodsAfter:Supporting clients in returning to services to facilitate both voluntary contraceptive continuation and follow-up for clients whose treatment requires return visitsKey challenges in the delivery of high-quality PAC services arise before, during, and after a PAC client\u2019s visit to a facility.While additional formal evaluation of social and behavior change in the context of PAC is needed, lessons learned from programmatic experience in this and other areas of reproductive health suggest that intentional use of behavior change principles and approaches is necessary to address common challenges in PAC programming.,,Seeking care at the first sign of complication is essential to effective treatment of spontaneous and induced abortions. Facilitating timely care seeking requires attention to barriers to accessing services, which may be specific to a given context or client group. Lack of information about the warning signs of spontaneous abortion, dangerous complications of spontaneous and induced abortion, and where to seek PAC prevents women from seeking help.\u2013\u2013PAC programs have successfully intervened at the community level to address barriers to care seeking and reinforce supportive norms. In Kenya and Somalia, community education, training of community health workers and community preparedness have effectively increased awareness, acceptance, and utilization of PAC, including voluntary use of postabortion family planning.PAC programs have successfully intervened to address community-level barriers to care seeking and reinforce supportive norms.\u2013before emergency care is required. PAC programs must consistently apply proven practices in behavioral design, including systematic diagnosis of barriers to service utilization among key client groups. In addition to addressing the common barriers cited above, implementers should employ formative research approaches used in behavioral programming as a means to generate insights about client perceptions and motivations. In particular, immersive and participatory approaches grounded in human-centered design show promise as a means to better understand and address barriers to care seeking. Human-centered design is an iterative process that includes developing a deep understanding of the people affected by a problem, identifying opportunities for design to address that problem, prototyping potential solutions, and repeatedly testing and refining those prototypes.providers may treat clients with disrespect or restrict care due to norms or attitudes associated with abortion, sexuality, and sexual health among specific client groups; circumstances such as a subsequent abortion or failure to use family planning; and/or use of family planning after pregnancy loss.,\u2013providers may not adequately explain healthy spacing of pregnancy. The World Health Organization recommends women delay pregnancy for at least 6 months after an abortionproviders may not adequately explain return to fertility, which can occur within 2 weeks after a first trimester spontaneous or induced abortion.providers may fail to counsel PAC clients on the full range of family planning methods available to them and fail to offer these methods prior to discharging the client.,\u2013The client-provider interaction during health care provision represents a critical opportunity to build trust and establish healthy behaviors pertaining to family planning and reproductive health care seeking. Four distinct but interrelated challenges may influence the quality of care offered during a PAC client\u2019s visit to a health facility. Failing to prevent these challenges can ultimately hinder adoption of voluntary family planning methods that enable women and their partners to achieve their desired fertility. First, ,,,To prevent these challenges, PAC programming has successfully employed a range of approaches to influence provider behaviors pertaining to counseling PAC clients, particularly about postabortion family planning. Many PAC programs have integrated discussions of provider attitudes and values into trainings that seek to reduce stigma toward women and adolescents who need reproductive health services, dispel misconceptions about contraceptive methods, and build effective counseling skills. These discussions offer opportunities for providers to reflect on how their own values and beliefs influence their interactions with clients.PAC programming has successfully employed several approaches to influence provider behaviors in counseling PAC clients.PAC programs can build on the rapidly growing evidence base for provider behavior change as a means to improve not only the knowledge and skills that underpin effective counseling, but the full range of motivational and normative influences affecting providers. To do so, implementers must use formative research to analyze specific drivers of provider behavior. As with programs targeting PAC clients themselves, the insights derived from this research can inform segmentationBehavioral design may deepen the impact of traditional knowledge- and skills-based interventions to improve client-provider interaction.PAC programs can further improve the quality of client-provider interaction through continued attention to the drivers of client behavior, specificity in behavior change messaging, and promotion of client engagement during care and counseling. Counseling and other communication approaches should acknowledge and address barriers to postabortion family planning, including social norms regarding fertility and couples\u2019 communication.PAC programming must address challenges relating to support for voluntary contraceptive initiation or continuation and care for clients who require follow-up treatment. Clients who receive counseling and choose a voluntary family planning method may require assistance with accessing ongoing supplies of short-acting methods,Social and behavior change interventions within PAC programs enhance a client\u2019s follow-up care, including family planning, and reinforce linkages between the client\u2019s home and health care workers. Client communication materials facilitate follow-up care. Several international professional associations and development partners recommend that PAC clients should receive simple written instructions for the use of their method, along with concise information about common side effects and benefits.Social and behavior change interventions within PAC programs enhance a client\u2019s follow-up care.Mobile phone-based communication has shown promise to facilitate access to health information and services in low-resource settings. A randomized control trial in Cambodia found that follow-up communication through mobile phones supports postabortion contraceptive use. It helped women retain family planning information provided during PAC and prompted women who wanted a long-acting method but did not receive one during the initial PAC visit to return for an implant or intrauterine device.,,Evidence suggests that engaging the male partners of PAC clients in counseling, when acceptable to clients themselves, can improve health outcomes. PAC programs in Bolivia and Tanzania found that engaging partners by informing them of the client\u2019s condition and providing both with family planning counseling helped to ensure safe recovery and increased voluntary family planning continuation.In general, promotion of voluntary contraceptive continuation or return to services remains less understood than either creation of initial demand for services or improvement of client-provider interaction. Improved design and measurement of activities addressing behavioral initiation or maintenance after a client leaves a facility is an area of increasing collaboration between social and behavior change and service delivery professionals. The concerns of PAC program implementers constitute an important component of this discourse. The rapidly evolving thinking in this area affords PAC program implementers an opportunity to build upon emerging practices and develop innovative solutions to the challenges they face. For example, a growing body of gray literature pertaining to understanding and grouping similar behaviors and the attributes of those behaviors,We should build our understanding of how to address behavioral initiation or maintenance after a client leaves a facility.PAC programs have successfully used community-based social and behavior change approaches and provider behavior change interventions to support clients in accessing postabortion services and adopting voluntary family planning. To ensure that all women have access to high-quality PAC, implementers must build upon this important foundation through continued application of proven practices in behavior change, including formative research, audience segmentation, and the use of iterative, multichannel communication approaches that target clients, providers, and community members. Concomitantly, implementers should seize the opportunity to play a leading role in the application of social and behavior change approaches for PAC by leveraging new trends in behavioral economics, human-centered design, and attribute-based models of behavior change and increasing alignment between demand-side and supply-side programming."}
+{"text": "Plant growth dynamics are shaped by the diversity of associating pathogenic, saprotrophic, and mutualistic soil fungi. Feedbacks between plants and soil microbial communities play an important role in vegetation dynamics, but the underlying mechanisms remain unresolved. Here, we show that the diversity of putative pathogenic, mycorrhizal, and saprotrophic fungi is a primary regulator of plant-soil feedbacks across a broad range of temperate grassland plant species. We show that plant species with resource-acquisitive traits, such as high shoot nitrogen concentrations and thin roots, attract diverse communities of putative fungal pathogens and specialist saprotrophs, and a lower diversity of mycorrhizal fungi, resulting in strong plant growth suppression on soil occupied by the same species. Moreover, soil properties modulate feedbacks with fertile soils, promoting antagonistic relationships between soil fungi and plants. This study advances our capacity to predict plant-soil feedbacks and vegetation dynamics by revealing fundamental links between soil properties, plant resource acquisition strategies, and the diversity of fungal guilds in soil. The accumulation of host-specific pathogenic fungi in plant rhizospheres has been identified as an important driver of negative density dependence in plant populations. These negative plant-soil feedbacks underlie plant species coexistence and positive diversity-productivity relationships . Physicochemical properties, such as cation exchange capacity, pH, and soil carbon (C), nitrogen (N), and phosphorus (P) concentrations, formed another axis of variation reflecting inherent soil fertility that was not significantly affected by conditioning with different plant species . Therefore, the experiment captured variation in soil abiotic properties resulting from both plant species conditioning and inherent variability in soil fertility at the site of soil collection. This enabled us to gauge the relative importance of both biotic and abiotic drivers of plant-soil feedbacks.Replicated monocultures of 14 common temperate grassland species, encompassing a broad spectrum of functional traits . After tR2 = 0.32, F13,41 = 2.9, P = 0.004) but not in the accumulation of specialist AM and saprotrophic fungi . Plant species identity had little influence on soil bacterial communities, which were primarily determined by soil abiotic conditions (fig. S1). The distinct effects of plant species on soil fungal communities became more pronounced when fungi were split into putative plant pathogens and saprotrophs  released into the soil , but the effect was considerably weaker than that of the richness of putative pathogens and AM fungi . In support of this conclusion, variation in biotic feedback was more correlated with differences in the richness of putative pathogenic  and AM fungi  than with differences in the composition of these fungal groups . These findings provide compelling evidence that plant-soil feedback is regulated by the diversity of soil fungi and indicate that diversity effects of soil organisms are not only positive . Soil collected from the grassland site exhibited natural spatial heterogeneity in soil properties, and this variation was preserved when filling the mesocosms with soil collected randomly from across the grassland. Plant traits, soil abiotic properties, and microbial communities were measured for each mesocosm at the end of the conditioning stage  were polymerase chain reaction amplified and used to characterize the microbial communities. The amplicons were sequenced on an Illumina MiSeq instrument with 2 \u00d7 151 base pair kits.Microbial community structure was determined as in . AM fungi were represented with 126 ESVs . Saprotrophs were represented by 338 ESVs . Detailed functional data are not currently available for soil bacteria and protists. We therefore only assessed the composition of bacterial and protist communities, and the relative abundance and richness of well-known pathogenic oomycete ESVs (Pythium and Phytophthora genera), as predictors of plant-soil feedbacks. We found that the composition of bacterial and protist communities was strongly correlated with that of saprotrophic fungi (table S2). Only the latter was included in the subsequent path analysis as a representative characteristic of overall microbial community composition.Exact sequence variant  counts were determined from raw sequence data using the DADA2 pipeline . For each soil sample, the relative abundance, ESV richness, and exponential Shannon diversity (effective species number) were calculated for each fungal functional group and specialist and generalist sequences within each functional group. Asymptotic exponential Shannon diversity was calculated for each fungal group using the package iNEXT in R  was characterized using principal coordinate analysis (using Bray-Curtis distances and Hellinger transformation of read abundance data). The first two principal coordinates for each fungal group and the first two principal component axes of plant traits and soil abiotic properties were used as predictors of plant-soil feedback in the analysis described below. The importance of plant species identity and the first principal component of abiotic soil properties in explaining variation in plant traits and soil microbial properties was analyzed using variance partitioning for univariate traits (comparison of linear fixed-effects models) and redundancy analysis for multivariate data [package vegan, function dbrda in R 3.4.0 (The best predictors of soil feedback were selected on the basis of Akaike information criterion (AIC) from five groups of variables: plant traits, soil abiotic properties, and soil fungal community properties . Each variable was tested in a separate linear model as a predictor of soil feedback, and predictors yielding the lowest AIC scores within each variable set were retained for use in the path analysis to explore possible paths by which plant traits and soil properties jointly affect soil feedback (table S1). Additional variables explaining more than 10% of variation in the feedback index, and not strongly correlated with the best predictor within each variable group, were also included in the path analysis. Within the set of abiotic soil properties, many variables were highly correlated and aligned closely with the first principal component. Hence, the latter was included in the path analysis to reflect the major axis of variation in abiotic soil properties. For the analysis of specific feedback, AIC scores with a sample size of 55 were calculated, as our dataset contained 55 mesocosms in the conditioning stage, representing true replicates in plant trait and soil measurements.P values higher than 0.1 were sequentially dropped (table S4).Path analysis was used to test whether fungal communities  in conspecific and heterospecific soil affected plant-soil feedback and whether soil abiotic properties and plant traits have a direct or microbially mediated indirect effect on plant-soil feedback. Plant traits could be affected by soil abiotic conditions [i.e., phenotypic plasticity . For conspecific soil properties, paths significant at To confirm that the diversity of putative pathogens and AM fungi were better predictors of biotic feedback than differences in fungal composition, Mantel tests were performed to assess the correlation between biotic feedback and fungal composition (based on Bray-Curtis distances and Hellinger-transformed data). The strength of this correlation was compared to the correlation between biotic feedback and fungal diversity obtained from the analogous Mantel test.To test for the sensitivity of specific soil feedback to variation in soil fungal composition, pairwise dissimilarities between individuals of each species grown in conspecific versus heterospecific soils were calculated using log-transformed biomass and fungal sequencing data. Microbial dissimilarity was calculated as the Bray-Curtis distance based on the relative abundance data with Hellinger transformation [package vegan, function vegdist in R 3.4.0 ("}
+{"text": "Habitat contamination can alter numerous biological processes in individual organisms. Examining multiple individual-level responses in an integrative fashion is necessary to understand how individual health or fitness reflects environmental contamination. Here we provide an example of such an integrated perspective based upon recent studies of an amphibian  that experiences several, disparate changes when larval development occurs in a trace element\u2013contaminated habitat. First, we present an overview of studies focused on specific responses of individuals collected from, or transplanted into, a habitat contaminated by coal combustion residues (CCR). These studies have reported morphological, behavioral, and physiological modifications to individuals chronically interacting with sediments in the CCR-contaminated site. Morphological abnormalities in the oral and tail regions in contaminant-exposed individuals influenced other properties such as grazing, growth, and swimming performance. Behavioral changes in swimming activities and responses to stimuli appear to influence predation risk in the contaminant-exposed population. Significant changes in bioenergetics in the contaminated habitat, evident as abnormally high energetic expenditures for survival (maintenance) costs, may ultimately influence production pathways  in individuals. We then present a conceptual model to examine how interactions among the affected systems  may ultimately bring about more severe effects than would be predicted if the responses were considered in isolation. A complex interplay among simultaneously occurring biological changes emerges in which multiple, sublethal effects ultimately can translate into reductions in larval or juvenile survival, and thus reduced recruitment of juveniles into the population. In systems where individuals are exposed to low concentrations of contaminants for long periods of time, research focused on one or few sublethal responses could substantially underestimate overall effects on individuals. We suggest that investigators adopt a more integrated perspective on contaminant-induced biological changes so that studies of individual-based effects can be better integrated into analyses of mechanisms of population change."}
+{"text": "Relationships with adult children play an important role in older adults\u2019 well-being. However, little is known about the association between parent-child relations and aging parents\u2019 sleep quality, which is an emerging health issue that is closely related to individuals\u2019 physical and mental well-being in later life. With the largest aging population, China has experienced rapid changes of family structure and traditional norms regarding parent-child ties. This study focused on different dimensions of parent-child relationships  in Chinese aging families. This study examined the association between parent-child relationships and older parents\u2019 sleep quality, comparing one-child and multiple-children Chinese families. Utilizing the 2014 wave of the Chinese Longitudinal Aging and Social Survey, we analyze data from 8,450 respondents (aged 60+) who had at least one living child. Descriptive analysis showed that parents with multiple children engaged in more intense financial exchanges, less frequent instrumental support, and lower levels of emotional closeness with their adult children compared to their counterparts with only one child. Logistic regression models revealed that older parents who received more instrumental support were more likely to report sleep difficulty in both one-child and multiple-children families. For parents with multiple children, the overall level of financial transfers from children was negatively associated with having sleep difficulties, while the variability of financial transfers across multiple children was positively associated with having sleep difficulty. Findings highlight the importance of considering family dynamics in studying sleep quality among Chinese older adults."}
+{"text": "To review recent studies investigating hypothalamic-pituitary-adrenal axis function in children and adolescents with disruptive behavior disorders (DBDs) and adults with antisocial personality disorder. We consider key concepts and methodological issues in cortisol assessment and review studies investigating basal cortisol secretion and stress reactivity in antisocial populations. Lastly, we consider whether cortisol abnormalities predict prognosis or treatment outcomes and the impact of exposure to adversity on hypothalamic-pituitary-adrena (HPA) axis activity.Studies tracking cortisol levels across the day and assessing cortisol awakening responses (CARs) have reported broadly intact, but flatter, diurnal rhythms and lower CARs in children and adolescents with DBDs, whereas findings in antisocial adults have been mixed. Cortisol hyporeactivity to stress is consistently reported in male antisocial populations, whereas no comparable data exist in females.Severe antisocial behavior is associated with cortisol hyporeactivity to stress, and such hyporeactivity predicts poor treatment outcomes. Further research investigating sex differences and the impact of adversity is needed. Harmonization of methods for assessing hypothalamic-pituitary-adrenal axis function and antisocial behavior would enhance progress in this area. In this article, we review recent research on hypothalamic-pituitary-adrenal (HPA) axis function in child and adult antisocial populations, focusing particularly on conduct disorder (CD) in children and antisocial personality disorder (ASPD) and psychopathy in adults. To test theories proposing that low physiological arousal or hyporeactivity is causally related to the etiology of antisocial behavior, researchers have investigated whether CD or ASPD is associated with lower basal cortisol levels or blunted cortisol responses to stress. We start by providing an overview of the HPA axis and its functions, and outline key methodological developments in this area. We then review evidence for disturbances in basal cortisol secretion and cortisol hyporeactivity in children and adolescents with CD and disruptive behavior disorders (DBDs) more generally . We subsequently consider studies on cortisol secretion under basal conditions and stress reactivity in adults with ASPD or psychopathy. Finally, we discuss whether HPA axis abnormalities predict treatment outcomes or normalize following successful treatment, and also whether such abnormalities reflect the consequences of exposure to early adversity which is frequently present in these individual backgrounds.The HPA axis is the main physiological system which mediates the body\u2019s stress response. The paraventricular nucleus of the hypothalamus releases corticotrophin-releasing hormone in response to threat signals from brain regions such as the amygdala . CorticoGiven this rhythmicity and physiological response to waking, it is important to assess patterns of cortisol secretion across the day (including the CAR) when assessing whether individuals with psychiatric disorders display HPA axis abnormalities. However, relatively few studies on antisocial behavior have adopted such methodological approaches, instead largely relying on single-point determinations of cortisol levels . In fact, rather than just assessing cortisol several times within the same day, some researchers have argued that cortisol should be measured over multiple days to yield robust findings . It is aIn the following sections, we consider recent studies investigating diurnal cortisol secretion and the CAR, as well as cortisol reactivity to stress, in children and adolescents with DBDs and adults with ASPD or psychopathy. Given that the ASPD diagnostic criteria require the individual to have had CD prior to age 15 , substanIn an important early study, Popma et al. (2007) investigated diurnal cortisol secretion and the CAR in adolescent boys attending a delinquency diversion program, comparing those with and without DBD diagnoses with healthy controls \u2022. AlthouFairchild et al. (2008) adopted a similar design, investigating diurnal cortisol rhythms and the CAR over three consecutive days in males with either childhood-onset or adolescence-onset CD and healthy controls. The aim was to assess whether cortisol abnormalities were specific to childhood-onset CD . There were no significant group differences in morning cortisol levels or CAR magnitudes, although evening cortisol levels were elevated in both CD subgroups, consistent with a flatter diurnal rhythm overall \u2022.n\u2009=\u200936) and typically developing boys (n\u2009=\u200936). Although broadly similar cortisol diurnal rhythms were observed in both groups, there was some evidence for an attenuated CAR and lower cortisol levels at 12:00\u00a0h in the CD group. When the childhood-onset CD group was split into those with versus without callous-unemotional (CU traits), the CD/CU+ group showed a smaller CAR than the controls, although there were no group differences in diurnal cortisol secretion [Extending this work, von Polier et al. (2013) investigated the CAR and diurnal rhythm in boys with childhood-onset CD  of detained adolescents and healthy controls . The authors assessed the impact of CU traits and impulsivity to examine whether low cortisol was specifically associated with CU traits. There were no group differences in overall cortisol secretion or diurnal slope, and no significant associations between CU traits or impulsivity and cortisol levels. However, the study relied on self-report measures of CU traits and impulsivity did not assess the CAR, and the \u2018healthy control\u2019 group included participants with subclinical levels of CD symptoms.Another recent study  investigAlthough they did not use categorical CD/ODD diagnoses, Ruttle et al. (2011) and Salis et al. (2016) examined concurrent and longitudinal associations between externalizing behavior and cortisol secretion in children. Ruttle et al. (2011) found that externalizing behavior was related to blunted cortisol rhythms, both concurrently and longitudinally, but the longitudinal associations with cortisol were stronger \u2022. This iIn another important study, Platje et al. (2013) examined longitudinal relationships between the CAR and aggressive and rule-breaking behavior in a large community sample of adolescents. Persistently elevated aggression was associated with smaller CARs over a 3-year period, whereas there was no association between rule-breaking behavior and CAR magnitudes \u2022\u2022, suggecortisol reactivity to stress in children and adolescents with DBDs. These studies have yielded a more consistent pattern of results\u2014particularly those using effective stressors such as the trier social stress test for children Trier Social Stress Test for Children (TSST-C) or the frustration/provocation task.Having reviewed recent work investigating basal cortisol secretion, we now consider studies examining Van Goozen and colleagues , 21 condPopma et al. (2006) investigated cortisol and subjective responses to stress  in adolescents referred to a delinquency diversion program, with versus without DBD diagnoses, and a healthy control group. The DBD+ group again showed lower cortisol responses to stress than the controls, despite displaying the expected increase in negative mood . On the n\u2009=\u2009165), but was limited by relying on retrospective reports regarding the age-of-onset of CD (thus some participants may have been misclassified), and did not investigate the impact of CU traits on cortisol reactivity.Fairchild et al. (2008) extended this work by examining whether cortisol hyporeactivity to stress was specific to childhood-onset CD. The authors compared male adolescents with childhood-onset and adolescence-onset forms of CD and a healthy control group. Both CD subgroups showed attenuated cortisol (and cardiovascular) responses to stress compared with controls, despite reporting strong increases in negative feelings during the experiment, which used the frustration/provocation task \u2022. This sStadler et al. (2011) addressed the latter issue when examining cortisol reactivity to stress in a sample of children with a primary diagnosis of ADHD, many of whom had comorbid DBDs, by splitting their sample into those with high versus low levels of CU traits. The participants with elevated CU traits showed weaker cortisol responses to the TSST-C than the low CU traits subgroup, even though these subgroups did not differ in subjective mood responses . Unfortucortisol recovery following stress. Lower basal cortisol levels were observed in the pure ODD/CD group alone. No differences in cortisol reactivity were observed between the ODD/CD and control groups, although CD symptoms were inversely related to reactivity on a dimensional level and ODD/CD + ANX participants tended to show higher  cortisol reactivity than their pure ODD/CD counterparts [cortisol recovery following stress, and distinguishing between those with and without comorbid anxiety disorders. It suggests that failing to take account of internalizing comorbidity might explain some of the inconsistent findings in the DBD literature. Hartman et al. (2013) provided further evidence to support this notion by studying a large, mixed-sex sample of adolescents with preadolescent externalizing or internalizing diagnoses. Self-reported internalizing symptoms predicted greater cortisol secretion, whereas self-reported externalizing symptoms predicted lower cortisol secretion under stressful conditions [Recent studies have examined the impact of common comorbidities on cortisol reactivity to stress in CD. Schoorl et al. (2016) compared boys with ODD/CD alone and ODD/CD plus comorbid anxiety disorders (ODD/CD + ANX) in terms of basal cortisol, cortisol reactivity to stress, and terparts \u2022. Finallnditions . Associan\u2009=\u200995) and those with ADHD+CD (n\u2009=\u2009107) in terms of basal cortisol levels and cortisol reactivity to stress. There were no differences between these groups in basal cortisol, whereas the ADHD+CD group showed blunted cortisol reactivity to stress relative to the ADHD-only group [positively related to baseline cortisol, but negatively related to cortisol reactivity to stress. CU traits were not significantly related to either cortisol measures. This study provides further evidence that ADHD is not associated with cortisol reactivity in its own right, rather, it is CD/ODD that leads to cortisol hyporeactivity.In another interesting study, Northover et al. (2016) compared male children and adolescents with pure ADHD  are associated with cortisol hyporeactivity to stress . Such hyporeactivity is observed in children and adolescents and appears to be present in both childhood-onset and adolescence-onset forms of CD. As some studies have indicated that CU traits may be an important determinant of cortisol hyporeactivity, whereas others have shown no impact of CU traits, an important issue for future research is whether CD symptoms or CU traits are more influential in determining cortisol reactivity. This should be addressed in both clinical samples in which the full range of CD symptoms and CU traits are observed and in high-risk and community samples. The statistical analyses should also test whether CD symptoms and CU traits exert effects in opposite directions . Furthermore, as previous studies focused largely on males, cortisol diurnal rhythms and stress reactivity should be investigated in females with DBDs and varying levels of CU traits.Cima and colleagues (2008) investigated morning and afternoon cortisol secretion in male psychopathic and nonpsychopathic prisoners and a healthy control group . All three groups showed a normal diurnal profile, with cortisol levels being significantly higher in the morning than in the afternoon. Neither prisoner group differed from controls at any time-point, but the nonpsychopathic prisoners had higher cortisol levels than the psychopathic prisoners at two of the four time-points (8:00 and 14:00\u00a0h), suggesting hyperarousal in the former group \u2022. HoweveSimilarly to Cima, Loomans et al. (2016) measured the CAR and afternoon and evening cortisol levels in male psychiatric inpatients and two healthy comparison groups . The authors investigated whether diurnal cortisol rhythms could differentiate between ASPD and psychopathic patients, and also between those with personality disorders and the general population. No differences in cortisol secretion between the personality-disordered groups were found, whereas both the ASPD and psychopathic groups  tended to show higher cortisol levels than the general population sample . This wan\u2009=\u200949) [A few studies have investigated relationships between psychopathic traits and cortisol reactivity to stress. For example, Johnson et al. (2015) assessed baseline cortisol levels and cortisol responses to the TSST in young adult male offenders (n\u2009=\u200949) . There wn\u2009=\u200949) , whereasn\u2009=\u200949) . A limitpositive associations. Nevertheless, studies with stronger methodological designs (including measurements of the CAR) are needed to draw firmer conclusions and investigate which aspects of the diurnal profile are affected.The majority of the studies described above investigated HPA axis activity in males alone. However, both sexes may display severe antisocial behavior and it is therefore important to consider similarities and differences between the sexes. Studies examining relationships between basal cortisol and CD symptoms in community samples have yielded mixed results, with Young et al. (2012) finding a positive association between CD symptoms and salivary cortisol levels in females, whereas a nonsignificant negative association was observed in males . SimilarIn terms of cortisol reactivity to stress, Kobak et al. (2009) found that sex moderated associations between antisocial behavior and cortisol responses to conflict discussions with caregivers in a community sample of adolescents . SpecifiAn early study by van der Wiel et al. (2004) investigated this important issue, examining whether cortisol reactivity to stress predicted treatment response in boys with oppositional defiant disorder. Lower cortisol reactivity at baseline predicted higher posttreatment aggression levels , suggestMore recently, Schoorl et al. (2017) investigated whether cortisol reactivity to stress or recovery after stress predicted outcomes in boys with DBDs who were treated using a parent training intervention. Boys who showed higher reactivity and more pronounced recovery following stress at baseline showed greater reductions in aggression over a 1-year period . Althougadaptation to early life stress or chronic adversity that would otherwise overwhelm the HPA axis and lead to neurotoxic effects of elevated stress hormones on the developing brain [An important question is whether cortisol hyporeactivity to stress or lower CARs in those with antisocial behavior are genetically determined or whether such abnormalities represent an ng brain \u2022\u2022. Exposng brain , 41, andng brain \u2022. It theng brain , may undng brain \u2022. A corosubjective responses to stress or lower basal cortisol, is difficult to reconcile with existing theoretical models, such as the sensation-seeking, underarousal, or fearlessness models of antisocial behavior [The finding that severe antisocial behavior is associated with cortisol hyporeactivity to stress, but not attenuated behavior , 45. Thebehavior , it seembehavior . Blair hbehavior . In contbehavior . HoweverIn summary, recent research using state-of-the-art methods to characterize the cortisol diurnal rhythm and CAR in children, adolescents, and adults with severe antisocial behavior has yielded mixed findings. Overall, the diurnal rhythm appears to be intact in antisocial populations, although flatter diurnal slopes and smaller CARs have been reported\u2014especially in adolescents with DBDs. In contrast to these mixed, but mostly negative, findings for basal cortisol, studies investigating cortisol reactivity to stress have yielded consistent evidence for hyporeactivity in children and adolescents with DBDs and adults with ASPD or psychopathy. Nevertheless, heterogeneity within antisocial behavior and psychiatric comorbidity both appear to influence cortisol reactivity, as CU traits appear to be associated with a more pronounced pattern of hyporeactivity whereas comorbid internalizing disorders predict heightened cortisol reactivity and impaired recovery following stress. As most research has focused on males, an important direction for future research is to investigate diurnal cortisol rhythms and stress reactivity in girls with DBDs and women with APSD. Researchers should also move away from using single-point determinations of cortisol, instead tracking cortisol levels across the day and the CAR to deepen our understanding of HPA axis-antisocial behavior relationships. Finally, longitudinal research designs that allow researchers to examine whether cortisol abnormalities predict the emergence or escalation of antisocial behavior over time, and also whether cortisol secretion normalizes in those who desist from antisocial behavior, will be important in understanding causal relationships between these constructs and identifying intervention targets."}
+{"text": "Although life longevity has increased across the world, evidence suggests some heterogeneity of the ageing process across individuals. To investigate different ageing patterns, the ATHLOS project harmonised data from 411,000 individuals across 17 existing cohort studies. The harmonised dataset provides comparable information on functioning measures, cognition, mental health, sociodemographic and lifestyle behaviours. To measure the process of healthy ageing across time and cohorts, we employed a Bayesian Multilevel Item Response Theory(IRT) and created a common metric of health status by using items of functioning. The IRT measurement model includes parameters describing the difficulty and discriminatory power of each item. We adopted the Bayesian Multilevel framework as it allows item parameters to vary among studies and the simultaneous estimation of all parameters under a Markov Chain Monte Carlo(MCMC) method. Finally, we assessed the predictive validity of the metric against mortality by performing a Receiver Operating Characteristic(ROC) curve analysis."}
+{"text": "Factor V Leiden (FVL) is the most common inherited hypercoagulable condition. It is a genetic disorder caused by a missense mutation that prevents inactivation of Factor V in the clotting cascade, leading to overproduction of thrombin and excess clotting. This pathophysiological process is especially unfavorable in patients undergoing free tissue transfer. Many authors have noted a propensity for both venous and arterial thrombosis leading to partial or complete flap loss. To date, there have been no published reports of patients with FVL undergoing deep inferior epigastric perforator flap reconstruction without flap complications. Here, the authors present two cases of successful free tissue transfer for breast reconstruction in patients with diagnosed FVL. The perioperative thromboelastography lab values are evaluated to help guide anticoagulation regimen for these high-risk procedures. Microsurgical procedures performed by skilled surgeons have shown a relatively low complication rate. In those rare instances of adverse events, the most common indication for reoperation in microvascular surgery is pedicle thrombosis . Most miThe first case describes a 48-year-old female who had an established diagnosis of heterozygous FVL with a positive family history and was diagnosed with left breast cancer in October 2010. She presented to our institution in November 2013 with painful capsular contracture from prior implant-based reconstruction and a desire for bilateral autologous reconstruction. After detailed counseling regarding her operative risks, she underwent bilateral implant removal, capsulectomy and bilateral sensate DIEP flaps. There were no significant perioperative adverse events. The patient received 3000 IU of intravenous unfractionated heparin (UFH) after both sets of anastomoses were performed. At her 2-year follow-up at our institution in early 2016, the patient was in good health with her flaps sensate and well-perfused . The authors adhered to the Declaration of Helsinki at all times."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Incomplete spinal cord injury (iSCI) is a life-long disability that typically results in a profound loss of locomotion capability. Current rehabilitation methods rarely restore full community ambulation, which in turn limits quality of life. Most individuals with iSCI exhibit persistent deficits in eccentric muscle control and reach recovery plateaus below the levels necessary for independent community ambulation. Eccentric motor control is essential during the weight acceptance phase of gait, which is emphasized during downhill walking. METHODS/STUDY POPULATION: The overground locomotion of subjects with chronic iSCI was analyzed both prior to and following a 12-week downhill body-weight-supported treadmill training regimen and compared to that of matched healthy controls in terms of kinematics, kinetics, and EMG activation. RESULTS/ANTICIPATED RESULTS: We expect to find significant differences between the controls and subjects with iSCI, with deficits in eccentric motor control accounting for some of these differences. In addition, we expect the downhill training to yield significant improvement in eccentric muscle control that translates into improvements in functional, overground walking for the subjects with iSCI. DISCUSSION/SIGNIFICANCE OF IMPACT: The goal is to determine if downhill training can improve eccentric motor control and extend recovery beyond established plateaus. OpenSim modeling of the experimental data will help quantify changes in eccentric control of individual muscles to clarify where specific gains are made."}
+{"text": "Transcranial Doppler (TCD) is a bedside, low-cost, and non-invasive technique able to evaluate cerebral hemodynamics ; the impWe discussed herein on how we use TCD in neuro-critically ill patients for hemodynamic indications; some of these proposals could also be used in non-brain injured critically ill patients at a high risk of cerebral complications.When the indications for invasive intracranial pressure (ICP) monitoring are met, we recommend intraparenchymal or intraventricular probes, as TCD cannot substitute invasive ICP measurement . HoweverAlthough the diagnosis of brain death is based on neurological examination, we use routinely TCD as an ancillary test to demonstrate the absence of cerebral blood flow (CBF) . We use We assess cerebral autoregulation (CA) at the bedside as altered CA is related with a poor outcome in many diseases and may increase the risk of cerebral damage . In caseDetection of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is crucial as this is one of the main determinants of delayed cerebral ischemia and poor neurological outcome in this setting . AlthougWe often use TCD to monitor brain hemodynamics in critically ill patients. Future TCD development, such as the assessment of the compliance of arterial and cerebrospinal fluid compartment as well as critical capillary closing pressure, will further expand its use in this setting .Additional file 1: Table S1. Factors that may influence pulsatility index (PI) and flow velocities. (DOCX 13 kb)"}
+{"text": "Tribulus terrestris were more prominent in raising LH and Testosterone levels  whileThe mechanisms of action of these phytotherapics are poorly understood, especially for the less-studied Anacyclus pyrethrum. This herb has been proposed for different conditions , althprimum non nocere which should be always applied when proposing any therapy, including herbal therapies. When studying any treatment for a specific condition, is important to have a more global perspective, evaluating potential side-effects of the proposed medication. Specifically, for Tribulus terrestris, our group recently showed this herb leads to arterial blood pressure increase and renal morphology alteration with glomerular loss (Since the ancient Greece Hippocrates advocated the principle of lar loss . This ki"}
+{"text": "Dear Editor,Organophosphate insecticides (OPI), derived from phosphoric, phosphonic or phosphinic acids, find application as agents for controlling insect pest populations. OPIs elicit their characteristic toxicity by phosphorylating and inhibiting the enzyme, acetylcholinesterase (AChE). Cholinergic stress resulting from overstimulation of nicotinic- and muscarinic acetylcholine receptors is the chief mechanism of acute toxicity of OPI (Fukuto, 1990; Abou-DoA large number of animal studies explicitly demonstrate that OPIs have the propensity to cause hyperglycemia, perturbations in carbohydrate metabolism and endocrine dysregulations. Repeated exposure to OPI precipitates insulin resistance (studies listed in Table 1Authors are thankful to Jain University, Bangalore for the support.The authors declare no conflict of interest."}
+{"text": "This research examined the relation between physical activity, pain, and mood among older adults with osteoarthritis (OA). Physical activity is associated with long-term maintenance of function in persons with chronic pain , but less is known about the association between objective measures of activity and transient mood states. Therefore, we captured the activity and mood levels of 218 older adults with knee OA over a seven-day period. Wrist and waist accelerometers captured small and large motor movements. Self-reported momentary pain and affect were collected through phone calls four times daily. We examined average and peak activity levels over the 4-hour windows between self-reports. Cross-sectionally, there was no association between momentary pain and activity. Average large motor movement was positively associated with positive affect and negatively associated with negative affect. Analyses revealed one association between affect and average previous activity; small motor movements predicted greater positive affect. Peak levels of both movements predicted greater positive affect, but only peak wrist activity predicted negative affect. Peak small motor movement at the previous call was associated with both positive and negative affect. These results provide insight into the unique contributions of small and large motor activity to mood and pain states. It appears that average large motor movements and prior small motor activity may have the greatest impact on momentary affect. Further study of distinct activity types and mood will be important for understanding and improving the quality of life among individuals diagnosed with OA (Supported by R01-AG041655)."}
+{"text": "Individuals who identify as lesbian, gay, bisexual, transgender or other non-heterosexual or binary gender identifiers (LGBTQ) face tremendous obstacles in search of quality healthcare. Older LGBTQ adults face these obstacles in the setting of more complex health problems with few social services and support. Negative treatment from healthcare professionals has proven to be one of the most pervasive barriers to care faced by older LGBTQ adults. Sensitization training with the film, Gen Silent, is one way knowledge gaps and biases of healthcare professionals has been addressed. By utilizing the survey previously validated by Porter et al., health professionals\u2019 knowledge, perceptions, and attitudes toward LGBTQ older adults before and after viewing Gen Silent were assessed in Lehigh Valley Health Network (LVHN)-affiliated primary care practices. The principle outcome of this study was a statistically significant change in responses. Primary care practices were recruited for 45-minute sessions that included the showing of an educational, abbreviated version of Gen Silent to available staff. It was preceded by administration of a pretest survey and followed by a posttest survey and discussion. A paired t-test was conducted to determine significance of differences between pre- and posttest responses. Seventeen individuals (N=17) viewed the film and finished pre- and posttest surveys. Nearly all questions exhibited changes between pre- and posttests. Significantly, respondents indicated increased awareness of additional barriers to care faced by LGBTQ older adults compared to heterosexual peers. While limited, these results indicate that primary care professionals would benefit from training specific to the aging LGBT population."}
+{"text": "This study operationalized the third dimension of Rowe & Khan\u2019s Successful Aging model, social engagement, as neighborhood connectedness. We examined 2820 older adults in the MIDUS III dataset to assess the impact of neighborhood connectedness on life satisfaction and daily spiritual experiences. A composite scale for neighborhood connectedness (Cronbach = .745) was created. Linear regression analysis was undertaken for life satisfaction on daily spiritual experience, neighborhood connectedness, neighborhood environment and age controlling for gender, co-habitation, income, and disability. Regression analysis was also conducted for daily spiritual experience on the same variables. Analysis for each outcome variable was run three times to explore changes across three age groups of older adults . Results of regression analysis found frequency of daily spiritual experience was a substantial and significant predictor of life satisfaction for all age groups  Additionally, regression analysis revealed a higher level of neighborhood connectedness was the most powerful predictor of daily spiritual experience across all age groups  This study demonstrates the applicability of operationalizing the Successful Aging model\u2019s social engagement dimension as neighborhood connectedness. This study also contributes evidence of the impact of daily spiritual experience on life satisfaction. Finally, the study supplies promising new evidence linking neighborhood connectedness with spiritual well-being."}
+{"text": "The benefits of mobility devices for knee Osteoarthritis Patients include reducing burden of knee joint, enhancing confidence and increasing autonomy, yet many who might benefit from using mobility devices do not use them. The purpose of this study is to explore the cognition and using experiences about mobility devices use in patients with knee osteoarthritis of China. Naturalistic inquiry research was adopted, 15 patients with knee osteoarthritis were recruited and Semi-structured interviews were conducted. Data were analyzed based on conventional content analysis methodology. Two themes of using experiences about mobility devices were extracted, including positive feelings, negative feelings. Cognition about mobility devices use included light consciousness, incorrect attitude. Mobility devices have a positive effect on knee osteoarthritis patients, but some patients lack sufficient understanding and face many problems in the use of mobility devices. Policy Support, greater physician involvement, positive peer modules, and safe, visually appealing devices would promote greater acceptance and satisfaction of mobility devices with knee osteoarthritis patients."}
+{"text": "Transcranial Direct Current Stimulation (tDCS) is a potentially useful tool to improve upper limb rehabilitation outcomes after stroke, although its effects in this regard have shown to be limited so far. Additional increases in effectiveness of tDCS in upper limb rehabilitation after stroke may for example be achieved by (1) applying a more focal stimulation approach like high definition tDCS (HD-tDCS), (2) involving functional imaging techniques during stimulation to identify target areas more exactly, (3) applying tDCS during Electroencephalography (EEG) (EEG-tDCS), (4) focusing on an effective upper limb rehabilitation strategy as an effective base treatment after stroke. Perhaps going even beyond the application of tDCS and applying alternative stimulation techniques such as transcranial Alternating Current Stimulation (tACS) or transcranial Random Noise Stimulation (tRNS) will further increase effectiveness of upper limb rehabilitation after stroke. Impaired arm function after stroke is both frequent and a considerable burden for people with stroke and their caregivers. An emerging approach for enhancing neural plasticity after acute and chronic brain damage, thus enhancing rehabilitation outcomes in the upper limb rehabilitation after stroke, is non-invasive brain stimulation (NIBS), for example delivered by transcranial direct current stimulation (tDCS) . tDCS isMany small trials regarding the effects of tDCS on arm motor function poststroke were undertaken in the past with partly promising but not conclusive results , 3. BaseThe problem of limited focal specificity of tDCS may lead to an ineffective stimulation and in turn may be reduced by the application of HD-tDCS, which involves up to five small electrodes, arranged in a ring, instead of two big conventional sponge electrodes for delivering direct current. The positioning of HD-tDCS for improving arm motor function after stroke has been described elsewhere.  On the oTDCS during fMRI has already successfully been applied in language production tasks in healthy people and in people with stroke . MeinzerBased on EEG data, it is possible to measure cortical activity after or even during tDCS with superior temporal resolution . There aSince tDCS enhances neuroplasticity by modulating cortical activity, the application of an efficient base therapy, resulting in sufficient cortical activity, is still crucial. Therefore is has to be kept in mind that tDCS has to be applied in combination with an appropriate and individually selected and effective arm training: For instance in people with severe arm paresis it makes sense to apply electromechanically-assisted arm training whereas in people with only minor arm paresis a forced use paradigm seems to be promising to improve arm function and to overcome learned non use. There is a considerable evidence base regarding effective base treatments during tDCS for improving upper limb rehabilitation outcomes poststroke.An alternative to tDCS could be the application of transcranial Alternating Current Stimulation (tACS) to increase excitability . tACS aiAnother recent non-invasive approach to brain stimulation is transcranial Random Noise Stimulation (tRNS) . tRNS deThe mode of action of tDCS is not fully understood yet, which has implications for its clinical application: for example, tDCS suffers from a lack of focality of stimulation, and attaining neurophysiological data in adequate spatial and temporal resolution for further exploration of its mode of action remains challenging. HD-tDCS may be a one tool for reducing variability in future tDCS trials in upper limb rehabilitation after stroke by increasing focality of stimulation. Together with tDCS during fMRI, which allows for superior spatial resolution, online EEG-tDCS delivering superior temporal resolution could give valuable insights into tDCS mechanisms. Hopefully, this will improve our understanding of tDCS in upper limb rehabilitation in people with stroke and corollary also its clinical application. However, with tDCS being rather a facilitatory intervention thus needing an effective base treatment resulting in sufficient neuroplasticity, it requires efficient interventions delivered by therapists .Particularly from the perspective of clinicians, it eventually should be kept in mind that despite the currently considerable research interest in tDCS, it is still likely that tDCS reveals only small or even no additional benefits to arm rehabilitation after stroke."}
+{"text": "There is solid epidemiological evidence demonstrating that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing colorectal cancer, and to a lesser extent gastric and esophageal cancers[1]. Importantly, NSAIDs suppress colon polyp formation and progression in patients diagnosed with familial adenomatous polyposis coli (APC)[2]. In many animal studies, NSAIDs have been shown to prevent tumor formation and slow tumor progression, thus confirming and extending the clinical observations. Recent findings have demonstrated that NSAIDs inhibit angiogenesis, suggesting that the tumor suppressive activity of these drugs may be due, at least in part, to their ability to inhibit tumor angiogenesis[6]. The study of the mechanism by which NSAIDs suppress tumor angiogenesis, is matter of intense research."}
+{"text": "Cognitive health, physical function, and chronic disease represent interdependent health outcomes that may exert influence on the course of each other\u2019s development. To investigate the association between baseline health in each domain and developmental change across domains, we estimated trajectories of working memory, mobility limitations, and comorbidity among US adults age 65 and older over 18 years. We drew observations from the nationally-representative Health and Retirement Study with an analytic sample consisting of 5,963 adults age 65 and over in 1998. Immediate word recall, an 11-item Nagi scale of mobility limitations, and a summary count of eight doctor-diagnosed chronic conditions were measured biennially from 1998 to 2016. Parallel-process quadratic growth models with individually-varying time scores were used to estimate non-linear trajectories of each health measure, allowing identification of associations between baseline health and developmental change in each health process at both earlier and later stages of older adulthood. All estimates adjusted for covariates, complex survey design, and missing data. Greater baseline immediate word recall was associated with less rapid increase in mobility limitations at earlier ages. More baseline mobility limitations were associated with faster increase in comorbidity at earlier ages. Greater baseline chronic conditions were associated with more rapid increase in mobility limitations at later ages. These results highlight the importance of conceptualizing health among older adults as an interdependent and developmental process and should help clinicians recognize that single-domain health status may influence the progression of other health outcomes at different stages of older adulthood."}
+{"text": "Background: Thoracic Aortic Injury (TAI) due to penetrating or blunt chest trauma is a critical life-threatening aortic injury. Its diagnosis and treatment always is challenging.mmHg despite multiple anti-hypertensive drugs. Trans-Thoracic Echocardiography (TTE) revealed abnormal Doppler flow pattern in proximal descending thoracic aorta suggestive for probable coarctation of aorta. Chest CT scan revealed pseudoaneurysm of the descending thoracic aorta just below the isthmus. Due to uncontrolled hypertension, persistent hemothorax and probable aortic pseudoaneurysm presenting as aortic luminal narrowing, surgical resection of the aneurysm was planned.An 18-year-old male was admitted due to blunt chest trauma after a high-impact road traffic collision. According to presenting dyspnea, an emergency chest-x-ray revealed left hemothorax for which chest tube was inserted. Hemodynamic monitoring demonstrated uncontrolled hypertension with systolic blood pressure of 200\u2013220 The postoperative course was uneventful and blood pressure normalized without any drugs. Patient is normotensive after 8 years follow up. Thoracic Aortic Injury (TAI) due to penetrating or blunt (more common) chest trauma is the most frequent type of traumatic aortic injury and is a catastrophic and also final scenario in most circumstances . Blunt TAs aortic dissection may be associated with a hypertensive crisis, the patients must be ICU admitted and dedicated control of blood pressure is very important to reduce the progressive process of dissection.Once the clinical suspicion of acute aortic dissection is suggested, intravenous (IV) antihypertensive regimen should be started as soon as possible in emergency department in all non-hypotensive patients and continued in the intensive care unit or the operation room. Systemic blood pressures, urine output, consciousness, and focal neurologic signs should be regularly checked for any derangement owing to complications.Surgical techniques can be open surgery with a clamp-and-sew technique, surgery with the use of a vascular graft, and using heparin-less partial cardiopulmonary bypass. Recently new endovascular techniques have been largely introduced as a therapeutic choice in traumatic and non-traumatic aortic injury in descending and abdominal aorta.mmHg despite multiple anti-hypertensive drugs. Another CT scan revealed pseudoaneurysm of the descending thoracic aorta.An 18-year-old man with shortness of breath and left sided bloody pleural effusion was admitted in this center. The patient did not have any underlying disease. The patient was pale and bilateral lower extremity pulses were not palpable. There was history of blunt chest trauma after an acceleration- deceleration traffic collision 12 days ago. After resuscitation and stabilization of the patient, because of dyspnea and hemothorax, an emergency chest-x-ray showed left hemothorax and chest tube was inserted. Patient referred to tertiary lung disease center due to persistent dyspnea and admitted to ICU because of low O2 saturation. Hemodynamic monitoring in ICU demonstrated severe refractory uncontrolled hypertension with systolic blood pressure of 200\u2013220 Bedside Trans-Thoracic Echocardiography (TTE) from suprasternal notch revealed abnormal continuous Doppler flow pattern in proximal descending thoracic aorta suggestive for probable coarctation of aorta  and aortThe patient underwent left sided thoracotomy and a transection of aorta in the posterior surface of aorta just after the isthmus was found which resulted in pseudoaneurysm formation. After excision, the aorta was repaired with a 16 mm Gore-Tex interposing graft .th post-operative day. Follow up imaging with Magnetic Resonance Imaging (MRI) revealed normal anatomy of the aorta without luminal narrowing two weeks after operation. No complication occurred and patient had normal blood pressure after 8 years follow up.The postoperative course was uneventful and blood pressure normalized without any drugs and the patient had full recovery on the 7Traumatic damages to aorta are accomplished with wide range of aortic damages including minimal aortic injury, aortic laceration or transverse aortic tearing. Aortic transection is also known as aortic rupture, aortic pseudoaneurysm and aortic intramural hematoma.Supine chest-x-ray is the initial screening test in the traumatic patient. A large autopsy survey reported that 97% of victims of aortic injury had additional traumatic damages in other regions. Indirect signs suggestive for aortic injury are mediastinal hematoma and widening or concomitant multiple rib fractures. Other imaging tests such as contrast enhanced-CT scan, Magnetic Resonance Angiogram (MRA), or aortic angiogram may be used to determine if aortic tear is present. Another noninvasive diagnostic test that may be used is bedside echocardiography that had been conducted for this patient and demonstrated TAI.Regarding the mechanism of refractory hypertension in this case, aortic luminal narrowing or kinking just after aortic injury site in isthmus with a pseudocoarctation physiology presenting as continuous Doppler flow pattern in descending aorta was completely normalized after successful surgical aortic repair.There are different guidelines for medical treatment of hypertension in these patients . Over thThe striking aspects of the case were new-onset refractory hypertension in previously normotensive young man and echocardiographic findings mimicking aortic coarctation as result of traumatic transection of aorta and amenability of lesion to surgery and complete correction of hypertension after surgical repair.Blunt traumatic TAI is a deadly catastrophe with disappointing survival rates, as confirmed by previous studies and immediate death rate of more than 75% , 12. In"}
+{"text": "Active citizenship is romanticized in policy for its role in keeping older adults healthy, and rural communities sustainable. However, as proportions of older adults resident in rural communities continue to increase, the gerontological literature has begun to highlight challenges associated with both the capacity and desire of rural older adults to be active citizens. Through an integrative review of the international literature, this paper interrogates how active citizenship trends among rural older adults support or hinder healthy aging in rural settings. Findings indicate that active citizenship among older adults can increase rural age-friendliness and facilitate individual wellbeing. However, practices associated with active citizenship among this cohort can disenfranchise certain groups of older adults, through reshaping societal norms relating to citizenship, age-friendliness and rurality. These findings indicate that programs designed to promote active citizenship must both consider, and account for, diverse capacities and desires for active citizenship among rural older adults."}
+{"text": "Resting-state functional connectivity (FC), which measures the temporal correlation of spontaneous hemodynamic activity between distant brain areas, is a widely accepted method in functional magnetic resonance imaging (fMRI) to assess the connectome of healthy and diseased human brains. A common assumption underlying FC is that it reflects the temporal structure of large-scale neuronal activity that is converted into large-scale hemodynamic activity. However, direct observation of such relationship has been difficult. In this commentary, we describe our recent progress regarding this topic. Recently, transgenic mice that express a genetically encoded calcium indicator (GCaMP) in neocortical neurons are enabling the optical recording of neuronal activity in large-scale with high spatiotemporal resolution. Using these mice, we devised a method to simultaneously monitor neuronal and hemodynamic activity and addressed some key issues related to the neuronal basis of FC. We propose that many important questions about human resting-state fMRI can be answered using GCaMP expressing transgenic mice as a model system. Temporal correlation of spontaneous hemodynamic signals, commonly referred to as FC , is one Several groups have recently used transgenic mice expressing a genetically encoded calcium indicator (GCaMP) in neocortical neurons  to simulUsing this method, we examined the relationship between fast spatiotemporal patterns of neuronal calcium activity and the spatial pattern of FC. We found a significant relationship between two seemingly different types of large-scale spontaneous neuronal activities \u2013 namely, global waves propagating across the neocortex and transient coactivations among cortical areas sharing high FC. Different sets of cortical areas, sharing high FC within each set, were coactivated at different timings of the propagating global waves, suggesting that spatial information of cortical network characterized by FC was embedded in the phase of the global waves . FurtherThe proposed method also allows us to ask questions related to newly developed analyses methods for FC in human fMRI . In contThe temporal fluctuation of FC across short time-windows does not necessarily indicate non-stationary FC. Indeed, recent studies using resting-state fMRI in humans reported that the temporal fluctuation of FC cannot be distinguished from that in a model assuming stationary FC and statistical sampling error ,24. ApplThere are several future applications of the proposed method. For example, resting-state FC in mouse models of mental diseases can be used to examine the possibility of diagnosis based on resting-state FC . Genetic"}
+{"text": "Gerardo Ferbeyre , Francis Rodier,  and Daohong Zhou . In his welcoming speech, Dr. Ferbeyre summarized the key aspects that have attracted so much interest in cellular senescence including its ability to act as a tumor suppressor mechanism but also to promote aging and age-linked diseases , ICSA president Manuel Serrano  and NCI director Ned Sharpless . Dr. Sharpless presented in his keynote lecture how the key senescence gene and tumor suppressor p16INK4A acts as a double-edged sword to regulate aging, health span and cancer incidence.More than two hundred scientists gathered in Montreal on July 8, 2018 for the International Cellular Senescence Association (ICSA) Meeting to discuss the biological and medical impact of cellular senescence. The meeting was organized by diseases . The duaFrederic Lessard from the Ferbeyre laboratory , described the senescence-associated ribosome biogenesis defects and how they are linked to the inhibition of CDK4 via accumulation of ribosome-free RPS14. This work expands the extraribosomal functions of ribosomal proteins, which are now linked to both the p53 and the RB tumor suppressor pathways [Guadalupe-Elizabeth Jimenez  showed an intriguing connection between B-distroglycan and the nucleolus in senescent cells. Jiri Bartek , delivered the EMBO Keynote lecture summarizing the role of replication stress and the DNA damage response in cellular senescence [Fred Dick , presented novel roles of RB suppressing the expression of satellite repeats and regulating chromosome condensation [Karl Riabowol  presented a link between senescence and endocytosis via RB in cells that express the ING1a epigenetic regulator. Jesus Gil  and Mathieu Desch\u00eanes  presented data linking the control of alternative splicing to cellular senescence.nescence . Recent Xiaolu Yang  explained how p53 represses major forms of NADPH generation via distinct mechanisms, clarifying why reactive oxygen species and oxidative damage accumulate in senescent cells. Talks form Eiji Hara , Maria Grazia Vizioli  and Andrea Ablasser , provided links between DNA metabolism, the activation of the cGAS-STING pathway and the regulation of the senescence-associated secretory phenotype (SASP). Masashi Narita  summarized the dual role of autophagy in cancer and presented a mouse model where conditional inactivation of ATG5 altered cancer susceptibility. Fr\u00e9d\u00e9rick A. Mallette  presented an intriguing connection between cholesterol 25-hydroxylase (CH25H) and cellular senescence. In a mouse model of retinopathy [Ch25h mRNA levels increased and correlated with induction of features of cellular senescence in the retina. Perhaps, related to this discovery, Dr. Hara presented evidence that another cholesterol metabolite, deoxycholic acid (DCA), induced senescence in liver cells; interestingly, DCA is produced by the gut microbiota during obesity in mice and facilitates the development of hepatocellular carcinoma [Several talks described a clear connection between senescence and metabolism. arcinoma .Andrei Gudkov  challenged several existing views of senescence from the analysis of the transcriptome of senescent cells and cells arrested by contact inhibition. Using principal component analysis he proposed that the gene expression pattern of senescent cells is a superposition of two components: one, which depends on the time cells are in culture without dividing, and the other one, which depends on the type of treatment. Oliver Bishof  also presented a kinetic transcriptome analysis of cells rendered senescent by oncogenic ras. He described an intriguing dynamic gene expression program driven by a hierarchical network of transcription factors reminiscent of a developmental process. Along the same lines, Judith Campisi discussed how multiple functional senescence-associated phenotypes are interlaced and dynamic in the senescence program, particularly in different cells types and tissue contexts, and presented a new effort to globally identify senescent cells surface molecules.Scott Lowe , who together with Manuel Serrano discovered the process of oncogene induced senescence, presented data explaining how cancer cells can be forced into an RB-dependent but p53-independent senescence using a combination of a MEK inhibitor with the CDK4 inhibitor palbociclib. Intriguingly, this treatment also engages NK cells to kill senescent tumor cells, underscoring the view that pro-senescence cancer therapies benefit from immune surveillance mechanisms. Regarding immune clearance of senescent cells, Christian Beausejour  revealed his efforts to develop novel humanized mouse models to better mimic interactions between senescent cells and immune cells. He showed that senescent human cells are not always immunogenic in this context, suggesting strong context-dependent effects and the importance of using relevant models. The importance of the elimination of senescent cells after treatment was highlighted in several talks. Clemens Schmitt  was the first keynote speaker of the meeting. He presented evidence for an underlying stemness gene expression signature in senescent cells. Cells that managed to escape from senescence, take advantage of this stemness program to form aggressive cancers [Konstantinos Evangelou  also focused on cells that escaped from senescence as demonstrated with a novel senescence biomarker (SenTraGorTM) [Corinne Abbadie  characterized the senescence response to irradiation in fibroblasts at the margin of an irradiated field. She explained that these cells accumulate single- stranded breaks but not double-stranded DNA breaks and they were able to escape from senescence giving rise to a progeny of mutated cells. From a more clinical angle, Francis Rodier explored the occurrence of therapy-induced senescence in human cancer patients particularly demonstrating that senescence occurs in response to ovarian cancer chemotherapy. Interestingly, the presence of senescence hallmarks in treated ovarian tumors predicted beneficial outcomes in patients, suggesting that senescence biomarkers could help inform cancer treatment strategies and that senescence becomes a target for pharmacological manipulation in human ovarian cancer therapy. Olivier Coqueret  presented data on TSP1 acting as a cytokine that prevents escape from senescence and described how its receptor CD47 regulates escape from the senescent arrest. Dr. Serrano presented data indicating that palbociclib, a CDK4 inhibitor approved for the treatment of some cancers, accumulates in lysosomes and this prolongs its biochemical effects explaining the induction of senescence even after a short period of exposure to the drug. The storage of palbociclib into lysosomes also accounts for its delayed and long-term release to the external milieu and the efficient induction of paracrine senescence, which in this case is mostly due to the drug and not to the SASP. Marco Demaria  further expanded on the use of CDKi to induce a potentially less inflammatory senescence response in normal and cancer cells, as he demonstrated the lack of a typical SASP in this context. He suggested that this could be beneficial in some therapeutic contexts, but harmful in others, as SASP-less senescence might alter normal immune clearance of senescent cancer cells. In summary, a theme emerged that any therapy that aims to induce or reinforce senescence in tumors should also be combined with strategies to prevent escape from senescence or to stimulate the elimination of senescent cells.A number of talks solidified the view that senescence is a powerful tumor suppressor mechanism.  cancers . KonstanraGorTM) . EscapedraGorTM) ,10. CoriJan Van Deursen  presented recent evidence that the elimination of senescent cells can induce regression of advanced atherosclerosis without any detectable side effects. Jennifer Hartt Elisseeff  showed that clearance of senescent cells using senolytics attenuates osteoarthritis development. The connection between senescent cells and immune responses to injury and repair was presented. Darren Baker  presented experimental evidence that senescent cells promote neurodegeneration in mutant tau mice [James Kirkland , showed that transplanting senescent cells to young mice caused frailty, diabetes and osteoporosis accelerating death from all causes. A cocktail of quercetin and dasatinib, a SRC-family kinase inhibitor, can kill senescent cells and revert their pathological effects both in senescent-cells transplanted young mice or in naturally aged mice, extending median life span up to 36% [Salvador Macip  found another kinase, BTK, which activates the tumor suppressor p53 inducing senescence [Irina Conboy  used parabiosis to demonstrate the presence of factors in the serum of old mice that can induce senescence in young mice suggesting that some senescent cells in vivo may originate from extrinsic factors. She also presented interesting data on enhanced myogenesis and reduced liver adiposity, but no improvement in hippocampal neurogenesis in the old 3MR mice, when p16-high cells were experimentally ablated. Albert Davalos (Buck Institute for Research on Aging) followed-up on his earlier discovery that the alarmin HMGB1 is a key regulator of the proinflammatory SASP [Myriam Gorospe,  identified proteins expressed at the surface of senescent cells. SCAMP4 was found to favor the SASP [Mei Wang  presented her work showing that mesenchymal stem/progenitor cells (MSPCs) in primary spongiosa of long bone during late puberty undergo a normal programed senescence. MSPC senescence is epigenetically controlled by the polycomb histone methyltransferase Ezh2 and its H3K27me3 mark. Loss of Ezh2-H3K27me3 in young mice leads to premature cellular senescence followed by impaired osteogenesis and bone loss, and antagonizing cellular senescence by manipulating epigenetic factors may be a potential approach to treat pediatric or juvenile osteoporosis. Maria Almeida  discussed the role of senescent osteocytes in age-related bone loss via production of increased levels of RANKL and the therapeutic potential of senolytic agents in preventing and treating osteoporosis by targeting senescent cells in the bones [Claude LeSaux  reported some new interesting findings that eicosanoids such as prostaglandins and leukotrienes may function as new SASP factors and play an important role in the pathogenesis of pulmonary fibrosis. Together these studies show the tremendous potential of senolytics to improve health at old ages.One of the most exiting trends in senescence research is the concept of senolysis or the specific elimination of senescent cells . Jan Vantau mice  and theip to 36% . Salvadonescence . Ibrutinory SASP  by showithe SASP . Mei Wanhe bones . Claude Daohong Zhou  presented some new development of Bcl-xl-targeted senolytic agents using proteolysis targeting chimera (PROTAC) technology. These Bcl-xl PROTACs that target Bcl-xl to an E3 ligase for ubiquitination and degradation exhibit an improved potency against senescent cells but reduced toxicity to normal cells and platelets compared to navitoclax or ABT-263 and thus have the potential to be developed as a safer senolytic agent. John Lewis  described a clinically viable gene therapy consisting of a suicide gene under a senescent cell promoter delivered in vivo with fusogenic lipid nanoparticles (LNPs) to deplete senescent cells. This approach represents a first-in-class therapeutic that targets cells based on transcriptional activity, rather than surface markers or metabolism. Guangrong Zheng  identified a dietary natural product, piperlongumine, as a novel senolytic agent. It can selectively kill senescent cells by targeting oxidation resistance 1 (OXR1), an important oxidative stress sensor that regulates the expression of a variety of antioxidant enzymes. His finding may lead to the development of better senolytic agents [Daniel Munoz-Espin  described the design of a new targeted-drug delivery system to senescent cells using the technology of the encapsulation of drugs with galacto-oligosaccharides because of the high lysosomal \u03b2-galactosidase activity of senescent cells. He showed that gal-encapsulated cytotoxic drugs can selectively target senescent cells in a tumor xenograft mouse model to improve tumor regression and toxicity. This senescent cell selective drug delivery method opens new diagnostic and therapeutic applications for senescence-associated disorders. At the end of the meeting Ned David  delivered a talk summarizing how his company is translating basic research on senescence into clinical trials using several senolytics. Senescence is undoubtedly at the forefront of biomedical research. The next ICSA meeting in Athens 2019 will reveal additional exiting research: stay tuned!The promise that clearance of senescent cells with a therapeutic agent may prolong the health span and treat age-related diseases stimulates the research in finding new senolytic agents, therapeutic strategies, and delivery methods. c agents . Daniel"}
+{"text": "Aging of the vasculature is the leading risk factor for cardiovascular and cerebrovascular disease . As suchThe healthy artery comprises endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and the extracellular matrix (ECM), all of which are susceptible to damage or disruption during aging . The intRapid advances in geroscience have identified a \u2018Molecular Signature\u2019 for the aged vessel that represents distinct underlying intracellular and extracellular molecular processes . IntraceAlthough all of these processes are associated with vascular aging, it is unclear whether they are a cause or consequence of aging, how they are inter-related, and whether targeting one or more is sufficient to prevent or delay vascular aging. For example, we recently reported that mitochondrial function progressively deteriorates with aging of mouse arteries, associated with reduced mitochondrial DNA copy number (mtCN) and expression of enzymes that regulate mitochondrial DNA synthesis; we showed that increasing mtCN enhanced mitochondrial function and delayed the onset of multiple structural and functional parameters of vascular aging . Althoug+) booster nicotinamide mononucleotide (NMN) promoted angiogenesis and recapitulated the benefits of exercise via sirtuin 1-mediated inhibition of Notch signalling in aged exercised mice [In contrast, the ability of enhanced mitochondrial function since birth  to delay vascular decline suggests that preventative and early intervention are key to delay vascular aging. Indeed, several studies have demonstrated beneficial effects of long-standing lifestyle changes such as caloric restriction (CR) and exercise, and compounds that mimic these processes. For example, \u03b2-hydroxybutyrate, a ketone released naturally during CR, enhances cell division and protects against DNA damage and cellular senescence in ECs and VSMCs in older fasted mice via the Oct4-mediated LaminB1 pathway [sed mice .Vascular stiffness is a major link between normal vascular aging and development of vascular complications. Although the marked changes in ECM content and structure in aging influence vascular mechanical properties directly, aging also affects cell-ECM interactions, and the stiffness of VSMCs themselves. For example, VSMCs can take on a stiffness phenotype  dependenIn summary, identification of the distinct molecular pathways involved in vascular aging provides great potential for therapeutics. Research efforts should focus on disentangling the complex interactions between the molecular processes involved, and testing the feasibility and timing of administration of potential therapeutics that can limit the effects of oxidative stress, mitochondrial dysfunction, cellular senescence, and DNA damage. Arterial stiffness and central blood pressure (cBP) are excellent predictors of age-related complications  and can"}
+{"text": "Older adults are increasingly occupying multiple life roles, including working, caregiving, and volunteering, creating the opportunity for role conflict. Such conflict occurs when stress and strain created by the demands of multiple life roles outstrips an individual\u2019s resources to successfully manage such demands. A two-phase research study was recently completed with 1,697 RSVP volunteers drawn from 55 RSVP program sites across the country (Phase I) with a follow-up survey of RSVP programs conducted with 17 sites (Phase II). Grounded in role theory, the Phase I volunteer survey explored role conflict in addition to self-reported strategies used to mitigate the experience of role conflict. The Phase II program survey gathered responses from volunteer managers and staff about the strategies used by their older adult volunteers to avoid and address role conflict. Based on findings from both surveys, caregivers engaged the following strategies in order to minimize role conflict: obtaining respite care, and volunteering alongside their care recipient. Worker-specific strategies focused largely on time management and included volunteering during off-work hours and completing time-limited volunteer assignments. While a high level of convergence was noted between volunteer manager and volunteer perspectives, two themes emerged from the volunteer survey that were not identified in program survey responses: seeking volunteer opportunities that leverage similar skills and experiences across roles and seeking volunteer opportunities that provide a different experience from that of other roles. Implications for future research and volunteer management strategies will be discussed."}
+{"text": "This presentation will review the design, methods, and early lessons learned from the Making Engagement Meaningful through Organized Routine Interaction (MEMORI) Corps trial recently funded by NIA. This trial is evaluating the feasibility and efficacy of the MEMORI Corps program, a novel 12-week activity-based companion care model designed to mobilize and equip senior volunteers to deliver individualized, evidence-based activity programming to persons with dementia PWD living at home and offer family CGs needed respite. The intervention synthesizes and adapts prior evidence-based work from the Tailored Activities Program\u00ae (an activity-based intervention persons with dementia), Experience Corps\u00ae , and MIND at Home\u00ae (a home-based dementia care coordination program) to simultaneously address unmet respite care needs of family CGs, provide PWD structured meaningful activities and social engagement, and provide meaningful engagement and peer support opportunities for senior volunteers."}
+{"text": "The Florida Department of Elder Affairs (DOEA) provides programs and services for over 65,300 older people and adults with disabilities. These individuals are uniquely vulnerable and may be displaced, and/or disoriented during natural disasters. DOEA clients are dependent upon community-based services to provide supervision or assistance to perform basic self-care, which often makes sheltering in place alone a danger to their health and well-being. During Hurricane Michael (2018) many older adults who previously were independent sought help for many issues including property damage, utility interruption, food and medicine scarcity, and physical or mental health problems associated with the storm and its aftermath. In normal conditions, DOEA identifies older populations via Census tracts and then conducts outreach events to inform the public how to access social services. However, after the widespread displacement post-storm, traditional outreach approaches were insufficient. A method was needed to remove areas that were rendered uninhabitable and find who remained in place. DOEA identified viable neighborhoods by overlaying property damage locations on base layers of Census tracts with concentrations of older adults and polling places with high percentage of age 60+ voter participation in the subsequent November election. Then in partnership with Feeding Florida, we provided information and registration assistance via local food distribution sites in those areas. This methodology of overlaying Division of Emergency Management property damage records and voter participation records against publicly available Census tract files is a strategy that could be replicated by other disaster and flood-prone communities or organizations that have similar needs."}
+{"text": "Caring relationships between older residents and nurse aides are fundamental in terms of service delivery in nursing homes. However, little is known for the nuanced dynamics of this relationship in China. The purpose of this study is to explore how caring relationships develop between older residents and nurse aides in the nursing home setting in urban China. Informed by the dyadic perspective, this study illustrates the development process and relational nuances by simultaneously eliciting residents\u2019 and nurse aides\u2019 perceptions. This qualitative study purposively sampled 20 matched resident-nurse aide dyads (N= 40) in a government-sponsored nursing home in Shanghai. Participants participated in semi-structured, in-depth interviews from January to June 2017. Thematic analysis was performed. The findings reveal that the caring relationship began with nursing home assignment and primarily focused on instrumental assistance. Gradually, emotional involvement grew within dyads and reciprocity emerged. Based on different dyadic perceptions, this study conceptualized four types of caring relationships: (a) parent-child alike, (b) mutually respectful, (c) solo performance, and (d) reasonably detached. The findings suggest that residents and nurse aides could have different views on caring relationships, which further influenced the relationship development. The four types of caring relationships shared some similar traits while differentiating from some of the common types of interactions found in the existing nursing evidence across the world. Chinese filial tradition also influenced the relationship dynamics."}
+{"text": "Purpose. to report malignant glaucoma and infectious crystalline keratopathy as complications after an uneventful Descemet Membrane Endothelial Keratoplasty (DMEK), and corneal clearance despite graft detachment after the surgery in a patient with pseudophakic bullous keratopathy. Method. A 81-year-old patient with high Intraocular Pressure (IOP) and flat anterior chamber with patent iridotomies after DMEK was diagnosed of malignant glaucoma. The medical approach being insufficient, the patient required a pars-plana vitrectomy, capsulo-hyaloidectomy, and surgical iridectomy. Results. The IOP was reduced and anterior chamber was repositioned after surgical management. Corneal clearance was observed despite graft detachment. The patient developed an infectious crystalline keratopathy after the resolution of malignant glaucoma. Conclusions. malignant glaucoma is a rare complication following DMEK. Corneal clearance can be attained despite graft detachment after DMEK probably due to an unintentional Descemet Membrane Endothelial Transfer (DMET). However, in low dosage, steroid treatment remains a risk factor for developing ICK. Abbreviations: PBK = Pseudophakic Bullous Keratopathy, DMEK = Descemet Membrane Endothelial Keratoplasty, DMET = Descemet Membrane Endothelial Transfer, IOP = Intraocular Pressure, BCVA = Best Corrected Visual Acuity, AC = Anterior Chamber, MG = Malignant Glaucoma, ICK = Infectious Crystalline Keratopathy  Nevertheless, DMEK is not without complications [2], graft detachment being the most common complication. Either air or expandable gas is used both in the straightforward surgery and in the \u201cre-bubbling\u201d procedure to treat graft detachment. The main cause of raised Intraocular Pressure (IOP) in the early postoperative period is usually a reverse pupillary block secondary to a full air or gas fill that pushes the iris backwards .Pseudophakic Bullous Keratopathy (PBK) is a common indication of corneal transplantation. Descemet Membrane Endothelial Keratoplasty (DMEK) is increasingly performed due to its excellent results, low graft rejection rate and reduced need of steroids . A careful differential diagnosis of MG should be undergone. Pupillary block presents a moderate depth of the central AC and iris bomb\u00e9e. Choroidal detachments and effusions are typically hypotonic. Suprachoroidal haemorrhage usually presents severe pain and is often preceded by hypotony [5]. Medical approach of MG is recommended during the first five days using mydriatic and cycloplegic agents in order to relax the ciliary muscle and retracting the lens-iris diaphragm. This can also be achieved by dehydrating the vitreous using hyperosmotics. Aqueous suppressants are used to decrease posterior pooling of aqueous humour. In refractory cases, Nd:YAG anterior hyaloidotomy should be considered in pseudophakic and aphakic eyes, allowing movement of fluid between the posterior and anterior segments of the eye. If ineffective, pars plana vitrectomy with capsulo-hyaloidectomy and lensectomy should be considered [5]. MG is defined as a uniform flattening of the AC in an eye with raised IOP in the presence of a patent iridotomy. It is thought that the cause is a misdirection of the aqueous humour towards the vitreous cavity, shifting the lens-iris diaphragm forward. MG is described as a complication of most intraocular surgeries, especially glaucoma surgery in patients with prior angle closure, being more frequent in hyperopic eyes . In the case we presented, we hypothesized that the irido-corneal contact, in the context of MG after DMEK, caused an almost fully detached graft, hence, the procedure ended up being an unintentional DMET. Interestingly, the corneal oedema improved in the following months. Several cases of corneal oedema resolution in presence of DMEK graft detachment, or even descemetorhexis with no posterior graft transplant have been reported. Dirisamer et al. proposed that contact between donor and host cornea is required to achieve corneal clearance as they reported successful results in patients with partial or large detachments, but not in eyes with a \u201cfree-floating graft roll\u201d in the anterior chamber . Our case matched these findings, as the graft was not completely detached. Descemet Membrane Endothelial Transfer (DMET) is performed by injecting the donor graft consisting in Descemet Membrane and endothelium into the anterior chamber after descemetorhexis, without fully unfolding it, but with some contact area between graft and host cornea [8]. Shah et al. reported an increase in endothelial population despite the extraction of the graft and in descematorrhexis-alone procedures, suggesting a possible mechanism of host endothelial cell migration [9]. Dirisamer also had similar results and hypothesized that the recipient endothelium must be primarily involved due to the difference in clinical outcome of DMET in PBK and FED. Hence, DMET is ineffective in eyes with total deficiency of endothelial cells (PBK), yet if performed after descematorrhexis in patients with a pathologically altered subcellular matrix (FED) results in re-endothelialization and corneal clearance [9]. However, in our patient with severe PBK the corneal oedema improvement was evident despite the graft being detached. Although the mechanism is uncertain, we reason that DMET might have contributed to recover partially the corneal transparency [6].Birbal et al. reported unsuccessful long-term results in eight patients receiving DMET. They experienced corneal clearance in eyes with Fuchs endothelial dystrophy (FED) but not PBK, suggesting that the mechanism of DMET might be to stimulate host endothelial migratory response rather than to supply functional cells .One year after the surgery, our patient developed ICK, probably because of the combination of topical corticosteroids and bandage contact lens, as ICK typically occurs after an epithelial defect from a surgical procedure and is potentiated by localized immunosuppression, commonly steroids. Many pathogens can cause ICK although Although rare, malignant glaucoma can be a complication after DMEK surgery, and we must suspect it in postoperative patients with high IOP and flat AC in the presence of a patent iridotomy. Although steroid dosage is usually lower after DMEK compared to other keratoplasty techniques, it remains a risk factor for the growth of stromal biofilm that could ultimately lead to ICK, especially if bandage contact lens is worn.DisclosuresPatient informed consent was obtained.Conflict of interestConflicts of interest and source of funding: none.AcknowledgementsNone."}
+{"text": "This Forum article synthesizes the current evidence on the links between predator-prey interactions, protected areas and spatial variations in Lyme disease risk in Fennoscandia. I suggest key research directions to better understand the role of protected areas in promoting the persistence of diverse predator guilds. Conserving predators could help reducing host populations and Lyme disease risk in northern Europe. There is an urgent need to find possible win-win solutions for biodiversity conservation and human health in ecosystems facing rapid global environmental change. Borrelia burgdorferi sensu lato (s.l.) species complex, carried and transmitted by several species of Ixodes ticks, the most common in Europe being Ixodes ricinus , which take a single blood meal from a wide range of hosts before molting to the next stage , or reproducing and dying   is the most common tick-borne disease in temperate forested regions of North America and Eurasia, with increased number of reported cases worldwide  Increasing incidence of LD cases have been reported in Finland  host population trends in the study area; (2) how trophic interactions could affect these main host species; finally (3) how PAs may impact predator abundance, host species and thus tick abundance and LD risk.Sorex araneus) and small rodents (Microtus and Myodes voles and Apodemus mice) are the most important hosts of larval I. ricinus in Fennoscandia , see Ecke et al. Insectivores  and lagomorphs (Lepus timidus and L. Europaeus) are important feeding hosts for adult Ixodes ticks  are known to be key hosts for nymphal ticks in Europe  are still present, offering a unique opportunity to study intra-guild relationships between these species, their potential impact on mesocarnivore abundance  reducing the most important host species abundance or changing the host community composition and (2) inducing fear-mediated changes in habitat use of the main host species, which could decrease LD transmission risks  is a common prey of the lynx  influence the trophic pathways identified above and impact LD risk at various scales  and combining empirical, experimental and modeling approaches at local and global scales. Existing nation-wide datasets of LD incidence and wildlife community composition can be used in several northern European countries to assess the environmental drivers of LD incidence. Comparative designs inside and outside PAs, where host abundance, predator community structure, tick density and infection prevalence in ticks and hosts are sampled, would help determine how multi-level trophic cascades influence LD risk in boreal ecosystems.In conclusion, it is time for research to strive to understand the top-down processes regulating LD transmission in Fennoscandia. Such research could improve public attitude toward predators and provide powerful motivation for society to preserve complex ecological networks in boreal ecosystems currently facing the combined effects of land cover change and climate change."}
+{"text": "We developed SNPnexus to meet this need by assessing the potential significance of known and novel SNPs on the major transcriptome, proteome, regulatory and structural variation models. Since its previous release in 2012, we have made significant improvements to the annotation categories and updated the query and data viewing systems. The most notable changes include broader functional annotation of noncoding variants and expanding annotations to the most recent human genome assembly GRCh38/hg38. SNPnexus has now integrated rich resources from ENCODE and Roadmap Epigenomics Consortium to map and annotate the noncoding variants onto different classes of regulatory regions and noncoding RNAs as well as providing their predicted functional impact from eight popular non-coding variant scoring algorithms and computational methods. A novel functionality offered now is the support for neo-epitope predictions from leading tools to facilitate its use in immunotherapeutic applications. These updates to SNPnexus are in preparation for its future expansion towards a fully comprehensive computational workflow for disease-associated variant prioritization from sequencing data, placing its users at the forefront of translational research. SNPnexus is freely available at  SNPnexus is a popular analytical tool that was designed to meet this need  and neo-epitope prediction for the immunotherapeutic application (for hg38). These will be added to other assemblies as soon as the primary datasets are made available from their respective sources. A complete list of the annotation categories is provided in http://www.roadmapepigenomics.org/) and the FANTOM project  , Roadmap project  have beeThe vast majority of germline and somatic variations occur in the noncoding part of the genome, only a small fraction of which are believed to be functional. From the tens of thousands of noncoding variations detectable in each genome, distinguishing the potential functional variants from non-functional ones is a challenge. Going beyond SIFT and PolyPhen predictions for deleterious effect of coding variants on protein functions, SNPnexus users can now obtain the predicted functional impact of noncoding variants from eight popular noncoding variant scoring algorithms, namely CADD , DeepSEAhttp://hapmap.ncbi.nlm.nih.gov/), the new release also provides minor allele frequency (MAF) data generated from the 1000 Genomes (1KG) Project . 1KG data covers 26 different populations around the globe grouped together in 5 super populations: AFR (African), AMR (Ad Mixed American), EAS (East Asian), EUR (European) and SAS (South Asian). Since the release of Phase 3 data in 2013 with information on over 84 million genetic variants (MAF > 1%), the 1KG project has overshadowed the utility of HapMap data and established itself as a research standard for population genetics. SNPnexus also provides MAF data generated as part of the Exome Aggregation Consortium (ExAC)  . ExAC coWith ever-increasing number of association studies identifying new relationships among genetic variation and phenotypes, SNPnexus has added another resource ClinVar  along wihttps://doi.org/10.1101/174243) and NetTepi  molecule is considered as the essential factor for determining the viability of a peptide as neo-epitope. For user-specified human leukocyte antigen (HLA) allele type corresponding to MHC-I protein, SNPnexus employs NetMHCpan and MHCflurry to report the predicted peptide-MHC (pMHC) binding affinity of each n-mer mutated and wild-type peptide pair in nanoMolar (nM) unit. SNPnexus also reports prediction scores from NetTepi, which integrates pMHC binding affinity with pMHC stability and T-cell propensity in its calculations. By reporting scores from multiple immunogenicity prediction methods, SNPnexus enables users to make a better-informed decision on subsequent wet-lab investigations.It has now become well established that somatic variation within a tumour gives rise to neo-epitopes  that may make strong candidates for personalized cancer immunotherapy vaccines . Assumin NetTepi . For eacSNPnexus utilizes primary annotation datasets from different sources to instantly calculate and report variant-centric functional annotations. Currently, we maintain three separate databases for GRCh38/hg38, GRCh37/hg19 and NCBI36/hg18 assemblies. The primary datasets for annotation categories present in the previous release remain unchanged. Most of the primary datasets for hg38 assembly are downloaded from either UCSC genome annotation database or Ensembl 90 data dumps. Among others, the 1KG Project datasets are downloaded from the International Genome Sample Resource (IGSR) FTP site. ExAC, COSMIC and miRBase data are downloaded from their respective FTP sites. The most recent ClinVar data are extracted from the NCBI ClinVar FTP site. Most of the non-coding variant scoring tools except DeepSEA provide pre-computed genome-wide scores, which are downloaded. No such pre-computed scores are available for DeepSEA, for which the respective standalone tool is installed in SNPnexus server and executed for each submission. Similarly, the standalone versions of the three neo-epitope prediction tools are installed and executed from the SNPnexus server. The complete list of data sources for SNPnexus annotation categories is provided in About section with an overview of the available annotation categories. The User Guide compiles the sources of primary annotation data, followed by exhaustive descriptions of query format and output data types. An Example section is available, with practical demonstrations of how to use SNPnexus.The query interface has been redesigned with dedicated navigation tabs for different sequence assemblies. It allows users to analyse variants mapped on different assemblies with greater ease. The results are presented with easier navigation facility and in an interactive tabular format with filtering, pagination and sorting options, and are available for download in multiple formats. Where appropriate, results are also summarized in graphical format using the open source visualization library Google Charts. The website contains an SNPnexus and other similar resources work on the principle of aggregating/calculating variant annotation information from disparate sources, which would be otherwise laborious for researchers to explore individually. As such, users need to apply their own discretion when interpreting findings reported in SNPnexus, notably those from the prediction algorithms  with varying efficiency. Users should consult the individual resources and related peer-reviewed publications to check the reliability of the results generated by these algorithms.http://wannovar.wglab.org), the freely accessible web version of ANNOVAR, doesn\u2019t provide all the functionalities provided by its command line version. With the provision of predicted functional impact of noncoding variants and putative neo-antigen detection, SNPnexus also surpasses the functionalities offered by the Ensembl VEP Web (http://www.ensembl.org/vep).To the best of our knowledge, no single tool, or combinations thereof, available in the public domain provides the range of functionalities offered by SNPnexus. A few command-line-based tools such as ANNOVAR ,\u00a0EnsemblThe enhancements made in the current release of SNPnexus ensure that it remains a cutting-edge tool and continues to contribute toward maximizing the knowledge extracted from sequence variation data. Looking forward, the analytical focus of SNPnexus will expand toward multi-sample cohort study. This will allow users to build genetic variation profiles within and between samples, highlighting the shared variants and significantly mutated genes contributing to the phenotype studied. Based on the fully annotated variant results in one individual and/or across multiple samples, SNPnexus could then derive a prioritized list of putative disease-associated variants and genes for further investigation of clinical utility. At the same time, the addition of neoepitope prediction feature has propelled SNPnexus to the forefront of personalized medicine with the potential to intersect genomics and immunology. We are planning further useful expansions, for example, mining a candidate neoepitope in known antigen databases and assessing the expression pattern of the corresponding mutated gene, to grow SNPnexus\u2019 application in personalized immunotherapy.Supplementary DataClick here for additional data file."}
+{"text": "Recent genomic studies identified a putative rdh gene in an uncultured deltaproteobacterial genome that was not accompanied by an rdhB gene, but contained transmembrane helixes in N-terminus. Therefore, rather than having a separate membrane anchor protein, this putative RDase is likely a hybrid of RdhA and RdhB, and directly connected to the membrane with transmembrane helixes. However, functionality of the hybrid putative RDase remains unknown. Further analysis showed that the hybrid putative rdh genes are present in the genomes of pure cultures and uncultured members of Bacteriodetes and Deltaproteobacteria, but also in the genomes of the candidate divisions. The encoded hybrid putative RDases have cytoplasmic or exoplasmic C-terminus localization, and cluster phylogenetically separately from the existing RDase groups. With increasing availability of (meta)genomes, more diverse and likely novel rdh genes are expected, but questions regarding their functionality and ecological roles remain open.Attempts for bioremediation of toxic organohalogens resulted in the identification of organohalide-respiring bacteria harbouring reductive dehalogenases (RDases) enzymes. RDases consist of the catalytic subunit (RdhA, encoded by  Recent genomic analysis revealed putative reductive dehalogenase genes from extreme subsurface environments that unlike known reductive dehalogenases have membrane integral domains. With the advent of the Industrial Revolution, human impacts on the environment increased dramatically. Hazardous halogenated organic compounds, organohalogens, were widely distributed in the natural environment through careless use and indiscriminate disposal, and caused major public concerns due to possible effects on human and environmental health H\u00e4ggblom . In atteet al. rdh) have a conserved operon structure that consists of rdhA, coding for the catalytic subunit (RdhA); rdhB, coding for a small putative membrane anchor (RdhB) that (presumably) locates the A subunit to the outside of the cytoplasmic membrane; and a variable set of accessory genes (e.g. rdhCTKZED)  in the N-terminus. Whereas the known respiratory RDases do not have membrane-integral domains, most RdhBs have three TMHs . Although the existence of rdh genes lacking the TAT motif and rdhB were reported in the genomes of strain NaphS2 and D. sandiegensis  by reoxidation of respiratory cofactors for membrane-bound RDases, and catabolic reductive dehalogenation for cytoplasmic RDases  RDases? Detoxification of organohalogens and thereby securing a hospitable environments for themselves and the nearby organisms? Providing carbon sources for themselves (catabolic RDase) or others (respiratory RDase)?et al. rdh genes  RDases be involved in the production of halogenated bioactive compounds as was shown for biosynthesis of marine bacterial pyrroles mediated by a reductive debrominase that utilizes a redox thiol mechanism (El Gamal Genomics and allied technologies have greatly increased the diversity of putative ce Table\u00a0, Antarct"}
+{"text": "Hepatic arterioportal fistulae are frequent vascular complications due to neoplasm, trauma and iatrogenic injury. On the other hand, fistulae between the hepatic arteries and hepatic veins (arteriohepatic venous fistula) are rare. We report the case of a 45-year-old male who suffered from a blunt abdominal trauma with abdominal distension. Initial cross-sectional imaging revealed laceration of the right lobe of liver with an arteriovenous fistula and hemoperitoneum. The diagnosis of arteriohepatic venous fistulae was confirmed on digital subtraction angiography (DSA) and treated angiographically with superselective coil embolization. Post-embolization angiogram showed complete occlusion of arteriovenous fistulae. We emphasis on the management part of the fistulae and endovascular treatment. We emphasis on the management part of the fistulae and endovascular treatment.Hepatic arterioportal fistulae are frequent vascular complications due to neoplasm, trauma and iatrogenic injury. On the other hand, fistulae between the hepatic arteries and hepatic veins (arteriohepatic venous fistula) are rare. We report the case of a 45-year-old male who suffered from a blunt abdominal trauma with abdominal distension. Initial cross-sectional imaging revealed laceration of the right lobe of liver with an arteriovenous fistula and hemoperitoneum. The diagnosis of arteriohepatic venous fistulae was confirmed on digital substraction angiography (DSA) and treated angiographically with superselective coil embolization. Post-embolization angiogram showed complete occlusion of arteriovenous fistulae. Hung et alA 45-year-old male with history of blunt abdominal trauma was brought to casualty with abdominal distension and drop in haemoglobin levels. Initial ultrasound imaging revealed free fluid in the abdomen. Exploratory laprotomy was done that show hemoperitoneum, and liver laceration in the right lobe. Perihepatic packing was done to achieve hemostasis.CT imaging done on day two revealed replaced right hepatic artery arising from superior mesenteric artery (SMA) with hepatic laceration involving segment VI and VII. Arterial phase CT images showed a prominent segmental branch of the right hepatic artery with a fistulous track communicating with the right hepatic vein \u20132. Two dFrom a transfemoral approach, the superior mesenteric artery was catheterized with 6F catheter (Chuang-William Cook Europe APS). Selective angiogram showed two prominent hepatic artery segmental branches leading to the lacerated liver parenchyma with early filling of the right hepatic vein suggesting post-traumatic arteriovenous fistulae . The rep2 congenital anomaly,3 trauma and iatrogenic injuries like needle biopsy and percutaneous drainage.4The most common cause of liver injury is blunt abdominal trauma. The incidence of hepatic vascular injuries after blunt trauma is much lower than that after penetrating injury. Traumatic intrahepatic arteriovenous fistulae are rarely encountered which generally involve arterial to portal venous connection  and rarely result in arterial to hepatic vein connection. The leading cause of arteriovenous fistulae are neoplasm,4 in his series of patients after needle biopsy and percutaneous biliary drainage demonstrated arterioportal fistula in eight patients and arteriohepatic venous fistula in one patient on angiography. Fistulae of systemic venous system can lead to cardiovascular compromise with high output cardiac failure.5 Infrequent cause of arteriohepatic venous fistulas may be attributed to the larger distance between artery and hepatic vein. Post-traumatic arterioportal shunts are more frequent as these vessel systems are in close proximity at the portal tract. Dessousky et al6 in his series of patients with intrahepatic vascular shunts proposed a strategy for early identification, classification and management of shunts.Okuda et al7 Congestive cardiac failure, portal hypertension, portosystemic encephalopathy, cholangitis and atypical cirrhosis have been reported as possible serious complications related to this condition. Thus, a correct diagnosis is important and diagnostic imaging has a fundamental role in the evaluation of shunts and determination of the appropriate management.8 Two types of shunts were identified- arteriovenous (72%) and venovenous (28%). Arteriovenous shunts can be further classified into arterioportal and arteriohepatic shunts, whereas venovenous shunts can be further classified into portovenous, portoportal and venovenous shunts.6Intrahepatic vascular shunts (IHVSs) are abnormal communications between intrahepatic vasculature involving the arterial, portal or hepatic venous systems. The etiology of these shunts is controversial and may be either acquired, as those associated with cirrhosis or hepatocellular carcinoma, those that occur after traumatic injuries to the liver or interventional transhepatic procedures , or they may appear in the form of congenital and idiopathic vascular malformations, as in Rendu\u2013Osler\u2013Weber syndrome (hereditary hemorrhagic telangiectasia).6 proposed a practical strategy with therapeutic implication based on both imaging and clinical findings and categorized patients into three groups as follows: Group I included asymptomatic patients with small non-neoplastic shunts (3\u20136\u2009mm) and with shunt ratio <\u200930%. They were followed by Doppler and clinical examination at 3 to 6 months interval. If the shunt did not change or regressed, and no signs or symptoms developed, then conservative management was applied according to the type of shunt.Dessousky et alGroup II included patients with symptomatic shunts, large (15\u201323\u2009mm) or aneurysmal shunt (28\u201345\u2009mm), those with shunt ratio >30% or neoplastic shunt. These shunts are usually managed by interventional technique.Group III included patents with diffuse shunts or with shunt ratio >60%, and were planned directly for surgery.In our case, as the patient was symptomatic and as the size of the fistulae were >15\u2009mm, management with embolization was considered.9 Early angiographic embolization decreases the incidence of blood transfusion and number of liver-related operations.8 Transcatheter arterial embolization has proved to be effective in treatment of arterioportal shunts, and its associated complications are rare.103D post-processing of CT angiography with multiplanar reformation (MPR), maximal intensity projection (MIP) and volume rendering technique (VRT) is especially helpful in detection of vascular injuries. In this case, CT promptly showed the hypertrophic segmental branches leading to the fistulae. Interventional techniques, especially angiographic embolization, are well-known as useful adjunct in non-operative management of blunt liver trauma.Arteriovenous shunts are rare complication of blunt trauma. Arteriohepatic shunts are rarer than arterioportal shunts. Multiphasic MDCT can be very helpful in proper planning before an interventional procedure. Angiographic embolization can decrease the incidence of transfusion and surgical procedures. Intrahepatic vascular shunts can be managed by interventional technique, and surgery depending on clinical presentation and shunt ratio.Arteriohepatic venous shunts can occur rarely when compared with arterioportal shunts in abdominal trauma.Management of arteriohepatic venous shunts is similar to arterioportal shunts by interventional technique like micro coil embolization depending on the shunt ratio and clinical presentation.Written informed consent was obtained from the patient(s) for publication of this case report, including accompanying images."}
+{"text": "Social relationships are a well-established correlate of late-life well-being. Extensive research finds social support is associated with fewer depressive symptoms, yet few studies distinguish fine-grained types of support from spouse, children, other family and friends, nor whether these linkages differ by gender and marital status. Studies exploring coarse associations between support and well-being may conceal gender and marital status differences. We use data from two waves of the Health and Retirement Study  to study fine-grained linkages between diverse types of relationship strain and support and depressive symptoms (CESD) among adults aged 51+. The results show that the association between support/strain and depressive symptoms varies based on the source of support. For instance, among married/partnered older adults, spousal support is negatively associated with depressive symptoms whereas friend strain is positively associated with depressive symptoms. Among widowed respondents, friend support is negatively associated with depressive symptoms. These marital status patterns differed by gender however, such that the impact of friend strain on depressive symptoms was especially large for divorced men. Our results suggest that no single form of social support (or strain) is uniformly protective (or distressing), so services and interventions to enhance late-life mental health should more fully consider older adults\u2019 social location, including gender and marital status. For current cohorts of older adults, who have lower rates of marriage and childbearing than their predecessors, it is critically important to understand both the levels and impacts of alternative sources of support from other kin and friends."}
+{"text": "Cardiac resynchronization therapy (CRT) is an effective treatment for patients with heart failure (HF) and conduction abnormalities. Conceptually, CRT works by improving myocardial contraction synchrony and performance with a parallel left ventricular (LV) reverse remodeling and subsequent improvement in morbidity and mortality -3. CurreCRT mechanically ameliorates the activation delay between opposing contracting walls of LV by an extra lead implanted into LV free wall. Echocardiography can provide the additional necessary improvement in selection of patients by identifying more precisely the asymmetry in contraction and activation delay between the opposing contracting walls of LV. Over the years, a number of echocardiographic techniques have been introduced to identify this asymmetry more commonly known as mechanical dyssynchrony . DespiteRecent studies applied some new echocardiographic techniques focusing on the physiology of a how a CRT works which have shown promising results in small-scale studies , 3. One This editorial focusses on the sub-study performed on the Echocardiography guided cardiac resynchronization therapy (EchoCRT) trial data by Tayal et al. . In EchoThis study highlights the limitation of time-to-peak dyssynchrony methods, bringing forward the discussion on the role of dyssynchrony in patients treated with CRT and its physiology. Future trials applying these newer echocardiographic techniques in selection of patients with wide QRS (> 130ms) for CRT in multicenter randomized settings can provide more convincing evidence. Specifically focusing on groups where the guidelines are still ambiguous, such as LBBB patients with intermediate QRS duration (130-149 ms) and non-LBBB morphology (> 130ms) would be of benefit by reducing unnecessary implants."}
+{"text": "Dually eligible individuals  often have worse health and greater functional limitations than patients eligible for Medicare only. For dually eligible patients receiving inpatient rehabilitation services following a major illness or injury, improvement in function may be lower than for Medicare-only patients. To our knowledge, this is the first study to examine the relationship of dual eligibility on improvement in mobility for inpatient rehabilitation facility (IRF) patients by 13 primary diagnosis groups . Data was collected on the IRF-Patient Assessment Instrument at admission and discharge for all IRF patients discharged during 2017 . A generalized linear model was run for each primary diagnosis group to examine the effect of dual eligibility on change in mobility during an IRF stay, adjusting for sociodemographic factors, clinical factors, and comorbidities. The proportion of patients who were dually eligible varied among primary diagnosis groups . Compared to patients who were non-dually eligible, dually eligible patients had lower improvement in mobility across all 13 diagnostic groups. The strongest effect of dual eligibility on lower improvement in mobility was among patients with hip and/or knee replacements  and patients with non-traumatic spinal cord dysfunction . This research indicates that dually eligible patients may have worse functional mobility outcomes than non-dually eligible patients for some IRF primary diagnosis groups, and these patients may need additional support after discharge."}
+{"text": "Eucalyptus nitens breeding population focused on improvement for solid wood production. A high-density SNP chip (EUChip60K) was used to genotype 691 individuals in the breeding population, which represented two seed orchards with different selection histories. Phenotypic records for growth and form traits at age six, and for wood quality traits at age seven were available to build genomic prediction models using GBLUP, which were compared to the traditional pedigree-based alternative using BLUP. GBLUP demonstrated that breeding value accuracy would be improved and substantial increases in genetic gains towards solid wood production would be achieved. Cross-validation within and across two different seed orchards indicated that genomic predictions would likely benefit in terms of higher predictive accuracy from increasing the size of the training data sets through higher relatedness and better utilization of LDGenomic selection is expected to enhance the genetic improvement of forest tree species by providing more accurate estimates of breeding values through marker-based relationship matrices compared with pedigree-based methodologies. When adequately robust genomic prediction models are available, an additional increase in genetic gains can be made possible with the shortening of the breeding cycle through elimination of the progeny testing phase and early selection of parental candidates. The potential of genomic selection was investigated in an advanced  Eucalyptus nitens (Deane & Maiden), is the most important commercial eucalypt species in New Zealand, with an advanced breeding programme moving towards its fourth generation  breeding population, therefore, some inaccuracy in breeding values is expected due to unknown paternal contribution and plausible pedigree errors. Precisely recorded pedigrees and known ancestors of the breeding population individuals are prerequisites for accurate genetic evaluation and consequently, efficient breeding programme management and boosted genetic gain in forest tree species.Shining gum, Genomic selection was proposed as a tool to predict individual breeding values on the basis of information from high-density genetic marker panels through multiple regression models  was estimated in terms of status number as following \u019f is group co-ancestry of individuals  individuals per family used for genomic prediction analysis for which genomic information and phenotypic trait records were available. The Waiouru seed orchard was represented by 431 genotyped individuals with effective population size of 133.2, while the Tinkers seed orchard was represented by 236 genotyped individuals with effective population size of 64.7. The effective population size . The marker data were filtered for genTrain score\u2009>\u20090.5, GenCall\u2009>\u20090.15, minor allele frequency\u2009>\u20090.01, SNP call rate\u2009>\u20090.6 and pairwise LD in terms of a composite estimate (r2\u2009<\u20090.9), with 12,236 SNPs selected to train genomic prediction models. The missing data were imputed through expectation-maximisation algorithm implemented in \u201crrBLUP\u201d package   following A is the average numerator relationship matrix  is set nested within replication following e following X and Z1, Z2 and Z3 are incidence matrices assigning fixed and random effects to measurements in vector y  from breeding cycles and selections based only on genetic markers. It was estimated as follows:The full efficiency of genomic selection was investigated by comparing genetic gains per generation using pedigree-based estimated breeding values (BLUP) with genetic gains using genomic marker-based estimated breeding values (GBLUP). Both of these individual based estimated genetic gains included the availability of phenotypic records for all traits. The mean value of BLUP and GBLUP breeding values of the 20% of selected individuals was the measurement for the estimated genetic gain.Pedigree-based analysis showed low to moderate within seed orchard heritabilities in both seed orchards Table . PedigreAcross seed orchard heritability estimates were generally higher using marker-based breeding values than pedigree-based with only a few exceptions Table . RecondiMarker-based breeding values had consistently higher accuracies than pedigree-based breeding values. Generally, accuracies of breeding values were higher for both seed orchards when using marker-based rather than pedigree-based estimated breeding values. However, there were some inconsistencies, with the Tinkers seed orchard showing lower genomic breeding value accuracies for radial wood shrinkage, DBH and height than for the same traits using pedigree-based models, reflecting the pattern in heritability.The cross-validation analysis showed no, or very low, predictive accuracy for breeding values for one seed orchard when based on a model trained in an alternative seed orchard, using pedigree-based or marker-based models Table . Within Generally estimated absolute genetic gains per generation were as expected higher when using GBLUP breeding values rather than BLUP breeding values Table . The estThe benefits of using information from genomic markers in the genetic evaluation were apparent in the current study, where both within seed orchard and across seed orchard estimations supported the use of GBLUP over BLUP predictions. The reduced number of SNPs after filtering still provided sufficient genomic information to perform efficient marker-based predictions, which improved breeding value accuracies when compared with pedigree-based evaluations. A gain in accuracy of breeding values would likely be even more substantial when increasing the size of training population by additional genotyping. Grattapaglia and Resende  estimateForest tree breeding programmes are generally in the very early stages compared to animal and crop breeding programmes with faster generation turnover  plays a significant role in forestry tree breeding (Li et al. Estimated absolute genetic gains based on GBLUP breeding values per generation indicate that genomic selection would significantly improve the efficiency of selection for solid wood properties. The major benefit of genomic selection in accelerating the rate of genetic improvement would be derived from the ability to shorten the generation interval through the very early selection at the seedling stage (Resende et al. E. nitens breeding population. A question remains as to how well prediction models perform after several breeding cycles (Resende et al. E. nitens breeding population is required to find the best possible methodology, including additional data infusions of wider breeding population that will reflect better the future selection population than in the current study. We expect further data infusions to result in considerably higher predictive accuracy of genomic breeding values compared to pedigree-based methods. Increasing the training population size as well as applying different statistical methods that can account efficiently for the accuracy due to LD may give further confidence in implementing GEBVs in the breeding programme (Habier et al. The potential to make faster selections by skipping progeny testing should be pursued in this E. nitens was possible by implementing genomic marker-based prediction compared to pedigree-based prediction. The greatest improvement in genetic parameters was obtained for tangential air-dry wood shrinkage and growth strain, which are the key traits in selection for solid wood production in eucalypts. Wood shrinkage traits had moderate heritabilities, which mainly increased further with genomic prediction.This study showed that a significant improvement in breeding value accuracy and genetic gains for selection of wood properties in Results from cross-validation analysis implied that further infusions of additional seed-orchard material into the training data would be useful to increase the efficiency of genomics in the selection, regarding breeding value accuracy and predictive accuracy. Further analysis, including more progeny trial sites to investigate the transferability of these models across generations and environments is recommended.Data available from Dryad: 10.5061/dryad.pf58510."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: To develop a robust spatial normalization pipeline for brains of individuals with focal cortical lesions. METHODS/STUDY POPULATION: Individuals with chronic focal cortical lesions from stroke. RESULTS/ANTICIPATED RESULTS: We have developed a robust spatial normalization pipeline for brains of individuals with focal cortical lesions, and demonstrate how the pipeline overcomes obfuscated neuroanatomy to yield both consistent and excellent results. DISCUSSION/SIGNIFICANCE OF IMPACT: Our robust normalization pipeline will enable group analyses of individuals with cortical lesions with greater spatial precision. This greater spatial precision will improve answers to questions about functional localization in the brain, and ultimately allow translation of findings from neuroimaging studies in individuals with cortical lesions to the clinic."}
+{"text": "The two branches of the autonomic nervous system (ANS) have been individually linked to age-related changes in cognitive functioning: The parasympathetic nervous system (PNS) is thought to support healthy cognitive aging, whereas the sympathetic nervous system (SNS) has been linked to heightened cognitive decline. Despite these separate findings and despite the integrative nature of the ANS, little work has examined the two branches simultaneously to better understand their interactive effects on age-related cognitive changes. We examined cognitive change in two waves of the MIDUS cognitive project and indexed PNS and SNS activity from heart rate variability and epinephrine levels (respectively) from the MIDUS biomarker project . Our findings indicate that higher PNS levels attenuate cognitive decline, but only among individuals with low SNS levels; at higher SNS levels, the beneficial effects of the PNS are blocked. Further, lower PNS levels can be somewhat compensated for by increased SNS levels. This pattern was most robust among individuals transitioning to mid-life . These results suggest that interventions targeting the ANS as a modifiable factor in cognitive aging should consider both ANS branch\u2019s effects simultaneously, particularly in the early stages of midlife."}
+{"text": "Cancer cell dormancy is an important source of treatment failure. We studied the molecular characteristics and functional behaviour of dormant colorectal cancer cells finding them to be a differentiated yet plastic population. Organoid drug screening identified itraconazole perturbs dormancy through non-canonical hedgehog signalling effects on the WNT pathway. Functional heterogeneity can be defined as differences in both the identity and phenotype of cancer cells and has been shown to poorly correlate with mutational background.3 Studies seeking to understand functional heterogeneity have tended to focus on understanding the nature of highly clonogenic so-called cancer stem cell populations. Efforts to explore cell cycle-defined functional heterogeneity have been limited despite the well-established connection between cell cycle progression and clonogenic status.Heterogeneity exists at multiple levels in colorectal cancer (CRC) and over the last decade, major progress has been made cataloguing and quantifying inter-tumoral genetic differences.4 The study of tumour dormancy is technically difficult as there are only a small number of suitable experimental assays that can be used to identify dormant cells. The most common technique used to identify and isolate dormant cells is through label-retention. Label-retaining assays involve initially marking all cells of interest with a visible label. Following labelling, proliferative cells will gradually dilute out the marker with subsequent divisions whereas dormant cells will retain a visible label (label-retaining cells).Adjuvant CRC therapy relies on s-phase cytotoxics, which target exclusively dividing cells. Therefore, it is of vital clinical importance to effectively identify and target dormant CRC cell populations as potential drivers of disease recurrence. Prevalent prolonged intermission between primary disease treatment and representation with metastases in CRC patients indicates that reactivation of chemotherapy-resistant quiescent cancer cells may indeed be key in disease relapse. Having previously defined the nature of quiescent cells in the normal murine intestinal epithelium we sought to apply insights from normal stem cell biology to aid the identification of dormant CRC cells.5 Cells were grown in spheroid culture to permit the simultaneous culture of both clonogenic and differentiated cells thereby mirroring primary CRC cellular heterogeneity. In other cancers dormant cells have commonly been found to possess cancer stem cell features, however we unexpectedly found dormant CRC cells to reside in a differentiated state. Furthermore, upon re-culture in a permissive environment, we found dormant cells readily re-entered the cell cycle and acquired a cancer stem cell identity. These surprising results are consistent with a recent report from Toshiro Sato\u2019s group who lineage-traced LGR5+ (leucine-rich repeat-containing G-protein coupled receptor 5) cancer stem cells and KRT20+ (keratin 20) differentiated cells in murine CRC xenografts.6 In agreement with our findings, Sato and colleagues observed that following elimination of LGR5+ cancer stem cells, KRT20+ cells de-differentiated and acquired cancer stem cell features. This plasticity of cancer cell identity and functionality demonstrated by ourselves and the Sato group resembles the previously described reversion of partially differentiated intestinal progenitors to a stem cell state upon perturbation of homeostasis.7To define the molecular landscape of CRC cell dormancy we applied a label-retaining approach, to a panel of cell lines representing the molecular diversity found in CRC, in combination with transcriptomic profiling.We hypothesised that perturbing dormancy would render the tumour, as a whole, more sensitive to conventional chemotherapy. Therefore, to identify compounds that could alter the dormant state of label-retaining cells we carried out a functional murine organoid drug screen. The most striking phenotype identified from our drug screen was found with the anti-fungal itraconazole. Itraconazole generated profound organoid collapse, almost complete loss of dormant cells  followed by global senescence. We validated our murine organoid findings in human CRC cell lines, human primary and metastatic patient-derived organoids, and performed transcriptomic analysis to examine the mechanism of the itraconazole derived phenotype.8 Itraconazole has previously been shown to inhibit canonical hedgehog signalling by binding smoothened (SMO).9 Unexpectedly, we found hedgehog pathway inhibition was inconsistently associated with itraconazole responsiveness. Conversely, WNT pathway inhibition was uniformly correlated with the itraconazole response and phenotype. We hypothesised that suppressor of fused (SUFU) may link an apparent hedgehog pathway inhibitor with WNT inhibition. Indeed, siRNA knockdown of SUFU rescued the itraconazole phenotype and WNT signalling thereby confirming the novel effect of itraconazole on the key regulatory pathway of CRC development (in vivo pre-clinical validation studies indicating that itraconazole causes irreversible tumour growth arrest, WNT pathway inhibition and synergistic activity with classical s-phase cytotoxics.Canonical hedgehog signalling in CRC is predominantly paracrine with pathway activation found in the stromal microenvironment alone.elopment . Finally10 Our findings and that of Lange and colleagues are highly compatible with the exception that Regan et al. propose that the non-canonical hedgehog derived effect is Patched-1 dependent. However, our data show this to be SMO and SUFU mediated. Interestingly, we found that another classical smoothened inhibitor, cyclopamine failed to reproduce the findings found with itraconazole. This suggests that SMO inhibitors may induce distinctive structural changes which may differentially alter the subsequent interaction between SMO and SUFU and potentially explain the difference between Lange\u2019s findings and ours.Autocrine non-canonical hedgehog effects on WNT signalling and differentiation status in CRC has been recently described by Martin Lange\u2019s group.High CRC and also renders dormant cells temporarily vulnerable to cytotoxic therapy prior to entering permanent senescence paving the way for future clinical studies.Cumulatively, our study provides evidence that a safe FDA-approved compound generates profound growth retardation in WNT"}
+{"text": "Recent Zika virus (ZIKV) epidemics necessitate the urgent development of effective drugs and vaccines, which can be accelerated by an enhanced understanding of ZIKV biology. One of the ZIKV structural proteins, precursor membrane (prM), plays an important role in the assembly of mature virions through cleavage of prM into M protein. Recent studies have suggested that prM protein might be implicated in the neurovirulence of ZIKV. Most vaccines targeting ZIKV include prM as the immunogen. Here, we review progress in our understanding of ZIKV prM protein and its application in ZIKV vaccine development. Zika virus (ZIKV) was first isolated in 1947 from a rhesus monkey taken from the Zika Forest in Uganda . Prior tZika virus outbreaks from 2015 onward have been of major public health concern due to their associated clinical complications, such as Guillain-Barre syndrome in adults and neonatal microcephaly, suggesting mother to child transmission of the virus . Owing tZika virus is mainly transmitted to humans through mosquito-borne vectors , though trans-Golgi network before release of mature virions  and dengue virus. ZIKV has an approximately 11 kb positive-stranded RNA genome, with untranslated regions flanking the 5\u2032 and 3\u2032 ends of its open reading frame. The genome is translated into structural proteins  and non-structural (NS) proteins  [reviewed in ]. The NS virions . The prMiviruses . A conseiviruses . Therefoiviruses . This shTable 1). These genomic variations might have been driven by ZIKV adopting an urban-based transmission cycle targeting humans as hosts rather than the original sylvatic mode of transmission that normally involves Aedes mosquitoes and non-human primates    . These sroteins) .pr peptide of prM protein might not be present in the final vaccine formulation.The ZIKV vaccines currently under development are mainly based on purified inactivated viruses, plasmid DNA, or mRNA platforms . ImportaA vaccine produced by immunizing mice with VLPs that incorporates full-length ZIKV structural proteins (C-prM-E) can also endow full protection against ZIKV and induces production of more ZIKV-neutralizing antibodies than DNA vaccines . A chimeSuccessful immunization and neutralizing antibody production in C57BL/6 mice has been demonstrated for an RNA nanoparticle vaccine based on prM-E . This vaModified mRNA vaccines based on ZIKV prM-E proteins have also been developed . These mZika virus has become a major public health concern, with outbreaks of the disease spreading across the globe and resulting in congenital birth defects in some instances. Evolutionary and purifying selection pressures might have facilitated modifications of the ZIKV genome that enhance its replication efficiency and reduce host immune efficiency as it adapted to new hosts in urban environments. This has led to virus strains being categorized as either pre-epidemic or epidemic, with the latter being associated with recent infection outbreaks. Thus far, the S139N amino acid substitution of prM protein has been linked to increased neurovirulence, suggesting that alterations of ZIKV prM protein may enhance viral virulence. Further studies on other observed amino acid substitutions in all viral proteins should be carried out to establish their roles in viral replication efficiency.Various platforms have been employed to generate vaccines against ZIKV infections, including purified inactivated virus, plasmid DNA, and mRNA nanoparticles. Despite these platforms having been adapted from studies of other flaviviruses, the resulting vaccines have exhibited experimental success when a combination of both prM and E proteins are utilized. In contrast, sole use of ZIKV prM protein in vaccines against ZIKV has not yet proven as effective as prM-E combinations.It remains unclear if future epidemics will have the same clinical implications as the most recent epidemic or which viral protein modifications are more likely to result in another epidemic. Furthermore, whether the ZIKV vaccines currently under development can be effective against future epidemics is uncertain. These basic questions should guide research efforts for the prevention, control and therapeutic strategies of ZIKV. Additional focused studies on the molecular and structural biology of ZIKV prM may accelerate our ability to tackle this emerging public health concern.PN wrote the manuscript. W-CS contributed to the framework and the editing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Oxidative stress has a role in the initiation and progression of breastcancer .OxidatiBy damaging DNA, activating oncogenes, and producing genomic instability,reactive oxygen species can initiate carcinogenesis . ReactivBreast cancer tumors with enhanced proliferative capacity produce high levelsof reactive oxygen species during their chronic cycles of ischemia, reperfusion, andangiogenesis, resulting in growth signaling . Cancer Many chemotherapeutic drugs and radiation treatments eliminate tumors throughthe induction of reactive oxygen species in cancer cells . HoweverEndogenous antioxidants, including non-enzyme and enzyme antioxidant defensesystems  act to prevent or limit tissue damage by scavenging free radicals incells . SuperoxExogenous antioxidants from dietary intake such as vitamin A, vitamin E, andVitamin C, may also have a role in the alleviation of oxidative stress, which couldreduce risk of breast cancer or slow progression of the disease . HoweverResults from observational epidemiologic studies conducted over the pastseveral decades demonstrate that physical activity and weight control are importantdeterminants of breast cancer risk and progression . OxidatiIn order to inform future studies of antioxidant chemo-preventive agents thatmay reduce risk of breast cancer initiation or progression, the complexities of howredox imbalance contributes to cancer and other chronic diseases should beconsidered. This includes the observation that although high levels of reactiveoxygen species disrupt cellular processes, lower levels of reactive oxygen speciescan act as cell signaling messengers by reversibly oxidizing protein thiol groupsand modifying protein structure . Thus, t"}
+{"text": "A 76-year-old male with a small bowel neuroendocrine tumor with hepatic metastases presented with new onset lower extremity swelling, bloating, and weight gain which ultimately lead to cardiac magnetic resonance (CMR) to evaluate for cardiac involvement of disease. CMR showed right and left ventricular myocardial metastases along with findings suggestive of carcinoid heart disease. The patient had severe tricuspid valve regurgitation necessitating surgical valve repair. The patient underwent bioprosthetic tricuspid valve replacement and debulking of the metastases with surgical pathology confirming neuroendocrine tumor metastases. Follow-up clinical evaluations at 3, 6, and 9 months postoperatively showed improvement in cardiac function and stable hepatic tumor burden. This case demonstrates the utility of CMR to diagnose myocardial metastases and carcinoid heart disease complicated by severe tricuspid regurgitation, which guided surgical management. Neuroendocrine tumors (NETs) are a diverse group of tumors arising from neuroendocrine cells, and they can cause primary tumors in many different organs including the lungs, small intestine, rectum, pancreas, and other organs . Within NETs of the midgut  commonly release vasoactive substances including 5-hydroxytryptamine (serotonin), histamine, tachykinins, and prostaglandins . When thIn rare cases, NETs can metastasize to the heart , 11. CarA 76-year-old male with stage IV, small bowel NET metastatic to the liver had been followed by our institution for 4 years with stable hepatic metastatic disease on octreotide long-acting release (LAR) therapy. Originally, the tumor Ki-67 index was 5% and 24-hour urine 5-hydroxyindole acetic acid (5-HIAA) was 105\u2009mg. The patient presented with mild progression of disease on abdominal magnetic resonance imaging (MRI)  after apCMR  showed aThe patient underwent bioprosthetic tricuspid valve replacement and biopsy and debulking of the myocardial tumors. The myocardial tumors were histologically confirmed as NET metastases. The patient recovered well from surgery, and follow-up clinical visits demonstrated significant improvement in his carcinoid heart disease. As of the latest visit, the patient has excellent cardiac function with resolution of tricuspid regurgitation. His 9-month postoperative follow-up CT scan showed relatively stable disease, and his urine 5-HIAA was improving. The patient is continuing on octreotide LAR 30\u2009mg.We present a unique case of carcinoid heart disease and myocardial metastases both contributing to this patient's severe symptomatic tricuspid regurgitation. The tricuspid valve thickening is a specific finding of carcinoid heart disease, and well-defined lesions with arterial perfusion in the RV and LV walls are specific for metastases. Previous authors have suggested that vasoactive mediators associated with myocardial metastases may accelerate the onset of carcinoid heart disease, which could explain the case described here , 16.Carcinoid heart disease manifests via the accumulation of carcinoid plaque composed of smooth muscle, myofibroblasts, and elastic tissue . Plaque Echocardiography serves as first line screening for cardiac involvement in patients with carcinoid syndrome. Common echocardiographic features of carcinoid heart disease include morphologic changes to the tricuspid valve causing a thick retracted appearance with decreased mobility and enlargement of the right atrium and ventricle related to valvular insufficiency . SurgicaCMR offers more specific evaluation of cardiac lesions to help differentiate benign lesions from metastases compared to echocardiography evaluation which is based on lesion intrinsic signal and perfusion characteristics . While eThis case demonstrates the importance of CMR to evaluate for carcinoid heart disease and cardiac metastases. The results of the CMR exam in our case lead to characterization of myocardial metastases and allowed for planning of metastasis resection during the tricuspid valve bioprosthetic surgery. The case also serves as a reminder for providers that while echocardiography may offer first line screening for cardiac involvement when carcinoid heart disease is suspected, CMR may be useful when myocardial metastases are suspected for potential surgical planning."}
+{"text": "Seven enterprises that have had recent Cleaner Production (CP) audits in Beijing were interviewed to identify whether these enterprises implemented the audit recommendations. If enterprises did implement the recommendations, their reasons and the results were analyzed. Finally, some suggestions on how to promote enterprise-wide CP were given."}
+{"text": "Utilizing two-photon fluorescence lifetime imaging microscopy and the phasor analysis method, we have observed AD-related variations of endogenous fluorescence of reduced nicotinamide adenine dinucleotide (NADH) in vivo. We collected NADH FLIM images from the cerebral cortices of both APPswe:PS1dE9 mice to model amyloid Disruptions and alterations to cerebral energy metabolism play a vital role in the onset and progression of many neurodegenerative disorders and cerebral pathologies. In order to precisely understand the complex alterations underlying Alzheimer\u2019s disease (AD) progression,  Current estimates indicate that AD accounts for 60% to 80% of dementia cases,\u2013in vitro conditions, oxygen levels can be adjusted and metabolic substrates can be added such that the sample\u2019s NADH can reversibly be adjusted between its fully oxidized and fully reduced states, therefore providing calibration for the minimal and maximal detectable NADH fluorescence signal. Confounds arising from toxicity prevent calibration and absolute quantitation in living organisms; however, evaluating relative changes of in vivo NADH fluorescence intensity still provides a useful indication of pathology-induced variations of mitochondrial function and intracellular oxygen requirements.in vivo measurement techniques\u2019 utility was greatly extended by coupling NADH fluorescence with 2-photon microscopy (2PM),,,,\u2013in vivo FLIM measurements can resolve disruptions to the TCA cycle, electron transport chain, and oxidative phosphorylation.\u2013For several decades, measurements of reduced nicotinamide adenine dinucleotide (NADH) have been utilized as a nondestructive tool to characterize mitochondrial respiratory chain activities. NADH is an electron carrier molecule residing in almost all eukaryotic cells both in cytosol and mitochondria, and it performs vital roles in both anaerobic glycolysis and aerobic oxidative metabolism.In this report, we apply two-photon fluorescence lifetime imaging microscopy (2P-FLIM) of endogenous cortical NADH for minimally invasive characterization of AD-induced variations in cerebral metabolism in a mouse model of AD. We utilized phasor analysis to show that amyloid 2,Our imaging experiments were performed under a protocol approved by the Institutional Animal Care and Use Committee at Massachusetts General Hospital. For our studies, we utilized female transgenic APPswe:PS1dE9 mice . By integrating the photon count matrices along the time axis, intensity images were generated and used for preprocessing. First, to isolate parenchymal NADH fluorescence, features such as blood vessels were masked out manually, as well as constituents displaying endogenous fluorescence such as lipofuscin granules. The boundaries for ,The coordinates, 3We sought to evaluate AD-related alterations to mitochondrial function by measuring NADH in the living cortex of AD mouse models. Similar to flavin adenine dinucleotide (FAD), NADH is endogenous and ubiquitous within most eukaryotic cells, and it participates in multiple steps of glucose breakdown and ATP synthesis. Monitoring the fluorescence of these electron carriers uniquely enables nondisruptive assessment of energy metabolism within living biological tissue.,in vivo and in vitro. Conversely, lipofuscin phasor clusters were broad and dispersed over a range of short lifetimes. For both endogenous fluorophores, phasor clusters corresponding to measurements taken from regions near After masking, phasor computations were performed on all measurements and grouped using our custom software. ,To evaluate the spatial extent of metabolic variations around in vitro observations of impaired respiration and mitochondrial toxicity induced by intracellular Although further validation is required, the present, phasor-based observations of endogenous NADH fluorescence from living cortices of AD mouse models strongly indicate a pronounced influence of ,,Conversely, our observations of plaque-induced variations in lipofuscin fluorescence lifetime were unanticipated and raise intriguing questions regarding the nature and mechanisms of plaque-related toxicity. Often regarded as an aging-related pigment, lipofuscin granules are chemically and morphologically hetereogeneous masses primarily comprised of oxidatively modified protein and lipid residues that resist degradation by lysosomes. Lipofuscin is considered \u201cbiological garbage\u201d that progressively accumulates within several tissues with age, but the rate of accumulation can be accelerated in the presence of higher oxygen or reduced by administration of antioxidants.in vivo measurements of endogenous fluorescence are useful for characterizing distinct variations in mitochondrial metabolism and lipofuscin accumulation in the presence of Our study shows that phasor-based"}
+{"text": "Background: According to the notion of maturational dualism, the link between mind and body weakens with age and this weakening has important consequences for emotional experiences. Specifically, it is hypothesized that age-related decline in interoceptive awareness and physiological reactivity reduce the ability to use bodily states to guide judgments about emotions. If this hypothesis is valid, then age may moderate the association between explicit measures  and implicit measures  of affective reactivity. Purpose: To investigate whether age moderates the association between explicit and implicit measures of negative affective reactivity. Methods: A sample of 275 participants (age range=20-78) viewed 25 pictures validated to induce negative emotions. Participants filled in the PANAS assessing explicit affect and the IPANAT assessing implicit affect before and after viewing the pictures. Emotional reactivity was operationalized as residualized gain scores derived from regressions of baseline affect on affect following picture viewing. Results: Age moderated the association between implicit negative affective reactivity and explicit negative affective reactivity (B=60). Discussion: The results showed a reduced association between explicit and implicit negative affective reactivity with age. This finding is consistent with the notion of maturational dualism and may indicate that older adults use affective processes that are not represented consciously  less than young adults when judging their emotional state."}
+{"text": "Breast cancer may affect young women who have not yet completed childbearing.Assisted reproductive technology (ART) provides alternatives for fertilitypreservation such as oocyte, embryo or ovarian tissue cryopreservation. Wereviewed the published literature on fertility-preserving management in breastcancer, aiming at finding evidence to answer the following questions: (1) Whatare the fertility sparing options available?; (2) How do these women respond toIVF? and (3) Can pregnancy influence breast cancer recurrence? There is apaucity of publications describing clinical experience and outcome data whichlimits accessibility to fertility preservation in this setting. Presently,oocyte or embryo cryopreservation are the main options for fertilitypreservation. IVF success rates are comparable to the ones of non-oncologicalpopulations according to the woman's age but current published studies lack dataon definitive success rates following embryo banking for cancer patients. Theperception that IVF and pregnancy may worsen cancer prognosis remains, despitethe lack of scientific evidence to support this notion. Published studies showreassuring results for pregnancies occurring >2 years after breast cancerdiagnosis. The best published evidence suggests pregnancy after breast cancerdoes not increase the risk of disease recurrence, thus pregnancy should not beforbidden once treatment is completed. Decision making for women diagnosed withcancer requires up-to-date knowledge of the efficacy and safety of availableoptions. Providing consultation with a reproductive specialist and appropriateinformation on fertility preservation for these women should be an essentialaspect of their supportive care. Cancer still represents an enormous global health burden, and published data revealedabout 14.1 million new cases and 8.2 million deaths in 2012 worldwide  estimates that there will be 252,710 cases of invasive breast cancerdiagnosed in US women and 40,610 deaths. Data also shows that breast cancer isresponsible for 30% of new cancer cases, and 1 in 8 women will develop breast cancerduring their lifetime ,but only a small part of the patients (10%) used fertility preservation  is achieved by subcutaneousinjection of gonadotropins for 8 to 14 days, along with pituitary blockagewith GnRH analogues. Follicular growth is monitored by transvaginalultrasound and final oocyte maturation can be triggered by hCG or GnRH-a.However, due to the concerns pertaining to the effects of supraphysiologicalhormonal concentrations, several different protocols have been studied in anattempt to minimize possible worsening in oncological prognosis  and embryoor oocyte cryopreservation is the most effective option for fertilitypreservation in breast cancer. Ovarian stimulation significantly increasesestradiol levels, which raises concerns regarding safety of such a procedure aswell as the possible role of malignancy and BRCA mutation in reducing ovarianresponse to stimulation , as wellas comparable live-birth-rates   in comparison to the electivecryopreservation group  considers that evidence on anydifference in prognosis between pregnant and nonpregnant women with breastcancer is lacking, and it does not recommend pregnancy termination regardless oftumor status (Overall, the literature is reassuring and does not show a worse outcome for womenwith previously diagnosed and treated breast cancer who seek to become pregnantafterwards. Some data even suggest a better survival outcome. Those findingsshould bring comfort to physicians and to women with a previous breast cancerdiagnosis.In summary, the best available published evidence so far suggests that pregnancyafter breast cancer does not increase a woman's risk of disease recurrence.Pregnancy should not be forbidden after breast cancer treatment solely becauseof concerns on cancer recurrence and death, since current available data israther reassuring. If pregnancy is an option, these women must receive carefullycoordinated multidisciplinary approach. More large randomized prospective trialsare nedded to develop appropriate protocols in this setting.Hundreds of thousands of women in their reproductive years are diagnosed with cancereach year. Advances in breast cancer treatment result in increased numbers of femalepatients who survive cancer raising the demand for effective and individualizedfertility preservation options. Unfortunately fertility counseling remains asecondary issue for many breast cancer specialists. The perception that IVF andpregnancy may worsen cancer prognosis remains, despite the lack of scientificevidence to support this notion. Currently there are limited clinical options forfertility preservation, and the paucity of publications describing clinicalexperience and outcome data has limited accessibility to these options. Decisionmaking for patients diagnosed with cancer requires up-to-date knowledge of theefficacy and safety of available techniques. Providing consultation with areproductive specialist and appropriate information on fertility preservation forwomen with breast cancer should be an essential aspect of their supportive care."}
+{"text": "Current research must utilize nationally-representative samples of older adults and their family caregivers to accurately reflect the growing diversity of the United States. This study aims to use a stress process model to examine potential racial differences in caregiving in a population-based sample of 844 White and 389 Black family caregivers in the United States. We conducted 3 x 2 x 2 (relationship type x race x dementia care status) factorial ANOVAs to examine potential differences in caregiving stressors, appraisals, resources, and mental and physical health outcomes among primary family caregivers. Results indicated significant racial differences in caregiving on several stress process measures. Although Black caregivers reported more caregiving stressors, compared to White caregivers, they tended to report more positive appraisals of caregiving and more caregiving resources. Dementia caregivers tended to report greater caregiving stressors and worse measures of appraisal compared to non-dementia caregivers. There was a significant two-way interaction among relationship type and dementia care status for the caregiving stressor, hours of care. A stress process model can allow researchers to investigate various factors associated with racial differences in caregiving."}
+{"text": "South African adolescents experience high levels of trauma, including various types of childhood maltreatment. Different types of maltreatment often co-occur. Previous research suggests that childhood maltreatment provokes a latent liability to internalising and externalising dimensions of psychopathology. Our objective was to examine the effects of childhood maltreatment on internalising and externalising disorders in trauma-exposed adolescents and to assess the mediating effect of post-traumatic stress disorder (PTSD) on these associations.A cross-sectional study was conducted with 262 trauma exposed adolescents (aged 12\u201318 years) in South Africa. Childhood maltreatment and PTSD severity were assessed using the Childhood Trauma Questionnaire and the Child PTSD Checklist, respectively. Psychiatric disorders were diagnosed utilising the Kiddie Schedule for Affective Disorders and Schizophrenia \u2013 Present and Lifetime version \u2013 and were grouped into internalising and externalising disorders. Hierarchal logistic regression was used to assess the association between childhood maltreatment types and internalising and externalising disorders, controlling for statistically significant socio-demographic characteristics, with PTSD severity added to the final model as a potential mediator.B = 0.07, p = 0.011), although this effect was mediated by PTSD severity . In contrast, physical abuse  and gender  were associated with externalising disorders, but the addition of PTSD severity did not significantly alter these associations.Sexual abuse was significantly associated with internalising disorders (The association between sexual abuse and internalising disorders was fully mediated by PTSD symptom severity. Gender and physical abuse severity, but not PTSD severity, was associated with the presence of externalising disorders. Adolescents displaying internalising or externalising psychopathology need to be assessed for exposure to childhood physical and sexual abuse and PTSD comorbidity."}
+{"text": "Aspergillus spp. spores found ubiquitously in the ambient environment is uncommon in immunocompetent patients. Previous reports of invasive upper airway aspergillosis in immunocompetent patients have generally demonstrated the efficacy of treatment regimens utilizing antifungal agents in combination with periodic endoscopic debridement, with symptoms typically resolving within months of initiating therapy.The development of respiratory infections secondary to Aspergillus fumigatus was isolated on tissue culture. Several months of oral voriconazole monotherapy failed to resolve her symptoms and she underwent mechanical debridement for symptom control. Following transient improvement, her symptoms subsequently returned and failed to fully resolve in spite of increased voriconazole dosing and multiple additional tissue debridements over the course of many years.A 43-year-old previously healthy female presented with worsening respiratory symptoms after failing to respond to long-term antibiotic treatment of bacterial sinusitis. Biopsy of her nasopharynx and trachea revealed extensive fungal infiltration and Invasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients. In the rare instances that such infections do occur, combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach. However, some patients may continue to experience refractory symptoms. In such cases, continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved. Invasivpatients \u20137.Immunocompetent patients suffering from invasive upper airway aspergillosis can be particularly challenging to diagnose given that many initially present with indolent sinus symptoms easily mistaken for bacterial sinusitis , 8. WithA 43-year-old female with no significant past medical history presented with a chief complaint of worsening respiratory symptoms that included purulent nasal secretions, dysphagia, mild dysphonia and dyspnea with chronic cough. The symptoms had begun approximately 2 years previously and had failed to completely resolve in spite of multiple rounds of empiric antibiotic therapy for a presumed bacterial upper respiratory infection. She denied previous tobacco use and had no pertinent family history. Her physical exam was notable for erythematous nasal mucosa and a small anterior septal perforation. Blood work demonstrated a white blood cell count (WBC) of 11,400/uL (neutrophils 93.8%) and an erythrocyte sedimentation rate (ESR) of 11\u2009mm/h. Electrolytes were all within normal limits and a random glucose was 96\u2009mg/dL. Head and chest computed tomography (CT) showed air-fluid levels in the bilateral maxillary sinuses and irregular thickening along the left lateral and posterior tracheal wall just above the level of the medial clavicles but was negative for lung parenchymal changes.Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa but showed no fungal growth. As such, the patient was treated with intravenous vancomycin and cefepime in addition to steroids and nebulized treatments. Her breathing significantly improved during the course of her hospitalization and she was subsequently discharged with plans to continue outpatient intravenous antibiotics for an additional 2 months.Given these imaging findings in the setting of worsening dyspnea, the patient underwent a laryngoscopic examination, which revealed subglottic crusting with diffuse purulent secretions, anterolateral cricoid inflammation, and vocal cord inflammation. Her nasal cavity also demonstrated thick purulent secretions in the middle meatus bilaterally extending to the nasopharynx. Biopsies of the trachea, subglottis, and nasal septum demonstrated purulent, atypical squamous epithelium and necrotic tissue with bacterial colonies. Cultures from these sites were positive for methicillin-resistant Aspergillus fumigatus. Given a new diagnosis of invasive pseudomembranous aspergillosis, the patient was started on oral voriconazole  with close outpatient follow-up.Several months later, the patient returned for follow-up and was found to have similar upper airway symptoms despite completing her antibiotic regimen. She again underwent endoscopic examination that revealed multiple regions of white, friable pseudomembranous patches spanning her mid-trachea, subglottis, and nasopharynx Fig.\u00a0. BiopsieAspergillus fumigatus. A formal immunological workup during this time was non-revealing with normal immunoglobulin levels, CD4+ T cell counts, absolute neutrophil counts, and complement levels. HIV testing was negative. Given her poor response to antifungal monotherapy, she was initiated on topical amphotericin B (100 mcg/ml) and budesonide (10 mcg/ml) nasopharyngeal rinses twice daily for symptomatic flares in addition to an increased dose of oral voriconazole .Over the following year, despite continuous antifungal treatment, the patient continued to experience tenacious, mucoid secretions, worsening dysphonia, nighttime pharyngitis, and frequent low-grade fevers. She required two separate inpatient admissions due to symptom escalation requiring endoscopic debridement of her trachea, pharynx, and nasal passages. Repeat tissue biopsies during this time period continued to demonstrate necrotic exudates in the presence of fungal hyphae with cultures continuing to grow pan-sensitive The patient continued on this regimen for 2 months and was found to have marked improvement on repeat endoscopic examination, at this point 18\u2009months after her initial diagnosis of invasive aspergillosis. Her larynx and subglottis had near normal appearance; her nasal cavities were dry bilaterally; her nasopharynx demonstrated mild scarring but otherwise demonstrated significantly less mucopurulence than on previous exams. However, in spite of this transient improvement, the patient again began developing upper airway symptoms over the following year, correlating with increased purulence in the nasal cavities along with the reformation of pseudomembranous, brown-mucoid layering in the nasopharynx seen on endoscopic exam. Increases in her voriconazole dosing to as high as 300\u2009mg, twice daily were attempted but did not result in significant improvement and were further complicated by vision changes attributed to supratherapeutic voriconazole trough drug levels. Additionally, while the frequency of mechanical debridement had previously averaged once every four to 6 months, the patient began requiring nearly monthly endoscopic suctioning of her nasal passage and pharynx for symptom control.Approximately 6 years after her initial diagnosis of invasive aspergillosis the patient continued to experience chronic symptoms including dysphagia, persistent dysphonia, and purulent secretions. Erosive changes to her posterior nasopharynx resulted in velopharyngeal insufficiency. Of note, serial chest x-rays during the course of her treatment never demonstrated abnormal parenchymal findings suggesting long-standing upper airway disease without progression to lower airway involvement. In the setting of persistently positive fungal hyphae seen on upper airway tissue biopsy, she was continued on oral antifungal therapy in combination with oral rinses and periodic mechanical debridement for symptomatic relief.Invasive aspergillosis of the respiratory tract is a rare but serious airway disease typically seen in immunocompromised patients. However, it is becoming increasingly clear that these infections can also occur in patients lacking the classic risk factors normally associated with underlying immunodeficiency. In the preceding case report, we presented the clinical course of an immunocompetent patient with clinical, microbiological, and histopathologic evidence of invasive pseudomembranous upper airway and tracheal aspergillosis persisting for many years in spite of longstanding treatment efforts. In our reading of the literature, this appears to be one of the most chronic cases of respiratory aspergillosis reported in an immunocompetent patient.aspergillus-related respiratory infections typically should have a formal immunological evaluation to rule-out primary and secondary causes of immunodeficiency. While different screening studies can be performed, enumeration of T cells and neutrophil counts are particularly important given their essential role in clearing fungal infections [Patients found to have invasive fections . Given tfections , more adfections .aspergillus-related respiratory infections develop in immunocompetent patients is poorly understood and difficult to study given the infrequency with which such cases occur and are reported. Interestingly, many of the comorbidities previously reported in immunocompetent patients diagnosed with invasive upper airway and tracheobronchial disease were notably absent in the case of our patient. D\u2019Anza et al. [The mechanism by which a et al.  identifia et al.  identifiaspergillus invasion in the absence of any other overt systemic predisposing risk factors. This is also potentially hinted at by the anatomical distribution of fungal disease seen in this case which appears to have mirrored the involvement of pre-existing invasive bacterial infection both histologically and on culture from the patient\u2019s trachea and nasopharynx during her initial course. We also note that concurrent infection of the upper airway and tracheobronchial tree appears to be a particularly rare anatomic distribution for invasive respiratory aspergillosis, with infection of these sites typically occurring in isolation of one another or in combination with lung parenchymal involvement when the disease becomes particularly widespread and aggressive [Given the absence of these previously described comorbidities, the question as to what initially predisposed our patient to her longstanding infection still remains. It does seem noteworthy that prior to presenting to our care, the patient was treated for mixed MRSA/pseudomonal bacterial sinusitis for approximately 2 years before developing evidence of aspergillosis on biopsy and culture data. Several case reports seem to suggest that chronic invasive aspergillosis may develop as a secondary infection following initial respiratory infections in immunocompetent patients. While these cases seem to be associated more often with viral etiologies such as influenza or even dengue , 12, it gressive , 13.Aside from the challenges in identifying the source of our patient\u2019s infection, understanding her poor response to combinatorial systemic antifungal therapy and mechanical debridement has proven equally challenging. In accordance with current treatment guidelines for invasive aspergillosis, oral voriconazole was started and continued for the duration of her disease course \u201316. HoweWhen used in combination, voriconazole and endoscopic debridement of infected tissue typically results in excellent outcomes in immunocompetent patients. Looking specifically at cases of upper airway aspergillosis, the patients described by D\u2019Anza et al.  all requBased on this previous work, the expectation at the outset of our patient\u2019s treatment was that this combinatorial approach would be efficacious, particularly given her benign past medical history. However, it is notable that after years of active invasive infection, the patient had no radiographic involvement of the lung parenchyma on serial imaging, suggesting that while unable to completely resolve her disease, her treatment appears to have at least slowed her disease progression. The use of topical amphotericin B and steroid rinses, while more conventionally used for treatment of allergic fungal rhinosinusitis , 18 rathAlthough invasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients, such patients with chronic sinusitis and respiratory symptoms should be evaluated for the possibility of secondary invasive fungal infections, particularly those who fail to improve with appropriate antibiotic therapy. Although combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach, some patients may continue to experience refractory symptoms, in which case continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved. Ultimately, this case highlights the possibility of refractory invasive aspergillosis in an immunocompetent patient and demonstrates the importance of further investigation into the pathogenesis of invasive fungal disease in the absence of overt systemic immunosuppression."}
+{"text": "Traditional approaches aimed at delaying or preventing age-dependent diseases view each disease as a distinct entity, resulting from separate pathophysiological chains of events. However, it is becoming increasing clear that even in adult animals there remains significant plasticity in terms of ageing trajectories and lifespan, suggesting that targeting ageing processes directly may be a promising alternative strategy. However, to date effects of even the most efficacious pharmacological interventions are smaller than those of ageing mutations, even when targeting the same ageing pathways. Interestingly, it has been shown that simultaneously targeting multiple ageing pathways can result in lifespan benefits that are synergistic (more than additive). We have recently shown that dramatic lifespan and healthspan extension can also be archived by leveraging interactions between drugs targeting distinct subsets of the gene-regulatory network controlling ageing of C. elegans. These interventions were highly efficacious, even when animals were treated only as adults."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: To describe how Michigan Institute for Clinical & Health Research (MICHR) has engaged communities in its leadership and governance structure. This presentation will describe these practices, how they are being evaluated, and future plans for institute-wide engagement of communities in translational research. METHODS/STUDY POPULATION: Engaged partners from various communities across Michigan in various ways within MICHR\u2019s Community Engagement Program. RESULTS/ANTICIPATED RESULTS: MICHR has utilized participatory practices in the development of the CAB to strengthen existing relationships and build new ones with potential partners. DISCUSSION/SIGNIFICANCE OF IMPACT: MICHR-wide Community Advisory Board (CAB) will ensure community voices are heard and utilized in leadership and strategic decisions for CTSA activities."}
+{"text": "Cardiac lipomas are rare benign primary cardiac tumours primarily composed of mature adipocytes. They are usually well defined, encapsulated masses, but rarely demonstrate malignant characteristics by infiltrating the myocardium. This causes diagnostic uncertainty as it becomes a priority to rule out primary malignant cardiac tumours such as sarcoma which often carry a poor prognosis.A 61\u2009year old female presenting with chest pain was found to have an infiltrating right atrial hypertrophic mass. Mutli-disciplinary team (MDT) discussions along with the presence of symptoms and likelihood of malignancy led to the recommendations for surgery.Intraoperatively this involved the right pulmonary veins and superior vena cava (SVC). The mass was resected with good margins and reconstruction of the right atrium, pulmonary veins and SVC was done using porcine pericardial patch. The patient made a good postoperative recovery and was discharged home in sinus rhythm with no significant valvular lesions. This was further confirmed at 6\u2009month follow up. Final histology was that of infiltrating lipoma.In this rare case of infiltrating cardiac lipoma in a relatively young patient, the diagnostic uncertainty despite multimodal imaging meant surgery was indicated due to the high suspicion of cancer. Even in benign cases, fatty infiltration can lead to conduction defects and embolisation. Technical difficulties in sectioning these specimens is caused by intra-tumour variability and current recommendations are for excision biopsy, for best characterisation.The management of these patients requires an MDT with Cardiac surgery being a safe approach providing definitive management. Primary cardiac neoplasms are rare with post-mortem incidence estimates ranging from 0.001% to 0.03% . CardiacFurthermore, myocardial infiltration can result in conduction defects causing rhythm disturbances .A 61 year old female with a background of asthma, hypertension and previous smoking, presented with chest pain and was found to have an infiltrating right atrial hypertrophic mass suspicious for sarcoma on transthoracic echocardiography and cardiac MRI.Coronary angiogram showed no flow-limiting lesions and cardiac echocardiogram showed restrictive changes with epicardial thickening in the right atrium and around the superior vena cava (SVC). Cardiac computed tomography (CT)Fig.  and magnFollowing multi-disciplinary team (MDT), patient and family discussions, the patient consented to surgery.Intraoperatively, there was a fatty infiltrating mass involving the right atrium, right superior pulmonary vein and SVC. The patient was placed onto cardiopulmonary bypass using bicaval cannulation with the SVC cannulated as distal as possible. The mass was resected with good margins. Right atrium, pulmonary veins and proximal SVC were reconstructed using porcine pericardium.Tissue was sent for histology, Sections showed lipomatous tumour entrapping myocardial cells, composed of lobules of mature adipocytes and very thin fibro-vascular septa. No significant cytological atypia was observed. On molecular genetic testing, MDM2 gene amplification was negative by interphase FISH ruling out a malignant liposarcoma. A diagnosis of infiltrating lipoma involving the right atrium was established.The patient made a good postoperative recovery and was discharged in sinus rhythm with no significant valvular lesions. This was confirmed at six months review.Infiltrating cardiac lipoma provides a diagnostic challenge. It cannot be distinguished from primary malignant cardiac lesions such as liposarcoma based on clinical presentation or non- invasive diagnostic modalities. Cardiac liposarcomas are aggressive malignant mesenchymal neoplasms which carry poor prognosis and hence represent important differentials to be ruled out . Intra-cIn a literature review, we found seven cases of infiltrating cardiac lipoma. Three of these cases describe lipomas originating on the epicardial aspect infiltrating into the underlying ventricular myocardium one of which reported multiple infiltrating lipomas \u201313. The Due to the rarity of cardiac lipomas, there have been no large cohort studies or randomised trials to produce guidelines on treatment. Prompt surgical management can however lead to complete cure resulting in excellent long-term prognosis. Even if benign, infiltrating cardiac lipomas can manifest in fatal clinical sequelae such as arrythmias and heart failure. The management of infiltrating lipomas provides for diagnostic challenges and hence requires an MDT approach and comprehensive patient counselling. We have demonstrated cardiac surgery in this setting is safe and provides good medium to long-term results."}
+{"text": "Mice that overexpress mutant human tau in forebrain neurons develop many features of Alzheimer\u2019s disease (AD), including behavioral impairments and neurodegeneration by 5 months of age. While an appropriate model to study AD-like pathology, the transgene\u2019s high neurotoxicity makes it difficult to investigate how aging impacts AD onset and progression. The removal of endogenous mouse tau decreases the transgene\u2019s neurotoxicity in young mice, which has allowed us to age mice to 20 months of age and investigate behavior at a more AD-relevant stage of life. Interestingly, the tau transgenic mice show increased discrimination between familiar and unfamiliar objects than non-transgenic littermates (p = 0.02) suggesting tau transgenic mice have better memory. The transgenic mice also displayed increased physical activity in the Open Field Test than non-transgenic littermates . Their improved behavioral performance occurred despite significant forebrain atrophy . Interestingly, the non-transgenic control mice lacking endogenous mouse tau developed insulin resistance and obesity, and had significantly smaller cerebellum than transgenic mice . These data suggest that insulin resistance and obesity contribute more profoundly to poor behavioral performance than forebrain neurodegeneration. Moreover our study suggests that the cerebellum, recognized primarily for its role in coordination and motor function, may be an important mediator of late life cognitive function, especially in the presence of insulin resistance and obesity."}
+{"text": "Although functional mobility limitations are associated with increased healthcare needs in later life, little research explores how older adults with varying functional mobility trajectories experience healthcare quality. To this end, we explore the effects of functional mobility trajectories on differences in healthcare treatment satisfaction, perceived disability discrimination in healthcare settings, and perceived everyday disability discrimination. We analyzed 9 waves of the Health and Retirement Study . First, we estimate age-specific group-based trajectories of functional mobility across age using finite mixture models. Second, we use multinomial logistic regression to identify sociodemographic factors that place individuals at elevated risk of membership in each group. Third, we explore how membership in one disability trajectory group over another affects healthcare satisfaction, perceptions of everyday discrimination in the context of healthcare treatment settings, and perceived discrimination in everyday life. Regression models include clustered standard errors to account for heteroscedasticity across repeated observations of individuals over time. We identify six group-based trajectories of functional mobility limitation among aging Americans. Black, female, and less-educated Americans are at higher risk of membership in disadvantaged trajectories, characterized by more rapidly increasing counts of functional mobility limitations, than their counterparts. Disadvantaged functional limitation trajectories are associated with lower levels of healthcare satisfaction, higher levels of perceived physical disability discrimination in healthcare treatment settings, and higher levels of perceived physical discrimination in other contexts of everyday life. The present study advances our knowledge of how older adults experience healthcare settings and discrimination across functional mobility status trajectories."}
+{"text": "Biases against older adults and people with disabilities can lead to discriminatory behaviors. One way to better understand attitudes towards these populations is through the examination of implicit (unconscious) factors. This paper utilizes The Implicit Association Test, a computer-based categorization task designed to assess implicit or unconscious attitudes, to assess the impact of an intergenerational service-learning course created to support the human animal bond between vulnerable pet owners and their companion animals. This study, using the Wilcoxon signed-rank test, assessed the impact of college students\u2019 interactions with older pet owners on these students\u2019 implicit attitudes. Pre- and post-assessment of participating students found statistically significant decreased biases towards older people and people with disabilities after completing the course (p=.032). Results from this study suggest that participating in an intergenerational service-learning course centered around the human animal bond can positively affect implicit attitudes towards older adults or people with disabilities."}
+{"text": "STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that  Stimulator of Interferon Genes (STING) in conferring host defense during WNV infection in a murine model. Our studies revealed that STING is essential for restricting pathology in the CNS during WNV infection. Further, STING is required for effective programming of the innate and adaptive immune response to WNV. In the absence of STING, aberrant immune development leads to ineffective viral clearance and immunopathology in the CNS. These studies uncover a critical and previously unidentified role for STING in the restriction of WNV that may have broader implications for a role in conferring host defense against RNA viruses.In recent years, outbreaks of emerging and re-emerging neuroinvasive West Nile virus (WNV) infection have brought about a critical need to understand host factors that restrict neuropathology and disease. WNV infection in humans typically is either asymptomatic or results in a mild febrile illness, but in some cases virus spreads to the central nervous (CNS) causing a more severe form of neuropathological disease. Previous studies established that both innate and adaptive immune responses are essential for controlling WNV disease and restricting the virus from the CNS. In this study, we examined the role of  Flavivirus infections, including West Nile virus (WNV), are ongoing or emerging threats to global health  BME and [40ng/mL] murine MCSF (mMCSF). Cells were cultured for 7 days in non-TC coated plates, then scraped, washed with PBS and seeded at 1E6 cells/well in 12-well TC coated plates with cDMEM+BME+mMCSF. Cells were infected or transfected the next day.in vivo work, while WNV-TX ic (infectious clone) stocks were utilized for cell culture (in vitro) studies. Working stocks were propagated in Vero-E6  and titered by standard plaque assay on VeroWHO and BHK21  cells as previously described . Images acquired using [Allen Brain Institute Brain Explorer 2]. Available from: [http://mouse.brain-map.org/static/brainexplorer].STING localization in the brain is centralized to the hind/mid-brain, hippocampus, primary motor-cortex and olfactory bulb in the brain. Square: midbrain/thalamus region. Oval: hindbrain (cerebellum and brain-stem). Image is from the Allen Institute for Brain Science. [Allen Mouse Brain Atlas]. Available from: [(TIF)Click here for additional data file."}
+{"text": "Summary: Today\u2019s American elders are increasingly being seen as an asset to society through civic engagement. A new challenge facing America now and in the years ahead is how to tap such asset. Formal organizations should play a leading role in institutionalizing American elders\u2019 civic engagement. Due to a structural lag between social changes and organizational practices, however, many organizations are not ready to engage the large number of American elders. To address this issue, formal organizations first need to know which factors affect American elders\u2019 civic engagement and then are able to come up with effective solutions. Although some studies have investigated the contributing factors of American elders\u2019 civic engagement, there are very few systematic syntheses of these factors from various different studies. To fill this gap, the authors conducted a mixed methods systematic literature review using meta-summary. Through electronic search of five databases and hand search of bibliographies, 22 articles were used in final analysis based on eligibility criteria, including 19 quantitative studies, two qualitative studies and one mixed methods study. Findings: The review identified six themes and 28 factors related to American elders\u2019 civic engagement. These themes encompassed socio-demographic factors (eight factors), health status (four factors), program characteristics (four factors), engagement opportunities (three factors), engagement outcomes (five factors) and social capital (four factors). Applications: Formal organizations are advised to develop relevant competencies to capture the influences of identified factors. Social workers are also required to develop multilevel competencies to better engage American elders with the organizational settings."}
+{"text": "Pain and depression, two of the common symptoms among chronically ill older adults, have been found to be related in various populations; however, further knowledge is needed about their relationships and moderating factors among community-dwelling, chronically ill older adults, particularly in lower-income, rural areas with limited healthcare resources. Therefore, this study aimed to examine the association between pain level and depression among chronically ill older adults in rural areas. A total of 100 residents of a rural county in West Alabama, who are 55+ and have chronic illnesses and pain, were recruited from four community senior centers and were interviewed using a structured questionnaire. Pain levels were assessed by the Philadelphia Geriatric Center (PGC) Pain Scale, and depression by an abbreviated version of the Center for Epidemiologic Studies Depression Scale (CES-D). Bivariate correlation and multivariate analysis were conducted. The correlation between pain and depression was significantly positive . The results of the model indicated that pain scores and other control variables explained approximately 18 percent of the variance in depression. The multivariate analysis results confirmed that those who had higher pain scores were significantly likely to have increased depression scores . Education marginally significantly moderated the relationship between pain and depression (p = .059). The previously reported positive pain-depression relationship exists among chronically ill older adults in rural areas, calling for tailored interventions to reduce their pain and its impact on depression."}
+{"text": "This study aimed to understand the movement behaviour and utilization distributions of Kori bustards in space and time in the Serengeti ecosystem. A total of 14 individuals were tracked with the aid of GPS  satellite transmitters, and their sexes were identified using DNA analysis. A species utilization distribution was estimated using the Brownian bridge movement model (hereafter dBBMM) in which the probability of being in an area is conditioned by starting and ending (GPS) relocations. Resource selections were analysed by comparing the GPS relocations with locations randomly placed within each individual\u2019s region of utilization in a spatio-temporal approach. Vegetation information was derived from a Serengeti GIS vegetation map and Data Centre and was reclassified as Open grassland, Dense grassland, Shrubbed grassland, Treed grassland, Shrubland, and Woodland. The Shannon diversity index for vegetation was calculated based on the original vegetation classification. Used versus non-used habitats were contrasted using a generalized linear mixed-effects model with a binomial distribution. The results indicated that males were 21.5% more mobile than females, and movements were 6.3% more diffuse during the non-breeding period compared to the breeding period . Contrasting models indicated that males preferred more open grasslands during the non-breeding period and also preferred closed and shrubbed grassland during the breeding period. Females preferred more woody vegetation during the non-breeding season compared to the breeding season. The most parsimonious model indicated that females preferred to stay closer to rivers and diverse areas during the non-breeding period whereas males preferred areas that were farther from rivers and homogenous. Homogeneous areas were preferred during the breeding period, and heterogeneous areas were preferred during the non-breeding period. We conclude that the movement behaviours of Kori bustards changes with the season and habitat. Further research is needed to understand the factors driving the seasonal movement of Kori bustards in the Serengeti ecosystem. Habitat selection in animals helps maximize their fitness \u20134. HowevPeriods of reproduction may affect both the home range size and habitat selection. In birds, breeding pairs with chicks may have smaller home ranges because breeding birds require habitats with abundant food and safety for their young. Similarly, incubating females may have relatively small home ranges because their nests depend on incubation and protection . HoweverThe Kori bustard is the heaviest flying bird that is indigenous to the grasslands and lightly wooded savannahs of southern and east Africa ; howeverArdeotis kori struthiunculus is listed as near threatened by the IUCN and is included in Appendix II of the list of CITES species ). Whereas males preferred more open grasslands, females preferred to use more woody vegetation . Females preferred to stay closer to rivers, even more so during the non-breeding period . Females preferred more diverse areas contrary to males, who preferred more homogenous areas  in different seasons may be due to the tendencies of some individuals to have strong movements, while these tendencies may be absent in other individuals. According to , Kori bu [Tetrax tetrax) showed similar differences in habitat preferences between males and females [The spatial configuration of the habitats available within the Kori bustard minimum convex polygons and contrasting models based on AIC showed a species preference to woody vegetation, which is more heterogeneous and closer to rivers. The most parsimonious model explained the sexual differentiation in response to seasonal habitat/vegetation preferences wherein males preferred more open grasslands, and females preferred to use more woody vegetation. These preferences may reflect the species\u2019 breeding system, where males and females require different microhabitats, as also observed in the Bengal florican alensis) . Males ralensis) , 47, 48. females , 49. TheArdeotis kori kori, female home ranges are confined by environmental conditions and the accessibility of resources [The most parsimonious model explaining the selection for distance to rivers indicated sexual differentiation in the seasonal responses to habitat preference . Femalesesources .Our study highlights how spatial use and habitat preferences shape the movements of Kori bustards in the Serengeti ecosystem. Overall, our results note the presence of distinct movement patterns related to breeding (December-June) and non-breeding (July-November) periods. We conclude that different movement patterns exist among individual Kori bustards during breeding and non-breeding periods, as females perform partial movements in their habitat of preference, whereas males migrate from one habitat to another. The Kori bustard habitat preferences in the Serengeti ecosystem are sex-specific and differ during different periods of the year, with males utilizing mostly shrubbed grassland and open grassland and females utilizing mostly woody vegetation with increasing habitat diversity. Finally, we recommend further studies on the factors that influence habitat preferences and differential movements of the Kori bustard in their ecosystem during different seasonal periods.S1 Fig6 km2) over Julian days from capture for six male (blue) and eight female (red) Kori bustards in the Serengeti Ecosystem during the breeding  and non-breeding period .Net-squared displacement (in 10(TIFF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file."}
+{"text": "This report describes the first case of extensive macular atrophy with pseudodrusen (EMAP) imaged with optical coherence tomography angiography (OCTA). A 58-year-old Caucasian man presented with decreased central vision in both eyes. Fundus examination showed large areas of macular atrophy centered on the fovea surrounded by diffuse reticular pseudodrusen. Spectral domain OCT (SDOCT) revealed outer retinal and choriocapillaris atrophy. OCTA demonstrated marked absence of choriocapillaris flow. Extensive macular atrophy with pseudodrusen is a rare clinical entity and a new extreme phenotype of macular degenerations that could shed more light on the role of pseudodrusen and choriocapillaris compromise in the pathogenesis of AMD. Extensive macular atrophy with pseudodrusen (EMAP) is a rare clinical entity that was first described by Hamel et al. in 18 patients with bilateral well-delineated chorioretinal atrophy extending to the temporal arcades without sparing the fovea and widespread pseudodrusen throughout the posterior pole and peripheral retina. Earlier onset, more rapid progression of atrophy, and severe visual loss were noted in contrast to age-related macular degeneration (AMD) .Optical coherence tomography angiography (OCTA) is a relatively new, fast, noninvasive imaging modality that analyzes high-speed OCT images, measures changing reflectance, and reconstructs high-resolution blood flow maps of the retina, allowing en face imaging of the retinal capillary plexuses and choroidal vasculature.The author describes the first case of EMAP imaged with optical coherence tomography angiography (OCTA).A 58-year-old Caucasian male presented with progressively decreasing central vision in both eyes over the past five years. He also complained of mild night blindness. There was no significant medical history and no family history of retinal disease. Best-corrected visual acuity was 20/60 in the right eye and 20/200 in the left eye with mild nuclear sclerotic cataracts. Fundoscopic examination revealed large areas of macular atrophy centered on the fovea surrounded by reticular pseudodrusen. Peripapillary atrophy was also present along with scattered areas of peripheral pavingstone degeneration OU Figures . There wExtensive macular atrophy with pseudodrusen (EMAP) is a retinal dystrophy that affects patients in their sixth decade and is defined by bilateral symmetric widespread macular atrophy centered on the fovea surrounded by diffuse macular and midperipheral pseudodrusen. Pavingstone lesions can also be found peripherally . An assoExtensive macular atrophy with pseudodrusen may be a new extreme phenotype of macular degenerations that could shed more light on the role of pseudodrusen and choriocapillaris compromise in the pathogenesis and progression of AMD. An association between pseudodrusen and decreased choroidal thickness has been documented  as has a"}
+{"text": "An abundance of research involving adults who care for family members with dementia has guided the creation of supportive programs/services. Much less is known about adolescents who are dementia caregivers. This descriptive secondary analysis utilized data collected during a qualitative examination into the psychological well-being of adolescent dementia caregivers. Eleven adolescent/adult dyads who provided dementia care for a family member completed surveys prior to the adolescents\u2019 participation in focus groups. Five male and six female adolescents ages 12 to 17 and eleven female adults were asked similar questions about caregiving tasks, education resources, and demographic information. Using descriptive statistics, the results of the surveys provide a snapshot of caregiving among a group of adolescents living in northwest Ohio and highlight differences reported by the dyads. Adult accounts of adolescent preparatory education were incongruent with the adolescents\u2019 and did not report their use of books or online caregiving resources. Conversely, three adults (27%), but no adolescents, identified hands-on and observational opportunities as education resources. Adults reported greater adolescent involvement in ten activities of daily living (71%), especially related to bathing, shopping, transportation, and managing medication and finances. Adolescents reported helping with tasks such as eating and laundry more often than adults. While the sample size was small, these findings suggest a need for triangulation when seeking knowledge about adolescent caregiving. These results may inform researchers wishing to investigate the role of adolescent caregivers, as well as guide supportive agencies who provide education materials to families caring for individuals with dementia."}
+{"text": "Humic substances are breakdown products of decaying organic matter that co-extract with proteins from fossils. These substances are difficult to separate from proteins in solution and interfere with analyses of fossil proteomes. We introduce a method combining multiple recent advances in extraction protocols to both concentrate proteins from fossil specimens with high humic content and remove humics, producing clean samples easily analysed by mass spectrometry (MS). This method includes: (i) a non-demineralizing extraction buffer that eliminates protein loss during the demineralization step in routine methods; (ii) filter-aided sample preparation (FASP) of peptides, which concentrates and digests extracts in one filter, allowing the separation of large humics after digestion; (iii) centrifugal stage tipping, which further clarifies and concentrates samples in a uniform process performed simultaneously on multiple samples. We apply this method to a moa fossil (approx. 800\u20131000 years) dark with humic content, generating colourless samples and enabling the detection of more proteins with greater sequence coverage than previous MS analyses on this same specimen. This workflow allows analyses of low-abundance proteins in fossils containing humics and thus may widen the range of extinct organisms and regions of their proteomes we can explore with MS."}
+{"text": "Lack of positive attitudes towards aging has shown to cause challenges within intergenerational networks in employment situations. These can include job satisfaction, intrinsic motivation to work, and ageism subjectivity as underlying determinants and consequences. The collaborative intervention pilot training program goals were two-fold: 1) To expose and understand ageism as a discriminatory action. 2) To create a more positive social dynamic network in a diverse workplace in regard to general expectations of ageism. Two team-based learning intervention programs were created in order to increase collaborative awareness of ageism and were presented to a medium size intergenerational department staff (N=64) as part of a professional development series on equity, diversity and inclusion. Through three multidimensional self-help training activities, learning was done individually, within similar age employee groups, and within intergenerational employee groups. Participants were able to discuss and express general understandings and expectations of aging and learning tools such as intergenerational reactivity and emotion regulation strategies were presented. Within survey responses at the completion of the trainings, key findings showed that respondents had a better understanding of ageism (76%) and felt better equipped to work within an employment team of diverse ages (71%). Additionally, the subject matter of this pilot training program resulted in re-conceptualized positive aging (61%). Future implications and goals for the program include interventions to further increase positive intergenerational understanding and workplace generational inclusiveness."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: The objectives of this study are to determine whether high-frequency ipsi-lesion or low-frequency contra-lesion ECS improves forelimb function following experimental stroke in aged animals with focal and large strokes. We also want to investigate whether ECS-induced improvements in motor function are related to an enhancement of neural structural plasticity (dendrites and synapses) and changes in growth promoting (BDNF) and growth inhibiting (NOGO-A) expression in the infarcted motor cortex in young and aged animals. METHODS/STUDY POPULATION: We will investigate whether excitatory ECS of the infarcted cortex or inhibition of the noninfarcted cortex combined with daily impaired-forelimb rehabilitative training (RT) results in greater motor functional recovery compared to RT alone. Immunohistochemical (IHC) analyses and unbiased stereological techniques will be performed to investigate changes in proteins associated with dendritic restructuring (MAP2), synaptic plasticity (PSD95 and synaptophysin), and alteration in the expression of BDNF and NOGO-A. RESULTS/ANTICIPATED RESULTS: We expect that inhibitory ECS of the noninfarcted motor cortex will improve behavioral outcomes in moderate to severe stroke animals compared with excitatory ECS or no stimulation  animals. We predict that the ECS condition that improves motor performance most significantly compared with RT alone will have a corresponding greater increase in remaining ipsi-infarct motor cortical dendritic and synaptic plasticity , and greater expression of BDNF. It is unknown, but also expected that better behavioral recovery will coincide with a greater reduction in NOGO-A in the injured motor cortex. DISCUSSION/SIGNIFICANCE OF IMPACT: These studies will aid in creating a model that will allow for a better understanding of the relationship between brain stimulation, severity of injury and, in future studies, aging. These studies will also help clarify previous conflicting brain stimulation results."}
+{"text": "Aerobic training has been shown to be effective at improving cognitive and brain outcomes in older adults with mild subcortical ischemic vascular cognitive impairment (SIVCI). However, uncertainty remains regarding the underlying neurobiological mechanisms by which exercise elicits these improvements in cognition. Increased aberrant functional connectivity of the default mode network has been highlighted as a factor contributing to cognitive decline in older adults with cognitive impairment. Greater connectivity of the DMN at rest is associated with poorer performance on attention-demanding tasks, indicative of a lack of ability to deactivate the network on task. Our previous work on a randomized controlled trial of participants with mild SIVCI, demonstrated that 6-months of thrice weekly aerobic training led to improved global cognitive function, as measured by Alzheimer\u2019s disease Assessment Scale-Cognitive subscale (ADAS-Cog), compared with a health education program. Thus, we conducted secondary analyses to investigate whether these changes in global cognitive function were associated with changes in resting state DMN connectivity. A subsample of 21 participants underwent a resting state functional magnetic resonance imaging (fMRI) scan before and after trial completion. Change in resting state DMN connectivity was found to significantly predict change in ADAS-Cog score  after controlling for age, intervention group, and baseline functional capacity = 3.507, p=.031). These findings suggest that functional connectivity of the DMN may underlie changes in global cognitive function. Furthermore, aerobic exercise is a promising intervention by which to elicit these changes in older adults with mild SIVCI."}
+{"text": "The causes of chronic cough in children are mainly dependent on the setting and age of the child. Protracted bacterial bronchitis is a frequent cause of morbidity in childhood, and antibiotic treatment is beneficial. Prompt recognition and early treatment is important both to prevent inappropriate use of asthma medications and also progression to bronchiectasis, but the diagnosis should not be made uncritically, because chronic wet cough is not necessarily due to lower airway disease. Upper Airway Cough Syndrome (UACS) is considered by some to cause chronic cough in childhood. Underlying UACS are many common conditions, including allergic rhinitis, adenoiditis and rhinosinusitis. Diagnosis relies on a combination of clinical criteria that are relatively sensitive but non-specific. The role of nasal endoscopy in children with chronic cough and signs suggesting UACS is unclear. Nasal saline solution irrigation is commonly used in UACS, but most studies have methodological biases, and efficacy data are scanty. Randomized controlled trials are urgently required. However, if saline washes, rather than oral antibiotics, can effectively treat some children with wet cough associated with upper airway conditions, antibiotic resistance could potentially be reduced. There is a need to further study wet cough and not to assume it to be equivalent to lower airway infection in all children. All that coughs is not bronchitisCough is common in childhood . SpontanThis article aims to suggest a practical approach in children with wet cough and concomitant nasal symptoms through a vignette describing \u201ca child\u201d typical of those referred to outpatient services of two tertiary level Italian hospitals  by primary care pediatricians. The diagnostic work-up and the treatment options in this clinical setting are critically discussed.A preschool boy presented with a 3-weeks history of a troublesome cough that had developed after an acute respiratory infection (ARI). Cough was initially dry, but gradually became wet. A runny nose, nasal obstruction and snoring at night were other features. He had received a 10-days course of oral amoxicillin-clavulanate with minimal effect. The family history was unremarkable. The personal history revealed frequent episodes of ARI during winter since starting attending day care. There was no history of wheeze. Parents were concerned about the frequency of respiratory episodes and had wished for \u201csome tests\u201d over the previous year. Routine laboratory tests including full blood count, erythrocyte sedimentation rate and C-reactive protein, were normal. Pharyngeal swab was also normal. Skin prick testing revealed minor sensitization to house dust mites. Physical examination revealed only a moist cough. A \u201crattle\u201d sound was audible over the chest. The ear/nose/throat (ENT) examination revealed yellowish mucus dripping down into the oropharynx, a cobblestone pharyngeal mucosa and swollen turbinates. Nasal endoscopy revealed mild adenoidal hypertrophy with no evidence of sinus involvement. A diagnosis of adenoiditis was made and a 7-days course of nasal douching with hypertonic solution was prescribed. At 2-weeks follow-up, his cough had completely disappeared and physical examination was unremarkable. He remained well with no antibiotic therapy until a new ARI recurred after 2 months.(PPB-micro) and new definitions were introduced  comprised a history of chronic wet cough, importantly a positive bronchoalveolar lavage (BAL) culture for a respiratory pathogen, and response to a 2-weeks course of oral amoxicillin-clavulanate . Since utroduced . PBB-cliPBB-clinical definition lacks specificity and inherently has limitations. First, many cases of PBB may be \u201cprolonged acute cough\u201d lasting 4\u20138 weeks, which most commonly follows a viral ARI and typically resolves without intervention  and quality (wet or productive) of cough, and excluding other causes of wet cough. The proposed rvention . Second,rvention . Differervention . In chilrvention . Interesrvention ; neverthrvention . Fourth,rvention . FinallyPBB-clinical definition may lead to substantial over-diagnosis and increased prescription of antibiotics if not meticulously verified. The evidence-base for benefits of antibiotic therapy in children with PBB mainly rely on a single randomized controlled study (RCT) involving children with chronic cough in Australia  , the optPost-nasal drip (PND) is the drainage of secretions from the nose or paranasal sinuses into the pharynx. The suspicion of PND rests on the patient recognizing that something is dripping down into the throat and/or is suffering from frequent throat clearing. The finding of mucoid secretions in the pharynx or a cobblestone aspect of pharyngeal mucosa is suggestive.The causal role of PND in chronic cough is a controversial issue both in adults  and in cThe reported incidence of UACS in children with chronic cough varies widely. Asilsoy et al.  used theThe ACCP guidelines for adults explicitly state that the treatment options for UACS-induced cough are somewhat dependent on the subcategory of disease that is present . AntihisNasal saline solution irrigation (NSSI) has recently gained popularity in selected settings . An ItalThe exact mechanism of action of NSSI is not known , but mechanical cleaning of the nasal mucosa, which leads to the removal of inflammatory mediators and temporary improvement of mucociliary clearance, may be important. This may favor to resolve inflammation/infection spontaneously or with drugs.Despite being used in daily practice, NSSI is only briefly mentioned in the guidelines for the treatment of RS , 39. SysAll children cough, but most of them are \u201cexpected\u201d  or merely a normal part of common childhood respiratory infections. Isolated dry cough in a community setting in an otherwise well child is unlikely to betoken any serious underlying condition. On the other hand, children with chronic wet cough often pose a diagnostic and management dilemma to the physician. Children similar to the one described in the vignette are frequently seen in primary care.The clinical presentation of the case described does not fulfill the diagnostic criteria for PBB since the cough lasted only 3 weeks. Therefore, the prescription of antibiotics was inappropriate. Parents are often disturbed by cough and ask that \u201csomething is done.\u201d In a prospective study in Australian children, a high proportion of parents thought antibiotics should be given for post-infectious cough (34%) or were unsure (24%); surprisingly, antibiotics were prescribed in 14% of episodes characterized by isolated dry cough with no fever . Post-inThe patient presented with a clinical history and physical signs consistent with UACS. There is no mention of nasal symptoms and/or signs in the recently extended list of cough pointers for the management of children with chronic wet cough . Some spIn the vignette, the diagnosis of adenoiditis was made by nasal endoscopy. The inflammatory involvement of adenoids is common in children, especially those attending day care , as uppeCough in the above child had not disappeared after antibiotic therapy but did a few days after treatment with NSSI; however, spontaneous resolution cannot be excluded. In a prospective study, most children with suspected UACS had cough which resolved after treatment with NSSI . Cough ibefore prescribing an antibiotic; and this includes making the diagnosis of \u201cnormal child\u201d and reassuring the family. Unfortunately, available data demonstrate that is difficult not to give in to this temptation. Respiratory diseases are the most common reason for the prescription of antibiotics in primary care, but many of them are unnecessary , Amoroso Angelo (Pescara), Andreozzi Americo (Macerata), Basile Lucio (Pescara), Beghella Massimo (Ancona), Bellucci Nazareno (Todi), Bernacchi Stefania (Perugia), Bosco Fiorella (Pescara), Brachelente Linda (Perugia), Cappellucci Domenico (Pescara), Carnevale Maurizio (Pescara), Castiglione Giovanni Battista (Pescara), Chioccoloni Roberta (Marsciano), Coronati Valeria (Ancona), Della Vedova Giacomo (Spello), Di Filippo Antonella (Giulianova), Di Florio Rossana (Pescara), Di Giampietro Tiziana (Pescara), Di Girolamo Franca (San Benedetto del Tronto), Gabbanelli Gianna (Ancona), Gabriele Piera (Pescara), Gobbi Costantino (Macerata), Gonnellini Rita (Deruta), Guerrieri Arcangela (Ancona), Laguardia Luigi (Montesilvano), Liberati Marina (Ascoli Piceno), Martello Cecilia (Perugia), Merluzzi Angela (Citt\u00e0 di Castello), Migliori Cesare (Ancona), Minucci Maria Giovanna (Foligno), Mora Marina (Ancona), Nuzzaci Roberto (Castelfidardo), Passali Maria Grazia (Pescara), Piermattei Loredana (Tolentino), Rossi Laura (Foligno), Ruggeri Anna Grazia (Matelica), Sardo Infirri Margherita (Spoleto), Solinas Lucia (Foligno), Truffarelli Francesca (Foligno).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Felton Institute has been working to eliminate isolation and loneliness in San Francisco since its inception as a community social service agency 130 years ago. Felton offers culturally and linguistically appropriate programs and services that foster community and social connections among socially isolated, low income older adults, including those living with serious mental illness and those residing in local long-term care facilities. Examples include workforce programs for older adults; the foster grandparent program; and the senior companion program which includes friendly visiting, senior counseling, and peer escort services. This session will highlight lessons learned from these successful programs as well as how they have led to the development of new initiatives focused on conducting outreach, providing trauma-informed services, offering wellness classes, and organizing meaningful activities including a choir, intergenerational gardening, arts and dance classes, and cultural exchange opportunities to isolated older adults living in poverty in San Francisco\u2019s Visitacion Valley."}
+{"text": "Fundamental watershed-scale processes governing chemical flux to neighboring ecosystems are so poorly understood that effective strategies for mitigating chemical contamination cannot be formulated. Characterization of evapotranspiration, surface runoff, plant uptake, subsurface preferential flow, behavior of the chemicals in neighboring ecosystems, and an understanding of how crop management practices influence these processes are needed. Adequate characterization of subsurface flow has been especially difficult because conventional sampling methods are ineffective for measuring preferential flow of water and solutes. A sampling strategy based on ground-penetrating radar (GPR) mapping of subsurface structures coupled with near real-time soil moisture data, surface topography, remotely sensed imagery, and a geographic information system (GIS) appears to offer a means of accurately identifying subsurface preferential flow pathways. Four small adjacent watersheds draining into a riparian wetland and first-order stream at the USDA-ARS Beltsville Agricultural Research Center, Beltsville, MD are being studied with this protocol. The spatial location of some preferential flow pathways for chemicals exiting these agricultural watersheds to the neighboring ecosystems have been identified. Confirmation of the pathways is via examination of patterns in yield monitor data and remote sensing imagery."}
+{"text": "Regulated hemostasis, inflammation and innate immunity entail extensive interactions between platelets and neutrophils. Under physiological conditions, vascular inflammation offers a template for the establishment of effective intravascular immunity, with platelets providing neutrophils with an array of signals that increase their activation threshold, thus limiting collateral damage to tissues and promoting termination of the inflammatory response. By contrast, persistent systemic inflammation as observed in immune-mediated diseases, such as systemic vasculitides, systemic sclerosis, systemic lupus erythematosus or rheumatoid arthritis is characterized by platelet and neutrophil reciprocal activation, which ultimately culminates in the generation of thrombo-inflammatory lesions, fostering vascular injury and organ damage. Here, we discuss recent evidence regarding the multifaceted aspects of platelet-neutrophil interactions from bone marrow precursors to shed microparticles. Moreover, we analyse shared and disease-specific events due to an aberrant deployment of these interactions in human diseases. To restore communications between the pillars of the immune-hemostatic continuum constitutes a fascinating challenge for the near future. The circulatory system provides functional integration to tissues throughout the body and constitutes a dynamic platform for tasks, such as immune patrolling and defense against threats \u20133. ConsiCellular membranes allow the segregation of selected information in compartments and modulate their subsequent effects on the environment by integrating multiple stimuli. Circulating membrane-endowed players in the immuno-hemostatic network encompass leukocytes, platelets and microparticles, with the endothelium as a fourth static counterpart , 13. PlaHemostasis and inflammation counterbalance the effect of injuring external stimuli. Selective regulation and polarization of these pathways enhance homeostatic responses at sites of tissue or vascular injury and minimize the detrimental effects to the host. Multiple mechanisms have developed, including variability in the lifespan of players involved in the immune-hemostatic balance and availability of soluble or membrane-bound moieties. Emission of membrane-endowed subcellular particles fine-tunes cellular activation and converts locally concentrated high-intensity responses into a sum of smaller but widespread and reciprocally independent biological events. Generation of extracellular vesicles enables the extension of the total membrane area interacting with the environment as well as of the range of potential cellular targets. In addition, segregation of information in multiple signaling quanta discloses the possibility of independent interactions with distinct cellular counterparts according to the differential needs of target tissues. Platelets are anucleate cell fragments released by megakaryocytes. After a multi-stage process of cytoplasm compartmentalisation and concentration of bioactive compounds into granules taking place over the course of days, platelets are released as elongated precursors (proplatelets), which undergo multiple iterative fission events to reach their final size. Preplatelets are round-shaped precursors constituting a reversible intermediate stage in the transition from proplatelets to platelets . Small vIncreased platelet demand and/or consumption during acute systemic inflammation warrants adaptation of megakaryocytes. Inflammatory cytokines, such as IL6 promote megakaryocyte increase in ploidy and prompt thrombocytopoiesis through increased liver synthesis of thrombopoietin as part of the acute phase response . PlateleControlled exocytosis or integration of bioactive compounds into platelet membrane is crucial for these tasks. Platelets are endowed with three classes of granules: alpha-granules; dense granules and few lysosomes. Some authors also described \u201cT granules\u201d equipped with Toll-like receptor 9 as a potential fourth platelet compartment \u201328. BesiNeutrophils constitute the most abundant leukocyte population in the blood and are in charge of the early innate effector response to noxious stimuli . NeutropPhagocytosis and digestion of invading pathogens constitutes the default-mode defensive task performed by neutrophils. However, frustrated microbial phagocytosis promotes the generation of extracellular traps (NETs) , i.e., tNeutrophils also account for tissue and vascular damage in immune-mediated diseases including inflammatory bowel diseases, systemic lupus erythematosus (SLE) rheumatoid arthritis (RA) and vasculitides either directly or through NET-induced facilitation of thrombosis , 74\u201376. Platelets interact productively with multiple cells types , althougVital neutrophil internalization (emperilopolesis) into megakaryocytes occurs in the bone marrow. Engulfed neutrophils provide megakaryocytes with activating stimuli (causing a rise in platelet production) and donate membrane segments causing enhanced phosphatidylserine expression by chimeric daughter platelets . It is tPlatelets and megakaryocytes communicate long-range with neutrophils through exocytosed mediators and microparticles with enhancing actions on neutrophil activation , 95. TheThe interaction between platelets and neutrophils impacts on multiple stereotyped pathological manifestations . A firstPatients with inflammatory diseases of the blood vessels , 131, coAberrant coagulation is detectable in immune mediated diseases , 119. AlThrombotic microangiopathy, consisting in diffuse deposition of thrombi along small vessels due to widespread endothelial activation with hemolysis and platelet consumption, might complicate SLE, SSc, antiphospholipid syndrome and other immune-mediated diseases \u2013185. UndThe lung is a major inflammatory target . NeutropSystemic vasculitides encompass a very large set of immune-mediated diseases characterized by vascular injury and downstream organ ischemia as the core pathophysiological event . They caNeutrophils cause vascular damage in small-vessel vasculitis, possibly reflected by the accumulation of leukocyte cellular debris in peri-vasculitic lesions (leukocytoclasia). In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), neutrophil mediated vascular injury is part of a vicious circle linking exposure of myeloperoxidase (MPO) and/or proteinase-3 from granules to neutrophil surface or into the setting of NETs  to the dIn large vessel-vasculitides, activation of platelets may contribute to promote vascular remodeling through the release of signals, such as VEGF . Platelevasa vasorum and entailing aberrant platelet-neutrophil cross-talk.Little is known on platelet-leukocyte interactions in large vessel vasculitides, although relative depletion of neutrophil granule content has been reported in giant cell arteritis in association with platelet activation , 132. NoSLE is a multi-organ autoimmune disease with a wide spectrum of clinical manifestations and pathogenic mechanisms . FailureCardiovascular manifestations are frequent in patients with SLE and a cause of morbidity and mortality . AccelerEndothelial derived microparticles constitute the most abundant microparticle subset in patients with SLE and correlate with endothelial dysfunction and interferon-\u03b1 signature , 232. HoMechanistically, platelet activation in SLE might depend on circulating immunocomplexes, which are abundant in SLE patients biological fluids and are recognized on platelet surface by Fc\u03b3RIIA and Toll-like receptor 4,7 . PD\u03bcP thSSc is a systemic autoimmune disease, characterized by unrelenting inflammation with a wound repair response consisting in mesenchymal extracellular matrix deposition leading to fibrosis, and by microvascular dysfunction and aberrant neoangiogenesis , 238. PlActivated platelets in SSc contribute to impaired vascular tone  anRheumatoid arthritis is a relatively frequent autoimmune disease characterized by prominent involvement of the synovial joints. Although extra-skeletal manifestations are relatively less frequent compared to other immune-mediated diseases, patients with RA show an increased ischemic risk, pointing to the existence of a core pathophysiological event linking inflammatory manifestations to vascular dysfunction .Neutrophils undergoing NET generation might provide autoantigens in RA. Patients in fact frequently develop antibodies against citrullinated peptides (ACPA). Citrullination occurs thanks to the activity of deiminating enzymes, such as protein-arginine deiminase 4 (PAD4), abundantly expressed in neutrophils . CitrullPlatelets can be activated by collagen through the megakaryocyte lineage-specific glycoprotein VI and thus prompted to generate microparticles. Boilard and colleagues  showed tPlatelets and neutrophils are major determinants of the immune-hemostatic continuum and extensively interact based on cell-cell contact and/or exchange of soluble signals and microparticles to synergise in contrasting the noxious effects of endogenous or environmental stimuli toward vessel and tissue integrity and to promote physiological tissue renewal and homeostasis. These events, part of a set of simple, innate, but evolutionarily preserved stereotyped responses, are disproportionately active and self-sustained in patients with immune-mediated diseases, such as systemic vasculitides, SLE, SSc, RA and possibly allergic disorders and might account for the development of either some inflammatory manifestations and of cardiovascular complications. Patients with immune-mediated diseases consistently show signs of platelet (and/or PD\u03bcP) activation, possibly prompting either the formation of heterotypic aggregates with neutrophils (as in giant cell arteritis) or neutrophil activation toward enhanced survival and eventually NET generation . Diagnostic and therapeutic strategies currently employed in the setting of autoimmune diseases to prevent disease progression and the occurrence of secondary complications are generally not targeted on these pathogenic mechanisms, suggesting the existence of a largely unexplored window of opportunity to improve survival and quality of life for patients by dampening sustained neutrophil-platelet interactions.GR and NM collected the literature data, drafted, and revised the manuscript. AM revised the manuscript and provided critical analysis of intellectual content. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work will appropriately be investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Exercise/therapy interventions). Six of the seven training studies were concerned with upper limb function , and one examined the effect of foot drop stimulator training. The six upper limb studies used a variety of training modalities including Wii-based upper limb therapy (two papers from one group), EMG-driven robotic devices with or without neuromuscular electrical stimulation (NMES) (three papers), and traditional physical/occupational therapy (one paper).The nineteen papers of the research topic Electromyography (EMG) Techniques for the Assessment and Rehabilitation of Motor Impairment Following Stroke highlight a variety of ways that EMG may be used to better understand and treat stroke-induced brain damage. Seven papers addressed the impact of weekly training on EMG properties and function post-stroke, and one paper examined the effect of a robotic exoskeleton on gait during a single training session (Mechanisms of motor impairment). These included one study that addressed coupling between the index finger and thumb, whereas another addressed upper limb synergies during reaching. One paper examined EMG co-contraction during gait, and one addressed gait EMG during obstacle crossing. One group examined reticulospinal pathways during elbow flexor activity using startling acoustic stimulation. Another studied masticatory muscle activity following brainstem stroke. Finally, one group addressed coupling between the electroencephalogram (EEG) and EMG signals during upper limb movements.Another seven papers were focused on using EMG to examine motor impairment after stroke ((Novel EMG processing techniques). These included new approaches to intramuscular EMG decomposition, coherence of motor unit firing patterns from surface EMG, clustering index analysis of surface EMG, and pattern recognition from high density surface EMG.Four studies used novel EMG processing techniques to study motor control and impairment post-stroke A number of studies examined the effects of an exercise/therapy program, or a single exercise session, on EMG and motor function. Some also addressed the associated cortical plasticity.Hesam-Shariati et al. examined changes in upper limb EMG activity resulting from the standardized 14-day Wii-based Movement Therapy program  in chronic stroke survivors. They found that training lead to different patterns of EMG changes that were related to the level of motor deficit. In their companion paper Hesam-Shariati et al. they quantified muscle synergies during therapy  based on EMG activity of the affected arm muscles using a non-negative matrix factorization algorithm. They were able to identify differences in the number of muscle synergies used by patients as a function of the level of motor deficit.Many addressed the effect of exercise/therapy on upper limb muscle activation properties. Lu et al. used forearm EMG signals to detect a stroke survivor's motion intent, and then used the EMG to drive a hand exoskeleton to assist with finger motion in real time. After 10-weeks of robot-assisted hand therapy, the patient showed improved grip strength and hand function. The results demonstrate the feasibility of robot-assisted training driven by myoelectric pattern recognition in chronic stroke survivors.Device-assisted interventions offer a way to study and train patients with more severe limb impairment. In a case study, Qian et al. evaluated the effects of 1 month (20 sessions) of EMG-driven NMES combined with robotic assistance, targeting the elbow, wrist, and fingers of subacute stroke survivors. EMG parameters, including the co-contraction index and the activation level of targeted muscles were used to monitor the muscle coordination patterns. They found that the NMES combined with robotic training could achieve higher motor outcomes at the distal joints and more effective reduction in muscle tone than traditional therapy.After a stroke, it is critically important to start rehabilitation early to take advantage of the highly plastic period of the neural system. In a pilot randomized control trial, Wilkins et al. found EMG-driven NMES task-specific arm/hand training (7 weeks) improved hand opening and functional use in chronic stroke survivors with moderate to severe motor impairments. Functional improvement was paralleled with functional reorganization in the ipsilesional primary sensorimotor cortex. The neural plastic reorganization after functional improvement was also seen with strengthened corticomuscular coupling. In a case study of a subacute stroke subject, Zheng et al. evaluated corticomuscular coupling between EEG and EMG (biceps) signals during elbow flexion before and after 1 month of regular physical and occupational therapy. Corticomuscular coherence was increased in the affected limb with functional improvement, but not in the non-affected limb. These results exemplify that stroke survivors with severe motor impairments may still have the potential to improve hand function if appropriate interventions are used to induce neural plasticity.Some investigators also addressed training-related cortical plasticity and corticomuscular coupling. Pilkar et al. used different EMG-based indices to quantify the effects of a foot drop stimulator on muscle activation during gait over a 6 month period of community walking. A wavelet-based time-frequency analysis approach was used to quantify activation changes of multiple ankle muscles in chronic stroke survivors. The findings suggest alterations in motor unit recruitment strategies after foot drop stimulator use. The outcomes establish the efficacy of a foot drop stimulator as a rehabilitation intervention that may promote motor recovery in addition to reducing foot drop.Androwis et al. used novel EMG analysis (Burst Duration Similarity Index) to quantify the intensity and timing of muscle activation during a single session of robotic gait therapy in acute stroke survivors. The authors showed that a robotic exoskeleton can reduce the soleus and rectus femoris muscle activity in the affected limb during stance phase, and can also improve the timing of muscle activation in the affected limb.Quantitative and continuous monitoring of muscle activation is necessary to adjust training protocols in a timely manner. Jones and Kamper studied the coupling of the index finger and thumb during close-open pinching motions in chronic stroke survivors. A Cable-Actuated Finger Exoskeleton was used to perturb joints of the index finger during pinching motions, while finger/thumb muscle surface EMG and finger kinematics were recorded. They found that involuntary finger-thumb coupling was present during the dynamic pinching task, with perturbation of the index finger impacting thumb activity. This finding reveals a potential mechanism to improve hand mobility following stroke. Li et al. analyzed motor synergies during arm reaching based on surface EMG recordings from multiple muscles and correlated with reaching kinematics. They were able to detect task-specific deficits in reaching movements after strokeSurface EMG together with other signals recorded peripherally or centrally provides a means to assess mechanisms of motor impairment. Ma et al. studied lower limb muscle activity during obstacle crossing using surface EMG in chronic stroke survivors. EMG activity of the leading limb during the swing phase was larger in all muscles in the stroke compared to the control group, and TA activity increased with obstacle height in both groups. Co-contraction between agonist-antagonist muscle pairs was larger in the stroke group in the leading/ trailing limb during certain phases. The authors suggested that the greater muscle activation during obstacle crossing following stroke may have a negative impact on balance.Banks et al. quantified surface EMG co-contraction of agonist-antagonist muscle pairs in three ways  and determined their association with gait impairment during treadmill walking. Co-contraction during the terminal stance phase was not different between healthy controls and the stroke subjects, regardless of the normalization method. Normalization also did not impact the ability to resolve group differences. Furthermore, the correlation between stance phase co-contraction and walking speed was modest. Pathological co-contraction may not be a primary factor contributing to impaired gait in most stroke survivors. The authors suggest other approaches that account for timing and amplitude components of the EMG  may better capture the relevant deficits.It remains unclear whether co-contraction of agonist-antagonist muscles is excessive and impacts gait significantly following stroke. In chronic stroke survivors, Gao et al. studied subacute stroke patients completing tasks such as hand gripping and elbow bending. Stroke subjects demonstrated greater strength in the bi-directional corticomuscular coupling between the EEG and EMG signals. Such changes suggest a compensational strategy after the brain lesion.The coupling strength between the EEG and EMG signals during motion is instructive in assessing motor function. in vivo even with the most advanced neuroimaging techniques. Startling acoustic stimulation is known to stimulate the reticulospinal pathways, thus allowing the opportunity to assess the role of brainstem motor system indirectly. Li et al. analyzed changes in EMG and force in response to startling acoustic stimulation during isometric elbow flexion in stroke survivors and healthy controls. They reported that the sound-induced force and EMG increase in stroke survivors was not significantly different from those in healthy controls. As such, there results suggest that the reticulospinal projections do not increase their contributions to muscle strength in stroke. Jian et al. analyzed surface EMG signals of bilateral masticatory muscles in stroke survivors after brainstem stroke using multiple EMG parameters. In addition to expected differences between muscles and sides, they did not observe the head position effect on muscle activation on both sides. These are valuable information as the results could advance the understanding whether head positions alter chewing and swallowing activities in stroke survivors.It is difficult to assess activities of brainstem nuclei Ren et al. developed a new intramuscular EMG decomposition technique to improve the accuracy of EMG decomposition with interference patterns. The technique was implemented by using six stages of analysis including feature extraction, clustering, refinement of the classification, and splitting of the superimposed MUAPs. A high accuracy of MUAP detection was reported in 8 subacute stroke survivors (88%) and 20 healthy control participants (94%).Examining motor unit discharge and recruitment patterns post-stroke can disclose valuable information pertaining to impaired spinal versus supraspinal motor control. EMG decomposition into constituent motor unit action potential (MUAP) trains, however, is challenging with severe superposition of multiple MUAPs. Dai et al. quantified the different types of connectivity in the spinal networks and changes in their relative contributions after a stroke. By comparing the coherence of motor unit firing pattern across different isometric contractions, they identified significant changes in coherence in three frequency bands: delta (1\u20134 Hz), alpha (8\u201312 Hz), and beta (15\u201330 Hz) in the paretic hand muscles. These changes reflect increased common synaptic inputs in the subcortical pathway and provide evidence on different origins of impaired muscle activation in stroke.Tang et al. applied clustering index analysis to examine surface EMG in the distal and proximal muscles of the upper limb from 12 stroke survivors. They observed abnormally high or low clustering index values in the paretic muscles compared to healthy controls. This finding may indicate that both neurogenic and myopathic changes may occur in paretic muscles.To further differentiate neurogenic and myopathic changes in the muscle, Wang et al. developed a novel pattern recognition technique for precise discrimination of 20 hand/upper limb functional movements in stroke survivors. Specifically, they applied wavelet packet to extract the neural control features and used the Fisher's class separability index and the sequential feedforward selection analyses to select appropriate channels in high density surface EMG. Such implementation can facilitate use of surface EMG control in stroke rehabilitation.Selection of appropriate features from surface EMG is essential for development of highly effective pattern recognition algorithms in the EMG-controlled devices. All authors made an equal contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The hypothalamic-pituitary-ovarian (HPO) axis is a tightly regulated system controlling female reproduction. HPO axis dysfunction leading to ovulation disorders can be classified into three categories defined by the World Health Organization (WHO). Group I ovulation disorders involve hypothalamic failure characterized as hypogonadotropic hypogonadism. Group II disorders display a eugonadal state commonly associated with a wide range of endocrinopathies. Finally, group III constitutes hypergonadotropic hypogonadism secondary to depleted ovarian function. Optimal evaluation and management of these disorders is based on a careful analysis tailored to each patient. This article reviews ovulation disorders based on pathophysiologic mechanisms, evaluation principles, and currently available management options. The hypothalamic-pituitary-ovarian (HPO) axis must be viewed as an entity that works in concert to allow for procreation by means of cyclic production of gonadotropic and steroid hormones. This cycle is tightly regulated to select a dominant follicle for ovulation, meanwhile priming the endometrium for implantation. The ovary plays a pivotal role in the production of steroid hormones necessary for follicular development and oocyte maturation. It contains a finite number of oocytes that a woman will have for the span of her reproductive life and influences the hormonal milieu required for oocyte maturation and fertilization. This complex regulation can be negatively impacted when pathologies occur within any juncture of the HPO axis.Ovulatory disorders are the leading cause of infertility classified into three categories according to the World Health Organization (WHO ). Group Here, we provide an overview of ovulation disorders categorized by pathophysiologic mechanism from recent literature, along with guidance on evaluation and currently available management options.Group I ovulation disorders, hypothalamic-pituitary failure (HPF) manifests as hypogonadotropic hypogonadism. Females with HPF typically present with delayed or impaired pubertal development, primary or secondary amenorrhea, and infertility. Idiopathic hypogonadotropic hypogonadism (IHH) due to a congenital absence of gonadotropic releasing hormone (GnRH) is the most common cause of HPF. IHH associated with anosmia is termed Kallmann syndrome, which results from failure of GnRH neuronal migration from the olfactory placode during embryonic development. This disorder has a multimodal genetic inheritance pattern and can be transmitted in an X- linked, autosomal dominant, autosomal recessive, or oligogenic fashion with variable penetrance. Several gene mutations in association with this disorder have been identified, most notably ANOS1 . The nasAcquired causes include panhypopituitarism, characterized by >50% deficiency of one or more tropic hormones secreted by the pituitary gland. Etiologies leading to panhypopituitarism involve tissue necrosis (secondary to acute ischemia or pituitary gland apoplexy), autoimmune or infectious hypophysitis and compression by pituitary adenomas or adjacent brain tumors. Postpartum hemorrhage and significant head trauma may temporarily or permanently impact hormone production from the anterior pituitary. Similarly, intracranial tumors may compress the anterior pituitary stalk disrupting axonal communication between the hypothalamus and pituitary gland. Craniopharyngioma, a benign brain tumor deriving from a Rathke\u2019s pouch, is the most common brain tumor causing delayed puberty and primary amenorrhea. In addition to dysregulation of the HPO axis, bitemporal hemianopsia and chronic headaches may be observed if the optic nerve is compressed . AdditioLangerhans cell histiocytosis should be considered when more common causes of HPF are ruled out. This condition is marked by uncontrolled proliferation of dendritic cells associated with the monocyte-macrophage system . When LaA patient\u2019s medical history can help delineate between the various etiologies, to tailor evaluation and management. Basic evaluation includes follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2). In some instances, further evaluation is advisable to exclude central hypothyroidism (low TSH), hypocortisolism (low ACTH) and low growth hormone, which are a hallmark of panhypopituitarism.Commonly, a head MRI is indicated to rule out morphologic pituitary anomalies or presence of a tumor . OverallGroup II, eugonadal ovulatory dysfunction, accounts for the majority of ovulation disorders and comprises a wide spectrum of disorders. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive aged women with a prevalence of 6\u201310% . It is tExtremes of weight and body fat distribution, influences the regulation of ovulation. Obesity, particularly central type, interferes with endocrine and paracrine mechanisms involved in reproductive cycle regulation. Loss of normal GnRH pulsatility is commonly due to excessive aromatization of androgen precursors, DHEA and testosterone, to estrone in adipose tissue, decreased levels of sex hormone binding globulin (SHBG) and elevated production leptin by adipocytes . FurtherIn contrary, in underweight patients, GnRH pulsatility is affected by depletion of circulating leptin, excessive cortisol and neuropeptide Y production, in addition to elevated centrogenic opioid and endorphin secretion. Hyperprolactinemia is a common cause for ovulatory dysfunction. There are many known causes of hyperprolactinemia including anterior pituitary adenomas, prolactinomas, primary hypothyroidism with thyrotropin releasing hormone (TRH) stimulation of prolactin, renal failure with abnormal clearance of prolactin, and psychotropic medications altering dopamine release. Primary hypothyroidism hinders regulation of the HPO axis since excessive TRH secretion will interfere with GnRH pulsatility. Furthermore, abnormal thyroid function affects folliculogenesis and oocyte quality. Some studies have suggested thyroid stimulation hormone (TSH) > 2.5 \u03bcIU/mL may be enough to lead to disordered ovulation; however additional studies have presented conflicting data. The literature has demonstrated that during controlled ovarian hyperstimulation, TSH is noted to increase and if baseline TSH exceeds 3 \u03bcIU/mL, patients will experience clinical hypothyroidism ,17,18. AThe ultimate goal for anovulation caused by eugonadal hypothalamic-pituitary dysfunction is to correct the underlying etiology. The majority of endocrinopathy related infertility is reversible and can be managed medically. Patients who present with menstrual dyscrasias should undergo initial evaluation with AMH, TSH and total T4, and prolactin level. If clinical signs of hyperandrogenism are apparent, 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEA-S) and total testosterone should be measured to rule out presence of ovarian or adrenal androgen secreting tumors. It is important to consider that multiple endocrinopathies may co-exist and must be treated concurrently. Prior to medical management, preconceptual counseling and lifestyle optimization should be emphasized, particularly weight loss and exercise. Thyroid deficiency and hyperprolactinemia, when corrected often will lead to successful ovulation and pregnancy. Patients suffering with PCOS commonly require ovarian suppression with combined oral contraceptive pills (OCPs), unless conception is desired. Multiple non-contraceptive benefits exist with the use of OCPs in this setting including reversing hyperandrogenism with shrinkage of exaggerated ovarian stroma, regulation of menses and reducing the risk of ovarian and endometrial cancer . Those dGroup III ovulatory disorders is defined as ovarian insufficiency or failure with a hypergonadotrophic-hypogonadic profile that affects 5% of women with ovulatory dysfunction . Women pDespite a low incidence, the most common genetic form of POI remains Turner syndrome, 45 XO, with either complete or partial X chromosome deletions. These patients commonly present with primary amenorrhea due to accelerated oocyte depletion. The second most common cause of POI is chromosomal aberrations. Approximately 10\u201330% of cases appear to be familial, primarily exhibiting an x-linked inheritance pattern with varying penetrance ,24. SeveNOBOX) and factor in germline alpha (FIGLA) that are responsible for gonadal differentiation and folliculogenesis [Additional candidate genes have been proposed to be causative, however lack sufficient evidence. New headways illustrating causes for POI includes mutations in transcription factors such as nuclear receptor subfamily five group A member 1 (NR5A1), newborn ovary homeobox , type I and II, associated with endocrine gland and extra-glandular tissue destruction reported to cause POI. APS type I affects younger children, with 60% of girls affected experiencing primary amenorrhea and POI. Type II causes gonadal failure in 4% of affected individuals . AssociaCommon gynecologic disorders may also contribute to accelerated reproductive aging. Endometriosis affects 10% of reproductive aged women. In addition to structural pathologies, ovarian endometriosis may lead to ovarian destruction and consequently a hypoestrogenic state. A study performed by Cahill et al. described endometriosis related diminished LH levels in serum and follicular fluid impacting ovulation . InevitaA number of environmental toxins may lead to POI. Effects of cigarette smoking have been extensively investigated. Smoking is associated with accelerated follicular atresia, displayed by significant lower AMH and earlier onset of menopause . EnvironAs oncologic treatments continue to improve, and the number of cancer survivors continue to increase, so does the rate of iatrogenic ovarian insufficiency. Cancer therapy causes oocyte depletion in several ways, the most common being inhibiting growth and proliferation of cells that support oocytes. How chemotherapeutic drugs affect immature oocytes is still unclear, however commonly used toxins including alkylating agents, work by interlinking DNA causing breaks that damage the cell . AdditioPelvic and total body irradiation has significant ramifications on ovarian function. Radiation doses as low as 4\u20135 Gy results in permanent loss of ovarian function. Knowing these treatment modalities confer poor prognosis for post-therapy gonadal and uterine function, careful consideration can be made in planning for future fertility. The field of onco-fertility is ever growing, with fertility preservation becoming increasingly available. Both the quantity and quality of available oocytes significantly diminishes once a woman reaches 35 years of age with exponential decline until menopause. Ovarian insufficiency can be diagnosed by measuring AMH, estradiol, FSH levels and antral follicle count. Though spontaneous pregnancy is not impossible, it is certainly much more difficult to achieve without intervention. Patients faced with such a diagnosis should be provided reassurance and guidance to the alternate reproductive options currently available. Evaluation approach is dependent on medical history and physical examination. Reproductive aged women less than 35 years old with rapidly declining ovarian reserve warrant genetic and infectious disease testing. If genetic testing is abnormal, genetic counseling is prudent.Patients with Turner syndrome may present with lack of pubertal milestone or primary amenorrhea. Mosaic Turner syndrome patients may be aware of their diagnosis prior to complete follicular atresia and can salvage their fertility by means of oocyte and/or embryo cryopreservation. With newer vitrification techniques, oocyte cryopreservation has become a reliable and available method for fertility preservation . In factOnco-fertility patients also greatly benefit from oocyte or embryo preservation prior to gonadotoxic therapy. In recent years, random start ovarian hyperstimulation in preparation for egg retrieval allows physicians to shorten treatment duration to proceed with chemoradiotherapy . In a spIVF with donor oocytes currently remains the most successful treatment modality for women with POI or age related diminished ovarian reserve. Currently available options of fresh or frozen or known vs. unknown donors provides patients with more options. Furthermore, women may opt to have their young relatives, with abundant ovarian reserve, to donate oocytes to them . The use of mesenchymal stem cells (MSCs) has been emerging as a treatment option for patients with POI. Stem cell therapy has particularly been studied in the setting of iatrogenic ovarian destruction and shown great promise. Various sources of stem cells under investigation for this purpose include umbilical cord MSCs (UCMSCs), induced pluripotent adult stem cells (iPSCs), and embryonic stem cells. Mouse models with chemotherapy induced ovarian insufficiency undergoing subsequent treatment with UCMSCs have demonstrated improved ovarian function with recovery of sex steroid levels and decreased cumulus cell apoptosis ,46. The More novel therapeutic options are beginning to make strides for age related oocyte quality improvement. One suggested mechanism responsible for depleted ovarian reserve involves mitochondrial dysfunction . Though Those affected by POI have health implications if they remain in a chronic hypoestrogenic state including as cardiovascular risk, sexual function and bone health. Hormone replacement therapy (HRT) should be encouraged through use of estrogen therapy with cyclic progestin if a woman still has her uterus. Those who no longer have a uterus, estrogen replacement alone is recommended. HRT is important to reduce the risk of morbidity and mortality as it mimics normal ovarian function until the natural age of menopause . Dose tiIn summary, this review outlines an up to date classification of ovulatory disorders to serve as a guide for its evaluation and management. As ongoing research in etiology and pathogenesis emerges, novel treatment approaches continue to develop. Familiarity with ovulatory disorders will enable practitioners to provide high quality medical care and be a beacon of hope to a wide array of patients."}
+{"text": "A dearth of research investigates socio-environmental mechanisms of health disparities. Therefore, this paper tests the association between neighborhood characteristics and telomere length (TL), a biomarker of cellular age, and examines if this relationship differs by race and urban residence. Data from US-born, non-Hispanic Black and White midlife and older adults  in the 2008 Health and Retirement Study was analyzed to test the relationship between TL and perceived neighborhood safety, cleanliness, and social cohesion. Linear regression models stratified by race included interaction terms between neighborhood characteristics and urban residence. Negative perceptions of neighborhood characteristics were associated with shorter TL in Blacks, with urban-dwelling Blacks having shorter TL than Blacks in less urban areas. Findings suggest that negatively perceived neighborhoods may be more detrimental to TL for urban compared to rural Blacks. Future research should elucidate the biobehavioral consequences of socially disadvantaged urban neighborhoods on healthy aging among Black adults."}
+{"text": "Ochotona curzoniae) populations distributed along an altitudinal gradient of the Tibetan Plateau. We predicted that high-altitude pika would be more docile and less active.Animals inhabiting high altitudes consistently show slow life-histories. The pace-of-life syndrome (POLS) hypothesis posits behavioural, physiological and/or morphological traits that mediate the trade-off between current and future reproduction or survival, which have coevolved along a slow-fast life history continuum. Previous studies have shown that the life histories of plateau pikas varied across altitude, high-altitude individuals showed slow pace of life which were characterized by few litters per year with small litter sizes. Thus, we hypothesized that pikas populations at higher altitudes would also express personalities characteristic associated with slow life history, such as high sociability, low activity or aggressiveness. We tested this hypothesis by comparing the activity and docility of three plateau pika (The behaviour of 556 pikas, from which 120 individuals were measured at least twice, was quantified. We observed that plateau pikas at high altitudes were less active and more docile than pika at lower altitudes. Activity and docility were significantly and negatively correlated in populations from high altitudes but not in populations from low altitudes.Our results support the POLS hypothesis, highlight the existence of personality variation among populations distributed along an altitudinal gradient and emphasise the importance of environmental selection on personality divergence. Species with wide ranges usually exhibit geographic variation in life history traits, such as growth and reproduction \u20133. GeogrJunco hyemalis) bred at high elevations showed delayed development of structures necessary for reproduction, reduced duration of reproductive period and fewer broods than low-elevation conspecifics ) and moderately  repeatable, respectively, indicating that variation in these two personality traits varies consistently among individuals over time.Activity and docility were highly  and ZK  populations but showed no correlation with docility in the GN  population.Three populations at different altitudes showed our predicted differences in activity and docility Table\u00a0. ActivitWe investigated the phenotypic divergence of personality traits among plateau pika populations along an altitudinal gradient. Previous work on plateau pika populations indicates that the life-histories of high-altitude populations are slow. In support of the POLS hypothesis, we observed that higher-altitude populations also possessed personality traits that have been characterized as slow, i.e., less active and more docile, compared with the lower-altitude populations.The differences in activity and docility among plateau pika altitude-associated populations can be attributed to the differing life history strategies that have evolved in response to different climates and environments Table . Low-altOur findings indicate that differences in environmental conditions resulted in specific associations between behavioural traits of plateau pikas. These results indicate that behavioural syndromes could be adaptive, such that associations between behaviour may vary substantially in accordance with prevailing environmental conditions. Activity and docility were negatively associated in pikas from high- and medium-altitude sites. Correlations between these traits may corroborate the POLS hypothesis . In the We analysed behavioural differences among populations at the phenotypic level. As a result, we cannot rule out whether phenotypic differences reflect genetic differences or developmental plasticity . RegardlWe were unable to conclusively identify the precise divergences in the personality of pika populations distributed at higher altitudes, given that we focused on the traits of pika populations distributed within a limited altitude range. Nevertheless, our data reveal that the personality of pikas differs across altitudinal sites. Our study also provides valuable information regarding the effects of ecological conditions on the behavioural traits of animals at the population levels . AlthougPlateau pikas exhibit significant differences in activity and docility along the altitudinal gradient, supporting the POLS hypothesis. Future studies are needed to explore the mechanism and ecological consequences of personality divergences at large spatial-temporal scales and combine the animal personality with global climate changes."}
+{"text": "Declining stem cell function during aging leads to impaired tissue function and contributes to delayed tissue repair following damage. In adult skeletal muscle, loss of myofiber integrity caused by mechanical injuries or diseases are repaired by resident muscle stem cells (MuSCs), called satellite cells, which promptly exit from quiescence after disruption of muscle architecture to expand, differentiate and drive tissue regeneration. The fate of MuSCs fundamentally depends on the \u201cniche\u201d, their local environment, which is orchestrated by diverse cellular and acellular elements. Aging causes cell-extrinsic changes to the MuSC niche and dysregulates signaling pathways, which collectively alter the regenerative function of MuSCs . The lowFibro/adipogenic progenitors (FAPs) constitute a population of interstitial mesenchymal cells in skeletal muscle which are devoid of myogenic potential, but support muscle stem cell commitment and can differentiate to the adipogenic or fibrotic lineages  drives the perturbed support of aged FAPs to MuSCs. Genetic invalidation of WISP1 disrupts the communication between FAPs and MuSCs and leads to abnormal regeneration of skeletal muscle. Mechanistically, WISP-1 controls MuSC asymmetric expansion by activating Akt signaling. Importantly, this new paracrine mechanism can be targeted therapeutically by administering recombinant WISP-1 systemically. Altogether, our work reveals that loss of WISP1 from FAPs directly contributes to MuSC dysfunction in aged muscle and demonstrates that adipogenic progenitors are not just quiescent precursors waiting for pathological cues to elicit pathological conversions, but actually constitute bona fide elements of the stem cell niche, which regulate an active cross-talk with stem cells via paracrine signaling [The decline of MuSC function and muscle regenerative capacity during aging is under the control of a wide range of signals, out of which many arise from extrinsic cues coming from the local or systemic environment . In a reignaling .Along similar lines, a subpopulation of stromal progenitors in adipose tissue has recently been identified using single-cell RNA sequencing as a negative regulator of adipogenesis which represses the differentiation of adipocytes and keeps fat expansion in check . FAPs ar"}
+{"text": "OBJECTIVES/SPECIFIC AIMS: (i) Digitally quantify pathologically relevant glomerular microcompartmental structures in murine renal tissue histopathology images. (ii) Digitally model disease trajectory in a mouse model of diabetic nephropathy (DN). METHODS/STUDY POPULATION: We have developed a computational pipeline for glomerular structural compartmentalization based on Gabor filtering and multiresolution community detection (MCD). The MCD method employs improved, efficient optimization of a Potts model Hamiltonian, adopted from theoretical physics, modeling interacting electron spins. The method is parameter-free and capable of simultaneously selecting relevant structure at all biologically relevant scales. It can segment glomerular compartments from a large image containing hundreds of glomeruli in seconds for quantification\u2014which is not possible manually. We will analyze the performance of our computational pipeline in healthy and streptozotocin induced DN mice using renal tissue images, and model the structural distributions of automatically quantified glomerular features as a function of DN progression. The performance of this structural-disease model will be compared with existing visual quantification methods used by pathologists in the clinic. RESULTS/ANTICIPATED RESULTS: Computational modeling will reveal digital biomarkers for early proteinuria in DN, able to predict disease trajectory with greater precision and accuracy than manual inspection alone. DISCUSSION/SIGNIFICANCE OF IMPACT: Automated detection of microscopic structural changes in renal tissue will eventually lead to objective, standardized diagnosis, reflecting cost savings for DN through discovery of digital biomarkers hidden within numerical structural distributions. This computational study will pave the path for the creation of new digital tools which provide clinicians invaluable quantitative information about expected patient disease trajectory, enabling earlier clinical predictions and development of early therapeutic interventions for kidney diseases."}
+{"text": "Following presentation with abnormal liver function enzymes, confusion and fatigue, a 65-year-old male with alcoholic cirrhosis underwent spectral Doppler sonography that showed tardus parvus-like morphology in the main and left hepatic arteries, although peak systolic velocities and resistive indices remained normal. The patient\u2019s continuing clinical symptoms prompted CT angiography, which demonstrated an unexpected, haemodynamically significant stenosis of the celiac artery. Although the stenosis was successfully stented and the hepatic arterial waveforms normalized, the transplanted liver had already undergone ischaemic necrosis, with resulting failure and the need for retransplantation. Recognition of abnormal waveforms, despite normal peak systolic velocities and resistive indices, with prompt definitive imaging evaluation of the arterial tree beyond just the main hepatic artery, may lead to the diagnosis of unexpected flow-limiting lesions in time to allow revascularization and thus prevent ischaemic transplant failure. CT angiography 2 days thereafter revealed not only a normal main hepatic artery and patent surgical arterial anastomosis, but also an unexpected, haemodynamically significant stenosis (exceeding 50% diameter2) at the origin of the celiac artery  should be pursued promptly when an abnormal hepatic arterial waveform is recognized in the setting of graft dysfunction.9 Some authors have noted that celiac artery compression by the arcuate ligament occurs in as many as 10% of patients undergoing liver transplantation.7 It is rarely symptomatic, owing to efficient arterial collateralization from the superior mesenteric and the gastroduodenal arteries; however, in patients without sufficient collateralization, symptomatic hepatic arterial insufficiency and/or thrombosis may result. Fortunately, the stenting procedure for our patient restored flow such that, for either possible cause, the patient\u2019s retransplantation can proceed with adequate arterial inflow.It is essential to consider feeding vessels in addition to the main hepatic artery itself, such as the celiac artery, when searching for flow-limiting lesions. In the present case, the haemodynamically significant celiac stenosis undoubtedly developed after the patient\u2019s original, successful transplant surgery. Because no calcifications were demonstrated at the site of the celiac stenosis by CT angiography, the differential diagnosis would include non-calcified atherosclerotic plaque as well as the median arcuate ligament syndrome.In summary, abnormal hepatic arterial waveforms following hepatic transplantation, even when other values such as RIs and peak systolic velocities are not abnormal, should elicit a prompt search for flow-limiting lesions using definitive imaging modalities such as CT angiography, with careful evaluation for lesions not only at the arterial anastomosis but also at other sites within the arterial tree supplying the transplanted liver.Abnormal hepatic arterial waveforms in hepatic transplant patients, despite normal peak systolic values and normal RIs, should elicit a search for flow-limiting arterial lesions.Definitive imaging, such as CT angiography, should be pursued promptly in the search for flow-limiting arterial lesions.Severe complications following liver transplantation may result from unexpected flow-limiting arterial lesions at sites other than the typical location at the donor/recipient anastomosis.Our institutional review board approved this study and waived informed consent in view of its retrospective nature. All procedures were conducted in compliance with the Health Insurance Portability and Accountability Act."}
+{"text": "When patients develop destructive osteomyelitis, clinicians must always consider the possibility of SAPHO syndrome because even extremely destructive osteomyelitis can be cured by NSAIDs. YT: involved in manuscript drafting and clinical care of the patient. SY: involved in study conception and manuscript revision."}
+{"text": "Sociedade Portuguesa de CuidadosIntensivos summarizes the current evidence and gives six clinicalstatements and an algorithm aiming to provide a standardized prescribing policyfor the use of stress ulcer prophylaxis in the intensive care unit.Critically ill patients are at risk of developing stress ulcers in the upperdigestive tract. Agents that suppress gastric acid are commonly prescribed toreduce the incidence of clinically important stress ulcer-relatedgastrointestinal bleeding. However, the indiscriminate use of stress ulcerprophylaxis in all patients admitted to the intensive care unit is not warrantedand can have potential adverse clinical effects and cost implications. Thepresent guidelines from the  Systemic hemodynamic andlocal alterations result in gastric mucosal blood flow impairment with subsequentischemic mucosal injury. However, the crucial factor for the development ofulceration and gastric bleeding is the high gastric intraluminal acidity, which ispotentiated by fasting.(3) less than 50% ofpatients will have occult bleeding (defined as guaiac-positive gastric aspirate orguaiac-positive stool) and approximately 5%(5)will have overt bleeding . However, this does not necessarily translate into clinicallysignificant gastrointestinal bleeding ,(6) whose incidence seems to have decreased over theyears. In studies published before 1999, the incidence of clinically significantgastrointestinal bleeding was between 2% and 6% in patients not receivingprophylaxis.(6) However, in studies published since 2001, theincidence has been reported to range between 0.1% and 4% with or withoutprophylaxis,(7) which is related to better overall critical care,including the increased use of early enteral feeding. This, along with concernsrelated to the reported increasing frequency of infectious complications ,(9) has challenged thetraditional cornerstone of pharmacological prophylaxis with agents that suppressgastric acid for stress ulcer prophylaxis.(10)Endoscopically evident upper gastrointestinal lesions may be found in up to 90% ofcritically ill patients within 3 days of admission;Sociedade Portuguesa de Cuidados Intensivosaims to summarize current evidence and give clinical recommendations for the use ofstress ulcer prophylaxis in the intensive care unit (ICU) to provide a standardizedprescribing policy and avoid injudicious use.This guideline from the A multidisciplinary task force was assembled. The task force comprised physicians, nurses, pharmacistsand economists with special interest and expertise in stress ulcer prophylaxisand/or evidence-based medicine. All members of the task force declared that noconflict of interest influenced the development of the guidelines.(11) The availability of a Cochranereview(12) relevant to the clinical questions was confirmed bysearching the Cochrane Database of Systematic Reviews. A further complementaryliterature search of PubMed\u00ae was performed. Trial data identifiedby the search strategies were considered to represent the best-quality evidence. TheGrading of Recommendations Assessment, Development, and Evaluation (GRADE) systemprinciples(13) was used to assess the quality of evidence fromhigh to very low and to determine the strength of recommendations.Task force members participated in a discussion via e-mail, and six clinicalquestions were built for evidence evaluation. Each working member took charge of oneclinical question and built search queries in the PICO  format.(14) This was done according to the GRADE system andconsidered the following factors: evidence quality, certainty in the balance betweenadvantages and disadvantages, certainty or similarity in values and preferences, andresource implications. Arriving at a consensus required an average level ofagreement of \u2265 80%. When the agreement level was < 80%, furtherdiscussions and voting were conducted.Finally, the task force determined the direction (for or against) and strength(strong or weak) of the recommendations using a two-round (self-administeredquestionnaire with no meetings among the participants) simple Delphimethod.A strong recommendation was worded as \"we recommend\" and a weak recommendation as \"wesuggest\".Sociedade Portuguesa de Cuidados Intensivos in Oporto anddiscussed by the panel and audience members.The key recommendations were presented at the annual symposium of theWe recommend maintaining (or initiating) agents that suppressgastric acid  in patients with compellingindications for acid suppression. Strong recommendation, moderate qualityof evidence.Several clinical situations require gastric acid suppression , and indications should be respected, both in the ambulatory andhospital (including intensive care) settings.Patients with compelling indications include the following:Helicobacter pylori-negative ulcers; need tocontinue NSAID or failure to eradicate Helicobacterpylori; ulcers complicated at the outset; and giant(> 2cm), refractory or recurrentulcers].(15)- Known peptic ulcer disease in the healing phase and maintenancephase in selected circumstances  is comparingproton-pump inhibitors and histamine-2-receptor antagonists, and the results areexpected to provide more relevant data.(27)The efficacy of proton-pump inhibitors and histamine-2-receptor antagonists inpreventing stress-ulcer bleeding in critically ill patients has been compared inseveral randomized control trials and meta-analyses.(51) focused on the comparison betweenhistamine-2-receptor antagonists and proton pump inhibitors for the prophylaxisof stress ulcerrelated gastrointestinal bleeding. The results are contradictory,mainly due to the use of different clinical inputs, and there is no strongevidence regarding which is the most effective alternative. Data from the mostrecent meta-analysis of clinical trials indicate that proton pump inhibitorsshould be used. However, if one relies on a propensity score-matchedobservational cohort study, histamine-2-receptor antagonists are the preferredoption.(51) The only clear conclusion is that, as the costof prophylaxis is small when compared to the costs of complications, the mosteffective alternative will constitute a dominantalternative.(51)There are multiple pharmacoeconomic analyses(53) It is acknowledgedthat the published literature on this issue derives from heterogeneouspopulations of critically ill patients who may differ from the populations atrisk identified by the previous recommendation.Although the quality of evidence is suboptimal, proton-pump inhibitors have beenthe preferred regimen in intensive care units across Europe, the United Statesand Canada.(54) provided evidenceof an increase in pneumonia with proton-pump inhibitor use; however, this studywas related only to cardiac surgery patients, and confidence intervals werewide. Small randomized trials (55)) and a case-control study showed anincreased adjusted risk for Clostridium difficile infectionsduring treatment with proton-pump inhibitors, but this was more related to theduration of exposure.(56)Additionally, the expected adverse effects of proton-pump inhibitors are aconcern and must be taken into account. A cohort studyUltimately, the desirable consequences of stress ulcer prophylaxis withproton-pump inhibitors are expected to outweigh the undesirable consequencesamong the population at risk.We make no recommendation regarding specific proton-pump inhibitorregimens.The ideal drug regimen should be effective in reducing the risk of ulceration,with a low potential for adverse effects and drug interactions andpharmacokinetic characteristics that facilitate its use in patients with organdysfunction; it should also be cost-effective.a prioridefined subgroup analysis of at least one meta-analysis suggests that the routeof administration  and dosing (onceversus twice a day) do not affect theresults.(45)There is no direct comparison between different proton-pump inhibitor-basedregimens , and heterogeneity across studies (comparing proton-pump inhibitorsto other regimens) impairs the comparison of effects between the individualproton-pump inhibitor regimens tested to date. An e.g., vasopressor use, altered gastric emptying andmotility, feeding tube and nutrient interactions) may influence enteralabsorption in critically ill patients, and the intravenous route is generallypreferred.(57) This is disputed by a study showing that,despite a lower bioavailability, enteral lansoprazole suppressed acid inintensive care unit patients better than the intravenousformulation.(58) However, this has not been confirmed by furtherstudies, and lansoprazole requires a complex and labor-intensive galenicformulation for feeding tube administration.In relation to the route of administration, multiple factors(qd) may be a reasonable choice.(59) However, thedefinitive choice of the specific proton-pump inhibitor regimen should be basedon individual patient and medical values, experience, product labeling,cost-benefit analyses, anticipated risks of drug-drug interactions and adverseeffects.Due to its safety in (at least moderate) organ dysfunction, lower probability ofdrug-drug interactions, and available formulations, intravenous pantoprazoleThe most recent and comprehensive meta-analysis(61) found that therapywith agents that suppress gastric acid was associated with a significant risk ofClostridium difficile infections but that the risk waslower for histamine-2-receptor antagonists than with proton-pump inhibitors.Accumulating evidence suggests that the use of agents that suppress gastric acidmay increase the frequency of infectious complications.Clostridiumdifficile infections is still controversial because meta-analysisis weak in detecting a modest increase in these events.(62) Nevertheless, therisk of Clostridium difficile infections remains higher inpatients receiving proton-pump inhibitors compared with patients receivinghistamine-2-receptor antagonists.(8) Moreover, observationalstudies(64) have shown thatcontinued proton-pump inhibitor use during incident Clostridiumdifficile infections increases the risk of recurrence.In the critically ill population, the increased risk for Clostridium difficile infections, proton-pumpinhibitors should be avoided, and histamine-2-receptor antagonists should be thepreferred therapy when stress ulcer prophylaxis isindicated.(62)Based on available data and given the significant disease burden and mortalityassociated with We recommend stopping prophylaxis with agents that suppress gastricacid when risk factors are no longer present and the patient is receivingenteral nutrition. Strong recommendation, low quality ofevidence.(65) This is inagreement with studies that have concluded that 88.5% of stress ulcerprophylaxis in nonintensive care unit patients isinappropriate(66) and that a relatively restrictive stress ulcerprophylaxis program not only reduces inappropriate use without increasing therates of hospital-related gastrointestinal bleeding but also results in anestimated annualized cost savings of more than US$200.000.(67)Acid suppressants are inappropriately continued in a large proportion of patientsafter the resolution of risk factors and even after intensive care unit orhospital discharge, thus extending the potential risks and costs associated withstress ulcer prophylaxis beyond the intensive care unit.(26) there is some evidence to suggest that inpatients receiving enteral feeding, pharmacologic stress ulcer prophylaxis isnot beneficial, and combined interventions may even increase the risk of someinfectious complications. However, the evidence is still insufficient to justifywithholding stress ulcer prophylaxis from patients who are at high risk forgastrointestinal bleeding. It is sufficiently compelling to support thecessation of prophylaxis when risk factors are no longer present and the patientis receiving enteral nutrition.As previously described,(68) As one of the more common indications forstress ulcer prophylaxis is mechanical ventilation, extubation is crucial toidentify and possibly discontinue acid suppressiontherapy.(62)Patients should thus be evaluated daily during multidisciplinary care rounds forthe continued need for prophylaxis, and once the patient is receiving enteralnutrition and risk factors are no longer present, stress ulcer prophylaxisshould be discontinued. This strategy will reduce the overuse and unnecessarycontinuation of agents that suppress gastric acid upon discharge and in theoutpatient setting.Clostridiumdifficile infection, for which histamine-2-receptor antagonists arepreferred (Statement 5). Once the patient is receiving enteral nutrition andrisk factors are no longer present, stress ulcer prophylaxis should bediscontinued (Statement 6). The general algorithm for the prophylaxis of stress ulcer bleeding in theintensive care unit is presented in The authors suggest that the practices recommended in this guideline arecontinuously evaluated and monitored and that this guideline is updated as newevidence becomes available."}
+{"text": "Housing coordination, a central component of the Money Follows the Person program, allows older adults and people with disabilities to experience greater independence and sense of well-being . This study was part of the 2017 Money Follows the Person (MFP) Process Evaluation involving 26 key informants (KIs) who completed telephone interviews sharing their experiences about program implementation. Of these, 13 KIs providing housing coordination services to the MFP transition team were asked about the housing coordination training they received and suggestions to improve the training. They were also asked about housing resources, how they develop their housing inventory, and recommendations for a \u201cHousing Best Practices Report.\u201d Interviews were audio-taped and transcribed. Data were analyzed using ATLAS.ti. Results demonstrate a need for more training and assistance to enable housing coordinators to expand their knowledge of housing alternatives, increase their awareness of housing policy/process changes, and further inform consumers about housing choices. Suggestions to improve housing coordination included offering more creative solutions during monthly housing coordination phone calls. Housing inventory challenges mentioned by KIs included time constraints, limited staff, administrative delays, and lack of affordable housing. Suggestions for housing inventory development focused on improving the management/maintenance of housing inventories. Best housing practices underscored the importance of communicating, teaming, building relationships with landlords and management companies, and standardizing housing policies and procedures. Overall recommendations included strengthening collaboration among housing coordinators to identify and implement best practices and improving housing inventory development to widen housing options for consumers."}
+{"text": "In conclusion, even under deep propofol sedation, apneas and hypopneas can be terminated without cortical arousal. However, extensive suppression of the arousal threshold can lead to critical hypoxemia suggesting careful respiratory monitoring.Recent evidences suggest that non-arousal mechanisms can restore and stabilize breathing in sleeping patients with obstructive sleep apnea. This possibility can be examined under deep sedation which increases the cortical arousal threshold. We examined incidences of cortical arousal at termination of apneas and hypopneas in elderly patients receiving propofol sedation which increases the cortical arousal threshold. Ten elderly patients undergoing advanced endoscopic procedures under propofol-sedation were recruited. Standard polysomnographic measurements were performed to assess nature of breathing, consciousness, and occurrence of arousal at recovery from apneas and hypopneas. A total of 245 periodic apneas and hypopneas were identified during propofol-induced sleep state. Cortical arousal only occurred in 55 apneas and hypopneas (22.5%), and apneas and hypopneas without arousal and desaturation were most commonly observed (65.7%) regardless of the types of disordered breathing. Chi-square test indicated that incidence of no cortical arousal was significantly associated with occurrence of no desaturation. Higher dose of propofol was associated with a higher apnea hypopnea index ( Patency of the pharyngeal airway is state-dependent in patients with obstructive sleep apnea (OSA). Reduction of upper airway (UA) dilating muscle activity during loss of consciousness appears to account for UA obstruction during sleep . Burst o2-mediated genioglossus muscle activity [Younes, however, recently proposed that cortical arousals are coincidental events that occur just prior to arousal-independent airway opening through analysis of the breathing and cortical activity in experimentally-induced apneas or hypopneas ,5,6. In activity  and to dactivity . Furtheractivity .Despite physiological evidence suggesting advantages of arousal threshold reduction, cortical arousal was observed to occur at apnea termination even under light sedation . ConsequWe performed a prospective observational study after obtaining approval from the institutional Ethics Committee  and written informed consent from each subject. Ten adult patients  undergoing ESD surgery for early gastric cancer under propofol sedation participated in the study. Relatively higher incidence of obstructive apneas and hypopneas was found in the elderly patients under propofol sedation as the primary result of the study , this seThe patient lying on the left side received 2 L/min oxygen through a nasal prong. In order to minimize body movements during the endoscopic submucosal dissection (ESD), relatively deep sedation maintaining Ramsey score 5 to 6   was achi2), and snoring over a microphone were recorded and stored in a computer for later analyses. For research purposes, a standard polysomnography was performed . Bilateral central and occipital electroencephalograms (EEG), bilateral electrooculograms (EOG), submental electromyogram (EMG), electrocardiogram, airflow measurement with a nasal pressure prong and an oro-nasal thermistor, thoraco-abdominal wall motions with piezo respiratory effort sensors, oxygen saturation , presence or absence of thoraco-abdominal respiratory movements , and presence or absence of cortical arousal evidenced by the electroencephalograms upon restoration from apneas and hypopneas . Apnea hypopnea index (AHI) was determined as the frequencies of apneas and hypopneas per hour of sleep for each of the category combinations with and without the 3 features of apneas and hypopneas [Polysomnography data were manually reanalyzed for this secondary analysis by a certified sleep technician (RK) and an investigator (SI) using a dedicated computer software . Consciousness states (awake or sleep) were determined for each 30 s polysomnography recordings by using the criteria of Rechtschaffen and Kales , and breypopneas .p < 0.05 was considered statistically significant, and all p-values were two sided. All statistical analyses were performed by using a computer software . Arousal rate defined as the ratio between the incidence of respiratory disturbances with cortical arousal and total incidence of the respiratory disturbances occurring in all participants was calculated for each of the categories. Comparison of the arousal rates with and without desaturation was performed by using Chi-square test. Values were presented as frequencies and proportions for categorical data, and means and standard deviations (SD) for continuous variables. A value of \u22121. Thirty-eight more apneas and hypopneas were identified in this secondary analysis than in the primary analysis [r = 0.673, p = 0.033, n = 10). AHI without desaturation was significantly greater than AHI with desaturation (p = 0.024).Patients\u2019 characteristics and details of the sedation are presented in analysis . Total AThis is the first study which assessed the occurrence of cortical arousal in response to apneas and hypopneas during propofol-induced sleep in elderly patients undergoing endoscopic surgery. Cortical arousal only occurred in 55 of 245 apneas and hypopneas (22.5%) during propofol-induced sleep. Apneas and hypopneas without arousal and desaturation was most commonly observed (65.7%) regardless of types of disordered breathing. The results strongly suggest that cortical arousal is possibly a coincidental event to the non-arousal recovery from respiratory disturbances and is not always necessary to restore breathing even in the elderly.Propofol is a potent GABA agonist and used as a general anesthetic as well as a sedative depending on the administration dose . It doseAccording to recent accumulated knowledge of arousal and obstructive sleep apnea , interacIn contrast, propofol increases arousal threshold over the UA opening threshold and decreases respiratory drives to the diaphragm and UA muscles B. It is Despite common UA obstruction episodes under propofol sedation, few critical respiratory events occurred in this study, which may reflect few reports of fatal complications under propofol sedation for endoscopic procedures ,20. HoweThere are several limitations in this study. Firstly, the sample size is very small and the patient population is severely limited to non-obese elderly without previous OSA diagnosis. Only few respiratory disturbances occurred during propofol sedation resulting in severe hypoxemia commonly observed in patients with severe OSA. Obviously, our study design does not allow generalization of the findings. However, we believe that incidences and natures of respiratory disturbances and restorative capacity without cortical arousals were objectively assessed by polysomnographies during the sedation. Certainly, four electroencephalograms used in this study were probably not able to cover the whole brain activities and undetected cortical arousal may have occurred during recovery from the respiratory disturbance. However, we consider this possibility unlikely due to the propofol dose used in this study ,21. SecoEffects of various types of hypnotics and sedatives on OSA have been assessed in many previous studies, but the results are diverse; some studies demonstrated an increase of AHI and apnea duration, but clinically meaningful AHI reduction without increase of apnea duration was reported particularly in studies using nonmyorelaxant sedatives such as eszopiclone ,24. JordPharmacological sedation is becoming frequently used in various clinical situations such as invasive endoscopy, minor surgery, radiological examinations for children, and mechanical ventilation in ICU ,25,26,27Obstructive apneas and hypopneas during propofol sedation were spontaneously terminated without cortical arousal while repeated periodically. The appropriative depth of propofol sedation appears to reduce both the UA dilating muscle activity and its oscillation, possibly stabilizing respiration and decreasing frequency of respiratory disturbances. However, extensive suppression of the arousal threshold with higher doses of propofol can lead to prolonged apnea and critical hypoxemia suggesting careful respiratory monitoring with both pulse oximetry and nasal pressure monitor during advanced GI endoscopy under propofol sedation."}
+{"text": "This synthetic method features a silane-driven catalytic intramolecular Wittig reaction as a key annulation step and represents the first successful application of catalytic Wittig reaction in multicomponent cascade reaction.Tri- or tetrasubstituted furans have been prepared from terminal activated olefins and acyl chlorides or anhydrides by a multicomponental convergent synthesis mode. Instead of stoichiometric  A broad scope of substrates, bearing various reducible functional groups including ketone, acyl chloride, olefin, nitro, cyano, and ester, are all well tolerated in the presence of reducing agent silane. This synthetic method features a silane-driven catalytic intramolecular Wittig reaction as a key step and represents the first successful application of catalytic Wittig reaction in a multicomponent cascade reaction. Future efforts in our laboratory will be directed toward exploring the asymmetric reactions involving catalytic chiral phosphine mediated Wittig reaction, the results of which will be reported in due course.In conclusion, a convergent synthetic method for tri- or tetra-substituted furans has been developed by catalytic phosphine mediated multicomponental cascade reactions. Instead of stoichiometric"}
+{"text": "Orbital emphysema occurs when air enters the soft tissue surrounding the orbit. Although orbital blowout fractures are often caused by face trauma, nontraumatic orbital fractures can also occur but have been rarely described. Here, a case of orbital and palpebral emphysema caused by forceful nose-blowing is presented. Examination uncovered gross swelling of the right eye and discernable subcutaneous emphysema. The patient had normal eye movement and visual acuity. Orbital computed tomography (CT) revealed orbital emphysema secondary to an orbit floor fracture into the maxillary sinus, resulting from high intranasal pressure upon blowing her nose. The patient received conservative management with antibiotics and was given instructions not to sneeze or blow her nose. She fully recovered and all her symptoms completely resolved. Orbital emphysema is a somewhat rare clinical event. A collection of air within the orbits or eyelids is most commonly associated with fracture and trauma of an orbital bone. Although trauma is the most common etiology of orbital emphysema, nontraumatic spontaneous orbital emphysema due to coughing, sneezing, nose blowing, or any type of straining as a result of iatrogenic otolaryngeal and dental procedures and infectious gas-producing microorganisms have been described \u20135.We describe a patient with orbital emphysema presenting swelling surrounding the left eye several hours after blowing her nose. Most cases of orbital emphysema resolve spontaneously; however, emergency physicians should be aware that early recognition of orbital emphysema is crucial to prevent possible vision-threatening complications if unrecognized . Since oA 59-year-old healthy Japanese female with chronic rhinitis was taken to our emergency department due to a sudden and painless left periorbital swelling following forceful nose-blowing. Examination revealed a gross swelling of the left eye. There was painless palpable emphysema around her left eye; she had normal eyeball movement and visual activity. By ophthalmic consultation, the intraocular pressure was found to be slightly higher in her left eye (20\u2009mmHg) compared to the right (13\u2009mmHg). Noncontrast CT revealed orbital subcutaneous and subconjunctival emphysema and fracture of the median orbital wall of the left eye. Focal herniation of extraconal fat into the ethmoid air cells was noted . OtherwiThis case highlights spontaneous orbital emphysema caused by forceful nose-blowing, which may pose a diagnostic challenge. In our patient, orbital emphysema developed when the patient blew her nose by air transfer from the paranasal sinuses into the orbit along a pressure gradient, causing a one-way valve forcing air into the orbit. Orbital fat may function like a ball-valve, becoming displaced from the fracture site during insufflation but falling back to seal the opening under the pressure of trapped air.Gwaltney et al. measured intranasal pressure during coughing, sneezing, and nose-blowing using fluid dynamic modeling with sinus CT. They reported a mean maximal intranasal pressure of 66\u2009mm Hg during nose-blowing, 4.6\u2009mmHg during sneezing, and 6.6\u2009mmHg during coughing. Intranasal pressures greater than 190\u2009mmHg have been measured during nose blowing with maximal expiratory efforts, offering evidence that air can be introduced into the orbit under substantial pressure . Old traIn our patient, chronic inflammation in the maxillary sinus associated with chronic rhinitis may have caused weakening of the orbital floor, making it more susceptible to fracture with high pressure with forceful nose-blowing.Most orbital emphysema cases require no treatment. However, with progressive emphysema, urgent decompression of the trapped air and acute orbital compartment syndrome is necessary to avoid irreversible vision loss because of mechanical optic nerve stretching or vascular compromise. Extraocular muscle motility and visual acuity are the two most important ophthalmologic functions that should be evaluated emergently in patients with acute orbital trauma. Assessing these abilities may be challenging at times due to head injury severity, level of periorbital soft tissue edema, lack of complete cooperation in alert patients, and reduced consciousness.Reduced vision after trauma may be caused by intraorbital emphysema, retrobulbar hemorrhage, optic nerve thickening presumably secondary to edema, ruptured globe, detached retina, and optic nerve impingement. These complications are ophthalmic emergencies requiring immediate intervention. Therefore, differentiating benign orbital emphysema from an ophthalmic emergency is critical to avoid adverse sequelae. In nontraumatic cases, the most important differential diagnosis to exclude in acute unilateral eye swelling is orbital cellulitis, which may present with pain on eye movement, visual loss, chemosis, and fever .The diagnosis can be easily made by palpation of the pathognomonic cracking and crepitation on the eyelids. CT plays a crucial role in assessing the intraorbital contents of patients with orbital trauma. Most patients with compromised visual acuity or decreased extraocular muscle motility caused by trauma have abnormalities shown by orbital CT.Most cases of orbital emphysema resolve spontaneously, and no treatment is needed. Experts generally recommend prophylactic oral antibiotics to treat sinus pathogens for patients with orbital fracture into a sinus . A 23-gaIn conclusion, clinicians should investigate all suspected orbital blowout fractures with imaging and full ophthalmological examination regardless of trauma history to avoid possible complications like vision loss because of infection and pressure."}
+{"text": "Images were parcellated into 278 regions of interest (ROI) based on Shen et al. (2013). Connectivity between each ROI pair was described by Pearson correlation coefficient. Brain regions were grouped into 7 canonical RSNs as described by Yeo et al. (2015). Pearson correlation values were then averaged across pairs of ROIs in each network and averaged across individuals in each group. These values were used to determine relative expression of FC in each RSN (intranetwork) and create RSN profiles for each group. RESULTS/ANTICIPATED RESULTS: Our findings support previous literature which shows that limbic networks are disrupted in FTLD participants compared with AD and age-matched controls. In addition, interactions between different RSNs was also examined and a significant difference between controls and AD subjects was found between FP and DMN RSNs. Similarly, previous literature has reported a disruption between executive  network and default mode network in AD compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT: Our approach allows us to create profiles that could help compare intranetwork FC in different neurodegenerative diseases. Future work with expanded samples will help us to draw more substantial conclusions regarding differences, if any, in the connectivity patterns between RSNs in various neurodegenerative diseases.OBJECTIVES/SPECIFIC AIMS: Recent evidence from resting-state fMRI studies have shown that brain network connectivity is altered in patients with neurodegenerative disorders. However, few studies have examined the complete connectivity patterns of these well-reported RSNs using a whole brain approach and how they compare between dementias. Here, we used advanced connectomic approaches to examine the connectivity of RSNs in Alzheimer disease (AD), Frontotemporal dementia (FTD), and age-matched control participants. METHODS/STUDY POPULATION: In total, 44 participants  from an ongoing study at Indiana University School of Medicine were used. Resting-state fMRI data was processed using an in-house pipeline modeled after Power"}
+{"text": "Traumatic spinal cord injury (SCI) leads to disruption of sensory, motor and autonomic function, and triggers structural, physiological and biochemical changes that cause reorganization of existing circuits that affect functional recovery. Propriospinal neurons (PN) appear to be very plastic within the inhibitory microenvironment of the injured spinal cord by forming compensatory circuits that aid in relaying information across the lesion site and, thus, are being investigated for their potential to promote locomotor recovery after experimental SCI. Yet the role of PN plasticity in autonomic dysfunction is not well characterized, notably, the disruption of supraspinal modulatory signals to spinal sympathetic neurons after SCI at the sixth thoracic spinal segment or above resulting in autonomic dysreflexia (AD). This condition is characterized by unmodulated sympathetic reflexes triggering sporadic hypertension associated with baroreflex mediated bradycardia in response to noxious yet unperceived stimuli below the injury to reduce blood pressure. AD is frequently triggered by pelvic visceral distension (bowel and bladder), and there are documented structural relationships between injury-induced sprouting of pelvic visceral afferent C-fibers. Their excitation of lumbosacral PN, in turn, sprout and relay noxious visceral sensory stimuli to rostral disinhibited thoracic sympathetic preganglionic neurons (SPN) that manifest hypertension. Herein, we review evidence for maladaptive plasticity of PN in neural circuits mediating heightened sympathetic reflexes after complete high thoracic SCI that manifest cardiovascular dysfunction, as well as contemporary research methodologies being employed to unveil the precise contribution of PN plasticity to the pathophysiology underlying AD development. Propriospinal neurons (PN) have intraspinal origins and project to interneurons in other spinal cord segments as reported in electrophysiological and tract-tracing studies in feline and rodent models  SCI, in which transcutaneous electrical stimulation of lower limb nerves evoke motor responses in distal forearms  in the thoracolumbar intermediolateral cell column (IML), which results in the loss of sympathetic modulation from the caudal and rostral ventrolateral medulla  in the brainstem that then modulates the sympathetic response, accordingly. Supraspinal denervation results in the sudden depletion of descending excitatory signals resulting in a 50\u201370% loss of innervation to SPN  neutralizing antibody or trkA-IgG fusion protein in T4 spinal transected rats decreases CGRP-fiber density in association with reduced AD symptoms in experimental rats undergoing experimental colorectal distension (CRD; Christensen and Hulsebosch, via interneurons that may be excitatory or inhibitory in nature depending on the type and location of the stimuli (Chau et al., Autonomic PN are pre-sympathetic as they innervate the SPN to control their level of excitation (Gebber and McCall, de novo by visceral stimuli following SCI.BDA anterograde tracer injected into the central gray matter at rat L6-S2 spinal levels shows that ascending PN extend projections up to cervical levels through lamina X, and retrograde labeling using wheat germ agglutinin-horseradish peroxidase show projections to laminae VII and VIII at lumbar and thoracic levels indicating the anatomical locations of ascending PN (Matsushita, Ascending PN plasticity is believed to contribute to the development of AD. These neurons relay visceral sensory information towards the SPN in the thoracic cord (Rabchevsky, via intraspinal projection neurons (Pascual et al., via interneurons. After SCI, the supraspinal control is lost but the SPN are activated by peripheral afferent stimuli whose signal is relayed via ascending PN to trigger a sympathetic response, resulting in hypertension (Accordingly, BDA tracers injected into the lumbosacral cord following T4 transection show more labeling of ascending lumbosacral PN fibers that originate at the DGC and terminate proximal to Fluorogold-labeled thoracic SPN (Hou et al., rtension .Excitatory interneuron connectivity with SPN preferentially increases after T3 spinal transection in mice, and repeated CRD induces an increase in these excitatory interneurons co-labeled with vGlut2 (Ueno et al., Electrophysiology and retrograde tract-tracing are the most common tools used to identify the tracts involved in autonomic function. Although several studies labeling long descending PN and short tract PN exist, it is still highly challenging to specifically target and label ascending propriospinal tracts after injury due to unintended labeling of fibers en passage. Moreover, it is reported that transsynaptic labeling by pseudorabies virus is significantly reduced in the T4 transected spinal cord (Duale et al., In this regard, Kinoshita et al.  reversibPN plasticity after traumatic SCI plays a critical role in improving not only spontaneous motor function but also potentially aggravating autonomic dysfunction. In addition to afferent C-fiber sprouting and loss of supraspinal regulation of the IML, maladaptive plasticity of PN below the level of high thoracic SCI appears essential for manifesting chronic autonomic dysfunction. Thus, while selectively promoting PN sprouting might serve as a promising therapeutic target for specific motor functional recovery, it may also be prevented selectively to combat AD development and/or severity, and the advancement of strategies to reversibly silence these interneurons will help further our understanding on their role in AD.FM wrote the first draft of the manuscript. SP reviewed the manuscript. AR critically evaluated the manuscript and wrote the final revised version. All authors contributing to the manuscript have read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Metastatic dissemination of epithelial ovarian cancer (EOC) predominantly occurs through direct cell shedding from the primary tumor into the intra-abdominal cavity that is filled with malignant ascitic effusions. Facilitated by the fluid flow, cells distribute throughout the cavity, broadly seed and invade through peritoneal lining, and resume secondary tumor growth in abdominal and pelvic organs. At all steps of this unique metastatic process, cancer cells exist within a multidimensional tumor microenvironment consisting of intraperitoneally residing cancer-reprogramed fibroblasts, adipose, immune, mesenchymal stem, mesothelial, and vascular cells that exert miscellaneous bioactive molecules into malignant ascites and contribute to EOC progression and metastasis via distinct molecular mechanisms and epigenetic dysregulation. This review outlines basic epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulators, and summarizes current knowledge on reciprocal interactions between each participant of the EOC cellular milieu and tumor cells in the context of aberrant epigenetic crosstalk. Promising research directions and potential therapeutic strategies that may encompass epigenetic tailoring as a component of complex EOC treatment are discussed. Epithelial ovarian cancer (EOC), a histopathologically, morphologically, and molecularly heterogeneous group of neoplasms , is the EOC initiation results from accumulation of genetic mutations and epigenetic changes resulting in malicious transformation of epithelial cells, stem cells, or transient metaplastic regions at the primary site, either ovary or the fallopian tube fimbriae ,16,17,18DNA methylation\u2014addition of methyl groups to DNA CpG sites without altering DNA nucleotide sequence. Methylation occurs by means of enzymes called DNA methyltransferases (DNMTs), which place methyl groups on symmetric cytosine residues in double-stranded CpG sites ,47. HypeHistone modifications\u2014various posttranslational modifications (PTMs) at histone protein N-terminal tails, which impair proper interactions between adjacent nucleosomes to affect the compact packing of the chromatin and impede the binding ability of other factors/enzymes that are involved in gene transcription ,58. The Chromatin remodeling\u2014rearrangement of chromatin organization through complete or partial nucleosome repositioning and altering gene access for transcription. Chromatin remodeling can occur via nucleosome sliding (movement of the core histone octamer nexus across DNA segment with no evident disintegration of the octamer itself), nucleosome ejection (nucleosome segregation from the chromatin chain), or histone eviction  ,66,67. TAltogether, the three epigenetic mechanisms that are described above work closely to mediate DNA (un)coiling around the core histones and ensure dynamic chromatin reassembly between heterochromatin  and euchromatin  states.9 methylation with RNA interference machinery, followed by DNA methylation and gene transcription repression) and heterochromatic silencing . . 155]. DWhile the overwhelming majority of research work is focused on the elucidation of cell signaling pathway implications, the epigenetic interplay between MSCs and EOC remains largely unexplored. While considering the well accepted role of epigenetic aberrations in CSC reprogramming (comprehensively outlined in ), emergiTECs refer to endothelial cells that line the inner walls of newly formed blood vessels in tumors. TECs support blood flow, tumor tissue trophics, and accelerate tumor progression. TECs are genetically non-malignant cells, however, they differ from normal endothelial cells by exhibiting cytogenetic abnormalities , distortTECs exhibit considerable heterogeneity (reviewed in ), and di4 methylation was reported, and re-expression of ICAM-1 in TECs by DNMT and HDAC inhibitors successfully restored leukocyte-TEC adhesion and leukocyte infiltration of vessel walls in vitro and in vivo, respectively . . 247]. IEpigenetic regulation of hematopoietic stem cell lineage commitment and subsequent differentiation of dendritic cell precursors into specific dendritic subtypes (including PDCs) and interferon response in the context of chromatin remodeling, miRNA and lncRNAs interference are well documented ,259,260 MCs are simple squamous epithelial cells that line the intra-abdominal cavity as an upper single layer (mesothelium) of the peritoneum, immediately supported by the basal membrane, underneath which is the collagen-rich extracellular matrix A. MCs fuThe bidirectional interplay between EOC cells and MCs has been recently assessed in a study by Matte et al. , who repThe growing body of information on epigenetic control of ovarian cancer metastatic advancement and acquisition of resistance to standard-of-care chemotherapy make epigenomic alterations attractive prognostic markers and druggable targets to improve therapeutic outcomes in EOC patients especially with platinum-resistant and recurrent disease. Our group and others are actively exploiting DNA hypermethylation, modifications of histone marks, and aberrant expression of non-coding RNAs in malignant EOC cells in an attempt to treat EOC, re-sensitize ovarian tumors to conventional chemotherapy, and prevent/delay disease recurrence A. We andContinuous accumulation of knowledge on epigenomic perturbations in ovarian TME cellular compartments in the context of their communication with EOC cells holds great translational promise. The fact that non-malignant stromal cells lack genetic mutations and acquire potentially reversible tumor-specific molecular traits and cancer-indulgent functions via epigenetic reprogramming by EOC cells suggests the epigenetic tailoring of ovarian TME as a promising strategy in ovarian cancer management. Given the varying stroma representation in ovarian malignancies  and higTreatment of different stromal components with HMAs demonstrated tumor-restrictive potential. In particular, the exposure of adipocytes to guadecitabine attenuated HGSOC cells metastasis-associated behaviors . HMA decAlternatively, similarly to an improved anticancer effect of a DNMT/HDAC inhibitor combination on ovarian tumors  and otheGiven that CAF reprogramming is shown to repress ovarian tumor advancement , preventExploiting host immune system in managing ovarian cancer growth and metastatic spread has emerged as another key research and therapeutic direction ,295,296.To summarize, a deeper understanding of epigenomic involvement in reciprocal EOC tumor-stroma interrelationship is essential and it will help to determine pharmacological routes to alter the TME, which in turn could inhibit EOC metastatic progression and the development of chemoresistance and tumor recurrence. Furthermore, we believe epigenetically-mediated pharmacological engagement of certain TME players, such as immune cells, to boost immune responses towards complete malignant cell elimination has tremendous potential."}
+{"text": "Subjective tinnitus is an auditory phantom perceptual disorder without an objective biomarker. Bothersome tinnitus in single-sided deafness (SSD) is particularly challenging to treat because the deaf ear can no longer be stimulated by acoustic means. We contrasted an SSD cohort with bothersome tinnitus  against an SSD cohort with no or non-bothersome tinnitus  using resting-state functional magnetic resonance imaging (fMRI). All study participants had normal hearing in one ear and severe or profound hearing loss in the other. We evaluated corticostriatal functional connectivity differences by placing seeds in the caudate nucleus and Heschl\u2019s Gyrus (HG) of both hemispheres. The TIN cohort showed increased functional connectivity between the left caudate and left HG, and left and right HG and the left caudate. Within the TIN cohort, functional connectivity between the right caudate and cuneus was correlated with the Tinnitus Functional Index (TFI) relaxation subscale. And, functional connectivity between the right caudate and superior lateral occipital cortex, and the right caudate and anterior supramarginal gyrus were correlated with the TFI control subscale. These findings support a striatal gating model of tinnitus and suggest tinnitus biomarkers to monitor treatment response and to target specific brain areas for innovative neuromodulation therapies. The search for physiological substrates that account for tinnitus persistence and tinnitus severity has led investigators to evaluate the central nervous system (CNS) using a variety of techniques. Some documented CNS changes are synchronous hyperactivity5, tonotopic map cortical plasticity8, thalamocortical dysrhythmia10, and gamma band oscillations13.Tinnitus is a common auditory phantom perceptual disorder where conventional audiometric hearing loss profiles alone cannot help clinicians to distinguish between patients who merely experience tinnitus from those who are troubled by tinnitus15, case reports17, and an early clinical trial18 focused on the caudate nucleus of the basal ganglia support a striatal gating model15 of tinnitus awareness. This model delineates modulators of tinnitus persistence and tinnitus severity, where corticostriatal connections between the striatum and auditory cortex act to gate auditory phantom representations to reach perceptual awareness and connections between the striatum and limbic structures act to modulate auditory phantom distress.Human physiological studies20 or is driven by abnormal auditory-limbic interactions23. Neuroimaging studies in support of abnormal striatal connectivity as a potential biomarker of chronic tinnitus25 have been reported in cohorts with inhomogeneous hearing loss profiles. Those studies used post-hoc statistical techniques to address the possible confound of hearing loss levels on neural correlates of tinnitus. However, there is not yet a neuroimaging investigation that incorporates a specific hearing loss pattern in a cohort contrast study design that could isolate differential network connectivity findings to chronic tinnitus.A striatal gating model of phantom percept awareness is complementary to other CNS hypotheses, including those that posit tinnitus is primarily an expectation mismatch within the auditory system26, although this is not necessarily the case in congenital SSD27. Tinnitus localized to the deaf ear eliminates the treatment option of masking sound delivery to the defective sensory end organ, as it is unresponsive to acoustic stimulation. Moreover, acoustic therapies  directed to the better hearing ear are of minimal to no benefit30. Behavioral therapies  may be beneficial in modulating tinnitus distress, but without effective sound therapy to the deaf ear, have little to no effect on tinnitus loudness32. Neuromodulation of the auditory periphery by cochlear implantation of the deaf ear, an alternative method of auditory system stimulation, often reduces tinnitus severity similar to acoustic therapies in an ear with hearing loss36. However, this intervention requires surgical implantation of hardware to the skull and complicates future head magnetic resonance imaging (MRI) examinations.Patients with bothersome tinnitus in single-sided deafness (SSD) or unilateral severe to profound hearing loss and normal or nearly normal thresholds in the only hearing ear represent an exceptional opportunity to study tinnitus not confounded by hearing loss variations. Bothersome tinnitus in adult acquired SSD is expected to be localized to the deaf ear37 within the TIN cohort.The goal of this study was to identify candidate biomarkers to monitor tinnitus treatment response and targets for brain-based neuromodulation approaches. We evaluated basal ganglia and cortical connectivity patterns by contrasting an SSD cohort with bothersome tinnitus (TIN) against an SSD cohort no or non-bothersome tinnitus (NO TIN). We used resting-state functional magnetic resonance imaging (fMRI) to define whole-brain connectivity patterns of the caudate nucleus and auditory cortex. We report on connectivity differences between TIN and NO TIN cohorts, and voxelwise connectivity strength correlations with subscale scores of the validated Tinnitus Functional Index (TFI)Data on TFI score, age, sex, deafness duration, diagnosis of vestibular schwannoma, and deaf ear laterality for SSD TIN and SSD NO TIN cohorts are shown in Table\u00a0Resting-state functional connectivity maps were reconstructed for TIN and NO TIN cohorts for the four seed regions (Heschl\u2019s gyrus (HG), and caudate, bilaterally). Functional connectivity seeded from the left caudate was significant with the right caudate, and with multiple regions of pre-frontal cortex (PFC) in both TIN and NO TIN cohorts Fig.\u00a0. The TINWithin the TIN cohort, voxelwise correlations with TFI subscales showed increased connectivity between the right caudate and cuneus for the relaxation subscale, where increased connectivity was correlated with higher interference with the ability to relax Fig.\u00a0. Voxelwi18. The striatum is believed to be normally restrictive, blocking out phantom percepts, but becomes dysfunctionally permissive in chronic tinnitus. Initial evidence in support of this model stems from results of acute direct stimulation of the striatum at the junction of the head and body subdivisions (area LC) during deep brain stimulation (DBS) surgery in movement disorders patients with chronic tinnitus, where auditory phantom loudness can be modulated14. In those without tinnitus, caudate DBS can trigger auditory phantom percepts15 and vascular infarction of the dorsal striatum results in enduring tinnitus loudness reduction16. Furthermore, chronic caudate DBS has been shown to significantly improve TFI in some patients with severe, chronic tinnitus18. Although the exact physiological mechanisms are not clear, alteration of excitation and inhibition balance either within the caudate nucleus or in its connections to auditory cortex may be modulating phantom percept gating permissiveness39. Findings from this study extend generalizability of results from human neurophysiological18 and resting-state fMRI25 studies in binaural patients.The key finding of this study is increased connectivity between the caudate nucleus and auditory cortex in the SSD cohort with chronic, bothersome tinnitus. All patients relied on monaural hearing with normal audiometric thresholds, thereby removing hearing loss variation as a possible confound and isolating abnormal striatal functional connectivity to chronic tinnitus. This independent replication of the critical finding in our prior studies, where tinnitus cohorts had variable hearing loss profiles, further supports a striatal gating model of tinnitus awareness where the limbic system may be driving tinnitus severity40, as measured by the Tinnitus Handicap Inventory41 (THI) score, is positively correlated with pre-treatment activities of the left insula42. Increased functional connectivity between the caudate and the insula observed in this study suggests that the left insula may be an important structure within corticostriatal loops that link the auditory system with language networks and the limbic system44. Tinnitus awareness burden is negatively correlated with delta band activity of rostral and dorsal anterior cingulate cortices. Those areas are considered to be at the core of a descending noise cancellation system whose dysfunction may contribute to the percentage of daytime tinnitus awareness45. Increased striatal functional connectivity between the left caudate and the right supplementary motor area (SMA) observed in this study may possibly include neighboring dorso-rostral anterior cingulate cortices, thereby contributing to overall tinnitus distress.Other tinnitus neuroimaging studies using EEG methodologies have yielded interesting insights that are relevant to our findings. Tinnitus severity response to Tinnitus Retraining Therapy24. Increased connectivity with the superior lateral occipital cortex and anterior supramarginal gyrus is correlated with reduced sense of control over the phantom percept, regions that are part of task-positive visual and dorsal attention networks, suggesting enhanced attentional engagement for control of tinnitus46. Although the right caudate connectivity shows significant correlation with TFI subscale scores, it did not survive across cohort differences in functional connectivity, most likely due to the underlying small sample size. Nevertheless, the highest connectivity of the right caudate is with the left caudate , constant, non-pulsatile tinnitus  to collect both high-resolution structural T1-weighted fast spoiled gradient echo brain volume images  and to collect spontaneous fMRI data using a resting-state echo planar imaging (EPI) sequence . Foam earplugs with a 32\u2009dB noise reduction rating were inserted into both ears during data acquisition.https://www.nitrc.org/projects/artifact_detect/), tissue segmentation, spatial normalization to the Montreal Neurological Institute (MNI) template, and spatial smoothing (using a 8\u2009mm FWHM kernel). Prior to functional connectivity analyses, resting-state data were temporally filtered (0.008Hz-0.09\u2009Hz bandpass) and denoised by applying a regression model using 12 realignment parameters and the global mean signal of the white matter.Resting-state fMRI data were spatially preprocessed using a standardized pipeline implemented in the CONN toolbox. Imaging data preprocessing steps were as follows: functional realignment and unwarping, translation to center, outlier detection using Artifact Detection Tools  as implemented in the CONN toolbox. Correlation coefficients were computed across all voxels of these pre-defined regions of interest (ROIs) with the rest of the brain. Voxelwise regression analyses were performed only within the TIN cohort (n\u2009=\u200915) between functional connectivity and TFI subscale scores. Voxelwise analyses within and between groups (TIN versus NO TIN) were performed using parametric one-tailed t-tests for determining regions with increased and decreased connectivity separately for each of the four seeds. We report on within and across-group whole-brain analyses that survived a threshold of p\u2009<\u20090.05 following a false discovery rate based cluster-mass correction for multiple comparisons59.All functional connectivity and group analyses were performed using the CONN toolbox. For resting-state functional connectivity, four seed regions (right/left Heschl\u2019s gyrus (HG); right/left caudate) were anatomically defined using AAL labelled regions ("}
+{"text": "As populations age, identifying factors that foster the maintenance of health is crucial for improving the health and well-being of older adults. Yet, most psychological, biomedical, and public health efforts have focused on reducing harmful risk factors. While the risk management approach has contributed greatly to prevention and treatment programs, our aging society continues to grapple with the steadily rising tide of chronic conditions. Expanding the focus to include upstream, health-promoting psychosocial assets may help inform a more comprehensive response effort. Mounting research suggests that different dimensions of psychological well-being are uniquely associated with reduced risk of chronic conditions. However, the mechanisms underlying these associations remain understudied. This symposium presents 4 studies evaluating potential mechanisms. The first talk presents research evaluating how a spouse\u2019s level of optimism may be uniquely associated with an individual\u2019s cognitive health over time . A second talk, draws upon a multi-burst daily diary study and focuses on affective stress response as a potentially modifiable target that could explain the health benefits of optimism. A third talk evaluates how baseline levels purpose in life might be associated with repeated measures of five key health behaviors over time. A fourth talk discusses results from a longitudinal-burst daily diary study determining the reciprocal relationships among optimism, pain interference, and goal-directed activity among older women who experience pain. Overall, these studies add to the growing research on psychological well-being and physical health by providing evidence around potential biobehavioral pathways."}
+{"text": "An 8-year-old male patient presented after suffering blunt trauma to the left side of the face during a football game. On initial evaluation, the patient denied malocclusion or chin deviation. Computed tomography (CT) identified a displaced intracapsular left-sided mandibular condylar fracture , and conWhat is the etiology of pediatric mandibular fractures?How are pediatric patients affected by condylar fractures?What are the different methods of treatment of pediatric condylar fractures?What are the benefits of closed reduction with dynamic elastic therapy?Several types of traumatic mandibular injury are seen in the pediatric population. According to one recent study, the most common events leading to mandibular fractures were sports injuries, falls, and road traffic accidents.Several differences exist between pediatric and adult condylar fractures. Pediatric bones are more likely to remodel, which can partially compensate for malunion unlike mandibular fractures in adolescents and adults.,Treatment modalities for pediatric condylar fractures include conservative management with liquid diet, jaw rest, and careful clinical follow-up, closed reduction with maxillomandibular fixation (MMF), or open reduction with internal fixation (ORIF). Most authors advocate for closed management due to the lack of outcomes data on open surgery and due to the risks of damaging growth centers with open treatment. Remodeling and dental evolution can also overcome malocclusion in closed treatment, especially in patients with primary/deciduous dentition, as there will be more dental evolution compared with patients with secondary teeth.6Closed reduction of pediatric condylar fractures with MMF may be accomplished through several methods but can be difficult in pediatric patients when attaching arch bars, brackets, or screws to primary or deciduous dentition. Prior work discusses risks of tooth avulsion and damage to developing dentition.Dynamic elastic therapy is suitable for the management of condylar fractures with any degree of displacement or dislocation in pediatric patients and offers superior or similar results compared with rigid maxillomandibular fixation while minimizing patient discomfort."}
+{"text": "The high mortality rate associated with pancreatic cancer necessitates accurate and early detection methods. Computed tomography currently is the primary diagnostic modality used; however, subtle imaging features in concert with novel clinical presentations may obscure the initial diagnosis. Here, we describe a unique initial presentation of pancreatic cancer as a pancreatic leak, with subtle initial CT evidence of malignancy. An 83-year-old female with prior surgical history of open splenectomy and ventral hernia repair presented with two weeks of vague abdominal pain and leukocytosis. Initial CT revealed abdominal peripancreatic fluid collections. Interventional radiology-guided drain placement was performed, which revealed amylase-rich pancreatic fluid within the collections. Repeat CT scan revealed subtle pancreatic duct dilation with slow resolution of the fluid collections. Ultimately, endoscopic ultrasound identified an ill-defined pancreatic mass, revealed to be pancreatic adenocarcinoma. The patient subsequently underwent an open distal pancreatectomy. Diagnosis of pancreatic cancer relies heavily on cross-sectional imaging, with no screening tests currently available. However, subtle radiographic features and unique clinical presentations may delay accurate diagnosis and staging. EUS may be a useful tool for initial evaluation of high-risk individuals. Pancreatic cancer has one of the lowest five-year survival rate of all malignancies 8.5%), accounting for 10.9 out of 100,000 deaths in the US \u20134. When %, accounHere, we describe an unusual case of pancreatic adenocarcinoma initially presenting as pancreatic duct disruption in a patient with a prior splenectomy. Initial CT did not suggest pancreatic cancer; however, EUS was eventually used to evaluate subtle pancreatic duct dilation and revealed the presence of pancreatic adenocarcinoma. Our experience demonstrates that EUS is an accurate modality for detecting pancreatic cancer with both an initial negative CT and a complex clinical presentation.An 83-year-old female presented to the emergency department with two weeks of vague abdominal pain. Her past medical history was significant for open splenectomy for spontaneous rupture three years prior to presentation and subsequent ventral hernia repair with mesh. She denied history of pancreatitis, diabetes mellitus, nor family history of gastrointestinal disease or malignancy. She was found to have a UTI and leukocytosis of 20,000, with LFTs and lipase within normal limits. Initial CT demonstrated abdominal fluid collections around the stomach and pancreatic tail, extending to segment two of the liver Figures . She wasHere, we describe a diagnosis of pancreatic cancer in an 83-year-old female patient characterized by a unique clinical presentation and equivocal initial radiologic findings. EUS revealed the ill-defined pancreatic mass, and EUS-guided biopsy confirmed pancreatic adenocarcinoma. Given the high morbidity and mortality of this disease, evaluation and improvement of current diagnostic techniques is crucial.Initial clinical symptoms of pancreatic cancer are vague and nonspecific, and patients typically present with abdominal pain and weight loss . PainlesCT, the recommended first line imaging modality for pancreatic cancer evaluation, has high sensitivity for large lesions and is useful in disease staging . Recent As demonstrated in this case of pancreatic cancer presenting initially as peripancreatic fluid collection, an atypical clinical presentation coupled with negative initial imaging studies may obscure the underlying diagnosis of pancreatic cancer. EUS has high diagnostic accuracy and allows for immediate tissue biopsy. Thus, EUS should be rigorously evaluated to determine its potential use in the initial screening of patients with high clinical suspicion for pancreatic cancer."}
+{"text": "Research efforts in these areas have already yielded critical insights into pathophysiological mechanisms and will continue to stimulate innovation in this promising area of translational research.Neural circuits are the underlying functional units of the human brain that govern complex behavior and higher-order cognitive processes. Disruptions in neural circuit development have been implicated in the pathogenesis of multiple neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia. Until recently, major efforts utilizing neurological disease modeling platforms based on human induced pluripotent stem cells (hiPSCs), investigated disease phenotypes primarily at the single cell level. However, recent advances in brain organoid systems, microfluidic devices, and advanced optical and electrical interfaces, now allow more complex hiPSC-based systems to model neuronal connectivity and investigate the specific brain circuitry implicated in neurodevelopmental disorders. Here we review emerging research advances in studying brain circuitry using  Neural circuits can be detected as early as 18\u201322 weeks gestational age (GA) during human brain development. Transient circuitries in the brain are initially established in the subplate, formed by afferent inputs from multiple brain regions, including the basal forebrain, brainstem, and somatosensory thalamus . Then thin vitro  are emerging to complement these animal models. Since hiPSCs were first generated \u201321, patiin vitro disease modeling has significantly accelerated following the generation of hiPSCs in 2007. The ability to harness patient-specific somatic cells and reprogram them into pluripotent stem cells indistinguishable from human embryonic stem cells (hESCs) has opened a novel area of research for modeling neurodevelopmental disorders. Development of robust hiPSC reprogramming methodologies has been an area of intense research with more than a dozen methods currently available  the ability to physically segregate cell bodies of different neural subtypes while still allowing axonal growth between compartments (ii) compatibility with high-resolution video microscopy to investigate morphological and functional connectivity (iii) the ability to control axonal growth and monitor stages from early synaptic formation through late synaptic maturation. Thus, microfluidic chip platforms provide compelling systems to investigate neural circuit dysfunction in neurodevelopmental disorders.The development of compartmentalized microfluidic devices has further enabled innovative methods to model human brain circuitry with an unmatched level of control. Microfluidic chip devices provide several novel features as platforms to model circuit-level connectivity As a proof of concept, a five-compartment microfluidic device was developed to model a mid-brain neural circuit composed of GABAergic, glutamatergic, and dopaminergic (DA) neurons . Using dIn another study, a microfluidic chip platform modeled the hippocampal dentate gyrus (hDG)-Cornu Ammonis region 3 (CA3) circuit of schizophrenic patients . An effiA similar two-compartment microfluidic device reconstructed cortico-striatal circuits using primary neurons from a mouse model of Huntington's disease (HD). Though the main focus of this review is based on hiPSCs, this innovative system was included to emphasize the value of microfluidic systems in modeling brain circuitry. Data from this study suggested that presynaptic cortical dysfunction was both necessary and sufficient to induce pathogenic properties within post-synaptic striatal neurons, thus highlighting the critical value of these systems in providing mechanistic insights into disease pathogenesis . Throughin vivo conditions , assays could be developed to record the electrophysiological properties of brain organoids in the context of normal development or exposure to environmental factors. Further, MEAs could be utilized as functional readout tools to phenotypically profile abnormal electrical activity arising from diseased brain organoids, thereby allowing for drug screening approaches to identify potential therapies that rescue electrophysiological deficits. Additional applications for MEAs include analysis of network topological properties and functional connectivity graphs within brain organoids based on spike train data, which could be derived using information-theory based network analysis \u201369. AddiIn conjunction with neural circuit analysis within single brain organoids, regionally diverse brain organoids could be combined into assembloids to model long-range circuits such as those implicated in neurodevelopmental disorders and drug addiction. The same optical and electrical interface tools could then also be applied to these long-range circuit models. To further enhance the fidelity and reproducibility of assembloid-based platforms in modeling long-range circuits, microfluidic devices could segregate organoids into different compartments, while still allowing inter-compartmental projections and synaptic contacts between the separated organoids . Thus, cin vitro platforms for modeling human brain circuitry, it is critical to remember the developmental context of many neurological disorders. Some neurodevelopmental disorders may be triggered early, potentially resulting from environmental exposures in combination with a susceptible genetic makeup; common examples are cases of parenteral heavy metal    or intranganese) \u201378. Othenganese) \u201381 or thnganese) \u201384. New AH and MH conceived the main ideas and developed the structure of the paper. AH, MH, NM, and CM wrote the manuscript. AH prepared the figure and the table. All authors critically reviewed and approved the final manuscript for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors MH."}
+{"text": "Within California, older adults living in rural counties have reported higher rates of falls than urban dwelling older adults. Although many Indigenous people live in rural areas, it is unclear whether the rate of falls among Indigenous older adults is similar to that of non-indigenous older adults living in rural areas. Thus, the purpose of this study was to examine fall risk behaviors and intrinsic risk factors for falls in rural dwelling Indigenous (N = 89), and non-Indigenous (N = 68) older adults 60-95 years of age living in California. Results showed that both Indigenous and non-Indigenous older adults share similarly high fall rates, but there are a much greater number of Indigenous older adults falling multiple times a year. Moreover, fall risk behaviors and intrinsic fall risk factors were significantly different between Indigenous and non-Indigenous rural-dwelling older adults. Future studies should investigate falls and fall risk factors in different tribes/locations of Indigenous older adults to better understand whether these risk factors differ among tribes. Moreover, it would be beneficial for future studies to assess the effectiveness of fall prevention exercises on fall risk in these communities. Information gained from this study helps to inform clinicians and researchers alike about the prevalence of falls and factors contributing to falls among Indigenous older adults living in rural communities; and helps to influence decisions in the future of programs for reducing fall risk in this often neglected population."}
+{"text": "While considerable progress has been made in studying genetic and cellular aspects of metastasis with in vitro cell culture and in vivo animal models, the driving mechanisms of each step of metastasis are still relatively unclear due to their complexity. Moreover, little progress has been made in understanding how cellular fitness in one step of the metastatic cascade correlates with ability to survive other subsequent steps. Engineered models incorporate tools such as tailored biomaterials and microfabrication to mimic human disease progression, which when coupled with advanced quantification methods permit comparisons to human patient samples and in vivo studies. Here, we review novel tools and techniques that have been recently developed to dissect key features of the metastatic cascade using primary patient samples and highly representative microenvironments for the purposes of advancing personalized medicine and precision oncology. Although improvements are needed to increase tractability and accessibility while faithfully simulating the in vivo microenvironment, these models are powerful experimental platforms for understanding cancer biology, furthering drug screening, and facilitating development of therapeutics. Metastatic progression of solid tumors can be divided into five major steps: (1) invasion of the basement membrane and cell migration; (2) intravasation into the surrounding vasculature or lymphatic system; (3) survival in the circulation; (4) extravasation from vasculature to secondary tissue; and finally, (5) colonization at secondary tumor sites .5 PDXs and primary cells obtained directly from patients are more rigorous predictors of clinical outcomes by incorporating patient-specific genomics absent from cell lines. Notably, PDXs can accurately predict clinical response to targeted cancer therapeutics.6 Although these must be maintained in immunocompromised mice long term and can be only used for a limited number of passages in vitro, the ability to assimilate primary human samples into engineered models is a significant advance over traditional animal models and microfabricated platforms.Numerous cell lines have been isolated from human or murine tumors to provide homogeneous samples that possess genomic alterations consistent with their native tissue sources.7 Tissue specimens from diagnostic surgery can be procured and manipulated to obtain primary human cells which can be immortalized for long term use by treating with human telomerase.8 Immortalized primary cells retain many traits from the primary tissue specimen while still undergoing multiple passages, and they can recapitulate cancer cell signaling and extracellular matrix (ECM) remodeling.8 The ability to incorporate primary samples into in vitro models of each metastatic stage has the potential to transform these devices into more precise and impactful predictors of clinical outcomes.With tissue banks becoming more readily available for research use, both normal and cancerous tissue samples from patients can be obtained.9 Invasion through the basement membrane is considered the differentiating step between pre-cancerous neoplasia and malignant cancer in which increased collagen deposition, fiber thickness, and linearized fiber architecture contribute to a stiffer environment.11 Cells mechanically remodel ECM through a cycle of cell protrusion and contraction, and chemically degrade the matrix using metalloproteinases as they migrate.12 In addition, cancer cell contractility and matrix stiffness create a positive feedback loop causing downstream effects on cell behavior during metastatic progression.13 As such, accurate invasion and migration models must incorporate ECM with tunable stiffness, adjustable pore size, and measurable and/or controllable degradability.Metastasis is initiated during invasion and migration where cancer cells penetrate the basement membrane and navigate as single cells or via collective means through the stromal microenvironment, respectively., in vitro tumor models rarely capture the full complexity of spatiotemporal heterogeneities inherent in tumor progression due to cell culture time scales and construct size limits. The use of organoids partly overcomes these limitations by better representing genotypic and phenotypic diversity in a structured in vitro microenvironment. These structures, derived directly from human tumor tissue samples, preserve three-dimensional architecture and patient-specific phenotypes while in culture  posts modeling various levels of substrate rigidity, and synthesized networks of tunable porosity mimic features in tumor architecture during disease progression.32 To observe confined migration in a more physiologically relevant system, collagen can be micro-molded to create tracks of tunable geometries recapitulating in vivo collagen structures  differentiation into endothelial cells which assembled into perfusable, capillary-like networks, and capturing endothelial response to different environmental biochemical and biophysical cues.43 Incorporation of patient-derived hiPSCs in platforms such as these lays the foundation for personalized characterization of tumor angiogenesis and endothelial cell response to cancer therapeutics. In addition, the hyaluronic hydrogel used in this platform has been shown to induce cell migration, and thus further modifications to this design could potentially be used to simultaneously investigate invasion and migration in a defined microenvironment.Since blood flow and interstitial pressure influence tumor angiogenesis, most microfluidic systems focus on recapitulating these in vitro. Models utilizing micromolding and bioprinting techniques have been used to fabricate endothelialized tissue constructs to visualize real-time endothelial cord formation during tubulogenesis.44 In addition, tremendous inter-tumor heterogeneity in angiogenic activity depends partly on the organ of origin and cancer subtype, due to organ-specific differences in the pro- and anti-angiogenic molecule secretion profiles of stromal cell populations.35 Thus, the development of more specific, personalized experimental systems will enable characterization of angiogenic behavior within different tumor types and for individual patients, leading to improvements in drug-screening models.Although current in vitro models contain essential features of angiogenesis, further work should be aimed at incorporating tissue-specific cell types and ECM features found at organ-specific primary tumors sites, such as recapitulating low permeability vascular beds present at the blood\u2013brain barrier or highly permeable vascular beds of liver sinusoids.45 The tumor microenvironment provides both chemical and physical cues to induce tumor cell intravasation. For example, stiffened ECM has been correlated with increased endothelial permeability which potentially promotes tumor cell intravasation.47 Although tumor cells secrete pro-angiogenic factors influencing the vascular phenotype, vascular cells actively regulate invasion.49 Thus, co-culture models representing the complex interactions between cancer cells, endothelium, and surrounding stroma are necessary to characterize intravasation.In addition to providing nutrients, tumor vasculature also facilitates intravasation, the process by which cells infiltrate the vasculature.50 For example, one of these systems incorporating cancer, endothelial, and immune cells supports the role of macrophage-assisted intravasation correlating with clinical results.48 Thus, these platforms serve as models to examine potential immune cell involvement in intravasation.Microfluidic systems allow for the incorporation of fluid flow and are amenable to real-time imaging capability. Recently, commercially available microchannel systems were used to observe intravasation events after vascular network formation.51 Circulating tumor cells (CTC) arrest in a vessel and extravasate through two primary mechanisms: physical occlusion and adhesion after rolling (Fig. Although few cancer cells reach the circulation, even fewer survive the hemodynamic shear forces, immune stresses, and red blood cell collisions they encounter once there.ing Fig. . During 55 These platforms often employ surfaces functionalized with CTC-specific adhesion proteins or antibodies to optimize adhesion dynamics for CTCs while minimizing that of leukocytes also present in whole blood.55 Physical entrapment under flow can also be utilized to isolate CTC clusters that have been suggested to have increased metastatic potential compared to single CTCs.54 Recent work has shown that single-cell encapsulation of CTCs into microdroplets can be utilized to profile enzyme secretion.56 In addition, single-cell RNA sequencing of human patient CTCs has been optimized to assess inter- and intra-patient heterogeneity and identify potential therapeutic targets using a microfluidic platform and barcoding technique.57 As the methods to capture viable CTCs become more tractable, further probing of later stages of metastasis using isolated CTCs could provide insight into the properties of these rare but crucial cells. Engineered platforms have the potential to elucidate the changes CTCs may undergo as they transition from solid tissue to the circulation, as well as determine the properties of CTCs best suited for extravasation and colonization.Microfluidic and microtubing systems enabling the collection of both single and clustered CTCs from patient blood have contributed greatly to understanding cancer metastasis.59 and study the interactions of CTCs with neutrophils, platelets, and endothelial monolayers.62 Efforts to increase throughput have led to the development of a cone viscometer platform that interfaces with standard 96-well plates to enable more streamlined testing.63 Although cone and plate viscometers facilitate highly controlled, reproducible exposure to shear conditions, they lack relevant vessel-like architecture and do not allow for real-time imaging during shear exposure.Cone and plate viscometers are often used to expose cancer cells to physiological shear forces in cell culture medium or whole blood65 Parallel plate flow chambers can be used to assess rolling-adhesion interactions between circulating cells perfused over a substrate coated with ECM, ligands, or endothelial monolayers.67 Others assess the rolling and adhesion of cancer cells to physiologically relevant proteins using controlled perfusion through functionalized microtubing.70Numerous commercially available, relatively inexpensive platforms are used to produce shear stresses in vitro. Motorized expulsion through a needle has been used to assess cancer cell viability and conditioning after shear stress exposure.71 More complete microfluidic models can incorporate spatially defined chemokine gradients and or organ-specific cells, such as primary lung endothelial cells or osteo-differentiated bone marrow derived stem cells.74 Although numerous microfluidic platforms mimic the vasculature, CTCs can also travel through the lymphatic system. Notably, it was observed that low shear stresses mimicking lymphatic flow induced cancer cell motility while high shear stresses mimicking arterial and venous flows inhibited cell motility in a YAP1-dependent manner, highlighting the importance of selecting physiologically relevant shear stresses since different ranges can elicit divergent cell behaviors.75Microfluidic systems provide an immense degree of customization, with the ability to incorporate complex structures and dynamic flow patterns in perfused channels that can be coated with ECM or endothelial monolayers.76 For example, a microfluidic device with capillary-sized channels was used to show that CTC clusters isolated from patient blood can traverse these constrictions while remaining intact.77Tumor cell arrest during extravasation can also occur through cancer cell occlusion in capillary networks. Serial deformation and transmigration chambers in microfluidic devices have been designed to mimic constrictions in capillaries and relevant endothelial/ECM barriers that cells must bypass to transmigrate after arresting.78 To stabilize self-assembled networks, co-culturing fibroblasts segregated from endothelial cells provides the necessary paracrine signaling for network stabilization, while co-seeding with pericytes regulates vessel diameter and decreases vessel permeability.79 Although self-assembled microvascular networks do not necessarily require specialized equipment, control over network formation is limited.Recently, self-assembled perfusable microvascular networks have been developed to investigate physical occlusion and rolling-adhesion events leading to extravasation.80 Although geared towards improving tissue engineering designs, this platform could be adapted to study extravasation in capillary networks. Live-cell lithography was developed to better control cell placement for in vitro vascular network assembly.81 In this system, multiple optical tweezers are used to manipulate placement of cells in three dimensions allowing the controlled addition of pericytes, smooth muscle cells, and fibroblasts outside of the vessel. Advances like these lay the foundation for systems that better recapitulate the complexity of the tumor microenvironment. As patient CTC capture platforms improve, further incorporation of these precious clinical samples into downstream assays will be crucial towards investigation of CTC performance during subsequent stages of metastasis. If assays can be streamlined and correlated with clinical data, theranostic platforms with CTCs isolated from patient blood have the potential to improve clinical outcomes.Three-dimensional printing of carbohydrate glass sacrificial fibers can create highly controlled, multiscale, and perfusable vascular networks.82 After extravasation, cancer cells have one final task to complete: colonization of secondary sites. This process is thought to be extremely inefficient with only a minute percentage of CTCs growing into lesions.83 Metastatic niches possess cell types and ECM compatible for tumor cell survival and growth,83 including perivascular niches, spaces around blood capillaries where cancer cells can seed. Extravasation and colonization models require tissue-specific cell types, microenvironmental cues, and vascularization. Leveraging tissue engineering advancements to model metastatic sites may be key in understanding factors driving colonization as it is possible to tailor the site to isolate roles of cells types, growth factors, and ECM architectures.Following arrest within the vessel, cancer cells must extravasate from the vessel to colonize new sites. This process differs from intravasation, where cancer cells navigate tumor-modified stroma via chemotactic and durotactic gradients toward leaky, nascent vasculature without experiencing hemodynamic stressors; rather, during extravasation, the vasculature that is breached by cancer cells is healthier, and cancer cells actively experience fluid shear stresses due to blood flow.84 Osteo-differentiated mesenchymal stem cells, mineralized hydroxyapatite-incorporated ECM, and ex vivo bone scaffolds have all been shown to elicit relevant cell behavior in in vitro bone tissue models.88 Incorporation of perfusable vascular networks in these models allows for cancer cells to be flowed though, recapitulating extravasation events at the metastatic site. Bioreactors can be used to create complex, mature tissue constructs for seeding as well as to expose seeded scaffolds to tunable, physiological compressive forces to observe colonization behavior.90As bone metastasis occurs frequently in breast and prostate cancers and correlates with shortened patient prognoses, many models of metastatic colonization in bone have been created.91 Moreover, decellularization provides a scaffold that can then be re-seeded with cancer cells to examine colonization in a simplified yet physiological setting.92 Decellularization proves a powerful technique to enhance and inform tissue-engineered constructs of metastatic colonization sites and assess cancer cell-ECM interactions. LiverChip\u00ae is a commercialized microfluidic model of the hepatic niche used to observe interactions between cancer cells, hepatocytes, and non-parenchymal cells.93 Infiltration of the brain\u2013blood barrier has been modeled by adding cancer cells to numerous permutations of co-cultures containing endothelial cells, pericytes, glial cells, astrocytes, and cancer-associated fibroblasts.98 As lung, liver, brain, and lymph node are all extremely common metastatic sites, further work should be directed towards developing more complex, physiologically relevant in vitro models for assessment of cancer cell metastatic colonization at these distinct locations.Several different models have been exploited to assess colonization in various organ systems. Decellularization of tissues including mammary fat pad, lymph node, and lungs has been used to three-dimensionally map the spatial distribution of ECM components of these tissues in health and disease.Currently, metastatic colonization assays are in their infancy relative to assays focusing on earlier stages. As colonization is the stage where metastasis gains its lethality and where confounding events like drug-resistance and dormancy often occur, it is promising as a key point of intervention. While much emphasis is placed on the personalized side of patient-specific cancer cells, understanding patient-specific, non-tumor cells in metastatic sites may help explain drug-resistance and dormancy.While in vivo models can be used to study the entirety of the cascade, the complexity and timescale of metastasis limits their utility. In vitro models successfully recapitulate individual steps in metastasis, yet few encompass more than one stage in the process.99 Specifically, microfluidic chambers containing a gut tissue-like \u2018source\u2019 seeded with colon cancer cells and a liver tissue-like \u2018sink\u2019 are connected by a perfused flow channel. In this model, cancer cells can exit the gut chamber and spread to the liver chamber. This three-dimensional construct facilitates drug-screening and visualization of metastasis, though it still lacks important features like endothelial barrier function, intravasation, and extravasation. Despite limitations, it marks one of the first steps toward an in vitro model distilling the key components representing the diverse microenvironments cancer cells encounter during metastasis.Recent work to develop a more complete metastatic platform has resulted in a microfluidic metastasis-on-a-chip model where hydrogels embedded with host tissue cells are combined with microfluidics to represent the spread of metastatic cells from primary to secondary tissue.100 However, metastasis is a dynamic, multi-step process and by simplifying models to exclude parts of the cascade, we are only gaining insight as to how well cancer cells perform specific steps out of context. Thus, it is critical that more complete models be developed so that metastasis can be observed in the correct series of events.Although there are still limitations hindering in vitro recapitulation of the full metastatic cascade, approaches that stitch together multiple sequential steps into a single assay have fewer impediments. Reductionist models that incorporate a primary tumor site and a metastatic niche site separated by ECM serve as a simplified approach to assessing metastatic potential.Engineered in vitro models have greatly expanded our understanding of cancer metastasis. Incorporation of primary cells and tissue within metastatic models provides more physiologically relevant and clinically applicable findings that often correlate with patient outcomes, aiding in drug-screening and personalized medicine to advance precision oncology. As tissue banks become more common and access to primary human samples increases, metastatic models are moving towards more faithful representations of native in vivo cell interactions and behaviors Fig. .Fig. 4Pr15With the addition of primary patient blood or tumor tissue samples into established in vitro models of the metastatic cascade, personalized characterization of metastatic cancer cell behavior is gaining tractability. Further, coupling these patient-specific assays with high-throughput drug-screening approaches could aid in optimizing patient treatment plans as well as facilitate drug discovery. For example, patient-derived organoids can serve as effective preclinical models for rapidly assessing therapeutics, shown to exhibit similar responses to chemotherapeutic drugs such as topotecan and melphalan consistent with clinical outcomes.99 Moving forward on the path towards personalized cancer theranostics, ameliorations to existing in vitro models, including the addition of patient-derived samples and integration of multiple steps of the metastatic cascade into one platform, will be essential.As microfabrication techniques and biomaterials advance, models are gaining the ability to recapitulate multiple tissue-specific microenvironments connected in a physiologically relevant manner as pioneered primarily for pharmaceutical toxicity studies. Adaptation of these systems to simulate key elements of multiple metastatic stages in sequence could provide novel insight. In addition, more comprehensive models such as the metastasis-on-a-chip model that elegantly incorporates multiple steps still lack essential components in their design, such as endothelial barriers to study intravasation and extravasation effects.Further information on research design is available in the Reporting Summary"}
+{"text": "Tasks of increasing difficulty require increasing levels of cognitive engagement from participants. The costs associated with cognitive engagement rise with age in response to normative cognitive decline. Additionally, previous studies have shown an interaction between age and task difficulty, with age differences in effort expenditure increasing along with task demands. Motivational accounts of effort allocation predict the opposite relationship, where increased task difficulty in the face of declining cognitive abilities result in disengagement among older adults, comparatively lowering their effort expenditure relative to younger adults that remain committed to the task. The current study quantitatively reviews the available literature on age and effort expenditure across tasks of increasing difficulty. An initial meta-analysis found no age differences in effort across task difficulty, but inspection of the significantly heterogeneous effect sizes indicated that measurement domain might account for some of the variance found between the effect sizes. A second, post-hoc meta-analysis was conducted, recoding effect sizes giving preference to subjective measures. Subsequent moderator variable analyses found that the combined effect of age and domain of effort measurement explained a sufficient portion of the variance across effect sizes. When using physiological measures, effort was not found to differ across task difficulty for either age group. Alternatively, when measured subjectively, effort was reported to greatly increase (>1 standard deviation) with difficulty, with a larger increase in younger adults. Results are discussed in terms of effort mobilization across adulthood and the importance of measurement domain in the interpretation of results."}
+{"text": "Sitophilus zeamais (Motschulsky) and Prostephanus truncatus (Horn). Other insects of lesser economic importance also were observed in the visual surveys, including Sitotroga cerealella (Olivier) (Lepidoptera: Gelechiidae), and Tribolium castaneum (Herbst). This study demonstrated that the use of acoustic technology with visual surveys and pitfall traps can help managers to identify and target infestations within their warehouses, enabling them to reduce postharvest losses. With most warehouses being located in relatively noisy urban or peri-urban areas, background noise considerations are being incorporated into the design of future acoustic detectors for stored pest infestations. Kenya must import grain yearly to meet consumption needs; however, if the current yearly postharvest losses of 20\u201330% in warehouses decreased, import costs could be reduced considerably.Grain production is an important component of food security in Kenya but due to environmental conditions that favor rapid growth of insect populations, farmers and other agricultural stakeholders face ongoing and novel challenges from crop and stored product pest insects. To assist development of methods to reduce economic losses from stored product insect pests in Kenya, acoustic, visual, and pitfall trap surveys were conducted in five grain storage warehouses. Two commercially available acoustic systems successfully detected the pests of greatest economic importance,  Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) [fall armyworm] into sub-Saharan Africa will lead to 20\u201350% maize yield loss , Sitophilus zeamais (Motschulsky) (Coleoptera: Curculionidae) [maize weevil], Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae) [red flour beetle] and Sitotroga cerealella (Olivier) (Lepidoptera: Gelechiidae) [Angoumois grain moth] are the major maize pests in sub-Saharan Africa , T. castaneum, and possibly other postharvest pests have been developing resistance to phosphine  and Oryzaephilus surinamensis (Linnaeus)  [sawtoothed grain beetle].Pitfall trap counts provide sampling information about local insect populations that can be useful for pest management programs . Two of  also in . Though AEC and IMC systems provided consistent quantitative measurements. Previous research has shown, however, that among the commercially available detection systems, piezoelectric sensors have greater sensitivity to insect-produced sounds because the signals encounter less attenuation as signals traverse from the insects to the sensors across different media [The results of the visual and acoustic assessments of infestation of the 50 kg storage bags suggest that both the nt media . In addiAEC probe system than for the IMC system. Such results were in agreement with Leblanc et al. [Proximity of the insects to the sensors is known to be another important factor contributing to the sensitivity of an acoustic system to detect insect infestation. The use of waveguide probes can improve the detection range by increasing the volume of grain close enough to the sensor for detection, thus improving the accuracy of detection. In this study, the rates of insect sound bursts detected and the rate of burst impulses, were consistently greater for the c et al. , who comTo improve the sensitivity and accuracy of detection in the presence of background noise, efforts have been directed towards constructing sound-attenuating boxes lined with foam and fitted with piezoelectric sensors, an example of which is shown in . These iP. truncatus and S. zeamais pest species, which provides earlier detection. However, the effects of distance between insect and sensor on detectability noted above, as well as the considerable variation of an insect\u2019s level of activity over time [The statistically significant correspondence between the magnitude of insect sound burst rates and counts of insects captured in the probe traps confirms that acoustic detection is a useful tool for detecting and monitoring infestations in Kenyan grain warehouses. An important benefit of acoustic systems is their identification of hidden as well as visible infestations of important ver time , and thever time , combinever time ,24 in inver time  and hermver time .It is worth noting that several cell phone sound detection apps have been developed, e.g., , some ofExperience gained from the Kenyan stored product insect acoustic detection study indicates that acoustic, visual, and pitfall trap surveys all contribute information useful for early detection and management of visible and hidden pest infestations but suggests that challenges remain in designing user-friendly acoustic systems that automatically discriminate out background noise often present in warehouses. Efforts are in progress to incorporate additional spectral and temporal pattern features of sounds produced by target insects into cost-effective acoustic detection systems. Knowledge of early infestation can assist warehouse managers in maintaining strategic grain reserves with scarce resources. Improved monitoring combined with innovations such as hermetic storage bags may enable reduced reliance on grain imports."}
+{"text": "Facial appearance served great function in social interactions, especially for older adults in making trustworthiness judgements. Previous literatures have consistently shown that when making trustworthiness judgements older adults tended to rely more on facial cues rather than behaviors, due to declines in cognition. However, one question remains unsolved, whether older adults could make accurate trustworthiness judgements if evaluative information  is easily accessible. Sixty younger adults (YAs) and sixty older adults (OAs) were recruited, and asked to make investment decisions for different brokers in ninety-six trials. In each trial, brokers\u2019 facial appearance (trustworthy and untrustworthy looking) and different behavioral evaluative information  were displayed simultaneously on screen to facilitate investment decisions. Brokers\u2019 facial appearances and behaviors were set to be independent to each other. The results indicated that YAs\u2019 and the majority of OAs\u2019 proportions of correct investment increase, gradually reaching a stable high correction rate, although OAs needed more trials than did YAs. The findings extended prior work by suggesting that both OAs and YAs had similar abilities to distinguish different brokers according to easily accessible evaluative information. However, and surprisingly, a small subgroup of OAs (with low economic status) still had a lower correction rate even after ninety-six trials, suggesting that they could not distinguish brokers based on their evaluations at all, who might be at risk for fraud."}
+{"text": "Second, Lindsey will introduce technological innovations used in the I-CONECT project including development of user-friendly video-chat devices, recording of audio and video data and innovative recruitment efforts. Third, Asgari will share results on how speech utterance and characteristics collected through the project could distinguish those with mild cognitive impairment from those with normal cognition using machine learning modelling approaches. Finally, Cerino and his team will show results of the study which examined whether cognitive improvements through conversation-based intervention depend on an individual\u2019s personality, laying the groundwork for a personalized intervention trial in the future. The symposium is of interest for those who study social isolation and its prevention, the link among cognition, social isolation and personality, as well as those who focus on technology as a tool for improving well-being of older adults.Epidemiological studies have demonstrated that larger social networks or more frequent social interactions may have protective effects against cognitive decline and the incidence of dementia. Therefore, increasing social interaction could be a promising intervention for improving cognitive well-being in socially isolated older adults. We have conducted multiple NIH-funded randomized controlled trials (RCT) over 10 years, examining whether conversational interactions through webcam and internet can improve cognitive functions and enhance cognitive reserve. In this symposium, we will introduce this series of behavioral intervention trials through 4 presentations. First, Dodge will provide background and results of their previous RCT where they showed efficacy of conversational intervention on domain-specific cognitive functions and introduce the ongoing larger project called I-CONECT ("}
+{"text": "Mammalian guts harbor indigenous microbes that are integral to host health. Microbiome research using sophisticated model organisms has provided insights into intricate interactions between microbiota and host animals. However, it remains unclear how these animal-microbe associations developed. We have recently addressed this question via comparative analyses of chordates, given that complex biological systems can be resolved into ancestral and derived elements when examined in an evolutionary framework (Nat Commun 9: 3402). Results support the view that microbial colonization of the mucus layer that overlies mammalian gastrointestinal epithelium was established upon loss of ancestral chitin-based barrier immunity. Comparative approaches enable us to arrange ongoing biological processes into host natural history for better understanding of intestinal animal-microbe associations. Mammalian intestines are home to indigenous microbial communities. High-throughput sequencing approaches revealed that these microbes are taxonomically diverse and distinct from those of the surrounding environment. Omics analyses of germ-free animals, combined with manipulation of gut flora, provided growing evidence for complex cellular and molecular mechanisms that underlie reciprocal interactions between microbiota and hosts. Nonetheless, we know little about how these intimate animal-microbe associations developed. Biological systems result from a series of evolutionary processes. Thus, in principle, regardless of their complexity, they can be discriminated into ancestral and derived elements when examined in a proper biological setting. Accordingly, we have conducted comparative analyses of chordates.In animal phylogeny, chordates form a branch of deuterostomes and consist of two invertebrate groups, lancelets and tunicates, as well as vertebrates. Gill slits are a key anatomical feature of deuterostomes, which enable water flow from the mouth to the gill slits. This water flow through the pharynx was prerequisite for their particulate feeding. Invertebrate chordates further employ unique net-like structures secreted from the endostyle, a chordate-specific pharyngeal glandular organ, to establish efficient filter-feeding. Using tunicates, we addressed if this chordate lineage that feeds on environmental microbes harbors indigenous microbes in their gut space similarly to mammals.Ciona intestinalis Type A revealed that the gut space was radially compartmentalized by an unknown membranous structure. Microbes captured by filtration were confined to a luminal space enclosed by this membrane, while a peripheral space over the gut epithelium appeared almost free of bacteria. A combination of chemical and physical analyses demonstrated that the membrane was formed of multilayered, meshed chitin nanofibers embedded in a proteinaceous matrix. The chitinous membranes were secreted and delaminated from the gut epithelium. When chitin synthesis was chemically inhibited, the membrane and axenic space disappeared and food microbes directly contacted with the enterocytes, thereby causing an increased death rate of Ciona. These data showed that the endogenous chitinous membranes are essential for formation of the axenic space and contribute to gut homeostasis by acting as a physical barrier .Transmission electron microscopy of gut sections of the tunicate Ciona membrane, as these structures are framed with meshed chitin nanofibers produced by homologous chitin synthases. On the other hand, these structures have distinct matrix protein compositions. While invertebrate peritrophic matrix consists of protein with chitin-binding and/or proline-threonine-serine-domains, Ciona membranes are comprised of anti-bacterial proteins and gel-forming mucin, which is the main constituent of the mammalian mucus layer that covers the gut epithelium. Briefly, the Ciona membrane provides molecular evidence for a possible link between the invertebrate peritrophic matrix and the mammalian mucus layer, which are considered analogous, i.e. with no common descent . To test this idea, we have examined the following chordate lineages that occupy phylogenetic positions between invertebrates and mammals: a basal chordate Branchiostoma floridae (lancelet), a jawless vertebrate Eptatretus atami (hagfish), and a jawed vertebrate Oreochromis mossambicus (ray-finned fish). All these organisms possessed intestinal chitinous membranes.Similar chitinous barrier membranes have been well studied in several invertebrate lineages. So-called invertebrate peritrophic matrices structurally resemble the O. mossambicus, seemingly contradicts the common view that gut mucosal surfaces of ray-finned fish are covered with a mucus layer that is colonized by indigenous microbes as in mammals. Actually, 16S ribosomal RNA gene analysis showed the presence of indigenous microbes in the gut of O. mossambicus, but this microbial community was enclosed by chitinous membranes and was segregated from the surrounding mucus layer secreted by crypt goblet cells. In contrast, we were unable to detect chitin in the guts of mice, where gut microbiota directly interact with goblet cell-derived mucus.The finding of chitinous membranes in the ray-finned fish, In conclusion, this comparative study provides a glimpse of evolutionary changes in the intestinal mucosal surfaces of chordates. We proposed a transition from a chitin-based ancestral condition to a mucin-based derived state . Radial compartmentalization of the gut space by chitinous membrane seems to be an ancestral feature of chordates. In tunicates, filter-fed microbes transiently pass through the intestine, while being confined to the luminal space by the chitinous barrier. Ray-finned fishes retain this chitin-based barrier immunity, but viable passage of ingested microbes was prevented by bactericidal gastric juice, an invention of jawed vertebrates. This would have offered the subsequent gut space as a new ecological niche for surviving microbes. Because mammals lack the chitinous barrier, gut microbes interact directly with the surrounding goblet cell-derived mucus. Thus, it seems that chitin-based barrier immunity and its loss predated mucus colonization by indigenous gut microbiota.There are considerable variations in intestinal mucus-microbe interactions. In mice, ileum mucus is loose, yet it limits microbial access to host tissues through joint actions with diffusible molecules like RegIII\u03b3. Colon mucus forms two layers with the outer layer extensively colonized by microbes and the densely packed inner layer devoid of microbes. The degree of mucus penetrability varies among bacterial species. These variations can be explained in the context of regional adaptation driven by local functional demands since the onset of direct mucus-microbe interaction. Accordingly, comparative approaches enable us to arrange ongoing biological processes into host natural history to decipher the complex animal-microbe association."}
+{"text": "This symposium examines how social and psychological factors including formal schooling, subjective memory, and neuropsychological symptoms impact cognitive function among older adults in China and the U.S. The first paper used the WHO\u2019s Study on global AGEing and adult health Wave-1 data to examine the relationship between subjective cognitive function, perceived memory decline, and objective cognitive function among older adults in China. The results showed worse subjective cognitive function was associated with poorer working memory and verbal fluency, whereas greater perceived memory decline was associated only with poorer working memory. Furthermore, using data from the Health and Retirement Study, the second paper applied group-based trajectory modeling to assess dual trajectories of subjective memory impairment and objective cognitive decline. Four distinct dual-trajectory typologies were identified, suggesting complex co-occurring changes in subjective memory and objective cognition in older adults. The third paper characterized the trajectories of three neuropsychological symptoms  prior to dementia onset. Using data from the National Health and Aging Trends Study, the study found older adults with dementia exhibit distinct trajectory of depression before dementia onset than those without dementia. Trajectories of pain and insomnia did not differ before dementia onset. The last paper examined the effect of education on cognitive decline among lower educated older adults using data from the Longitudinal Study of Older Adults in Anhui Province, China. Results suggest that older adults with some formal schooling had slower cognitive decline; the gap in cognition between the literate and illiterate widened with age."}
+{"text": "Interventions to improve nursing home care have been developed and tested. However readily disseminated interventions are lacking. Barriers include low staffing levels contributing to limited time for education and high turnover of direct care and administrative staff. Educational interventions must be accessible to accommodate busy staff. Meaningful outcome measures are needed and interventions must fit varied nursing home sizes, ownership, resident population, and regions. Changing Talk Online (CHATO) was adapted from the effective, yet time-intensive, Changing Talk program addressing nursing home staff communication. The original classroom-based program significantly improved staff communication with residents and resulted in subsequent reductions in resident behavioral and psychological symptoms of dementia. Strategies for marketing and recruiting nursing homes and to engage administrators and staff will be discussed as implemented in the Changing Talk Online (CHATO) R61 trial. Approaches addressing unique nursing home challenges to implementation are essential for successful dissemination to improve care."}
+{"text": "Collectivism refers to the social practice of investing in and relying on one\u2019s social network, rather than formal institutions, to ensure personal security. Using the re-engineered 2014 Survey of Income and Pension Participation (SIPP), we investigate how collectivist practices affect life course health disparities at older ages in the US. Indicators of Collectivism include measures of caregiving, inter and intrahousehold financial and material support and help from charities, friends and family members. Regression results indicate that increased collectivist interactions are associated with improved self-reported health status outcomes. Government support for collectivist behaviors can thus yield a low cost means of improving health outcomes among the elderly."}
+{"text": "Falls are common, costly, and the leading cause of fatal and nonfatal injuries for older Americans. Reports show that fall death rates are increasing. Healthcare providers play an important role in fall prevention but few talk to their patients about falls. This lack of communication demonstrates the need for more physician-initiated fall prevention. The Centers for Disease Control and Prevention (CDC) created the Stopping Elderly Accidents, Deaths, and Injuries (STEADI) initiative to help providers talk to their patients about falls. Specifically, CDC\u2019s new STEADI-based fall prevention program, the Coordinated Care Plan to Prevent Older Adult Falls (CCP) and Evaluation Guide for Older Adult Clinical Fall Prevention Programs can assist healthcare providers in integrating and evaluating new fall prevention programs that screen older adults for fall risk, assess patients\u2019 modifiable fall risk factors, and implement evidenced-based fall prevention interventions . The CCP offers guidance for incorporating a STEADI-based fall prevention program including how to engage leadership, integrate with existing clinic workflow and electronic health records, and strategies on how to obtain reimbursement for fall prevention. The Evaluation Plan offers details on how to engage stakeholders, collect data, interpret findings and how to share results for maximum impact. Both documents were based on lessons learned from successful implementation of STEADI-based programs in primary care. A STEADI-based program in New York found fewer fall-related hospitalizations among at-risk patients who received a fall prevention care plan compared to at-risk patients who did not receive a care plan."}
+{"text": "Undernutrition affects millions of children in low- and middle-income countries (LMIC) and underlies almost half of all deaths among children under 5 years old. The growth deficits that characterize childhood undernutrition (stunting and wasting) result from simultaneous underlying defects in multiple physiological processes, and current treatment regimens do not completely normalize these pathways. Most deaths among undernourished children are due to infections, indicating that their anti-pathogen immune responses are impaired. Defects in the body's first-line-of-defense against pathogens, the innate immune system, is a plausible yet understudied pathway that could contribute to this increased infection risk. In this review, we discuss the evidence for innate immune cell dysfunction from cohort studies of childhood undernutrition in LMIC, highlighting knowledge gaps in almost all innate immune cell types. We supplement these gaps with insights from relevant experimental models and make recommendations for how human and animal studies could be improved. A better understanding of innate immune function could inform future tractable immune-targeted interventions for childhood undernutrition to reduce mortality and improve long-term health, growth and development. In low- and middle-income countries (LMIC) childhood undernutrition manifests as growth deficits which can result in a child being too short for their age  score <-2), and/or too thin for their height  score <-2), which are both associated with a greater risk of all-cause mortality . Severe Stunting and wasting are the most readily measurable indicators of undernutrition, but these anthropometric deficits result from underlying defects in multiple physiological processes . The mosIn this review we will discuss the current evidence for the role of innate immune cell dysfunction in undernutrition, focusing on children living in LMIC. We will draw on population studies and supplement knowledge gaps from existing undernutrition research with insights from experimental models. Our goal is to highlight the potential for innate immune cell dysfunction to shape clinical outcomes of undernutrition and outline how future studies could be used to improve our understanding of these pathways.in utero: a principal predictor of postnatal growth is maternal nutritional status during pregnancy, and length and weight at birth  recurrent symptomatic infections and sub-clinical pathogen carriage; (2) chronic systemic inflammation and immune activation; (3) impaired gut function, enteropathy and dysbiosis of the gut microbiome , 13; (4)at birth . These iat birth . The resat birth . Immune at birth . For exaat birth . Micronuat birth . The comat birth .In the past decade, substantial advances in experimental approaches to study the microbiome have been used to demonstrate a causal association between dysbiosis in the gut and malnutrition . Hoin vitro. Addition of Vitamin A to monocyte cultures treated with BCG led to an inhibitory histone methylation mark (H3K9me3) that suppressed monocyte cytokine responses upon re-stimulation relative to monocytes treated with BCG alone  is present and associated with colonization with pathogenic microorganisms, dysbiosis, innate leukocyte recruitment, and reduced gut functional capacity . Not allStudies among children hospitalized with SAM suggest that systemic and intestinal inflammation independently contribute to mortality , 43, 44.Inclusion of functional analysis of immune cells in cohort studies of children in LMIC is uncommon. Of the studies conducted, many demonstrate innate and adaptive immune cell dysfunction during undernutrition [summarized in a systematic review by Rytter et al. ]. HowevePlasmodium parasites has shaped a distinct myelopoietic niche in the bone marrow resulting in a characteristic neutropenia among the majority of people of African ancestry . The interaction between HIV, inflammation and undernutrition was demonstrated in a recent study of children starting antiretroviral therapy in Uganda and Zimbabwe . A propory alone . CarefulNo studies to our knowledge have assessed innate immune cell function in stunting in LMIC beyond soluble inflammatory biomarkers (discussed above). There has also been limited assessment of innate immune cell function in undernourished tissues, with an understandable majority of studies focusing on more readily accessible innate immune cells in peripheral blood. Despite the limitations of existing studies, a number demonstrate innate immune cell dysfunction in undernutrition  and basal (from the lamina propria) signaling via polarized expression of receptors and tight regulation of membrane permeability. Immunohistochemical analysis of intestinal biopsy specimens indicates that this regulation by epithelial cells is disrupted in children with SAM  in gut biopsy specimens from severely undernourished Gambian children compared to adequately-nourished controls from the same community . Epithelsphatase \u2014a mechansphatase . Murine nfection . Intestinfection . After enfection . Defectsnfection . Thus, bDisrupted epithelial cell responses have also been observed in enteropathy associated with other health conditions. For example, diabetic enteropathy in adults causes defects in colonic epithelial stem cell mobilization due to reduced levels of circulating IGF-1 and IGFBP3 , both ofper se . In a sin vitro ; both dein vitro . Interfein vitro . The assin vitro , 8 and din vitro , suggestin vitro, even when NK-to-tumor cell ratios were high  or antibody ligation of NK1.1 surface antigens relative to NK cells isolated from ad libitum-fed controls  share some of the functions of adaptive T cells, but respond to challenges with the rapid kinetics of innate immune cells [reviewed by Eberl et al. ]. NK celIn this review we have outlined knowledge gaps in the function of all innate immune cell types during childhood undernutrition. A concerted effort is needed to translate immunological paradigms from animal models into human cohort studies. Furthermore, whilst assays of soluble immune biomarkers, proteome, transcriptome, epigenome, and metabolome profiling in peripheral samples provide insights into immune and immune-metabolic derangement, direct measurements of immune function will rely on cell- and tissue-based assays. In the long-term, developing high-quality assays of innate immune cell function for well-powered population studies in LMIC will rely on leveraging existing laboratory capacity for immunology research and developing capacity where it is not currently available. Such efforts would be accelerated by adaptation of existing technologies for assessing immune cell function in high-income settings to affordable standardized field-deployable formats. Cohort studies of innate immune function should be: (i) powered adequately to detect differences in highly heterogeneous immune responses; (ii) longitudinal in design to distinguish short-term fluctuations from persistent functional defects; and, (iii) ideally nested within studies that also characterize concurrent immunological stimuli , which are necessary to accurately interpret immune cell behavior. To identify localized changes in innate immune cells and learn more about the function of tissue-resident cells during undernutrition, sampling from a more diverse range of anatomical sites will be necessary. For example, despite respiratory tract infections being a frequent cause of mortality among undernourished children , we knowBeyond understanding the basic immunology of childhood undernutrition, developing novel therapies targeting innate immune dysfunction will require cohort studies to assess whether innate immune cell function is associated with clinical outcomes, and identify the pathways that lead to dysfunction. Identifying immune biomarkers of prognostic value for stunting, wasting and infectious mortality has proven challenging to-date due to the multiple mediators that are simultaneously altered , 10, 12.vice versa has been bolstered by studies of nutrient deprivation in animals  Environmental toxin exposure, such as exposure to mycotoxins derived from molds that contaminate staple crops, which is extremely common amongst pregnant mothers and children in some settings . SeveralExisting studies have been critical to our understanding of innate immune cell function in childhood undernutrition, but considerable knowledge gaps remain. Studies among undernourished children demonstrate impairments in a range of innate immune responses, but the pathways underlying these defects are unclear. Experimental animal models provide a clearer picture of how individual features of the undernourished state  can drive changes in innate immune cell function, but do not recapitulate the multiple simultaneous immune challenges that are typical during childhood undernutrition in LMIC. It is increasingly apparent that novel therapeutic approaches are required to improve health outcomes for children with undernutrition, given the complex pathology that underlies wasting and stunting. Since infections are the leading cause of death , a betteCB wrote the manuscript with input and critical commentary from KJ and AP.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Family caregivers of persons with dementia experience guilt for various reasons when placing their family member into residential long-term care (RLTC). Research has shown a relationship between guilt and overall caregiver burden; however, literature on predictors of guilt related to caregiving following RLTC placement is limited. The Residential Care Transition Module (RCTM) provides counseling and psychoeducation to family caregivers who have recently moved their family member with Alzheimer\u2019s disease or a related dementias into RLTC. This semi-structured intervention provides counseling on various topics including guilt, grief, and family dynamics. Using treatment group data (N=87) from the parent RCTM randomized controlled trial, we identified the impact of caregiver status , sense of caregiver competence, and relationship closeness on baseline measures of guilt status and magnitude. Preliminary analyses showed that adult child status was associated with greater prevalence of guilt (37.5%) compared to spousal caregivers (26.7%). In addition, qualitative case notes were coded to identify common themes of experiences of guilt to inform practice. Examples include: Guilt related to no longer being able to care for the family member at home; not meeting self-dictated expectations ; and feeling guilted into being a caregiver in the first place. The current analyses aim to help practitioners better predict risk for placement-related guilt and highlight specific issues practitioners should consider to help mitigate such feelings. Specific opportunities for intervention are discussed."}
+{"text": "Modifying neighborhood environments to target well-established risk factors for cardiovascular disease may reduce health disparities by complementing clinical services. Prior research, however, includes limited measures of neighborhoods and does not adequately account for individual-level processes known to mediate health outcomes. We combine baseline data from the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) dataset with neighborhood-level data to yield a diverse sample of Black and white middle-aged and older residents of Baltimore City (N=2707). We use structural equation modeling to examine associations between neighborhood environments and obesity (BMI>=30), focusing on individual-level mediators. Initial direct associations between neighborhoods and obesity  are mediated by healthcare access and health behaviors. Additional indirect pathways exist through health behaviors . These findings highlight the importance of considering indirect pathways to cardiovascular health promotion among aging adults in different neighborhood contexts."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Incomplete spinal cord injury typically results in life-long disability, often in the form of profound loss of locomotion capability. Individuals who have experienced incomplete spinal cord injury exhibit persistent eccentric motor deficits, which are particularly prevalent in the weight acceptance phase of gait and emphasized in sagittal plane knee motion and frontal plane hip motion. METHODS/STUDY POPULATION: Motion analysis can capture the kinematic and joint-level deficits of these individuals, but it is impossible to directly calculate the contributions of individual muscles to weight acceptance due to the complexity of the musculoskeletal system. Instead, those muscle contributions must be simulated in order to approximate muscle power during locomotion. RESULTS/ANTICIPATED RESULTS: The traditional method for driving these simulations with electromyography readings is unavailable for individuals who have neuromuscular deficits , due to the need to generate reliable maximum voluntary isometric contractions for baseline purposes. Instead, this research develops a novel method for using resting electromyography data to drive musculoskeletal simulations using a muscle activation threshold paradigm. DISCUSSION/SIGNIFICANCE OF IMPACT: The simulation results of this method more closely resemble experimental results, but further simulation refinement is needed to fully capture the true muscle activity."}
+{"text": "A 69-year-old man presented with precordial pain and a dilated ascending aorta with the suspicion of an intramural hematoma. At emergency operation, the aorta appeared grossly thickened with diffuse intimal scarring. Retrospectively, the patient tested positive to serologic screening for syphilis with histologic findings also compatible with a syphilitic aortitis. A 69-year-old man, previously asymptomatic and with an unremarkable clinical history, presented with dyspnea and precordial pain at our emergency unit. He denied any risky sexual behavior and did not show any signs or symptoms related to secondary syphilis. An angio computed tomographic (CT) scan showed a fusiform aneurysm of the ascending aorta with a maximum diameter of 65\u2009mm, with a thickened wall raising the suspicion of an intramural hematoma . Other Histology of the aortic wall showed full-thickness infiltrates involving all layers with adventitial fibrosis surrounding thickened vasa vasorum ,B witAortitis is the main manifestation of a syphilitic cardiovascular infection, but aortic aneurysms due to tertiary infection are substantially uncommon in the modern era;Syphilitic aortitis is usually diagnosed combining histologic and laboratory data, although cases of negative laboratory testing have been reported.Our experience demonstrates that luetic infection still remains a potential cause of ascending aortic aneurysms."}
+{"text": "One consequence of modern longevity is the growing number of older adults with very old parents. While family members are often interdependent in their development and aging, less is known about how intergenerational relationships may influence individuals\u2019 attitudes toward their own aging in later life. Using 70 dyads of oldest-old parents (Mage = 93) and their children (Mage = 67) from the Boston Aging Together Study, we examined the dyadic concordance in positive attitudes toward own aging, and how perceptions of giving and receiving care are associated with attitudes toward own aging for parents and children. On average, parents reported more negative attitudes toward own aging than did children. In less than half of all dyads (46%), both parents and children reported positive  attitudes toward own aging. T-test results showed that the dyads with positive attitudes toward own aging had more within-dyad age difference, better average self-rated health, fewer depressive symptoms and less loneliness than others. For children, higher level of caregiver\u2019s burden was associated with more negative attitudes toward own aging. For parents, perception of received support was not associated with their attitudes toward own aging. This study sheds light on how both individual and family characteristics may influence individuals\u2019 aging perceptions. Findings suggest the context of parent-child ties may particularly be relevant to those older adults who may have to deal with their own aging- related challenges as well as those of their parents."}
+{"text": "When students from two or more professions learn about, from, and with one another in joint learning activities, interdisciplinary perceptions and attitudes improve and collaborative knowledge and skills increase.3 Most, more or less, hinge on the development of competencies deemed necessary for effective collaborative practice, such as communication and ethical values.The contribution of these skill sets to the positive and productive function of patient care teams is both apparent and universal. For example, abilities to listen and constructively consult, discuss, and debate are obvious elements for collegial interactions. Respecting patient dignity and maintaining confidentiality reflects a commitment to professional conduct and engenders trusting relationships. Such behaviours and attitudes are further recognized as collective competencies given they have been adopted by many North American health professional training programs as discipline-specific educational outcomes. By both accounts, these principles also apply to the scholar competency role.Different frameworks exist to guide integration of IPE programming into health professional curricula worldwide.4Similarly, the American Association of Medical Colleges outlines an entrustable professional activity milestone whereby trainees \u2018form clinical questions and retrieve evidence to advance patient care\u2019.5Albarqouni et al recently enlisted over 200 multidiscipline clinicians and academics from 28 countries to agree upon a set of evidence-based practice competencies for health professional teaching and learning.6 Through Delphi survey and consensus processes,they arrived at a set of 68 core competencies further organized into introductory concepts and five main evidence-based practicesteps including: ask, acquire, appraise and interpret, apply, and evaluate.While the authors acknowledge somecompetencies likely require modification to suit specific needs of any given discipline, most are indeed fundamental skills broadly applicable across professions. Examples include converting clinical questions into structured, answerable formats; constructing and carrying out an appropriate search strategy; distinguishing evidence-based from opinion-based clinical practice guidelines; explaining the evidence to patients and integrating their preferences into decision-making processes; and managing clinical decision-making uncertainty in practice. The consensus statement represents an important step towards unifying expectations of evidence-based practice. The details can guide instructional and assessment design and delivery in health professional curricula and for a number of programs, these may fall within the scholar competency role  .From 50 years agowhen McMaster University launched a novel medical program where students first learned about patient problems concurrent with epidemiology and biostatistics, Canadian physicians-in-training today are meant to \u2018identify pertinent evidence, evaluate it using specific criteria, and apply it in their practice\u2019 as part of the scholar competency role.nt care) .7 That is, how are these competencies truly interprofessional in nature and not simply common skills expected by many different professions? First, this set of competencies is an acknowledgement that a majority of professionals employ evidence-based practice in patient care. Although decision-making may occur within the discrete scope of a profession\u2019s practice, we can be assured of a common language when this care is informed by reported literature, such as randomized controlled trials, meta-analyses, or clinical practice guidelines. Like the fundamental aspects of interprofessional communication  these competencies represent an opportunity for standardization of practice principles across patient care providers. Furthermore, when teams of various disciplines convene to develop treatment protocols or care pathways, there is a shared understanding of how the evidence under consideration may be interpreted.Clinicians may enlist similar approaches to navigate incomplete available data or ambiguous study findings to make treatment choices.If as Nandiwada&Kormos further contend, this work substantiates the existence and importance of evidence-based practice competencies across health professions, howdo they expressly promote shared or collaborative care?Interprofessional competencies are meant to promote collaborative care that ultimately improves patient outcomes. Integration of evidence-based competencies into shared decision-making clearly has the potential to do so. Patient adherence may be enhanced when care providers can clearly explain the data underpinning the rationale for the selected treatment and offer realistic estimates of potential risk. Clinicians who can interpret and synthesize a wide array of literature may have greater abilities to individualize care while also incorporating patient preferences. In this regard, optimal evidence-based practice must be enabled by the communication and collaboration skills endorsed by both profession-specific and interprofessional competency frameworks. Just as effective team-based care must draw upon the collective contributions of its diverse members, quality healthcare also relies on this complement of a clinician\u2019s knowledge, skills, and behaviors."}
+{"text": "Aortic dissection is the most devastating sequelae of aortopathy other than aortic rupture. However, aortic dissection can be asymptomatic in the acute phase with delayed symptomatic presentation or incidental diagnosis upon chest imaging. We report a case of a 63-year-old male who was diagnosed with pericardial effusion upon preoperative workup for elective cholecystectomy. Further investigations confirmed hemorrhagic pericardial effusion secondary to a chronic dissecting ascending aortic aneurysm. The patient condition was successfully managed with open surgical repair with an uneventful postoperative course. This case demonstrates an extremely rare presentation of incidental hemorrhagic pericardial effusion caused by a chronic dissecting ascending aortic aneurysm. A 63-year-old male with a history of hypertension, 20 pack-years of smoking, thyroid cancer in remission with partial thyroidectomy, and chronic obstructive lung disease (COPD) presented to the emergency department (ED) with acute abdominal pain. Abdominal ultrasound showed gallstones with no evidence of cholecystitis or biliary obstruction. The patient was diagnosed with biliary colic and discharged home with a plan to perform an elective cholecystectomy. Computed tomography (CT) scan of the abdomen was performed as an outpatient as part of the preoperative workup which showed evidence of gallstones, small bilateral pleural effusions, and moderate pericardial effusion with high density suggestive of hemorrhage . ConsequAcute Stanford type A aortic dissection (AD) is a life-threatening condition that serves as an impetus to immediate surgical repair aiming to prevent dissection-associated complications such as acute aortic regurgitation, aortic rupture, myocardial or cerebral ischemia, and pericardial tamponade . HoweverThe first clue for CTAD diagnosis was the detection of high-density pericardial effusion note on abdominal CT scan before elective cholecystectomy. Given the lake of symptoms, transudation of fluid across the wall of the false lumen into the pericardial cavity is the most plausible mechanisms. Also, hemopericardium in our case could be a sign of silent contained rupture.All patients with aortic dissections will need immediate surgical evaluation independent of location . PatientOur patient had an aorta diameter of 7.5 cm; furthermore, his dissection was complicated by hemorrhagic pericardial effusion and moderate aortic regurgitation. Thus, the open surgical repair was the chosen approach. According to a recent review of a 696 type A patients, following open repair, patients with CTAD had lower in-hospital mortality and longer five- and ten-year survival compared to the acute type A dissection patients [Chronic type A aortic dissection is a challenging diagnosis with a wide range of clinical presentations including incidental hemorrhagic pericardial effusion. Pericardial puncture in pericarial effusion complicating type A dissection can result in the propagation of the rupture. Accordingly, obtaining a CT scan of the chest prior to any diagnostic pericardial puncture is highly recommended. Surgical repair is the treatment of choice for complicated chronic type A aortic dissection."}
+{"text": "Promoting healthy aging does not end when people enter skilled nursing facilities (SNF) where the demands for clinical and psychosocial care are likely to be greatest. Many chronic conditions present opportunities for better SNF care and thus, healthier aging. Such conditions cannot wait for the often-long path to discovery that is typical of most traditional randomized controlled clinical trials. Conversely, pragmatic clinical trials are real-world investigations that offer the possibility of immediate benefit while answering important research questions. Depression and disrupted sleep are two examples of treatable conditions with opportunities for immediate benefit through pragmatic trials and applied best practices. How best to support best-practice integration has received increasing attention but identifying the most effective strategies continues to evolve. We report two different SNF-mentorship models utilizing Minimum Data Set (MDS) data for depression and environmental (noise-level) data for disrupted sleep, which have supported better SNF practices and presumably, healthier aging."}
+{"text": "Although CGRP has been implicated in numerous physiological processes , the precise physiological roles of CGRP remain to be elucidated. To provide a better understanding of the physiological role(s) mediated by this peptide neurotransmitter, we have generated aCGRP-null mice by targeted modification in embryonic stem cells."}
+{"text": "A 54-year-old man presented to the emergency department with confusion and Parkinsonian features after suspected heroin snorting. He had magnetic resonance imaging of the brain demonstrating isolated symmetric bilateral globus pallidus (GP) restricted diffusion and edema consistent with hypoxic ischemic encephalopathy. In contrast to other anoxic/ischemic insults, where the GP is preferentially spared, autopsy reports on intravenous heroin users have found the GP to be specifically affected, often demonstrating symmetric bilateral lesions. Opioid toxicity should be considered in patients presenting with Parkinsonian features on examination or pallidal lesions on imaging, especially in younger adults where infarction is less common. On arrival to the ED he was awake but confused and noted to have bilateral upper and lower extremity rigidity along with sustained clonus, hyperreflexia in upper and lower extremities, and complained of \u201cfoot cramping.\u201d A non-contrast computed tomography of the brain was normal (A 54-year-old man presented to the emergency department (ED) after receiving naloxone for a suspected opioid overdose. He was found in bed unresponsive, hypoxemic to SpOs normal . Brain ms normal .In autopsies on patients with heroin use disorder, bilateral GP lesions were noted to be frequently encountered.The patient was admitted to the hospital where he admitted to snorting heroin powder. He had resolution of his symptoms by hospital day five. Hypoxic ischemic insult, including opioid toxicity, should be considered in patients with Parkinsonian features on exam and/or isolated pallidal lesions on imaging without history of overt cardiorespiratory arrest, especially in adolescents and younger adults where infarction is less common.What do we already know about this clinical entity?Bilateral Globus Pallidus (GP) lesions have been noted in autopsies of patients with heroin use disorder. The etiology is unclear as anoxic-ischemic insults typically affects other brain areas.What is the major impact of the image(s)?Toxin induced Globus pallidus injury is a recognized finding in carbon monoxide, methanol, and cyanide poisoning. This magnetic resonance imaging finding should prompt a differential that includes opioid use.How might this improve emergency medicine practice?Recognition of GP lesions may identify a patient at high risk of future opioid related injury or death; who would benefit from counseling, substance use referral, and other resources."}
+{"text": "RESULTS/ANTICIPATED RESULTS: Results: The symptom of auditory hallucination was significantly more endorsed in AA bipolar patients than EA bipolar patients . Conversely, the symptom of elevated or euphoric mood was significantly less endorsed in AA bipolar patients than in EA patients . AA, in comparison to EA bipolar patients, had a significantly higher prevalence of lifetime exposure to haloperidol  and fluphenazine . In contrast, AA, in comparison to EA bipolar patients, had a significantly lower prevalence rate of lifetime exposure to lithium , and lamotrigine . DISCUSSION/SIGNIFICANCE OF IMPACT: Conclusion: The higher rate of psychotic symptom endorsement and lower rate of core manic symptom endorsement represent differential illness presentation that may contribute to misdiagnosis in African-American bipolar patients. The higher rate of high potency typical antipsychotic treatment and lower rate of classic mood stabilizing treatment may also contribute poorer bipolar treatment outcome. While structured diagnostic interviews are the gold standard in diagnostic confirmation, this study is limited by lack of knowledge of clinician/expert interviewer interpretation of symptom endorsement which may contribute to symptom misattribution and misdiagnosis. Incorporation of additional African American participants in research is a critical future direction to further delineate symptom presentation and diagnosis to serve as validation for these results.OBJECTIVES/SPECIFIC AIMS: Learning Objectives of this session: Identify possible reasons for misdiagnosis of bipolar patients of African ancestry by reviewing differences in symptom presentation between African American (AA) and European American (EA) bipolar individuals. Introduction: Bipolar disorder is a chronic mental illness with a prevalence rate up to 5.5% of the US population and is associated with substantial personal and economic morbidity/mortality. Misdiagnosis is common in bipolar disorder, which can impact treatment and outcome. Misdiagnosis disproportionally affects racial/ethnic minorities; in particular, AAs are often misdiagnosed with schizophrenia. There is interest in better understanding the contribution of differential illness presentation and/or racial bias to misdiagnosis. METHODS/STUDY POPULATION: Patients and Methods Utilizing the Genetic Association Information Network (GAIN) public database, this study compared clinical phenomenology between bipolar patients of African Versus European ancestry (AA=415 vs. EA=1001). The semi-structured Diagnostic Interview for Genetic Studies (DIGS) was utilized to evaluate individual symptom endorsement contributing to diagnostic confirmation. A \u03c7"}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Modulation of autophagy has the potential to treat inflammatory bowel disease (IBD). IBD is characterized by dysregulated inflammatory pathways and a defective intestinal epithelial barrier. We sought to better understand how autophagy can be utilized to regulate both inflammation and the intestinal barrier. METHODS/STUDY POPULATION: We examined mice with an autophagy defect in only macrophages in an animal model of IBD. To understand the phenotype, we utilized macrophages to investigate the mechanism behind autophagy and proinflammatory cytokine secretion. In addition, we analyzed the development of colonoids in a co-culture system with macrophages with or without a functional autophagy pathway. Lastly, pharmacological modulation of autophagy to control inflammation was assessed. RESULTS/ANTICIPATED RESULTS: Mice with autophagy-deficient macrophages were highly susceptible to intestinal barrier disruption. Susceptibility was due to enhanced proinflammatory cytokine secretion and intestinal permeability. Furthermore, proinflammatory macrophages (due to an autophagy defect) co-cultured with colonoids, significantly decreased the number of mucus producing goblet cells. Finally, pharmacologically modulation of autophagy reduced the secretion of proinflammatory cytokine by macrophages and reduced intestinal permeability. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results strongly suggest autophagy modulation can dampen inflammation and enhance the intestinal epithelial barrier."}
+{"text": "Older adults are at risk for altered nutritional status and functional impairment due to physiological  and psychosocial factors . Those with alterations in nutritional and/or functional status are at risk for poor health outcomes-including delayed healing of chronic wounds. We will discuss our lessons learned when devising nutrition assessment protocols from our ongoing double-blind randomized control clinical trial testing the effectiveness of ultrasound treatment on healing chronic leg wounds. The discussion will focus on the following measures: the Mini-Nutritional Assessment, hand-grip strength assessment, and inflammatory biomarkers."}
+{"text": "Oral history narratives of nine childless centenarians  from the Oklahoma 100 Year Life Project were reviewed to investigate loneliness. Oral history narratives were assessed qualitatively, using content analysis to determine themes. We predicted that childless centenarians would feel lonely due to \u201celder orphanhood.\u201d Findings revealed little indication of loneliness. Centenarians admitted they voluntarily chose to remain childless due to raising siblings earlier in life or delaying marriage. However, most remained socially well-adjusted and connected to extended family, particularly nieces. When confronted by social network losses due to death or relocation, most adapted by actively seeking and forming new relationships. In some cases, childless centenarians remained gainfully employed and working. Childlessness does not appear to make centenarians lonely. Rather, purposeful pursuit of intrapersonal and interpersonal sources of lifelong emotional contentment may render childless centenarians immune from conditions of loneliness."}
+{"text": "Foreign body ingestion is an important problem in adult with psychological disorders. In literature ingestion such as fish bone, fork and several metallic elements were reported. The first attempt, after diagnosis, is endoscopic removalA 25-year-old male deaf patient was admitted in emergency department with complaint of abdominal pain and unable to communicate anything of his clinical history. Physical examination was normal except an epigastric tenderness. Laboratory results were normal. Direct radiography revealed a circular shaped metallic object in stomach and other several metallic objects in gastrointestinal tract A. An emeA delay in the diagnosis an dextraction of sharp or large sized foreign objects can lead to severe complications including mucosal laceration, obstruction, hemorrhage, and perforation. Therapeutic esophagogastroduodenoscopy with an esophageal overtube should be the first choice retrieval of large sized foreign bodies to avoid mucosal laceration, perforation and the surgical treatment."}
+{"text": "Negative affect (NA) and positive affect (PA) vary from moment-to-moment and these variations are associated with cognitive health. Past work has primarily focused on valence (negative/positive), however, largely ignoring the potential import of arousal (high/low). We address this gap by assessing the impact of high and low arousal NA and PA on daily cognition. A sample of 238 older adults  completed mobile surveys up to four times daily for 14 days. Participants reported current levels of high and low arousal NA and PA and performed processing speed and working memory tasks. For processing speed, there were significant within-person affect by age interactions. Moments when low arousal NA was higher than usual were associated with slower processing speed , and this effect was amplified in older participants . Moments when high arousal PA was higher than usual were associated with faster processing speed , and this effect was amplified in younger participants . For working memory, a significant within-person high arousal PA by age interaction emerged  such that moments when high arousal PA was higher than usual were marginally associated with worse working memory performance only among older participants . Results suggest momentary increases in low arousal NA and high arousal PA may confer greatest risk to daily cognitive health among older adults with more limited capacity and/or cognitive resources, whereas affective influences may be more facilitative among comparatively younger adults."}
+{"text": "Carpopedal spasm have various causes ranging from dsyselecrolytemia, syndromic, metabolic or endocrine causes. Any of these could cause a decrease in ionized calcium and tetany. Excessive vomiting leading to alkalosis, hypokaleamia and decreased ionised calcium should be kept in mind for early etiological diagnosis of carpopedal spasm. We report a case of 4-year-old boy presenting with a history of recurrent painful spasm and flexion of bilateral hands following excessive vomiting and electrolyte derangement. Carpopedalspasms are frequent and involuntary muscle contractions in the hands and feet with associated pain. Hypocalcemia, low calcium levels can cause carpopedal spasms as a warning sign . It occu2. Abdomen is flat, soft and moves with respiration. Vital signs are normal and physical examination revealed mild dehydration as evidenced by dry oral mucosa, and tender bilateral carpopedal spasm (A 4-year-old boy was brought to the children emergency department of Wesley Guild Hospital Ilesa with painful spasm and flexion of bilateral hands . He had al spasm . LaboratIonized calcium was the active form responsible for tetany . AlkalosExcessive vomiting leads to alkalosis, hypokaleamia and decreased ionised calcium and carpopedal spasm. Hence, serum electrolyte including serum calcium, magnesium, potassium and bicarbonate should be done promptly in all patients with persistent vomiting from any cause to detect dyselectrolytemia early and forestall late complication such as carpopedal spasm and tetany.The authors declare no competing interests."}
+{"text": "The term, ageism, refers to any form of personal or institutional prejudice or discrimination based on chronological age. Ageism may encompass attitudes and prejudices, as well as behaviors, highlighting the complex nature of ageist behaviors observed among students and professionals alike . We examined the prevalence of self-reported ageist behaviors in a sample of college students who ranged in age from 18 to 44 years to test the hypothesis that aging knowledge would be associated with self-reported ageist behaviors (positive and negative). The study sample was comprised of adults who were enrolled in classes at Louisiana State University (n = 110). Most of these students were traditional aged college students (18-25 years old). Participants completed the Relating to Older People Evaluation , the Facts on Aging Quiz , and the Knowledge of Memory Aging Questionnaire . Results indicated that positive ageist behaviors were more frequent than negative ageist behaviors. Men endorsed positive and negative ageism items more than women reported. Follow-up analyses on participants\u2019 responses to the two aging knowledge questionnaires showed that increased knowledge of aging was significantly correlated with diminished reports of negative ageist behaviors, after controlling for age and gender. These results imply that self-reported ageist behaviors are associated with aging knowledge. Strengthening college curricula by including course offerings in adult development and aging may improve self-reported ageist behaviors among college students."}
+{"text": "Receptor-mediated gene delivery capitalises on the presence of specific cell surface molecules for DNA uptake into cells and represents a particularly appealing approach for targeting vector DNA to specific cell types in vivo and in vitro. Various ligand/DNA and antibody/DNA transfer complexes were generated that, following binding to cells, are internalised and reach the endosomal compartment. Vector complexes contain endosomolytic components that ensure vector release from the endosome and translocation of vector DNA into the nucleus where transcription occurs. Thus, receptor-mediated gene delivery encompasses several critical steps that must be considered when designing and applying such vector systems."}
+{"text": "Magnetotactic bacteria biomineralize intracellular magnetic nanocrystals surrounded by a lipid bilayer called magnetosomes. Due to their unique characteristics, magnetite magnetosomes are promising tools in Biomedicine. However, the uptake, persistence, and accumulation of magnetosomes within mammalian cells have not been well studied. Here, the endocytic pathway of magnetite magnetosomes and their effects on human cervix epithelial (HeLa) cells were studied by electron microscopy and high spatial resolution nano-analysis techniques. Transmission electron microscopy of HeLa cells after incubation with purified magnetosomes showed the presence of magnetic nanoparticles inside or outside endosomes within the cell, which suggests different modes of internalization, and that these structures persisted beyond 120 h after internalization. High-resolution transmission electron microscopy and electron energy loss spectra of internalized magnetosome crystals showed no structural or chemical changes in these structures. Although crystal morphology was preserved, iron oxide crystalline particles of approximately 5 nm near internalized magnetosomes suggests that minor degradation of the original mineral structures might occur. Cytotoxicity and microscopy analysis showed that magnetosomes did not result in any apparent effect on HeLa cells viability or morphology. Based on our results, magnetosomes have significant biocompatibility with mammalian cells and thus have great potential in medical, biotechnological applications. C) STEM-HAADF image of magnetosomes inside endosome, showing crystalline structures near the magnetosome (white square) displayed with greater exposure on the inset. D) Higher magnification of the region indicated by the square in (C) showing a crystalline structure near the magnetosome; inset shows FFT corresponding to the white square area, with a plane lattice distance of (TIF)Click here for additional data file."}
+{"text": "Aging the detrimental molecular changes that occur in lymphatics with age [The diverse etiologies of age-related diseases, from osteoarthritis to Alzheimer\u2019s disease, all share an impairment, or slow loss, of tissue function. Aging tissue homeostasis shifts towards progressive, low-grade inflammation and a dampened immune response. The lymphatic vasculature is the key regulator of tissue homeostasis in health and disease. Lymphatics transport antigens and other macromolecules, excess interstitial fluid, and activated immune cells during inflammation. Shang and colleagues recently reviewed for with age . Here weAging review \u201cPathophysiology of aged lymphatic vessels\u201d, Shang and authors have summarized research focused on lymphatic collecting vessels finding that lymphatic muscle contractions are reduced in amplitude and frequency and can become irregular with age [Lymphatic vessels are structurally quite different from blood vessels, beginning with blind-ended capillaries possessing leaf-like cell junctions that lead to large, unidirectionally-valved collecting vessels. These larger vessels are surrounded by lymphatic muscle cells that provide intrinsic pumping to maintain lymph flow. In their with age . The Gaswith age ,2. They Chronic tissue degeneration is a common feature of age-associated disorders like osteoarthritis (OA). A series of collaborative studies from the Schwarz and Xing groups have extensively detailed lymphatic involvement in several models of arthritis. They have demonstrated that inflammatory lymphangiogenesis and increased pumping initially facilitate the removal of immune cells and fluid to the draining lymph nodes, but that over time lymphatics regress and collecting lymphatic vessels lose contractility . In theiRecently mapped pathways by which fluid and immune cells enter lymphatic vessels may play important roles in neurological decline, notably in Alzheimer\u2019s disease (AD). The Proulx laboratory used near infrared dynamic imaging of macromolecule transport to identify several outflow pathways for the egress of cerebral spinal fluid (CSF) to lymphatics . FurtherCardiovascular (CV) disease and diabetes are progressive pathologies whose diagnoses increase with age, and the side effects, treatment, and recovery are more difficult to manage in older patients. Lymphatic vessels have demonstrated a critical role and therapeutic potential in several CV pathologies including atherosclerosis, myocardial infarction, hypertension, and diabetes . AtherosIn conclusion, the pathophysiology of aging lymphatic vessels reviewed by Shang and colleagues reduces lymphatic fluid clearance, immune migration, and inflammatory responsiveness. Research in several disease models including osteoarthritis, Alzheimer\u2019s disease, and CV disease has identified that enhancing lymphatic function may provide therapeutic benefit. Understanding the mechanisms of lymphatic decline and identifying maintenance or therapeutic regimens targeting lymphatic physiology is therefore important in addressing age-related disease."}
+{"text": "Pinus ponderosa) forests. However, the extent, characteristics, and predictability of ponderosa pine fire refugia are largely unknown. Within 23 fires in ponderosa pine-dominated forests of the Colorado Front Range (1996\u20132013), we evaluated the spatial characteristics and predictability of refugia: first using Monitoring Trends in Burn Severity (MTBS) burn severity metrics, then using landscape variables . Using 1-m resolution aerial imagery, we created a binary variable of post-fire conifer presence (\u2018Conifer Refugia\u2019) and absence (\u2018Conifer Absence\u2019) within 30-m grid cells. We found that maximum patch size of Conifer Absence was positively correlated with fire size, and 38% of the burned area was \u2265 50m from a conifer seed source, revealing a management challenge as fire sizes increase with warming further limiting conifer recovery. In predicting Conifer Refugia with two MTBS-produced databases, thematic burn severity classes (TBSC) and continuous Relative differenced Normalized Burn Ratio (RdNBR) values, Conifer Absence was high in previously forested areas of Low and Moderate burn severity classes in TBSC. RdNBR more accurately identified post-fire conifer survivorship. In predicting Conifer Refugia with landscape variables, Conifer Refugia were less likely during burn days with high maximum temperatures: while Conifer Refugia were more likely on moister soils and closer to higher order streams, homes, and roads; and on less rugged, valley topography. Importantly, pre-fire forest canopy cover was not strongly associated with Conifer Refugia. This study further informs forest management by mapping post-fire patches lacking conifer seed sources, validating the use of RdNBR for fire refugia, and detecting abiotic and topographic variables that may promote conifer refugia.Forested fire refugia (trees that survive fires) are important disturbance legacies that provide seed sources for post-fire regeneration. Conifer regeneration has been limited following some recent western fires, particularly in ponderosa pine ( We determined connectivity of Conifer Refugia and Conifer Absence patches by grouping contiguous pixels of the same classification using an eight-cell neighborhood . To determine whether the proportion of Conifer Refugia within fires changed over the study period, we analyzed the percent area of Conifer Refugia in each fire and used ordinary least squares regression to test the significance of a temporal trend 1996\u20132014 (\u03b1 = 0.05) . To deteTo inform local management plans for potential post-fire recovery programs, we evaluated the reliability of two readily available MTBS databases to represent the locations of post-fire surviving conifers. We calculated the TBSC  and RdNBR values for pixels of Conifer Refugia and Conifer Absence across all fires. We graphed the percent of Conifer Refugia and Conifer Absence in different thematic burn severity classes. We assessed the power of TBSC and RdNBR to predict Conifer Refugia and Conifer Absence in a Classification and Regression Tree model (CART) in R ,70. CARTTo examine factors influencing patterns of Conifer Refugia and Conifer Absence, we first constructed spatial overlays with Pre-fire Forest Cover and daily fire weather variables and compared the distributions in the two classes across equal interval bins of each predictor variable. These descriptive statistics aided in interpretation of subsequent predictive models and associated predictor importance.To assess how well weather, anthropogenic, abiotic, and biotic factors predict the locations of Conifer Refugia and Conifer Absence, we used Random Forests  in R R ,73. We tOver 147,000 ha were mapped within the 23 fire perimeters in ponderosa pine-dominated forests of the CFR from 1996\u20132013 . For all2 = 0.85, p \u22640.0001, The proportion of Conifer Refugia within fire perimeters did not significantly decrease or increase over time between 1996 and 2013 p \u22650.05, . We founBoth TBSC and RdNBR maps showed relationships with the locations of Conifer Refugia and Conifer Absence across the study area . Within Overlays of fires with Pre-fire Forest Cover reveal that 95% of the total burned area had pre-fire forest cover (>1%), with over half (55%) of the total area having dense pre-fire forests  aerial imagery to map post-fire Conifer Refugia within 23 fires that burned ponderosa pine-dominated forests of the CFR from 1996\u20132013 allowed us to thoroughly examine the spatial characteristics and predictability of Conifer Refugia in this region. Our study of post-fire surviving trees found that over one-third of the area burned in the CFR resulted in large contiguous patches without surviving trees at distances greater than the common dispersal distance of ponderosa pine seeds, presenting a potential forest recovery challenge. We generally found that abiotic and topographic landscape variables, many indicative of moister microsites, were the most important predictors of conifer refugia, except under high maximum temperatures and the most extreme fire weather, in which case conifers were generally less likely to survive. The lack of a strong relationship between pre-fire forest cover and post-fire Conifer Refugia may have strong implications for forest management aimed at increasing the resilience of ponderosa pine to wildfire through tree thinning. We recommend prioritizing RdNBR over TBSC as a management tool to more accurately identify post-fire conifer refugia, evaluate patch metrics of surviving post-fire conifers, and plan for post-fire recovery.Post-fire forested refugia are important disturbance legacies providing seed sources and microsites for recovery of ponderosa pine forests ,22,24,75Evaluating both the spatial and temporal trends in Conifer Refugia proved critical to understanding the potential effectiveness of these legacies in promoting post-fire recovery. We found a consistent proportion of Conifer Refugia across time in the CFR, similar to findings during the last two decades in the northern Rockies . AlthougIn the Southern Rockies, from 1984 to 2006 there was a trend of increasing area burned , which mLimited long-distance dispersal into high-severity patches has been documented . Such diThe use of high-resolution imagery allowed us to accurately map conifers at very low densities and thoroughly evaluate the ability of coarser scale burn severity indices to detect these conifer refugia. We found that post-fire conifer refugia are not consistently detected by MTBS TBSC and that these classes generally under-estimated conifer loss in the ponderosa pine cover type in our region. Although thematic burn severity metrics typically capture changes in all organic matter above and below ground, such as soil, understory vegetation, and canopy mortality , we focuRdNBR provided a more robust method for detecting post-fire surviving conifers and we recommend its use in post-fire recovery planning in ponderosa pine-dominated forests. RdNBR is more consistent in classifying burn severity in areas with low forest cover and has identified fire refugia in other regions ,78. Our Conifer refugia were least likely to survive wildfires occurring under the highest temperatures, highest wind speeds, and driest conditions. Higher daily maximum temperature was the highest ranked variable in the primary random forest model predicting higher tree mortality. Our findings generally corroborate other studies showing the decreased importance of topographic variables in predicting fire severity and fire refugia under warmer, drier, and more extreme burning conditions ,30,31,78Our hypothesis that abiotic factors have an influential role in providing post-fire refugia across the CFR was generally supported. The most important landscape variables in predicting Conifer Refugia were related to soil characteristics, proximity to higher order streams, less rugged terrain, valley landforms, and lower elevation in drainages. The partial dependence plots of the Random Forest model suggest that post-fire conifer survivorship in ponderosa pine dominated forests is generally predicted in moister or less steep sites. Conifer survivorship in locations near the floodplain or watershed drainage is most likely influenced by soil properties, microclimates, and topography. Wetlands, stream confluences, riparian areas, valley bottoms and cold air drainages can have decreased fire severities ,89\u201392. ASoil properties in the top five centimeters heavily influenced the presence of Conifer Refugia. Quantitative studies of ponderosa pine densities and soil texture in the Southwest have shown that soils with a high clay content are less favorable for ponderosa pine and more favorable for competing grasses ,94,95. AAnthropogenic influences also promoted conifer survivorship within our study area. Both proximate distance to homes and distance to roads were consistently ranked in the top ten predictors of Conifer Refugia. Roads may serve as natural fuel breaks or be used to strategically locate active fire suppression efforts, both promoting survivorship of trees in the area. Homes are also actively protected from oncoming wildfires with wildfire suppression tactics and numerous private land owners in the CFR treat fuels adjacent to their homes ,97. TreeBiotic variables, distance to savanna and pre-fire forest cover, were not strong predictors of Conifer Refugia. Overlays showed that forest cover under 60% was only slightly more likely to survive these wildfires and half of the area with forest cover between 20% and 50% had no surviving conifers. Although forest cover overall had a very weak relationship with tree survivorship, the proximate distance to savannas (open areas and forest cover \u2264 20%) had a stronger influence. While elevation is historically the single most important predictor of low-severity fire within the CFR , forestsThe importance and decline of small meadows in ponderosa pine has been documented in Colorado . BetweenIn addition to the decline in area of meadows along the CFR, there appears to be a surprising lack of resistance to recent fire in the remaining savannas. Nearly half of the canopy cover of the savannas within the fire perimeters did not survive. The maintenance and protection of large, old trees is important for both ecosystem services and carbon storage . The higOur analysis highlights specific opportunities regarding forest management to enhance forest resilience in the face of increased wildfires under a warming climate \u2013109: 1) Although 42% of the total burned area contained surviving post-fire conifers in our study of 23 fires, mechanisms of resilience of ponderosa pine systems to wildfire may be declining along the CFR. We highlight four general findings that underscore the potential declining resilience of ponderosa pine forests in Colorado with a continued trend of increasing area burned under a warming climate: 1) large fires are expected to have large patches approximately a third the size of the fire area that lack surviving conifers and therefore seed sources for regeneration; 2) wetter areas and topographic low points generally have a higher likelihood of conifer presence following wildfires; 3) forest cover was not a strong predictor of conifers surviving wildfire; and 4) conifers are less likely to survive under extreme fire weather and burning conditions. Research in the CFR and elsewhere has reported decreased ponderosa pine regeneration in response to warmer drier climates following wildfires. These same climate conditions are promoting large wildfires with extensive treeless patches, further compromising post-fire resilience to wildfire. For ponderosa pine forests in the CFR, the combination of larger fires and warmer-drier burning conditions poses a potentially great threat of forest loss with a lack of post-fire recovery due to lack of seed sources alone. Even patches of the lowest tree cover in ponderosa pine forests suffered high mortality in recent fires along the CFR. Our results suggest numerous management implications including: the preference of RdNBR over TBSC to evaluate post-fire surviving seed sources, the importance of including soil and topographic variables into management planning to promote post-fire conifer refugia, the increased use of prescribed fire in existing meadows and woodlands to potentially increase the survivorship of conifer trees, and a reprioritization that may include wide-scale planting of seedlings for this forest type in areas lacking seed sources but at sites where they are more likely to survive future fires.S1 TablePercent cover of forest and woodlands in the 2001 LANDFIRE Existing Vegetation Types within 23 fires that burned ponderosa pine-dominated forests along Colorado\u2019s Front Range 1996\u20132013.(DOCX)Click here for additional data file.S2 TableTotal percent cover and area of forest and woodlands in the 2001 LANDFIRE Existing Vegetation Types across 23 fires that burned ponderosa pine-dominated forests along Colorado\u2019s Front Range 1996\u20132013.(DOCX)Click here for additional data file.S3 TableImportance and data sources for landscape variables generated for the random forest model meant to classify Conifer Refugia and Conifer Absence. Selected variables in more than six of 11 Random forest models are indicated by *. An expected positive relationship between the variable and Conifer Refugia is denoted with (+) and an expected negative relationship with (-). All variables are at 30-m resolution.(DOCX)Click here for additional data file.S4 TableMaximum, mean, and standard deviation of distance to potential pre- and post-fire seed source for the 23 fires that burned ponderosa pine-dominated forests along Colorado\u2019s Front Range 1996\u20132013.(DOCX)Click here for additional data file.S1 FigThree examples of Conifer Refugia within 23 fires that burned ponderosa pine-dominated forests along Colorado\u2019s Front Range 1996\u20132013 as shown by 2015 NAIP aerial imagery.(TIF)Click here for additional data file.S1 Text(DOCX)Click here for additional data file."}
+{"text": "Immune checkpoint blockade (ICB) has elicited durable therapeutic responses across a number of cancer types. However, the impact of ICB on mCRPC has been disappointing, which may signal the need to combine mechanistically-distinct ICB agents and/or override immunosuppression in the tumor microenvironment. Our objective is to determine if robust immunotherapy responses in mCRPC may be elicited by the combined actions of ICB agents together with targeted agents that neutralize MDSCs yet preserve T cell function. METHODS/STUDY POPULATION: We created a novel embryonic stem cell-based chimeric mouse model of mCRPC engineered with signature mutations to study the response to single and combination immunotherapy. The efficacy studies were followed with detailed mechanistic investigation and clinical validation. RESULTS/ANTICIPATED RESULTS: Consonant with early stage clinical trials experience, anti-CTLA4 or anti-PD1 monotherapy failed to impact disease progression. Similarly, modest anti-tumor activity was observed with combination ICB as well as monotherapy with targeted agents including Cabozantinib (tyrosine kinase inhibitor), Dactolisib (PI3K/mTOR inhibitor), and Dasatinib (tyrosine kinase inhibitor). In contrast, mCRPC primary and metastatic disease showed robust responses to dual ICB treatment together with either Cabozantinib or Dactolisib, but not with Dasatinib which impaired T cell infiltration in the tumor. Detailed intratumoral immune profiling with mass cytometry (CyTOF) showed that combined ICB and Cabozantinib or Dactolisib was associated with significant depletion of MDSCs. Cabozantinib and Dactolisib blocked the PI3K signaling activity in MDSCs and reduced their immunosupppresive activity. Mechanistically, the combination efficacy was due to the upregulation of IL-1RA and suppression of MDSC-promoting cytokines secreted by mCRPC cells. DISCUSSION/SIGNIFICANCE OF IMPACT: We demonstrated that an antibody cocktail targeting CTLA4 and PD1 was insufficient to generate effective anti-tumor response, but combination of ICB with targeted therapy that inactivates PI3K signaling displayed superior synergistic efficacy through impairing MDSCs in the tumor microenvironment. These observations illuminate a clinical path hypothesis for combining ICB with MDSC-targeted therapies in the treatment of mCRPC. Importantly, conclusions from the study on PCa may have implications in combination immunotherapy for aggressive breast cancer which is also largely resistant to immune checkpoint blockade and replete with immunosuppressive myeloid cells.OBJECTIVES/SPECIFIC AIMS: Prostate cancer (PCa) is the most common noncutaneous malignancy in men in the United States. A significant fraction of advanced PCa treated with androgen deprivation therapy experience relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). The PCa tumor microenvironment is comprised of a complex mixture of epithelial and stroma cell types engaged in multifaceted heterotypic interactions functioning to maintain tumor growth and immune evasion. We recently uncovered the important role played by myeloid-derived suppressor cells (MDSCs) to mediate tumor immune evasion in aggressive PCa (Wang, Lu"}
+{"text": "Cicatricial organizing pneumonia is an uncommon form of organizing pneumonia, which may manifest as persisting linear opacities on computerized tomography (CT) scan mimicking a fibrosing interstitial pneumonia. It may also manifest with pulmonary ossification, which is a metaplastic bone formation within the lung tissue. The latter presentation could be either nodular or dendriform, both secondary to underlying lung disease and rarely idiopathic. Dendriform pulmonary ossification (DPO) has rarely been described as a cause of spontaneous pneumothorax. We present a case of a 55-year-old male with history of recurrent pneumothoraces and worsening dyspnea on exertion. A CT of the chest revealed progressive bilateral sub-pleural and peribronchovascular reticular opacities associated with densely ossified branching and nodular opacities. Video-assisted thoracoscopic biopsy of the lung demonstrated cicatricial organizing pneumonia with areas of marked diffuse DPO. The case highlights that dendriform pulmonary ossification arising from cicatricial organizing pneumonia should be considered in the differential diagnosis of recurrent pneumonias among patients with lower lobe sub-pleural reticular opacities. The case highlights that dendriform pulmonary ossification rarely can cause spontaneous pneumothorax and can be associated with cicatricial organizing pneumonia and reticular opacities on imaging. Organizing pneumonia (OP) is characterized by the presence of organizing fibromyxoid proliferations within the lumens of respiratory bronchioles and alveolar ducts. Peripheral and /or peribronchiolar consolidations are the most frequent findings of OP on a computerized tomography (CT) scan. These opacities could be migratory in nature. OP is often steroid-responsive and reversible with total resolution of radiological opacities, but occasionally may recur , 2.Cicatricial OP (OPc) is a newly described entity in the pathology literature , 4 and dA 55 year-old, nonsmoker male presented with a recurrent large left pneumothorax requiring a chest tube placement. He had a same side pneumothorax three and six years earlier, also requiring a chest tube placement. The patient also reported dyspnea on exertion with stairs and inclines, which had progressed over last three years along with a dry cough.He had a remote exposure to quails while training hunting dogs. He was known to have hypertension and suffered with symptoms of gastroesophageal reflux disorder (GERD). His physical examination was unremarkable. A review of his pulmonary function revealed gradual decline in his FEV1, FVC and diffusion capacity over the past seven years .Review of serial chest CT imaging revealed progressive bilateral sub-pleural and peribronchovascular branching dense opacities suggestive of DPO . He undeOrganizing pneumonia is usually steroid-responsive and pathologically characterized by presence of loose fibromyxoid plugs within the lumens of the respiratory bronchioles and alveolar ducts , 2. CicaOn CT, conventional OP presents as patchy bilateral peribronchial and subpleural consolidations \u201319, whicPulmonary ossification is a metaplastic process where mature bone is present in the alveolar interstitium and/or alveolar spaces. Pulmonary ossification is classified into DPO and NPO. NPO is usually a localized process of lamellar bone and can occur in the setting of chronic congestion as seen in mitral valve stenosis. Unlike DPO, NPO usually does not contain bone marrow (fat or hematopoietic cells) . On CT, DPO manifests on CT as small  nodules, which are seen predominantly in the peripheral interstitium . These nodules form contiguous and branching pattern resembling tree branches. In most instances these nodules are of high attenuation, reflecting the underlying ossification. The detection of small high-attenuation foci is improved using thin slices and maximum-intensity-projection images. DPO has tendency to affect lower lobes and posterior aspect of upper lobes. Association with recurrent aspiration and DPO has been suggested . The preSpontaneous pneumothorax has been reported in several cases of DPO \u201314 incluThe case we present showed evidence of radiographic progression and worsening restrictive pattern on PFT over several years. The reported cases of cicatricial OP by Churg and his colleagues  have beeIn summary, we present a case of cicatricial OP with DPO presenting with recurrent pneumothoraces and slow progressive pulmonary physiologic restrictive impairment. Cicatricial OP should be considered in the differential diagnosis of peribronchial or subpleural reticular opacities with DPO. Radiologists and clinicians alike should be aware of this newly described entity as distinct from other classical fibrosing processes, its potential association with DPO, and the presumed association between subpleural DPO and spontaneous pneumothorax."}
+{"text": "Rapid changes in family structures have expanded caregiving boundaries beyond the level of lineal kin to include extended and fictive kin. Guided by stress process and health behavior models, we analyzed semi-structured interviews with 120 family caregivers of persons with dementia (PWD) in rural Appalachia to explore personal/family circumstances that influence the responsibilities nonlineal kin assumed to meet the needs of PwD. Compared to spouse and adult children caregivers, nonlineal caregivers reported that PWD had similar behavioral problems, but greater ADL limitations. They also expressed greater burden, overload and role captivity; yet, they reported higher personal mastery, and perseverance. Although sisters and nieces did not report using any paid services to care for PwD, grandchildren and fictive kin used paid services such as meal delivery, personal care, and respite services. Findings provide new insights into a more elaborated conception of caregiving that considers the transformations occurring in family life today."}
+{"text": "Correction to: Antimicrob Resist Infect Control (2019) 8:77https://doi.org/10.1186/s13756-019-0524-4The original article  containsAs such, the authors would like to clarify that in the context of this manuscript, LCMV needlestick injuries may only lead to life-threatening infections in immunosuppressed persons.The Conclusions sub-section of the Abstract should instead state:\u201cThis is the first case report of a PCR-documented LCMV meningitis, coupled with seroconversion, following needlestick injury. It highlights the importance of infection prevention practices that comprise particularly well established safety precaution protocols in research laboratories handling this pathogenic virus, because exposure to LCMV can lead to a severe infection.\u201dThe latter part of the penultimate paragraph of the Background section should instead state:\u201cTherefore, prevention of stab wounds with contaminated sharp objects, bite of infected mice and inhalation of contagious droplets, is indispensable to protect laboratory worker from occupational infection.\u201dThe final paragraph of the Background section should instead state:\u201cThis highlights the importance of infect prevention strategies that comprise particularly well established safety precaution protocols in research laboratories handling this pathogenic virus, because exposure to LCMV can lead to a severe infection.\u201dA middle sentence in the Discussion and conclusion section should instead only state:\u201cPrevention of stab wounds with contaminated sharp objects, bite of infected mice and inhalation of contagious droplets, is crucial to protect laboratory worker from iatrogenic infection.\u201dThe latter half of the penultimate paragraph of the Discussion and conclusion section should instead state the following:\u201cWhen working with LCMV in research laboratories, standard biosafety 2 laboratory practices are mandatory. This includes an appropriate ventilation system as well as wearing high quality gloves and protective gowns when working with LCMV. Surfaces should be routinely disinfected using a registered compound active against LCMV. In addition, a standard operating procedure should be available for the management of unintentional exposure to the virus. Pregnant women and immunosuppressed persons must be taught that exposure to this virus can lead to a severe, life-threatening infection.\u201dThe final paragraph of the Discussion and conclusion section should instead only state:\u201cIn conclusion, this well-documented case of LCMV-meningitis after needlestick injury highlights the importance of infection prevention practices in research laboratories and the need of safe handling of this virus.\u201dThe affected statements in the manuscript and their corrected version can be viewed ahead:"}
+{"text": "The dentate gyrus continually produces new neurons throughout life. Behavioral studies in rodents and network models show that new neurons contribute to normal dentate functions, but there are many unanswered questions about how the relatively small population of new neurons alters network activity. Here we discuss experimental evidence that supports multiple cellular mechanisms by which adult-born neurons contribute to circuit function. Whereas past work focused on the unique intrinsic properties of young neurons, more recent studies also suggest that adult-born neurons alter the excitability of the mature neuronal population via unexpected circuit interactions. Thus, GCs integrate sensory and spatial information to help generate a neural representation of a context5. Interestingly, resident neural stem cells produce new GCs throughout adulthood, and these adult-born GCs receive synapses from cortical neurons via the perforant path and form output synapses with downstream neurons to participate in hippocampal network activity. Although the majority of neuroblasts undergo programmed cell death, surviving neurons are permanently incorporated into the DG and acquire properties similar to GCs generated early in development8. While adult-born GCs may replace a fraction of the developmentally generated population that is lost over time10, their continuous addition accounts for the substantial increase in GC number across the first year of life in rodents12. How this process contributes to hippocampal learning and memory is an intriguing neurobiological question. Current insight into this question relies on experimentally tractable rodent models, but evidence of DG neurogenesis in healthy humans across the lifespan14 suggests that it could have implications for human cognition.The dentate gyrus (DG) is viewed as the main entry point for neural activity into the hippocampus, a brain region essential for learning and memory. The principal neurons, the dentate granule cells (GCs), are innervated by neurons of the entorhinal cortex that encode information about objects, spatial location, and details of the environment16. Brain regions involved in associative learning, such as the cerebellum and hippocampus, use circuits that perform pattern separation as a \u201cpre-processing\u201d step to help discriminate input patterns carrying sensory or contextual cues17. Sparse population activity, wherein only a small fraction of principal neurons are active at a given time, is thought to be a critical component of pattern separation17. In the DG, sparse activity is predicted to allow distinct GC ensembles to encode similar  patterns of afferent activity, with a large capacity to transform overlapping patterns in the cortex into non-overlapping patterns in CA319. Interestingly, selective manipulations of adult-born GCs are sufficient to alter behavior paradigms thought to rely on DG pattern separation ergic interneurons that inhibit mature GCs, a circuit motif called feedback inhibition. Consistent with this idea, reducing neurogenesis with focal X-irradiation generated bursts of GC activityin vivo35 and hypersensitivity to a chemoconvulsant52. While these studies assayed excitability across the population of GCs, subsequent work acutely silencing young GCsin vivo andex vivo using designer receptors exclusively activated by designer drugs (DREADDs) also revealed enhanced excitability of individual mature GCs consistent with feedback inhibition53.Some of the first evidence that adult-born GCs alter the excitability of mature GCs came from voltage-sensitive dye imaging of hippocampal slices from mice with enhanced or ablated neurogenesis56 58. Whereas feedback inhibition generated by 8-week-old GCs suppressed perforant path-induced spiking, inhibition evoked by the same number of 4-week-old GCs had little effect -mediated currents in mature GCs even when polysynaptic activity was blocked by \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonists. Such recurrent connectivity contrasts sharply with the conventional view that GCs provide a unidirectional glutamatergic projection, except in pathological conditions like epilepsy62. Yet the possibility that young GCs release both GABA and glutamate is consistent with a long-standing literature showing a transient dual-neurotransmitter phenotype, although the nature and prevalence of GABAergic signaling from young GCs has been controversial65.The plot thickened as subsequent work proposed that ChR2 activation of adult-born GCs younger than 7 weeks old provides strong inhibitory responses in neighboring GCs66 first showed that silencing adult-born GCs increased mature GC responses evoked by stimulation of the lateral perforant path (LPP), whereas it reduced mature GC responses evoked by stimulation of the medial perforant path (MPP). Since the LPP carries sensory information and the MPP carries spatial information3, adult-born GCs might selectively gate different forms of information during the creation of DG contextual representations in mature GCs. This unexpected pathway-specific regulation was attributed to activation of postsynaptic glutamate receptors on mature GCs rather than feedback inhibition. In fact, blocking GABAA receptors did not block the responses evoked by new GCs, suggesting that feedback inhibition generated by young GCs is not a major circuit function in this paradigm.Even as the efficacy of GABAergic feedback inhibition recruited by young GCs remains debated, a recent study further expands the potential repertoire of adult-born GC circuit functions by focusing on the direct glutamatergic signaling from young GCs to mature GCs . Luna an68. Luna and colleagues showed that optogenetic activation of young GCs evoked NMDAR-mediated excitatory postsynaptic potentials (EPSPs) in mature GCs as well as slow inhibitory postsynaptic potentials (IPSPs) driven by mGluRs. Such NMDAR- and mGluR-driven responses are characteristic of spillover signaling, wherein receptors located outside of synapses are activated by glutamate acting at a distance from the release site. Spillover transmission can occur in the absence of anatomically defined synaptic junctions or in addition to conventional point-to-point synaptic transmission71. The authors suggest that when a small number of young GCs are activated by LPP stimulation, the relatively low level of glutamate spillover favors mGluR-mediated inhibition, whereas a larger population of young GCs activated by MPP stimulation recruit stronger NMDAR-mediated depolarization that overrides mGluR inhibition. Thus, the number of young GCs recruited will affect their circuit function  coupled to potassium channels that cause hyperpolarizationunction . In thiset al.66 described circuit interactions that enable adult-born GCs to rapidly modify mature GC excitability in response to network activity, neurogenesis also changes synaptic structure and function of existing GCs over a longer time window as young GCs integrate into the circuit. The possibility that newborn GCs compete for synaptic input with existing GCs was implied by evidence that the survival of newborn GCs is competitively regulated by NMDAR activation72. Subsequent anatomical analysis showed that immature dendritic spines transiently receive a high proportion of synapses from multiple-synapse boutons that could represent an intermediate structure in the transfer of cortical synapses from old to new GCs74 (but see77. In accordance with a redistribution of available presynaptic and postsynaptic elements, ablating GCs enhances the density of GABAergic somatic synapses on remaining GCs78 and increasing the number of new GCs does not appear to alter the density of spines and synapses in the molecular layer79. Recent support for the hypothesis that new GCs integrate into the circuit by competing for pre-existing synapses was provided by complementary studies showing that reducing the spine density of mature GCs enhanced the integration of new GCs80 and that manipulating the number of newborn GCs inversely regulated synaptic connectivity of mature GCs81. Thus, synaptic competition and subsequent redistribution of cortical connectivity may provide an additional mechanism for neurogenesis to contribute to sparsity and decorrelation of mature GC activity20.Whereas Luna but see. Whetheret al.66 propose that dual signaling allows young GCs to differentially regulate mature GC excitability depending on the strength of LPP versus MPP activity that differs between behavioral states and in the superior and inferior blade. Another possibility is that direct excitation/inhibition exerts local effects on neighboring GCs, whereas feedback influences GCs over a larger spatial domain as dictated by the extensive axonal arbors of GABAergic interneurons. Untangling the consequences of these multifaceted circuit interactions on hippocampal encoding and behavior will be an interesting challenge.The possibility that young GCs influence mature GC excitability by direct glutamatergic excitation and inhibition suggests an unexpectedly complex regulation layered upon additional secondary influences including feedback inhibition and synaptic competition. On the surface, it is difficult to envision the purpose of simultaneous direct excitation and inhibition. Luna82? Finally, what is the temporal relationship and relative efficacy of direct glutamatergic signaling in comparison with feedback inhibition and synaptic competition at each stage of new GC maturation? While the existing evidence indicates that the integration of new GCs has complex consequences for the local circuit, there is still a long way to go to understand how a few cells affect the many. The multi-layered complexity of the circuit interactions, in combination with activity-dependent regulation of adult neurogenesis, implies that continual neurogenesis provides extraordinary flexibility for adaptation to environmental changes and cognitive demands. Further exploring the cellular mechanisms by which adult-born GCs modify DG excitability and downstream hippocampal activity, along with cell-type-specific manipulations in behaving rodents to test their influence on behavior (reviewed inMany questions also remain about the mechanisms of these interactions at the cellular and synaptic level. For example, how is glutamate released from young GCs in a manner that generates receptor activation reminiscent of spillover signaling and where does this signaling occur? What is the efficiency of this novel signaling mechanism in controlling mature GC spiking, especially considering the stimulation of a single or small number of young GCs is insufficient to engage these interactions? How does the MPP recruit a larger population of young GCs than the LPP in light of evidence that the LPP preferentially innervates young GCsAMPAR, \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ChR2, channelrhodopsin-2; DG, dentate gyrus; EPSP, excitatory postsynaptic potential; GABA, gamma-aminobutyric acid; GC, granule cell; IPSP, inhibitory postsynaptic potential; LPP, lateral perforant path; mGluR, metabotropic glutamate receptor; MPP, medial perforant path; NMDAR, N-methyl-D-aspartate receptor."}
+{"text": "Gastric outlet obstruction can be caused by various pathologies, including peptic ulcer disease, gastric polyps, and malignancies. The incidence rate of breast cancer metastasis to the stomach is only 0.3%. We describe a rare case of an 83-year-old female with a remote history of breast cancer who presented with symptoms of nausea and vomiting. She underwent an upper endoscopy, and biopsies revealed chronic gastritis. However, when she presented for the second time with similar symptoms, she underwent endoscopic ultrasound (EUS)-guided biopsies, which clinched the diagnosis of breast cancer metastasis causing gastric outlet obstruction. This case describes the importance of keeping a wide differential diagnosis for the causes of gastric outlet obstruction and the significance of deeper EUS-guided biopsies if initial endoscopic biopsies are inconclusive. Gastric outlet obstruction (GOO) has multiple etiologies, including peptic ulcer disease, malignancies, and gastric polyps. With the identification of Helicobacter pylori and the use of proton pump inhibitors, the etiology of gastric outlet obstructions has changed over the years with malignancy now being the most common cause . The mosAn 83-year-old female presented to our emergency department with complaints of nausea and vomiting for four days. She had been diagnosed with right-sided, multicentric, infiltrating lobular carcinoma of the breast , progesterone receptor positive (PR+), human epidermal growth factor receptor 2 negative (HER2-) 10 years ago. She had undergone a right mastectomy, and her sentinel lymph nodes, which were sampled during surgery, were negative for metastases. Previously, she had been treated with adjuvant anastrozole for five years, and yearly mammograms had been negative for recurrence.One year prior to this presentation, she was evaluated at our hospital for similar complaints of nausea and vomiting. A computed tomography (CT) scan of her abdomen and pelvis on admission revealed a mass-like thickening of the gastric antrum and distension of the proximal stomach, as illustrated in Figure An upper endoscopy (EGD) was performed, which revealed esophagitis and gastric stenosis. This was dilated using a through-the-scope controlled radial expansion (CRE) balloon  to a maximum balloon size of 12 mm without fluoroscopic guidance. Biopsy of the gastric stenosis revealed gastric mucosa of antral type with minimal chronic inactive gastritis. No morphologic evidence of a Helicobacter pylori infection was detected. The patients\u2019 symptoms of nausea and vomiting improved following balloon dilation. She was subsequently discharged on a daily proton pump inhibitor.The patient underwent endoscopic ultrasound (EUS) 12 weeks later. Gastric stenosis was found at the pylorus and duodenal bulb, which was dilated again with a CRE balloon to a maximum dilation of 13.5 mm. Diffuse wall thickening of the antrum of the stomach was visualized endosonographically. The gastric wall measured up to 11 mm in thickness. Thickening within the deep mucosa, submucosa, and muscularis propria was noted. EUS-guided biopsies were taken, which revealed invasive poorly differentiated metastatic breast adenocarcinoma, as shown in Figure Tumor immunohistochemistry and morphology revealed ER+, PR+, and HER2- negative lobular breast adenocarcinoma as demonstrated in Figure This case highlights the importance of keeping a broad differential diagnosis for cases presenting with gastric outlet obstruction, especially in patients with a history of cancer. A diagnosis of breast cancer metastases to the gastrointestinal tract is often challenging because of its low incidence. Distinguishing between metastatic breast carcinoma and primary gastric adenocarcinoma cannot always be done using histological examination alone, and superficial biopsies may not be sufficient. Invasive lobular breast carcinoma and primary gastric cancer can have similar histopathology, as both can show signet ring cells. Immunohistochemistry is needed to make a distinction between the two, based on staining for estrogen and progesterone receptors . As in oAn important differential diagnosis for patients with concurrent gastric and breast adenocarcinoma includes hereditary diffuse gastric cancer (HDGC), which is an inherited cancer syndrome associated with an increased risk for primary gastric cancer and lobular breast carcinoma and is characterized by a poor prognosis. CDH1 gene mutations are frequently associated with HDGC and patients with this syndrome may benefit from genetic counseling.Ulmer et al. described a similar case to ours where previous gastric mucosal biopsies had been negative; however, a EUS-guided fine needle aspiration clinched the final diagnosis of metastatic lobular breast carcinoma causing gastric outlet obstruction . Of noteAlthough case reports of breast cancer metastasis causing GOO do exist in the literature, our case emphasizes the need to be diligent and thorough with a low threshold for EUS-guided biopsies if the initial endoscopic biopsy is inconclusive. This is critical in order to avoid delay in care for a patient with metastatic carcinoma."}
+{"text": "Nursing homes that fostered open communication and teamwork were more likely to change their practices and adopt the \u201cIt\u2019s Not OK to Fall\u201d program. This pilot study evaluated the feasibility and acceptance of a team-building approach for developing leadership skills to three groups of coworkers: Administrators/Directors of Nursing, charge nurses, and certified nursing assistants (CNA) employed by nursing homes in Oklahoma. Each coworker group received one day of job specific leadership training, with another one half-day session where all levels engaged in team-building exercises. Participant satisfaction with course content ranged from agree-to-strongly agree. All stated that they could apply the leadership strategies at their facility. Administrators/Directors of Nursing found tools for tracking turnover/retention and strategies for improving staff communication helpful. Charge nurses and certified nursing assistants seldom viewed themselves as leaders, found coworker group communication very fragmented, and felt least knowledgeable about nursing home care best practices."}
+{"text": "Widespread changes to the epigenome occur with aging. DNA methylation is one of the most commonly studied epigenetic mechanisms, reflects lifetime exposures that impact aging, and is associated with age-related disease risk. Many longitudinal cohort studies have existing cross-sectional or longitudinal DNA methylation data along with genotype and expression data permitting investigation of relationships between DNA methylation markers, exposures, and disease. The data can be leveraged to conduct large epigenome-wide association studies (EWAS) of aging and age-related disease to identify DNA methylation biomarkers and lead to insights into novel biologic pathways for development of interventions to delay aging. DNA methylation age measures robustly predict chronologic age and associate with both healthspan and lifespan. During the workshop, examples from cohort studies and the CHARGE consortium will be presented."}
+{"text": "The Diverse Elders Coalition, in partnership with its six member organizations and the Benjamin Rose Institute on Aging, completed a national survey of 840 family and friend caregivers from diverse racial, ethnic, and sexual orientation communities to understand their unique caregiving issues and challenges. Data from a subsample of 404 caregivers identifying as Hispanic/Latino, Asian, Southeast Asian or from multiple ethnicities were examined to determine the relationship between difficulties performing culture-related care tasks  and a variety of caregiver outcomes. Regression analysis controlling for background and context characteristics showed caregivers experiencing more culture-related task difficulties had significantly higher levels of several negative caregiving consequences, including health strain , relationship strain , work strain,  isolation , and symptoms of depression . Moreover, higher levels of strain and depression among caregivers who reported high levels of culture-related task difficulties ranged from 26%-54%. More difficulties with culture-related tasks also were significantly related to dissatisfaction with support resources, including lower ratings of the quality of care receivers\u2019 healthcare , and lower satisfaction with support they and their care receivers received from family and friends . Results suggest caregivers from diverse communities struggling with culture-related tasks experience more negative consequences of caregiving and less helpful social support. Service providers working with caregivers from diverse communities should assess for culture-related task difficulties, recognizing these problems may be a window into a variety of adverse caregiving effects."}
+{"text": "The 1.7 million older adults receiving long-term services often do not receive end of life care consistent with their wishes. Advance directives (ADs) can help, yet only one-third of Americans have completed ADs. The limited effectiveness of traditional interventions to increase AD completion may be because they do not address the behavioral aspects of advance care planning. Behavioral Design is an innovative approach that combines design thinking and behavioral economics to identify predictable behavioral bottlenecks and create real-time solutions. This study used Behavioral Design to address low AD completion rates of long-term care residents. Consistent with the Behavioral Design process, an interdisciplinary team compiled evidence from 10 diverse data sources to identify behavioral bottlenecks to AD completion. These barriers were analyzed using the cognitive bias codex to determine behavioral levers for intervention. Informed by these findings, the study team designed multicomponent interventions to address behavioral aspects of AD completion. Four behavioral bottlenecks incorporating ten behaviorally mediated causes for lack of AD completion were identified. For example, AD completion is affected by complexity mediated by hassle factor, choice overload, and ambiguity effect. Three interventions were designed to address these behaviorally mediated causes. For example, the intervention HeAD Start would provide a simple, easy to read AD (addressing choice overload) to residents upon admission (addressing hassle factor) with scheduled follow-up by trained staff (addressing ambiguity effect). Behavioral Design incorporates design thinking and leverages behavioral economic principles to create behaviorally mediated AD interventions. Next steps include testing behaviorally informed designs in practice."}
+{"text": "Background and Objectives: The relationship between objective and subjective cognitive function and depressive symptoms is complex and potentially multidirectional. This longitudinal prospective study examined the directionality of their relationship among a community sample of older people with no known diagnosis or treatment for dementia or depression. Research Design and Methods: We examined the temporal relationship between objective cognitive functioning, subjective cognitive complaints, and depressive symptoms in 1,814 community-dwelling older people at baseline and one-year follow-up using regression and two-wave cross-lagged panel analyses, after controlling for demographic and health confounders. Results: Cross-lagged analysis showed that depressive symptoms at follow-up were directly predicted by baseline subjective cognitive complaints, but not baseline objective cognitive functioning. The effect differed across objective cognitive functioning levels. In people with clinically significant cognitive impairment at baseline, objective cognitive decline but not baseline subjective cognitive complaints predicted depressive symptoms. In people with mild objective cognitive impairment at baseline, baseline subjective complaints but not objective cognitive decline predicted depressive symptoms. Discussion and Implications: The effects of objective and subjective cognitive decline on depressive symptoms varied across older people with different levels of cognitive impairment. Awareness and insight of one\u2019s cognitive status may contribute to the development/progression in depressive symptom in people with mild cognitive impairment. Mechanisms unrelated to appraisal may be involved in increased depressive symptoms among older persons with significant objective cognitive impairment."}
+{"text": "Background: Substance Use Disorder (SUD) and behavioral addictions are common and require a multidisciplinary approach. New technologies like Virtual Reality could have the potential to improve assessment and treatment of these disorders.Objective: In the present paper, we therefore present an overview of Virtual Reality (Head Mounted Devices) in the field of addiction medicine for craving assessment and treatment.Method: We conducted a systematic review by querying PubMed database for the titles of articles published up to March 2019 with the terms [virtual] AND [addictive] OR [addiction] OR [substance] OR [alcohol] OR [cocaine] OR [cannabis] OR [opioid] OR [tobacco] OR [nicotine] OR [methamphetamine] OR [gaming] OR [gambling].Results: We screened 319 abstracts and analyzed 37 articles, dividing them into two categories, the first for assessment of cue reactivity  and the second for intervention, each drug  being detailed within each category.Conclusions: This overview suggest that VR provide benefits in the assessment and treatment of substance use disorders and behavior addictions and achieve high levels of ecological validity. While, craving provocation in VR is effective across addiction disorders, treatments based exclusively on virtual exposure to drug related cues as shown heterogenous results. Substance Use Disorder (SUD) and behavioral addictions are prevalent in many countries , attention bias and drug seeking behaviors triggered by stimuli previously associated with drug use  or cognitive behavioral therapy (CBT)-driven techniques applied in real time. VR may also facilitate the link between clinician and patients and improve our understanding of addictive behavior.Until recently, VR was limited by its cost and by the quality of the multimedia content. There has been a recent democratization of these systems  concomitant with the video game industry's growing interest in this technology. Decreasing costs and increasing power are making it useful for performing an ecological assessment of cognition, emotions, and behavior in real-time.The purpose of this systematic review is to evaluate the usefulness and efficacy of immersive VR in cue reactivity assessment and craving management for patients undergoing SUD or behavioral addictions. To this end, the proposed systematic review will answer the following questions:- When compared to VR neutral stimuli, are VR cues able to elicit cue reactivity in adult patients suffering from addictive disorders? Is there an advantage of using VR cue reactivity over traditional cue reactivity methods?- Can VR be used as an effective tool for craving reduction compared to standard therapy in this aforementioned population?To identify appropriate resources and search for relevant evidence. We used a PICOS framework, to form a well-focused question and facilitate the literature search  and the second for treatment, each drug being detailed within each category.See PRISMA diagram .A brief description of the concepts underlying virtual reality (VR) and cue features in the field of addiction is summarized in Studies and results described below are summarized in n = 465) assessed cue reactivity after virtual nicotine-related cues in adult smokers. Nicotine addiction criteria were reported in 13 studies, using DSM 4  in VR showed craving induction in adult smokers. Various cues  were associated with craving induction.All studies investigating craving , complex cues were evaluated and often compared to other types of cues  . All studies reported a significant increase of attentional bias compared to virtual neutral environments. Adding olfactory nicotine cues were surprisingly not associated with greater attention to cue in Traylor et al.  or the Smoking Attention Scale (SAS)  assessed cue reactivity after presentation of virtual alcohol-related cues in adults suffering from alcohol use disorder  showed its induction after VR cue exposure   suffering from cocaine use disorder (DSM-IV)  Guze,  assessedCraving induction through virtual cues has been demonstrated with contextual and complex environments compared to neutral virtual environments in cocaine-dependent subjects. Craving assessment was performed using single-item VAS. Situations triggering highest craving are those related to cocaine use and interactions with a dealer.Physiological reactivity was also measured. Heart rate increased in a manner comparable to craving in scenes of cocaine use and interaction with a dealer compared to neutral scenes. Besides, there was no change in skin conductance measurements between virtual neutral exposure or virtual cocaine-related exposure.n = 20) suffering from cannabis use disorder (DSM-IV)  Guze,  assessedBordnick et al.  showed cIn this study  were induced after exposure to a virtual and real slot machine environments in Bouchard et al. . Cravingn = 34) suffering from internet gaming disorder [DSM-5 . One VET trial was effective on craving and cigarette consumption reduction  after 5 weekly sessions on 48 subjects with low to moderate nicotine dependence in association with a tobacco education group  studied VCBT in nicotine addiction reduction  in Korea evaluated virtual exposure therapy, including aversive exposure situations on alcohol craving reduction  suggest that greater craving can be triggered by complex environments. Moreover, recent interest in proximal stimuli has emerged  and new studies on other substance consumption behavior in virtual reality could further enrich the exposition realism.Social interaction with avatars can efficiently induce cravings for multiple substances, mainly assessed in cigarette smoking and alcohol studies. However, difficulties persist in separating social craving from context craving. Indeed, several questions remain regarding stimuli specification assessment in VR craving induction. A significant number of studies were exposed to carry over effect while a better understanding of craving stimuli characteristics could be obtained by using a two by two comparison protocols or by an effective carry over effect control .The lack of stimuli comparability resulting from the craving ceiling effect may have been increased by VAS widespread use by limiting the measurement to its intensity level, while a dimensional analysis of scales such as QSU could have revealed interesting qualitative differences (Rosenberg, in vivo scenarios. However, metanalyses report disappointing results (Mellentin et al., Traditional Cue Exposure Therapy studies' designs are mainly on substance-related cues detached from social environmental or In the future, attention to potential limits should be considered:Cost-effective studies are needed.Access to VR and therapists training need to be evaluated.Ethical considerations remain regarding the use of aversive exposures.Cybersickness could represent a threat to virtual reality usability and effectiveness and would also require integration in future studies (Gallagher and Ferr\u00e8, Patient's adherence should be accurately assessed before implementing aversion therapy in routine practice.Both positive and negative studies show numerous methodological biases: confusion bias due to the absence of control groups, selection bias due to the absence of randomization, attrition bias due to little intent to treat analysis, altogether indicating low internal validity and limiting the possibility of drawing clear conclusions.Future studies appear necessary and should evaluate dependence and abstinence maintenance as primary endpoint, offer more long-term follow-up, and include more control treatment groups to limit confusion bias.Efficacy of treatment based exclusively on virtual exposure to drug related cues appears to be limited, but interesting results point the great potential of implementing VR in CBT. Pericot-Valverde et al.  shows hoDespite these limitations, VR has the potential to offer new opportunities for treatment through its ability to provide a more ecological environment with more control and safety over exposition. The ability to fine-tune environments composition according to patient's preferences and most relevant data makes it a future tool for personalized medicine.Because VR has the potential to be disruptive [for review (Freeman et al., Besides its acceptability, its accessibility also raises questions. It could be limited due to the lack of financial support. The populations suffering from substance disorders being frequently in situation of social precariousness. The question of the cost of VR will also have to be evaluated in order to consider its wide implementation in health centers.The studies presented in this review suggest that VR provide benefits in the assessment and treatment of substance use disorders, behavior addictions and achieve high levels of ecological validity. While, craving provocation in VR is effective across addiction disorders, treatments based exclusively on virtual exposure to drug related cues as shown heterogenous result. The addition of learning coping strategies in VRCBT studies are promising, however more rigorous methodological studies are warranted.The datasets generated for this study are available on request to the corresponding author.TS and TB screening and abstract analysis, both authors contributed equally to the writing. AB, SM, and FF conceptual framework, supervised development of work, helped in data interpretation and manuscript evaluation. C-SP and J-VB helped to evaluate and edit the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "To date, there is a dearth of interdisciplinary simulation education and research that involves LGBT older adults within schools of social work and nursing. The purpose of this mixed method study was to examine the use of an intervention among social work and nursing students to determine if lecture and simulations impacted their health-related knowledge and cultural sensitivity/awareness of health provisions with LGBT older adults. Interprofessional faculty created lecture and interdisciplinary simulations with actual members of the older LGBT communities using simulation clinic/lab and health care scenarios. An adapted survey with permission from Grubb et al (2013) was used to include quantitative and qualitative measures of cultural awareness with LGBT populations. Pre-Post test data were analyzed using Generalized Linear Models in SAS software. Results indicated that the intervention positively changed perceptions and increased knowledge among  allied health students. Statistically significant change experiences in their work with LGBT individuals were noted to positively alter their beliefs about sexuality, gender identity, and sexual development =26.51, p<0.001). Qualitative findings include four primary themes about how gender identity and sexual orientation influences health: (a) bias of health care providers, (b) access to quality care, (c) specific health care needs, and (d) health risks of LGBT older adults. As older adults continue to be the largest population needing health care, it is imperative that professionals are trained to give culturally sensitive health care and demonstrate this competency in their practice and interpersonal interactions with clients."}
+{"text": "Here we highlight two areas of research where multiple talks provided new insights. POLE/POLD1 mutations resulting in hypermutation and response to immune therapy. Imielinski\u2019s group presented 10 signatures that were based on the pattern of structural variation within tumors. The method utilized to generate SV signatures combined features derived from classic as well as motif-based patterns of structural variation. The expectation is that these patterns may also subsequently allow recognition of patterns that will implicate specific cancer treatments e.g. homology-directed repair deficiency and response to polyADP ribose polymerase (PARP) inhibition.In the Cancer and Medical Genomics session, Marcin Imielinski of the New York Genome Center highlighted the enormous complexity of structural rearrangements that can be found in individual cancer genomes. This complexity has challenged current genome presentations and Imielinksi described new tools for the generation of cancer genome graphs (gGraphs) and analysis of complex structural variation . Somatic mutation signatures based on single nucleotide variants (SNVs) have been previously described. Specific SNV signature patterns has provided insight to underlying genetic variation and, in some cases, these signatures identify tumors that may be responsive to specific cancer treatments, e.g. Similar to the focus on structural variation as opposed to SNV\u2019s in protein coding genes, there were a number of excellent talks defining variation in non-coding regions from genome sequencing datasets of different patient populations. Patrick Short from Matthew Hurles\u2019 group at the Wellcome Sanger Institute investigated the de novo mutation rate in regulatory elements using over 10,000 whole genome sequencing samples from the Deciphering Developmental Disorders (DDD) study and found that de novo mutations (DNMs) in these individuals are enriched within the ultra-conserved elements and these variants may contribute to 1\u20133% of subjects without a diagnostic finding. There was substantial overlap between DNMs identified in cohorts diagnosed with developmental delay and autism-spectrum disorders. To facilitate analysis of this type of non-coding variation dataset, the group is now developing a non-coding constraint metric .Taking a different approach based on gene expression, Pejman Mohammadi  presented work utilizing allele-specific gene expression data to identify genetic regulatory outliers in a cohort of patients with muscular dystrophy using Analysis of Expression Variance- Dosage Outlier Test (ANEVA-DOT). These talks and a number of posters at the meeting illustrate our need to develop consistent ways to describe clinically relevant regulatory \u201cgrammar\u201d.The two keynote addresses provided new insights into chromosomal and chromatin regulation in normal and disease states. Wendy Bickmore (University of Edinburgh) described the role of regulatory variation in developmental genes in Mendelian diseases. Bickmore highlighted the central role of chromosomal decompaction in transcriptional regulation as mediated by PARP through phase separation or by Lmbr1 through chromosomal looping.In the second keynote address, David Page (Whitehead Institute) investigated overlapping sets of genes retained on sex chromosomes over the course of evolution from autosomes see Fig. . InteresWith regard to the \u201cBiology\u201d of genomes, several talks provided early results of elegant, yet massive, screens to better understand the biological and functional consequence of variation seen in either genomic disorders or cancer. Parisa Razaz from Michael Talkowski\u2019s lab at Massachusetts General Hospital modeled isogenic 16p11.2 reciprocal gene disorder using CRISPR mediated deletions and duplications in induced pluripotent stem cells (iPSCs) and mouse models. These models were then used to investigate gene expression differences and the genes which altered expression due to copy number change were enriched in genes expressed at early and late developmental stages and for genes within autism spectrum disorder risk pathways.Trey Ideker of University of California San Diego described findings from the Cancer Cell Map Initiative (CCMI) designed to generate large protein interaction maps of tumor cells. By integration of somatic RNA expression, whole genome sequencing, and enhancer-gene networks, his group identified 193 somatic eQTLs. Additionally, using hierarchical structured data from yeast, the team developed a deep neural network model (DCell) to predict mechanistic genotype-phenotype relationships giving useful insights into cell structure and function.BRCA1 based on CRISPR mediated saturation genome editing. The functional screen identified pathogenic missense variants in BRCA1 with high accuracy. The increasing use of CRISPR methodologies to facilitate large-scale genetic screens or assist functional assessment of thousands of possible variants within clinically relevant genes is expected to have a high impact on clinical interpretation of variants identified through genetic testing, particularly for rare variants where there is not sufficient patient and/or population related data to determine the pathogenicity of the variant.Sidi Chen of Yale University presented work from functional cancer genome atlas project that used in vivo AAV-CRISPR screen to reveal a functional map of frequently mutated driver genes in hepatocellular carcinoma and glioblastomas. Gregory Findlay from Jay Shendure\u2019s laboratory at the University of Washington described functional classification of nearly all possible SNVs  in functional domains of"}
+{"text": "Most individuals with dementia are undiagnosed or they/their families are unaware of the diagnosis. Implications of dementia diagnosis and awareness are poorly understood. Our objective was to determine whether undiagnosed dementia or unawareness increases risk of hospitalization or emergency department (ED) visits, outcomes with recognized risk in diagnosed dementia. We linked National Health and Aging Trends Study (NHATS) data to fee-for-service Medicare claims for 4,311 community-living participants in the nationally representative cohort. We assessed probable versus no dementia using validated NHATS dementia criteria, undiagnosed versus diagnosed using Medicare claims, and aware versus unaware using NHATS self or proxy report of diagnosis. Cox proportional hazards models evaluated hospitalization and ED visit risk by time-varying dementia diagnosis and awareness status, adjusting for sociodemographic characteristics, functional impairment, medical comorbidities, and prior hospitalization. Compared to no dementia, persons with dementia who were unaware but diagnosed had greater risk of hospitalization  and ED visits . Persons unaware but diagnosed also had greater risk compared to persons aware and diagnosed . Persons with undiagnosed dementia demonstrated hospitalization risk similar to persons with no dementia  and similar or potentially lower than persons aware and diagnosed ; ED visit findings were similar. Results suggest that being unaware of dementia diagnosis may affect healthcare utilization. Strategies to improve communication and understanding of dementia could potentially reduce hospitalizations and ED visits."}
+{"text": "Persons living with dementia-related disorders (PwD) can experience challenging behavioural and psychological symptoms (BPSD) as their illness progresses. There is a continued reliance on antipsychotic drugs (APD) in long-term care to manage this issue despite the well-documented risks of adverse events and increased morbidity and mortality. This study examines the role of culture of care in relation to efforts at reducing inappropriate APD use in managing BPSD within long-term care. Culture of care consists of shared norms, beliefs, and cognitive frames which guide clinical practice and inform the development and implementation of care strategies. Findings were obtained from three Canadian long-term care facilities working on reducing inappropriate use of APD. Data came from interviews with 6 nurses, 18 licenced practical nurses, 14 health care assistants, 4 activity leaders, 4 directors of care, 1 chaplain, and 10 physicians. We found that direct care providers initially varied in their perceived ability to develop and use alternate care strategies with health care assistants being most concerned about safety and exposure to violence. Change involved detective work and innovative thinking in assessing possible causes of BPSD beyond psychosis, including pain and feelings of confusion. Informal reciprocal patterns of communication emerged among health care assistants to identify effective non-pharmaceutical strategies to manage BPSD. Overall, the study shows how shared beliefs in the need for and value of alternate care practices among direct care providers along with the existence of effective informal communication can contribute to successful reduction in APD use when managing BPSD in PwD."}
+{"text": "In a post hoc study of the multicenter FINNAKI trial, Tverring et al. recently reported that measuring heparin-binding protein (HBP) on admission in the intensive care unit (ICU) improved prediction of sepsis-induced acute kidney injury (AKI). In addition, high plasma HBP levels were associated with a significantly higher fluid balance within 24\u00a0h, more organ failure within the first week, and increased 28-day mortality . These oHBP is stored in azurophilic granules and secretory vesicles of neutrophils and is quickly and abundantly secreted when neutrophils are activated and mobilized. Once released, HBP displays a strong proinflammatory activity. In the blood stream, HBP chemoattracts and activates more neutrophils but also T-lymphocytes and monocytes. Binding of HBP to \u03b22-integrins of monocytic cells initiates intracellular signaling processes which evoke a release of chemokines and proinflammatory mediators . SheddinHBP proved to be a valuable diagnostic marker in suspected sepsis  and demoDevelopment and progression of sepsis-related AKI are determined by endothelial leakage, renal tubular cell inflammation, and an adaptive cell-cycle shutdown effect . These iTargeting HBP modulatory effects in sepsis could prove therapeutically useful. Either preventing HBP receptor binding or HBP release from neutrophils are theoretically attractive options. However, evidence that decreasing HBP plasma levels would improve global or renal outcome is still scarce. Moreover, a specific receptor for HBP has not been identified and unselective blocking of crucial immunologic effects of frontline neutrophils may expose patients to unexpected or unwanted side effects. HBP is highly positively charged and thus can be neutralized by negatively charged molecules such as heparin and colloid solutions. Unfractionated and low molecular weight heparin block HBP-induced endothelial cell permeability  and rena"}
+{"text": "Ficedula hypoleuca, collects information about nest predation risk from indirect cues of predators visiting nests of heterospecific birds. Furthermore, we investigated whether the migratory birds can associate such information with a specific nest site characteristic and generalize the information to their own nest site choice.Breeding site choice constitutes an important part of the species niche. Nest predation affects breeding site choice, and has been suggested to drive niche segregation and local coexistence of species. Interspecific social information use may, in turn, result in copying or rejection of heterospecific niche characteristics and thus affect realized niche overlap between species. We tested experimentally whether a migratory bird, the pied flycatcher Our results demonstrate that flycatchers can use the fate of heterospecific nesting attempts in their own nest site choice, but do so selectively. Young flycatcher females, when making the decision quickly, associated the fate of an artificial nest with nest-site characteristics and avoided the characteristic associated with higher nest predation risk.Copying nest site choices of successful heterospecifics, and avoiding choices which led to failed attempts, may amplify or counter effects of nest predation on niche overlap, with important consequences for between-species niche divergence-convergence dynamics, species coexistence and predator-prey interactions.The online version of this article (10.1186/s12862-018-1301-3) contains supplementary material, which is available to authorized users. The niche concept is a central tenet in the theory of species coexistence and community ecology, stating that two species cannot coexist without adequate niche differences \u20134. One iBreeding site choice driven by varying nest predation pressure has been shown to be an important mechanism affecting species coexistence \u20137. This Direct observations of often stealthy, widely ranging and quickly moving nest predators are relatively rare events for an observer, and therefore offer little information for decision-making. Encounters with nest predators may also threaten the observer itself e.g. , 15). Ye. Ye15]).and convergence of realized niches, and both could conceivably be amplified by social information use. Resulting dynamics can be complex, scale-sensitive, and highly dependent on local conditions and community composition.Heterospecific social information use is expected to be most useful between ecologically similar species , in thisFicedula hypoleuca), collects information about nest predation risk from indirect cues of predators visiting nests of a heterospecific resident bird, the great tit (Parus major). We then investigated whether the migratory bird can associate such information with a specific nest site characteristic, are able to generalize the perceived information and use it in guiding their own nest-site choice. Great tits and flycatchers are putative competitors )This study demonstrates that birds i) can detect indirect cues of predation risk from observing heterospecifics nesting attempts and ii) can associate nesting site characteristics with that predation risk infromation and iii) can \u2013 but only conditionally do \u2013 develop preference for \u201csafer\u201d characteristics in their own nest site choice. Such interspecific social information use in relation to nest predation risk may affect realized niche dynamics among coexisting species with important implications for species coexistence and community dynamics. These findings also add to the accumulating evidence of between-individual variation in social information use patterns; both due to age-related differences and also due to within-age-group variation. Given the substantial potential of individual level variation in behaviour to affect key ecological and demographic processes, also including species coexistence and community ecology and evolution \u201357, we sAdditional file 1:The data set supporting the article. (XLSX 16 kb)"}
+{"text": "Cigarette smoking and nicotine dependence commonly co-occur with alcohol dependence. However, treatment for tobacco dependence is not routinely included in alcohol treatment programs, largely because of concerns that addressing both addictions concurrently would be too difficult for patients and would adversely affect recovery from alcoholism. To the contrary, research shows that smoking cessation does not disrupt alcohol abstinence and may actually enhance the likelihood of longer-term sobriety. Smokers in alcohol treatment or recovery face particular challenges regarding smoking cessation. Researchers and clinicians should take these circumstances into account when determining how best to treat these patients\u2019 tobacco dependence. Cigarette smoking and alcohol dependence co-occur at high rates. Research indicates that approximately 80 percent of people with alcoholism smoke cigarettes and that most of these smokers are nicotine dependent . ConversDespite the fact that 60 to 75 percent of patients in alcoholism treatment are tobacco dependent and about 40 to 50 percent are heavy smokers , treatmeSmoking is more benign than alcoholism. The short-term effects of alcoholism may appear more dangerous than those of cigarette smoking. However, mortality statistics suggest that more people with alcoholism die from smoking-related diseases than from alcohol- related diseases . In addicf.cf.Smokers with comorbid alcoholism have either no interest or no ability to quit smoking. It is interesting to note that although addiction treatment programs routinely address multiple substances of addiction , tobacco is frequently the sole excluded substance. The scientific literature also frequently describes treatment of multiple nontobacco substances simultaneously, making it difficult to evaluate the impact of smoking cessation on alcoholism treatment per se cf.. Still, Inclusion of smoking as a target for intervention does not appear to reduce patients\u2019 commitment to broader addiction treatment. For example, incorporating smoking cessation treatment into inpatient addiction treatment centers has not substantially reduced longterm treatment completion  . In addicf.Evidence suggests that a history of alcohol use difficulties may not impede a specific smoking cessation attempt, though it does seem to reduce the likelihood of quitting smoking during one\u2019s lifetime . ResearcMyth: Smoking is more benign than alcoholism.More people with alcoholism die from smoking-related diseases than from alcohol-related illness .Comorbid smoking and alcoholism result in synergistic exacerbation of health risks .Myth: Smokers with comorbid alcoholism have either no interest or no ability to quit smoking.cf.The majority (up to 80 percent) of individuals in addiction treatment are interested in quitting smoking cf..Inclusion of smoking cessation treatment into other addiction programs does not negatively affect rates of treatment completion or motivation for abstinence  that patients must choose between abstinence from cigarettes and abstinence from alcohol. In contrast to this concern, research suggests that treating tobacco dependence within broader addiction programs does not adversely influence recovery from alcoholism (or illicit substances). Although not universal e.g., , the majThe mechanisms of action responsible for the potential benefits of smoking cessation interventions provided during alcoholism treatment remain largely unexplored. However, possible explanatory factors may include greater clinical contact time, reduced exposure to substance use cues, relapse prevention and/or coping skills practice, increased mastery or self-efficacy, and broader healthy lifestyle choices . Self-inAlcohol-dependent patients who quit smoking while in recovery from alcohol problems also do so without negative consequences to their alcohol or drug abstinence . Data suNot only does the preponderance of evidence suggest that smoking cessation does not compromise alcohol abstinence, but multiple studies indirectly suggest that continued smoking may place alcohol-dependent smokers at risk for alcohol relapse . These dUnfortunately, even with today\u2019s best interventions for tobacco cessation, smokers in alcohol treatment or recovery face particular challenges to their cessation efforts. On average, compared with smokers who do not abuse substances, alcoholic smokers are more addicted to nicotine, smoke higher nicotine cigarettes, smoke more per day, and score higher on nicotine dependence measures and on carbon monoxide assessment . Many smDespite concerns to the contrary, the majority of empirical evidence indicates that smoking cessation  does not pose a risk to successful alcoholism treatment. Not only does smoking cessation not disrupt alcohol abstinence, it actually may enhance the likelihood of longer-term sobriety. Although research has yet to determine the extent to which smoking cessation is impeded by active alcohol use difficulties, the presence of these difficulties does not prohibit achievement of tobacco abstinence. Given the substantial negative health consequences of co-occurring cigarette smoking and alcoholism, smoking cessation efforts in the context of treatment for alcoholism are likely to yield important benefits to patients physically, emotionally, socially, and economically."}
+{"text": "Radiofrequency (RF) wire recanalization of short segments of central venous obstruction has been considered safe; however its use for recanalization of long segments of inferior vena cava (IVC) has not been reported.A 55-year-old female with recurrent massive hematemesis was found to have systemic venous upper esophageal varices on endoscopy and an extensive chronic IVC occlusion on CT. Using both a percutaneous transhepatic and transfemoral approach IVC recanalization was performed. A snare was advanced to the cavo-atrial junction via transhepatic venous access. From the groin utilizing RF wire steerable guide sheaths, endovascular reconstruction of the IVC was performed. Post recanalization venography demonstrated patent stented IVC and marked decrease in the intraabdominal-pelvic collaterals. No recurrence of hematemesis was noted. After 6 months, patient remained asymptomatic and had functioning right femoral arteriovenous hemodialysis graft.Using appropriate techniques, Power wire recanalization of long occlusive segments of IVC can be safe and effective. Recanalization of central venous obstruction with RF wire has been considered safe and effective based on outcomes of prior reports (Guimaraes et al., The patient is a 55-yo-female with past medical history of end stage renal failure on hemodialysis with chronic SVC and IVC occlusions from prior hemodialysis accesses. She also had a history of chronic pancreatitis, coronary artery disease. She presented with recurrent massive episodes of hematemesis. Upper GI endoscopy 3showed varices only in the upper esophagus but none in the lower esophagus. The patient did not have liver disease. Cross sectional imaging at that time revealed extensive IVC occlusion Fig.  and multOne month later, the patient returned for follow up venography, which demonstrated widely patent stented IVC and removal of the transhepatic permcath Fig. . NephrolRF wire recanalization has been successfully used to treat pulmonary atresia, to create atrial septal perforation, to recanalize completely occluded thoracic aorta and to recanalize chronic or malignant central venous obstructions after failure of conventional endovascular techniques (Guimaraes et al., In order to safeguard neighboring critical structures, we used following techniques. We placed indicator VCF-1 catheter in the aorta and constantly monitored Power wire tip to avoid deviation towards periaortic area. Unpredictable movement of the RF wire tip was a major concern while crossing long occlusive segment in caudal to cranial direction, especially when the flexible tip moves away from the power generator towards the beating heart. Use of steerable sheath allowed us to have better control of RF wire tip. Also by placing a 25\u00a0mm snare tip at the IVC-atrial junction, Power wire trajectory was given a precise target.Due to easy penetrability of heated tip of RF wire, prior studies used techniques such as short duration of RF energy delivery and very small advancements of RF wire tip (Guimaraes et al., Multiple cranial and/or femoral access approaches have been reported in the literature to treat chronic complex central venous occlusions (Massmann et al.,"}
+{"text": "The choices we make can have long-lasting effects on our health. Repetitive stress; diet; use of cigarettes, drugs, or alcohol; and work-related exposure to environmental toxins often exhibit no immediate effects. Symptoms can appear later on, sometimes many decades later, making it challenging to assign specific blame to behaviors that occurred in the past.Drosophila melanogaster males is caused by an early spermatogenesis arrest. Instead of proceeding through development normally, precursor germline and somatic cells accumulate as immature progenitors, causing a nearly complete block in spermatogenesis. Through careful investigation, the authors discovered that continuous mating causes developmental arrest indirectly, via induction of inflammation signals in the muscle sheath that surrounds the testes. Thus, it appears that muscle exhaustion or mating-associated muscle damage impacts cell fate determination nonautonomously.Most impactful are behaviors that cause irreversible changes to impair tissue function. The paper by Yi-Chieh Chang and colleagues  describeGamete quality is paramount for maintenance of species, with multiple mechanisms contributing to age-associated fertility arrest . The besChang and colleagues focus on the effects of aging on the non-self-renewing daughters of GSCs and CySCs . Reciprodpp by poorly differentiated cyst cells blocks germ cell differentiation. However, reducing dpp expression has no effect on accumulation of poorly differentiated cyst cells, indicating that a previously undiscovered mechanism must regulate cyst cell differentiation.Numerous studies have demonstrated the critical role of transforming growth factor beta (TGF\u03b2) signaling in promoting GSC and CySC self-renewal by blocking differentiation . The autUsing clever deductive reasoning, Chang and colleagues determined that c-Jun N-terminal kinase (JNK) activity within cyst cells blocks their differentiation. They narrowed down the source of the JNK activating ligand to the muscle sheath surrounding the testes, finding that the tumor necrosis factor (TNF) ligand Eiger is both necessary and sufficient to inhibit cyst cell differentiation via JNK activation. The data support the model that excess muscle use leads to increasing Eiger production with age, with receipt of the signal by the TNF receptor Grindelwald on the cyst cell surface triggering JNK activity and the resulting differentiation block.For years, scientists have noted the inverse impact of reproduction on fertility. This study defines a novel mechanism in which inflammatory signals in tissue-associated muscle prevent gamete production, resulting in fertility arrest. The results are congruous with the disposable soma theory, in which the germline is protected at the expense of the soma . In thisWhy does this mechanism exist? One idea is that fertility arrest occurs because of increasing genetic mutations over time, resulting in gamete defects and unsuccessful reproduction. However, Chang and colleagues show that aged, never-mated males produce differentiated sperm and can productively mate to produce progeny. This calls into question the idea that passive mutation accumulation over time is the key mechanism driving fertility arrest. Perhaps TNF produced by damaged muscle induces mutations in developing germ cells. Eiger is expressed throughout the entire muscle sheath surrounding the testes in continuously mated males , suggest"}
+{"text": "Recently published article by Pieri\u2019s group suggested that follicle-stimulating hormone (FSH) activates canine testicular spermatogonial stem cells (SSCs) and results in increased expression of pluripotent markers and formation of germ cell clumps possibly via indirect paracrine effect of Sertoli cells. We disagree with their interpretations and herewith provide a better explanation to their findings. We have earlier reported the presence of pluripotent, very small embryonic-like stem cells (VSELs) as a sub-group among the SSCs in human and mouse testes and that both VSELs and SSCs express FSH receptors. Thus, FSH exerts a direct stimulatory action on the testicular stem/progenitor cells whereby VSELs undergo asymmetrical cell divisions to self-renew (result in upregulation of pluripotent markers) and give rise to slightly bigger SSCs which undergo symmetrical cell divisions and \u201cclonal expansion\u201d (rapid proliferation with incomplete cytokinesis) which was noted by the authors as \u201cclump\u201d formation. This action of FSH is mediated via alternately spliced FSHR3 rather than the canonical FSHR1 receptor isoform, and FSH exerts similar action on ovarian and uterine stem/progenitor cells also. Being quiescent by nature, VSELs survive chemotherapy. Transplanted germ cells colonize chemoablated tubules but do not differentiate into sperm since the testicular stem cell niche comprising Sertoli cells gets functionally compromised by chemotherapy. Transplanting healthy niche cells  can restore spermatogenesis in chemoablated testes. Pieri et al.  have pubTestis harbors OCT-4-positive pluripotent stem cells in addition to SSCs: We have reported that both adult human and mouse testicular stem cells include a sub-group of pluripotent stem cells termed very small embryonic-like stem cells (VSELs) along with SSCs [ith SSCs \u20134. VSELsith SSCs , 5 and aith SSCs  and endoith SSCs  similar Effect of FSH on stem cells in adult mammalian testis: FSH treatment upregulated pluripotent markers in the testis. We have reported an increase in pluripotent OCT-4-positive stem cells after FSH treatment in mouse testis, ovaries, and uterus [d uterus \u20134, 7. InFSH stimulates SSCs to expand and form clumps or \u201ccolonies\u201d: FSH activated the SSCs to undergo proliferation resulting in a clump formation, with paracrine influence by the Sertoli cells as suggested by the authors. Rather, the testicular stem cells including VSELs and SSCs express FSHR, and FSH has a direct effect as reported for the first time in the literature by our group for both the testis [e testis  and ovare testis . We havee testis . Similare testis . Pluripoe testis , 8, 9.Transplanted SSCs colonize and expand in response to FSH but fail to differentiate in chemoablated mouse testis: This needs to be clearly understood. We have reported that VSELs survive chemotherapy whereas the Sertoli cells get functionally compromised. The authors observed long-term survival and colonization of cSSCs in chemoablated mouse testis, but they did not differentiate since Sertoli cells become non-functional as a result of chemotherapy. Transplantation of mesenchymal cells directly in the chemoablated testis (not intratubular route through the rete testis) helped to achieve differentiation since they provided an improved paracrine support to the surviving VSELs to restore spermatogenesis [ogenesis , 10.Both bone marrow and testicular VSELs when cultured on a Sertoli cell bed and in the presence of Sertoli cell-conditioned medium differentiate into germ cells and sperm .The purpose to write this commentary is because major interpretations and conclusions reported by Pieri\u2019s group need to be re-examined. Their findings are correct but still lack clarity on the role of FSH in adult testis that needs to be understood in proper perspective. We would like to discuss several facets of our findings to provide a novel understanding of the role of FSH on adult testicular stem cells.To conclude, FSH action is not limited to only the ovary and testis, and besides Sertoli and granulosa cells, it exerts a direct action on the stem cells to undergo self-renewal and clonal expansion. Alternately spliced FSH receptor isoform biology needs to be studied in greater details, and one needs to acknowledge both the stem cells and their niche to ensure regeneration of chemoablated testis."}
+{"text": "Adenocarcinomas account for approximately 40% of small bowel cancers. They are typically mucosal lesions with distinctive features on endoscopy. We describe a rare case of duodenal adenocarcinoma presenting as a subepithelial lesion which posed a diagnostic challenge. An 85-year-old male patient presented for investigation of iron deficiency anaemia. Initial upper endoscopy found a subepithelial duodenal lesion with central depression but otherwise normal appearing mucosa. Superficial biopsies of the duodenal lesion were unremarkable. Subsequent antegrade single balloon enteroscopy revealed active bleeding from the lesion which was refractory to endoscopic treatment. A complete local excision of the lesion via laparotomy was necessary to achieve haemostasis. Histopathology from the lesion showed a moderately differentiated duodenal adenocarcinoma with invasion into the submucosa but no evidence of lymphovascular spread. Duodenal adenocarcinomas are rare gastrointestinal tumours associated with a poor prognosis. This case report outlines a rare presentation of duodenal adenocarcinoma and highlights the importance of judicious assessment of lesions found on endoscopy. Advances in endoscopic diagnostic modalities could facilitate early diagnosis and improve therapeutic outcomes. Adenocarcinomas account for 40% of cancers in the small intestine and the most common site of involvement is the duodenum . They arAn 85-year-old male patient was referred for investigation of iron deficiency anaemia. His comorbidities included ischemic heart disease and localized prostate cancer with previous transurethral resection (TURP) and external beam radiotherapy (EBRT). Gastroscopy found the presence of two Forrest grade III antral ulcers which were biopsied. Histopathology from the gastric antral biopsies showed moderate chronic gastritis and focal intestinal metaplasia. His colonoscopy was unremarkable. CT abdomen pelvis with oral and intravenous contrast did not find a source of bleeding, evidence bowel obstruction or mural thickening suspicious for malignancy. He subsequently underwent capsule endoscopy for investigation of occult gastrointestinal bleeding which found a non-bleeding lesion in the duodenum. Antegrade single balloon enteroscopy again identified the 1.5\u2009cm polypoid, subepithelial lesion in the lateral wall of the second part of the duodenum, distal to the major papilla. The lesion had central depression and minor ulceration but otherwise normal appearing mucosa on endoscopy . Initialth edition, Stage I, T1bN0M0)  has demonstrated utility in the assessment of subepithelial lesions found on endoscopy. It provides a minimally invasive method of acquiring tumour characteristics such as size, layer of infiltration, and the presence of local lymphadenopathy which holds prognostic value and guides the use of biopsy techniques. EUS itself can be combined with fine needle aspiration (EUS-FNA) and fine needle biopsy (EUS-FNB) techniques for the sampling of lesions arising from the submucosa and muscularis propria . EUS-FNBThe treatment approach for duodenal adenocarcinoma differs from that of other subepithelial lesions in the small bowel. The American Society of Gastrointestinal Endoscopy (ASGE) outlines an approach for the management of subepithelial lesions, which takes into account histological features, size, layers involved, distal spread, symptomatology, and other patient factors . EndoscoAlthough rare, there have been previous reports of duodenal adenocarcinoma presenting as a subepithelial lesion. Kojima et al. reported this presentation in a 63-year-old female patient undergoing investigation for epigastric pain . The lesThis case report describes an unusual presentation of duodenal adenocarcinoma as a subepithelial lesion with initially unremarkable superficial biopsies. The diagnosis was only made retrospectively following complete excision of the lesion. The failure of initial biopsies to successfully diagnose the underlying lesion exposes the limitations of current techniques in the sampling of subepithelial lesions not accessible via endoscopic ultrasound. Improvements in endoscopic modalities for the assessment of subepithelial lesions could facilitate early diagnosis and improve therapeutic outcomes."}
+{"text": "Although metabolic alterations are one of the hallmarks of cancer, there is a lack of understanding of how metabolic landscape is reconstituted according to cancer progression and which genetic alterations underlie its heterogeneity within cancer cells. Here, the configuration of the metabolic landscape according to genetic alteration is examined across 7648 subjects representing 29 cancers. The metabolic landscape and its reconfiguration according to the accumulated mutation maintained characteristics of their tissue of origin. However, there were some common patterns across cancers in terms of the association with cancer progression. Carbohydrate and pyrimidine metabolism showed the highest positive correlation with tumor metabolic burden and they were also common poor prognostic pathways in several cancer types. We additionally examined whether genetic alterations associated with the heterogeneity of metabolic landscape. Genetic alterations associated with each metabolic pathway differed between cancers, however, they were a part of cancer drivers in most cancer types.The online version of this article (10.1186/s12943-018-0895-9) contains supplementary material, which is available to authorized users. Cancer cells reorganize their metabolism to fulfill their biosynthetic requirements for tumor growth and proliferation . BesidesHere, we aim to investigate the metabolic landscape of multiple cancer types and its configuration according to the progression. We also aim to find answers for whether there are common features in genetic alterations related to the metabolic landscape across cancer types. An integrated analysis of genomic and transcriptomic profiles of 29 different solid cancers was performed. We demonstrate that some common metabolic pathways exhibit the close relationship with TMB and clinical outcome across several cancer types. We also show that genetic alterations associated with cancer metabolic heterogeneity were a part of cancer drivers in most cancer types.We compared the median values of metabolic signatures manually curated considering cancer-related pathways for each cancer type . Of note, glycolysis, the well-known cancer metabolic feature, showed relatively weak correlation with TMB. LUSC showed the highest carbohydrate metabolism and TMB among 29 cancer types . In general, carbohydrate and nucleotide metabolism were associated with poor prognosis. Specifically, poor prognostic metabolic signatures include carbohydrate metabolism, ribonucleotide synthesis, pyrimidine metabolism, purine metabolism, and glycolysis, whereas good prognostic signatures include peroxisomal lipid metabolism, fatty acid oxidation, and biological oxidation.Several metabolic signatures were associated with overall survival across all cancer samples  were included in cancer drivers Fig. . In otheAccording to the results, cancer transcripts and protein networks consisting of metabolic pathways may be changed by cancer drivers instead of alterations of genes participated in the networks. It corresponds to the Darwinian selection of cancer cells which carry driver mutations facilitate cellular survival and growth by changing a favorable metabolic landscape . The reshttps://choih.shinyapps.io/metabolicsignatures) according to cancer type and its reconstitution according to cancer progression can contribute to developing appropriate diagnostics and therapeutics targeting metabolism for cancer subtypes.Among several metabolic signatures, carbohydrate metabolism representing overall nutrient demand and nucleotide metabolism showed the closest association with TMB and clinical outcome. Genetic alterations closely associated with metabolic heterogeneity were a part of cancer drivers in most cancers rather than genes affiliated to metabolic pathways. It supports the role of cancer drivers in the evolution process in constituting metabolic landscape appropriate for tumor growth. Our database of the metabolic landscape"}
+{"text": "Television viewing is a risk factor for poor physical and cognitive health. Yet, we know little about associations between current health and frequency of television viewing throughout the day. This study examined associations between multiple assessments of physical and cognitive well-being and television viewing. Participants (N = 313) from the Daily Experiences and Well-being Study completed an initial interview assessing their health and well-being. They also wore an Electronically Activated Recorders (EAR) to capture sound in the environment and an Actical to measure physical activity for 5 days. Coders rated the audiofiles for television viewing. Multilevel models revealed that participants who spent a greater proportion of time tuned into television had: higher BMI, poorer health, expended less energy, were more sedentary, and reported drinking more alcohol and eating more junk food. We discuss findings with regard to potential reciprocal influences between television viewing and poor health."}
+{"text": "Reperfusion injury follows ischemia/reperfusion events occurring during myocardial infarction, stroke, embolism, and other peripheral vascular diseases. Decreased blood flow and reduced oxygen tension during ischemic episodes activate cellular pathways that upregulate pro-inflammatory signaling and promote oxidant generation. Reperfusion after ischemia recruits inflammatory cells to the vascular wall, further exacerbating oxidant production and ultimately resulting in cell death, tissue injury, and organ dysfunction. Diving mammals tolerate repetitive episodes of peripheral ischemia/reperfusion as part of the cardiovascular adjustments supporting long duration dives. These adjustments allow marine mammals to optimize the use of their body oxygen stores while diving but can result in selectively reduced perfusion to peripheral tissues. Remarkably, diving mammals show no apparent detrimental effects associated with these ischemia/reperfusion events. Here, we review the current knowledge regarding the strategies marine mammals use to suppress inflammation and cope with oxidant generation potentially derived from diving-induced ischemia/reperfusion. The ability to manage body oxygen stores in the face of environmental hypoxia constrains the life history of many vertebrate taxa. In humans, oxygen management is critically important in clinical settings where both acute and chronic conditions such as organ transplantation and intermittent hypoxia contribute to ischemic injuries. Diving mammals, however, experience fluctuations in blood flow and oxygen saturation without sustaining such injuries. A range of physiological mechanisms for coping with finite oxygen availability has been identified to date  is considered the master regulator of the molecular response to hypoxia across taxa . Functiop apneas . MoreoveRecent phylogenomic studies have begun to uncover additional molecular mechanisms underpinning ischemia/reperfusion tolerance in marine mammals, including the expansion and positive selection of several gene families related to oxidative stress tolerance and oxygen management. Most work has considered cetacean species; pinniped genomes have generally been less available. In strong agreement with the current physiological understanding of antioxidants in both cetaceans and pinnipeds, several genes in the glutathione system \u2013 including glutathione reductase, glutathione peroxidases, and \u03b3-glutamylcysteine ligase \u2013 are expanded, under positive selection, and/or have amino acid changes in cetaceans . Two perManaging body oxygen stores and tissue oxygen supply while diving is of paramount importance for marine mammals. Hemoglobin and myoglobin are central to this process; both are under positive selection in cetaceans . In the ex vivo systems that are amenable to physiological manipulation and molecular perturbation in an effort to provide the missing link between genomic- and organismal-level investigations. Identifying the drivers of ischemic and hypoxemic tolerance in marine mammals can provide a mechanistic understanding of natural tolerance to such conditions while aiding in translation to clinical applications.Marine mammals experience diving-induced hypoxemia and ischemia/reperfusion events without apparent detrimental effects. Physiological, biochemical, and genomic studies have begun to uncover the mechanisms underlying such extreme tolerance. Among those mechanisms, coordinated body-wide responses to delay the onset of tissue hypoxia, counteract oxidant generation and prevent inflammation are critical. Convergent genomic changes across marine mammal lineages hint at the evolutionary underpinnings of the physiological adaptations supporting mammalian diving . The incKA and JV-M wrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Adults who remain cognitively active may be protected from age-associated changes in white matter (WM) and cognitive decline. To determine if cognitive activity is a precursor for WM plasticity, the available literature was systematically searched for Region of Interest (ROI) and whole-brain studies assessing the efficacy of cognitive training (CT) on WM microstructure using Diffusion Tensor Imaging (DTI) in healthy adults (> 40 years). Seven studies were identified and included in this review. Results suggest there are beneficial effects to WM microstructure after CT in frontal and medial brain regions, with some studies showing improved performance in cognitive outcomes. Benefits of CT were shown to be protective against age-related WM microstructure decline by either maintaining or improving WM after training. These results have implications for determining the capacity for training-dependent WM plasticity in older adults and whether CT can be utilised to prevent age-associated cognitive decline. Additional studies with standardised training and imaging protocols are needed to confirm these outcomes."}
+{"text": "Papio ursinus) and assesses their relative importance. Our results show that oestrous females initiate fewer copulations in the presence of adult male bystanders, irrespective of whether they are mate-guarded or not. This inhibitory effect probably reflects a response to indirect sexual coercion by males, whose close proximity may dissuade females to initiate copulations with rival males to avoid punishment and/or aggressive mating interference. By contrast, females initiate more matings with their mate-guard in the presence of higher-ranking female bystanders, which may reflect an attempt to secure bodyguard services from their mate when they feel threatened. These results emphasize the importance of intra- and intersexual conflicts in shaping female sexual behaviour in this promiscuous society.In social species, female mating strategies can be constrained by both male and female groupmates through sexual conflict and reproductive competition, respectively. This study tests if females adjust their sexual behaviour according to the presence of male and female bystanders in wild chacma baboons ( For example, dominant females often harass other females and interfere with their mating attempts, and monopolize resources that are necessary to breed, such as shelters, mates or offspring care . SimilarTheropithecus gelada) )"}
+{"text": "The combination of aging and losing an only adult child challenges an increasing number of older adults in China. Current literature primarily focuses on older parents\u2019 bereavement but seldom examines how they restore their lives. Guided by the Dual Process Model, this study explores how older parents who lost their only adult child restore their lives and prepare for future care in Shanghai. Twenty-four older adults were purposively sampled and participated in face-to-face, in-depth interviews. The findings suggest that participants tried to restore their lives by rationalizing grief and expanding their social networks. Despite their losses, participants remained in favor of family caregiving and reluctantly prepared for future care. They showed ambivalent attitudes toward current government support while proposing their preferred services. This study informs social work practice to incorporate caregiving plan services and emotional support for this vulnerable group."}
+{"text": "The current achievements in treating glioblastoma (GBM) patients are not sufficient because many challenges exist, such as tumor heterogeneity, the blood brain barrier, glioma stem cells, drug efflux pumps and DNA damage repair mechanisms. Drug combination therapies have shown increasing benefits against those challenges. With the help of nanocarriers, enhancement of the efficacy and safety could be gained using synergistic combinations of different therapeutic agents. In this review, we will discuss the major issues for GBM treatment, the rationales of drug combinations with or without nanocarriers and the principle of enhanced permeability and retention effect involved in nanomedicine-based tumor targeting and promising nanodiagnostics or -therapeutics. We will also summarize the recent progress and discuss the clinical perspectives of nanocarrier-based combination therapies. The goal of this article was to provide better understanding and key considerations to develop new nanomedicine combinations and nanotheranostics options to fight against GBM. GBM therapeutics need to be able to cross this barrier and penetrate the brain to reach the tumor. However, only small lipophilic chemotherapeutic agents with a molecular weight less 400 Da and 8 hydrogen bonds can passively pass through the BBB The blood brain barrier (BBB) is a particularly formidable challenge in developing therapeutics for brain tumors. Brain microvascular endothelial cells, pericytes, astrocytes, tight junctions, neurons and the basement membrane together form a physical barrier to protect the brain and maintain a well-defined intracranial environment Another difficulty is found in the heterogeneity of GBM. Genomic research has shown that GBM contains many different cell types depending on their origin or subsequent genetic and epigenetic conversions in vitro and in vivo. Consequently, populations of glioma stem cells remain alive after initial treatment and reinitiate tumor recurrence This genetic drift can result in self-renewing, tumorigenic glioblastoma stem cells (GSCs) that contribute to tumor initiation and therapeutic resistance MDR1 gene has been mostly considered as the cause of anti-cancer drug resistance. MDR1 P-gp is present in the brain capillaries of the BBB, as well as in many other tissues. Many drugs exhibit significantly improved brain penetration when drug efflux transporters are inhibited Multidrug resistance (MDR) presents another major barrier for chemotherapeutic drugs to get access to brain tumor cells effectively. Among the different mechanisms of MDR, ATP-binding cassette (ABC) transporter-mediated exocytosis was mostly noticed. The P-glycoprotein (P-gp) which is encoded by the human Because of these challenges, combining drugs with different working mechanisms has gained great attention in recent years. The right combination of compounds could enhance efficacy by targeting these issues in a synergistic or additive manner. However, the efficiency of many chemotherapeutic agents is also limited by their dose-related toxicities. As the BBB shields the brain from most systemically administrated compounds, high doses are given to achieve intracranial therapeutic drug levels. Increasing the dose of a specific anticancer drug will inevitably lead to significant toxicity. Many GBM chemotherapeutic drugs have demonstrated off-target toxicity at the doses needed to reach an intracranial effect. For example, TMZ is associated with lymphopenia, thrombocytopenia and neutropenia With growing investigation of the tumor microenvironment and by unravelling biological and molecular pathways, increasingly more potential drug combinations are emerging. However, just combining cytotoxic compounds does not address the problems associated with poor drug distribution at the desired tumor site. Different approaches have been raised to defeat unfavorable drug distribution in the brain In this review, we will discuss and address the advantages of drug combinations with or without nanocarriers, nanomedicine-based tumor targeting strategies, current preclinical drug combinations, and promising nanotherapeutics and nanodiagnostics. The aim of this review was to highlight the importance and potential of drug combinations and give a comprehensive understanding of different combination strategies for GBM therapy.Poor drug delivery, tumor heterogeneity and drug resistance pathways have prevented single compound therapies to show significant benefits for GBM patients Drug delivery to GBM is notoriously difficult due to the inability of most drugs to cross the BBB and penetrate the tumor tissue. Only few systemically administrated drugs reach the tumor site in a therapeutic dose. Various approaches, such as chemical modification of chemotherapeutic drugs, BBB altering strategies and efflux transporter inhibitors, are being investigated to enhance the systemic delivery of potential anti-GBM drugs. For instance, drugs can be modified to a more lipophilic form by adding lipid groups to the polar ends of therapeutic molecules. A log P (octanol-water) value ranging from 1.5 to 2.5 of lipophilic analogs has better brain permeability Alternatively, hyperosmotic agents, bioactive molecules, surfactants and ultrasound or electromagnetic waves have been used to alter the permeability of the BBB. Yet, such approaches are often associated with risks such as possible tumor diffusion to the periphery, and exposure of the brain to neurotoxins.In addition, inhibition of ABC efflux gene families can increase drug penetration into the brain without compromising the integrity of the tight junctions and endothelial layers. However, this approach will also reduce the efflux of potential neurotoxic compounds. In fact, many of these efflux pumps transporters could not be fully inhibited due to various reasons, including multifactorial multidrug resistance and genomically unstable tumor cells via convection enhanced delivery. The Ommaya reservoir is a reservoir capsule connected to a catheter located in the lateral ventricle. The capsule is embedded under the scalp and is easily accessible for cerebrospinal fluid (CSF) aspiration or drug delivery directly into the ventricular CSF and relies on the flow of CSF to distribute chemotherapeutics, radioactive compounds, antibodies, viruses or cells throughout the brain Local intracranial delivery not only overcomes BBB-associated drug delivery issues but also prevents systemic compound clearance and/or degradation and reduces systemic side effects. As such, much lower dosages are needed. Local drug delivery to the brain and further distribution within the brain can be mediated by simple diffusion using a reservoir-catheter system or positive pressure bulk flow via convection-enhanced delivery (CED). The positive pressure drives convective local transport of therapeutic concentrations of anti-tumor drugs into the interstitial tumor space. This technique achieved higher drug concentrations in the targeted tumor tissue compared with diffusion-limited delivery Alternatively, drugs are administered to the brain continuously with a positive pressure bulk flow \u00ae wafer for newly diagnosed malignant and recurrent GBM. However, the success of Gliadel\u00ae wafers is restricted by the limited penetration of the active compound, carmustine, into the brain tumor tissue. Moreover, use of the wafers has been associated with several adverse events, including intracranial infections, wafer migration, cerebral edema, CSF leakage and seizures Locally implanted (biodegradable) drug delivery depots have increasingly gained interest. Currently, the only FDA-approved biodegradable implant is the GliadelNevertheless, the concept of local delivery by implanting drug-releasing depots in the tumor resection cavity remains intriguing for the treatment of GBM. Films, foams and gels have been investigated for their use in local drug delivery. Particularly hydrogels have gained much attention in recent years. In general, hydrogels are injectable, biocompatible, biodegradable and mechanically comparable to soft tissue, making them attractive for intracranial implantation. They provide a versatile drug delivery system because they can be loaded with small-molecule drugs, biomacromolecules (such as DNA or protein) or cells. The gels can be engineered to tune the release of their contents in a timeframe ranging from hours up to several months Different drug combination strategies have been explored in clinical trials to tackle known drawbacks of GBM treatment. A non-exhaustive summary of combination therapy trials is presented in table 6-methylguanine-DNA methyltransferase (MGMT inhibitor) O6-benzylguanine (O6-BG) to rebuild drug sensitivity in TMZ-resistant anaplastic glioma. Indeed, O6-BG was able to restore TMZ sensitivity in TMZ-resistant anaplastic glioma, but not in TMZ-resistant GBM Another phase II clinical trial combined TMZ with an OMore often than not, promising preclinical anti-tumor strategies disappoint in clinical trials due to various reasons. For example, a phase I/II trial to determine the efficacy of vorinostat + erlotinib versus vorinostat + erlotinib + TMZ in patients with recurrent GBM multiforme was terminated because of unanticipated toxicities (NCT01110876). A trial that combined the histone deacetylase inhibitor vorinostat and proteasome inhibitor bortezomib to treat recurrent GBM, reported that no patient achieved 6-month PFS and only one patient showed a partial response according to the Macdonald Criteria, probably due to brain delivery issues in vitro results can be explained by several factors  therapeutics, which has led to disappointing clinical outcomes table . For GBM\u00ae, Doxil\u00ae, DaunoXome\u00ae) mainly reduce toxicity of the parent compound and thereby improve its therapeutic index. Small interfering RNAs (siRNA) show great therapeutic promise but have disappointing clinical relevance due to stability and delivery issues. The only currently FDA approved siRNA therapeutic is Patisiran\u00ae, which is based on a lipid NP formulation that improves siRNA stability.Depending on the materials, nanoformulations are able to load hydrophilic and hydrophobic drugs, ensure sustained drug release and enhance the half-life of the drug in the circulation. For example, the half-life of TMZ was enhanced to 13.4 h compared to 1.8 h of the free drug by encapsulation in a chitosan-based nanoparticle Two decades have passed since the first NP-based cancer treatment was approved by the FDA, with an increasing number of clinical trials now ongoing, including many for GBM. A variety of systems based on polymers , inorganic materials  and/or lipids  have been investigated for drug delivery to the brain. The therapeutic drugs can be loaded in these particles by encapsulation, covalent linking or surface adsorption Passive tumor targeting is based on the observation that certain sized particles tend to accumulate in tumor tissue much more than they do in healthy tissues. This is known as the enhanced permeability and retention effect (EPR) effect, which was first described by Matsumura and Maeda in 1986 i) heterogeneity or lack of fenestrations in the tumor endothelium, (ii) presence of acidic and hypoxic areas (iii) lower or heterogeneous pericyte and basement membrane coverage, (iv) and high interstitial fluid pressure (IFP) induced by dense extracellular matrix, explaining the difficulty in translating the EPR effect from bench to bedside However, within the last couple of years, more and more researchers have realized that the EPR effect is highly heterogeneous both intra- and intertumorally, varies during tumor development and does not always hold up in clinical settings Figure . MoreoveInterestingly, GBM is characterized by robust endothelial proliferation resulting in tortuous, disorganized and highly permeable vasculature First of all, when comparing different imaging modalities, it becomes clear that T1-weighted MRI alone does not visualize the entire tumor. Beyond the contrast-enhancing region, essentially all of GBM show non-enhancing edema on T2-weighted or fluid attenuation inversion recovery imaging Other key pathological features of GBM are hypoxic areas surrounded by hypercellular rings of actively migrating tumor cells Due to the differences in EPR effect between and within tumors, approaches to still take advantage of it may vary. In certain situations, one might benefit from tumor vasculature normalization 64Cu-labeled long-circulating particles of different size were systemically administered and tracked via MRI and positron-emission tomography (PET) in an intracranial rat GBM model. It was demonstrated that 7 hours after systemic injection, the uptake of 20 nm NPs is significantly greater than those of 110 nm. It also showed that PET/MRI co-registration of brain images may contribute to the monitoring of disease progression and determining what drug delivery approach is feasible The extent of EPR in a tumor could be tested prior to treatment using imaging modalities. In a preclinical study, the relative blood volume was found to correlate with the tumor accumulation of polymeric drug carriers. With the help of contrast-enhanced ultrasound imaging, this vascular parameter proved useful in predicting EPR-mediated tumor accumulation of NPs and could possibly be used to preselect patients eligible for nanotherapeutic treatment The high variability of the EPR effect is considered as one of the major challenges for translating nanomedicine into the clinic. This issue can be addressed by indirect EPR imaging, utilizing companion diagnostics or developing systems with both diagnostic and therapeutic properties (theranostics). Indirect EPR imaging can non-invasively visualize and quantify the key EPR-determining parameters of the tumor vasculature, while theranostics or companion diagnostics can give insight in NPs distribution and tumor responses.via the secretion of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and CXC-chemokine ligand 2, paving the way for hypervascularity as seen in GBM et al. developed an albumin-based biomimetic NPs with transferrin receptor-binding peptide T12 and mannose as targeting ligands for codelivery of the disulfiram/copper complex and the macrophage modulator regorafenib. The T12 peptide can enhance BBB permeability and glioma cell uptake. The mannose ligand can bind to mannose receptors on TAM2. This system efficiently inhibited the glioma cell proliferation, successfully induced the protumor TAM2 towards antitumor TAM1 and triggered macrophage-directed anti-glioma immunotherapy via TAM, regulatory T cells, CD8+ T cells and cytokines Many cancers are preceded by infections or (chronic) inflammation and it is increasingly clear that the immune system plays a central role not only in cancer development but also in tumor progression et al. show that NPs predominantly accumulate in tumor associated immune cells rather than tumor cells. They used fluorescently labeled polymeric NP (100 nm) together with magnetic NP (20 nm) in several tumor mouse models to predict NP tumor accumulation and treatment outcome. It appeared that NP distribution was mainly determined by vascularization and permeability at early time points, but at later time points by cellular uptake. Both NPs were mostly taken up by host phagocytes (> 90%). High local TAM counts correlated with increased NP accumulation and as such proved an important component of the EPR effect In vitro studies show monocyte mediated transfer of NP over an endothelial monolayer In vivo, TAM with ingested NPs has been observed to cross the BBB and migrate to (distant) tumors. As such, NPs were shuttled between contralateral CNS tumors via migrating TAMs via these cells.The inflammatory response observed in GBM results in increased vascular permeability as well. In turn, this will not only allow for extravasation of immune cells, but also of therapeutics including NPs. Furthermore, extracellular matrix (ECM) remodeling can influence NPs transport through the interstitial space e.g. ATP, calreticulin, high-mobility group box 1(HMGB1) and chemokine ligand 10 (CL10), allowing dendritic cells to recognize the dying cell and initiate an anti-tumor immune response to clear tumor cells Another point that might influence the immune microenvironment-based therapy for GBM is the immunosuppressive effects of chemotherapy. Indeed, systemic chemotherapy might suppress the bone marrow and consequently impact the amount and activation state of immune cells When passive targeting is insufficient, active targeting of NPs can facilitate their transport over the BBB. With polymeric NPs this is often achieved by modifying their surface with surfactants or BBB- or glioma-specific ligands. For example, doxorubicin (DOX) loaded poly butyl-cyanoacrylate NPs were more effective when coated with the surfactant P80 and increased the survival time of GBM tumor bearing rats compared to the non-coated group \u00ae) resulted in a significantly higher intratumoral concentration of DOX than normal brain tissue in GBM patients via RME and promote tumor specific uptake. Transferrin conjugated liposomes increased brain delivery of 5-fluorouracil by 13 times compared to non-conjugated liposomes Lipid NPs, liposomes in particular, are also widely investigated in the drug delivery field. Liposomes can encapsulate hydrophilic compounds in the aqueous compartment and hydrophobic compounds in the bilayer making it a versatile delivery vehicle. Covering the surface of these particles  with polyethylene glycol (PEG) neutralizes surface charge but thereby ensures prolonged circulation and increases the EPR effect. Radiotherapy supplemented with PEGylated liposomal DOX (CaelyxLipid nanocarriers (LNCs) are also able to load both hydrophilic and hydrophobic molecules in an aqueous core by formation of reversed micelles 131I-labeded CTX-functionalized polyethylenimine-entrapped gold nanoparticles as a multifunctional glioma-targeting nanoprobe was generated. After incubation with the NPs, C6 cells displayed much stronger fluorescence intensities than those treated with negative controls under the same conditions by confocal imaging. This CTX-loaded NP could also act as a nanoprobe for the targeted single photon emission computed tomography (SPECT)/ computed tomography (CT) imaging of glioma cells and in a subcutaneous tumor model Sometimes NPs are made by organic-inorganic hybrid materials as the magnetic and optical features of metallic NPs can be used to actively target to tumor site and monitor delivery non-invasively. In an U87MG orthotopic tumor model, magnetic targeting treatment with superparamagnetic iron oxide (SPIO) and PTX coloaded PLGA NPs significantly enhanced the median survival time compared with the passive targeting treatment group via passive targeting, while active targeting might be employed to increase this accumulation in hard to reach tumors such as GBM. Imaging (whether direct or indirect) can give an indication of the potential of certain tumors to be treated with NP formulations, thereby preselecting patients and possibly improving treatment success.Overall, NPs show great potential in preclinical studies. They often improve accumulation of therapeutic compounds Nanocarrier formulations additionally offer the opportunity to incorporate imaging features facilitating diagnostic as well as monitoring features. Accurate diagnosis is essential for adequate cancer treatment. For GBM, imaging is pivotal as the alternative diagnostics (e.g. biopsies or surgery) are highly invasive. As such, imaging is crucial for (preliminary) tumor characterization and localization, planning of surgical strategies and monitoring of treatment response.Generally, maximal gross resection is correlated with increased survival via compromised and leaky vasculature, amino acid linked PET tracers can transverse the intact BBB Where conventional contrast enhancers and tracers can only enter the brain Coupling the integrin targeting ligand RGD to PET tracers increased their tumor specificity in mouse models via fluorescence imaging ex vivoet al. designed a carbon-based QD that could emit red light. Intravenously injected dots accumulated in xenograft HeLa tumors via EPR and allowed in vivo fluorescent as well as PA imaging. Moreover, the dots could be used as photothermal inducers, as a large percentage of the absorbed energy is converted to heat, facilitating thermal ablation of tumor tissue Preclinically, novel materials and approaches are being investigated such as quantum dots (QDs), metallic NPs, protein conjugates and polymeric particles 64CuCl2. These particles could be imaged using PET scans in a xenograft GBM mouse model. The dots were self-luminescent via cerenkov resonance energy transfer, making it possible to visualize tumors via luminescence imaging as the EPR effect resulted in tumor accumulation of the PEGylated particles via PET imaging and showed promising fluorescence imaging opportunities in an earlier mouse study Alternatively, QDs can be coupled to other imaging agents such as radioactive tracers to allow deeper tissue imaging. PEGylated radioactive QDs were made using metal chlorides and via MRI allowing tracking of the particles and simultaneously present a way of directing the particles toward their goal via magnetic fields. A second biocompatible layer reduces toxicity and extends circulation via magnetic targeting, assisted by ultrasound-targeted microbubble destruction of the BBB. They were visualized by MRI (SPION) and fluorescent imaging (using the QD). The fluorescent signal was able to improve gross resection while the loaded cinglitide could inhibit tumor growth \u00ae for hyperthermal treatment of primary and recurrent GBM. The particles are injected intratumorally, followed by applying alternating magnetic fields to produce cell killing heat. Combined with radiotherapy, NanoTherm\u00ae prolonged survival in 66 patients with recurrent GBM As mentioned in the section of active targeting, superparamagnetic iron oxide nanoparticles (SPIONs) are extensively investigated as standalone theranostic particles as well. The magnetic iron core can be visualized As more and more information is gathered on the presence of different cellular compositions in different tumor regions, subtype specific diagnostic/ theranostic NPs might be used to elucidate the tumor make up and provide tailored therapy e.g. Bortezomib and HDAC; O6-BG and TMZ) in vitro. Intravenous administration of NPs encapsulating the compounds in their optimal ratio significantly inhibited tumor growth in a U87 subcutaneous model in vivoDue to differences in BBB permeability, drug stability and pharmacokinetics, therapeutic efficacy may be disappointing when simply administering two or more theoretically synergistic compounds  in several tumor models Besides the optimal ratios, the timing and order in which drugs are administered can have significant effects on the treatment outcome. For instance, the complex tumor microenvironment can greatly impair drug distribution within the tumor p53 gene plasmid was loaded in a transferrin targeted liposome (SGT-53) which could sensitize human glioma cells to TMZ. Moreover, pretreatment of TMZ resistant tumors with SGT-53 reversed TMZ resistance, while co-delivery of SGT-53 and TMZ postponed the development of TMZ resistance in an intracranial mouse GBM model p53 inhibitors MDMX and MDM2 which was loaded in an RGD-targeted micelle. The micelles could reach an intracranial tumor and exert potent p53-dependent anti-proliferative activity. In addition, activating p53 sensitized the tumors for subsequent TMZ treatment The timing and order of treatments can also significantly affect the way tumors respond to certain insults on a cellular level, a factor that often seems overlooked. Knocking down epidermal growth factor receptor (EGFR) signaling in triple-negative breast cancer cells markedly increased their sensitivity to subsequent DOX treatment. Reverse order or simultaneous administration had no such effect and could even be inhibitory, emphasizing the importance of timing rather than just co-administration Intelligent designs of NPs As single drug therapies often seem insufficient for the treatment GBM, the focus has shifted to combination therapies. It is important to find combinations that act synergistically and preferably on different targets as tumor heterogeneity and emergence of resistance pathways need to be considered. Genetic profiling of tumors can help in finding the most promising approach. Incorporating established therapies in combination approaches will ensure faster translation to the clinic while adding compounds for novel targets such as the tumor immune microenvironment has shown promising results. However, simply administering two compounds systemically will most likely result in underwhelming results. Brain delivery of most compounds has proven challenging and seems to be insufficiently acknowledged as few clinical trials investigate or report brain concentrations of the used compounds.in vivo studies, results fail to translate to the clinic. This is partly due to too simplistic (murine) models that don't represent the complex human tumor heterogeneity.Intracranial delivery of therapeutics is promising but still needs significant optimization before it is sufficiently practical to be implemented in standard care. Systemic delivery is predominantly hampered by the BBB. There is increasing interest in nanoformulations for the delivery of drugs to the brain and has shown promising results in preclinical  animal studies. The ideal design of a nanosized delivery system depends predominantly on the encapsulated molecules, the preferred release profile of each compound (simultaneous or time staggered) and which cells are targeted. Nevertheless, certain characteristics seem to be universally beneficial. PEGylating the particle and keeping the size around 20-75nm ensures prolonged circulation and at the same time allows sufficient tissue penetration. Factors such as the partition coefficient, the molecular weight and the synergistic ratio of the payloads have to be considered as well. Although nanocarrier based brain delivery shows promising results in preclinical p53 and/or Rb knock-down and the activation of pro-survival RTK and Ras signaling to allow for de novo tumor formation. With GEMMs, it could be possible to investigate the function of tight junction proteins, transporters, or ECM components in BBB development and biology as well. On the other hand, GEMMs also failed to recapitulate the intratumoral heterogeneity seen in patients. Other limitations like expensive breeding and low tumor penetrance have to be considered In order to have a more accurate prediction of clinical outcome of novel therapeutic strategies, an ideal mouse glioma model should be orthotopic and highly reproducible with predictable tumor growth, bear a genetic similarity to human glioma, show cellular heterogeneity and angiogenic-like growth Additionally, EPR based passive brain targeting of NPs as seen in animal models fails to translate to the clinic. Active targeting is often suggested to improve tumor accumulation yet it is most likely more favorable to pre-select for patients that are suited for NP based treatment. Novel imaging modalities as well as the rise of nanotheranostics will provide the opportunity to pre-select patients with appropriate tumor characteristics such as high tumor perfusion and large relative blood volumes. Additionally, nanotheranostics will provide a way to monitor drug delivery and possibly visualize treatment outcome.The preclinical success of immunotherapy of GBM has not been replicated in human clinical trials. Both vaccines as single therapy and immune check point inhibitors have led to disappointing clinical results GBM is a complicated cancer that involves various sophisticated molecular pathways, gene mutations, and tumor microenvironments. Despite plentiful investigations, an unmet medical need persists for the treatment of invasive GBM. Here we have described the current strategies for nanomedicine-based drug combination therapies. With increasing knowledge of GBM molecular pathways, increasingly more intelligent drug combination strategies will be developed. Nanocarriers will be designed to improve delivery and allow targeting of different pathways within the tumor microenvironment. Future approaches will exploit different nanocarrier-based combinations, the most promising being immunotherapy and nanotheranostics, to enhance the therapeutic benefits for GBM. With the broad knowledge and efforts of researchers, nanocarrier-based combination therapies are expanding the way for success in the battle for GBM treatment."}
+{"text": "Cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) improve survival of patients with colorectal peritoneal metastases (PM).,Therefore, identification of practical clinicopathologic prognostic variables is key to optimize treatment for patients with PM. Patients who experience PM despite previous adjuvant chemotherapy after primary tumor resection are thought to benefit less from cytoreduction and HIPEC, and several studies and guidelines exclude these patients from a potentially curative HIPEC treatment.3This study evaluated all relevant clinicopathologic variables potentially associated with oncologic outcome in a large prospectively obtained cohort of 175 patients who had colorectal PM and were treated with cytoreduction and HIPEC.Future guidelines should incorporate the identified clinicopathologic prognosticators into clinical practice. Before clinical implementation, however, these variables require further prospective validation. A combined effort, with prospectively collected consecutive data from patients with PM, is key for this purpose. Currently, ongoing clinical trials with patients who have colorectal PM are addressing perioperative systematic chemotherapy, the additional value of HIPEC versus cytoreduction alone, and novel chemotherapeutic HIPEC agents. Future research to optimize treatment of patients with PM should focus on identification of molecular tumor characteristics that could improve patient selection. In addition, the substantial progress regarding the use of blood samples as liquid biopsies could provide prognostic (epi-)genetic information. Knowledge of tumor biology not only could help in selecting the right patients, but also could provide guidance regarding the optimal chemotherapeutic drug for the HIPEC treatment. Ultimately, a personalized profile consisting of both clinical and molecular characteristics will provide a way toward tailored treatment for patients with colorectal PM."}
+{"text": "Extrachromosomal gene amplification refers to copy number gains of DNA fragments that are not contiguous with the twenty-three canonical chromosomes. Unlike typical chromosomes, they are composed of circular DNA fragments without centromeric sequences . They arEGFR) is, by far, the most commonly altered oncogene in glioblastomas, the most common form of primary brain cancer. It is mutated or amplified in 60% of glioblastomas [EGFR gene. EGFRvIII-positive glioblastomas exhibit unique molecular physiologies associated with distinct therapeutic response profiles and an overall tumor aggressiveness [Epidermal growth factor receptor gene (lastomas . OncogenEGFR deletion variants.Breakpoint junctions in EGFRvIII are highly variable between tumor samples due to 120-kb-long intron one of this gene where one of the breaks take place. Breakpoint sequence analyses implicate contribution by multiple DNA strand-break repair mechanisms, including non-homologous end joining, micro-homology mediated end joining, and other forms of replication mediated repair . These fEGFRvIII is that a single tumor can harbor multiple, independent EGFRvIII variants -- each with distinct breakpoint junctions. These variants as well as the accompanied amplified full-length EGFR share common allelic profiles, suggesting that the deleted variants arose from a common ancestral amplified EGFR. A corollary of this hypothesis is that distinct additional genomic rearrangements of amplified full-length EGFR in glioblastoma subpopulations gave rise to polyclonal EGFRvIII breakpoint species (Figure Another interesting observation pertaining to s Figure .EGFR variant formation and EGFR amplification. Is extrachromosomal EGFR amplification a requisite precursor of EGFRvIII? For instance, this acquisition of glioblastoma specific EGFR deletion mutation might be associated with the fact that amplified EGFR in glioblastoma mostly resides in extrachromosomal DNA that is selectively captured in micronuclei [EGFRvIII.An important mechanistic question in this context involves the sequence of events that led to ronuclei , where cronuclei . In thisEGFRvIII is formed, not only do cells expressing this mutant transform to a more aggressive phenotype as mentioned above, but surrounding tumor cells without mutant EGFR are also benefited in terms of growth and cell survival by paracrine effects through cytokines such as interleukin-6 [EGFR yielding EGFRvIII that establishes an ecosystem supportive of aggressive tumor growth. Elucidation of this mechanisms of further rearrangements of extrachromosomal amplicons should yield opportunities for future therapeutic development and mechanistic insight.Once leukin-6 , or throleukin-6  (Figure"}
+{"text": "Drug targeting has opened a new paradigm in therapeutics with development of delivery vectors like liposomes and polymeric nanoparticles. Although their clinical application is crippled by limited biological adaptability. Off-target toxicity and biocompatibility still remains one of the critical problems in anticancer therapeutics that can be life-threatening. Here we report a quick, simple and facile method of engineering human platelets to generate drug loaded platelet-derived microparticles (PMPs) by top-down approach, which are biocompatible and naturally target leukemia cells. Drug loaded PMPs and cancer cell uptake were characterized by flow cytometry, confocal microscopy, Nanoparticle Tracking Analysis and fluorimetry. Effective drug delivery was tested in cancer cell lines as well as in clinical samples from leukemia patients. We explored that PMPs are capable of carrying multiple drug payloads, have long shelf life and can be harvested in large quantity in short period. Importantly, PMPs exhibited remarkably higher toxicity towards cancer cells than free drug and had lower escape into extravascular spaces. Transfer of drug to cancer cells of leukemia patients was significantly higher than free drug, when delivered through PMPs. Our experiments validated therapeutic application of PMPs as biocompatible drug delivery vector against cancer cells with minimal off-target delivery. Off-target toxicity is presently one of the main issues associated with drug administration, especially anticancer therapy . Being pTargeting drugs to specific sites of action through nano-sized vehicles has opened new paradigm in therapeutics . Despitein vivo, as well as overcoming biological barriers such as the blood-brain barrier  under informed consent. Leukemia diagnosis was confirmed by presence of >90% blast cells with high nuclear-cytoplasmic ratio in peripheral blood and bone marrow examinations. Aliquots (100 \u03bcl) of whole blood from each sample were treated either with vehicle (buffer without Dox), or free drug (0.15\u20130.2 \u03bcg/ml DoX), or equivalent PMPDox for 1 h. WBCs were separated using RBC lysis reagent (Puregene), fixed with 2% paraformaldehyde and Dox uptake was evaluated by flow cytometry. Comparison with normal leukocytes was carried out with blood obtained from healthy donors following similar procedure.t-test was used for evaluation of significance and values of p < 0.05 were considered significant. This study was approved by ethical committee of Institute of Medical Sciences, Banaras Hindu University.All data are representative of at least three independent experiments. Two-tailed Student\u2019s In this report we discussed a quick and facile top-down approach of generating drug-loaded PMPs that behave as natural vectors targeted against leukemia and other cancers. PMPDox engineered from autologous human platelets are physiological, biocompatible, non-immunogenic and inherently targeted towards cancer cells, thus obviating the need for implantation of exogenous targeting molecules on the particle surface. PMPDox is also capable of carrying multiple therapeutic payloads. Platelets can be easily accessed from blood and harvested in large quantity. PMPDox can be generated in huge number from donor platelets, stored for several days without loss of stability and exhibit targeted delivery and higher toxicity against leukemia cells than free drug. Successful drug delivery and compatibility in whole blood samples from leukemia patients confirmed potential practical application of this approach. Multimodality is also feasible in our approach as multiple anticancer drugs and/or contrasting agent can be loaded into PMP. Reduced extravascular escape of drug from PMPDox would minimize off-target adverse effects including cardiac and hepato- toxicity, making it far safer approach for anticancer therapy."}
+{"text": "V600E can be targeted with selective inhibitors, such as vemurafenib. Despite initial positive tumor responses of regression and decreased viability, both single agent or combination agent drug treatments provide a selective pressure for drug resistant evolving clones within the overall heterogeneous tumor. Also, there are evidences suggesting that sequential monotherapy is ineffective and selects for resistant and ultimately lethal tumor clones. Reconstructing both clonal and subclonal thyroid tumor heterogeneous cell clusters for somatic mutations and epigenetic profile, copy number variation, cytogenetic alterations, and non-coding RNA expression becomes increasingly critical as different clonal enrichments implicate how the tumor may respond to drug treatment and dictate its invasive, metastatic, and progressive abilities, and predict prognosis. Therefore, development of novel preclinical and clinical empirical models supported by mathematical assessment will be the tools required for estimating the parameters of clonal and subclonal evolution, and unraveling the dormant vs. non-dormant state of thyroid cancer. In sum, novel experimental models performing the reconstruction both pre- and post-drug treatment of the thyroid tumor will enhance our understanding of clonal and sub-clonal reconstruction and tumor evolution exposed to treatments during ultra-precision targeted therapies. This approach will improve drug development strategies in thyroid oncology and identification of disease-specific biomarkers.The introduction of ultra-precision targeted therapy has become a significant advancement in cancer therapeutics by creating treatments with less off target effects. Specifically with papillary thyroid carcinoma (PTC), the cancer's hallmark genetic mutation BRAF V600E mutation. Constitutive activation of the BRAF proto-oncogene  leads to activation of ERK1/2 pathway and other intracellular pathways associated with abnormal cell proliferation and growth (Papillary thyroid carcinoma (PTC) is the most frequent type of thyroid cancer, accounting for almost 80% of thyroid cancer cases. The genetic hallmark of human PTC is the somatic BRAFd growth .V600E can be targeted with selective inhibitors such as vemurafenib, the first FDA approved orally administered inhibitor  and suppression of growth signals. Part of a cell's evolution to evade these signals involves genetic mutations, which predisposes the cells to being able to survive with mutations that would otherwise not survive in non-cancerous or malignant cells. Tumorigenesis requires increased mutability in order for tumor cells to bypass regulatory and apoptotic pathways and signals. Increased mutability of cells is achieved through down regulation of genomic maintenance mechanisms, including P53 gene inactivation . The dowV600E in PTC  resistant subclones , some tumor cells will respond to the treatment and die  gene, targeted drug treatment therapy positively selected for a number of drug resistant clones and drove tumor clonal evolution  gene family mutations . In . In V600t cancer . Single Combination therapy is seen as the best treatment option for overcoming resistance to single agent targeted therapy . HoweverV600E, Tg mutations were more likely passenger mutations that are advantageous in the malignant evolution of PTC as opposed to the actual drivers of PTC. Since Tg mutations are associated with mutations in genes encoding components of the MAPK signaling pathway, it is possible that some subclones harboring both driver and maybe passenger mutations, such as RBM gene family mutations   gene were associated with poorer clinical prognosis . Additio0, RBMX) , could s0, RBMX) .Another experimental model focusing on tumor heterogeneity in breast cancers identified a subclonal genetic marker associated with CD44+ breast cancer stem cells. Previous studies had demonstrated that CD44+ cells displayed increased tumorigenesis compared to CD44\u2013 cells . Given tV600E and CDKN2A\u2212/\u2212 mutant PTC's and for overcoming both innate/primary and secondary tumor resistance mechanisms.In the PTC experimental model, an understanding of the subclonal construction of the tumor having chromosome 5 amplifications and RBM gene family mutations, revealed potential pathways for secondary resistance. This knowledge of both the clonal and subclonal configuration of the tumor, allowed for a more effective solution to treating BRAFBeyond elucidating better understandings of potential cellular pathways and genes involved in drug therapy resistance, clonal and subclonal reconstructions of tumors can also reveal biomarkers for early detection of aggressive thyroid cancer that could dictate future tumor behavior. With regard to thyroid cancers, PTC is classified as a differentiated thyroid cancer, and other types of thyroid carcinomas, such as anaplastic thyroid carcinoma (ATC), are classified as undifferentiated thyroid cancer. The transition from PTC to undifferentiated thyroid carcinoma is still poorly understood and furthermore effective treatments of ATC represent a large unmet clinical need. Clonal and subclonal reconstructions of both heterogeneous PTC  and ATC Importantly, ATC show increased mutational burden compared to PTC. In one study examining the genetic profile of 196 ATC samples, only 41% (81 tumors) harbored BRAF mutations . If ATC In sum, some bioinformatics models have been designed and are being used to reconstruct the clonal and subclonal heterogeneity of tumors. However, we need novel experimental models performing the clonal and subclonal reconstruction both pre- and post-drug treatment(s) of the thyroid tumor for somatic mutational and epigenetic profile, copy number variation, cytogenetic alterations, and non-coding RNA expression. Clonal and subclonal evolution of tumor cell clusters is also driven by the selective pressure of targeted drug therapy, therefore the pre-treatment reconstruction and the post-treatment reconstruction would identify all clones and subclones that drug treatments positively select, those that are responsive to drug treatments and die, and clones containing passenger genetic alterations conferring secondary tumor resistance.CN: design. CN and EM: editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Abstract Global new-born mortality has shown steady decline over the last two decades, but this decline has been slowest in Sub-Saharan Africa (SSA). Perinatal asphyxia (PA) is a major cause of new-born deaths in this region and as such SSA now contributes a disproportionate large percentage of global asphyxia-related deaths. In this paper, we examine regional challenges affecting primary, secondary and tertiary prevention of PA and proffers locally adaptable solutions to these identified challenges. Global newborn mortality has shown steady decline over the preceding two decades, but this has been slowest in Sub-Saharan Africa (SSA), where newborn deaths now accounts for 38 percent of global neonatal mortality . In thisEnding preventable newborn deaths currently feature prominently in the global health agenda and this is reflective in the Sustainable Development Goals, specifically Goal 3 . To achiIn this paper, we examine challenges faced in the prevention and management of perinatal asphyxia by countries within this region, and we suggest possible solutions to the current issues.These challenges relate to identifying and limiting the risk of pregnant women who without intervention might deliver asphyxiated babies. They hinder effective demand and supply of obstetric services within the region.In SSA, attendance of ante-natal care, which should connect the \u2018at-risk pregnant woman\u2019 with the formal health system, is poor, as under 40 percent of women attend at least four visits . Within Despite widespread regional poverty, 40 to 54 percent of people access healthcare primarily out-of-pocket which hinders health service demand . In instRegional sociocultural norms such as child marriages also negatively affect antenatal care attendance. A recent review of demographic and health survey data in 31 SSA countries documented a third of girls were married by age 18 in more than half of the studied countries . In thesThese relate to three service delivery gaps: coverage, equity and quality gaps. The coverage gap connotes insufficient manpower to address regional obstetric needs. The global health worker shortage is greatest in SSA, where the majority of countries have health worker to population densities below 2.5 per 1000 population, starkly contrasting developed country estimates which are between two and ten times this number . The ine15Additionally, existing quality gaps affect obstetric supply. In a review of data from 20 SSA countries, 71 percent of women did not have intermittent preventive treatment for malaria in pregnancy despite attending at least 4 antenatal care visits . SimilarSecondary prevention of asphyxia involves resuscitation of newborn infants with breathing problems who are at risk of developing perinatal asphyxia. One major challenge to this is the large proportion of out-of-hospital births occurring in the presence of unskilled birth attendants who lack knowledge and skill of neonatal resuscitation . More thWhen births occur in-facility, obstetric service providers frequently do not have the basic skills or equipment necessary to provide quality neonatal resuscitation . A regioTertiary prevention of asphyxia involves treating acute complications and mitigating their progression to long-term disabling morbidities. This requires functional multidisciplinary rehabilitative care teams which are lacking in SSA. Countries within the region have rehabilitative worker densities below 0.01 per 10,000 population, contrasting developed countries where these figures are almost a thousand times this number . AdditioFocusing on primary prevention within the region is most likely to have the greatest impact on asphyxia burden and this would entail stimulating a demand for obstetric services while improving supply. Infrastructural and human capacity development are key to improving regional obstetric demand. Road networks, transportation, referral, communication and information systems, all of which have direct effects on service demand would need to be upgraded . Additio8Community engagement is also fundamental to stimulating demand and should entail changing community perceptions regarding orthodox obstetric services through health education, local media and provision of holistic, culturally acceptable and easily accessible obstetric services. In these settings, the buy-in of prominent local community, traditional and religious leaders is crucial to programmatic success.From a supply perspective, an obvious solution to tackle the existing coverage gaps would be to attract skilled birth attendants through competitive remuneration. However, this is not feasible in the short term, as many SSA countries are currently economically challenged. Task-shifting, a practice which involves delegating roles and responsibilities otherwise carried out by senior health staff to lower and mid-health care workers can serve as a short term measure . Local r27Equitable distribution of obstetric human resources across geographical divides needs to be ensured through health worker tax rebates and provision of rural allowances to encourage their retention in these areas. Nigeria and Zambia have instituted rural midwives\u2019 and rural health worker retention schemes which have shown modest successes 30. Rural31Regional governments need to increase budgetary allocations to the health sector to improve quality of obstetric care. Local services would also need to be more effectively organized by developing strong bottom-up referral systems which centralize high-risk pregnancies to tertiary obstetric health centers and those considered low-risk to primary healthcare. In addition, proper supervision and monitoring of existing obstetric facilities using methods such as perinatal audits, obstetric checklists, regular in-house staff training and drills will also improve quality of care .Despite being controversial among policy makers , traininTo improve tertiary prevention of asphyxia, capacity building for rehabilitative service providers is essential. Local health facilities would need to establish collaborative links with international agencies and centers with specialized rehabilitative care that can offer voluntary services and develop local capacity. Vital registration of all births and deaths in SSA needs to be improved for accurate data on local asphyxia burden and for managing regional government development plans.Challenges to successfully preventing perinatal asphyxia in SSA might seem herculean. The key to solving these would be the institution of pragmatic locally adapted solutions that take into cognizance existing realities in the region. These would need to target safer pregnancy and delivery outcomes with a focus on accessible quality neonatal resuscitation and human capacity development."}
+{"text": "Here we report optimization, expression and binding of DMAbs based on anti-PD1 CPI and discuss the potential of DMAbs in checkpoint immunotherapy.Checkpoint inhibitors (CPI) have revolutionized the treatment of many solid tumors. However, difficulties in production, stability, the requirement of frequent high doses for antibody administration and long intravenous administration are recurring issues. Synthetically designed DNA-encoded monoclonal antibodies (DMAbs) are a novel delivery method for antibody therapy which could potentially address many of these issues, simplifying design and implementation of MAb-based therapies. DMAbs delivered through plasmid DNA injection and electroporation have been used in preclinical models for the treatment or prophylaxis of infectious diseases, cancer and cardiovascular disease. Our group has recently reported that immune checkpoint blockers can be optimized and delivered  Checkpoint inhibitors (CPI) have revolutionized the treatment of many solid tumors. These therapies have generated an increase in the percentage of cancer long-term survivors by \u2018releasing the brakes\u2019 of the immune system to potentiate its antitumor effect in those patients who respond . HoweverSynthetically designed DNA-encoded monoclonal antibodies (DMAbs) are a novel delivery method for antibody therapy which could potentially address many of these issues, as well as open up novel approaches for design and implementation of MAb based therapies. DMAbs represent a simple, scalable development system, with the additional benefit of higher stability and simpler storage than protein biologicals. DMAbs are administered locally by intramuscular injection and allow simple coformulation, permitting the generation of CPI with a unique profile of expression and potency, suggesting they could be considered as a new tool for study in this important therapeutic arena.DMAbs delivered through plasmid DNA injection and electroporation (EP) have been used in pre-clinical models for the treatment or prophylaxis of infectious diseases , 5, cancin vivo advancing further DMAb technology [in vivo expression for several months. These first studies in mice, while encouraging, require additional examination in other models, including additional optimization in other species to further understand the implications with an eye towards subsequent clinical evaluation. Furthermore, studies in combinations and with additional genetic modifications for functional enhancement by the Fc portion of the Ig heavy chain can be much more easily developed and studied as DMAbs than as protein biologicals to advance new CPI-like forms with improved functions resulting in improved tumor impact advancing clinical benefit. Under this concept the development of additional CPI targets as DMAbs appears important.In support, Duperret et al., recently reported that immune checkpoint blockers can be optimized and delivered chnology . In the chnology  or tremechnology . These sThe PD-1-PD-L1 signaling pathway was first discovered in 1992 and monoclonal antibodies targeting this suppressive pathway were moved towards clinical testing in 2006. These MAb have made a major positive impact in the clinic resulting in FDA approvals for treating a variety of different tumor types due to exciting clinical benefit for treatment of diverse cancer types including melanoma, non-small cell lung carcinoma, renal cell carcinoma, high microsatellite instability cancers, Hodgkin\u2019s disease, hepatocellular carcinoma, urothelial carcinoma, bladder carcinoma, Merkel cell carcinoma and gastroesophageal junction [in vivo expression while retaining their required binding ability and functionality. These DMAbs expressed for several months and exhibited the specificity and cell binding of the parental antibodies. The recent development of DMAbs encoding anti-CTLA4 [in vivo production is likely to provide unique research and ultimately clinical benefit in the cancer arena.Accordingly, the development of forms of DMAbs encoding anti-PD-1 like antibodies are important. Engineered DMAb forms mimicking highly impactful anti-PD-1 monoclonal antibodies were studied in an effort to optimize direct DMAb ti-CTLA4  and for ti-CTLA4 , 12 or DIn summary, DMAbs are a new tool that conceptually simplifies antibody therapies and their combinations, including checkpoint blockade, which if successful would likely expand their applications bringing CPI therapies to a much larger patient population. Further translational study of the DMAb platform for impacting cancer is worthy of consideration."}
+{"text": "Recent breakthroughs in cancer immunotherapy have led to curative efficacy and significantly prolonged survival in a subset of patients of multiple cancer types; and immunotherapy has become the newest pillar of cancer treatment in addition to surgery, chemotherapy, radiotherapy and precision targeted therapies. In the metastatic disease setting, responses to immunotherapy are heterogeneous depending on the metastatic organ sites. The tissue-specific immuno-biology in the tumor microenvironments (TMEs) contributes to the differential therapeutic responses. Herein, we review the impact of tissue-specific tumor microenvironment on the efficacy of immunotherapy, with a focus on historically under-represented central nervous system (CNS) metastasis, which was excluded from most clinical trials. Retrospective examination of patient specimens and prospective clinical studies with immune checkpoint blockade (ICB) have established that brain can harbor an \u201cactive\u201d immune microenvironment for effective immunotherapy. Regulation by the innate immune microglial cells and remodeling of the blood\u2013brain barrier (BBB) may contribute to immunotherapeutic responses mediated by T lymphocytes. How to convert an \u201cinactive\u201d (cold) brain microenvironment into an \u201cactive\u201d (hot) brain TME should be the focus of future efforts. Thus, procurement and complete examination of clinical specimens from brain metastases as well as development of appropriate preclinical brain metastasis models susceptible to external manipulation of the TME are critical steps towards that goal. A deeper understanding of the immuno-biology in distinct organ microenvironments will help to expand the benefits of immunotherapy to more needed patients. The idea of immunotherapy was conceptualized more than 100\u00a0years ago when German pathologist Rudolf Virchow first described the involvement of immune cells in human tumors . Even thBeginning in the 1980s, therapeutic monoclonal antibodies, a bioengineered version of the naturally secreted immune molecule, emerged as a versatile platform of therapeutic agents against cancer , 5. AfteIt has long been known that CD8+ effector T cells have cytolytic capability that kills cancer cells . In-deptDifferent cancer types tend to colonize specific organ sites, as depicted by the \u201cseed and soil\u201d hypothesis of metastasis . Many ofA common clinical observation with advanced cancer patients is the differential responses to systemic treatments where some metastatic lesions may be less or more responsive to therapy compared to lesions located at other anatomical sites. Such frequently encountered clinical phenomenon strongly suggests that the local TME plays crucial roles in modulating therapeutic responses. For example, in a retrospective study of 371 metastatic melanoma patients treated with the first FDA-approved \u201cmodern\u201d immunotherapy high-dose IL-2, the response rate in patients with cutaneous or subcutaneous metastasis was\u2009~\u200950% whereas with visceral metastases it was only 13%; more strikingly, in individual patients harboring both cutaneous/subcutaneous and visceral metastases, tumor regression took place only at cutaneous/subcutaneous lesions whereas visceral metastases progressed upon the same systemic IL-2 therapy . FurtherDespite the clear relevance derived from multiple clinical studies, further in-depth mechanistic investigations that require procuring clinical specimens from multiple metastatic organ sites can be logistically challenging. To that end, an exceptional case study reported a single patient with high-grade serous ovarian cancer who was treated with multiple chemotherapy regimens and exhibited regression of some metastatic lesions with concomitant progression of other lesions . After cTo broadly elucidate the underlying biological mechanisms of the organ specific TME impact on immunotherapy responses, multiple studies have used preclinical murine models harboring metastases at multiple anatomical sites and having treatments by various immunotherapy agents. For example, implanting murine 4T1 mammary cancer cells at subcutaneous or intratibial sites and FACS profiling of isolated tumor-associated immune cells revealed significant differences in the immune composition  depending on the sites of tumor growth . AdditioUnfortunately, despite fair amount of effort by the research community to compare differential anatomic responses to cancer therapies, the brain, one common metastasis organ site, has been adversely neglected , 34. WitWhile the primary regulatory and cognitive functions of the central nervous system (CNS) are conducted by neuronal circuitry, it is also essential to maintain a homeostatic environment of stable metabolism and inflammation, which tasks fall on the large number of stromal cells in the brain, including astrocytes and microglia cells . To thatIntracranial malignant neoplasms can arise either from primary brain tumors (mainly glioma) or from secondary cancers metastatic to the CNS. Lung cancer, breast cancer and melanoma are the major sources of brain metastases, which collectively outnumber primary malignant brain tumors by\u2009~\u200910:1 , 47. WhiIntriguingly, infiltration with adaptive immune T lymphocytes is highly heterogenous in brain metastasis lesions, varying from total absence to very dense infiltration , 59. A sLastly, how do adaptive immune T cells infiltrate brain metastatic lesions in the presence of blood\u2013brain barrier (BBB)? Pharmacodynamic studies in preclinical murine models of breast cancer brain metastasis showed that BBB permeability could be compromised, and vascular leakiness became highly heterogeneous depending on the progression of brain metastatic outgrowth . FurtherBrain is conventionally regarded a major organ site of metastasis with sanctuary immune status; hence, up till recently, most clinical trials exclude patients with CNS metastases , 38. WitBased on these clinical studies showing early signals of positive intracranial activity, a landmark trial of treating melanoma brain metastasis with ICB combination of anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab has been conducted  . It was Despite these promising results, the advances are still in the early stage and most patients with CNS metastases remain difficult to treat; the benefit must also be extended to brain metastases from other primary cancer types in addition to melanoma. Additionally, the underlying mechanism of resistance versus response of the intracranial tumors to systemically administered ICB remains a fundamentally unanswered question. Because immune cells are highly dynamic in response to physiological alterations, their biological functions must be tightly coupled to the cellular metabolism that provides the underlying material and energetic support. From in vitro studies, it was believed that activation of T cells shifts cellular metabolism towards glycolysis which takes place in the cytosol and produces more biological building blocks in preparation of cell proliferation and clonal expansion, and that na\u00efve and memory T cells are more dependent on mitochondrion-dependent oxidative phosphorylation (OXPHOS) which yields more ATP to confer higher spare respiratory capacity . HoweverCurrently, immunotherapy benefits a small number of patients across multiple cancer types, and the immuno-biological microenvironments at distinct metastatic organ sites are important determinants for differences in efficacy. In particular, the local immuno-biological TME at metastatic organ sites, partly mediated by the tissue-resident innate immune cells, interacts with the systemic adaptive immune system to determine responses to immunotherapy. Therefore, the major goal of future efforts should be deepening the understanding of underlying immuno-biological mechanisms responsible for the organ-specific anti-tumor immune responses and based on such knowledge developing strategies to expand the benefits of immunotherapy to more patients with advanced metastatic cancer. To that end, it is important to analyze clinical specimens of immunotherapy treated metastases of all cancer types  to examine immune cell infiltration and composition, as well as local stromal cell alterations, which will reveal novel insight into the response mechanism of immunotherapy in distinctive metastatic TMEs. Additionally, it is necessary to perform mechanistic studies and functional validations using appropriate animal models in order to better understand the immuno-biology underlying effective immunotherapy.In the CNS, it has been convincingly established, by retrospective examinations of brain metastasis specimens and prospective clinical studies of ICB treatment of patients with brain metastases, that in some patients the brain can harbor an \u201cactive\u201d immune microenvironment that respond to immunotherapy. Enrichment of mitochondrion mediated OXPHOS is a unique metabolic trait of brain metastasis; modulating the OXPHOS activity in the brain TME may impact efficacy of ICB treatments. To overcome the immunosuppressive TME in the CNS, future efforts should also include combining checkpoint inhibitors with other treatments . The rapid progress in clinical investigations and preclinical studies will pave the way for effective modulation of the brain metastasis tumor microenvironment that allows effective T cell-mediated responses and enables more brain metastasis patients to benefit from immunotherapy.In summary, persistent endeavor in clinical investigations and preclinical studies to explore effective ways of manipulating the local immuno-biological microenvironment will likely enhance and expand the efficacy of immunotherapy to more metastatic diseases."}
+{"text": "The STOMP trial is a multicenter, randomized, phase II trial  that incClinicalTrials.gov: NCT02680587), comparing observation versus SBRT in oligometastatic hormone-sensitive prostate cancer, are comparable to those observed in the STOMP trial, validating the safety and efficacy of SBRT in this setting.Despite some inherent limitations such as the small patient cohort and the use of a treatment-related primary endpoint, the STOMP trial represents the first randomized study exploring the role of MDT compared to standard of care in oligorecurrent patients. Of note, preliminary results of the phase II randomized Baltimore ORIOLE trial  [It is noteworthy that the optimal treatment of oligorecurrent patients remains a challenging and open question, based mainly on, even if promising, retrospective and heterogeneous data. The possibility to treat a metastatic disease with a potentially curative intent collects an increasing interest, with expert panels considering MDT a valid treatment option for these patients . Of noteent ADT) . Some poFirst, although oligorecurrent prostate cancer with exclusive nodal involvement is a common clinical situation  and the 68Ga prostate-specific membrane antigen (PSMA) PET-CT [Second, improvements in the diagnostic procedures such as use of ) PET-CT  will surLastly, implementation in trials of translational analysis of leading-edge laboratory measuring circulating tumor cells, circulating tumor DNA, and circulating T-cell receptor repertoires will surely help to better characterize the oligomestatic status by identifying patients with potentially curable metastatic disease and evaluating the effects of MDT on disease response .ClinicalTrials.gov: NCT03569241), a randomized phase II trial for the Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases, will surely help to answer some of these open questions. By randomizing patients between MDT (SBRT or sLND) versus MDT combined with WPRT (adjuvant WPRT after sLND or WPRT with boost to the positive nodes), and implementing modern imaging techniques and liquid biopsies, the study aims at finding the better treatment strategy in terms of extrapelvic metastasis-free survival as primary endpoint for this subset of patients.The recently opened Belgian-Swiss PEACE V STORM trial  and European Society for Radiotherapy and Oncology (ESTRO) OligoCare observational basket study should be encouraged."}
+{"text": "Fructans are fructose-based oligo- and polymers that serve as reserve carbohydrates in many plant species. The biochemistry of fructan biosynthesis in dicots has been resolved, and the respective cDNAs have been cloned. Recent progress has now succeeded in elucidating the biochemistry and molecular biology of fructan biodegradation in chicory, an economically important species used for commercial inulin extraction. Unlike fructan biosynthetic genes that originated from vacuolar-type invertase, fructan exohydrolases (FEHs) seem to have evolved from a cell-wall invertase ancestor gene that later obtained a low iso-electric point and a vacuolar targeting signal. Expression analysis reveals that fructan enzymes are controlled mainly at the transcriptional level. Using chicory as a model system, northern analysis was consistent with enzymatic activity measurements and observed carbohydrate changes throughout its development."}
+{"text": "Siphoviridae, Myoviridae and Podoviridae), where members of the same family were generally far more divergent and often not detectably homologous to each other. Analysis of the 20 currently classified prokaryotic virus families indeed split them into 70 separate clusters of tailed phages genetically equivalent to family-level assignments of eukaryotic viruses. It further divided several bacterial  and archaeal (Lipothrixviridae) families. We also found that the subfamily-level groupings of tailed phages were generally more consistent with the family assignments of eukaryotic viruses, and this supports ongoing reclassifications, including Spounavirinae and Vi1virus taxa as new virus families. The current study applied a common benchmark with which to compare taxonomies of eukaryotic and prokaryotic viruses. The findings support the planned shift away from traditional morphology-based classifications of prokaryotic viruses towards a genome-based taxonomy. They demonstrate the feasibility of a unified taxonomy of viruses into which the vast body of metagenomic viral sequences may be consistently assigned.Genome Relationship Applied to Virus Taxonomy (GRAViTy) is a genetics-based tool that computes sequence relatedness between viruses. Composite generalized Jaccard (CGJ) distances combine measures of homology between encoded viral genes and similarities in genome organizational features (gene orders and orientations). This scoring framework effectively recapitulates the current, largely morphology and phenotypic-based, family-level classification of eukaryotic viruses. Eukaryotic virus families typically formed monophyletic groups with consistent CGJ distance cut-off dividing between and within family divergence ranges. In the current study, a parallel analysis of prokaryotic virus families revealed quite different sequence relationships, particularly those of tailed phage families ( Currently, 4404 species are assigned to 735 genera, which in turn are assigned to 122 families ]. Similarly, the list of unclassified archaeal viruses with complete genomes was retrieved using the search terms . Only those from the GenBank database were collected. In total, the list comprised 576 whole genomes of unclassified bacterial viruses, and eight unclassified archaeal viruses (Table S4). The search was performed in February 2018. The genome of unclassified bacteriophages and archaeal viruses were run through the GRAViTy pipeline to identify which virus groups they might belong to. Our results (Table S5) show that 580 of the unclassified bacteriophages (573 viruses) and archaeal viruses (seven viruses) exhibit some similarity to group I dsDNA. A bootstrapped dendrogram depicting relationship among these unclassified viruses and the classified dsDNA viruses is shown in The list of unclassified bacteriophages with complete genomes was compiled from the NCBI database using the search terms [Click here for additional data file.Click here for additional data file."}
+{"text": "Research on bile acids has increased dramatically due to recent studies demonstrating their ability to significantly impact the host, microbiome, and various disease states \u20133. AlthoMembers of the gastrointestinal tract (GIT) microbiota initiate bile acid metabolism via a critical first step catalyzed by bile salt hydrolases (BSHs) . These eA recent review by Dong and colleagues has reported in depth on many of the biochemical and structural features of BSHs that are summarized here . BSHs beClostridium perfringens BSH (Protein Data Bank ID 2BJF) has been captured with a hydrolyzed taurodeoxycholic acid (TDCA) substrate in its active site [Despite the conservation of their active sites and the similarity of their overall topology , BSHs haive site . Even wiLactobacillus and Bifidobacterium because these species are associated with deconjugation in the small intestine and harboring a BSH is thought to be a beneficial feature of probiotics [Clostridium and Enterococcus similarly display a high occurrence of BSH-positive strains. Recent work characterizing BSH encoding members of the Bacteroidetes phylum has begun to elucidate the phenotypes of gram-negative BSH activity [The broad distribution and abundance of BSHs in the GIT suggests that bile acid deconjugation is a selected adaptive trait of several bacterial species for symbiosis or pathogenesis within the host , 18. Theobiotics , 18, 19.activity , 21.Despite their single hydrolytic function, BSHs can be advantageous in various ways. Because some bile acids are toxic molecules due to their acidic nature and detergent-like properties , 23, BSHBrucella abortus BSH activity leads to membrane modifications resisting phagocytosis [Listeria monocytogenes exploits its BSH for survival in the bile acid-rich liver and gall bladder [Clostridioides difficile, which can use taurocholate (TCA) as a spore germinant, but vegetative cells are sensitive to most secondary bile acids [Lactobacillus johnsonii BSH activity has been shown to limit the eukaryotic pathogen Giardia duodenalis in vivo [Bacterial pathogens, like some commensals, use BSHs to persist and survive during host infection. ocytosis . Listeri bladder , 29. Altle acids . Similar in vivo . The varThe bile acid pool, influenced in part by microbial-encoded BSHs, in turn shapes the microbiome composition and function . This biDuring enterohepatic recirculation, circulating bile acids interact with BARs in all major organs to impart signals that regulate metabolic and homeostatic processes inside and outside of the gut, in which their transformations originate . The nucEscherichia coli engineered to express Lactobacillus BSHs were able to mimic these effects by modifying the bile acid pool, curbing lipid and cholesterol metabolism, and protecting mice from weight gain [Bacteroides thetaiotaomicron native BSH to modify the germfree mouse bile acid pool in a manner that reflects the BSH\u2019s in vitro substrate preferences, further supporting the notion that these enzymes can be delivered in a targeted manner to selectively manipulate the bile acid pool [Several studies have used mouse models to bridge the gaps between weight gain and/or obesity, the microbiota, and bile acids through the FXR signaling. Mouse models of diet-induced obesity have demonstrated that both the microbiome and FXR signaling are necessary for weight gain, implicating deconjugated primary and secondary bile acids as regulators of host metabolism , 36. Furght gain . Similarcid pool .Bile acid dysregulation has also been implicated in other diseases, though the role of BSHs in their etiology is not well understood. A mouse model of nonalcoholic fatty liver disease (NAFLD) demonstrated that symptoms could be relieved by inhibiting bile acid reabsorption, leading to a reduction in conjugated bile acids, and a reduction in FXR antagonism . BSH actCan BSHs be used to alter the bile acid pool to rationally alter the gut microbiota and shape host physiology?Are BSHs required for general bacterial fitness and competition for nutrients? Is this context dependent? What happens in the face of inflammation and other disease states?Can BSHs be engineered with increased activity and substrate specificity for certain bile acids? What amino acid residues are important for determining bile acid substrate specificity?How do BSHs with different activity and substrate specificity alter the bile acid pool, microbiota, and host response in different regions of the GIT? How will BSHs be delivered to the different regions of the GIT?"}
+{"text": "Cumulative Dis/Advantage (CDA) theory concerns how societal structure influences individual developmental and health trajectory across the life span, but few studies have applied CDA in the international setting with gender comparisons. This study provides a cross-national perspective to test CDA in explaining health inequality between developing and developed countries. Cross-sectional harmonized data from the international Health Retirement Study-series  in 2013-2014 were used . Four health indicators were included: self-reported health, depressive symptoms, functional ability, and memory. Sociodemographic information and health behaviors were used as covariates. Regression models were fitted to examine the moderation roles of country and gender in health trajectory in later life. Results indicate self-reported health and mental health remained steady while functional ability and memory declined across late life span. Older Chinese and Mexican respondents had poorer health status than their British and American counterparts consistently except for memory in the Mexican data. Cumulative health gaps between developing and developed countries existed only for functional ability. Females in the four countries had poorer health than their male counterparts except their memory status. We conclude that CDA explains only the temporal decline of functional ability and its increasing gaps in later life between countries. Health inequality between countries could be attributed to the limited availability of healthcare and social resources in developing countries. However, other health status, including general health and mental health, depend more on individuals\u2019 intrinsic capacity and human agency."}
+{"text": "CareSearch is an Australian Government Department of Health funded repository of evidence-based palliative care information and resources. The CareSearch Allied Health Hub was developed in 2013 to support all allied health professionals working with palliative care clients in all clinical settings. This cross-sectional online survey sought to elicit allied health professionals palliative care experiences and subsequent considerations for educational and clinical practice needs. The survey was disseminated nationally via a range of organisations. Data was collected about palliative care knowledge, experience working with palliative care clients and professional development needs. Data were evaluated by profession, experience and practice setting. In total, 217 respondents answered one or more survey questions (94%). Respondents (65%) reported seeing >15 palliative care clients per month with 84% seen in hospital and community settings. Undergraduate education underprepared or partially prepared allied health professionals to work with these clients (96%) and 67% identified the need for further education. Access to postgraduate professional development was limited by available backfill and funding. Study findings support the importance of free, accessible, relevant educational and professional development resources to support clinical practice. This is particularly relevant for allied health professionals who have limited opportunities to attend formal professional development sessions. The World Health Assembly Resolution 2014) recommends palliative care be considered as a component of comprehensive care throughout the life course due to rapidly increasing numbers of people with palliative care needs [4 recommeAllied health professionals play a key role in the care of people with palliative care needs in all health care settings . They bring profession-specific knowledge and skills that can be essential in addressing the person\u2019s individual care needs. They can provide non-pharmacological symptom control options alongside pharmacological interventions. Their care approaches enable continuing participation in essential and valued daily activities ,4. AllieAllied health professionals can make important contributions in the treatment and non-pharmacological management of symptoms, alongside improving the quality of life for palliative care patients and caregivers. Increasing numbers of allied health professionals employ a rehabilitative approach to optimise function of palliative care patients . ManagemLittle research considers the type of end-of-life care interventions being provided outside of specialist palliative care settings, the experiences of allied health professionals and their education and practice needs in these non-specialist settings. The purpose of this study was to survey allied health professionals across Australia on their understanding and views about palliative care, of its relevance to practice, their knowledge, and their clinical information education needs. The aim of this paper is to present survey results pertaining to palliative care training and continuing educational needs. Qualitative survey results presenting allied health professionals\u2019 knowledge and views about palliative care are presented elsewhere .This study was a purpose-designed cross-sectional survey of Australian Allied Health Professionals. For the purposes of this survey, allied health professionals included were those most likely to work with palliative care clients in specialist or generalist settings. Survey functionality and face validity was determined by piloting the questions with the Executive Officer of Allied Health Professions Australia (AHPA) and representatives of the CareSearch Allied Health Hub advisory group prior to distribution (available from authors on request). The survey design and conduct were reviewed against the CHERRIES checklist . Ethics approval for this study was provided by the Flinders University Social and Behavioural Research Ethics Committee (Project 7014). Participant consent was implied through commencement of the online questionnaire. Allied health professionals were recruited to complete the survey through member newsletters of the Allied Health Professions of Australia and through social media channels such as CareSearch, LinkedIn and Twitter. Allied health professionals approached to participate in the survey included occupational therapists, physiotherapists, speech pathologists, social workers, dietitians, psychologists and music therapists. These allied health disciplines were represented in the CareSearch Allied Health Hub. It is not possible to determine how many people were offered the opportunity to participate in the survey due to the variety of approaches via member networks and social media but it is estimated that the networks alone represented more than 120,000 allied health professionals.Participants accessed the participant information sheet and the online survey through embedded hyperlinks within newsletters or social media posts. Data were collected from 1 November 2015 to 30 April 2016, and included 42 items on palliative care education and professional development, practice, and attitude.n) and proportion (%). As it was not compulsory to respond to each survey item, there are varying levels of missing data for every question. Individual n values are presented for each item to indicate completeness of responses. Differences in proportions between groups were evaluated using Chi-square statistics. Statistical analyses were conducted using IBM SPSS version 23.0 (IBM Corp) and statistically significant differences (p < 0.05) are highlighted in bold.This paper reports on demographic data and descriptive statistics. Categorical data are reported as number of respondents  were incomplete. Sociodemographic characteristics are reported in Occupational therapists, social workers, physiotherapists and dietitians comprised 86% of the sample . Fifty sOver half of allied health professionals felt their undergraduate training did not prepare (54%), or only partially prepared them (42%) to care for palliative care patients and/or their families. Many allied health professionals had previously undertaken professional development in palliative care, most frequently by reading and short in-service training sessions within their workplace. Palliative care educational opportunities appeared to be frequent, with 68% reporting their most recent opportunity was within the last year. Over one-third (39%) had completed online learning modules. While approximately 10% had specific qualifications in palliative care, 67% indicated that they needed additional education to better inform their clinical practice when working with palliative care patients. However, respondents reported barriers to accessing education, most frequently citing time (41%) and funding (33%) as primary limitations. Lack of available leave or backfill to cover clinical caseloads and limited knowledge about specialised or relevant educational opportunities also prevented access to education .There were no significant differences in palliative care qualifications or need to access palliative care education by allied health discipline. However, speech pathologists (70%) and physiotherapists (75%) felt the least prepared by undergraduate education and reported needing higher levels of postgraduate training in order to work effectively with palliative care patients (data not shown).Further training in grief and loss (56%) and symptom management (54%) were identified as priorities by the majority of disciplines . HoweverWhen asked to reflect on difficulties encountered in their most recent palliative care experience, most allied health professionals reported caseload or time demands as limiting (57%), while some reported feeling overwhelmed discussing non-medical topics (15%), and at their inability to take time out (14%). The proportion of allied health professionals who reported changing mindsets about working with palliative care patients differed by years of experience post-training. Those with the least experience reported this to be a greater problem at more than double the number of professionals overall (46% versus 23%). Additionally, the proportion citing a lack of palliative care knowledge or skills making their palliative care experiences difficult was significantly higher for those with less experience and those working outside of specialist palliative care settings. Forty-three percent of all respondents noted that access to postgraduate professional development was limited by available time, cost/funding, workload pressures and backfill. Further, allied health professionals working outside of a palliative care service were far more likely to report feeling overwhelmed discussing non-medical topics compared with medical topics than those working within this setting.A diverse allied health workforce delivers patient care in metropolitan, regional, rural, and remote settings. Each setting brings with it specific workforce issues and needs. Given lower life expectancies and high levels of chronic disease in lower socioeconomic areas, existing allied health models of care need to take into consideration ways to best support patients and caregivers at the end-of-life . For exaA recent study of occupational groups working in long-term care settings highlighted the differences in palliative care-specific educational needs and the intensity of inter-professional collaboration . UnderstOnline resources targeting context-specific needs have been found to build confidence of allied health professionals who work with palliative care patients and were accessed by survey respondents. Australian palliative care resources that specifically address the allied health context such as the Allied Health section on the CareSearch website  and the This study had some limitations. Respondents were a self-selecting sample of allied health professionals, some of whom already worked in palliative care. This may have led to under-representation of generalist clinician professional development needs. Numbers of respondents are small and not equal for all disciplines, hence their responses may not be representative of individual discipline educational needs.Allied health professionals have an active role to play in the physical, social, emotional and spiritual care of palliative care patients and their caregivers. However, in order to do this allied health professionals require access to evidence-based education to enable better support of patients and their caregivers as deterioration ensues. Allied health professionals working in rural and remote locations often take on specialist generalist roles but require adequate support to provide quality care to patients with complex palliative care needs. Generalist allied health professionals in particular require targeted post-graduate education, particularly around grief and loss and non-pharmacological symptom management. Online resources such as CareSearch and End-of-Life Essentials and clinical placements such as those offered through PEPA can support all allied health professionals in non-specialist palliative care settings to develop and sustain clinical skills through best available evidence and clinical networking."}
+{"text": "Patients\u2019 survival for most cancer types is slightly improving due to progress in faster diagnosis and advances in treatment. However, median period of survival time of patients with pancreatic cancer, glioblastoma, metastatic melanoma, metastatic lung tumors, high-grade serous subtype epithelial ovarian cancer, abdominal bowel and esophagus tumors treated with standard therapies is extremely low. There are several reasons for this therapeutic failure. Tumor initiating cells are resistant to drugs, have the ability of self-renewal and can be source of metastatic spread. Other additional major drawbacks of standard therapies lie in a lack of tumor specificity of anti-cancer drugs and the emergence of drug-resistant cell subpopulations after radio and/or chemotherapy. Further progress in cancer therapy  requires novel therapeutic modalities.HSV-MSC/GCV system [Physiological role of human mesenchymal/stromal stem cells (MSCs) is to regenerate damaged and used tissues in the body. MSCs possess the ability to migrate to the site of injury and secrete a variety of soluble factors and extra-cellular nanovesicles \u2013 exosomes capable of a number of functions inducing and supporting regenerative processes in the damaged tissue. MSCs recognize tumor as an injury, home in the tumor and, together with other cells, form the tumor stroma. Based on our experience with virus mediated cancer gene therapy, the tumor-specific tropism of MSCs inspired us to develop a targeted prodrug gene therapy mediated by MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase fusion gene (yCD::UPRT), yCD::UPRT-MSC/5-FC system  and MSCsV system . Both syV system . SpecifiV system  melanomaV system  and prosV system . In all HSV-MSC/GCV system. Tumor specificity of MSC suicide gene exosomes is rather broad, but tissue origin of MSCs can influence the tumor cell targeting and augment the suicide gene therapeutic effect. Exosomes secreted by MSCs derived from placenta selectively inhibit growth of prostate cancer cells. Generally, MSC-exosomes display a unique anti-tumor effect thanks to a variety of molecular species such as micro-RNAs within their cargo and the capability to activate multiple gene pathways [The explanation came when we found release of extracellular vesicles - exosomes from yCD::UPRT gene transduced MSCs. Exosomes incorporated mRNA of suicide gene in their cargo. Such exosomes we call MSC suicide gene exosomes. Size-exclusion chromatography of the secretome released from yCD::UPRT-MSCs revealed that the biological activity was clearly localized in the exosome fractions. These exosomes migrate to tumor similarly like MSCs, internalized tumor cells, therefore they kill tumor cells by intracellular conversion of prodrug 5-FC to cytostatic drug 5-FU and to 5-FUMP . Similarpathways . Since Mpathways .Exosomes from suicide gene modified MSCs have the potential to be a new class of highly selective cancer-targeted therapeutics. Composition of exosomes released from MSCs might be purposely modified to create therapeutically interesting exosomes for cancer treatment. Recently we reported a dual action of MSCs-yCD-UPRT-MSCs exosomes possessing beside mRNA of suicide gene also iron oxide nanoparticles. These nanoparticles were able to act both as a prodrug dependent therapeutic and hyperthermia inducing factor when tumor cells were exposed to alternating magnetic field .Our present research direction is headed to development of suicide gene exosomes for metastases. Human tumor cell specific exosomes with suicide gene we found to induce tumor cell death in a similar way as MSC exosomes (article in preparation). It was reported that aggressive tumor cells release exosomes creating pre-metastatic niche in body organs. Integrins of tumor exosomes determine organotropic metastasis. Therefore suicide gene exosomes prepared from primary human tumor might be used in future as a therapeutic tool for the patient-tailored therapy of metastases. The usefulness of prodrug gene therapy for cancer mediated by MSC suicide gene exosomes is now validated by animal studies.Described findings open new exciting possibilities for cancer gene therapy of human tumors that do not respond to standard therapies such as grade IV glioblastoma multiform. MSC suicide gene exosomes carry mRNA of suicide gene protected by the plasma membrane. They can travel long distances in the body, when administered intravenously might execute their therapeutic effect at a distant location. Accumulating evidence indicates that cancer therapy using MSC exosomes has multiple advantages over cell therapy. CM or exosomes are stable after intravenous administration and exhibit a superior safety profile.To be innovative cancer therapy curative; it must differ from standard therapies. The therapy should be targeted not only to tumor mass, but also specifically to tumor cells, drugs should be able to internalize both cancer stem cells and cancer cells and act intracellular. In this way it could be possible to avoid side effects, to prevent development of resistance and even kill already resistant tumor cells . Suicide"}
+{"text": "Gorilla g. gorilla) from Dzanga Sangha Protected Areas, Central African Republic. We examined 43 fecal samples for GIPs and quantified strongylid nematodes. We characterized fecal microbiome composition through 454 pyrosequencing of the V1-V3 region of the bacterial 16S rRNA gene. Entamoeba spp. infections were associated with significant differences in abundances of bacterial taxa that likely play important roles in nutrition and metabolism for the host, besides being characteristic members of the gorilla gut microbiome. We did not observe any relationships between relative abundances of several bacterial taxa and strongylid egg counts. Based on our findings, we suggest that there is a significant relationship between fecal microbiome and Entamoeba infection in wild gorillas. This study contributes to the overall knowledge about factors involved in modulating GIM communities in great apes.Relationships between gastrointestinal parasites (GIPs) and the gastrointestinal microbiome (GIM) are widely discussed topics across mammalian species due to their possible impact on the host's health. GIPs may change the environment determining alterations in GIM composition. We evaluated the associations between GIP infections and fecal microbiome composition in two habituated and two unhabituated groups of wild western lowland gorillas ( The mammalian gastrointestinal microbiome (GIM) is essential in providing access to nutrients, regulating epithelial development, and shaping immunity Berg, . Thus, dGorilla gorilla gorilla showed that feeding behavior, geographical range and increased anthropogenic pressure may be important modulators of the gorilla GIM. Moreover, the GIMs of two gorilla species G. gorilla and G. beringei exhibit significantly different patterns, but the GIMs converge when hosts face similar dietary constraints, associated with low fruit availability in their habitats suggesting that in primates dietary constraints triggered during their adaptive radiation were potential factors behind the species-specific GIM patterns observed today  infections on the composition and activity of the GIM has received increasing attention and several studies have been conducted in humans and animals   that may change the gut environment, potentially leading to alterations in GIM composition proteins, which may function as proteases or pore-forming proteins that could affect epithelial integrity) can suppress innate and adaptive pro-inflammatory immune responses  has been hypothesized to decrease gluten sensitivity and could serve as a potential treatment for celiac disease  in Dzanga Sangha Protected Areas (DSPA), Central African Republic , which are highly prevalent in studied gorillas  Does the fecal microbial diversity differ between individuals positive and negative for particular GIP? (ii) Does the abundance of specific bacterial taxa differ between individuals positive and negative for particular GIP? (iii) Is there a relationship between fecal microbial diversity and surrogate measures of intensity of parasite strongylid infection (egg counts)? (iv) Is there a relationship between abundances of specific bacterial taxa and surrogate measures of intensity of parasite strongylid infection (egg counts)?As a part of the long-term non-invasive monitoring of GIP infections and fecal microbiome/GIM of western lowland gorillas (G. g. gorilla) were collected at two research sites: Mongambe  and Bai Hokou  in the Dzanga sector of the Dzanga-Ndoki National Park (part of the DSPA complex), Central African Republic . Samples were diluted with water up to 50 ml volume and centrifuged for 5 min at 2,000 rpm. The sediment was weighed and re-suspended to 10 ml with 4% formaldehyde. For coprological examinations, Sheather's flotation with modified sugar solution was used (specific gravity 1.33) , Hasegawa et al. (Oesophagostomum or Necator. Therefore we divided the strongylid eggs found in gorilla samples into two categories: (i) Necator/Oesophagostomum and (ii) Mammomonogamus.We reported parasite presence/absence and for strongylid nematodes, also the intensity of infection expressed as EPG. Although the number of parasite eggs shed in feces may not be linearly correlated with the intensity of infection  and 534r . Amplicon purification was done using the QIAquick PCR Purification Kit . Amplicons were multiplexed and pyrosequenced using 454 FLX-Titanium technology as described previously  according to the manufacturer's protocol. The V1-V3 region of the 16S rRNA gene was PCR amplified  using primers 27f  with Entamoeba status as a predictor variable and gorilla social group as a covariate was fitted using MASS package ; eggs of Strongyloides, Necator/Oesophagostomum, Mammomonogamus, Bertiella, and Spirurida fam. gen  and 3.13 EPG , respectively (see Table We detected: trophozoites of en Table . The medEntamoeba positive (Ent+) and Entamoeba negative (Ent-) individuals , weighted UniFrac , and unweighted UniFrac .We obtained a median sampling depth of 6,458 reads per gorilla fecal sample  after sequence quality control  with Entamoeba status as a predictor variable and gorilla social group as a covariate  reached higher levels in Ent+ individuals. At the family level, Peptostreptococcaceae reached significantly higher levels in Ent\u2212 individuals , while unknown Selenomonadales , Erysipelotrichaceae , unknown Mollicutes , and Anaeroplasmataceae  reached higher levels in Ent+ individuals. At the genus level, unknown Selenomonadales , unknown Erysipelotrichaceae , unknown Molicutes , unknown Deltaproteobacteria , Olsenella , and Dorea  reached significantly higher levels in Ent+ individuals. Three out of six indicator taxa on genus level belonged among the 26 most abundant bacterial genera . We did not find significant differences in relative abundances of any other bacterial taxa between individuals positive or negative for other detected parasites (data not shown).We detected significant differences in relative abundances of indicator taxa, detected by Species indicator analysis and Random forest classifier, in te Table . Specifia Figure . AlthougEnt+ and Ent- individuals, even though they reached higher values in Ent+ individuals . Analyses of multivariate dispersion of communities or inter-individual variation within groups also did not show differences between Ent+ and Ent- individuals  did not significantly differ between Necator/Oesophagostomum and Mammomonogamus (EPG) and overall fecal microbiome composition, as described by the first NMDS axis, NMDS1 . We found weak relationships only between relative abundances of members of phylum Verrucomicrobia, family Verrucomicrobia subdivision 5 and Necator/Oesophagostomum egg counts based on Spearman's rank correlations and linear regression models . We did not find any significant relationship between relative abundances of any bacterial taxa and Mammomonogamus egg counts using Spearmans rank correlation analyses and linear regression model (data not shown).Using linear regression models we found no relationships between egg counts of  Figures , but wheNecator/Oesophagostomum  and egg count of Entamoeba spp. is associated with the abundance of specific bacterial taxa in the gorilla gastrointestinal tract. The mechanism behind these observations is unknown, however, this may be a reflection of either direct or indirect interaction between entamoebas, the GIM, and the host immune system. The genus Entamoeba contains both pathogenic and commensal species  and taxa that seem to be a signature of the fecal microbiome of gorillas even if they belong among minor taxa   in gorillas must be tested molecularly, by specifically targeting the presence and expression of known parasite-associated virulence factors. Since large diversity of Entamoeba spp. has been observed in wild great apes  that are not reflected in the fecal microbiome composition , the host immune machinery, and the other microbiota. To gain further insight into the specific nature of these interactions, it will be necessary to apply additional molecular approaches to assess GIP diversity and function at the mucosal level to understand how the host immune system reacts to the GIPs and their virulence factors, with subsequent consequences for gut bacterial communities. Likewise, the role of diet in this interaction should be clarified from a molecular perspective in terms of metabolic impact on the GIPs and the other microbiota. For more complex analyses adding other factors affecting fecal microbiome of great apes, e.g., sex and age would be also beneficial, nevertheless, it would require studying captive or larger number of habituated animals. Moreover, future work may be directed into analyzing the evolutionary correlates of GIP infections for health and disease in humans and great apes. Our results can have implications for understanding host-microbe interactions and gorilla welfare in both wild and captive conditions. Absence of GIP in captive apes may be responsible for particular health or digestive problems (together with other factors like diet), on the other hand, it is well-known that particular GIP in captive apes can reach higher intensities than in the wild and infected animals suffer from clinical outcomes which are rarely observed in the wild.Here, we examined the associations between GIP infections and the GIM composition of wild lowland gorillas. Although we did not observe notable changes in global bacterial community profiles in connection with GIP infections, we found significant relationships between KV and AG conceived the initial project design, with inputs from KP; BP KP and AT designed the field study and collected the samples; KV, AG, MT performed the microbial community analyses; BP performed parasitological analyses; KV analyzed the data with significant contributions from AG; KP, DM, KN, BreW, BryW, CY, RS, SL provided the financial support; KV wrote the initial manuscript with significant contributions from AG and KP. All authors reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AK and handling Editor declared their shared affiliation."}
+{"text": "Family caregivers play a crucial role in supporting older adults through home health (HH) episodes; yet no prior research examines factors affecting the adequacy of caregiver support during HH. We use a novel dataset linking nationally-representative survey data with HH assessment data for community-dwelling older adults  to identify older adult characteristics associated with adequate caregiver support in four task categories  during a subsequent HH episode. Weighted, multivariable logistic regression is used to model the likelihood of adequate caregiver support in each category. Multiple older adult characteristics prior to the HH episode were associated with greater likelihood of adequate caregiver support during HH, including: prior caregiver assistance with mobility, self-care, and health care tasks, living with others, and cognitive impairment. These findings reveal new risk factors for consideration in risk assessment and payment adjustments related to social determinants of health."}
+{"text": "Obesity has been linked to multiple conditions including cardiovascular disease, cancer, and metabolic syndrome. While the relationship between obesity and these diseases is well-established, the relationship between obesity and changes in cognitive function is less clear. This study examined the effects of overweight and obese status on performance in tests of executive function and memory. It was hypothesized that overweight and obese individuals would perform worse than normal weight individuals. Data from 547 individuals who participated in the Midlife in the United States Refresher cohort were used. Body mass index (BMI) and waist circumference (WC) were employed as measures of obesity. Both variables were examined continuously and categorically (from NHBLI-defined cutoffs). Z-scores were computed for each cognitive test and averaged together to create separate composite scores for executive function and memory. When measuring BMI and WC continuously, higher BMI was significantly associated with lower executive function ; no significant association between executive function and WC was found (p=.162). When measuring BMI and WC with clinical thresholds, participants with overweight or obese WC had significantly lower executive function (p=.030). No overall association between BMI-based thresholds and executive function was found (p=.682). Memory did not differ between overweight/obese participants and healthy weight controls with continuous or clinical threshold specifications. These findings suggest that: 1) obesity may relate to poorer executive function but not worse memory, and 2) the way in which obesity is measured reflects saliently in the results. Future researchers should consider conducting sensitivity analyses with different obesity criteria."}
+{"text": "Self-neglect includes persistent inattention to personal hygiene and the conditions of one\u2019s immediate living environment and is known to be associated with an increased risk of mortality among older adults. Although previous studies have shown that many individual factors predict self-neglect, neighborhood characteristics have received much less attention. Extant research has yet to consider connections between the conditions of one\u2019s neighborhood and self care over time. Using nationally representative longitudinal data from the National Social Life, Health, and Aging Project (NSHAP), we consider several features of neighborhood context in later life, including self-reported perceptions of neighborhood cohesion and neighborhood danger, neighborhood disorder (measured by interviewer ratings), and concentrated neighborhood disadvantage (using census data). Adjusting for individual-level factors , results from both lagged dependent variable and cross-lagged panel models find higher levels of neighborhood disorder to be associated with higher self-neglect scores (measured by interviewer ratings) over time. Social cohesion, perceived neighborhood danger, and collective efficacy were not associated with self-neglect when controlling for neighborhood disorder. These findings suggest that improving neighborhood disorder may be an effective approach for self-neglect prevention in later life"}
+{"text": "The potential life-threatening consequences of catecholamine use for emergency circulatory support in Takotsubo cardiomyopathy-related acute heart failure is a major challenge in cardiovascular emergences. In their recent work in BMC Cardiovascular Disorders Ansari U. et al. demonstrated the harmful effects of catecholamines on the outcome of patients with Takotsubo cardiomyopathy. Concerning this matter we emphasize the usefulness of speckle-tracking-derived echocardiography for early recognition of an acute phase of a Takotsubo syndrome in order to avoid the deleterious effects of a catecholamine therapy in patients with Takotsubo-associated acute heart failure. We read with great interest the publication by Ansari U. et al. , in whicAlthough the etiopathogenesis of TTS is still under debate, the role of catecholamines appears central to the pathophysiology of TTS. There is increasing evidence that the reversible change in left ventricular (LV) shape  associated with potentially life-threatening LV dysfunction, which characterize the acute phase of TTS reflect an uncommon myocardial response to sympathetic stimulation \u20134 PatienCatecholamines are still the first-line therapeutics in cardiogenic shock following acute myocardial infarction (MI), but are absolutely contraindicated in TTS patients, regardless of the severity of hemodynamic compromise. The potentially life-threatening consequences of catecholamine use for emergency circulatory support if the underlying cause of acute LV dysfunction is unrecognized TTS are therefore the main problem that can derive from diagnostic errors , 4, 5.c) reached up to 7 times higher value in the apex than in basal regions [c can be high enough to oppose circumferential myocardial fiber shortening which mainly generates the visible inward movement in this region and thus could explain the visually akinetic appearance of the apical regions in spite of the unequivocal prove of myocardial viability provided by the longitudinal strain data [Transthoracic echocardiography can be useful for early distinction between TTS and acute apical MI if attention is focused on regional myocardial function using the advantages of strain imaging.In patients with life-threatening acute HF, before coronary angiography becomes possible, echocardiography including also STE can identify a highly probable acute phase of TTS and in such patients, if absolutely necessary, any administration of cathecholamines should be continuously monitored by echocardiography and immediately stopped if the signs for TTS become more evident.Clinically (including laboratory tests), electrocardiographically, and even echocardiographically using only conventional echocardiographic techniques, TTS-related acute LV disorders closely mimic acute apical MI and without coronary angiography data these two etiopathogenically different diseases are almost indistinguishable. The only helpful conventional echocardiography signs which indicate that any sympathomimetic treatment can be deleterious are the detection of mitral valve systolic anterior movement (SAM) and high LV outflow tract (LVOT) pressure gradients. However, even during acute stress-induced LV dysfunction, LVOT obstruction because of mitral valve SAM is not evident in all patients with TTS . On the  regions . Such anain data , 5. Suchain data . All the"}
+{"text": "Choir interventions confer psychological benefits for persons with dementia (PwD) and their caregivers. However, less is known about whether physiological function also exhibits improvements pursuant to such social-cognitive interventions. The present study, based upon a subsample of the Voices in Motion (ViM) project, explored whether participation in an intergenerational choir results in systematic improvements in gait velocity  for both informal caregivers  and PwD . Longitudinal burst data from the first of three cohorts spanning 4 assessments over 3.5 months was analysed using multilevel modeling. Whereas caregivers exhibited significant improvements (p<.05) in gait velocity, PwD showed no improvement. Ongoing analyses are exploring additional cohorts, and whether improvements in gait dynamically covary with reductions in comorbidities . These results underscore the potential of choir for facilitating both psychosocial and physiological function for caregivers and PwD."}
+{"text": "Traumatic lesions of the wrist occur frequently and may give rise to underdiagnosed secondary abutment syndromes. The latter are a common cause of incapacitating pain and limited range of motion, despite minimal or even absent alterations on radiographs. Moreover, the complex wrist anatomy often results in ignorance or underappreciation of these syndromes.This paper presents a pictorial review of frequent and rare secondary abutment syndromes at the wrist joint, which \u2013 in contrast to primary abutment syndromes \u2013 are not based on anatomical variants or congenital deformations. The merit of each imaging modality is briefly mentioned. Traumatic wrist lesions occur frequently. Subsequently, secondary abutment syndromes (SAS), a common cause of incapacitating pain and limited range of motion in spite of minimal or absent alterations on radiographs, may arise. They are often underappreciated due to the complex wrist anatomy and call for a thorough analysis of all wrist components.The aim of this pictorial review is to present an overview of SAS and to highlight the role of imaging.The wrist is a complex structure of cartilaginous joints with little intrinsic stability, but mainly relies on soft tissue constraints from various ligaments. The three-dimensional motion is very susceptible to disturbances of their complex surfaces and to ligamentous lesions .Wrist fractures are frequently missed on radiographs . LigamenThe secondary repetitive bony impaction may result in contusion  with theSAS may give rise to complaints, sometimes appearing years after trauma. The predominant symptoms are restricted motion and incapacitating pain, exacerbated by activity. SAS may have a negative impact on the three-dimensional hand positioning during daily activities .Intra-articular fractures of the radius may heal with a residual step-off , seen onLunate bone impaction on its articular fossa may cause SAS. Parasagittal radial fractures Figure  need carDistal radioulnar joint (DRUJ) fractures are difficult to evaluate on radiographs, particularly coronal sigmoid notch fractures Figure  and B. BA relative ulnar shortening may appear after trauma, causing a DRUJ impingement Figure  and F. EStyloid process fractures may fail to heal, resulting into fragmentation and collision during ulnar deviation. MRI highlights neo-articulation and BMO Figure . The tri9Due to styloid process length increase, impaction with the triquetral bone may appear Figure . As in tIn secondary positive ulnar variance, the latter abuts the lunate and/or triquetral bone and eventually leads to ulnar head deformation Figure . It may Extensive destruction of extrinsic ligaments leads to a proximal-ulnar carpal shift , creatinFractures appear most frequently at the scaphoid waist . Radial Avascular necrosis \u2013 probably due to chronic microtraumata \u2013 with deformation starts at the radial side . Due to On radiographs Figure , a widenMRI may also show this ligamentous tear Figure  and the Hamatolunar abutment is related to lunate bony variants (Viegas type II). However, a posttraumatic disturbance of the carpal row alignment (Gilula)  may induQuadrangular joint traumata may result in bony carpal boss . AlthougA large variety of pathologies may cause SAS. This underscores the need for a thorough posttraumatic joint evaluation. Follow-up radiographs and MRI are mandatory in the presence of clinical symptoms. Concerns about the prognosis \u2013 certainly in expert or insurance-related files \u2013 should encourage detailed assessment, as even small lesions may be very functionally disabling.Posttraumatic SAS may interfere with a large variety of normal daily activities, as the wrist is a crucial structure in the three-dimensional positioning of the hand. Some are fairly unknown and, due the complex anatomy of the wrist, a SAS is also often ignored or underappreciated."}
+{"text": "Thousands of physicians attend scientific conferences each year. While recent data indicate that variation in staffing during such meetings impacts survival of non-surgical patients, the association between treatment during conferences and outcomes of a surgical population remain unknown. The purpose of this study was to examine mortality resulting from traumatic injuries and the influence of hospital admission during national surgery meetings.Retrospective analysis of in-hospital mortality using data from the Trauma Quality Improvement Program (2010\u20132011). Identified patients admitted during four annual meetings and compared their mortality with that of patients admitted during non-conference periods. Analysis included 155 hospitals with 12,256 patients admitted on 42 conference days and 82,399 patients admitted on 270 non-conference days. Multivariate analysis performed separately for hospitals with different levels of trauma center verification by state and American College of Surgeons (ACS) criteria.Patient characteristics were similar between meeting and non-meeting dates. At ACS level I and level II trauma centers during conference versus non-conference dates, adjusted mortality was not significantly different. However, adjusted mortality increased significantly for patients admitted to trauma centers that lacked ACS trauma verification during conferences versus non-conference days , particularly for patients with penetrating injuries, whose mortality rose from 11.6% to 15.9% (p = 0.006).Trauma mortality increased during surgery conferences compared to non-conference dates for patients admitted to hospitals that lacked ACS trauma level verification. The mortality difference at those hospitals was greatest for patients who presented with penetrating injuries. Variation in hospital staffing has been associated with increases in risk of patient morbidity and mortality. Mortality for both critically ill patients and those requiring emergent surgical intervention, for example, has been found to increase during nights and weekends, the so-called \u201cweekend effect.\u201d , 2 SimilDespite efforts to maintain high levels of quality healthcare delivery at all times, trauma centers continue to experience regular fluctuations in staffing, and the potential risks associated with those periods remains largely unclear. Multiple times each year, thousands of surgeons leave their respective institutions to travel to academic conferences. A recent study found that during national cardiology meetings, mortality decreased for high-risk patients hospitalized with heart failure and cardiac arrest. As the aIn this study, we examine the association between national surgery conferences and in-hospital trauma mortality. We also perform subgroup analysis on specific trauma populations and hospitals according to their different forms of trauma center accreditation. We hypothesize that mortality resulting from traumatic injuries increases during national surgery conferences, presumably due to fluctuations in staffing.We conducted a retrospective cohort study of trauma patients treated at hospitals participating in the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP). The primThe study population consisted of patients meeting inclusion criteria for the ACS TQIP. TQIP is We included injured patients admitted to TQIP participating centers between January 2010 and December 2011. The data excludes children (age less than 16 years) and patients who lacked records for date and time of admission to the Emergency Department. We excluded patients who presented to emergency departments without signs of life, defined as an initial systolic blood pressure of zero, heart rate of zero, and Glasgow Coma Scale motor score of one. Rates ofa priori and obtained meeting dates from publicly available conference announcements. After identifying dates of each individual meeting, we created a composite \u201cmeeting\u201d variable that consisted of all surgery conference periods combined. The control group consisted of patients admitted three weeks before and after each meeting.The primary exposure variable was hospital admission during national surgery conferences that are consistently well attended by trauma surgeons. Conferences included annual meetings of the American College of Surgeons, the Eastern Association for the Surgery of Trauma, the Western Trauma Association, and the American Association for the Surgery of Trauma. We selected these conferences When modeling the influence of conference periods on mortality, we adjusted the probability of death for patients using the ISS, the motor component of the Glasgow Coma Scale, age, gender, race, initial systolic blood pressure in the Emergency Department, mechanism of injury, inter-hospital transfer status, payer type, and hospital teaching status.We first performed descriptive statistics using chi-square and Student t tests to compare patient characteristics in both cohorts. All tests were two tailed with \u03b1 = 0.05. We then performed risk adjustment of patient level factors and hospital teaching status using multivariable logistic regression models, clustering at the hospital level. We constructed the mortality model using forward selection, and the order of variable entry was determined by the c-index, a measure of the ability of a parameter to discriminate outcome. Continuous data (systolic blood pressure) exhibited a right-skewed distribution and was natural log-transformed in a manner consistent with the TQIP mortality model. We testeWe performed several sensitivity analyses. We first conducted falsification analyses to assess for potential confounding in the relationship between surgery meeting and non-meeting periods.\u201317 SpeciThe ACS TQIP registry included a total of 94,566 trauma patient admissions reported from 156 hospitals during the study period. Of those patients, 12,256 patients (13%) presented during national surgical conferences. Patients in both cohorts, those admitted during meeting compared with non-meeting periods, were similar with respect to their demographic and injury characteristics. The majority of patients were male and white, and falls were the most common mechanism of injury. The majority of patients in each cohort were treated at ACS level I university hospitals, and approximately one third of the patients in each cohort were transferred from other facilities, suggesting that patients were not diverted away from academic centers during surgical conferences. Patient and injury characteristics of each cohort are summarized in The study included data collected from 145 hospitals (2010\u20132011), with an addition ten hospitals included in 2011. The majority of participating hospitals had an ACS trauma verification level (I or II), however, a considerable number of hospitals without ACS trauma verification contributed data as well . We provided a summary of hospital characteristics in Overall risk-adjusted in-patient mortality was similar for trauma patients admitted during meetings compared with non-meeting periods (approximately 6%). Also, when we stratified patients by injury type (blunt and penetrating), patient mortality exhibited no difference between meeting and non-meeting cohorts. However, we found that when stratified by ACS trauma verification level, mortality increased significantly during meetings among trauma patients admitted to hospitals that lacked ACS trauma verification . That association was particularly pronounced at non-ACS verified trauma centers among patients with penetrating injuries, whose predicted mortality increased from 12% to 16%. We found in subgroup analysis by state verification level that the conference effect in non-ACS trauma centers was entirely driven by state verified level I trauma centers. In contrast, mortality remained unchanged during meetings compared with non-meeting periods for injured patients who presented to ACS verified trauma centers.When stratified by injury acuity (ISS\u226415 and ISS>15), we found no evidence in the overall patient cohort of conference effect among low-acuity patients  and high-acuity patients . At trauma centers that lacked ACS trauma verification, we found statistically insignificant trends towards increased mortality during meetings among both low- and high-acuity patients . The association only reached statistical significance among high-acuity patients with penetrating injuries . We found no evidence of interaction effects between number of trauma surgeons and meetings, meaning the number of trauma surgeons did not contribute to mortality differences during meetings, so we did not include that variable in the final mortality model. Additionally, we found no evidence of interaction between patient characteristics  and surgery meetings with regards to mortality risk. Odds ratios and predicted probability of risk-adjusted in-patient mortality during meetings compared with non-meeting periods are summarized for each patient cohort in We tested the robustness of our model and found no evidence that unmeasured confounding contributed to differences in in-patient mortality between national surgical meetings and non-meeting periods. Risk-adjusted mortality of trauma patients was similar during national meetings for oncology and health services research when compared with the three weeks before and after those meetings. That analysis included 114,918 patients, 17,154 patients admitted during meetings and 97,764 patients admitted during non-meeting periods. Subgroup analysis, stratifying patients by hospital ACS trauma verification level and injury type, produced no difference in mortality between cohorts (meeting and non-meeting) for non-surgery conferences. Results of those tests are summarized in We found substantial increases in mortality among trauma patients admitted to hospitals that lack trauma center verification by the ACS during national surgery conferences, particularly for patients who presented with penetrating injuries. Since typical risk factors such as ISS, age, and transfer status did not differ significantly between patients admitted during meeting and non-meeting periods, it is unlikely that high-risk patients were directed to or from particular hospitals during meetings. The increased mortality during meetings is most likely attributable to the selective decline of surgeons and changes in hospital staff composition that occur, potentially leaving hospitals with decreased capacity and/or capability to effectively treat injured patients. The finding that mortality increased among patients with penetrating injuries, in particular, supports this explanation, since those patients often require surgical intervention compared with patients whose injuries result from blunt mechanisms.Study of the conference effect phenomenon is limited. Cardiology conferences have been associated with decreases in both percutaneous coronary interventions (PCI) and cardiovascular mortality, whereas we found surgery conferences were associated with increased mortality for trauma patients. These diIt is also noteworthy that we found no such association between surgery meetings and increased mortality for patients admitted to ACS verified trauma centers. This finding may be due to trauma center adherence to the ACS guidelines. The American College of Surgeons Committee on Trauma (ACS-COT) has maintained guidelines for regionalized trauma systems since 1979, and the a priori for the purposes of this study. The study does not include a comprehensive assessment of all surgery, trauma, and critical care conferences. Inclusion of both additional specialty conferences and more granular attendance data, including the clinical experience of the attendees, may clarify the relationship between fluctuations in staffing during surgery conferences and trauma patient mortality.The primary limitation of our study was the inability to establish specific mechanisms by which patients admitted during national surgery conferences to hospitals lacking ACS verification had increased risk of mortality. Further study of variation in processes of care such as resuscitation practices and procedures may explain the influence of surgical meetings on clinical outcomes. Another limitation is that we selected four surgery conferences In this study, we identified a \u201cconference effect\u201d for trauma patients treated at non-ACS verified trauma centers, and we identified patients with penetrating injuries as particularly at-risk of increased mortality during national surgery meetings. Staffing criteria of trauma center verification by the American College of Surgeons appears to protect against the conference effect. These findings have important implications for both how hospitals prepare for conferences with regards to staffing and, potentially, how conferences themselves are structured to allow for increased remote participation.S1 TableAppendix A and Appendix B.(DOCX)Click here for additional data file.S1 File(DTA)Click here for additional data file."}
+{"text": "Ductal adenocarcinoma is the most common pancreatic neoplasm. A variety of pancreatic lesions mimic pancreas ductal adenocarcinoma (PDAC), such as high-grade neuroendocrine tumors, small solid pseudopapillary tumors, metastases, focal autoimmune pancreatitis, and groove pancreatitis. These occasionally look similar in images, but they have differential diagnosis points. Familiarity with the imaging features of PDAC and its mimics is paramount for correct diagnosis and management of patients. In this essay, we describe imaging findings of PDAC and its mimics for differential diagnosis. Pancreas ductal adenocarcinoma (PDAC) accounts for 85\u201390% of all pancreatic neoplasms and is one of the leading causes of death worldwide 2. Variou3438Computed tomography (CT) is a useful modality for detecting and staging PDACs . PDACs u12Pancreatic NETs originate from the islet cells of Langerhans and are divided into low-, intermediate-, and high-grade according to the World Health Organization classification . High-gr71417SPTs are uncommon neoplasms with low malignancy potential, occurring predominantly in young women 19. Calci202222A previous study  reported24Autoimmune pancreatitis (AIP) is an uncommon form of chronic pancreatitis caused by an autoimmune mechanism . It is a282930Groove pancreatitis is an uncommon type of pancreatitis affecting the pancreaticoduodenal groove, defined as the potential space between the pancreatic head, common bile duct, and duodenum . This in9259Neoplastic lesions such as high-grade NETs, small SPTs, and metastases and inflammatory lesions including focal AIP and groove pancreatitis can mimic PDAC. Abrupt narrowing of a dilated pancreatic duct is a usual imaging finding of PDAC. Although some mimics occasionally accompany pancreatic duct dilatation, they have points of differential diagnosis: presence of tumor thrombus and hypervascular liver metastases, absence of adjacent vascular invasion, and delayed enhancement pattern. In addition to these imaging findings, the shape of the narrowed pancreatic duct is a key imaging feature for discrimination of PDAC from other disease entities. Familiarity with the imaging features of PDAC and its mimics is paramount for managing patients in daily practice."}
+{"text": "Research suggests that older adults with neurodegenerative diseases are at increased risk of developing a subsequent neurodegenerative or comorbid psychiatric disorder or both. Depression and other psychiatric conditions, though prevalent, are often under-diagnosed and under-treated among those with neurodegenerative conditions potentially leading to more rapid disease progression, poorer health outcomes and increased health care use. Few population-based studies have comprehensively examined the risk and temporal ordering of common neurodegenerative and psychiatric conditions, including whether these associations differ by age or sex. Initial findings regarding the incidence of ordered pairs of neurological conditions  and psychiatric disorders  will be summarized. This population-based retrospective cohort study will provide essential data to allow policymakers, planners and providers to better anticipate the prognosis and care needs of older adults with comorbid neurodegenerative and psychiatric conditions."}
+{"text": "Hosts must recognize pathogen invasion and respond rapidly. The need for speed requires a low threshold for triggering a response, causing occasional false alarms. Host immune systems therefore require strong negative regulators to shut down unnecessary responses. The evolutionary consequences of rapid trigger dynamics balanced by negative regulators have received little attention. Here, we emphasize four aspects that influence the evolutionary genetics of immunity: diverse gene families of rapidly acting triggers opposed by slower-acting negative regulators, pathogen attack against negative regulators, diversifying selection of negative regulators by pathogen pressure, and heritability of immune-related disease from imbalance between triggers and negative regulators.Acropora digitifera has around 500 genes, sea urchins have approximately 200, and zebrafish have about 385 [A broad sensor array of receptors, located on the cell surface or in the cytosol, recognize pathogen-associated molecular patterns and trigger innate immunity. Common triggers include the peptidoglycan recognition proteins, gram-negative binding proteins, Toll-like receptors (TLRs), nucleotide-binding domain leucin-rich repeats (NLRs), and the cyclic GMP-AMP synthase (cGAS) system that detects double-stranded DNA (dsDNA) , 2. In tbout 385 . SpongesThese receptors trigger immune cascades that are often evolutionarily ancient within groups or across broad domains of life. Key components of such cascades include nuclear factor-\u03baB (NF-\u03baB) transcription factors, interferons (IFNs), interleukins, and Toll and immune deficiency (IMD) pathways \u20139. The pThe need for speed in immune response  demands All organisms have an impressive array of negative regulators. Post-transcriptional modification of innate sensors and downstream molecules suppress the effect of the pattern recognition receptor triggers , 14. TriDifferent organisms will tune the tradeoff between faster response and lower error rates in different ways. A focus on the tuning of that tradeoff may lead to interesting comparative insights about the design of immune regulation.Leishmania exploits a negative TLR regulator to suppress production of key proinflammatory cytokines [Attackers use diverse mechanisms to block the expression of host innate immunity , 25\u201327. ytokines , virusesytokines , and manytokines .Invaders of insects alter the expression of an impressive variety of miRNAs, including negative regulators. Some pathogens express their own miRNAs to alter host immunity. The function of most miRNAs remains unknown, providing a rich topic for further study .Tumors also evolve to down-regulate immunity against cancer cells and often manipulate the normal repressors of immunity. For example, Vinay and colleagues  note thaHosts gain by altering the specific sequences of their negative regulators to avoid recognition or mimicking by pathogen effectors. Negative immune regulators that are under attack may form diverse gene families and evolve relatively rapidly. Few prior studies have focused explicitly on the diversity and evolutionary rate of negative regulators.Drosophila, Lee and Ferrandon [Drosophila, genes involved in the response signaling cascade tended to be more conserved than recognition proteins, but those that functioned primarily in modulating the immune response showed evidence for positive selection far above the genomic average [In errandon  note tha average .The nature of diversifying selection depends on the specificity of mechanisms by which attackers manipulate host immunity. In human immunity, attack against negative immune regulators may be relatively nonspecific, in the sense that the attackers may not be differentially targeting molecules based on sequence variability. By contrast, for the small RNAs that regulate immunity in plants, insects, and other organisms, the RNA sequences and the mechanisms of manipulation are likely to be highly specific. The more sequence-specific the mechanisms that attackers use to manipulate negative immune regulators, the stronger the diversifying selection will be.Regulation by strongly opposed triggers and repressors is prone to failure ( discussePlants may use miRNAs to tune the threshold for the triggering of immunity by the NLR pattern recognition receptors. Canto-Pastor and colleagues  found thSimilarly, constitutively expressed inhibitors of the type I IFN response in human immunity may \u201cdetermine a threshold of activation of an antiviral response\u201d . A quantGenetic variability in triggers and negative regulators can lead to mismatches in the opposing regulatory components of innate immunity and various types of immune-related disease. One possibility concerns the various immune-related disorders associated with misexpression of type I IFN . AnotherOur hypothesis and these preliminary examples suggest that further study of genetic variability in the positive and negative regulators of immune cascades may lead to interesting insights about the heritability of immune misregulation."}
+{"text": "Social capital is essential for healthy living in later life, and evidence indicates the importance of neighborhood context in facilitating access to this resource. However, additional research is needed to compare how objective and subjective indicators of context shape this association. We examine links between objective (census tract-level population density and composition) and subjective (perceived safety and quiet) indicators of neighborhoods and social capital . Data include participants age 65+ (N=259) from Wave 3 (2015) of the longitudinal Social Relations Study based in Detroit, Michigan. Multivariate analyses indicate respondents living in more densely populated neighborhoods reported more frequent contact with network members. Those perceiving their neighborhood as safe reported larger networks, more trust in and greater support exchanged among neighbors. Findings suggest both objective and subjective indicators of neighborhood context shape access to social capital, but perceptions play a larger role."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: The objective of this project is the application of complex fusion models, which combine observed and modeled data, to areas with sparse monitoring networks with multiple chemical components is under-developed. Such models could provide improved accuracy and coverage for air quality measurement predictions, an area greatly limited by the amount of missing data. METHODS/STUDY POPULATION: This project focuses on the development of methods for improved estimation of pollutant concentrations when only sparse monitor networks are found. Sparse monitoring networks are defined as areas where fewer than three criteria air pollutants (based on EPA standards) are monitored. Particularly, a multivariate air pollutant statistical model to predict spatio-temporally resolved concentration fields for multiple pollutants simultaneously is developed and evaluated. The multivariate predictions allow monitored pollutants to inform the prediction of nonmonitored pollutants in sparse networks. RESULTS/ANTICIPATED RESULTS: Daily, ZIP code level pollutant concentration estimates will be provided for 8 pollutants across South Carolina, and goodness of fit metrics for model variants and previously established methods will be compared. DISCUSSION/SIGNIFICANCE OF IMPACT: These methods utilize only widely available data resources, meaning that the improved predictive accuracy of sparsely monitored pollutant concentrations can benefit future studies in any US area by improving estimation of health effects and saving resources needed for supplemental air pollutant monitoring campaigns. Our method for estimation attempts to improve predictive accuracy and data availability for sparsely monitored pollutants and areas."}
+{"text": "A 78-year old male presented to the emergency department after accidental dislodgement of his chronic gastrostomy tube. A replacement gastrostomy tube was passed easily through the existing stoma and flushed without difficulty. Confirmatory abdominal radiography demonstrated contrast in the proximal small bowel, but the patient subsequently developed epigastric pain and refractory vomiting. Computed tomography revealed the tip of the gastrostomy tube terminating in the pylorus or proximal duodenum. This case highlights gastric outlet obstruction complicating the replacement of a gastrostomy tube and the associated radiographic findings. A 78-year-old male with a history of stroke presented to the emergency department after accidental dislodgement of his chronic gastrostomy tube approximately five hours prior. The patient offered no other complaints and denied abdominal pain, nausea, or vomiting. On examination, he appeared comfortable with unremarkable vital signs. His abdomen was non-tender and demonstrated a patent, mature gastrostomy stoma. A replacement gastrostomy tube was passed easily through the existing stoma and flushed without difficulty. Confirmatory abdominal radiography revealed contrast in the duodenum and proximal jejunum, but no portion of the stomach was outlined . ShortlyGastric outlet obstruction related to gastrostomy tubes is rare.4What do we already know about this clinical entity?Dislodged gastrostomy tubes are commonly repositioned or replaced in the emergency department. Gastric outlet obstruction is a potential, albeit rare, complication.What is the major impact of the image(s)?Emergency physicians should be familiar with the appearance of gastric outlet obstruction due to gastrostomy tube malposition on contrast-enhanced plain radiography.How might this improve emergency medicine practice?Early identification of gastric outlet obstruction on plain radiography can prevent patient discomfort and the need for additional advanced imaging."}
+{"text": "Notopteridae  represents an old fish lineage with ten currently recognized species distributed in African and Southeastern Asian rivers. Their karyotype structures and diploid numbers remained conserved over long evolutionary periods, since African and Asian lineages diverged approximately 120 Mya. However, a significant genetic diversity was already identified for these species using molecular data. Thus, why the evolutionary relationships within Notopteridae are so diverse at the genomic level but so conserved in terms of their karyotypes? In an attempt to develop a more comprehensive picture of the karyotype and genome evolution in Notopteridae, we performed comparative genomic hybridization (CGH) and cross-species (Zoo-FISH) whole chromosome painting experiments to explore chromosome-scale intergenomic divergence among seven notopterid species, collected in different African and Southeast Asian river basins. CGH demonstrated an advanced stage of sequence divergence among the species and Zoo-FISH experiments showed diffuse and limited homology on inter-generic level, showing a temporal reduction of evolutionarily conserved syntenic regions. The sharing of a conserved chromosomal region revealed by Zoo-FISH in these species provides perspectives that several other homologous syntenic regions have remained conserved among their genomes despite long temporal isolation. In summary, Notopteridae is an interesting model for tracking the chromosome evolution as it is (i) ancestral vertebrate group with Gondwanan distribution and (ii) an example of animal group exhibiting karyotype stasis. The present study brings new insights into degree of genome divergence vs. conservation at chromosomal and sub-chromosomal level in representative sampling of this group. This ancestral teleost lineage retained primitive anatomical features 4 and, considering their very ancient origin (200 Mya), their current distribution pattern could reflect the vicariance events occurring after the Gondwana\u2019s break-up6. While some osteoglossiform families  are restricted to Africa, other ones  exhibit a patchy distribution, with species endemic to different continents7.The monophyletic fish order Osteoglossiformes represents an ancient teleost group with a geographic distribution restricted to the freshwater river basins13]. This lack of data is probably due to the worldwide distribution of the whole group and, on the other hand, the endemic status of majority of its species, thus hindering integrative studies that allow a globalized view of its evolutionary process.Their wide geographic distribution and basal position in the teleost phylogeny, qualifies this group as an excellent model for systematic, genomic, cytogenetic and evolutionary studies. However, only few cytogenetic and genomic studies have been undertaken so far, covering a limited number of osteoglossiform species , and CGH homology (intraclade genomic similarity). The groups/species relationships  followed phylogenetic hypothesis based on DNA molecular markers available for family"}
+{"text": "We highlight a range of strategies for establishment of three dimensional (3-D) airway and intestinal organoid models and evaluate the limitations and potential improvements in each system, focusing on their application in CF. The in vitro CFTR functional assays in patient-derived organoids allow for preclinical pharmacotherapy screening to identify responsive patients. It is likely that organoids will be an invaluable preclinical tool to unravel disease mechanisms, design novel treatments, and enable clinicians to provide personalized management for patients with CF.Cystic fibrosis (CF) is an inherited disorder where individual disease etiology and response to therapeutic intervention is impacted by CF transmembrane regulator (CFTR) mutations and other genetic modifiers. CFTR regulates multiple mechanisms in a diverse range of epithelial tissues. In this Review, we consolidate the latest updates in the development of primary epithelial cellular model systems relevant for CF. We discuss conventional two-dimensional (2-D) airway epithelial cell cultures, the backbone of  It is cMajor advances in symptom management have been instrumental in delaying disease progression in CF. Administration of enzyme replacement therapy, nutritional support, mucolytic agents airway clearance techniques, and antibiotics for bacterial lung infection, along with early detection of disease  has dramatically improved life expectancy in CF patients over the last 4 decades. The median age of death is now above 40 years  airway and rectal organoids. We also discuss their emerging use as More than 2,000 CFTR mutations have been identified so far and at least 336 of these are reported to lead to symptoms characteristic of CF , reduced episodes of pulmonary exacerbations and improved body mass index (BMI)   restored F508del-CFTR channel activity to 15% of wild-type CFTR in in vitro  epithelial cell lines. It is thus not surprising that this model has a higher propensity of false-positive and false-negative \u201chits\u201d compared to that performed in primary human bronchial epithelial (HBE) cells.One of the major hurdles to the development of novel treatment regimens in CF is the bench-to-bedside translation of scientific knowledge. Many drugs that perform well in a laboratory setting fail to advance in clinical trials, largely due to inappropriate selection of Although CF is a monogenic disease, the diverse mutation variants identified within the CFTR gene as well as the presence of modifier genes (known and unknown), warrants adoption of new technologies to extend research capabilities. There is a clear unmet need for a representative library of patient-specific epithelial cell models for disease modeling, preclinical testing of drug response, and biobanking for future drug discovery. The cell models can be derived from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or tissue-resident adult stem cells. Whereas, ethical concerns pertaining the source of human ESC, limit their use in research, generation of CFTR gene corrected iPSC lines enable disease modeling, drug discovery and toxicology studies [reviewed in  fluid and induced sputum samples usually do not provide sufficient cell counts to initiate culture. Therefore, supply of CF patient-derived HBE cells are often limited and hard to come by.The pulmonary epithelium is divided into three regions; upper , lower (trachea and primary bronchi), and distal small airway epithelia . Persistent inflammation, bacterial colonization, and airway structural changes in CF occur in the lower respiratory tract. Primary HBE cells are therefore the gold standard for studying CF disease pathogenesis and evaluating CFTR functional response  cells are increasingly used as surrogates for the lower airway epithelium in CF research  values . Expansion of epithelial cells is often necessary in the initial passages for biobanking purposes and to generate enough cell numbers needed to differentiate cells under air-liquid interface (ALI) conditions. HBE cells are most \u201c\u2212 transport in these cells is also preserved.Conditionally reprogrammed cells (CRCs) are generated by co-culturing patient-derived airway epithelial cells with irradiated fibroblast feeder cells. Specialized conditioned media (termed F-Media) which contains Rho-associated protein kinase (ROCK) inhibitor, promotes serial passages of airway epithelial cells and enhances population doubling without compromising the characteristic epithelial cell morphology. Both ROCK inhibitor and the feeder layer are essential in maintaining the stem cell-like phenotype evident in CRCs  demonstrated some advantage over the standard CRCs. The modified CRCs could support airway epithelial cell growth up to passage 10 with robust formation of pseudostratified epithelium at the extended passage, although a modest decrease in CFTR-dependent Cl+ currents and Cl\u2212 conductance declined fairly rapidly after serial passage 6  and bone morphogenic protein (BMP), showed airway epithelial cells could be expanded up to 18\u201325 passages without loss of proliferative potential  or are cultured in such a manner that they develop ECM-like scaffolds between them, thus mimicking the in vivo phenotype more faithfully. While cell-derived ECMs such as Matrigel have been most commonly used for development of organoids, their undefined components introduce inconsistency in replicating the native 3-D culture environment , which establishes intercellular cues or network in the Different methods for generating organoids (or spheroids) from human lung cells have been described to date, each producing organoids with distinct definitive structure and cellular compositions. Barkauskas and colleagues have elegantly reviewed the different lung organoids (airway organoids inclusive) established from varying lung progenitor cell populations, including basal cells in the proximal airways, secretory club Clara cells in bronchioles and alveolar type II cells in the alveoli, as well as those from embryonic and iPSCs , patient-derived intestinal epithelial cells also present an invaluable resource in characterizing the relationship between the CFTR gene mutation and the disease phenotype. More recently, they play an important role in the development of HTS strategies to elucidate novel drugs for the treatment of CF.ex vivo conditions. Other limitations to the use of rectal biopsies include the small number of biopsies collected (4\u20138 biopsies) and the need for all biopsies to be tested on collection day i.e., the biopsies cannot be preserved for further testing.Compared to human airway tissue, colon tissue damage in CF patients is minimal and the rectal epithelium is accessible in a less invasive manner. The abundant expression of CFTR in the distal colon makes rectal biopsies an attractive cellular source for interrogating CFTR function , inhibitors of TGF-\u03b2 and BMP signaling and the basement membrane matrix (matrigel). Intestinal organoids can be indefinitely cultured and remain genetically and phenotypically stable upon repeated passaging and long term culture  overcome these limitations by extending the use of rectal biopsies in cultures. Intestinal organoids can be grown from crypts isolated from freshly isolated rectal biopsies. Crypts are rich in Lgr5The primary functional assay to assess CFTR activity in organoids, the forskolin-induced swelling (FIS) assay is CFTR dependent. This approach does not measure the net transepithelial ionic transport. Rather, forskolin is used to stimulate intracellular cAMP production which then activates CFTR at the plasma membrane. CFTR activation drives chloride and fluid flux to the organoid lumen , causing rapid swelling of organoids with functional CFTR or those derived from non-CF subjects. This swelling effect is significantly reduced or absent in organoids derived from CF subjects who exhibit differing rates of FIS with different classes of CFTR mutations and also between individuals with the same CFTR mutation , are either absent or present in negligible amounts in the gut to be functional (Rajendran et al., SAW, NTA, and SLW wrote the manuscript with critical input from CKH, LKF, AK and AJ.AK is a scientific advisor for Unizyme Laboratories A/S. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Acute traumatic patellar dislocations are encountered with relative frequency, making up 3% of all knee injuries. Typically witnessed in younger patients following sporting injuries, this injury can be debilitating, potentially leading to recurrent dislocation, pain, reduction in activity and patellofemoral osteoarthritis.Management of this injury remains controversial, and as such detailed magnetic resonance imaging (MRI) is increasingly recommended to help illustrate the exact nature of osteochondral and soft tissue injury, with a view to assessing the anatomical sequelae of patellar dislocation as well as the potential of recurrence and dictating the need for either conservative or surgical management in the acute setting. As such, awareness of the typical MRI findings in traumatic patellar dislocations may potentially aid in pursuing appropriate intervention for this pathology.This case describes a 33-year-old gentleman presenting to the emergency department following patellar dislocation. After failed departmental closed reduction, this patient progressed on to definitive anatomical MRI assessment followed by acute surgical intervention in the form of\u00a0medial patellofemoral ligament (MPFL) repair. This case allows for both illustration and discussion of typical radiological features associated with traumatic patellar dislocation. Acute traumatic patellar dislocations are encountered with relative frequency, making up 3% of all knee injuries . TypicalAssessment of a primary traumatic patellar dislocation is multifaceted, involving initial clinical history and examination followed by initial plain radiographic evaluation involving anteroposterior, lateral and axial views . While pThe following case report allows for illustration and discussion of some of the typical MRI findings one may encounter following acute patellar dislocation that may potentially precipitate subsequent definitive surgical intervention.A 33-year-old gentleman presented to the emergency department describing substantial right knee pain and swelling following a rotational injury. Inspection indicated significant joint effusion and subsequent examination showed absence of straight leg raise on the affected side. Plain radiographic evaluation of the knee showed lateral displacement of the patella Figure  confirmiRadiological investigations displayed evidence of lateral patellar dislocation on plain radiograph Figure , as wellIn the context of failed closed reduction as well as confirmation of the diagnosis, associated soft-tissue injuries and presence of risk factors for recurrent dislocation, this patient subsequently proceeded to definitive surgical treatment in the form of MPFL repair, with excellent postoperative function and no further dislocation at 46 months postoperatively.Acute patellar dislocations are debilitating, with up to 58% of patients noting persistent limitation to strenuous activity and 55% failing to return to sport at six months following index injury ,4. WhileDetailed anatomical illustration of the patellofemoral joint and surrounding structures at time of injury has thus become increasingly important aspect of initial evaluation following this injury -8. This Given both the increased diagnostic role of MRI and the relative frequency in which this injury is encountered, particularly in the adult population, awareness of both the plain radiographic features and more importantly the MRI findings associated with acute traumatic patellar dislocation as\u00a0discussed above may aid in improved detection, earlier management and prevention of recurrent dislocations, hence reducing the potential debilitating effect of this injury ,2.Traumatic patellar dislocations most commonly occur laterally and are associated with injury to both the medial patellofemoral ligament and medial patellar retinaculum. MRI is becoming an increasingly important diagnostic tool in assessment of traumatic patellar dislocations, useful in both detecting associated cartilage and soft tissue disruption as well as risk factors for recurrent dislocation. As such, awareness of the typical MRI findings in traumatic patellar dislocations outlined in the above case may potentially aid in pursuing either definitive conservative or surgical treatment in this pathology."}
+{"text": "Innate immune cells trigger sophisticated intracellular signaling pathways via innate immune receptors, including membrane-bound or cytosolic receptors3. Host innate immune activation results in the production of multiple effector molecules, including cytokines and chemokines as well as antimicrobial proteins, to combat invading pathogens and parasites4. In addition, innate immune cells, such as macrophages and dendritic cells, are the principal antigen-presenting cells that activate T cells, which are involved in more specific and delicate immune responses6. In particular, Th1 cell-mediated interferon (IFN)-\u03b3 can efficiently promote cell-autonomous host defenses against intracellular parasitic and mycobacterial infections through various effectors, including IFN-inducible GTPases, inducible nitric oxide synthase, and autophagy proteins8.Host\u2013pathogen interaction is considered a highly dynamic process between diverse microbial pathogens and hosts in all stages of pathogenic infection, from invasion to dissemination. Upon pathogenic infection, innate immune systems respond to pathogen-associated molecular patterns and activate immediate host inflammatory and antimicrobial responsesHere, a special issue of articles presents recent findings on how host immune and pathological responses are generated by intracellular signaling machinery, which can be activated at various stages of host\u2013pathogen interaction, and further describes how pathogens subvert host protective responses to establish an infection in the harsh environment inside host cells. In addition, this special issue includes invited reviews that discuss current knowledge of host defensive components and pathways, i.e., immune receptors, cytokines, signaling molecules, autophagy, and the microbiota. We further describe recent innovative trials based on studies of the host\u2013pathogen interface involving the therapeutic utilization of bacteria in the context of anticancer treatments. A comprehensive understanding of host\u2013pathogen interaction will provide new insights into the identification of novel targets for both host effectors and microbial factors and will lead to new therapeutic treatments for infections and other human diseases.9. Lee and coworkers provide a comprehensive summary of viral strategies that evade host cytosolic sensing to facilitate intracellular infection and replication of viruses. Although innate immune responses are essential for combating viral infections, they should be tightly regulated to prevent harmful host responses. Lee and coworkers also review recent findings on the positive and negative regulatory mechanisms for intracellular sensors in-host cells. Recent studies have uncovered key signaling molecules that participate in the recognition of cytosolic pathogen-associated molecular patterns (PAMPs) and the activation of innate immune responses against viral infection11. Ahn and Barber highlight the immune regulatory functions of stimulators of interferon genes and cyclic dinucleotides that can recognize microbial DNA from various pathogens, including bacteria, viruses, and parasites, as well as cytosolic DNA of self-origin from host cells. Investigations on the abundance of in-host effector mechanisms and pathogenic strategies will provide an ideal opportunity to develop innovative tools that can be utilized to modulate microbial pathogenesis.When encountering the host defense system, numerous intracellular pathogens employ a variety of evolved strategies to escape, modulate, and hijack host immunity during infection14. Jo and coworkers summarize the function of autophagy and xenophagy in mycobacterial infection and how to manipulate autophagy pathways to promote host-targeted therapeutics against mycobacterial infection. A more comprehensive understanding of the elaborate mechanisms by which host autophagy pathways overcome bacterial pathogenesis strategies may lead to more efficient antimicrobial defense strategies against numerous intracellular pathogens that can reside and replicate within the host cell cytoplasm16.Autophagy, a cell-autonomous catabolic pathway involving lysosomal degradation of cargos, is becoming recognized as an innate effector mechanism to enhance pathogen control and resolution of tissue pathology associated with infection18. Recent studies have also revealed the function of cytokines, including type I IFNs, IL-15, and IL-18, in the bystander activation of CD8\u2009+\u2009T cells, which are responsible for tissue injury in viral infections20. Shin and Kim will present a new concept of bystander response, which leads to pathological or protective outcomes, depending on the context. An understanding of the IFN-inducible responses in various aspects of host\u2013pathogen interactions will be essential for the development of effective therapeutics that also minimize tissue damage.When considering the role of type I and II interferons (IFNs) in the activation of antiviral and Th1 immune responses, respectively, it is generally accepted that IFN actions are typically required for protective immune responses against viruses and intracellular bacteria. Yamamoto and Sasai discuss recent progress on the cell-intrinsic defense mechanisms by which IFN-inducible GTPase-dependent host defenses exhibit antiparasitic and antibacterial responses. IFN-\u03b3-inducible GTPases, including guanylate binding proteins (GBPs) and immunity-related GTPases (IRGs), are essential in various aspects of immune protective functions, including the release of bacterial components, production of reactive nitrogen species, inflammasome activation, and autophagy21. To date, the majority of studies on host\u2013pathogen interactions have focused on comprehensive elucidation of the innate and adaptive immune responses during infection. Recently, several efforts have been made to manipulate genetically modified bacteria for utilization as a new form of therapeutic agent for the treatment of cancer22. Min and coworkers review the current trials, perspectives, and limitations of therapeutic approaches using live bacteria with tumor-targeting ability and discuss recent advances in our understanding of bacterium-tumor cell interactions.Accumulating evidence supports the importance of the gut microbiota in human health and diseases. Takeda and Maeda summarize the recent findings of molecular details in-host-microbe interactions in rheumatoid arthritis and how alterations at the interface between the host and microbes result in excessive inflammation and infection. In addition, this review will introduce multiple metabolic and immunological mechanisms by which the gut and oral microbiota induce the development of arthritisIn revealing a vast array of strategies adopted by host cells and pathogens during various stages of infection, paradigms are shifting. Accumulating evidence indicates a more diverse impact of pathogenic manipulations of host cells than previously known. This special issue highlights recent advances in studies that extend traditional concepts of host\u2013pathogen interactions toward new insights on innate and adaptive immune signaling, molecular pathogenesis, host-directed therapy, and manipulation of bacteria for anticancer therapy. We believe that the cutting-edge reviews presented here will provide novel insights into the growing area of host\u2013pathogen interface signaling, thereby expanding basic knowledge for use in clinical applications. Studying the basic and applied fields relating to this topic will promote our knowledge of highly complex host\u2013pathogen relationships and facilitate future investigations in this area for the development of improved therapies against infections."}
+{"text": "PARKIN gene cause early-onset Parkinson\u2019s disease (PD). Despite the high proportion of still missing phenotyping data in the literature devoted to early-onset PD, studies suggest that, as compared with late-onset PD, PARKIN patients show dystonia at onset and extremely dose-sensitive levodopa-induced dyskinesia (LID). What pathophysiological mechanisms underpin such early and atypical dyskinesia in patients with PARKIN mutations? Though the precise mechanisms underlying dystonia and LID are still unclear, evidence suggests that hyperkinetic disorders in PD are a behavioral expression of maladaptive functional and morphological changes at corticostriatal synapses induced by long-term dopamine (DA) depletion. However, since the dyskinesia in PARKIN patients can also be present at onset, other mechanisms beside the well-established DA depletion may play a role in the development of dyskinesia in these patients. Because cortical and striatal neurons express parkin protein, and parkin modulates the function of ionotropic glutamatergic receptors (iGluRs), an intriguing explanation may rest on the potential role of parkin in directly controlling the glutamatergic corticostriatal synapse transmission. We discuss the novel theory that loss of parkin function can dysregulate transmission at the corticostriatal synapses where they cause early maladaptive changes that co-occur with the changes stemming from DA loss. This hypothesis suggests an early striatal synaptopathy; it could lay the groundwork for pharmacological treatment of dyskinesias and LID in patients with PARKIN mutations.Mutations in the  PARKIN gene cause autosomal recessive juvenile parkinsonism (ARJP) (PARKIN mutations differ from those observed in idiopathic Parkinson\u2019s disease (iPD). Unlike iPD, neuronal loss is greater in the substantia nigra pars compacta (SNpc) than in the locus coeruleus in most parkin cases. Also, Lewy bodies are not detected in the majority of parkin cases, suggesting a difference in the pathogenic processes between PARKIN-related disease and iPD  . Autopsy and iPD . Also, Pfeatures , 2018. Efeatures . Early d and DJ1 . Since PPARKIN mutations and the recent evidence that parkin modulates glutamatergic neurotransmission. We discuss the hypothesis that early hyperkinetic symptoms of PD patients with PARKIN mutation may be considered manifestations of corticostriatal synaptopathy. These features can be linked to dopamine depletion, a well-recognized mechanism in the literature, but they also may be related to a potential direct effect of parkin on the corticostriatal synapse.Here, we review the clinical evidence for early hyperkinetic symptoms in patients with PARKIN gene in two families , prompts screening for PARKIN mutations along with GTP cyclohydrolase 1 and tyrosine hydroxylase in clinically diagnosed DRD patients  . MSNs arThe molecular signatures that have recently emerged as key signals in LIDs are ERK1/2 phosphorylation , abnormaPARKIN patients. Clinical studies with [18F] Dopa as a marker of the functional integrity of pre-synaptic dopamine nerve terminals have shown that Parkin mutated patients have widespread pre-synaptic dopaminergic deficits  and thus regulates its function: loss of parkin increases KAR levels in the human cortex and KAR function in glutamatergic hippocampal neurons in vitro (in vitro study showing that parkin-deficient hippocampal neurons exhibit significantly reduced AMPA receptor-mediated currents (PARKIN mutations disturb glutamatergic synaptic transmission by directly changing NMDAR, AMPAR, and KAR receptor function. Since parkin is widely expressed in various brain regions and neuron types, including cortical neurons and MSNs, (in vitro . At the in vitro . The rolcurrents . The sugcurrents . Hence, nd MSNs,  it is coParkin gene. Unfortunately, studies on the nigrostriatal pathway revealed many discrepancies probably deriving from different experimental conditions and/or from in vivo age-dependent compensatory mechanisms. Increased spontaneous DA release from SNc DA neurons was found in Parkin-knockout mice aged 8 to 9 months (Parkin knockout mice (Parkin-knockout mice, DA levels were reported to be indistinguishable (Parkin-knockout mice (Parkin-knockout mice. Studies on corticostriatal synapses performed by intracellular recordings of MSNs revealed impairment in long-term depression and long-term potentiation in Parkin-knockout mice (Parkin-knockout mice do not show DA neuron loss, motor impairment, dystonic phenotype or hypersensitivity to levodopa (PARKIN mutations were observed to potentiate glutamatergic transmission by modifying synaptic vesicle function at the pre-synaptic site of the corticostriatal synapse (PARKIN mutations. In particular, as compared with control neurons, the parkin-deficient neurons had a stronger response to the activation of D1-class dopamine receptors (These studies on the localization of parkin and its capacity to directly regulate excitatory transmission constitute an important step toward understanding the functions of parkin at the synapses . The com9 months . Decreasout mice . In the uishable . DA overout mice . Indeed,out mice . These rlevodopa . The autlevodopa ; nonethe synapse . Moreoveeceptors .This raises the possibility that parkin could be involved in D1 receptor hypersensitization after dopaminergic denervation, an important mechanism underlying the dyskinesia in iPD . AccordiTaken together, these findings suggest that parkin orchestrates a complex remodeling of corticostriatal synapses through multiple mechanisms. These mechanisms are likely to include changes due to DA depletion as well as those due to loss of parkin function at these synapses: alterations in the trafficking of glutamate vesicles at the glutamatergic pre-synapse and/or dysregulation of glutamate receptor levels on MSNs and/or dysregulation of D1-signaling. These mechanisms may be responsible for the precocious maladaptive plasticity of the corticostriatal synapses that leads to early dyskinesia .PARKIN mutation affects corticostriatal transmission, leading to early maladaptive changes in this glutamatergic synapse. This alteration could produce changes due to corticostriatal-induced depletion of DA at the synapses. What does this scenario imply for the development of specific and effective treatments? The only currently available drug for symptomatic treatment of dyskinesia is amantadine, an antiviral agent introduced in the early 1970s that also displays NMDA receptor antagonism (PARKIN patients and late-onset PD patients could be relevant for devising precision medicine strategies for parkin patients. The recent discovery that LID is caused by a distinct and stable group of striatal neurons (Since the parkin protein modulates glutamatergic receptor function and possibly glutamate release as well, it is conceivable that tagonism . With a tagonism . Moreove neurons  paves thPARKIN mutation.In conclusion, published data support the hypothesis of an early corticostriatal synaptopathy in parkin patients caused by parkin modulating the glutamatergic synapse. This hypothesis could provide a biological basis for studying the disease phenotype and lay the groundwork for the pharmacological treatment of PD patients with JS wrote first draft of the manuscript. FV and AC reviewed and critically revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Background: The current study examines the cross-sectional association between everyday discrimination and kidney function among older adults. Methods: We use cross-sectional data from a nationally representative sample of older adults to examine this relationship. Our measure of kidney function derives from the estimated glomerular filtration rate (eGFR) obtained by the Chronic Kidney Disease Epidemiology Collaboration equation, while our indicator of everyday discrimination is drawn from self-reports. Results: Results from our ordinary least squared regression models reveals that, after adjusting for demographic characteristics, everyday discrimination was associated with lower mean eGFR . The relationship between everyday discrimination and kidney function was not explained by cardiovascular, metabolic, or economic factors. Conclusions: Findings suggest this study suggest that everyday discrimination may be a unique risk factor for poorer kidney function among older adults. Because these findings are cross-sectional, additional research is needed to determine whether the observed associations persist over time."}
+{"text": "Molecular Cancer, Wang and colleagues\u2019 work revealed the common and histopathological subtype-specific circular RNA (circRNA) expression patterns between LUAD and LUSC and highlighted the important diagnostic potential of circRNAs in lung cancer [Few studies have used high-throughput RNA sequencing for functional characterization of patients with non-small cell lung cancer (NSCLC) including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In a study recently published in g cancer .p-value \u22640.05 and fold change \u22652), differential expression of 50 and 172 circRNAs was identified in tumor tissues of LUAD and LUSC, respectively. In addition, 26 circRNAs were commonly deregulated in both tumors. Moreover, another independent cohort of 67 lung cancer patients\u2019 samples were subjected to experimentally validation of RNA-sequencing data. Results were consistent and validated the accuracy and robustness of the circRNA analysis pipeline.To obtain a comprehensive and accurate quantification of circRNAs, the authors analyzed high-throughput RNA sequencing data from 10 pairs of lung tumors and their adjacent normal tissues using five computational tools. Results revealed 17,952 circRNAs including 2593 previously unidentified circRNAs. Using stringent criteria  curve analysis of several selected circRNAs and revealed high diagnostic potential of hsa_circ_0077837 and hsa_circ_0001821 in discriminating NSCLC from normal tissues. Authors\u2019 results also highlighted the potential application of hsa_circ_0001073 and hsa_circ_0001495 for diagnostic in the histopathological subtyping of NSCLC. Collectively, this study demonstrated that LUAD and LUSC as the major subtype of NSCLC share a common differential expression pattern, but also have their unique circRNA expression signatures. Identified circRNAs may serve as and new clinical tools for diagnosis of pathological subtypes of NSCLC and therapeutic intervention."}
+{"text": "Dear Editor,The study by Terregino et al , outlineThe ECRS scale was tested with videos of students participating in objective structured clinical examinations (OSCEs) . CompariThe ECRS could also be used for a wide range of scenarios, including those appearing acutely medical. For example, a case about anaphylaxis allows the student to communicate with the patient and their family whilst prioritising acute management of the life-threatening condition. Additional notes could be added to the ECRS about how students balance emergency medical management with their communication towards the patient and family. This would allow students to act like physicians who manage medical problems alongside patient ideas, concerns and expectations. Focusing training on empathy ensures students display empathy in real-life scenarios as future doctors .Additionally, a modified ECRS could be used to practice other realistic clinical encounters including consultations across a language barrier. Although interpreters should be available for consultations, issues including administrative errors mean this may not happen. Non-native speakers may not pick up on empathetic phrases and therefore rely on nonverbal, compassionate behaviours that cross-cultural boundaries .To conclude, the ECRS appears to be a useful tool to assess medical student empathy in OSCEs to ensure students develop patient-centred communication skills . Whilst"}
+{"text": "Circulating tumor cells (CTCs) slough off primary tumor tissues and are swept away by the circulatory system. These CTCs can remain in circulation or colonize new sites, forming metastatic clones in distant organs. Recently, CTC analyses have been successfully used as effective clinical tools to monitor tumor progression and prognosis. With advances in next-generation sequencing (NGS) and single-cell sequencing (SCS) technologies, scientists can obtain the complete genome of a CTC and compare it with corresponding primary and metastatic tumors. CTC sequencing has been successfully applied to monitor genomic variations in metastatic and recurrent tumors, infer tumor evolution during treatment, and examine gene expression as well as the mechanism of the epithelial-mesenchymal transition. However, compared with cancer biopsy sequencing and circulating tumor DNA sequencing, the sequencing of CTC genomes and transcriptomes is more complex and technically difficult. Challenges include enriching pure tumor cells from a background of white blood cells, isolating and collecting cells without damaging or losing DNA and RNA, obtaining unbiased and even whole-genome and transcriptome amplification material, and accurately analyzing CTC sequencing data. Here, we review and summarize recent studies using NGS on CTCs. We mainly focus on CTC genome and transcriptome sequencing and the biological and potential clinical applications of these methodologies. Finally, we discuss challenges and future perspectives of CTC sequencing. Circulating tumor cell (CTC) studies began in 1869 Ashworth , which hPrevious CTC studies have mainly focused on the development of CTC enrichment technology  technology in NCBI PUBMED and found 19 CTC publications  or to delete immune cells (CD45\u2212) , genome or transcriptome amplification, and sequencing and analysis Fig.\u00a0. SeveralAfter CTC enrichment from the blood, zero to several hundred CTCs may be retained in a thousand to ten thousand background cells, resulting in a low efficiency for sequencing and analysis of these cell pools  CTC variation detection rate in a mean depth of 1500X of 14 CTCs. These authors concluded that there exists a high inter- and intra-patient heterogeneity in CTC mutational status  is also frequently altered during cancer evolution. Ni et al. surveyed the CTC CNVs from a small-cell lung cancer (SCLC) patient during sequential chemotherapy treatment and observed that the evolution of CNV was consistent along the therapeutic stage, indicating that the reproducible CNV pattern was not affected by drug treatment (Ni et al. Previous studies have highlighted particular molecular pathways involved with cancer metastasis, such as TGF-\u03b2 signaling (Akhurst and Derynck WNT2 gene mediated the metastasis-associated survival signal, consistent with observations of the upregulation of multiple Wnt genes in pancreatic patients (Yu et al. Yu et al. first utilized single-molecule RNA sequencing and a mouse pancreatic cancer model and found that the The EMT of adherent epithelial cells to a migratory mesenchymal state has been implicated in tumor metastasis in pre-clinical models. Yu et al. characterized the dynamic cell fates in breast cancer CTCs and found an association of mesenchymal CTCs with disease progression (Yu et al. As shown in this review, CTC sequencing can now be used as an efficient liquid biopsy tool to investigate the spectrum of somatic variation and gene expression changes in primary, metastatic, and recurrent cancer patient tumors non-invasively. The somatic alterations could either be used to understand the origin, ITH, and evolution of tumors or to monitor disease progression during cancer treatment. The most important clinical implication of CTC sequencing is for personalized medicine, or so-called precision medicine, according to the variation spectrum detected, which indicates the selection of target therapy based on the CTC variation spectrum. With the development of CTC capture and SCS technologies, we can expect the establishment of more comprehensive cancer origins and evolution models in the near future. Moreover, more novel biomarkers or potential drug targets for cancer metastasis or drug resistance prevention or treatment can be identified through CTC sequencing.However, as mentioned above, sequencing a CTC genome or transcriptome faces technical challenges. Obtaining enough cells for library preparation and sequencing is the first critical step in CTC sequencing. However, various conclusions can be drawn from different studies based on different isolation method and cancer types. Some cancer types tend to generate more CTCs than other cancer types (Allard et al. More importantly, bioinformatics analyses of CTC sequencing data require additional quality evaluation and assessment, particularly the biases introduced during sample and sequencing library preparation Fig.\u00a0. Allele Despite the development of advanced microfluidics approaches, several novel sequencing technologies show promise for solving the technological hurdles to CTC sequencing. For example, scientists can now perform in situ DNA or RNA sequencing, even on samples fixed on slides (Lee et al."}
+{"text": "Both affective and blood pressure (BP) reactivity are associated with long term risk of chronic disease and mortality. Thus, understanding age-related changes in negative affect and BP responses to everyday demands is vital for promoting healthy aging. However, few studies have examined both psychological and BP reactivity simultaneously, which would provide more comprehensive understanding of regulatory processes at play. For the present study, 232 adults aged 50-70 years were assessed at baseline and 6 years later with ambulatory BP monitoring and momentary electronic diaries. Reactivity coefficients were output from multilevel models and used to test changes in negative affective and ambulatory BP reactivity to task demand, longitudinally. Results indicate that both systolic and diastolic BP reactivity increase with age, while negative affect reactivity does not change with age. Results are discussed in the context of life course theories of role strain and role changes and socioemotional theories of aging."}
+{"text": "Microbial consortia execute collaborative molecular processes with contributions from individual species, on such basis enabling optimized molecular function. Such collaboration and synergies benefit metabolic flux specifically in extreme environmental conditions as seen in acid mine drainage, with biofilms as relevant microenvironment. However, knowledge about community species composition is not sufficient for deducing presence and efficiency of composite molecular function. For this task molecular resolution of the consortium interactome is to be retrieved, with molecular biomarkers particularly suited for characterizing composite molecular processes involved in biofilm formation and maintenance. A microbial species set identified in 18 copper environmental sites provides a data matrix for deriving a cross-species molecular process model of biofilm formation composed of 191 protein coding genes contributed from 25 microbial species. Computing degree and stress centrality of biofilm molecular process nodes allows selection of network hubs and central connectors, with the top ranking molecular features proposed as biomarker candidates for characterizing biofilm homeostasis. Functional classes represented in the biomarker panel include quorum sensing, chemotaxis, motility and extracellular polysaccharide biosynthesis, complemented by chaperones. Abundance of biomarker candidates identified in experimental data sets monitoring different biofilm conditions provides evidence for the selected biomarkers as sensitive and specific molecular process proxies for capturing biofilm microenvironments. Topological criteria of process networks covering an aggregate function of interest support the selection of biomarker candidates independent of specific community species composition. Such panels promise efficient screening of environmental samples for presence of microbial community composite molecular function. Microbial communities display cooperation and leverage on synergies, all embedded on the level of entangled molecular processes across individual species. Occurrence of such traits is tightly controlled via given species genotypes and environmental conditions, and centers on cost and benefit . ExtremeCooperation displays as higher order function, i.e. molecular processes executed by the community being not reducible to any of its individual species alone. Higher order molecular functions may alter local environmental parameters, in turn imposing a feedback on cooperation mechanisms, individual species abundance and specific involvement. Examples for such community properties include occupation of sites lacking viable conditions for individual species, division of labor, and fostering significant increase in metabolic flux .Microbial communities hold profound relevance in industrial processes. One example is bioleaching, i.e. extraction of base metals from sulfide ores . A seconRational design and optimization of community function was recently demonstrated for copper bioleaching . HoweverExtrapolation from a species inventory to capabilities of embedded community molecular function is limited, as resolution of species interaction on a molecular function level is needed. Next to allowing optimization of given consortia properties such knowledge promises particular utility in molecular function prospecting. Such scenario focuses on identification of communities in environmental samples exhibiting specific aggregate molecular function of interest .Recalling that increased efficiency in bioleaching resembles a composite molecular process in the sense of a microbial community aggregate function, a relevant proxy for such molecular configuration is given as molecular biomarkers. Use of molecular biomarkers is further supported by recently identified evidence that function and underlying molecular processes of a community may be preserved while the species composition of a community exhibits a dynamic flux . FurtherBiomarker identification approaches include explorative methods, involving comprehensive functional gene arrays as well as various omics tools. For example, Roume et al. integrated omics profiling results on molecular interaction networks for characterizing the impact of environmental conditions on microbial communities relevant in biological waste water treatment . On the M composed of n individual microbial species mi, mj, \u2026 mn which together constitute the community. A higher order function results out of a composite molecular process pi, principally grounded on the set of protein coding genes gi, gj of all community species, hence the community genome G.Analysis of molecular context is of particular value when aiming at characterizing composite function. Microbial community representation has to focus on the species set G for deriving the specific set of cross-species processes pi, pj responsible for triggering phenotypic community characteristics. A biomarker in its definition serves as proxy for the status of a molecular process. Having identified candidate processes pi, pj responsible for a molecular function of interest in turn allows selecting corresponding candidate biomarkers bi, bj, where bi monitors the state of process pi, and bj of pj, respectively. Recalling the finding of community stability in terms of composite function but not in terms of species composition, such a biomarker panel may offer generalization in prospecting of environmental samples. Further, such biomarker panel approach realized as multiplexed assay may prove efficient for high throughput analysis of environmental samples.The composite molecular process sees involvement of molecular functionality (gene products) from different species, needing modeling of the microbial community on the level of in silico workflow for identifying biomarker candidate panels aimed at reflecting aggregate microbial community properties. Starting with a reference inventory of a functionally relevant subset of G further combined with interaction information allows deriving a molecular process graph. On the graph level, topological parameters aiming at resembling molecular process proxies as well as species coverage considerations are used for biomarker candidate selection. The resulting candidate biomarker panel is thus specific for the function in focus but to some degree agnostic regarding actual species composition. Such candidate panel promises generic applicability in bioprospecting regarding a composite molecular function of interest.On this basis we propose an While the workflow is applicable for studying various instances of microbial community aggregate function we in the following focus on community cooperation in forming a biofilm microenvironment in copper bioleaching/AMD. Biofilms can be instantiated by certain individual microbial species, however, in most environmental settings multiple species contribute molecular function to this microenvironment. In selected scenarios such environment provides grounds for emergent community phenotypes, including significant increase in bioleaching efficiency or initiation of AMD \u201315.The workflow illustrated in In a first step scientific literature is screened for microbial communities reported as relevant in a given focus (as copper bioleaching/AMD) for cataloguing constituent species genomes. In addition, biological community aggregate molecular functions reported as relevant are extracted. In a second step, catalogued genes are assigned to community molecular functions. Third, an all-against-all ortholog map is created for the gene set assigned to the biological function term in focus (e.g. biofilm formation), followed by consolidating protein-protein interaction information for the set of orthologs (step 4). With a gene set and respective interaction data at hand a molecular process model approximating the function term is retrieved (step 5), on this basis deriving topological parameters of the interaction network for guiding biomarker candidate selection (step 6). Finally, candidate biomarkers are forwarded to experimental evaluation (step 7).A list of natural acid mine drainage sites, major industrial bioleaching operations as well as suitable laboratory scale experiments, in the following referred to as \u2018sites\u2019, was compiled by mining the National Library of Medicine (NCBI) PubMed scientific literature repository in publication title and abstract for the terms \u2018bioleaching\u2019 and \u2018acid mine drainage\u2019. For all identified sites respective mineral endowment was extracted. For industrial mining sites additional mineral composition data were sourced from the Mindat database . AltogetNext, scientific literature covering the sites was screened for inventorying involved microbial species. 133 microbial species could be retrieved, of which 42 are specifically associated with one or more of the 18 copper sites.For each of the copper site-associated microbial species gene-centric annotation was retrieved from public databases as described previously . BrieflyEach copper site-associated species was evaluated for availability of annotation data for assigning protein coding genes to functional groups (COG) , and forA matrix of biological function terms and genes of relevance in copper bioleaching was obtained by manual data extraction from scientific publications reporting species given in Leptospirillum ssp. Group IV \u2018UBA BS\u2019 and T. arsenitoxydans) were sourced from the NCBI RefSeq database.A comprehensive all-against-all ortholog screening of the 25 species holding COG annotation was executed using the InParanoid pipeline (version 4.1) with default settings . As inpuProtein interaction information was retrieved from STRING  and subsequently aggregated across all 25 species using ortholog screening results to obtain an interactome on the ortholog level. This procedure allowed inclusion of protein coding genes of species as such not represented in the STRING database on the level of identified ortholog sequences from respective species being covered in STRING. The resulting interaction matrix was used to derive an ortholog network.Topological parameters of the ortholog graph were calculated using the NetworkAnalyzer application of Cytoscape version 3.2.1 , networkFor evaluation of candidate biomarkers selected on the ortholog graph level resembling the composite process of biofilm formation available omics profiles were used. A scientific literature review identified omics profiles in scope of bioleaching/AMD providing a resolution on the level of protein coding gene products. Data sets of specific interest needed to resemble meta-transcriptomics or -proteomics profiles covering microbial communities exhibiting biofilms in various environmental or laboratory conditions.Leptospirillum and Ferroplasma species. To assess biofilm functional traits quantitative proteomics comparison of natural versus laboratory settings was conducted, complemented by determining biomass to estimate in situ chemoautotrophic production. Productivity in the laboratory biofilm community was nearly five times lower compared to its natural equivalent, being reflected in differential abundance of a range of metabolic proteins. The authors concluded that the differences in both production as well as protein expression profiles reflect metabolic stress in the laboratory biofilm. After optimization of laboratory culture conditions , community proteomics profiles resembled the environmental setting particularly in respect to expression of stress response proteins and community growth rates.Two data sets appeared particularly suitable with respect to biofilm formation serving as surrogate of bioleaching/AMD. The first study conducted by Belnap et al. covers proteomics profiling . The autFor calculation of differences in expression in the proteomics data the respective log2-ratios of abundance when comparing the optimized laboratory culture with a natural biofilm sample were subtracted from the respective abundance values comparing a standard laboratory culture with a natural biofilm. Respective fold changes are therefore indicative for the level of biofilm formation and are used in biomarker candidate evaluation with respect to prospecting the capacity of forming a composite biofilm microenvironment.A. ferrooxidans as well as L. ferriphilum and L. ferrooxidans, respectively. Further community members worth noting include Acidimicrobium ferrooxidans as well as several Acidiphilum, Ferroplasma and Sulfobacillus species, respectively. The study compared transcriptional profiles of natural planktonic and biofilm-associated consortia to gain insights into physiological differences between free and the sessile community fractions. This approach allowed a precise assessment of biofilm physiology determined on a genomic array of L. ferrooxidans, identifying as main contributors to the biofilm situation genes coding for quorum sensing, motility and chemotaxis, as well as matrix component production and transport.A second data source originates from a transcriptomics profiling study on bacterial communities isolated from the Rio Tinto acid mine drainage system  published by Moreno-Paz et al. . The comIn biomarker evaluation the fold changes (log2-ratios) are used contrasting planktonic and biofilm status in focus of biofilm formation capacity.L. ferriphilum in continuous vs. bioleaching conditions, the latter being grown on 2% (wt/vol) chalcopyrite [A third study conducted by Christel et al. compared a culture of copyrite . The autThis study serves as negative control experiment for candidate biomarker evaluation, utilizing fold changes (log2-ratios) comparing cultures in absence and presence of chalcopyrite.Protein coding genes addressed in the three experimental studies were assigned to the ortholog graph via Basic Local Alignment Search Tool 2 (BLAST2) , selectiA. ferrooxidans (identified in 11 sites), L. ferrooxidans (9 sites), L. ferriphilum (7 sites) and A. cryptum, A. ferrivorans, A. thiooxidans and F. myxofaciens (4 sites each). Each site further reports a diverse and distinctive array of less frequent species.An important prerequisite for candidate biomarkers to be used in microbial community screening is applicability in absence of prior information about specific community species composition. Therefore a meta-analysis approach is applied starting with an inventory of microbial communities being involved in either bioleaching or acid mine drainage. Consortia retrieved from 70 environmental sites in focus of bioleaching/AMD provide 133 individual species. 18 sites report on copper sulfite ores with in total 42 individual microbial species. The majority (32) is comprised of Bacteria, complemented by Archaea. The four most prevalent species are Manual literature curation of molecular features involved in molecular processes relevant in acid mine drainage and/or bioleaching together with their molecular functional annotation identifies 14 molecular function categories holding 1,696 protein coding genes . The Clu20 of the 26 COG terms are addressed in the AMD/bioleaching context, with specific function terms seeing varying assignment to COG terms. For instance, chemotaxis is associated with 5 COG terms, on a gene count level mainly involving cell motility (N) and signal transduction (T). Other terms are considerably more complex, specifically the function term biofilm formation involving 19 COG terms. Main contributions come from cell wall/membrane/envelope biogenesis (M), cell motility (N), signal transduction (T), intracellular trafficking and secretion (U) as well as extracellular structures (W). Other complex functions with diverse COG term involvement include quorum sensing together with toxicant and copper resistance. Genes lacking COG annotation or being assigned to the unspecific COG terms R  and S (Function Unknown) are not further considered.Related function terms map to similar COG term combinations. For biofilm formation, COG terms include cell wall biogenesis, signal transduction and trafficking/secretion categories. Comparable patterns of COG category involvement are found for quorum sensing and chemotaxis, reflecting close biological relationship.For deriving a biomarker candidate panel capturing major molecular aspects of relevance in both AMD and copper bioleaching, function terms covering a broad set of COG terms appear preferential, ideally further seeing broad involvement of microbial species. Of the 14 function terms, biofilm formation exhibits particularly broad COG term assignment as well as species coverage across the original catalogue of 25 copper mineral associated microbes, providing all ingredients for establishment of higher order molecular function. Furthermore, from a biological function perspective, establishment of biofilms is relevant in both acid mine drainage as well as bioleaching. As demonstrated, enrichment of consortia with microbes particularly competent in formation of biofilms significantly boosts bioleaching process efficiency . BiofilmAccordingly, the set of genes assigned to the aggregate function of biofilm formation is used as basis for deriving a protein coding gene interaction network, subsequently serving for biomarker panel selection.According to data retrieval and functional category assignment 272 protein coding genes are identified in the molecular context of biofilm formation. Ortholog screening of this set in the genomes of the 25 species provides 3,106 orthologs, identifying at least one ortholog for all but 23 genes. 57 of the 272 genes hold orthology to other members of the biofilm gene set and are removed to avoid biases from multiple sequence representation in subsequent molecular network retrieval.Ortholog information allows utilizing interaction information across species to derive an ortholog graph, thereby complementing interaction data by aggregation. This procedure enables inclusion of interaction information for finally 191 unique molecular features of the biofilm gene set  in a sinL. ferrodiazotrophum, a diazotrophic mesophilic bacterium also found in AMD biofilms [L. ferrodiazotrophum efficiently fixes nitrogen, but its genome lacks annotation including COG term assignment and interaction data in STRING. The nitrogenase cassette is highly homolog to features found in other diazotrophic bacteria such as L. ferrooxidans and Acidithiobacillus ssp., i.e. the cassette is considered at the ortholog level.The ortholog network allows capturing molecular function of species as such not included in a species set. Representative for such an organism is biofilms . L. ferrThe ortholog graph serves as basis for identifying biomarker candidates according to network topology. Topological parameters characterizing the centrality of a given node capture properties related to the functional importance within its network context. Specifically, node degree and stress centrality resemble properties prone to biomarker candidate selection. Both centrality measures reflect affectedness of state changes in molecular processes, hence serving as proxies for molecular process status. Nodes with high degree centrality establish a large number of interactions, i.e. serve as network hubs . Nodes eThe relevance of degree and stress becomes apparent from Accordingly, biomarker candidates from the ortholog graph of biofilm formation showing high degree and stress centrality are deemed to serve as relevant proxy for the entire process, and promise sensitivity in monitoring the presence of biofilm formation.Relevance of network topology aspects is evaluated using proteomics profiles published by Belnap et al., contrasting a generic and an optimized laboratory setting with environmental samples in focus of biofilm formation efficiency . ProteomAnnotation of nodes of the ortholog graph with fold change values assigned to biofilm formation in combination with computation of the topological parameters degree as well as stress centrality allow determining significance in difference of graph measure distributions. Degree as well as stress centrality are found to be different for nodes holding a significant fold change compared to nodes not found to be affected according to the proteomics data  positive correlation is identified , aside lBased on the observed association of degree and stress centrality with a probability of abundance change under varying biofilm conditions, a rank score of both graph measures and species coverage is determined. Each individual parameter is ranked starting with the maximum value, with the rank score reflecting the mean of the sum of each individual parameter rank for a given protein. L. ferrooxidans, significant orthology of sequences selected in the biomarker panel render fold changes as indicative for biomarker expression on the background of the ortholog network.For evaluation of the biomarker candidate panel two omics studies appear particularly useful due to providing i) substantial coverage of the entire molecular feature space represented in the biofilm network, and ii) showing differential readout for biofilm formation under varying conditions. The first study conducted by Moreno-Paz et al. resembles a prospecting situation and reports transcriptomics profiling comparing planktonic versus biofilm associated bacterial consortia in a natural AMD site . The stuA monitoring/process optimization situation can be approximated via comparing proteomics data of the generic and the optimized laboratory condition as provided in Belnap et al. . With opL. ferrooxidans cultivated in an agitated-tank bioreactor [The third data set prepared by Christel et al. compared gene expression of a continuous and a bioleaching  culture of oreactor . This sporeactor  and Moreoreactor ), and isA. ferrooxidans on pyrite [A further data set provided by Vera et al. implemented shotgun proteomics for characterizing early biofilm formation of n pyrite . In thisThe most prominent function category involved in the biomarker set is chaperones with four protein-coding genes. High ranking in degree centrality reflects broad involvement in folding and arrangement of macromolecular structures as well as their propensity to associate with hub proteins. This property meets with the processes of biofilm formation, but questions specificity, as activity of these proteins is supposedly relevant in a variety of molecular processes beyond the aggregate function in focus.Still, given chaperones hold specific evidence in the biofilm context in an acidic environment. GroEL chaperones are generally known as stress response proteins and are frequently found in acidophilic bacteria  when grown on elementary sulfur. A more specific role of the protein family is modulation of fatty acid components of bacterial cell walls deemed essential during biofilm maturation . The putA second prominent function term covers central biofilm components involved in the synthesis of extracellular polymeric substances. Members include a uridine diphosphate (UDP)-glucose 4-epimerase converting uridine diphosphate galactose to UDP-glucose, a precursor for the osmoprotectant trehalose, as well as several exopolysaccharides , 39. FurThe third term set covers chemotaxis, sensing and motility, of apparent relevance in structuring the community microenvironment in a biofilm. For dimethyladenosine transferase a more specific function in quorum sensing was discovered and involves environmental adaptation through cross-species synchronization . As secoTaken together, the panel members represent core functional elements required in establishing a biofilm microenvironment, covering chemotaxis, motility, quorum sensing as well as the production of extracellular matrix components. The prominent representation of chaperones of the GroEL-Dnak-GrpE system not only points to adaptation processes allowing communities to establish in the extreme environments, but also reflects the need for a proper orchestration of the biofilm formation processes . Genes fStill, the exposed network topology of the panel members being hubs and connectors and on top being encoded in a wide range of species, in various instances covering more than 20 of the in total 25 microbial species involved, may in part be driven by annotation biases of network nodes and interactions, at present not allowing for evidence-based correction. Aside this aspect the need for specialist species for driving aggregate molecular processes is to be addressed. Analyzing species coverage of nodes in the network neighborhood of degree and stress centrality hubs sees more sparse species coverage, indicating the need for marginal consortia members on the molecular process level . As examMolecular features involved in biofilm formation are identified in a range of organisms commonly isolated in AMD and bioleaching sites. For a subset of organisms a sufficient depth of annotation is available both on functional as well as on protein interaction level. Lack of annotation per design removes a subset of protein coding genes from integrative analysis, although eventually resembling excellent biomarker candidates. However, coding regions displaying no orthology to annotated sequences of an extended species set retrieved in a meta-analysis approach may be fairly specific for certain species. In consequence, biomarkers from such subset may lack generalization capacity, in turn limiting sensitivity in a species-agnostic prospecting approach.Available interaction data allow deriving an ortholog network to approximate the community molecular process of biofilm formation. By integrating orthology information in the network some major limitations, given by unknown or incompletely characterized genes, lack of functional annotation as well as of interaction data can be addressed to some extent. The interaction data source used in this work provides interactions holding experimental evidence and candidate interactions resting on computational inference. With lack of completeness of experimentally derived interactomes together with biases introduced by experimental protocols, inference of interactions from heterogeneous data sources in part addresses given limitations and biases. This approach at the same time introduces probabilistic assignments. In consequence, resulting networks primarily serve hypothesis generation, demanding subsequent experimental evaluation. On the other hand, correlation of abundance of sequences with unknown function and annotated nodes of a mechanistic network model may support candidate function assignment .Combining various functionalities deemed necessary for effective biofilm formation in a multimarker panel promises improved sensitivity as well as specificity. The functional diversity of the process of forming a biofilm microenvironment, specifically beyond enzymes, points to an important aspect for selecting a comprehensive network model. For example, approaches restricted to metabolic networks by e.g. utilizing KEGG orthology (KO) terms of enzymes (nodes) connected by metabolites (edges) cover less than half of the network nodes included in the biofilm orthology graph . In addiThe workflow discusses candidate biomarker retrieval for prospecting of an aggregate biological function executed by microbial consortia in environmental samples. The approach leverages on cross-species interaction consolidated as ortholog network, and utilizes topological properties of network nodes for molecular feature selection.Identification of candidate panel members is based on a molecular process model tailored at representing the molecular context of biofilm formation. The candidate biomarkers are selected according to a rank score of degree and stress centrality as well as species coverage, thus focusing on prevalent proteins being deemed essential for establishing a biofilm microenvironment. Evaluating candidate biomarkers via utilizing public domain omics profiles indicates relevance in biofilm formation. Applicability of the method is not restricted to biofilm prospecting in copper mineral decomposition, but is expandable to alternative microbial community functions including as examples biofertilization in agriculture or microbial communities serving in oil spill bioremediation.de novo functional characterization of unknown species.Practical implementation on the mRNA level, e.g. via quantitative polymerase chain reaction (qPCR)-based methods, demands conserved sequence regions as probes. The approach of defining a set of biomarkers designed to screen for a given molecular function being at least to some extent independent of the executing microbes bears the promise to significantly facilitate prospecting of novel bacterial consortia. The precise composition of consortia is in most cases unknown at the point of screening. A species-robust screening tool supersedes the need for any prior knowledge on likely species occurrence. In line with prospecting goals a biomarker panel allows a first evaluation of samples, and in case of positive biomarker readout providing grounds towards a more detailed molecular analysis e.g. via metagenomics. This is particularly useful in cases where potential prospecting areas are large and diverse, or where a fast and frequent read-out, e.g. in a monitoring situation, is needed. Further, the approach facilitates the targeted discovery of new species in a functional context in focus, particularly if combined with novel techniques such as methods for In conclusion, interaction networks offer a methodology for characterization of community aggregate molecular functions via integrating individual species contributions into a molecular process network. Next to adding to our understanding of molecular mechanisms of aggregate function such networks allow selecting candidate biomarkers grounded on network topology characteristics. Such biomarkers promise support in microbial function prospecting as well as in industrial process monitoring in a range of application areas, with bioleaching and bioremediation as examples.S1 TableSpreadsheet \u201csites\u201d: Copper site-specific scientific references; spreadsheet \u201cspecies\u201d: Microbial species-specific scientific references; spreadsheet \u201cfunctions\u201d: key scientific references covering molecular function terms.(XLSX)Click here for additional data file.S2 TableProvided is the protein name together with identifiers from database references of UniProt, PATRIC and IMG.(XLSX)Click here for additional data file.S3 TableThe listing holds genes assigned to the functional term biofilm formation embedded in the ortholog network, respective topology measures of degree and stress centrality, species coverage, and ranked sum of topological parameters and species coverage.(XLSX)Click here for additional data file."}
+{"text": "In Sub-Saharan Africa, there is an increase in trypanosome non-susceptibility to multiple trypanocides, but limited information on judicious trypanocide use is accessible to smallholder farmers and agricultural stakeholders in disease endemic regions, resulting in widespread multi-drug resistance. Huge economic expenses and the laborious nature of extensive field studies have hindered collection of the requisite large-scale prospective datasets required to inform disease management. We examined the efficacy of community-led data collection strategies using smartphones by smallholder farmers to acquire robust datasets from the trypanosomiasis endemic Shimba hills region in Kenya. We used Open Data Kit, an open-source smartphone application development software, to create a data collection App.Our study provides proof of concept for the viability of using smartphone Apps to remotely collect reliable large-scale information from smallholder farmers and veterinary health care givers in resource poor settings. We show that these datasets can be reliably collated remotely, analysed, and the findings can inform policies that improve farming practices and economic wellbeing while restricting widespread multi-drug resistance. Moreover, this strategy can be used to monitor and manage other infectious diseases in other rural, resource poor settings.The online version of this article (10.1186/s13104-019-4198-z) contains supplementary material, which is available to authorized users. Trypanosoma congolense, Trypanosoma brucei, and Trypanosoma vivax) is endemic to Shimba hills, in Kwale County, Kenya, a resource poor setting inhabited by smallholder farmers [2 (23% of the country), putting livestock and people at risk of infection [Animal African trypanosomiasis (AAT), a life-threatening neglected tropical disease that affects cattle, goats and sheep, caused by trypanosomes parasites  , 22. IntAlthough performing financial transactions using mobile phones is predominant , there iCommunity engagement when implementing mobile phone-based strategies is important for gaining trust, educating on use and importance of data collected, and easy reporting of feedback . Kwale CThis pilot study was part of a larger study evaluating evolutionary markers of trypanocide non-susceptibility conducted among two smallholder livestock farming communities of different ethnicities from Mbegani and Kizibe in Shimba hills, Kwale County, Kenya . We obtaWe used Open Data Kit (ODK) an open-source smartphone App development software to create a data collection App . ODK hasWe used multiple correspondence analysis (MCA), a data reduction technique which permits the identification of complex patterns in a dataset of categorical variables , to deteWe conducted a pilot study on the efficacy of a community-led data collection approach by conveniently sampling from two communities of smallholder farmers (n\u2009=\u200947) from: Kizibe (n\u2009=\u200923) and Mbegani (n\u2009=\u200924) to acquire information on trypanocide non-susceptibility and perceptions of smallholder farmers on trypanosomiasis. There was a disproportionately lower number of female smallholder farmers , who also had less cattle ownership  compared to their male counterparts Fig.\u00a0a. These A large proportion of smallholder farmers and veterinary health care givers interviewed  welcomed the smartphone App developed on the ODK platform as a method of trypanosomiasis data collection. The farmers with dissenting views about using the App were illiterate. Our multiple correspondence analysis results show variation between the two communities from the overall mean, which would not be detected if knowledge on community ethnicity was not considered.Kwale is one of the most resource poor Counties in Kenya. Kizibe and Mbegani, in Shimba hills, Kwale, are trypanosomiasis endemic regions with varying economic capacities and different farming practices, which have made understanding temporal trends in trypanocide non-susceptibility challenging. Previous studies have used generalised cross-sectional survey approaches that lumped together findings from different communities in Kwale making it challenging to pinpoint subtle differences in farmers perceptions and disease management practices . We estaWe used multiple correspondence analysis (MCA) to highlight subtle variation in farming practices by the smallholder farmers in Kizibe and Mbegani, which could be used to inform trypanosomiasis management. Similar approaches have been used to assess animal African trypanosomiasis (AAT) vulnerability in cattle-owning communities of sub-Saharan Africa . Our resMobile phone affordability and technology uptake has increased tremendously in Kenya , suggestThe limitation in this pilot study was focus on a restricted set of questions to establish proof of concept, but other pertinent research questions based on study design can be included for prospective research. We also anticipate some recall bias during data collection. We currently underpowered to estimate the extent of this bias, but anticipate that a much larger dataset from prospective data collection will reduce confounding during analysis. This study was conducted using datasets from smallholder farmers due to insufficient data from the small number of veterinary healthcare workers. Another setback was the intermittent mobile network coverage by some mobile service providers. We were able to circumvent this challenge by transmitting information to the central database once connected to a strong network.Additional file 1. Questionnaire used to develop the ODK-based mobile App. The App questions were divided into two: (i) questions to animal health care workers (ii) questions to smallholder farmers."}
+{"text": "The addictive brain undergoes dramatic changes as a result of drug exposure. A growing body of evidence suggests a wide range of brain areas, including ventromedial prefrontal cortex (VMPFC), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC) and other subcortical regions, namely anterior cingulate cortex (ACC), striatum, and anterior insula, are involved in drug-related cue processing  over left VMPFC could change the cue-related FC, which was examined by fMRI scans before and after cTBS (Kearney-Ramos et al., These understandings were addressed in a recent study published on the journal of Another extensive line of research has demonstrated VMPFC-limbic connections are altered in addicts (Ma et al., In conclusion, the current study demonstrated that cTBS of VMPFC-limbic circuits could change drug cue reactivity. Their results are likely to inspire more therapeutic interventions targeting drug-bias attention and self-awareness to modify previously inappropriate rewarded behavior for this chronic repeated relapsing disease. The approach combining fMRI with rTMS will be widely used to understand the underlying pathophysiologic neural circuits, and to design individualized treatment intervention. Nevertheless, although such evidence seems to be informative to us, it cannot effectively reduce drug-induced craving or relieve addiction syndrome. Our previous results indicated more participants respond to five repeated sessions with a better effect on craving in comparison to those who only receive a single session (Shen et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Middle-age and older adults vary widely in their physical health. This symposium describes studies that identify diverse daily experiences that account variation in health using multiple indicators of well-being . Fingerman et al. assessed daily TV viewing among older adults and found that more frequent television watching was associated with poorer physical health, worse health behaviors, and less energy expenditure . Leger et al., examined links between daily affect and sleep. Greater variability in daily positive affect is associated with fewer hours of sleep and greater morning tiredness even after adjusting for mean levels of affect. Luong et al. examined links between daily stress and affect. Interpersonal stressors were associated with greater affect reactivity than non-interpersonal stressors and links were reduced among older adults. Birditt et al. assessed links between daily social interactions and cardiovascular reactivity. More frequent social interactions and negative social interactions were associated with increased heart rate and links varied by gender and race. Polenick et al. examined links between daily social interactions and salivary DHEA-S (a marker of the stress response). Positive interactions predicted greater DHEA-S over the course of the day and links between negative interactions and DHEA-S varied by age group such that younger individuals appeared to be more reactive. These studies offer important clues regarding how daily experiences get under the skin to influence health and well-being."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Listening effort is needed to understand speech that is degraded by hearing loss and/or a noisy environment. Effortful listening reduces cognitive spare capacity (CSC). Predictive contexts aid speech perception accuracy, but it is not known whether the use of context reduces or preserves CSC. Here, we compare the impact of predictive context and cognitive load on behavioral indices of CSC in elderly, hearing-impaired adults. METHODS/STUDY POPULATION: Elderly, hearing-impaired adults listened in a noisy background to spoken sentences in which sentence-final words were either predictable or not predictable based on the sentence context. Cognitive load was manipulated by asking participants to remember either short or long sequences of visually presented digits. Participants were divided into low or high cognitive capacity groups based on a pretest of working memory. Accuracy and response times were examined for report of both sentence-final words and digit sequences. RESULTS/ANTICIPATED RESULTS: Preliminary results indicate that accuracy and response times for both words and digits were facilitated by sentence predictability, suggesting that the use of predictive sentence context preserves CSC. Response times for both words and digits and accuracy for digits were impaired under cognitive load. Trends were similar across high and low cognitive capacity groups. The preliminary results support the idea that habilitation strategies involving context use could potentially support CSC in elderly, hearing-impaired adults. DISCUSSION/SIGNIFICANCE OF IMPACT: These preliminary results support the concept that habilitation strategies involving context use could potentially support CSC in elderly, hearing-impaired adults."}
+{"text": "While caloric restriction (CR) provides highly robust improvements to longevity and health, dietary restriction of the essential amino acid methionine can provide similar benefits including improved metabolic function and increased longevity. Despite these similarities between CR and methionine restriction (MR), there is growing evidence to suggest they may be mediated by different mechanisms that require further elucidation. The sulfur side-chain of methionine is highly prone to oxidation, even in vivo, with redox changes of these residues potentially altering protein function and interfering with its use as a substrate. An entire family of enzymes, methionine sulfoxide reductases, have evolved in aerobic organisms to regulate the redox status of methionine. We tested the role of methionine sulfoxide reductase A (MsrA) in the physiological and metabolic benefits of MR. After three months of MR, mice lacking MsrA (MsrA KO) showed significant loss of weight, including both fat and lean mass, in comparison to wild-type mice under MR. Both MsrA KO and wild-type mice responded to MR with improvements to both glucose and insulin tolerance. However, MR MsrA KO mice showed lower HbA1c and reduced leptin compared to MR wild-type mice. Overall, our results show mice lacking MsrA have a stronger response to MR suggesting that methionine redox may play an important role in some of the mechanisms responsible for these metabolic outcomes. Further studies clarify whether MsrA could also be a potential regulator of the longevity benefits of MR."}
+{"text": "In meiosis, DNA break formation and repair are essential for the formation of crossovers between homologous chromosomes. Without crossover formation, faithful meiotic chromosome segregation and sexual reproduction cannot occur. Crossover formation is initiated by the programmed, meiosis\u2010specific introduction of numerous DNA double\u2010strand breaks, after which specific repair pathways promote recombination between homologous chromosomes. Despite its crucial nature, meiotic recombination is fraud with danger: When positioned or repaired inappropriately, DNA breaks can have catastrophic consequences on genome stability of the resulting gametes. As such, DNA break formation and repair needs to be carefully controlled. Within centromeres and surrounding regions , meiotic crossover recombination is repressed in organisms ranging from yeast to humans, and a failure to do so is implicated in chromosome missegregation and developmental aneuploidy. (Peri)centromere sequence identity and organization diverge considerably across eukaryotes, yet suppression of meiotic DNA break formation and repair appear universal. Here, we discuss emerging work that has used budding and fission yeast systems to study the mechanisms underlying pericentromeric suppression of DNA break formation and repair. We particularly highlight a role for the kinetochore, a universally conserved, centromere\u2010associated structure essential for chromosome segregation, in suppressing (peri)centromeric DNA break formation and repair. We discuss the current understanding of kinetochore\u2010associated and chromosomal factors involved in this regulation and suggest future avenues of research. Fusion of two gametes upon fertilization reconstitutes the diploid genome of the zygote. Meiosis relies on the same basic molecular machinery as mitosis but requires additional dedicated events \u2010sized regions directly adjacent to centromeres  pericentromeres prevented? Ectopic targeting experiments by Robine et al.  revealedTaken together, a localized regulation of Red1 function within budding yeast pericentromeres could play a role in controlling DSB formation, in a manner that might share foundational principles within the fission yeast system. However, clear differences between fission and budding yeast regulation of DSB formation and repair exist. Most importantly, whereas in fission yeast, DSB regulation involves cohesin (Nambiar & Smith, 4As discussed here, fascinating new aspects of localized control of meiotic DSB formation and repair have recently been revealed. Despite structural differences within pericentromeres, a common thread is a key role for cohesin in controlling local DSB formation and repair (Nambiar & Smith,"}
+{"text": "Pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs), ESCs derived by somatic cell nuclear transfer (ntESCs), and induced pluripotent stem cells (iPSCs) have unlimited capacity for self-renewal and pluripotency and can give rise to all types of somatic cells. In order to maintain their self-renewal and pluripotency, PSCs need to preserve their telomere length and homeostasis. In recent years, increasing studies have shown that telomere reprogramming is essential for stem cell pluripotency maintenance and its induced pluripotency process. Telomere-associated proteins are not only required for telomere maintenance in both stem cells, their extra-telomeric functions have also been found to be critical as well. Here, we will discuss how telomeres and telomere-associated factors participate and regulate the maintenance of stem cell pluripotency. Telomeres are ends of linear chromosomes that are bound by a host of protein factors and form a complex nucleoprotein structure. In mammalian cells, telomeres are consisted of repetitive [TTAGGG]n sequences and protected by the core six-protein shelterin/telosome complex , including embryonic stem cells (ESCs), nuclear transfer ESCs (ntESCs) and induced pluripotent stem cells (iPSCs), have the potential of unlimited-proliferation and the capacity to differentiate into any cell type. Therefore, PSCs can be used for any cell type replacement and have great value for regenerative medical. Proper regulation of telomere length and telomere-binding proteins is critical for telomere function and genomic stability, both in somatic cells and PSCs. Mouse ESCs and/or iPSCs with short telomeres exhibited unsuccessful teratoma formation and chimera production and failed to produce ES/iPS mice  capable of completely counteracting normal telomere shortening. PSCs can proliferate indefinitely while maintaining pluripotency and avoid telomere attrition and genome instability by elongating and protecting their telomeres. Short telomeres in ESCs lead to reduced pluripotency and unstable differentiation , could activate telomerase genes during reprogramming. For example, OCT3/4 and NANOG could bind to the TERC promoter and activate TERC transcription  and three proteins with no demonstrable DNA-binding activities  , increased TRF1 expression was observed before the onset of telomere elongation  was initially discovered as a protein that could interact with TRF1 (Kim et al., Repressor/activator protein 1 or RAP1 localizes to telomere via its interaction with TRF2 (Li et al., Multiple links have been established between telomere homeostasis and stem cell pluripotency maintenance. Sufficient telomere length is critical for unlimited self-renewal of PSCs. Telomere length and integrity may serve as general signatures to evaluate the quantity of ESCs and iPSCs. Longer telomeres would be advantageous for human ESCs and iPSCs in the application of PSCs in regenerative medicine. However, excessive telomere elongation heightens sensitivity of hESCs to replication stress at overly long telomeres, and causes the formation of C-circles (Rivera et al., Telomere length maintenance in ESCs and iPSCs is regulated by telomere-binding modulators and epigenetic modifications. Additionally, higher level of the shelterin/telosome component TRF1 also correlates with higher pluripotency of stem cells. Numerous studies have elucidated the roles of these telomere-binding proteins in telomere homeostasis. In the future, more focused effort should be made to delineate how stem cell pluripotency is regulated by telomere-binding modulators. Epigenetic changes at telomeres are acquired during reprogramming and ESC differentiation, these epigenetic modifications may provide a more flexible and efficient system to control of telomere length regulation in pluripotent cells. Future studies into how these telomeric chromatin status is regulated and contributes to the telomere homeostasis would provide insights to understand the mechanism of pluripotency maintenance and aging.In vivo studies will be necessary to fully understand the molecular functions of telomere-binding proteins in somatic stem cells and tissue development.Mutations in telomere proteins have been identified in many human diseases including DC. Our previous systematic analysis of human shelterin/telosome knockout cells has revealed functional differences between human and mouse telomeric proteins in telomere length homeostasis and end-protection (Kim et al., The role of telomere binding proteins in the stem cell self-renewal and pluripotency maintenance has been well discussed. However, the functions of these binding proteins in stem cell differentiation are still rarely studied. During the differentiation process, the gradually shorter telomeres may release some of the telomere binding proteins from telomeres or recruit some new factors to telomeres, which may affect the process of differentiation. Future studies should focus on the specific role of these telomere binding modulators in stem cell differentiation. In addition, telomere shortening or uncapping in stem cells leads to cell senescence and aging. However, previous studies usually focus on cellular level, but rarely mention individual level. What are the differences of telomere binding proteins in stem cells between young and elder individuals? How these differences contribute to individual stem cell therapy? Further studies are needed."}
+{"text": "Here we present an inexpensive widefield ratiometric fibred OEM system capable of enhancing the contrast between similar spectra of pathologically relevant fluorescent signals without the burden of complex spectral unmixing. As an exemplar, we demonstrate the potential of the platform to detect fluorescently labelled Gram-negative bacteria in the challenging environment of highly autofluorescent lung tissue in whole ex vivo human lungs.Fibre-based optical endomicroscopy (OEM) permits high resolution fluorescence microscopy in endoscopically accessible tissues. Fibred OEM has the potential to visualise pathologies targeted with fluorescent imaging probes and provide an  Future work will include assessing performance in lung tissue with existing infection, in exploiting the capability to unmix multiple targets over multiple wavelengths, and in a label-free imaging regime of lung and other tissues, see appendix, and"}
+{"text": "Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis and is expected to become the second leading cause of cancer mortality in the United States by 2030 . The disPtf1aCreERTM; KrasG12D/+) [in vitro and in vivo, highlighting the significant role of smoking in both tumor formation and progression. In addition to direct effects on PDAC tumor cells, NNK exposure also exerts significant changes in the tumor microenvironment (TME). This includes enhanced infiltration of immunosuppressive cell populations into the TME, including regulatory T-cells (Tregs) and tumor-associated macrophages (TAMs). Additionally, the progression of stromal fibrosis, a major contributor of therapeutic resistance in PDAC, is also heavily influenced by smoking carcinogens, as NNK exposure in vivo results in a marked increase in tumor desmoplasia. Through mechanistic studies, we have demonstrated that the oncogenic effects of NNK exposure are mediated through the activation of CREB through downstream stimulation of the AKT/PI3K pathway. Moreover, inhibition of CREB has shown both direct and indirect influences on PDAC tumor growth, wherein it has directly impeded NNK-induced tumor cell proliferation and indirectly reduced immunosuppressive cell infiltration into TME and stromal fibrosis in PDAC [Cigarette smoking has been extensively described as a major risk factor in the development of numerous solid organ malignancies including pancreatic cancer. Our findings show that exposure to a nicotine-derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), significantly accelerates pancreatic precancerous lesion (PanIN) formation in a genetically engineered mouse model of PDAC (sG12D/+) . Further in PDAC .in vivo through activation of the AKT/PI3K pathway [Chronic alcohol consumption is implicated in the pathogenesis of multiple pancreatic disorders through the induction of acinar cell injury. Chronic alcohol exposure prompts a profound inflammatory response through repeated cellular damage in the pancreas, eventually leading to neoplastic transformation and the subsequent development of PDAC. Recent reports have shown that alcohol exerts its pro-tumorigenic effects by initiating a cellular reprogramming event known as acinar-to-ductal metaplasia, eventually advancing to PanIN formation and invasive cancer  pathway . We have pathway . Further pathway . TherefoObesity is another well-established risk factor in PDAC development. Obesity is known to induce a pro-inflammatory state that differentially regulates pro-oncogenic cytokines and growth factors that are key mediators of PDAC progression. We have previously reported that the IL-6/STAT3 pathway is the critical regulator of obesity-induced PDAC growth . There iThe association among multiple modifiable risk factors on the initiation and progression of PDAC is well described; however, our understanding of the diverse cellular mechanisms that are affected by these pathologic states remains unclear. It is apparent that smoking, alcohol exposure, and morbid obesity induce oncogenic effects through direct interaction with PDAC cells, but additionally they seem to exert profound effects on the immune cell population and architecture of the microenvironment that may mediate disease progression and resistance to therapy. Our studies have provided fundamental insights into PDAC carcinogenesis induced by these risk factors and suggest CREB as a key oncogenic driver and therapeutic target in these processes. Further investigations into the central role of CREB in risk factor-associated PDAC are needed to promote our understanding and expand the treatment options available for this deadly malignancy."}
+{"text": "Additionally, students whose interviewees experienced intense physical suffering or physical limitations or students who were enrolled in a course with intensive VPD and vaccine curriculum had significantly increased vaccine attitudes. This suggests that introducing students to VPDs can decrease vaccine hesitancy.In 2019, the World Health Organization (WHO) listed vaccine hesitancy in its top ten threats to global health. Vaccine hesitancy is a \u201cdelay in acceptance or refusal to vaccinate despite availability of vaccination services\u201d. Urban areas with large amounts of vaccine hesitancy are at risk for the resurgence of vaccine-preventable diseases (VPDs). Many vaccine-hesitant (VH) parents may be unfamiliar with the consequences of VPDs, and thus might be swayed when confronted with the symptoms and dangers of VPDs. As such, we sought to educate college students (future parents) in an urban vaccine-hesitant hotspot by assigning them to interview family or community members who had experienced a VPD. Student vaccine attitudes were assessed by surveys before and after the interviews. Vaccine-hesitant students who conducted a VPD interview but received no additional vaccine educational materials were significantly more likely (interaction term  For months she couldn\u2019t leave the house.\u201d This interview led the student to explain  having students interview individuals who had experienced a VPD or (2) providing intensive vaccine- and VPD-related course material. Combining intervention styles allowed us to assess the strength of each intervention. VPD interviews (intervention group) were most successful at swaying student vaccine attitudes when the coursework did not discuss vaccines or if the interviews had strong themes of physical suffering and limitations. The majority of students in the intervention group who became pro-vaccine and the resulting increase in vaccine attitude scores mirrored those achieved through intensive education (MMBio 261). Thus, encouraging students to conduct VPD interviews may be an easy and effective intervention when the course has little to do with VPDs or lacks vaccine-related content.In courses that do address vaccines, it may be advantageous to first rigorously introduce students to VPD consequences before addressing, lightly, vaccine safety and societal implications. While Bio 100 introduces vaccines through a homework assignment that seeks to correct misconceptions about vaccine safety and societal implications, MMBio 261 begins with rigorous weeks-long sections on immunity and VPDs but only briefly discusses vaccine safety and herd immunity. This may explain why Bio 100 VH students did not have significantly increased post-intervention VASs, only a suggestive upward trend, whereas MMBio 261 VH students had significantly improved post-intervention VASs. The comparison between Bio 100 and MMBio 261 students mirrors earlier research that discussing VPD ramifications has a greater impact on combating vaccine hesitancy than correcting flawed assumptions or asserting an absence of risk about vaccines ,13,14,15This study does have limitations. We did not examine whether an interview-based intervention would be successful in a non-science course. Any biological instruction discussing vaccines might provide some boost to vaccine attitudes. Additionally, for logistical reasons, we did not assess whether the increase in VAS is meaningful by following whether students vaccinate their current and future children. Furthermore, this study focuses on college students and may not be expandable to the general population. Nonetheless, despite these limitations, interview-based interventions and intensive VPD-dependent vaccine education does significantly increase vaccine attitudes, in a population susceptible to anti-vaccine attitudes. Vaccine hesitancy is a complex, situation-dependent problem, and requires unique and tailored interventions. Interview-based interventions are easy to implement and can supplement courses or even community outreach programs seeking to address vaccine hesitancy. Predisposing students to think more favorably about vaccinations by openly discussing the consequences of vaccine-preventable diseases may improve their prospective individual and familial vaccine uptake. Future research should tease apart the contributions of science education and personal familiarity with VPDs towards improving vaccine attitudes in diverse populations.There are two major conclusions of this work. First, an interview-based intervention, where students discuss vaccine-preventable diseases with people who have actually experienced these diseases, can significantly improve attitudes towards vaccination. Second, the subject matter used while teaching about vaccine-preventable diseases matters. In the class with extensive discussion of the diseases themselves, there was a strong increase in vaccine attitudes among vaccine-hesitant students, while this effect was not seen in the class that discussed mostly vaccine safety. Taken together, these findings indicate that increasing familiarity with vaccine-preventable diseases leads to improved attitudes towards vaccination. This should help to create solutions to the worldwide problem of vaccine hesitancy or denial, by indicating aspects of education that are important for affecting those attitudes."}
+{"text": "In this study, we examine the association between perceived age discrimination at the workplace and job stress, with depressive symptoms among currently working late-middle-aged adults. In particular, we investigate whether the association between these work-related factors and depression varies by the strength of their social networks. We use data from the Panel on Ageing and Transitions in Health Survey (PATHS) a national study of 1654 Singaporean citizens and permanent residents aged 50 to 59 years, conducted in 2016-2017. We account for age and other sociodemographic characteristics, measures of economic status, occupation, early retirement intentions, personality traits, as well as multiple physical health measures. Our findings indicate that age discrimination at work and job stress are both positively associated with higher depressive symptom scores. The relationship between age discrimination and depressive symptoms however varies by social networks, with age discrimination negatively associated with depressive symptom scores among those with larger friends-based social networks. Our findings indicate that while psychological wellbeing of late middle-aged workers is adversely affected by age discrimination and job stress, these workers benefit from wider and deeper social connections with friends. Our results provide empirical support to previous research that suggests that friends-based social networks yield distinct benefits in terms of subjective well-being and increased self-worth."}
+{"text": "Recent technological developments provide individuals with vision impairment the transformative ability to upload pictures they take and promptly receive descriptions from remote workers. This study aimed to: identify challenges for visually impaired individuals to use such technology to obtain health-related information and provide recommendations for crowd-workers and the future development of assistive artificial intelligence (AI) design. In spring and summer of 2019, we analyzed 265 images of medication packages submitted by users of a visual question answering (VQA) application called VizWiz -- a smartphone application that provides near realtime assistance to visually impaired users by employing crowd-workers. We developed a 4-category coding scheme to analyze image quality, with two independent coders achieving excellent intercoder reliability (85%-95%). Of the 265 images, we found less than half were legible (46%), contained clear indicators for information sought (40%), or had minimum background noise (40%); while only a small percentage contained complete information (6%). Through thematic analysis of the data, we also highlight seven challenges with queries submitted by vision impaired users . Based on our findings, we make recommendations for the future design of VQA technologies, such as VizWiz, for visually impaired users. We also suggest that there is both great need and potential for user-centered design research to significantly enhance such assistive technologies. While this study did not focus exclusively on data submitted by aging adults, many VizWiz users are, in fact, aging adults, and such assistive technologies have strong implications for the design of assistive technology for this age group."}
+{"text": "This paper explores how perceptions of unfair treatment shape healthcare satisfaction across race/ethnicity. We investigate the overall impact of life course exposure to healthcare discrimination on current healthcare satisfaction across race/ethnicity among a sample of midlife and older Black, Latinx, and White Americans age 50+ in the Health and Retirement Study. We then test whether everyday healthcare discrimination mediates the impact of major medical discrimination on healthcare satisfaction, controlling for sociodemographic factors, mental and physical health characteristics, functional status, life course stress exposure, and lifetime and everyday discrimination in contexts beyond healthcare settings. Black Americans had poorer healthcare satisfaction than White Americans. Everyday discrimination in healthcare settings mediated a modest amount of the relationship between lifetime healthcare discrimination and healthcare satisfaction, and this association varied in strength across White, Black, and Latinx Americans. Results underscore the need for future work identifying and addressing mechanisms shaping healthcare satisfaction."}